Heterocyclic urea compounds

The present invention provides a compound of the following formula, racemates, enantiomers and salts thereof. Also provided is the use of these compounds as antibacterials, compositions comprising them and processes for their manufacture.

FIELD OF THE INVENTION

The present invention relates to a novel class of compounds, their use as antibacterials, compositions comprising them and processes for their manufacture.

BACKGROUND

Type II topoisomerases catalyse the interconversion of DNA topoisomers by transporting one DNA segment through another. Bacteria encode two type II topoisomerase enzymes, DNA gyrase and DNA topoisomerase IV. Gyrase controls DNA supercoiling and relieves topological stress. Topoisomerase IV decatenates daughter chromosomes following replication and can also relax supercoiled DNA. Bacterial type II topoisomerases form a heterotetrameric complex composed of two subunits. Gyrase forms an A2B2complex comprised of GyrA and GyrB whereas topoisomerase forms a C2E2complex comprised of ParC and ParE. In contrast eukaryotic type II topoisomerases are homodimers. Ideally, an antibiotic based on the inhibition of bacterial type II topoisomerases would be selective for the bacterial enzymes and be relatively inactive against the eukaryotic type II isomerases. The type II topoisomerases are highly conserved enzymes allowing the design of broad-spectrum inhibitors. Furthermore, the GyrB and ParE subunits are functionally similar, having an ATPase domain in the N-terminal domain and a C-terminal domain that interacts with the other subunit (GyrA and ParC respectively) and the DNA. The conservation between the gyrase and topoisomerase IV active sites suggests that inhibitors of the sites might simultaneously target both type II topoisomerases. Such dual-targeting inhibitors are attractive because they have the potential to reduce the development of target-based resistance.

Type II topoisomerases are the target of a number of antibacterial agents. The most prominent of these agents are the quinolones. The original quinolone antibiotics included nalidixic acid, cinoxacin and oxolinic acid. The addition of fluorine yielded a new class of drugs, the fluoroquinolones, which have a broader antimicrobial spectrum and improved pharmacokinetic properties. The fluoroquinolones include norfloxacin, ciprofloxacin, and fourth generation quinolones gatifloxacin and moxifloxacin. The coumarins and the cyclothialidines are further classes of antibiotics that inhibit type II topoisomerases, however they are not widely used because of poor permeability in bacteria, eukaryotic toxicity, and low water solubility. Examples of such antibiotics include novobiocin and coumermycin A1, cyclothialidine, cinodine, and clerocidin. However, the continual emergence of antibiotic resistance demands that novel classes of antibiotics continue to be developed and alternative compounds that inhibit bacterial topoisomerases are required.

SUMMARY

According to a first aspect there is provided a compound of formula (I), racemates, enantiomers and salts thereof:

wherein
X is selected from C(═X1), S(═O) and SO2;
X1is selected from O, S and NR4;
R1is optionally substituted and selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, (CH2)tC3-10cycloalkyl, (CH2)tC3-10cycloalkenyl, (CH2)tC6-10aryl, (CH2)t3-10-membered heterocyclyl and (CH2)t5-10-membered heteroaryl, CR5(R6)2, NR4SO2R5, OR6, SR6, NH2, NR5R6and NRaRbwhere Raand Rbjoin with the N to which they are attached to form an optionally substituted 5-10 membered heterocyclic ring;
R2is optionally substituted and selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, (CH2)tC3-10cycloalkyl, (CH2)tC3-10cycloalkenyl, (CH2)tC6-10aryl, (CH2)t3-10-membered heterocyclyl and (CH2)t5-10-membered heteroaryl;
R3is an optionally substituted C1-6alkyl;
R4is H or an optionally substituted C1-6alkyl;
R5is optionally substituted and selected from C1-6alkyl, C1-6alkoxyl, C2-6alkenyl, C2-6alkynyl, (CH2)tC3-10cycloalkyl, (CH2)tC3-10cycloalkenyl, (CH2)tC6-10aryl, (CH2)t3-10-membered heterocyclyl and (CH2)t5-10-membered heteroaryl;
Each R6is H or is optionally substituted and selected from C1-6alkyl, C1-6alkoxyl, C2-6alkenyl, C2-6alkynyl, (CH2)tC3-10cycloalkyl, (CH2)tC3-10cycloalkenyl, (CH2)tC6-10aryl, (CH2)t3-10-membered heterocyclyl and (CH2)t5-10-membered heteroaryl;
t is an integer selected from 0, 1, 2 and 3 preferably 0, 1 or 2 and wherein each (CH2)twhen present may be independently optionally substituted;
Z1, Z2and Z3are each independently selected from CR7and N where R7is selected from H, halo or an optional substituent and further where at least one of Z1, Z2or Z3is N; and
each cycloalkyl, cycloalkenyl, aryl, heteorcyclyl and heteroaryl ring may be a monocyclic or fused bicyclic ring system.

In one embodiment X is C(═X1), X1is selected from O, S and NR4, preferably O, and R1is selected from NH2, NR5R6and NRaRb, preferably NR5R6and NRaRb. In a particularly preferred embodiment, R1is NR5R6and in an even more preferred embodiment R6is H or C1-6alkyl.

In another embodiment, R3is optionally substituted C1-3alkyl with unsubstituted ethyl being particularly preferred.

According to a second aspect there is provided a method for the treatment of a bacterial infection comprising administration of a compound of Formula I, racemates, enantiomers or pharmaceutically acceptable salts thereof to a subject suffering from said infection. In one embodiment, the infection is a Gram positive bacterial infection. In a further embodiment the Gram positive infection is caused by a bacterial strain selected fromS. aureus, E. faecalisandS. pyogenes, even more preferablyS. aureus. In another embodiment, the infection is a Gram negative bacterial infection. In a further embodiment the Gram negative infection is caused by a bacterial strain ofH. influenzae. According to a third aspect there is provided a compound of Formula I, racemates, enantiomers or pharmaceutically acceptable salts thereof for use in the treatment of a bacterial infection.

According to a fourth aspect there is provided an antibacterial agent comprising a compound of Formula I, racemates, enantiomers or pharmaceutically acceptable salts thereof.

According to a fifth aspect there is provided a composition comprising a compound of Formula I, racemates, enantiomers or salts thereof and an excipient or carrier. In one embodiment the composition is a pharmaceutical composition, the salt is a pharmaceutically acceptable salt and the excipient or carrier is a pharmaceutically acceptable excipient or carrier.

According to a sixth aspect there is provided a compound of Formula I, racemates, enantiomers or pharmaceutically acceptable salts thereof for use as a gyrase inhibitor. In one embodiment the compound of formula I is active against the ATPase enzyme. According to a seventh aspect there is provided a process for the manufacture of a compound of Formula I via an intermediate of general formula (II):

where R′ is a halo or NH2group; or
via an intermediate of general formula (III):

where R″ is H or C1-6alkyl; or
via an intermediate of general formula (IV):

According to an eighth aspect, there is provided a method of treating bacterial contamination of a substrate comprising applying to the site of such contamination an amount of a compound of Formula I racemates, enantiomers or pharmaceutically acceptable salts thereof sufficient to inhibit bacterial growth.

According to a ninth aspect, there is provided the use of a compound of Formula I, racemates, enantiomers or pharmaceutically acceptable salts thereof in the preparation of a medicament for the treatment of a bacterial infection in a subject.

DETAILED DESCRIPTION

The present invention is predicated on the discovery of a new class of compounds that have shown on-target gyrase enzyme activity. Accordingly, in one embodiment the compounds of Formula I are useful in modulating the activity of gyrase, more particularly as gyrase inhibitors.

Compounds of this class also exhibit antibacterial activity more particularly antibacterial activity against strains of Gram-positive and/or Gram-negative classes, such as staphylococci, enterococci, streptococci and haemophili for exampleStaphylococcus aureus, Enterococcus faecalis, Streptococcus pyogenesandHaemophilus influenzae. The compounds with which the invention is concerned are therefore useful for the treatment of bacterial infection or contamination, for example in the treatment of, inter alia, Gram-positive infections and community acquired pneumonias. Accordingly, in one embodiment the compounds of Formula (I) are useful in the treatment of bacterial infections caused by Gram positive bacterial strains.

In another embodiment, the compounds of Formula (I) are useful in the treatment of bacterial infections caused by Gram negative bacterial strains.

The development of antibacterial resistance is particularly common in a hospital setting. Hospital patients are therefore especially at risk of infection by resistant strains of bacteria.

DEFINITIONS

The term “C1-6alkyl” encompasses optionally substituted straight chain or branched chain hydrocarbon groups having from 1, 2, 3, 4, 5 or 6 carbon atoms or a range comprising any of two of those integers. Examples include methyl (Me), ethyl (Et), propyl (Pr), isopropyl (i-Pr), butyl (Bu), isobutyl (i-Bu), sec-butyl (s-Bu), tert-butyl (t-Bu), pentyl, neopentyl, hexyl and the like. Unless the context requires otherwise, the term “C1-6alkyl” also encompasses alkyl groups containing one less hydrogen atom such that the group is attached via two positions i.e. divalent. Such groups are also referred to as “C1-6alkylene” groups. C1-3alkyl and C1-3alkylene groups are preferred. The term “C2-6alkenyl” refers to optionally substituted straight chain or branched chain hydrocarbon groups having at least one double bond of either E or Z stereochemistry where applicable and 2, 3, 4, 5 or 6 carbon atoms or a range comprising any of two of those integers. Examples include vinyl, 1-propenyl, 1- and 2-butenyl, 2-methyl-2-propenyl, hexenyl, butadienyl, hexadienyl, hexatrienyl and the like. Unless the context requires otherwise, the term “C1-6alkenyl” also encompasses alkenyl groups containing one less hydrogen atom such that the group is attached via two positions i.e. divalent. Such groups are also referred to as “C2-6alkenylene” groups. C2-3alkenyl and C2-3alkenylene groups are preferred.

The term “C2-6alkynyl” refers to optionally substituted straight chain or branched chain hydrocarbon groups having at least one triple bond and 2, 3, 4, 5 or 6 carbon atoms or a range comprising any of two of those integers. Examples include ethynyl, 1-propynyl, 1- and 2-butynyl, 2-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl and the like. Unless the context indicates otherwise, the term “C2-6alkynyl” also encompasses alkynyl groups containing one less hydrogen atom such that the group is attached via two positions i.e. divalent. Such groups are also referred to as “C2-6alkynylene” groups. C2-3alkynyl and C2-3alkynylene groups are preferred.

The term “C3-8cycloalkyl” refers to non-aromatic cyclic hydrocarbon groups having from 3, 4, 5, 6, 7 or 8 carbon atoms or a range comprising any of two of those integers including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl and the like. It will be understood that cycloalkyl groups may be saturated such as cyclohexyl or unsaturated such as cyclohexenyl. C3-6cycloalkyl groups are preferred.

The terms “hydroxy” and “hydroxyl” refer to the group —OH.

The term “oxo” refers to the group ═O.

The term “C1-6alkoxyl” refers to the group OC1-6alkyl. Examples include methoxy, ethoxy, propoxy, isoproxy, butoxy, tert-butoxy, pentoxy and the like. The oxygen atom may be located along the hydrocarbon chain, and need not be the atom linking the group to the remainder of the compound. C1-3alkoxyl groups are preferred.

The term “aryloxy” refers to the group —Oaryl and may include variations thereof such as “alkoxyaryl”, wherein aryl is defined herein. Examples include, but are not limited to, phenoxy and naphthoxy and benzyloxy.

The term “C1-6alkylhalo” refers to a C1-6alkyl which is substituted with one or more halogens. C1-3alkylhalo groups are preferred, such as for example, —CHF2and —CF3.

The term “C1-6alkoxylhalo” refers to a C1-6alkoxyl which is substituted with one or more halogens. C1-3alkoxylhalo groups are preferred, such as for example, —OCHF2and —OCF3.

The term “carboxylate” or “carboxyl” refers to the group —COO−or —COOH.

The term “ester” refers to a carboxyl group having the hydrogen replaced with, for example a C1-6alkyl group (“carboxylC1-6alkyl” or “alkylester”), an aryl or aralkyl group (“arylester” or “aralkylester”) and so on. CO2C1-3alkyl groups are preferred, such as for example, methylester (CO2Me), ethylester (CO2Et) and propylester (CO2Pr) and includes reverse esters thereof (e.g. —OCOMe, —OCOEt and —OCOPr).

The term “cyano” refers to the group —CN.

The term “nitro” refers to the group —NO2.

The term “amino” refers to the group —NH2.

The term “substituted amino” or “secondary amino” refers to an amino group having a hydrogen replaced with, for example a C1-6alkyl group (“C1-6alkylamino”), an aryl or aralkyl group (“arylamino”, “aralkylamino”) and so on. C1-3alkylamino groups are preferred, such as for example, methylamino (NHMe), ethylamino (NHEt) and propylamino (NHPr).

The term “disubstituted amino” or “tertiary amino” refers to an amino group having the two hydrogens replaced with, for example a C1-6alkyl group, which may be the same or different (“dialkylamino”), an aryl and alkyl group (“aryl(alkyl)amino”) and so on. Di(C1-3alkyl)amino groups are preferred, such as for example, dimethylamino (NMe2), diethylamino (NEt2), dipropylamino (NPr2) and variations thereof (e.g. N(Me)(Et) and so on).

The term “acyl” or “aldehyde” refers to the group —C(═O)H.

The term “substituted acyl” or “ketone” refers to an acyl group having a hydrogen replaced with, for example a C1-6alkyl group (“C1-6alkylacyl” or “alkylketone” or “ketoalkyl”), an aryl group (“arylketone”), an aralkyl group (“aralkylketone”) and so on. C1-3alkylacyl groups are preferred.

The term “amido” or “amide” refers to the group —C(O)NH2.

The term “aminoacyl” refers to the group —NHC(O)H.

The term “substituted amido” or “substituted amide” refers to an amido group having a hydrogen replaced with, for example a C1-6alkyl group (“C1-6alkylamido” or “C1-6alkylamide”), an aryl (“arylamido”), aralkyl group (“aralkylamido”) and so on. C1-3alkylamide groups are preferred, such as for example, methylamide (—C(O)NHMe), ethylamide (—C(O)NHEt) and propylamide (—C(O)NHPr) and includes reverse amides thereof (e.g. —NHMeC(O)—, —NHEtC(O)— and —NHPrC(O)—).

The term “disubstituted amido” or “disubstituted amide” refers to an amido group having the two hydrogens replaced with, for example a C1-6alkyl group (“di(C1-6alkyl)amido”) or “di(C1-6alkyl)amide”), an aralkyl and alkyl group (“alkyl(aralkyl)amido”) and so on. Di(C1-3alkyl)amide groups are preferred, such as for example, dimethylamide (—C(O)NMe2), diethylamide (—C(O)NEt2) and dipropylamide (—C(O)NPr2) and variations thereof (e.g. —C(O)N(Me)Et and so on) and includes reverse amides thereof.

The term “thiol” refers to the group —SH.

The term “C1-6alkylthio” refers to a thiol group having the hydrogen replaced with a C1-6alkyl group. C1-3alkylthio groups are preferred, such as for example, thiolmethyl, thiolethyl and thiolpropyl.

The term “thioxo” refers to the group ═S.

The term “sulfinyl” refers to the group —S(═O)H.

The term “substituted sulfinyl” or “sulfoxide” refers to a sulfinyl group having the hydrogen replaced with, for example a C1-6alkyl group (“C1-6alkylsulfinyl” or “C1-6alkylsulfoxide”), an aryl (“arylsulfinyl”), an aralkyl (“aralkyl sulfinyl”) and so on. C1-3alkylsulfinyl groups are preferred, such as for example, —SOmethyl, —SOethyl and —SOpropyl.

The term “sulfonyl” refers to the group —SO2NH2.

The term “substituted sulfonyl” refers to a sulfonyl group having the hydrogen replaced with, for example a C1-6alkyl group (“sulfonylC1-6alkyl”), an aryl (“arylsulfonyl”), an aralkyl (“aralkylsulfonyl”) and so on. SulfonylC1-3alkyl groups are preferred, such as for example, —SO2Me, —SO2Et and —SO2Pr.

The term “sulfonylamido” or “sulfonamide” refers to the group —SO2NH2.

The term “substituted sulfonamido” or “substituted sulphonamide” refers to a sulfonylamido group having a hydrogen replaced with, for example a C1-6alkyl group (“sulfonylamidoC1-6alkyl”), an aryl (“arylsulfonamide”), aralkyl (“aralkylsulfonamide”) and so on. SulfonylamidoC1-3alkyl groups are preferred, such as for example, —SO2NHMe, —SO2NHEt and —SO2NHPr and includes reverse sulfonamides thereof (e.g. —NHSO2Me, —NHSO2Et and —NHSO2Pr).

The term “disubstituted sulfonamido” or “disubstituted sulphonamide” refers to a sulfonylamido group having the two hydrogens replaced with, for example a C1-6alkyl group, which may be the same or different (“sulfonylamidodi(C1-6alkyl)”), an aralkyl and alkyl group (“sulfonamido(aralkyl)alkyl”) and so on. Sulfonylamidodi(C1-3alkyl) groups are preferred, such as for example, —SO2NMe2, —SO2NEt2and —SO2NPr2and variations thereof (e.g. SO2N(Me)Et and so on) and includes reserve sulfonamides thereof.

The term “sulfate” refers to the group OS(O)2OH and includes groups having the hydrogen replaced with, for example a C1-6alkyl group (“alkylsulfates”), an aryl (“arylsulfate”), an aralkyl (“aralkylsulfate”) and so on. C1-3sulfates are preferred, such as for example, OS(O)2OMe, OS(O)2OEt and OS(O)2OPr.

The term “sulfonate” refers to the group SO3H and includes groups having the hydrogen replaced with, for example a C1-6alkyl group (“alkylsulfonate”), an aryl (“arylsulfonate”), an aralkyl (“aralkylsulfonate”) and so on. C1-3sulfonates are preferred, such as for example, SO3Me, SO3Et and SO3Pr.

The term “phosphate” refers to a group OP(O)(OH)2and includes groups having each hydrogen independently replaced with, for example a C1-6alkyl group (“alkylphosphate”), an aryl (“arylphosphate”), an aralkyl (“aralkylphosphate”) and so on.

The term “phosphonate” refers to a group P(O)(OH)2and includes groups having each hydrogen independently replaced with, for example a C1-6alkyl group (“alkylphosphonate”), an aryl (“arylphosphonate”), an aralkyl (“aralkylphosphpmate”) and so on.

The term “aryl” refers to any group containing a carbocyclic (non-heterocyclic) aromatic ring and may be a mono-, bi- or tri-cyclic ring system. The aromatic ring or ring system is generally composed of 6 or 10 carbon atoms. Such groups may contain fused ring systems (such as naphthyl, tetrahydronaphthyl, fluorenyl, indenyl, azulenyl, anthracenyl and the like), linked ring systems (such as biphenyl groups), and may be substituted or unsubstituted. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl and tetrahydronaphthyl. Phenyl is preferred.

The term “aralkyl” refers to an aryl group substituted with a C1-6alkyl group. Examples include benzyl and phenethyl.

The term “heterocyclyl” refers to a moiety obtained by removing a hydrogen atom from a ring atom of a heterocyclic compound which moiety has from 3 to 10 ring atoms (unless otherwise specified), of which 1, 2, 3 or 4 are ring heteroatoms each heteroatom being independently selected from O, S and N.

Heterocyclyls also encompass aromatic heterocyclyls and non-aromatic heterocyclyls. Such groups may be substituted or unsubstituted.

The term “aromatic heterocyclyl” may be used interchangeably with the term “heteroaromatic” or the term “heteroaryl” or “hetaryl”. The heteroatoms in the aromatic heterocyclyl group may be independently selected from N, S and O.

“Heteroaryl” is used herein to denote a heterocyclic group having aromatic character and embraces aromatic monocyclic ring systems and polycyclic (e.g. bicyclic) ring systems containing one or more aromatic rings. The term aromatic heterocyclyl also encompasses pseudoaromatic heterocyclyls. The term “pseudoaromatic” refers to a ring system which is not strictly aromatic, but which is stabilized by means of delocalization of electrons and behaves in a similar manner to aromatic rings. The term aromatic heterocyclyl therefore covers polycyclic ring systems in which all of the fused rings are aromatic as well as ring systems where one or more rings are non-aromatic, provided that at least one ring is aromatic. In polycyclic systems containing both aromatic and non-aromatic rings fused together, the group may be attached to another moiety by the aromatic ring or by a non-aromatic ring.

Examples of heteroaryl groups are monocyclic and bicyclic groups containing from five to ten ring members. The heteroaryl group can be, for example, a five membered or six membered monocyclic ring or a bicyclic structure formed from fused five and six membered rings or two fused six membered rings or two fused five membered rings. Each ring may contain up to about four heteroatoms typically selected from nitrogen, sulfur and oxygen. The heteroaryl ring will contain up to 4 heteroatoms, more typically up to 3 heteroatoms, more usually up to 2, for example a single heteroatom. In one embodiment, the heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atoms in the heteroaryl rings can be basic, as in the case of an imidazole or pyridine, or essentially non-basic as in the case of an indole or pyrrole nitrogen. In general the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents of the ring, will be less than five.

Aromatic heterocyclyl groups may be 5-membered or 6-membered mono-cyclic aromatic ring systems.

Examples of 5-membered monocyclic heteroaryl groups include but are not limited to furanyl, thienyl, pyrrolyl, oxazolyl, oxadiazolyl (including 1,2,3 and 1,2,4 oxadiazolyls and furazanyl i.e. 1,2,5-oxadiazolyl), thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl, imidazolyl, triazolyl (including 1,2,3, 1,2,4 and 1,3,4 triazolyls), oxatriazolyl, tetrazolyl, thiadiazolyl (including 1,2,3 and 1,3,4 thiadiazolyls) and the like. Examples of 6-membered monocyclic heteroaryl groups include but are not limited to pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyranyl, oxazinyl, dioxinyl, thiazinyl, thiadiazinyl and the like. Examples of 6-membered heteroaryl groups containing nitrogen include pyridyl (1 nitrogen), pyrazinyl, pyrimidinyl and pyridazinyl (2 nitrogens). It will be understood that, such as in the case of pyridyl when substituted with an oxo (═O) substituted the group may be interchangably referred to as a pyridinone group.

Aromatic heterocyclyl groups may also be bicyclic or polycyclic heteroaromatic ring systems such as fused ring systems (including purine, pteridinyl, napthyridinyl, 1H thieno[2,3-c]pyrazolyl, thieno[2,3-b]furyl and the like) or linked ring systems (such as oligothiophene, polypyrrole and the like). Fused ring systems may also include aromatic 5-membered or 6-membered heterocyclyls fused to carbocyclic aromatic rings such as phenyl, naphthyl, indenyl, azulenyl, fluorenyl, anthracenyl and the like, such as 5- or 6-membered aromatic heterocyclyls fused to a phenyl ring including 5-membered aromatic heterocyclyls containing nitrogen fused to a phenyl ring, 5-membered aromatic heterocyclyls containing 1 or 2 nitrogens fused to a phenyl ring and such as 5- or 6-membered aromatic heteroaryls fused to a 6-membered aromatic or non-aromatic heterocyclyls.

A bicyclic heteroaryl group may be, for example, a group selected from: a) a benzene ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; b) a pyridine ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; c) a pyrimidine ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; d) a pyrrole ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; e) a pyrazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; f) an imidazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; g) an oxazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; h) an isoxazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; i) a thiazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; j) an isothiazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; k) a thiophene ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; 1) a furan ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; m) a cyclohexyl ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; and n) a cyclopentyl ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms.

Particular examples of bicyclic heteroaryl groups containing a five membered ring fused to another five membered ring i.e. 8-membered fused bicyclic rings include but are not limited to imidazothiazole (e.g. imidazo[2,1-b]thiazole) and imidazoimidazole (e.g. imidazo[1,2-a]imidazole).

Particular examples of bicyclic heteroaryl groups containing a six membered ring fused to a five membered ring i.e. 9-membered fused bicyclic rings include but are not limited to benzofuran, benzothiophene, benzimidazole, benzoxazole, isobenzoxazole, benzisoxazole, benzothiazole, benzisothiazole, isobenzofuran, indole, isoindole, indolizine, indoline, isoindoline, purine (e.g., adenine, guanine), indazole, imidazopyridine (e.g. imidazo[1,2-a]pyridine and imidazo[4,5-b]pyridine], pyrazolopyrimidine (e.g. pyrazolo[1,5-a]pyrimidine), benzodioxole and pyrazolopyridine (e.g. pyrazolo[1,5-a]pyridine) groups. A further example of a six membered ring fused to a five membered ring is a pyrrolopyridine group such as a pyrrolo[2,3-b]pyridine group.

The term “non-aromatic heterocyclyl” encompasses optionally substituted saturated and unsaturated rings which contain at least one heteroatom selected from the group consisting of N, S and O.

Non-aromatic heterocyclyl rings may also be bicyclic heterocyclyl rings such as linked ring systems (for example uridinyl and the like) or fused ring systems. Fused ring systems include non-aromatic 5-membered, 6-membered or 7-membered heterocyclyls fused to carbocyclic aromatic rings such as phenyl, naphthyl, indenyl, azulenyl, fluorenyl, anthracenyl and the like. Examples of non-aromatic 5-membered, 6-membered or 7-membered heterocyclyls fused to carbocyclic aromatic rings include indolinyl, benzodiazepinyl, benzazepinyl, dihydrobenzofuranyl and the like.

Optional substituents in the case of heterocycles containing N may also include but are not limited to alkyl i.e. N—C1-3alkyl, more preferably methyl, particularly N-methyl. It will be understood that suitable derivatives of aromatic heterocyclyls containing nitrogen include N-oxides thereof.

Embodiments will now be described.

In one embodiment C3-10cycloalkyl groups (and groups comprising them) are selected from optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl and optionally substituted cyclohexyl.

In one embodiment C6-10aryl groups (and groups comprising them) are selected from optionally substituted phenyl and optionally substituted naphthyl with optionally substituted phenyl being particularly preferred.

In one embodiment, 5-10 membered heterocycles (and groups comprising them) are selected from optionally substituted 5-membered moncyclic heterocyclyls, optionally substituted 6-membered monocyclic heterocyclyls, optionally substituted 9-membered fused bicyclic heterocyclyls and optionally substituted 10-membered fused bicyclic heterocyclyls and in each case the heterocyclyl contains at least one heteroatom selected from O, N or S. Examples of 5-, 6-, 9- and 10-membered heterocyclyls includes those as previously defined.

In one embodiment, 5-10 membered heteroaryls (and groups comprising them) are selected from optionally substituted 5-membered moncyclic heteroaryls, optionally substituted 6-membered monocyclic heteroaryls, optionally substituted 9-membered fused bicyclic heteroaryls and optionally substituted 10-membered fused bicyclic heteroaryls and in each case the heteroaryl contains at least one heteroatom selected from O, N or S. Examples of 5-, 6-, 9- and 10-membered heteroaryls include those as previously defined.

In one embodiment the compound is of formula (Ia):

wherein
X1is selected from O, S or NR4, preferably X1is O;
R1is selected from NH2, NR5R6and NRaRbwhere Raand Rbjoin with the N to which they are attached to form an optionally substituted 5-10 membered heterocyclic ring, preferably a 5- or 6-membered heterocyclic ring;
R2is optionally substituted and selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, (CH2)tC3-10cycloalkyl, (CH2)tC3-10cycloalkenyl, (CH2)tC6-10aryl, (CH2)t3-10-membered heterocyclyl and (CH2)t5-10-membered heteroaryl;
R3is an optionally substituted C1-6alkyl, preferably C1-3alkyl, particularly ethyl;
R4is H or an optionally substituted C1-6alkyl;
R5is optionally substituted and selected from C1-6alkyl, C1-6alkoxyl, C2-6alkenyl, C2-6alkynyl, (CH2)tC3-10cycloalkyl, (CH2)tC3-10cycloalkenyl, (CH2)tC6-10aryl, (CH2)t3-10-membered heterocyclyl and (CH2)t5-10-membered heteroaryl;
R6is H or is optionally substituted and selected from C1-6alkyl, C1-6alkoxyl, C2-6alkenyl, C2-6alkynyl, (CH2)tC3-10cycloalkyl, (CH2)tC3-10cycloalkenyl, (CH2)tC6-10aryl, (CH2)t3-10-membered heterocyclyl and (CH2)t5-10-membered heteroaryl; preferably R6is H or optionally substituted C1-6alkyl, more preferably H or optionally substituted C1-3alkyl and most preferably H;
t is an integer selected from 0, 1, 2 and 3 preferably 0, 1 or 2 and wherein each (CHA when present may be independently optionally substituted;
Z1, Z2and Z3are each independently selected from CR7and N where each R7is independently selected from H, halo or an optional substituent and further where at least one of Z1, Z2or Z3is N.

In a further embodiment one of Z1, Z2or Z3is N and the two remaining are each CR7where each R7is independently selected from selected from H, halo or an optional substituent and in a particularly preferred embodiment each R7is H.

In yet another particular embodiment Z2is N and Z1and Z3are each CR7where each R7is independently selected from selected from H, halo or an optional substituent and in a particularly preferred embodiment each R7is H. In an alternative embodiment, Z1is CH, Z2is CH and Z3is N.

In still another embodiment, two of Z1, Z2or Z3are N and the one remaining is CR7where R7is independently selected from selected from H, halo or an optional substituent and in a particularly preferred embodiment R7is H. In a further embodiment, Z1and Z2are both N and Z3is CH. In an alternative embodiment, Z1is N, Z2is CH and Z3is N. In still another alternative embodiment, Z1is CH, Z2is N and Z3is N.

In yet a further embodiment R2is selected from an optionally substituted cyclohexyl, an optionally substituted (CH2)tphenyl, an optionally substituted 5-6-membered heterocyclyl and an optionally substituted (CH2)t5-6-membered heteroaryl ring where t is 0 or 1.

In still another embodiment R2is an optionally substituted (CH2)tphenyl or an optionally substituted (CH2)t5-6-membered heteroaryl ring where t in each case is independently 0 or 1.

Particularly preferred (CH2)t5-membered heteroaryl rings include an optionally substituted pyrazolyl or an optionally substituted isoxazolyl.

Particularly preferred (CH2)t6-membered heteroaryl rings include an optionally substituted pyridyl, an optionally substituted CH2pyridyl, an optionally substituted pyrimidinyl or an optionally substituted pyridinonyl.

In a particularly preferred embodiment R2is an optionally substituted phenyl.

In one embodiment R1is NR5R6.

In a further embodiment R5is optionally substituted and selected from C1-3alkyl, (CH2)tC3-10cycloalkyl, (CH2)tC3-10cycloalkenyl, (CH2)tC6-10aryl, (CH2)t3-10-membered heterocyclyl and (CH2)t5-10-membered heteroaryl where t is an integer 0, 1 or 2.

In yet a further embodiment R5is selected from an optionally substituted C1-3alkyl, an optionally substituted C3-6cycloalkyl, an optionally substituted (CH2)tphenyl, an optionally substituted 5-6-membered heterocyclyl, an optionally substituted (CH2)t5-6-membered heteroaryl ring and an optionally substituted 9-10-membered heteroaryl ring where t is an integer 0, 1 or 2.

In still another embodiment R2and R5are each independently selected from an optionally substituted (CH2)tphenyl, an optionally substituted (CH2)t5-6-membered heterocyclyl, an optionally substituted (CH2)t5-6-membered heteroaryl ring and an optionally substituted (CH2)t9-10-membered heteroaryl ring where t is an integer 0, 1 or 2 preferably 0 or 1 and R6is H.

In another embodiment R1is NRaRb.

In a further embodiment when R1is NRaRb, Raand Rbjoin with the N to which they are attached to form an optionally substituted 5- or 6-membered heterocyclic ring. In a particular embodiment NRaRbforms an optionally substituted 6-membered heterocyclic ring, for example, such as an optionally substituted piperidine, an optionally substituted piperazine or an optionally substituted morpholine.

and NHC1-6alkyl optionally substituted with a C3-6cycloalkyl and CO2H or CO2C1-3alkyl (particularly

where * represents the point of attachment;
and where q is an integer independently selected from 1, 2 or 3, preferably 1 or 2.

Accordingly, in a further embodiment the compound is of formula (Ib)

In one embodiment R2is optionally substituted and selected from (CH2)tC3-10cycloalkyl, (CH2)tC3-10cycloalkenyl, (CH2)tC6-10aryl, (CH2)t3-10-membered heterocyclyl and (CH2)t5-10-membered heteroaryl where t is 0 or 1.

In yet a further embodiment R2is selected from an optionally substituted (CH2)tphenyl, an optionally substituted 5-6-membered heterocyclyl and an optionally substituted (CH2)t5-6-membered heteroaryl ring where t is 0 or 1.

In still another embodiment R2is an optionally substituted (CH2)tphenyl or an optionally substituted (CH2)t5-6-membered heteroaryl ring where t in each case is independently 0 or 1.

Particularly preferred (CH2)t5-membered heteroaryl rings include an optionally substituted pyrazolyl or an optionally substituted isoxazolyl.

Particularly preferred (CH2)t6-membered heteroaryl rings include an optionally substituted pyridyl, an optionally substituted CH2pyridyl, an optionally substituted pyrimidinyl or an optionally substituted pyridinonyl.

In a particularly preferred embodiment R2is an optionally substituted phenyl.

In one embodiment R5is optionally substituted and selected from C1-3alkyl, (CH2)tC3-10cycloalkyl, (CH2)tC3-10cycloalkenyl, (CH2)tC6-10aryl, (CH2)t3-10-membered heterocyclyl and (CH2)t5-10-membered heteroaryl where t is an integer 0, 1 or 2.

In yet a further embodiment R5is selected from an optionally substituted C1-3alkyl, an optionally substituted C3-6cycloalkyl, an optionally substituted (CH2)tphenyl, an optionally substituted 5-6-membered heterocyclyl, an optionally substituted (CH2)t5-6-membered heteroaryl ring and an optionally substituted 9-10-membered heteroaryl ring where t is an integer 0, 1 or 2.

In a particularly preferred embodiment R5is an optionally substituted phenyl.

In still another embodiment R2and R5are each independently selected from an optionally substituted (CH2)tphenyl, an optionally substituted (CH2)t5-6-membered heterocyclyl, an optionally substituted (CH2)t5-6-membered heteroaryl ring and an optionally substituted (CH2)t9-10-membered heteroaryl ring where t is an integer 0, 1 or 2 preferably 0 or 1 and R6is H.

In a further preferred embodiment R2is an optionally substituted phenyl and R5is an optionally substituted phenyl.

Suitable optional substituents for R2and R5are as previously defined.

and NHC1-6alkyl optionally substituted with a C3-6cycloalkyl and CO2H or CO2C1-3alkyl (particularly

where * represents the point of attachment; and where q is an integer independently selected from 1, 2 or 3, preferably 1 or 2.

In one embodiment the compound is selected from the group consisting of:

and racemates, enantiomers and salts thereof.

The salts of the compound of Formula I are preferably pharmaceutically acceptable, but it will be appreciated that non-pharmaceutically acceptable salts also fall within the scope of the present invention, since these are useful as intermediates in the preparation of pharmaceutically acceptable salts.

Base salts include, but are not limited to, those formed with pharmaceutically acceptable cations, such as sodium, potassium, lithium, calcium, magnesium, zinc, ammonium, alkylammonium such as salts formed from triethylamine, alkoxyammonium such as those formed with ethanolamine and salts formed from ethylenediamine, choline or amino acids such as arginine, lysine or histidine. General information on types of pharmaceutically acceptable salts and their formation is known to those skilled in the art and is as described in general texts such as “Handbook of Pharmaceutical salts” P. H. Stahl, C. G. Wermuth, 1stedition, 2002, Wiley-VCH. Basic nitrogen-containing groups may be quarternized with such agents as lower alkyl halide, such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl and diethyl sulfate; and others such as alkylphosphonates or phosphoramidates.

Hydroxyl groups may be esterified with groups including lower alkyl carboxylic acids, such as acetic acid and 2,2-dimethylpropionic acid, or sulfonated with groups including alkyl sulfonic acids, such as methyl sulfonic acid or phosphorylated with groups including alkylphosphonic acids, such as methylenephosphonic acid, or directly attached to phosphonate esters, phosphinate esters, or phosphate esters.

It will be recognised that the compounds of formula I may possess asymmetric centres and are therefore capable of existing in more than one stereoisomeric form. The invention thus also relates to compounds in substantially pure isomeric form at one or more asymmetric centres eg., greater than about 90% ee, such as about 95% or 97% ee or greater than 99% ee, as well as mixtures, including racemic mixtures, thereof. Such isomers may be prepared by asymmetric synthesis, for example using chiral intermediates, or by chiral resolution.

This invention also encompasses prodrugs of compounds of formula I. Compounds of formula I having free amino, amido, hydroxy or carboxylic groups can be converted into prodrugs.

The present invention provides a method for the treatment of an antibacterial infection comprising administration of a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject suffering from said infection.

The compounds of the present invention may be administered by any suitable means, for example, orally, parenterally, such as by subcutaneous, intravenous, intramuscular, or intracisternal injection or infusion techniques (e.g., as sterile injectable aqueous or non-aqueous solutions or suspensions).

The present invention also provides compound of Formula I or a pharmaceutically acceptable salt thereof for use in the treatment of an antibacterial infection.

There is also provided a composition comprising a compound of Formula I or a salt thereof. Preferably, the composition further comprises a pharmaceutically acceptable carrier, diluent or excipient.

The compositions of the present invention may be formulated, for example, by employing conventional solid or liquid vehicles or diluents, as well as pharmaceutical additives of a type appropriate to the mode of desired administration (for example, excipients, binders, preservatives, stabilizers, flavors, etc.) according to techniques such as those well known in the art of pharmaceutical formulation.

Pharmaceutical formulations include those for oral, rectal, nasal, topical (including buccal and sub-lingual), vaginal or parenteral (including intramuscular, sub-cutaneous and intravenous) administration or in a form suitable for administration by inhalation or insufflation. The compounds of the invention, together with a conventional adjuvant, carrier or diluent, may thus be placed into the form of pharmaceutical compositions and unit dosages thereof, and in such form may be employed as solids, such as tablets or filled capsules, or liquids as solutions, suspensions, emulsions, elixirs or capsules filled with the same, all for oral use, in the form of suppositories for rectal administration; or in the form of sterile injectable solutions for parenteral (including subcutaneous) use. In addition to primates, such as humans, a variety of other mammals can be treated according to the method of the present invention. For instance, mammals including, but not limited to, cows, sheep, goats, horses, dogs, cats, guinea pigs, rats or other bovine, ovine, equine, canine, feline, rodent or murine species can be treated.

However, the method can also be practiced in other species, such as avian species (e.g., chickens).

The subjects treated in the above method are mammals, including, but not limited to, cows, sheep, goats, horses, dogs, cats, guinea pigs, rats or other bovine, ovine, equine, canine, feline, rodent or murine species, and preferably a human being, male or female.

The term “effective amount” means the amount of the subject composition that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.

The terms “administration of” and or “administering a” compound should be understood to mean providing a compound of the invention to the individual in need of treatment.

In the treatment or prevention of bacterial infections, an appropriate dosage level will generally be about 0.01 to 500 mg per kg patient body weight per day which can be administered in single or multiple doses. For oral administration, the compositions are preferably provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient.

Compounds of the invention may be generally prepared by the following general method(s).

General Method A

Step a: The chloro-amino analogue was subjected to standard iodination conditions (eg. NIS) in an organic solvent (eg. DMF).

Step b: The iodo-chloro-amino analogue was subjected to cyanation condition using a metal cyanide (eg. Zn(CN)2), a palladium catalyst (eg. Pd(PPh3)4) in a suitable organic solvent (eg. NMP).

Step c: The cyano analogue was subjected to standard hydrolysis using an aqueous acid (eg. H2SO4).

Step d: The acid was subjected to amide coupling conditions using common coupling reagents (eg. EDCI+HOBt) with a suitable amine (eg. m-toluidine) in an organic solvent (eg. DMF).

Step e: The free amine analogue was reacted with a suitable isocyanate (eg. ethyl isocyanate) in an organic solvent (eg. 1,4-dioxane).

General Method B

Step a: The heterocyclic ester was formed by the condensation of 1,3-acetonedicarboxylate with an orthoformate (eg. trimethylorthoformate) in acetic anhydride followed by treatment with ammonia.

Step b: (i)/(ii) The dihydroxy analogue (i) or pyrimidine analogue (ii) was subjected to dehydrative chlorination using a suitable reagent (eg. POCl3).

Step c: The dichloro analogue was subjected to Buchwald coupling conditions with a suitable urea (eg. N-ethyl urea) in the presence of a palladium catalyst (eg. Pd(OAc)2), a co-catalyst (eg. Xantphos) and a base (eg. KOtBu) in a suitable organic solvent (eg. 1,4-dioxane).

Step d: The dichloro analogue was subjected to selective displacement by a suitable amine (eg. aniline), in the presence of a base (eg. NaH) or an acid (eg. HCl) in an organic solvent (eg. DMF).

Step e: The amino-chloro analogue was subjected to displacement conditions with a suitable protected amine (eg. p-methoxybenzylamine) in a suitable organic solvent (eg. toluene).

Step f: The protected amine was deprotected using standard conditions (eg. TFA+Et3SiH in DCM for a PMB group).

Step g (i): The amino analogue was reacted with a suitable isocyanate (eg. N-ethyl isocyanate) to form a urea analogue.

Step g (ii): The chloro-urea analogue was subjected to selective displacement by a suitable amine (eg. m-toluidine) in the presence of a base (eg. NaH) or an acid (eg. HCl) in an organic solvent (eg. DMF).

Step h: The ester analogue was hydrolysed to an acid with a suitable aqueous base (eg. NaOH) in a suitable solvent (eg. EtOH).

Step i: The acid was subjected to amide coupling conditions using common coupling reagents (eg. EDCI+HOBt) with a suitable amine (eg. m-toluidine) in an organic solvent (eg. DMF).

Step j: The chloro-amino analogue was subjected to Buchwald coupling conditions with a suitable urea (eg. N-ethyl urea) in the presence of a palladium catalyst (eg. Pd(OAc)2), a co-catalyst (eg. Xantphos) and a base (eg. KOtBu) in a suitable organic solvent (eg. 1,4-dioxane).

Step k: The ester was reacted with a suitable amine (eg aniline) in the presence of a Lewis acid (eg. trimethylaluminium) in a suitable solvent (eg. THF).

General Method C

where R in the general reaction scheme represents an acid (CO2H), an ester (CO2alkyl) or the group —X—R1where X and R1are as previously defined.

Step a: The dichloro acid was converted to an amide by activation to the acid chloride with a suitable reagent (eg. thionyl chloride) in an organic solvent (eg. THF) with catalytic DMF, followed by reaction with a suitable amine (eg. 3-aminopyridine) in the presence of a base (eg. TEA) in an organic solvent (eg. THF).

Step b: (i) The dichloro analogue was subjected to selective displacement by a suitable amine (eg. aniline), in the presence of a base (eg. NaH) or an acid (eg. HCl) in an organic solvent (eg. DMF).

Step b (ii): The dichloro analogue was subjected to Buchwald coupling conditions with a suitable urea (eg. N-ethyl urea) in the presence of a palladium catalyst (eg. Pd(OAc)2), a co-catalyst (eg. Xantphos) and a base (eg. KOtBu) in a suitable organic solvent (eg. 1,4-dioxane).

Step c (i): The chloro-amino analogue was subjected to Buchwald coupling conditions with a suitable urea (eg. N-ethyl urea) in the presence of a palladium catalyst (eg. Pd(OAc)2), a co-catalyst (eg. Xantphos) and a base (eg. KOtBu) in a suitable organic solvent (eg. 1,4-dioxane).

Step c (ii): The chloro-urea analogue was subjected to selective displacement by a suitable amine (eg aniline), in the presence of a base (eg. NaH) or an acid (eg. HCl) in an organic solvent (eg. DMF).

In one embodiment there is provided an intermediate of general formula (II):

where R′ is a halo or NH2group and R1, R2, X, Z1, Z2and Z3are as previously defined for formula (I).

Accordingly, there is provided a process for the manufacture of a compound of formula (I) via an intermediate of formula (II). In one embodiment, R′ is halo and the process comprises the step of coupling said intermediate of formula (II) with an N—C1-6alkyl urea under Buchwald coupling conditions. In another embodiment, R′ is NH2and the process comprises the step of reacting said intermediate of formula (II) with a C1-6alkyl isocyanate under suitable reaction conditions.

In another embodiment there is provided an intermediate of general formula (III):

where R″ is H or C1-6alkyl and R2, R3, Z1, Z2and Z3are as previously defined for formula (I).

Accordingly, there is provided a process for the manufacture of a compound of formula (I) wherein X—R1is C(═O)NR5R6or C(═O)NRaRb, via an intermediate of formula (III) wherein the process comprises the step of reacting said intermediate of formula (III) with a reagent of formula NHR5R6or NHRaRbunder amide formation conditions such as amide coupling (e.g. using coupling reagents such as HOBt/EDCI, HATU, HBTU) or acid catalysis (e.g. Lewis acid); or alternatively, activating the —CO2R″ group of formula (III) to form an acid chloride or acid anhydride thereof then reacting with said reagent of formula NHR5R6or NHRaRb.

In another embodiment there is provided an intermediate of general formula (IV):

Accordingly, there is provided a process for the manufacture of a compound of formula (I) via an intermediate of formula (IV) wherein the process comprises the step of reacting said intermediate of formula (IV) under nucleophilic displacement/substitution conditions (e.g. in the presence of base or acid/base or acid catalysed) with a reagent of formula NH2R2.

EXAMPLES

Those skilled in the art will appreciate that the invention described herein is susceptible to variations and modifications other than those specifically described. The invention will now be described without limitation by reference to the examples which follow.

Compound Synthesis

1H NMR spectra were recorded on either a Brüker Avance DRX 400, AC 200 or AM 300 spectrometer. Spectra were recorded in deuterated solvents (CDCl3, MeOD, DMSO-d6, CD3CN, or Acetone-d6) using the residual solvent peak as a reference. Chemical shifts are reported on the δ scale in parts per million (ppm) using the following conventions to assign the multiplicity: s (singlet), d (doublet), t (triplet), q (quartet), p (pentet), m (multiplet) and prefixed br (broad). Mass spectra (ESI) were recorded on either a Micromass Platform QMS or Thermo Finnigan LCQ Advantage spectrometer. Flash chromatography was performed on 40-63 μm silica gel 60 (Merck No. 9385). Automated flash chromatography was performed either on a Combi-Flash™ purification system using Combi-Flash™ silica gel columns or on a Biotage SP4 purification system using either GraceResolv™ silica gel cartridges, Grace Reveleris™ C-18 reverse phase silica gel cartridges or Biotage SNAP™ C-18 reverse phase silica gel cartridges. Preparative HPLC was carried out using either a Gilson 322 pump with a Gilson 215 liquid handler and a HP1100 PDA detector or an Agilent 1200 Series mass detected preparative LCMS using a Varian XRs C-18 100×21.2 mm column. Unless otherwise specified, the HPLC systems employed Phenomenex C8(2) columns using either acetonitrile or acetonitrile containing 0.06% TFA in water, water containing 0.1 TFA or water containing 0.1% formic acid.

During the reactions a number of the moieties may need to be protected. Suitable protecting groups are well known in industry and have been described in many references such as Protecting Groups in Organic Synthesis, Greene T W, Wiley-Interscience, New York, 1981.

All amines used were commercially available unless otherwise stated. The following amines were prepared synthetically.

n-BuLi (1.15M in hexane) (10.1 mL, 11.6 mmol) was added dropwise to a solution of diisopropylamine (1.64 mL, 11.6 mmol) in THF (20 mL) in a dry ice/acetone bath. The mixture was stirred and warmed to ˜−50° C. before being cooled again and methyl 2-methylpropanoate (1.3 mL, 11 mmol) was added over 5 min. The mixture was stirred for 30 min before a solution of the nitrobenzyl bromide (2 g in 15 mL THF) was added dropwise over 20 min. The temperature was kept below −65° C. during the addition then left in the cool bath to warm slowly to RT and stirred for 16 hr. The mixture was quenched with NH4Cl (sat.) and left at RT for 9 days. The quenched reaction mixture was diluted with water and EtOAc and extracted into EtOAc (3×40 mL). The organics were combined, dried with brine, then solid MgSO4, filtered and the solvent removed to afford a crude oil. The oil was dissolved in ˜2 mL DCM and applied to a silica column to afford (i) 1.4 g (64%).1H NMR (400 MHz, CDCl3) δ 8.13 (d, J=8.8 Hz, 2H), 7.27 (d, J=9.6 Hz, 2H), 3.67 (s, 3H), 2.96 (s, 2H), 1.21 (s, 6H).

Compound (i) (736 mg, 3.06 mmol) was dissolved in MeOH (15 mL) at RT and this solution degassed with N2. Palladium on carbon (10%) (25 mg) was suspended in water/MeOH (0.5 mL/2 mL) and added to the substrate solution. The mixture was again degassed with N2and then vacuum/flushed with H2. The mixture was stirred under a H2balloon overnight at RT. The mixture was filtered through celite, washed with MeOH and the filtrate evaporated to dryness to afford a clear oil which was placed under high vacuum for 1 h to afford the desired product (ii), 620 mg.1H NMR (400 MHz, CDCl3) δ 6.88 (d, J=8.3 Hz, 2H), 6.60 (d, J=8.3 Hz, 2H), 3.64 (s, 3H), 2.74 (s, 2H), 1.15 (s, 6H).

Sodium hydrosulphite (2.08 g, 10.15 mmoll) in water (7.5 mL) was added to a refluxing solution of (i) (1 g, 4.06 mmol) in EtOH (15 mL). After 5 minutes another solution of sodium hydrosulphite (2.08 g, 10.15 mmoll) in water (7.5 mL) was added. The mixture refluxed for 5 min After that time the mixture was poured onto water. The reaction mixture was extracted with EtOAc and DCM/iPrOH. The organic fractions were dried (MgSO4), filtered and concentrated in vacuo to give a residue that was purified by flash chromatography on silica gel, eluting with a MeOH gradient in DCM to afford the desired product (ii) (480 mg).1H NMR (400 MHz, DMSO) δ 7.06 (dd, J=2.5, 1.9 Hz, 1H), 6.96-6.90 (m, 3H), 6.59-6.53 (m, 2H), 6.22 (dd, J=3.9, 2.6 Hz, 1H), 5.25 (s, 2H), 3.60 (s, 3H).

A solution of (i) (205 mg, 0.92 mmol) in 50:50 acetic acid:ethanol (10 mL) was treated with zinc dust (370 mg, 5.53 mmol) then stirred at RT under N2for 4 hr. The mixture was concentrated under vacuum and the residue suspended in EtOAc (20 mL). The solution was filtered to remove undissolved zinc, and then washed with water (50 mL). The aqueous layer was neutralised then extracted with EtOAc (3×20 mL). The organic extracts were combined and concentrated to give (ii). Sample was used in subsequent reactions without further purification.1H NMR (400 MHz, CDCl3) δ 8.20-8.15 (m, 2H), 7.55-7.50 (m, 2H), 3.76-3.70 (m, 4H), 3.59 (s, 2H), 2.49-2.42 (m, 4H).

4-iodoaniline (400 mg, 1.8263 mmol) was mixed with sodium L-ascorbic acid (90 mg, 0.46 mmol) in DMSO (25 mL). A solution of sodium azide (241 mg, 3.65 mmol) in water (6.5 mL) was added followed by N,N′-dimethylethane-1,2-diamine (30 mg, 0.4 mmol) and copper iodide (30 mg, 0.2 mmol). The mixture was then heated at 100° C. for 6 h. The mixture was then mixed with a large amount of water (80 mL) and then extracted with EtOAc (3 times). The organics were dried (MgSO4), filtered and concentrated in vacuo to give a residue that was purified by flash chromatography (silica, eluting with MeOH in DCM) to give 4-azidoaniline (150 mg).1H NMR (400 MHz, DMSO) δ 6.81-6.75 (m, 2H), 6.63-6.57 (m, 2H), 5.13 (s, 2H).

Example(s) of General Method A

Concentrated sulfuric acid (98%, 0.5 mL) was added dropwise to a stirred suspension of compound iii (0.020 g, 0.130 mmol) in water (1 mL). The reaction mixture was heated to 100° C. for 18 h, cooled to room temperature and added dropwise to a slurry of ice in saturated sodium bicarbonate solution (2 mL). The pH after addition was pH-2. The resulting precipitate was filtered, washed with water (2 mL) and air-dried to give compound iv. (0.019 g, 0.110 mmol, 84%) as a colourless powder, [M+H]+m/z=173.0.

Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride and 1-hydroxybenzotriazole monohydrate were added to a stirred solution of compound iv in DMF (3 mL) at room temperature. After 15 min, the m-toluidine was added and the reaction mixture stirred at the specified temperature for 24 h. The mixture was cooled to room temperature, poured onto water and extracted with EtOAc (3×30 mL). The combined organic phase was washed with water (20 mL), saturated aqueous sodium bicarbonate (20 mL) and brine (2×20 mL), dried (MgSO4), and reduced in vacuo to give the v as a crude brown gum, which was used in the next step without further purification.

Example(s) of General Method B

(E. Wallace, B. Hurley, H. W. Yang, J. Lyssikatos and J. Blake. Int. Pat. App. WO200523759, 2005) Trimethylorthoformate (5.95 mL, 54.4 mmol) was added to a solution of diethyl 1,3-acetonedicarboxylate (i) (8.98 mL, 49.5 mmol) in acetic anhydride (9.34 mL, 99.0 mmol). The reaction mixture was heated under N2(g) to 120° C. for 2 h, cooled to room temperature and the excess solvent removed in vacuo. The resulting dark orange residue was cooled to 0° C. and treated with an aqueous solution of ammonia (33%, 4 mL) followed by water (15 mL). The mixture was stirred at room temperature for 18 h and the resulting heavy tan precipitate filtered, washed with water (20 mL) and air dried to give compound ii. (5.00 g, 27.3 mmol, 55%) as a light tan solid, [M+H]+m/z=184.1.

(Wallace, E., et. al., ibid.) A stirred suspension of compound ii (1.40 g, 7.67 mmol) in phosphorus (V) oxychloride (15 mL) was heated to 110° C. for 2.5 h with a guard tube (CaCl2) fitted. The reaction mixture was cooled to room temperature, reduced in vacuo and the resulting dark brown residue taken up in a small volume of DCM (˜5 mL) and transferred dropwise onto a slurry of ice in water (250 mL) whilst stirring vigorously. The aqueous mixture was extracted with EtOAc (3×100 mL), the organic extracts combined, dried (MgSO4) and evaporated to dryness to afford the crude product as an orange gum. Column chromatography (SiO2), eluting with 15:1 Hexanes-EtOAc, afforded compound iii. (1.33 g, 6.14 mmol, 79%) as a colourless oil; [M+H]+m/z=220.0.

(Wallace, E., et. al., ibid.) m-toluidine (0.47 mL, 4.34 mmol) and conc. HCl (1 drop) were added to a solution of compound iii (1.00 g, 4.57 mmol) in ethanol (10 mL). The reaction mixture was heated at 80° C. for 3 h, cooled to room temperature and partitioned between water (15 mL) and EtOAc (20 mL). The aqueous phase was extracted with EtOAc (3×20 mL). The combined organic phase was dried (MgSO4) and reduced in vacuo to give the crude product as a brown oil. Column chromatography (SiO2), eluting with 12:1 Hexanes-EtOAc, gave compound iv. (0.670 g, 2.31 mmol, 51%) as a light orange oil, which solidified on standing, [M+H]+m/z=291.0.

Amide Coupling Methods

All amines used were commercially available unless otherwise stated.

General Amide Coupling Method 1

1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.092 g, 0.480 mmol) and 1-hydroxybenzotriazole monohydrate (0.073 g, 0.480 mmol) were added to a stirred solution of the appropriate acid (0.100 g, 0.320 mmol) in DMF or DMA (3 mL) at room temperature. After 15 min, the appropriate amine (0.480 mmol) was added and the reaction mixture stirred at the specified temperature for 24 h. The mixture was treated with water (5 mL) and the resulting colourless precipitate filtered, washed with water, air-dried and recrystallized from EtOH to give the desired nicotinamide. Alternatively, the mixture was cooled to room temperature, poured onto water and extracted with DCM or EtOAc (3×30 mL). The combined organic phase was washed successively with water (20 mL), saturated aqueous sodium bicarbonate (20 mL) and brine (2×20 mL), dried (MgSO4), and reduced in vacuo to give the crude product which could be purified by column chromatography, trituration or recrystallization as required.

General Amide Coupling Method 1 was used to make Compounds 3 and 4 as follows.

N,N-Diethylaniline (1.5 mL, 9.45 mmol) was added to a suspension of 5-carbethoxyuracil, i (1.00 g, 5.43 mmol), in phosphorus (V) oxychloride (10 mL). The mixture was heated under reflux for 2 h, cooled to room temperature and reduced in vacuo. The resulting syrupy residue was transferred carefully onto stirred ice water (50 mL). After 1 h, the resulting beige solid was collected by filtration, washed with water (10 mL) and air-dried to give compound ii (0.97 g, 4.41 mmol, 81%) as a light beige powder.1H NMR (300 MHz, CDCl3): δ 9.04 (1H, s), 4.46 (2H, q, J 7.2), 1.43 (3H, t, J 7.2); [M+H]+m/z=221.0.

To a solution of ii (6.40 g, 23.18 mmol) in 1,4-dioxane (200 mL) was added N-ethylurea (2.60 g, 29.0 mmol) followed by Cs2CO3(11.50 g, 34.80 mmol). The resulting solution was purged with nitrogen for 15 min followed by addition of Pd(OAc)2(0.16 g, 0.70 mmol) and Xantphos (0.81 g, 1.40 mmol). The reaction mixture was again purged with nitrogen for 15 min and then heated at 80° C. for 16 h. The reaction mass was cooled to room temperature and filtered through a celite bed. The celite bed was washed with EtOAc and the combined filtrates concentrated under reduced pressure. Water was added to the residue and extracted with EtOAc (3×20 mL). The combined organic phase was washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude residue was purified over silica gel (60-120 M, 50-75% EtOAc-hexane) to obtain a solid residue. This was purified further by trituration with 25% ether-hexane to afford compound iii as an off-white solid (7.0 g, 92%).1H-NMR (400 MHz, DMSO-d6): δ 9.14 (s, 1H) and 9.64 (s, 1H), 8.61 (s, 1H), 7.70 (br s, 1H), 7.27-7.45 (m, 5H), 7.21 (t, J=7.20 Hz, 1H), 4.32 (q, J=7.20 Hz, 2H), 3.11 (m, 2H), 1.34 (t, J=7.20 Hz, 3H), 1.04 (t, J=7.20 Hz, 3H). [M+H]+m/z=329.14.

To a solution of iii (0.90 g, 2.74 mmol) in MeOH (25 mL) was added a solution of NaOH (0.55 g, 13.70 mmol) in H2O (5 mL). The resulting solution was heated at 70° C. for 3-4 h then cooled to RT and the solvent removed in vacuo. Water was added to the residue and this mixture extracted with EtOAc (2×50 mL). The organic layer was discarded, and the aqueous portion was carefully acidified (under ice-cooling) with 6N HCl till pH 5. The resulting precipitate was filtered, washed with ice-cold water and ether. The off-white solid thus obtained was dried under high vacuum to obtain compound iv (0.70 g, 85%).1H-NMR (400 MHz, DMSO-d6): δ10.60 (br s, 1H), 9.07 (br s, 1H), 8.55 (s, 1H), 8.0 (br s, 1H), 7.13-7.42 (m, 6H), 3.12 (m, 2H), 1.05 (t, J=7.20 Hz, 3H); [M+H]+m/z=301.21.

Amide Coupling Methods

All amines used were commercially available unless otherwise stated.

General Amide Coupling Method 1

As described in examples for Scheme 3 was used to make Compound 8 as follows.

General Amide Coupling Method 2

To an ice-cold solution of 6-(3-ethylureido)-4-(phenylamino)nicotinic acid (50 mg, 0.16 mmol, 1.0 eq) in DMF (2.0 mL) was added HBTU (1.50 eq) followed by DIPEA (3.0 eq) and finally the appropriate amine (1.20 eq). The resulting reaction mixture was stirred overnight at room temperature. The reaction mass was then poured onto the ice-cold water followed by extraction with EtOAc (3 times). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified over silica gel (60-120 M, 1-2.5% MeOH-DCM) to obtain the desired product. General Amide Coupling Method 2 was used to make Compound 9 as follows.

General Amide Coupling Method 3

To an ice-cold solution of 6-(3-ethylureido)-4-(phenylamino)nicotinic acid (50 mg, 0.16 mmol, 1.0 eq) in DMF (2.0 mL) was added HATU (1.50 eq) followed by HOBt (1.50 eq), DIPEA (1.50 eq) and finally the appropriate amine (1.50 eq). The resulting reaction mixture was stirred overnight at room temperature. The reaction mass was then poured onto the ice-cold water followed by extraction with EtOAc (3 times). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified over silica gel (60-120 M, 1-2.5% MeOH-DCM) to obtain the desired product.

General Amide Coupling Method 3 was used to make Compound 10 as follows.

General Amide Coupling Method 4

An ice-cold solution of methane sulfonyl chloride (18 μL, 0.23 mmol) in DMA (2.0 mL) was stirred for 10 min followed by sequential drop wise addition of a solution of the appropriate acid (0.16 mmol) in DMA (5.0 mL) and 2,6-lutidine (55.4, 0.46 mmol). The resulting reaction mixture was stirred at 0° C. for 30 min followed by addition of a solution of the appropriate aniline (0.25 mmol) in DMA (1.0 mL). The reaction mass was further stirred at 0° C. for 10 min and then heated at 50° C. for 4 h. The reaction mass was then cooled to 0-5° C. and then quenched with H2O (5.0 mL) followed by addition of conc. HCl (0.50 mL). The resulting solution was stirred for 5 min followed by extraction with EtOAc (3×50 mL). The combined organics was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified via chromatography or crystallisation as appropriate.

General Amide Coupling Method 4 was used to make Compound 11 as follows.

General Amide Coupling Method 5

To an ice-cold suspension of 6-(3-ethylureido)-4-(phenylamino)nicotinic acid (50 mg, 0.16 mmol) in dichloromethane (5 mL) was added oxalyl chloride (0.082 mL, ˜6 eq.) followed by a catalytic amount of DMF (0.005 mL). The mixture was allowed to warm to RT and stirred for 16 h. The mixture was concentrated in vacuo and the yellow residue then dissolved in dichloromethane (2.5 mL). This solution was added dropwise to a solution of the appropriate amine in pyridine (1 mL) at 0° C. The mixture was allowed to warm to room temperature and stirred for 3 h. The reaction mixture was quenched with NH4Cl (sat.), diluted with water and extracted into EtOAc (3×20 mL). The organics were combined, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by normal or reverse phase chromatography to afford the amide product.

General Amide Coupling Method 5 was used to make Compound 12 as follows.

Compound 112 was formed from a Weinreb amide, compound 83, as follows.

4-anilino-6-(ethylcarbamoylamino)pyridine-3-carboxylic acid (i) (200 mg, 0.67 mmol), dimethylhydroxylamine hydrochloride (65 mg, 0.67 mmol), 4-dimethylaminopyridine (81 mg, 0.67 mmol) and N-hydroxybenzotriazole (90 mg, 0.67 mmol) were added to a dry RBF which was flushed with N2. DMF (1.5 mL) was added and the mixture stirred. 3-(ethyliminomethyleneamino)-N,N-dimethyl-propan-1-amine hydrochloride (150 mg, 0.80 mmol) was dissolved in DMF (1.5 mL) in a separate vial and this solution added to the reaction mixture at RT. The mixture was stirred overnight at RT.

After 8 days at RT, the mixture was diluted with water and extracted into EtOAc (3×30 mL) and the organics dried with brine then Na2SO4. The cloudy EtOAc suspension (conatins some unreacted acid) was filtered and the clear filtrate evaporated to dryness. The residue was dissolved in DCM (2 mL) and applied to a silica column, eluting with EtOAc/heptane, to afford Compound 83 (90 mg).

Compound 83 (15 mg, 0.044 mmol) was dissolved in dry THF (0.8 mL) and this solution added to the phenyl magnesium bromide (1M, 0.2 mL, 0.20 mmol) at 0° C. The mixture was stirred and allowed to warm slowly to RT. The mixture was quenched with MeOH/HCl (2M) (1 mL:0.1 mL) then NH4Cl (sat.) added and the mixture diluted with water and EtOAc (pH of aqueous ˜7). The mixture was extracted into EtOAc and the organics combined and dried with brine then Na2SO4. The solvent was removed to afford 20 mg crude residue. This was dissolved in DCM (2 mL) and applied to a silica column, eluting with EtOAc/heptane, to afford Compound 112 (13 mg).).

Example(s) of General Method C

To a suspension of 4,6-Dichloropyridine-3-carboxylic acid (5.0 g, 26 mmol) in THF (100 mL) was added thionyl chloride (4 mL, 52 mmol) and catalytic DMF (5 drops). The solution was heated at 60° C. for 20 minutes. The mixture was concentrated in vacuo to afford the acid chloride as a yellow residue. The acid chloride was dissolved in THF (50 mL) was and added to a cooled (icewater bath) solution of triethylamine (11 mL, 78 mmol) and 3-aminopyridine (4.9 g, 52 mmol) in THF (50 mL). The mixture was allowed to warm to room temperature while stirring for 40 h. The reaction mixture was concentrated, diluted with water (100 mL) and washed with DCM (3×100 mL). The organic extracts were combined, washed with brine (2×20 mL), dried over MgSO4and concentrated. The resultant residue was purified by flash chromatography (120 g GraceResolv silica cartridge, 50-90% EtOAc in cyclohexane) to afford compound ii as a white crystalline solid (3.52 g, 50%).). [M+H]+m/z=268.13, 270.11.

Compound ii (1.0 g, 3.7 mmol) and N-ethylurea (362 mg, 4.1 mmol) were dissolved in degassed dioxane (50 mL) under an atmosphere of argon. Potassium tert-butoxide (628 mg, 5.6 mmol), Xantphos (129 mg, 0.22 mmol) and palladium(0)bis(dibenzylideneacetone) (65 mg, 0.11 mmol) were added sequentially. The mixture was heated at 100° C. with stirring under argon for 16 h. Additional palladium(0)bis(dibenzylideneacetone) (65 mg, 0.11 mmol) and N-ethylurea (560 mg, 6.4 mmol) were added and the mixture heated at reflux for 5 h. The mixture was cooled to RT, diluted with acetonitrile (100 mL) and then adsorbed on to silica by concentration in vacuo. The crude product was purified by flash chromatography (40 g GraceResolv silica cartridge, 0-10% MeOH in EtOAc) to afford iii as a light brown solid (244 mg, 20%). [M+H]+m/z=320.05.

It will be understood that the particular examples which are described herein may undergo further functionalization using methods known in the art, for example, including, but not limited to the following.

3-[4-[[4-anilino-6-(ethylcarbamoylamino)pyridine-3-carbonyl]amino]phenyl]propanoic acid (Compound 78) (14.5 mg, 0.032 mmol) and dimethyl hydroxylamine (3.8 mg, 0.039 mmol) were dissolved in DMF (1 mL) and the DIPEA (17 μL, 0.098 mmol) added, followed by [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]-dimethyl-ammonium hexafluorophosphate (15 mg, 0.039 mmol). The mixture was stirred at RT. After 1 h the mixture was diluted with EtOAc and evaporated to dryness. The residue was dissolved in DCM and applied to a silica column, eluting with MeOH/DCM, to afford Compound 123 (8 mg).

Methylmagnesium chloride (100 μmol, 0.3 mmol) was added to THF (1 mL) and cooled to 0° C. Compound 123 (8 mg, 0.016 mmol) was dissolved in THF (1 mL) and this solution added dropwise to the Grignard at 0° C. The mixture was allowed to warm slowly to RT over 1 h then quenched with NH4Cl and diluted with water and EtOAc. The mixture was extracted into EtOAc and the organics combined and dried with brine then Na2SO4then evaporated to dryness. The residue was applied to a silica column in DCM (1 mL) and MeOH (2 drops) and eluted with MeOH in DCM to afford Compound 122 (4 mg).

The following compounds were similarly prepared with reference to the general method(s) and/or examples previously described.

Biological Data

On-Target Enzyme Assay: Determination of Gyrase ATPase Activity

Gyrase converts ATP into ADP and inorganic phosphate. The released phosphate can be detected by the addition of malachite green solution and measured by monitoring the increase in absorbance at 600 nm. The ATPase assay is carried out in a buffer containing 10 nM Gyrase enzyme (A2B2complex fromStaphylococcus aureus), 0.08 mg/mL double-stranded DNA, 40 mM HEPES.KOH pH 7.6, 500 mM K glutamate, 10 mM Mg acetate, 2 mM DTT, 0.01 mg/mL BSA, 1 mM ATP and 5% DMSO solution containing the inhibitor. Alternatively, the ATPase assay is carried out in a buffer containing 10 nM Gyrase enzyme (A2B2complex fromEscherichia coli), 0.08 μg/mL ssDNA, 35 mM Tris pH 7.5, 24 mM KCl, 2 mM MgCl2, 6.5% Glycerol, 2 mM DTT, 0.1 mg/mL BSA, 1 mM ATP and 1% DMSO solution containing the inhibitor. The reaction is started by adding ATP to a final concentration of 1 mM and allowed to incubate at 30° C. for 60 minutes. The reaction is stopped by adding 200 μL of malachite green solution (0.034% malachite green, 10 mM ammonium molybdate, 1 M HCl, 3.4% ethanol, 0.01% tween 20). Colour is allowed to develop for 5 minutes and the absorbance at 600 nm is measured spectrophotometrically. The IC50values are determined from the absorbance readings using no compound and no enzyme controls.

The compounds of the invention demonstrated on target enzyme activity with the majority of compounds tested showing Gyrase ATPase activity IC50values equal to or less than 10 μg/mL.

Surprisingly when the comparator compounds A, B, C and D below having a phenyl core in place of a heteroaryl core were tested in the same enzyme assay they did not demonstrate any measurable on-target activity (i.e. IC50≧200 μg/mL).

Bacterial Assay

Determination of Antibacterial Activity

Compounds of the invention were tested for antimicrobial activity by susceptibility testing in liquid or on solid media. MICs for compounds against each strain were determined by the broth microdilution or agar dilution method according to the guidelines of the Clinical Laboratories and Standards Institute, formerly the National Committee for Clinical Laboratory Standards (Clinical Laboratories and Standards Institute.Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard—Seventh Edition. Document M7-A7. CLSI, Wayne, Pa., 2006; Clinical Laboratories and Standards Institute. The Gram positive bacterial strains tested includeS. aureus(Staphylococcus aureus(Isolate ID ATCC 29213)),E. faecalis(Enterococcus faecalis(Isolate ID ATCC 29212)) andS. pyogenes(Streptococcus pyogenes(Isolate ID ATCC 51339)). The Gram negative bacterial strains tested includeH. influenzae(Haemophilus influenzae(Isolate ID ATCC 49247)).

Gram Positive Antibacterial Activity

Representative compounds of the invention were tested for activity against one or more Gram positive bacterial strains and the results are presented in Tables 2, 3 and 4.

Gram Negative Antibacterial Activity

Selected compounds of the invention were also tested for activity against the Gram negative bacterial strainH. influenzae(ATCC 49247) and the results are presented in Table 5.