MXPA06002549A - Gyrase inhibitors - Google Patents

Abstract

Compounds comprising an indazolyl group and a thiazolyl group, preferably 7-substituted 3-(thiazol-2-yl)-1H-indazole compounds in which the indazolyl group and a thiazolyl group are each independently optionally substituted, are useful for the treatment or prophylaxis of bacterial infections in mammals. The compounds are believed to function by inhibiting gyrase B.

Description

GIRASE INHIBITORS BACKGROUND OF THE INVENTION Field of the invention This invention relates to antibacterial compounds and methods of using same for treating bacterial infections. Description of the Related Art Bacterial resistance to drugs leads to a continuing need for new antibacterial agents to which the bacterium has not developed resistance. DNA gyrase is an enzyme found in many gram-positive and gram-negative bacteria. It is believed that DNA gyrase participates in the unfolding of the double helix of DNA that occurs prior to DNA replication by catalyzing the negative super-coiling of the ATP-dependent DNA. It is believed that DNA gyrase contains a complex of dimeric subunits, called gyrases A and B, which form an active enzyme complex A2B2. It is also believed that the A2 subunit performs DNA binding, cleavage and assembly, while the B2 subunit mediates ATPase activity. Antibacterial agents that target subunit A, such as quinolones, currently find increasing resistance among clinically important bacterial pathogens. Attempts to inhibit the B subunit of gyrase have not yet been entirely satisfactory. It has been found that agents that inhibit the catalysis of ATP hydrolysis by subunit B (eg, coumarins, such as novobiocin, and cyclothialidines) have low antimicrobial activities and unfavorable toxicity profiles (unrelated to the mechanism of action ). U.S. Patent Nos. 6,608,087 and 6,632,809 describe other gyrase inhibitors. U.S. Patent Nos. 5,140,034; 5,208,248 and 6,555,539 describe thiazolyl indazoles and their use as therapeutic agents, but these compounds are not known to be useful in inhibiting the B subunit of gyrase. Therefore, there is a need for new antibacterial compounds, and particularly those that target the B subunit of bacterial DNA gyrase while overcoming the drawbacks of existing inhibitors. SUMMARY OF THE INVENTION The present invention provides compounds comprising an indazolyl group and a thiazolyl group, preferably 7-substituted 3- (thiazol-2-yl) -1H-indazole compounds in which each of the indazolyl group and the thiazolyl group are independently optionally substituted. In preferred embodiments, the compounds are useful for the treatment or prophylaxis of bacterial infections in mammals. A preferred embodiment provides a compound comprising an indazolyl group and a thiazolyl group, wherein said compound is represented by the structure wherein R7 is selected from the group consisting of C? -C6 hydrocarbon, lower alkoxy, lower thioalkoxy, CN, NO2, halogen, CF3 and OCF3; and wherein the C? -C6 hydrocarbon, indazolyl group and thiazolyl group are optionally substituted on carbon; or a pharmaceutically acceptable salt, ester, solvate or prodrug thereof. Preferably, the compound of formula (I) is produced synthetically. A compound of formula (I) in isolated and purified form is preferred. Another embodiment provides a composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier. Another preferred embodiment provides a method of treating or preventing a bacterial infection in a mammal, which comprises administering to the mammal an effective amount of a compound of formula (I) or a composition thereof. Another preferred embodiment provides a method for making a compound of formula (I), which comprises: treating an optionally substituted indazole represented by the formula wherein R7 is selected from the group consisting of hydrocarbon CI-CT, lower alkoxy, lower thioalkoxy, CN, halogen NO2, CF3 and OCF3; wherein the C C6 hydrocarbon is optionally substituted; and where LG represents a leaving group; with a cyanide salt to form an optionally substituted nitrile indazole represented by the formula These and other embodiments are described in more detail below. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS Definitions The technical terms used herein have the meanings ascribed to them in the McGraw-Hill Dictionary of Scientific and Technical Terms, 6th ed., McGraw-Hill, New York, 2003, unless otherwise indicated another thing. The term "hydrocarbon" as used herein includes alkyl, cycloalkyl, alkenyl, alkynyl, aryl, and combinations thereof. The terms "alkoxy" or "alkoxy" refer to groups of hydrocarbons bonded to the parent structure through an oxygen atom. The term "lower alkoxy" refers to groups containing from one to four carbon atoms. The term "aryl" refers to aromatic carbocyclic rings, 5- or 6-membered monocyclic, 9- or 10-membered bicyclic, and 13- or 14-membered tricyclic rings, optionally having one or more substituents. Non-limiting examples of such rings include benzene, naphthalene, indane, tetralin and fluorene, and of suitable substituents include halogen, R1, -OR1, -OH, -SH, -SR1, protected OH (such as acyloxy), phenyl optionally substituted (Ph), optionally substituted heterocycles, -NO2, -CN, optionally substituted amino groups, optionally substituted carboxamide groups, -NHCONHR1, -NHCONR1R2, -NR1COR2, -NHCO2R1, -CO2R1, -CO2H, -COR1, -CONHR1, -CONR1R2, -S (O) 2R1, -SONH2, -S (O) R1, -SO2NHR1 and -NHSO2R1, wherein R1 and R2 are optionally substituted aliphatic groups. The term "heteroaryl" refers to aryl groups containing up to three N, O and / or S heteroatoms. Non-limiting examples include: midazole, pyridine, indole, thiophene, benzopyranone, thiazole, thiadiazole, furan, benzimidazole, quinoline, isoquinoline , quinoxaline, pyrimidine, pyrazine, tetrazole and pyrazole. The term "heterocycle" refers to a cycloalkyl or aryl group in which one to three carbon atoms are replaced by N, O and / or S heteroatoms. The nitrogen and sulfur heteroatoms may be oxidized, and the nitrogen heteroatom it may be optionally quaternized or substituted with substituents such as R1, COR1, SO2R1 and CO2R1, where R1 is an optionally substituted aliphatic group. In addition to the heteroaryl groups indicated above, examples of heterocycles include piperidine, morpholine, thiomorpholine, piperazine, pyrrolidine, pyrrole, pyridazine, oxazole, oxadiazole, oxazoline, isoxazole, dioxane, tetrahydrofuran and phenothiazine. The term "substituted" with respect to, for example, an alkyl group or another group refers to the replacement of H atoms in that group by one or more of the following: lower alkyl; allyl; halogen; haloalkyl; hydroxy; lower alkoxy; lower hydroxyalkyl; carboxy; carboalkoxy (also called alkoxycarbonyl); carboxyalkoxy; carboxamido (also referred to as alkylaminocarbonyl); cyano; formyl; acyl; nitro; Not me; alkylamino; dialkylamino; aniline; mercapto; alkylthio; sulfoxide; sulfone; acylamino; amidino; phenyl; benzyl; heteroaryl; heterocycle; phenoxy; benzoyl; benzoyl substituted with amino, hydroxy, methoxy, methyl or halo; benzyloxy or heteroaryloxy. When the group that is substituted contains an alkyl segment, two hydrogen atoms on the same carbon atom can be replaced by oxo (= O). A substitutable nitrogen atom on a heterocyclic ring may be optionally substituted with substituents such as R1, COR1, SO2R1 and CO2R1, where R1 is an aliphatic group or a substituted aliphatic group. The term "produced synthetically" means produced in a laboratory or manufacturing process, unlike that produced in vivo through procedures that occur in nature. The term "aliphatic" as used herein means straight chain, branched or cyclic C 1 -C 12 hydrocarbons, both saturated and unsaturated. Non-limiting examples of aliphatic groups include alkyl groupsalkenyl, linear, branched or cyclic alkenyl, substituted or unsubstituted, and hybrids thereof such as (cycloalkyl) alkyl, (cycloalkenyl) alkyl or (cycloalkyl) alkenyl. The term "pharmaceutically acceptable salt" as used herein refers to salts that are within the scope of medical judgment, and that are suitable for use in contact with the tissues of humans and lower animals without inducing toxicity, irritation , allergic response and the like, and are in a proportion with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge, et al., Discloses pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19. The salts can be prepared in situ during the final isolation and purification of the compounds of formula (I) as described below, or separately by reaction of the free base with a suitable organic acid. Representative acid addition salts include acetate salts, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphor sulfonate, citrate, cyclopentane propionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate , heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurysulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, palmoate, pectinate , persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, valerate and the like. Representative alkaline or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium and the like, as well as non-toxic ammonium, quaternary ammonium and amine cations, including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine and the like. The term "pharmaceutically acceptable ester" as used herein refers to esters that are hydrolyzed in vivo and include those that are easily broken in the human body to leave the parent compound or a salt thereof. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, wherein each alkyl or alkenyl moiety advantageously has no more than 6 carbon atoms. Examples of particular esters include formates, acetates, propionates, butyrates, acrylates and ethylsuccinates.

The term "pharmaceutically acceptable solvate" as used herein refers to an aggregate comprising one or more molecules of the solute, such as a compound of formula (I), with one or more molecules of a solvent. When the solvent is water, the resulting solvate can be termed "hydrate". The term "pharmaceutically acceptable carrier" as used herein refers to a non-toxic vehicle that can be administered to a patient, together with a compound of this invention, and which does not adversely affect the pharmacological activity of the compound. The term "prodrug" as used herein refers to compounds that are transformed in vivo to produce a compound of formula (I) below, or a salt or metabolite thereof. The transformation can be carried out by various mechanisms, such as hydrolysis in blood. A discussion on the use of prodrugs is provided by T. Higuchi and W. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers ¡n Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987. For example, if a compound of formula (I) contains a carboxylic acid functional group, a prodrug may comprise an ester formed by replacement of the hydrogen atom of the acid group by a group such as alkyl (Ci-Cs), (C2-C-i2) alkanoyloxy-methyl, 1- (alkanoyloxy) ethyl having from 4 to 9 carbon atoms, 1-methyl-1- (alkanoyloxy) -ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1- (alkoxycarbonyloxy) ethyl having from 4 to 7 carbon atoms, 1-methyl-1- (alkoxycarbonyloxy) ethyl having from 5 to 8 carbon atoms, N- (alkoxycarbonyl) aminomethyl having from 3 to 9 carbon atoms, 1- (N- (alkoxycarbonyl) amino) ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl, di-N, N-alkyl (C? -C2) -amino-(C2-C3) alkyl (such as 6-dimethylaminoethyl), carbamoyl-(C1-C2) alkyl, N, N -di-alkyl (C1-C2) -carbamoyl-alkyl (C- | -C2) and piperidin-, pyrrolidin- or morpholin-(C2-C3) alkyl. Likewise, if a compound of formula (!) Comprises an alcohol functional group, a prodrug can be formed by replacement of the hydrogen atom of the alcohol group with a group such as (C 1 -C 6) alkanoyloxymethyl, 1- (alkanoyloxy ( C? -Ce)) - ethyl, 1-methyl-1- (alkanoyloxy (C? -Ce)) - ethyl, alkoxy (CrCe) -carbonyloxymethyl, N-alkoxy-carbonyl (C? -C6) - aminomethyl, succinoyl, alkanoyl (CrC6), a-amino-alkanoyl (C1-C4), arylacyl and a-aminoacyl, or a-aminoacyl-a-aminoaile, where each a-aminoacyl group is independently selected from the L-amino acids that found in nature, P (O) (OH) 2, -P (O) (O-C6 alkyl) 2 or glycosyl (the radical resulting from the removal of a hydroxyl group from the hemiacetal form of a carbohydrate ). If a compound of formula (I) comprises an amine functional group, a prodrug can be formed by replacement of a hydrogen atom of the amine group by a group such as R-carbonyl, RO-carbonyl,? RR'-carbonyl where each of R and R 'is independently (alkyl (CrC-10), cycloalkyl (C3-C), benzyl or R-carbonyl is a natural a-aminoacyl or natural a-aminoacyl natural-a-aminoacyl, -C (OH) C ( O) OY where (Y is H, alkyl (CrCe) or benzyl), -C (OY0) Y? Where Y0 is (C4) alkyl and Yi is (C6 alkyl), carboxy-alkyl (C6-C6) ), amino-alkyl (CrC4) or mono-N- or di-N, N-alkyl (C? -C6) -aminoalkyl, -C (Y2) Y3 where Y2 is H or methyl and Y3 is mono-N- or di- NN-alkyl (CrC6) -amino, morpholino, piperidin-1-yl or pyrrolidin-1-yl Compounds and compositions A preferred embodiment provides compounds of formula (i) comprising an indazolyl group and a thiazolyl group: In the formula (I), R7 is preferably selected from the group consisting of hydrocarbon C Ce, lower alkoxy, lower thioalkoxy, C ?,? O2, halogen, CF3 and OCF3. More preferably, R7 is selected from the group consisting of methyl, ethyl, propyl, allyl, F, Cl and Br. The CrC6 hydrocarbon, the indazolyl group and the thiazolyl group are optionally substituted, preferably substituted on carbon. Preferably, the indazolyl group has at least one substituent selected from the group consisting of optionally substituted CrCβ hydrocarbon (eg, methyl, ethyl, propyl, allyl, methylcyclopropyl), lower alkoxy, optionally substituted heterocycle, C ?,? O2, halogen ( for example, F, Cl, Br, I), CF3 and OCF3. Preferably, the substituent is bonded to a carbon atom of the indazolyl group rather than to a nitrogen atom. Preferably, the thiazolyl group bears at least one substituent selected from the group consisting of optionally substituted CrC-io hydrocarbon (eg, methyl, ethyl), optionally substituted C1-C10 heterocycle, optionally substituted carboxamido, optionally substituted aminocarboxi, optionally substituted CrCß alkoxy , optionally substituted dCß alkoxycarbonyl (e.g., COOCH3, COOCH2CH3), OH, COOH, COOR3 and CONR8R9; where R3 is selected from the group consisting of optionally substituted heterocycle and CrCe alkyl substituted with heterocycle; wherein R8 and R9 are independently selected from the group consisting of H, optionally substituted heterocycle and optionally substituted CrCβ hydrocarbon, wherein R8 and R9 can together form an optionally substituted four, five or six membered heterocyclic ring including the N atom to which they are joined R8 and R9, and where for said ring one to three carbon atoms can optionally be independently replaced each by an atom selected from the group consisting of N, O and S. In this manner, examples of substituents include methyl , ethyl, OH, phenyl, COOH, COOCH3, COOCH2CH3 and N (CH3) (CH CH3). In preferred embodiments, the thiazolyl group is attached to a carbonyl carbon of at least one substituent represented by a structure selected from the group consisting of "O? - ^ For compounds of formula (I) in which the thiazolyl group has a phenyl substituent, said phenyl is optionally substituted with at least one substituent selected from the group consisting of OH, OCH3, F, Cl, Br, piperazin-1-yl optionally substituted and optionally substituted morpholin-4-yl. Examples of phenyl groups include 3-hydroxyphenyl, 4-hydroxyphenyl, 3-methoxyphenyl, 3-fluorophenyl, 4-fluorophenyl, 4-fluoro-3-hydroxy-phenyl, 3,4-difluoro-phenyl, 3,5-difluoro- phenyl, 4-bromo-3-methoxy-phenyl, 4- (4-methyl-piperazin-1-yl) -phenyl, and 4- (morpholin-4-yl) -phenyl. For the compounds of formula (I) wherein the thiazolyl group has a pyridyl substituent, said pyridyl is optionally substituted with at least one substituent selected from the group consisting of CrCß alkyl, F, Cl, Br, I, CF3, 3, 5-dimethyl-piperazin-1-yl and morpholin-4-yl. Examples of pyridyl groups include pyridin-3-yl, 6-methyl-pyridin-3-yl, 6-chloro-pyridin-3-yl and 6-trifluoromethyl-pyridin-3-yl. It is obvious from the foregoing that the thiazolyl group can optionally have two substituents. Preferably, each of the two substituents of the thiazolyl group is independently selected from the group consisting of optionally substituted C1-C10 hydrocarbon, COOH, optionally substituted CrCe-carbonyl alkoxy, OH, COOR3 and CONR8R9, where R3 is selected from the group consisting of optionally substituted heterocycle and CrCβ alkyl substituted with heterocycle; wherein R8 and R9 are independently selected from the group consisting of H, optionally substituted heterocycle and optionally substituted CrCe hydrocarbon, wherein R8 and R9 can together form an optionally substituted four, five or six membered heterocyclic ring including the N atom to which they are joined R and R ', and where for said ring of one to three carbon atoms can each be optionally replaced independently by an atom selected from the group consisting of N. O and S.

Those skilled in the art will appreciate that certain compounds of formula (I) may exist in tautomeric forms, all of these forms being within the scope of the invention. Unless otherwise indicated, the structures depicted in this document also encompass all the stereochemical forms of the structure, including the R and S configurations for each asymmetric center. Therefore, the individual stereochemical isomers as well as the enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the invention. The preferred compounds of formula (I) are produced synthetically to provide a substantially pure and isolated form according to the synthetic procedures described below. Those skilled in the art will understand that the in vivo effects that occur as a result of the administration of the compounds of formula (I) may be derived not from the compounds themselves, but by one or more degradation products, such as by a metabolic procedure. Thus, those skilled in the art will understand that references herein to a compound of formula (I) include esters, amides, salts (e.g., salts of metals), pharmacologically acceptable hydrates, and other derivatives thereof (known in the art as "prodrugs") that undergo biotransformation, producing the active drug. In general, prodrugs are described, for example, in Goodman and Gilman's "Biotransformation of Drugs," in the Pharmacological Basis of Therapeutics, 8th ed., McGraw Hill, Int. Ed. 1992, pages 13-15. Particularly preferred derivatives or prodrugs are those that increase the bioavailability of the compounds of formula (I) when said compounds are administered to a mammal (e.g., allowing an orally administered compound to be absorbed more readily in the blood) or that improve the release of the parent compound in a biological compartment (for example, the brain or lymphatic system) with respect to the precursor species. A preferred embodiment provides compositions comprising a compound of formula (I) and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers useful in these compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, whey proteins, such as human serum albumin, buffering substances such as phosphates, glycine, sorbic acid, potassium sorbate. , mixture of partial glycerides 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, polyvinylpyrrolidone, substances based on cellulose, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, wool grease and self-emulsifying drug release systems (SEDDS) such as a-tocopherol, polyethylene glycol succinate 1000 or other polymeric release matrices Similar. Certain compounds of formula (I) possess an acidic or basic group, and can therefore form salts with pharmaceutically acceptable cations or anions. All of these pharmaceutically acceptable salts are included in the present invention. The identities of pharmaceutically acceptable cations and anions are well known in the art, and appear in compendia such as Physicians' Desk Reference, 56th ed., Medical Economics Company, Inc., Montvale, NJ, 2002. Compounds can also form hydrates or exist in substantially anhydrous form. Pharmaceutical compositions for parenteral administration, such as by intravenous injection, preferably contain a pharmaceutically acceptable amount of a compound of formula (I) in the form of a soluble salt dissolved in a pharmaceutically acceptable liquid carrier such as, for example, water for injection and a buffer to provide a suitably buffered isotonic solution having, for example, a pH of about 3.5-6. Buffering agents include, for example, trisodium orthophosphate, sodium bicarbonate, sodium citrate, N-methylglucamine, /. (+) -lysin and. (+) - arginine. In general, the compounds of formula (I) will be dissolved in the vehicle in an amount sufficient to provide a pharmaceutically acceptable injectable concentration of about 1 mg / ml to about 400 mg / ml of solution. The resulting liquid pharmaceutical composition will be administered in this manner to obtain a dose effective against the bacteria. Non-limiting examples of preferred compounds of formula (I) include: 1- [2- (5,7-dimethyl-1H-indazol-3-yl) -5-pyridin-3-yl-thiazol-4-yl] - 2- (1-methyl-piperidin-4-yl) -ethanone; [2- (5,7-D-methyl-1H-indazol-3-yl) -5-pyridin-3-yl-thiazol-4-yl] - (4-methyl-piperazin-1-yl) -methanone; (3-dimethylamino-pyrrolidin-1-yl) - [2- (6-fluoro-7-methyl-1 H -indazol-3-yl) -5-pyridin-3-yl-thiazol-4-yl] -methanone; (3-dimethylamino-pyrrolidin-1-yl) - [2- (6-fluoro-7-methyl-1H-indazol-3-yl) -5- (6-methyl-pyridin-3-yl) -thiazole -4-yl] -metanone; (3-dimethylamino-pyrro! Idin-1-yl) - [2- (7-methyl-1 H -indazol-3-yl) -5-pyridin-3-yl-thiazol-4-yl] -methanone; (3-dimethylamino-pyrrolidin-1-yl) - [2- (7-methyl-1 H -indazol-3-yl) -5- (6-methyl-pyridin-3-yl) -thiazol-4-yl] -metanone; (3,5-dimethyl-piperidin-1-yl) - [2- (7-methyl-1 H -indazol-3-yl) -5-pyridin-3-yl-thiazol-4-yl] -methanone; (3-dimethylamino-pyrrolidin-1-yl) - [2- (7-methyl-1H-indazol-3-yl) -5- (6-trifluoromethyl-pyridin-3-yl) -thiazol-4-yl] - methanone; (3-dimethylamino-pyrrolidin-1-yl) - [2- (7-methyl-1 H -indazol-3-yl) -5-pyridin-3-yl-thiazol-4-yl] -methanone; (3-dimethylamino-pyrrolidin-1-yl) - [5- (3-methoxy-phenyl) -2- (7-methyl-1 H -indazol-3-yl) -thiazol-4-yl] -methanone; (3-dimethylamino-pyrrolidin-1-yl) - [5- (4-hydroxy-phenyl) -2- (7-methyl-1A / -ndazol-3-yl) -thiazol-4-yl] -methanone; (3-hydroxy-azetidin-1-yl) - [2- (7-methy1-1 H -indazol-3-yl) -5-pyridin-3-yl-thiazol-4-yl] -methanone; (3-hydroxy-pyrrolidin-1-yl) - [2- (7-methyl-1H-indazol-3-yl) -5- (6-morpholin-4-yl-pyridin-3-yl) -thiazole-4 -yl] -metanone; (3-hydroxy-pyrrolidin-1-yl) - [2- (7-methyl-1-indazol-3-yl) -5-pyridin-3-yl-thiazole-4-yl] -metanone; [2- (6-chloro-7-methyl-1H-indazol-3-yl) -5-pyridin-3-yl-thiazol-4-yl] - (4-methyl-piperazin-1-yl) -methanone; [2- (6-chloro-7-methyl-1H-indazol-3-yl) -5-pyridin-3-yl-thiazo! -4-yl] - (3-hydroxy-pyrrolidin-1-yl) -metanone; [2- (6-Chloro-7-methyl-1 W -ndazol-3-yl) -5-pyridin-3-yl-thiazoI-4-yl] - (3-dimethylamino-pyrrolidin-1-yl) -metanone; [2- (7-methyl-1 H -indazol-3-yl) -5-pyridin-3-yl-thiazol-4-yl] - (4-methyl-p-eperazin-1-yl) -methanone; [2- (7-methyl-1 H -indazol-3-yl) -5-pyridin-3-yl-thiazol-4-yl] - (4-pyridin-4-yl-piperazin-1-yl) -methanone; [2- (7-methyl-1 H -indazol-3-yl) -5-pyridin-3-yl-thiazol-4-yl] -morpholin-4-yl-methanone; [2- (7-methyl-1 H -indazol-3-yl) -5-pyridin-3-yl-thiazol-4-yl] -piperidin-1-yl-methanone; [5- (3,4-difluoro-phenyl) -2- (7-methyl-1 H -indazol-3-yl) -thiazol-4-yl] - (3-dimethylamino-pyrrolidin-1-yl) -methanone; [5- (3,4-difluoro-phenyl) -2- (7-methyl-1H-indazol-3-yl) -thiazol-4-yl] - (3-hydroxy-pyrrolidin-1-yl) -methanone; [5- (3,4-difluoro-phenyl) -2- (7-methyl-1H-indazol-3-yl) -thiazol-4-yl] - (4-methyl-piperazin-1-yl) -methanone; [5- (3,5-difluoro-phenyl) -2- (7-methyl-1 H -indazol-3-yl) -thiazol-4-yl] - (3-hydroxy-pyrrolidin-1-yl) -methanone; [5- (3,5-difluoro-phenyl) -2- (7-methyl-1 r -indazol-3-yl) -thiazol-4-yl] - (4-methyl-piperazin-1-yl) -methanone; [5- (3-fluoro-phenyl) -2- (7-methyl-1H-indazol-3-yl) -thiazol-4-yl] - (4-methyl-piperazin-1-yl) -methanone; [5- (4-fluoro-3-hydroxy-phenyl) -2- (7-methyl-1H-indazol-3-yl) -thiazol-4-yl] - (4-methyl-piperazin-1-yl) - methanone; [5- (4-fluoro-phenyl) -2- (7-methyl-1H-indazol-3-yl) -thiazol-4-yl] - (3-hydroxy-pyrrolidin-1-yl) -methanone; [5- (4-fluoro-phenyl) -2- (7-methyl-1 H -indazol-3-yl) -thiazol-4-yl] - (4-methyl-piperazin-1-yl) -methanone; [5- (6-chloro-pyridin-3-yl) -2- (7-methyl-1H-indazol-3-yl) -thiazole-4-yl] - (3-dimethylamino-pyrrolidin-1-yl) ) -metanone; [5- (6-chloro-pyridin-3-yl) -2- (7-methyl-1H-indazol-3-yl) -thiazol-4-yl] - (3-hydroxy-pyrrolidin-1-yl) - methanone; [5- [6- (3,5-dimethyl-piperazin-1-yl) -pyridin-3-yl] -2- (7-methyl-1H-indazol-3-yl) -thiazole-4-yl] ] - (3-hydroxy-pyrrolidin-1-yl) -methanone; . { 4- [2- (1 H -indazol-3-yl) -thiazol-4-yl] -phenyl} - (4-methyl-piperazin-1-yl) -methanone; . { 4- [2- (1 H -indazol-3-yl) -thiazol-4-yl] -phenyl} -mori: olin-4-yl-methanone; 1 - [2- (7-methyl-1 H -indazol-3-yl) -5-pyridin-3-yl-thiazole-4-carbonyl] -piperidine-4-carboxylic acid; 2- (1H-indazol-3-yl) -4-phenyl-thiazole-5-carboxylic acid ethyl ester; 2- (1 / t-indazol-3-yl) -5-phenyl-thiazol-4-ol; 2- (1H-indazol-3-yl) -5-phenyl-thiazole-4-carboxylic acid (2,3-dihydroxy-propyl) -amide; 2- (1H-indazol-3-yl) -5-phenyl-thiazole-4-carboxylic acid (2-dimethyl-amino-ethyl) -amide; 2- (1H-indazol-3-yl) -5-phenyl-thiazole-4-carboxylic acid (2-methoxy-ethyl) -amide; 2- (1H-indazol-3-yl) -5-phenyl-thiazole-4-carboxylic acid cyclopropylmethyl-amide; 2- (1 / - / - indazol-3-yl) -5-phenyl-thiazole-4-carboxylic acid methyl ester; 2- (4-chloro-7-methyl-1r / -indazol-3-yl) -5-pyridin-3-ylthiazole-4-carboxylic acid methyl ester; 2- (6-Chloro-7-methyl-1H-indazol-3-yl) -5-pyridin-3-yl-thiazole-4-carboxylic acid methyl ester; 2- (7-ethyl-1 r -indazol-3-yl) -5-phenyl-thiazole-4-carboxylic acid methyl ester; 2- (7-Methyl-1yr-indazol-3-yl) -5- (6-trifluoromethyl-pyridin-3-yl) -thiazole-4-carboxylic acid methyl ester; 2- (7-Methyl-1H-indazol-3-yl) -5-phenyl-thiazole-4-carboxylic acid 2-morpholin-4-yl-ethyl ester; 2- (7-methyl-1H-indazol-3-yl) -5-phenyl-thiazole-4-carboxylic acid methyl ester; 2- (7-methyl-1H-indazoI-3-yl) -5-pyridin-3-yl-thiazole-4-carboxylic acid ethyl-methyl-amide; 2- (7-methyl-1H-indazol-3-yl) -5-pyridin-3-yl-thiazole-4-carboxylic acid methyl-piperidin-4-yl ester; 2- (7-methyl-1H-indazol-3-yl) -5-pyridin-3-yl-thiazole-4-carboxylic acid methyl-pyrrolid? N-3-yl ester; 2- (7-methyl-1 / V-indazol-3-yl) -5-pyridin-3-yl-thiazole-4-carboxylic acid (2-dimethylamino-ethyl) -methyl-amide; 2- (7-Methyl-1 / - / - indazoI-3-H) -5-pyridin-3-yl-thiazole-4-carboxylic acid (1-methyl-piperidin-4-yl) -amide; 2- (7-methyl-1H-indazol-3-yl) -5-pyridin-3-yl-thiazole-4-carboxylic acid; 2- (7-Methyl-1-indazol-3-yl) -5-pyridin-3-yl-thiazole-4-carboxylic acid (2-diethylamino-ethyl) -amide; 2- (7-methyl-1H-indazol-3-yl) -5-pyridin-3-yl-thiazole-4-carboxylic acid methyl ester; 2- (7-methyl-1H-indazol-3-yl) -5-pyridin-3-yl-thiazole-4-carboxylic acid ethyl ester; 2- [2- (1 H -indazol-3-yl) -thiazol-4-yl] -phenol; 2-bromo-5- [2- (1W-indazol-3-yl) -4-methyl-thiazol-5-yl] -phenol; 2-hydroxy-5- [2- (1? -indazol-3-yl) -5-methyl-thiazol-4-yl] -benzoic acid; 3- (4,5-diphenyl-thiazol-2-y!) - 1H-indazole; 3- (4-ethyl-5-phenyl-thiazol-2-yl) -1H-indazole; 3- (4-ethyl-thiazol-2-yl) -1 / 7-ndazole; 3- (4-naphthalen-2-yl-thiazol-2-yl) -1H-indazole; 3- (4-phenyl-thiazol-2-yl) -1H-indazole; 3- (4-p-tolyl-thiazol-2-yl) -1H-indazole; 3- (4-pyridin-2-yl-thiazol-2-yl) -1H-indazole; 3- (4-pyridin-3-yl-thiazol-2-yl) -1 H-indazole; 3- (5-methyl-4-phenyl-thiazol-2-yl) -1H-indazole; 3- (5-phenyl-thiazol-2-yl) -1H-indazole; 3- (5-phenyl-thiazol-2-yl) -1H-indazole; 3- [2- (1 H -indazol-3-yl) -4-methyl-thiazol-5-yl] -phenol; 3- [2- (1 H -indazol-3-yl) -4-methyl-thiazol-5-yl] -phenol; 3- [2- (1 -indazol-3-yl) -thiazol-4-yl] -benzoic acid; 3- [2- (7-chloro-1-indazol-3-yl) -4-methyl-thiazol-5-yl] -phenol; 3- [4- (2,5-dimethyl-phenyl) -thiazol-2-yl] -1H-indazole; 3- [4- (2-fluoro-phenyl) -thiazol-2-yl] -1H-indazole; 3- [4- (2-methoxy-phenyl) -thiazol-2-yl] -1 H -indazole; 3- [4- (3,4-dichloro-phenyl) -thiazol-2-yl] -1H-indazole; 3- [4- (3,4-difluoro-phenyl) -thiazol-2-yl] -1H-indazole; 3- [4- (3-bromo-phenyl) -thiazol-2-yl] -1tf-indazole; 3- [4- (3-fluoro-phenyl) -thiazol-2-yl] -1H-indazole; 3- [4- (3-methoxy-phenyl) -thiazole-2-yl-1H-indazole; 3- [4- (4-chloro-phenyl) -thiazol-2-yl] -1H-indazole; 3- [4- (4-methanesulfonyl-phenyl) -thiazol-2-yl] -1H-indazole; 3- [4- (4-methoxy-phenyl) -thiazol-2-yl] -1H-indazole; 3- [4- (4-morpholin-4-yl-phenyl) -thiazol-2-yl] -1H-indazole; 3- [4- (4-pyrrolidin-1-yl-phenyl) -thiazol-2-yl] -1 / - / - indazole; 3- [4-methyl-5- (4-morpholin-4-yl-phenyl) -thiazol-2-yl] -1H-indazole; 3- [5- (3-methoxy-phenyl) -4-methyl-thiazol-2-yl] -1 / - / - indazole; 3- [5- (3-methoxy-phenyl) -4-methyl-thiazol-2-yl] -1-indazole; 3- [5- (4-bromo-3-methoxy-phenyl) -4-methyl-thiazol-2-yl] -1 / - / - indazole; 3- [5- (6-chloro-pyridin-3-yl) -4-methyl-thiazol-2-yl] -1H-indazole; 3-. { 4-methyl-5- [4- (4-methyl-piperazin-1-yl) -phenyl] -thiazol-2-yl} -1H-indazole; 4- [2- (1H-indazol-3-yl) -thiazol-4-yl] -benzoic acid methyl ester; 4- [2- (1 H -indazol-3-yl) -thiazol-4-yl] -benzoic acid; 4- [2- (1 H -indazol-3-yl) -thiazol-4-yl] -benzonitrile; 5- (3-Fluoro-phenyl) -2- (7-methyl-1 / -indazol-3-yl) -thiazole-4-carboxylic acid methyl ester; 5- (4-Fluoro-phenyl) -2- (7-methyl-1A / -indazo! -3-yl) -t? 'azol-4-carboxylic acid ethyl ester; 5- (4-hydroxy-phenyl) -2- (7-methyl-1A-indazol-3-yl) -thiazole-4-carboxylic acid methyl ester; - (6-chloro-pyridin-3-yl) -2- (7-methyl-1H-indazol-3-yl) -thiazole-4-carboxylic acid methyl ester; 7-chloro-3- [5- (3-methoxy-benzyl) -thiazol-2-yl] -1H-indazole; 7-chloro-3- [5- (3-methoxy-phenyl) -4-methyl-thiazol-2-yl] -1-indazole; diethyl- { 4- [2- (1 H -indazol-3-yl) -thiazol-4-yl] -phenyl} -amina; N- (2-Dimethylamino-ethyl) -3- [2- (1-V-ndazol-3-yl) -thiazol-4-yl] -benzamide. Processes for Making Compounds and Compositions The compounds of formula (I) are preferably prepared according to the following synthetic scheme: Acetylation Acetylation preferably comprises reacting an arylamine with an acetyl halide to form an optionally substituted arylamide represented by the formula (II) ): R7 is preferably selected from the group consisting of hydrocarbon CrCß, lower alkoxy, lower thioalkoxy, C ?,? O2, halogen, CF3 and OCF3; wherein the CrCß hydrocarbon and the aryl ring of the arylamide are optionally substituted. The acetylation is illustrated below: An arylamine such as aniline (82.5 mmol) is dissolved in 400 ml of dichloromethane and cooled to 0 ° C. To this solution is added dropwise acetyl chloride (71 ml, 1 mole) followed by a solution of 200 ml of triethylamine (140 ml, 1 mole).

This solution is stirred until the reaction is complete. The resulting solid is removed by filtration and the filtrate is poured into brine, extracted twice with dichloromethane, dried, filtered and concentrated to give the acetylated amine. Cyclization Preferably, the cyclization comprises reacting the optionally substituted arylamide with an alkyl nitrite in the presence of an acid to form an optionally substituted indazole represented by the formula (III): Cyclization is illustrated below: An acetylated amine such as N- (2,6-dimethylphenyl) -acetamide (1 equiv.) Is dissolved in dichloroethane. To this solution is added acetic acid (1.1 equiv.) Followed by the dropwise addition of isoamyl nitrite (1.1 equiv.). Then, the reaction is refluxed overnight, poured into water and extracted twice more with dichloromethane. The extracts are combined, washed with saturated bicarbonate and then with brine and dried with magnesium sulfate, filtered before being concentrated to a solid. Typically, 80% yields. Iodination Preferably, the iodization comprises reacting the indazole optionally substituted with iodine in the presence of a base to form an optionally substituted iodated indazole represented by the formula (IV): av) The iodination is illustrated below: The optionally substituted indazole represented by the formula (III) (1 equiv.) Is dissolved in DMF (0.5 M) and to this solution are added iodine crystals (3 equiv.) And granules of KOH (5 equiv.). This reaction is allowed to stir at RT until complete by thin layer chromatography (TLC), about 3 hours. The solution is concentrated to approximately one third of its volume and then poured into a 5% solution of NaHSO 3 and extracted 3 times with ether. The ether extracts are washed with water followed by saturated brine solution and dried over magnesium sulfate. The drying agent is removed by filtration and the ether solution is concentrated to an orange solid in quantitative yields of 3-iodo-indazole. Those skilled in the art will appreciate that the iodine is a leaving group (LG) and other leaving groups may be used in place of iodine in the compound represented by the formula (IV), thereby forming a compound represented by the formula (V): (V) For the compound represented by the formula (V), LG represents a leaving group. Preferred leaving groups include chlorine, bromine, iodine, trifluoromethanesulfonate, methanesulfonate, p-toluenesulfonate and trifluoroacetate. Iodine is a very preferred leaving group. Displacement with nitrile Preferably, displacement with nitrile comprises reacting the iodinated indazole optionally substituted with a cyanide salt to form an optionally substituted indazole nitrile represented by the formula (VI): The displacement with nitrile is illustrated below: The optionally substituted iodated indazole is dissolved in anhydrous N-methylpyrrolidinone (0.5 M). To this solution are added sodium cyanide (2 equivalents) and copper cyanide (I) (3 equivalents). The solution is heated at 135 ° C for 6 hours or until complete by TLC or HPLC. The reaction is then concentrated to 1/3 of its volume and partitioned between ether and water. The resulting suspension is filtered through diatomaceous earth. The filtrate is separated and extracted with two more portions of ether. The combined extracts are washed with water and brine, dried over magnesium sulfate, filtered and concentrated to an off-white solid. (50% yield).

Those skilled in the art will understand that iodine is an example of a leaving group, and further that displacement with nitrile can also be performed in a similar manner using compounds of formula (V). Thioamide Formation Preferably, the thioamide formation comprises reacting the indazole nitrile optionally substituted with hydrogen sulfide in the presence of a base to form an optionally substituted indazole thioamide represented by the formula (VII): (vn) The formation of thioamide is illustrated below: The optionally substituted indazole nitrile is dissolved in 20% triethylamine in pyridine and cooled to 0 ° C. Then, the solution is saturated for 10 minutes with hydrogen sulfide gas. The reactor is sealed and allowed to stir while heating to room temperature. After 3 hours, or when the reaction is complete by TLC, degas with a slight vacuum before concentrating to a yellow solid. The solid is suspended in hexane and filtered in vacuo. The solid is then dried under high vacuum with P2O5 until it is dried at a constant weight. Cyclization Preferably, the cyclization comprises reacting the optionally substituted indazole thioamide with a carbonyl compound to form a compound of formula (I). Preferably, the carbonyl compound is substituted with a leaving group in the alpha to carbonyl position. Preferred carbonyl compounds include optionally substituted α-LG aldehyde, optionally substituted α-LG ketone and optionally substituted α-LG ester. The cyclization is illustrated below in Examples 3-4. It will be understood by those skilled in the art that additional or alternative chemical or process steps or reactions may be employed in addition to or in place of those indicated in the synthetic scheme outlined above. In this way, the knowledge of those skilled in the art can be combined with the teachings provided herein to prepare a wide variety of compounds of formula (I). For example, Table 1 provides the names and structures of various preferred compounds of formula (I) prepared according to the methods described herein.

Table 1 Methods of using the compounds and compositions Preferred compounds of formula (I) show antimicrobial activity against a variety of pathogens. This invention is not associated with any theory of operation, but it is believed that the compounds of formula (I) exert their antimicrobial action by inhibiting gyrase B in the target bacterium in vivo and in vitro. A preferred embodiment provides methods for treating or preventing a bacterial infection in a mammal, which comprises administering to the mammal a therapeutically effective amount of a compound of formula (I). References in this document to the use of a compound of formula (I) will be understood as including references to pharmaceutical compositions thereof, as well as pharmaceutically acceptable salts, esters, solvates and / or prodrugs thereof. The prophylactic or therapeutic dose of the compounds of the present invention, in the treatment of a bacterial infection will vary with the severity of the infection and with the route by which the drug is administered, such as orally, topically, transdermally and / or or parenteral. The compounds of this invention are advantageously administered orally in solid or liquid dosage forms, with the dosage and perhaps the dosage frequency, varying according to the age, body weight and response of the individual patient. In general, the total daily dosage range of the present compounds for a 70 kg person is from about 1 mg to about 2000 mg, in unit or divided doses, but one skilled in the art can easily determine appropriate doses through known.

Preferred compounds of formula (i) have useful activity against a variety of organisms. The activity of the compounds can be tested by standard assay methods such as the determination of the minimum inhibitory concentration (MIC) by agar dilution as described in "Approved Standard Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically", 3a ed., published in 1993 by the National Committee for Clinical Laboratory Standards, Villanova, Pa., USA. Several compounds of formula (I) shown in Table 1 show activity against one or more pathogenic bacteria such as Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pneumoniae, Streptococcus pyogenes, Enterococcus faecalis, Moraxella catarrhalis and H. influenzae. For example, Table 2 provides the names and structures of compounds of formula (I) that have been found to have a MIC of about 10 μM or less in the methicillin-resistant Staphylococcus aureus assay performed as described below in the Examples 25-154. EXAMPLES General chemical procedures. The proton NMR spectra were performed at 300 MHz on a Bruker Avance 300 spectrometer, and the chemical shifts are reported in parts per million (d) downfield of tetramethylsilane as the internal standard. The electrospray electrospray mass spectra at atmospheric pressure and LCMS were recorded on an Agilent 1100 Series LC / MSD-SL 1946 D spectrometer with an Agilent 100 series HPLC System. Silica gel 60 (230-400 mesh) from EM Science was used for column chromatography, and analytical or preparative thin layer chromatography was performed using EM Science Kieselgel 60 F254 plates. Agilent 1100 Series HPLC was used with a Reverse phase Agilent Zorbax Eclipse XDB-C8 (4.6 x 150 mm) for analytical analysis by HPLC. The preparative RP-HPLC was performed on a Gilson instrument with a MetaSil AQUEOUS 10 m C18 column. The elution buffer was an A / B gradient; A = H O-0.1% trifluoroacetic acid, B = CH 3 CN-0.1% trifluoroacetic acid. In general, the products were characterized by 1 H NMR, CL and / or LC-MS. For reactions carried out under anhydrous conditions, the glassware was dried in the oven or the flame and the reaction was carried out under positive nitrogen pressure. Anhydrous solvents were used as purchased from commercial sources. Unless otherwise indicated, the reagents were purchased from commercial sources and used without further purification. The reported yields are the actual isolated yields of the purified material and have not been optimized. Examples 1-11 shown below describe the preparations of various specific compounds and illustrate the various materials and techniques that can be employed in the synthesis of the compounds of formula (I). Examples 12-24 describe various steps in the synthesis of a particular compound of formula (1). Table 1 provides the names and structures of various preferred compounds of formula (I) prepared according to the methods described herein. Examples 25-154 describe the methicillin-resistant Staphylococcus aureus assay used to determine the activity of the compounds shown in Table 2. EXAMPLE 1 Dimethylaniline was dissolved (100 g, 82.5 mmol; Scheme 1) in 400 ml of dichloromethane and cooled to 0 ° C. To this solution was added dropwise acetyl chloride (71 ml, 1 mole) followed by a solution of 200 ml of triethylamine (140 ml, 1 mole). This solution was stirred until it was completed. Remove the solid by filtration and pour the filtrate into brine, extract twice with dichloromethane, dry filter and concentrate, yielding 127.3 g (95% yield) of the acetylated amine as a tan solid. NMR data (300 MHz, CDCl 3) for 7-methyl indazoles: 7-methyl indazole: 8.14 (s, 1 H); 7.62 (d, 1 H, J = 8.8 Hz); 7.18 (m, 1H); 7.09 (m, 2H); 2.6 (s, 3H); 3-iodo-7-methyl indazole: 7.36 (d, 1 H, J = 8.8 Hz); 7.24 (dd, 1 H, J = 1 Hz, 6.7 Hz); 2.55 (s, 3H); 3-cyano-7-methyl indazole: 11 (s a, 1H); 7.7 (m, 1H), 7.3 (m, 2H); 2.6 (s, 3H). Scheme 1. Synthesis of 3-cyanoindazoles Scheme 2. Synthesis of substituted thiazolyl indazoles EXAMPLE 2 Representative preparation of thioamide 1H-indazole-3-carboxymidothioic acid (16, R1 = R2 = H, Scheme 2). A solution of 1H-indazole-3-carbonitrile (11, R1 = R2 = H) (0.150 g, 1.05 mmol) in 20% Et3N / pyridine (10 mL) was cooled to -78 ° C. Then, through this, H2S gas was bubbled for 20 minutes and then the vessel was sealed, allowed to warm to room temperature and stirred overnight. The residual H2S was removed in vacuo and the mixture was concentrated. The resulting ivory solid was suspended in hexane, collected by filtration and dried, yielding 0.178 g, (95%) of product 16. EXAMPLES 3-4 Representative thiazole preparations 3- [4- (4-bromo-phenyl ) -5-methyl-thiazol-2-yl] -1 H-indazole (17a, R1 = R2 = H, R3 = CH3, Ar = 3-bromophenyl, "Scheme 2) A mixture of 1H-indazole-3 acid - carboximidothioic acid (16, R1 = R2 = H) (354 mg, 2 mmol) and 2,4'-dibromopropiophenone (584 mg, 2 mmol) in dry MeOH (10 ml) was heated to 50 ° C for 20 h. The reaction mixture was filtered and the solids were washed with MeOH and dried, giving 430 mg (58%) of the product 17a as a tan solid. 2- (1H-indazol-3-yl) -5-phenyl-thiazol-4-ol (18, R1 = R2 = H, Scheme 2). Similarly, 1H-indazole-3-carboximidothioic acid (16, R1 = R2 = H) (0.150 g, 0.85 mmol), methyl a-bromophenylacetate (0.195 g, 0.85 mmol), and NaHCO3 were dissolved. (0.142 g, 1.7 mmol) in dry methanol and stirred overnight. The solution was concentrated and the residue was purified by preparative RP-HPLC to give 12 mg (5%) of the desired product 18 as an orange solid. EXAMPLES 5-6 Representative amination of palladium-mediated aryl Scheme 3 3-. { 5-Methyl-4- [4- (4-methyl-piperazin-1-yl) -phenyl] -thiazol-2-yl} -1H-indazole (19a, R1 = R2 = H, R4 = R5 = cyclo-CH2CH2N (CH3) CH2CH2, - Scheme 3). A oven-dried round bottom flask was charged with 3- [4- (4-bromo-phenyl) -5-methyl-thiazol-2-yl] -1-1 H-indazole (17, R1 = R2 = H, R3 = CH3) (37 mg, 0.1 mmol), 1-methylpiperazine (67 μL, 0.6 mmol), NaOtBu (14 mg, 0.14 mmol) and anhydrous dimethyl ether (2 mL). The reaction mixture was evacuated and refilled several times with N2. The catalyst, Pd2 (dba) 3 (9 mg, 0.01 mmol) and the ligand, 2- (dicyclohexylphosphino) biphenyl (14 mg, 0.04 mmol) were added. The reaction mixture was evacuated and refilled with N2 and then refluxed overnight after which HPLC analysis indicated complete consumption of the starting material. The mixture was concentrated in vacuo, dissolved in EtOAc (20 ml), washed with H2O (2 x 5 ml) and brine (1 x 5 ml) and dried over anhydrous Na2SO4. Removal of the solvent gave the crude product which was purified by RP-HPLC to give 10 mg of the product 19a (25%) as a light yellow solid. 3- [5-Methyl-4- (4-morpholin-4-yl-phenyl) -thiazol-2-yl] -1H-indazole (19b, R1 = R2 = H, R4 = R5 - cyc! Or-CH2CH2 CH2CH2, Scheme 3) A furnace-dried round bottom flask was charged with (17, R1 = R2 = H, R3 = CH3) (37 mg, 0.1 mmol), morpholine (52 μL, 0.6 mmol), NaOtBu (14 mg, 0.14 mmol) and anhydrous toluene (2 ml) The reaction mixture was evacuated and refilled several times with N. The catalyst, Pd (dba) 3 (9 mg , 0.01 mmol) and the ligand, BINAP (18 mg, 0.03 mmol) The reaction mixture was evacuated and refilled with N2 and then heated to reflux overnight, after which the analysis HPLC indicated complete consumption of the starting material The mixture was concentrated in vacuo, dissolved in EtOAc (20 ml), washed with H2O (2 x 5 ml) and brine (1 x 5 ml) and dried over Na2SO4. Anhydrous The removal of the solvent gives the crude product 19b which was purified by RP-HPLC.

Scheme 4 OH OH EXAMPLE 7 2-Hydroxy-3-pyridin-3-yl-acrylic acid methyl ester (Scheme 4). To a mixture of dry ethanol (0.2 ml) and ether (20 ml) was added NaH (60% dispersion in oil, 800 mg, 20 mmol) at 0 ° C and left to stand for 10 min. After that, N, N-dimethylglycine methyl ester (3.5 g, 30 mmol) and 3-pyridine carboxyaldehyde (944 μl, 10 mmol) were added. The reaction mixture was stirred first at 0 ° C and then at room temperature overnight. The mixture was diluted with ethyl acetate and washed with water. The organic phase was mixed with HCl 1? and stirred well. A saturated solution of? AHCO3 was added to neutralize the aqueous phase, and the product was extracted three times with ethyl acetate. The combined organic phases were concentrated, giving a solid mass which was then treated with the minimum amount of ethyl acetate and filtered to give the product 2-hydroxy-3-pyridin-3-yl-acrylic acid methyl ester. EXAMPLE 8 3-Bromo-2-oxo-3-pyridin-3-yl-propionic acid methyl ester bromide (Scheme 4). To a solution of 2-hydroxy-3-pyridin-3-yl-acrylic acid methyl ester (579 mg, 3 mmol, 1 equiv.) In 30 ml of THF was added dropwise bromine (154 μl, 3 mmol , 1 equiv.) In THF, followed by the addition of methanol to dissolve the precipitate. The reaction mixture was allowed to stir at room temperature for 0.5 h and was concentrated at room temperature with trituration a few times with THF and ethyl acetate. Then, the hydrobromide product of 3-bromo-2-oxo-3-pyridin-3-yl-propionic acid methyl ester was dried under high vacuum and used without further purification. EXAMPLE 9 2- (6-Chloro-7-methyl-1H-indazol-3-yl) -5-pyridin-3-yl-thiazole-4-carboxylic acid methyl ester (Scheme 4). To a round bottom flask loaded with 3-bromo-2-oxo-3-pyridin-3-yl-propionic acid methyl ester hydrobromide (obtained above, 353 mg, 1 mmol, 2 equiv.) And 5 ml of methanol Anhydrous was added to collidine (158 μl, 1.2 mmol, 2.4 equiv.) at 0 ° C, followed by thioamide (112 mg, 0.5 mmol, 1 equiv.). Then, the reaction mixture was brought to 50 ° C and stirred for 2 h. CL-MS showed the complete consumption of thioamide and the formation of a cycled intermediate (before dehydration). At this time, ethanesulfonic acid (98 μL, 1.2 mmol, 2.4 equiv.) Was added and the reaction mixture was stirred at 50 ° C overnight. The reaction mixture was concentrated and the residue was purified by RP-HPLC or used for the next step (hydrolysis).

EXAMPLE 10 2- (6-Chloro-7-methyl-1 H -indazol-3-yl) -5-pyridin-3-yl-thiazoi-4-carboxylic acid (Scheme 4). The ester obtained above (2- (6-chloro-7-methyl-1 H-indazol-3-yl) -5-pyridin-3-yl-thiazole-4-carboxylic acid methyl ester) was hydrolyzed in methanol reflux in the presence of 1 N NaOH. Then, the reaction mixture was concentrated and diluted with water. Then, HCl was added to acidify the solution. The precipitate was filtered and washed with water. The solid was dried under high vacuum. The product was finally purified by RP-HPLC. EXAMPLE 11 [2- (6-Chloro-7-methyl-1H-indazol-3-yl) -5-pyridin-3-yl-thiazol-4-yl] -methanone hydrochloride. To a mixture of the acid, 2- (6-chloro-7-methyl-1H-indazol-3-yl) -5-pyridin-3-yl-thiazole-4-carboxylic acid (1 equiv.), Triethylamine (3 equiv.) .) and the amine (5-10 equiv.) in DMF, was added O- (7-azabenzotriazol-1-yl) -1,1, 3,3-tetramethyluronium hexafluorophosphate (1.4 equiv.). The reaction was completed normally in a few minutes. The product was purified by RP-HPLC. The trifluoroacetate salt was transferred to the hydrochloride salt.

Scheme 5 RM-A Acetamide Indazole (2) Trimetllaniline (1) P. Mol .: 177.24 P, Mol .: 146.19 P. Mol .: 135.21 Yodoindazole (3) Ciapoip azole (4) Thioamide A (5) P. Mol .: 272.09 P. Mol .: 171.20 P. Mol.:205.28 Stage 6 Step 7: HBr salt of bromopyruvate B (9) P..Mol .: 353.01 P. Mol .: 205.28 Thiazolyester (10) P. Mol .: 364.42 Thiazole acid (11) API (15) P. Mol .: 35Ó.40 P. Mol .: 487.62 EXAMPLE 12 N- (2,4,6-tr? Methyl-phenyl) -acetamide (Scheme 5, step 1). A solution of 2,4,6-trimethyl-phenylamine (1) (50 g, 0.370 mol) in CH 2 Cl 2 (500 mL) was cooled to 0 ° C (ice-water bath). To this was added acetyl chloride (29.8 g, 27 ml, 380 mmol) for 5 minutes by means of an addition funnel; This was followed by portionwise addition of Et3N (38.5 g, 53 ml, 380 mmol). The ice bath was removed and the solution was allowed to warm to room temperature and stirred for 2 h. The resulting ivory solid was collected by filtration and dried in vacuo. To remove the residual Et 3 N HCl, the solid was suspended in H 2 O (600 ml), stirred for 0.5 h, collected by filtration and dried to a constant weight. The original organic filtrate was washed with H2O (3 x 100 ml) and brine (1 x 100 ml), dried (MgSO4), filtered and concentrated to give more product. It was combined with the material collected from the water, providing 60.2 g (99% yield) of the desired acetamide. RP-HPLC procedure: 2-100% B in 2 minutes. EXAMPLE 13 5,7-DimetiM H-indazole (2) (Scheme 5, step 2). N- (2,4,6-Trimethyl-phenyl) -acetamide (23.8 g, 133 mmol) (prepared as described in Example 12) was dissolved in a mixture of toluene (300 ml) and glacial AcOH ( 10.4 g, 173 mmol, 1.3 equiv.) And then slowly treated with isoamyl nitrite (20.3 g, 23.2 mL, 173 mmol, 1.3 equiv.). The mixture was heated to reflux overnight or until all of the starting material was consumed as determined by TLC (30% EtOAc-hexanes). Then, the solution was poured into H2O (1.3 L) and extracted with EtOAc (2 x 300 mL). Then, the combined organic extracts were washed with an ac solution. saturated? aHCO3 (2 x 200 ml) and brine (1 x 100 ml). The extracts were dried (MgSO 4), filtered and concentrated to give 19.5 g of 5,7-dimethyl-1 H-indazole 2 as a red waxy solid. This material was used without further purification. RP-HPLC procedure: B at 2-100% in 2 minutes EXAMPLE 14 3-Iodo-5,7-dimethyl-1 H-indazole (3) (Scheme 5, step 3). Indazole 2 (27.2 g, 186 mmol) in DMF (500 ml) was treated with iodine crystals (143.9 g, 567 mmol, 3 equiv.) And KOH (52.9 g, 945 mmol, 5 equiv. .). The mixture was stirred at room temperature for 2 h or until complete as determined by TLC (30% EtOAc-hexanes). The solution was concentrated to half its volume, poured into NHSO3 aq. at 5% (250 ml) and extracted with Et2O (3 x 250 ml). The organic extracts were combinedwere washed with H2O (2 x 200 ml) and brine (1 x 200 ml) dried (MgSO4), filtered and concentrated. The resulting dark solid was suspended in hot EtOAc (300 ml), treated with hexane (600 ml) and then allowed to cool for 2 h. The solids were collected by filtration to provide 17.50 g of culture 1. The filtrate was concentrated and culture 2 was isolated by filtration on a bed of silica gel. (20% EtOAc -hexanes). The concentration of the appropriate "filotography" fractions yielded 9.5 g of material that was combined with culture 1, giving a total of 27 g (total yield of 53% from acetanilide) of 3-iodo-5,7- dimethyl-1 H-indazole 3. RP-HPLC procedure: 2-100% B in 2 minutes. EXAMPLE 15 5,7-Dimethyl-1H-indazole-3-carbonitrile (4) (Scheme 5, step 4). Iodide 3 (20 g, 74.0 mmol) was dissolved in anhydrous NMP (300 mL). To this solution were added CuCN (19.9 g, 222 mmol, 3 equiv.) And NaCN (7.25 g, 148 mmol, 2 equiv.) And the mixture was heated at 130 ° C for 18 h in an atmosphere inert. Then, this solution was poured into 0.25 M KH2PO4 (1.5 L) and Et2O (750 ml) and celite (~ 100 g) were added. The suspension was stirred vigorously for 0.5 h and then filtered through a sintered glass funnel. The phases were separated and the aqueous phase was extracted with Et2O (3 x 200 ml). The combined organic extracts were washed with HO (2 x 200 ml) and brine (1 x 200 ml), dried (MgSO4), filtered and concentrated, yielding 8.3 g (65% yield) of 5.7 -Dimethyl-1H-indazole-3-carbonitrile 4. The nitrile was used as such for the next reaction. RP-HPLC procedure: B at 2-100% in 2 minutes. EXAMPLE 16 5,7-Dimethyl-1H-indazole-3-carboxymidothioic acid A (5) (Scheme 5, step 5). A solution of nitrile 4 (3.90 g, 22.0 mmol) in 20% Et3N-pyridine (v / v, 50 ml) was cooled to 0 ° C (ice-water bath) and then saturated with H2S. bubbling H2S gas through it for 5 minutes. The reaction vessel was sealed with stoppers and Parafilm film, removed from the cooling bath and stirred for 1.5 h, or until the consumption of starting material was completed as determined by TLC (50% EtOAc - hexanes). After it was complete, the solution was stirred under vacuum to remove excess H2S and then concentrated, leaving a brown solid. The crude product was suspended in hexane (250-300 ml), collected by vacuum filtration and dried over P2O5 in vacuo to give 4.2 g (93% yield) of A (5) as a solid. yellow. RP-HPLC procedure: B at 30-95% in 4.5 minutes. EXAMPLE 17 2-Hydroxy-3-pyridin-3-yl-acrylic acid ethyl ester (8) (Scheme 5, step 6). A 1 l dry round bottom flask was charged with anhydrous Et 2 O (500 ml) and cooled to 0 ° C (ice-water bath). After it was rinsed with hexane, NaH (60% w / w suspension in mineral oil, 16 g, 400 mmol, 2 equiv., Weight before rinsing) was added followed by absolute EtOH (23.2 ml, 400 mol. , 2 equiv.). After 10 minutes, a mixture of 3-pyridine carboxaldehyde (18.8 ml, 200 mmol, 1 equiv.) And ethyl ester of N, N-dimethylglycine (84.8 ml, 3 equiv.) (The methyl ester was added. of N, N-dimethyl glycine is also suitable for this preparation) for 1 minute. This mixture was stirred overnight at room temperature, heated at 30 ° C for 1 h and then transferred to a 2 liter separatory funnel. The mixture was diluted with EtOAc (500 ml) and H 2 O (500 ml) and the organic phase was transferred to a beaker and stirred with 1 HCl. (500 ml) at room temperature for 10 minutes. The mixture was checked to confirm a pH = 1 and then the phases were separated. The aqueous phase was retained and slowly neutralized by the addition of solid α aHCO3. This solution was extracted with EtOAc (3 x 300 ml) and the combined extracts were dried (α2 SO4), filtered and concentrated to a yellow solid. Crystallization from EtOAc-Hexanes (4: 1) gave 20.0 g (52% yield) of 8 pale yellow. RP-HPLC procedure: B at 2-100%. EXAMPLE 18 3-Bromo-2-oxo-3-pyridin-3-yl-propionic acid ethyl ester Bromhydrate B (9) (Scheme 5, step 7). To a solution of pyruvate 8 (19.3 g, 100.0 mmol) in dry THF (400 mL) was added dropwise bromine (5.12 mL, 100.0 mmol), followed by the addition of methanol ( -10 ml) to maintain homogeneity. The reaction mixture was stirred for 30 minutes at room temperature and then concentrated in vacuo at a bath temperature at or below 25 ° C. The resulting solid was triturated three times with THF (50 ml) and EtOAc (50 ml). The resulting bromo-pyruvate hydrobromide was isolated as a yellow foam after drying under high vacuum in quantitative yields. The solid was used without further purification. (Occasionally, the crude bromo-pyruvate product is dried in a thick gum.) In this case, the material was dried as thoroughly as possible, dissolved in MeOH (0.5 mmol / ml) and used as such in the following stage.) RP-HPLC procedure: B at 30-95% in 8 minutes. EXAMPLE 19 3-Bromo-2-oxo-3-pyridin-3-yl-propionic acid ethyl ester (10) (Scheme 5, step 11). A suspension of the thioamide A (5) (4.5 g, 22.0 mmol) in dry MeOH (100 ml) contained in a 2-neck round bottom flask was heated to 50 ° C. Separately, a solution of bromopyruvate B (9) (15.5 g, 44.0 mmol) in anhydrous MeOH (88 mL) was treated with collidine (10.2 mL, 77.0 mmol) at 0 ° C. The bromo-pyruvate / collider solution was added dropwise to the thioamide suspension maintained at 50 ° C. The mixture, which becomes homogeneous during the addition of the bromo-pyruvate solution, is heated at 50 ° C for 2 h, or until the thioamide consumption is completed as determined by RP-HPLC-MS (the intermediate not dehydrated, condensed, expected mass + 18). After this time, EtSO 3 H acid (6.3 ml, 77.0 mmol) was added and the heating was continued at 50 ° C overnight. The mixture was concentrated and the oily residue was treated with a saturated aqueous solution of sodium bicarbonate (-100 ml). The resulting solid is collected by vacuum filtration, rinsed with water (2 x 30 ml) and dried in vacuo. The solid is purified by filtration through a silica gel pad: an initial eluent of 100% CH 2 Cl 2 removes the nitrile 4 formed (typically 1-3%) and the subsequent elution with 2-5% MeOH-CH 2 Cl 2 provides the mixture of methyl and ethyl ester. RP-HPLC procedures: B at 30-95% in 8 minutes for the non-dehydrated intermediate. B at 10-95% in 8 minutes for the dehydrated final product. EXAMPLE 20 2- (5,7-Dimethyl-1H-indazol-3-yl) -5-pyridin-3-yl-thiazole-4-carboxylic acid (11) (Scheme 5), stage 12). A solution of the esters 10 (8 g, -22 mmol) in MeOH (100 ml) and 1 N NaOH (50 ml) was heated to reflux for 2 hours. The mixture was concentrated, acidified with 1 N HCl (100 ml) and the resulting solid was collected by vacuum filtration. The solid was rinsed with H2O (3 x 20 ml) and dried under high vacuum, giving a total of 7.9 g, (51%) from thioamide 5. RP-HPLC procedure: 10-95% B in 8 minutes EXAMPLE 21 1-Benzhydril-azetidin-3-yl ester of methanesulfonic acid (12) (Scheme 5, step 8). To a solution of 1-benzhydryl-azetidin-3-ol (15.0 g, 62.7 mmol) in dry CH2Cl2 (1 mL) at 0 ° C (ice-water bath) under nitrogen atmosphere was added Et3N dry (25 ml, 94.0 mmol). Then, to this was added dropwise a solution of methanesulfonyl chloride (5.8 ml, 75.2 mmol) in dry CH2Cl2 (50 ml) by means of a pressure equalizing addition funnel. After the addition was complete, the cooling bath was removed and the mixture was stirred for 2 h. The heterogeneous mixture was treated with H 2 O (70 ml), the phases were separated and the aqueous phase was extracted with CHaCl 2 (2 x 100 ml). The combined organic extracts were dried (MgSO4), filtered and concentrated, leaving a clear colorless oil. After the addition of hexanes (100 ml), the viscous oil product solidified and was collected by vacuum filtration. Drying under high vacuum afforded 19.7 g (100% yield) of 12 as a colorless solid. EXAMPLE 22 i- (1-Benzhydril-azetidin-3-yl) -4-methyl-piperazine (13) (Scheme 5, step 9). To a suspension of methanesulfonic acid 1-benzhydryl-azetidin-3-yl ester (12) (18 g, 56.7 mmol) in f-BuOH (150 mL) was added 1-methyl piperazine (17.04 g, 18.8 ml, 170.1 mmol) in an inert atmosphere. After heating at reflux temperature for 12 h, the mixture was concentrated to dryness, treated with saturated NaHCO3 (250 mL) and extracted with EtOAc (3 X 250 mL). The combined organic phases were washed with H2O (1 x 250 mL) and brine (1 x 250 mL) and dried (Na2SO4). Filtration and removal of the solvent left an oil which was purified by filtration with silica gel (-300 g) (first wash with EtOAc, then with 100% ammonia CH2Cl2-5% MeOH / ammoniacal CH2Cl2), yielding 7, 6 g (42%) of 13 in the form of a colorless waxy solid. The ammoniacal CH2Cl2 is prepared as follows: concentrated NH4OH (100 ml) is extracted with CH CI2 (1 x 500 ml), the phases are separated and the CH2Cl2 phase is dried and stored on anhydrous K2CO3. EXAMPLE 23 1-Azetidin-3-l-4-methyl-piperazine C (14) dichloride hydrochloride (Scheme 5, step 10). A mixture of 1- (1-benzhydryl-azetidin-3-yl) -4-methyl-piperazine (13) (1.13 g, 3.5 mmol), 20% wet Pd (OH) 2 / C (0 , 6 g) or 10% wet Pd / C degussa quality (0.22 g), MeOH (50 ml) and 4 N HCl in MeOH solution (1.8 ml, 7.0 mmol) was stirred in a H2 gas atmosphere (344,737 kPa (50 psig)) for 12 h. The catalyst was removed by filtration over Ceiite; the filter bed was rinsed with MeOH (3 x 10 ml), the filtrate was evaporated to dryness and the residue was rinsed with a mixture of Et 2 O (2 ml) and hexanes (10 ml) to remove the diphenylmethane. Product C (14) crystallized after a standing period, yielding 0.77 g (96% yield) of a colorless hygroscopic material which was used as such in the following steps. EXAMPLE 24 [2- (5,7-Dimethyl-1H-indazol-3-yl) -5-pyridin-3-yl-thiazol-4-yl] - [3- (4-methyl-piperazin-1-yl) -azetidin-1-yl] -metanone (15) (Scheme 5, step 13). A mixture of acid 11 (1.04 g, 3.07 mmol) and azetidine dihydrochloride C (14) (0.77 g, 3.37 mmol) in dry DMF (20 ml) was treated with dry EfeN (2). , 14 mL, 15.34 mmol) in an inert atmosphere. Then, HATU (1.46 g, 3.84 mmol) was added thereto. Effective couplings were also achieved using PyBop (1.4 equivalents based on 11) as the coupling agent. After stirring for 0.25 h, the RP-HPLC indicates the complete reaction. The mixture was transferred to concentrated NH 4 OH under stirring (400 ml) and the resulting brown solid was collected by vacuum filtration. Rinsing with H2O (2 x 10 mL) and drying in vacuo afforded 0.64 g (44% yield) of 15 as the free base. Concentration of the filtrate, resuspension in concentrated NH4OH (7 ml) and collection by vacuum filtration gave 90 mg more than 15. EXAMPLES 25-154 Biological assays Enzymatic assay with ATPase: the activities of DNA gyrase B following the release were determined gyrase B dependent on inorganic phosphate from ATP hydrolysis and subsequent detection using a spectrophotometric assay with 7-methyl-6-thioguanosine / phosphorylase. Assays were performed in 25 mM Tris-HCl buffer (pH 7.6), 2 mM MgCl2, and 125 mM NaCl, 0.2 M methyl 7-thioguanosine, purine nucleoside phosphorylase (1 unit / ml), ATP 0.4 mM and various concentrations of the inhibitor compounds prepared in Me2SO. The final concentration of Me2SO in each reaction was 2.5%. The compounds of the formula (I) shown in Table 1 were tested against one or more of Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pneumoniae, Streptococcus pyogenes, Enterococcus faecalis, Moraxella catarrhalis and H. influenzae. The concentration of the enzyme in the assay varied from 65 nM for full length gyrase B from E. faecaiis to 1 μM for full length gyrase B from H. influenzae. The reactions were initiated with the addition of ATP, and monitored at 360 nm at room temperature for 30 min. A strong binding kinetic analysis (Morrison, J.F. Biochim, Biophys, Acta 1969, 185, 269-286) was used to determine K, if the concentration of inhibitor was not greater than that of the enzyme. Antimicrobial activity assay (MIC determination) Bacterial preparations: Bacterial colonies in 0.9% NaCl were suspended overnight at a turbidity that is approximately comparable to the MacFarland standard. The spectrometer was calibrated (600 nm) using a pattern suspended in a well. 0.5 ml of bacterial suspension was placed in a cuvette and the absorbance was measured. A solution of 0.9% NaCl was added to the cuvette, mixed and measured until the absorbance is 0. From this, the dilution factor (to achieve an absorbance of 0) was calculated for the mother bacterial solution . A bacterial solution at this dilution is defined as a stock solution of 1x108 bacteria / ml. A final concentration of 5 x 10 5 bacteria per well was used for MIC determinations. Preparation of compounds: The test compounds of the formula (I) were tested over a wide range of concentrations using serial dilutions, the concentration falling by half in each step. The controls included wells that did not contain drug (growth control not inhibited), controls without additive (without serum etc.), and controls for contamination (additives but not drugs or bacteria). It was found that the compounds of formula (I) shown in Table 1 showed activity against one or more of Staphylococcus aureus., Staphylococcus epidermidis, Streptococcus pneumoniae, Streptococcus pyogenes, Enterococcus faecalis, Moraxella catarrhalis and H. influenzae. Table 2 provides the names and structures of compounds of formula (I) that were found to have a MIC of about 10 μM or less in the methicillin-resistant Staphylococcus aureus assay. Those skilled in the art will appreciate that various omissions, additions and modifications to the methods described above may be made without departing from the scope of the invention, and all such modifications and changes are intended to be included within the scope of the invention, as defined by the claims. Attached Table 2

Claims (43)

1. A compound comprising an indazolyl group and a thiazolyl group, the compound being represented by the structure wherein R7 is selected from the group consisting of hydrocarbon d-Cß, lower alkoxy, lower thioalkoxy, CN, NO2, halogen, CF3 and OCF3; and wherein the C Cß hydrocarbon, indazolyl group and thiazolyl group are optionally substituted on carbon; or a pharmaceutically acceptable salt, ester, solvate or prodrug thereof.

2. The compound of claim 1, wherein R7 is selected from the group consisting of methyl, ethyl, propyl, allyl, F, Cl, and Br.

3. The compound of claim 2, wherein the propyl is cyclopropyl.

4. The compound of claim 2, wherein R7 is selected from the group consisting of methyl, ethyl, F, and Cl.

5. The compound of claim 4, wherein R7 is methyl.

6. The compound of claim 1, wherein the indazolyl group carries at least one substituent selected from the group consisting of hydrocarbon Optionally substituted C-i-Cβ, optionally substituted heterocycle, lower alkoxy, CN, NO 2, F, Cl, Br, CF 3, and OCF 3.

7. The compound of claim 6, wherein the indazolyl carries at least one substituent selected from the group consisting of hydrocarbon Ci-Cβ optionally substituted, F, and Cl.

8. The compound of claim 7, wherein the indazolyl group carries at least one substituent selected from the group consisting of methyl, ethyl, propyl, allyl, methylcyclopropyl, F, and Cl.

9. The compound of claim 8, wherein the indazolyl group carries at least one substituent selected from the group consisting of methyl, ethyl, F, and Cl.

10. The compound of claim 1, wherein the thiazolyl group carries at least one substituent selected from the group consisting of optionally substituted CiC-io hydrocarbon, optionally substituted C1-C10 heterocycle, optionally substituted carboxamido, optionally substituted aminocarboxi, Ci-Cβ alkoxy optionally substituted, optionally substituted C6-C6 alkoxycarbonyl, OH, and COOH.

11. The compound of claim 10, wherein the thiazolyl group carries at least one substituent selected from the group consisting of methyl, ethyl, OH, COOH, COOCHs, and COOCH2CH3.

12. The compound of claim 10, wherein the thiazolyl group bears at least one substituent selected from the group consisting of optionally substituted C 1 -C 10 hydrocarbon, optionally substituted C 1 -C 6 alkoxycarbonyl, COOH, OH, COOR 3, and CONR 8 R 9, wherein R3 is selected from the group consisting of optionally substituted heterocycle and C- | -C6 alkyl substituted with heterocycle; wherein R8 and R9 are independently selected from the group consisting of H, optionally substituted heterocycle, and optionally substituted C-? -C6 hydrocarbon; wherein R8 and R9 can together form an optionally substituted heterocyclic ring of four, five or six members including the N atom to which R8 and R9 are attached; and wherein for said ring one to three carbon atoms can optionally be independently replaced each by an atom selected from the group consisting of N, O and S.

13. The compound of claim 10, wherein the thiazolyl group bears substituents, each of which is independently selected from the group consisting of optionally substituted C 1 -C 10 hydrocarbon, COOH, optionally substituted C 1 -C alkoxycarbonyl, OH, COOR 3, and CONR8R9, wherein R3 is selected from the group consisting of optionally substituted heterocycle and C? -C6 alkyl substituted with heterocycle; wherein R8 and R9 are independently selected from the group consisting of H, optionally substituted heterocycle, and optionally substituted C6 hydrocarbon, wherein R8 and R9 can together form an optionally substituted four, five or six membered heterocyclic ring including the N atom to which R and R 'are attached; and wherein for said ring one to three carbon atoms can optionally be independently replaced each by an atom selected from the group consisting of N, O and S.

14. The compound of claim 12, wherein the substituent is selected from the group consisting of methyl, ethyl, OH, phenyl, COOH, COOCH3, COOCH2CH3, and N (CH3) (CH2CH3).

15. The compound of claim 12, wherein the thiazolyl group is attached to a carbonyl carbon of at least one substituent represented by a structure selected from the group consisting of

16. The compound of claim 10, wherein the substituent is selected from the group consisting of phenyl and pyridyl, wherein the phenyl is optionally substituted with at least one second substituent selected from the group consisting of OH, OCH3, F, Cl , Br, optionally substituted piperazin-1-yl, and optionally substituted morpholin-4-yl; and wherein the pyridium is optionally substituted with at least one third substituent selected from the group consisting of Ci-Cß alkyl, F, Ci, Br, I, CF 3, 3,5-dimethyl-piperazin-1-yl, and morpholine -4-ilo.

17. The compound of claim 16, wherein the optionally substituted phenyl is selected from the group consisting of 3-hydroxyphenyl, 4-hydroxyphenyl, 3-methoxyphenyl, 3-fluorophenyl, 4-fluorophenyl, 4-fluoro-3-hydroxy-phenyl , 3,4-difluoro-phenyl, 3,5-difluoro-phenyl, 4-bromo-3-methoxy-phenyl, 4- (4-methyl-piperazin-1-yl) -phenyl, and 4- (morpholin-4) -yl) -phenyl.

18. The compound of claim 16, wherein the pyridyl is selected from the group consisting of pyridin-3-yl, 6-methyl-pyridin-3-yl, 6-chloro-pyridin-3-yl, and -trifluoromethyl-pyridin-3-yl.

19. The compound of claim 1, wherein the compound is (3-dimethylamino-pyrrolidin-1-yl) - [2- (7-methyl-1H-indazol-3-yl) -5-pyridin-3-yl- thiazol-4-yl] -metanone.

20. The compound of claim 1, wherein the compound is (3- (S) -dimethylamino-pyrrolidin-1-yl) - [2- (7-methyl-1H-indazol-3-yl) -5-pyridin- 3-yl-thiazol-4-yl] -methanone.

21. The compound of claim 1, wherein the compound is (3-dimethylamino-pyrrolidin-1-yl) - [2- (6-fluoro-7-methyl-1 H -ndazol-3 -l) -5-pyridin-3-yl-thiazol-4-yl] -methanone.

22. The compound of claim 1, wherein the compound is (3- (S) -d-methylamino-pyrrolidin-1-yl) - [2- (6-fluoro-7-methyl-1 H -ndazol-3- il) -5-pyridin-3-yl-thiazol-4-yl] -methanone.

23. The compound of claim 1, wherein the compound is a (3-dimethylamino-pyrrolidin-1-yl) - [2- (6-fluoro-7-methyl-1H-indazol-3-) il) -5-pyridin-3-yl-thiazol-4-irj-methanone in which the pyridyl is substituted with methyl.

24. The compound of claim 1, wherein the compound is (3-dimethylamino-pyrrolidin-1-yl) - [2- (7-methy1-1H-indazol-3-yl) -5- (6 -methyl-pyridin-3-yl) -thiazol-4-yl] -methanone.

25. The compound of claim 1, wherein the compound is (3- (S) -dimethalamino-pyrrolidin-1-yl) - [2- (7-methyl-1H-indazol-3-ii) - 5- (6-Methyl-pyridin-3-yl) -thiazol-4-yl] -methanone.

26. The compound of claim 1, wherein the compound is (3-dimethylamino-pyrrolidin-1-yl) - [2- (6-fluoro-7-methyl-1H-indazol-3-yl) -5- (6 -methyl-pyridin-3-yl) -thiazol-4-yl] -methanone.

27. The compound of claim 1, wherein the compound is (3- (S) -dimethylamino-pyrrolidin-1-yl) - [2- (6-fluoro-7-methyl-1H-indazol-3-yl) - 5- (6-Methyl-pyridin-3-yl) -thiazol-4-yl] -methanone.

28. The compound of claim 1, wherein the compound is [2- (5,7-dimethyl-1H-indazol-3-yl) -5-pyridin-3-yl-thiazo-4-yl] - (4-methy1p-piperazin-1-yl) -methanone.

29. The compound of claim 1, wherein the compound is 1- [2- (5,7-dimethyl-1H-indazol-3-yl) -5-pyridin-3-yl-thiazol-4-yl] -2 - (1-methyl-piperidin-4-yl) -ethanone.

30. The compound of claim 1, wherein the compound is [2- (5,7-dimethyl-1H-indazol-3-yl) -5-pyridin-3-yl-thiazol-4-yl] - [3- (4-methyl-piperazin-1-yl) -azetidin-1-yl] -methanone.

31. The compound of claim 1, wherein the compound is [2- (5,7-d.methyl-1H-indazol-3-yl) -5-pyridin-3-yl-thiazol-4-yl. ] - (3-morpholin-4-yl-azetidin-1-yl) -methanone.

32. The compound of claim 1, wherein the compound is [2- (5,7-dimethyl-1H-indazol-3-yl) -5-pyrridin-3-yl-thiazol-4-yl] - [3- (ethyl-methyl-amino) -azetidin-1-yl] -methanone.

33. The compound of claim 1 which is produced synthetically.

34. The compound of claim 1 isolated and purified.

35. A composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.

36. A method for treating or preventing a bacterial infection in a mammal, comprising administering to the mammal an effective amount of the composition of claim 35.

37. A method for treating or preventing a bacterial infection in a mammal, comprising administering to the mammal an effective amount of the compound of claim 1.

38. The method of claim 37, which comprises identifying a mammal suffering from the bacterial infection.

39. A process for making the compound of claim 1, comprising: treating an optionally substituted indazole represented by the formula wherein R7 is selected from the group consisting of lower alkoxy hydrocarbon, lower thioalkoxy, CN, NO2, halogen, CF3, and OCF3; wherein the C-i-Cß hydrocarbon is optionally substituted; and in which LG represents a leaving group; with a cyanide salt to form an optionally substituted nitrile nitrile represented by the formula

40. The process of claim 39, wherein the leaving group is selected from the group consisting of chlorine, bromine, iodine, trifluoromethanesulfonate, methanesulfonate, p-toluenesulfonate, and trifluoroacetate.

41. The method of claim 40, wherein the leaving group is iodine.

42. The use of the compound of claim 1 in the manufacture of a medicament for treating or preventing a bacterial infection in a mammal.

43. The use of the composition of claim 35 in the manufacture of a medicament for treating or preventing a bacterial infection in a mammal.