CHEMICAL COMPOUNDS

BACKGROUND 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.

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. The compounds of the present invention are regarded as effective against both Gram-positive and certain Gram-negative pathogens.

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 infections, also caused by certain Gram negative strains including H. influenzae and M.catarrhalis.

Consequently, in 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 in 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 subunits, encoded by gyrA and gyrB, forming an A ₂ B ₂ 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 (Drlica, 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 primarily 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 ₀ 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. 47: 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 topoisomeraseIV are known in the art. For example, coumarin-containing compounds are described in patent application number WO 99/35155, 5,6-bicyclic heteroaromatic compounds are described in patent application WO 02/060879, and pyrazole compounds are described in patent application WO 01/52845 (US patent US 6,608,087).

We have discovered a new class of compounds which are useful for inhibiting DNA gyrase and / or topoisomerase IV.

SUMMARY OF THE INVENTION Therefore the present invention provides a compound of formula (I):

(D

R ¹ is selected from hydrogen, nitro, hydroxy, halo, cyano, Ci _-4 alkyl, Ci _-4 alkoxy, C ₂ . ₄ alken.yl, C _2-4 alkynyl, Ci _-4 alkanoyl, Ci _-4 alkylS(O) _a wherein a is 0 to 2 and C _3-6 cycloalkyl; wherein R ¹ may be optionally substituted on carbon by one or more halo or cyclopropyl; R ² is selected from hydrogen, nitro, hydroxy, halo, cyano, C^alkyl, C _1-4 alkoxy, C _2-4 alkenyl, C _2-4 alkynyl, C^alkanoyl, C _1-4 alkylS(O) _a wherein a is 0 to 2 and C _3-6 cycloalkyl; wherein R ² may be optionally substituted on carbon by one or more halo or C _3-6 cycloalkyl;

R ³ is selected from hydrogen, nitro, hydroxy, halo, cyano, Q^alkyl, Ci _-4 alkoxy, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkanoyl, C _1-4 alkylS(O) _a wherein a is 0 to 2 and C ₃ . ₆ cycloalkyl; wherein R ³ may be optionally substituted on carbon by one or more halo or C _3-6 cycloalkyl; W is -O-, -N(R ⁶ )- or -C(R ⁷ )(R ⁸ )-;

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 R ⁹ ;

R ⁴ and R ⁵ are substituents on carbon and are independently selected from azido, halo, nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, sulfo, formyl, ureido, hydroxyiminomethyl, iV-hydroxyformamido, hydrazinocarbonyl, iV-hydroxyethanimidoyl, amino(hydroxyimmo)methyl, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkoxy, C _1-4 alkanoyl, JV,JV-(C _1-4 alkyl) ₂ amino, C _1-4 alkanoylamino, JV-(C i^alky^carbamoyl, JV, JV-(C _1-4 alkyl) ₂ carbamoyl, JV-(C _1-4 alkoxy)carbamoyl, JV'-(C _1-4 alkyl)ureido, JV'JV'-(C _1-4 alkyl)2ureido, JV-(C _1-4 alkyl)-JV-(C _1-4 alkoxy)carbamoyl, C _1-4 alkylS(O) _a wherein a is 0 to 2, C _1-4 alkoxycarbonyl, C _1-4 alkoxycarbonylamino, JV-(C _1-4 alkyl)sulphamoyl, JV,JV-(C _1-4 alkyl) ₂ Sulphamoyl, C _1-4 alkylsulphonylamino, Ci _-4 alkylsulphonylaminocarbonyl, JV'-(C _1-4 alkyl)hydrazinocarbonyl, JV' ₎ JV'-(C _1-4 alkyl) ₂ hydrazinocarbonyl, carbocyclyl-R ¹⁰ - or heterocyclyl-R ¹¹ -; wherein R ⁴ and R ⁵ independently of each other may be optionally substituted on carbon by one or more R ¹² ; and wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R ¹³ ;

R , R and R are independently selected from hydrogen or C _1-4 alkyl; n is 0-4; wherein the values of R ⁴ may be the same or different; m is 0-4; wherein the values of R ⁵ may be the same or different; R ¹² is selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, Ci _-4 alkyl, C _2-4 alkenyl, C2-4alkynyl, C _1-4 alkoxy, C _1-4 alkanoyl, C _1-4 alkanoyloxy, JV-(Ci- ₄ alkyl)amino, JV,JV-(C _1-4 alkyl)2amino, C _1-4 alkanoylamino, JV-(C _1-4 alkyl)carbamoyl, JV,JV-(C _1-4 alkyl)2carbamoyl, C _1-4 alkylS(O) _a

wherein a is 0 to 2, C _1-4 alkoxycarbonyl, TV-(C _1-4 alkyl)sulphamoyl, C _1-4 alkylsulphonylamino, C _1-4 alkoxycarbonylamino, carbocyclyl-R ¹⁴ - or lieterocyclyl-R ¹⁵ -; wherein R ¹² may be optionally substituted on carbon by one or more R ¹⁶ ; and wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R ;

R ⁹ , R ¹³ and R ¹⁷ are independently selected from C _1-4 alkyl, C _1-4 alkanoyl, C _1-4 alkylsulphonyl, C _1-4 alkoxycarbonyl, carbamoyl, TV-(C i _-4 alkyl)carbamoyl, TV,TV-(C _1-4 alkyl)carbamoyl, benzyl, benzyloxycarbonyl, benzoyl and phenylsulphonyl;

R ¹⁰ , R ¹¹ , R ¹⁴ and R ¹⁵ are independently selected from a direct bond, -O-, -N(R ¹⁸ )-, -C(O)-, -N(R ¹⁹ )C(O)-, -C(O)N(R ²⁰ )-, -S(O) _P -, -SO ₂ N(R ²¹ )- or -N(R ²² )SO ₂ -; wherein R ¹⁸ , R ¹⁹ ,

R , R and R are independently selected from hydrogen or C _1-4 alkyl and p is 0-2;

R ¹⁶ is selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, carboxy, carbamoyl, mercapto, sulphamoyl, methyl, ethyl, ethenyl, ethynyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, TV-methyl-TV-ethylamino, acetylamino, TV-methylcarbamoyl, TV-ethylcarbamoyl,

TV,TV-dimethylcarbamoyl, λζTV-diethylcarbamoyl, TV-methyl-TV-ethylcarbamoyl, methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl, ethylsulphonyl, methoxycarbonyl, ethoxycarbonyl, TV-methylsulphamoyl, TV-ethylsulphamoyl, λζTV-dimethylsulphamoyl, AζTV-diethylsulphamoyl or TV-methyl-TV-ethylsulphamoyl; or a pharmaceutically acceptable salt thereof.

The invention also provides a compound which is one of the Examples, or a pharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION OF THE INVENTION DEFINITIONS In this specification the term alkyl includes both straight and branched chain alkyl groups. For example, "C _1-4 alkyl" includes methyl, ethyl, propyl, isopropyl and t-butyl. However references to individual alkyl groups such as propyl are specific for the straight chain version only. 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 -CH ₂ - group can optionally be replaced by a -C(O)- and a ring nitrogen and / or a ring sulphur atom may be optionally oxidised to form the JV- or S-oxide(s). In one aspect of the invention a "heterocyclyl" is a saturated or partially saturated monocyclic ring containing 6 or 7 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 -CH ₂ - group can optionally be replaced by a -C(O)-and a ring sulphur atom may be optionally oxidised to form the S-oxides. Examples and suitable values of the term "heterocyclyl" are morpholino, piperidyl, pyridyl, pyranyl, pyrrolyl, pyrazolyl, isothiazolyl, indolyl, quinolyl, thienyl, 1,3-benzodioxolyl, thiadiazolyl, piperazinyl, thiazolidinyl, pyrrolidinyl, thiomorpholino, pyrrolinyl, homopiperazinyl, 3,5-dioxapiperidinyl, tetrahydropyranyl, imidazolyl, pyrimidyl, pyrazinyl, pyridazinyl, isoxazolyl, iV-methylpyrrolyl, 4-pyridone, 1-isoquinolone, 2-pyrrolidone, 4-thiazolidone, pyridine-JV-oxide and quinoline-JV-oxide. Further examples and suitable values of the term "heterocyclyl" are thiazolyl, quinolinyl, benzothiazolyl, pyrimidinyl and pyridinyl. A "carbocyclyl" is a saturated, partially saturated or unsaturated, mono or bicyclic carbon ring that contains 3-12 atoms; wherein a -CH ₂ - 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, tetralinyl, indanyl or 1-oxoindanyl. A particular example of "carbocyclyl" is phenyl.

An example of "C _1-4 alkanoyloxy" is acetoxy.

Examples of "C _1-4 alkoxycarbonyl" include methoxycarbonyl, ethoxycarbonyl, n- and t-butoxycarbonyl.

Examples of "C _1-4 alkoxycarbonylamino" include methoxycarbonylamino, ethoxycarbonylamino, n- and t-butoxycarbonylamino.

Examples of "C _1-4 alkoxy" include methoxy, ethoxy and propoxy.

Examples of "C _1-4 alkanoylamino" include formamido, acetamido and propionylamino.

Examples of "C _1-4 alkylS(O) _a wherein a is 0 to 2" include methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl and ethylsulphonyl. Examples of "C _1-4 alkanoyl" include propionyl and acetyl. Examples of

"JV-(C _1-4 alkyl)amino" include methylamino and ethylamino.

Examples of "AfJV-(C _{1 -4} alkyl) ₂ amino" include di-JV-methylamino, di-(JV-ethyl)amino and JV-ethyl-JV-methylamino.

Examples of "C _2-4 alkenyl" are vinyl, allyl and 1-propenyl.

Examples of "^^alkynyl" are ethynyl, 1-propynyl and 2-propynyl.

Examples of "VV-(C i _-4 alkyi)sulphamoyl" are JV-(methyl)sulphamoyl and N-(ethyl)sulphamoyl. Examples of 'W,iV-(C _1-4 alkyl) ₂ sulphamoyl" are JV,N-(dimethyl)surphamoyl and

N-(methyl)-iV-(ethyl)sulpliamoyl.

Examples of 'W-(C _1-4 alkyl)carbamoyl" are methylaminocarbonyl and ethylaminocarbonyl.

Examples of "iV,iV-(C _1-4 alkyl) ₂ carbamoyl" are dimethylaminocarbonyl and methylethylaminocarbonyl.

Examples of "τV-(C _1-4 alkoxy)carbamoyl" are methoxyaminocarbonyl and isopropoxyaminocarbonyl.

Examples of 'W-(C _1-4 alkyl)-iV-(C _1-4 alkoxy)carbamoyl" are -/V-methyl-JV- methoxyaminocarbonyl and Af-methyl-iV-ethoxyaminocarbonyl. Examples of "Cs- _ό cycloalkyl" are cyclopropyl, cyclobutyl, cyclopropyl and cyclohexyl.

Examples of "JV-(C _1-4 alkyl)ureido" are JV'-methylureido and iV-isopropylureido.

Examples of 'W,N'-(C _1-4 alkyl) ₂ ureido" are NW'-dimethylureido and N'-methγl-N'- isopropylureido. Examples of 'W-(C _{1 -4} alkyl)hydrazinocarbonyl" are N-methylhydrazinocarbonyl and

N'-isopropylhydrazinocarbonyl.

Examples of "W,N'-(C _1-4 alkyl) ₂ hydrazinocarbonyr' are N'N'- dimethylhydrazinocarbonyl and iV-methyl-jV-isopropylhydrazinocarbonyl.

Examples of "C _1-4 alkylsulphonylamino" include methylsulphonylamino, isopropylsulphonylamino and t-butylsulphonylamino.

Examples of "C _1-4 alkylsulphonylaminocarbonyl" include methylsulphonylaminocarbonyl, isopropylsulphonylaminocarbonyl and t-buty lsulphonylaminocarbonyl .

Examples of "C _1-4 alkylsulphonyl" include methylsulphonyl, isopropylsulphonyl and t-butylsulphonyl.

A compound of formula (I) may form stable acid or basic salts, and in 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 (less preferably) 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 or potassium, an alkaline earth metal salt for example calcium or magnesium, an organic amine salt for example triethylamine, morpholine, iV-methylpiperidine, iV-ethylpiperidine, procaine, dibenzylamine, λζiV-dibenzylethylamine, tris-(2-hydroxyethyl)amine, tromethamine, N-methyl d-glucamine and amino acids such as glycine or 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. A preferred 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 preferred whether pharmaceutically-acceptable or not. Within 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 within 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 DNA gyrase and/or topoisomerase IV and is not to be limited merely to any one tautomeric form utilised within the formulae drawings. The formulae drawings within 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 certain compounds of formula (I) contain an asymmetrically substituted carbon and/or sulphur atom, and accordingly may exist in, and be isolated in, optically-active and racemic forms. Some compounds may exhibit polymorphism. It is to be understood that the present invention encompasses any racemic, optically-active, polymorphic or stereoisomeric form, or mixtures thereof, which form possesses properties useful in the inhibition of DNA gyrase and/or topoisomeraselV, it being well known in the art how to prepare optically-active forms (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) and how to determine efficacy for

the inhibition of DNA gyrase and/or topoisomeraseIV by the standard tests described hereinafter.

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.

It is also to be understood that certain compounds of the formula (I) 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 possess DNA gyrase and/or topoisomerase IV inhibitory activity.

Particular values of variable groups are as follows. Such values may be used where appropriate with any of the definitions, claims or embodiments defined hereinbefore or hereinafter. Each stated species represents a particular and independent aspect of the invention. R ¹ is selected from C _1-4 alkyl.

R ¹ is methyl.

R is selected from halo.

R is chloro.

R ³ is selected from halo. R ³ is chloro.

R ¹ is methyl, R ² is chloro and R ³ is chloro.

W is -N(R ⁶ )- wherein R ⁶ is hydrogen.

R ¹ is methyl, R ² is chloro, R ³ is chloro and W is -N(R ⁶ )- wherein R ⁶ is hydrogen.

Ring A is heterocyclyl; wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R ⁹ .

Ring A is carbocyclyl.

Ring A is heterocyclyl.

Ring A is thiazole or pyridine.

Ring A is thiazol-2-yl or pyridin-4-yl. n is O.

R ⁵ is a substituent on carbon and is selected from carboxy, C _1-4 alkanoyl, N-(C _1-4 alkyl)carbamoyl, C _t ^alkoxycarbonyl or heterocyclyl-R ¹¹ -; wherein R ⁵ may be

optionally substituted on carbon by one or more R ¹² ; and wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R ¹³ ;

10

R is C _1-4 alkoxy; R ¹³ is C _1-4 alkyl; and R ¹¹ is a direct bond.

R ⁵ is carboxy or Ci^alkoxycarbonyl.

R ⁵ is a substituent on carbon and is selected from carboxy, acetyl, iV-methylcarbamoyl, JV-(isopropyi)carbamoyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, imidazol-2-yl-R ¹¹ - orl,2,4-triazol-5-yl-R ^u -; wherein R ⁵ may be optionally substituted on carbon by one or more R ¹² ; and wherein said imidazolyl and triazolyl may be optionally substituted on nitrogen by a group selected from R ¹³ ; R is methoxy; R is methyl; and R is a direct bond. R ⁵ is a substituent on carbon and is selected from carboxy, acetyl, iV-methylcarbamoyl, iV-(l-methoxyprop-2-yl)carbamoyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, 1 -methylimidazol-2-yl or 1 -methyl- 1 ,2,4-triazol-5-yl.

R ⁵ is carboxy, methoxycarbonyl or isopropoxycarbonyl. m is 1. m is 1 or 2; wherein the values of R ⁵ may be the same or different.

Therefore, in a further aspect of the invention there is provided a compound of formula (I) (as depicted above) wherein: R ¹ is selected from C _1-4 alkyl; R ² is selected from halo; R ³ is selected from halo;

W is -N(R ⁶ )- wherein R ⁶ is hydrogen; Ring A is heterocyclyl; n is O;

R ⁵ is a substituent on carbon and is selected from carboxy, Ci _-4 alkanoyl, JV-(C _1-4 alkyl)carbamoyl, Ci _-4 alkoxycarbonyl or heterocyclyl-R ¹¹ -; wherein R ⁵ may be optionally substituted on carbon by one or more R ¹² ; and wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R ¹³ ; R ¹² is C _1-4 alkoxy;

R ¹³ is C _1-4 alkyl;

R ¹ ' is a direct bond; and m is 1 or 2; wherein the values of R ⁵ may be the same or different; or a pharmaceutically acceptable salt thereof. Therefore, in a further aspect of the invention there is provided a compound of formula (I) (as depicted above) wherein:

R ¹ is selected from C _1-4 alkyl;

R ² is selected from halo;

R ³ is selected from halo; W is -N(R ⁶ )- wherein R ⁶ is hydrogen;

Ring A is heterocyclyl; n is O;

R ⁵ is carboxy or C _1-4 alkoxycarbonyl; m is 1; or a pharmaceutically acceptable salt thereof.

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

R ¹ is methyl;

R ² is chloro; R ³ is chloro;

W is N(R ⁶ ) wherein R ⁶ is hydrogen;

Ring A is thiazol-2-yl or pyridin-4-yl; n is O;

R ⁵ is a substituent on carbon and is selected from carboxy, acetyl, /V-methylcarbamoyl, JV-(I -methoxyprop-2-yl)carbamoyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, 1 -methylimidazol-2-yl or 1 -methyl- 1 ,2,4-triazol-5-yl; m is 1 or 2; wherein the values of R ⁵ may be the same or different; or a pharmaceutically acceptable salt thereof.

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

R ¹ is methyl;

R ² is chloro;

R ³ is chloro;

W is N(R ⁶ ) wherein R ⁶ is hydrogen;

Ring A is thiazol-2-yl or pyridin-4-yl; n is 0;

R ⁵ is carboxy, methoxycarbonyl or isopropoxycarbonyl; m is 1; or a pharmaceutically acceptable salt thereof. Preparation of Invention Compounds

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) for compounds of formula (I) wherein W is -C(R ⁷ )(R ⁸ )-; converting a compound of formula (II):

wherein R ^a is cyano and R ^b is dimethy amino or diethylamino; or R ^a and R ^b are independently selected from C _1-4 alkylthio; or R ^a and R ^b together form 1,3-dithianyl or 1,3-dithiolanyl; into a compound of formula (I); or Process b) for compounds of formula (I) wherein W is -O-; reacting a compound of formula (III):

(III) with a compound of formula (IV):

or

Process c) for compounds of formula (I) wherein W is -N(R ⁶ )-; reacting a compound of formula (V):

(V) with a compound of formula (IV) or an activated acid derivative thereof; or Process d) for compounds of formula (I) wherein W is -C(R ⁷ XR ⁸ )-; reacting a compound of formula (VI):

(VI) wherein L is a displaceable group; with a compound of formula (VII):

or

Process e) for compounds of formula (I) wherein W is -C(R ⁷ )(R ⁸ )-; reacting a compound of formula (VIII):

(VIII) wherein M is an organometallic group; with a compound of formula (IX):

(IX) wherein L is a displaceable group; or Process f) reacting a compound of formula (X):

with a compound of formula

(XI) wherein D is a displaceable group; and thereafter if necessary or desirable: 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 halo, for example chloro and bromo, pentafluorophenoxy and 2,5-oxopyrrolidin-l-yloxy. D is a displaceable group. Suitable values for D include halo, for example chloro, bromo and iodo, tosylate and mesylate.

M is an organometallic group, suitable values for M include organocuprates, for example CuLi, organozincs, Zn, or a Grignard reagent for example MgG where G is halo for example chloro.

Specific reaction conditions for the above reaction are as follows. Process a) Compounds of formula (II) may be converted into compounds of formula (I): (i) where R ^a is cyano and R is dimethyamino or diethylamino; in the presence of a base for example sodium hydroxide, in a suitable solvent for example aqueous methanol at room temperature.

(ii) wherein or R ^a and R ^b are independently selected from or R ^a and R ^b together form 1,3-dithianyl or 1,3-dithiolanyl; in the presence of a reagent such as a mercury, copper or silver salt for example Hg(C10 ₄ ) ₂ , CuCl ₂ or AgN0 ₃ /Ag ₂ 0 in the presence of a suitable solvent for example methanol, acetone or ethanol from a temperature ranging from room temperature to reflux.

Compounds of formula (II) may be prepared according to Scheme 1 :

Scheme 1 wherein Pg is a hydroxy protecting group as defined hereinbelow; and D is a displaceable group as defined hereinabove.

Deprotection of hydroxy protecting groups are well known in the art. Examples of such deprotections are given hereinbelow.

FGI stands for Functional Group Interconversion. In the above scheme such conversions between a hydroxy group and a D group are well known in the art and are well within the capabilities of a person skilled in the art.

Compounds of formula (Ua) and (Hd) are known in the literature, or they are prepared by standard processes known in the art.

Process b) Compounds of formula (III) and (IV) may be reacted together may be reacted together in the presence of a coupling reagent, for example dicyclohexylcarbodiimide or EDC, in a suitable solvent, for example dichloromethane, THF or diethylether.

Compounds of formula (III) may be prepared according to Scheme 2:

i) Conditions of Process f) + (XI) ϋ) Deprotection _(ffl)

Scheme 2 wherein Pg is a hydroxy protecting group as defined hereinbelow. Deprotection of hydroxy protecting groups are well known in the art. Examples of such deprotections are given hereinbelow.

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

Process c) Compounds of formula (V) and (IV) 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 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/λyZ-pyridines such as 2,6-lutidine or 2,6-di-tert- 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°C.

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°C.

Compounds of formula (V) may be prepared according to Scheme 3:

Scheme 3 wherein Pg is a amino protecting group as defined hereinbelow. The skilled reader will appreciate that where R ⁶ is hydrogen, this hydrogen also needs protecting by way of a suitable protecting group.

Deprotection of amino protecting groups are well known in the art. Examples of such deprotections are given hereinbelow.

Compounds of formula (Va) are commercially available compounds, or they are known in the literature, or they are prepared by standard processes known in the art. Process d) Compounds of formula (VI) and (VII) may be reacted in a suitable solvent such a DCM or 1,2-dichloroethane, optionally in the presence of a Lewis acid, for example AlCl ₃ , from 0 °C to room temperature.

Compounds of formula (VI) may be prepared according to Scheme 4:

Scheme 4 wherein R ^a OC(O) is an ester group.

Suitable values for R ^a include C _1-6 alkyl. Deprotection of the R ^a carboxy protecting group may be achieved under standard conditions, for example acid or base hydrolysis, such as those conditions give hereinbelow.

FGI stands for Functional Group Interconversion. In the above scheme such conversions between an acid group and a -C(O)L group are well known in the art and are well within the capabilities of a person skilled in the art.

Compounds of formula (Via) and (VII) are commercially available compounds, or they are known in the literature, or they are prepared by standard processes known in the art. Process e) Compounds of formula (VIII) and (IX) may be reacted in a suitable aprotic solvent such as THF or ether, at temperatures in the range of -78 °C to 0 °C.

Compounds of formula (VIII) may be prepared from compounds of formula (lie) under standard conditions known in the art. For example where M is an organocuprous reagent such compounds could be prepared according to Scheme 5: i) n-BuLi , THF, -78 ⁰ C ii) CuI

(Hc) (VIII)

Scheme 5

Compounds of formula (IX) are commercially available compounds, or they are known in the literature, or they are prepared by standard processes known in the art. Process f) Compounds of formula (X) and (XI) may be reacted in a suitable solvent such as DMF, iV-methylpyrrolidinone or dimethylacetamide in the presence of a base such as triethylamine or diisopropylethylamine under thermal conditions or a microwave reactor. Compounds of formula (X) may be prepared according to Scheme 6:

Scheme 6 wherein M is an organometallic group as defined hereinabove.

Compounds of formula (Xa), (Xb) and (XI) are commercially available compounds, or they are known in the literature, or they are 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 t-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 t-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 alkylamine, for example dimethylaminopropylamine 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 t-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.

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.

When an optically active form of a compound of the invention is required, it 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. Reinach, 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 niM ammonium acetate, 5.5 mM magnesium chloride, 0.5 mM ethylenediaminetetraacetic acid, 5% glycerol, 1 mM 1 ,4-Dithio-DL-threitol, 200 nM bovine serum albumin, 1.5 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 IC ₅₀ 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 tnM 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 E. coli ParC, 2.5 nM E. coli ParE, 160 μM ATP, and compound in dimethylsulfoxide. Compound potency may be based on IC ₅₀ measurements determined from reactions performed in the presence of 10 different compound concentrations. Compounds of the Examples could be expected to have IC ₅₀ values of <100μg/ml in one or both assays described herein above. For Example the following results were obtained in a GyrB ATPase inhibition activity assay substantially similar to the above wherein the figure quoted may be an average of two or more results.

Bacterial Susceptibility Testing Methods

Compounds may be tested for antimicrobial activity by susceptibility testing in liquid media. Compounds may be dissolved in 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 μL. Plates can be incubated under appropriate conditions at 37 °C for 24 lirs prior to reading. The Minimum

Inhibitory Concentration (MIC) may be determined as the lowest drug concentration able to reduce growth by 80% or more.

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 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 "infection" 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 haemolyticiis. 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 johnsonii. 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 Burkholderia 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 Enter ococcus faecalis. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Enter ococcus 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

Haemophihis 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 invention 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 Methicillin-resistant Staphylococcus aureus. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Methicillin-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 Penicillin- 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 infection" 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 saprophytic us. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Streptoccocus 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 maltophilia. 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 Vancomycin-Resistant Enterococcus faecalis. 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 Vancomycin-Resistant Staphylococcus epidermis.

In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Acinetobacter 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 Streptoccocus 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 infection 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 in 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-acceptable 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 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 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 in 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 theinhibition 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 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 in 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 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.

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 antibacterial 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 gyraseand/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 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 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, (hereinafter in this section relating to pharmaceutical composition "a compound of this invention") 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 in another aspect the present invention provides a pharmaceutical composition that 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 that 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 producing an anti-bacterial effect in an warm-blooded animal, such as a human being.

According to a further aspect of the invention there is provided a pharmaceutical composition that 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 inhibition of bacterial DNA gyrase and/or topoisomerase IV in an warm-blooded animal, such as a human being.

According to a further aspect of the invention there is provided a pharmaceutical composition that 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 an 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 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 in 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 dosing 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 within 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, polyvinyl-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 poly oxy ethylene 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 Hansen; Chairman of Editorial Board), Pergamon Press 1990.

In addition to the compounds of the present invention the pharmaceutical composition of this invention may also contain or be co-administered (simultaneously, sequentially or separately) with one or more known drugs selected from other clinically useful antibacterial agents (for example, macrolides, quinolones, β-lactams or aminoglycosides) and/or other anti-infective agents (for example, an antifungal triazole or amphotericin). These may include carbapenems, for example meropenem or imipenem, to broaden the therapeutic effectiveness. Compounds of this invention may also contain or be co-administered with bactericidal/permeability-increasing protein (BPI) products or efflux pump inhibitors to improve activity against gram negative bacteria and bacteria resistant to antimicrobial agents.

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. Preferably 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. 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- vivo test systems for the evaluation of the effects of inhibitors of DNA gyrase 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; quinolones e.g. ciprofloxacin or levofioxacin; 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 oxazolidinones; 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-infective 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 carried out after removal of residual solids by filtration; (ii) operations were carried out at ambient temperature, that is typically in the range 18-26

°C 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), and/or ISCO Redi Sep Normal Phase columns, 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; mass spectral sample data has been collected using a variety of Waters quadrupole mass spectrometer that have been interfaced with Agilent 1100 liquid chromatographs and equipped with SEDEX evaporative light scattering detectors. For ionization, the mass spectrometers have been run in either electrospray ionization (ESI) or atmospheric pressure chemical ionization (APCI) with positive (+) ion and negative (-) ion data being collected. Positive ion data generates a (M+H) ⁺ response and negative ion data generates a (M-H) ^" response, and unless otherwise stated, all examples provided are ESI+, reported as the (M+H) ⁺ value. Optical rotations were determined at 589 nm at 20 °C using a Perkin Elmer Polarimeter 341, cell pathlength is 10 cm with a 1 mL volume; (vi) each intermediate was 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 HPLC, TLC, or NMR and identity was determined by infra-red spectroscopy (IR), mass spectroscopy or NMR spectroscopy as appropriate; (vii) in which the following abbreviations may be used :- EDC l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride;

HOBt 1-hydroxybenzotriazole;

THF tetrahydrofuran;

NMM JV-methylmorpholine;

DIEA diisopropylethylamine; NMP JV-methylpyrrolidinone; and

DMSO dimethylsulphoxide

(viii) temperatures are quoted as ⁰ C;

(ix) Smith Microwave Synthesizer refers to an equipment that uses microwave energy to heat organic reactions in a short period of time; it was used according to the manufacturers instruction and was obtained from Personal Chemistry Uppsala AB;

(x) Kugelrohr distillation refers to a piece of equipment that distils liquids and heats sensitive compounds using air-bath oven temperature; it was used according to the manufacturers instruction and was obtained from Buclii, Switzerland or Aldrich, Milwaukee, USA;

(xi) Where cis(±) or trans(±) is used it is to be understood that this refers to a racemic mixture of the cis or the trans isomers, (-) or (+) refers to the single enantiomer as does R ₅ R or S ₅ S where quoted; and

(xii) GCMS is Gas phase chromatography (model 6890N) with Mass Spectrometer(model 5973) manufactured by Agilent and was used according to manufacturers instructions.

Example 1

5 -Thiazolecarboxylic acid, 2- [4- \\(3 ,4-dichloro-5 -methyl- lH-pyrrol-2-vD carbonyllaminolhexahydro-lH-azepin-l-yl] A solution of methyl 2-(4~{[(3,4-dichloro-5-methyl-lH-pyrrol-2- yl)carbonyl]amino}azepan-l-yl)-l,3-thiazole-5-carboxylate (Example 9, 42 mg, 0.1 mmol) and 200 μL (0.2 mmol) of 1 N NaOH in 4 mL MeOH was heated at 110 ⁰ C for 90 min in a microwave reactor. MeOH was removed and the aqueous residue was diluted with water and acidified with IN HCl forming a precipitate. The precipitate was filtered, washed with water and dried in vacuo to afford 31 mg of product. MS (ES) (MH ⁺ ): 417 for C ₁₆ H ₁₈ Cl ₂ N ₄ O ₃ S; NMR: 1.6 (m, IH) ₅ 1.9 (m, 4H), 2.0 (m, IH), 2.2 (s, 3H), 3.4-4.0 (m, 4H) ₅ 7.2 (d, IH) ₅ 7.8 (s, IH), 12.0 (s, IH).

Example 2 2-(4-{[(3,4-Dichloro-5-methyl-liJ ^r -pyrrol-2-yl ^> )carbonyl]amino>azepan-l-yl ^' )isonicotinic acid

A solution of isopropyl 2-(4-{[(3,4-dichloro-5-methyl-l/f-pyrrol-2- yl)carbonyl]amino}azepan-l-yl)-isonicotinate (Example 10, 75 mg, 0.17 mmol) and 330 μL (0.33 mmol) of 1 N NaOH in 3 mL MeOH was heated at 80 ⁰ C for 30 min in a microwave reactor. The mixture was quenched with 330 μL of 1 N HCl and diluted with water. The water was saturated with NaCl and extracted 2 times with THF. The THF was dried (MgSO ₄ ) and concentrated. Product (20 mg) was obtained by trituration with Et ₂ O and dried in vacuo. MS (ES) (MH ⁺ ): 411 for C ₁₈ H ₂₀ Cl ₂ N ₄ O ₃ ; NMR: 1.6 (m, IH), 1.8 (m, 4H), 2.0 (m, IH), 2.2 (s, 3H), 3.4-4.0 (m, 4H) ₅ 3.8 (m, IH), 4.0 (m, IH), 7.0 (d, IH), 7.05 (s, IH), 8.2 (d, IH), 12.0 (s, IH).

Example 3

2-(4- 1 IY3 λ-Dichloro-S-methyl- 17f-Pyrrol-2-yl)carbonyllamino I azepan- 1 -yl>4-( U(lS)-2- methoxy- 1 -methylethyl] amino } carbonvD- 1.3 -thiazole-5 -carboxylic acid

To a suspension of ethyl 2-(4-{ [(3, 4-dichloro-5 -methyl- lH-pyrrol-2- yl)carbony 1] amino } azepan- 1 -y l)-4-( { [( 15)-2-methoxy- 1 -methylethyl] amino } carbonyl)- 1,3- thiazole-5-carboxylate (0.10Og, 0.34mmol, Example 11) in methanol was added lithium hydroxide (1 mL, lmmol, IN). The reaction was stirred at room temperature for 6 hours. The crude reaction was diluted with water and acidified with IN HCl. The resulting precipitate was filtered, washed with water, and dried (0.02Ig). MS (ES) M+H ⁺ : 533 for C ₂₁ H ₂₇ Cl ₂ N ₅ O ₅ S; NMR: 1.17 (dd, 3H), 1.62 (q, IH), 1.90 (m, 4H), 2.05 (m, IH), 2.16 (s, 3H), 3.26 (s, 3H), 3.37 (m, IH), 3.49 (m, 2H), 3.59 (m, 2H), 4.00 (m, 2H), 4.22 (p, IH), 7.22 (m, IH), 8.87 (d, IH), 11.97 (s, lH).

Examples 4-8 The following Examples were prepared by the procedure described in Example 3 from the starting materials (SM) indicated.

Example 9

Methyl 2-(4-{[(3,4-dichloro-5-metliyl-lH-pyrrol-2-yl)carbonyllamino >azepan-l-yl)-l, 3- thiazole-5 -carboxy late A solution of 53 mg (0.27 mmol) 3,4-dichloro-5-methyl-lH-pyrrole-2-carboxylic acid

(53 mg, 0.27 mmol)(Motekaitis, R. J.; Heinert, D. H.; Martell, Arthur E. J. of Org. Chem. 35(8), 2504 (1970)), 50 mg (0.27 mmol), methyl 2-(4-aminoazepan-l-yl)-l,3-thiazole-5- carboxylate hydrochloride (Intermediate 1, 50 mg 0.27 mmol), 0.37 gm HOBt (0.27 mmol), 97 mg (0.51 mmol) EDC and 56 μL (0.51 mmol) of NMM in 3 mL CH ₂ Cl ₂ was stirred at room temperature overnight. The mixture was diluted with EtOAc and washed with IN HCl ₅ water, aqueous Na ₂ CO ₃ , water and brine. Drying (MgSO ₄ ) and removal of solvent gave a solid that was chromatographed on silica gel (100% CH ₂ Cl ₂ with gradient elution to 100% EtOAc) to afford 45 mg of product as a white solid. MS (ES) (MH ⁺ ): 431 for C ₁₇ H ₂₀ Cl ₂ N ₄ O ₃ S; NMR: 1.6 (m, IH) ₅ 1.9 (m, 4H) ₅ 2.0 (m, IH), 2.2 (s, 3H) ₅ 3.6 (m, 2H) ₅ 3.7 (s, 3H) ₅ 4.0 (m, IH), 7.2 (d, IH) ₅ 7.9 (s, IH) ₅ 12.0 (s, IH).

Example 10

Isopropyl 2-(4- { f(3 ,4-dichloro-5 -methyl- lH-pyrrol-2-yl)carbonyl]amino I azepan- 1 -vD- isonicotinate

Using the procedure of Example 3, isopropyl 6-(4-aminoazepan-l-yl)nicotinate hydrochloride (Intermediate 2) was converted to the title compound. MS (ES) (MH ⁺ ): 453 for C ₂₁ H ₂₆ Cl ₂ N ₄ O ₃ ; NMR: 1.6 (m, IH), 1.8 (m, 4H), 2.0 (m, IH), 2.2 (s, 3H), 3.4-4.0 (m, 4H), 3.8 (m, IH), 4.0 (m, IH), 7.0 (d, IH), 7.05 (s, IH), 8.2 (d, IH), 12.0 (s, IH).

Example 11 Ethyl 2-(4-{rr3.4-dichloro-5-methyl-lH-pyrrol-2-vncarbonyllamino&g t;azepan-l-ylV4-({r(iy>- 2-methoxy-l-methylethyl]amino)carbonviyi,3-thiazole-5-carbox ylate

A suspension of iV-azepan-4-y 1-3 ,4-dichloro~5 -methyl- lH-pyrrole-2-carboxamide (Intermediate 6, 0.060 g, 0.206 mmol), ethyl 2-chloro-4-({[(lS)-2-methoxy-l- methylethyl]amino}carbonyl)-l,3-thiazole-5-carboxylate (WO2006087543, 0.0457 g, 0.206 mmol), and triethylamine (0.03mL, 0.226mmol, Aldrich) in DMF (3ml) was heated in the microwave for 60 minutes at 100 ⁰ C. LCMS indicated conversion of starting material to product. The crude reaction mixture was purified on normal phase silica gel using a 5:1 mixture of hexanes/ethyl acetate yielding a solid that was dried under vacuum (0.012g). MS (ES) M+H ⁺ : 560 for C ₂₃ H ₃₁ Cl ₂ N ₅ O ₅ S; NMR: 1.11 (d, 3H), 1.22 (t, 3H), 1.63 (q, IH), 1.89 (m, 4H), 2.05 (m, IH), 2.16 (s, 3H), 3.21 (m, IH), 3.27 (s, 3H), 3.38 (m, IH), 3.55 (m, 3H), 4.00 (m, 3H), 4.15 (q, 2H), 7.22 (d, IH), 8.27 (s, IH), 11.93 (s, IH).

Examples 12-16

The following Examples were prepared by the procedure described in Example 11 from the starting materials (SM) indicated.

Preparation of Starting Materials

Intermediate 1

Methyl 2-f4-aminoazepan-l-vD-l ,3-thiazole-5-carboxylate hydrochloride A solution of 200 mg methyl 2- {4-[(fer^-butoxycarbonyl)amino]azepan- 1 -yl} - 1 ,3- thiazole-5-carboxylate (Intermediate 3) in 6 niL of 4N HCl in dioxane was stirred at room temperature overnight. Precipitated solids were filtered, washed with Et ₂ O and dried in vacuo to give 165 mg of product. MS (ES) (MH ⁺ ): 431 for C ₁₁ H ₁₇ N ₃ O ₂ S; NMR: 1.4-2.2 (m, 6H) ₅ 3.2

(m, IH), 3.5 (m, 2H), 3.7 (s and m, total of 4H), 7.9 (s, IH), 8.1 (s, 3H).

Intermediate 2

Isopropyl 2-(4-aminoazepan-l-yDisonicotinate hydrochloride

Using the procedure of Intermediate 1, isopropyl 2-{4~[(tert- butoxycarbonyl)amino]azepan-l-yl}isonicotinate (Intermediate 4) was converted to the title compound. MS (ES) (MH ⁺ ): 278 for C ₁₅ H ₂₃ N ₃ O ₂ ; NMR: 1.5 (m, IH), 1.7 (m, 2H), 2.0 (m,

2H), 2.2 (m, IH), 3.2 (m, IH), 3.6 (m, 2H), 3.9-4.1 (m, IH), 5.1 (septet, IH), 7.0 (d, IH), 7.2

(s, IH), 8.0 (s, broad, 3H), 8.2 (d, IH).

Intermediate 3 Methyl 2-{4-[(fert-butoxycarbonyl)aminolazepan-l-yU-1.3-thiazole-5- carboxylate

A solution of 200 mg (0.93 mmol) oftert-butyl azepan-4-ylcarbamate (Commercially available from Tyger, Inc), 207 mg (0.93 mmol), methyl 2-bromo-l,3-thiazole-5-carboxylate (Commercially available from Combiblocks) and 200 μL DIEA in 4 mL NMP was heated at 100 ⁰ C for 60 min in a microwave reactor. The mixture was diluted with EtOAc and washed 3 times with water and once with brine. Combined aqueous washings were extracted with EtOAc, which was washed twice more with water and with brine. Combined EtOAc extracts were dried (MgSO ₄ ) and concentrated. Product was purified by chromatography (100% CH ₂ Cl ₂ with gradient elution to 40% EtOAc in CH ₂ Cl ₂ ) to afford 220 mg of product as a white solid. MS (ES) (MH ⁺ ): 431 for C ₁₇ H ₂₀ Cl ₂ N ₄ O ₃ S; NMR: 1.4 (s and m, 10H), 1.5-2.0 (m, 5H), 3.3-3.7 (m, 5H), 3.7 (s, 3H), 6.9 (d, IH), 7.9 (s, IH).

Intermediate 4 Isopropyl σ-H-fffert-butoxycarbonvDaminolazepan-l-vUisonicotinate

Modifying the procedure of Intermedaite 3 by heating at 150 ⁰ C for 4 hours, isopropyl 2-fluoroisonicotinate (Intermediate 5) was converted to the title compound. MS (ES) (MH ⁺ ): 378 for C ₂₀ H ₃₁ N ₃ O ₄ ; NMR: 1.3 (d, 6H), 1.35 (s, 9H), 1.4-2.0 (m, 6H), 3.2-3.8 (m, 2H), 5.1 (m, IH), 6.8 (d, IH), 6.9 (d, IH), 7.0 (s, IH), 8.2 (d, IH).

Intermediate 5

Isopropyl 2-fluoroisonicotinate A mixture of 2-fiuoroisonicotinic acid and 16 ml triisopropylorthoformate in 100 ml toluene was heated at reflux for 2 h. The mixture as stirred with IN HCl for 30 min before being partitioned between EtOAc and water. The EtOAc was separated, washed with water and brine, dried (MgSO ₄ ) and concentrated. Chromatography on silica gel (100% hexanes with gradient elution to 100% CH ₂ Cl ₂ gave product as an oil. NMR (CDCl ₃ ): 1.4 (d, 6H), 5.3 (septet, 3H), 7.5 (m, IH), 7.7 (m, IH), 8.35 (d, IH).

Intermediate 6 iV-Azepan-4-yl-3 ,4-dichloro-5-methyl- lH-pyrrole-2-carboxamide ter t-Buty 1 4- { [(3 ,4-dichloro-5 -methyl- 1 H-pyrrol-2-y l)carbony 1] amino } azepane- 1 - carboxylate (Intermediate 7, 1.21 g, 3.10 mmol) was solubilized in 15mL CH ₂ Cl ₂ to which was added (4.6ImL, 62.01 mmol, trifluoroacetic acid) and the solution was allowed to stir for 12 hours at room temperature under a nitrogen atmosphere. LCMS indicated complete conversion of starting material to product. The crude reaction mixture was diluted with water (10OmL) and the solution made neutral using 5% NaOH. The aqueous layer was extracted with CH ₂ Cl ₂ (3x10OmL), the organic layers were collected, dried with anhydrous sodium sulfate, filtered, solvent removed under vacuum, and the yellow-tan solid dried for several days in a vacuum desiccator. MS (ES) M+H ^1" : 291 for Ci ₂ H ₁₇ Cl ₂ N ₃ O; NMR (CDCl ₃ ): 1.69- 1.92 (m, 5H), 2.07 (m, IH), 2.27 (s, 3H), 2.94 (m, 2H), 3.05 (m, 2H) ₅ 4.38 (m, IH), 7.18 (d, IH), 9.93 (bs, IH).

Intermediate 7 fert-ButvH-lffS^-dichloro-S-methyl-lH-pyrrol-σ-vDcarbonvnam inol azepane-l-carboxylate To a suspension of 3,4-dichloro-5-methyl-lH-pyrrole-2-carboxylic acid (0.906g, 4.67 mmol, WO2006087543) was added l-N-t-butoxycarbony-hexahydro-lH-azepin-4-amine (purchased from Magical Scientific LLP, 1.00 g, 4.67 mmol), EDC (1.45g, 9.33mmol), NMM (0.944g, 9.33mmol), and HOBt (0.63 Ig, 4.67mmol) and the mixture was allowed to stir for 12 hours at room temperature under a nitrogen atmosphere. LCMS indicated no remaining starting material with good conversion to product. The mixture was diluted with CH ₂ Cl ₂ (10OmL) and organic phase was extracted with IM HCl (3x50mL) and the aqueous layers collected and combined. The aqueous phase was then made basic (pH~9) with 10% NaOH and extracted with CH ₂ Cl ₂ (3x5 OmL). The organic layers were collected and combined, dried with anhydrous sodium sulfate, filtered, solvent removed under vacuum, and the white solid dried overnight under vacuum. MS (ES) M+H ⁺ : 391 for C ₁₇ H ₂₅ Cl ₂ N ₃ O ₃ ; NMR (CDCl ₃ ): 1.49 (s, 9H), 1.70 (m, 3H), 1.89 (m, IH), 2.00 (m, IH), 2.13 (m, IH), 2.30 (s, 3H), 3.26 (m, IH), 3.51 (m, 3H), 4.17 (m, IH), 6.76 (d, IH), 10.92 (s, IH).

Intermediate 8

Methyl 2-chloro-4-( 1 -methyl- 1 H- 1.2.4-triazol-5-ylV 1.3 -thiazole-5-carboxylate

Methyl 2-amino-4-( 1 -methyl- IH-1 ,2,4-triazol-5-yl)- 1 ,3 -thiazole-5-carboxylate (Intermediate 11; 0.55 g, 2.2 mmol) was suspended in glacial acetic acid (20 ml) and concentrated HCl (30 ml). The solution was cooled to 0 ⁰ C and to this a solution of sodium nitrite in water (15 ml) was added dropwise. After stirring at 0 ⁰ C for 10 mins, the reaction was slowly warmed to room temperature and stirred for 1 hour. Once complete by LCMS, a solution of urea (0.25 g) in water (10 ml) was added dropwise. After stirring at room temperature for 30 mins, solvent was removed under reduced pressure. The residue was partitioned with sat. NaHCO ₃ (aq) and EtOAc. Extraction with EtOAc (x3), drying with MgSO ₄ and concentrating yielded an orange oil which was used without purification (0.20 g). MS (ES) (M+H) ⁺ : 259 for C ₈ H ₇ ClN ₄ O ₂ S. NMR: 3.92 (s, 6H), 8.04 (s, IH).

Intermediate 9

The following compound was prepared by the procedure of Intermediate 8 using the appropriate starting material (SM).

Intermediate 10

Methyl 2-amino-4-(l-methyl-lH-imidazol-2-yl)-L3-thiazole-5-carboxyl ate iV-Iodosuccinimide (9.3 g, 41 mmol) was added to a mixture of 7.52 g (41 mmol) 5 methyl 3-(l-methyl-lH-imidazol-2-yl)-3-oxopropanoate (Intermediate 13) and 7.5 g

Amberlyst-15 resin in 400 ml EtOAc followed by stirring for 1 hour at room temperature. The resin was filtered off and rinsed with EtOAc. Solvent was removed from the filtrate and the residue was taken up in diethyl ether. Insoluble material was filtered off and rinsed with additional ether. Solvent was removed from the filtrate and the residue was dissolved in 200 10 ml MeOH before added 4.7 g (62 mmol) thiourea. The mixture was heated at reflux for 1 hour. Solvent was removed and the residue was taken up in aqueous Na ₂ CO ₃ . Insoluble material was collected by filtration and rinsed well with water. The solids were dried in vacuo affording 4.51 g of product: MS (ES) (M+H) ⁺ : 239 for C ₉ H ₁₀ N ₄ O ₂ S; NMR: 3.48 (s, 3H), 3.57 (s, 3H), 6.90 (s, IH), 7.12 (s, IH), 7.98 (s, 2H).

15

Intermediate 11

The following compound was prepared by the procedure of Intermediate 10 using the appropriate starting material (SM).

20 Intermediate 12

Methyl 3-(l-methyl-lH-l .2,4-triazol-5-ylV3-oxopropanoate

NaH (7.84 g, 196 mmol of a 60% dispersion in oil) was added portionwise to a solution of 6.18 g (34.5 mmol) of l-(l-methyl-l/i-l,2,4-triazol-5-yl)ethanone (Ohta, S.; Kawasaki, L; Fukuno, A.; Yamashita, M.; Tada, T.; Kawabata, T. Chem. Pharm. Bull. (1993), 25 41(7), 1226-31) in 100 ml dimethylcarbonate. The mixture was heated to 90 °C for 2 hour

forming a thick slurry. After cooling to room temperature, the mixture was slowly transferred to IN HCl over ice. The pH of the mixture was brought to about 7 with NaHCO ₃ before being saturated with NaCl and extracted 4 times with EtOAc. The EtOAc was dried (MgSO ₄ ) and concentrated to give an oil that was chromatographed on silica gel (100% DCM followed by gradient elution to 50% EtOAc in DCM). Product (5.3 g) was obtained as an oil. NMR: 3.78 (s, 3H), 4.11 (s, 2H) ₅ 4.22 (s, 3H), 7.94 (s, IH).

Intermediate 13

The following compound was prepared by the procedure of Intermediate 12 using the appropriate starting material (SM).

Intermediate 14

Isopropyl 2-chloro-4-[(methylamino ^> )carbonyl]-l,3-thiazole-5-carboxylate

A solution 2.7 g (10.8 mmol) of 2-chloro-5-(isopropoxycarbonyl)-l,3-thiazole-4- carboxylic acid (Intermediate 15) in 30 ml SOCl ₂ was heated at reflux for 20 min. Solvent was removed, the residue was taken up in CH ₂ Cl ₂ and solvent was again removed. The residue was dissolved in 20 ml CH ₂ Cl ₂ with cooling in an ice water bath. 2,6-Lutidine (1.3 ml, 11 mmol) was added slowly followed by 5.5 ml (11 mmol) of 2N methylamine in THF. After stirring for 3 h, solvent was removed and the residue was dissolved in EtOAc and washed with IN HCl saturated with NaCl. Drying (MgSO ₄ ) and removal of solvent gave 2.7 g of a white solid. MS (ES) M+Na ⁺ : 285 for C ₉ H ₁₁ BClN ₂ O ₃ S. ¹ H NMR (DMSO): 1.25 (d, 6H), 2.75 (d, 3H), 5.1 (septet, IH), 8.6 (m, IH).

Intermediate 15 2-Chloro-5-(isopropoxycarbonyr)-l, 3-thiazole-4-carboxylic acid

A solution of 2.3 g (23 mmol) CrO ₃ in 12 ml water and 4 ml H ₂ SO ₄ chilled in an ice water bath was added dropwise to a solution of 2.74 g (11.6 mmol) of isopropyl 2-chloro-4-

(hydroxymethyl)-l,3-thiazole-5-carboxylate (Intermediate 16) in 50 ml acetone cooled in an ice water bath. After stirring for 4 h, a few ml isopropanol was added and the mixture was stirred for 15 min. The mixture was diluted with water and extracted 3 times with EtOAc, each extract being washed with water and brine. The combined EtOAc extracts were dried (MgSO ₄ ) and concentrated to give 2.86 g of product as a viscous oil. ¹ H NMR (DMSO): 1.3 (d, 6H), 5.1 (m, IH), 14.1 (s, IH).

Intermediate 16

Isopropyl 2-chloro-4-(hvdroxymethyl)- 1 ,3 -thiazole-5 -carboxylate A mixture of 3.4 g ( 16 mmol) of 5 -thiazolecarboxylic acid 2-amino-4-

(hydroxymethyl)-, 1-methylethyl ester (Intermediate 17) and 3.2 g (24 mmol) CuCl ₂ was cooled in an ice water bath before 3.1 ml (23.5 mmol) of t-butylnitrite was added dropwise. The mixture was warmed to room temperature with stirring for 2 h before being treated with aqueous NaHSO ₃ and extracted with EtOAc 3 times. Each extract was washed with water and brine. The combined extracts were dried (MgSO ₄ ) and concentrated to give an oil that was chromatographed on silica gel (100% CH ₂ Cl ₂ followed by gradient elution to 60% EtOAc in CH ₂ Cl ₂ ) to afford 2.75 g of product as an oil. ¹ H NMR (DMSO): 1.3 (d, 6H), 4.75 (d, 2H), 5.1 (septet, IH), 5.4 (t, IH).

Intermediate 17

5-Thiazolecarboxylic acid 2-amino-4-(hydroxymethylV, 1-methylethyl ester

A solution of 5.0 g (37 mmol) 3-chlorofuran-2,4(3H,5H)-dione and 3.7 g (49 mmol) thiourea in 30 ml isopropanol was heated at reflux overnight. Solvent was removed and the residue was dissolved in water. Insoluble particulates were removed by filtration. The filtrate was treated with aqueous Na ₂ CO ₃ to afford a heavy precipitate. The solids were filtered, rinsed with water and dried in vacuo to give 3.4 g of product. ¹ H NMR (DMSO): 1.2 (d, 6H),

4.55 (d, 2H), 4.9 (t, IH), 5.0 (m, IH), 7.7 (s, 2H).