The present invention relates to the field of neurodegenerative disorders, in particular to Alzheimer's disease (AD).

AD is the most common form of dementia and no treatment exists which can stop, let alone reverse, progression of the disease. The memory and other mental health implications of AD are well known but the disease is also a killer; the average life expectancy after diagnosis is about 7 years as bodily functions are gradually lost. This is a common degenerative condition, generally affecting people over 65, and it is recognised as placing a significant burden on carers, health services and society in general as life expectancy continues to rise and the numbers of people affected by AD increases.

AD is characterised by loss of neurons and synapses in the cerebral cortex and some subcortical regions. Amyloid plaques and neurofibrillary tangles are observed in the brains of those with AD.

Amyloid plaques form on the outside of neurones and are made up of peptides of 39-43 amino acids called beta-amyloid (A _p ), these are fragments of amyloid precursor protein, a trans-membrane protein that penetrates the neuron's membrane and is critical to neuron growth, survival and repair.

Neurofibrillary tangles are aggregates of the microtubule-associated protein tau which have become hyperphosphorylated and accumulated in the neurons. In healthy neurones, tau serves to stabilise the microtubules of the neuronal cytoskeleton. Certain conditions are characterised by an increase in these tau tangles and this group of conditions are referred to as tauopathies. Tauopathies include Parkinson's disease, Pick's disease and progressive supernuclear palsy, as well as AD. While an increase in amyloid plaques may be seen decades before the onset of symptoms of AD, the symptoms of AD are often observed just after a noticeable increase in tau protein is seen.

While it is generally accepted that these two proteins have a role in AD, the pathological mechanism and the causal events are not known. It had been postulated that the formation of amyloid plaques caused AD but therapies which successfully reduced plaque formation did not give significant improvement in symptoms such as dementia.

Current medication for AD shows limited benefit. Acetycholinesterase inhibitors such as tacrine and donepezil are used to decrease the rate at which acetylcholine (ACh) is broken down in the brain, in order to counteract the reduction in cholinergic neuron activity which is associated with AD. These therapies have shown some benefit, at least in mild to moderate AD. The NMDA receptor antagonist memantine has been shown to have very modest efficacy in the treatment of moderate to severe AD.

There is undoubtedly an urgent need for further therapeutic options in the treatment of AD and other neurodegenerative conditions, whether to slow or halt disease progression, improve symptoms or delay onset; the tools available to the clinician at present are completely inadequate.

The present inventors have developed compounds which act as inhibitors of

DyrkIA (dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1A), a kinase thought to be important in neonates and in the early stages of life. DyrkIA is a kinase whose over-activity has recently been implicated in the pathogenesis of AD and other tauopathies. The DyrkIA gene is copied in triplicate in patients that have Down Syndrome (DS), who are themselves more likely to develop AD; between 50 and 70% of DS patients develop dementia by age 60 and nearly all DS patients have amyloid plaques and neurofibrillary tangles above the age of 30. DyrkIA is thought to play a role in the development of AD, both by increasing amyloid plaque formation and increasing intracellular tau protein tangles. Studies have identified DyrkIA as the priming kinase of multiple phosphorylation of the tau protein and studies of the brains of patients with AD showed increased expression of DyrkIA in neurons affected by tau tangles.

Ogawa et al. in Nature Communications, 5 October 2010 (1 ) Article 86 describe a DyrkIA inhibitor called INDY, a benzothiazoylidene. INDY binds at the ATP binding cleft. INDY is not well able to cross cell membranes and has the complication that it must be administered as a prodrug. Harmine is a potent inhibitor of DyrkIA but is hallucinogenic.

Thus there is a need for alternative and/or improved inhibitors of DyrkIA. In particular for highly selective kinase inhibitors so that off-target effects on other kinases are reduced. It is also necessary for the compounds to pass the blood brain barrier. The present inventors have identified a new class of DyrkIA inhibitor which possess some or all of these advantageous features.

According to one aspect, the present invention provides a compound of formula (I)

wherein:

Y represents a C or N atom which may be substituted or form a cyclic group with R'" but may not be a quaternary C atom;

R' is -ORi , -CONH ₂ , -CF ₃ , F, -OH, -N0 ₂ , -CN or -OCOR1 in which R-, is Ci _-3 alkyl and each may be in the beta or gamma position;

R" is Ci-3 alkyl or H; and

R'" is H or a group consisting of 1 -12 non-hydrogen atoms and may be linear, branched and/or incorporate one or more cyclic groups, cyclic groups may be aromatic and/or heterocyclic and 2 or more cyclic groups may be linked or fused and each may be substituted; or a salt, hydrate or solvate of a compound of formula (I) for use in the treatment or prevention of a neurodegenerative disorder by inhibiting formation of neurofibrillary (tau) tangles.

The compounds of formula (I) are DyrkIA inhibitors and preferably can cross the blood brain barrier. In a further aspect the present invention provides a compound of formula (I) as defined herein, or a salt, hydrate or solvate of a compound of formula (I), for use in the treatment or prevention of a

neurodegenerative disorder by inhibiting DyrkIA.

A quaternary C atom is one bonded to 4 other C atoms. In a further aspect, the present invention provides a method of treating preventing a neurodegenerative disease in a subject comprising administering therapeutically effective amount of a compound of formula (I)

Y represents a C or N atom which may be substituted or form a cyclic group with R'" but may not be a quaternary C atom;

R' is -ORi , -CONH ₂ , -CF ₃ , F, -OH, -N0 ₂ , -CN or -OCOR1 in which R-, is d _-3 alkyl and each may be in the beta or gamma position;

R" is Ci-3 alkyl or H; and

R'" is H or a group consisting of 1 -12 non-hydrogen atoms and may be linear, branched and/or incorporate one or more cyclic groups, cyclic groups may be aromatic and/or heterocyclic and 2 or more cyclic groups may be linked or fused and each may be substituted; or a salt, hydrate or solvate of a compound of formula (I) to said subject, with the proviso that the compound of formula (I) is not:

(i) one of the following compounds of formula (II)

(II) in which R is benzyl substituted as follows:

or (e) R is pyridyl, or

(ii) selected from

(f) N-(6-cyano-2-benzothiazolyl)-N-[(4-methoxyphenyl)methyl]-ure a

(g) ethyl 2-(3-(6-fluorobenzo[d]thiazole-2-yl)ureido)acetate

(h) ethyl 2-(3-(6-methoxybenzo[d]thiazole-2-yl)ureido)acetate

(i) potassium 2-(3-(6-methoxybenzo[d]thiazole-2-yl)ureido)acetate (j) 2-(3-(6-methoxybenzo[d]thiazole-2-yl)ureido)acetic acid

(k) N-(2,6-dimethylphenyl)-N-(6-fluoro-2-benzothiazolyl)urea

(I) benzeneacetamide,3,5-difluoro-N-[(1 S)-1 -[[(6-methoxy-2- benzothiazolyl)amino]carbonyl]propyl]. A therapeutically effective amount is preferably one which is able to inhibit formation of neurofibrillary (tau) tangles (and thereby treat or prevent a neurodegenerative disorder). A therapeutically effective amount is preferably one which inhibits DyrkIA (and thereby treats or prevents a neurodegenerative disorder). Preferably the compounds of formula (I) for use according to, and in the methods of, the present invention do not include the following compounds:

(m) 2-(3,5-dimethylphenoxy)-N-(6-nitrobenzothiazol-2-yl) acetamide

(n) 1 -(6-fluorobenzothiazol-2-yl)-3-(4-fluorophenyl)urea

(o) 1 -(4-fluorophenyl)-3-(6-methoxybenzothiazol-2-yl) urea

4-[3-(6-fluorobenzothiazol-2-yl)ureido]benzoic acid ethyl ester benzeneacetamide, a-ethyl-N-(6-methoxy-2-benzothiazolyl)

Y is preferably carbon and preferably forms a cyclic group with R'", preferably an aromatic cyclic group. If Y forms a cyclic group with R'" then together the moiety -YR'" consists of no more than 13 non-hydrogen atoms. If Y is substituted, it is preferably by a Ci _-3 alkyl group but in other preferred embodiments it is unsubstituted. If the Y atom is unsubstituted and not part of a cyclic group with R"\ then Y is -CH ₂ - or -NH-.

R" is preferably H or methyl, most preferably H.

R' is preferably attached to the β carbon atom unless it is -CF ₃ , -CONH ₂ ,

-NO ₂ or -CN, in which case it is preferably attached to the γ carbon atom. -CF ₃ , -NO ₂ and -CN are particularly preferred in the γ position. Preferably R' is not F.

Ri is preferably methyl and thus -OCH ₃ is a preferred R' moiety, if R' is -OCH ₃ it is preferably attached to the β carbon atom.

R'" may, in certain preferred embodiments, be hydrogen and in this case

YR'" together are preferably -NH ₂ or -CH ₃ , most preferably CH ₃ .

In a further preferred embodiment R'" is Ci _-5 alkyl, which may be linear or branched, or a derivative thereof which may optionally be substituted, e.g. by oxygen, nitrogen or a halogen. Preferred alkyl derivatives are those in which one of the carbon atoms is replaced by a nitrogen or oxygen atom. Thus, for example, R'" may be -CONH ₂ , -CH ₂ COCH ₃ , -CH ₂ CHNH ₂ CH ₃ , -NHCOCH ₃ , -CH ₂ CH ₃ ,

-CH ₂ CH ₂ CH ₃ , -COCH ₃ , -COCH ₂ CH ₃ , -CONHCH ₃ .

In further preferred embodiments R'" is an amino acylated amino acid or an acylated dipeptide. The acyl group is preferably acetyl. The amino acid(s) are preferably genetically encoded amino acids, more preferably selected from alanine, phenylalanine, tyrosine, proline or serine.

Alternatively, R'" or YR'" together may contain 1 -3, preferably 1 or 2 cyclic groups, most preferably 1 cyclic group. For example, R'" or YR'" together may consist of one cyclic group of 3 to 7 ring atoms, preferably 3, 5 or 6 ring atoms, where at most 3 ring atoms are non-carbon atoms. Preferred non-carbon atoms are nitrogen, oxygen and sulphur, more preferably nitrogen and oxygen, most preferably nitrogen. The cyclic group may or may not be aromatic, but an aromatic ring is preferred.

The cyclic group is optionally substituted with one or more substituents containing a total of up to 8 non-hydrogen atoms. The substituents may be small (e.g. C1-3) alkyl groups including cyclopropyl, but are preferably polar in nature. Examples of suitable substituents are presented in Table A below.

In alternative embodiments, R'" or YR'" together may contain two fused cyclic groups, for example two fused five membered rings, one five membered ring fused to a six membered ring or two fused six membered rings. The fused rings together may contain 0 - 5 non-carbon atoms (e.g. 1 -3 non-carbon atoms), preferably nitrogen, oxygen or sulphur, more preferably nitrogen or oxygen, most preferably nitrogen. Neither, either or both, preferably both, of the fused rings may be aromatic.

One or more of the fused cyclic groups are optionally substituted with one or more substituents containing a total of up to 5 non-hydrogen atoms. The substituents may be small (e.g. Ci _-3 ) alkyl groups, including cyclopropyl, but are preferably polar in nature. Examples of suitable substituents are presented in Table A below.

In alternative embodiments, R'" or YR'" together may contain two linked cyclic groups. The link may be direct forming a biaryl system or through a linking atom, usually carbon, nitrogen or oxygen. The linked rings together may contain 0 - 5 non-carbon atoms (e.g. 1 -3 non-carbon atoms), preferably nitrogen, oxygen or sulphur, more preferably nitrogen or oxygen, most preferably nitrogen. Neither, either or both, preferably both, of the linked cyclic groups may be aromatic.

One or more of the linked cyclic groups are optionally substituted with one or more substituents containing up to 3 non-hydrogen atoms. The substituents may be small alkyl groups (e.g. Ci _-3 ), including cyclopropyl, but are preferably polar in nature. Examples of suitable substituents are presented in Table A below. Table A. Preferred substituents to the cyclic group(s) of -R'" or -YR'", ordered by the number of non-hydrogen atoms:

Preferred linking groups include -CH ₂ -, -NR-, -O- and -S-, wherein R is H or C1-2 alkyl.

If R'" or YR'" together contain two or more cyclic groups these may be the same or different and if they are substituted, the substituents may be the same or different.

If R'" or YR'" together comprise two or more aromatic groups, then preferably no more than one of these groups is carbocyclic.

Suitable cyclic groups for R'" or YR'" together include cyclohexyl, phenyl, pyridine, pyrimidine, pyrazole, imidazole, thiazole, oxazole, diazolone, morpholine and piperidine.

Preferred substituents of the cyclic group(s) of R'" (or YR'") include: -OH, -OR, -NRR, -C=0-OR, -C=0-NRR, -S0 ₂ -NRR, -NR-S0 ₂ R, -S0 ₂ R, -NR-C=OR and a halogen (e.g. F or CI), wherein each R (which may be the same or different) is H or C-i-3 alkyl, preferred substituents are Ci _-3 alkyl or a derivative thereof which may itself be substituted (e.g. by oxygen, -CH ₃ , NH ₂ or a halogen such as F).

In preferred embodiments, YR'" together form a single cyclic group, preferably aromatic and preferably 6 membered, most preferably, pyrimidinyl, pyridyl or phenyl; the cyclic group is optionally and preferably substituted, e.g. by NH ₂ or a Ci _-3 alkyl or derivative thereof which may itself be substituted e.g. by oxygen, nitrogen or a halogen. Preferred alkyl derivatives are those in which one of the carbon atoms is replaced by a nitrogen or oxygen atom. The substituent of the cyclic group may preferably be selected from the group comprising -CONH ₂ , -CH ₂ COCH ₃ , -CH ₂ CHNH ₂ CH ₃ , -NHCOCH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -OCH ₃ , -COCH ₃ , -COCH ₂ CH ₃ and -CONHCH ₃ .

Pharmaceutically acceptable salts, hydrates and solvates are well known in the art.

Neurodegenerative disorders according to the present invention include

Alzheimer's disease, Parkinson's disease, Pick's disease, progressive supranuclear palsy, corticobasal degeneration and agyrophilic grain disease. In particular the present invention concerns the treatment or prevention of Alzheimer's disease, more particularly the treatment or prevention of Alzheimer's disease in patients with Down Syndrome. Tauopathies are a particular target for treatment according to the present invention.

Treatment includes an improvement in one or more of the symptoms of the disorder or a delay in onset of one or more symptoms as assessed by a clinician, optionally together with patient feedback. Symptoms of AD include memory loss, confusion, mood and personality changes, hallucinations, delusions and paranoia, problems with communication, weight loss, seizures, skin infections, difficulty in swallowing and lack of control of bowel and bladder.

Treatment includes slowing or halting disease progression and thus treatment may not result in significant observable benefits unless a comparison is made with expected (untreated) progression of the disorder. Likewise, treatment may be beneficial if an anticipated symptom is delayed in its appearance.

The subject will typically have been identified as in need of treatment. This may be determined based on assessment of cognitive performance or any other measure which leads to a diagnosis that the patient has a neurodegenerative disorder or is at risk of developing such a disorder. In the case of AD this determination may be achieved through microscopic histological or other investigations to observe the formation of amyloid plaques and/or neurofibrillary tangles.

Prevention of a neurodegenerative disorder may include prevention for a period of time, in other words delayed onset. Suitable patients for prevention include those with DS, in particular, DS patients over the age of 20 or 30.

Generally, if a patient has been shown to have one or more markers of a neurodegenerative disorder but no symptoms as yet, such a patient is considered to be "treated" in accordance with the present invention. "Prevention" assumes the patient has neither symptoms nor confirmed clinical markers of disease.

The present invention typically involves inhibition of the formation of neurofibrillary tangles. Without wishing to be bound by theory, this is believed to be key to the clinical success of the present invention and at least part of the mechanism by which the disclosed DyrkIA inhibitors are effective against neurodegenerative disorders. These (tau) tangles can be assessed by any convenient method known in the art, for example using a microscope to observe the aggregates of the tau protein, a suitable method is described by Armstrong in Folia Neuropathol. 2008; 46 (1 ): 26-31 .

Inhibition may be observed on treatment through a reduction in the size of the tangles or in the extent of their distribution. Their formation is "inhibited" even if the amount observed has not decreased on treatment, if the amount would have been expected to increase without treatment. Of course, such examinations of a patient may not be possible during a treatment regimen, but suitable studies can easily be performed to select a compound from within the definition of compounds of formula (I).

Alternatively viewed, the compounds described herein treat or prevent neurodegenerative disorders through inhibition of DyrkIA. A method to measure inhibition of DyrkI A is described in the Examples hereto. A suitable assay could be performed using ADP-Glo™ kinase assay of Promega. Compounds of the invention preferably can achieve at least 30, more preferably at least 50 or 60, most preferably at least 70 or 80% inhibition of DyrkIA in such assays.

In a further aspect, the present invention provides a method of inhibiting DyrkIA and/or a reaction catalysed by DyrkIA, the method comprising contacting said kinase with a compound of formula (I) as defined herein or a salt, hydrate or solvate of a compound of formula (I). Such methods may be in vivo or ex vivo, e.g. in vitro.

In a further aspect, the present invention provides the use of a compound of formula (I) or a salt, hydrate or solvate of a compound of formula (I) in the manufacture of a medicament for the treatment of a neurodegenerative disorder.

Animals which may be treated include domestic animals, in particular cats and dogs and livestock animals such as pigs, cows, sheep or goats as well as horses. Laboratory animals, mice, rabbits etc. may also be treated. Treatment of humans is nevertheless preferred.

Methods for the synthesis of compounds of the invention are described in the Examples hereto, non-exemplified compounds can be prepared by methods which are analogous to the schemes and protocols described herein.

Methods of synthesising compounds of the invention, in particular methods described in the Examples, constitute a further aspect of the present invention.

All novel compounds, defined generically by the formulae herein or individual compounds recited, in particular in the Examples, constitute a further aspect of the present invention.

The compositions according to the invention may be presented, for example, in a form suitable for oral, nasal, parenteral, intravenal, topical or rectal administration.

The active compounds defined herein may be presented in the conventional pharmacological forms of administration, such as tablets, coated tablets, nasal sprays, inhalers, solutions, emulsions, liposomes, powders, capsules or sustained release forms. As used herein, the term "pharmaceutical" includes veterinary applications of the products of the invention.

Conventional pharmaceutical excipients as well as the usual methods of production may be employed for the preparation of these forms. Tablets may be produced, for example, by mixing the active ingredient or ingredients with known excipients, such as for example with diluents, such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talcum, and/or agents for obtaining sustained release, such as carboxypolymethylene,

carboxymethyl cellulose, cellulose acetate phthalate, or polyvinylacetate.

The tablets may if desired consist of several layers. Coated tablets may be produced by coating cores, obtained in a similar manner to the tablets, with agents commonly used for tablet coatings, for example, polyvinyl pyrrolidone or shellac, gum arabic, talcum, titanium dioxide or sugar. In order to obtain sustained release or to avoid incompatibilities, the core may consist of several layers too. The tablet coat may also consist of several layers in order to obtain sustained release, in which case the excipients mentioned above for tablets may be used.

Injection solutions may, for example, be produced in the conventional manner, such as by the addition of preservation agents, such as

p-hydroxybenzoates, or stabilizers, such as EDTA. The solutions are then filled into injection vials or ampoules.

Nasal sprays administration may be formulated similarly in aqueous solution and packed into spray containers either with an aerosol propellant or provided with means for manual compression.

Capsules containing one or several active ingredients may be produced, for example, by mixing the active ingredients with inert carriers, such as lactose or sorbitol, and filling the mixture into gelatin capsules.

Suitable suppositories may, for example, be produced by mixing the active ingredient or active ingredient combinations with the conventional carriers envisaged for this purpose, such as natural fats or polyethyleneglycol or derivatives thereof.

Tablets for oral administration are preferred.

Pharmaceutical compositions comprising a compound of formula (I) may additionally comprise further active ingredients, including, for example, other active agents for the treatment or prevention of a neurogenerative disorder. Likewise the medical uses and methods of treatment may additionally comprise further active ingredients, including, for example, other active agents for the treatment or prevention of a neurogenerative disorder, e.g AD.

In employing such compositions systemically (intra-muscular, intravenous, intraperitoneal), the active molecule is generally present in an amount to achieve a serum level of the active molecule of at least about 1 - 10 micromolar Such serum levels may be achieved by incorporating the bioactive molecule in a composition to be administered systemically at a dose of from 50 mg - 250 mg.

It is appreciated that appropriate dosages will vary from patient to patient dependent on age, sex, previous treatments, severity of symptoms presented etc.

The above description describes numerous features of the present invention and in most cases preferred embodiments of each feature are described. It will be appreciated that each preferred embodiment of a given feature may provide a molecule, use, method etc. of the invention which is preferred, both when combined with the other features of the invention in their most general form and when combined with preferred embodiments of other features. The effect of selecting multiple preferred embodiments may be additive or synergistic. Thus all such combinations are contemplated unless the technical context obviously makes them mutually exclusive or contradictory. In general each feature and preferred embodiments of it are independent of the other features and hence combinations of preferred embodiments may be presented to describe sub-sets of the most general definitions without providing the skilled reader with any new concepts or information as such.

The invention will now be further described with reference to the following non-limiting Examples. Not all of the compounds synthesised and tested are within the scope of the present invention, some are provided for comparative purposes and highlight the efficacy of the molecules of the invention.

Examples

A. Preparation of the compounds of the invention.

Overview

The amide compounds of the invention can conveniently be prepared by acylation of 2-aminobenzo-1 ,3-thiazoles. The acylation could be performed by treating the 2- aminobenzo-1 ,3-thiazoles with acetyl chloride or acetyl anhydride ( R=CH ₃ ) or by treatment of a carboxylic acid (R≠CH ₃ ) under coupling conditions (e.g. using HBTU or other coupling reagents typically used for peptide synthesis).

The 2-aminobenzo-1 ,3-thiazoles themselves can be prepared in a two-step sequence from the corresponding aniline as outlined below. The aniline derivative is treated with potassium thiocyanate forming a thiourea derivative that is

subsequently cyclised by addition of bromine.

Compounds with a "reversed" amide bond, included as comparative examples, can be prepared from 2-benzo-1 ,3-thiazole carboxylic acid derivatives by performing a HBTU mediated coupling to a suitable amine or aniline derivative.

Urea derivatives can be prepared by the reaction between 2-aminobenzo-1 ,3- thiazole derivatives and suitable alkyl- or aryl isocyanates as shown in the scheme below.

Example 1.

yV-(5-hydroxybenzo[cf]thiazol-2-yl)acetamide

Step 1. 1-(3-methoxyphenyl)thiourea

3-Methoxyaniline (approx 57 mmol) was added to a mixture of sodium thiocyanate (1 ,5 eqv) in isopropylacetate (56 mL) at room temperature. Trifluoroacetic acid (1 1 mL (2,5 eqv)) was then added portionwise ensuring that the temperature of the mixture was maintained at 40°C or less. The temperature of the mixture was then raised to 85°C and stirred for 16 hours. The mixture was cooled and 7 mL of distilled water were added before further cooling to 0°C. The crude product was isolated by vacuum filtration. The crude yield was in the range of 80 %

Step 2. 5-Methoxybenzo[d]thiazol-2-amine

The thiourea above (5.5 mmol) was dissolved in acetic acid (10 mL) and lithium bromide (1.5 eqv) was added at room temperature. Bromine (1 eqv) was added portionwise (the reaction is very exothermic) ensuring that the temperature mixture did not exceed 30°C. The reaction vessel was then heated to 40°C The reaction is stirred and subsequently cooled room temperature. The product is isolated by vacuum filtration and washed twice with 5% sodium carbonate solution and twice with distilled water before drying. The crude yield was in the range of 75 %. Step 3. 5-Hydroxyoxybenzo[d]thiazol-2-amine

Borontribromide (2 ml) was added to a suspension of 5-methoxybenzo[c/]thiazol-2- amine (0.18 mmol) in dichlorormethane at 0°C before overnight stirring at ambient temperature. The reaction mixture was carefully quenched with water before extraction with ethyl acetate. The crude product was isolated by evaporation of the solvent under reduced pressure.

Step 4. N-(5-Hydroxybenzo[d]thiazol-2-yl)acetamide

The 2-aminobenzothiazole above (0.5 mmol) and acetic anhydride (2.2 eqv. ) were dissolved in 2 mL of DMF. DIPEA (3 eqv) was added and the mixture was placed in a microwave oven and irradiated at 60°C for 2 h. The mixture was triturated into 50 mL of 5% NaHS0 ₄ and stirred for 15 min. The crude product was hydrolysed in 5% NaOH before pH adjustment to 7-7.5 where the N-acetylated product precipitated.

In a similar manner the following products were prepared:

^* = comparative example

Example 2.

Methyl 3-((6-(trifluoromethyl)benzo[ |thiazol-2-yl)carbamoyl)benzoate

6-(trifluoromethyl)benzo[c/]thiazol-2-amine (commercially available or prepared according to Step 1 and 2 of Example 1 ) (1 eq), 3-(methoxycarbonyl)benzoic acid (1 .05 eq) and DIPEA (5 eq) were dissolved in DMF (2 ml). HBTU (1 .2 eq) was added and the reaction were stirred overnight at ambient temperature before extraction with ethylacetate, washed thoroughly 2 times with dilute acid and dried. The crude product, methyl 3-((6-(trifluoromethyl)benzo[c ]thiazol-2- yl)carbamoyl)benzoate, was isolated by evaporation of the solvent under reduced pressure.

In a similar manner the following products were prepared:

Example 3. (Comparative Example)

N-(3-acetamidophenyl)-6-hydroxybenzo[d]thiazole-2-carboxamid e

Step 1. 6-Methoxybenzo[d]thiazol-2-carboxylic acid

6-Methoxybenzo[c/]thiazole-2-carbonitrile (1 mmol) and concentrated HCI (5ml) was placed in a sealed microwave vial and heated at 90°C for one hour with the microwave set for a high-absorbance mixture. The mixture was then diluted with water and the product was isolated by vacuum evaporation.

Step 2. N-(3-acetamidophenyl)-6-methoxybenzo[d]thiazole-2- carboxamide

3-Acetamidoaniline (1 eq), 6-methoxybenzo[c ]thiazol-2-carboxylic acid (1.05 mmol) and DIPEA (5 mmol) were dissolved in DMF (2 ml). HBTU (1.2 mmol) was added and the reaction were stirred overnight at ambient temperature before extraction with ethyl acetate and washed thoroughly dilute acid and dried. The crude product was isolated by evaporation under vacuum. Step 3. N-(3-acetamidophenyl)-6-hydroxybenzo[d]thiazole-2- carboxamide

Borontribromide (2 ml) was added to a suspension of /V-(3-acetamidophenyl)-6- methoxybenzo[c/]thiazole-2-carboxamide (0.18 mmol) in dichlorormethane at 0°C before overnight stirring at ambient temperature. The reaction mixture was carefully quenched with water before extraction with ethyl acetate. The crude product was isolated by evaporation under vacuum. In a similar manner the following products were prepared:

Example 4.

1 -(6-fluorobenzo[cf]thiazol-2-yl)-3-phenylurea

Phenyl isocyanate (107 mg, 0.9 mmol) was added to a solution of 2-amino-6- fluorobenzothiazole (100 mg, 0.6 mmol) in dry DCM under argon . The reaction was allowed to proceed at R.T. for 16 hours before the product was isolated by filtration.

In a similar manner the following product was prepared:

B. Kinase Activity

1. Profiling kinase inhibitory activity

DYRK 1 A assay.

DYRK 1A (5-20 mU of diluted in 50 mM Tris pH7.5, 0.1 mM EGTA) is assayed against Woodtide (KKISGRLSPIMTEQ) (SEQ ID NO. 1 ) in a final volume of 25.5μΙ containing 50 mM Tris pH 7.5, 0.1 mM EGTA, 350 μΜ substrate peptide, 10 mM Magnesium acetate and 0.05 mM [33P-g-ATP](50-1000 cpm/pmole) and incubated for 30 min at room temperature. Assays are stopped by addition of 5 μΙ of 0.5 M (3%) orthophosphoric acid and then harvested onto P81 Unifilter plates with a wash buffer of 50 mM orthophosphoric acid.

Similar assays were performed for the other kinases in the tables which follow using the ADP-Glo™ kinase assay of Promega (products V9101 , V9102, V9103 and V9 104). Results

Data showing residual kinase activity at 100 micromolar inhibitor concentration is given in the tables which follows. The values are on an absolute scale such that 100 is no change in the presence of putatitic inhibitor, any value over 100 shows kinase activation. Any value less that 25 is considered to be highly significant inhibition.

Results for compounds of Example 1 (except 03-20 and 08-70)

nds of Example 2

Results for compounds of Example 3

Results for compound of Example 4

2. Determination of IC50 values for selected inhibitors from Example 1 against DYRKIa

IC 50 values were determined by measuring the inhibition of DYRKI a caused by each compound at a compound concentration of 100 μΜ, 30 μΜ, 10 μΜ, 3 μΜ, 1 μΜ, 0.3 μΜ, 0.1 μΜ, 0.03 μΜ, 0.01 μΜ and 0.003 μΜ. The kinase assay was carried out using Multidrop 384's at room temperature in a total assay volume of 25.5 μΙ. To plates containing 0.5 μΙ of compounds, DMSO controls or acid blanks, 15 μ I of an enzyme mix containing the DYRKI a enzyme and peptide/protein substrate in buffer was added. Compounds were pre-incubated in the presence of the enzyme and peptide/protein substrate for 5 minutes before initiation of the reaction by addition of 10 μΙ of ATP (final concentration selected for each kinase at 5, 20 or 50 μΜ). Assays were carried out for 30rminut.es at room temperature before termination by the addition of 5 μΙ

orthophosphoric acid. The assay plates were then harvested onto P81 Unifilter Plates by a Packard Harvester (wash buffer is 50mM orthophosphoric acid) and dried in air. The dry Unifilter plates were then sealed by the addition of MicroScint O and counted in Packard Topcount NXT scintillation counters. The measurements were performed in duplicate and the average determined and reported as the IC50 value and presented in the table below.

Table. Determined IC50 values (in μΜ) for inhibitors against DYRKI a.

R=CH ₃

X Compound IC 50 (μΜ)

γ-ΟΗ 01-71 28.1

β-ΟΗ 01-66 0.8

γ-OCHs 03-20 12.3

β-OCHs 03-21 0.4

γ-F 03-94 23.6

β-F 03-77 3.9 y-CF ₃ 01-90 1.1 β-CFs 03-73 26.5 γ-CN 01-94 1.3 γ-Ν0 ₂ 13-10 0.7 y-C0NH ₂ 08-70 15.7