WO2003068773A1

WO2003068773A1 - Pyrazolopyridine derivatives

Info

Publication number: WO2003068773A1
Application number: PCT/GB2003/000576
Authority: WO
Inventors: Jason Witherington
Original assignee: Glaxo Group Limited
Priority date: 2002-02-12
Filing date: 2003-02-12
Publication date: 2003-08-21
Also published as: AU2003245700A1

Abstract

Certain compounds of formula (I), or a salt thereof, or a solvate thereof, wherein R1, R2, R3 and R4 are as defined in the specification, a procees for the preparation of such compounds, a pharmaceutical composition comprising such compounds and the use of such compounds in medicine. For the treatment of conditions associated with a need for inhibition of GSK-3 such as diabetes, conditions associated with diabetes, chronic neurodegenerative conditions including dementias such as Alzheimer's disease, Parkinson's disease, progressive supranuclear palsy, subacute sclerosing panencephalitic parkinsonism, postencephalitic parkinsonism, pugilistic encephalitis, guam parkinsonism-dementia complex, Picks's disease, corticobasal degeneration, frontotemporal dementia, Huntingdon's disease, AIDS associated dementia, amyotrophic lateral sclerosis, multiple sclerosis and neurotraumatic diseases such as acute stroke, mood disorders such as schizophrenia and bipolar disorders, promotion of functional recovery post stroke, cerebral bleeding (for example, due to solidary cerebral amyloid angiopathy), hair loss, obesity, atherosclerotic cardiovascular disease, hypertension, polycystic ovary syndrome, syndrome X, ischaemia, traumatic brain injury, cancer, leukopenia, Down's syndrome, Lewy body disease, inflammation, and immunodeficiency.

Description

PYRAZO OPYRIDINE DERIVATIVES

This invention relates to novel compounds, in particular to novel pyrazolopyridine derivatives, to processes for the preparation of such compounds, to pharmaceutical compositions containing such compounds and to the use of such compounds in medicine. GSK-3 is a serine/threonine protein kinase composed of two isoforms (α and β) which are encoded by distinct genes. GSK-3 is one of several protein kinases which phosphorylates glycogen synthase (GS) (Embi et al, Eur. J. Biochem., (107), 519-527, (1980)). The and β isoforms have a monomeric structure and are both found in mammalian cells. Both isoforms phosphorylate muscle glycogen synthase (Cross et ah, Biochemical Journal, (303), 21-26, (1994)) and these two isoforms show good homology between species (e.g. human and rabbit GSK-3α are 96% identical).

Type II diabetes (or Non-Insulin Dependent Diabetes Mellitus, NTDDM) is a multifactorial disease. Hyperglycaemia is due to insulin resistance in the liver, muscle and other tissues coupled with inadequate or defective secretion of insulin from pancreatic islets. Skeletal muscle is the major site for insulin-stimulated glucose uptake and in this tissue, glucose removed from the circulation is either metabolised through glycolysis and the TCA cycle, or stored as glycogen. Muscle glycogen deposition plays the more important role in glucose homeostasis and Type II diabetic subjects have defective muscle glycogen storage.

The stimulation of glycogen synthesis by insulin in skeletal muscle results from the dephosphorylation and activation of glycogen synthase (Villar-Palasi C. and Lamer J., Biochim. Biophys. Acta., (39), 171-173, (1960), Parker PJ. et al, Eur. J. Biochem., (130), 227-234, (1983) and Cohen P., Biochem. Soc. Trans., (21), 555-567, (1993)). The phosphorylation and dephosphorylation of GS are mediated by specific kinases and phosphatases. GSK-3 is responsible for phosphorylation and deactivation of GS, while glycogen bound protein phosphatase 1 (PP1G) dephosphorylates and activates GS. Insulin both inactivates GSK-3 and activates PP1G (Srivastava A.K. and Pandey S.K., Mol. and Cellular Biochem., (182), 135-141, (1998)). Chen et al. (Diabetes, (43), 1234-1241, (1994)) found that there was no difference in the mRNA abundance of PP1G between patients with Type II diabetes and control patients, suggesting that an increase in GSK-3 activity might be important in Type II diabetes. It has also recently been demonstrated that GSK-3 is overexpressed in Type II diabetic muscle and that an inverse correlation exists between skeletal muscle GSK-3α activity and insulin action (Nikoulina et al, Diabetes, (49), 263-271, (2000)). Overexpression of GSK-3 β and constitutively active GSK-3 β(S9A, S9E) mutants in HEK-293 cells resulted in suppression of glycogen synthase activity (Eldar-Finkelman et ah, PNAS, (93), 10228-10233, (1996)) and overexpression of GSK-3β in CHO cells, expressing both insulin receptor and insulin receptor substrate 1 (IRS-1), resulted in an impairment of insulin action (Eldar-Finkelman and Krebs, PNAS, (94), 9660-9664, (1997)). Recent evidence for the involvement of elevated GSK-3 activity and the development of insulin resistance and type II diabetes in adipose tissue has emerged from studies undertaken in diabetes and obesity prone C57BL/6J mice (Eldar-Finkelman et al., Diabetes, (48), 1662-1666, (1999)).

GSK-3 has been shown to phosphorylate other proteins in vitro including the eukaryotic initiation factor eIF-2B at Serine⁵⁴⁰ (Welsh et ah, FEBS Letts., (421), 125- 130, (1998)). This phosphorylation results in an inhibition of eIF-2B activity and leads to a reduction in this key regulatory step of translation, hi disease states, such as diabetes, where there is elevated GSK-3 activity this could result in a reduction of translation and potentially contribute to the pathology of the disease.

Several aspects of GSK-3 functions and regulation in addition to modulation of glycogen synthase activity indicate that inhibitors of this enzyme may be effective in treatment of disorders of the central nervous system. GSK-3 activity is subject to inhibitory phosphorylation by PI 3 kinase-mediated or Wnt-1 class-mediated signals that can be mimicked by treatment with lithium, a low mM inhibitor of GSK-3 (Stambolic V., Ruel L. and Woodgett J.R., Curr. Biol., (6), 1664-8, (1996)). GSK-3 inhibitors may be of value as neuroprotectants in treatment of acute stroke and other neurotraurnatic injuries. Roles for PI 3-kinase signalling through PKB/akt to promote neuronal cell survival are well established, and GSK-3 is one of a number of PKB/akt substrates to be identified that can contribute to the inhibition of apoptosis via this pathway (Pap and Cooper, J. Biol. Chem., (273), 19929-19932, ((1998)). Evidence suggests that astrocytic glycogen can provide an alternative energy source to facilitate neuronal survival under conditions of glucose deprivation (for example, see Ransom B.R. and Fern R., Glia, (21), 134-141, (1997) and references therein). Lithium is known to protect cerebellar granule neurons from death (D'Mello et ah, Exp. Cell Res., (211), 332- 338, (1994) and Volonte et ah, Neurosci. Letts., (172), 6-10, (1994)) and chronic lithium treatment has demonstrable efficacy in the middle cerebral artery occlusion model of stroke in rodents (Nonaka and Chuang, Neuroreport, (9), 2081-2084, (1998)). Wnt- induced axonal spreading and branching in neuronal culture models has been shown to correlate with GSK-3 inhibition (Lucas and Salinas, Dev. Biol., (192), 31-44, (1997)) suggesting additional value of GSK-3 inhibitors in promoting neuronal regeneration following neurotraumatic insult.

Tau and β-catenin, two known in vivo substrates of GSK-3, are of direct relevance in consideration of further aspects of the value of GSK-3 inhibitors in relation to treatment of chronic neurodegenerative conditions. Tau hyperphosphorylation is an early event in neurodegenerative conditions such as Alzheimer's disease (AD), and is postulated to promote microtubule disassembly. Lithium has been reported to reduce the phosphorylation of tau, enhance the binding of tau to microtubules, and promote microtubule assembly through direct and reversible inhibition of glycogen synthase kinase-3 (Hong M., Chen D.C., Klein P.S. and Lee V.M., J. Biol. Chem., (272), 25326- 32, (1997). β-catenin is phosphorylated by GSK-3 as part of a tripartite complex with axin, resulting in β-catenin being targetted for degradation (Ikeda et ah, J. EMBO., (17), 1371-1384, (1998)). Inhibition of GSK-3 activity is a key mechanism by which cytosolic levels of catenin are stabilised and hence promote β-catenin-LEF-1/TCF transcriptional activity (Eastman, Grosschedl, Curr. Opin. Cell. Biol., (11), 233, (1999)). Rapid onset AD mutations in presenilin-1 (PS-1) have been shown to decrease the cytosolic β-catenin pool in transgenic mice. Further evidence suggests that such a reduction in available β- catenin may increase neuronal sensitivity to amyloid mediated death through inhibition of β-catenin-LEF-1/TCF transcriptional regulation of neuroprotective genes (Zhang et ah, Nature, (395), 698-702, (1998)). A likely mechanism is suggested by the finding that mutant PS-1 protein confers decreased inactivation of GSK-3 compared with normal PS-1 (Weihl C.C., Ghadge G.D., Kennedy S.G., Hay N., Miller R.J. and Roos R.P., J. Neurosci., (19), 5360-5369, (1999)). International Patent Application Publication Number WO 97/41854 (University of

Pennsylvania) discloses that an effective drug for the treatment of manic depression is lithium, but that there are serious drawbacks associated with this treatment. Whilst the precise mechanism of action of this drug for treatment of manic depression remains to be fully defined, current models suggest that inhibition of GSK-3 is a relevant target that contributes to the modulation of AP-1 DNA binding activity observed with this compound (see Manji et ah, J. Clin. Psychiatry, (60) (suppl 2), 27-39, (1999) for review). GSK-3 inhibitors may also be of value in treatment of schizophrenia. Reduced levels of β-catenin have been reported in schizophrenic patients (Cotter D., Kerwin R., al- Sarraji S., Brion J.P., Chadwich A., Lovestone S., Anderton B., and Everall L, Neuroreport, (9), 1379-1383, (1998)) and defects in pre-pulse inhibition to startle response have been observed in schizophrenic patients (Swerdlow et ah, Arch. Gen. Psychiat., (51), 139-154, (1994)). Mice lacking the adaptor protein dishevelled- 1, an essential mediator of Wnt-induced inhibition of GSK-3, exhibit both a behavioural disorder and defects in pre-pulse inhibition to startle response (Lijam N., Paylor R., McDonald M.P., Crawley J.N., Deng C.X., Herrup K., Stevens K.E., Maccaferri G., McBain C.J., Sussman D.J., and Wynshaw-Boris A., Cell, (90), 895-905, (1997)). Together, these findings implicate deregulation of GSK-3 activity as contributing to schizophrenia. Hence, small molecule inhibitors of GSK-3 catalytic activity may be effective in treatment of this mood disorder.

The finding that transient β-catenin stabilisation may play a role in hair development (Gat et al, Cell, (95), 605-614, (1998)) suggests that GSK-3 inhibitors could be used in the treatment of baldness.

Studies on fibroblasts from the GSK-3 β knockout mouse (Hoeflich K.P. et ah, Nature, (406), 86-90, (2000)) support a role for this kinase in positively regulating the activity of NFkB. This transcription factor mediates cellular responses to a number of inflammatory stimuli. Therefore, pharmacologic inhibition of GSK-3 maybe of use in treating inflammatory disorders through the negative regulation of NFkB activity.

The compounds of the present invention are pyrazolopyridine derivatives. Other pyrazolopyridine derivatives have been described previously for use in alternative medicinal applications. For example, International Patent Application Publication Numbers WO 97/23480 and WO 98/43962 describe various fused heterocyclic compounds, which may include pyrazolopyridazines, which are useful as antagonists of the α_vβ3-hιtegrm and related cell surface adhesive protein receptors. Such compounds are indicated to be useful in the treatment of conditions such as angiogenic disorders, inflammation, bone degradation, cancer metastasis, diabetic retinopathy, thrombosis, restenosis, macular degeneration, and other conditions mediated by cell adhesion and/or cell migration and/or angiogenesis. International Patent Application Publication Number WO 00/26211 describes various fused heterocyclic compounds, which may include pyrazolopyridines, which are useful in inhibiting thrombin and associated thrombotic occlusions. Such compounds are indicated to be useful in the treatment of conditions such as angina, myocardial infarction, thrombotic stroke, embolic stroke and the like. International Patent Application Publication Number WO 02/24694 describes a series of pyrazolopyridine and pyrazolopyridazine derivatives as inhibitors of GSK-3.

We have now discovered that a series of pyrazolo[3,4-b]pyridines are potent and selective inhibitors of GSK-3. These compounds are indicated to be useful for the treatment and/or prophylaxis of conditions associated with a need for inhibition of GSK- 3, such as diabetes, conditions associated with diabetes, chronic neurodegenerative conditions including dementias such as Alzheimer's disease, Parkinson's disease, progressive supranuclear palsy, subacute sclerosing panencephalitic parkinsonism, postencephalitic parkinsonism, pugilistic encephalitis, guam parkinsonism-dementia complex, Pick's disease, corticobasal degeneration, frontotemporal dementia, Huntingdon's disease, AIDS associated dementia, amyotrophic lateral sclerosis, multiple sclerosis and neurotraumatic diseases such as acute stroke, mood disorders such as schizophrenia and bipolar disorders, promotion of functional recovery post stroke, cerebral bleeding (for example, due to solitary cerebral amyloid angiopathy), hair loss, obesity, atherosclerotic cardiovascular disease, hypertension, polycystic ovary syndrome, syndrome X, ischaemia, traumatic brain injury, cancer, leukopenia, Down's syndrome, Lewy body disease, inflammation, and immunodeficiency. Accordingly, in a first aspect, the present invention provides a compound of formula (I),

or a salt thereof, or a solvate thereof, wherein,

R¹ is -NR⁵COR⁶, -NHCONHR⁷ or -NHCO R⁸;

R² is H;

R³ is H, halo, -CN, -NO₂, -NH₂, alkyl, alkenyl, -C(OR10)=CHR13, -NHCOR^{1 1}, - NHSO₂R¹², -CO₂R¹³, -COCH₂R¹³, -B(OR¹⁴)₂, -CONHR¹⁵, -SPh, heteroaryl or aryl wherein the aryl group may be optionally substituted by one or more halo substituents; R⁴ is H, cycloC3_g alkyl, heterocyclyl, heteroaryl wherein the heteroaryl group maybe optionally substituted by alkyl and di-alkylaminoalkyl; or aryl wherein the aryl group may be optionally substituted by one or more groups selected from halo, -OH, -CF3, -CN, alkoxy and arylalkoxy, or may be fused to a heterocyclic ring to form a bicyclic group; R⁵ is H or alkyl;

R6 is alkyl, alkenyl, cyck>C3_8 alkyl, cyck>C3_g alkenyl, di-alkylaminoalkyl, arylalkyl, arylalkenyl, heterocyclyl wherein the heterocyclyl group may be optionally substituted by one or more groups selected from alkyl, arylalkyl and alkoxyalkyl; heterocyclylalkyl wherein the heterocyclyl may be optionally substituted by one or more groups selected from alkoxyalkyl, aryloxyalkyl, arylalkyl and alkyl; heteroarylalkyl wherein the heteroaryl may be optionally substituted by one or more groups selected from alkyl; heteroaryl wherein the heteroaryl may be optionally substituted by one or more groups selected from aryl and heteroaryl; aryl wherein the aryl group may be optionally substituted by heterocyclylalkyl and di-alkylaminoalkyl; alkoxyalkyl wherein the alkoxy group may be optionally substituted by alkoxy;

R is alkyl or aryl wherein the aryl group may be optionally substituted by one or more groups selected from alkyl, alkoxy, -CN and -CO₂R9; R8 is alkyl or arylalkyl; and R9 is alkyl; R¹⁰ is alkyl;

Ri 1 is alkyl, alkoxyalkyl, arylalkyl or aryl wherein the aryl group may be optionally substituted by one or more groups selected from halo; and R¹² is alkyl; R¹³ is alkyl;

R!4 is alkyl or two R ⁴ groups together form a ring system which may be further substituted by one or more alkyl group(s); R.15 is di-alkylaminoalkyl; with the proviso that when R is -NR^COR" wherein R⁵ is H and R" is as hereinbefore defined, and R² and R⁴ are H then R³ is selected from H, halo, -CN, -NO₂, -NH₂, alkyl, alkenyl, -C(OR¹⁰)=CHR¹³, -NHCOR¹¹, -NHSO₂R¹², -CO₂R¹³ -COCH₂R¹³, - CONHR¹⁵ or -SPh.

Suitably, Rl is -NR^COR⁶. More suitably, R¹ is -NHCOMe, -NHCOPr¹*, - NHCOPr¹, -N(Et)COPrⁿ, -NHCOBu^s, -NHCO(CH₂)₄-thiomorpholin-4-yl, -NHCOcyclo- Propyl, -NHCOcyclo-Pentyl, -NHCO-4-(N-Me-Piperidyl), -NHCO(CH₂)₃-(4-Et- Piperazin-1-yl), -NHCO(CH₂)₃NMe₂, -NHCO(CH₂)₂(6-Me-Pyridin-3-yl), -NHCO-[3- (pyrid-2-yl)-Ph], -NHCO-[4-(CH₂(pyrrolidin-l-yl)-Ph], -NHCO-[6-(3-Pyridyl)-pyrid-3- yl], -NHCO-3-(N-CH₂Ph-Pyrrolidinyl), -NHCO-4-(N-((CH₂) OMe)-Piperidyl), - NHCOCH(Me)(CH₂)₂-(4-Et-piperazin- 1 -yl), -NHCOCH₂(N-(CH₂)₂OMe-Piperidin-4- yl), -NHCOCH₂(N-(CH₂)₂OPh-Piperidin-4-yl), -NHCOCH₂(N-CH₂Ph-Piperidin-4-yl), - NHCOCH₂(N-Et-Piperidin-4-yl), -NHCOCH₂O(CH₂) OMe, -NHCOCH₂OMe, - NHCO(CH₂) -morpholin-4-yl, -NHCO(CH₂)₃(pyrrolidin-l-yl), -NHCO-[4-

(CH₂(piperidin-l-yl)-Ph], -NHCO-[4-(CH₂NEt₂)-Ph], -NHCO-4-(N-(CH₂)₂OEt- Piperidyl) or -NHCOCH₂NMe₂.

Suitably, R¹ is -NHCONHR⁷. More suitably, R¹ is NHCONHEt, -NHCONH(2- Me-Ph), -NHCONH(2-MeO-Ph), -NHCONH(2-CN-Ph), or-NHCONH(2-CO₂Me-Ph). Suitably, R¹ is NHCO₂R⁸. More suitably, R¹ is -NHCO₂Et, -NHCO₂Pri or -

NHCO₂CH₂Ph.Most suitably, R¹ is -NHCOMe, -NHCOPr¹¹, -NHCOPr¹, -N(Et)COPrⁿ, -NHCOBu^s, -NHCO(CH₂)₄-thiomorpholin-4-yl, -NHCOcyclo-Propyl, -NHCOcyclo- Pentyl, -NHCO-4-(N-Me-Piperidyl), -NHCO(CH₂)3-(4-Et-Piperazin-l-yl), - NHCO(CH₂)₃NMe₂, -NHCONHEt, -NHCONH(2-Me-Ph), -NHCONH(2-MeO-Ph), - NHCONH(2-CN-Ph), -NHCONH(2-CO₂Me-Ph), -NHCO₂Et, -NHCOPr¹, - NHCO₂CH₂Ph, -NHCO(CH₂)₂(6-Me-Pyridin-3-yl), -NHCO-[3-(pyrid-2-yl)-Ph], - NHCO-[4-(CH₂(pyrrolidin-l-yl)-Ph], -NHCO-[6-(3-Pyridyl)-pyrid-3-yl], -NHCO-3-(N- CH₂Ph-Pyrrolidinyl), -NHCO-4-(N-((CH₂)₂OMe)-Piperidyl), -NHCOCH(Me)(CH₂)₂- (4-Et-piperazin-l-yl), -NHCOCH₂(N-(CH₂)₂OMe-Piperidin-4-yl), -NHCOCH₂(N- (CH2)₂OPh-Piperidin-4-yl), -NHCOCH₂(N-CH₂Ph-Piperidin-4-yl), -NHCOCH₂(N-Et- Piperidin-4-yl), -NHCOCH₂O(CH₂)₂OMe, -NHCOCH₂OMe, -NHCO(CH₂)₂- morpholin-4-yl, -NHCO(CH₂)₃(pyrrolidin-l-yl), -NHCO-[4-(CH₂(piperidin-l-yl)-Ph], - NHCO-[4-(CH NEt₂)-Ph], -NHCO-4-(N-(CH₂)₂OEt-Piperidyl) and -NHCOCH₂NMe₂. Suitably, R³ is H, halo, -CN, -NO₂ or alkyl. Suitably, R³ is aryl wherein the aryl group may be optionally substituted by one or more halo substituents. Most suitably, R³ is H, methyl, phenyl, bromo, chloro, iodo, cyano, pinacolboronato, -CH₂CH=CH₂, - CH=CH₂, -C(OEt)=CH₂, 2-fluorophenyl, -COMe, 3 -fluorophenyl, -NO , -NHCOMe, - NHCOPr¹, -NHSO₂Me, -NH₂, -NHCOPh, -NHCO(2,3-difluorophenyl), -NHCOCH₂Ph, -NHCOCH₂OMe, 3-pyridyl, -CO₂Et, -CONH(CH₂)₂NMe₂ and -SPh. Suitably, R⁴ is H. Suitably, R⁴ is cycloC3_g alkyl, heterocyclyl, heteroaryl wherein the heteroaryl group may be optionally substituted by alkyl and di-alkylaminoalkyl. Suitably, R⁴ is aryl wherein the aryl group may be optionally substituted by one or more groups selected from halo, -OH, -CF3, -CN, alkoxy and arylalkoxy, or may be fused to a heterocyclic ring to form a bicyclic group. Most suitably, R⁴ is H, phenyl, 4- chlorophenyl, 3-trifluoromethylphenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4- hydroxyphenyl, 3,4-dihydroxyphenyl, 3,4-methylenedioxyphenyl, 4-benzyloxyphenyl, 2- methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4-pyridyl, 3-chloro-4- hydroxyphenyl, 3-bromo-4-hydroxyphenyl, 2-thienyl, 2-furyl, 2-thiazolyl, 3-CN-Ph, 5- (CH₂NMe₂)-Furan-2-yl, 5-Me-Furan-2-yl and cyclo-Propyl. Suitably, R⁵ is H. Suitably, R⁵ is alkyl. h a preferred aspect of the present invention there is provided a subset of compounds of formula (I), of formula (IA),

or a salt thereof, or a solvate thereof, wherein,

R¹ is -NR⁵COR⁶, -NHCONHR? or -NHCO₂R⁸;

R² is H;

R³ is H, halo, -CN, -NO₂, -NH₂, alkyl, alkenyl, -C(OR¹⁰)=CHR¹³, -NHCOR^{1 1}, -NHSO₂R¹² -CO₂R¹³, -COCH₂R¹³, -B(OR¹⁴)₂, -CONHR¹⁵, -SPh, heteroaryl or aryl wherein the aryl group may be optionally substituted by one or more halo substituents;

R⁴ is H, cycloC3_g alkyl, heterocyclyl, heteroaryl wherein the heteroaryl group may be optionally substituted by alkyl and di-alkylaminoalkyl; or aryl wherein the aryl group may be optionally substituted by one or more groups selected from halo, -OH, - CF3, -CN, alkoxy and arylalkoxy, or may be fused to a heterocyclic ring to form a bicyclic group;

R⁵ is H or alkyl;

R6 is alkyl, cycloC3__§ alkyl, di-alkylaminoalkyl, heterocyclyl wherein the heterocyclyl group may be optionally substituted by one or more groups selected from alkyl, arylalkyl and alkoxyalkyl; heterocyclylalkyl wherein the heterocyclyl may be optionally substituted by one or more groups selected from alkoxyalkyl, aryloxyalkyl, arylalkyl and alkyl; heteroarylalkyl wherein the heteroaryl may be optionally substituted by one or more groups selected from alkyl; heteroaryl wherein the heteroaryl may be optionally substituted by one or more groups selected from aryl and heteroaryl; aryl wherein the aryl group may be optionally substituted by heterocyclylalkyl and di- alkylaminoalkyl; alkoxyalkyl wherein the alkoxy group may be optionally substituted by alkoxy; R⁷ is alkyl or aryl wherein the aryl group may be optionally substituted by one or more groups selected from alkyl, alkoxy, -CN and CO₂R^;

R⁸ is alkyl or arylalkyl;

R⁹ is alkyl;

R¹⁰ is alkyl;

Ri 1 is alkyl, alkoxyalkyl, arylalkyl or aryl wherein the aryl group may be optionally substituted by one or more groups selected from halo; and

R¹² is alkyl;

R¹³ is alkyl;

Ri⁴ is alkyl or two R^⁴ groups together form a ring system which may be further substituted by one or more alkyl group(s);

Ri⁵ is di-alkylaminoalkyl; with the proviso that when Ri is -NR⁵COR6 wherein R⁵ is H and R^ is as hereinbefore defined, and R² and R⁴ are H then R³ is selected from H, halo, -CN, -NO₂, -NH₂, alkyl, alkenyl, -C(OR¹⁰)=CHR¹³, -NHCOR¹¹, -NHSO₂R¹² -CO₂R¹³ ,-COCH₂R¹³ - CONHR¹⁵ or -SPh.

Suitably R³ is H, chloro, bromo, iodo, cyano, alkyl and aryl. i a further preferred aspect of the present invention there is provided a subset of compounds of formula (I), of formula (IB),

or a salt thereof, or a solvate thereof, wherein,

R¹ is -NHCOMe, -NHCOPr¹¹, -NHCOPr¹, -N(Et)COPrⁿ, -NHCOBu^S, - NHCO(CH₂)4-thiomorpholin-4-yl, -NHCOcyclo-Propyl, -NHCOcyclo-Pentyl, -NHCO- 4-(N-Me-Piperidyl), -NHCO(CH₂)₃-(4-Et-Piperazin-l-yl), -NHCO(CH₂)₃NMe2, - NHCONHEt, -NHCONH(2-Me-Ph), -NHCONH(2-MeO-Ph), -NHCONH(2-CN-Ph), - NHCONH(2-CO₂Me-Ph), -NHCO₂Et, -NHCOPr¹, -NHCO₂CH₂Ph, NHCO(CH₂)₂(6- Me-Pyridin-3-yl), NHCO-[3-(pyrid-2-yl)-Ph], NHCO-[4-(CH₂(pyrrolidin-l-yl)-Ph], NHCO-[6-(3-Pyridyl)-pyrid-3-yl], NHCO-3-(N-CH₂Ph-Pyrrolidinyl), NHCO-4-(N- ((CH₂)₂OMe)-Piperidyl), NHCOCH(Me)(CH₂)₂-(4-Et-piperazin-l-yl), NHCOCH₂(N- (CH₂)₂OMe-Piperidin-4-yl), NHCOCH₂(N-(CH₂)₂OPh-Piperidin-4-yl), NHCOCH₂(N- CH₂Ph-Piperidin-4-yl), NHCOCH₂(N-Et-Piperidin-4-yl), NHCOCH2θ(CH₂)₂OMe, NHCOCH₂OMe, -NHCO(CH₂)₂-moφholin-4-yl, -NHCO(CH₂)₃(pyrrolidin-l-yl), - NHCO-[4-(CH₂(piperidin-l-yl)-Ph], -NHCO-[4-(CH₂NEt₂)-Ph], -NHCO-4-(N- (CH₂)₂OEt-Piperidyl) and -NHCOCH₂NMe₂; R² is H; R³ is H, methyl, phenyl, bromo, chloro, iodo, cyano, pinacolboronato, - CH₂CH=CH₂, -CH=CH₂, -C(OEt)=CH₂, 2-fluorophenyl, -COMe, 3 -fluorophenyl, - NO₂, -NHCOMe, -NHCOPr¹, -NHSO₂Me, -NH₂, -NHCOPh, -NHCO(2,3- difluorophenyl), -NHCOCH Ph, -NHCOCH₂OMe, 3-pyridyl, -CO₂Et, - CONH(CH₂)₂NMe₂, and -SPh;

R⁴ is H, phenyl, 4-chlorophenyl, 3-trifluoromethylphenyl, 2-hydroxyphenyl, 3- hydroxyphenyl, 4-hydroxyphenyl, 3,4-dihydroxyphenyl, 3,4-methylenedioxyphenyl, 4- benzyloxyphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4-pyridyl, 3- chloro-4-hydroxyphenyl, 3-bromo-4-hydroxyphenyl and 2-thienyl, 2-furyl 2-thiazolyl, 3- CN-Ph, 5-(CH₂NMe₂)-Furan-2-yl, 5-Me-Furan-2-yl and cyclopropyl; with the proviso that when R¹ is -NHCOMe, -NHCOPrⁿ, -NHCOPr¹, - NHCOBus, -NHCO(CH₂)4-thiomoφholin-4-yl, -NHCOcyclo-Propyl, -NHCOcyclo- Pentyl, -NHCO-4-(N-Me-Piperidyl), -NHCO(CH₂)₃-(4-Et-Piperazin-l-yl), - NHCO(CH₂)3NMe₂._J NHCO(CH₂)₂(6-Me-Pyridin-3-yl), NHCO-[3-(pyrid-2-yl)-Ph], NHCO-[4-(CH₂φyrrolidin-l-yl)-Ph], NHCO-[6-(3-Pyridyl)-pyrid-3-yl], NHCO-3-(N- CH₂Ph-Pyrrolidinyl), NHCO-4-(N-((CH₂)₂OMe)-Piperidyl), NHCOCH(Me)(CH₂)₂-(4- Et-piperazin- 1 -yl), NHCOCH₂(N-(CH₂)₂OMe-Piperidin-4-yl), NHCOCH₂(N-

(CH₂)₂OPh-Piperidin-4-yl), NHCOCH₂(N-CH₂Ph-Piperidin-4-yl), NHCOCH₂(N-Et- Piperidin-4-yl), NHCOCH₂O(CH₂)₂OMe, NHCOCH₂OMe, -NHCO(CH₂)₂-moφholin- 4-yl, -NHCO(CH₂)₃(pyrrolidin-l-yl), -NHCO-[4-(CH₂(piperidin-l-yl)-Ph], -NHCO-[4- (CH₂NEt₂)-Ph], -NHCO-4-(N-(CH₂)₂OEt-Piperidyl) and -NHCOCH₂NMe₂; and R² and R⁴ are H, then R³ is selected from H, methyl, bromo, chloro, iodo, cyano, -

CH₂CH=CH₂, -CH=CH₂, -C(OEt)=CH₂, -COMe, -NO₂, -NHCOMe, -NHCOPr¹, - NHSO₂Me, -NH₂, -NHCOPh, -NHCO(2,3-difluorophenyl), -NHCOCH₂Ph - NHCOCH₂OMe, CO₂Et, CONH(CH₂)₂NMe₂, and -SPh.

Particularly preferred compounds of formula (I) which are of special interest as agents useful in the treatment and/or prophylaxis of conditions associated with a need for inhibition of GSK-3 are provided in Table 1 below.

Certain compounds of formula (I) may contain chiral atoms and/or multiple bonds, and hence may exist in one or more stereoisomeric forms. The present invention encompasses all of the isomeric forms of the compounds of formula (I) whether as individual isomers or as mixtures of isomers, including geometric isomers and racemic modifications.

As used herein the tenn "alkyl" as a group or part of a group refers to a straight or branched chain saturated aliphatic hydrocarbon radical containing 1 to 12 carbon atoms, suitably 1 to 6 carbon atoms. Such alkyl groups in particular include methyl ("Me"), ethyl ("Et"), n-propyl ("Pr¹¹"), iso-μropyl ("Pr¹"), n-butyl ("Bu¹¹"), sec-butyl ("Bu^s"), tert-butyl ("But"), pentyl and hexyl. Where appropriate, such alkyl groups maybe substituted by one or more groups selected from halo (such as fluoro, chloro, bromo), -CN, -CF3, -OH, -OCF3, C₂_6 alkenyl, C^-β alkynyl, Cχ_g alkoxy, aryl and di-Cχ_g alkylamino.

As used herein the term "alkenyl" as a group or part of a group refers to a straight or branched chain mono- or poly-unsaturated aliphatic hydrocarbon radical containing 2 to 12 carbon atoms, suitably 2 to 6 carbon atoms. References to "alkenyl" groups include groups which may be in the E- or Z-form or mixtures thereof. Such alkenyl groups in particular include ethenyl, propenyl, butenyl, pentenyl and hexenyl. Where appropriate, such alkenyl groups may be substituted by one or more groups selected from halo (such as fluoro, chloro, bromo), -CN, -CF3, -OH, -OCF3, C\. alkyl, C3.6 alkynyl, Cj.β alkoxy, aryl and di-C \ _g alkylamino.

As used herein the term "alkynyl" refers to hydrocarbon groups of either straight or branched configuration with one or more carbon-carbon triple bonds which may occur at any stable point in the chain, containing 3 to 12 carbon atoms, suitably 3 to 6 carbon atoms. Such alkynyl groups in particular include propynyl, butynyl and pentynyl. Where appropriate, such alkynyl groups may be substituted by one or more groups selected from halo (such as fluoro, chloro, bromo), -CN, -CF3, -OH, -OCF3, Cχ_6 alkyl, C₂_6 alkenyl, Cχ_6 alkoxy, aryl and di-Cχ_6 alkylamino. As used herein, the term "alkoxy" as a group or part of a group refers to an alkyl ether radical, wherein the term "alkyl" is defined above. Such alkoxy groups in particular include methoxy, ethoxy, n-propoxy, zsø-propoxy, n-butoxy, zsø-butoxy, sec-butoxy and tert-butoxy. Where appropriate, such alkoxy groups may be substituted by one or more groups selected from halo (such as fluoro, chloro, bromo), -CN, -CF3, -OH, -OCF3, Cχ_g alkyl, C₂_g alkenyl, C3.6 alkynyl, aryl and di-Cχ_6 alkylamino.

As used herein, the term "aryl" as a group or part of a group refers to a carbocyclic aromatic radical. Suitably such aryl groups are 5-6 membered monocyclic groups or 8-10 membered fused bicyclic groups, especially phenyl ("Ph"), biphenyl and naphthyl, particularly phenyl. Such aryl groups may be optionally substituted with one or more substituents, which may be the same or different, selected from halo (such as fluoro, chloro, bromo), -CN, -CF₃, -OH, -OCF3, -NO₂, Cι _6 alkyl, C₂_g alkenyl, C3.6 alkynyl, Cχ_6 alkoxy and di-Cχ_β alkylamino.

As used herein, the term "heteroaryl" as a group or part of a group refers to stable heterocyclic aromatic single and fused rings containing one or more hetero atoms independently selected from nitrogen, oxygen and sulfur. A fused heteroaryl ring system may include carbocyclic rings and need include only one heteroaryl ring. Such heteroaryl groups include furyl, thienyl, pyridazinyl, pyridyl, quinolinyl, indolyl, thiazolyl, benzoxazolyl, and benzothiazolyl. Each ring may be optionally substituted with one or more substituents, which may be the same or different, selected from halo (such as fluoro, chloro, bromo), -CN, -CF₃, -OH, -NO₂, -OCF3, C\. alkyl, C₂_6 alkenyl, C3.6 alkynyl, Cχ_6 alkoxy, aryl, heteroaryl, and di-Cχ_6 alkylamino.

As used herein, the terms "heterocyclyl" and "heterocyclic" as a group or part of a group refer to stable heterocyclic non-aromatic single and fused rings containing one or more hetero atoms independently selected from nitrogen, oxygen and sulfur. A fused heterocyclyl ring system may include carbocyclic rings and need include only one heterocyclic ring. Such heterocyclyl groups include piperazinyl, piperidinyl and moφholinyl. Each ring may be optionally substituted with one or more substituents, which may be the same or different, selected from halo (such as fluoro, chloro, bromo), - CN, -CF₃, -OH, -NO2, -OCF3, Ci_₆ alkyl, C₂.₆ alkenyl, C₃.₆ alkynyl, Cy₆ alkoxy, aryl, heteroaryl, and di-Cχ_g alkylamino. As used herein the terms "halo" include iodo, bromo, chloro or fluoro, suitably bromo, chloro and fluoro, especially bromo and chloro.

Composite terms such as "alkoxyalkyl" and "arylalkyl" refer to substituents comprising two interlinked groups, with the group named latterly in the term being the linking group, so that "alkoxyalkyl" means -(alkyl)-(alkoxy) whilst "arylalkyl" means - (alkyl)-(aryl).

The compounds of formula (I) or their salts or solvates are preferably in pharmaceutically acceptable or substantially pure form. By pharmaceutically acceptable form is meant, inter alia, having a pharmaceutically acceptable level of purity excluding normal pharmaceutical additives such as diluents and carriers, and including no material considered toxic at normal dosage levels.

A substantially pure form will generally contain at least 50% (excluding normal pharmaceutical additives), preferably 75%, more preferably 90% and still more preferably 95% of the compound of formula (I) or its salt or solvate. One preferred pharmaceutically acceptable form is the crystalline form, including such form in pharmaceutical composition, h the case of salts and solvates the additional ionic and solvent moieties must also be non-toxic.

Suitable salts are pharmaceutically acceptable salts.

Suitable pharmaceutically acceptable salts include the acid addition salts with the conventional pharmaceutical acids, for example maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic, tartaric, succinic, benzoic, ascorbic and methanesulphonic.

Suitable pharmaceutically acceptable salts include salts of acidic moieties of the compounds of formula (I) when they are present, for example salts of carboxy groups or phenolic hydroxy groups.

Suitable salts of acidic moieties include metal salts, such as for example aluminium, alkali metal salts such as lithium, sodium or potassium, alkaline earth metal salts such as calcium or magnesium and ammonium or substituted ammonium salts, for example those with lower alkylamines such as triethylamine, hydroxyalkylamines such as 2-hydroxyethylamine, bis-(2-hydroxyethyl)-amine or tri-(2-hydroxyethyl)-amine; cycloalkylamines such as bicyclohexylamine, or with procaine, dibenzylpiperidine, N-benzyl-β-phenethylamine, dehydroabietylamine, N,N'-bisdehydroabietylamine, glucamine, N-methylglucamine or bases of the pyridine type such as pyridine, collidine, quinine or quinoline.

Suitable solvates are pharmaceutically acceptable solvates.

Suitable pharmaceutically acceptable solvates include hydrates. For the avoidance of doubt when used herein the term "diabetes" includes diabetes mellitus, especially Type 2 diabetes, and conditions associated with diabetes mellitus.

The term "conditions associated with diabetes" includes those conditions associated with the pre-diabetic state, conditions associated with diabetes mellitus itself and complications associated with diabetes mellitus. The term "conditions associated with the pre-diabetic state" includes conditions such as insulin resistance, impaired glucose tolerance and hyperinsulinaemia.

The term "conditions associated with diabetes mellitus itself includes hyperglycaemia, insulin resistance and obesity. Further conditions associated with diabetes mellitus itself include hypertension and cardiovascular disease, especially atherosclerosis and conditions associated with insulin resistance. Conditions associated with insulin resistance include polycystic ovarian syndrome and steroid induced insulin resistance.

The term "complications associated with diabetes mellitus" includes renal disease, especially renal disease associated with Type II diabetes, neuropathy and retinopathy. Renal diseases associated with Type II diabetes include nephropathy, glomerulonephritis, glomerular sclerosis, nephrotic syndrome, hypertensive nephrosclerosis and end stage renal disease.

The term "neurotraumatic diseases" includes both open or penetrating head trauma, such as caused by surgery, or a closed head trauma injury, such as caused by an injury to the head region, ischaemic stroke including acute stroke, particularly to the brain area, transient ischaemic attacks following coronary by-pass and cognitive decline following other transient ischaemic conditions.

According to a further aspect of the present invention there is provided a process for the preparation of a compound of formula (I) wherein R^ is -NR^COR^ and wherein R², R³, R⁴, R5 and R^ are as hereinbefore defined, or a salt and/or solvate thereof, which process comprises reacting a compound of formula (H),

wherein R², R³, R⁴ and R^ are as defined in relation to formula (I) with a compound of formula (EL),

wherein R" is as defined in relation to formula (I) and X is a suitable leaving group and thereafter, if required, carrying out one or more of the following optional steps: (i) converting a compound of formula (I) to a further compound of formula (I); (ii) removing any necessary protecting group; (iii) preparing an appropriate derivative of the compound so formed.

Suitably X is chloro. It will be appreciated that compounds of formula (DI) may also include related carboxylic acid anhydrides.

It will be appreciated that where R^ is alkyl, compounds of formula (II) maybe prepared from other compounds of formula (H) where R^ is H, by conventional procedures, such as acylation and subsequent reduction.

The reaction between the compounds of formulae (H) and (111) is carried out in a suitable solvent, under conventional conditions, at a suitable temperature, providing a suitable rate of formation of the required product, over a suitable reaction time. A suitable solvent is pyridine. Suitable reaction temperatures include those in the range of 20°C to 220°C and, as appropriate, the reflux temperature of the solvent. Suitable reaction times are those in the range 0.1 to 72 hours. The reaction products are isolated using conventional methods. Conventional methods of heating and cooling may be employed, for example thermostatically controlled oil baths and ice/salt baths respectively. The reaction products are typically purified by conventional methods, such as crystallisation, chromatography and trituration. Crystalline product may be obtained by standard methods. hi a preferred aspect, a compound of formula (in), such as acetic anhydride, is added to a solution of the compound of formula (H) in pyridine, with stirring. The reaction mixture is heated under reflux for 16 hours, allowed to cool to ambient temperature and then treated with a suitable acid, such as hydrochloric acid. The resulting solid is isolated by filtration, washed with a suitable solvent, such as water, and recrystallised from a suitable solvent, such as dimethylformamide, to afford the desired compound of formula (I). h a further preferred aspect, to a compound of formula (H) in pyridine is added a compound of formula (in), such as butyrylchloride. The reaction mixture is heated under reflux, with stirring, for 16 hours. Upon cooling the solvent is removed in vacuo, to afford a residue which is taken up in a suitable solvent, such as methanol, and passed through an SCX cartridge with a suitable solvent, such as methanol. Product material is eluted using a suitable solvent such as methanolic ammonia solution. Further purification using silica chromotagraphy with one or more suitable solvents, such as 10% methanol in dichloromethane, affords a residue which is triturated with a suitable solvent, such as dichloromethane, to afford the desired compound of formula (I).

In still a further preferred aspect, to a stirred solution of a compound of formula (H) in dry pyridine is added a compound of formula (ID), such as cyclopropyl carbonyl chloride. The solution is heated under reflux with stirring for 1 hour, allowed to cool and the resulting mixture concentrated. The resulting residue is triturated with dichloromethane/methanol to afford the desired compound of formula (I). hi still a further preferred aspect, a compound of formula (in), such as isobutyryl chloride, is added to a solution of a compound of formula (H) in hot pyridine. The reaction mixture is stirred under reflux for 55 hours, allowed to cool, and the solvent removed in vacuo. The resulting residue is purified using silica gel chromatography with one or more suitable solvents, such as 10% methanol/dichloromethane, to afford the desired compound of formula (I). h still a further preferred aspect, a compound of formula (IT) is added to a stirred solution of a compound of formula (III), such as 4-(4-ethylpiperazin-l-yl)-butyryl chloride hydrochloride salt, in dry pyridine at room temperature under an argon atmosphere. The mixture is heated under reflux for 16 hours, allowed to cool, and water is added to the resulting solution, which is subsequently evaporated to dryness. Ethanol is added to the residue and the resulting solution is evaporated to dryness. The residue is dissolved in a suitable solvent, such as dimethylformamide, and purified by preparative HPLC with one or more suitable solvents, such as a gradient of 10-90% acetonitrile (0.1% trifluoroacetic acid) in water (0.1% trifluoroacetic acid). The resulting product is passed through an SCX cartridge with a suitable solvent, such as methanol. Product material is eluted using a suitable solvent such as methanolic ammonia solution. The resulting solution is then evaporated to dryness, dissolved in methanol and treated with a suitable acid, such as maleic acid to give the desired compound of formula (I).

Compounds of formula (I) wherein Ri is -NR^COR^ and wherein R², R³, R⁴, R5 and R are as hereinbefore defined, or a salt and/or solvate thereof, may also be prepared by reaction of a compound of formula (11),

wherein R², R³, R⁴ and R^ are as defined in relation to formula (I) with a compound of formula (IV),

wherein R^ is as defined in relation to formula (I), in the presence of a suitable coupling reagent and a suitable base and thereafter, if required, carrying out one or more of the following optional steps:

(i) converting a compound of formula (I) to a further compound of formula (I);

(ii) removing any necessary protecting group;

(iii) preparing an appropriate derivative of the compound so formed; thereby constituting a further aspect of the present invention.

The reaction between the compounds of formulae (IT) and (IV) is carried out in a suitable solvent, under conventional conditions, at a suitable temperature, providing a suitable rate of formation of the required product, over a suitable reaction time. A suitable coupling reagent is O-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate. A suitable base is a tertiary amine. A suitable solvent is dimethylformamide. Suitable reaction temperatures include those in the range of 20°C to 60°C and, as appropriate, the reflux temperature of the solvent. Suitable reaction times are those in the range 12 to 72 hours. The reaction products are isolated using conventional methods. Conventional methods of heating and cooling may be employed, for example thermostatically controlled oil baths and ice/salt baths respectively. The reaction products are typically purified by conventional methods, such as crystallisation, chromatography and trituration. Crystalline product may be obtained by standard methods.

In a preferred aspect, to a stirred solution of a compound of formula (II) in dimethylformamide is added a compound of formula (D), such as 3-methylbutyric acid, O-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate and a suitable base, such as triethylamine. The solution is stirred under ambient conditions for 16 hours. Additional O-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate and base are added to the reaction mixture and it is allowed to stir for a further 3 hours. The resulting mixture is concentrated in vacuo to afford a residue, which is passed through an SCX cartridge with a suitable eluant such as methanol. Typically, the mixture is further purified by preparative HPLC using one or more suitable solvents, such as a gradient of 10-90% acetonitrile containing 0.01% trifluoroacetic acid. The solvent is removed from the resulting solution to afford the desired compound of formula (I).

According to a further aspect of the present invention there is provided a process for the preparation of a compound of formula (I) wherein Ri is -NHCONHR⁷ and wherein R², R³, R⁴ and R⁷ are as hereinbefore defined, or a salt and/or solvate thereof, which process comprises reacting a compound of formula (K),

wherein R², R³, R⁴ are as defined in relation to formula (I) and R^ is H, with a compound of formula (V),

R⁷— NCO _(γ)

wherein R⁷ is as defined in relation to formula (I) and thereafter, if required, carrying out one or more of the following optional steps:

(i) converting a compound of formula (I) to a further compound of formula (I); (ii) removing any necessary protecting group; (iii) preparing an appropriate derivative of the compound so formed.

The reaction between the compounds of formulae (II) and (V) is carried out in a suitable solvent, under conventional conditions, at a suitable temperature, providing a suitable rate of formation of the required product, over a suitable reaction time. A suitable solvent is pyridine. Suitable reaction temperatures include those in the range of 20°C to 220°C and, as appropriate, the reflux temperature of the solvent. Suitable reaction times are those in the range 12 to 48 hours. The reaction products are isolated using conventional methods. Conventional methods of heating and cooling may be employed, for example thermostatically controlled oil baths and ice/salt baths respectively. The reaction products are typically purified by conventional methods, such as crystallisation, chromatography and trituration. Crystalline product may be obtained by standard methods. hi a preferred aspect, to a stirred solution of a compound of formula (IT) in dry pyridine is added a compound of formula (1TI) such as ethyl isocyanate. After 18 hours, a suitable acid, such as hydrochloric acid, is added to the reaction mixture. The resulting precipitate is isolated by filtration to afford the desired compound of formula (I).

According to a further aspect of the present invention there is provided a process for the preparation of a compound of formula (I) wherein R is -NHCO₂R⁸ and wherein R², R³, R⁴ and R⁸ are as hereinbefore defined, or a salt and/or solvate thereof, which process comprises reacting a compound of formula (11),

wherein R², R³, R⁴ are as defined in relation to formula (I) and R^ is H, with a compound of formula (VI),

wherein R⁸ is as defined in relation to formula (I) and thereafter, if required, carrying out one or more of the following optional steps:

(i) converting a compound of formula (I) to a further compound of formula (I);

(ii) removing any necessary protecting group;

(iii) preparing an appropriate derivative of the compound so formed.

The reaction between the compounds of formulae (IT) and (VI) is carried out in a suitable solvent, under conventional conditions, at a suitable temperature, providing a suitable rate of formation of the required product, over a suitable reaction time. It will be appreciated that the reaction between a compound of formula (H) and a compound of formula (VI) may be assisted by the presence of a suitable catalyst such as 4- (dimethylaminopyridine). Suitable solvents include pyridine and tetrahydrofuran. Suitable reaction temperatures include those in the range of 20°C to 220°C and, as appropriate, the reflux temperature of the solvent. Suitable reaction times are those in the range 12 to 48 hours. The reaction products are isolated using conventional methods. Conventional methods of heating and cooling maybe employed, for example thermostatically controlled oil baths and ice/salt baths respectively. The reaction products are typically purified by conventional methods, such as crystallisation, chromatography and trituration. Crystalline product may be obtained by standard methods. hi a preferred aspect, to a compound of formula (fl) in dry pyridine is added 4- (dimethylamino)pyridine and a compound of formula (VI), such as ethyl chloroformate. The reaction mixture is heated in an argon atmosphere, under reflux, for 16 hours. Upon cooling, the reaction mixture is evaporated in vacuo to afford a residue, which is triturated with a suitable solvent, such as dichloromethane. The resulting solid is purified by silica gel chromatography using one or more suitable solvents, such as 5% methanol/dichloromethane to afford the desired compound of formula (I).

In a still further preferred aspect, to a stirred suspension of a compound of formula (Ii) in dry tetrahydrofuran is added 4-(dimethylamino)pyridine and a compound of formula (VI), such as isopropyl chloroformate. The reaction mixture is stirred for 16 hours and subsequently concentrated in vacuo. The resulting solid is purified by silica gel chromatography with one or more suitable solvents, such as 10% acetonitrile/dichloromethane, to afford the desired compound of formula (I).

Compounds of formula (I) wherein Ri is -NHCO₂R⁸ and wherein R², R³, R⁴ and R° are as hereinbefore defined, or a salt and/or solvate thereof, may also be prepared by reaction of a compound of formula (Vπ),

wherein R², R³, R⁴ and R⁸ are as defined in relation to formula (I) with an amine and thereafter, if required, carrying out one or more of the following optional steps: (i) converting a compound of formula (I) to a further compound of formula (I); (ii) removing any necessary protecting group; (iii) preparing an appropriate derivative of the compound so formed; thereby constituting a further aspect of the present invention.

The reaction between the compound of formula (VIE) and an amine is carried out optionally in a suitable solvent, under conventional conditions, at a suitable temperature, providing a suitable rate of formation of the required product, over a suitable reaction time. Suitably the reaction is carried out using the amine as a solvent. Suitable amines include primary and secondary amines. Suitable reaction temperatures include those in the range of 20°C to 100°C and, as appropriate, the reflux temperature of the solvent. Suitable reaction times are those in the range 12 to 48 hours. The reaction products are isolated using conventional methods. Conventional methods of heating and cooling may be employed, for example thermostatically controlled oil baths and ice/salt baths respectively. The reaction products are typically purified by conventional methods, such as crystallisation, chromatography and trituration. Crystalline product may be obtained by standard methods .

In a preferred aspect, the compound of formula (Vfi) is dissolved in a suitable amine, such as piperidine, and stirred for 12 hours under ambient conditions. The amine is then removed in vacuo to afford a residue which is typically purified using silica gel chromatography with one or more suitable solvents, such as a solvent gradient of 10-30% acetonitrile/dichloromethane, to afford the desired compound of formula (I).

The above-mentioned conversions of a compound of formula (I) into another compound of formula (I) include any conversion, which maybe effected using conventional procedures, but in particular the said conversions include any combination of: (i) converting one group R into another group R ; (ii) converting one group R³ into another group R³; (iii) converting one group R⁴ into another group R⁴.

The above-mentioned conversions (i), (ii) and (iii) may be carried out using any appropriate method under conditions determined by the particular groups chosen. Suitable conversions of one group R³ into another group R³, as in conversion (ii) above, include:

(a) converting a group R³ which represents halo, such as bromo, into another group R³ which represents H. Such a conversion may be performed using an appropriate dehalogenation procedure, for example, by treating a compound of formula (I) wherein R³ is halo, such as bromo, with a suitable base, such as sodium carbonate, in the presence of a suitable catalyst, such as Pd(PPh3)4. (b) converting a group R³ which represents halo, such as bromo, into another group R³ which represents alkyl, alkenyl or -C(OR¹⁰)=CHR¹³ wherein R¹⁰ and R¹³ are defined in relation to formula (I). Such a conversion may be performed using an appropriate alkylation or vinylation procedure, for example, by treating a compound of formula (I) wherein R³ is halo, such as bromo, with a suitable reagent, such as an alkyl tin complex, for example (1-ethoxyvinyl) tributyltin, in the presence of a suitable catalyst, such as Pd(PPh3)4.

(c) converting a group R³ which represents -C(ORl0)=CHRⁱ³ wherein R*0 and R^ are defined in relation to formula (I), into another group R³ which represents - COCH₂R1³ wherein R^³ is defined in relation to formula (I). Such a conversion may be performed, for example, by treating a compound of formula (I) wherein R³ is - C(OR10)=CHR^{I 3} wherein R^O and R ³ defined in relation to formula (I), with a suitable acid, such as hydrochloric acid, and thereafter, if necessary, treating the resulting product with an acid chloride or an acid anhydride, such as butyryl chloride. (d) converting a group R³ which represents -NO₂ into another group R³ which represents -NH₂. Such a conversion may be performed using an appropriate hydrogenation procedure, for example, by treating a compound of formula (I) wherein R³ is -NO₂ with a H₂ in the presence of a suitable catalyst, such as 10% PdVC.

(e) converting a group R³ which represents -NH₂ into another group R³ which represents -NHCORl 1 or -NHSO₂R1² wherein Ri 1 and R^l2 are defined in relation to formula (I). Such a conversion may be performed using an appropriate acylation or sulphonation procedure, for example, by treating a compound of formula (I) wherein R³ is -NH₂ with an acetyl or sulphonyl chloride, such as phenylacetyl chloride.

(f) converting a group R³ which represents halo, such as bromo, into another group R³ which represents alkyl or aryl, such as phenyl. Such a conversion may be performed using an appropriate alkylation or arylation procedure, for example, by treating a compound of formula (I) wherein R³ is halo, such as bromo, with a boronic acid, such as phenyl boronic acid, in the presence of a suitable catalyst, such as PdCl₂(dppf). Alternatively, a group R³ which represents halo, such as bromo, may be converted into another group R³ which represents pinacolboronate, using bis pinacolato diboron in the presence of a suitable catalyst, such as PdCl (dppf). The resulting pinacolboronate substituent (R³) may be further converted into another group R³ which represents aryl or heteroaryl, by treatment with an appropriate aryl or heteroaryl halide, such as phenyl bromide in the presence of a suitable catalyst such as tetrakis(triphenylphosphine)palladium (0).

Suitable conversions of one group R⁴ into another group R⁴, as in conversion (iii) above, include:

(g) converting a group R⁴ which represents aryl substituted by arylalkoxy, such as 4- benzyloxyphenyl, into another group R⁴ which represents aryl substituted by -OH, such as 4-hydroxyphenyl. Where R⁴ represents aryl substituted by arylmethyloxy such a conversion may be performed using an appropriate hydrogenation procedure, for example, by treating a compound of formula (I) wherein R³ is aryl substituted by arylalkoxy, such as 4-benzyloxyphenyl, with H₂ in the presence of a suitable catalyst such as 10%Pd/C. Where R⁴ represents aryl substituted by arylalkoxy or alkoxy such a conversion may be performed using a suitable ether cleavage reagent such as hydrobromic acid or boron tribromide; and (h) converting a group R⁴ which represents heteroaryl, such as furan-2-yl, into another group R⁴ which represents heteroaryl substituted by di-alkylamino, such as 5- dimethylaminofuran-2-yl. Such a conversion may be performed using an appropriate animation procedure, for example, by treating a compound of formula (I) wherein R⁴ is an electron rich heteroaryl group with N,N-dimethylmethylene ammonium iodide. Compounds of fonnula (H) where R^ is H may be prepared by reaction of a compound of formula (VflT),

(vm) wherein, R², R³ and R⁴ are as defined in relation to formula (I), with hydrazine or a hydrate thereof.

The reaction between the compound of formula (VIE) and hydrazine or a hydrate thereof, is carried out in a suitable solvent at a suitable temperature, generally an elevated temperature, providing a suitable rate of formation of the required product, over a suitable reaction time. Suitable solvents include pyridine and ethanol. Suitable reaction temperatures include those in the range of 60 °C to 220 °C and, as appropriate, the reflux temperature of the solvent. Suitable reaction times are those in the range 1-48 hours. The reaction products are isolated using conventional methods. Typically, the reaction mixture is cooled, the product isolated by filtration, and dried. Conventional methods of heating and cooling may be employed, for example thermostatically controlled oil baths and ice/salt baths respectively. The reaction products may, if desired, be purified by conventional methods, such as crystallisation, chromatography and trituration. In a preferred aspect, hydrazine or a hydrate thereof, such as hydrazine hydrate, is added to a stirred solution of the compound of formula (Vπi) in pyridine. The reaction mixture is stirred at reflux for 6 hours and cooled. The crude product is isolated by filtration and dried. The crude product may be used without purification.

Certain compounds of formula (IT) are believed to be novel and accordingly form a further aspect of the present invention.

Compounds of formula (Viπ) may be prepared by reaction of a compound of formula (VTV),

(VIV) wherein, R², R³ and R⁴ are as defined in relation to formula (I), with a mixture of phosphorus oxychloride and phosphorus pentachloride.

The reaction between the compound of formula (VIV) and a mixture of phosphorus oxychloride and phosphorus pentachloride is carried out at a suitable temperature, generally an elevated temperature, providing a suitable rate of formation of the required product, over a suitable reaction time. Suitable reaction temperatures include the reflux temperature of the mixture. Suitable reaction times are those in the range 1-48 hours. The reaction products are isolated using conventional methods. Typically, the reaction mixture is cooled, and added cautiously to iced water. The solution is then basified with a suitable base such as sodium carbonate and the product isolated by filtration. The product is then washed and dried. Conventional methods of heating and cooling may be employed, for example thermostatically controlled oil baths and ice/salt baths respectively. The reaction product may, if desired, be purified by conventional methods, such as crystallisation, chromatography and trituration. hi a preferred aspect, the compound of formula (VTV) is added to a suspension of phosphorus oxychloride and phosphorus pentachloride. The suspension is stirred at reflux for 1 hour, cooled, and cautiously added to iced water. The solution is adjusted to pH 11 with sodium carbonate and the product isolated by filtration, washed with water, and dried to afford the desired compound of formula (VIS). The crude product may be used without purification.

Compounds of formula (VIV) are either commercially available or are prepared by analogy with known conventional literature procedures, for example those disclosed in Reel. Trav. Chim. Pays-Bas, 1974, 93, 233, J. Med. Chem., 1994, 37, 3303 or in standard reference texts of synthetic methodology such as J. March, Advanced Organic Chemistry,

4th Edition, 1992, Wiley Interscience.

However, compounds of formula (VIV) where R² is as defined in relation to formula (I) and R³ is halo and R⁴ is aryl and heteroaryl may be prepared by reaction of a compound of formula (X),

(X)

wherein R² is as defined in relation to formula (I) and R⁴ is aryl and heteroaryl, with a suitable halogenating agent, such as an N-halosuccinimide. Compounds of formula (VIV) where R² is as defined in relation to formula (I), R³ is halo and R⁴ is aryl and heteroaryl are believed to be novel and accordingly form a further aspect of the present invention.

Certain compounds of formula (X) are believed to be novel and accordingly form a further aspect of the present invention.

Compounds of formula (Vπ) may be prepared by reaction of a compound of formula (IL) with a compound of formula (VI).

Compounds of formula (VET) are believed to be novel and accordingly form a further aspect of the present invention.

Compounds of formulae (I), (IT) and (VTV) and (X) may exist as tautomers. The present invention encompasses all tautomeric forms of the compounds of (I), (IT) and (VLV)and (X).

As stated above, the compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof, are indicated to be useful as inhibitors of glycogen synthase kinase-3.

The invention therefore provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use as an inhibitor of GSK-3.

Accordingly, the present invention also provides a method for the treatment of conditions associated with a need for inhibition of GSK-3 such as diabetes, conditions associated with diabetes, chronic neurodegenerative conditions including dementias such as Alzheimer's disease, Parkinson's disease, progressive supranuclear palsy, subacute sclerosing panencephalitic parkinsonism, postencephalitic parkinsonism, pugilistic encephalitis, guam parkinsonism-dementia complex, Pick's disease, corticobasal degeneration, frontotemporal dementia, Huntingdon's disease, AIDS associated dementia, amyotrophic lateral sclerosis, multiple sclerosis and neurotraumatic diseases such as acute stroke, mood disorders such as schizophrenia and bipolar disorders, promotion of functional recovery post stroke, cerebral bleeding (for example, due to solitary cerebral amyloid angiopathy), hair loss, obesity, atherosclerotic cardiovascular disease, hypertension, polycystic ovary syndrome, syndrome X, ischaemia, traumatic brain injury, cancer, leukopenia, Down's syndrome, Lewy body disease, inflammation, and immunodeficiency, which method comprises the admimstration of a pharmaceutically effective, non-toxic amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.

The present invention further provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use as an inhibitor of glycogen synthase kinase-3, and especially for use in the treatment of conditions associated with a need for the inhibition of GSK-3, such as diabetes, conditions associated with diabetes, chronic neurodegenerative conditions including dementias such as Alzheimer's disease, Parkinson's disease, progressive supranuclear palsy, subacute sclerosing panencephalitic parkinsonism, postencephalitic parkinsonism, pugilistic encephalitis, guam parkinsonism- dementia complex, Pick's disease, corticobasal degeneration, frontotemporal dementia, Huntingdon's disease, AIDS associated dementia, amyotrophic lateral sclerosis, multiple sclerosis and neurotraumatic diseases such as acute stroke, mood disorders such as schizophrenia and bipolar disorders, promotion of functional recovery post stroke, cerebral bleeding (for example, due to solitary cerebral amyloid angiopathy), hair loss, obesity, atherosclerotic cardiovascular disease, hypertension, polycystic ovary syndrome, syndrome X, ischaemia, traumatic brain injury, cancer, leukopenia, Down's syndrome, Lewy body disease, inflammation, and immunodeficiency.

The present invention also provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use in the manufacture of a medicament for the treatment of conditions associated with a need for the inhibition of GSK-3, such as diabetes, conditions associated with diabetes, chronic neurodegenerative conditions including dementias such as Alzheimer's disease, Parkinson's disease, progressive supranuclear palsy,' subacute sclerosing panencephalitic parkinsonism, postencephalitic parkinsonism, pugilistic encephalitis, guam parkinsonism-dementia complex, Pick's disease, corticobasal degeneration, frontotemporal dementia,

Huntingdon's disease, AIDS associated dementia, amyotrophic lateral sclerosis, multiple sclerosis and neurotraumatic diseases such as acute stroke, mood disorders such as schizophrenia and bipolar disorders, promotion of functional recovery post stroke, cerebral bleeding (for example, due to solitary cerebral amyloid angiopathy), hair loss, obesity, atherosclerotic cardiovascular disease, hypertension, polycystic ovary syndrome, syndrome X, ischaemia, traumatic brain injury, cancer, leukopenia, Down's syndrome, Lewy body disease, inflammation, and immunodeficiency. In a further aspect of this invention, there is provided a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use as an active therapeutic substance.

Preferably, the compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof, are administered as pharmaceutically acceptable compositions.

Accordingly, the invention also provides a pharmaceutical composition which comprises a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

The active compounds are usually administered as the sole medicament agent but they may be administered in combination with other medicament agents as dictated by the severity and type of disease being treated.

The said combination comprises co-administration of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, and an additional medicament agent or the sequential administration of a compound of formula (I), or a pharmaceutically acceptable derivative thereof, and the additional medicament agent.

Co-administration includes administration of a pharmaceutical composition which contains both a compound of formula (I), or a pharmaceutically acceptable salto or solvate thereof, and the additional medicament agent or the essentially simultaneous administration of separate pharmaceutical compositions of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, and the additional medicament agent.

The compositions of the invention are preferably adapted for oral administration. However, they may be adapted for other modes of administration. The compositions may be in the form of tablets, capsules, powders, granules, lozenges, suppositories, reconstitutable powders, or liquid preparations, such as oral or sterile parenteral solutions or suspensions, h order to obtain consistency of administration it is preferred that a composition of the invention is in the form of a unit dose. Preferably the composition are in unit dosage form. A unit dose will generally contain from 0.1 to 1000 mg of the active compound. Generally an effective administered amount of a compound of the invention will depend on the relative efficacy of the compound chosen, the severity of the disorder being treated and the weight of the sufferer. However, active compounds will typically be administered once or more times a day for example 2, 3 or 4 times daily, with typical total daily doses in the range of from 0.1 to 800 mg/kg/day.

Suitable dose forms for oral administration may be tablets and capsules and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate; disintegrants, for example starch, polyvinylpyrrolidone, sodium starch glycollate or microcrystalline cellulose; or pharmaceutically acceptable wetting agents such as sodium lauryl sulphate. The solid oral compositions may be prepared by conventional methods of blending, filling or tabletting. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are of course conventional in the art. The tablets may be coated according to methods well known in normal pharmaceutical practice, in particular with an enteric coating.

Oral liquid preparations may be in the form of, for example, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel, hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid; and if desired conventional flavouring or colouring agents.

For parenteral administration, fluid unit dosage forms are prepared utilizing the compound and a sterile vehicle, and, depending on the concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions the compound can be dissolved in water for injection and filter sterilized before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, a preservative and buffering agents can be dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilization cannot be accomplished by filtration. The compound can be sterilized by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.

The formulations mentioned herein are carried out using standard methods such as those described or referred to in reference texts such as the British and US Pharmacopoeias, Remington's Pharmaceutical Sciences (Mack Publishing Co.), Martindale The Extra Pharmacopoeia (London, The Pharmaceutical Press) or the above- mentioned publications.

Suitable methods for preparing and suitable unit dosages for the additional medicament agent, such as the antidiabetic agent mentioned herein include those methods and dosages described or referred to in the above-mentioned reference texts.

GSK-3 Assay

GSK-3 assays used to test the compounds of the invention include the following protocol winch is based on the ability of the kinase to phosphorylate a biotinylated 26 mer peptide, Biot- KYRRAAVPPSPSLSRHSSPHQ(S)EDEEE, the sequence of which is derived from the phosphorylation site of glycogen synthase, where (S) is a pre- phosphorylated serine as in glycogen synthase in vivo and the three consensus sites for GSK-3 specific phosphorylation are underlined. The phosphorylated biotinylated peptide is then captured onto Streptavidin coated SPA beads (Amersham Technology), where the signal from the ³³P is amplified via the scintillant contained in the beads. Using microtitre plates, GSK-3 was assayed in 50 mM MOPS buffer, pH 7.0, containing 5% glycerol, 0.01% Tween-20, 7.5 mM 2-mercaptoethanol, 10 mM magnesium acetate, 8 uM of the above peptide, and 10 uM [³³P]-ATP. After incubation at room temperature, the reaction was stopped by addition of 50 mM EDTA solution containing the Streptavidin coated SPA beads to give a final 0.2 mgs. Following centrifugation, the microtitre plates are counted in a Trilux 1450 microbeta liquid scintillation counter (Wallac). IC50 ^{va es axG} generated for each compound by fitting to a four parameter model. The most potent compounds of the present invention show IC50 values in the range of 1 to 500 nM.

No adverse toxicological effects are expected for the compounds of the invention, when administered in accordance with the invention. The following Descriptions and Examples illustrate the invention, but do not limit it in any way.

Synthetic Method A Example 1 N-[6-(4-Chlorophenyl-lJ3-pyrazolo[3,4-b]pyridin-3-yl]acetamide

Acetic anhydride (49 mg, 0.445 mmol) was added to a solution of 6-(4-chlorophenyl)-lH- pyrazolo[3,4-b]pyridin-3-ylamine (99 mg, 0.40 mmol) in pyridine (0.5 mL). The reaction mixture was stirred at reflux for 16 hours, allowed to cool and treated with 5N hydrochloric acid (5 mL). Solid was filtered off, washed with water and recrystallised from dimethylformamide to afford the title compound as a solid.

MS (APCI+ve): [M+H]+ at m/z 287/289 (C₁₄H_πClN₄O requires [M+H]+ at m z

287/289).

1H NMR δ (DMSO-d₆): 2.13 (3H, s), 7.59 (2H, d), 7.74 (1H, d), 8.19 (2H, d), 8.47 (1H, d),

10.7 (lH, s), 13.2 (lH, br s).

Synthetic Method B

Example 4 l-Ethyl-3-(5-phenyI-lH-pyrazolo[3,4-b]pyridinyl)-urea

To a stirred solution of 5-phenyl-lH-pyrazolo[4,3-b]pyridin-3-ylamine (100 mg, 0.48 mmol) in dry pyridine (5 mL) was added ethyl isocyanate (38 μl, 0.48 mmol). After 18 hours IN hydrochloric acid (10 mL) was added and the resulting precipitate was filtered to afford the title compound.

MS (APCI +ve): [M+H]+ at m/z 282 (C₁₅H₁₅N₅O requires [M+H]+ at m/z 282).

1H NMR 5 (DMSO-d₆): 1.11-1.19 (3H, t), 3.30-3.37 (2H, m), 7.41-7.45 (1H, m), 7.52- 7.56 (2H, m), 7.71-7.73 (2H, m), 8.89 (1H, s), 9.33 (1H, s).

The starting material for Example 4 may be prepared as shown in Descriptions 1 and 2. Description 1 2-Chloro-5-phenyl-l-nicotinonitrile

2-Oxo-5-phenyl-l,2-dihydropyridine-3-carbonitrile (2.50 g, 12.7 mmol) was added to a suspension of phosphorus oxychloride (1.5 mL) and phosphorus pentachloride (7.35 g) at room temperature. The suspension was then stirred at reflux for 1 hour. The reaction mixture was cooled to room temperature and added cautiously to iced water. The solution was then adjusted to pH 11 with sodium carbonate and the resulting white solid was filtered, washed with water, then dried in vacuo to afford the title compound as a solid. 1H NMR δ (DMSO-d6): 8.8 (d, 1H), 8.2 (d, 1H), 7.6-7.5 (m, 5H).

Description 2 5-Phenyl-lH-pyrazoIo[3,4-b]pyridin-3~ylamine

Hydrazine hydrate (1.42 g, 28 mmol) was added to a stirred solution of 2-chloro-5- phenyl- 1-nicotinonitrile (2.45 g, 11.4 mmol) in pyridine (25 mL). The reaction mixture was stirred at reflux for 6 hours, cooled and the resulting solid was filtered and dried in vacuo, affording the title compound as a solid.

1H NMR δ (DMSO-d₆): 8.7 (d, 1H), 8.4 (d, 1H), 7.7 (d, 2H), 7.5 (appt, 2H), 7.4 (d, 1H),

5.6 (s, 2H).

Synthetic Method C

Example 9

N-(5-Bromo-lH-pyrazoIo[3,4-6]pyridin-3-yl)-butyramide

To 5-bromo-lH-pyrazolo[3,4-b]pyridin-3-ylamine (100 mg, 0.47 mmol) in pyridine (3 mL) was added butyryl chloride (48 μL, 0.47 mmol) and the solution heated under reflux conditions for 16 hours. The solvent was removed in vacuo and then the compound taken up in methanol and run through an SCX cartridge with methanol as the eluant. Product was eluted using 2 normal methanolic ammonia solution. Purification was achieved using silica chromatography (10% methanol in dichloromethane as eluant). Trituration with dichloromethane yielded the title compound as a solid.

MS (APCI +ve): [M+H]+ at m/z 283/285 (C₁₀H„ON₄Br requires [M+H]+ at m/z

283/285). 1H NMR δ (DMSO-d₆): 0.94 (3H, t), 1.66 (2H, m), 2.39 (2H, t), 8.55 (IH, s), 8.61 (IH, s) 10.74 (lH, s), 13.43 (lH, s).

Synthetic Method C Example 33

Cyclopropanecarboxylic acid (5-bromo-6-phenyl-lH-pyrazolo[3,4-b]pyridin-3-yl)- amide.

To a stirred solution of 5-bromo-6-phenyl-lH-pyrazolo[3,4-b]pyridin-3-ylamine (1 g, 3.5 mmol) in dry pyridine (20 mL) was added cyclopropyl carbonyl chloride (362 mg, 3.5 mmol). The solution was stirred at reflux for 1 hour and then allowed to cool. The reaction mixture was concentrated and the residue was triturated with dichloromethane/methanol to afford the title compound as a solid.

MS (APCI +ve): [M+H]+ at m/z 357/359 (C₁₆H₁₃BrN₄O requires [M+H]⁺ at m/z

357/359). 1H NMR δ (DMSO-d₆): 0.82-0.94 (4H, m), 1.93-2.00 (IH, m), 7.38-7.41 (3H, m), 7.60-

7.69 (2H, m), 8.80 (IH, s), 11.15 (IH, s), 13.40 (IH, s).

Descriptions 3-6 illustrate the general synthesis of the parent amines, wherein the R3 substituent is halogen in conjunction with an R4 substituted aryl. The starting material for Example 33 above is prepared analogously. The amine product described in Description 6 is the precursor for Examples 64, 65, 73, 75, 77 and 80.

Description 3 5-Bromo-3-cyano-6-(4-methoxyphenyl)-2-oxo-l,2-dihydropyridine A solution of 3-cyano-6-(4-methoxyphenyl)-2-oxo-l ,2-dihydropyridine (1.0 g, 4.42 mmol) and N-bromosuccinimide (0.79 g, 4.42 mmol) in dimethylformamide (20 mL) was stirred at reflux for 1 hour, allowed to cool and added to water (100 mL). The solid was filtered, washed successively with water, ethanol and ether and dried under vacuum to afford the title compound as a solid. MS (APCI -ve): [M-H]^" at m/z 303/305 (C₁₃H₉N₂O₂ requires [M-H]" at m/z 303/305). 1HNMR δ (DMSO-d₆): 12.95 (IH, s), 8.48 (IH, s), 7.52 (2H, d), 7.06 (2H, d), 3.83 (3H, s). Description 4 5-Bromo-2-chloro-3-cyano-6-(4-methoxyphenyl)pyridine

A solution of 5-bromo-3-cyano-6-(4-methoxyphenyl)-2-oxo-l,2-dihydropyridine (1.17 g, 3.83 mmol) in phosphoryl chloride (15 mL) and dimethylformamide (0.5 mL) was stirred at reflux for 18 hours, allowed to cool and added to ice (150 mL). The mixture was extracted with ethyl acetate (3x100 mL). The combined extracts were dried over magnesium sulphate and concentrated. Purification by column chromatography (20%) v/v ethyl acetate in hexane) afforded the title compound as a solid. 1H NMR δ (CDC1₃) 8.20 (IH, s), 7.79 (2H, d), 7.01 (2H, d), 3.88 (3H, s).

Description 5 5-Bromo-6-(4-methoxyphenyl)-lH-pyrazolo[3,4-b]pyridin-3-ylamine

A mixture of 5-bromo-2-chloro-3-cyano-6-(4-methoxyphenyl)pyridine (582 mg, 1.80 mmol), hydrazine hydrate (0.25 mL, 5.15 mmol) and ethanol (8 mL) was stirred at reflux for 3 hours, allowed to cool and concentrated. Purification by column chromatography

(5% v/v methanol in dichloromethane) afforded the title compound as a solid.

MS (APCI +ve): [M+H]⁺ at m/z 319/321 (C₁₃H_nBrN₄O requires [M+H]+ at m/z

319/321). 1H NMR δ (DMSO-d₆): 12.1 (IH, s), 8.50 (IH, s), 7.57 (2H, d), 7.02 (2H, d), 5.67 (2H, s), 3.82 (3H, s).

Description 6 5-Bromo-6-(4-hydroxyphenyl)-lH-pyrazolo[3,4-b]pyridin-3-ylamine A mixture of 5-bromo-6-(4-methoxyphenyl)-lH-pyrazolo[3,4-b]pyridin-3-ylamine (170 mg, 0.53 mmol), boron tribromide (1M solution in dichloromethane, 4 mL) and dichloromethane (20 mL) was stirred at ambient temperature for 16 hours. Methanol (5 mL) was slowly added and the mixture concentrated. Water (10 mL) was added and the mixture treated to pH 7 with 2M sodium hydroxide solution. The resulting solid was filtered, washed with water and dichloromethane and dried under vacuum to afford the title compound as a solid. MS (APCI +ve): [M+H]+ at m/z 305/307 (C₁₂H₉BrN₄O requires [M+H]⁺ at m/z 305/307). 1H NMR δ (DMSO-de) 12.15 (IH, s), 9.77 (IH, s), 8.55 (IH, s), 7.54 (2H, d), 6.90 (2H, d), 5.72 (2H, s).

Where R⁴ is 2-thienyl the pyridone precursor is prepared by the method of Description 7

Description 7 2-Oxo-6-thiophen-2-yl-l,2-dihydropyridine-3-carbonitrile

Sodium methoxide (43 g, 800 mmol) was added to a solution of ethyl formate in tetrahydrofuran (200 mL) and diethyl ether (200 mL). A solution of 2-acetyl thiophene (32 g, 300 mmol) in tetrahydrofuran (200 mL) was added dropwise over 1 hour. After the addition was complete the reaction mixture was heated to 40 °C for 3 hours then the solvents were removed by distillation (90 °C). The residue was dissolved in water (400 mL) and acetic acid was added until pH 8 was reached. Cyanoacetamide was added (50 g) and the reaction mixture was heated at reflux for 18 hours. The reaction mixture was cooled, acidified with 2N hydrochloric acid and the resulting solid precipitates were filtered and dried affording the title compound as a solid.

!H NMR δ (DMSO-d₆): 7.00-7.20 (IH, br s), 7.20 (IH, dd), 7.90 (IH, d), 7.90 (IH, dd), 8.10 (IH, d), 12.60-12.90 (IH, br s)

Similarly for compounds where R³ is a methyl group, the following Descriptions 8-12 illustrate the preparation of the amine intermediate that can be acylated by standard procedures (e.g. Synthetic Method C) to give Examples 54-57, 68, 71 and 74.

Description 8 3-Dimethylamino-l-(4-methoxyphenyl)-2-methylpropenone

A solution of 4'-methoxypropiophenone (16.42 g, 0.1 mol) and N,N-dimethylformamide dimethyl acetal (11.35 g, 0.11 mol) in dry dimethylformamide (100 mL) was heated at 100°C for 24 hours. More dimethylformamide dimethyl acetal (9.29 g, 0.09 mol) was added and the solution was heated for a further 16 hours at 100°C then for 5 hours at 120°C. The solution was evaporated to low volume and the residue was taken up in ethyl acetate (250 mL) and washed with water (x3), brine, dried over magnesium sulphate and evaporated to an oil. This was triturated with petroleum ether to give the title compound as a solid.

MS (ES +ve): [M+H]+ at m/z 220 (C₁₃H₁₇NO₂ requires [M+H]+ at m/z 220). 1H NMR δ (DMSO-d₆): 2.00 (3H, s), 3.00 (6H, s), 3.78 (3H, s), 6.87 (IH, s), 6.93 (2H, m), 7.30 (2H, m).

Description 9 3-Cyano-5-methyl-6-(4-methoxyphenyl)~2-pyridone

A mixture of 3-dimethylamino-l-(4-methoxyphenyl)-2-methylpropenone (16.35 g, 74.6 mmol), cyanoacetamide (6.27 g, 74.6 mmol) and sodium methoxide (8.05 g, 149 mmol) in dry dimethylformamide (100 mL) was heated at 100°C for 5 hours. The mixture was cooled and poured into water (500 mL). 2N Hydrochloric acid was added to pH 4 and the resulting solid was filtered off and washed with water to give the title compound as a solid. MS (ES +ve): [M+H]⁺ at m/z 241 (C₁₄H₁₂N₂O₂ requires [M+H]⁺ at m/z 241).

1HNMR δ (DMSO-d₆): 1.99 (3H, s), 3.82 (3H, s), 7.05 (2H, m), 7.43 (2H, m). 8.11 (IH, s), 12.40 (IH, s).

Description 10 2-Chloro-3-cyano-5-methyl-6-(4-methoxyphenyl)pyridine

3-Cyano-5-methyl-6-(4-methoxyphenyl)-2-pyridone (13.96 g, 58 mmol) was suspended in phosphoryl chloride (50 mL), dimethylfonnamide (0.25 mL) added and the mixture heated at reflux for 5 hours. The mixture was cooled and poured with vigorous stirring into ice (500 g). Dichloromethane (400 mL) was added and the mixture was filtered. The layers were separated and the organic layer was washed with water at pH 7 (sodium hydroxide) and brine, dried over magnesium sulphate and evaporated to a solid. This was taken up in dichloromethane and filtered through a bed of silica gel, washing through with more dichloromethane. The filtrate was evaporated and the residue triturated with ether to give the title compound as a solid. MS (APCI +ve): [M+H]+ at m/z 259/261 (C₁₄H_uClN₂O requires [M+H]+ at m/z 259/261). 1H NMR δ (DMSO-d₆): 2.40 (3H, s), 3.84 (3H, s), 7.07 (2H, m), 7.62 (2H, m), 8.41 (IH, s).

Description 11 3-Amino-5-methyl-6-(4-methoxyphenyl)-lH-pyrazolo[3,4-b]pyridine

A mixture of 2-chloro-3-cyano-5-methyl-6-(4-methoxyphenyl)pyridine (9.68 g, 37.4 mmol) and hydrazine hydrate (6.74g, 114 mmol) in pyridine (40 mL) was heated at reflux for 7 hours. The mixture was evaporated to dryness and the residue treated with water (100 mL) and the solid broken up well and filtered off to give the title compound as a solid.

MS (ES +ve): [M+H]+ at m/z 255 (C₁₄Hι₄N₄O requires [M+H]+ at m z 255).

1H NMR δ (DMSO-d₆): 2.34 (3H, s), 3.82 (3H, s), 5.46 (2H, s), 7.01 (2H, m), 7.50 (2H, m), 7.97 (lH, s), 11.75 (lH, s).

Description 12

3-Amino-5-methyl-6-(4-hydroxyphenyl)-lH-pyrazolo[3,4-b]pyridine

3-Amino-5-methyl-6-(4-methoxyphenyl)-lH-pyrazolo[3,4-b]pyridine (2.54 g, 10 mmol) in 48% aqueous hydrobromic acid (50 mL) was heated at reflux overnight. The solution was evaporated to a solid which was dissolved in water (50 mL) and 40% sodium hydroxide solution was added to pH4 then aqueous sodium bicarbonate to pH 7.5. After standing for 15 mins the mixture was filtered to give the title compound as a solid.

MS (APCI +ve): [M+H]+ at m/z 241 (C₁₃H₁₂N₄O requires [M+H]+ at m/z 241).

1H NMR δ (DMSO-d₆): 2.34 (3H, s), 5.44 (2H, s), 6.84 (2H, m), 7.39 (2H, m), 7.94 (IH, s), 9.60 (lH, s), 11.70 (lH, s).

Synthetic Method C

Example 27

N-[3-(2-Methylpropanoylamino)-lH-pyrazolo[3,4-ft]pyridin-5-yl]-benzamide

Isobutyryl chloride (105 mg, 0.988 mmol) was added to a solution of N-(3-amino-lH- pyrazolo[3,4-b]pyridin-5-yl)-benzamide (250 mg, 0.988 mmol) in hot pyridine. The reaction was stirred at reflux for 55 hours and then the solvent was evaporated in vacuo. The residue was chromatographed on silica (10% methanol/dichloromethane) to yield the title compound as a solid.

MS (APCI+ve): [M+H]+ at m/z 324 (C₁₇H₁₇N₅O₂ requires [M+H]+ at m/z 324). !H NMR δ (DMSO-d₆): 1.16 (6H, d), 2.75 (IH, m), 7.55 (2H, t), 7.62 (IH, m), 8.01 (2H, d), 8.65 (IH, s), 8.80 (IH, s), 10.5 (IH, br s), 10.6 (IH, br s), 13.15 (IH, br s).

The starting material for Example 27 is prepared according to Descriptions 13-15 below.

Description 13 5-Amino-2-chloronicotinonitrile

2-Chloro-5-nitronicotinonitrile (Fanta et ah, JACS, 1955, 77, 1045), (10 g, 0.054 mol), was suspended in ether (50 mL), and to this solution was added slowly (exotherm) a solution of tin II chloride dihydrate (45 g, 0.199 mol) in concentrated hydrochloric acid (90 mL). The reaction was then stirred until the internal temperature reached 30°C, then diluted with water (200 mL), made strongly basic with 50% sodium hydroxide, cooled and filtered. The solid was washed thoroughly with water, then dried under vacuum at 45°C to yield the title compound as a solid.

MS (APCI+ve): [M+H]+ at m/z 154 (C₆H₄C1N₃ requires [M+H]+ at m/z 154). 1H NMR δ (DMSO-d6): 6.02 (2H, s), 7.39 (IH, s), 7.96 (IH, s).

Description 14 iV-(6-Chloro-5-cyano-pyridin-3-yl)-benzamide

5-Amino-2-chloro-nicotinonitrile (450 mg, 2.93 mmol) was dissolved in dry tetrahydrofuran (10 mL), and to this solution was added dry pyridine (0.26 mL, 3.22 mmol) followed by benzoyl chloride (453 mg, 3.22 mmol). The reaction mixture was heated under reflux for 16 hours under argon. The solvent was then evaporated in vacuo and the resulting residue partitioned between ethyl acetate and water and the aqueous layer further extracted with ethyl acetate (x3). The combined organics were washed with brine, then dried over anhydrous magnesium sulfate and evaporated in vacuo to yield the title compound as a solid.

MS (APCI+ve): [M+H]+ at m/z 258 (C₁₃H₈ClN₃O requires [M+H]+ at m z 258). !H NMR δ (DMSO-d₆): 7.58 (2H, t), 7.67 (IH, t), 8.13 (2H, d), 8.77 (IH, s), 9.00 (IH, s), 10.85 (IH, s).

Description 15 N-(3-Amino-lH-pyrazolo [3,4-6]pyridin-5-yl)-benzamide

N-(6-Chloro-5-cyano-pyridin-3-yl)-benzamide was suspended in ethanol (15 mL) and hydrazine monohydrate (379 mg, 7.58 mmol) was added and the reaction was heated under reflux for 16 hours. The reaction was then filtered hot, and the product was washed thoroughly with ethanol to yield the title compound as a solid. MS (APCI+ve): [M+H]⁺ at m/z 254 (C₁₃H_uΝ₅O requires [M+H]⁺ at m/z 254). iH NMR δ (DMSO-d₆): 5.55 (2H, br s), 7.55 (2H, t), 7.61 (IH, t), 7.99 (2H, d), 8.51 (IH, d), 8.54 (IH, d), 10.35 (IH, br s), 11.9 (IH, br s).

Synthetic Method D Example 10

N-(lH-Pyrazolo[3,4-b]pyridin-3-yl)-butyramide.

To a stirred and degassed solution of N-(5-bromo-lH-pyrazolo[3,4-b]pyridin-3-yl)- butyramide (150 mg, 0.53 mmol) and sodium carbonate (168 mg, 1.59 mmol) in dimethylformamide (1.5 mL), ethanol (0.75 mL) and water (0.75 mL) was added Pd(PPh₃)₄ (30 mg, 0.03 mmol). The reaction mixture was stirred at 100°C for 18 hours then allowed to cool. Water was added and the resultant precipitate was filtered and dried.

After trituration with dichloromethane the title compound was obtained as a solid.

MS (APCI +ve): [M+H]+ at m/z 205 (C₁₀H₁₂N₄O requires [M+H]+ at m/z 205).

1H NMR δ (DMSO-d₆): 0.92-0.98 (3H, t), 1.59-1.73 (2H, m), 2.36-2.42 (2H, q), 7.09- 7.14 (IH, m), 8.32-8.37 (IH, m), 8.46-8.49 (IH, m), 1.56 (IH, s), 13.17 (IH, s).

Synthetic Method E

Example 19

[5-(2-Fmorophenyl)-lH~pyrazolo[3,4-6]pyridin-3-yl]-carbamic acid ethyl ester 5-(2-Fluorophenyl)-lH-pyrazolo[3,4-b]pyridin-3-ylamine was dissolved in dry pyridine (10 mL), and to this solution was added 4-(dimethylamino)pyridine (10 mg 0.082 mmol) followed by ethyl chloroformate (95 mg, 0.88 mmol). The reaction was then heated at reflux for 16 hours under argon. After cooling the pyridine was evaporated in vacuo and the residue triturated with dichoromethane to yield a solid. This crude product was chromatographed on silica (5% methanol/dichloromethane) to yield the title compound as a solid. MS (APCI+ve): [M+H]+ at m/z 301 (C₁₅H₁₃FN₄O₂ requires [M+H]+ at m/z 301).

!H NMR δ (DMSO-d6): 1.25 (3H, t), 4.17 (2H, q), 7.36 (2H, m), 7.50 (IH, m), 7.60 (IH, t), 8.47 (IH, s), 8.65 (IH, s), 10.2 (IH, s), 13.25 (IH, s).

Synthetic Method F Example 13

N-r5-(4,4,5,5-Tetramethviri,3.21dioxaboroIan-2-yl)-lH-pyrazolor3.4-b1pyridin-3-yll- butyramide

To a stirred and degassed solution of N-(5-bromo-lH-pyrazolo[3,4-b]pyridin-3-yl)- butyramide (5 g, 17.8 mmol), bis pinacolato diboron (5 g, 19.6 mmol) and potassium acetate (5.2 g, 53.4 mmol) in dry dimethylsulfoxide (50 mL) was added PdCl₂(dppf) (0.46 g, 0.5 mmol). The solution was heated at 100°C overnight then reaction mixture was allowed to cool. The reaction mixture was filtered through celite, taken up in ethyl acetate (200 mL) and washed with brine (3 x 200 mL). The organic extract was dried (anhydrous magnesium sulfate) and concentrated to afford a brown solid. This solid was triturated with ethyl acetate and filtered to afford the title compound as a solid.

MS (APCI +ve): [M+H]+ at m/z 331 (C₁₆H₂₃BN₄O₃ requires [M+H]+ at m/z 331). 1H NMR δ (DMSO-d₆): 0.84-0.87 (4H, m), 1.33 (12H, s), 1.96-1.99 (IH, m), 8.63-8.64 (IH, d), 8.79 (IH, d), 11.02 (IH, s), 13.28 (IH, s).

Synthetic Method G Example 14 N-(5-Bromo-lH-pyrazolo[3,4-Z>]pyridin-3-yl)-3-methylbutyramide

To 5-bromo-lH-pyrazolo[3,4-b]pyridin-3-ylamine (95 mg, 0.45 mmol) in dimethylformamide (5 mL) was added 3-methylbutyric acid (48 μL, 0.45 mmol), O-(7- azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (104 mg, 0.45 mmol) and triethylamine (62 μL, 0.45 mmol). The solution was stirred for 16 hours under ambient conditions. An additional equivalent of the O-(7-azabenzotriazol-l-yl)- N,N,N',N'-tetramethyluronium hexafluorophosphate and triethylamine was added and the reaction allowed to continue for a further 3 hours. The solvent was removed in vacuo and the compound dissolved in methanol and loaded onto an SCX isolute cartridge. After elution with methanol further purification was achieved by preparative HPLC (C18 column, gradient of 10-90% acetonitrile (containing 0.01% trifluoroacetic acid) in water (containing 0.1% trifluoroacetic acid)). The solvent was removed to yield the title compound as a solid.

MS (APCI +ve): [M+H]⁺ at m z 297/299 (C_πH₁₂ON₅Cl requires [M+H]+ at m/z 297/299). 1H NMR δ (DMSO-d₆): 0.96 (6H, d), 2.12 (IH, m), 2.29 (2H, d), 8.55 (IH, s), 8.59 (IH, s) 10.74 (IH, s), 13.43 (IH, s).

Synthetic Method H Example 18 N- [5-(l -Ethoxy vinyl)-l H-pyrazolo [3 ,4-b] py ridin-3-yl] -butyramide

To a stirred and degassed solution of N-(5-bromo-lH-pyrazolo[3,4-b]pyridin-3-yl)- butyramide (150 mg, 0.53 mmol) and (1-ethoxyvinyl) tributyltin (191 mg, 0.53 mmol) in dry dioxane (5 mL) under argon was added Pd(PPh₃)₄ (20 mg, 0.02 mmol). After stirring at reflux for 18 hours the reaction was concentrated in vacuo, taken up in ethyl acetate (20 mL) and washed with water (20 mL). The organic extract was dried (anhydrous magnesium sulfate) and concentrated. The residue was purified by chromatography on silica (0% to 2% methanol/dichloromethane) to afford the title compound as a solid. MS (APCI -ve): [M-H]" at m/z 273 (C₁₄H₁₈N₄O₂ requires [M-H]" at m/z 273). 1H NMR δ (DMSO-d₆): 0.93-0.97 (3H, t), 1.35-1.39 (3H, t), 1.61-1.71 (2H, m), 2.38-2.40 (2H, t), 3.92-3.98 (2H, q), 4.34 (IH, dd), 4.77 (IH, dd), 8.53 (IH, dd), 8.75 (IH, dd), 10.59 (IH, s), 13.25 (IH, s).

Synthetic Method I Example 20 N-(5-Acetyl-lH-pyrazolo[3,4-b]pyridinyl)-butyramide

To a stirred solution of N-[5-(l-ethoxyvinyl)-lH-pyrazolo[3,4-b]pyridin-3-yl]-butyramide (80 mg, 0.29 mmol) in dry methanol (5 mL) was added a solution of 1M hydrochloric acid in diethyl ether (lmL, 1 mmol). After stirring for 18 hours at 25°C the mixture was concentrated to afford crude 5-acetyl-lH-pyrazolo[3,4-b]pyridin-3-ylamine (40 mg, 0.23 mmol) as a solid. The solid was dissolved in pyridine (2.5 mL) and butyryl chloride was added (24 μl, 0.23 mmol). The reaction mixture was heated at reflux for 5 hours and then cooled to room temperature. The reaction mixture was concentrated and trituration of the crude oil with dichloromethane afforded the title compound as a solid. MS (APCI +ve): [M+H]+ at m/z 247 (C₁₂Hι₄N₄O₂ requires [M+H]⁺ at m/z 247). 1H NMR δ (DMSO-d₆): 0.93-0.97 (3H, t), 1.62-1.72 (2H, m), 2.40-2.44 (2H, t), 2.63 (3H, s), 9.04-9.06 (2H, m), 10.80 (IH, s), 13.53 (IH, s).

Synthetic Method J

Example 21

[5-(3-Fluorophenyl)-lH-pyrazolo[3,4-ft]pyridin-3~yl]-carbamic acid benzyl ester

5-(3-Fluorophenyl)-l 7J-pyrazolo[3,4-b]pyridin-3-ylamine (500 mg, 2.19mmol), was dissolved in dry tefrahydrofuran (75 mL) after vigorous stirring. 4-

(Dimethylamino)pyridine (293 mg, 2.40 mmol) was then added followed by benzyl chloroformate (410 mg, 2.40 mmol), and the reaction was stirred at room temperature for 16 hours. The solvent was then evaporated in vacuo to yield a crude residue which was chromatographed on silica (solvent gradient 10-50% acetonitrile/dichlorornethane) to yield a crude solid, identified as bis-acylated material.

MS (APCI+ve): [M+H]⁺ at m/z 497 (C₂₈H₂₁FN₄O₄ requires [M+H]+ at m/z 497). The crude material was dissolved in dry piperidine (3 mL) and stirred overnight at room temperature. The piperidine was then evaporated in vacuo to yield a crude oil, which was chromatographed on silica (solvent gradient 10-30% acetonitrile/dichlorornethane) to yield the title compound as a solid.

MS (APCI+ve): [M+H]+ at m/z 363 (C₂₀H₁₅FN₄O₂ requires [M+H]+ at m/z 363). iH NMR δ (DMSO-d₆): 5.21 (2H, s), 7.25 (IH, m), 7.35 (3H, m), 7.43 (2H, m), 7.56 (3H, m), 8.52 (IH, s), 8.83 (IH, s), 10.3 (IH, br s), 13.25 (IH, br s). Synthetic Method K

Example 22

[5-(3-Fluorophenyl)-lH-pyrazolo[3,4-£]pyridin-3-yl]-carbamic acid isopropyl ester

5 -(3 -Fluorophenyl)- lH-pyrazolo [3 ,4-b]pyridin-3-ylamine (200 mg, 0.876mmol) was stirred as a slurry in dry tetrahydrofuran (30 mL), and to the suspension was added 4- (dimethylamino)pyridine (246 mg, 2.01 mmol) followed by isopropyl chloroformate (246 mg, 2.01 mmol), and the reaction was stirred at room temperature for 16 hours. The now homogeneous mixture was evaporated in vacuo to yield a crude solid which was chromatographed on silica (10%) acetonitrile/dichloromethane) to yield the title compound as a solid.

MS (APCI+ve): [M+H]+ at m/z 315 (C₁₆H₁₅FN₄O₂ requires [M+H]+ at m/z 315). iHNMR δ (DMSO-d6): 1.27 (6H, d), 4.95 (IH, m), 7.23 (IH, m), 7.56 (2H, m), 7.60 (IH, d), 8.55 (IH, s), 8.83 (IH, s), 10.1 (IH, s), 13.2 (IH, s).

Synthetic Method L Example 26 N-(5-Amino-lH-pyrazolo[3,4-b]pyridin-3-yl)isobutyramide

N-(5-Nitro-lH-pyrazolo[3,4-b]pyridin-3-yl)isobutyramide (Example 23, 0.215 g, 0.863 mmol) was hydrogenated in ethanol (30 mL) with 10% palladium on charcoal (0.12 g) for 4 hours. The catalyst was filtered off using kieselguhr, and the filtrate was evaporated in vacuo to give the title compound as a yellow solid.

MS (APCI +ve): [M+Η]+ at m/z 220. (C₁₀H₁₃N₅O requires [M+H]+ at m/z 220).

!H NMR δ (DMSO-d₆): 1.15 (6H, d), 2.70 (IH, m), 5.01 (2H, br s), 7.28 (IH, d), 8.00

(IH, d), 10.20, (IH, s), 12.63 (IH, s).

Synthetic Method M

Example 29 iV-[5-(Phenylacetylamino)-lH-pyrazolo[3,4-b]pyridin-3-yl]isobutyramide

^(S-Amino-lH-pyrazolotS^-blpyridin-S-y^isobutyramide (Example 26, 0.140 g, 0.639 mmol) was stirred in a mixture of dry dichloromethane (10 mL) and dry pyridine (1 mL), and phenylacetyl chloride (0.093 mL, 0.703 mmol) was added dropwise. This mixture was stirred for 6 hours, evaporated to dryness, dissolved in dichloromethane, washed with saturated sodium hydrogen carbonate solution and brine, dried (anhydrous magnesium sulphate) and evaporated to give a gum. This was purified by silica gel chromatography using (successively) 0%, 2.5%, 5% and 7.5% v/v methanol in dichloromethane as eluent, affording the title compound as a solid. MS (APCI +ve): [M+H]+ at m/z 338. (C₁₈H₁₉N₅O₂ requires [M+H]+ at m/z 338).

ΪH NMR δ (CD₃OD): 1.15 (6H, d), 2.65 (IH, m), 3.62 (2H, s), 7.10-7.30 (7H, m), 8.42 (IH, d), 8.50 (IH, d).

Synthetic Method N Example 37

Cyclopropanecarboxylic acid (5,6-diphenyl-lH-pyrazolo [3,4-b] pyridin-3-yl)-amide.

To a stirred and degassed solution of cyclopropanecarboxylic acid (5-bromo-6-phenyl- lH-pyrazolo[3,4-b]pyridin-3-yl)-amide (200 mg, 0.56 mmol), phenyl boronic acid (137 mg, 1.12 mmol) and potassium acetate (165 mg, 1.68 mmol) in dimethylformamide (2 mL), ethanol (1 mL) and water (ImL) was added PdCl₂(dppf) (20 mg, 0.02 mmol). The reaction mixture was stirred at 100°C for 18 h then the solution was allowed to cool.

Water was added and the resulting precipitate was filtered and washed with diethyl ether.

This solid was purified by chromatography (30%> ethyl acetate/hexane) to afford the title compound as a solid. MS (APCI +ve): [M+H]⁺ at m/z 355 (C₂₂H₁₈N₄O requires [M+H]+ at m/z 355).

1H NMR δ (DMSO-d₆): 0.82-0.86 (4H, m), 1.92-1.99 (IH, m), 7.13-7.17 (2H, m), 7.23-

7.34 (8H, m), 8.40 (IH, s), 11.7 (IH, s), 13.24 (IH, s).

As an alternative to the above Suzuki coupling methodology 5,6-diaryl compounds may be prepared via the pyridone preparation detailed in Descriptions 16 and 17.

Description 16 3-Diethylamino-l-(4-methoxyphenyl)-2-phenylpropenone

Diethylaminostyrene (8.51 g, 50 mmol) and triethylamine (7 mL, 50 mmol) were dissolved in dry toluene(150 mL) and a solution of anisoyl chloride in toluene (150 mL) was added dropwise. The mixture was refluxed overnight, cooled to room temperature and water (200 mL) added. The layers were separated and the organic layer was washed with water and brine, dried over magnesium sulphate and evaporated to an oil. This was chromatographed on silica gel using dichloromethane-diethyl ether (gradient from 50:1 to

10:1 v/v) as eluent to afford the title compound as an oil.

MS (APCI +ve): [M+H]⁺ at m/z 241 (C₁₃Hι₂N₄O requires [M+H]+ at m/z 241).

Description 17

3-Cyano-5-phenyl-6-(4-methoxyphenyl)-2-pyridone

A mixture of 3-diethylamino-l-(4-methoxyphenyl)-2-phenylpropenone (5.23 g, 16.9 mmol), cyanoacetamide (1.42 g, 16.9 mmol) and sodium methoxide (1.83 g, 33.8 mmol) in dry dimethylformamide (100 mL) was heated at 100°C for 5 hours. The mixture was cooled and poured into water (250 mL). 2N hydrochloric acid was added to pH4.5 giving an oil which slowly solidified. This was filtered off and washed well with ether to give the title compound as a solid.

MS (APCI -ve): [M-H]" at m/z 301 (C₁₉H₁₄N₂O₂ requires [M-H]" at m/z 301). !H NMR δ (DMSO-d₆): 3.74 (3H, s), 6.86 (2H, d), 7.06 (2H, m), 7.20 (5H, m), 8.19

(IH, s), 12.65 (IH, s).

Synthetic Method O Example 38 Cyclopropanecarboxylic acid [6-(4-hydroxyphenyl-lH-pyrazolo[3,4-b]pyridin-3-yl]- amide

10% Palladium on carbon (100 mg) was added to a solution of cyclopropanecarboxylic acid [6-(4-benzyloxyphenyl-lH-pyrazolo[3,4-b]pyridin-3-yl]-amide (77 mg, 0.20 mmol) in ethanol (25 mL) and dimethylformamide (10 mL) and the mixture hydrogenated at 50 psi for 60 hours. After removal of the catalyst by filtration and concentration of the filtrate, purification by column chromatography (10%) v/v methanol in dichloromethane) afforded the title compound as a solid.

MS (APCI+ve): [M+H]⁺ at m/z 295 (C₁₆H₁₄N₄O₂ requires [M+H]+ at m/z 295).

1H NMR δ (DMSO-d₆): 0.86 (4H, m), 1.96 (IH, m), 6.89 (2H, d), 7.59 (IH, d), 8.00 (2H, d), 8.37 (IH, d), 9.83 (IH, s), 10.95 (IH, s), 13.05 (IH, s). Synthetic Method P Example 82

N-(5-Bromo-6-phenyl-lH-pyrazolo[3,4-6]pyridin-3-yl)-4-(4-ethylpiperazin-l-yl)- butyramide maleate salt 5-Bromo-6-phenyl-lH-pyrazolo[3,4-b]pyridin-3-ylamine (0.10 g, 0.346 mmol) was added to a stirred mixture of 4-(4-ethylpiperazin-l-yl)-butyryl chloride hydrochloride salt (0.353 g, 1.38 mmol) in dry pyridine (10 mL) at room temperature under argon and then heated at reflux overnight. Water (10 mL) was added and the solution was evaporated to dryness under reduced pressure. Ethanol (10 mL) was then added and the solution again evaporated to dryness. The residue was redissolved in dimethylformamide (6 mL) and purified by preparative HPLC on a Supelco ABZ+plus column (250 cm by 21.2 mm, 12 μm) using a 10-90% acetonitrile (0.1 % trifluoroacetic acid) in water (0.1% trifluoroacetic acid) gradient. A solution of the resulting trifluoroacetate salt in methanol was loaded onto an SCX column and washed with methanol (50 mL). The free base of the product was then eluted with ammonia (2M) in methanol and the solution was evaporated to dryness under reduced pressure. A solution of the resulting free base in methanol (25 mL) was then treated with an equivalent of maleic acid to give the title compound as a solid after evaporation of solvents. MS (APCI +ve): [M+H]⁺ at m/z 471 and m/z 473 (C₂₂H₂₇BrN₆0 requires [M+H]⁺ at m/z 471 and m/z 473).

1H NMR δ (MeOH-0₄): 1.26 (3H, t), 1.99 (2H, quintet), 2.58 (2H, t), 2.67 (2H, t), 2.84 (4H, br. app. s), 3.03 (2H, q), 3.18 (4H, br. app. s), 6.26 (2H, s), 7.43-7.51 (3H, m), 7.60- 7.68 (2H, m), 8.81 (lH, s).

Synthetic Method Q Example 119

Cyclopropanecarboxylic acid (5-cyano-6-phenyl-lH-pyrazolo[3,4-6]pyridin-3-yl)- amide

Cyclopropanecarboxylic acid (5-iodo-6-phenyl-lH-pyrazolo[3,4-b]pyridin-3-yl)-amide (0.100 g, 0.25 mmol) was dissolved in dimethylformamide (5 mL) and treated with copper (I) cyanide (0.034 g, 0.38 mmol). The reaction mixture was heated to reflux for 16 hours and then concentrated in vacuo. The product was purified by silica gel chromatography eluting with dichloromethane/methanol (99:1) to yield the title compound as a solid.

MS (APCI +ve): [M+H]+ at m/z 304. (C₁₇H₁₃N₅O requires [M+H]+ at m/z 304). 1H NMR δ (DMSO-d₆): 0.90 (4H, m), 1.98 (IH, m), 7.59 (3H, m), 7.87 (2H, m), 9.05 (IH, s), 11.35 (IH, s), 13.81 (IH, s).

Synthetic Method R Example 164

Cyclopropanecarboxylic acid [5-bromo-6-(5-dimethylaminomethylfuran~2-yl)-lH~ pyrazolo[3,4-b]pyridin~3-yl]-amide

Cyclopropanecarboxylic acid (5-bromo-6-(furan-2-yl)-lH-pyrazolo[3,4-b]pyridin-3-yl)- amide (0.300 g, 0.86 mmol) was dissolved in acetic acid (5 mL) and treated with Eschenmoser's salt (N,N-dimethylmethylene ammonium iodide) (0.500 g, 2.6 mmol). The reaction mixture was heated to reflux for 3 hours and then concentrated in vacuo. The product was purified by silica gel chromatography eluting with 5% methanol

(containing 10% of 0.880 ammonia) in dichloromethane, then applied to a SCX column eluting with methanol first and then ammonia/methanol (10% 0.880 ammonia in methanol) to yield, after evaporation to dryness, the title compound as a solid. MS (APCI -ve): [M-H]" at m/z 402/404. (C₁₇H₁₈BrN₅O₂ requires [M-H]" at m/z 402/404).

1H NMR δ (MeOH-0₄): 0.90 (2H, m), 1.00 (2H, m), 1.90 (IH, m), 2.35 (6H, s), 3.68 (2H, s), 6.54 (IH, d), 7.43 (IH, d), 8.76 (IH, s).

Further Examples of the invention are illustrated in Table 1. The further Examples described herein were prepared by analogy with Synthetic Methods A-R described above. Table 1

Claims

1. A compound of formula (I),

or a salt thereof, or a solvate thereof, wherein, R¹ is -NR⁵COR⁶, -NHCONHR? or -NHCO₂R⁸; R² is H;

R3 is H, halo, -CN, -NO₂, -NH₂, alkyl, alkenyl, -C(OR¹⁰)=CHR¹³, -NHCOR¹¹, - NHSO₂R¹², -CO₂R¹³, -COCH₂R¹³, -B(OR¹ )₂, -CONHR¹⁵, -SPh, heteroaryl or aryl wherein the aryl group may be optionally substituted by one or more halo substituents; R4 is H, cycloC3_g alkyl, heterocyclyl, heteroaryl wherein the heteroaryl group may be optionally substituted by alkyl and di-alkylaminoalkyl; or aryl wherein the aryl group may be optionally substituted by one or more groups selected from halo, -OH, -CF3, -CN, alkoxy and arylalkoxy, or may be fused to a heterocyclic ring to form a bicyclic group; R5 is H or alkyl; R6 is alkyl, alkenyl, cycloC3_g alkyl, cycloC3_g alkenyl, di-alkylaminoalkyl, arylalkyl, arylalkenyl, heterocyclyl wherein the heterocyclyl group may be optionally substituted by one or more groups selected from alkyl, arylalkyl and alkoxyalkyl; heterocyclylalkyl wherein the heterocyclyl may be optionally substituted by one or more groups selected from alkoxyalkyl, aryloxyalkyl, arylalkyl and alkyl; heteroarylalkyl wherein the heteroaryl may be optionally substituted by one or more groups selected from alkyl; heteroaryl wherein the heteroaryl may be optionally substituted by one or more groups selected from aryl and heteroaryl; aryl wherein the aryl group may be optionally substituted by heterocyclylalkyl and di-alkylaminoalkyl; alkoxyalkyl wherein the alkoxy group may be optionally substituted by alkoxy; R is alkyl or aryl wherein the aryl group may be optionally substituted by one or more groups selected from alkyl, alkoxy, -CN and -CO R9;

R8 is alkyl or arylalkyl; and

R⁹ is alkyl;

R¹⁰ is alkyl;

R¹² is alkyl;

R¹³ is alkyl;

Rl4 is alkyl or two Rl4 groups together form a ring system which may be further substituted by one or more alkyl group(s);

R!5 is di-alkylaminoalkyl; with the proviso that when R is -NR^COR^ wherein R^ is H and R^ is as hereinbefore defined, and R² and R⁴ are H then R³ is selected from H, halo, -CN, -NO , -NH2, alkyl, alkenyl, -C(OR¹⁰)=CHR¹³, -NHCOR¹¹, -NHSO₂R¹², -CO₂R¹³,-COCH₂R¹³, -

CONHRl5 ₀r -SPh.

2. A compound of formula (I), as claimed in claim 1, of formula (IA),

or a salt thereof, or a solvate thereof, wherein,

R¹ is -NR⁵COR⁶, -NHCONHR⁷ or -NHCO₂R⁸;

R² is H; R³ is H, halo, -CN, -NO₂, -NH , alkyl, alkenyl, -CCOR¹ O^CHR¹³, -NHCOR¹1 , -

NHSO₂R1², -CO₂R¹³, -COCH₂R¹³, -B(OR¹⁴)₂, -CONHR¹⁵, -SPh, heteroaryl or aryl wherein the aryl group may be optionally substituted by one or more halo substituents;

R⁴ is H, cycloC3_g alkyl, heterocyclyl, heteroaryl wherein the heteroaryl group maybe optionally substituted by alkyl and di-alkylaminoalkyl; or aryl wherein the aryl group may be optionally substituted by one or more groups selected from halo, -OH, -CF3, -CN, alkoxy and arylalkoxy, or may be fused to a heterocyclic ring to form a bicyclic group;

R5 is H or alkyl;

R6 is alkyl, cycloC3_g alkyl, di-alkylaminoalkyl, heterocyclyl wherein the heterocyclyl group may be optionally substituted by one or more groups selected from alkyl, arylalkyl and alkoxyalkyl; heterocyclylalkyl wherein the heterocyclyl may be optionally substituted by one or more groups selected from alkoxyalkyl, aryloxyalkyl, arylalkyl and alkyl; heteroarylalkyl wherein the heteroaryl may be optionally substituted by one or more groups selected from alkyl; heteroaryl wherein the heteroaryl may be optionally substituted by one or more groups selected from aryl and heteroaryl; aryl wherein the aryl group may be optionally substituted by heterocyclylalkyl and di-alkylaminoalkyl; alkoxyalkyl wherein the alkoxy group may be optionally substituted by alkoxy;

R is alkyl or aryl wherein the aryl group may be optionally substituted by one or more groups selected from alkyl, alkoxy, -CN and CO₂R9; R⁸ is alkyl or arylalkyl;

R9 is alkyl;

R¹⁰ is alkyl;

R ¹ is alkyl, alkoxyalkyl, arylalkyl or aryl wherein the aryl group may be optionally substituted by one or more groups selected from halo; and R¹² is alkyl;

R¹³ is alkyl;

Rⁱ⁴ is alkyl or two R¹⁴ groups together form a ring system which may be further substituted by one or more alkyl group(s);

Rl5 is di-alkylaminoalkyl; with the proviso that when R is -NR^COR^ wherein R^ is H and R^ is as hereinbefore defined, and R² and R⁴ are H then R³ is selected from H, halo, -CN, -NO₂, -NH₂, alkyl, alkenyl, -C(OR¹⁰)=CHR¹³, -NHCOR¹¹, -NHSO₂R¹², -CO₂R ³,-COCH₂R¹³ -

CONHR¹⁵ or-SPh.

3. A compound of formula (I), as claimed in claim 1, of formula (IB),

or a salt thereof, or a solvate thereof, wherein,

R¹ is -NHCOMe, -NHCOPr^ -NHCOPri, -N(Et)COPrⁿ, -NHCOBu^S, -NHCO(CH₂)₄- thiomorpholin-4-yl, -NHCOcyclo-Propyl, -NHCOcyclo-Pentyl, -NHCO-4-(N-Me- Piperidyl), -NHCO(CH₂)3-(4-Et-Piperazin-l-yl), -NHCO(CH₂)3NMe₂, -NHCONHEt, - NHCONH(2-Me-Ph), -NHCONH(2-MeO-Ph), -NHCONH(2-CN-Ph), -NHCONH(2- CO₂Me-Ph), -NHCO₂Et, -NHCO₂Pri, -NHCO₂CH₂Ph, NHCO(CH₂)₂(6-Me-Pyridin-3- yl), NHCO-[3-(pyrid-2-yl)-Ph], NHCO-[4-(CH₂(pyrrolidin-l-yl)-Ph], NHCO-[6-(3- Pyridyl)-pyrid-3-yl], NHCO-3-(N-CH₂Ph-Pyrrolidinyl), NHCO-4-(N-((CH2)2θMe)- Piperidyl), NHCOCH(Me)(CH₂)₂-(4-Et-piperazin-l-yl), NHCOCH₂(N-(CH )₂OMe- Piperidin-4-yl), NHCOCH₂(N-(CH₂)₂OPh-Piperidin-4-yl), NHCOCH₂(N-CH₂Ph- Piperidin-4-yl), NHCOCH₂(N-Et-Piperidin-4-yl), NHCOCH₂O(CH₂)₂OMe,

NHCOCH₂OMe, -NHCO(CH₂)₂-morpholin-4-yl, -NHCO(CH₂)₃(pyrrolidin-l-yl), - NHCO-[4-(CH₂(piperidin-l-yl)-Ph], -NHCO-[4-(CH₂NEt₂)-Ph], -NHCO-4-(N- (CH₂)₂OEt-Piperidyl) and -NHCOCH₂NMe₂; R² is H; R³ is H, methyl, phenyl, bromo, chloro, iodo, cyano, pinacolboronato, -CH₂CH=CH₂, - CH=CH₂, -C(OEt)=CH₂, 2-fluorophenyl, -COMe, 3 -fluorophenyl, -NO₂, -NHCOMe, - NHCOPri, -NHSO₂Me, -NH₂, -NHCOPh, -NHCO(2,3-difluorophenyl), -NHCOCH₂Ph, -NHCOCH₂OMe, 3-pyridyl, -CO₂Et, -CONH(CH₂)₂NMe₂, and -SPh; R⁴ is H, phenyl, 4-chlorophenyl, 3-trifluoromethylphenyl, 2-hydroxyphenyl, 3- hydroxyphenyl, 4-hydroxyphenyl, 3,4-dihydroxyphenyl, 3,4-methylenedioxyphenyl, 4- benzyloxyphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4-pyridyl, 3- chloro-4-hydroxyphenyl, 3-bromo-4-hydroxyphenyl and 2-thienyl, 2-furyl 2-thiazolyl, 3- CN-Ph, 5-(CH₂NMe₂)-Furan-2-yl, 5-Me-Furan-2-yl and cyclopropyl; with the proviso that when R¹ is -NHCOMe, -NHCOPr*¹, -NHCOPr¹, -NHCOBu^s, - NHCO(CH )4-thiomorpholin-4-yl, -NHCOcyclo-Propyl, -NHCOcyclo-Pentyl, -NHCO- 4-(N-Me-Piperidyl), -NHCO(CH₂)₃-(4-Et-Piperazin-l-yl), -NHCO(CH₂)3NMe₂, NHCO(CH₂)₂(6-Me-Pyridin-3-yl), NHCO-[3-(pyrid-2-yl)-Ph], NHCO-[4- (CH₂(pyrrolidin-l-yl)-Ph], NHCO-[6-(3-Pyridyl)-pyrid-3-yl], NHCO-3-(N-CH₂Ph- Pyrrolidinyl), NHCO-4-(N-((CH₂)₂OMe)-Piperidyl), NHCOCH(Me)(CH₂)₂-(4-Et- piperazin- 1 -yl), NHCOCH₂(N-(CH₂)₂OMe-Piperidin-4-yl), NHCOCH₂(N-(CH₂)₂OPh- Piperidin-4-34), NHCOCH₂(N-CH Ph-Piperidin-4-yl), NHCOCH₂(N-Et-Piperidin-4-yl), NHCOCH₂O(CH₂)₂OMe, NHCOCH₂OMe, -NHCO(CH₂)₂-morpholin-4-yl, - NHCO(CH₂)₃(pyrrolidin-l-yl), -NHCO-[4-(CH₂(piperidin-l-yl)-Ph], -NHCO-[4-

(CH₂NEt₂)-Ph], -NHCO-4-(N-(CH₂)₂OEt-Piperidyl) and -NHCOCH₂NMe₂; and R² and R⁴ are H, then R³ is selected from H, methyl, bromo, chloro, iodo, cyano, - CH₂CH=CH₂, -CH=CH₂, -C(OEt)=CH₂, -COMe, -NO₂, -NHCOMe, -NHCOPri, - NHSO₂Me, -NH₂, -NHCOPh, -NHCO(2,3-difluorophenyl), -NHCOCH₂Ph - NHCOCH₂OMe, CO₂Et, CONH(CH₂)₂NMe₂, and -SPh.

4. A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, as claimed in claim 1, substantially as hereinbefore described with reference to any one of the Examples.

A process for the preparation of a compound of formula (I) wherein R is - NR5COR6 and wherein R², R³, R⁴, R5 and R^ are as hereinbefore defined, or a salt and/or solvate thereof, which process comprises reacting a compound of formula (H),

wherein R², R³, R⁴ and R^ are as defined in relation to formula (I) with a compound of formula (IH),

wherein R^ is as defined in relation to formula (I) and X is a suitable leaving group and thereafter, if required, carrying out one or more of the following optional steps: (i) converting a compound of formula (I) to a further compound of formula (I); (ii) removing any necessary protecting group; (iii) preparing an appropriate derivative of the compound so formed.

6. A process for the preparation of a compound of formula (I) wherein R is -

NHC0NHR7 and wherein R², R³, R⁴ and R are as hereinbefore defined, or a salt and/or solvate thereof, which process comprises reacting a compound of formula (H),

R— NCO (V)

(i) converting a compound of formula (I) to a further compound of formula (I);

(ii) removing any necessary protecting group;

(iii) preparing an appropriate derivative of the compound so formed.

7. A process for the preparation of a compound of formula (I) wherein R is -

NHCO₂R⁸ and wherein R², R³, R⁴ and R⁸ are as hereinbefore defined, or a salt and/or solvate thereof, which process comprises reacting a compound of formula (H),

8. A pharmaceutical composition which comprises a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in claim 1, and a pharmaceutically acceptable carrier.

9. A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, as claimed in claim 1, for use as an inhibitor of GSK-3.

10. A method for the treatment of conditions associated with a need for inhibition of GSK-3 such as diabetes, conditions associated with diabetes, chronic neurodegenerative conditions including dementias such as Alzheimer's disease, Parkinson's disease, progressive supranuclear palsy, subacute sclerosing panencephalitic parkinsonism, postencephalitic parkinsonism, pugilistic encephalitis, guam parkinsonism-dementia complex, Pick's disease, corticobasal degeneration, frontotemporal dementia, Huntingdon's disease, AIDS associated dementia, amyotrophic lateral sclerosis, multiple sclerosis and neurotraumatic diseases such as acute stroke, mood disorders such as schizophrenia and bipolar disorders, promotion of functional recovery post stroke, cerebral bleeding (for example, due to solitary cerebral amyloid angiopathy), hair loss, obesity, atherosclerotic cardiovascular disease, hypertension, polycystic ovary syndrome, syndrome X, ischaemia, traumatic brain injury, cancer, leukopenia, Down's syndrome, Lewy body disease, inflammation, and immunodeficiency, which method comprises the administration of a pharmaceutically effective, non-toxic amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, as claimed in claim 1.

11. A compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in claim 1 , for use in the manufacture of a medicament for the treatment of conditions associated with a need for the inhibition of GSK-3, such as diabetes, conditions associated with diabetes, chronic neurodegenerative conditions including dementias such as Alzheimer's disease, Parkinson's disease, progressive supranuclear palsy, subacute sclerosing panencephalitic parkinsonism, postencephalitic parkinsonism, pugilistic encephalitis, guam parkinsonism-dementia complex, Pick's disease, corticobasal degeneration, frontotemporal dementia, Huntingdon's disease, AIDS associated dementia, amyotrophic lateral sclerosis, multiple sclerosis and neurotraumatic diseases such as acute stroke, mood disorders such as schizophrenia and bipolar disorders, promotion of functional recovery post stroke, cerebral bleeding (for example, due to solitary cerebral amyloid angiopathy), hair loss, obesity, atherosclerotic cardiovascular disease, hypertension, polycystic ovary syndrome, syndrome X, ischaemia, traumatic brain injury, cancer, leukopenia, Down's syndrome, Lewy body disease, inflammation, and immunodeficiency.