Field of the invention

The present invention relates to new multi-functional compounds that have a beneficial influence on biological processes involved in the ageing process, to the preparation of the compounds, and to compositions including the compounds. The present invention also relates to the use of the compounds, as well as compositions including the compounds, in treating or preventing aetiologies that may result in age- related disorders.

Background of the invention The ageing process involves a multitude of physiological changes, a number of which have been implicated in the development of some of the most common age- related disorders, such as Alzheimer's disease.

Alzheimer's disease (AD), and other related neurodegenerative disorders, are multi-faceted, with a number of contributing pathological alterations including: protein misfolding and β-amyloid aggregation with plaque formation; oxidative stress and reactive oxygen species (ROS) generation; and dysregulation of autophagy, which limits the recycling of misfolded proteins.

While the precise role of ROS in neurodegeneration is unclear, evidence does suggest that redox-active metals and ROS are involved. Notably, Alzheimer's disease is a disease of advancing age, and as iron levels also increase as a function of age, this may lead to increased ROS generation.

In addition, senile plaques have remarkably high iron, copper and zinc levels, and copper and zinc ions are known to facilitate β-amyloid aggregation by modulating amyloid peptide conformation. The role of iron in Alzheimer's disease is further supported by the fact that expression of amyloid precursor protein (APP) is up-regulated by increased cellular iron (as APP plays a role in iron efflux from neuronal cells).

These data led to the assessment of various iron chelators for treatment of Alzheimer's disease. One such chelator (i.e., clioquinol) binds copper and zinc ions, is able to cross the Blood Brain Barrier (BBB) and clinically attenuates cognitive loss. However, clioquinol is associated with myelinopathies and does not decrease brain β- amyloid.

Therefore, there is a need for agents that are effective in treating and/or preventing a number of aetiologies linked to age-related disorders.

Reference to any prior art in the specification is not an acknowledgment or suggestion that this prior art forms part of the common general knowledge in any jurisdiction, or that this prior art could reasonably be expected to be understood, regarded as relevant, and/or combined with other pieces of prior art by a skilled person in the art.

Summary of the invention

The present inventors have surprisingly found that the issues with current agents used in anti-ageing therapy could be overcome by developing one multifunctional agent that is able to address a number of age-related issues, including targeting the main hallmarks of neurodegenerative disorders, as well as increasing a patient's longevity by including other moieties in the agent, such as those that lead to an increase in nicotinamide adenine dinucleotide (NAD).

In a first aspect, the present invention relates to a compound of formula (I):

(I) or a pharmaceutically acceptable salt or prodrug thereof, wherein:

R is independently selected from:

, which group is optionally further substituted by one or more substituents selected from halogen, alkyl and heteroalkyl, and , wherein R ³ is independently selected from H and alkyl, A ¹ , A ² ,

A ³ , A ⁴ and A ⁵ are independently selected from CH and N, and the aromatic ring containing A ¹ , A ² , A ³ , A ⁴ and A ⁵ is optionally substituted with one or more substituents independently selected from halogen, OH, alkyl and heteroalkyl, and is optionally fused to an aryl group, and

R ² is a heteroaryl group.

R ¹ may be , which may be optionally further substituted by one or more substituents independently selected from halogen (e.g., fluorine, chlorine and/or bromine), an alkyl group and a heteroalkyl group.

R ¹ may be . R ³ may be H. R ³ may be Ci to C ₃ alkyl (i.e., methyl, ethyl or propyl). The aromatic ring containing A ¹ , A ² , A ³ , A ⁴ and A ⁵ may be substituted with OH, and one or more additional substituents. The aromatic ring containing A ¹ , A ² , A ³ , A ⁴ and A ⁵ may be substituted with one additional substituent. The one additional substituent may be halogen (e.g., bromine, chlorine or fluorine). The one additional substituent may be an alkyl group (e.g., Ci to C ₃ alkyl). The one additional substituent may be a heteroalkyl group e.g., O-alkyl (such as OCH ₃ , OCH ₂ CH ₃ or OCF ₃ ). The aromatic ring containing A ¹ , A ² , A ³ , A ⁴ and A ⁵ may be substituted with two additional substituents, which may be the same or different {e.g., two halogens, which may be the same or different, or two OH groups). The halogens may be selected from bromine, chlorine and fluorine.

One of A ¹ , A ² , A ³ , A ⁴ and A ⁵ may be N i.e., the aromatic ring containing A ¹ , A ² , A ³ , A ⁴ and A ⁵ may be a heteroaryl group. The heteroaryl group may not be further substituted. Alternatively, the heteroaryl group may be substituted with one or more substituents. The one or more substituents may be independently selected from OH, an alkyl group (e.g. , methyl or ethyl) and a heteroalkyl group (e.g. , CH ₂ OH or CH ₂ CH ₂ OH).

The aromatic ring containing A ¹ , A ² , A ³ , A ⁴ and A ⁵ may be fused (e.g. , at A ² and A ³ , or A ⁴ and A ⁵ ) to an aryl group, to give a bicyclic aryl or heteroaryl group (for example, naphthyl or quinoline). The bicyclic aryl or heteroaryl group may be substituted with one or more substituents selected from OH, alkyl and heteroalkyl.

The N and/or OH substituents may be situated on the aromatic ring containing A ¹ , A ² , A ³ , A ⁴ and A ⁵ such that the compound of formula (I) is able to chelate metal ions (e.g. , iron). Therefore, A ¹ may be selected from N or C-OH. Preferably, A ¹ is C-OH. R ² may be pyridine.

In a second aspect, the present invention relates to a pharmaceutical composition including a compound of formula (I) (according to the first aspect of the invention) together with a pharmaceutically acceptable carrier, diluent or excipient.

Compounds and pharmaceutical compositions according to the present invention may be suitable for treating and/or preventing an aetiology that results in age-related disorders. Accordingly, in another aspect, the present invention relates to a method of treating and/or preventing a detrimental age-related aetiology in a subject, the method including administering to the subject an effective amount of a compound of formula (I) according to the first aspect of the invention or a pharmaceutical composition according to the second aspect of the invention.

In a further aspect the present invention relates to the use of a compound of formula (I) according to the first aspect of the invention or a pharmaceutical composition according to the second aspect of the invention in the manufacture of a medicament for treating and/or preventing a detrimental age-related aetiology. In a further aspect the present invention relates to the use of a compound of formula (I) according to the first aspect of the invention or a pharmaceutical composition according to the second aspect of the invention for the treatment and/or prevention of a detrimental age-related aetiology in a subject.

In a further aspect the present invention relates to a compound of formula (I) according to the first aspect of the invention or a pharmaceutical composition according to the second aspect of the invention for use in the treatment and/or prevention of a detrimental age-related aetiology in a subject. The detrimental age-related aetiology may be due, in part, to: increased ion levels, wherein the ions are selected from one or more of iron, copper and zinc ions (particularly leading to increased levels of these metal ions in the brain); development of plaques that contain high levels of metal ions (e.g., iron, copper and/or zinc); and decreased NAD levels.

The compounds of formula (I) may be used in therapy alone or in combination with one or more other therapeutic agents, for example, as part of a combination therapy.

Further aspects of the present invention and further embodiments of the aspects described in the preceding paragraphs will become apparent from the following description, given by way of example and with reference to the accompanying drawings.

Brief description of the drawings

Figure 1. Effect of compounds 1 -12 on ⁵⁹ Fe mobilisation from prelabelled SK-N-MC cells. Experiment was carried out by pre-labelling cells with ⁵⁹ Fe ₂ -Tf (0.75 μΜ) for 3 h at 37°C followed by washing four times with ice-cold PBS. The cells were then incubated with media alone (control) or media containing the chelators (25 μΜ) for another 3 h at 37°C. Results are presented as the mean ± SD of three independent experiments. ***p < 0.001 versus DFO.

Figure 2. Effect of compounds 1 -12 on inhibiting ⁵⁹ Fe uptake from ⁵⁹ Fe-transferrin ( ⁵⁹ Fe ₂ -Tf) by SK-N-MC neuroepithelioma cells. In these studies, cells were incubated with ⁵⁹ Fe ₂ -Tf (0.75 μΜ) alone (control) or with the chelators (25 μΜ) for 3 h at 37 °C. The cells were then washed four times with ice-cold PBS and subsequently incubated with pronase (1 mg/mL) for 30 min at 4°C. Results are expressed as the mean ± SD of three independent experiments. ***p < 0.001 versus DFO. ^* "p < 0.001 versus CQ. Figure 3. Effect of iron complexes of chelators 1 -12 on the oxidation of ascorbate. The assay was performed using an iron-binding equivalent (IBE) of 1 . The iron(lll) complexes of EDTA, Dp44mT and DFO were used as controls (see text for details). The activity of the control group containing FeC only was taken to be 100%. Results are mean + SD (3 experiments). ***p < 0.001 versus the control. ^* "p < 0.001 versus EDTA. ⁰⁰⁰ p < 0.001 versus Dp44mT. Detailed description of the embodiments

It will be understood that the invention disclosed and defined in this specification extends to all alternative combinations of two or more of the individual features mentioned or evident from the text or drawings. All of these different combinations constitute various alternative aspects of the invention.

Compounds are generally described herein using standard nomenclature. For compounds having asymmetric centres, it will be understood that, unless otherwise specified, all of the optical isomers and mixtures thereof are encompassed. Compounds with two or more asymmetric elements can also be present as mixtures of diastereomers. In addition, compounds with carbon-carbon double bonds may occur in Z and E forms, with all isomeric forms of the compounds being included in the present invention unless otherwise specified. Where a compound exists in various tautomeric forms, a recited compound is not limited to any one specific tautomer, but rather is intended to encompass all tautomeric forms. Recited compounds are further intended to encompass compounds in which one or more atoms are replaced with an isotope, i.e., an atom having the same atomic number but a different mass number. By way of general example, and without limitation, isotopes of hydrogen include tritium and deuterium and isotopes of carbon include ¹¹ C, ¹³ C, and ¹⁴ C.

Compounds according to the formula provided herein, which have one or more stereogenic centres, have an enantiomeric excess of at least 50%. For example, such compounds may have an enantiomeric excess of at least 60%, 70%, 80%, 85%, 90%, 95%, or 98%. Some embodiments of the compounds have an enantiomeric excess of at least 99%. It will be apparent that single enantiomers (optically active forms) can be obtained by asymmetric synthesis, synthesis from optically pure precursors, biosynthesis or by resolution of the racemates, for example, enzymatic resolution or resolution by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example, a chiral HPLC column.

Certain compounds are described herein using a general formula that includes variables such as R ¹ , R ² , R ³ and R ⁴ . Unless otherwise specified, each variable within such a formula is defined independently of any other variable, and any variable that occurs more than one time in a formula is defined independently at each occurrence. Therefore, for example, if a group is shown to be substituted with 0, 1 or 2 R ^* the group may be unsubstituted or substituted with up to two R ^* groups and R ^* at each occurrence is selected independently from the definition of R ^* Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds, i.e., compounds that can be isolated, characterized and tested for biological activity.

A "pharmaceutically acceptable salt" of a compound disclosed herein is an acid or base salt that is generally considered in the art to be suitable for use in contact with the tissues of human beings or animals without excessive toxicity or carcinogenicity, and preferably without irritation, allergic response, or other problem or complication. Such salts include mineral and organic acid salts of basic residues such as amines, as well as alkali or organic salts of acidic residues such as carboxylic acids.

Suitable pharmaceutically acceptable salts include, but are not limited to, salts of acids such as hydrochloric, phosphoric, hydrobromic, malic, glycolic, fumaric, sulfuric, sulfamic, sulfanilic, formic, toluenesulfonic, methanesulfonic, benzenesulfonic, ethane disulfonic, 2-hydroxyethylsulfonic, nitric, benzoic, 2-acetoxybenzoic, citric, tartaric, lactic, stearic, salicylic, glutamic, ascorbic, pamoic, succinic, fumaric, maleic, propionic, hydroxymaleic, hydroiodic, phenylacetic, alkanoic (such as acetic, HOOC-(CH ₂ ) _n -COOH where n is any integer from 0 to 6, i.e., 0, 1 , 2, 3, 4, 5 or 6), and the like. Similarly, pharmaceutically acceptable cations include, but are not limited to sodium, potassium, calcium, aluminum, lithium and ammonium. A person skilled in the art will recognize further pharmaceutically acceptable salts for the compounds provided herein. In general, a pharmaceutically acceptable acid or base salt can be synthesized from a parent compound that contains a basic or acidic moiety by any conventional chemical method. Briefly, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two. Generally, the use of nonaqueous media, such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile, is preferred.

It will be apparent that each compound of formula (I) may, but need not, be present as a hydrate, solvate or non-covalent complex. In addition, the various crystal forms and polymorphs are within the scope of the present invention, as are prodrugs of the compounds of formula (I) provided herein. A "prodrug" is a compound that may not fully satisfy the structural requirements of the compounds provided herein, but is modified in vivo, following administration to a subject or patient, to produce a compound of formula (I) provided herein. For example, a prodrug may be an acylated derivative of a compound as provided herein. Prodrugs include compounds wherein hydroxy, carboxy, amine or sulfhydryl groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxy, carboxy, amino, or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate, phosphate and benzoate derivatives of alcohol and amine functional groups within the compounds provided herein. Prodrugs of the compounds provided herein may be prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved in vivo to generate the parent compounds.

A "substituent" as used herein, refers to a molecular moiety that is covalently bonded to an atom within a molecule of interest. For example, a "ring substituent" may be a moiety such as a halogen, alkyl group, heteroalkyl group, haloalkyl group or other substituent described herein that is covalently bonded to an atom, preferably a carbon or nitrogen atom, that is a ring member. The term "substituted," as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated substituents, provided that the designated atom's normal valence is not exceeded, and that the substitution results in a stable compound, i.e., a compound that can be isolated, characterized and tested for biological activity. When a substituent is oxo, i.e., =0, then two hydrogens on the atom are replaced. An oxo group that is a substituent of an aromatic carbon atom results in a conversion of -CH- to -C(=0)- and a loss of aromaticity. For example a pyridyl group substituted by oxo is a pyridone. Examples of suitable substituents are alkyl (including haloalkyl e.g., CF ₃ ), heteroalkyl, halogen (for example, fluorine, chlorine, bromine or iodine atoms), C(0)OH, C(0)H, OH, =0, SH, SO ₃ H, NH ₂ , NH-alkyl, =NH, N ₃ and NO ₂ groups.

The term "alkyl" refers to a saturated, straight-chain or branched hydrocarbon group that contains from 1 to 20 carbon atoms, preferably from 1 to 10 carbon atoms, for example a n-octyl group, especially from 1 to 6, i.e., 1 , 2, 3, 4, 5, or 6, carbon atoms. Specific examples of alkyl groups are methyl, ethyl, propyl, /so-propyl, n-butyl, /so-butyl, sec-butyl, fe/f-butyl, n-pentyl, /so-pentyl, n-hexyl and 2,2-dimethylbutyl. The term "heteroalkyl" refers to an alkyl group as defined above that contains one or more heteroatoms selected from oxygen, nitrogen and sulphur (especially oxygen and nitrogen). Specific examples of heteroalkyl groups are methoxy, trifluoromethoxy, ethoxy, n-propyloxy, /so-propyloxy, butoxy, fe/f-butyloxy, methoxym ethyl, ethoxym ethyl, -CH2CH2OH, -CH2OH, methoxyethyl, 1 -methoxyethyl, 1 -ethoxyethyl, 2-methoxyethyl or 2-ethoxyethyl, methylamino, ethylamino, propylamino, iso-propylamino, dimethylamino, diethylamino, /so-propyl-ethylamino, methylamino methyl, ethylamino methyl, di-/so- propylamino ethyl, methylthio, ethylthio, /so-propylthio, enol ether, dimethylamino methyl, dimethylamino ethyl, acetyl, propionyl, butyryloxy, acetyloxy, methoxycarbonyl, ethoxycarbonyl, propionyloxy, acetylamino, propionylamino, carboxym ethyl, carboxyethyl, carboxypropyl, /V-ethyl-/V-methylcarbamoyl and /V-methylcarbamoyl. Further examples of heteroalkyl groups are nitrile, /so-nitrile, cyanate, thiocyanate, iso- cyanate, /so-thiocyanate and alkylnitrile groups.

The term "aryl" refers to an aromatic group that contains one or more rings containing from 6 to 14 ring carbon atoms, preferably from 6 to 10 (especially 6) ring carbon atoms. Examples are phenyl, naphthyl and biphenyl groups.

The term "heteroaryl" refers to an aromatic group that contains one or more rings containing from 5 to 14 ring atoms, preferably from 5 to 10 (especially 5 or 6) ring atoms, where one or more of the ring atoms are replaced with one or more (preferably 1 , 2, 3 or 4) oxygen, nitrogen, phosphorus or sulfur ring atoms (preferably 0, S or N). Examples are pyridine, imidazole thiazole, /so-thiazole, 1 ,2,3-triazole, 1 ,2,4-triazole, oxadiazole, thiadiazole, indole, indazole, tetrazole, pyrazine, pyrimidine, pyridazine, oxazole, isoxazole, triazole, tetrazole, isoxazole, indazole, benzimidazole, benzoxazole, benzisoxazole, benzthiazole, pyridazine, quinoline, isoquinoline, pyrrole, purine, carbazole, acridine, and iso-quinoline groups.

The expression "halogen" or "halogen atom" as used herein means fluorine, chlorine, bromine, or iodine.

The term "optionally substituted" refers to a group in which one, two, three or more hydrogen atoms have been replaced independently of each other by, for example, halogen (for example, fluorine, chlorine, bromine or iodine atoms), C(0)OH, C(0)H, OH, =O, SH, =S, SO3H, NH ₂ , NH-alkyl, =NH, N ₃ or NO ₂ groups. This expression also refers to a group that is substituted by one, two, three or more alkyl or heteroalkyl groups. These groups may themselves be substituted. For example, an alkyl group substituent may be substituted by one or more halogen atoms (i.e., may be a haloalkyl group). The term "haloalkyl" refers to an alkyl group (as defined above) that is substituted by one or more halogen atoms (as also defined above). Specific examples of haloalkyl groups are trifluoromethyl, dichloroethyl, dichloromethyl and iodoethyl.

As used herein a wording defining the limits of a range of length such as, for example, "from 1 to 5" means any integer from 1 to 5, i.e., 1 , 2, 3, 4 and 5. In other words, any range defined by two integers explicitly mentioned is meant to comprise and disclose any integer defining said limits and any integer comprised in said range.

As discussed above, the present invention relates to a compound of formula (I):

or a pharmaceutically acceptable salt or prodrug thereof, wherein: R ¹ is independently selected from:

which group is optionally further substituted by one or more substituents selected from halogen, alkyl and heteroalkyl, and

, wherein R ³ is independently selected from H and alkyl, A ¹ , A ² ,

A ³ , A ⁴ and A ⁵ are independently selected from CH and N, and the aromatic ring containing A ¹ , A ² , A ³ , A ⁴ and A ⁵ is optionally substituted with one or more substituents independently selected from halogen, OH, alkyl and heteroalkyl, and is optionally fused to an aryl group, and

R ² is a heteroaryl group. R may be , which may be optionally further substituted by one or more substituents selected from halogen (e.g. , fluorine, chlorine or bromine), alkyi and heteroalkyi. R ¹ may be substituted with one more substituent (e.g. , one halogen). Preferably, the further substituent(s) are present on the aromatic ring.

R may be

R ³ may be H. R ³ may be Ci to C3 alkyi (i.e. , methyl, ethyl or propyl).

The aromatic ring containing A ¹ , A ² , A ³ , A ⁴ and A ⁵ may be substituted with OH, and one or more additional substituents. The aromatic ring containing A ¹ , A ² , A ³ , A ⁴ and A ⁵ may be substituted with one additional substituent selected from halogen, an alkyi group and a heteroalkyi group. The halogen may be bromine, chlorine or fluorine. The alkyi group may be Ci to C ₃ alkyi (methyl, ethyl or propyl). The heteroalkyi group may be O-alkyl (such as OCH ₃ or OCH ₂ CH ₃ ) or OCF ₃ . The aromatic ring containing A ¹ , A ² , A ³ , A ⁴ and A ⁵ may be substituted with two additional substituents, which may be the same or different (e.g., two halogens, which may be the same or different, or two OH groups). The halogens may be selected from bromine, chlorine and fluorine.

One of A ¹ , A ² , A ³ , A ⁴ and A ⁵ may be N i.e., the aromatic ring containing A ¹ , A ² , A ³ , A ⁴ and A ⁵ may be a heteroaryl group. The heteroaryl group may not be further substituted. Alternatively, the heteroaryl group may be substituted with one or more substituents. The one or more substituents may be independently selected from OH, an alkyi group (e.g., methyl or ethyl) and a heteroalkyi group (e.g. , CH ₂ OH or CH ₂ CH ₂ OH).

The aromatic ring containing A ¹ , A ² , A ³ , A ⁴ and A ⁵ may be fused (e.g. , at A ² and A ³ , or A ⁴ and A ⁵ ) to an aryl group, to give a bicyclic aryl or heteroaryl group (for example, naphthyl or quinoline). The bicyclic aryl or heteroaryl group may therefore be,

for example,

In the compounds of formula (I), the N and/or OH substituents may be situated on the aromatic ring containing A ¹ , A ² , A ³ , A ⁴ and A ⁵ such that the compound of formula (I) is able to chelate metal ions (e.g. , iron). Therefore, A ¹ may be selected from N or C- OH. Preferably, A ¹ is C-OH

R ² may be pyridine, for example

Specific examples of the compounds of the present invention are given in Table 1 , below.

Table 1. Examples of compounds of the present invention.

The compounds of the present invention can be synthesised by any suitable method known to a person skilled in the art. One general synthesis is given below in Scheme 1 .

R ³ is H, and R ⁴ is:

R ³ and R ⁴ are

The compounds of the present invention are multifunctional agents that may be effective in treating and/or preventing a number of aetiologies linked to age-related disorders. The compounds of the present invention may achieve this by targeting the main hallmarks (such as protein mis-folding and β-amyloid aggregation with plaque formation, oxidative stress and ROS generation, and dysregulation of autophagy) of neurodegenerative disorders, as well as increasing a patient's longevity by including other moieties in the agent, such as those that lead to an increase in nicotinamide adenine dinucleotide (NAD). As discussed above, increased iron, copper and/or zinc levels are thought to lead to β-amyloid aggregation with plaque formation, and ROS generation. Without wishing to be bound by theory, the present inventors postulate that the compounds of the present invention (in particular, the hydrazone moiety, in conjunction with the N or C-OH functionality on the aromatic ring) may be effective metal chelators. Therefore, the compounds of the present invention may be effective at preventing or ameliorating the aggregation of β-amyloid, and may also inhibit production of ROS, resulting in prevention or amelioration of ROS-induced cell death. Particularly preferred in this regard are compounds having a "hard" donor atom (such as O) at A ¹ (e.g. , in the form of a C-OH group), as such compounds strongly chelate Fe ³⁺ , thereby preventing reduction of Fe ³⁺ to Fe ²⁺ (Fe ²⁺ is the iron species that is considered to be responsible for the aetiologies involved in neurodegenerative disorders).

The present inventors also postulate that the depletion of iron (via chelation of the metal) may induce pro-survival autophagy (specifically, beneficial clearing of deleterious protein aggregates).

The present inventors also believe that a NAD-like moiety (i.e. , nicotinic acid hydrazide) may improve the ability for the compounds to act as NAD donors. The NAD- donating capacity of the compound of the present invention is important in terms of achieving a longevity effect (as decreased NAD levels, which lead to a decrease in metabolic ability, are associated with ageing). Therefore, by including NAD-like moieties, the compounds of the present invention may increase a patient's longevity.

The compounds of the present invention are also highly lipophilic, which contributes to their BBB permeability.

The present inventors have also found that the absence of substitution at R ³ (or minimal substitution at this position) results in the compounds of the present invention having lower cytotoxicity compared with compounds that are substituted at this position (by, for example, a larger group, such as an aryl or heteroaryl group). Thus, while compounds having substitution at this position may be useful in anti-cancer therapy, they would not be expected to be useful in other therapies (e.g. , for treatment of neurodegenerative disorders), due to their cytotoxicity.

The therapeutic use of compounds of formula (I), their pharmaceutically acceptable salts, solvates or hydrates and also formulations and pharmaceutical compositions (including mixtures of the compounds of formula (I)) are within the scope of the present invention. Accordingly, the present invention also relates to pharmaceutical compositions including a therapeutically effective amount of the compounds of formula (I), or its pharmaceutically acceptable salt, solvate or hydrate thereof, and one or more pharmaceutically acceptable excipients. Pharmaceutical compositions may be formulated for any appropriate route of administration including, for example, topical (for example, transdermal or ocular), oral, buccal, nasal, vaginal, rectal or parenteral administration. The term parenteral as used herein includes subcutaneous, intradermal, intravascular (for example, intravenous), intramuscular, spinal, intracranial, intrathecal, intraocular, periocular, intraorbital, intrasynovial and intraperitoneal injection, as well as any similar injection or infusion technique. In certain embodiments, compositions in a form suitable for oral use or parenteral use are preferred. Suitable oral forms include, for example, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Aqueous suspensions contain the active ingredient(s) in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as naturally-occurring phosphatides (for example, lecithin), condensation products of an alkylene oxide with fatty acids such as polyoxyethylene stearate, condensation products of ethylene oxide with long chain aliphatic alcohols such as heptadecaethyleneoxycetanol, condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol mono-oleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides such as polyethylene sorbitan monooleate. Aqueous suspensions may also comprise one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more colouring agents, one or more flavouring agents, and one or more sweetening agents, such as sucrose or saccharin. Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and/or flavouring agents may be added to provide palatable oral preparations. Such suspensions may be preserved by the addition of an antioxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, such as sweetening, flavouring and colouring agents, may also be present. Pharmaceutical compositions may also be in the form of oil-in-water emulsions.

The oily phase may be a vegetable oil such as olive oil or arachis oil, a mineral oil such as liquid paraffin, or a mixture thereof. Suitable emulsifying agents include naturally- occurring gums such as gum acacia or gum tragacanth, naturally-occurring phosphatides such as soy bean lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides such as sorbitan monoleate, and condensation products of partial esters derived from fatty acids and hexitol with ethylene oxide such as polyoxyethylene sorbitan monoleate. An emulsion may also comprise one or more sweetening and/or flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, such as glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also comprise one or more demulcents, preservatives, flavouring agents and/or colouring agents.

A composition may further include one or more components adapted to improve the stability or effectiveness of the applied formulation, such as stabilizing agents, suspending agents, emulsifying agents, viscosity adjusters, gelling agents, preservatives, antioxidants, skin penetration enhancers, moisturizers and sustained release materials. Examples of such components are described in Martindale - The Extra Pharmacopoeia (Pharmaceutical Press, London 1993) and Martin (ed.), Remington's Pharmaceutical Sciences. Formulations may comprise microcapsules, such as hydroxymethylcellulose or gelatin-microcapsules, liposomes, albumin microspheres, microemulsions, nanoparticles or nanocapsules.

A pharmaceutical composition may be formulated as inhaled formulations, including sprays, mists, or aerosols. For inhalation formulations, the compounds provided herein may be delivered via any inhalation methods known to a person skilled in the art. Such inhalation methods and devices include, but are not limited to, metered dose inhalers with propellants such as CFC or HFA or propellants that are physiologically and environmentally acceptable. Other suitable devices are breath operated inhalers, multidose dry powder inhalers and aerosol nebulizers. Aerosol formulations for use in the subject method typically include propellants, surfactants and co-solvents and may be filled into conventional aerosol containers that are closed by a suitable metering valve.

Inhalant compositions may comprise liquid or powdered compositions containing the active ingredient that are suitable for nebulization and intrabronchial use, or aerosol compositions administered via an aerosol unit dispensing metered doses. Suitable liquid compositions comprise the active ingredient in an aqueous, pharmaceutically acceptable inhalant solvent such as isotonic saline or bacteriostatic water. The solutions are administered by means of a pump or squeeze-actuated nebulized spray dispenser, or by any other conventional means for causing or enabling the requisite dosage amount of the liquid composition to be inhaled into the patient's lungs. Suitable formulations, wherein the carrier is a liquid, for administration, as for example, a nasal spray or as nasal drops, include aqueous or oily solutions of the active ingredient.

Pharmaceutical compositions may also be prepared in the form of suppositories such as for rectal administration. Such compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Suitable excipients include, for example, cocoa butter and polyethylene glycols.

Pharmaceutical compositions may be formulated as sustained release formulations such as a capsule that creates a slow release of modulator following administration. Such formulations may generally be prepared using well-known technology and administered by, for example, oral, rectal or subcutaneous implantation, or by implantation at the desired target site. Carriers for use within such formulations are biocompatible, and may also be biodegradable. Preferably, the formulation provides a relatively constant level of modulator release. The amount of modulator contained within a sustained release formulation depends upon, for example, the site of implantation, the rate and expected duration of release and the nature of the condition to be treated or prevented. For the prevention and/or treatment of the aetiologies discussed herein, the dose of the biologically active compound according to the invention may vary within wide limits and may be adjusted to individual requirements. Active compounds according to the present invention are generally administered in a therapeutically effective amount. Preferred doses range from about 0.1 mg to about 140 mg per kilogram of body weight per day (e.g., about 0.5 mg to about 7 g per patient per day). The daily dose may be administered as a single dose or in a plurality of doses. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Dosage unit forms will generally contain between about 1 mg to about 500 mg of an active ingredient.

It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination (i.e., other drugs being used to treat the patient), and the severity of the particular disorder undergoing therapy.

The terms "therapeutically effective amount" or "effective amount" refer to an amount of the compound of formula (I) that results in an improvement or remediation of the detrimental aetiology.

Preferred compounds of the invention will have certain pharmacological properties. Such properties include, but are not limited to oral bioavailability, such that the preferred oral dosage forms discussed above can provide therapeutically effective levels of the compound in vivo. The compounds of the present invention are preferably administered to a patient

(for example, a human) orally or parenterally, and are present within at least one body fluid or tissue of the patient. Accordingly, the present invention further provides methods for treating and/or preventing aetiologies that result in age-related disorders. As used herein, the term "treatment" encompasses both disorder-modifying treatment and symptomatic treatment. It refers to therapeutic treatment, i.e., after the onset of symptoms, in order to reduce the severity and/or duration of symptoms, and/or to cure the condition or disorder. As used herein, the term "prevention" encompasses prophylactic treatment, i.e., before the onset of symptoms, in order to prevent, delay or reduce the severity of symptoms and/or the condition or disorder. Patients may include, but are not limited to, primates, especially humans, domesticated companion animals such as dogs, cats, horses, and livestock such as cattle, pigs, sheep, and poultry, with dosages as described herein. Compounds of the present invention may be useful for the treatment and/or prevention of detrimental age-related aetiologies in a subject. Accordingly, the present invention also relates to a method of treating or preventing a detrimental age-related aetiology in a patient including administration to the patient of a therapeutically effective amount of a compound of formula (I), or a pharmaceutically-acceptable salt, solvate or hydrate thereof. The present invention also relates to the use of a therapeutically effective amount of a compound of formula (I), or a pharmaceutically-acceptable salt, solvate or hydrate thereof, for treating or preventing a detrimental age-related aetiology. The present invention also provides a pharmaceutical composition for use in treating or preventing a detrimental age-related aetiology, in any of the embodiments described in the specification. The present invention also relates to the use of a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate or hydrate thereof, for the manufacture of a medicament for treating or preventing a detrimental age-related aetiology.

The present invention also relates to a compound of formula (I), or a pharmaceutically acceptable salt, solvate or hydrate thereof, when used in a method of treating or preventing a detrimental age-related aetiology. The present invention also relates to a composition having an active ingredient for use in treating or preventing a detrimental age-related aetiology, wherein the active ingredient is a compound of formula (I), or a pharmaceutically acceptable salt, solvate or hydrate thereof. The present invention also relates to the use of a pharmaceutical composition containing a compound of the formula (I), or a pharmaceutically acceptable salt, solvate or hydrate thereof, in treating or preventing a detrimental age-related aetiology, such as described above. In one embodiment, the compound of formula (I) is essentially the only active ingredient of the composition. In one embodiment, the detrimental age-related aetiology is due, in part, to: increased ion levels, wherein the ions are selected from one or more of iron, copper and zinc ions (particularly leading to increased levels of these metal ions in the brain); development of plaques that contain high levels of metal ions (e.g., iron, copper and/or zinc); and decreased NAD levels. It is also within the present invention that the compounds according to the invention are used as or for the manufacture of a diagnostic agent, whereby such diagnostic agent is for the diagnosis of the disorders and conditions which can be addressed by the compounds of the present invention for therapeutic purposes as disclosed herein.

For various applications, the compounds of the invention can be labelled by isotopes, fluorescence or luminescence markers, antibodies or antibody fragments, any other affinity label like nanobodies, aptamers, peptides etc., enzymes or enzyme substrates. These labelled compounds of this invention are useful for mapping the location of receptors in vivo, ex vivo, in vitro and in situ such as in tissue sections via autoradiography and as radiotracers for positron emission tomography (PET) imaging, single photon emission computerized tomography (SPECT) and the like, to characterise those receptors in living subjects or other materials. The labelled compounds according to the present invention may be used in therapy, diagnosis and other applications such as research tools in vivo and in vitro, in particular the applications disclosed herein.

In a first embodiment, the present invention relates to a compound of formula (I):

(I)

or a pharmaceutically acceptable salt or prodrug thereof, wherein: R ¹ is independently selected from:

- , which group is optionally further substituted by one or more substituents selected from halogen, an alkyl group and a heteroalkyl group, and

_ wherein R ³ is independently selected from H and alkyl, A ¹ , A ² ,

A ³ , A ⁴ and A ⁵ are independently selected from CH and N, and the aromatic ring containing A ¹ , A ² , A ³ , A ⁴ and A ⁵ is optionally substituted with one or more substituents independently selected from halogen, OH, alkyl and heteroalkyl, and is optionally fused to an aryl group, and

R ² is a heteroaryl group. In a second embodiment, the present invention relates to a compound of formula

(I) according to the first embodiment, wherein R ¹ is

In a third embodiment, the present invention relates to a compound of formula (I) according to the second embodiment, wherein R ¹ is further substituted by one or more substituents independently selected from halogen, alkyl and heteroalkyl. In a fourth embodiment, the present invention relates to a compound of formula

(I) according to the third embodiment, wherein the substituent is halogen.

In a fifth embodiment, the present invention relates to a compound of formula (I)

according to the first embodiment, wherein R ¹ is

In a sixth embodiment, the present invention relates to a compound of formula (I) according to the fifth embodiment, wherein R ³ is H.

In a seventh embodiment, the present invention relates to a compound of formula (I) according to the fifth embodiment, wherein R ³ is Ci to C3 alkyl.

In an eighth embodiment, the present invention relates to a compound of formula (I) according to the seventh embodiment, wherein R ³ is methyl or ethyl. In a ninth embodiment, the present invention relates to a compound of formula (I) according to any of the fifth to eighth embodiments, wherein the aromatic ring containing A ¹ , A ² , A ³ , A ⁴ and A ⁵ is substituted with OH and one or more additional substituents.

In a tenth embodiment, the present invention relates to a compound of formula (I) according to the ninth embodiment, wherein the aromatic ring containing A ¹ , A ² , A ³ , A ⁴ and A ⁵ is substituted with one additional substituent. In an eleventh embodiment, the present invention relates to a compound of formula (I) according to the tenth embodiment, wherein the additional substituent is halogen.

In a twelfth embodiment, the present invention relates to a compound of formula (I) according to the eleventh embodiment, wherein the halogen is bromine, chlorine or fluorine.

In a thirteenth embodiment, the present invention relates to a compound of formula (I) according to the tenth embodiment, wherein the one additional substituent is an alkyl group. In a fourteenth embodiment, the present invention relates to a compound of formula (I) according to the thirteenth embodiment, wherein the alkyl group is Ci to C3 alkyl.

In a fifteenth embodiment, the present invention relates to a compound of formula (I) according to the tenth embodiment, wherein the one additional substituent is a heteroalkyi group.

In a sixteenth embodiment, the present invention relates to a compound of formula (I) according to the fifteenth embodiment, wherein the heteroalkyi group is 0- alkyl.

In a seventeenth embodiment, the present invention relates to a compound of formula (I) according to the sixteenth embodiment, wherein the heteroalkyi group is

In an eighteenth embodiment, the present invention relates to a compound of formula (I) according to the ninth embodiment, wherein the aromatic ring containing A ¹ , A ² , A ³ , A ⁴ and A ⁵ is substituted with two additional substituents. In a nineteenth embodiment, the present invention relates to a compound of formula (I) according to the eighteenth embodiment, wherein the two additional substituents are halogens.

In a twentieth embodiment, the present invention relates to a compound of formula (I) according to the nineteenth embodiment, wherein the two halogens are different. In a twenty-first embodiment, the present invention relates to a compound of formula (I) according to the nineteenth or twentieth embodiment, wherein the halogens are selected from bromine, chlorine and fluorine.

In a twenty-second embodiment, the present invention relates to a compound of formula (I) according to the eighteenth embodiment, wherein the two additional substituents are OH groups.

In a twenty-third embodiment, the present invention relates to a compound of formula (I) according to any of the ninth to twenty-second embodiments, wherein A ¹ is C-OH. In a twenty-fourth embodiment, the present invention relates to a compound of formula (I) according to any of the fifth to eighth embodiments, wherein one of A ¹ , A ² , A ³ , A ⁴ and A ⁵ is N to give a heteroaryl group.

In a twenty-fifth embodiment, the present invention relates to a compound of formula (I) according to the twenty-fourth embodiment, wherein A ¹ or A ³ is N. In a twenty-sixth embodiment, the present invention relates to a compound of formula (I) according to the twenty-fourth or twenty-fifth embodiment, wherein the heteroaryl group is substituted with one or more substituents.

In a twenty-first embodiment, the present invention relates to a compound of formula (I) according to the twenty-sixth embodiment, wherein the one or more substituents are independently selected from OH, an alkyl group and a heteroalkyl group.

In a twenty-eighth embodiment, the present invention relates to a compound of formula (I) according to the twenty-seventh embodiment, wherein the alkyl group is methyl or ethyl. In a twenty-ninth embodiment, the present invention relates to a compound of formula (I) according to the twenty-seventh embodiment, wherein the heteroalkyl group is CH ₂ OH or CH ₂ CH ₂ OH.

In a thirtieth embodiment, the present invention relates to a compound of formula (I) according to any of the fifth to twenty-ninth embodiments, wherein the aromatic ring containing A ¹ , A ² , A ³ , A ⁴ and A ⁵ is fused to an aryl group to give a bicyclic aryl or heteroaryl group. In a thirty-first embodiment, the present invention relates to a compound of formula (I) according to the thirtieth embodiment, wherein the bicyclic aryl or heteroaryl group is selected from naphthalene and quinoline.

In a thirty-second embodiment, the present invention relates to a compound of formula (I) according to the thirtieth or thirty-first embodiment, wherein the aromatic ring containing A ¹ , A ² , A ³ , A ⁴ and A ⁵ is fused to the aryl group at A ² and A ³ or A ⁴ and A ⁵

In a thirty-third embodiment, the present invention relates to a compound of formula (I) according to any of the first to thirty-second embodiments, wherein R ² is pyridine.

In a thirty-fourth embodiment, the present invention relates to a pharmaceutical composition including a compound of formula (I):

(I) or a pharmaceutically acceptable salt or prodrug thereof, wherein: R ¹ is independently selected from:

- , which group is optionally further substituted by one or more substituents selected from halogen, an alkyl group and a heteroalkyl group, and

_ wherein R ³ is independently selected from H and alkyl, A ¹ , A ² ,

A ³ , A ⁴ and A ⁵ are independently selected from CH and N, and the and the aromatic ring containing A ¹ , A ² , A ³ , A ⁴ and A ⁵ is optionally substituted with one or more substituents independently selected from halogen, OH, alkyl and heteroalkyl, and is optionally fused to an aryl group, and

R ² is a heteroaryl group, together with a pharmaceutically acceptable carrier, diluent or excipient.

In a thirty-fifth embodiment, the present invention relates to a pharmaceutical composition according to the thirty-fourth embodiment, wherein the composition is suitable for parenteral or oral administration. In a thirty-sixth embodiment, the present invention relates to a pharmaceutical com osition according to the thirty-fourth or thirty-fifth embodiment, wherein R ¹ is

In a thirty-seventh embodiment, the present invention relates to a pharmaceutical composition according to the thirty-sixth embodiment, wherein R ¹ is further substituted by one or more substituents independently selected from halogen, alkyl and heteroalkyl.

In a thirty-eighth embodiment, the present invention relates to a pharmaceutical composition according to the thirty-seventh embodiment, wherein the substituent is halogen.

In a thirty-ninth embodiment, the present invention relates to a pharmaceutical composition according to the thirty-third or thirty-fourth embodiment, wherein R ¹ is

In a fortieth embodiment, the present invention relates to a pharmaceutical composition according to the thirty-ninth embodiment, wherein R ³ is H.

In a forty-first embodiment, the present invention relates to a pharmaceutical composition according to the thirty-ninth embodiment, wherein R ³ is Ci to C ₃ alkyl.

In a forty-second embodiment, the present invention relates to a pharmaceutical composition according to the forty-first embodiment, wherein R ³ is methyl or ethyl.

In a forty-third embodiment, the present invention relates to a pharmaceutical composition according to any of the thirty-ninth to forty-second embodiments, wherein the aromatic ring containing A ¹ , A ² , A ³ , A ⁴ and A ⁵ is substituted with OH and one or more additional substituents. In a forty-fourth embodiment, the present invention relates to a pharmaceutical composition according to the forty-third embodiment, wherein the aromatic ring containing A ¹ , A ² , A ³ , A ⁴ and A ⁵ is substituted with one additional substituent.

In a forty-fifth embodiment, the present invention relates to a pharmaceutical composition according to the forty-fourth embodiment, wherein the one additional substituent is halogen.

In a forty-sixth embodiment, the present invention relates to a pharmaceutical composition according to the forty-fifth embodiment, wherein the halogen is bromine, chlorine or fluorine. In a forty-seventh embodiment, the present invention relates to a pharmaceutical composition according to the forty-fourth embodiment, wherein the one additional substituent is an alkyl group.

In a forty-eighth embodiment, the present invention relates to a pharmaceutical composition according to the forty-seventh embodiment, wherein the alkyl group is Ci to C ₃ alkyl.

In a forty-ninth embodiment, the present invention relates to a pharmaceutical composition according to the forty-fourth embodiment, wherein the one additional substituent is a heteroalkyi group.

In a fiftieth embodiment, the present invention relates to a pharmaceutical composition according to the forty-ninth embodiment, wherein the heteroalkyi group is O-alkyl.

In a fifty-first embodiment, the present invention relates to a pharmaceutical composition according to the fiftieth embodiment, wherein the heteroalkyi group is

In a fifty-second embodiment, the present invention relates to a pharmaceutical composition according to the forty-third embodiment, wherein the aromatic ring containing A ¹ , A ² , A ³ , A ⁴ and A ⁵ is substituted with two additional substituents.

In a fifty-third embodiment, the present invention relates to a pharmaceutical composition according to the fifty-second embodiment, wherein the two additional substituents are halogens. In a fifty-fourth embodiment, the present invention relates to a pharmaceutical composition according to the fifty-third embodiment, wherein the two halogens are different.

In a fifty-fifth embodiment, the present invention relates to a pharmaceutical composition according to the fifty-third or fifty-fourth embodiment, wherein the halogens are selected from bromine, chlorine and fluorine.

In a fifty-sixth embodiment, the present invention relates to a pharmaceutical composition according to the fifty-second embodiment, wherein the two additional substituents are OH groups. In a fifty-seventh embodiment, the present invention relates to a pharmaceutical composition according to any of the thirty-ninth to fifty-sixth embodiments, wherein A ¹ is C-OH.

In a fifty-eighth embodiment, the present invention relates to a pharmaceutical composition according to any of the thirty-ninth to fifty-sixth embodiments, wherein one of A ¹ , A ² , A ³ , A ⁴ and A ⁵ is N to give a heteroaryl group.

In a fifty-ninth embodiment, the present invention relates to a pharmaceutical composition according to the fifty-eighth embodiment, wherein A ¹ or A ³ is N.

In a sixtieth embodiment, the present invention relates to a pharmaceutical composition according to the fifty-eighth or fifty-ninth embodiment, wherein the heteroaryl group is substituted with one or more substituents.

In a sixty-first embodiment, the present invention relates to a pharmaceutical composition according to the sixtieth embodiment, wherein the one or more substituents are independently selected from OH, an alkyl group and a heteroalkyl group.

In a sixty-second embodiment, the present invention relates to a pharmaceutical composition according to the sixty-first embodiment, wherein the alkyl group is methyl or ethyl.

In a sixty-third embodiment, the present invention relates to a pharmaceutical composition according to sixty-first embodiment, wherein the heteroalkyl group is CH ₂ OH or CH ₂ CH ₂ OH. In a sixty-fourth embodiment, the present invention relates to a pharmaceutical composition according to any of the thirty-ninth to sixty-third embodiments, wherein the aromatic ring containing A ¹ , A ² , A ³ , A ⁴ and A ⁵ is fused to an aryl group to give a bicyclic aryl or heteroaryl group.

In a sixty-fifth embodiment, the present invention relates to a pharmaceutical composition according to the sixty-fourth embodiment, wherein the bicyclic aryl or heteroaryl group is selected from naphthalene and quinoline.

In a sixty-sixth embodiment, the present invention relates to a pharmaceutical composition according to the sixty-fourth or sixty-fifth embodiment, wherein the aromatic ring containing A ¹ , A ² , A ³ , A ⁴ and A ⁵ is fused to the aryl group at A ² and A ³ or A ⁴ and A ⁵ .

In a sixty-seventh embodiment, the present invention relates to a pharmaceutical composition according to any of the thirty-ninth to sixty-sixth embodiments, wherein R ² is pyridine.

In a sixty-eighth embodiment, the present invention relates to a method of treating or preventing a detrimental age-related aetiology in a subject, the method including administering to the subject of a therapeutically effective amount of a compound of formula (I):

(I) or a pharmaceutically acceptable salt or prodrug thereof, wherein:

R is independently selected from:

group is optionally further substituted by one or more substituents selected from halogen, an alkyl group and a heteroalkyl group, and _ wherein R ³ is independently selected from H and alkyl, A ¹ , A ² ,

A ³ , A ⁴ and A ⁵ are independently selected from CH and N, and the aromatic ring containing A ¹ , A ² , A ³ , A ⁴ and A ⁵ is optionally substituted with one or more substituents independently selected from halogen, OH, alkyl and heteroalkyl, and is optionally fused to an aryl group, and

R ² is a heteroaryl group.

In a sixty-ninth embodiment, the present invention relates to a method according to the sixty-eighth embodiment, wherein the detrimental age-related aetiology is selected from: increased ion levels, wherein the ions are selected from one or more of iron, copper and zinc ions; development of plaques that contain iron, copper and/or zinc; and decreased NAD levels.

In a seventieth embodiment, the present invention relates to a method according

to the sixty-eighth or sixty-ninth embodiment, wherein R ¹ is

In a seventy-first embodiment, the present invention relates to a method according to the seventieth embodiment, wherein R ¹ is further substituted by one or more substituents independently selected from halogen, alkyl and heteroalkyl.

In a seventy-second embodiment, the present invention relates to a method according to the seventy-first embodiment, wherein the substituent is halogen.

In a seventy-third embodiment, the present invention relates to a method

according to the sixty-eighth or sixty-ninth embodiment, wherein R ¹ is

In a seventy-fourth embodiment, the present invention relates to a method according to the seventy-third embodiment, wherein R ³ is H. In a seventy-fifth embodiment, the present invention relates to a method according to the seventy-third embodiment, wherein R ³ is Ci to C ₃ alkyl.

In a seventy-sixth embodiment, the present invention relates to a method according to the seventy-fifth embodiment, wherein R ³ is methyl or ethyl. In a seventy-seventh embodiment, the present invention relates to a method according to any of the seventy-third to seventy-sixth embodiments, wherein the aromatic ring containing A ¹ , A ² , A ³ , A ⁴ and A ⁵ is substituted with OH and one or more additional substituents.

In a seventy-eighth embodiment, the present invention relates to a method according to the seventy-seventh embodiment, wherein the aromatic ring containing A ¹ , A ² , A ³ , A ⁴ and A ⁵ is substituted with one additional substituent.

In a seventy-ninth embodiment, the present invention relates to a method according to the seventy-eighth embodiment, wherein the additional substituent is halogen. In an eightieth embodiment, the present invention relates to a method according to the seventy-ninth embodiment, wherein the halogen is bromine, chlorine or fluorine.

In an eighty-first embodiment, the present invention relates to a method according to the seventy-eighth embodiment, wherein the one additional substituent is an alkyl group. In an eighty-second embodiment, the present invention relates to a method according to the eighty-first embodiment, wherein the alkyl group is Ci to C3 alkyl.

In an eighty-third embodiment, the present invention relates to a method according to the seventy-eighth embodiment, wherein the one additional substituent is a heteroalkyl group. In an eighty-fourth embodiment, the present invention relates to a method according to the eighty-third embodiment, wherein the heteroalkyl group is O-alkyl.

In an eighty-fifth embodiment, the present invention relates to a method according to the eighty-fourth embodiment, wherein the heteroalkyl group is OCH ₃ , OCH ₂ CH ₃ or OCF ₃ . In an eighty-sixth embodiment, the present invention relates to a method according to the seventy-seventh embodiment, wherein the aromatic ring containing A ¹ , A ² , A ³ , A ⁴ and A ⁵ is substituted with two additional substituents.

In an eighty-seventh embodiment, the present invention relates to a method according to the eighty-sixth embodiment, wherein the two additional substituents are halogens.

In an eighty-eighth embodiment, the present invention relates to a method according to the eighty-seventh embodiment, wherein the two halogens are different.

In an eighty-ninth embodiment, the present invention relates to a method according to the eighty-seventh or eighty-eighth embodiment, wherein the halogens are selected from bromine, chlorine and fluorine.

In a ninetieth embodiment, the present invention relates to a method according to eighty-sixth embodiment, wherein the two additional substituents are OH groups.

In a ninety-first embodiment, the present invention relates to a method according to any of the seventy-third to ninetieth embodiments, wherein A ¹ is C-OH.

In a ninety-second embodiment, the present invention relates to a method according to any of the seventy-third to ninetieth embodiments, wherein one of A ¹ , A ² , A ³ , A ⁴ and A ⁵ is N to give a heteroaryl group.

In a ninety-third embodiment, the present invention relates to a method according to the ninety-second embodiment 92, wherein A ¹ or A ³ is N.

In a ninety-fourth embodiment, the present invention relates to a method according to the ninety-second or ninety-third embodiments, wherein the heteroaryl group is substituted with one or more substituents.

In a ninety-fifth embodiment, the present invention relates to a method according to the ninety-fourth embodiment, wherein the one or more substituents are independently selected from OH, an alkyl group and a heteroalkyi group.

In a ninety-sixth embodiment, the present invention relates to a method according to ninety-fifth embodiment, wherein the alkyl group is methyl or ethyl.

In a ninety-seventh embodiment, the present invention relates to a method according to the ninety-fifth embodiment, wherein the heteroalkyi group is CH ₂ OH or CH ₂ CH ₂ OH. In a ninety-eighth embodiment, the present invention relates to a method according to any of the seventy-third to ninety-seventh embodiments, wherein the aromatic ring containing A ¹ , A ² , A ³ , A ⁴ and A ⁵ is fused to an aryl group to give a bicyclic aryl or heteroaryl group.

In a ninety-ninth embodiment, the present invention relates to a method according to the ninety-eighth embodiment, wherein the bicyclic aryl or heteroaryl group is selected from naphthalene and quinoline.

In one hundredth embodiment, the present invention relates to a method according to the ninety-eighth or ninety-ninth embodiment, wherein the aromatic ring containing A ¹ , A ² , A ³ , A ⁴ and A ⁵ is fused to the aryl group at A ² and A ³ or A ⁴ and A ⁵ .

In a one hundred and first embodiment, the present invention relates to a method according to any of the sixty-eighth to one hundredth, wherein R ² is pyridine.

In a one hundred and second embodiment, the present invention relates to a method of treating or preventing a detrimental age-related aetiology in a subject, the method including administering to the subject of a therapeutically effective amount of a pharmaceutical composition including a compound of formula (I):

(I)

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

R is independently selected from:

, which group is optionally further substituted by one or more substituents selected from halogen, an alkyl group and a heteroalkyl group, and _ wherein R ³ is independently selected from H and alkyl, A ¹ , A ² ,

A ³ , A ⁴ and A ⁵ are independently selected from CH and N, and the aromatic ring containing A ¹ , A ² , A ³ , A ⁴ and A ⁵ is optionally substituted with one or more substituents independently selected from halogen, OH, alkyl and heteroalkyl, and is optionally fused to an aryl group, and

R ² is a heteroaryl group, together with a pharmaceutically acceptable carrier, diluent or excipient.

In a one hundred and third embodiment, the present invention relates to a method according to the one hundred and second embodiment, wherein the detrimental age-related aetiology is selected from: increased iron, copper and zinc ion levels; development of plaques that contain iron, copper and/or zinc; and decreased NAD levels.

In a one hundred and fourth embodiment, the present invention relates to a method according to the one hundred and second or one hundred and third

embodiment, wherein R ¹ is

In a one hundred and fifth embodiment, the present invention relates to a method according to the one hundred and fourth embodiment, wherein R ¹ is further substituted by one or more substituents independently selected from halogen, alkyl and heteroalkyl.

In a one hundred and sixth embodiment, the present invention relates to a method according to the one hundred and fifth embodiment, wherein the substituent is halogen. In a one hundred and seventh embodiment, the present invention relates to a method according to the one hundred and second or one hundred and third

embodiment, wherein R ¹ is

In a one hundred and eighth embodiment, the present invention relates to a method according to the one hundred and seventh embodiment, wherein R ³ is H.

In a one hundred and ninth embodiment, the present invention relates to a method according to the one hundred and seventh embodiment, wherein R ³ is Ci to C3 alkyl.

In a one hundred and tenth embodiment, the present invention relates to a method according to the one hundred and ninth embodiment, wherein R ³ is methyl or ethyl.

In a one hundred and eleventh embodiment, the present invention relates to a method according to any of the one hundred and seventh to one hundred and tenth embodiments, wherein the aromatic ring containing A ¹ , A ² , A ³ , A ⁴ and A ⁵ is substituted with OH and one or more additional substituents.

In a one hundred and twelfth embodiment, the present invention relates to a method according to the one hundred and eleventh embodiment, wherein the aromatic ring containing A ¹ , A ² , A ³ , A ⁴ and A ⁵ is substituted with one additional substituent.

In a one hundred and thirteenth embodiment, the present invention relates to a method according to the one hundred and twelfth embodiment, wherein the additional substituent is halogen.

In a one hundred and fourteenth embodiment, the present invention relates to a method according to the one hundred and thirteenth embodiment, wherein the halogen is bromine, chlorine or fluorine. In a one hundred and fifteenth embodiment, the present invention relates to a method according to the one hundred and twelfth embodiment, wherein the one additional substituent is an alkyl group. In a one hundred and first embodiment, the present invention relates to a method according to the one hundred and fifteenth embodiment, wherein the alkyl group is Ci to C ₃ alkyl.

In a one hundred and seventeeth embodiment, the present invention relates to a method according to one hundred and twelfth embodiment, wherein the one additional substituent is a heteroalkyl group.

In a one hundred and eighteenth embodiment, the present invention relates to a method according to the one hundred and seventeenth embodiment, wherein the heteroalkyl group is O-alkyl. In a one hundred and nineteenth embodiment, the present invention relates to a method according to the one hundred and eighteenth embodiment wherein the heteroalkyl group is OCH ₃ , OCH ₂ CH ₃ or OCF ₃ .

In a one hundred and twentieth embodiment, the present invention relates to a method according to the one hundred and eleventh embodiment, wherein the aromatic ring containing A ¹ , A ² , A ³ , A ⁴ and A ⁵ is substituted with two additional substituents.

In a one hundred and twenty-first embodiment, the present invention relates to a method according to the one hundred and twentieth embodiment, wherein the two additional substituents are halogens.

In a one hundred and twenty-second embodiment, the present invention relates to a method according to the one hundred and twenty-first embodiment, wherein the two halogens are different.

In a one hundred and twenty-third embodiment, the present invention relates to a method according to the one hundred and twenty-first or one hundred and twenty- second embodiments, wherein the halogens are selected from bromine, chlorine and fluorine.

In a one hundred and twenty-fourth embodiment, the present invention relates to a method according to the one hundred and twentieth embodiment, wherein the two additional substituents are OH groups.

In a one hundred and twenty-fifth embodiment, the present invention relates to a method according to any of the one hundred and seventh to one hundred and twenty- fourth embodiments, wherein A ¹ is C-OH. In a one hundred and twenty-sixth embodiment, the present invention relates to a method according to any of the one hundred and seventh to one hundred and twenty- fourth embodiments, wherein one of A ¹ , A ² , A ³ , A ⁴ and A ⁵ is N to give a heteroaryl group. In a one hundred and twenty-seventh embodiment, the present invention relates to a method according to the one hundred and twenty-sixth embodiment, wherein A ¹ or A ³ is N.

In a one hundred and twenty-eighth embodiment, the present invention relates to a method according to the one hundred and twenty-sixth or one hundred and twenty- seventh embodiments, wherein the heteroaryl group is substituted with one or more substituents.

In a one hundred and twenty-ninth embodiment, the present invention relates to a method according to the one hundred and twenty-eighth embodiment, wherein the one or more substituents are independently selected from OH, an alkyl group and a heteroalkyl group.

In a one hundred and thirtieth embodiment, the present invention relates to a method according to the one hundred and twenty-ninth embodiment, wherein the alkyl group is methyl or ethyl.

In a one hundred and thirty-first embodiment, the present invention relates to a method according to the one hundred and twenty-ninth embodiment, wherein the heteroalkyl group is CH ₂ OH or CH ₂ CH ₂ OH.

In a one hundred and thirty-second embodiment, the present invention relates to a method according to any of the one hundred and seventh to the one hundred and thirty-first embodiments, wherein the aromatic ring containing A ¹ , A ² , A ³ , A ⁴ and A ⁵ is fused to an aryl group to give a bicyclic aryl or heteroaryl group.

In a one hundred and thirty-third embodiment, the present invention relates to a method according to the one hundred and thirty-second embodiment, wherein the bicyclic aryl or heteroaryl group is selected from naphthalene and quinoline.

In a one hundred and thirty-fourth embodiment, the present invention relates to a method according to the one hundred and thirty-second or one hundred and thirty-third embodiment, wherein the aromatic ring containing A ¹ , A ² , A ³ , A ⁴ and A ⁵ is fused to the aryl group at A ² and A ³ or A ⁴ and A ⁵ . In a one hundred and thirty-fifth embodiment, the present invention relates to a method according to any of the one hundred and second to one hundred and thirty- fourth embodiments, wherein R ² is pyridine.

The nature of the present invention shall now be illustrated by the following non- limiting Examples.

Examples

Experimental Details

Materials and methods

All chemicals and reagents were used as received from Sigma-Aldrich without further purification. ¹ H NMR spectra were recorded at 400 MHz, and ¹³ C NMR spectra were recorded at 100 MHz (Bruker Advance 400) using DMSO-cf ₆ or CH ₃ OH-cf ₄ as a solvent. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and other chemicals used for biological studies were purchased from Sigma-Aldrich. Mass spectra were recorded on a Bruker amaZon SL mass spectrometer (ESI-MS) with an electrospray ionization (ESI) source in enhanced resolution mode. Elemental analysis was carried out on a Thermo Scientific Flash 2000 CHNS/O analyser.

1

White solid (0.85 g). Yield: 78%. ¹ H NMR: δ ppm (DMSO-d ₆ ) 6.97 (1 H, m, CH), 7.51 (2H, m, 2xCH), 7.60 (1 H, m, CH), 8.30 (1 H, d, J = 8.1 Hz, CH), 8.62 (1 H, s, CH=N), 8.80 (1 H, m, CH), 9.1 1 (1 H, d, J = 1 .7 Hz, CH), 12.28 (1 H, s, OH), 12.51 (1 H, s, NHCO). ¹³ C NMR: δ ppm (DMSO-d ₆ ) 120.0, 120.5, 120.9, 124.2, 128.7, 130.0, 132.0, 136.0, 149.1 , 149.6, 153.1 , 153.7, 162.0. ESI-MS in CH ₃ CN: found mass: 298.04 (100%), Calc. mass for dsH^NsOsCINa: 298.04 [M+Na ⁺ ] ⁺ . Anal. Calc. for Ci ₃ H ₁₀ N ₃ O ₂ CI H ₂ O (%): C 53.16, H 4.12, N 14.31 . Found (%): C 53.34, H 4.06, N 14.31 . 2

White solid (0.95 g). Yield: 75%. ¹ H NMR: δ ppm (DMSO-d ₆ ) 6.91 (1 H, t, J = 7.8 Hz, CH), 7.53 (1 H, dd, J = 7.7, 1 .3 Hz, CH), 7.61 (2H, m, 2xCH), 8.29 (1 H, d, J = 7.8 Hz, CH), 8.58 (1 H, s, CH=N), 8.80 (1 H, bs, CH), 9.12 (1 H, s, CH), 12.46 (1 H, s, OH), 12.53 (1 H, s, NHCO). ¹³ C NMR: δ ppm (DMSO-d ₆ ) 1 10.5, 1 19.8, 121 .1 , 124.2, 128.7, 130.9, 135.0, 136.0, 149.1 , 149.7, 153.1 , 154.7, 162.0. ESI-MS in CH ₃ CN: found mass: 341.97 (100%), Calc. mass for C ₁₃ H ₁₀ N ₃ O ₂ BrNa: 341.99 [M+Na ⁺ ] ⁺ - Anal. Calc. for C ₁₃ H ₁₀ N ₃ O ₂ Br(%): C 46.17, H 3.58, N 12.43. Found (%): C 46.41, H 3.62, N 12.33.

3

White crystals (0.78 g). Yield: 60%. ¹ H NMR: δ ppm (DMSO-d ₆ ) 7.03 (1H, d, J = 9.0 Hz, CH), 7.31 (1H, dd, J = 8.9, 2.6 Hz, CH), 7.59 (1H, dd, dt, J = 7.9, 4.8 Hz, CH), 7.66 (1H, d, J = 2.4 Hz, CH), 8.29 (1H, dt, J = 8.0, 1.7 Hz, CH), 8.69 (1H, s, CH=N), 8.79 (1H, d, J = 3.9 Hz, CH), 9.10 (1H, s, CH), 11.21 (1H, bs, OH), 12.31 (1H, bs, NHCO). ¹³ C NMR: δ ppm (DMSO-d ₆ ) 118.2, 119.4, 120.7 (J _C -F = 10.0 Hz), 122.0, 124.1, 124.9, 129.1, 136.0, 141.2, 146.3, 149.1, 153.0, 156.6, 162.1. ESI-MS in CH ₃ CN: found mass: 348.05 (100%), Calc. mass for C ₁₄ H ₁₀ N ₃ O ₃ F ₃ Na: 348.06 [M+Na ⁺ ] ⁺ . Anal. Calc. for C ₁₄ H ₁₀ N ₃ O ₂ F ₃ (%): C 51.70, H 3.10, N 12.92. Found (%): C 51.92, H 3.24, N 12.85.

4

Pale yellow-brown solid (1.20 g). Yield: 89%. ¹ H NMR: δ ppm (DMSO-d ₆ ) 7.60 (2H, m, 2xCH), 7.69 (1 H, s, CH), 8.29 (1 H, dt, J = 8.0, 1.7 Hz, CH), 8.64 (1 H, s, CH=N), 8.79 (1H, dd, J = 8.0, 1.3 Hz, CH), 9.10 (1H, d, J = 1.7 Hz, CH), 11.58 (1H, bs, OH), 12.44 (1H, s, NHCO). ¹³ C NMR: δ ppm (DMSO-d ₆ ) 109.8 (J _C -F = 9.0 Hz), 120.9 (J _C -F = 21.0 Hz), 123.6 (J _C -F=4.0 HZ), 124.1, 126.8 (J _C -F = 3.0 Hz), 128.9, 136.0, 145.1 (J _C -F = 14.0 Hz), 146.1 (Jc-F = 3.0 Hz), 149.2, 151.7 (J _C -F = 240.0 Hz), 153.1, 162.2. ESI-MS in CH ₃ CN: found mass: 359.98 (100%), Calc. mass for C ₁₃ H9N ₃ O ₂ BrFNa: 359.98 [M+Na ⁺ ] ⁺ . Anal. Calc. for C ₁₃ H ₉ N ₃ O ₂ BrF- H ₂ O (%): C 43.84, H 3.11 , N 11.80. Found (%): C 44.01, H 3.10, N 11.69.

5

Yellow crystals (0.70 g). Yield: 64%. ¹ H NMR: δ ppm (DMSO-d ₆ ) 2.23 (3H, s, CH ₃ ), 7.13 (1H, dd, J = 9.0, 2.9 Hz, CH), 7.25 (1H, dd, J = 9.0, 2.9 Hz, CH), 7.60 (1H, dd, J = 7.9, 4.8 Hz, CH), 8.29 (1 H, d, J = 8.1 Hz, CH), 8.55 (1 H, s, CH=N), 8.80 (1 H, d, J = 3.7, CH), 9.11 (1H, s, CH), 11.61 (1H, s, OH), 12.47 (1H, s, NHCO). ¹³ C NMR: δ ppm (DMSO-de) 16.0, 113.8 (J _C -F = 118.0 Hz), 118.0 ( J _C -F =8.5 Hz), 119.6 ( J _C -F = 119.6 Hz), 124.1 , 127.7 (J _C -F =7.7 Hz), 128.8, 136.0, 149.1 , 149.6 ( J _C -F =2.7 Hz), 152.7 ( J _C -F = 1.5 Hz), 153.1, 155.2 (J _C -F = 233.0 Hz), 162.0. ESI-MS in CH ₃ CN: found mass: 296.06 (100%), Calc. mass for C ₁₄ H ₁₂ N ₃ O ₂ FNa: 296.08 [M+Na ⁺ ] ⁺ - Anal. Calc. for C ₁₄ H ₁₂ N ₃ O ₂ F H ₂ O (%): C 57.73, H 4.85, N 14.43. Found (%): C 57.96, H 4.91, N 14.48. 6

White crystals (0.83 g). Yield: 77%. ¹ H NMR: δ ppm (DMSO-d ₆ ) 3.87 (3H, s, OCH ₃ ), 6.57 (2H, t, J = 7.4 Hz, 2xCH), 7.29 (1H, t, J = 8.3 Hz, CH), 7.59 (1H, dd, J =7.8, 4.8 Hz, CH), 8.30 (1H, dt, J =7.9, 1.9 Hz, CH), 8.79 (1H, d, J = 4.2 Hz, CH), 8.96 (1H, s, CH=N), 9.11 (1H, s, CH), 12.12 (1H, s, OH), 12.33 (1H, bs, NHCO). ¹³ C NMR: δ ppm (DMSO-de) 56.4, 102.2, 107.2, 109.9, 124.2, 128.8, 133.1, 135.9, 146.8, 149.1, 153.0, 159.1, 159.8, 161.6. ESI-MS in CH ₃ CN: found mass: 294.08 (100%), Calc. mass for Ci ₄ H ₁₃ N ₃ O ₃ Na: 294.09 [M+Na ⁺ ] ⁺ . Anal. Calc. for Ci ₄ H ₁₃ N ₃ O ₃ H ₂ O (%): C 58.13, H 5.23, N 14.53. Found (%): C 58.39, H 5.18, N 14.37. 7

White solid (0.83 g). Yield: 75%. ¹ H NMR: δ ppm (MeOH-d) 2.52 (3H, s, CH ₃ ), 6.90 (1 H, d, J = 8.8 Hz, CH), 7.42 (1 H, m, CH), 7.62 (1 H, dd, J = 7.8, 4.9 Hz, CH), 7.76 (1H, d, J = 2.2 Hz, CH), 8.38 (1H, d, J = 7.6, CH), 8.76 (1H, dd, J = 4.9, 1.5 Hz, CH), 9.11 (1H, s, CH). ¹ H NMR: δ ppm (DMSO-d ₆ ) 6.75 (2H, m, 2xCH), 7.59 (1H, ddd, J = 7.9, 4.8, 0.7 Hz, CH), 7.71 (1 H, m, CH), 8.29 (1 H, dt, J = 8.0, 1.9 Hz, CH), 8.79 (1 H, dd, J = 4.8, 1.6, CH), 9.09 (1H, s, CH), 11.55 (1H, s, OH), 13.77 (1H, s, NHCO). ¹³ C NMR: δ ppm (DMSO-de) 14.8, 104.4 (J _C -F= 24.0 Hz), 106.3 (J _C -F= 22.0 Hz), 116.8 (J _C -F = 3.0 Hz), 124.0, 129.2, 131.1 ( J _C -F = 10.0 Hz), 136.4, 149.4, 152.9, 158.5, 161.2 ( J _C -F = 13.0 Hz), 163.2 (Jc-F = 247.0 Hz), 163.5. ESI-MS in CH ₃ CN: found mass: 296.08 (80%), Calc. mass for C ₁₄ H ₁₂ N ₃ O ₂ FNa: 296.08 [M+Na ⁺ ] ⁺ , found mass: 569.10 (100%), Calc. mass for C28H ₂₄ N ₆ O ₄ F ₂ Na: 569.17 [2M+Na ⁺ ] ⁺ . Anal. Calc. for Ci ₄ H ₁₂ N ₃ O ₂ F (%): C 61.53, H4.43, N 15.38. Found (%): C 61.73, H 4.47, N 15.34.

8

Pale yellow-brown solid (0.90 g). Yield: 68%. ¹ H NMR: δ ppm (MeOH-cf ) 2.52 (3H, s, CH ₃ ), 6.66 (1H, s, CH), 6.69 (1H, m, CH), 7.62 (1H, dd, J = 7.3, 4.9 Hz, CH), 7.69 (1H, dd, J = 9.3, 6.6 Hz, CH), 8.37 (1H, d, J = 8.1, CH), 8.77 (1H, dd, J = 4.9, 1.5 Hz, CH), 9.09 (1 H, s, CH). ¹ H NMR: δ ppm (DMSO-d ₆ ) 6.90 (1 H, d, J = 9.0, 2.9 Hz, CH), 7.45 (1H, dd, J = 9.0, 2.9 Hz, CH), 7.58 (1H, dd, J = 7.9, 4.8 Hz, CH), 7.77 (1H, d, J = 8.1 Hz, CH), 8.28 (1H, s, CH), 8.80 (1H, d, J = 3.7 Hz, CH), 9.09 (1H, s, CH), 11.61 (1H, s, OH), 13.35 (1H, s, NHCO). ¹³ C NMR: δ ppm (DMSO-d ₆ ) 14.8, 110.1, 120.1, 121.9, 124.0, 129.2, 131.1, 134.2, 136.5, 149.5, 153.0, 157.6, 158.3, 163.6. ESI-MS in CH ₃ CN: found mass: 356.01 (100%), Calc. mass for C ₁₄ H ₁₂ N ₃ 0 ₂ BrNa: 356.00 [M+Na ⁺ ] ⁺ . Anal. Calc. for C ₁₄ H ₁₂ N ₃ 0 ₂ Br (%): C 50.32, H 3.62, N 12.57. Found (%): C 50.52, H 3.58, N 12.52.

9

White solid (0.90 g). Yield: 65%. ¹ H NMR: δ ppm (DMSO-d ₆ ) 1 .15 (3H, t, J = 7.4

Hz, CH ₃ ), 3.03 (2H, q, CH ₂ ), 6.92 (1 H, d, J = 8.8 Hz, CH), 7.46 (1 H, dd, J = 8.8, 2.2 Hz, CH), 7.59 (1 H, dd, J = 7.8, 5.0 Hz, CH), 7.75 (1 H, d, J = 2.2 Hz, CH), 8.25 (1 H, d, J = 8.1 Hz, CH), 8.80 (1 H, d, J = 3.7 Hz, CH), 9.05 (1 H, s, CH), 1 1.65 (1 H, s, OH), 13.40 (1 H, s, NHCO). ¹³ C NMR: δ ppm (DMSO-d ₆ ) 1 1 .7, 19.9, 1 10.2, 120.4, 123.9, 129.3, 130.7, 134.2, 136.6, 149.6, 152.9, 158.8, 160.7, 163.9. ESI-MS in CH ₃ CN: found mass: 370.01 (100%), Calc. mass for Ci ₅ H ₁₄ N ₃ O ₂ BrNa: 370.02 [M+Na ⁺ ] ⁺ . Anal. Calc. for Ci ₅ H ₁₄ N ₃ O ₂ Br (%): C 51.74, H 4.05, N 12.07. Found (%): C 51.80, H 4.03, N 12.04.

10

Pale yellow-brown solid (0.66 g). Yield: 62%. ¹ H NMR: δ ppm (DMSO-cf ₆ ) 3.09 (4H, m, 2xCH ₂ ), 6.77 (1 H, d, J = 8.1 Hz, CH), 6.91 (1 H, d, J = 7.3 Hz, CH), 7.31 (1 H, t, J = 7.7 Hz, CH), 7.57 (1 H, dd, J = 7.6, 4.9 Hz, CH), 8.24 (1 H, d, J = 7.8 Hz, CH), 8.77 (1 H, d, J = 3.7 Hz, CH), 9.05 (1 H, s, CH), 10.19 (1 H, s, OH), 1 1.26 (1 H, s, NHCO). ¹³ C NMR: δ ppm (DMSO-d ₆ ) 28.3, 29.0, 1 13.4, 1 16.9, 122.9, 124.0, 129.8, 133.2, 136.3, 149.3, 150.2, 152.6, 155.7, 162.8, 167.4. ESI-MS in CH ₃ CN: found mass: 290.08 (100%), Calc. mass for Ci ₅ H ₁₃ N ₃ O ₂ Na: 290.09 [M+Na ⁺ ] ⁺ . Anal. Calc. for d ₅ H ₁₃ N ₃ O ₂ (%): C 67.40, H 4.90, N 15.72. Found (%): C 67.63, H 4.82, N 15.60.

11

Yellow solid (0.82 g). Yield: 60%. ¹ H NMR: δ ppm (DMSO-d ₆ ) 3.05 (4H, m, 2xCH ₂ ), 6.77 (1 H, d, J = 8.8 Hz, CH), 7.46 (1 H, d, J = 8.8 Hz, CH), 7.57 (1 H, dd, J = 7.7, 5.0 Hz, CH), 8.23 (1 H, d, J = 7.8 Hz, CH), 8.77 (1 H, d, J = 3.7 Hz, CH), 9.04 (1 H, s, CH), 10.31 (1 H, s, OH), 1 1.36 (1 H, s, NHCO). ¹³ C NMR: δ ppm (DMSO-d ₆ ) 27.9, 30.6, 108.9, 1 16.2, 123.9, 124.7, 129.6, 135.1 , 136.3, 149.2, 149.4, 152.7, 155.0, 163.0, 166.3. ESI-MS in CH ₃ CN: found mass: 367.98 (100%), Calc. mass for Ci ₅ H ₁₂ N ₃ O ₂ BrNa: 368.00 [M+Na ⁺ ] ⁺ . Anal. Calc. for C ₁₅ H ₁₂ N ₃ O ₂ Br H ₂ O (%): C 49.47, H 3.88, N 11.54. Found (%): C 49.56, H 3.87, N 11.46. 12

Yellow solid (0.70 g). Yield: 63%. ¹ H NMR: δ ppm (DMSO-d ₆ ) 2.19 (3H, s, CH ₃ ), 3.07 (4H, broad singlet, 2xCH ₂ ), 6.81 (1 H, d, J = 7.6 Hz, CH), 7.19 (1 H, d, J = 7.6 Hz, CH), 7.57 (1 H, dd, J = 7.8, 4.8 Hz, CH), 8.24 (1 H, d, J = 7.8 Hz, CH), 8.77 (1 H, dd, J = 3.5, 1 .5 Hz, CH), 9.05 (1 H, s, CH), 10.34 (1 H, s, OH), 1 1 .24 (1 H, s, NHCO). ¹³ C NMR: δ ppm (DMSO-de) 14.8, 28.5, 1 16.4, 121 .8, 122.4, 124.0, 129.8, 134.5, 136.3, 147.5, 149.3, 152.6, 153.7, 162.8, 167.6. ESI-MS in CH ₃ CN: found mass: 304.10 (100%), Calc. mass for Ci6H ₁₅ N ₃ O ₂ Na: 304.1 1 [M+Na ⁺ ] ⁺ . Anal. Calc. for Ci6H ₁₅ N ₃ O ₂ (%): C 68.31 , H 5.37, N 14.94. Found (%): C 68.24, H 5.42, N 14.90. Effect of the Compounds 1 -12 on Mobilising Cellular ⁵⁹ Fe

The effect of compounds 1 -12 on ⁵⁹ Fe mobilisation in SK-N-MC cells was determined by ⁵⁹ Fe efflux experiments using a standard protocol. ¹ The human SK-N-MC neuroepithelioma cell line was chosen for these initial studies as it is a neural cell line that has been used as a preliminary model for AD. ^2,3 Furthermore, it is a well characterised cell line for examining the effect of iron chelating agents. ⁴ Briefly, SK-N- MC cells were seeded in 6-well plates and incubated overnight. The cell growth medium was aspirated and then the cells prelabelled with ⁵⁹ Fe ₂ -Tf (0.75 μΜ) in MEM media (1 mL) for 3 h at 37°C. Cells were washed four times with ice-cold PBS to remove extracellular ⁵⁹ Fe ₂ -Tf and then loaded with medium alone (control) or medium containing chelator (25 μΜ) and incubated for 3 h at 37°C. The known iron chelators, desferrioxamine (DFO), di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone (Dp44mT), clioquinol (CQ), salicylaldehyde benzoylhydrazone (SBH) and salicylaldehyde isonicotinoyi hydrazone (SIH) and were also included as positive controls. After incubation, cells were placed on ice and the media containing released ⁵⁹ Fe was separated without dislodging cells. To the cells, PBS (1 mL) was added and then scraped using a plastic spatula. Radioactivity was measured in both the cell suspension and supernatant using a γ-scintillation counter (Wallac Wizard 3, Turku, Finland).

Effect of Compounds 1 -12 at Preventing Cellular ⁵⁹ Fe Uptake In order to estimate the ability of compounds 1 -12 to prevent the cellular uptake of ⁵⁹ Fe from the Fe transport protein, ⁵⁹ Fe ₂ -Tf, ⁵⁹ Fe uptake experiments were performed using standard procedures. ¹ Briefly, SK-N-MC cells were incubated with ⁵⁹ Fe ₂ -Tf (0.75 μΜ) and the compounds (25 μΜ) in MEM media for 3 h at 37°C. The media was then removed and cells washed four times with ice-cold PBS to eliminate an excess of extracellular ⁵⁹ Fe ₂ -Tf and the chelator. Subsequently, cells were incubated with Pronase (1 mg/ml_; Sigma-Aldrich), a general protease, for 30 min at 4°C. The monolayer of cells was then scraped using a plastic spatula and centrifuged at 14,000 rpm for 3 min at 4°C. The supernatant media that contain membrane-bound ⁵⁹ Fe was removed and the settled pellet containing internalised ⁵⁹ Fe was resuspended in 1 ml_ of PBS and the ⁵⁹ Fe levels in both supernatant and cell suspension were measured on a γ-scintillation counter. Internalised ⁵⁹ Fe uptake was calculated as a percentage of the control (medium alone). The well characterised chelators, DFO, Dp44mT, CQ, SBH and SIH were included in this study as positive controls for appropriate comparison.

Effect of Compounds 1 -12 on Cell Viability by MTT assay

The cytotoxic potential of compounds 1 -12 was determined by the [1 -(4,5- dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium] (MTT) assay against SK-N-MC cells using standard techniques. ⁵ The cells were seeded in 96-well microtiter plates at the density of 1 .5 χ 10 ⁴ cells/well. The compounds were dissolved in DMSO (20 mM) and diluted further using MEM media to result in a final concentration of DMSO <0.5% (v/v) at which DMSO has no effect on cellular proliferation. ⁵ After 24 h, the cells were exposed to various concentrations of chelators (0-100 μΜ) and incubated for 72 h at 37°C. After this incubation, 10 μί of MTT (5 mg/ml_ in PBS) was added to each well and incubated further for 2 h at 37°C. Culture medium was aspirated carefully and 100 μΙ_ of DMSO was added to dissolve the formazan crystals. The plates were shaken for 5 min and the absorbance was measured at 570 nm using a scanning multi-well spectrophotometer. The half maximal inhibitory concentration (IC50) was defined as the chelator concentration necessary to reduce the absorbance to 50% of the untreated control.

Ascorbate Oxidation Assay

The ability of the iron complexes of compounds 1 -12 to catalyse the oxidation of ascorbate was examined as previously described. ⁶ The assay was carried out in PBS buffer (10 mM, pH = 7.4) containing 5% (v/v) acetonitrile and sodium citrate (500 μΜ). Freshly prepared sodium ascorbate (50 μΜ) was incubated with FeC alone (10 μΜ, control) or in the presence of chelators at an iron-binding equivalent (IBE) of 1 . This IBE results in a fully occupied coordination sphere of Fe(lll) upon complexation (Fe(lll)- EDTA (1 : 1 ratio), Fe(lll)-DFO (1 : 1 ratio), Fe(lll)-Dp44mT (1 :2 ratio), and Fe(lll)- compound 1 -12 (1 :2 ratio)). The standard iron chelators, ethylenediaminetetraacetic acid (EDTA), Dp44mT, and DFO were included as controls. The absorbance at 265 nm was measured using UV-visible spectrophotometer after 10 and 40 min of incubation at RT and the decrease in absorbance between the two time points was calculated and expressed as a percentage of ascorbate oxidation relative to the control (100%).

Results

Effect of Compounds 1 -12 on ^S3 Fe Release from Prelabe!led Cells

Iron dyshomeostasis is a major risk factor in ageing, ⁷ as well as for age-related diseases, such as Alzheimer's disease ⁸ and Parkinson's disease, ⁹ which often leads to oxidative stress ⁹ through the generation of excess ROS and β-amyloid aggregation. ¹⁰ We examined the effect of compounds 1 -12 on iron efflux from cells with the aim of evaluating their efficacy to chelate intracellular iron and release it out of the cell. These results were compared with six controls, namely: (1 ) nicotinic acid hydrazide (NH), a common precursor implemented for synthesizing compounds 1 -12; (2) DFO, a bacterial siderophore used for the treatment of iron overload diseases; ¹¹ (3) Dp44mT, a well characterised thiosemicarbazone with high iron mobilisation efficacy; ¹² (4) CQ, a chelator used in clinical trials for AD therapy; ¹³ and also (5) SBH ⁵ and (6) SIH ⁵ which are tridentate chelators with structural similarity to the current series of compounds that have effective Fe-chelation activity. ¹⁴

As reported in the literature, ⁴ the incubation of SK-N-MC cells with control medium alone resulted in minimal cellular ⁵⁹ Fe release (5 ± 1 % of total cellular iron) from prelabelled SK-N-MC cells (Fig. 1 ). NH, a common precursor used for synthesizing compounds 1 -12, did not induce any significant (p > 0.05) amount of ⁵⁹ Fe release compared to the control. In terms of positive controls, DFO released moderate amounts of intracellular ⁵⁹ Fe (13 ± 1 % of total cellular iron) from cells, whereas Dp44mT and CQ were markedly effective at inducing ⁵⁹ Fe release (i.e., 41 ± 3% and 38 ± 3% of total cellular iron, respectively; Fig. 1 ). The structurally-related positive controls, SBH and SIH, caused significantly (p < 0.001 ) high amounts of ⁵⁹ Fe release compared to DFO, and their activities were comparable to that exhibited by the positive controls, Dp44mT and CQ.

Importantly, compounds 1 -12 demonstrated high ⁵⁹ Fe chelation efficacy and mobilised 37-42% of cellular ⁵⁹ Fe (Fig. 1 ). Their iron chelation efficacy was comparable to that of the positive controls, Dp44mT, CQ, SBH and SIH, and was significantly (p < 0.001 ) greater than that of DFO (Fig. 1 ). This high activity demonstrates their potential as agents that may be suitable for the treatment of diseases related to ageing that result in the accumulation of iron.

Effect of Compounds 1 -12 on Inhibiting ⁵⁹ Fe Uptake from ⁵⁹ Fe-Transferrin Considering the marked activity of compounds 1 -12 on inducing cellular iron release, experiments were then performed to examine the activity of these agents at inhibiting the uptake of iron by SK-N-MC cells from ⁵⁹ Fe ₂ -Tf (Fig. 2). As in the iron efflux studies above, six controls were utilised, namely: NH, DFO, Dp44mT, CQ, SBH and SIH. The common precursor control, NH, slightly reduced Fe uptake from ⁵⁹ Fe ₂ -Tf to 78 ± 9% of the control value, having efficacy that was similar to the positive control, DFO (Fig. 2). In contrast, Dp44mT demonstrated marked inhibition of iron uptake decreasing it to 4 ± 1 % of the control value. On the other hand, CQ was less effective than Dp44mT and decreased iron uptake to 20 ± 2% of the control (Fig. 2). Both SBH and SIH showed chelation activity that was greater than DFO and CQ, resulting in a significant (p < 0.001 ) decrease in Fe uptake to 7 ± 1 % of the control. Compounds 1 -12 all showed marked activity that was significantly (p < 0.001 ) greater than DFO, decreasing iron uptake to 5-19% of the control value (Fig. 2). Again, these data confirm the high activity of these agents for treating age-related iron dyshomeostasis.

Effect of the Iron Complexes of Compounds 1 -12 on Ascorbate Oxidation An important property of chelators for the treatment of iron-loading conditions, including those due to age-related pathologies, is that they should form iron complexes that are not redox active. This is critical in diseases such as Alzheimer's disease where Fe accumulation occurs within plaques and has been reported to play a role in oxidative stress. ⁸ Hence, the removal of the iron accumulation without the generation of redox stress is an important property of compounds with therapeutic potential. To examine this property, the Fe(lll) complexes of compounds 1 -12 were assessed in terms of their activity to catalyse ascorbate oxidation via iron-mediated Fenton chemistry. ⁶ In these studies, ascorbate was used as a substrate because of its abundance in neurons and its strong anti-oxidant potential to protect these cells from oxidative stress. ¹⁵ For comparison, the well-known, redox-active Fe(lll) complexes of EDTA and Dp44mT were included as positive controls. ¹⁴ On the other hand, DFO was also used as a redox-inactive Fe(lll) complex. ¹⁴

In accordance with previously published results, ^14,16 the EDTA- and Dp44mT- iron(lll) complexes markedly and significantly (p < 0.001 ) accelerated the oxidation of ascorbate to 458% and 188% of the control, respectively (Fig. 3). In contrast, the redox inactive Fe(lll)-DFO complex significantly (p < 0.001 ) reduced ascorbate oxidation, decreasing it to 20% relative to the control, confirming its anti-oxidative behaviour.

Interestingly, none of the iron complexes derived from compounds 1 -12 showed marked pro-oxidative activity, being significantly (p < 0.001 ) less than both the iron complexes of EDTA and Dp44mT (Fig. 3). Interestingly, several of these agents (including compounds 5, 7 and 10) significantly (p < 0.001 ) inhibited ascorbate oxidation relative to the control. Notably, the iron(lll) complexes of compounds 1 -4, 6, 8, 9, 1 1 and 12, did not display marked ascorbate oxidation with activities that were comparable to the control (100%). In conclusion, this study demonstrated that compounds 1 -12 form redox inactive Fe complexes, and thus, have appropriate properties for treating age- related iron-loading.

Cytotoxicity of Compounds 1 -12 in SK-N-MC Neuroepithelioma Cells

Having demonstrated that compounds 1 -12 exhibited effective iron chelation activity, studies then assessed their cytotoxicity in SK-N-MC cells (Table 2). Five controls were utilised, including the well-known iron chelators, DFO and Dp44mT, as their anti-proliferative activity is well described in this cell-type. ^12,17 Moreover, we also assessed the cytotoxicity of CQ, and also the structurally-related chelators, SBH and SIH. In these studies, DFO and Dp44mT displayed IC ₅ o values of 20.91 ± 1 .17 and 0.009 ± 0.002 μΜ, respectively (Table 2). Additionally, CQ, SBH and SIH had IC ₅₀ values of 17.45, 9.43 and 19.38 μΜ, respectively. Compounds 1 -12 demonstrated a range of activity in terms of cytotoxicity, with IC ₅₀ values that ranged from 0.56-19.47 μΜ. The ketone-derived analogues (i.e., compounds 7-12) generally showed greater cytotoxicity (i.e., IC50: 0.56-5.23 μΜ) than the aldehyde-derived analogues 1 -6 (i.e., IC50: 1 .81 -19.47 μΜ). Of all the analogues, compounds 1 , 3 and 6 displayed IC ₅₀ values greater than 10 μΜ, with compounds 1 and 6 having IC50 values comparable to DFO (Table 2). Hence, several of these agents demonstrate low toxicity in cell culture and showed properties suitable for the treatment of age-related pathologies.

Table 2. Cytotoxicity of compounds 1-12 and the iron chelators, DFO, Dp44mT, CQ, SBH and SIH in human SK-N-MC neuroepithelioma cells as determined by the MTT assay. IC50 values are presented as mean ± SD from three independent experiments.

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1 . A compound of formula (I):

(I) or a pharmaceutically acceptable salt or prodrug thereof, wherein:

R is independently selected from:

, which group is optionally further substituted by one or more substituents selected from halogen, an alkyl group and a heteroalkyl group, and

, wherein R ³ is independently selected from H and alkyl, A ¹ , A ² ,

A ³ , A ⁴ and A ⁵ are independently selected from CH and N, and the aromatic ring containing A ¹ , A ² , A ³ , A ⁴ and A ⁵ is optionally substituted with one or more substituents independently selected from halogen, OH, alkyl and heteroalkyl, and is optionally fused to an aryl group, and

R ² is a heteroaryl group.

2. The compound of claim 1 , wherein R ¹ is

3. The compound of claim 2, wherein R ¹ is further substituted by one or more substituents independently selected from halogen, alkyl and heteroalkyl.

4. The compound of claim 3, wherein the substituent is halogen.