[0001] The present invention relates to compounds thereof that have the ability to inhibit lysine biosynthesis via the diaminopimelate pathway in certain organisms. As a result of this activity these compounds can be used in applications where inhibition of lysine biosynthesis is useful, including the use of the compounds as herbicides and anti-bacterial agents.

Background of Invention

[0002] In the 20 ^th century, there has been widespread use by man of chemical agents for a number of applications including as pharmaceutical agents, herbicides, pesticides and the like. Unfortunately, due to the widespread use of these agents many compounds that demonstrated useful activities no longer work as the target species has developed some form of resistance to the active agent. Resistance to active agents is observed in respect of both anti-bacterial agents and herbicides.

[0003] The development of resistance in bacterial populations has been well documented and is the ability of bacteria to resist the effects of an agent previously used to treat that particular bacterial species. It is generally accepted that resistance arises through one of three ways namely (1) natural resistance in certain types of bacteria, (2) genetic mutation of a bacteria to a resistant form and/or (3) by one species acquiring resistance from another. Bacterial resistance can appear spontaneously because of random mutations; although it is more common that the resistance develops gradually over time. It is thought that the gradual build-up of resistance over time is as a result of overuse of anti-bacterial agents such as over prescription of anti-bacterial agents and patients not completing their course of medication.

[0004] The development and use of herbicides has had a significant impact on the ability to feed the ever growing world population. Herbicides have assisted farmers with weed management in crops and have also facilitated no-till crop production to conserve soil and moisture. Their use has therefore had a significant positive impact on crop yields and productivity per hectare.

[0005] Unfortunately, as with anti-bacterial agents, the repeated application of herbicides with the same mechanism of action to a crop or field has resulted in the development of herbicide-resistant weeds. It is thought that weeds develop herbicide resistance as a result of herbicide selection pressure whereby those weeds that have some form of resistance are favoured once the herbicide has been applied leading to a selection advantage for the resistant weed. [0006] As will be appreciated due to the development of both anti-bacterial and herbicide resistance, there is a continual need to develop new agents that can be used as replacement active agents for those agents that no longer work in the field due to the development of resistance. Accordingly, there is an ongoing need to develop new compounds or identify existing compounds that can be used as either anti-bacterial agents or herbicides.

[0007] One challenge in the development of active agents as either anti-bacterial agents or herbicides is to ensure that the agent developed has an acceptable safety profile upon exposure to humans as ideally the agent would be either non-toxic or minimally toxic to humans and preferably mammals as a whole.

[0008] With this in mind one attractive target for the development of agents of this type is the biosynthesis of the amino acid lysine and its immediate precursor meso-diaminopimelate (meso-DAP). This is an attractive pathway for study as whilst the lysine biosynthetic pathway occurs in plants and bacteria it does not occur in mammals. Mammals lack the ability to produce lysine biosynthetically and it is therefore one of the 9 essential amino acids that must be provided from a dietary source. The occurrence of the lysine biosynthetic pathway in plants and bacteria but not in mammals suggest that specific inhibitors of this biosynthetic pathway would display novel activity and low mammalian toxicity.

[0009] Accordingly, it would be desirable to develop inhibitors of the lysine biosynthetic pathway as it would be anticipated that these would potentially have interesting anti-bacterial and/or herbicidal activity.

Summary of the Invention

[0010] The present applicants have therefore studied the diaminopimelate pathway in order to identify potential inhibitors of lysine biosynthesis that could potentially find application as either anti-bacterial and/or herbicidal agents.

[001 1] As a result of these studies the applicants have identified compounds that have the ability to inhibit lysine biosynthesis.

[0012] Accordingly in one embodiment the present invention provides a compound of Formula (1):

Formula (1) [0013] wherein

[0014] X is selected from the group consisting of:

[0015] Z is selected from the group consisting of NCH ₃ and NR ^a ; [0016] at each instance R ^a is H, or two R ^a on adjacent nitrogen atoms when taken together form a double bond;

[0017] R is a group of the formula:

— L-B

[0018] wherein L is a linking group containing from 3 to 11 atoms in the normal chain; [0019] B is a binding moiety containing at least one carbonyl group;

[0020] Ar is an optionally substituted C ₆ -Ci ₈ aryl or an optionally substituted

Ci-Ci ₈ heteroaryl group;

[0021] or a salt or N-oxide thereof.

[0022] As stated above the applicants have discovered that compounds of this type have the ability to inhibit lysine biosynthesis in an organism.

[0023] Accordingly, yet a further embodiment the present invention provides a method of inhibiting lysine biosynthesis in an organism in which the diaminopimelate biosynthesis pathway occurs, the method comprising contacting the organism with an effective amount of a compound of the Formula (1) as described above. [0024] As part of their studies into the inhibition of lysine biosynthesis and in the preparation of compounds of Formula (1) the applicants have also discovered that a family of known compounds are also inhibitors of lysine biosynthesis. These compounds are compounds of Formula (2):

Formula (2)

[0025] wherein R ⁵ is selected from the group consisting of H and CrCi ₂ alkyl;

[0026] m is an integer selected from the group consisting of 3, 4, 5, 6, 7 and 8.

[0027] Accordingly, yet a further embodiment the present invention provides a method of inhibiting lysine biosynthesis in an organism in which the diaminopimelate biosynthesis pathway occurs, the method comprising contacting the organism with an effective amount of a compound of the Formula (2) as described above.

[0028] Without wishing to be bound by theory it is felt that the compounds are active in inhibiting lysine biosynthesis by inhibiting the diaminopimelate (DAP) pathway in the organism. In particular it is thought that the compounds inhibit this pathway by inhibiting dihydrodipicolinate synthase (DHDPS) activity in the organism.

[0029] As a result of the ability of the compounds to inhibit the lysine biosynthetic pathway the applicants have also found that the compounds can be used as herbicides as the lysine biosynthetic pathway is an essential pathway in plants.

[0030] Accordingly, in yet an even further aspect the present invention provides a method for controlling undesired plant growth the method comprising contacting the plant with a herbicidal effective amount of a compound of the Formula (1) as described above.

[0031] Accordingly, in yet an even further aspect the present invention provides a method for controlling undesired plant growth the method comprising contacting the plant with a herbicidal effective amount of a compound of the Formula (2) as described above.

[0032] In addition as the compounds have the ability to inhibit the lysine biosynthetic pathway they can also be used as antibacterial agents.

[0033] In yet an even further aspect the present invention provides a method for treating a bacterial infection in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of Formula (1) as described above. [0034] In yet an even further aspect the present invention provides a method for treating a bacterial infection in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of Formula (2) as described above.

[0035] In the methods of the present invention the bacteria may be a Gram-positive bacteria or a Gram-negative bacteria.

Brief Description of Drawings

[0036] Figure 1 shows the diaminopimelate biosynthesis pathway in bacteria and plants.

[0037] Figure 2 shows the structures of meso-DAP (A) and lysine (B).

[0038] Figure 3 shows the first step in the diaminopimelate biosynthesis pathway catalysed by DHDPS.

[0039] Figure 4 shows DHDPS enzyme structures of the head-to-head dimer-of-dimers observed for most bacterial species (A), back-to-back dimer-of-dimers observed for plant species (B), and dimeric form observed for some bacterial species (C), where a, b, c and d refers to monomeric units of the protein.

Detailed Description

[0040] In this specification a number of terms are used that are well known to a skilled addressee. Nevertheless for the purposes of clarity a number of terms will be defined.

[0041] Throughout the description and the claims of this specification the word“comprise” and variations of the word, such as“comprising” and“comprises” is not intended to exclude other additives, components, integers or steps.

[0042] The term “subject in need thereof” means a human or an animal that has the condition referred to. For example“treating a bacterial infection in a subject in need thereof” implies that the subject has a bacterial infection.

[0043] The term “effective amount” means an amount sufficient to achieve a desired beneficial result. In relation to a herbicide an effective amount is an amount sufficient to control undesired plant growth. In relation to a bacterial infection an effective amount is an amount effective to achieve a desired clinical benefit to the subject.

[0044] The term“inhibit” and variations thereof such as“inhibiting” means to prevent, block or reduce the function of the thing being inhibited. The term does not require complete inhibition with a reduction of activity at least 50% being considered inhibition. [0045] The term “controlling” in relation to plant growth means to reduce or eliminate growth of the plant. This may involve killing the plant but also includes within its scope stunting or reducing plant growth.

[0046] The term“or a salt thereof” refers to salts that retain the desired biological activity of the above-identified compounds, and include acid addition salts and base addition salts. Suitable acceptable acid addition salts of compounds of Formula (I) may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, sulfuric, and phosphoric acid. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, heterocyclic carboxylic and sulfonic classes of organic acids, examples of which are formic, acetic, propanoic, pyruvic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, fumaric, maleic, alkyl sulfonic and arylsulfonic. Additional information on pharmaceutically acceptable salts can be found in P. H. Stahl and C.G. Wermuth Handbook of Pharmaceutical Salts, Properties, Selection, and Use, 2 ^nd Revised Edition, Wiley- VCH 2011. In the case of agents that are solids, it is understood by those skilled in the art that the inventive compounds, agents and salts may exist in different crystalline or polymorphic forms, all of which are intended to be within the scope of the present invention and specified formulae.

[0047] The term "organism" as used throughout the specification is to be understood to mean any contiguous living system and includes animals, plants, fungus, and bacteria.

[0048] The term "optionally substituted" as used throughout the specification denotes that the group may or may not be further substituted or fused (so as to form a condensed polycyclic system) with one or more non-hydrogen substituent groups. In certain embodiments the substituent groups are one or more groups independently selected from the group consisting of halogen, =0, =S, -CN, -N0 ₂ , -CF ₃ , -OCF ₃ , alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, heteroarylalkyl, arylalkyl, cycloalkyl alkenyl, heterocycloalkylalkenyl, arylalkenyl, heteroarylalkenyl, cycloalkyl heteroalkyl, heterocycloalkylheteroalkyl, arylheteroalkyl, heteroarylheteroalkyl, hydroxy, hydroxyalkyl, alkyloxy, alkyloxyalkyl, alkyloxycycloalkyl, alkyloxyheterocycloalkyl, alkyloxyaryl, alkyloxyheteroaryl, alkyloxycarbonyl, alkylaminocarbonyl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, phenoxy, benzyloxy, heteroaryloxy, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonylamino, sulfinylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, sulfinyl, alkylsulfinyl, arylsulfinyl, aminosulfinylaminoalkyl, -C(=0)OH, -C(=0)R ^e , -C(=0)OR ^e , C(=0)NR ^e R ^f , C(=NOH)R ^e , C(=NR ^e )NR ^f R ⁹ , NR ^e R ^f , NR ^e C(=0)R ^f , NR ^e C(=0)OR ^f , NR ^e C(=0)NR ^f R ⁹ , NR ^e C(=NR ^f )NR ⁹ R ^h , NR ^e S0 ₂ R ^f , -SR ^e , S0 ₂ NR ^e R ^f , -OR ^e OC(=0)NR ^e R ^f , OC(=0)R ^e and acyl, [0049] wherein R ^e , R ^f , R ⁹ and R ^h are each independently selected from the group consisting of H, C Csalkyl, C ₁ -C ₁₂ haloalkyl, C ₂ -C ₁₂ alkenyl, C ₂ -C ₁₂ alkynyl, CrC^heteroalkyl, C ₃ - C ₁₂ cycloalkyl, C ₃ -C ₁₂ cycloalkenyl, CrC^heterocycloalkyl, CrC^heterocycloalkenyl, C ₆ -C ₁₈ aryl, Ci-Ci ₈ heteroaryl, and acyl, or any two or more of R ^e , R ^f , R ⁹ and R ^h , when taken together with the atoms to which they are attached form a heterocyclic ring system with 3 to 12 ring atoms.

[0050] Examples of particularly suitable optional substituents include F, Cl, Br, I, CH ₃ , CH ₂ CH ₃ , CH ₂ NH ₂ , OH, OCH ₃ , SH, SCH _S , C0 ₂ H, CONH ₂ , CF ₃ , OCF ₃ , N0 ₂ , NH ₂ , and CN.

[0051] In the definitions of a number of substituents below it is stated that“the group may be a terminal group or a bridging group”. This is intended to signify that the use of the term is intended to encompass the situation where the group is a linker between two other portions of the molecule as well as where it is a terminal moiety. Using the term alkyl as an example, some publications would use the term “alkylene” for a bridging group and hence in these other publications there is a distinction between the terms“alkyl” (terminal group) and “alkylene” (bridging group). In the present application no such distinction is made and most groups may be either a bridging group or a terminal group.

[0052] "Alkyl" as a group or part of a group refers to a straight or branched aliphatic hydrocarbon group, preferably a Ci-Ci ₂ alkyl, more preferably a Ci-Ci ₀ alkyl, most preferably Cr C ₆ unless otherwise noted. Examples of suitable straight and branched CrC _s alkyl substituents include methyl, ethyl, n-propyl, 2-propyl, n-butyl, sec-butyl, t-butyl, hexyl, and the like. The group may be a terminal group or a bridging group.

[0053] "Alkoxy" refers to an alkyl-O- group in which alkyl is as defined herein. Preferably the alkoxy is a CrC ₆ alkoxy. Examples include, but are not limited to, methoxy and ethoxy. The group may be a terminal group or a bridging group.

[0054] "Alkoxyalkyl" refers to an alkoxy-alkyl- group in which the alkoxy and alkyl moieties are as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkyl group.

[0055] "Aryl" as a group or part of a group denotes (i) an optionally substituted monocyclic, or fused polycyclic, aromatic carbocycle (ring structure having ring atoms that are all carbon) preferably having from 5 to 12 atoms per ring. Examples of aryl groups include phenyl, naphthyl, and the like; (ii) an optionally substituted partially saturated bicyclic aromatic carbocyclic moiety in which a phenyl and a C _5.7 cycloalkyl or C _5.7 cycloalkenyl group are fused together to form a cyclic structure, such as tetrahydronaphthyl, indenyl or indanyl. The group may be a terminal group or a bridging group. Typically an aryl group is a C ₆ -C ₁₈ aryl group. [0056] “Haloalkyl” refers to an alkyl group as defined herein in which one or more of the hydrogen atoms has been replaced with a halogen atom selected from the group consisting of fluorine, chlorine, bromine and iodine. A haloalkyl group typically has the formula C _n H ₍ 2 _n+i-m) X _m wherein each X is independently selected from the group consisting of F, Cl, Br and I. In groups of this type n is typically from 1 to 10, more preferably from 1 to 6, most preferably 1 to 3. m is typically 1 to 6, more preferably 1 to 3. Examples of haloalkyl include fluoromethyl, difluoromethyl and trifluoromethyl.

[0057] “Heteroalky I" refers to a straight- or branched-chain alkyl group preferably having from 2 to 12 carbons, more preferably 2 to 6 carbons in the chain, in which one or more of the carbon atoms (and any associated hydrogen atoms) are each independently replaced by a heteroatomic group selected from S, O, P and NR’ where R’ is selected from the group consisting of H, optionally substituted CrC ₁₂ alkyl, optionally substituted C ₃ -C ₁₂ cycloalkyl, optionally substituted C ₆ -C ₁₈ aryl, and optionally substituted C C^heteroaryl. Exemplary heteroalkyls include alkyl ethers, secondary and tertiary alkyl amines, amides, alkyl sulfides, and the like. Examples of heteroalkyl also include hydroxyC Csalkyl, C CealkyloxyC Csalkyl, aminoCrC ₆ alkyl, CrC ₆ alkylaminoCi-Csalkyl, and di(Ci-C ₆ alkyl)aminoCi-C ₆ alkyl. The group may be a terminal group or a bridging group.

[0058] "Heteroaryl" either alone or part of a group refers to groups containing an aromatic ring (preferably a 5 or 6 membered aromatic ring) having one or more heteroatoms as ring atoms in the aromatic ring with the remainder of the ring atoms being carbon atoms. Suitable heteroatoms include nitrogen, oxygen and sulphur. Examples of heteroaryl include thiophene, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, naphtho[2,3-b]thiophene, furan, isoindolizine, xantholene, phenoxatine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, tetrazole, indole, isoindole, 1 H-indazole, purine, quinoline, isoquinoline, phthalazine, naphthyridine, quinoxaline, cinnoline, carbazole, phenanthridine, acridine, phenazine, thiazole, isothiazole, phenothiazine, oxazole, isooxazole, furazane, phenoxazine, 2-, 3- or 4- pyridyl, 2-, 3-, 4-, 5-, or 8- quinolyl, 1-, 3-, 4-, or 5- isoquinolinyl 1-, 2-, or 3- indolyl, and 2-, or 3-thienyl. A heteroaryl group is typically a C C ₁₈ heteroaryl group. The group may be a terminal group or a bridging group.

[0059] The term“normal chain” refers to the direct chain joining the two ends of a linking moiety. The number of atoms in the normal chain refers only to the atoms in the backbone of the chain and does not include the substituent atoms. By way of example if a linking moiety is a propyl group of formula: -CH ₂ CH ₂ CH ₂ - then this would be classified as containing 3 atoms in the normal chain.

[0060] As shown in Figure 1 the synthesis of lysine in bacteria via the diaminopimelate pathway starts from the combination of pyruvate (PYR) and L-aspartate semialdehyde (ASA) to synthesise 2,3,4,5-tetrahydro-/_,L-dipicolinic acid (HTPA) in the presence of dihydrodipicolinate synthase (DHDPS). HTPA will dehydrate and dihydrodipicolinate (DHDP) will generate via a non-enzymatic step. DHDP will be reduced by the enzyme dihydrodipicolinate reductase (DHDPR), which is a NAD(P)H dependent enzyme, to form 2,3,4,5-tetrahydrodipicolinate (THDP). THDP will then undergo one of the four sub-pathways; succinylase, acetylase, dehydrogenase or aminotransferase, which depends upon the species of bacteria and plants. All sub-pathways lead to the synthesis of a common, biologically important compound meso- /.,/. -2,6-diaminopimalate (meso-DAP). meso-DAP is then decarboxylated by the enzyme diaminopimelate decarboxylase (DAPDC) leading to the formation of lysine. Generated meso- DAP is used as a cross linking moiety in the peptidoglycan layer of the cell wall of Gram negative bacteria and also in Gram-positive bacteria such as Bacillus sp. Lysine also forms peptidoglycan cross-links in the bacterial cell wall of most Gram-positive bacteria and is used in the synthesis of proteins in both bacteria and plants. Accordingly, lysine is essential for cell function and viability of both bacteria and plants.

[0061] With reference to Figure 1 the first step of the diaminopimelate biosynthesis pathway requires the enzyme dihydrodipicolinate synthase (DHDPS). An expanded view of this first step is shown in Figure 3. As can be seen the step involves the combination of pyruvate (PYR) and /.-aspartate semialdehyde (ASA) in the presence of dihydrodipicolinate synthase (DHDPS) to form 2,3,4,5-tetrahydro-Z_,Z_-dipicolinic acid (HTPA). As this step in the diaminopimelate biosynthetic pathway is common to all bacteria and plants it was felt that it presented an attractive target in the development of inhibitors of lysine biosynthesis.

[0062] The enzyme dihydrodipicolinate synthase (DHDPS) was characterised in 1965, after purification from Escherichia coli ( E . coli). Following characterisation of the enzyme it has been extensively studied with crystal structure work of the enzyme having been carried out.

[0063] As can be seen from Figure 4 the quaternary structure of DHDPS in most bacterial species consists of four monomer units joining together in a manner that only one monomer interacts with two other monomers (Figure 4A). The tetramer structure, which is also known as a “head-to-head” dimer-of-dimers, has a large cavity filled with water. Two monomer interactions are tighter than the other two monomer interactions therefore they are known as a tight dimer interface and a weak dimer interface, respectively, as shown in Figure 4A. The active site of the enzyme is located at the tight dimer interface. In the active site of E. coli DHDPS, Threonine 44 and Tyrosine 133 are present, Tyrosine 107 interdigitates across the two monomers at the tight dimer interface giving rise to two active sites per dimer.

[0064] The structure of DHDPS in plants also consists of a tetramer, but the conformation is a“back-to-back” dimer-of-dimers (Figure 4B). DHDPS in some bacterial species, such as Staphylococcus aureus and Pseudomonas aeruginosa, exist as only a dimer consisting of a tightly bound dimer interface (Figure 4C).

[0065] As can be seen as the first step in the diaminopimelate biosynthesis pathway is common in plants and bacteria and thus represents an attractive target for compound development in the anti-bacterial and herbicide spaces.

[0066] As discussed above the applicants of the present invention have identified compounds that have the ability to inhibit lysine biosynthesis via the diaminopimelate pathway.

[0067] Accordingly, in one embodiment the present invention provides a method of inhibiting lysine biosynthesis in an organism in which the diaminopimelate biosynthesis pathway occurs, the method comprising contacting the organism with an effective amount of a compound of the Formula (I). A skilled worker in the field would readily understand the organisms in which the diaminopimelate biosynthesis pathway occurs. Nevertheless for the avoidance of doubt we note that all species in the kingdoms of Archaea, Eubacteria (both Gram-negative and Gram-positive species) and Plants (from moss species through to higher plants) utilise the diaminopimelate pathway and therefore would be considered organisms in which the diaminopimelate pathway occurs.

[0068] The compounds of the present invention are compounds of Formula (1):

Formula (1)

[0069] wherein

[0070] X is selected from the group consisting of:

[0071] Z is selected from the group consisting of NCH ₃ and NR ^a ;

[0072] at each instance R ^a is H, or two R ^a on adjacent nitrogen atoms when taken together form a double bond; [0073] R is a group of the formula:

— -L-B

[0074] wherein L is a linking group containing from 3 to 11 atoms in the normal chain; [0075] B is a binding moiety containing at least one carbonyl group;

[0076] Ar is an optionally substituted C ₃ -Ci ₈ aryl or an optionally substituted

Ci-C ₁₈ heteroaryl group;

[0077] or a salt or N-oxide thereof.

[0078] As stated above in the compounds of the present invention Z is selected from the group consisting of NCH ₃ and NR ^a . In one embodiment Z is NCH ₃ . In one embodiment Z is NR ^a . It is preferred that Z is NR ^a wherein R ^a is H such that Z is NH.

[0079] In one embodiment Z is NCH ₃ and the compounds are compounds of Formula 1 b:

Formula 1 b [0080] where Ar, X, R ^a and R, are as described above.

[0081] In one embodiment Z is NR ^a and the compounds are compounds of Formula 1c:

Formula 1c

[0082] where Ar, X, R ^a and R, are as described above. [0083] In the compounds of the present invention at each instance R ^a is H, or two R ^a on adjacent nitrogen atoms when taken together form a double bond. [0084] In one embodiment of the compounds of formula 1c each Ra is H and the compounds are compounds of Formula 1ca:

Formula 1ca [0085] where Ar, X and R, are as described above.

[0086] In one embodiment of the compounds of formula 1c two R ^a on adjacent nitrogen atoms when taken together form a double bond and the compounds are compounds of Formula 1cb:

X— R

/

N=N

Ar /

Formula 1cb

[0087] where Ar, X and R, are as described above.

[0088] In the compounds of the present invention X is selected from the group consisting of:

[0089] In one embodiment X is a group of the formula:

[0090] In one embodiment X is a group of the formula:

[0091] In one embodiment of the compounds of the present invention, Z is NR ^a , each R ^a is H and X is a group of the formula:

[0092] and the compounds are compounds of Formula 2a:

— R

bi N- - °>

Ar ^¬ /

Formula 2a

[0093] where Ar, and R, are as described above.

[0094] where Ar, and R, are as described above. [0095] In one embodiment of the compounds of the present invention, Z is NR ^a , each R ^a is

H and X is a group of the formula:

[0096] and the compounds are compounds of Formula 2c:

Formula 2c [0097] where Ar, and R, are as described above.

[0098] In the compounds of the present invention that are used in the methods of the present invention and specifically in the compounds of Formula 1 , 1b, 1c, 1ca, 1cb, 2a, and 2c, Ar is an optionally substituted C ₆ -C ₁₈ aryl or an optionally substituted C _r C ₁₈ heteroaryl group.

[0099] In some embodiments the group Ar is an optionally substituted C ₆ -Ci ₈ aryl. Examples of this group include optionally substituted phenyl and optionally substituted naphthyl.

[0100] In some embodiments the group Ar may be any optionally substituted C _r Ci ₈ heteroaryl group. Suitable heteroaryl groups include thiophene, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, naphtho[2,3-b]thiophene, furan, isoindolizine, xantholene, phenoxatine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, tetrazole, indole, isoindole, 1 H-indazole, purine, quinoline, isoquinoline, phthalazine, naphthyridine, quinoxaline, cinnoline, carbazole, phenanthridine, acridine, phenazine, thiazole, isothiazole, phenothiazine, oxazole, isooxazole, furazane, phenoxazine, pyridyl, quinolyl, isoquinolinyl, indolyl, and thienyl. In each instance where there is the possibility of multiple sites of substitution on the heteroaryl ring all possible attachment points are contemplated. Merely by way of example if the heteroaryl is a pyridyl moiety it may be a 2- pyridyly, a 3- pyridyl or a 4-pyridyl.

[0101] In some embodiments Ar is an aromatic moiety selected from the group consisting of:

[0102] wherein each A ¹ , A ² , A ³ , A ⁴ and A ⁵ are independently selected from the group consisting of N and CR ¹ ;

[0103] each V ¹ , V ² , V ³ and V ⁴ are independently selected from the group consisting of N and CR ¹ ; [0104] Y is selected from the group consisting of S, O, and NH;

[0105] each R ¹ is independently selected from the group consisting of H, halogen, OH,

and acyl;

[0106] or any two R ¹ on adjacent carbon atoms when taken together with the carbon atoms to which they are attached form a 5 or 6 membered cyclic moiety;

[0107] each R ² is selected from the group consisting of H, CrC ₆ alkyl, and CrC ₆ heteroalkyl. [0108] In some embodiments Ar is an aromatic moiety of the formula:

[0109] wherein A ¹ , A ² , A ³ , A ⁴ and A ⁵ are as defined above.

[01 10] In some embodiments Ar is an aromatic moiety of the formula:

[011 1] wherein A ^1’ , A ² , A ³ , and A ⁴ are selected from N and CH;

[0112] R ¹ is as defined above.

[0113] In some embodiments Ar is an aromatic moiety selected from the group consisting of:

[0114] In one embodiment of the compounds of the present invention, Z is NR ^a , each R ^a is H and X is a group of the formula:

[0115] and Ar is Ar-1 and the compounds are compounds of Formula 3a:

Formula 3a

[0116] where R and R ¹ are as described above. [0117] In one embodiment of the compounds of the present invention, Z is NR ^a , each R ^a is H and X is a group of the formula:

[0118] and Ar is Ar-2 and the compounds are compounds of Formula 3b:

Formula 3b

[0119] where R and R ¹ are as described above.

[0120] In one embodiment of the compounds of the present invention, Z is NR ^a , each R ^a is H and X is a group of the formula:

[0121] and Ar is Ar-3 and the compounds are compounds of Formula 3c:

Formula 3c

[0122] where R and R ¹ are as described above. [0123] In one embodiment of the compounds of the present invention, Z is NR ^a , each R ^a is

H and X is a group of the formula:

[0124] and Ar is Ar-4 and the compounds are compounds of Formula 3d:

Formula 3d

[0125] where R is as described above.

[0126] In one embodiment of the compounds of the present invention, Z is NR ^a , each R ^a is H and X is a group of the formula:

[0127] and Ar is Ar-5 and the compounds are compounds of Formula 3e:

Formula 3e [0128] where R is described above.

[0129] In one embodiment of the compounds of the present invention, Z is NR ^a , each R ^a is H and X is a group of the formula:

[0130] and Ar is Ar-1 and the compounds are compounds of Formula 5a:

Formula 5a [0131] where R and R ¹ are as described above.

[0132] In one embodiment of the compounds of the present invention, Z is NR ^a , each R ^a is H and X is a group of the formula:

[0133] and Ar is Ar-2 and the compounds are compounds of Formula 5b:

Formula 5b

[0134] where R and R ¹ are as described above.

[0135] In one embodiment of the compounds of the present invention, Z is NR ^a , each R ^a is H and X is a group of the formula:

[0136] and Ar is Ar-3 and the compounds are compounds of Formula 5c:

Formula 5c

[0137] where R and R ¹ are as described above.

[0138] In one embodiment of the compounds of the present invention, Z is NR ^a , each R ^a is H and X is a group of the formula:

[0139] and Ar is Ar-4 and the compounds are compounds of Formula 5d:

Formula 5d [0140] where R is as described above.

[0141] In one embodiment of the compounds of the present invention, Z is NR ^a , each R ^a is H and X is a group of the formula:

[0142] and Ar is Ar-5 and the compounds are compounds of Formula 5e:

Formula 5e

[0143] where R is described above. [0144] In some embodiments Ar is selected from the group consisting of:

[0145] each V ¹ , V ² , V ³ and V ⁴ are independently selected from the group consisting of N and CR ¹ ;

[0146] Y is selected from the group consisting of S, O, and NH. [0147] In one embodiment Ar is selected from the group consisting of:

[0148] wherein R ¹ is as described above.

[0149] In one embodiment Ar is selected from the group consisting of:

[0150] In one embodiment of the compounds of the present invention R ¹ is selected from the group consisting of H, N0 ₂ , CN, C0 ₂ H and C0 ₂ R ² .

[0151] In the compounds of the present invention R is a group of the formula:

— L-B

[0152] wherein L is a linking group containing from 3 to 11 atoms in the normal chain; [0153] B is a binding moiety containing at least one carbonyl group;

[0154] L is a linking moiety containing from 3 to 1 1 atoms in the normal chain. In one embodiment L has 3 atoms in the normal chain. In one embodiment L has 4 atoms in the normal chain. In one embodiment L has 5 atoms in the normal chain. In one embodiment L has 6 atoms in the normal chain. In one embodiment L has 7 atoms in the normal chain. In one embodiment L has 8 atoms in the normal chain. In one embodiment L has 9 atoms in the normal chain. In one embodiment L has 10 atoms in the normal chain. In one embodiment L has 11 atoms in the normal chain.

[0155] In principle the linker moiety can be any entity providing the required spacing between the X group and the binding moiety in order to facilitate the positioning of the binding moiety to bind to the biological target of interest. [0156] In certain embodiments the linking group is a group of the formula:

-(CH ₂ ) ₀ -

[0157] Where o is an integer selected from the group consisting of 3, 4, 5, 6, 7, 8, 9 and 10. [0158] In certain embodiments the linking group is a group of the formula:

-(CH ₂ ) _n -W-(CH ₂ ) _p -

[0159] where n is an integer selected from the group consisting of 0, 1 , 2, 3, 4, 5, 6, 7, and 8;

[0160] W is selected from the group consisting of -O-, -S-, -CH _2. , -CH=CH-, -NH-, - C(=0)0-, -OC(=0)- -NHC(=0)- , -C(=0)NH- and 1 ,2,3-triazole; [0161] p is an integer selected from the group consisting of 0, 1 , 2, 3, 4, 5, 6, 7, and 8; and

[0162] n and p are selected such that the sum of n + p is from 3 to 9.

[0163] In this embodiment W is selected from the group consisting of -O-, -S-, -CH ₂ _, - CH=CH-, -NH-, -C(=0)0-, -OC(=0)- -NHC(=0)- and -C(=0)NH-. In one embodiment W is -O-. In one embodiment W is -S-. In one embodiment W is -CH ₂ - In one embodiment W is - CH=CH-. In one embodiment W is -N H-. In one embodiment W is -C(=0)0-. In one embodiment W is -OC(=0)-. In one embodiment W is -NHC(=0)- . In one embodiment W is - C(=0)NH- In one embodiment W is 1 ,2,3-triazole.

[0164] Examples of suitable L groups include:

[0165] The B group in the compounds of the present invention is a binding moiety containing at least one carbonyl group. Examples of suitable B groups include aldehydes, diketones, ureas, alkyl ureas, amides and carboxylic acids.

[0166] In one embodiment B is selected from the group consisting of COH, C0 ₂ R ³ , COCOR ³ , NHCONR ³ , CONR ³ R ⁴ and C0C0 ₂ R ³ wherein R ³ and R ⁴ are selected from the group consisting of H and CrCi ₂ alkyl. [0167] In one embodiment B is a group of the formula:

[0168] Examples of specific compounds of formula (I) include the following:

5 6

or a salt or A/-oxide thereof.

[0169] As stated above the applicant has also identified a number of known compounds of Formula (2) that are also active. These compounds have the following formula:

Formula (2) [0170] wherein R ⁵ is selected from the group consisting of H and CrC^alkyl; [0171] m is an integer selected from the group consisting of 3, 4, 5, 6, 7 and 8. [0172] Examples of compounds of this type are as follows:

30 31

[0173] The compounds of the invention as disclosed above have the ability to inhibit lysine biosynthesis in an organism in which the diaminopimelate biosynthesis pathway occurs by contacting the organism with an effective amount of the compound. Accordingly, the present invention also provides a method of inhibiting lysine biosynthesis in an organism in which the diaminopimelate biosynthesis pathway occurs the method comprising contacting the organism with an effective amount of a compound of Formula (1) or a compound of Formula (2). [0174] The organism is typically contacted with the compound of Formula (1) or a compound of Formula (2) by contacting the organism with a composition containing the compound. In addition to the compound the compositions typically contain a suitable solvent or carrier as detailed below for herbicidal compositions. The concentration of the compound of Formula (1) or a compound of Formula (2) in the composition may vary although it is typically between 50 micromolar to 4000 micromolar. In one embodiment the concentration is from 50 micromolar to 2000 micromolar. In one embodiment the concentration is from 50 micromolar to 1000 micromolar. In one embodiment the concentration is from 100 micromolar to 1000 micromolar. In one embodiment the concentration is from 200 micromolar to 1000 micromolar. As would be appreciated by a skilled worker in the field higher concentrations would work but the higher the concentration the more expensive the treatment becomes.

[0175] The organism may be any organism in which lysine biosynthesis occurs. In one embodiment the organism is selected from, the group consisting of plants and bacteria. In one embodiment the organism is a plant. In another embodiment the organism is a bacteria. In one embodiment the organism is a Gram-positive bacteria. In one embodiment the organism is a Gram-negative bacteria.

[0176] Without wishing to be bound by theory it is felt that the compounds of the invention inhibit lysine biosynthesis by inhibiting the diaminopimelate (DAP) pathway in the organism. Accordingly, in some embodiments the compounds inhibits lysine biosynthesis by inhibiting the diaminopimelate (DAP) pathway in the organism. In some embodiments the compound inhibits lysine biosynthesis by inhibiting DHDPS activity in the organism.

[0177] In use in inhibiting lysine biosynthesis the compound of the invention is typically used in the form of a composition which may be a herbicidal composition or a pharmaceutical composition as discussed below.

Herbicidal Composition

[0178] A herbicidal composition containing the active agent may be in the form of a liquid or a solid composition and as such the composition may be in the form of a concentrate, a wettable powder, granules and the like. Typically these are intended to be admixed with other materials prior to application as a herbicide. In these formulations the active agent is typically present in from 1wt% to 90wt% based on the total weight of the composition with the remainder of the composition being made up of a solid or a liquid a carrier and other additives as discussed below. In one embodiment the active agent is present in from 0.1 wt% to 90 wt% based on the total weight of the composition. In one embodiment the active agent is present in from 0.1 wt% to 50 wt% based on the total weight of the composition. In one embodiment the active agent is present in from 0.1 wt% to 10 wt% based on the total weight of the composition. In one embodiment the active agent is present in from 0.1 wt% to 5 wt% based on the total weight of the composition. In one embodiment the active agent is present in from 0.1 wt% to 1 wt% based on the total weight of the composition. In one embodiment the active agent is present in from 0.1 wt% to 0.5 wt% based on the total weight of the composition.

[0179] As would be appreciated by a skilled worker in the field the concentration of the active compound in the composition used to contact the plant can vary greatly depending upon a number of factors. In one embodiment the concentration is greater than 31.3 micromolar. In one embodiment the concentration is greater than 62.5 micromolar. In one embodiment the concentration is greater than 125 micromolar. In one embodiment the concentration is greater than 250 micromolar. In one embodiment the concentration is greater than 500 micromolar. In one embodiment the concentration is greater than 1000 micromolar. In one embodiment the concentration is from 15.6 micromolar to 500 micromolar. In one embodiment the concentration is from 31.3 micromolar to 2000 micromolar. In one embodiment the concentration is from 62.5 micromolar to 2000 micromolar. In one embodiment the concentration is from 125 micromolar to 2000 micromolar. In one embodiment the concentration is from 125 micromolar to 1000 micromolar. In one embodiment the concentration is from 250 micromolar to 1000 micromolar.

[0180] A suitable solid carrier for use in the herbicidal compositions include but are not limited to clays such as kaolinite, diatomaceous earth, synthetic hydrated silicon oxide and bentonites; talcs and other inorganic materials such as calcium carbonates, activated carbon, powdered sulphur, and powdered quartz; and inorganic fertilizers such as ammonium sulfate, ammonium nitrate, ammonium chloride and the like.

[0181] A suitable liquid carried may include water; alcohols such as methanol, ethanol, 2- ethylhexanol and n-octanol, halogenated hydrocarbons such as dichloroethane and trichloroethane; aromatic hydrocarbons such as toluene, xylene and ethyl benzene; non aromatic hydrocarbons such as hexane, cyclohexane and the like; ketones such as acetone, methyl ethyl ketone, and cyclohexanone; esters such as ethyl acetate and butyl acetate; nitriles such as acetonitrile, isobutyronitrile and the like; ethers such as dioxane and diisopropyl ether; and acid amides such as dimethyl formamide and dimethylacetamide or organosulfur compound such as dimethylsulfoxide. In some embodiments the liquid carrier is a mixture of one or more of these materials.

[0182] The composition may include one or more additional additives such as surfactants; crystallisation inhibitors, viscosity-modifying substances, suspending agents, dyes, antioxidants, foaming agents, light absorbers, mixing aids, anti-foams, complexing agents, neutralising or pH-modifying substances and buffers, corrosion-inhibitors, fragrances, wetting agents, absorption improvers, plasticisers, lubricants, dispersants, thickeners, and the like. [0183] The surfactants that may be used in herbicidal compositions of the invention are well known in the art and include, salts of alkyl sulfates, such as diethanolammonium lauryl sulfate; salts of arylsulfonates, such as calcium dodecylbenzenesulfonate; alkylphenol-alkylene oxide addition products, such as nonylphenol ethoxylate; alcohol-alkylene oxide addition products, such as tridecyl alcohol ethoxylate; soaps, such as sodium stearate; salts of alkylnaphthalenesulfonates, such as sodium dibutylnaphthalenesulfonate; dialkyl esters of sulfosuccinate salts, such as sodium di(2-ethylhexyl)sulfosuccinate; sorbitol esters, such as sorbitol oleate; quaternary amines, such as lauryl trimethylammonium chloride; polyethylene glycol esters of fatty acids, such as polyethylene glycol stearate; block copolymers of ethylene oxide and propylene oxide; and salts of mono- and di-alkyl phosphate esters.

[0184] The additional additives that may be present in the herbicidal compositions are those that are well known in the art. The herbicidal compositions are typically prepared by combining each of the desired ingredients into a formulation mixer with mixing to produce the final formulation.

[0185] A skilled worker in the field of herbicidal formulation could easily prepare a suitable herbicide formulation containing the compounds of Formula (1).

Use as a Herbicide

[0186] As stated previously the compounds of Formula (1) or a compound of Formula (2) can be used as herbicides. As such in one embodiment the present invention provides a method for controlling undesired plant growth the method comprising contacting the plant with a herbicidal effective amount of a compound of the formula (I) or a salt or N- oxide thereof.

[0187] Whilst in principle the compounds may be used to control the growth of any plant they are typically used to control the growth of undesirable plants such as weeds particularly in agricultural settings.

[0188] Examples of plants that may be controlled using the methods of the present invention include Bindii, Bindweed, Mullumbimby couch, stinging nettle, pampas grass, lantana, capeweed, common sow thistle, African box thorn, asparagus fern, asthma weed, black nightshade, blue morning glory, bridal creeper, ox-eye daisy, sorrel, lippie, purple nut grass, onion grass, onion weed, paspalum, wandering trad, dandelion, boneseed, soursob, broad leafed privet, small leafed privet, golden bamboo, blackberry, annual rye grass, Barley grass, Black bindweed, bladder ketmia, brome grass, doublegee, fleabane, Funmitory, Indian hedge mustard, Liverseed, Muskweed, Paradoxa grass, Silver grass, Sweet summer grass, turnip weed, wild oats, Wild radish, Windmill grass, and Wire weed. [0189] The compounds of Formula (1) or a compound of Formula (2) can be administered to a plant in any way known in the art. Nevertheless the compounds are typically used in this method in the form of a herbicidal composition as discussed above. In this form the administration of the compound to the plant typically involves a composition containing the active agent is being applied to the plant as such or by dilution of the composition in a solvent such as water followed by application of the diluted composition to the plant. Accordingly, administration of the compound to the plant typically involves contacting the plant with the compound either neat or in the form of a herbicidal composition. The compound may be administered by contact with any part of the plant but this typically occurs through the roots, leaves or stem of the plant.

[0190] Application of the composition to the plant by contact may be by any method known in the art. Thus for small scale applications the composition containing the compound may be painted or applied to the plant by hand. For larger scale applications the composition containing the compound is typically applied by spraying as would be well understood by a worker skilled in the art. The rate of application will vary depending on the plant to be controlled, the application rate, the maturity of the plant to be controlled and its extent of infestation of the land to be treated. In one embodiment application rate is typically from 0.1 kg to 1000 kg per hectare. In one embodiment the application rate is from 0.1 kg to 100 kg per hectare. In one embodiment the application rate is from 0.1 kg to 50 kg per hectare. In one embodiment the application rate is from 10 kg to 50 kg per hectare. In one embodiment application rate is typically from 0.1 kg to 50 kg per hectare. In one embodiment the application rate is from 0.1 kg to 10 kg per hectare. In one embodiment the application rate is from 1.0 kg to 0 kg per hectare. In one embodiment the application rate is from 1.0 kg to 5 kg per hectare.

[0191] Aqueous concentrate compositions may be diluted in an appropriate volume of water and applied, for example by spraying, to unwanted vegetation to be controlled. Compositions prepared by the method may be applied at rates in the range of for example from about 0.1 to about 5 kilograms per hectare (kg/ha), occasionally more. Typical rates for control of annual and perennial grasses and broadleaves are in the range from about 0.3 to about 3 kg/ha. Compositions of the invention may be applied in any convenient volume of water, most typically in the range from about 30 to about 2000 liters per hectare (l/ha). Compositions prepared by the method of the invention also include solutions which may be applied by spraying for example. In these solutions, the concentration of the active agent is selected according to the volume per unit area of spray solution to be used and the desired rate of application of the active per unit area. For example, conventional spraying is done at 30 to 5000 liters (particularly 50-600 liters) of spray solution per hectare, and the rate of application of the active is typically 0.125 to 1.5 kg of active per hectare. Spray solution compositions can be prepared by diluting the aqueous liquid concentrates preferably comprising surfactant adjuvants or by tank mixing the aqueous concentrates formed by the method with adjuvants as described above.

Treatment of Bacterial Infections

[0192] Administration of compounds within Formula (I) or a compound of Formula (2) to subjects to treat bacterial infections can be by any of the accepted modes for enteral administration such as oral or rectal, or by parenteral administration such as subcutaneous, intramuscular, intravenous and intradermal routes, or by inhaled compound delivery. Injection can be bolus or via constant or intermittent infusion. Examples of routes include topical administration, enteral administration (i.e. via the intestines, such as oral, gastric tube, or rectally) or parenteral administration (such as injections, e.g. intravenous, intramuscular, subcutaneous or intraperitoneal injection).

[0193] The active compound is typically included in a pharmaceutically acceptable carrier or diluent and in an amount sufficient to deliver to the patient a therapeutically effective dose.

[0194] In using the compounds of the invention they can be administered in any form or mode which makes the compound bioavailable. One skilled in the art of preparing formulations can readily select the proper form and mode of administration depending upon the particular characteristics of the compound selected, the condition to be treated, the stage of the condition to be treated and other relevant circumstances. We refer the reader to P. H. Stahl and C.G. Wermuth (Eds), Handbook of Pharmaceutical Salts, Properties, Selection, and Use, 2 ^nd Revised Edition, Wiley-VCH (2011) for further information.

[0195] The compounds of the present invention can be administered alone or in the form of a pharmaceutical composition in combination with a pharmaceutically acceptable carrier, diluent or excipient. The compounds of the invention, while effective themselves, are typically formulated and administered in the form of their pharmaceutically acceptable salts as these forms are typically more stable, more easily crystallised and have increased water-solubility.

[0196] The compounds are, however, typically used in the form of pharmaceutical compositions which are formulated depending on the desired mode of administration. As such in some embodiments the present invention provides a pharmaceutical composition including a compound of Formula (I) or a compound of Formula (2) and a pharmaceutically acceptable carrier, diluent or excipient. The compositions are prepared in manners well known in the art.

[0197] The invention in other embodiments provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention. In such a pack or kit can be found a container having a unit dosage of the agent(s). The kits can include a composition comprising an effective agent either as concentrates (including lyophilized compositions), which can be diluted further prior to use or they can be provided at the concentration of use, where the vials may include one or more dosages. Conveniently, in the kits, single dosages can be provided in sterile vials so that the physician can employ the vials directly, where the vials will have the desired amount and concentration of agent(s). Associated with such container(s) can be various written materials such as instructions for use, or a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration.

[0198] The compounds of the invention may be used or administered in combination with one or more additional drug(s) for the treatment of the disorder/diseases mentioned. The components can be administered in the same formulation or in separate formulations. If administered in separate formulations the compounds of the invention may be administered sequentially or simultaneously with the other drug(s).

[0199] Pharmaceutical compositions of this invention for parenteral injection comprise pharmaceutically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0200] Examples of compositions suitable for topical administration include creams, lotions, eye drops, ear drops, sprays, inhalants, or as an embedded preparation or as a transmucosal preparation through nasal cavity, rectum, uterus, vagina, lung, etc. and the like. Examples of compositions suitable for enteral administration include tablets, pills, granules, powders, capsules, liquid formulations, elixirs, suspensions, wafers, emulsions, syrups, suppositories, and the like. Examples of compositions suitable for parenteral administration include injections or depot preparations such as an implantable pellet, and the like.

[0201] These compositions may also contain excipients such as preservative, wetting agents, emulsifying agents, buffering agents, pH controller, isotonic agent and dispersing agents. Prevention of the action of micro-organisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride, and the like. These excipients are well known to those skilled in the art. [0202] Examples of suitable preservatives are benzoic acid esters of para-hydroxybenzoic acid, 20 phenols, phenylethyl alcohol or benzyl alcohol. Examples of suitable buffers are sodium phosphate salts, citric acid, tartaric acid and the like. Examples of suitable stabilisers are antioxidants such as alpha-tocopherol acetate, alpha-thioglycerin, sodium metabisulphite, ascorbic acid, acetylcysteine, 8-hydroxyquinoline, and chelating agents such as disodium edetate. Examples of suitable viscosity enhancing agents, suspending, 25 solubilizing or dispersing agents are substituted cellulose ethers, substituted cellulose esters, polyvinyl alcohol, polyvinylpyrrolidone, polyethylene glycols, carbomer, polyoxypropylene glycols, sorbitan monooleate, sorbitan sesquioleate, polyoxyethylene hydrogenated castor oil 60.

[0203] Examples of suitable pH controllers include hydrochloric acid, sodium hydroxide, buffers and the like. Examples of suitable isotonic agents are glucose, D-sorbitol or D-mannitol, sodium chloride.

[0204] Prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminium monostearate and gelatin. These agents are well known to those skilled in the art.

[0205] If desired, and for more effective distribution, the compounds can be incorporated into slow release or targeted delivery systems such as polymer matrices, liposomes, and microspheres.

[0206] The injectable formulations can be sterilized, for example, by heat, irradiation or by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.

[0207] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents. [0208] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

[0209] The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.

[0210] The active compounds can also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.

[021 1] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3- butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.

[0212] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavouring, and perfuming agents.

[0213] Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminium metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.

[0214] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

[0215] Dosage forms for topical administration of a compound of this invention include powders, patches, sprays, ointments and inhalants. The active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives, buffers, or propellants which may be required.

[0216] Suitable compositions can be prepared by methods commonly employed using conventional, organic or inorganic additives, such as an excipient. Such excipients may be selected from fillers or diluents, binders, disintegrants, lubricants, flavouring agents, preservatives, stabilizers, suspending agents, dispersing agents, surfactants, antioxidants or solubilizers.

[0217] Examples of fillers or diluents include sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate or calcium carbonate, and the like. Examples of binders include cellulose, carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxy-propylmethylcellulose, polypropylpyrrolidone, polyvinylpyrrolidone, gelatin, gum arabic, polyethyleneglycol or starch, and the like. Examples of disintegrants include sodium starch glycolate or croscarmellose sodium, and the like. Examples of lubricants include magnesium stearate, light anhydrous silicic acid, talc or sodium lauryl sulfate, and the like. Examples of flavoring agents include citric acid or menthol, and the like. Examples of preservatives include sodium benzoate, sodium bisulfite, methylparaben or propylparaben, and the like. Examples of stabilizers include citric acid, sodium citrate or acetic acid, and the like. Examples of suspending agents include methylcellulose, polyvinyl pyrrolidone or aluminium stearate, and the like. Examples of dispersing agents include hydroxypropylmethylcellulose, and the like. Examples of surfactants include sodium lauryl sulfate, polaxamers, polysorbates, and the like. Examples of antioxidants include ethylene diamine tetraacetic acid (EDTA), butylated hydroxyl toluene (BHT), and the like. Examples of solubilizers include polyethylene glycols, SOLUTOL®, GELUCIRE®, and the like.

[0218] The amount of compound administered will preferably treat and reduce or alleviate the condition. A therapeutically effective amount can be readily determined by an attending diagnostician by the use of conventional techniques and by observing results obtained under analogous circumstances. In determining the therapeutically effective amount a number of factors are to be considered including but not limited to, the species of animal, its size, age and general health, the specific condition involved, the severity of the condition, the response of the patient to treatment, the particular compound administered, the mode of administration, the bioavailability of the preparation administered, the dose regime selected, the use of other medications and other relevant circumstances.

[0219] A preferred dosage will be a range from about 0.01 to 300 mg per kilogram of body weight per day. A more preferred dosage will be in the range from 0.1 to 100 mg per kilogram of body weight per day, more preferably from 0.2 to 80 mg per kilogram of body weight per day, even more preferably 0.2 to 50 mg per kilogram of body weight per day. A suitable dose can be administered in multiple sub-doses per day.

[0220] The compounds of the invention may be used to treat both Gram-positive and Gram-negative bacterial infections. In one embodiment the bacterial infection is a Gram-positive bacterial infection. In one embodiment the bacterial infection is a Gram-negative bacterial infection.

Synthesis of Compounds

[0221] The compounds for use in the methods of the present invention may be prepared using the reaction routes and synthesis schemes as described below, employing the techniques available in the art using starting materials that are readily available. The preparation of particular compounds of the embodiments is described in detail in the following examples, but the artisan will recognize that the chemical reactions described may be readily adapted to prepare a number of other agents of the various embodiments. For example, the synthesis of non-exemplified compounds may be successfully performed by modifications apparent to those skilled in the art, e.g. by appropriately protecting interfering groups, by changing to other suitable reagents known in the art, or by making routine modifications of reaction conditions. A list of suitable protecting groups in organic synthesis can be found in T.W. Greene's Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons, 1991. Alternatively, other reactions disclosed herein or known in the art will be recognized as having applicability for preparing other compounds of the various embodiments.

[0222] The invention will now be illustrated by way of examples; however, the examples are not to be construed as being limitations thereto. Additional compounds, other than those described below, may be prepared using methods and synthetic protocols or appropriate variations or modifications thereof, as described herein.

[0223] All materials were purchased from Sigma-Aldrich as reagent grade. Melting points taken were uncorrected and recorded on a Reichert “Thermopan” microscope hot stage apparatus.

[0224] Nuclear magnetic resonance (NMR) spectra were obtained on a Bruker Avance-400 spectrometer at 400.13 MHz for ¹ H nuclei and 100.62 MHz for ¹³ C nuclei. Proton chemical shifts are reported in parts per million (ppm) from an internal standard of residual chloroform at d 7.26 ppm or dimethylsulfoxide at d 2.50 ppm. All chemical shifts were recorded as d values in parts per million (ppm) and coupling constants ( J) were recorded in hertz (Hz). For reporting of an NMR spectrum, the following terms were used; singlet (s), doublet (d), triplet (t), multiplet (m), broad (br). [0225] Electrospray ionisation (ESI) mass spectrometry was carried out using a Bruker Daltonics (Germany) Esquire ⁶⁰⁰⁰ ion trap mass spectrometer at 140 °C with a flow rate of 4 pL/min, a mass range of 50 - 3000 m/z and a scan rate of 5500 m/z per second in positive ion mode. Methanol was used with 0.1 % formic acid was used as the mobile phase.

[0226] Thin layer chromatography (TLC) was used to monitor reactions and chromatographic fractions on Merck Kieselgel 60 F254 aluminium backed plates. Silica gel 60 F254 was used as the stationary phase to perform flash chromatography. Gradient elution using ethyl acetate (EtOAc) and hexane, analytical grade were used unless otherwise stated.

[0227] Analytical reverse phase high performance liquid chromatography (RP-HPLC) was performed on a Shimadzu LC-20AB Prominence system fitted with a Phenomenex® Luna C18(2) 100 A column (250 mm x 4.6 mm, 10 pm), using a buffered binary solvent system; Solvent A: Milli Q water; Solvent B: acetonitrile. Gradient elution was performed using a gradient of 5 % solvent A to 95% solvent B over 25 minutes with a flow rate of 1 mL/min, monitored at 220 nm.

[0228] All glassware used in reactions requiring anhydrous conditions, was oven-dried and then cooled under nitrogen prior to use.

[0229] The compounds used in the present invention may potentially be synthesised by a number of different synthetic approaches which would be well known to a skilled worker in the field.

[0230] Nevertheless a majority of the compounds of the invention are made following either the route outlined in scheme 1 , the route outlined in scheme 2 or a variation thereof. In scheme 1 the appropriate starting material is the amino substituted Ar group whereas in scheme 2 the starting material is the halogenated Ar group. The choice of route will be determined based on the availability of the appropriate Ar starting material and the reactivity of other substituents.

Route 1 - Amine Starting Material

[0231] The general scheme for the formation of the compounds of the inventions is shown in scheme 1 below which can be modified depending on the variables chosen for Ar, and R in the final product. In general the appropriate amino starting material (S-1) is converted to the corresponding hydrazine (S-2) by diazotisation followed by reduction using slight modifications of standard conditions for reactions of this type. For example, aniline was reacted with hydrochloric acid prior to making the diazonium salt to avoid the formation of the diazohydroxide. The nitrosating agent chosen was fresh nitrous acid which was generated in situ by the combination of sodium nitrite with acid, most commonly hydrochloric acid. In our procedure NaN0 ₂ was dissolved in water, then added to an acidic aniline hydrochloride solution for the in situ generation of nitrous acid. Formation of the diazonium salt was undertaken in temperatures of between 0 - 5 °C to avoid the formation of phenol, when the temperature is above 5 °C and to avoid having unreacted aniline, which occurs when the temperature is below 0 °C. Facilitation of the reaction was carried out by cooling both the aniline solution and sodium nitrite solution in ice baths before mixing. External cooling was continued during the reaction to maintain the required temperature conditions.

[0232] With the hydrazine in hand it can then be converted to the final product by reaction with a suitably substituted acid chloride. The coupling reaction is a S _N 2 type, in which the lone pair of nitrogen acts as the nucleophile and the chloride ion leaves the acid chloride as the leaving group. The insolubility of the product in water typically results in the precipitation of compound S-3 from solution.

.

H

2. Deprotection* n = 1 , 2, 3

S-3

* If required

Scheme 1

Route 2 - Halogenated Starting Material

[0233] The route from the halogenated starting material produces a common intermediate as shown in scheme 2, A suitably halogenated aromatic (S-4) is reacted with hydrazine hydrate to form the corresponding hydrazinyl moiety (S-5). With the hydrazine in hand it can then be converted to the final product by reaction with a suitably substituted acid chloride. The coupling reaction is a S _N 2 type, in which the lone pair of nitrogen acts as the nucleophile and the chloride ion leaves the acid chloride as the leaving group. The insolubility of the product in water typically results in the precipitation of compound S-6 from solution.

2. Deprotection* n = 1 , 2, 3

* If required

Scheme 2 [0234] It should be noted that in the two reaction schemes above the entire R group is added in a single step. This is the preferred course where a suitable acid chloride can be produced for the desired R group. As will be appreciated by a skilled organic chemist this is not always possible. In these instances the scheme above is used to insert a precursor to the final R group which is then elaborated further to the final product. [0235] Almost all of the compounds of the invention can be produced using the procedure described above with minor modifications that would be within the skill of an organic synthetic chemist.

Starting Material A 2-Amino-A/ ^, -phenylethane-1-sulfonohydrazide

Step 1 - Synthesis of Tetrabutylammonium 2-((ferf-butoxycarbonyl) amino)ethane-1- sulfonate

[0236] To a solution of taurine (300 mg, 2.39 mmol) in water (2.4 mL), tetrabutylammonium hydroxide (0.2 M, 12 mL) was added followed by the dropwise addition of a solution of Boc ₂ 0 (523 mg, 2.39 mmol) in acetone (8 mL). The mixture was stirred overnight at room temperature. The reaction mixture was then concentrated to remove acetone and the remaining water mixture was extracted with dichloromethane. The organic layers were combined, dried and concentrated to obtain a pale yellow oil (1.1 1 g, quantitative yield). d _H (400 MHz, CDCI ₃ ) 3.53 (m, 2H, CH ₂ ), 3.28 (m, 8H, 4 CH ₂ ), 2.91 (m, 2H, CH ₂ ), 1.64 (m, 8H, 4 CH ₂ ), 1.44 (m, 8H, 4 CH ₂ ), 1.39 (s, 9H, 3 CH ₃ ), 1.00 (t, 12H, 4 CH ₃ ).

Step 2 - Synthesis of fert-Butyl (2-(chlorosulfonyl)ethyl)carbamate

[0237] Tetrabutylammonium 2-((ferf-butoxycarbonyl)amino)ethane-1-sulfonate (770 mg, 1.65 mmol) was dissolved in dry tetrahydrofuran (5 mL) in a two neck flask under nitrogen. Addition of triphosgene (795 mg, 0.65 mmol) performed and the reaction mixture was stirred for 30 minutes. The reaction mixture was concentrated under vacuum and the resulting yellow oil was purified by column to obtain the product as a white solid (240 mg, 60%). d _H (400 MHz, CDCI ₃ ) 5.10 (br, 1 H, NH), 3.90 (m, 2H, CH ₂ ), 3.77 (m, 2H, CH ₂ ), 1.44 (s, 9H, 3 CH3).

Step 3 - Synthesis of fert-Butyl (2-((2-phenylhydrazinyl)sulfonyl)ethyl)carbamate

[0238] To a stirred solution of phenyl hydrazine (48 pL, 0.48 mmol) in dry tetrahydrofuran (5 mL), 4-methylmorpholine (140 pL, 0.92 mmol) was added and the solution was cooled to 0 °C. Dropwise addition of a solution of ted- butyl (2-(chlorosulfonyl)ethyl)carbamate (100 mg, 0.41 mmol) in dry tetrahydrofuran (10 mL) was performed while maintaining the temperature. The reaction mixture was stirred for 1 hour at 0 °C and then at room temperature overnight. The reaction mixture was concentrated under vacuum and the resulting crude was diluted with ethyl acetate and washed consecutively with 1 M KHS0 ₄ (aq), brine, 5% NaHC0 ₃ (aq) and brine. The organic layer was dried and concentrated under vacuum to obtain the product as a red-orange oil (129 mg, 79%). d _H (400 MHz, CDCI ₃ ) 9.13 (s, 1 H, NH), 7.26 (t, 2H, ArH), 6.99 (d, 2H, ArH), 6.93 (t, 1 H, ArH), 6.30 (s, 1 H, NH), 6.04 (br, 1 H, NH), 4.05 (t, 2H, CH ₂ ), 3.29 (t, 2H, CH ₂ ), 1.54 (s, 9H, 3 CH ₃ ).

Step 4 - Synthesis of 2-Ami no-W-phenylethane-1-sulfonohydrazide

[0239] Tert-butyl (2-((2-phenylhydrazinyl)sulfonyl)ethyl)carbamate (30 mg, 0.09 mmol) was dissolved in dichloromethane (2 ml.) and cooled, followed by addition of trifluoacetic acid (20 mI_, 0.19 mmol) and the reaction was warmed to room temperature and stirred for 3 hours. The reaction mixture was washed with saturated sodium bisulfite solution. The organic layer was dried and concentrated to obtain the product in quantitative yield as an orange oil (20 mg). d _H (400 MHz, CDCI ₃ ) 9.14 (s, 2H, NH ₂ ), 7.96 (t, 2H, ArH), 7.66 (d, 1 H, ArH), 7.60 (t, 2H, ArH), 4.04 (m, 2H, CH ₂ ), 3.15 (m, 2H, CH ₂ ).

Starting material B 2-Amino-/V'-(5-nitropyridin-2-yl)ethane-1-sulfonohydrazide

Step 1 - Synthesis of tert- Buty (2-((2-(5-nitropyridin-2- yl)hydrazinyl)sulfonyl)ethyl)carbamate

[0240] To a stirred solution of 2-hydrazinyl-5-nitropyridine (486 mg, 2.87 mmol) in dry tetrahydrofuran (10 ml_), 4-methylmorpholine (983 pL, 8.93 mmol) was added and the solution was cooled to 0 °C. Dropwise addition of a solution of ferf-butyl

((chlorosulfonyl)methyl)carbamate (700 mg, 2.87 mmol) in dry tetrahydrofuran (20 ml_) was performed while maintaining the temperature. The reaction mixture was stirred for 1 hour at 0 °C and then at room temperature overnight. The reaction mixture was concentrated under vacuum and the resulting crude was diluted with ethyl acetate and washed consecutively with 1 M KHS0 ₄ (aq), brine, 5% NaHC0 ₃ (aq) and brine. The organic layer was dried and concentrated under vacuum. Obtained crude product was purified through column chromatography to obtain the product as a brown oil (600 mg, 20%). d _H (400 MHz, CDCI ₃ ) 8.98 (s, 1 H, NH), 8.53 (s, 1 H, NH), 8.32 (d, 1 H, ArH), 7.29 (s, 1 H, ArH), 7.21 (d, 1 H, ArH), 5.1 1 (d, 1 H, NH), 3.73 (m, 2H, CH ₂ ), 3.46 (m, 2H, CH ₂ ), 2.01 (s, 9H, 3 CH ₃ ).

Step 2 - Synthesis of 2-Amino-/V'-(5-nitropyridin-2-yl)ethane-1 -sulfonohydrazide

[0241] ferf-Butyl (2-((2-(5-nitropyridin-3-yl)hydrazinyl)sulfonyl)ethyl)carbam ate (200 mg, 0.553 mmol) was dissolved in dichloromethane (15 mL) and cooled on an ice bath, followed by the addition of trifluoroacetic acid (850 mI_, 1.10 mmol). The reaction was allowed to warm to room temperature and stirred for 3 hours. The reaction mixture was washed with saturated sodium bisulfite solution. The organic layer was dried and concentrated to obtain the product in quantitative yield as an orange oil (66 mg). d _H (400 MHz, CDCI ₃ ) 9.00 (s, 2 H, NH ₂ ), 8.53 (s, 1 H, NH), 8.32 (d, 1 H, ArH), 7.29 (s, 1 H, ArH), 7.21 (d, 1 H, ArH), 5.11 (d, 1 H, NH), 3.87 (m, 2H, CH ₂ ), 3.73 (m, 2H, CH ₂ ). Starting material C 1-Amino-A/-phenylmethanesulfonohydrazide

Step 1 - Synthesis of fert-Butyl (((2-phenylhydrazinyl)sulfonyl)methyl)carbamate [0242] To a stirred solution of phenyl hydrazine (56 mI_, 0.57 mmol) in dry tetrahydrofuran

(5 ml_), 4-methylmorpholine (167 mI_, 1.52 mmol) was added and the solution was cooled to 0 °C. Dropwise addition of a solution of ferf-butyl ((chlorosulfonyl)methyl)carbamate (112 mg, 0.48 mmol) in dry tetrahydrofuran (10 mL) was performed while maintaining the temperature at 0 °C. The reaction mixture was stirred for 1 hour at 0 °C and at room temperature overnight. The reaction mixture was concentrated under vacuum and the resulting crude was diluted with ethyl acetate and washed consecutively with 1 M KHS0 ₄ (aq), brine, 5% NaHC0 ₃ (aq) and brine. The organic layer was dried and concentrated under vacuum to obtain the product as a red- orange oil (129 mg, 79%). d _H (400 MHz, CDCI ₃ ) 7.76 (d, 2H, ArH), 7.49 (m, 2H, ArH), 6.83 (d, 1 H, ArH), 4.13 (m, 1 H, CH ₂ ), 3.75 (m, 1 H, CH ₂ ), 1.56 (s, 9H, 3 CH ₃ ). Step 2 - Synthesis of 1-Amino-/V'-phenylmethanesulfonohydrazide

[0243] fe/ -Butyl (((2-phenylhydrazinyl)sulfonyl)methyl)carbamate (100 mg, 0.331 mmol) was dissolved in dichloromethane (10 mL) and cooled, followed by the addition of trifluoroacetic acid (50 pL, 0.663 mmol). The reaction was allowed to warm to room temperature and stirred for 3 hours. The reaction mixture was washed with saturated sodium bisulfite solution, then the organic layer was dried and concentrated to obtain the product in quantitative yield as an orange oil (66 mg). d _H (400 MHz, CDCI ₃ ) 7.89 (d, 2H, ArH), 7.58 (m, 2H, ArH), 6.78 (d, 1 H, ArH), 4.15 (m, 2H, CH ₂ ).

Starting Material D 1-Amino-/V'-(5-nitropyridin-2-yl)methanesulfonohydrazide

Step 1 - Synthesis of fert-Butyl (((2-(5-nitropyridin-2- yl)hydrazinyl)sulfonyl)methyl)carbamate

[0244] To a stirred solution of 2-hydrazinyl-5-nitropyridine (78 mg, 0.50 mmol) in dry tetrahydrofuran (5 ml_), 4-methylmorpholine (157 mI_, 1.42 mmol) was added and the solution was cooled to 0 °C. Dropwise addition of a solution of ferf-butyl (2-

(chlorosulfonyl)ethyl)carbamate (112 mg, 0.46 mmol) in dry tetrahydrofuran (10 ml_) was performed while maintaining the temperature at 0 °C. The reaction mixture was stirred for 1 hour at 0 °C then allowed to warm to room temperature overnight. The reaction mixture was concentrated under vacuum and the resulting crude was diluted with ethyl acetate and washed consecutively with 1 M KHS0 ₄ (aq), brine, 5% NaHC0 ₃ (aq) and brine. The organic layer was dried and concentrated under vacuum to obtain the product as an orange oil (88 mg, 57%). d _H (400 MHz, CDCI ₃ ) 8.35 (s, 1 H, NH), 8.04 (d, 1 H, NH), 8.32 (d, 1 H, ArH), 7.29 (s, 1 H, ArH), 7.21 (d, 1 H, ArH), 4.60 (s, 2H, CH ₂ ), 1.46 (s, 9H, 3 CH ₃ ).

Step 2 - Synthesis of 1-Amino-/V'-(5-nitropyridin-2-yl)methanesulfonohydrazide

[0245] fenf-Butyl (((2-(5-nitropyridin-2-yl)hydrazinyl)sulfonyl)methyl)carbama te (50 mg, 0.143 mmol) was dissolved in dichloromethane (5 ml.) and cooled, followed by addition of trifluoroacetic acid (22 mI_, 0.287 mmol) and the reaction was warmed to room temperature and stirred for 3 hours. The reaction mixture was washed with saturated sodium bisulfite solution. The organic layer was dried and concentrated to obtain the product in quantitative yield as an orange oil (35 mg). d _H (400 MHz, CDCI ₃ ) 8.40 (s, 1 H, NH), 8.04 (d, 1 H, NH), 8.32 (d, 1 H, ArH), 7.80 (m, 1 H, ArH), 7.29 (s, 1 H, ArH), 4.75 (s, 2H, CH ₂ ).

Example 1 - Synthesis of 2,6-Dioxo-6-(2-phenylhydrazinyl)hexanoic acid

[0246] Freshly prepared 6-chloro-2,6-dioxohexanoic acid (153 mg, 0.861 mmol) was dissolved in dichloromethane (15 mL) and cooled. Triethylamine (360 mI_, 2.58 mmol) and phenylhydrazine (93 mI_, 0.947 mmol) was added and the reaction mixture was stirred on the ice bath for 1 hour, allowed to warm to room temperature and then stirred overnight at room temperature. The resulting solution was washed with water, brine, then dried and concentrated. Column chromatography using 30% ethyl acetate: hexane gave the product as a brown oil (60 mg, 22%). d _H (400 MHz, CDCI ₃ ) 7.96 (m, 3H, ArH), 7.66 (m, 2H, ArH), 3.01 (m, 2H, CH ₂ ), 2.67 (m, 4H, 2CH ₂ ).

Example 2 - Synthesis of 2,7-Dioxo-7-(2-phenylhydrazinyl)heptanoic acid

[0247] Freshly prepared 7-chloro-2,7-dioxoheptanoic acid (190 mg, 0.98 mmol) was dissolved in dichloromethane (15 ml.) and cooled. Triethylamine (413 pl_, 2.97 mmol) and phenylhydrazine (107 mI_, 1.08 mmol) were added and the reaction mixture was stirred on an ice bath for 1 hour. After allowing the reaction to warm to room temperature, the reaction was then stirred at overnight at room temperature. The reaction was washed with water and then brine, then dried and concentrated. Column chromatography using 30% ethyl acetate: hexane gave the product as a brown oil (15 mg, 23%). d _H (400 MHz, CDCI ₃ ) 7.89 (t, 2H, ArH), 7.72 (d, 1 H, ArH), 7.58 (t, 2H, ArH), 3.48 (m, 4H, 2CH ₂ ), 2.91 (m, 4H, 2CH ₂ ).

Example 3- Synthesis of Methyl 2,8-dioxo-8-(2-phenylhydrazinyl)octanoate

[0248] Freshly prepared methyl 8-chloro-2,8-dioxooctanoate (36 mg, 0.161 mmol) was dissolved in dichloromethane (5 ml.) and cooled. Triethylamine (67 mI_, 0.43 mmol) and phenylhydrazine (20 mI_, 0.177 mmol) were then added. The reaction mixture was stirred on an ice bath for 1 hour, allowed to warm to room temperature then stirred overnight at room temperature. The resulting solution was washed with water and brine, then dried and concentrated in vacuo to obtain the crude material. Column chromatography using 30% ethyl acetate: hexane gave the product as a brown oil (15 mg, 23%). d _H (400 MHz, CDCI ₃ ) 8.32 (d, 1 H, NH), 8.17 (d, 1 H, NH), 7.51 (m, 3H, ArH), 7.39 (m, 2H, ArH), 3.35 (s, 3H, CH ₃ ), 3.65 (m, 4H, 2CH ₂ ), 3.40 (m, 4H, 2CH ₂ ), 2.19 (m, 2H, CH ₂ ).

Example 4 - Synthesis of 2,8-Dioxo-8-(2-phenylhydrazinyl)octanoic acid [0249] Methyl 2,8-dioxo-8-(2-phenylhydrazinyl)octanoate (20 mg, 0.068 mmol) from example 3 was dissolved in methanol, then methanolic sodium hydroxide (2M, 70 pL) was added. The reaction mixture was heated to 50 °C for 2 hours then concentrated. The residue was diluted with ethyl acetate and washed with 2M HCI, water and then dried. Concentration under vacuum gave the pure compound as a pale yellow oil (11 mg, 58%). d _H (400 MHz, CDCI ) 7.48 (m, 3H, ArH), 7.21 (m, 2H, ArH), 2.64 (m, 4H, 2CH ₂ ), 2.35 (m, 4H, 2CH ₂ ), 2.11 (m, 2H, CH ₂ ).

Example 5 - Synthesis of Ethyl 2-oxo-2-((2-((2-phenylhydrazinyl)sulfonyl)ethyl) amino)acetate

[0250] 2-Amino-/V'-phenylethane-1-sulfonohydrazide (30 mg, 0.135 mmol) was dissolved in dry dichloromethane (3 ml.) and the mixture was cooled on an ice bath. Addition of triethylamine (40 pL, 0.278 mmol) was followed by dropwise addition of a solution of ethylchlorooxoacetate (16 pL, 0.135 mmol). The reaction mixture was warmed to room temperature slowly and stirred at room temperature overnight. The reaction mixture was washed with water, 2M HCI, saturated sodium bicarbonate and brine. The organic layer was dried and concentrated. The crude product was washed with ether to obtain the product as a pale yellow oil (10 mg, 22%). d _H (400 MHz, CDCI ₃ ) 7.96 (t, 2H, ArH), 7.66 (d, 1 H, ArH), 7.60 (t,

2H, ArH), 4.31 (m, 2H, CH ₂ ), 3.79 (m, 2H, CH ₂ ), 3.01 (m, 2H, CH ₂ ), 1.35 (m, 3H, CH ₃ ).

Example 6 - Synthesis of 2-Oxo-2-((2-((2-phenylhydrazinyl)sulfonyl)ethyl)amino)acetic acid

[0251] Ethyl 2-oxo-2-((2-((2-phenylhydrazinyl)sulfonyl)ethyl)amino)acetat e (25 mg, 0.079 mmol) was dissolved in ethanol. To the solution, addition of ethanolic sodium hydroxide (2M, 80 pL) was performed and the mixture was heated to 50 °C for 2 hours. The resulting mixture was concentrated and the residue was diluted with ethyl acetate. The resulting solution was washed with 2M HCI, water and dried prior to concentrating under vacuum to obtain the pure compound as a pale yellow oil (10 mg, 44%). d _H (400 MHz, CDCI ₃ ) 7.88 (t, 2H, ArH), 7.56 (d, 1 H, ArH), 7.50 (t, 2H, ArH), 4.25 (m, 2H, CH ₂ ), 3.98 (m, 2H, CH ₂ ). Example 7 - Synthesis of Methyl 2,6-dioxo-6-((2-((2-phenylhydrazinyl)sulfonyl)ethyl) amino)hexanoate

[0252] 2-Amino-/V'-phenylethane-1-sulfonohydrazide (70 mg, 0.325 mmol) was dissolved in dry dichloromethane (5 ml.) and the mixture was cooled on an ice bath. Addition of triethylamine (90 mI_, 0.650 mmol) was followed by dropwise addition of a solution of methyl 6- chloro-2,6-dioxohexanoate (63 mg, 0.325 mmol). The reaction mixture was warmed to room temperature slowly and stirred at room temperature overnight. The reaction mixture was washed with water, 2M HCI, saturated sodium bicarbonate and brine. The organic layer was dried and concentrated. The crude product was washed with ether to obtain the product as a yellow oil (74 mg, 56%). d _H (400 MHz, CDCI ₃ ) 7.96 (t, 2H, ArH), 7.66 (d, 1 H, ArH), 7.60 (t, 2H ArH), 3.93 (s, 3H, CH ₃ ), 3.73 (m, 2H , CH ₂ ), 3.46 (m, 2H, CH ₂ ), 2.99 (m, 2H, CH ₂ ), 2.58 (m, 4H

2CH ₂ ).

Example 8 - Synthesis of 2,6-Dioxo-6-((2-((2-phenylhydrazinyl)sulfonyl)ethyl)amino) hexanoic acid

[0253] Methyl 2,6-dioxo-6-((2-((2-phenylhydrazinyl)sulfonyl)ethyl)amino)he xanoate (50 mg, 0.134 mmol) was dissolved in methanol and addition of methanolic sodium hydroxide (2M, 140 pL) was performed. Reaction mixture was stirred at room temperature for 5 hours then concentrated. The residue was diluted with ethyl acetate and then washed with 2M HCI, water and dried prior to concentrating under vacuum to obtain the pure compound as a pale yellow oil (25 mg, 52%). d _H (400 MHz, CDCI ₃ ) 7.96 (t, 2H, ArH), 7.66 (d, 1 H, ArH), 7.60 (t, 2H , ArH), 2.66 (t, 2H, CH ₂ ), 2.10 (t, 4H, CH ₂ ), 1 .49 (m , 4H , CH2)..

Example 9 - Synthesis of Methyl 2,7-dioxo-7-((2-((2-phenylhydrazinyl)sulfonyl)ethyl) aminojheptanoate

[0254] 2-Amino-/V'-phenylethane-1-sulfonohydrazide (100 mg, 0.464 mmol) was dissolved in dry dichloromethane (10 ml_) and the mixture was cooled on an ice bath. Addition of triethylamine (130 pL, 0.929 mmol) was followed by dropwise addition of a solution of methyl 6- chloro-2,6-dioxohexanoate (92 mg, 0.464 mmol). The reaction mixture was allowed to warm to room temperature slowly overnight, then washed with water, 2M HCI, saturated sodium bicarbonate and brine. The organic layer was dried and concentrated. The crude product was washed with ether to obtain the product as an orange oil (83 mg, 46%). d _H (400 MHz, CDCI ₃ ) 7.96 (t, 2H, ArH), 7.66 (d, 1 H, ArH), 7.60 (t, 2H, ArH), 3.89 (s, 3H, CH ₃ ), 2.93 (m, 8H, 4CH ₂ ).

Example 10 - Synthesis of 2,7-Dioxo-7-((2-((2-phenylhydrazinyl)sulfonyl)ethyl)amino) heptanoic acid

[0255] Methyl 2,7-dioxo-7-((2-((2-phenylhydrazinyl)sulfonyl)ethyl)amino)he ptanoate (50 mg, 0.129 mmol) was dissolved in methanol and addition of methanolic sodium hydroxide (2M, 130 pl_) was performed. Reaction mixture was stirred at room temperature for 5 hours and the resulting mixture was concentrated and the residue was diluted with ethyl acetate. Resulted solution was washed with 2M HCI, water and dried prior to concentrating under vacuum for obtaining the pure compound as a pale yellow oil (20 mg, 41%). d _H (400 MHz, CDCI ₃ ) 7.88 (t, 2H, ArH), 7.75 (d, 1 H, ArH), 7.48 (t, 2H, ArH), 2.10 (m, 4H, 2 CH ₂ ), 1.48 (m, 4H, 2 CH ₂ ).

Example 11 - Synthesis of Methyl 2,8-dioxo-8-((2-((2-phenylhydrazinyl)sulfonyl)ethyl) amino)octanoate

[0256] 2-Amino-/V'-phenylethane-1-sulfonohydrazide (100 mg, 0.464 mmol) was dissolved in dry dichloromethane (10 mL) and the mixture was cooled on an ice bath. Addition of triethylamine (130 pL, 0.929 mmol) was followed by dropwise addition of a solution of methyl 8- chloro-2,8-dioxooctanoate (103 mg, 0.464 mmol). The reaction mixture was warmed to room temperature slowly and stirred at room temperature overnight. The reaction mixture was washed with water, 2M HCI, saturated sodium bicarbonate and brine. The organic layer was dried and concentrated. The crude product was washed with ether to obtain the product as an orange oil (96 mg, 52%). d _H (400 MHz, CDCI ₃ ) 7.96 (t, 2H, ArH), 7.66 (d, 1 H, ArH), 7.60 (t, 2H, ArH), 3.87 (s, 3H, CH ₃ ), 2.90 (t, 2H. CH ₂ ), 2.86 (t, 2H. CH ₂ ), 1.74 (m, 2H, CH ₂ ), 1.67 (m, 2H, CH ₂ ), 1.40 (m, 2H, CH ₂ ). Example 12 - Synthesis of 2,8-Dioxo-8-((2-((2-phenylhydrazinyl)sulfonyl)ethyl)amino) octanoic acid

[0257] Methyl 2,8-dioxo-8-((2-((2-phenylhydrazinyl)sulfonyl)ethyl)amino)oc tanoate (50 mg, 0.125 mmol) was dissolved in methanol and addition of methanolic sodium hydroxide (2M, 125 mI_) was performed. Reaction mixture was stirred at room temperature for 5 hours and the resulting mixture was concentrated and the residue was diluted with ethyl acetate. Resulted solution was washed with 2M HCI, water and dried prior to concentrating under vacuum for obtaining the pure compound as a pale yellow oil (23 mg, 48%). d _H (400 MHz, CDCI ₃ ) 7.96 (t, 2H, ArH), 7.66 (d, 1 H, ArH), 7.60 (t, 2H, ArH), 2.85 (t, 2H, CH ₂ ), 2.36 (t, 2H, CH ₂ ), 1.66 (m, 2H, CH ₂ ), 1.41 (m, 2H, CH ₂ ).

Example 13 - Synthesis of Methyl 2,6-dioxo-6-(2-phenylhydrazinyl)hexanoate

[0258] Freshly prepared methyl 6-chloro-2,6-dioxohexanoate (110 mg, 0.57 mmol) was dissolved in dichloromethane (10 mL) and cooled. Triethylamine (240 pL, 1.72 mmol) and phenylhydrazine (57 pL, 0.57 mmol) were then added. The reaction mixture was stirred on an ice bath for 1 hour, allowed to warm to room temperature then stirred overnight at room temperature. The resulting solution was washed with water and brine, then dried and concentrated in vacuo to obtain the crude material. Column chromatography using 20% ethyl acetate: hexane gave the product as a brown oil (250 mg, 44%). d _H 7.88 (m, 3H, ArH), 7.72 (m, 2H, ArH), 3.28 (s, 3H, CH ₃ ), 3.05 (m, 2H, CH ₂ ), 2.76 (m, 4H, 2CH ₂ ).

Example 14 - Synthesis of Methyl 2,7-dioxo-7-(2-phenylhydrazinyl)heptanoate

[0259] Freshly prepared methyl 7-chloro-2,7-dioxoheptanoate (108 mg, 0.53 mmol) was dissolved in dichloromethane (10 mL) and cooled. Triethylamine (222 mI_, 1.59 mmol) and phenylhydrazine (52 mI_, 0.531 mmol) were then added. The reaction mixture was stirred on an ice bath for 1 hour, allowed to warm to room temperature then stirred overnight at room temperature. The resulting solution was washed with water and brine, then dried and concentrated in vacuo to obtain the crude material. Column chromatography using 30% ethyl acetate: hexane gave the product as a brown oil (285 mg, 54%). d _H (400 MHz, CDCI ₃ ) 7.75 (t, 2H, ArH), 7.68 (d, 1 H, ArH), 7.52 (t, 2H, ArH), 3.58 (s, 3H, CH ₃ ),3.38 (m, 4H, 2CH ₂ ), 2.85 (m, 4H, 2CH ₂ ). Example 15 - Synthesis of Methyl 2,8-dioxo-8-((((2-phenylhydrazinyl) sulfonyl)

methyl)amino)octanoate

[0260] Freshly prepared methyl 8-chloro-2,8-dioxooctanoate (163 mg, 0.74 mmol) was dissolved in dichloromethane (10 ml.) and cooled. To the cold solution addition of triethylamine (310 pL, 2.22 mmol) followed by the addition of a solution of 1-amino-/V'-(5-nitropyridin-2- yl)methanesulfonohydrazide (150 mg, 0.74 mmol) in dichloromethane (3 ml_) was performed maintaining the temperature. The resulting reaction mixture was kept at 0 °C for 1 hour and overnight at room temperature. Reaction mixture was washed successively with water, brine and the dried dichloromethane layer was concentrated under vacuum. The crude product was subjected to column chromatography in 30% ethyl acetate: hexane to obtain the product as an orange oil (152 mg, 53%). d _H (400 MHz, CDCI ₃ ) 8.89 (t, 2H, ArH), 7.60 (d, 1 H, ArH), 7.52 (t, 2H, ArH), 4.68 (s, 2H, CH ₂ ), 3.60 (s, 3H, CH ₃ ), 1.84 (m, 4H, CH ₂ ), 1.72 (m, 4H, CH ₂ ), 1.34 (m, 2H, CH ₂ ).

Example 16 - Synthesis of 2,8-Dioxo-8-((((2-phenylhydrazinyl)sulfonyl)methyl)amino) octanoic acid

[0261] Methyl 2,8-dioxo-8-((((2-phenylhydrazinyl)sulfonyl)methyl)amino)oct anoate (100 mg, 0.260 mmol) was dissolved in methanol and addition of methanolic sodium hydroxide (2M, 250 pl_) was performed. Reaction mixture was stirred at room temperature for 3 hours and the resulting mixture was concentrated and the residue was diluted with ethyl acetate. The resulting solution was washed with 2M HCI, water and dried prior to concentrating under vacuum to obtain the pure compound as a pale orange oil (56 mg, 58%). d _H (400 MHz, CDCI ₃ ) 8.89 (t, 2H, ArH), 7.60 (d, 1 H, ArH), 7.52 (t, 2H, ArH), 4.70 (s, 2H, CH ₂ ),2.91 (t, 2H. CH ₂ ), 2.78 (t, 2H. CH ₂ ), 1.73 (m, 2H, CH ₂ ), 1.58 (m, 2H, CH ₂ ), 1.39 (m, 2H, CH ₂ ).

Example 17 - Synthesis of Methyl 8-((((2-(5-nitropyridin-2-yl)hydrazinyl)sulfonyl) methyl)amino)-2,8-dioxooctanoate

[0262] Freshly prepared methyl 8-chloro-2,8-dioxooctanoate (163 mg, 0.74 mmol) was dissolved in dichloromethane (10 ml_) and cooled. To the cold solution triethylamine (310 pl_, 2.22 mmol) was added followed by the addition of a solution of 1-amino-/V'-(5-nitropyridin-2- yl)methanesulfonohydrazide (163 mg, 0.74 mmol) in dichloromethane (3 ml_) was performed maintaining the temperature. The resulting reaction mixture was kept at 0 °C for 1 hour and overnight at room temperature. Reaction mixture was washed successively with water, brine and the dried dichloromethane layer was concentrated under vacuum. The crude product was subjected to column chromatography in 20% ethyl acetate: hexane to obtain the product as an bright red oil (153 mg, 48%). d _H (400 MHz, CDCI ₃ ) 8.32 (d, 1 H, ArH), 7.29 (s, 1 H, ArH), 7.21 (d, 1 H, ArH), 4.68 (s, 2H, CH ₂ ), 3.60 (s, 3H, CH ₃ ), 1.84 (m, 4H, CH ₂ ), 1.72 (m, 2H, CH ₂ ), 1.34 (m, 4H, CH ₂ ).

Example 18 - Synthesis of 8-((((2-(5-Nitropyridin-2-yl)hydrazinyl)sulfonyl)methyl) amino)- 2,8-dioxooctanoic acid

[0263] Methyl 8-((((2-(5-nitropyridin-2-yl)hydrazinyl)sulfonyl)methyl)amin o)-2,8- dioxooctanoate (76 mg, 177 mmol) was dissolved in dichloromethane (5 ml.) and methanol (2 ml_). Addition of methanolic sodium hydroxide (2M, 500 pl_) was performed and the reaction mixture was stirred at room temperature for 4 hours. The resulting solution was concentrated and diluted with ethyl acetate and washed with 2M HCI, water and brine. The dried organic layer was concentrated to obtain the pure product as a pale brown oil (50 mg, 67%). d _H (400 MHz, CDCI ₃ ) 8.30 (d, 1 H, ArH), 7.32 (s, 1 H, ArH), 7.41 (d, 1 H, ArH), 4.60 (s, 2H, CH ₂ ), 1.84 (m, 4H, CH ₂ ), 1.72 (m, 2H, CH ₂ ), 1.40 (m, 4H, CH ₂ ). Example 19 - Synthesis of Methyl 8-(2-(5-nitropyridin-2-yl)hydrazinyl)-2,8-dioxooctanoate

[0264] Freshly prepared methyl 8-chloro-2,8-dioxooctanoate (109 mg mg, 0.49 mmol) was dissolved in dichloromethane (10 mL) and cooled. Triethylamine (206 mI_, 1.48 mmol) and 2- hydrazinyl-5-nitropyridine (76 mg, 0.49 mmol) were then added. The reaction mixture was stirred on an ice bath for 1 hour, allowed to warm to room temperature then stirred overnight. The resulting solution was washed with water and brine, then dried and concentrated in vacuo to obtain the crude material. Column chromatography using 40% ethyl acetate: hexane gave the product as an orange oil (80 mg, 58%). d _H (400 MHz, CDCI ₃ ) 8.32 (s, 1 H, ArH), 8.17 (s, 1 H, ArH), 7.51 (s, 1 H, ArH), 3.65 (m, 4H, 2CH ₂ ), 3.45 (s, 3H, CH ₃ ), 3.40 (m, 4H, 2CH ₂ ), 2.19 (m, 2H, CH ₂ ).

Example 20 - Synthesis of Methyl 7-((2-((2-(5-nitropyridin-2-yl)hydrazinyl)sulfonyl)ethyl) amino)-2,7-dioxoheptanoate

[0265] Freshly prepared methyl 7-chloro-2,7-dioxoheptanoate (118 mg, 0.57 mmol) was dissolved in dichloromethane. To the cold solution triethylamine (310 pl_, 2.22 mmol) was added as well as 2-amino-A/'-(5-nitropyridin-2-yl)ethane-1-sulfonohydrazide (150 mg, 0.57 mmol) in dichloromethane (3 mL) whilst maintaining the temperature. The resulting reaction mixture was kept at 0 °C for 1 hour and overnight at room temperature. Reaction mixture was washed successively with water, brine and the dried dichloromethane layer was concentrated under vacuum. The crude product was subjected to column chromatography in 20% ethyl acetate: hexane to obtain the product as a red oil (102 mg, 41 %). d _H (400 MHz, CDCI ₃ ) 8.32 (d, 1 H, ArH), 7.29 (s, 1 H, ArH), 7.21 (d, 1 H, ArH), 4.20 (m, 2H, CH ₂ ), 3.99 (m, 2H, CH ₂ ), 3.89 (s, 3H, CH ₃ ), 2.93 (m, 4H, 4CH ₂ ), 2.76 (m, 4H, 4CH ₂ ). Example 21 - Synthesis of Methyl 2,6-dioxo-6-((3-((2-phenylhydrazinyl)sulfonyl)propyl) amino)hexanoate

[0266] Freshly prepared methyl 6-chloro-2,6-dioxohexanoate (46 mg, 0.264 mmol) was dissolved in dichloromethane (5 ml.) and the solution was cooled to 0 °C using an ice bath. The addition of triethylamine (1 10 mI_, 0.79 mmol) was followed by the addition of a solution of 3- amino-/V'-phenylpropane-1-sulfonohydrazide (60 mg, 0.26 mmol) in dichloromethane (2 mL) while maintaining the temperature. The resulting reaction mixture was stirred at 0 °C for 1 hour and then overnight at room temperature. After successive washes with water and brine, the dried dichloromethane layer was concentrated in vacuo. The crude product was subjected to column chromatography in 40% EtOAc: Hex to obtain the product as a red oil (75 mg, 78%). d _H (400 MHz, CDCIs) 8.80 (t, 2H, ArH), 7.78 (d, 1 H, ArH), 7.55 (t, 2H, ArH), 3.77 (m, 2H, CH ₂ ), 3.35 (m, 2H, CH ₂ ), 3.27 (s, 3H, CH ₃ ), 3.02 (m, 2H, CH ₂ ), 2.85 (m, 2H, CH ₂ ), 2.77 (m, 4H,CH ₂ ).

Example 22 - Synthesis of 2,6-Dioxo-6-((3-((2-phenylhydrazinyl)sulfonyl) propyl)amino)hexanoic acid

[0267] Methyl 2,6-dioxo-6-((3-((2-phenylhydrazinyl)sulfonyl)propyl)amino)h exanoate (50 mg, 0.129 mmol) was dissolved in methanol and then addition of methanolic sodium hydroxide (2M, 250 pl_) was performed. The reaction mixture was stirred at room temperature for 3 hours, then concentrated in vacuo and the residue was diluted with ethyl acetate. The resulting solution was washed with 2M HCI, water and dried prior to concentrating in vacuo to obtain the pure compound as a pale orange oil (40 mg, 85%). d _H (400 MHz, CDCI ₃ ) 8.80 (t, 2H, ArH), 7.77 (d, 1 H, ArH), 7.56 (t, 2H, ArH), 3.77 (m, 2H, CH ₂ ), 3.33 (m, 2H, CH ₂ ), 3.00 (m, 2H, CH ₂ ), 2.85 (m, 2H, CH ₂ ), 2.76 (m, 4H,CH ₂ ). Example 23 - Synthesis of Methyl 6-((3-((2-(5-nitropyridin-2-yl)hydrazinyl)sulfonyl)propyl) amino)-2,6-dioxohexanoate

[0268] Freshly prepared methyl 6-chloro-2,6-dioxohexanoate (44 mg, 0.252 mmol) was dissolved in dichloromethane (5 ml.) and the solution was cooled to 0 °C using an ice bath. Triethylamine (105 mI_, 0.75 mmol) was then added followed by the addition of a solution of 3- amino-N'-(5-nitropyridin-2-yl)propane-1-sulfonohydrazide (70 mg, 0.25 mmol) in dichloromethane (3 ml.) while maintaining the temperature. The solution was stirred at 0 °C for 1 hour and overnight at room temperature. Successive washing with water and brine was undertaken, them the dried dichloromethane layer was concentrated in vacuo. The crude product was subjected to column chromatography in 30% EtOAc: Hex to obtain the product as an orange red oil (78 mg, 72%). d _H (400 MHz, CDCI ₃ ) 8.98 (d, 1 H, ArH), 8.37 (d, 1 H, ArH), 7.30 (d, 1 H, ArH), 4.20 (t, 2H, CH ₂ ), 3.33 (m, 2H, CH ₂ ), 3.25 (s, 3H, CH ₃ ), 3.00 (m, 2H, CH ₂ ), 2.83 (m, 2H, CH ₂ ), 2.75 (m, 4H,CH ₂ ).

Example 24 - Synthesis of 6-((3-((2-(6-Nitropyridin-3-yl)hydrazinyl)sulfonyl)propyl) amino)-2,6-dioxohexanoic acid

[0269] Methyl 6-((3-((2-(5-nitropyridin-2-yl)hydrazinyl)sulfonyl)propyl)am ino)-2,6- dioxohexanoate (50 mg, 0.115 mmol) was dissolved in methanol followed by the addition of methanolic sodium hydroxide (2M, 250 pl_). The reaction mixture was stirred at room temperature for 3 hours and was then concentrated in vacuo. The residue was diluted with ethyl acetate and washed with 2M HCI, water. After drying and concentration in vacuo, the pure compound was obtained as a pale orange oil (32 mg, 66%). d _H (400 MHz, CDCI ₃ ) 8.99 (d, 1 H, ArH), 8.35 (d, 1 H, ArH), 7.35 (d, 1 H, ArH), 4.20 (t, 2H, CH ₂ ), 3.31 (m, 2H, CH ₂ ), 3.02 (m, 2H, CH ₂ ), 2.85 (m, 2H, CH ₂ ), 2.70 (m, 4H,CH ₂ ). Example 25 - Synthesis of 7-((2-((2-(5-nitropyridin-2-yl)hydrazinyl)sulfonyl)ethyl)ami no)- 2,7-dioxoheptanoic acid

[0270] Methyl 7-((2-((2-(5-nitropyridin-2-yl)hydrazinyl)sulfonyl)ethyl)ami no)-2,7- dioxoheptanoate (100 mg, 0.23 mmol) was dissolved in dichloromethane (5 ml.) and methanol (2 ml_). Addition of methanolic sodium hydroxide (2M, 750 pl_) was performed and the reaction mixture was stirred at room temperature for 4 hours. The resulting solution was concentrated and diluted with ethyl acetate and washed with 2M HCI, water and brine. The dried organic layer was concentrated to obtain the pure product as a pale brown oil (59 mg, 60%). d _H (400 MHz, CDCI ₃ ) 8.30 (d, 1 H, ArH), 7.30 (s, 1 H, ArH), 7.23 (d, 1 H, ArH), 4.20 (m, 2H, CH ₂ ), 3.89 (m, 2H, CH ₂ ), 2.90 (m, 4H, 4CH ₂ ), 2.70 (m, 4H, 4CH ₂ ).

Example 26 - Synthesis of 6-Methoxy-5,6-dioxohexanoic acid

Step 1 - Synthesis of Methyl 2-oxocyclopentane-1-carboxylate

O

⁽ /

[0271] Sodium hydride (60% dispersion in mineral oil) (140 mmol, 5.6 g) and toluene (80 ml.) were mixed, then dimethyl carbonate (125 mmol, 10.5 ml.) in toluene (13 ml_) was added. The reaction was refluxed for 1 hour. Dropwise addition of a solution of cyclopentanone (50 mmol, 4.5 ml.) in toluene (6 ml.) was performed via the dropping funnel. A suspension formed immediately. The mixture was refluxed for 3 hours. The reaction was cooled to room temperature slowly after the reflux and further cooling was performed on a salt-ice bath. Reaction was quenched by slow addition of acetic acid (200 ml.) and water (100 ml_). The mixture was extracted with ethyl acetate (3 times), dried over magnesium sulphate and concentrated to obtain the crude which was washed with hexane to obtain the product as a dark brown solid in quantitative yield (7.1 g). d _H (400 MHz, CDCI ₃ ) 3.75 (s, 3H, CH ₃ ), 3.17 (t, 1 H, CH), 1.87 (m, 2H, CH ₂ ), 1.70 (m, 4H, 2CH ₂ ). Step 2 - Synthesis of Synthesis of 6-Methoxy-5,6-dioxohexanoic acid

[0272] Sodium hydride (60% dispersion in mineral oil) (25.0 mmol, 0.59 g) and tetrahydrofuran (25 mL) were mixed, then a solution of methyl 2-oxocyclopentane-1-carboxylate (25.0 mmol, 3.5 g) in tetrahydrofuran (100 mL) was added dropwise at room temperature. The reaction mixture was cooled to 0 °C, followed by dropwise addition of a solution of nitrosobenzene (25.8 mmol, 2.21 g) in tetrahydrofuran (25 mL) while maintaining the temperature at 0 °C. The reaction mixture was slowly warmed to room temperature after the complete addition of nitrosobenzene solution. The reaction mixture was stirred for 30 minutes at room temperature. Reaction was quenched by adding 1M HCI (50 mL) dropwise to the reaction mixture at room temperature. The resulting mixture was extracted with ethyl acetate and combined organic layer were dried. Column chromatography was performed with 20% ethyl acetate and hexane to obtain the pure product as an orange brown oil (3.4 g, 80%). d _H (400 MHz, CDCI ₃ ) 3.87 (s, 3H,CH ₃ ), 2.96 (t, 2H, CH ₂ ), 2.45 (t, 2H, CH ₂ ), 1.98 (t, 2H, CH ₂

Example 27 - Synthesis of 2-Oxohexanedioic acid

[0273] 6-Methoxy-5,6-dioxohexanoic acid (175 mg, 1.12 mmol) was dissolved in 10% methanol: dichloromethane (5 mL) and addition of methanolic NaOH (2.5 M, 538 pL) was added dropwise. The yellow solid was collected after 1.5 hours in sufficient purity (110 mg, 60%). d _H (400 MHz, D ₂ 0) 2.66 (t, 2H, CH ₂ ), 2.10 (t, 4H, CH ₂ ).

Example 28 - Synthesis of 7-Methoxy-6,7-dioxoheptanoic acid

Step 1 - Synthesis of Methyl 2-oxocyclohexane-1-carboxylate

[0274] Sodium hydride (60% dispersion in mineral oil) (213 mmol, 5.10 g) and toluene (80 mL) were mixed then dimethyl carbonate (90 mmol, 7.6 mL) in toluene (8 mL) was added. The reaction was refluxed for 1 hour. Dropwise addition of a solution of cyclohexanone (36 mmol, 3.8 mL) in toluene (8 mL) was performed via the dropping funnel. A suspension formed immediately. The mixture was refluxed for 3 hours. The reaction was cooled to room temperature slowly after the reflux and further cooling was performed on a salt-ice bath. Reaction was quenched by slow addition of acetic acid (200 ml.) and water (100 ml_). The mixture was extracted with ethyl acetate (3 times), dried over magnesium sulphate and concentrated to obtain the crude. Colum chromatography was performed using 30% ethyl acetate: hexane to isolate the product as a dark brown oil in quantitative yield (5.6 g). d _H (400 MHz, CDCI ) 3.75 (s, 3H, CH ₃ ), 2.27 (t, 2H, CH ₂ ), 2.22 (t, 2H, CH ₂ ), 1.65 (m, 5H, CH ₂ , CH).

Step 2 - Synthesis of 7-Methoxy-6,7-dioxoheptanoic acid

[0275] Sodium hydride (60% dispersion in mineral oil) (36.0 mmol, 0.86 g) and tetrahydrofuran (36 ml.) were mixed and a solution of methyl 2-oxocyclohexane-1-carboxylate (36.0mmol, 5.62 g) in tetrahydrofuran (144 ml_) was added drop-wise at room temperature. The reaction mixture was cooled to 0 °C, followed by dropwise addition of a solution of nitrosobenzene (37.78 mmol, 4.04 g) in tetrahydrofuran (39 ml.) while maintaining the temperature at 0 °C. The reaction mixture was slowly warmed to room temperature after the complete addition of nitrosobenzene solution. The reaction mixture was stirred for 30 minutes at room temperature. Reaction was quenched by adding 1M HCI (200 mL) dropwise to the reaction mixture at room temperature. The resulting mixture was extracted with ethyl acetate and combined organic layer were dried. Column chromatography was performed with 20% ethyl acetate and hexane to obtain pure product as a brown oil (5.4 g, 79%). d _H (400 MHz, CDCI ₃ )

3.87 (s, 3H, CH ₃ ), 2.88 (t, 2H, CH ₂ ), 2.39 (t, 2H, CH ₂ ), 1.69 (t, 2H, CH ₂ ).

Example 29 - Synthesis of 2-Oxoheptanedioic acid

[0276] Methyl 7-chloro-2,7-dioxoheptanoate (200 mg, 1.06 mmol) was dissolved in 10% methanol: dichloromethane (5 mL) and addition of methanolic NaOH (2.5 M, 510 pL) was added dropwise. The solid was collected after 1.5 hours to obtain the pure compound as a yellow solid (110 mg, 60%). d _H (400 MHz, D ₂ 0) 2.10 (m, 4H, 2 CH ₂ ), 1.48 (m, 4H, 2 CH ₂ ).

Example 30 - Synthesis of 8-Methoxy-7,8-dioxooctanoic acid Step 1 - Synthesis of Methyl 2-oxocycloheptane-1-carboxylate

[0277] Sodium hydride (60% dispersion in mineral oil) (212.5 mmol, 5.10 g) and toluene (80 ml.) were stirred and dimethyl carbonate (90 mmol, 7.6 ml.) in toluene (8 ml.) was added. The reaction was refluxed for 1 hour. Dropwise addition of a solution of cycloheptanone (36 mmol, 4.3 mL) in toluene (6 mL) was performed via a dropping funnel. A suspension formed immediately. The mixture was refluxed for 3 hours. The reaction was then cooled to room temperature slowly and further cooling was performed on a salt-ice bath. The reaction was quenched by the slow addition of acetic acid (200 mL) and water (100 mL). The mixture was extracted with ethyl acetate (3 times), dried over magnesium sulphate and concentrated to obtain the crude material which was washed with hexane to give the product as a dark brown solid in quantitative yield (6.62 g). d _H (400 MHz, CDCI ₃ ) 3.72 (s, 3H, CH ₃ ), 3.55 (d, 1 H, CH ₂ ), 2.61 (m, 2H, CH ₂ ), 2.41 (m, 1 H, CH ₂ ), 1.86 (m, 2H, CH ₂ ), 1.44 (m,2H, CH ₂ ).

Step 2 - Synthesis of 8-Methoxy-7,8-dioxooctanoic acid

[0278] Sodium hydride (60% dispersion in mineral oil) (43.5 mmol, 1.04 g) and tetrahydrofuran (44 mL) were mixed and a solution of methyl 2-oxocycloheptane-1-carboxylate (43.5 mmol, 7.4 g) in tetrahydrofuran (174 mL) was added dropwise. The reaction mixture was cooled to 0 °C, followed by dropwise addition of a solution of nitrosobenzene (43.9 mmol, 4.7 g) in tetrahydrofuran (47 mL) while maintaining the temperature at 0 °C. The reaction mixture was slowly warmed to room temperature after the complete addition of nitrosobenzene solution. The reaction mixture was stirred for 30 minutes at room temperature. Reaction was quenched by adding 1M HCI (200 mL) dropwise to the reaction mixture at room temperature. The resulting mixture was extracted with ethyl acetate and combined organic layer were dried and concentrated in vacuo to yield crude product which was purified by washing with hexane to result in compound as a brown solid (7.4 g, 85%). d _H (400 MHz, CDCI ₃ ) 3.86 (s, 3H, CH ₃ ), 2.85

(t, 2H, CH ₂ ), 2.36 (t, 2H, CH ₂ ), 1.66 (m, 2H, CH ₂ ), 1.41 (m, 2H, CH ₂ ).

Example 31 - Synthesis of 2-Oxooctanedioic acid [0279] 8-Methoxy-7,8-dioxooctanoic acid (150 mg, 0.74 mmol) was dissolved in 10% methanol: dichloromethane (5 ml_) and addition of methanolic NaOH (2.5 M, 360 mI_) was added dropwise. The solid was collected after 1.5 hours to obtain the pure compound as an orange-brown solid (85 mg, 61 %). d _H (400 MHz, D ₂ 0) 2.66 (t, 2H, CH ₂ ), 2.08 (m, 4H, 2 CH ₂ ), 1.47 (m, 4H, 2 CH ₂ ).

Example 32 - DHDPS Inhibition

[0280] The compounds of the invention as discussed above were tested to determine their ability to inhibit DHDPS.

DHDPS-DHDPR Coupled Assay [0281] DHDPS enzyme activity was determined using the coupled DHDPS-DHDPR assay in a Cary 4000 UV/Vis spectrophotometer at 340 nm in 1 cm acrylic cuvettes. A master mix was prepared for each reaction as per Table 1. Reaction mixtures containing DHDPS, DHDPR, pyruvate, buffer and NADPH were incubated at 30°C for 12 mins before the addition of ASA to initiate the reaction. The oxidation of NADPH to NADP ⁺ was then monitored at 340 nm at 30°C as a function of time. The initial rate (AA ₃₄₀ min ') was calculated from the initial slope of the linear portion of the A ₃₄₀ versus time profile. All experiments were carried out in triplicate. The kinetic data were fitted using Equation 1.

Table 1 - Coupled assay master mix

*H ₂ 0 volume was varied according to experiment.

Note: Ec = Escherichia coli

Equation 1

[0282] V = F _max x [S ]I(K _M + [S])

[0283] Where:

[0284] V = initial rate [0285] V _m3K - maximal enzyme velocity/ activity

[0286] K _M = Michaelis-Menten constant

[0287] [S] = concentration of substrate being titrated

Dose Response Inhibitor Assays [0288] To determine /C ₅₀ values for the inhibitors, DHDPS enzyme activity was measured using the coupled assay (detailed above) in the presence of increasing concentrations of inhibitor. The initial rate was plotted as a function of the log ₁₀ of the inhibitor concentration and the /C ₅₀ determined according to Equation 2.

Equation 2

[0289] A = 100/(1 + 10 ^A ((log/C ₅₀ - [I]) * S))

[0290] Where: A = % activity [0291] /C ₅₀ = concentration resulting in 50% inhibition

[0292] [I] = inhibitor concentration S = slope

[0293] The /C ₅₀ values are given in Table 2.

Table 2 - /C ₅₀ values for selected compounds tested against recombinant Escherichia coli DHDPS enzyme. Errors represent standard deviation (n = 3).

[0294] Finally, it will be appreciated that various modifications and variations of the methods and compositions of the invention described herein would be apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the invention has been described in connection with specific preferred embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes for carrying out the invention that is apparent to those skilled in the art are intended to be within the scope of the present invention.