HK1142074A - Heteroarylamide-substituted pyrimidone derivatives for the treatment of neurodegenerative diseases - Google Patents

Description

Heteroaryl amide substituted pyrimidone derivatives for the treatment of neurodegenerative diseases

Technical Field

The present invention relates to a compound useful as an active ingredient of a medicament for the prophylaxis and/or treatment of neurodegenerative diseases caused by abnormal activity of GSK3 β.

Background

GSK3 β (glycogen synthase kinase 3 β) is a proline-directed serine, a threonine kinase that plays an important role in the control of metabolism, differentiation, and survival. It was originally identified as an enzyme that is capable of phosphorylating and thereby inhibiting glycogen synthase. Later, it was recognized that GSK3 β is identical to Tau kinase 1(TPK1), an enzyme that phosphorylates Tau at an epitope that has also been found to be hyperphosphorylated in alzheimer's disease and some tauopathies.

Interestingly, protein kinase b (akt) phosphorylation of GSK3 β can lead to loss of its kinase activity, and it has been suggested that this inhibition may mediate some of the effects of neurotrophic factors. In addition, since GSK3 β phosphorylates β -catenin, a protein involved in cell survival, it can be degraded by the ubiquitin-dependent proteasome pathway.

Thus, it appears that inhibition of GSK3 β activity may result in neurotrophic activity. Indeed, there is evidence that lithium (a non-competitive inhibitor of GSK3 β) can increase neurite formation in some models, and can also increase neuronal survival by inducing survival factors such as Bcl-2 and inhibiting expression of pro-apoptotic factors such as p53 and Bax.

Recent studies have shown that β -amyloid increases GSK3 β activity and tau protein phosphorylation. Furthermore, this hyperphosphorylation and neurotoxic effect of β -amyloid can be blocked by lithium chloride and GSK3 β antisense mRNA. These observations strongly suggest that GSK3 may be the two major pathological processes of alzheimer's disease: a linker between the abnormal APP (amyloid precursor protein) process and the tau protein hyperphosphorylation process.

Although tau hyperphosphorylation processes may lead to destabilization of the neuronal cytoskeleton, it is likely that the pathological consequences of aberrant GSK3 β activity are not solely due to pathological phosphorylation of tau proteins, since, as described above, overactivity of this kinase may influence survival by modulating expression of apoptotic and anti-apoptotic factors.

Furthermore, it has been shown that the increase in GSK3 β activity caused by β -amyloid protein can lead to phosphorylation and thus inhibition of pyruvate dehydrogenase, an enzyme that is critical in energy production and acetylcholine synthesis.

Taken together, all these experimental observations suggest that GSK3 β may find utility in the treatment of neuropathological sequelae and cognitive and attention deficits associated with Alzheimer's disease, as well as other acute and chronic neurodegenerative diseases and other pathologies with GSK3 β dysregulation (Nature Reviews Vol.3, June 2004, p.479-487; Trends in pharmaceutical Sciences Vol.25No.9, Sept.2004, p.471-480; Journal of neurochemistry 2004, 89, 1313-.

Neurodegenerative diseases include (by way of non-limiting example): parkinson's disease, tauopathies (e.g., frontotemporal dementia, corticobasal degeneration, pick's disease, progressive supranuclear palsy), Wilson's disease, Huntington's chorea (The Journal of biological chemistry Vol.277, No.37, Issue of September 13, pp.33791-33798, 2002), prion diseases (biochemistry.J.372, p.129-136, 2003) and other dementias, including vascular dementia; acute stroke and other traumatic injuries; cerebrovascular accidents (e.g., age-related macular degeneration); brain and spinal cord trauma; amyotrophic lateral sclerosis (European Journal of Neuroscience, Vol.22, pp.301-309, 2005) peripheral neuropathy; retinopathy and glaucoma. Recent studies have also shown that inhibition of GSK3 β can lead to neuronal differentiation of Embryonic Stem Cells (ESC) and support the renewal of human and mouse ESCs and their maintenance of pluripotency. This suggests that inhibitors of GSK3 β can be applied to regenerative Medicine (Nature Medicine 10, p.55-63, 2004).

Inhibitors of GSK3 β may also find use in the treatment of other neurological conditions such as bipolar disorder (manic-depressive illness). For example, lithium has been used as a mood stabilizer for over 50 years and is used for the primary treatment of bipolar disorder. The therapeutic effect of lithium was observed at doses (1-2mM) where lithium is the lead inhibitor of GSK3 β. Although the mechanism of action of lithium is not well understood, inhibitors of GSK3 β can be used to mimic the mood stabilising effect of lithium. The change of Akt-GSK 3beta signal is also related to the pathogenesis of schizophrenia.

Furthermore, inhibition of GSK3 β may be useful for the treatment of cancer, such as colorectal cancer, prostate cancer, breast cancer, non-small cell lung cancer, thyroid cancer, T or B cell leukemia and some virus-induced tumors. For example, it has been shown that an active form of GSK3 β is increased in tumors in colorectal cancer patients, and that inhibition of GSK3 β in colorectal cancer cells can activate p 53-dependent apoptosis and resist tumor growth. Inhibition of GSK3 β also increased TRAIL-induced apoptosis in prostate cancer cell lines. GSK3 β also plays a role in the dynamics of the mitotic spindle, and inhibitors of GSK3 β can prevent chromosome movement, leading to stabilization of microtubules and cessation of metaphase, similar to the effects observed with low doses of taxol. Other suitable uses of GSK3 β inhibitors include: treating non-insulin dependent diabetes mellitus (e.g., type II diabetes), obesity, and alopecia.

Inhibitors of human GSK3 β also inhibit pfGSK3 (an ortholog of this enzyme found in Plasmodium falciparum) and thus they are useful in the treatment of malaria (Biochimica et Biophysica acta 1697, 181-196, 2004).

Recently, both human genetic and animal studies have indicated that the Wnt/LPR5 pathway acts as a major regulator of increased skeletal mass. Inhibition of GSK3 β may result in subsequent activation of canonical Wnt signaling. Since defective Wnt signaling is associated with disorders of reduced bone mass, GSK3 β inhibitors may also be useful for the treatment of disorders of reduced bone mass (bone-related pathologies, osteoporosis).

According to current data, GSK3 β inhibitors may be used to treat or prevent pemphigus vulgaris.

Recent studies have shown that treatment with GSK3beta inhibitors improves the recovery of neutrophils and megakaryocytes. Therefore, GSK3 β inhibitors are useful for the treatment of neutropenia caused by cancer chemotherapy.

Previous studies have shown that GSK3 activity can reduce LTP (electrophysiological association of memory consolidation), suggesting that inhibitors of this enzyme may have predictive (cognitive) activity. The predictive (procignatitive) effect of the compounds can be used to treat alzheimer's disease, parkinson's disease, age-related memory impairment, mild cognitive impairment, brain trauma, schizophrenia and memory deficit characteristics of other conditions in which such deficit is observed.

Inhibitors of GSK3 β may also find use in the treatment of parenchymal Kidney disease (Nelson PJ, Kidney International advanced online publication 19dec 2007) and in the prevention or treatment of muscle atrophy (J-biol. chem (283)2008, 358-.

Disclosure of the invention

It is an object of the present invention to provide compounds useful as active ingredients of medicaments for the prevention and/or treatment of diseases caused by abnormal activity of GSK3 β, more particularly neurodegenerative diseases. More specifically, the present invention aims to provide novel compounds useful as an active ingredient of a medicament capable of preventing and/or treating neurodegenerative diseases such as Alzheimer's disease.

Thus, the inventors of the present invention have identified compounds having inhibitory activity against GSK3 β. As a result, they found that the compound represented by the following formula (I) has a desired activity and is useful as an active ingredient of a medicament for preventing and/or treating the above-mentioned diseases.

The present invention thus provides, as an object of the present invention, a pyrimidone derivative represented by formula (I) or a salt thereof, a solvate thereof, or a hydrate thereof:

wherein:

x represents two hydrogen atoms, sulfur atoms, oxygen atoms or C_1-2Alkyl and hydrogen atoms;

z represents a bond, an oxygen atom, a hydrogen atom or C_1-3An alkyl-substituted nitrogen atom, a sulfur atom, a methylene group optionally substituted with one or two groups selected from: c_1-6Alkyl, hydroxy, C_1-6Alkoxy radical, C_1-2Perhaloalkyl or amino;

r1 represents a 2, 4 or 5-pyrimidine ring or a 4-pyridine ring, which ring is optionally substituted by C_1-6Alkyl radical, C_1-6Alkoxy or halogen atom substitution;

r2 represents a 4-15 membered heterocyclic group, which group is optionally substituted by 1 to 4 substituents selected from: c_1-6Alkyl radical, halogen atom, C_1-2Perhaloalkyl radical, C_1-6Haloalkyl, hydroxy, C_1-6Alkoxy radical, C_1-2Perhaloalkoxy radical, C_1-6Haloalkoxy, nitro, cyano, amino,C_1-6monoalkylamino radical, C_2-12Dialkylamino radical, S- (C)_1-6-alkyl), a heterocyclic group, an aryl, a heteroaryl, an O-aryl or an S-aryl, said groups being optionally substituted with 1 to 4 substituents selected from: c_1-6Alkyl radical, halogen atom, C_1-6Alkoxy, C (O) O (C)_1-6-alkyl) or a c (O) O (aryl) group, the aryl group being optionally substituted with 1 to 4 substituents selected from: c_1-6Alkyl radical, halogen atom, C_1-6An alkoxy group;

r3 represents a hydrogen atom, C_1-6An alkyl group or a halogen atom;

r4 represents a hydrogen atom or C_1-6An alkyl group;

r5 represents a hydrogen atom, C_1-6An alkyl group;

r6 represents a hydrogen atom, C_1-6An alkyl group;

r7 represents a hydrogen atom or C_1-6An alkyl group; and

n represents 0 to 3, m represents 0,

in the form of the free base or of an addition salt with an acid.

According to another aspect of the present invention, there is provided a medicament comprising as an active ingredient a substance selected from the group consisting of: a pyrimidone derivative represented by formula (I) and physiologically acceptable salts thereof, and solvates and hydrates thereof. As preferred embodiments of the medicament, there are provided the above-mentioned medicament for preventing and/or treating a disease caused by abnormal GSK3 β activity, and the above-mentioned medicament for preventing and/or treating a neurodegenerative disease and another other disease such as:

non-insulin dependent diabetes mellitus (e.g., type II diabetes) and obesity; malaria, bipolar disorder (manic depressive illness); schizophrenia; alopecia or cancer such as colorectal cancer, prostate cancer, breast cancer, non-small cell lung cancer, thyroid cancer, T or B cell leukemia, some virus-induced tumors. It has also been found that the medicament can find application in regenerative medicine, pemphigus vulgaris, neutropenia and bone diseases.

As a further embodiment of the present invention, there is provided the above-mentioned medicament, wherein the disease is a neurodegenerative disease and is selected from the group consisting of: alzheimer's disease, Parkinson's disease, tauopathies (e.g., frontotemporal dementia, corticobasal degeneration, pick's disease, progressive supranuclear palsy), Wilson's disease, Huntington's disease, prion disease and other dementias, including vascular dementia; acute stroke and other traumatic injuries; cerebrovascular accidents (e.g., age-related macular degeneration); brain and spinal cord injuries; amyotrophic lateral sclerosis; peripheral neuropathy; retinopathy and glaucoma, and also provides the above-mentioned drugs in the form of pharmaceutical compositions containing the above-mentioned substances as active ingredients and one or more pharmaceutical additives.

As a further embodiment of the present invention, there is provided the above-mentioned medicament, wherein the disease is osteoporosis. The present invention further provides an inhibitor of GSK3 β activity comprising as an active ingredient a substance selected from the group consisting of: pyrimidone derivatives of formula (I) and salts thereof, and solvates and hydrates thereof.

According to a further aspect of the present invention, there is provided a method for preventing and/or treating a neurodegenerative disease caused by abnormal GSK3 β activity, the method comprising the step of administering to a patient a prophylactically and/or therapeutically effective amount of a pyrimidone derivative selected from the group consisting of formula (I) and physiologically acceptable salts thereof and solvates thereof and hydrates thereof; and the use of a substance selected from the group consisting of pyrimidone derivatives of formula (I) and physiologically acceptable salts thereof and solvates thereof and hydrates thereof for the preparation of the above-mentioned medicaments are provided.

C as used herein_1-6Alkyl represents a straight or branched chain or cycloalkyl group having 1 to 6 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, 1, 1-dimethylpropyl, n-hexyl, isohexyl, and the like.

A 4-15 membered heterocyclic group represents an unsaturated, fully saturated or partially saturated mono-or polycyclic group (e.g. 4 to 15 members) containing carbon atoms and 1 to 7 heteroatoms selected from N, O and S. Examples of heterocyclic groups include: pyrrole, furan, thiophene, pyrazole, imidazole, triazole, tetrazole, oxazole, isoxazole, oxadiazole, thiazole, isothiazole, thiadiazole, pyridine, pyrimidine, pyrazine, pyridazine, triazine, furofuran, thienothiophene, pyrrolopyrrole, furopyrrole, thienopyrrole, pyrrolopyrrole, pyrroloimidazole, furoimidazole, thienoimidazole, pyrrolopyrazole, furopyrazole, thienopyrazole, pyrrolotriazole, furotriazole, thienotriazole, imidazoloimidazole, furotetrazole, thienotetrazole, imidazopyrazole, pyrrolooxazole, pyrrolothiazole, imidazoloitriazole, imidazooxazole, imidazothiazole, triazolotriazole, pyrazolo-oxazole, pyrazolo-thiazole, pyrrolotetrazole, triazolooxazole, triazolothiazole, imidazotetrazole, imidazoloizoloimidazole, imidazoloitrazole tetrazole, furotetrazole, furo-oxazole, furo-thiazole, pyrazolotriazole, oxazolo-oxazole, oxazolo-thiazole, triazolotetrazole, oxazoloisoxazole, oxazoloisothiazole, pyrroloisoxazole, pyrroloisothiazole, imidazoloisoxazole, imidazoloisothiazole, pyrazolo-isoxazole, pyrazolo-isothiazole, triazolo-isoxazole, triazolo-isothiazole, isoxazolo-isoxazole, isoxazolo-isothiazole, furo-isoxazole, furo-isothiazole, isoxazolo-oxadiazole, isoxazolo-thiadiazole, pyrrolooxadiazole, pyrrolothiadiazole, imidazooxadiazole, imidazothiadiazole, pyrazole-oxadiazole, pyrazolothiadiazole, triazolo-oxadiazole, triazolo-thiadiazole, furo-oxadiazole, furo-thiadiazole, isoxazolo-oxadiazole, isoxazolo-thiadiazole, oxazolo-oxadiazole, oxazolo-thiadiazole, isothiazolo-thiadiazole, indole, isoindole, benzimidazole, indazole, indexazine, benzofuran, isobenzofuranyl, benzothiophene, benzo [ c ] thiophene, pyrrolopyridine, imidazopyridine, pyrazolopyridine, triazolopyridine, tetrazolopyridine, pyrrolopyrimidine, imidazopyrimidine, pyrazolopyrimidine, triazolopyrimidine, tetrazolopyrimidine, pyrrolopyrimidine, pyrrolopyrazine, imidazopyrazine, pyrazolopyrazine, triazolopyrazine, tetrazolopyrizine, pyrrolopyridazine, pyrazolopyridazine, triazolopyridazine, tetrazolopyridazine, pyrrolotriazine, imidazotriazine, triazolotriazine, tetrazolopyridine, furopyridine, furopyrimidine, furopyrazine, furopyridazine, furotriazine, oxazolopyridine, oxazolopyrimidine, oxazolopyrizine, oxazolopyridazine, oxazolotriazine, isoxazolopyridine, isoxazolopyrimidine, oxadiazoopyrimidine, oxadiazoopyridine, oxadiazoopyrimidine, oxadiazoopyridazine, oxadiazolo-triazine, benzoxazole, benzisoxazole, benzoxadiazole, thienopyridine, thienopyrimidine, thienopyrazine, thienopyridazine, thienotriazine, thiazolopyridine, thiazolopyrimidine, thiazolopyrazine, thiazolopyridazine, thiazolotriazine, isothiazolopyridine, isothiazolopyrimidine, isothiazolopyrizine, isothiazolopyrimidine, isothiazolopyridazine, isothiazolotriazine, isothiazolo-triazine, thiadiazolopyridine, thiadiazolopyrimidine, thiadiazolopyrazine, thiadiazolopyridazines, thiadiazolotriazines, benzothiazoles, benzisothiazoles, benzothiadiazoles, quinolines, isoquinolines, cinnolines, phthalazines, quinoxalines, quinazolines, naphthyridines, benzotriazines, pyridopyrimidines, pyridopyrazines, pyridotriazines, pyrimidopyrimidines, pyrimidopyridazines, pyrimidotriazines, pyrazinopyrazines, pyrazinotriazines, pyridazinopyridazines, pyridazinotriazines, triazinotriazines, benzotriazoles, benzodioxepines, benzodioxanones, benzodioxines, diazepanes. These heterocycles may also be present in partially or fully saturated forms, such as dihydrobenzofuran, tetrahydroquinoline, and the like.

Heteroaryl is an unsaturated 4-15 membered heterocyclic group;

the heterocyclic group is a saturated or partially saturated 4-15 membered heterocyclic group;

the 6-10 membered heterocyclic group represents an unsaturated, fully saturated or partially saturated mono-or polycyclic group (e.g. 6 to 10 members) containing carbon atoms and 1 to 7 heteroatoms selected from N, O and S. Examples of heterocyclic groups include: pyridine, pyrimidine, pyrazine, pyridazine, triazine, indole, isoindole, benzimidazole, indazole, indezine, benzofuran, isobenzofuranyl, benzothiophene, benzo [ c ] thiophene, pyrrolopyridine, imidazopyridine, pyrazolopyridine, triazolopyridine, tetrazolopyridine, pyrrolopyrimidine, imidazopyrimidine, pyrazolopyrimidine, triazolopyrimidine, tetrazolopyrimidine, pyrrolopyrazine, imidazopiperazine, pyrazolopyrazine, triazolopyrazine, tetrazolopyrazine, pyrrolopyrazine, imidazopyridazine, pyrazolopyridazine, triazolopyridazine, tetrazolopyridazine, pyrrolotriazine, imidazotriazine, pyrazolotriazine, triazolotriazine, tetrazolotriazine, furopyridine, furopyrimidine, furopyrazine, furopyridazine, furotriazine, oxazolopyridine, oxazolopyrimidine, oxazolopyridazine, oxazolotriazine, isoxazolopyridine, isoxazolopyrimidine, isoxazolopyrazine, isoxazolopyridazine, isoxazolotriazine, oxadiazolidopyridine, oxadiazolopyrimidine, oxadiazolopyrazine, oxadiazolopyridazine, oxadiazolizazine, benzoxazole, benzisoxazole, benzoxadiazole, thienopyridine, thienopyrimidine, thienopyrazine, thienopyridazine, thienotriazine, thiazolopyridine, thiazolopyrimidine, thiazolopyrazine, thiazolopyridazine, thiazolotriazine, isothiazolopyridine, isothiazolopyrimidine, isothiazolopyrizine, isothiazolopyridazine, isothiazolotriazine, thiadiazolopyridine, thiadiazolopyrimidine, thiadiazolopyridazine, thiadiazolotriazine, benzothiadiazolotriazine, benzisothiazole, benzothiadiazole, quinoline, isoquinoline, cinnoline, phthalazine, quinoxaline, quinazoline, naphthyridine, benzotriazine, pyridopyrimidine, pyridopyrazine, pyridopyridazine, pyridotriazine, pyrimidopyrimidine, pyrimidopyrazine, pyrimidopyridazine, pyrimidotriazine, pyrazinopyrazine, pyrazinopyridazine, pyrazinotriazine, pyridazinopyridazine, pyridazinotriazine, triazinotriazine, benzotriazole, benzodioxepine, benzodioxan, benzodioxine, diazepan. These heterocycles may also be present in partially or fully saturated forms, such as dihydrobenzofuran, tetrahydroquinoline, and the like.

C_1-6Alkoxy represents alkoxy having 1 to 6 carbon atoms, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc.;

halogen atom represents fluorine, chlorine, bromine or iodine atom;

C_1-2perhaloalkyl or alkoxy represents alkyl or alkoxy in which all hydrogen atoms are substituted by halogen, e.g. CF₃Or C₂F₅；O-CF₃Or O-C₂F₅；

C_1-6Haloalkyl represents alkyl in which at least one hydrogen is not substituted by a halogen atom;

C_1-6haloalkoxy represents alkoxy wherein at least one hydrogen is not substituted by a halogen atom;

C_1-6monoalkylamino radicals being represented by a C_1-6Alkyl-substituted amino groups such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, tert-butylamino, pentylamino, isopentylamino and the like;

C_2-12dialkylamino represents two C_1-6Alkyl-substituted amino groups such as dimethylamino, ethylmethylamino, diethylamino, methylpropylamino and diisopropylamino, and the like;

aryl represents aromatic mono-or bicyclic (e.g. 6 to 10 members) such as phenyl, naphthyl, pentalene, azulene, heptalene, cyclopentainylene (indacene), acenaphthylene, benzocyclooctatetraene, bicyclo [4.2.0] octa-1, 3, 5, 7-tetraene, bicyclo [5.1.0] octa-1, 3, 5, 7-tetraene, bicyclo [6.2.0] dec-1, 3, 5, 7, 9-pentaene.

The leaving group L represents a group which can be easily cleaved and substituted; such groups may be, for example, tosyl, mesyl, bromide, and the like.

The compound represented by the above formula (I) may form a salt. When acidic groups are present, examples of salts include: salts of alkali metals and alkaline earth metals, such as lithium, sodium, potassium, magnesium and calcium salts; salts of ammonia and amines, such as methylamine, dimethylamine, trimethylamine, dicyclohexylamine, tris (hydroxymethyl) aminomethane, N-bis (hydroxyethyl) piperazine, 2-amino-2-methyl-1-propanol, ethanolamine, N-meglumine, and L-glucosamine; or salts with basic amino acids such as lysine, delta-hydroxylysine and arginine. Base addition salts of acidic compounds are prepared using standard procedures well known in the art.

When a basic group is present, examples include: salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; salts with organic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, acetic acid, propionic acid, tartaric acid, fumaric acid, maleic acid, malic acid, oxalic acid, succinic acid, citric acid, benzoic acid, mandelic acid, cinnamic acid, lactic acid, glycolic acid, glucuronic acid, ascorbic acid, nicotinic acid and salicylic acid; or salts with acidic amino acids such as aspartic acid and glutamic acid.

Acid addition salts of basic compounds are prepared by standard procedures well known in the art, including, but not limited to: the free base is dissolved in an aqueous alcohol solution containing a suitable acid and the salt is isolated by evaporating the solution or is prepared by reacting the free base and acid in an organic solvent, in which case the salt may be isolated directly or precipitated with a second organic solvent or may be obtained by concentrating the solution. Acids useful for preparing acid addition salts preferably include: those acids which, when combined with the free base, produce a pharmaceutically acceptable salt, the anion of which is relatively harmless to the animal organism when the salt is used in a pharmaceutical dosage of the salt, so that the inherently advantageous properties of the free base are not impaired by side effects of the anion. Although pharmaceutically acceptable salts of basic compounds are preferred, all acid addition salts are within the scope of the present invention

In addition to the pyrimidone derivatives represented by the above formula (I) and salts thereof, their solvates and hydrates also fall within the scope of the present invention.

The pyrimidone derivative represented by the above formula (I) may have one or more asymmetric carbon atoms. As for the stereochemistry of such asymmetric carbon atoms, they may be independently of (R) and (S) structures, and the derivatives may exist in the form of stereoisomers such as optical isomers or diastereoisomers. Any stereoisomer in pure form, any mixture of stereoisomers, racemates and the like are within the scope of the present invention.

Objects of the present invention also include the compounds represented by formula (I) wherein m is 0 and defined by the different subgroups (1) to (10) individually or in combination with each other:

(1) r1 represents a 4 or 5-pyrimidine ring or a 4-pyridine ring; the ring being optionally substituted by C_1-2Alkyl radical, C_1-2Alkoxy or halogen atom substitution; and/or

(2) R2 represents a 6-10 membered heterocyclic group, which group is optionally substituted by 1 to 4 substituents selected from: c_1-6Alkyl radical, halogen atom, C_1-2Perhaloalkyl radical, C_1-6Haloalkyl, hydroxy, C_1-6Alkoxy radical, C_1-2Perhaloalkoxy radical, C_1-6Haloalkoxy, nitro, cyano, amino, C_1-6Monoalkylamino radical, C_2-12Dialkylamino radical, S- (C)_1-6-alkyl), a heterocyclic group, an aryl, a heteroaryl, an O-aryl or an S-aryl, said groups being optionally substituted with 1 to 4 substituents selected from: c_1-6Alkyl radical, halogen atom, C_1-6Alkoxy, C (O) O (C)_1-6-alkyl) or a c (O) O (phenyl) group, the phenyl group being optionally substituted with 1 to 4 substituents selected from: c_1-6Alkyl radical, halogen atom, C_1-6An alkoxy group;

(3) r3 represents a hydrogen atom, C_1-6Alkyl or halogenAn atom; and/or

(4) R4 represents a hydrogen atom or C_1-6An alkyl group; and/or

(5) R5 represents a hydrogen atom, C_1-6An alkyl group; and/or

(6) R6 represents a hydrogen atom, C_1-6An alkyl group; and/or

(7) R7 represents a hydrogen atom or C_1-6An alkyl group; and/or

(8) X represents two hydrogen atoms, an oxygen atom or C_1-2Alkyl and hydrogen atoms; and/or

(9) Z represents a bond, an oxygen atom, a hydrogen atom or C_1-3An alkyl-substituted nitrogen atom, a methylene group optionally substituted with one or two groups selected from: c_1-3Alkyl, hydroxy, C_1-3Alkoxy radical, C_1-2Perhaloalkyl or amino; and/or

(10) n represents a number of 0 to 3,

in the form of the free base or of an addition salt with an acid.

Another object of the invention comprises compounds represented by formula (I) wherein m is 0 and defined by different subgroups (1) to (10) individually or in combination with each other:

(1) r1 represents an unsubstituted 4-pyrimidine ring; and/or

(2) R2 represents a benzodioxin ring, a pyrimidine ring, a pyridazine ring, a pyridopyridine ring, a pyridine ring, a dihydrobenzodioxin, benzofuran, a dihydrobenzofuran ring, a benzothiazole ring, a benzothiophene ring, benzodioxole, a dihydrobenzodioxole ring, an imidazopyridine ring; the ring is optionally partially or fully saturated, and/or is optionally substituted with 1 to 4 substituents selected from: hydroxy, amino, C_1-6Alkyl radical, S- (C)_1-6Alkyl) group, halogen atom, C_1-2Perhaloalkyl radical, C_1-6Alkoxy radical, C_1-2Perhaloalkoxy or aryl optionally substituted by a halogen atom; and/or

(3) R3 represents a hydrogen atom; and/or

(4) R4 represents methyl; and/or

(5) R5 represents a hydrogen atom or a methyl group; and/or

(6) R6 represents a hydrogen atom; and/or

(7) R7 represents a hydrogen atom; and/or

(8) X represents an oxygen atom; and/or

(9) Z represents a bond or a nitrogen atom substituted by a hydrogen atom; and/or

(10) n and m represent 0 and are each a number,

in the form of the free base or of an addition salt with an acid.

Examples of the compounds of the present invention are shown in table 1 below. However, the scope of the present invention is not limited to these compounds. Nomenclature is given according to the IUPAC rules.

Further objects of the invention include a group of compounds of the formula of table 1, as defined below:

1.8-amino-7-chloro-2, 3-dihydro-benzo [1, 4] dioxine (dioxine) -5-carboxylic acid (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-ylmethyl) -amide

2.5-chloro-2-methylsulfanyl-pyrimidine-4-carboxylic acid (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-ylmethyl) -amide

3, 6-dimethoxy-pyridazine-4-carboxylic acid (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-ylmethyl) -amide

[1, 5] naphthyridine-2-carboxylic acid (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-ylmethyl) -amide

2-methoxy-N- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyridinyl-2-ylmethyl) -nicotinamide

6. Pyridine-2-carboxylic acid (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-ylmethyl) -amide

7.6-fluoro-4H-benzo [1, 3] dioxine-8-carboxylic acid (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-ylmethyl) -amide

[1, 6] naphthyridine-5-carboxylic acid (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-ylmethyl) -amide

N- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-ylmethyl) -nicotinamide

6-chloro-pyridine-2-carboxylic acid (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-ylmethyl) -amide

2, 3-dihydro-benzofuran-7-carboxylic acid (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-ylmethyl) -amide

2, 2-dimethyl-2, 3-dihydro-benzofuran-7-carboxylic acid (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-ylmethyl) -amide

13.5-bromo-benzofuran-2-carboxylic acid (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-ylmethyl) -amide

14. Benzothiazole-2-carboxylic acid (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-ylmethyl) -amide

15. Benzo [ b ] thiophene-2-carboxylic acid (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-ylmethyl) -amide

2, 2-difluoro-benzo [1, 3] dioxole-4-carboxylic acid (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-ylmethyl) -amide

(+/-) [1, 5] naphthyridine-2-carboxylic acid [1- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-yl) -ethyl ] -amide

18.3-hydroxy-pyridine-2-carboxylic acid (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-ylmethyl) -amide

(+/-) 6-chloro-pyridine-2-carboxylic acid [1- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-yl) -ethyl ] -amide

(+/-) 5-chloro-2-methylsulfanyl-pyrimidine-4-carboxylic acid [1- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-yl) -ethyl ] -amide

21.4-methoxy-pyridine-2-carboxylic acid (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-ylmethyl) -amide

(+/-) pyridine-2-carboxylic acid [1- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-yl) -ethyl ] -amide

(+/-)6- (2-fluoro-phenyl) -pyridine-2-carboxylic acid [1- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-yl) -ethyl ] -amide

(+/-) 3-methoxy-pyridine-2-carboxylic acid [1- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-yl) -ethyl ] -amide

(+/-) 2-methoxy-N- [1- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyridinyl-2-yl) -ethyl ] -nicotinamide

(+/-) benzo [ b ] thiophene-2-carboxylic acid [1- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-yl) -ethyl ] -amide

27.3H-imidazo [4, 5-b ] pyridine-6-carboxylic acid (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-ylmethyl) -amide

(+/-) 4-methoxy-pyridine-2-carboxylic acid [1- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-yl) -ethyl ] -amide

(+) -4-methoxy-pyridine-2-carboxylic acid [1- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-yl) -ethyl ] -amide

(-) -4-methoxy-pyridine-2-carboxylic acid [1- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-yl) -ethyl ] -amide

31.6-fluoro-4H-benzo [1, 3] dioxine-8-carboxylic acid [1- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-yl) -ethyl ] -amide

32.8-amino-7-chloro-2, 3-dihydro-benzo [1, 4] dioxine-5-carboxylic acid [1- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-yl) -ethyl ] -amide

33.5-bromo-2-methylsulfanyl-pyrimidine-4-carboxylic acid [1- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-yl) -ethyl ] -amide

(+) -2-methoxy-N- [1- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyridinyl-2-yl) -ethyl ] -nicotinamide

(-) -2-methoxy-N- [1- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyridinyl-2-yl) -ethyl ] -nicotinamide

36.2, 6-dimethoxy-N- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyridinyl-2-ylmethyl) -nicotinamide

As a further object, the present invention also relates to a process for producing the pyrimidone compound represented by the above formula (I). These compounds can be prepared, for example, according to the methods explained below.

Preparation method

The pyrimidone compound represented by the above formula (I) can be prepared according to the method described in scheme 1.

Reaction scheme 1

(in the above schemes, R1, R2, R3, R4, R5, R6, R7, m, n, X and Z have the same meanings as described for the compounds of formula (I)).

According to this method, a pyrimidone derivative represented by the above formula (III) (wherein R1, R3, R4, R5, R6 and m are as defined as the compound of the formula (I)) is reacted with a base such as triethylamine, sodium carbonate or potassium carbonate in a solvent such as tetrahydrofuran, N-methylpyrrolidone, N-dimethylacetamide, dimethylformamide or chloroform at an appropriate temperature of 0 to 130 ℃ in ordinary air, and then reacted with a compound of the formula (II) (wherein R2, X, Z and N are as defined as the compound of the formula (I) and L represents a leaving group, preferably chlorine, bromine) to obtain the compound of the above formula (I).

Alternatively, compounds of formula (I) wherein X represents two hydrogen atoms may be prepared as follows: the compounds of formula (II), wherein X represents an oxygen atom and L represents a hydrogen atom, are reductively aminated by compounds of formula (III), wherein R1, R3, R4, R5, R6 and m are as defined for the compounds of formula (I) and R7 is hydrogen, according to methods well known to the person skilled in the art.

The compounds of formula (II) are commercially available or may be synthesized according to methods well known to those skilled in the art.

The compounds of formula (III) can be prepared according to the methods defined in scheme 2.

Reaction scheme 2

(in the above reaction scheme, the definitions of R1, R3, R4, R5, R6 and m are the same as already described).

According to this process, a 3-ketoester of formula (IV) wherein R1 and R3 are as defined for a compound of formula (I) and R is an alkyl group such as methyl or ethyl, is reacted with a compound of formula (V) wherein R5, R6 and m are as defined for a compound of formula (I) and Pg is a suitable protecting group such as phthalimido or alkoxycarbonyl. The reaction may be carried out in the presence of a base such as potassium carbonate or sodium hydroxide, in an alcoholic solvent such as methanol, ethanol, etc. (or without a solvent), at a suitable temperature of 25 to 140 ℃, under ordinary air conditions, to obtain the compound of formula (VI) above. The compound of formula (VI) may be alkylated with a compound of formula R4L (wherein R4 is as defined for the compound of formula (I) and L represents a leaving group, preferably chlorine or bromine) in the presence of a base such as potassium carbonate or sodium hydride in a solvent such as dioxane or dimethylformamide to obtain the compound of formula (III) after removal of the protecting group (Pg).

In addition, the compound of formula (III) (wherein R3 represents a hydrogen atom) may be halogenated so as to obtain a compound of formula (III) (wherein R3 is a halogen atom, for example, a bromine atom or a chlorine atom). The reaction may be carried out in an acidic medium such as acetic acid or propionic acid, in the presence of bromosuccinimide or chlorosuccinimide or bromine.

Furthermore, a compound of the formula (IV) (wherein R3 represents a fluorine atom) can be obtained by a method similar to that described in the following documents: tetrahedron Letters, Vol.30, No.45, pp6113-6116, 1989.

Furthermore, compounds of formula (IV) can be obtained (wherein R3 represents a hydrogen atom) in a similar way to the process described in patent DE 2705582.

As a further object, the present invention also relates to compounds of formula (III) as intermediates for compounds of formula (I).

The compounds of formula (IV) are commercially available or may be synthesized according to methods well known to those skilled in the art.

For example, a compound of formula (IV) wherein R1 represents a pyrimidine ring optionally substituted by C1-6 alkyl, C1-6 alkoxy or a halogen atom, may be prepared as follows: isonicotinic acid or pyrimidine carboxylic acids, optionally substituted with C1-6 alkyl, C1-6 alkoxy or halogen, are each reacted with the corresponding malonic acid monoester. The reaction can be carried out using methods well known to those skilled in the art, for example, in the presence of a coupling agent such as 1, 1' -carbonyldi-1H-imidazole in a solvent such as tetrahydrofuran at a temperature in the range of 20 to 70 ℃.

The compounds of formula (V) may be synthesized according to methods well known to those skilled in the art.

For example, compounds of formula (V) wherein m, R5 and R6 are as defined for compounds of formula (I) and a suitable protecting group Pg such as phthalimido or alkoxycarbonyl may be prepared according to the procedures defined in scheme 3, starting from compounds of formula (VII). Conditions that can be used are given in the chemical examples.

Reaction scheme 3

The compounds of formula (VII) are commercially available or may be synthesized according to methods well known to those skilled in the art. The compound of formula (VIII) may be synthesized according to the method described in Bulletin of the Chemical society of Japan (1979), 52(10), 2938-41.

The compounds of formula (V) may be synthesized according to the methods described in WO96/14844 and Journal of organic chemistry (1981), 46(12), 2455-65. Alternatively, compounds of formula (III), wherein m represents 0, wherein R5 and R6 are as defined for compounds of formula (I), may be prepared according to the method defined in scheme 4.

Reaction scheme 4

(in the above reaction scheme, the definitions of R1, R3, R4, R5 and R6 are the same as already described).

The compounds of formula (IX) are commercially available or may be synthesized according to methods well known to those skilled in the art. The compounds of formula (XII) can be synthesized according to methods analogous to those described in the following documents: (East) (1986), 3pp, DD 238974.

In the above reaction, protection or deprotection of a functional group may be sometimes required. The suitable protecting group Pg may be selected according to the type of functional group, and the method described in the literature may be applied. Examples of protecting groups, protection and deprotection methods are given, for example, in the following: protective groups in Organic Synthesis Greene et al, 3rd Ed. (John Wiley & Sons, Inc., New York) 1999.

The compounds of the invention have inhibitory activity against GSK3 β. Accordingly, the compounds of the present invention are useful as active ingredients for the preparation of medicaments capable of preventing and/or treating diseases caused by abnormal GSK3 β activity, and more particularly neurodegenerative diseases such as Alzheimer's disease. Furthermore, the compounds of the present invention are also useful as active ingredients for the preparation of medicaments for the prevention and/or treatment of neurodegenerative diseases such as Parkinson's disease, tauopathies (e.g., frontotemporal dementia, corticobasal degeneration, pick's disease, progressive supranuclear palsy), Wilson's disease, Huntington's disease, prion diseases and other dementias, including vascular dementia; acute stroke and other traumatic injuries; cerebrovascular accidents (e.g., age-related macular degeneration); brain and spinal cord trauma; amyotrophic lateral sclerosis, peripheral neuropathy; retinopathy and glaucoma; and other diseases such as non-insulin dependent diabetes mellitus (e.g., type II diabetes) and obesity; malaria, manic depressive illness; schizophrenia; alopecia; cancers such as colorectal, prostate, breast, non-small cell lung, thyroid, T or B cell blood cancers and some virus-induced tumors and bone-related lesions. The drug also finds application in regenerative medicine.

The invention further relates to a method of treating neurodegenerative diseases caused by abnormal activity of GSK3 β and the above diseases, which method comprises administering to a warm-blooded animal organism in need thereof an effective amount of a compound of formula (I).

As the active ingredient of the medicament of the present invention, substances selected from: the compound represented by the above formula (I) and a pharmacologically acceptable salt thereof, and a solvate thereof and a hydrate thereof. The substance itself may be administered as a medicament according to the invention, however, it is desirable to administer the medicament in the form of a pharmaceutical composition comprising the substance as an active ingredient and one or more pharmaceutical additives. As the active ingredient of the medicament of the present invention, two or more of the above-mentioned substances may be used in combination. The above pharmaceutical composition may be added with an active ingredient of another drug for treating the above diseases. The type of the pharmaceutical composition is not particularly limited, and the composition may be provided in any form of preparation for oral or parenteral administration. For example, a pharmaceutical composition may be formulated, for example, in the following form: oral pharmaceutical composition forms such as granules, fine granules, powders, hard capsules, soft capsules, syrups, emulsions, suspensions, solutions and the like; or parenterally, for example, for intravenous, intramuscular or subcutaneous administration, intravenous infusion, transdermal, transmucosal, nasal drops, inhalant, suppository and the like. Injections or intravenous infusions may be prepared in the form of powdered preparations, for example, freeze-dried preparations, and may be dissolved in a suitable aqueous medium such as physiological saline immediately before use. Sustained release formulations such as those coated with a polymer can be administered directly intracerebrally.

The type of the pharmaceutical additive used for preparing the pharmaceutical composition, the content ratio of the pharmaceutical additive to the active ingredient, and the method for preparing the pharmaceutical composition may be appropriately selected by those skilled in the art. Inorganic or organic substances, or solid or liquid substances may be used as pharmaceutical additives. In general, the pharmaceutical additives may be incorporated in a proportion of 1 to 90% by weight (based on the weight of the active ingredient).

Examples of excipients used in the preparation of solid pharmaceutical compositions include, for example, lactose, sucrose, starch, talc, cellulose, dextrin, kaolin, calcium carbonate and the like. For the preparation of oral liquid compositions, conventional inert diluents such as water or vegetable oils may be used. In addition to inert diluents, the liquid compositions may also contain adjuvants such as wetting agents, suspending agents, sweetening, perfuming, coloring and preserving agents. The liquid composition may be filled in capsules made of an easily absorbable material such as a gel. Examples of solvents or suspending media for preparing compositions for parenteral administration (e.g., injections, suppositories) include water, propylene glycol, polyethylene glycol, benzyl alcohol, ethyl oleate, lecithin and the like. Examples of the base material used for the suppository include, for example, cacao butter, emulsified cacao butter, lauric lipid, witepsol.

The dose and frequency of administration of the drug of the present invention are not particularly limited, and may be appropriately selected according to, for example, the following conditions: the purpose of the prevention and/or treatment, the type of disease, the weight or age of the patient, the severity of the disease, etc. In general, the oral daily dose for an adult may be 0.01 to 1000mg (weight of active ingredient), and the dose may be administered once a day, or divided into several portions to be administered several times a day, or once in several days. When the drug is used in the form of an injection, preferably, the administration may be carried out continuously or intermittently, and the daily dose for an adult is 0.001 to 100mg (weight of the active ingredient).

Chemical examples

Example 1: compound 5 of Table 1

2-methoxy-N- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyridinyl-2-ylmethyl) -nicotinamide

1.12-methyl-1H- [4, 4' ] bipyridinyl-6-one

To a suspension of 200g (2.11mol) acetamidine hydrochloride (1: 1) in 1.2L ethanol were added 84g (2.11mol) sodium hydroxide and 410g (2.11mol) ethyl 3- (4-pyrimidinyl) -3-oxopropanoate (prepared analogously to the process described in DE 2705582). The resulting mixture was stirred at reflux for 12 hours. The cooled solution was evaporated and the solvent was removed. The mixture was treated with water and the precipitate was filtered and washed with diethyl ether and ethyl acetate. Precipitation was carried out for 30min with stirring in an ethanol/water mixture (ratio 2/1) to give 200g (50%) of the title compound as a brown powder. And Mp: 320 ℃ and 322 ℃.

RMN¹H(DMSO-d⁶；200MHz)δ(ppm)：12.70(br s，1H)；9.30(s，1H)；9.00(d，1H)；8.20(d，1H)；7.15(s，1H)；2.40(s，3H)。

1.21, 2-dimethyl-1H- [4, 4' ] bipyridinyl-6-one

To a suspension of 96g (0.51mol) 2-methyl-1H- [4, 4' ] bipyrimidinyl-6-one in 480mL anhydrous dimethylformamide was added 77.55g (0.56mol) potassium carbonate. The resulting mixture was stirred at room temperature for 15min, cooled at 0 deg.C, and 31.78mL (0.51mmol) of methyl iodide was added dropwise. The mixture was warmed and stirred at room temperature for 3 hours. Cooled water was added, the mixture was extracted with chloroform/methanol mixture (ratio 90/10), dried and evaporated. The residue was triturated with diisopropyl ether and filtered to give 81g (78%) of the pure product as a brown powder.

Mp：179-181℃.RMN¹H(DMSO-d⁶；200MHz)δ(ppm)：9.30(s，1H)；9.00(d，1H)；8.25(d，1H)；7.20(s，1H)；3.55(s，3H)；2.60(s，3H)。

1.32-iodomethyl-1-methyl-1H- [4, 4' ] bipyridinyl-6-one

To a 45mL aqueous suspension of 17g (0.084mol) of 1, 2-dimethyl-1H- [4, 4' ] bipyrimidinyl-6-one was added 8.5mL sulfuric acid, 25mL carbon tetrachloride and 9.6g (0.037mol) iodide. The resulting mixture was refluxed and 16.38mL of hydrogen peroxide (35% aqueous solution) was added dropwise. The mixture was stirred under reflux for 5 hours, cooled at room temperature, and 100mL of a saturated aqueous ammonium chloride solution and 100mL of chloroform were added. The resulting precipitate was filtered off, the filtrate was extracted with chloroform, dried and evaporated to give 13.6g of product, which was used as such in the next step.

1.42- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyridinyl-2-ylmethyl) -isoindole-1, 3-dione

To a solution of 14.80g (45.11mmol) 2-iodomethyl-1-methyl-1H- [4, 4' ] bipyrimidinyl-6-one in 30mL dry dimethylformamide was added 16.71g (90.21mmol) potassium phthalimide. The resulting mixture was stirred at 130 ℃ for 3 hours. After cooling, water was added and the resulting mixture was stirred at 0 ℃ for 12 hours. The precipitate was filtered, heated in ethyl acetate and filtered. The product was dried to yield 5.3g (30%) of pure compound as a brown solid. And Mp: 273 and 275 ℃.

RMN¹H(DMSO-d⁶；200MHz)δ(ppm)：9.40(s，1H)；8.85(d，1H)；8.20(m，4H)；7.50(d，1H)；7.40(s，1H)；5.35(s，2H)；3.80(s，3H)。

1.52-aminomethyl-1-methyl-1H- [4, 4' ] bipyridinyl-6-one

To a solution of 5.3g (15.26mmol)2- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-ylmethyl) -isoindole-1, 3-dione in 40mL ethanol was added 2.37mL (76.30mmol) hydrazine hydrate, and the resulting mixture was heated at reflux for 3 hours. The mixture was filtered, the solid obtained was triturated with dichloromethane for 24 hours, filtered, the filtrate obtained was evaporated to dryness, the residue was triturated with diethyl ether and filtered to obtain 1.8g of the pure compound as a solid. And Mp: 153-

RMN¹H(DMSO-d⁶；200MHz)δ(ppm)：9.40(s，1H)；9.10(d，1H)；8.50(d，1H)；7.30(s，1H)；3.95(s，2H)；3.50(s，3H)；2.15(br d，2H)。

1.62-methoxy-N- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyridinyl-2-ylmethyl) -nicotinamide

To a solution of 0.08g (0.37mmol) 2-aminomethyl-1-methyl-1H- [4, 4' ] bipyridinyl-6-one in 7.37mL dimethylformamide was added 0.056g (0.37mmol) 2-methoxy-nicotinic acid and 70. mu.l (0.44mmol) diethyl cyanophosphonate (DEPC). The resulting mixture was cooled at 0 ℃ and 60. mu.L (mmol) of triethylamine was added. The reaction mixture was stirred at room temperature for 1 hour.

Water was added and the mixture was extracted with dichloromethane. Drying the extract and evaporating. The residue was triturated with diethyl ether and filtered to give 0.088g (68%) of the title compound as a white powder. And Mp: 269-271 ℃.

RMN¹H(DMSO-d⁶；200MHz)δ(ppm)：9.35(s，1H)；9.10(m，2H)；8.50-8.20(m，3H)；7.35(s，1H)；7.20(m，1H)；4.80(d，2H)；4.10(s，3H)；3.60(s，3H)。

Example 2: (Compound 19 of Table 1)

(+/-) 6-chloro-pyridine-2-carboxylic acid [1- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-yl) -ethyl ] -amide

2.12-Ethyl-1H- [4, 4' ] bipyridinyl-6-one

In a similar manner to that described in example 1 (step 1.1), propionamidine hydrochloride (1: 1) was used in place of acetamidine hydrochloride (1: 1) to give the compound as a brown powder.

Mp.：227-229℃.RMN¹H(DMSO-d⁶；200MHz)δ(ppm)：9.30(s，1H)；9.10(d，1H)；8.30(d，1H)；7.15(s，1H)；3.50(brs，1H)；2.70(q，2H)；1.35(t，3H)。

2.22-Ethyl-1-methyl-1H- [4, 4' ] bipyridinyl-6-one

Using a method analogous to that described in example 1 (step 1.2), 2-Ethyl 1H- [4, 4']Bipyrimidinyl-6-one for 1, 2-dimethyl-1H- [4, 4']Bipyrimidinyl-6-one, the compound was obtained as a brown powder. Mp.: 150 ℃ and 152 ℃ RMN¹H(DMSO-d⁶；200MHz)δ(ppm)：9.40(s，1H)；9.10(d，1H)；8.40(d，1H)；7.30(s，1H)；3.60(s，3H)；3.00(q，2H)；1.40(t，3H)。

2.3(+/-)2- (1-iodo-ethyl) -1-methyl-1H- [4, 4' ] bipyridinyl-6-one

In a manner analogous to that described in example 1 (step 1.3), using 2-ethyl-1-methyl-1H- [4, 4 '] bipyridinyl-6-one instead of 1, 2-dimethyl-1H- [4, 4' ] bipyridinyl-6-one, this compound was used as such in the next step.

2.4(+/-)2- [1- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyridinyl-2-yl) -ethyl ] -isoindole-1, 3-dione

Using a method analogous to that described in example 1 (step 1.4), using (+/-)2- (1-iodo-ethyl) -1-methyl-1H- [4, 4 '] bipyridinyl-6-one instead of 2-iodomethyl-1H- [4, 4' ] bipyridinyl-6-one, this compound can be used as such in the next step.

2.5(+/-)2- (1-amino-ethyl) -1-methyl-1H- [4, 4' ] bipyridinyl-6-one

In a similar manner to that described in example 1 (step 1.5), the compound was obtained as a brown powder using (+/-)2- [1- (1-methyl-6-oxo-1, 6-dihydro- [4, 4 '] bipyrimidinyl-2-yl) -ethyl ] -isoindole-1, 3-dione instead of 2- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-ylmethyl) -isoindole-1, 3-dione.

Mp.：158-160℃。

RMN¹H(DMSO-d⁶；200MHz)δ(ppm)：9.40(s，1H)；9.20(d，1H)；8.70(d，1H)；8.50(brs，2H)；7.35(s，1H)；4.90(m，1H)；3.60(s，3H)；1.55(d，3H)。

2.6(+/-) 6-chloro-pyridine-2-carboxylic acid [1- (1-methyl-6-oxo-1, 6-dihydro [4, 4' ] bipyrimidinyl-2-yl) -ethyl ] -amide

In a manner analogous to that described in example 1 (step 1.6), using (+/-)2- (1-amino-ethyl) -1-methyl-1H- [4, 4 '] bipyridinyl-6-one instead of 2-aminomethyl-1-methyl-1H- [4, 4' ] bipyridinyl-6-one, the compound was obtained as a white powder.

Mp.：254-256℃.RMN¹H(DMSO-d⁶；200MHz)δ(ppm)：9.50(d，1H)；9.40(s，1H)；9.10(d，1H)；8.50(m，1H)；8.10(m，2H)；7.80(m，1H)；7.30(s，1H)；5.40(m，1H)；3.60(s，3H)；1.60(d，3H)。

Example 3: (Compound 29 of Table 1)

(+) -4-methoxy-pyridine-2-carboxylic acid [1- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-yl) -ethyl ] -amide

0.147g (0.40mmol) (+/-) -4-methoxy-pyridine-2-carboxylic acid (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyridinyl-2-ylmethyl) -amide (compound 28 of Table 1) was isolated by preparative Chirale HPLC (Daicel CHIRALCEL OD-H20 μm 50X220) eluting with a mixture of isopropanol/n-heptane (ratio 30/70) to give 0.052g of pure product (obtained as free base).

t_R：29.65min。

Mp.：178.2℃。[α]_D ²⁰＝+39.02°(c＝0.174，DMSO)。

RMN¹H(DMSO-d⁶；200MHz)δ(ppm)：9.35(d，1H)；9.08(d，1H)；9.04(d，1H)；8.42(d，1H)；8.22(d，1H)；7.60(m，1H)；7.50(m，1H)；7.30(s，1H)；5.42(m，1H)；3.85(s，3H)；3.62(s，3H)；1.60(s，3H)。

Example 4: (Compound 30 of Table 1)

(-) -4-methoxy-pyridine-2-carboxylic acid [1- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-yl) -ethyl ] -amide

0.147g (0.40mmol) (+/-) -4-methoxy-pyridine-2-carboxylic acid (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyridinyl-2-ylmethyl) -amide (compound 28 of Table 1) was isolated by Chirale preparative HPLC (Daicel CHIRALCEL OD-H20 μm 50X220) eluting with a mixture of isopropanol/n-heptane (30/70 ratio) to give 0.058g of pure product (obtained as free base).

t_R：43.18min。

Mp.：176.2℃.[α]_D ²⁰＝-44.96°(c＝0.224，DMSO)。

RMN¹H(DMSO-d⁶；200MHz)δ(ppm)：9.35(d，1H)；9.08(d，1H)；9.04(d，1H)；8.42(d，1H)；8.22(d，1H)；7.60(m，1H)；7.50(m，1H)；7.30(s，1H)；5.42(m，1H)；3.85(s，3H)；3.62(s，3H)；1.60(s，3H)。

A list of chemical structures and physical data illustrating the above compounds of formula (I) of the present invention is given in table 1. The compound has been prepared according to the methods of the examples. In table 1, Ph represents phenyl, (Rot.) represents the levorotatory or dextrorotatory nature of the enantiomeric compound, and m is 0.

TABLE 1

Test examples: the inhibitory activity of the drug of the invention against GSK3beta is as follows:

two different schemes may be used.

In a first aspect: 7.5 μ M of the pre-phosphorylated GS1 peptide and 10 μ M ATP (containing 300,000 cpm) were added in the presence of GSK3 β at room temperature³³P-ATP) in 25mM Tris-HCI (pH 7.5), 0.6mM DTT, 6mM MgCl₂0.6mM EGTA, 0.05mg/ml BSA buffer for 1 hour (total reaction volume: 100. mu.l).

In a second scenario: 4.1 μ M of the pre-phosphorylated GS1 peptide and 42 μ M ATP (containing 260,000 cpm) were added in the presence of GSK3 β at room temperature³³P-ATP) was cultured in 80mM MS-NaOH (pH 6.5), 1mM magnesium acetate, 0.5mM EGTA, 5mM 2-mercaptoethanol, 0.02% Tween 20, 10% glycerol buffer for 2 hours.

The inhibitor was dissolved in DMSO (final solvent concentration in the reaction medium is 1%).

With 100 microliters, 25g of polyphosphoric acid (85% P)₂O₅)、126ml 85％H₃PO₄、H₂O (to 500ml) was used after the reaction was terminated by diluting to 1: 100. An aliquot of the reaction mixture was then transferred to a Whatman P81 cation exchange filter and washed with the above solution. Determination of incorporation by liquid scintillation spectroscopy³³The radioactivity of P.

The phosphorylated GS-1 peptide has the following sequence:

NH2-YRRAAVPPSPSLSRHSSPHQS(P)EDEE-COOH.(Woodgett，J.R.(1989)Analytical Biochemistry 180，237-241)。

IC for GSK3beta inhibitory Activity of Compounds of the present invention₅₀Values represent, as an example, the IC of the compounds in Table 1₅₀Values range between 0.1 nanomolar to 3 micromolar.

For example, Compound 4 in Table 1 shows an IC of 0.005. mu.M₅₀The value is obtained.

Formulation examples

(1) Tablet formulation

The following components were mixed by a common method and compressed using a conventional apparatus.

The compound of example 1: 30mg of

Crystalline cellulose: 60mg of

Corn starch: 100mg of

Lactose: 200mg of

Magnesium stearate: 4mg of

(2) Soft capsule

The following ingredients were mixed by a general method and filled in a soft capsule.

The compound of example 1: 30mg of

Olive oil: 300mg

Lecithin: 20mg of

(1) Parenteral formulation

The following components were mixed by a usual method to prepare an injection in a 1ml ampoule.

The compound of example 1: 3mg of

Sodium chloride: 4mg of

Distilled water for injection: 1mL of

Industrial applicability

The compounds of the present invention have GSK3 β inhibitory activity and are useful as active ingredients of medicaments for the prevention and/or treatment of diseases caused by abnormal GSK3 β activity, and more particularly neurodegenerative diseases.

Claims (19)

1. A pyrimidone derivative represented by formula (I) or a salt thereof, or a solvate thereof or a hydrate thereof:

wherein:

x represents two hydrogen atoms, sulfur atoms, oxygen atoms or C_1-2Alkyl and hydrogen atoms;

z represents a bond, an oxygen atom, a hydrogen atom or C_1-3An alkyl-substituted nitrogen atom, a sulfur atom, a methylene group optionally substituted with one or two groups selected from: c_1-6Alkyl, hydroxy, C_1-6Alkoxy radical, C_1-2Perhaloalkyl or amino;

r1 represents a 2, 4 or 5-pyrimidine ring or a 4-pyridine ring, which ring is optionally substituted by C_1-6Alkyl radical, C_1-6Alkoxy or halogen atom substitution;

r2 represents a 4-15 membered heterocyclic group, which group is optionally substituted by 1 to 4 substituents selected from: c_1-6Alkyl radical, halogen atom, C_1-2Perhaloalkyl radical, C_1-6Haloalkyl, hydroxy, C_1-6Alkoxy radical, C_1-2Perhaloalkoxy radical, C_1-6Haloalkoxy, nitro, cyano, amino, C_1-6Monoalkylamino radical, C_2-12Dialkylamino radical, S- (C)_1-6-alkyl), a heterocyclic group, an aryl, a heteroaryl, an O-aryl or an S-aryl, said groups being optionally substituted with 1 to 4 substituents selected from: c_1-6Alkyl radical, halogen atom, C_1-6Alkoxy, C (O) O (C)_1-6-alkyl) or a c (O) O (aryl) group, the aryl group being optionally substituted with 1 to 4 substituents selected from: c_1-6Alkyl radical, halogen atom, C_1-6An alkoxy group;

r3 represents a hydrogen atom, C_1-6An alkyl group or a halogen atom;

r4 represents a hydrogen atom or C_1-6An alkyl group;

r5 represents a hydrogen atom, C_1-6An alkyl group;

r6 represents a hydrogen atom, C_1-6An alkyl group;

r7 represents a hydrogen atom or C_1-6An alkyl group; and

n represents 0 to 3, m represents 0,

in the form of the free base or of an addition salt with an acid.

2. A pyrimidone derivative or a salt thereof, or a solvate thereof or a hydrate thereof according to claim 1, wherein R1 represents an unsubstituted 4-pyrimidine ring.

3. A pyrimidone derivative or a salt thereof, or a solvate thereof or a hydrate thereof according to claim 1, wherein:

r1 represents a 4 or 5-pyrimidine ring or a 4-pyridine ring; the ring being optionally substituted by C_1-2Alkyl radical, C_1-2Alkoxy or halogen atom substitution; and/or

R2 represents a 6-10 membered heterocyclic group, which group is optionally substituted by 1 to 4 substituents selected from: c_1-6Alkyl radical, halogen atom, C_1-2Perhaloalkyl radical, C_1-6Haloalkyl, hydroxy, C_1-6Alkoxy radical, C_1-2Perhaloalkoxy radical, C_1-6Haloalkoxy, nitro, cyano, amino, C_1-6Monoalkylamino radical, C_2-12Dialkylamino radical, S- (C)_1-6-alkyl), a heterocyclic group, an aryl, a heteroaryl, an O-aryl or an S-aryl, said groups being optionally substituted with 1 to 4 substituents selected from: c_1-6Alkyl radical, halogen atom, C_1-6Alkoxy, C (O) O (C)_1-6-alkyl) or a c (O) O (phenyl) group, the phenyl group being optionally substituted with 1 to 4 substituents selected from: c_1-6Alkyl radical, halogen atom, C_1-6An alkoxy group;

r3 represents a hydrogen atom, C_1-6An alkyl group or a halogen atom; and/or

R4 represents a hydrogen atom or C_1-6An alkyl group; and/or

R5 represents a hydrogen atom, C_1-6An alkyl group; and/or

R6 represents a hydrogen atom, C_1-6An alkyl group; and/or

R7 represents a hydrogen atom or C_1-6An alkyl group; and/or

X represents two hydrogen atoms, an oxygen atom or C_1-2Alkyl and hydrogen atoms; and/or

Z represents a bond, an oxygen atom, a hydrogen atom or C_1-3An alkyl-substituted nitrogen atom, a methylene group optionally substituted with one or two groups selected from: c_1-3Alkyl, hydroxy, C_1-3Alkoxy radical, C_1-2Perhaloalkyl or amino; and/or

n represents a number of 0 to 3,

in the form of the free base or of an addition salt with an acid.

4. A pyrimidone derivative or a salt thereof, or a solvate thereof or a hydrate thereof according to claim 1, wherein:

r1 represents an unsubstituted 4-pyrimidine ring; and/or

R2 represents a benzodioxin ring, a pyrimidine ring, a pyridazine ring, a pyridopyridine (i.e., naphthyridine) ring, a pyridine ring, a dihydrobenzodioxin, benzofuran, dihydrobenzofuran ring, benzothiazole ring, benzothiophene ring, benzodioxole, dihydrobenzodioxole ring, imidazopyridine ring; the ring is optionally partially or fully saturated, and/or is optionally substituted with 1 to 4 substituents selected from: hydroxy, amino, C_1-6Alkyl radical, S- (C)_1-6Alkyl) group, halogen atom, C_1-2Perhaloalkyl radical, C_1-6Alkoxy radical, C_1-2Perhaloalkoxy or aryl optionally substituted by a halogen atom; and/or

R3 represents a hydrogen atom; and/or

R4 represents methyl; and/or

R5 represents a hydrogen atom or a methyl group; and/or

R6 represents a hydrogen atom; and/or

R7 represents a hydrogen atom; and/or

X represents an oxygen atom; and/or

Z represents a bond or a nitrogen atom substituted by a hydrogen atom; and/or

n and m represent 0 and are each a number,

in the form of the free base or of an addition salt with an acid.

5. A pyrimidone derivative or a salt thereof, or a solvate thereof or a hydrate thereof according to claim 1, selected from the group consisting of:

8-amino-7-chloro-2, 3-dihydro-benzo [1, 4] dioxine (dioxine) -5-carboxylic acid (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-ylmethyl) -amide

5-chloro-2-methylsulfanyl-pyrimidine-4-carboxylic acid (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-ylmethyl) -amide

3, 6-dimethoxy-pyridazine-4-carboxylic acid (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-ylmethyl) -amide

[1, 5] naphthyridine-2-carboxylic acid (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-ylmethyl) -amide

2-methoxy-N- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyridinyl-2-ylmethyl) -nicotinamide

Pyridine-2-carboxylic acid (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyridinyl-2-ylmethyl) -amide

6-fluoro-4H-benzo [1, 3] dioxine-8-carboxylic acid (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-ylmethyl) -amide

[1, 6] naphthyridine-5-carboxylic acid (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-ylmethyl) -amide

N- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-ylmethyl) -nicotinamide

6-chloro-pyridine-2-carboxylic acid (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-ylmethyl) -amide

2, 3-dihydro-benzofuran-7-carboxylic acid (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-ylmethyl) -amide

2, 2-dimethyl-2, 3-dihydro-benzofuran-7-carboxylic acid (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-ylmethyl) -amide

5-bromo-benzofuran-2-carboxylic acid (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-ylmethyl) -amide

Benzothiazole-2-carboxylic acid (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-ylmethyl) -amide

Benzo [ b ] thiophene-2-carboxylic acid (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-ylmethyl) -amide

2, 2-difluoro-benzo [1, 3] dioxol-4-carboxylic acid (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-ylmethyl) -amide

(+/-) [1, 5] naphthyridine-2-carboxylic acid [1- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-yl) -ethyl ] -amide

3-hydroxy-pyridine-2-carboxylic acid (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-ylmethyl) -amide

(+/-) 6-chloro-pyridine-2-carboxylic acid [1- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyridinyl-2-yl) -ethyl ] -amide

(+/-) 5-chloro-2-methylsulfanyl-pyrimidine-4-carboxylic acid [1- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-yl) -ethyl ] -amide

4-methoxy-pyridine-2-carboxylic acid (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-ylmethyl) -amide

(+/-) pyridine-2-carboxylic acid [1- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-yl) -ethyl ] -amide

(+/-)6- (2-fluoro-phenyl) -pyridine-2-carboxylic acid [1- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-yl) -ethyl ] -amide

(+/-) 3-methoxy-pyridine-2-carboxylic acid [1- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyridinyl-2-yl) -ethyl ] -amide

(+/-) 2-methoxy-N- [1- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyridinyl-2-yl) -ethyl ] -nicotinamide

(+/-) benzo [ b ] thiophene-2-carboxylic acid [1- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-yl) -ethyl ] -amide

3H-imidazo [4, 5-b ] pyridine-6-carboxylic acid (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-ylmethyl) -amide

(+/-) 4-methoxy-pyridine-2-carboxylic acid [1- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyridinyl-2-yl) -ethyl ] -amide

(+) -4-methoxy-pyridine-2-carboxylic acid [1- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyridinyl-2-yl) -ethyl ] -amide

(-) -4-methoxy-pyridine-2-carboxylic acid [1- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyridinyl-2-yl) -ethyl ] -amide

6-fluoro-4H-benzo [1, 3] dioxine-8-carboxylic acid [1- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-yl) -ethyl ] -amide

8-amino-7-chloro-2, 3-dihydro-benzo [1, 4] dioxine-5-carboxylic acid [1- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-yl) -ethyl ] -amide

5-bromo-2-methylsulfanyl-pyrimidine-4-carboxylic acid [1- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyrimidinyl-2-yl) -ethyl ] -amide

(+) -2-methoxy-N- [1- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyridinyl-2-yl) -ethyl ] -nicotinamide

(-) -2-methoxy-N- [1- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyridinyl-2-yl) -ethyl ] -nicotinamide

2, 6-dimethoxy-N- (1-methyl-6-oxo-1, 6-dihydro- [4, 4' ] bipyridinyl-2-ylmethyl) -nicotinamide

6. A medicament comprising as an active ingredient a substance selected from the group consisting of: a pyrimidone derivative represented by formula (I) or a salt thereof, or a solvate thereof or a hydrate thereof according to claims 1 to 5.

A GSK3 β inhibitor selected from the group consisting of pyrimidone derivatives represented by formula (I) according to claim 1 or salts thereof, or solvates thereof or hydrates thereof.

8. Compounds according to claims 1 to 5 for the prophylaxis and/or treatment of diseases which are caused by abnormal GSK3 β activity.

9. The compounds according to claims 1 to 5 for use in the prophylaxis and/or treatment of neurodegenerative diseases.

10. A compound according to claim 9 wherein the neurodegenerative disorder is selected from: alzheimer's disease, parkinson's disease, tauopathies, vascular dementia; acute stroke, traumatic injury; cerebrovascular accident, brain injury, spinal cord injury; peripheral neuropathy; retinopathy or glaucoma.

11. A compound according to claims 1 to 5 for use in the prevention and/or treatment of non-insulin dependent diabetes mellitus; obesity; manic depressive disorder; schizophrenia; alopecia; cancer; substantial kidney disease or muscle atrophy.

12. A compound according to claim 11 wherein the cancer is breast cancer, non-small cell lung cancer, thyroid cancer, T or B cell leukemia or a virus-induced tumor.

13. Compounds according to claims 1 to 5 for the prevention and/or treatment of malaria.

14. Compounds according to claims 1 to 5 for the prophylaxis and/or treatment of bone diseases.

15. The compounds according to claims 1 to 5 for the prophylaxis and/or treatment of pemphigus vulgaris.

16. The compound according to claims 1 to 5 for use in the prevention and/or treatment of neutropenia caused by cancer chemotherapy.

17. Compounds according to claims 1 to 5 for the treatment of diseases characterized by cognitive and memory deficits.

18. A pyrimidone derivative represented by formula (III) wherein

R1, R3, R4, R5, R6 and m are as defined for the compounds of formula (I) according to claim 1.

19. A process for the synthesis of compounds of general formula (I) as defined in claims 1 to 5 using intermediates as defined in claim 18.