WO2008020229A2 - Antibacterial pyrrolecarboxamides - Google Patents

Abstract

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

Description

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 A₂B₂ tetrameric complex. The A subunit of gyrase (GyrA) is involved in DNA breakage and resealing and contains a conserved tyrosine residue that forms the transient covalent link to DNA during strand passage. The B subunit (GyrB) catalyzes the hydrolysis of ATP and interacts with the A subunit to translate the free energy from hydrolysis to the conformational change in the enzyme that enables strand-passage and DNA resealing.

Another conserved and essential type II topoisomerase in bacteria, called topoisomerase IV, is primarily responsible for separating the linked closed circular bacterial chromosomes produced in replication. This enzyme is closely related to DNA gyrase and has a similar tetrameric structure formed from subunits homologous to Gyr A and to Gyr B. The overall sequence identity between gyrase and topoisomerase IV in different bacterial species is high. Therefore, compounds that target bacterial type II topoisomerases have the potential to inhibit two targets in cells, DNA gyrase and topoisomerase IV; as is the case for existing quinolone antibacterials (Maxwell, A. 1997, Trends Microbiol. 5: 102-109). DNA gyrase is a well-validated target of antibacterials, including the quinolones and the coumarins. The quinolones {e.g. ciprofloxacin) are broad-spectrum antibacterials that inhibit the DNA breakage and reunion activity of the enzyme and trap the GyrA subunit covalently complexed with DNA (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 QT₀ interval, has been cited as a toxicity concern for quinolones.

There are several known natural product inhibitors of DNA gyrase that compete with ATP for binding the GyrB subunit (Maxwell, A. and Lawson, D.M. 2003, Curr. Topics in Med. Chem. 3: 283-303). The coumarins are natural products isolated from Streptomyces spp., examples of which are novobiocin, chlorobiocin and coumermycin Al. Although these compounds are potent inhibitors of DNA gyrase, their therapeutic utility is limited due to toxicity in eukaryotes and poor penetration in Gram-negative bacteria (Maxwell, A. 1997, Trends Microbiol. 5: 102-109). Another natural product class of compounds that targets the GyrB subunit is the cyclothialidines, which are isolated from Streptomyces filipensis (Watanabe, J. et al 1994, J. Antibiot. Al: 32-36). Despite potent activity against DNA gyrase, cyclothialidine is a poor antibacterial agent showing activity only against some eubacterial species (Nakada, N, 1993, Antimicrob. Agents Chemother. 37: 2656-2661).

Synthetic inhibitors that target the B subunit of DNA gyrase and topoisomerase IV are known in the art. For example, coumarin-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 US6,608,087).

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):

(i) wherein: R¹ is selected from hydrogen, nitro, hydroxy, halo, cyano, C_1-4alkyl, C_1-4alkoxy, C_2-4alkenyl, C_2-4alkynyl, C_1-4alkanoyl, C_1-4alkylS(O)_a wherein a is 0 to 2 and C_3-6cycloalkyl; wherein R¹ may be optionally substituted on carbon by one or more halo or cyclopropyl;

R² is selected from hydrogen, nitro, hydroxy, halo, cyano, C^alkyl, C_1-4alkoxy, C_2-4alkenyl, C_2-4alkynyl, C_1-4alkanoyl, C_1-4alkylS(O)_a wherein a is 0 to 2 and C_3-6cycloalkyl; wherein R² may be optionally substituted on carbon by one or more halo or C_3-6cycloalkyl;

R³ is selected from hydrogen, nitro, hydroxy, halo, cyano, -CH=N-OR⁶, C_1-4alkyl, C_1-4alkoxy, C_2-4alkenyl, C_2-4alkynyl, C_1-4alkanoyl, C_1-4alkylS(O)_a wherein a is 0 to 2 and C_3-6cycloalkyl; wherein R³ may be optionally substituted on carbon by one or more halo or C_3-6Cy cloalkyl;

W is -O-, -N(R⁷)- or -C(R⁸)(R⁹)-;

X is a direct bond, -CH₂-, -C(O)- or S(O)_q- (wherein q is 1 or 2);

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 R¹⁰; R⁴ and R⁵ are substituents on carbon and are independently selected from azido, halo, nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, sulfo, formyl, ureido, hydroxyiminomethyl, C_1-4alkoxyiminomethyl, iV-hydroxyformamido, C_1-4hydrazino, hydrazinocarbonyl, iV-hydroxyethanimidoyl, amino(hydroxyimino)methyl, C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, C_1-4alkoxy, C_1-4alkanoyl, C_1-4alkanoyloxy, JV-(C _1-4alkyl)amino, JV,N-(C_1-4alkyl)2amino, C_1-4alkanoylamino, /V-(C_1-4alkyl)carbamoyl, N,N-(C_1-4alkyl)₂carbamoyl, iV-(C_1-4alkoxy)carbamoyl, N'-(C_1-4alkyl)ureido, iV'iV'-(C_1-4alkyl)₂ureido, N-(C_1-4alkyl)-N-(C_1-4alkoxy)carbamoyl, C_1-4alkylS(O)_a wherein a is 0 to 2, C_1-4alkoxycarbonyl, C_1-4alkoxycarbonylamino, N-(C_1-4alkyl)sulphamoyl, N,Λ/-(C_1-4alkyl)₂sulphamoyl, C_1-4alkylsulphonylamino, C_1-4alkylsulphonylaminocarbonyl, JV'-(C_1-4alkyl)hydrazinocarbonyl, iV'iV'-(C_1-4alkyl)₂hydrazinocarbonyl, carbocyclyl-R¹¹- or heterocyclyl-R¹² — ; wherein R⁴ and R⁵ independently of each other may be optionally substituted on carbon by one or more R ; and wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R¹⁴;

R⁶, R⁷, R⁸ and R⁹ are independently selected from hydrogen or C_1-4alkyl; n is 0 -4; wherein the values of R⁴ may be the same or different; m is 0-4; wherein the values of R⁵ may be the same or different;

R¹³ is selected from azido, halo, nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, Ci_-4alkyl, C2_-4alkenyl, C_2-4alkynyl, C_1-4alkoxy, C_1-4alkanoyl, C_1-4alkanoyloxy, N-(Ci₄alkyl)amino, ΛζN-(C_1-4alkyl)₂amino, C_1-4alkanoylamino, iV-(C_1-4alkyl)carbamoyl, N, iV-(C_1-4alkyl)₂carbamoyl, C_1-4alkylS(O)_a wherein a is 0 to 2, Ci_-4alkoxycarbonyl, N-(C_1-4alkyl)sulphamoyl, iV,iV-(C_1-4alkyl)₂Sulphamoyl, C_1-4alkylsulphonylamino, C_1-4alkoxycarbonylamino, carbocyclyl-R¹⁵ — or heterocyclyl-R¹⁶ — ; wherein R¹³ may be optionally substituted on carbon by one or more R¹⁷; and wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R¹⁸;

R¹⁰, R¹⁴ and R¹⁸ are independently selected from C_1-4alkyl, Ci_-4alkanoyl, C_1-4alkylsulphonyl, Ci.₄alkoxycarbonyl, N-(C_1-4alkyl)amino, JV,N-(C_1-4alkyl)₂amino, Ci_-4alkanoylamino, carbamoyl, iV-(C_1-4alkyl)carbamoyl, ΛζN-(C_1-4alkyl)carbamoyl, benzyl, benzyloxycarbonyl, benzoyl and phenylsulphonyl;

R¹¹, R¹², R¹⁵ and R¹⁶ are independently selected from a direct bond, -O-, -N(R¹⁹)-, -C(O)-, -N(R²⁰)C(O)-, -C(O)N(R²¹)-, -S(O)_P-, -SO₂N(R²²)- or -N(R²³)SO₂-; wherein R¹⁹, R²⁰, R²¹, R²² and R²³ are independently selected from hydrogen or C_1-4alkyl and p is 0-2; R¹⁷ 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, iV-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, iV-ethylcarbamoyl, AζJV-dimethylcarbamoyl, ΛζiV-diethylcarbamoyl, iV-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl, ethylsulphonyl, methoxycarbonyl, ethoxy carbonyl, N-methylsulphamoyl, iV-ethylsulphamoyl, iV,iV-dimethylsulphamoyl, iV,N-diethylsulphamoyl or iV-methyl-iV-ethylsulphamoyl; or a pharmaceutically acceptable salt thereof. The invention also provides a compound which is: a) Methyl 2-chloro-6-((3i?)-3-{[(3,4-dichloro-5-methyl-lH-pyrrol-2- yl)carbonyl]amino}pyrrolidin- 1 -yl)pyrimidine-4-carboxylate; b) Methyl 2-chloro-6-((35)-3-{[(3,4-dichloro-5-methyl-lH-pyrrol-2- yl)carbonyl] amino jpyn'olidin- 1 -yl)pyrimidine-4-carboxylate; c) Methyl 2-((3i?)-3-{[(3,4-dichloro-5-methyl-lH-pyrrol-2- y^carbonylJaminojpyrrolidin-l-y^-l^-thiazole-S-carboxylate; d) Methyl 2-((35)-3-{[(3,4-dichloro-5-methyl-lH-pyrrol-2yl)carbonyl]amino}pyrrolidin- l-yl)-l,3-thiazole-5-carboxylate; e) 2-Chloro-6-((3i?)-3-{[(3,4-dichloro-5-methyl-lH-pyrrol-2-yl)carbonyl]amino} pyrrolidin- 1 -yl)pyrimidine-4-carboxylic acid; j) 2-Chloro-6-((3,S)-3-{[(3,4-dichloro-5-methyl-lH-pyriOl-2 yl)carbonyl] amino} pyrrolidin- 1-yl) pyrimidine-4-carboxylic acid; g) 2-((35)-3- { [(3 ^-Dichloro-S-methyl- lH^"-pyrrol-2-yl)carbonyl]amino}pyrrolidin- 1 -yl)- l,3-thiazole-5-carboxylic acid; h) 2-((3i?)-3-{[(3,4-Dichloro-5-methyl-lH-pyrrol-2-yl)carbonyl]amino}pyrrolidin-l-yl)- l,3-thiazole-5-carboxylic acid; j) 2-((3i?)-3-{[(3,4-Dichloro-5-methyl-lH-pyrrol-2-yl)carbonyl]amino}pyrrolidin-l-yl)- JV-methoxy-1 ,3-thiazole-5-carboxamide; k) 2-((3₁S)-3-{[(3,4-Dichloro-5-methyl-lH^"-pyrrol-2-yl)carbonyl]amino}pyrrolidin-l-yl)-

N-methoxy-l,3-thiazole-5-carboxamide;

I) 2-Chloro-6-((3 S)-3 - { [(3 ,4-dichloro-5 -methyl- lH-pyrrol-2- yl)carbonyl]amino}pyrrolidin-l-yl)-iV-methoxypyrimidine-4-carboxamide; m) 2-Chloro-6-((3R)-3-{[(3,4-dichloro-5-methyl-lH-pyrrol-2- yl)carbonyl]amino}pyrrolidin-l-yl)-iV-methoxypyrimidine-4-carboxamide; n) Trans(±)methyl 2-(3- { [(3 ,4-dichloro-5 -methyl- lH-pyrrol-2-yl)carbonyl] amino} -4- hydroxypyrrolidin- 1 -yl)- 1 ,3 -thiazole-5-carboxylate; and o) Trans(±)benzyl (3<S',45)-3-[(tert-butoxycarbonyl)amino]-4-methoxypyrrolidine-l- carboxylate.

DETAILED DESCRIPTION OF THE INVENTION

DEFINITIONS

In this specification the term alkyl includes both straight and branched chain alkyl groups. For example, "C_1-4alkyl" 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 -CH₂- 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 N- or S-oxide(s). In one aspect of the invention a "heterocyclyl" is a saturated, partially saturated or unsaturated, monocyclic ring containing 5 or 6 atoms of which at least one atom is chosen from nitrogen, sulphur or oxygen, it may, unless otherwise specified, be carbon or nitrogen linked, a -CH₂- group can optionally be replaced by a -C(O)-and a ring sulphur atom may be optionally oxidised to form the S-oxides. In a further aspect of the invention a "heterocyclyl" is an unsaturated, carbon-linked, monocyclic ring containing 5 or 6 atoms of which at least one atom is chosen from nitrogen, sulphur or oxygen. Examples and suitable values of the term "heterocyclyl" are 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-iV-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 -CH₂- group can optionally be replaced by a -C(O)-. Particularly "carbocyclyl" is a monocyclic ring containing 5 or 6 atoms or a bicyclic ring containing 9 or 10 atoms. Suitable values for "carbocyclyl" include cyclopropyl, cyclobutyl, 1-oxocyclopentyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, phenyl, naphthyl, tetralinyl, indanyl or 1-oxoindanyl. A particular example of "carbocyclyl" is phenyl. An example of "Ci_-4alkanoyloxy" is acetoxy.

Examples of "C_1-4alkoxycarbonyl" include methoxycarbonyl, ethoxycarbonyl, n- and t-butoxycarbonyl. Examples of "C_1-4alkoxycarbonylamino" include methoxycarbonylamino, ethoxycarbonylamino, n- and t-butoxycarbonylamino.

Examples of "C_1-4alkoxy" include methoxy, ethoxy and propoxy. Examples of "C_1-4alkanoylamino" include formamido, acetamido and propionylamino. Examples of "Ci_-4alkylS(O)_a wherein a is 0 to 2" include methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl and ethylsulphonyl.

Examples of "Ci_-4alkanoyl" include propionyl and acetyl.

Examples of "iV-(C_1-4alkyl)amino" include methylamino and ethylamino. Examples of W,N-(Ci_-4alkyl)₂aimno" include di-N-methylamino, di-(N-ethyl)amino and N-ethyl-N-methylamino.

Examples of "C₂-₄alkenyl" are vinyl, allyl and 1-propenyl.

Examples of "C_2-4alkynyl" are ethynyl, 1-propynyl and 2-propynyl. Examples of 'W-(C_1-4alkyl)sulphamoyl" are iV-(methyl)sulphamoyl and

N-(ethyl)sulphamoyl.

Examples of "iV,N-(C_1-4alkyl)₂Sulphamoyl" are N,N-(dimethyl)sulphamoyl and N-(methyi)-N-(ethyl)sulphamoyl.

Examples of "N-(C_1-4alkyl)carbamoyl" are methylaminocarbonyl and ethylaminocarbonyl.

Examples of "N,N-(C_1-4alkyi)₂carbamoyl" are dimethylaminocarbonyl and methylethylaminocarbonyl.

Examples of "N-(C_1-4alkoxy)carbamoyl" are methoxyaminocarbonyl and isopropoxyaminocarbonyl. Examples of 'W-(C _1-4alkyl)- N-(C _1-4alkoxy)carbamoyl" are N-methyl- N- methoxyaminocarbonyl and N-methyl-N-ethoxyaminocarbonyl.

Examples of "Cs^cycloalkyl" are cyclopropyl, cyclobutyl, cyclopropyl and cyclohexyl.

are N -methylureido and N'-isopropylureido. Examples of "N', N'-(C_1-4alkyl)₂ureido" are N'N'-dimethylureido and N'-methyl-N'- isopropylureido.

Examples of "N-(C_{1 -4}alkyi)hydrazinocarbonyl" are N-methylhydrazinocarbonyl and N'-isopropylhydrazinocarbonyl.

Examples of "N',N'-(C_1-4alkyi)₂hydrazinocarbonyP' are N'N- dimethylhydrazinocarbonyl and N'-methyl-N -isopropylhydrazinocarbonyl.

Examples of "C_1-4alkylsulphonylamino" include methylsulphonylamino, isopropylsulphonylamino and t-butylsulphonylamino.

Examples of "Ci^alkylsulphonylaminocarbonyl" include methylsulphonylaminocarbonyl, isopropylsulphonylaminocarbonyl and t-butylsulphonylaminocarbonyl.

Examples of "C_1-4alkylsulphonyl" 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, JV-ethylpiperidine, procaine, dibenzylamine, JV.iV-dibenzylethylamine, tris-(2-hydroxyethyl)amine, tromethamine, iV-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 topoisomerase IV, 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 topoisomerase IV 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.

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.

R¹ is C_1-4alkyl. R¹ is methyl. R² is halo. R² is chloro.

R³ is halo. R³ is chloro.

R¹ is methyl, R² is chloro and R³ is chloro. W is -N(R⁷)- wherein R⁷ is hydrogen. R¹ is methyl, R² is chloro, R³ is chloro and W is -N(R⁷)- wherein R⁷ is hydrogen.

X is a direct bond.

R¹ is methyl, R² is chloro, R³ is chloro, W is -N(R⁷)- wherein R⁷ is hydrogen and X is a direct bond.

Ring A is heterocyclyl; wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R¹⁰. Ring A is carbocyclyl. Ring A is heterocyclyl. Ring A is thiazole or pyrimidine. Ring A is thiazol-2-yl or pyrimidin-4-yl. R⁴ is a substituent on carbon selected from C_1-4alkoxy or hydroxy.

R⁴ is a substituent on carbon selected from methoxy or hydroxy, n is selected from 0 or 1; wherein the values of R⁴ may be the same or different. n is O. n is 1.

R⁵ is a substituent on carbon selected from halo, carboxy, iV-(C_1-4alkoxy)carbamoyl or C _1-4alkoxycarbonyl.

R⁵ is a substituent on carbon selected from chloro, carboxy, JV-(methoxy)carbamoyl or methoxycarbonyl. m is selected from 1 or 2; wherein the values of R⁵ may be the same or different. m is 1. m is 2.

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

R¹ is C_1-4alkyl;

R² is halo;

R³ is halo;

W is -N(R⁷)- wherein R⁷ is hydrogen; X is a direct bond;

Ring A is heterocyclyl;

R is a substituent on carbon selected from C_1-4alkoxy or hydroxy; n is selected from 0 or 1 ; wherein the values of R⁴ may be the same or different;

R⁵ is a substituent on carbon selected from halo, carboxy, iV-(C_1-4alkoxy)carbamoyl or C_1-4alkoxycarbonyl; m is selected from 1 or 2; wherein the values of R⁵ 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: R¹ is methy;

R² is chloro;

R³ is chloro;

W is -N(R⁷)- wherein R⁷ is hydrogen;

X is a direct bond; Ring A is thiazole or pyrimidine;

R⁴ is a substituent on carbon selected from methoxy or hydroxy; n is selected from 0 or 1; wherein the values of R⁴ may be the same or different; R⁵ is a substituent on carbon selected from chloro, carboxy, iV-(metlioxy)carbamoyl or methoxycarbonyl; m is selected from 1 or 2; wherein the values of R⁵ may be the same or different; or a pharmaceutically acceptable salt thereof. Preparation of Invention Compounds

The present invention also provides a process for preparing compounds of formula (I) or pharmaceutically-acceptable salts thereof, comprising:

Process a) for compounds of formula (I) wherein W is -C(R⁸)(R⁹)-; converting a compound of formula (II):

(H) wherein R^a is cyano and R^b is dimethy amino or diethylamino; or R^a and R^b are independently selected from C_1-4alkylthio; 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

(HI):

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

(IV) or

Process c) for compounds of formula (I) wherein W is -N(R⁷)-; 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(R⁸)(R⁹)-; reacting a compound of formula (VI):

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

(VII) or

Process e) for compounds of formula (I) wherein W is

a compound of formula (VIII):

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

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

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

(XI) wherein D is a displaceable group; or

Process g) for compounds of formula (I) wherein X is -C(O)-; reacting a compound of formula (X) with a compound of formula (XII):

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^b 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 C_1-4alkylthio; 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(C10₄)₂, CuCl₂ or AgN0₃/Ag₂0 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 :

Conditions of

i) Deprotection ii) FGI

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 (Ha) 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: ocess f)

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 (Ilia) 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/&y/-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: H i) Conditions of Process f)

,⁷ I j + (XI) ϋ) Deprotection _(m)

(R⁴)n P§ <^Va)

Scheme 3 wherein Pg is a amino protecting group as defined hereinbelow. The skilled reader will appreciate that where R⁷ 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 AlCl₃, from 0 °C to room temperature.

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

Scheme 4 wherein R^aOC(O) is an ester group. Suitable values for R^a include C_1-6alkyl. 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, -78⁰C ii) CuI (lie) *- (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/) 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.

Process g) Compounds of formula (X) and (XII) may be coupled together under the conditions outlined in Process c). Compounds of formula (XII) 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 lOOμl reactions containing: 50 mM HEPES buffer pH 7.5, 75 mM 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 diniethylsulfoxide. 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 ICs₀ 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 niM 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 IC₅₀ measurements determined from reactions performed in the presence of 10 different compound concentrations. Compounds of the Examples could be expected to have IC₅₀ 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 hrs prior to reading. The Minimum Inhibitory Concentration (MIC) may be determined as the lowest drug concentration able to reduce growth by 80% or more. 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 haemofyticus. 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 Enterococcus faecium. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Escherichia coli. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Gardnerella vaginalis. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Haemophilus par ainfluenzae. 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 Peptosfreptococcus 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 Seiratia marcescens. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Staphylococcus aureus. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Staphylococcus epidermidis. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by

Staphylococcus saprophyticus. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by 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 Enter ococcus faecium. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by

Vancomycin-Resistant Enter ococcus 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 the inhibition of bacterial DNA gyrase and/or topoisomerase IV in a warm-blooded animal such as a human being.

Thus according to a further aspect of the invention there is provided 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 anti- bacterial effect in a warm-blooded animal such as a human being.

According to a further aspect of the invention there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof for use in inhibition of bacterial DNA 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)₅ 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 Hansch; 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 levofloxacin; ^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

⁰C and without exclusion of air unless otherwise stated, or unless the skilled person would otherwise work under an inert atmosphere;

(iii) column chromatography (by the flash procedure) was used to purify compounds and was performed on Merck Kieselgel silica (Art. 9385) unless otherwise stated;

(iv) yields are given for illustration only and are not necessarily the maximum attainable;

(v) the structure of the end-products of the invention were generally confirmed by NMR and mass spectral techniques [proton magnetic resonance spectra is quoted and was generally determined in DMSO-d₆ 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 :-

HATU O-(7-azabenzotriazol-l -yl)-Λζiy,iV^"',N'-tetramethyluronium hexafluorophosphate;

TSP 3,3',3"-phosphinidynetris(benzenesulfonic acid), trisodium salt TFA trifluoroacetic acid;

EDC l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride;

HOBt 1 -hydroxybenzotriazole ;

NMM iV-methylmorpholine;

HPLC high performance liquid chromatography; DMF dimethylformamide;

THF tetrahydrofuran;

DMAP 4-dimethylaminopyridine;

DIEA diisopropylethylamine;

NMP JV-methylpyrrolidinone; and DMSO dimethylsulphoxide.

(viii) temperatures are quoted as °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 Buchi, 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,R or S₅S 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.

Intermediate 1 fert-Butyi π-RVS-ll^'fSΛ-dichloro-S-methyl-lij-pyrrol-l-vπcarbonyllaminolpyrrolidine-l- carboxylate

To a stirred solution of 3,4-dichloro-5-methyl-lH-pyrrole-2-carboxylic acid (0.312 g, 1.61 mmol) (Motekaitis, R. J.; Heinert, D. H.; Martell, Arthur E. J. of Org. Chem. 35(8), 2504 (1970)) in DMF (3 niL) was added triethylamine (0.436 mL, 3.22 mmol) followed by the addition of HATU (0.612 g, 1.61 mmol) at room temperature. The resultant solution was stirred for 30 mins and tert-butyl (3i?)-3-aminopyrrolidine-l-carboxylate (0.300 g, 1.61 mmol) was added to it at once. The reaction was allowed to stir overnight. It was concentrated and the residue was partitioned between water and ethyl acetate. The layers separated and the aqueous was extracted with ethyl acetate two more times. The extracts were combined and washed with IN HCl, saturated NaHCO₃ solution followed by water and brine. It was dried over magnesium sulfate, concentrated under reduced pressure to give the product as a light brown solid. MS (ES): 362 (M+l) for C₁₅H₂₁Cl₂N₃O₃

¹H NMR (300 MHz): 1.39 (s, 9H); 1.95 (m, IH); 2.07 (m, IH); 2.17(s, 3H); 3.16 (m, IH); 3.37 (m, 2H); 3.50 (m, IH); 4.35 (m, IH); 7.47 (m, IH); 11.94 (s, IH).

Intermediate 2 ført-Buτyl (3^)-3-{rC3,4-dichloro-5-methyl-lH-pyrrol-2-yl)carbonyllamino>pyrrolidine-l- carboxylate

The title compound was synthesized by the method analogous to the (Intermediate 1) using fert-butyl (35)-3-aminopyrrolidine-l-carboxylate. MS (ES): 362 (M+l) for C₁₅H₂₁Cl₂N₃O₃

¹H NMR (300 MHz): 1.39 (s, 9H); 1.95 (m, IH); 2.07 (m, IH); 2.17 (s, 3H); 3.16 (m, IH);

3.37 (m, 2H); 3.50 (m, IH); 4.35 (m, IH); 7.47 (m, IH); 11.94 (s, IH).

Intermediate 3

3,4-Dichloro-5-methyl-N-r(3J?)-pyrrolidin-3-yl1-17f-pyrrole-2-carboxamide hydrochloride

4M hydrochloric acid in 1,4-dioxane (2.5 mL) was added to tert-butyl (3i?)-3-{[(3,4- dichloro-5 -methyl- 1 H-pyrrol-2-yl)carbonyl]amino } pyrrolidine- 1 -carboxylate (Intermediate 1 , 0.5 g) and the resulting solution was stirred at room temperature. After the completion of the reaction, the mixture was concentrated to give the desired product as a brown solid (0.44 g). MS (ES): 262 (M+l) for C₁₀H₁₃Cl₂N₃O.

Intermediate 4

3 ,4-Dichloro-5 -methyl-iV- [πSVpyrrolidin-S -yl^") - l/j-pyrrole-2-carboxamide hydrochloride The title compound was synthesized by the method analogous to the Intermediate 3 from Intermediate 2. MS (ES): 262 (M+l) for C₁₀H₁₃Cl₂N₃O.

Example 1 Methyl 2-chloro-6-((3i?V3-{r(3.4-dichloro-5-methyl-lH-pyrrol-2 yncarbonyllamino> pyrrolidin- 1 -yl)pyrimidine-4-carboxylate

To a solution of 3,4-dichloro-5-methyl-iV-[(3i?)-pyrrolidin-3-yl]-lH-pyrrole-2- carboxamide hydrochloride (Intermediate 3, 0.30 mg, 1.0 mmol) in DMF (3 mL) was added triethyl amine (0.27mL, 2.01 mmol) followed by the addition of methyl 2,6- dichloropyrimidine-4-carboxylate (0.21 mg, 1.0 mmol) at room temperature. The resulting solution was stirred for 15 minutes and then diluted with water and extracted with ethyl acetate. The extract was washed with IN HCl, saturated NaHCO₃ solution, water and brine. It was dried over magnesium sulfate, concentrated under reduced pressure to give the product as a light brown solid (0.40 g). It did not require further purification. MS (ES): 432 (M+l) for Ci₆H₁₆Cl₃N₅O₃. Example 2

Methyl 2-chloro-6-((3_lS^f)-3-{[(3,4-dichloro-5-methyl-lH-pyrrol-2-yl)carbonyllaimno> pyrrolidin- 1 -vπpyrimidine-4-carboxylate

The above compound was prepared by an analogous method to Example 1 from Intermediate 4 and methyl 2,6-dichloropyrimidine-4-carboxylate. MS (ES): 432 (M+l) for C₁₆H₁₆Cl₃N₅O₃.

Example 3

Methyl 2-(πi?V3-{r(3.4-dichloro-5-methyl-lH-pyrrol-2-yl)carbonyllamino>pyrrolidin-l-yl)- 1 ,3-thiazole-5-carboxylate

To a stirred solution of 3,4-dichloro-5-methyl-N-[(3i?)-pyrrolidin-3-yl]-lH-pyrrole-2- carboxamide hydrochloride (Intermediate 3, 270 mg, 0.91 mmol) and triethylamine (0.25 niL,

1.82 mmol) in DMF (3 mL), methyl 2-bromo-l,3-thiazole-5-carboxylate (0.2 g, 0.91 mmol) was added. The resulting solution was stirred at 60 °C overnight. Then it was diluted with water and extracted with ethyl acetate. During the work up process the product precipitated and was collected by filtration. It was dried (203 mg) and characterized by LCMS and ¹H

NMR.

MS (ES): 403 (M+l) for C₁₅H₁₆Cl₂N₄O₃S

¹H NMR (300 MHz): 2.10 (m, IH); 2.17 (s, 3H); 2.30 (m, IH); 3.41 (m, IH); 3.58 (m, 2H); 3.72 (m, IH); 3.73 (s, 3H); 4.59 (m, IH); 7.70 (d, IH); 7.88 (s, IH); 11.95 (s, IH).

Example 4

Methyl 2-((3y)-3-(r(3.4-dichloro-5-methyl-lH-pyrrol-2-yl^carbonynamino>pyrrolidin-l-ylV 13-thiazole-5-carboxylate The above compound was prepared by an analogous method to described for Example

3 from Intermediate 4 and methyl 2-bromo-l,3-thiazole-5-carboxylate. MS (ES): 403 (M+l) for C₁₅Hi₆Cl₂N₄O₃S; ¹HNMR (300 MHz): 2.10 (m, IH); 2.17 (s, 3H); 2.30 (m, IH); 3.41 (m, IH); 3.58 (m, 2H); 3.72 (m, IH); 3.73 (s, 3H); 4.59 (m, IH); 7.70 (d, IH); 7.88 (s, IH); 11.95 (s, IH). Example 5

2-Chloro-6-(Y3i?V3- { \(3 ^-dichloro-S-methyl- lH-ϋyrrol-2-yl)carbonyllamino>pyrrolidin- 1 - yl)pyrimidine-4-carboxylic acid

Methyl 2-chloro-6-((3i?)-3- { [(3 ,4-dichloro-5-methyl- lH-pyrrol-2- yl)carbonyl]amino}pyrrolidin-l-yl)pyrimidine-4-carboxylate (Example 1, 400 mg, 0.92 mmol) was taken in methanol (5 mL) and 2N lithium hydroxide (3 mL) was added to it. The resulting solution was stirred for one hour at room temperature. Then the solvent was removed and the aqueous was acidified with IN HCl to precipitate the product. It was collected by filtration and purified by reverse phase HPLC. MS (ES): 418 (M+l) for C₁₅H₁₄Cl₃N₅O₃

¹HNMR (300 MHz): 2.07 (m, IH); 2.17 (s, 3H); 2.28 (m, IH); 3.45 (m, IH); 3.58 (m, 2H);

3.77 (m, IH); 4.55 (m, IH); 6.99 (d, IH); 7.63 (t, IH); 11.94 (s, IH).

Examples 6-8 The following acids were prepared by an analogous method to Example 5.

Example 9

2-((3J?V3-{[(3,4-Dichloro-5-methyl-l/j-pyrrol-2-yl)carbonyl]amino>pyrrolidm-l-ylViV- methoxy-l,3-thiazole-5-carboxamide HATU (88 mg, 0.23 mmol) was added to a solution of diisopropylethylamine (0.120 ml, 0.69 mmol), 2-((3i?)-3-{[(3,4-dichloro-5-methyl-lH-pyrrol-2-yl)carbonyl]amino} pyrrolidin-l-yl)-l,3-thiazole-5-carboxylic acid (Example 8, 100 mg, 0.23 mmol) and methoxylamine hydrochloride (22mg, 0.23 mmol) in DMF (3 ml) under nitrogen. The resultant mixture was stirred overnight at room temperature, then diluted with ethyl acetate and water and the organic phase was separated. The organic phase was washed with IN HCl, saturated NaHCO₃ solution and brine. The aqueous layers were back extracted with ethyl acetate. The combined organic layers were dried over Na₂SO₄, filtered and concentrated under vacuum to give 80 mg of crude product, which was purified by preparative re versed-phase HPLC (water/acetonitrile gradient, 30-75%). MS (ESP): 418 (M+H) for C₁₅H₁₇Cl₂N₅O₃S

¹H NMR δ: 2.08 (m, IH); 2.17 (s, 3H); 2.27 (m, IH); 3.41 (m, IH); 3.58 (m, 2H); 3.65 (s, 3H); 3.72 (m, IH); 4.58 (m, IH); 7.67 (d, IH); 7.74 (s, IH); 11.29 (s, IH); 11.94 (s, IH).

Examples 10-12 The following examples were prepared by an analogous method to Example 9.

Intermediate 5

Benzyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate

Benzyl 2,5-dihydro-lH-pyrrole-l-carboxylate (9.92 g) was dissolved in DCM (200 mL) and mCPBA (13.20 g) was added. The reaction was allowed to stir at room temperature for 96 h. The reaction mixture was diluted with Et₂O and washed with saturated aqueous sodium thiosulfate solution, saturated aqueous NaHCO₃ solution and brine. The organic layer was dried (MgSO₄) and the organic solvent was removed in vacuo. The crude product was purified by silica gel column chromatography (gradient of 12.5 to 50% EtOAc in hexanes) to afford 9.13 g of product. MS (ES) MH⁺: 220 for C₁₂H₁₃NO₃; NMR: 3.33 (dd, 2H), 3.64 (dd, 2H), 3.77 (s, 2H)₅ 5.04 (s, 2H)₅ 7.34 (m₅ 5H). Intermediate 6

Trans(±)benzyl 3-azido-4-hvdroxypyrrolidine- 1 -carboxylate

Benzyl ό-oxa-S-azabicyclop.l.OJhexane-S-carboxylate (Intermediate 5, 9.09 g) was dissolved in MeOH (88 mL). To this was added water (15 mL), ammonium chloride (2.27 g), and sodium azide (5.47 g). The reaction mixture was heated to 65 ⁰C for 21 h. The solids were removed by filtration and the solvent was removed in vacuo. The residue was taken up in 15% aqueous sodium hydroxide and extracted with DCM. The organic layers were washed with brine, dried (MgSO₄) and the organic solvent was removed in vacuo to afford 10.73 g of product. MS (ES) MH⁺: 220 for C₁₂H₁₃NO₃; NMR: 3.17 (m, IH), 3.27 (m, IH), 3.42 (m, IH), 3.58 (m, IH), 3.96 (m, IH), 4.09 (m, IH), 5.05 (m, 2H), 7.34 (m, 5H).

Intermediate 7

Transf±^benzyl 3 -amino-4-hvdroxypyrrolidine- 1 -carboxylate

Trans(±)benzyl 3 -azido-4-hydroxypyrrolidine-l -carboxylate (Intermediate 6, 9.09 g) was dissolved in THF (400 mL) and water (40 mL). To this was added diphenylphosphino- polystyrene (47.01 g) and the reaction was allowed to stir at room temperature for 24 h. The solid-supported triphenylphosphine was filtered off and the organic solvent was removed in vacuo to afford the product. MS (ES) MH⁺: 237 for C₁₂Hi₆N₂O₃; NMR: 2.15 (m, 3H), 3.20 (m, IH), 3.34 (m, 2H), 3.73 (m, 2H), 4.00 (m, IH), 5.11 (s, 2H), 7.33 (m, 5H).

Intermediate 8

Trans(±)benzyl 3 -amino-4-hydroxypyrrolidine-l -carboxylate (Intermediate 7, 5.87 g) was dissolved in DCM (100 mL) and cooled to 0 °C. To this was added Et₃N (3.5 mL), DMAP (cat. amount) and di-tert-butyl dicarbonate (5.48 g). The reaction mixture was allowed to gradually warm to room temperature and was stirred for 91 h. The reaction mixture was diluted with Et₂O and washed with saturated aqueous NH₄Cl solution and brine. The organic layers were dried (MgSO₄) and concentrated in vacuo to afford the product. MS (ES) (MH - Boc)⁺: 237 for C₁₇H₂₄N₂O₃; NMR: 1.43 (s, 9H), 2.48 (m, IH), 3.26 (m, IH), 3.37 (m, IH), 3.73 (m, IH), 3.83 (m, IH), 3.93 (m, IH), 4.23 (m, IH), 4.69 (m, IH), 5.12 (s, 2H), 7.34 (m, 5H). Intermediate 9

Trans(±)fert-butyl (4-hydroxypyrrolidin-3 -vDcarbamate

A solution of trans(±)benzyl 3-[(tert-butoxycarbonyl)amino]-4-hydroxypyrrolidine-l- carboxylate (Intermediate 8, 5.59 g) and 10 wt% Pd on carbon (0.60 g) in MeOH (100 mL) was stirred under 1 atmosphere of hydrogen for 48 h. The reaction mixture was filtered through Celite and concentrated in vacuo to afford the product (3.48 g). NMR: 1.24 (s, 9H), 3.01 (dd, IH), 3.15 (m, IH), 3.19 (m, IH), 3.38 (dd, IH), 3.59 (m, IH), 3.81 (m, IH), 4.10 (m, 3H).

Intermediate 10

Trans(±)methyl 2-{3-r(fert-butoxycarbonyl)ammo]-4-hvdroxypyrrolidin-l-yl}-l,3-tliiazole-5- carboxylate

To a solution of trans(±)tert-butyl (4-hydroxypyrrolidin-3-yl)carbamate (Intermediate

9, 1.11 g) in MeCN (18 mL) was added DIPEA (1.40 mL) and methyl 2-bromo-l,3-thiazole- 5-carboxylate (1.25 g). The reaction was heated at 60 °C for 48 h before solvent removal in vacuo. The crude product was purified by column chromatography (gradient of 0.6 to 2.5 %

MeOH in DCM) to afford 0.86 g of product. NMR: 1.44 (s, 9H), 3.44 (m, IH), 3.52 (m, IH),

3.83 (s, 3H), 3.85 (m, IH), 3.92 (m, IH), 3.98 (m, IH), 4.14 (m, IH), 4.46 (m, IH), 4.91 (m,

IH), 7.88 (s, IH).

Intermediate 11

Trans(±)methyl 2- [3 -amino-4-hydroxypyrrolidin- 1 -yll -1,3 -thiazole-5 -carboxylate

Trans(±)methyl 2- { 3 - [(tert-butoxy carbony l)amino] -4-hy droxypyrrolidin- 1 -yl} - 1 ,3 - thiazole-5 -carboxylate (Intermediate 10, 0.86 g) was dissolved in DCM (10 mL) and 4N HCl in dioxane (5 mL) was added. After 18 h the solvent was removed in vacuo to afford the crude hydrochloride salt, which was freebased by treatment with MP-carbonate (5 equiv.) in

MeOH/DCM to afford the product (0.55 g). MS (ES) MH⁺: 244 for C₉H₁₃N₃O₃S; NMR: 3.04

(m, 4H), 3.62 (s, 3H), 3.64 (m, 2H), 3.88 (m, 2H), 4.41 (m, IH), 7.70 (s, IH). Example 13

Trans(±)methyl 2-(3-(r(3,4-dichloro-5-methyl-l/i-pyrrol-2-vDcarbonyllammol-4- hvdroxypyrrolidin- 1 -y IV 1 ,3 -thiazole-5-carboxylate

To a solution of trans(±)methyl 2-[3-amino-4-hydroxypyrrolidin-l-yi]-l,3-thiazole-5- carboxylate (Intermediate 11, 0.548 g) in DCM (30 mL) was added triethylamine (0.50 mL), DMAP (catalytic amount) and 3,4-dichloro-5-methyl-lH-pyrrole-2-carbonyl chloride (0.49 g). After 18 Ii the solvent was removed in vacuo and the crude product was purified by silica gel chromatography (gradient of 0.6 to 5% MeOH in DCM) to afford the title compound. MS (ES) MH⁺: 419 for C₁₅H₁₆Cl₂N₄O₄S; NMR: 2.00 (m, IH), 2.21 (s, 3H), 3.46 (m, IH), 3.57 (m, IH), 3.80 (m, IH), 3.81 (s, 3H), 3.84 (m, IH), 3.96 (m, IH), 4.48 (m, 2H), 5.48 (m, IH), 7.86 (S, IH).

Intermediate 12

Transfd=)benzyl 3 -azido-4-methoxypyrrolidine- 1 -carboxylate To a solution of trans(±)benzyl 3 -azido-4-hydroxypyrrolidine- 1 -carboxylate

(Intermediate 6, 4.97 g) in THF (60 mL) was added NaH (0.83 g, 60 % dispersion in mineral oil) at 0 °C followed by methyl iodide (1.3 mL). The reaction was allowed to warm to room temperature and was complete after 2 h. The solvent was removed in vacuo. The residue taken up in Et₂O, washed with water and brine, dried (MgSO₄) and concentrated in vacuo. The crude product was purified by silica gel chromatography (gradient of 7.5 to 30% EtOAc in hexanes) to afford the product (4.36 g). NMR: 3.30 (s, 3H), 3.37 (m, 2H), 3.50 (m, 2H), 3.85 (m, IH), 4.32 (m, IH), 5.07 (s, 2H), 7.35 (m, 5H).

Intermediate 13 Trans(±)benzyl 3 -amino-4-methoxypyrrolidine- 1 -carboxylate

A solution of trans(±)benzyl 3 -azido-4-methoxypyrrolidine-l -carboxylate (Intermediate 12, 4.33 g) in THF (100 mL) and water (10 mL) was treated with triphenylphosphine (4.50 g) for 1 h. The THF was removed in vacuo and the residue was dissolved in EtOAc. The EtOAc layer was washed with 15% aqueous citric acid and the aqueous layers were combined and made basic with concentrated aqueous ammonium hydroxide. The combined aqueous layers were extracted with EtOAc and the combined organic layers were washed with brine, dried (MgSO₄) and concentrated in vacuo to afford the product. NMR: 1.73 (m, IH), 3.00 (m, IH), 3.09 (m, IH), 3.23 (s, 3H), 3.26 (m, IH), 3.34 (m, 2H), 3.52 (m, IH), 3.70 (m, IH), 5.05 (s, 2H), 7.35 (m, 5H).

Intermediate 14 Transf±)benzyl 3-[(tert-butoxycarbonyl)aminol-4-niethoxypyrrolidine-l-carboxylate

Trans(±)benzyl 3-ammo-4-methoxypyrrolidine-l-carboxylate (Intermediate 13, 1.57 g) was dissolved in DCM (6 mL). To this was added Et₃N (1.3 rnL), DMAP (catalytic amount) and di-tert-butyl dicarbonate (1.77 g). After 48 h the reaction mixture was diluted with Et₂O and washed with saturated aqueous NH₄Cl solution and brine. Drying (MgSO₄) and concentration in vacuo afforded the product as a brown oil (2.39 g). NMR: 1.45 (s, 9H), 3.20 (m, IH), 3.26 (s, 3H), 3.31 (m, IH), 3.48 (m, 2H), 3.72 (m, IH), 4.04 (m, IH), 5.06 (s, 2H), 6.13 (m, IH), 7.35 (m, 5H).

Intermediate 15 Trans(±Vert-butvK4-methoxypyrrolidin-3-vDcarbamate

A solution of trans(±)benzyl 3-[(tert-butoxycarbonyl)amino]-4-methoxypyrrolidine-l- carboxylate (Intermediate 14, 1.95 g) in MeOH (100 mL) was added to 10 wt% Pd on carbon (0.24 g) and stirred under one atmosphere of hydrogen for 48 h. The reaction mixture was filtered through Celite and concentrated in vacuo to afford the product. NMR: 1.42 (s, 9H), 2.68 (m, 2H), 2.93 (m, 2H), 3.17 (m, 2H), 3.23 (m, 3H), 3.57 (m, 2H).

Intermediate 16

Trans(±)methyl 2- (3 - r(fert-butoxycarbonyl)amino1 -4-methoxypyrrolidin- 1-vU-l ,3 -thiazole- 5-carboxylate To a solution of trans(±)tert-butyl (4-methoxypyrrolidin-3-yl)carbamate (Intermediate

15, 1.06 g) in MeCN (20 mL) was added DIPEA (1.30 mL) and methyl 2-bromo-l,3-thiazole- 5-carboxylate (1.11 g). The reaction mixture was heated at 60 °C for 48 h. The solvent was removed in vacuo and the crude product was purified by silica gel column chromatography (gradient of 0.6 to 2.5 % MeOH in DCM) to afford the product. NMR: 1.41 (s, 9H), 3.31 (m, IH), 3.42 (s, 3H), 3.50 (m, IH), 3.71 (m, IH), 3.79 (s, 3H), 3.94 (m, IH), 4.25 (m, IH), 4.93 (m, IH), 7.85 (s, IH). Example 14

Transf±)2-(3- { 1Y3 ,4-dichloro-5-methyl- lff-pyrrol-2-yl)carbonyllamino> -4- methoxypyrrolidin- 1 -vD- 1.3 -thiazole-5 -carboxylic acid

To a solution of trans(±)methyl 2-{3-[(tert-butoxycarbonyi)amino]-4- methoxypyrrolidin-l-yl}-l,3-thiazole-5-carboxylate (Intermediate 16, 0.144 g) in DCM (3 niL) was added trifluoroacetic acid (2 mL). After 1 h the solvent was removed in vacuo and the crude trifluoroacetate salt was resuspended in DCM (4 mL). To this was added Et₃N (0.28 mL), DMAP (catalytic amount) and 3,4-dichloro-5-methyl-lH-pyrrole-2-carbonyl chloride (0.092 g). The reaction mixture was allowed to stir for 16 h at room temperature. The solvent was removed in vacuo and the residue was dissolved in MeOH (5 mL) and to this was added K₂CO₃ (0.46 g). After 120 h LiOH (0.069 g) was added and the reaction was allowed to stir an additional 48 h. The reaction mixture was the quenched with 2N aq. HCl solution (3.1 mL) and washed with Et₂O. Upon standing the product precipitated out of the aqueous phase and was filtered to afford the title compound as a white powder. MS (ES) MH⁺: 419 for C₁₅H₁₆Cl₂N₄O₄S; NMR: 2.11 (s, 3H), 3.26 (m, IH), 3.34 (s, 3H), 3.36 (m, 2H), 3.56 (m, 2H), 3.77 (m, IH), 4.50 (m, IH), 7.14 (s, IH), 9.60 (s, IH), 15.08 (s, IH).

Claims

Claims

1. A compound of formula (I) :

(I) wherein:

R¹ is selected from hydrogen, nitro, hydroxy, halo, cyano, C_1-4alkyl, C_1-4alkoxy, C_2-4alkenyl, C_2-4alkynyl, C_1-4alkanoyl, C_1-4alkylS(O)_a wherein a is 0 to 2 and C_3-6cycloalkyl; wherein R¹ may be optionally substituted on carbon by one or more halo or cyclopropyl; R² is selected from hydrogen, nitro, hydroxy, halo, cyano, C_1-4alkyl, C_1-4alkoxy,

C_2-4alkenyl, C_2-4alkynyl, C_1-4alkanoyl, C_1-4alkylS(O)_a wherein a is 0 to 2 and C_3-6cycloalkyl; wherein R² may be optionally substituted on carbon by one or more halo or C_3-6cycloalkyl;

R³ is selected from hydrogen, nitro, hydroxy, halo, cyano, -C=N-OR⁶, C_1-4alkyl, C_1-4alkoxy, C_2-4alkenyl, C_2-4alkynyl, C_1-4alkanoyl, C _1-4alkylS(0)_a wherein a is 0 to 2 and C_3-6cycloalkyl; wherein R³ may be optionally substituted on carbon by one or more halo or C_3-6cycloalkyl;

W is -O-, -N(R⁷)- or -C(R⁸)(R⁹)-;

X is a direct bond, -CH₂-, -C(O)- or S(O)_q- (wherein q is 1 or 2);

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 R¹⁰;

R⁴ and R⁵ are substituents on carbon and are independently selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, sulfo, formyl, ureido, hydroxyiminomethyl, C_1-4alkoxyiminomethyl, N-hydroxyformamido, Ci_-4hydrazino, hydrazinocarbonyl, JV-hydroxyethanimidoyl, amino(hydroxyimino)methyl, C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, C_1-4alkoxy, Ci_-4alkanoyl, C_1-4alkanoyloxy,

N~(C_1-4alkyl)amino, ΛζiV-(C_1-4alkyl)₂amino, C_1-4alkanoylamino, N-(C_1-4alkyl)carbamoyl, NN-tC^alkylhcarbamoyl, N-(C_1-4alkoxy)carbamoyl, N'-(C_1-4alkyl)ureido, N'.NHCwalkyl^ureido, N-(C _1-4alky I)-N-(C _1-4alkoxy)carbamoyl, C_1-4alkylS(O)_a wherein a is 0 to 2, C_1-4alkoxycarbonyl, C_1-4alkoxycarbonylamino, N-(C_1-4alkyl)sulphamoyl, JV,iV-(C_1-4alkyl)₂sulphamoyl, CMalkylsulphonylamino, C_1-4alkylsulphonylaminocarbonyl, iV'-(Ci_-4alkyl)hydrazinocarbonyl, JV',N'-(C_1-4alkyl)₂hydrazmocarbonyl, carbocyclyl-R¹¹- or heterocyclyl-R¹² — ; wherein R⁴ and R⁵ independently of each other may be optionally substituted on carbon by one or more R¹³; and wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R¹⁴; R⁶, R⁷, R⁸ and R⁹ are independently selected from hydrogen or C_1-4alkyl; n is 0 -4; wherein the values of R may be the same or different; m is 0-4; wherein the values of R⁵ may be the same or different; R¹³ is selected from azido, halo, nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C_1-4alkyl, C_2-4alkenyl, C2_-4alkynyl, C_1-4alkoxy, C_1-4alkanoyl, C_1-4alkanoyloxy, JV-(C _1-4alkyi)amino, N, N-(C_1-4alkyl)₂amino, C_1-4alkanoylamino, iV-(C_1-4alkyl)carbamoyl, N, N-(C_1-4alkyl)₂carbamoyl, C_1-4alkylS(O)_a wherein a is 0 to 2, C_1-4alkoxycarbonyl, JV-(C i_-4alkyl)sulphamoyl, JV,JV-(C_1-4alkyl)₂sulphamoyl, C_1-4alkylsulphonylamino, C_1-4alkoxycarbonylamino, carbocyclyl-R¹⁵ — or heterocyclyl-R¹⁶ — ; wherein R¹³ may be optionally substituted on carbon by one or more R¹⁷; and wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R ;

R¹⁰, R¹⁴ and R¹⁸ are independently selected from C_1-4alkyl, C_1-4alkanoyl, C_1-4alkylsulphonyl, C_1-4alkoxycarbonyl, JV-(Ci-₄alkyl)amino, JV, JV-(C _1-4alkyl)₂amino, C_1-4alkanoylamino, carbamoyl, N-(C_1-4alkyl)carbamoyl, JV, N-(C_1-4alkyl)carbamoyl, benzyl, benzyloxycarbonyl, benzoyl and phenylsulphonyl;

R¹¹, R¹², R¹⁵ and R¹⁶ are independently selected from a direct bond, -O-, -N(R¹⁹)-, -C(O)-, -N(R²⁰)C(O)-, -C(O)N(R²¹)-, -S(O)_P-, -SO₂N(R²²)- or -N(R²³)SO₂-; wherein R¹⁹, R²⁰, R²¹, R²² and R²³ are independently selected from hydrogen or C_1-4alkyl and p is 0-2; R¹⁷ 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, N-methyl-JV-ethylamino, acetylamino, iV-methylcarbamoyl, iV-ethylcarbamoyl, iV,JV-dimethylcarbamoyl, JV,JV-diethylcarbamoyl, N-methyl-JV-ethylcarbamoyl, methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl, ethylsulphonyl, methoxycarbonyl, ethoxycarbonyl, JV-methylsulphamoyl, JV-ethylsulphamoyl, JV,JV-dimethylsulphamoyl, JV, iV-diethylsulphamoyl or JV-methyl-JV-ethylsulphamoyl; or a pharmaceutically acceptable salt thereof. - SO -

2. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1 wherein R¹ is methyl.

3. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in either claim 1 or claim 2 wherein R² is chloro.

4. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1-3 wherein R is chloro.

5. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1-4 wherein W is -N(R⁷)- wherein R⁷ is hydrogen.

6. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1-5 wherein X is a direct bond.

7. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1-6 wherein Ring A is thiazole or pyrimidine.

8. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in aannyy oonnee oof claims 1-7 wherein R⁴ is a substituent on carbon selected from C_1-4alkoxy or hydroxy.

9. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1-8 wherein n is selected from 0 or 1; wherein the values of R⁴ may be the same or different.

10. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1-9 wherein R⁵ is a substituent on carbon selected from halo, carboxy, N-(C_1-4alkoxy)carbamoyl or Ci_-4alkoxycarbonyl.

11. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1-10 wherein m is selected from 1 or 2; wherein the values of R⁵ may be the same or different.

12. A compound of formula (I) :

(I) wherein: R¹ is methyl;

R² is chloro; R³ is chloro;

W is -N(R⁷)- wherein R⁷ is hydrogen; X is a direct bond;

Ring A is thiazole or pyrimidine;

R⁴ is a substituent on carbon selected from methoxy or hydroxy; n is selected from 0 or 1 ; wherein the values of R⁴ may be the same or different;

R⁵ is a substituent on carbon selected from chloro, carboxy, 7V-(methoxy)carbamoyl methoxycarbonyl; m is selected from 1 or 2; wherein the values of R⁵ may be the same or different; or a pharmaceutically acceptable salt thereof.

13. A compound of formula (I) :

(I) selected from: methyl 2-chloro-6-((3i?)-3-{[(3,4-dichloro-5-methyl-lϋr-pyrrol-2-yl)carbonyl]amino} pyrrolidin- 1 -yl)pyrimidine-4-carboxylate; methyl 2-chloro-6-((35)-3 - { [(3 ,4-dichloro-5-methyl- 1 H-pyrrol-2-yl)carbonyl]amino } pyrrolidin- 1 -yl)pyrimidine-4-carboxy late; methyl 2-((3i?)-3 - { [(3 ,4-dichloro-5-methyl- 1 H-pyrrol-2-yl)carbonyl] amino}pyrrolidin- 1 -yl)-

1 ,3-thiazole-5-carboxylate; methyl 2-((35)-3-{[(3,4-dichloro-5-methyl-lH-pyrrol-2-yl)carbonyl]amino}pyrrolidin-l-yl)-

1 ,3-thiazole-5-carboxylate; 2-chloro-6-((3i?)-3 - { [(3 ^-dichloro-S-methyl- lH-pyrrol-2-yl)carbonyl] amino }pyrrolidin- 1 - ^* yl)pyrimidine-4-carboxylic acid;

2-chloro-6-((35)-3-{[(3,4-dichloro-5-methyl-lH-pyrrol-2 yl)carbonyl]amino}pyrrolidin-l-yl) pyrimidine-4-carboxylic acid;

2-((35)-3 - { [(3 ,4-dichloro-5-methyl- 1 H-pyrrol-2-yl)carbonyl]amino }pyrrolidin- 1 -yl)- 1,3- tliiazole-5-carboxylic acid;

2-((3i-)-3-{[(3,4-dichloro-5-methyl-lif-pyπOl-2-yl)carbonyl]amino}pyrrolidin-l-yl)-l,3- thiazole-5-carboxylic acid;

2-((3i?)-3 - { [(3 ,4-dichloro-5-methyl- 1 H-pyrrol-2-yl)carbonyl]amino }pyrrolidin- 1 -y I)-N- methoxy- 1 ,3-thiazole-5-carboxamide; 2-((35)-3-{[(3,4-dichloro-5-methyl-lH-pyrrol-2-yl)carbonyl]amino}pyrrolidin-l-yl)-N- methoxy-l,3-thiazole-5-carboxamide;

2-chloro-6-((3S)-3-{[(3,4-dichloro-5-methyl-li^:/-pyrrol-2-yl)carbonyl]ammo}pyrrolidin-l- yl)-N-methoxypyrimidine-4-carboxamide;

2-chloro-6-((3R)-3-{[(3,4-dichloro-5-methyl-lH-pyrrol-2-yl)carbonyl]amino}pyrrolidin-l- yl)-N-methoxypyrimidine-4-carboxamide; trans(±)methyl 2-(3 - { [(3 ,4-dichloro-5 -methyl- 1 H-pyrrol-2-yl)carbony 1] amino } -4- hydroxypyrrolidin- 1 -yl)- 1 ,3 -thiazole-5-carboxylate; and trans(±)benzyl (35',4iS)-3-[(fe7t-butoxycarbonyl)amino]-4-methoxypyrrolidine-l-carboxylate; or a pharmaceutically acceptable salt thereof.

14. A process for preparing a compounds of formula (I) or a pharmaceutically-acceptable salt thereof, as claimed in claim 1 comprising:

Process a) for compounds of formula (I) wherein W is -C(R⁸)(R⁹)-; converting a compound of formula (II):

(H) wherein R^a is cyano and R^b is dimethy amino or diethylamino; or R^a and R^b are independently selected from d^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 (HI):

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

or

Process c) for compounds of formula (I) wherein W is -N(R⁷)-; 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(R⁸)(R⁹)-; reacting a compound of formula (VI):

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

(VII) or

Process e) for compounds of formula (I) wherein W is -C(R⁸)(R⁹)-; 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/) reacting a compound of formula (X):

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

(XI) wherein D is a displaceable group; or Process g) for compounds of formula (I) wherein X is -C(O)-; reacting a compound of formula (X) with a compound of formula (XII):

(XII)

5 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.

10 15. A pharmaceutical composition which comprises a compound of the formula (I) or a pharmaceutically-acceptable salt thereof, as claimed in any one of claims 1-13, and a pharmaceutically-acceptable diluent or carrier.

16. A compound of formula (I) or a pharmaceutically acceptable salt thereof, as claimed 15 in any one of claims 1 - 13 , for use as a medicament.

17. The use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-13, in the manufacture of a medicament for the inhibition of bacterial DNA gyrase and/or topoisomerase IV in a warm-blooded animal such as a human

20 being.

18. A pharmaceutical composition which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-13, in association with a pharmaceutically acceptable excipient or carrier for use in inhibition of bacterial DNA

25 gyrase and/or topoisomerase IV in an warm-blooded animal, such as a human being.

19. A method for inhibition of bacterial DNA gyrase and/or topoisomerase IV in a warm-blooded animal 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

30 thereof, as claimed in any one of claims 1-13.