WO2009027733A1

WO2009027733A1 - (2-pyridin-3-ylimidazo[1,2-b]pyridazin-6-yl) urea derivatives as antibacterial agents

Info

Publication number: WO2009027733A1
Application number: PCT/GB2008/050735
Authority: WO
Inventors: Jacques Dumas; Brian Sherer
Original assignee: Astrazeneca Ab; Astrazeneca Uk Limited
Priority date: 2007-08-24
Filing date: 2008-08-22
Publication date: 2009-03-05

Abstract

Compounds of formula (I) and their pharmaceutically acceptable salts are described. Processes for their preparation, pharmaceutical compositions containing them, their use as medicaments and their use in the treatment of bacterial infections are also described.

Description

(2-PYRIDIN-3-YLIMIDAZO[1,2-B]PYRIDAZIN-6-YL) UREA DERIVATIVES AS ANTIBACTERIAL AGENTS

Field of the Invention

The present invention relates to compounds which demonstrate antibacterial activity, processes for their preparation, pharmaceutical compositions containing them as the active ingredient, to their use as medicaments and to their use in the manufacture of medicaments for use in the treatment of bacterial infections in warm-blooded animals such as humans. In particular this invention relates to compounds useful for the treatment of bacterial infections in warm-blooded animals such as humans, more particularly to the use of these compounds in the manufacture of medicaments for use in the treatment of bacterial infections in warm-blooded animals such as humans.

Background of the Invention

The international microbiological community continues to express serious concern that the evolution of antibiotic resistance could result in strains against which currently available antibacterial agents will be ineffective. In general, bacterial pathogens may be classified as either Gram-positive or Gram-negative pathogens. Antibiotic compounds with effective activity against both Gram-positive and Gram-negative pathogens are generally regarded as having a broad spectrum of activity. Gram-positive pathogens, for example Staphylococci, Enterococci, Streptococci and mycobacteria, are particularly important because of the development of resistant strains which are both difficult to treat and difficult to eradicate from the hospital environment once established. Examples of such strains are methicillin resistant staphylococcus aureus (MRSA), methicillin resistant coagulase negative staphylococci (MRCNS), penicillin resistant Streptococcus pneumoniae and multiple resistant Enterococcus faecium.

The preferred clinically effective antibiotic for treatment of last resort of such resistant Gram-positive pathogens is vancomycin. Vancomycin is a glycopeptide and is associated with various toxicities, including nephrotoxicity. Furthermore, and most importantly, antibacterial resistance to vancomycin and other glycopeptides is also appearing. This resistance is increasing at a steady rate rendering these agents less and less effective in the treatment of Gram-positive pathogens. There is also now increasing resistance appearing towards agents such as β-lactams, quinolones and macrolides used for the treatment of upper respiratory tract mfections, also caused by certain Gram negative strains including H influenzae and M catarrhahs.

Consequently, m order to overcome the threat of widespread multi-drug resistant organisms, there is an on-going need to develop new antibiotics, particularly those with either a novel mechanism of action and/or containing new pharmacophoric groups

Deoxyribonucleic acid (DNA) gyrase is a member of the type II family of topoisomerases that control the topological state of DNA in cells (Champoux, J J , 2001 Ann. Rev. Biochem. 70: 369-413) Type II topoisomerases use the free energy from adenosine triphosphate (ATP) hydrolysis to alter the topology of DNA by introducing transient double-stranded breaks m the DNA, catalyzing strand passage through the break and resealing the DNA. DNA gyrase is an essential and conserved enzyme in bacteria and is unique among topoisomerases in its ability to introduce negative supercoils into DNA. The enzyme consists of two subumts, encoded by gyrA and gyrB, forming an A₂B₂ tetrameric complex. The A subunit of gyrase (GyrA) is involved in DNA breakage and resealing and contains a conserved tyrosine residue that forms the transient covalent link to DNA during strand passage. The B subunit (GyrB) catalyzes the hydrolysis of ATP and interacts with the A subunit to translate the free energy from hydrolysis to the conformational change in the enzyme that enables strand-passage and DNA resealing.

Another conserved and essential type II topoisomerase in bacteria, called topoisomerase IV, is primarily responsible for separating the linked closed circular bacterial chromosomes produced in replication. This enzyme is closely related to DNA gyrase and has a similar tetrameric structure formed from subunits homologous to Gyr A and to Gyr B. The overall sequence identity between gyrase and topoisomerase IV in different bacterial species is high. Therefore, compounds that target bacterial type II topoisomerases have the potential to inhibit two targets in cells, DNA gyrase and topoisomerase IV, as is the case for existing quinolone antibacterials (Maxwell, A. 1997, Trends Microbiol. 5: 102-109).

DNA gyrase is a well-validated target of antibacterials, including the quinolones and the coumarins The quinolones (e g. ciprofloxacin) are broad-spectrum antibacterials that inhibit the DNA breakage and reunion activity of the enzyme and trap the GyrA subunit covalently complexed with DNA (Drhca, K., and X. Zhao, 1997, Microbiol. Molec. Biol.

Rev. 61 : 377-392). Members of this class of antibacterials also inhibit topoisomerase IV and as a result, the primary target of these compounds varies among species. Although the quinolones are successful antibacterials, resistance generated by mutations in the target (DNA gyrase and topoisomerase IV) is becoming an increasing problem in several organisms, including S. aureus and Streptococcus pneumoniae (Hooper, D. C, 2002, The Lancet Infectious Diseases 2: 530-538). In addition, quinolones, as a chemical class, suffer from toxic side effects, including arthropathy that prevents their use in children (Lipsky, B. A. and Baker, C. A., 1999, Clin. Infect. Dis. 28: 352-364). Furthermore, the potential for cardiotoxicity, as predicted by prolongation of the QT_C interval, has been cited as a toxicity concern for quinolones.

There are several known natural product inhibitors of DNA gyrase that compete with ATP for binding the GyrB subunit (Maxwell, A. and Lawson, D. M. 2003, Curr. Topics in Med. Chem. 3: 283-303). The coumarins are natural products isolated from Streptomyces spp., examples of which are novobiocin, chlorobiocin and coumermycin Al . Although these compounds are potent inhibitors of DNA gyrase, their therapeutic utility is limited due to toxicity in eukaryotes and poor penetration in Gram-negative bacteria (Maxwell, A. 1997, Trends Microbiol. 5: 102-109). Another natural product class of compounds that targets the GyrB subunit is the cyclothialidines, which are isolated from Streptomyces filipensis

(Watanabe, J. et al 1994, J. Antibiot. Al: 32-36). Despite potent activity against DNA gyrase, cyclothialidine is a poor antibacterial agent showing activity only against some eubacterial species (Nakada, N, 1993, Antimicrob. Agents Chemother. 37: 2656-2661).

Synthetic inhibitors that target the B subunit of DNA gyrase and topoisomerase IV are known in the art. For example, coumarin-contaming compounds are described in patent application number WO 99/35155, 5,6-bicyclic he tero aromatic compounds are described in patent application WO 02/060879, and pyrazole compounds are described in patent application WO 01/52845 (US patent US6,608,087). AstraZeneca has also published certain applications describing anti-bacterial compounds: WO2005/026149, WO2006/087544, WO2006/087548, WO2006/087543, WO2006/092599, WO2006/092608, WO2007/071965, WO2008/020227, WO2008/020222, WO2008/020229, and WO2008/068470.

Summary of the Invention

We have discovered a new class of compounds which are useful for inhibiting DNA gyrase and / or topoisomerase IV. The compounds of the present invention are regarded as effective against both Gram-positive and certain Gram-negative pathogens.

According to the present invention there is provided a compound of formula (I):

(I)

R¹ is selected from Ci^alkyl, C₂-₆alkenyl, C₂-₆alkynyl or C₃.₆cycloalkyl; wherein R¹ may be optionally substituted on carbon by one or more R ; R² is selected from hydrogen or Ci^alkyl; wherein said Ci-βalkyl may be optionally substituted by one or more groups independently selected from halo, cyano, hydroxy, nitro and amino;

Ring A is carbocyclyl or heterocyclyl; wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R⁷; R³ and R⁴ are independently selected from hydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, Ci^alkyl, C₂-₆alkenyl, C₂-₆alkynyl, Ci-βalkoxy, Ci^alkanoyl, Q-βalkanoyloxy, N-(Ci-6alkyl)amino, N,N-(Ci.6alkyl)₂amino, Ci-βalkanoylamino, N-(Ci-6alkyl)carbamoyl, N,N-(Ci.6alkyl)2carbamoyl, N-(Ci_6alkoxy)carbamoyl, N,N-(Ci_6alkoxy)₂carbamoyl, Ci-6alkylS(O)_a wherein a is 0 to 2, Ci^alkoxycarbonyl, Ci-βalkoxycarbonylammo, N-(Ci.₆alkyl)sulphamoyl,

N,N-(Ci-6alkyl)2Sulphamoyl, Ci-βalkylsulphonylamino, carbocyclyl-R⁸- or heterocyclyl-R⁹-; wherein R³ and R⁴ may be optionally substituted on carbon by one or more R¹⁰; and wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R¹¹; R is a substituent on carbon is selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, Ci-βalkyl, C₂-6alkenyl, C₂-6alkynyl, Ci^alkoxy, Ci-βalkanoyl, Ci-βalkanoyloxy, N-(Ci-6alkyl)amino, 7V,N-(Ci.6alkyl)2amino, Ci^alkanoylamino, N-(Ci.₆alkyl)carbamoyl, NN-(Ci.₆alkyl)₂carbamoyl, N-(Ci_6alkoxy)carbamoyl, N,N-(Ci_6alkoxy)₂carbamoyl, Ci-6alkylS(O)_a wherein a is 0 to 2, Ci-βalkoxycarbonyl, Ci-ealkoxycarbonylamino, 7V-(Ci-6alkyl)sulphamoyl,

NN-(Ci_6alkyl)₂Sulphamoyl, Ci_6alkylsulphonylamino, carbocyclyl-R - or heterocyclyl-R -; wherein R⁵ may be optionally substituted on carbon by one or more R¹⁴; and wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R ⁵: n is 0-4, wherein the values of R⁵ may be the same or different;

R is selected from halo, mtro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl,

C₂-6alkenyl, C₂-6alkynyl, Ci.βalkoxy,

Ci-βalkanoyloxy, N-(Ci_6alkyl)ammo, NN-(Ci_6alkyl)₂amino, Ci_6alkanoylamino and C3 βcycloalkyl, R⁸, R⁹, R¹² and R¹³are independent selected from a direct bond, -O-, -N(R¹⁶)-, -C(O)-,

-N(R¹⁷)C(O)-, -C(O)N(R¹⁸)-, -S(O)₈-, -SO₂N(R¹⁹)- or -N(R²⁰)SO₂-; wherein R¹⁶, R¹⁷, R¹⁸, R¹⁹ and R²⁰ are independently selected from hydrogen or Ci ₆alkyl and s is 0-2; and

R⁷, R¹¹ and R¹⁵ are independently selected from Ci-βalkyl, C₃_₆cycloalkyl, Ci-βalkanoyl, Ci-galkylsulphonyl, Ci-galkoxycarbonyl, carbamoyl, N-(Ci_6alkyl)carbamoyl, NN-(Ci ₆alkyl)carbamoyl, benzyl, benzyloxycarbonyl, benzoyl and phenylsulphonyl;

R¹⁰ and R¹⁴ are independently selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, tπfluoromethyl, ammo, carboxy, carbamoyl, mercapto, sulphamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylammo, dimethylamino, diethylammo, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, NN-dimethylcarbamoyl, NN-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulphinyl, ethylsulphmyl, mesyl, ethylsulphonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulphamoyl, N-ethylsulphamoyl, NN-dimethylsulphamoyl, NN-diethylsulphamoyl or N-methyl-N-ethylsulphamoyl; or a pharmaceutically acceptable salt thereof. In another embodiment, the invention provides pharmaceutical compositions comprising a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.

In another embodiment, the invention provides a method of inhibiting bacterial DΝA gyrase and/or bacterial topoisomerase IV in a warm-blooded animal in need of such treatment, comprising administering to the animal an effective amount of a compound represented by formula (I), or a pharmaceutically acceptable salt thereof. In a particular embodiment, the warm-blooded animal is a human.

In another embodiment, the invention provides a method of producing an antibacterial effect in a warm-blooded animal in need of such treatment, comprising administering to the animal an effective amount of a compound represented by formula (I), or a pharmaceutically acceptable salt thereof. In a particular embodiment, the warm-blooded animal is a human.

In another embodiment, the invention provides a method of treating a bacterial infection in a warm-blooded animal in need thereof, comprising administering to the animal an effective amount of a compound represented by formula (I), or a pharmaceutically acceptable salt thereof. In a particular embodiment, the warm-blooded animal is a human. In one embodiment, the bacterial infection is selected from the group consisting of community- acquired pneumoniae, hospital-acquired pneumoniae, skin and skin structure infections, acute exacerbation of chronic bronchitis, acute sinusitis, acute otitis media, catheter-related sepsis, febrile neutropenia, osteomyelitis, endocarditis, urinary tract infections and infections caused by drug resistant bacteria such as Penicillin-resistant Streptococcus pneumoniae, methicillm- resistant Staphylococcus aureus, methicillm-resistant Staphylococcus epidermidis and Vancomycm-Resistant Enterococci. In a particular embodiment, the warm-blooded animal is a human.

In another embodiment, the invention provides the use of a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use in the production of an antibacterial effect m a warm-blooded animal. In a particular embodiment, the warm-blooded animal is a human. In another embodiment, the invention provides the use of a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use in inhibition of bacterial DNA gyrase and/or topoisomerase IV in a warm-blooded animal. In a particular embodiment, the warm-blooded animal is a human.

In another embodiment, the invention provides the use of a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use the treatment of a bacterial infection m a warm-blooded animal. In one embodiment, the bacterial infection is selected from the group consisting of community-acquired pneumoniae, hospital-acquired pneumoniae, skm and skm structure infections, acute exacerbation of chronic bronchitis, acute sinusitis, acute otitis media, catheter-related sepsis, febrile neutropenia, osteomyelitis, endocarditis, urinary tract infections, Penicillin-resistant Streptococcus pneumoniae, methicillm-resistant Staphylococcus aureus, methicillin-resistant Staphylococcus epidermidis and Vancomycm-Resistant Enterococci. In a particular embodiment, the warm-blooded animal is a human.

In another embodiment, the invention provides a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, for use m production of an anti-bacterial effect m a warm-blooded animal. In another embodiment, the invention provides a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, for use in inhibition of bacterial DNA gyrase and/or topoisomerase IV m a warm-blooded animal.

In another embodiment, the invention provides a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of a bacterial infection in a warm-blooded animal.

In another embodiment, the invention provides a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of community-acquired pneumoniae, hospital-acquired pneumoniae, skm and skm structure infections, acute exacerbation of chronic bronchitis, acute sinusitis, acute otitis media, catheter-related sepsis, febrile neutropenia, osteomyelitis, endocarditis, urinary tract infections, Penicillin-resistant Streptococcus pneumoniae, methicillm-resistant Staphylococcus aureus, methicillm-resistant Staphylococcus epidermidis or Vancomycin-Resistant Enterococci.

Detailed Description of the Invention

In this specification the term alkyl includes both straight and branched chain alkyl groups. For example, "Ci^alkyl" includes methyl, ethyl, propyl, isopropyl and £-butyl. However references to individual alkyl groups such as propyl are specific for the straight chain version only unless specified otherwise. An analogous convention applies to other generic terms.

Where optional substituents are chosen from one or more groups it is to be understood that this definition includes all substituents being chosen from one of the specified groups or the substituents being chosen from two or more of the specified groups.

A "heterocyclyl" is a saturated, partially saturated or unsaturated, mono or bicyclic ring containing 4-12 atoms of which at least one atom is chosen from nitrogen, sulphur or oxygen, which may, unless otherwise specified, be carbon or nitrogen linked, wherein a -CH₂- group can optionally be replaced by a -C(O)- and a ring sulphur atom may be optionally oxidised to form the S-oxide(s). In one aspect of the invention a "heterocyclyl" is a saturated, partially saturated or unsaturated, monocyclic ring containing 5 or 6 atoms of which at least one atom is chosen from nitrogen, sulphur or oxygen, it may, unless otherwise specified, be carbon or nitrogen linked, a -CH₂- group can optionally be replaced by a -C(O)-and a ring sulphur atom may be optionally oxidised to form the S-oxides. In a further aspect of the invention a "heterocyclyl" is an unsaturated, carbon-lmked, monocyclic ring containing 5 or 6 atoms of which at least one atom is chosen from nitrogen, sulphur or oxygen Examples and suitable values of the term "heterocyclyl" are morpholmo, pipeπdyl, pyridyl, pyranyl, pyrrolyl, pyrazolyl, isothiazolyl, indolyl, qumolyl, thienyl, 1,3-benzodioxolyl, thiadiazolyl, piperazmyl, thiazohdinyl, pyrrohdmyl, thiomorpholmo, pyrrolinyl, homopiperazmyl, 3,5-dioxapipeπdinyl, tetrahydropyranyl, lmidazolyl, pynmidyl, pyrazinyl, pyridazmyl, isoxazolyl, N-methylpyrrolyl, 4-pyridone, 1 -lsoqumolone, 2-pyrrolidone, 4-thiazolidone, pyridme-N-oxide and qumolme-N-oxide Further examples and suitable values of the term "heterocyclyl" are lmidazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, pyrazolyl, 1,2,4-triazolyl, pyridyl, benzothiazolyl, isoxazolyl, pyrazinyl, pyπmidinyl and thiazolyl A "carbocyclyl" is a saturated, partially saturated or unsaturated, mono or bicyclic carbon ring that contains 3-12 atoms; wherein a -CH₂- group can optionally be replaced by a -C(O)-. Particularly "carbocyclyl" is a monocyclic ring containing 5 or 6 atoms or a bicyclic ring containing 9 or 10 atoms Suitable values for "carbocyclyl" include cyclopropyl, cyclobutyl, 1 -oxocyclopentyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, phenyl, naphthyl, tetralmyl, mdanyl or 1-oxomdanyl. A particular example of "carbocyclyl" is phenyl.

An example of

is acetoxy Examples

are methoxycarbonyl, ethoxycarbonyl, n- and ^-butoxycarbonyl. Examples of "Ci^alkoxycarbonylamino" are methoxycarbonylammo, ethoxycarbonylammo, n- and

are methoxy, ethoxy and propoxy Examples of "Ci^alkanoylammo" are formarmdo, acetamido and propionylammo. Examples of "Ci_₄alkylS(O)a wherein a is 0 to 2" are methylthio, ethylthio, methylsulphmyl, ethylsulphmyl, mesyl and ethylsulphonyl. Examples of

are propionyl and acetyl. Examples of "N-(Ci.₄alkyl)amino" are methylammo and ethylammo. Examples of "N,N-(Ci-₄alkyl)₂ammo" are di-N-methylammo, di-(N-ethyl)ammo and N-ethyl-N-methylammo Examples of "C2-4alkenyl" are vinyl, allyl and 1-propenyl. Examples of "C₂-₄alkynyl" are ethynyl, 1-propynyl and 2-propynyl. Examples of

"N-(Ci.₄alkyl)sulphamoyl" are N-(methyl)sulphamoyl and N-(ethyl)sulphamoyl. Examples of "N,N-(Ci_4alkyl)2Sulphamoyl" are N,N-(dimethyl)sulphamoyl and N-(methyl)-N-(ethyl)sulphamoyl. Examples of "N-(Ci-₄alkyl)carbamoyl" are methylammocarbonyl and ethylammo carbonyl. Examples of "N,N-(Ci-₄alkyl)₂carbamoyl" are dimethylammocarbonyl and methylethylammocarbonyl. Examples of "N-(Ci-₄alkoxy)carbamoyl" are methoxyammocarbonyl and lsopropoxyammocarbonyl. Examples of "N-(Ci.₄alkyl)-N-(Ci.₄alkoxy)carbamoyl" are N-methyl-N-methoxyammocarbonyl and N-methyl-N-ethoxyammocarbonyl Examples of "N'-(Ci-₄alkyl)ureido" are N'-methylureido and N'-isopropylureido. Examples of "N',N '-(Ci.₄alkyl)₂ureido" are N'N-dimethylureido and N'-methyl-N^f-isopropylureido. Examples of "N-(Ci ₄alkyl)hydrazmocarbonyl" are N'-methylhydrazmocarbonyl and N'-isopropylhydrazmocarbonyl Examples of "N'_>N-(Ci_-4alkyl)₂hydrazinocarbonyl" are

N'N'-dimethylhydrazmocarbonyl and N'-methyl-N'-isopropylhydrazmocarbonyl. Examples of "Ci ₄alkylsulphonylammo" are methylsulphonylammo, isopropylsulphonylammo and l-butylsulphonylamino. Examples of "Ci^alkylsulphonylammocarbonyl" are methylsulphonylammocarbonyl, isopropylsulphonylammocarbonyl and ϊ-butylsulphonylammocarbonyl Examples of "Ci ₄alkylsulphonyl" are methylsulphonyl, isopropylsulphonyl and f-butylsulphonyl. Examples of "Cs^cycloalkyl" are cyclopropyl and cyclohexyl.

A compound of formula (I) may form stable acid or basic salts, and m such cases administration of a compound as a salt may be appropriate, and pharmaceutically acceptable salts may be made by conventional methods such as those described following.

Suitable pharmaceutically-acceptable salts include acid addition salts such as methanesulfonate, tosylate, α-glycerophosphate, fumarate, hydrochloride, citrate, maleate, tartrate and hydrobromide Also suitable are salts formed with phosphoric and sulfuric acid In another aspect suitable salts are base salts such as an alkali metal salt for example sodium, an alkaline earth metal salt for example calcium or magnesium, an organic amine salt for example tπethylamme, morpholme, N-methylpiperidme, N-ethylpipeπdme, procaine, dibenzylamine, NN-dibenzylethylamme, tπs-(2-hydroxyethyl)amme, N-methyl d-glucamme and ammo acids such as lysine. There may be more than one cation or anion depending on the number of charged functions and the valency of the cations or anions In one aspect of the invention the pharmaceutically-acceptable salt is the sodium salt

However, to facilitate isolation of the salt during preparation, salts which are less soluble in the chosen solvent may be utilised whether pharmaceutically-acceptable or not.

Withm the present invention it is to be understood that a compound of the formula (I) or a salt thereof may exhibit the phenomenon of tautomerism and that the formulae drawings withm this specification can represent only one of the possible tautomeric forms It is to be understood that the invention encompasses any tautomeric form which inhibits DΝA gyrase and / or topoisomerase IV and is not to be limited merely to any one tautomeric form utilised withm the formulae drawings. The formulae drawings withm this specification can represent only one of the possible tautomeric forms and it is to be understood that the specification encompasses all possible tautomeric forms of the compounds drawn not just those forms which it has been possible to show graphically herein. The same applies to compound names.

It will be appreciated by those skilled in the art that compounds of formula (I) may contain asymmetrically substituted carbon(s) and sulphur atom(s), and accordingly may exist in, and be isolated in, as far as those additional asymmetrically substituted carbon(s) and sulphur atom(s) are concerned, optically-active and racemic forms at those positions. It is to be understood that the present invention encompasses any racemic, optically-active, polymorphic or stereoisomers form, or mixtures thereof, at any additional asymmetrically substituted carbon(s) and sulphur atom(s), which possesses properties useful m the inhibition of DNA gyrase and / or topoisomerase IV.

Optically-active forms may be prepared by procedures known in the art for example, by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, by enzymatic resolution, by biotransformation, or by chromatographic separation using a chiral stationary phase.

Some compounds may exhibit polymorphism It is to be understood that the present invention encompasses any polymorphic form, or mixtures thereof, which form possesses properties useful m the inhibition of DNA gyrase and / or topoisomerase IV.

It is also to be understood that certain compounds of the formula (I) and salts thereof can exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms which inhibit DNA gyrase and / or topoisomerase IV

By way of clarity, compounds of the invention included all isotopes of the atoms present in formula (I) and any of the examples or embodiments disclosed herein. For example, H (or hydrogen) represents any isotopic form of hydrogen including ¹H, ²H (D), and ³H (T); C represents any isotopic form of carbon including ¹²C, ¹³C, and ¹⁴C; O represents any isotopic form of oxygen including O, ⁷O and O; N represents any isotopic form of nitrogen including ¹³N, ¹⁴N and ¹⁵N; P represents any isotopic form of phosphorous including ³¹P and ³²P; S represents any isotopic form of sulfur including ³²S and ³⁵S; F represents any isotopic form of fluorine including F and F; Cl represents any isotopic form of chlorine including ⁵Cl, ⁷Cl and Cl; and the like. In a preferred embodiment, compounds represented by formula (I) comprise isomers of the atoms therein in their naturally occurring abundance. However, in certain instances, it is desirable to enrich one or more atom in a - U -

particular isotope which would normally be present m less abundance For example, ¹H would normally be present m greater than 99.98% abundance; however, a compound of the invention can be enriched m H or H at one or more positions where H is present. In one embodiment, when a compound of the invention is enriched in a radioactive isotope, for example H and C, they may be useful in drug and/or substrate tissue distribution assays It is to be understood that the invention encompasses all such isotopic forms which inhibit DNA gyrase and / or topoisomerase IV

There follow particular and suitable values for certain substituents and groups referred to in this specification These values may be used where appropriate with any of the definitions and embodiments disclosed hereinbefore, or hereinafter For the avoidance of doubt each stated species represents a particular and independent aspect of this invention.

R¹ is selected from Ci-βalkyl.

R is selected from ethyl

R² is hydrogen. Ring A is carbocyclyl.

Ring A is phenyl

Ring A is heterocyclyl, wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R⁷

Ring A is heterocyclyl Ring A is carbocyclyl or heterocyclyl

Ring A is phenyl, pyridyl or oxadiazolyl

Ring A is phenyl, pyrid-3-yl or oxadiazol-5-yl.

Ring A is pyridyl.

Ring A is pyrid-3-yl. Ring A is isoxazolyl

Ring A is isoxazol-5-yl.

R³ is hydrogen.

R⁴ is hydrogen.

R⁵ is a substituent on carbon which is selected from cyano, carboxy or Ci-₆alkoxycarbonyl.

R⁵ is a substituent on carbon which is independently selected from cyano, carboxy, Ci-βalkoxycarbonyl, and N-(Ci_6alkyl)carbamoyl

R⁵ is a substituent on carbon is selected from cyano, carboxy or ethoxycarbonyl. R⁵ is a substituent on carbon which is independently selected from cyano, carboxy, ethoxycarbonyl, and N-methylcarbamoyl n is 0-1. n is 0. n is 1.

Ring A together with (R⁵)_n is 3-carboxy-phenyl.

Ring A together with (R⁵)_n is 3-cyano-phenyl.

Ring A together with (R⁵)_n is 3-(N-methyl-carbamoyl)-phenyl.

Ring A together with (R⁵)_n is pyπd-3-yl, 3-carboxy-isoxazol-5-yl, or 3- ethoxycarbonyl-isoxaxol-5-yl.

Therefore in a further aspect of the invention there is provided a compound of formula (I) (as depicted above) wherein:

R is selected from Ci_₆alkyl;

R² is selected from hydrogen; Ring A is phenyl, pyridyl or oxadiazolyl;

R is hydrogen;

R⁴ is hydrogen;

R⁵ is a substituent on carbon is selected from cyano, carboxy or Ci_₆alkoxycarbonyl; n is 0-1. or a pharmaceutically acceptable salt thereof.

R¹ is selected from Ci^alkyl;

R² is selected from hydrogen; Ring A is phenyl, pyridyl or oxadiazolyl,

R³ is hydrogen;

R⁴ is hydrogen;

R⁵ is a substituent on carbon which is selected from cyano, carboxy, Ci_6alkoxycarbonyl and N-(Ci_6alkyl)carbamoyl; n is 0-1. or a pharmaceutically acceptable salt thereof. Particular compounds of the invention are the compounds of the Examples, each of which provides a further independent aspect of the invention. In further aspects, the present invention also comprises any two or more compounds of the Examples.

In one embodiment of the invention are provided compounds of formula (I), in an alternative embodiment are provided pharmaceutically-acceptable salts of compounds of formula (I).

In a further aspect the present invention provides a process for preparing a compound of formula (I) or a pharmaceutically-acceptable salt thereof.

Thus, the present invention also provides that the compounds of the formula (I) and pharmaceutically-acceptable salts thereof, can be prepared by a process as follows (wherein the variables are as defined above unless otherwise stated): Process a): Reacting an amine of formula (II):

NH R²

(H) with an acid of formula (III):

(III) or an activated derivative thereof;

Process b): Reacting an acid of formula (IV):

(IV) or an activated derivative thereof; with an amine of formula (V):

(V)

Process c) for compounds of formula (I) wherein R² is hydrogen: Reacting an isocyanate of formula (VI):

(VI) with an amine of formula (V);

Process d): Reacting an isocyanate of formula (VII):

(VII) with an amine of formula (II);

Process e) for compounds of formula (I) wherein the five membered ring of formula (I) is attached to a double bond of Ring A: Reacting a compound of formula (VIII):

with a compound of formula

(IX) wherein one of X^a and X is a displaceable group "L" and the other is an organometallic reagent "M"; Process β: Reacting a compound of formula (X):

(X) with a compound of formula (XI):

(XI) and thereafter if necessary: i) converting a compound of the formula (I) into another compound of the formula (I); ii) removing any protecting groups; iii) forming a pharmaceutically acceptable salt.

L is a displaceable group, suitable values for L include chloro, bromo, tosyl and trifiuoromethylsulphonyloxy.

M is an organometallic reagent, suitable values for M include organoboron and organotin reagents, in particular B(OR^Z)₂ where R^z is hydrogen or Ci-βalkyl for example B(OH)₂; and Sn(R^y)₃ where R^y is Ci_-6alkyl for example Sn(Bu)₃.

Specific reaction conditions for the above reactions are as follows. Process a) and Process b) Amines and acids may be coupled together in the presence of a suitable coupling reagent. Standard peptide coupling reagents known in the art can be employed as suitable coupling reagents, or for example carbonyldiimidazole (CDI) and dicyclohexyl-carbodiimide, optionally in the presence of a catalyst such as dimethylaminopyridine or 4-pyrrolidinopyridine, optionally in the presence of a base for example triethylamine, pyridine, or 2,6-di-α/&y/-pyridines such as 2,6-lutidine or

2,6-di-te/t-butylpyridine. Suitable solvents include dimethylacetamide, dichloromethane, benzene, tetrahydrofuran and dimethylformamide. The coupling reaction may conveniently be performed at a temperature in the range of -40 to 40 ⁰C.

Suitable activated acid derivatives include acid halides, for example acid chlorides, and active esters, for example pentafluorophenyl esters. The reaction of these types of compounds with amines is well known in the art, for example they may be reacted in the presence of a base, such as those described above, and in a suitable solvent, such as those described above. The reaction may conveniently be performed at a temperature in the range of -40 to 40 ⁰C.

Compounds of formula (III) may be prepared according to the following scheme:

CDI

(V) (III)

Scheme 1 Compounds of formula (V) may be prepared according to the following scheme:

NH₃, alcohol heat & pressure

(V)

Scheme 2 wherein L' is -C(O)CH₂Br.

Compounds of formula (II), (IV), (Va) and (Vb) are commercially available compounds, or they are known in the literature or they may be prepared by standard processes known in the art.

Process c) and Process d) Isocyanates and amines may be coupled together in a suitable solvent such as chloroform, dicholormethane, toluene, or N-methylpyrrolidine in the presence of base such as triethylamine and with the addition of heat.

Compounds of formula (VII) may be prepared according to the following scheme: formic acid

(V) (VII) heat

Scheme 3

Compounds of formula (VI) are commercially available compounds, or they are known in the literature or they may be prepared by standard processes known in the art. Process e) Compounds of formula (VIII) and (IX) may be reacted together by coupling chemistry utilizing an appropriate catalyst. Such reactions are well known in the art. For example, where M is an organoboron group, Pd(PPli3)₄ and a suitable base such as sodium carbonate can be utilized. In the case where M is an organotin reagent, Pd(PPli₃)₄ can be utilized as the catalyst. The reactions take place in suitable solvents and may require thermal conditions.

Compounds of formula (VIII) may be prepared according to the following scheme:

Scheme 4 wherein Y is halo.

Compounds of formula (Villa), (VIIIb) and (IX) are commercially available compounds, or they are known in the literature or they may be prepared by standard processes known in the art.

Process β: Compounds of formula (X) and (XI) may be reacted together by coupling chemistry utilizing an appropriate catalyst in an oxygen free environment. Suitable catalyst is Pd(O Ac)2 combined with Xantphos and a suitable base such as potassium tert-butoxide. Compounds of formula (X) can be prepared as in scheme 2. Compounds of formula

(XI) are commercially available, or they are known in the literature or they may be prepared by standard processes known in the art.

The formation of a pharmaceutically-acceptable salt is within the skill of an ordinary organic chemist using standard techniques. It will be appreciated that certain of the various ring substituents in the compounds of the present invention may be introduced by standard aromatic substitution reactions or generated by conventional functional group modifications either prior to or immediately following the processes mentioned above, and as such are included in the process aspect of the invention. The reagents used to introduce such ring substituents are either commercially available or are made by processes known in the art.

Introduction of substituents into a ring may convert one compound of the formula (I) into another compound of the formula (I). Such reactions and modifications include, for example, introduction of a substituent by means of an aromatic substitution reaction, reduction of substituents, alkylation of substituents, oxidation of substituents, esterification of substituents, amidation of substituents, formation of heteroaryl rings. The reagents and reaction conditions for such procedures are well known in the chemical art. Particular examples of aromatic substitution reactions include the introduction of alkoxides, diazotization reactions followed by introduction of thiol group, alcohol group, halogen group Examples of modifications include; oxidation of alkylthio to alkylsulphinyl or alkylsulphonyl.

The skilled organic chemist will be able to use and adapt the information contained and referenced within the above references, and accompanying Examples therein and also the Examples herein, to obtain necessary starting materials, and products. If not commercially available, the necessary starting materials for the procedures such as those described above may be made by procedures which are selected from standard organic chemical techniques, techniques which are analogous to the synthesis of known, structurally similar compounds, or techniques which are analogous to the above described procedure or the procedures described in the examples. It is noted that many of the starting materials for synthetic methods as described above are commercially available and/or widely reported in the scientific literature, or could be made from commercially available compounds using adaptations of processes reported in the scientific literature. The reader is further referred to Advanced Organic Chemistry, 4^th Edition, by Jerry March, published by John Wiley & Sons 1992, for general guidance on reaction conditions and reagents

It will also be appreciated that in some of the reactions mentioned herein it may be necessary/desirable to protect any sensitive groups in compounds. The instances where protection is necessary or desirable are known to those skilled in the art, as are suitable methods for such protection. Conventional protecting groups may be used in accordance with standard practice (for illustration see T.W. Greene, Protective Groups in Organic Synthesis, John Wiley and Sons, 1991).

Examples of a suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, a silyl group such as trimethylsilyl or an arylmethyl group, for example benzyl. The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively a silyl group such as trimethylsilyl may be removed, for example, by fluoride or by aqueous acid; or an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation in the presence of a catalyst such as palladium-on-carbon. A suitable protecting group for an amino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or ^-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an acyl group such as a ^-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate). A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamme, for example dimethylammopropylamme or 2-hydroxyethylamine, or with hydrazine.

A suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a £-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or for example, an allyl group which may be removed, for example, by use of a palladium catalyst such as palladium acetate.

The protecting groups may be removed at any convenient stage in the synthesis using conventional techniques well known in the chemical art, or they may be removed during a later reaction step or work-up.

Optically active forms of a compound of the invention may be obtained by carrying out one of the above procedures using an optically active starting material (formed, for example, by asymmetric induction of a suitable reaction step), or by resolution of a racemic form of the compound or intermediate using a standard procedure, or by chromatographic separation of diastereoisomers (when produced). Enzymatic techniques may also be useful for the preparation of optically active compounds and/or intermediates. Similarly, when a pure regioisomer of a compound of the invention is required, it may be obtained by carrying out one of the above procedures using a pure regioisomer as a starting material, or by resolution of a mixture of the regioisomers or intermediates using a standard procedure

Enzyme Potency Testing Methods

Compounds may be tested for inhibition of GyrB ATPase activity using an ammonium molybdate/malachite green-based phosphate detection assay (Lanzetta, P. A., L. J. Alvarez, P. S. Remach, and O A Candia, 1979, 100: 95-97). Assays can be performed in multiwell plates in 100 μl reactions containing: 50 mM HEPES buffer pH 7 5, 75 mM ammonium acetate, 5.5 mM magnesium chloride, 0.5 mM ethylenediammetetraacetic acid, 5% glycerol, 1 mM 1 ,4-Dithio-DL-threitol, 200 nM bovme serum albumin, 5 μg/ml sheared salmon sperm DNA, 2.5 nM E. coli GyrA, 2.5 nM E coli GyrB, 250 μM ATP, and compound in dimethylsulfoxide. Reactions can be quenched with 150 μl of ammonium molybdate/malachite green detection reagent containing 1.2 mM malachite green hydrochloride, 8.5 mM ammonium molybdate tetrahydrate, and 1 M hydrochloric acid. Plates can be read in an absorbance plate reader at 650 nm and percent inhibition values may be calculated using dimethylsulfoxide (2%)-containing reactions as 0% inhibition and novobiocin-containing (2 μM) reactions as 100% inhibition controls. Compound potency can be based on IC50 measurements determined from reactions performed in the presence of 10 different compound concentrations

Compounds may be tested for inhibition of topoisomerase IV ATPase activity as described above for GyrB except the lOOμl reactions may contain the following: 20 mM TRIS buffer pH 8, 50 mM ammonium acetate, 8 mM magnesium chloride, 5% glycerol, 5 mM 1,4-dithio-DL-threitol, 0.005% Brij-35, 5 μg/ml sheared salmon sperm DNA, 2.5 nM Streptococcus pneumoniae ParE, 160 μM ATP, and compound in dimethylsulfoxide. Compound potency may be based on IC50 measurements determined from reactions performed in the presence of 10 different compound concentrations.

Compounds may be tested for inhibition of topoisomerase IV ATPase activity as described above for GyrB except the 30μl reactions contained the following 20 mM TRIS buffer pH 8, 50 mM ammonium acetate, 8 mM magnesium chloride, 5% glycerol, 5 mM 1 ,4- Dithio-DL-threitol, 0 005% Brij-35, 5 μg/ml sheared salmon sperm DNA, 1.25 nM Streptococcus pneumoniae ParE, 160 μM ATP, and compound in dimethylsulfoxide. Compound potency may be based on IC50 measurements determined from reactions performed in the presence of 10 different compound concentrations. Inhibition of Streptococcus pneumoniae ParE can be assessed by observing percent inhibition at a given compound concentration. Compounds in the following table were tested in an assay substantially similar to the assay described in this paragraph to determine percent inhibition of Streptococcus pneumoniae ParE at a compound concentration of 25 μM:

Compounds of the invention could be expected to have IC_5O values of <200μg/ml in one or both assays described herein above For example, Example 1 showed an IC₅₀ of

872 nM against Streptococcus pneumoniae ParE, Example 2 showed an IC₅₀ of 5 μM against Streptococcus pneumoniae ParE, and Example 3 showed an IC50 of 508 nM against Streptococcus pneumoniae ParE.

Bacterial Susceptibility Testing Methods

Compounds may be tested for antimicrobial activity by susceptibility testing in liquid media Compounds may be dissolved m dimethylsulfoxide and tested in 10 doubling dilutions in the susceptibility assays. The organisms used in the assay may be grown overnight on suitable agar media and then suspended in a liquid medium appropriate for the growth of the organism. The suspension can be a 0.5 McFarland and a further 1 in 10 dilution can be made into the same liquid medium to prepare the final organism suspension in 100 //L. Plates can be incubated under appropriate conditions at 37 ⁰C for 24 hrs prior to reading. The Minimum Inhibitory Concentration (MIC) may be determined as the lowest drug concentration able to reduce growth by 80% or more Example 3 had an MIC of 100.0 μg/ml against Streptococcus pneumoniae. According to a further feature of the invention there is provided a compound of the formula (I), or a pharmaceutically-acceptable salt thereof for use in a method of treatment of the human or animal body by therapy.

We have found that compounds of the present invention inhibit bacterial DNA gyrase and / or topoisomerase IV and are therefore of interest for their antibacterial effects. In one aspect of the invention the compounds of the invention inhibit bacterial DNA gyrase and are therefore of interest for their antibacterial effects. In one aspect of the invention the compounds of the invention inhibit topoisomerase IV and are therefore of interest for their antibacterial effects. In one aspect of the invention the compounds of the invention inhibit both DNA gyrase and topoisomerase IV and are therefore of interest for their antibacterial effects.

It is expected that the compounds of the present invention will be useful in treating bacterial infections. In one aspect of the invention "infection" or "bacterial infection" refers to a gynecological infection. In one aspect of the invention "infection" or "bacterial infection" refers to a respiratory tract infection (RTI). In one aspect of the invention "infection" or "bacterial infection" refers to a sexually transmitted disease. In one aspect of the invention "infection" or "bacterial infection" refers to a urinary tract infection. In one aspect of the invention "infection" or "bacterial infection" refers to acute exacerbation of chronic bronchitis (ACEB). In one aspect of the invention "infection" or "bacterial infection" refers to acute otitis media . In one aspect of the invention "infection" or "bacterial infection" refers to acute sinusitis. In one aspect of the invention "infection" or "bacterial infection" refers to an infection caused by drug resistant bacteria. In one aspect of the invention "infection" or "bacterial infection" refers to catheter-related sepsis. In one aspect of the invention "infection" or "bacterial infection" refers to chancroid. In one aspect of the invention "infection" or "bacterial infection" refers to chlamydia. In one aspect of the invention

"infection" or "bacterial infection" refers to community-acquired pneumonia (CAP). In one aspect of the invention "infection" or "bacterial infection" refers to complicated skin and skin structure infection. In one aspect of the invention "infection" or "bacterial infection" refers to uncomplicated skin and skin structure infection. In one aspect of the invention "infection" or "bacterial infection" refers to endocarditis. In one aspect of the invention "infection" or

"bacterial infection" refers to febrile neutropenia. In one aspect of the invention "infection" or "bacterial infection" refers to gonococcal cervicitis. In one aspect of the invention "infection" or "bacterial infection" refers to gonococcal urethritis. In one aspect of the invention "mfection" or "bacterial infection" refers to hospital-acquired pneumonia (HAP). In one aspect of the invention "infection" or "bacterial infection" refers to osteomyelitis. In one aspect of the invention "infection" or "bacterial infection" refers to sepsis. In one aspect of the invention "infection" or "bacterial infection" refers to syphilis In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Acinetobacter baumanii In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Acinetobacter haemolyticus . In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Acinetobacter junii. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Acinetobacter Johns onii. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Acinetobacter Iwoffi. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Bacteroides bivius. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Bacteroides fragilis. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Burkholdena cepacia In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Campylobacter jejuni. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Chlamydia pneumoniae. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Chlamydia urealyticus. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Chlamydophila pneumoniae. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Clostridium difficili. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Enterobacter aerogenes. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Enterobacter cloacae. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Enterococcus faecalis . In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Enterococcus faecium In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Escherichia coli. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Gardnerella vaginalis. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Haemophilus parainfluenzae. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Haemophilus influenzae. In one aspect of the mvention an "infection" or "bacterial infection" refers to an infection caused by Helicobacter pylori. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Klebsiella pneumoniae. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Legionella pneumophila. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by

Methicillm-resistant Staphylococcus aureus. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Methicillm-susceptible Staphylococcus aureus. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Moraxella catarrhalis. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Morganella morganii. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Mycoplasma pneumoniae. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Neisseria gonorrhoeae. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Pemcillm- resistant Streptococcus pneumoniae. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Penicillin-susceptible Streptococcus pneumoniae. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Peptostreptococcus magnus. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Peptostreptococcus micros. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by

Peptostreptococcus anaerobius. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Peptostreptococcus asaccharolyticus . In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Peptostreptococcus prevotii. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Peptostreptococcus tetradius. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Peptostreptococcus vaginalis. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Proteus mirabilis. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Pseudomonas aeruginosa In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Quinolone-Resistant Staphylococcus aureus. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Quinolone-Resistant Staphylococcus epidermis. In one aspect of the invention an "infection" or "bacterial mfection" refers to an infection caused by Salmonella typhi. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Salmonella paratyphi. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Salmonella enteritidis In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Salmonella typhimurium. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Serratia marcescens. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Staphylococcus aureus In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Staphylococcus epidermidis. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by

Staphylococcus saprophyticus. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Streptococcus agalactiae. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Streptococcus pneumoniae. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Streptococcus pyogenes . In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Stenotrophomonas maltophiha. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Ureaplasma urealyticum. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Vancomycin-Resistant Enterococcus faecium. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by

Vancomycm-Resistant Enterococcus faecahs. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Vancomycin-Resistant Staphylococcus aureus. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Vancomycm-Resistant Staphylococcus epidermis. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Acmetobacter spp . In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Bacteroides spp.. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Burkholderia spp. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Campylobacter spp.. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Chlamydia spp.. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Chlamydophila spp. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Clostridium spp.. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Enterobacter spp. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Enterococcus spp. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Escherichia spp.. In one aspect of the invention an "infection" or

"bacterial infection" refers to an infection caused by Gardnerella spp.. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Haemophilus spp. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Helicobacter spp.. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Klebsiella spp . In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Legionella spp. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Moraxella spp. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Morganella spp.. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Mycoplasma spp.. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Neisseria spp.. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Peptostreptococcus spp.. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Proteus spp.. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Pseudomonas spp. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Salmonella spp.. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Serratia spp.. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Staphylococcus spp.. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Strep toccocus spp.. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Stenotrophomonas spp.. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Ureaplasma spp . In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by aerobes. In one aspect of the invention an "infection" or

"bacterial infection" refers to an infection caused by obligate anaerobes. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by facultative anaerobes. In one aspect of the invention an "infection" or "bacterial infection" refers to an mfection caused by gram-positive bacteria. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by gram-negative bacteria. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by gram- variable bacteria. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by atypical respiratory pathogens.

According to a further feature of the present invention there is provided a method for producing an antibacterial effect m a warm blooded animal, such as man, in need of such treatment, which comprises administering to said animal an effective amount of a compound of the present invention, or a pharmaceutically-accep table salt thereof. According to a further feature of the invention there is provided a method for inhibition of bacterial DNA gyrase and / or topoisomerase IV in a warm-blooded animal, such as a human being, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined hereinbefore. According to a further feature of the invention there is provided a method of treating a bacterial infection in a warm-blooded animal, such as a human being, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined hereinbefore.

According to a further feature of the invention there is provided a method of treating a bacterial infection selected from a gynecological infection, a respiratory tract infection (RTI), a sexually transmitted disease, a urinary tract infection, acute exacerbation of chronic bronchitis (ACEB), acute otitis media , acute sinusitis, an infection caused by drug resistant bacteria, catheter-related sepsis, chancroid, chlamydia, community-acquired pneumonia (CAP), complicated skm and skm structure infection, uncomplicated skin and skin structure infection, endocarditis, febrile neutropenia, gonococcal cervicitis, gonococcal urethritis, hospital-acquired pneumonia (HAP), osteomyelitis, sepsis and /or syphilis in a warm-blooded animal, such as a human being, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined hereinbefore. A further feature of the present invention is a compound of formula (I) and pharmaceutically acceptable salts thereof for use as a medicament. Suitably the medicament is an antibacterial agent. According to a further aspect of the invention there is provided the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the production of an anti-bacterial effect m a warm-blooded animal such as a human being. According to a further aspect of the invention there is provided the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the inhibition of bacterial DNA gyrase and / or topoisomerase IV m a warm-blooded animal such as a human being.

Thus according to a further aspect of the invention there is provided the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a bacterial infection m a warm-blooded animal such as a human being.

Thus according to a further aspect of the invention there is provided the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a bacterial infection selected from a gynecological infection, a respiratory tract infection (RTI), a sexually transmitted disease, a urinary tract infection, acute exacerbation of chronic bronchitis (ACEB), acute otitis media, acute sinusitis, an infection caused by drug resistant bacteria, catheter-related sepsis, chancroid, chlamydia, community-acquired pneumonia (CAP), complicated skm and skm structure infection, uncomplicated skin and skin structure infection, endocarditis, febrile neutropenia, gonococcal cervicitis, gonococcal urethritis, hospital-acquired pneumonia (HAP), osteomyelitis, sepsis and / or syphilis in a warm-blooded animal such as a human being.

According to a further aspect of the invention there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof for use in the production of an anti- bacterial effect in a warm-blooded animal such as a human being

According to a further aspect of the invention there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof for use in inhibition of bacterial DNA gyrase and / or topoisomerase IV in a warm-blooded animal such as a human being.

Thus according to a further aspect of the invention there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof for use in the treatment of a bacterial infection in a warm-blooded animal such as a human being.

Thus according to a further aspect of the invention there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof for use in the treatment of a bacteπal infection selected from a gynecological infection, a respiratory tract infection (RTI), a sexually transmitted disease, a urinary tract infection, acute exacerbation of chronic bronchitis (ACEB), acute otitis media , acute sinusitis, an infection caused by drug resistant bacteria, catheter-related sepsis, chancroid, chlamydia, community-acquired pneumonia (CAP), complicated skin and skin structure infection, uncomplicated skin and skin structure infection, endocarditis, febrile neutropenia, gonococcal cervicitis, gonococcal urethritis, hospital-acquired pneumonia (HAP), osteomyelitis, sepsis and / or syphilis in a warm-blooded animal such as a human being.

In order to use a compound of the formula (I) or a pharmaceutically-acceptable salt thereof, for the therapeutic (including prophylactic) treatment of mammals including humans, in particular in treating infection, it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition

Therefore m another aspect the present invention provides a pharmaceutical composition which comprises a compound of the formula (I) or a pharmaceutically-acceptable salt thereof, and a pharmaceutically-acceptable diluent or carrier.

According to a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of formula (I) as defined hereinbefore or a pharmaceutically acceptable salt thereof, m association with a pharmaceutically acceptable excipient or carrier for use in producing an anti-bacterial effect in a warm-blooded animal, such as a human being.

According to a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of formula (I) as defined hereinbefore or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable excipient or earner for use in inhibition of bacterial DNA gyrase and / or topoisomerase IV in a warm-blooded animal, such as a human being.

According to a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of formula (I) as defined hereinbefore or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable excipient or carrier for use in the treatment of a bacterial infection in a warm-blooded animal, such as a human being.

According to a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of formula (I) as defined hereinbefore or a pharmaceutically acceptable salt thereof, m association with a pharmaceutically acceptable excipient or carrier for use m the treatment of a gynecological infection, a respiratory tract infection (RTI), a sexually transmitted disease, a urinary tract infection, acute exacerbation of chronic bronchitis (ACEB), acute otitis media , acute sinusitis, an infection caused by drug resistant bacteria, catheter-related sepsis, chancroid, chlamydia, community-acquired pneumonia (CAP), complicated skin and skin structure infection, uncomplicated skin and skin structure infection, endocarditis, febrile neutropenia, gonococcal cervicitis, gonococcal urethritis, hospital-acquired pneumonia (HAP), osteomyelitis, sepsis and/or syphilis in a warm-blooded animal, such as a human being.

The compositions of the invention may be m a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular or intramuscular dosmg or as a suppository for rectal dosing).

The compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art Thus, compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents.

Suitable pharmaceutically acceptable excipients for a tablet formulation include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulating and disintegrating agents such as corn starch or algenic acid; binding agents such as starch; lubricating agents such as magnesium stearate, stearic acid or talc; preservative agents such as ethyl or propyl p-hydroxybenzoate, and anti-oxidants, such as ascorbic acid Tablet formulations may be uncoated or coated either to modify their disintegration and the subsequent absorption of the active ingredient withm the gastrointestinal tract, or to improve their stability and/or appearance, in either case, using conventional coating agents and procedures well known in the art. Compositions for oral use may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin, or olive oil. Aqueous suspensions generally contain the active ingredient in finely powdered form together with one or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvmyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as lecithin or condensation products of an alkylene oxide with fatty acids (for example polyoxethylene stearate), or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives (such as ethyl or propyl p-hydroxybenzoate, anti-oxidants (such as ascorbic acid), colouring agents, flavouring agents, and/or sweetening agents (such as sucrose, saccharine or aspartame).

Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil (such as arachis oil, olive oil, sesame oil or coconut oil) or in a mineral oil (such as liquid paraffin). The oily suspensions may also contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol Sweetening agents such as those set out above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water generally contain the active ingredient together with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients such as sweetening, flavouring and colouring agents, may also be present The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, such as olive oil or arachis oil, or a mineral oil, such as for example liquid paraffin or a mixture of any of these. Suitable emulsifying agents may be, for example, naturally-occurring gums such as gum acacia or gum tragacanth, naturally-occurring phosphatides such as soya bean, lecithin, an esters or partial esters derived from fatty acids and hexitol anhydrides (for example sorbitan monooleate) and condensation products of the said partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening, flavouring and preservative agents.

Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, and may also contain a demulcent, preservative, flavouring and/or colouring agent

The pharmaceutical compositions may also be in the form of a sterile injectable aqueous or oily suspension, which may be formulated according to known procedures using one or more of the appropriate dispersing or wetting agents and suspending agents, which have been mentioned above. A sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example a solution in 1,3-butanediol.

Compositions for administration by inhalation may be in the form of a conventional pressurised aerosol arranged to dispense the active ingredient either as an aerosol containing finely divided solid or liquid droplets. Conventional aerosol propellants such as volatile fluorinated hydrocarbons or hydrocarbons may be used and the aerosol device is conveniently arranged to dispense a metered quantity of active ingredient.

For further information on formulation the reader is referred to Chapter 25.2 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990.

The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration For example, a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 2 g of active agent compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition. Dosage unit forms will generally contain about 1 mg to about 500 mg of an active ingredient. For further information on Routes of Administration and Dosage Regimes the reader is referred to Chapter 25.3 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990.

As stated above the size of the dose required for the therapeutic or prophylactic treatment of a particular disease state will necessarily be varied depending on the host treated, the route of administration and the severity of the illness being treated In one aspect of the mvention a daily dose in the range of 1-50 mg/kg is employed However the daily dose will necessarily be varied depending upon the host treated, the particular route of administration, and the severity of the illness being treated. Accordingly the optimum dosage may be determined by the practitioner who is treating any particular patient. As noted above, one embodiment of the present invention is directed to treating or preventing diseases caused by bacterial infections, wherein the bacteria comprise a GyrB ATPase or topoisomerase IV ATPase enzyme. "Treating a subject with a disease caused by a bacterial infection" includes achieving, partially or substantially, one or more of the following: the reducing or amelioration of the progression, severity and/or duration of the infection, arresting the spread of an infection, ameliorating or improving a clinical symptom or indicator associated with a the infection (such as tissue or serum components), and preventing the reoccurrence of the infection.

As used herein, the terms "preventing a bacterial infection" refer to the reduction m the risk of acquiring the infection, or the reduction or inhibition of the recurrence of the infection. In a preferred embodiment, a compound of the invention is administered as a preventative measure to a patient, preferably a human, before a surgical procedure is preformed on the patient to prevent infection.

As used herein, the term "effective amount" refers to an amount of a compound of this invention for treating or preventing a bacterial infection is an amount which is sufficient to prevent the onset of an infection, reduce or ameliorate the severity, duration, or progression, of an infection, prevent the advancement of an infection, cause the regression of an infection, prevent the recurrence, development, onset or progression of a symptom associated with an infection, or enhance or improve the prophylactic or therapeutic effect(s) of another therapy. In addition to its use in therapeutic medicine, compounds of formula (I) and their pharmaceutically acceptable salts are also useful as pharmacological tools in the development and standardisation of in-vitro and in-vιvo test systems for the evaluation of the effects of inhibitors of DNA gyrase and / or topoisomerase IV in laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice, as part of the search for new therapeutic agents.

In the above other, pharmaceutical composition, process, method, use and medicament manufacture features, the alternative and particular embodiments of the compounds of the invention described herein also apply.

Combinations The compounds of the invention described herein may be applied as a sole therapy or may involve, in addition to a compound of the invention, one or more other substances and/or treatments. Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate administration of the individual components of the treatment. Where the administration is sequential or separate, the delay in administering the second component should not be such as to lose the beneficial effect of the combination. Suitable classes and substances may be selected from one or more of the following: i) other antibacterial agents for example macrolides e.g erythromycin, azithromycin or clarithromycin; qumolones e.g. ciprofloxacin or levofloxacm; β-lactams e.g. penicillins e g. amoxicillin or piperacillin, cephalosporins e g ceftriaxone or ceftazidime; carbapenems, e.g meropenem or imipenem etc; aminoglycosides e.g. gentamicin or tobramycin; or oxazohdinones; and/or ii) anti-infective agents for example, an antifungal triazole e g. or amphotericin, and/or iii) biological protein therapeutics for example antibodies, cytokines, bactericidal/permeability- increasing protein (BPI) products; and/or iv) efflux pump inhibitors.

Therefore, in a further aspect of the invention there is provided a compound of the formula (I), or a pharmaceutically acceptable salt thereof and a chemotherapeutic agent selected from: i) one or more additional antibacterial agents; and/or ii) one or more anti-mfective agents; and/or iii) biological protein therapeutics for example antibodies, cytokines, bactericidal/permeability-increasing protein (BPI) products; and/or iv) one or more efflux pump inhibitors.

Examples

The invention is now illustrated but not limited by the following Examples in which unless otherwise stated :-

(i) evaporations were carried out by rotary evaporation in- vacuo and work-up procedures were earned out after removal of residual solids by filtration;

(ii) operations were generally carried out at ambient temperature, that is typically in the range 18-26 ⁰C and without exclusion of air unless otherwise stated, or unless the skilled person would otherwise work under an inert atmosphere; (iii) column chromatography (by the flash procedure) was used to purify compounds and was performed on Merck Kieselgel silica (Art. 9385) unless otherwise stated; (iv) yields are given for illustration only and are not necessarily the maximum attainable; (v) the structure of the end-products of the invention were generally confirmed by NMR and mass spectral techniques; proton magnetic resonance spectra is quoted and was generally determined in DMSO-dβ unless otherwise stated using a Bruker DRX-300 spectrometer operating at a field strength of 300 MHz. Chemical shifts are reported in parts per million downfield from tetramethysilane as an internal standard (δ scale) and peak multiplicities are shown thus: s, singlet; d, doublet; AB or dd, doublet of doublets, dt, doublet of triplets; dm, doublet of multiplets; t, triplet, m, multiplet; br, broad;

(vi) fast-atom bombardment (FAB) mass spectral data were generally obtained using a Platform spectrometer (supplied by Micromass) run in electrospray and, where appropriate, either positive ion data or negative ion data were collected or using Agilent 1 lOOseries LC/MSD equipped with Sedex 75ELSD, run in atmospheric pressure chemical iomsation mode and, where appropriate, either positive ion data or negative ion data were collected; mass spectra were run with an electron energy of 70 electron volts in the chemical ionization (CI) mode using a direct exposure probe; where indicated ionization was effected by electron impact (EI), fast atom bombardment (FAB) or electrospray (ES); values for m/z are given; generally, only ions which indicate the parent mass are reported; (vii) each intermediate was generally purified to the standard required for the subsequent stage and was characterised in sufficient detail to confirm that the assigned structure was correct; purity was assessed by high pressure liquid chromatography, thin layer chromatography, or NMR and identity was determined by infra-red spectroscopy (IR), mass spectroscopy or NMR spectroscopy as appropriate; (vii) the following abbreviations may be used'

SM is starting material;

DMSO is dimethylsulf oxide;

HATU is 2-(lH-7-azabenzotriazol-l-yl)-l,l,3,3-tetramethyl uronium hexafluorophosphate methanammium; LC is liquid chromatography;

MS is mass spectroscopy; and

TFA is trifluoroacetic acid;

Xantphos is 4,5-bis(diphenylphosphino)-9,9-dimethyl-xanthene; and (viii) temperatures are quoted as ⁰C.

Example 1

N-Ethyl-A/V2-pyridin-3-ylimidazo[l,2-&lpyridazm-6-yl)urea

In a 1-neck glass round bottom flask purged with nitrogen, Pd(OAc)₂ (7.01 mg, 10.41 μmol) and XAΝTPHOS (12.15 mg, 0.021 mmol) were combined and dissolved in dioxane (5 mL). The solution was degassed. 6-Chloro-2-(pyridin-3-yl)imidazo[l,2-b]pyridazine (Intermediate 1, 80 mg, 0.35 mmol), 1-ethylurea (30.6 mg, 0.35 mmol), potassium tert- butoxide (58.4 mg, 0.52 mmol) and water (9.36 mg, 0.52 mmol) were added successively to the flask. The reaction mixture was then heated to 100⁰C and monitored by LC/MS. The reaction was concentrated to dryness. The residue was dissolved in DMSO (2 mL). A few drops of concentrated HCl were added. Acetonitrile was added to precipitate out byproducts. The solids were removed by filtration and the mother liquor was concentrated. The resultant DMSO solution was then purified by Gilson HPLC (0-95% ACΝ / 0.1% TFA over 14 min.). The title compound began eluting at about 4 minutes. Fractions were collected and lyopholized. Isolation gave 8.4 mg of the title compound. MS (ES) M+H⁺: 283 for Ci₄Hi₄N₆O; NMR: 1.06 (m, 3H), 3.16 (m, 2H), 7.27 (m, IH), 7.52 (m, IH), 7.66 (m, IH), 8.02 (m, IH), 8.53 (m, IH), 8.57 (m, IH), 8.76 (s, IH), 9.20 (s, IH), 9.58 (s, IH).

Example 2 5-(6-(3-Ethylureido)imidazori,2-blpyridazin-2-yl)isoxazole-3-carboxylic acid

A suspension of ethyl 5-(6-(3-ethylureido)imidazo[l,2-b]pyridazm-2-yl)isoxazole-3- carboxylate (Example 4, 390 mg, 1.13 mmol) and sodium hydroxide (1.699 mL, 3.40 mmol) in ethanol (10 mL) was stirred at room temperature, then concentrated under reduced pressure, diluted with water and acidified to pH 4 with 10% HCl. The solid that formed was collected by filtration, then placed on a lyophilizer to remove residual solvent. MS (ES) M+H⁺: 317 for C_nH₁₂N₆O₄; NMR δ 1.12 (m, 3H), 3.24 (m, 2H), 7.01 (s, IH), 7.41 (br s, IH), 7.58 (d, J= 9 Hz, IH), 8.08 (d, J= 9 Hz, IH), 8.74 (s, IH), 9.71 (s, IH).

Example 3

3-(6-(3-Ethylureido)imidazori,2-b1pyridazin-2-yl)benzoic acid

A suspension of l-(2-(3-cyanophenyl)imidazo[l,2-b]pyridazin-6-yl)-3-ethylurea (Example 5, 297 mg, 0.97 mmol) and sodium hydroxide (155 mg, 3.88 mmol) in ethanol (5 mL) and water (5.00 mL) was heated to 70 ⁰C overnight. After 72 h, the reaction was cooled to room temperature. The reaction mixture was filtered and ethanol removed under reduced pressure. Water was added to the residue and the mixture was acidified to pH 4 with 10% HCl. The solid that formed was collected by filtration and placed on lyophilizer to remove residual water. MS (ES) M+H⁺: 326 for Ci₆Hi₅N₅O₃; NMR δ 1.13 (t, J= 7 Hz, 3H), 3.22 (m, 2H), 7.41 (m, IH), 7.58 (m, 2H), 7.88 (m, IH), 8.05 (m, IH), 8.56 (m, IH), 8.76 (s, IH), 9.62 (s, IH).

Examples 4-5 The following Intermediates were synthesized according to the procedure described for Example 1.

Example 6

3-(6-(3-Ethylureido)imidazori,2-b1pyridazin-2-yl)-N-methylbenzamide

HATU (95 mg, 0.25 mmol) was added to a stirred solution of 3-(6-(3- ethylureido)imidazo[l,2-b]pyridazin-2-yl)benzoic acid (Example 3, 74 mg, 0.23 mmol), methylamine hydrochloride (46.1 mg, 0.68 mmol) and triethylamine (0.095 mL, 0.68 mmol) in DMF (2 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered and the filtrate was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The solid that resulted was placed under high vacuum to remove residual solvent.

¹H NMR (300 MHz, DMSO-d₆) δ 1.13 (t, J = 7 Hz, 3H), 2.89 (s, 3H), 3.25 (m, 2H), 7.41- 7.52 (m, 3H), 7.75 (m, IH), 8.01-8.11 (m, 3H), 8.67 (s, IH), 9.59 (s, IH). Preparation of Starting Materials

Intermediate 1

6-Chloro-2-(pyridm-3-yDimidazo[ 1 ,2-b]pyπdazme

A suspension of 6-chloropyridazin-3 -amine (71 2 mg, 0.55 mmol) and 3- (bromoacetyl)-pyridine hydrobromide (132 mg, 0.66 mmol) in ethanol (2 mL) was heated 90 ⁰C for 5 h. Reaction mixture was cooled to room temperature and concentrated under reduced pressure. Water was added and the mixture was basified with solid sodium carbonate, extracted with methylene chloride, dried over sodium sulfate, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 7: 1 methylene chloride/methanol) provided the title compound (31 mg, 96%). MS (ES) M+H⁺: 231 for CnH₇ClN₄; NMR: 7.45 (m, IH), 7.54 (m, IH), 8.40 (m, IH), 8.57 (m, IH), 9.04 (s, IH), 9.25 (s, IH).

Intermediates 2-3

The following Intermediates were synthesized according to the procedure described for Intermediate 1.

Claims

Claim

1. A compound of formula (I):

(I)

R¹ is selected from d-βalkyl, C₂-₆alkenyl, C₂-₆alkynyl or C₃_₆cycloalkyl; wherein R¹ may be optionally substituted on carbon by one or more R⁶;

R² is selected from hydrogen or Ci^alkyl; wherein said Ci-βalkyl may be optionally substituted by one or more groups independently selected from halo, cyano, hydroxy, nitro and amino;

Ring A is carbocyclyl or heterocyclyl; wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R⁷;

R³ and R⁴ are independently selected from hydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, Ci^alkyl, C₂-6alkenyl, C₂-6alkynyl, Ci^alkoxy, Ci^alkanoyl, Ci^alkanoyloxy, N-(Ci.₆alkyl)amino, N,N-(Ci.₆alkyl)₂amino, Ci-βalkanoylamino, N-(Ci-6alkyl)carbamoyl, N,N-(Ci.6alkyl)2carbamoyl, N-(Ci_6alkoxy)carbamoyl, N₁N-(C i_6alkoxy)₂carbamoyl, Ci_6alkylS(O)_a wherein a is 0 to 2, Ci_6alkoxycarbonyl, Ci-βalkoxycarbonylammo, N-(Ci_6alkyl)sulphamoyl, N,N-(Ci.6alkyl)₂Sulphamoyl,

carbocyclyl-R - or heterocyclyl-R -; wherein R³ and R⁴ may be optionally substituted on carbon by one or more R¹⁰; and wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R¹¹;

R⁵ is a substituent on carbon is selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, Ci^alkyl, C₂-6alkenyl, C₂-6alkynyl, Ci^alkoxy, Ci-6alkanoyl, Ci-βalkanoyloxy, N-(Ci-6alkyl)amino, 7V,N-(Ci.6alkyl)2amino, Ci_6alkanoylamino, N-(Ci_6alkyl)carbamoyl, NN-(C i_6alkyl)₂carbamoyl, N-(Ci.₆alkoxy)carbamoyl,

Ci.₆alkylS(O)_a wherein a is 0 to 2, Ci_6alkoxycarbonyl, Ci-ealkoxycarbonylamino, 7V-(Ci-6alkyl)sulphamoyl, N,N-(Ci_6alkyl)₂Sulphamoyl, Ci_6alkylsulphonylamino, carbocyclyl-R - or heterocyclyl-R -; wherem R⁵ may be optionally substituted on carbon by one or more R¹⁴; and wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R ⁵; n is 0-4, wherein the values of R⁵ may be the same or different; R is selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, Ci^alkyl, C₂-6alkenyl, C₂-6alkynyl, Ci-βalkoxy, Ci-βalkanoyl, Ci-βalkanoyloxy, N-(Ci_₆alkyl)ammo, N₁N-(C i_₆alkyl)₂amino, Ci_₆alkanoylamino and C₃ βcycloalkyl,

R⁸, R⁹, R¹² and R¹³are independent selected from a direct bond, -O-, -N(R¹⁶)-, -C(O)-, -N(R¹⁷)C(O)-, -C(O)N(R¹⁸)-, -S(O)₈-, -SO₂N(R¹⁹)- or -N(R²⁰)SO₂-; wherein R¹⁶, R¹⁷, R¹⁸, R¹⁹ and R²⁰ are independently selected from hydrogen or Ci βalkyl and s is 0-2; and

R⁷, R¹¹ and R¹⁵ are independently selected from Ci^alkyl, Cs^cycloalkyl, Ci-βalkanoyl, Ci^alkylsulphonyl, Ci-βalkoxycarbonyl, carbamoyl, N-(Ci_6alkyl)carbamoyl, NN-(Ci ₆alkyl)carbamoyl, benzyl, benzyloxycarbonyl, benzoyl and phenylsulphonyl;

R¹⁰ and R¹⁴ are independently selected from halo, nitro, cyano, hydroxy, tnfluoromethoxy, tπfluoromethyl, ammo, carboxy, carbamoyl, mercapto, sulphamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylammo, dimethylamino, diethylammo, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, NN-dimethylcarbamoyl, NN-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulphinyl, ethylsulphmyl, mesyl, ethylsulphonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulphamoyl, N-ethylsulphamoyl, NN-dimethylsulphamoyl, NN-diethylsulphamoyl or N-methyl-N-ethylsulphamoyl; or a pharmaceutically acceptable salt thereof.

2. The compound according to Claim 1, wherein Ring A is a carbocyclyl.

3. The compound according to Claim 2, wherein Ring A is phenyl.

4. The compound according to Claim 1, wherein Ring A is heterocyclyl; wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R .

5. The compound according to Claim 4, wherein Ring A is pyridyl.

6. The compound according to Claim 4, wherein Ring A is isoxazolyl.

7. The compound according to any one of the preceding claims, wherein n is 1.

8. The compound according to any one of the preceding claims, wherein R⁵ is a substituent on carbon which is independently selected from cyano, carboxy, Ci_₆alkoxycarbonyl, and N-(Ci_₆alkyl)carbamoyl.

9. The compound according to any one of Claims 1 through 6, wherein n is 0.

10. The compound according to any one of the preceding claims wherein R³ is hydrogen.

11. The compound according to any one of the preceding claims wherein R is hydrogen.

12. The compound according to any one of the preceding claims wherein R¹ is selected from Ci.6alkyl.

13. The compound according to Claim 12, wherein R¹ is selected from ethyl.

14. The compound according to any one of the preceding claims, wherein R² is hydrogen.

15. The compound according to Claim 1, wherein

R¹ is selected from Ci^alkyl;

R² is selected from hydrogen; Ring A is phenyl, pyridyl or oxadiazolyl;

R³ is hydrogen;

R⁴ is hydrogen;

R⁵ is a substituent on carbon which is selected from cyano, carboxy, Ci_6alkoxycarbonyl and N-(Ci_6alkyl)carbamoyl; n is 0-1. or a pharmaceutically acceptable salt thereof.

16. A pharmaceutical composition comprising a compound of any one of Claims 1 through 15, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.

17. A method of inhibiting bacterial DNA gyrase and/or bacterial topoisomerase IV in a warm-blooded animal in need of such treatment, comprising administering to the animal an effective amount of a compound of any one of Claims 1 through 15, or a pharmaceutically acceptable salt thereof.

18. A method of producing an antibacterial effect in a warm-blooded animal in need of such treatment, comprising administering to the animal an effective amount of a compound of any one of Claims 1 through 15, or a pharmaceutically acceptable salt thereof.

19. A method of treating a bacterial infection in a warm-blooded animal in need thereof, comprising administering to the animal an effective amount of a compound of any one of

Claims 1 through 15, or a pharmaceutically acceptable salt thereof.

20. The method of Claim 19, wherein the bacterial infection is selected from the group consisting of community-acquired pneumoniae, hospital-acquired pneumoniae, skin and skm structure infections, acute exacerbation of chronic bronchitis, acute sinusitis, acute otitis media, catheter-related sepsis, febrile neutropenia, osteomyelitis, endocarditis, urinary tract infections and infections caused by drug resistant bacteria such as Penicillin-resistant Streptococcus pneumoniae, methicillm-resistant Staphylococcus aureus, methicillm-resistant Staphylococcus epidermidis and Vancomycm-Resistant Enterococci.

21. The method of any one of Claims 17 through 20, wherein the warm-blooded animal is a human.

22. The use of a compound of any one of Claims 1 through 15, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use in the production of an antibacterial effect in a warm-blooded animal.

23 The use of a compound of any one of Claims 1 through 15, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use in inhibition of bacterial DNA gyrase and/or topoisomerase IV in a warm-blooded animal.

24. The use of a compound of any one of Claims 1 through 15, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use the treatment of a bacterial infection m a warm-blooded animal

25. The use of Claim 24, wherein the bacterial infection is selected from the group consisting of community-acquired pneumoniae, hospital-acquired pneumoniae, skm and skm structure infections, acute exacerbation of chronic bronchitis, acute sinusitis, acute otitis media, catheter-related sepsis, febrile neutropenia, osteomyelitis, endocarditis, urinary tract infections, Penicillin-resistant Streptococcus pneumoniae, methicillm-resistant Staphylococcus aureus, methicillm-resistant Staphylococcus epidermidis and Vancomycm-Resistant Enterococci

26 The use of any one of Claims 22 through 25, wherein the warm-blooded animal is a human.

27. A compound of any one of Claims 1 through 15, or a pharmaceutically acceptable salt thereof, for use in production of an anti-bacterial effect in a warm-blooded animal

28. A compound of any one of Claims 1 through 15, or a pharmaceutically acceptable salt thereof, for use in inhibition of bacterial DNA gyrase and/or topoisomerase IV in a warmblooded animal.

29. A compound of any one of Claims 1 through 15, or a pharmaceutically acceptable salt thereof, for use in the treatment of a bacterial infection in a warm-blooded animal.

30. A compound of any one of Claims 1 through 15, or a pharmaceutically acceptable salt thereof, for use in the treatment of community-acquired pneumoniae, hospital-acquired pneumoniae, skin and skm structure infections, acute exacerbation of chronic bronchitis, acute sinusitis, acute otitis media, catheter-related sepsis, febrile neutropenia, osteomyelitis, endocarditis, urinary tract infections, Penicillin-resistant Streptococcus pneumoniae, methicillin-resistant Staphylococcus aureus, methicillin-resistant Staphylococcus epideπnidis or Vancomycin-Resistant Enterococci.