ZA200401845B

ZA200401845B - 3-substituted-4-pyrimidone derivatives.

Info

Publication number: ZA200401845B
Application number: ZA200401845A
Authority: ZA
Inventors: Fumiaki Uehara; Keiichi Aritomo; Aya Shoda; Shinsuke Hiki; Okuyama Masahiro Usu Yoshihiro; Mitsuru Ooizumi; Kazutoshi Watanabe
Original assignee: Mitsubishi Pharma Corp; Sanofi Aventis
Priority date: 2001-09-21
Filing date: 2004-03-05
Publication date: 2005-03-07
Also published as: CN1810802B; ZA200401850B; CN1810802A; CN101274928A

Description

DESCRIPTION

3-SUBSTITUTED-4-PYRIMIDONE DERIVATIVES ! Technical Field

The present invention relates to compounds that are useful as an active ingredient of a medicament for preventive and/or therapeutic treatment of diseases mainly caused by abnormal activity of tau protein kinase 1, such as neurodegenerative diseases (e.g. Alzheimer disease).

Background Art

Alzheimer disease is progressive senile dementia, in which marked cerebral cortical atrophy is observed due to degeneration of nerve cells and decrease of nerve cell number. Pathologically, numerous senile plaques and neurofibrillary tangles are observed in brain. The number of patients has been increased with the increment of aged population, and the disease arises a serious social problem. Although various theories have been proposed, a cause of the disease has not yet been elucidated.

Early resolution of the cause has been desired.

It has been known that the degree of appearance of two characteristic pathological changes of Alzheimer disease well correlates to the degree of intellectual dysfunction. Therefore, researches have been conducted from early 1980's to reveal the cause of the disease through molecular level investigations of components of the two pathological changes. Senile plaques accumulate extracellularly, and 8 . amyloid protein has been elucidated as their main component (abbreviated as “A387” hereinafter in the specification: Biochem. Biophys. Res. Commun., 120, 855 (1984);

EMBO J., 4, 2757 (1985); Proc. Natl. Acad. Sci. USA, 82, 4245 (1985)). In the other pathological change, i.e., the neurofibrillary tangles, a double-helical filamentous substance called paired helical filament (abbreviated as “PHF” hereinafter in the specification) accumulate intracellularly, and tau protein, which is a kind of microtubule-associated protein specific for brain, has been revealed as its main . component (Proc. Natl. Acad. Sci. USA, 85, 4506 (1988); Neuron, 1, 827 (1988)).

Furthermore, on the basis of genetic investigations, presenilins 1 and 2 were ) . found as causative genes of familial Alzheimer disease (Nature, 375, 754 (1995);

Science, 269, 973 (1995); Nature. 376, 775 (1995)), and it has been revealed that presence of mutants of presenilins 1 and 2 promotes the secretion of A8 (Neuron, 17, 1005 (1996); Proc. Natl. Acad. Sci. USA, 94, 2025 (1997)). From these results, it is considered that, in Alzheimer disease, AS abnormally accumulates and agglomerates due to a certain reason, which engages with the formation of PHF to cause death of ~ nerve cells. It is also expected that extracellular outflow of glutamic acid and activation of glutamate receptor responding to the outflow may possibly be important factors in an early process of the nerve cell death caused by ischemic cerebrovascular accidents (Sai-shin Igaku [Latest Medicine], 49, 1506 (1994)).

It has been reported that kainic acid treatment that stimulates the AMPA receptor, one of glutamate receptor, increases mRNA of the amyloid precursor protein (abbreviated as “APP” hereinafter in the specification) as a precursor of A 8 (Society for Neuroscience Abstracts, 17, 1445 (1991)), and also promotes metabolism of APP (The Journal of Neuroscience, 10, 2400 (1990)). Therefore, it has been strongly suggested that the accumulation of A 8 is involved in cellular death due to ischemic cerebrovascular disorders. Other diseases in which abnormal accumulation and agglomeration of AB are observed include, for example, Down syndrome, cerebral bleeding due to solitary cerebral amyloid angiopathy, Lewy body disease (Shin-kei .

Shinpo [Nerve Advance], 34, 343 (1990); Tanpaku-shitu Kaku-san Koso [Protein,

Nucleic Acid, Enzyme], 41, 1476 (1996)) and the like. Furthermore, as diseases showing neurofibrillary tangles due to the PHF accumulation, examples include progressive supranuclear palsy, subacute sclerosing panencephalitic parkinsonism, postencephalitic parkinsonism, pugilistic encephalitis, Guam parkinsonism-dementia complex, Lewy body disease and the like (Tanpakushitu Kakusan Koso [Protein,

Nucleic Acid, Enzyme], 36, 2 (1991); Igaku no Ayumi [Progress of Medicine], 158, 511 (1991); Tanpakushitu Kakusan Koso [Protein, Nucleic Acid, Enzyme], 41, 1476 (1996)).

The tau protein is generally composed of a group of related proteins that forms several bands at molecular weights of 48-65 kDa in SDS-polyacrylamide gel electrophoresis, and it promotes the formation of microtubules. It has been verified that tau protein incorporated in the PHF in the brain suffering from Alzheimer disease is abnormally phosphorylated compared with usual tau protein (J. Biochem., 99, 1807 (1986); Proc. Natl. Acad. Sci. USA, 83, 4913 (1986)). An enzyme catalyzing the abnormal phosphorylation has been isolated. The protein was named as tau protein kinase 1 (abbreviated as “TPK1” hereinafter in the specification), and its physicochemical properties have been elucidated (Seikagaku [Biochemistry], 64, 308 (1992); J. Biol. Chem., 267, 10897 (1992)). Moreover, cDNA of rat TPK1 was cloned from a rat cerebral cortex cDNA library based on a partial amino acid sequence of

TPK1, and its nucleotide sequence was determined and an amino acid sequence was deduced (Japanese Patent Un-examined Publication [Kokai] No. 6-239893/1994). As a result, it has been revealed that the primary structure of the rat TPK1 corresponds to that of the enzyme known as rat GSK-3 8 (glycogen synthase kinase 3 8, FEBS

Lett., 325, 167 (1993)).

It has been reported that A 8, the main component of senile plaques, is neurotoxic (Science, 250, 279 (1990)). However, various theories have been proposed as for the reason why A 8 causes the cell death, and any authentic theory has not yet been established. Takashima et al. observed that the cell death was caused by A 8 treatment of fetal rat hippocampus primary culture system, and then found that the

TPK1 activity was increased by A 8 treatment and the cell death by AS was inhibited by antisense of TPK1 (Proc. Natl. Acad. Sci. USA, 90, 7789 (1993); Japanese

Patent Un-examined Publication [Kokai] No. 6-329551/1994).

In view of the foregoing, compounds which inhibit the TPK1 activity may possibly suppress the neurotoxicity of AS and the formation of PHF and inhibit the ’ nerve cell death in the Alzheimer disease, thereby cease or defer the progress of the disease. The compounds may also be possibly used as a medicament for therapeutic treatment of ischemic cerebrovascular disorder, Down syndrome, cerebral amyloid angiopathy, cerebral bleeding due to Lewy body disease and the like by suppressing the cytotoxicity of A 8. Furthermore, the compounds may possibly be used as a medicament for therapeutic treatment of neurodegenerative diseases such as progressive supranuclear palsy, subacute sclerosing panencephalitic parkinsonism, postencephalitic parkinsonism, pugilistic encephalitis, Guam parkinsonism-dementia complex, Lewy body disease, Pick’s disease, corticobasal degeneration, frontotemporal dementia, vascular dementia, traumatic injuries, brain and spinal cord trauma, peripheral neuropathies, retinopathies and glaucoma, as well as other diseases such as non-insulin dependent diabetes, obesity, manic depressive illness, schizophrenia, alopecia, breast cancer, non-small cell lung carcinoma, thyroid cancer, T or B-cell leukemia, and several virus-induced tumors.

As structurally similar compounds to the compounds of the present invention represented by formula (I) described later, compounds represented by the following formula (A) are known:

NS des (A)

NZ

IN OH wherein R represents 2,6-dichlorobenzyl group, 2-(2-chlorophenyl)ethylamino group, 3-phenylpropylamino group, or 1-methyl-3-phenylpropylamino group (W098/24782).

The compounds represented by formula (A) are characterized to have 4-fluorophenyl group at the 5-position of the pyrimidine ring and a hydroxy group at the 4-position, and not falling within the scope of the present invention. Moreover, main pharmacological activity of the compounds represented by formula (A) is anti-inflammatory effect, whereas the compounds of the present invention represented by formula (I) are useful as a TPK1 inhibitor or a medicament for therapeutic treatment of peutodegenerative diseases, and therefore, their pharmacological activities are totally different to each other.

Object to be Achieved by the Invention

An object of the present invention is to provide compounds useful as an active ingredient of a medicament for preventive and/or therapeutic treatment of diseases such as Alzheimer disease. More specifically, the object is to provide novel compounds useful as an active ingredient of a medicament that enables radical prevention and/or treatment of the neurodegenerative diseases such as Alzheimer disease by inhibiting the TPK1 activity to suppress the neurotoxicity of AS and the formation of the PHF and by inhibiting the death of nerve cells.

Means to Achieve the Object

In order to achieve the foregoing object, the inventors of the present invention conducted screenings of various compounds having inhibitory activity against the phosphorylation of TPK1. As a result, they found that compounds ] represented by the following formula (I) had the desired activity and were useful as an active ingredient of a medicament for preventive and/or therapeutic treatment of ) the aforementioned diseases. The present invention was achieved on the basis of these findings.

The present invention thus provide a pyrimidone derivative represented by formula (I) or a salt thereof, or a solvate thereof or a hydrate thereof: ¢N

N

\=1-/

I

NT (1)

RN Oo ! wherein R! represents a C1-C1z alkyl group which may be substituted;

R represents any one of groups represented by the following formulas (II) to (V):

RS

R3 R? RENT

R4 iy

N~ (I) 0 x o H .

R” R 9 - 7 1 N (V) v oN N 7 (Iv) R10 .

XA 5 wherein R2? and R® independently represent a hydrogen atom or a C1-Cs alkyl group;

R¢ represents a benzene ring which may be substituted, a naphthalene ring which may be substituted, an indan ring which may be substituted, a tetrahydronaphthalene ring which may be substituted, or an optionally substituted * heterocyclic ring having 1 to 4 hetero atoms selected from the group consisting of oxygen atom, sulfur atom and nitrogen atom, and having 5 to 10 ring-constituting atoms in total;

RS represents a C1-Cs alkyl group which may be substituted, a C3-Cs cycloalkyl group which may be substituted, a benzene ring which may be substituted, a naphthalene ring which may be substituted, an indan ring which may be substituted, a tetrahydronaphthalene ring which may be substituted, or an optionally substituted heterocyclic ring having 1 to 4 hetero atoms selected from the group consisting of oxygen atom, sulfur atom, and nitrogen atom, and having 5 to 10 ring-constituting atoms in total;

RS represents a hydrogen atom, a C1-Cs alkyl group which may be substituted, a benzene ring which may be substituted; or R5 and Ré may bind to each other to form together with the carbon to which R5 and

RS are attached an optionally substituted spiro carbocyclic ring having 3 to 11 ring-constituting atoms in total;

R7 and R® independently represent a hydrogen atom or a Ci1-Cs alkyl group, or R7and

R8 may combine to each other to form a C2-Ceé alkylene group;

RY and R10 represent a C1-Cs alkyl group which may be substituted, a Cs-Cs cycloalkyl group which may be substituted, a benzene ring which may be substituted, a ; naphthalene ring which may be substituted, an optionally substituted heterocyclic ring having 1 to 4 hetero atoms selected from the group consisting of oxygen atom, sulfur atom, and nitrogen atom, and having 5 to 10 ring-constituting atoms in total, or R? and R!0 represent -N(R11)(R12) wherein R1! represents a hydrogen atom, a C1-Cs alkyl group; and R!? represents a C1-Cs alkyl group, a benzene ring which may be substituted, a naphthalene ring which may be substituted, or an optionally substituted heterocyclic ring having 1 to 4 hetero atoms selected from the group ] consisting of oxygen atom, sulfur atom, and nitrogen atom, and having 5 to 10 ring-constituting atoms in total; ) and X represents CHz, O or NR!3 wherein R!3 represents a hydrogen atom or a C1-Cs alkyl group.

According to preferred embodiments of the present invention, provided are: the aforementioned pyrimidone derivative or the salt thereof, or the solvate thereof or the hydrate thereof, wherein R! is methyl group; the aforementioned pyrimidone derivative or the salt thereof, or the solvate thereof or the hydrate thereof, wherein R is the group represented by formula an; the aforementioned pyrimidone derivative or the salt thereof, or the solvate thereof or the hydrate thereof, wherein each of R? and R? is hydrogen atom; the aforementioned pyrimidone derivative or the salt thereof, or the solvate thereof or the hydrate thereof, wherein R is the group represented by formula (III); the aforementioned pyrimidone derivative or the salts thereof, or the solvate thereof or the hydrate thereof, wherein RS is hydrogen atom; the aforementioned pyrimidone derivative or the salts thereof, or the solvate thereof or the hydrate thereof, wherein each of R7 and RS is hydrogen atom; the aforementioned pyrimidone derivative or the salts thereof, or the solvate thereof or the hydrate thereof, wherein each of R? and RS is methyl group; the aforementioned pyrimidone derivative or the salt thereof, or the solvate thereof or the hydrate thereof, wherein R is the group represented by formula (IV); . the aforementioned pyrimidone derivative or the salts thereof, or the solvate thereof or the hydrate thereof, wherein R? is a benzene ring which may be substituted;

the aforementioned pyrimidone derivative or the salts thereof, or the solvate thereof or the hydrate thereof, wherein X is CHz; the aforementioned pyrimidone derivative or the salts thereof, or the solvate thereof or the hydrate thereof, wherein X is O; : the aforementioned pyrimidone derivative or the salt thereof, or the solvate thereof or the hydrate thereof, wherein R is the group represented by formula (V); the aforementioned pyrimidone derivative or the salts thereof, or the solvate thereof or the hydrate thereof, wherein R10 is a benzene ring which may be substituted; and the aforementioned pyrimidone derivative or the salts thereof, or the solvate thereof or the hydrate thereof, wherein R1? is a heterocyclic ring having 1 to 4 hetero atoms selected from the group consisting of oxygen atom, sulfur atom, and nitrogen atom, and having total ring-constituting atoms of 5 to 10 which may be substituted.

From another aspect, the present invention provides a medicament comprising as an active ingredient a substance selected from the group consisting of the pyrimidone derivative represented by the aforementioned formula (I) and a salt thereof, and a solvate thereof and a hydrate thereof, and a tau protein kinase 1 inhibitor selected from the group consisting of the pyrimidone derivative represented by the aforementioned formula (I) and a salt thereof, and a solvate thereof and a hydrate thereof.

According to preferred embodiments of the aforementioned medicament, provided are the aforementioned medicament which is used for preventive and/or therapeutic treatment of a disease caused by tau protein kinase 1 hyperactivity; . the aforementioned medicament which is used for preventive and/or therapeutic treatment of a neurodegenerative disease; the aforementioned medicament, wherein the disease is selected from the group consisting of Alzheimer disease, ischemic cerebrovascular accidents, Down syndrome, cerebral bleeding due to cerebral amyloid angiopathy, progressive supranuclear palsy, subacute sclerosing panencephalitic parkinsonism, postencephalitic parkinsonism, pugilistic encephalitis, Guam parkinsonism-dementia } complex, Lewy body disease, Pick’s disease, corticobasal degeneration, frontotemporal dementia, vascular dementia, traumatic injuries, brain and spinal cord trauma, ) peripheral neuropathies, retinopathies and glaucoma; and the aforementioned medicament, wherein the disease is selected from the group consisting of non-insulin dependent diabetes, obesity, manic depressive illness, schizophrenia, alopecia, breast cancer, non-small cell lung carcinoma, thyroid cancer,

T or B-cell leukemia, and a virus-induced tumor.

According to further aspects of the present invention, there are provided a method for preventive and/or therapeutic treatment of a disease cansed by tan protein kinase 1 hyperactivity, which comprises the step of administering to a patient a preventively and/or therapeutically effective amount of a substance selected from the group consisting of the 3-substituted-4-pyrimidone derivative of formula (I) and the physiologically acceptable salt thereof, and the solvate thereof and the hydrate thereof; and a use of a substance selected from the group consisting of the 3-substituted-4-pyrimidone derivative of formula (I) and the physiologically acceptable salt thereof, and the solvate thereof and the hydrate thereof for the manufacture of the aforementioned medicament.

From further aspect of the present invention, provided are a pyrimidone derivative represented by formula (VI) or a salt thereof, or a solvate thereof or a hydrate thereof:

Cr =i=/

N ol v1

Hs oN 0 . R! wherein R! represents a C1-Ci12 alkyl group which may be substituted, and a pyrimidone derivative represented by formula (VII) or a salt thereof, or a solvate thereof or a hydrate thereof: & =|=/ ) x - ay 0] wherein R! represents a C1-C: alkyl group which may be substituted.

Best Mode for Carrying Out the Invention

The alkyl group used herein may be either linear or branched. The C1-Ci12 alkyl group represented by R! may be, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, isopentyl group, neopentyl group, 1,1-dimethylpropyl group, n-hexyl group, isohexyl group, or a linear or branched heptyl group, octyl group, nonyl group, decyl group, undecyl group or dodecyl group. . In the specification, when a functional group is defined as "which may be substituted" . or "optionally substituted”, the number of substituents as well as their types and substituting positions are not particularly limited, and when two or more substituents are present, they may be the same or different.

When the C1-Ciz alkyl group represented by R! has one or more substituents,

the alkyl group may have one or more substituents selected from the group consisting of a C1-Cs alkoxyl group such as methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, tert-butoxy group; amino group,

C1-Cs alkylamino group or C2-Cs dialkylamino group: a Ce-Cio aryl group such as phenyl group, 1-naphthyl group, and 2-naphthyl group; *

The C1-Cs alkyl group represented by R2 or R? may be, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, isopentyl group, neopentyl group, 1,1-dimethylpropyl group, n-hexyl group, isohexyl group, or a linear or branched heptyl group or octyl group.

When the benzene ring, the naphthalene ring, the indan ring, the tetrahydronaphthalene ring, or the heterocyclic ring represented by R4 or R5 has one or more substituents, the rings may have one or more substituents selected from the groups consisting of a C1-Cs alkyl group such as methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group, 1,1-dimethylpropyl group; Cs-Cs cycloalkyl group such as cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group; a C3-Cs cycloalkyloxy group such as cyclopropyloxy group, cyclobutyloxy group, cyclopentyloxy group, cyclohexyloxy group; a C1-Cs alkoxyl group such as methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, tert-butoxy group, pentyloxy group, and isopentyloxy group; a C4-C+ cycloalkylalkoxy group such as cyclopropylmethoxy group, cyclopentylmethoxy group; a C1-Cs alkylthio group such as methylthio group, ethylthio group, propylthio group, butylthio group, and pentylthio group; a C1-Cs alkylsulfonyl group such as - methanesulfonyl group, ethanesulfonyl group, propanesulfonyl group, butanesuifonyl group, and pentanesulfonyl group; a halogen atom such as fluorine atom, chlorine atom, bromine atom, and iodine atom; a C:1-Cs halogenated alkyl group such as trifluoromethyl group; a C1-Cs halogenated alkoxy group such as trifluoromethoxy group, 2,2,2-trifluoroethoxy group; hydroxyl group; cyano group; nitro group; formyl group; a C2-Cs alkylcarbonyl group such as acetyl group, propionyl group, butyryl group, and valeryl group; benzene ring which may be substituted, naphthalene ring ’ which may be substituted, an optionally substituted heterocyclic ring having 1 to 4 hetero atoms selected from the group consisting of oxygen atom, sulfur atom and nitrogen atom, and having 5 to 10 ring-constituting atoms, phenoxy group which may be substituted or phenylamino group which may be substituted; amino group; a C1-Cs monoalkylamino group such as methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, tert-butylamino group, pentylamino group, and isopentylamino group; a C2-C1o dialkylamino group such as dimethylamino group, ethylmethylamino group, diethylamino group, methylpropylamino group, and diisopropylamino group; a C2-C1o monoalkylaminomethyl group such as methylaminomethyl group, ethylaminomethyl group, propylaminomethyl group, isopropylaminomethyl group, butylaminomethyl group, isobutylaminomethyl group, tert-butylaminomethyl group, pentylaminomethyl : group, isopentylaminomethyl group; a Cs-Cu dialkylaminomethyl group such as dimethylaminomethyl group, diethylaminomethyl group, ethylmethylaminomethyl group, methylpropylaminomethyl group; pyrrolidinylmethyl group; piperidinylmethyl group; morpholinomethyl group; piperazinylmethyl group; pyrrolylmethyl group; imidazolylmethyl group; pyrazolylmethyl group; and triazolylmethyl group.

When the benzene ring, the naphthalene ring, the indan ring, the tetrahydronaphthalene ring or the heterocyclic ring has one or more substituents, the . substituent may further have one or more substituents selected from the group consisting of a C1-Cs alkyl group such as methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group, 1,1-dimethylpropy! group; Cs-Cs cycloalkyl group such as cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group; a C3-Ce cycloalkyloxy group such as cyclopropyloxy group, cyclobutyloxy group, cyclopentyloxy group, cyclohexyloxy group; a C1-Cs alkoxy group such as methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, tert-butoxy group, pentyloxy group, and isopentyloxy group; a C4-C7 cycloalkylalkoxy group such as cyclopropylmethoxy group, cyclopentylmethoxy group; a Ci-Cs alkylthio group such as methylthio group, ethylthio group, propylthio group, butylthio group, and pentylthio group; a C1-Cs alkylsulfonyl group such as methanesulfonyl group, ethanesulfonyl group, propanesulfonyl group, butanesulfonyl group, and pentanesulfonyl group; a halogen atom such as fluorine atom, chlorine atom, bromine atom, and iodine atom; a C:-Cs halogenated alkyl group such as trifluoromethyl group; a C1-Cs halogenated alkoxy group such as trifluoromethoxy group, 2.2,2-trifluoroethoxy group; hydroxyl group; cyano group; nitro group; formyl group; a

C2-Cs alkylcarbonyl group such as acetyl group, propionyl group, butyryl group, and valeryl group; amino group; a C1-Cs monoalkylamino group such as methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, tert-butylamine group, pentylamino group, and isopentylamino group; a C2-C1o dialkylamino group such as dimethylamine group, ethylmethylamino group, diethylamino group, methylpropylamino group, and diisopropylamino group; a C2-Ci0 monoalkylaminomethyl group such as methylaminomethyl group, ethylaminomethyl group, propylaminomethyl group, isoproylaminomethyl group, butylaminomethyl group, isobutylaminomethyl group, tert-butylaminomethyl group, pentylaminomethyl group, isopentylaminomethyl group; a C3-Cn dialkylaminomethyl group such as dimethylaminomethy! group, . diethylaminomethyl group, ethylmethylaminomethyl group, methylpropylaminomethyl group and the like.

The heterocyclic ring having 1 to 4 hetero atoms selected from the group consisting of oxygen atom, sulfur atom, and nitrogen atom, and having 5 to 10 ring-constituting atoms represented by R4 or R5 may be, for example, furan ring, dihydrofuran ring, tetrahydrofuran ring, pyran ring, dihydropyran ring, tetrahydropyran ring, benzofuran ring, dihydrobenzofuran, isobenzofuran ring, benzodioxole ring, chromene ring, chroman ring, isochroman ring, thiophene ring, benzothiophene ring, pyrrole ring, pyrroline ring, pyrrolidine ring, imidazole ring, imidazoline ring, imidazolidine ring, pyrazole ring, pyrazoline ring, pyrazolidine ring, triazole ring, tetrazole ring, pyridine ring, pyridine oxide ring, piperidine ring, pyrazine ring, piperazine ring, pyrimidine ring, pyridazine ring, indole ring, indoline ring, isoindole ring, isoindoline ring, indazole ring, benzimidazole ring, benzotriazole ring, tetrahydroisoquinoline ring, benzothiazolinone ring, benzoxazolinone ring, purine ring, quinolizine ring, quinoline ring, phthalazine ring, naphthyridine ring, quinoxaline ring, quinazoline ring, cinnoline ring, pteridine ring, oxazole ring, oxazolidine ring, isoxazole ring, isoxazolidine ring, oxadiazole ring, thiazole ring, benzothiazole ring, thiazylidine ring, isothiazole ring, isothiazolidine ring, benzodioxole ring, dioxane ring, benzodioxane ring, dithian ring, morpholine ring, thiomorpholine ring, and phthalimide ring.

The C1-Cs alkyl group represented by RS, Ré, R? or R8 may be, for example, methyl group, ethyl group, n-propyl group, isopropyl! group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, isopentyl group, neopentyl group, 1,1-dimethylpropyl group, n-hexyl group, isohexyl group, or a linear or branched heptyl group or octyl group.

The C3-Cs cycloalkyl group represented by RS may be, for example, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group or cyclooctyl group.

When the C1-Cs alkyl group or Cs-Cs cycloalkyl group represented by RS or the C1-Cs alkyl group represented by R¢ has one or more substituents, the group may have one or more substituents selected from the groups consisting of a halogen atom, a C1-Cs alkoxyl group, a C3-Cs cycloalkyl group, a benzene ring which may be substituted, a naphthalene ring which may be substituted, phenoxy group which may be substituted or phenylamino group which may be substituted; amino group, a C1-Cs alkylamino group, a C2-Ci2 dialkylamino group, 1-pyrrolidinyl group, 1-pyperidinyl ‘ group, 1-morpholinyl group, 1-(tetrahydro-1,2,3,4-quinolinyl) group, or 1-(tetrahydro- 1,2,3,4-isoquinolinyl) group.

When the benzene ring represented by R¢ has one or more substituents, the ring may have one or more substituents selected from the group consisting of a C:-Cs alkyl group such as methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group, 1,1-dimethyvlpropyl group; a Cz-Ce¢ cycloalkyl zroup such as cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group; a Ca-Ce cycloalkyloxy group such as cyclopropyloxy group, cyclobutyloxy group, cyclopentyloxy group, cyclohexyloxy group; a Ci;-Cs alkoxyl group such as methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, tert-butoxy group, pentyloxy group, and isopentyloxy group; a C4-C7 cycloalkylalkoxy! group such as cyclopropylmethoxy group, cyclopentylmethoxy group; a Ci1-Cs alkylthio group such as methylthio group, ethylthio group, propylthio group, butylthio group, and pentylthio group; a C1-Cs alkylsulfonyl group such as methanesulfonyl group, ethanesulfonyl group, propanesulfonyl group, butanesulfonyl group, and pentanesulfonyl group; a halogen atom such as fluorine atom, chlorine atom, bromine atom, and iodine atom; a Ci-Cs halogenated alkyl group such as trifluoromethyl group; a C1-Cs halogenated alkoxyl group such as trifluoromethoxy group, - 2,2,2-trifluoroethoxy group; hydroxyl group; cyane group; nitro group; formyl group; a

C2-Cs alkylcarbonyl group such as acetyl group, propionyl group, butyryl group, and valeryl group; a benzene ring which may be substituted, a naphthalene ring which may be substituted, an optionally substituted heterocyclic ring having 1 to 4 hetero atoms selected from the group consisting of oxygen atom, sulfur atom and nitrogen atom, and having 5 to 10 ring-constituting atoms, phenoxy group which may be substituted or phenylamino group which may be substituted; amino group; a C1-Cs ' monoalkylamino group such as methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamine group, tert-butylamino group, pentylamino group, and isopentylamino group; a C2-C1o dialkylamino group such as dimethylamino group, ethylmethylamino group, diethylamino group, methylpropylamino group, and diisopropylamino group; a Cz-C1o monoalkylaminomethyl group such as methylaminomethyl group, ethylaminomethyl group, propylaminomethyl group, isopropylaminomethyl group, butylaminomethyl group, isobutylaminomethyl group, tert-butylaminomethyl group, pentylaminomethyl group, isopentylaminomethyl group; a C3-C11 dialkylaminomethyl group such as dimethylaminomethyl group, diethylaminomethyl group, ethylmethylaminomethyl group, methylpropylaminomethyl group; pyrrolidinylmethyl group; pipelidinylmethyl group; morpholinomethyl group; piperazinylmethyl group; pyrrolylmethyl group; imidazolylmethyl group; pyrazolylmethyl group; triazolylmethyl group.

When the benzene ring represented by R¢ has one or more substituents, the substituent may further have one or more substituents selected from the groups consisting of a C1-Cs alkyl group such as methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group, 1,1-dimethylpropyl group; Cs-Cs cycloalkyl group such as cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group; a C3-Cs cycloalkyloxy group such as cyclopropyloxy group, cyclobutyloxy group, cyclopentyloxy group, cyclohexyloxy group; a Ci-Cs alkoxyl group such as methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, tert-butoxy group, pentyloxy group, and isopentyloxy group; a C+-C1 cycloalkylalkoxyl

: group such as cyclopropylmethoxy group, cyclopentylmethoxy group; a C1-Cs alkylthio group such as methylthio group, ethylthio group, propylthio group, butylthio group, and pentylthio group; a C1-Cs alkylsulfonyl group such as methanesulfonyl group, ethanesulfonyl group, propanesulfonyl group, butanesulfonyl group, and pentanesulfonyl group; a halogen atom such as fluorine atom, chlorine atom, bromine atom, and iodine atom; a C1-Cs halogenated alkyl group such as trifluoromethyl group; a C1-Cs halogenated alkoxyl group such as trifluoromethoxy group, 2,2,2-trifluoroethoxy group; hydroxyl group; cyano group; nitro group; formyl group; a

C2-Ce alkylcarbonyl group such as acetyl group, propionyl group, butyryl group, and valeryl group; amino group; a C1-Cs monoalkylamino group such as methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group. isobutylamino group, tert-hutylamine group, pentylamine group, and isopentylamino group; a C2-C1o dialkylamine group such as dimethylamino group, ethylmethylamino group, diethylamino group, methylpropylamino group, and diisopropylamino group; a C2-Cio monoalkylaminomethyl group such as methylaminomethyl group, ethylaminomethyl group, propylaminomethyl group, isopropylaminomethyl group, butylaminomethyl group, isobutylaminomethy! group, tert-butylaminomethyl group, pentylaminomethyl group, isopentylaminomethyl group; a C3-Cu dialkylaminomethyl group such as dimethylaminomethyl group, diethylaminomethyl group, ethylmethylaminomethyl group, methylpropylamino- methyl group.

When RS and R6 combine to each other to form a spiro carbocyclic ring, together with the carbon atom to which R5 and RS bind, the carbocyclic ring may be, for example, cyclopropyl ring, cyclobutyl ring, cyclopentyl ring, cyclohexyl ring, : cycloheptyl ring, tetrahydrobenzocycloheptene ring, tetrahydronaphthalene ring, indane ring, bicyclo[4,2,0)octa-1,3,5-triene ring.

The Ci1-Cs alkyl group represented by R9, R10, R11 R12 or R13 may be, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, isopentyl group, neopentyl group, 1,1-dimethylpropyl group, n-hexyl group, isohexyl group, or a linear or branched heptyl group or octyl group.

The C3-Cs cycloalkyl group represented by R® or R10 may be, for example, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group or cyclooctyl group.

When the C1-Cs alkyl group or Cs-Cs cycloalkyl group represented by R® or R10 has one or more substituents, the group may have one or more substituents selected from, for example, the groups consisting of a halogen atom, C3-Cs cycloalkyl group, a benzene ring which may be substituted, a naphthalene ring which may be substituted, an optionally substituted heterocyclic ring having 1 to 4 hetero atoms selected from the group consisting of oxygen atom, sulfur atom and nitrogen atom, and having 5 to ring-constituting atoms in total.

When the benzene ring, the naphthalene ring or the heterocyclic ring represented by R? or R10 has one or more substituents, the ring may have one or more substituents selected form the group consisting of a C1-Cs alkyl group such as methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group, 1,1-dimethylpropyl group; Cs-Cs cycloalkyl group such as cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group; a Cs-Cs cycloalkyloxy group such as cyclopropyloxy group, cyclobutyloxy group, cyclopentyloxy group, cyclohexyloxy group; a C1-Cs alkoxy group such as methoxy group, ethoxy group, propoxy group, isopropoxy ] group, butoxy group, isobutoxy group, tert-butoxy group, pentyloxy group, and isopentyloxy group; a C4-C7 cycloalkylalkoxyl group such as cyclopropylmethoxy group, cyclopentylmethoxy group; a C1-Cs alkylthio group such as methylthio group, ethylthio group, propylthio group, butylthio group, and pentylthio group; a C1-Cs alkylsulfonyl group such as methanesulfonyl group, ethanesulfonyl group, propanesulfonyl group, butanesulfonyl group, and pentanesulfonyl group; a halogen atom such as fluorine atom, chlorine atom, bromine atom, and iodine atom; a C;-Cs halogenated alkyl group such as trifluoromethyl group; a C1-Cs halogenated alkoxyl group such as trifluoromethoxy group, 2,2,2-trifluoroethoxy group; hydroxyl group; cyano group; nitro group; formyl group; a C2-Cs alkylcarbonyl group such as acetyl group, propionyl group, butyryl group, and valeryl group; a benzene ring which may be substituted, a naphthalene ring which may be substituted, an optionally substituted heterocyclic ring having 1 to 4 hetero atoms selected from the group consisting of oxygen atom, sulfur atom and nitrogen atom, and having 5 to 10 ring-constituting atoms in total; a phenoxy group which may be substituted; a phenylamino group which may he substituted; an amine group; a Ci-Cs monoalkylamino group such as methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, tert-butylamino group, pentylamino group, and isopentylamino group; a C2-Cio dialkylamino group such as dimethylamino group, ethylmethylamino group, diethylamino group, methylpropylamino group, and diisopropylamino group; a C1-Cs monoalkylaminomethyl group such as methylaminomethyl group, ethylaminomethyl group, propylaminomethyl group, isopropylaminomethyl group, butylaminomethyl group, isobutylaminomethyl group, tert-butylaminomethyl group, pentylaminomethyl group, isopentylaminomethyl group; a C2-C1o dialkylaminomethyl group such as dimethylaminomethyl group, diethylaminomethyl group, ethylmethylaminomethyl group, methylpropylaminomethyl group; pyrrolidinylmethyl group; piperidinylmethyl group; morpholinomethyl group; piperazinylmethyl group; pyrrolylmethyl group; - imidazolylmethyl group; pyrazolylmethyl group; and triazolylmethyl group.

The heterocyclic ring having 1 to 4 hetero atoms selected from the group consisting of oxygen atom, sulfur atom, and nitrogen atom, and having § to 10 ring-constituting atoms in total represented by R? or R10 may be, for example, furan ring, dihydrofuran ring, tetrahydrofuran ring, pyran ring, dihydropyran ring, tetrahydropyran ring, benzofuran ring, dihydrobenzofuran, isobenzofuran ring, benzodioxol ring, chromene ring, chroman ring, isochroman ring, thiophene ring, ) benzothiophene ring, pyrrole ring, pyrroline ring, pyrrolidine ring, imidazole ring, imidazoline ring, imidazolidine ring, pyrazole ring, pyrazoline ring, pyrazolidine ring, triazole ring, tetrazole ring, pyridine ring, pyridine oxide ring, piperidine ring, pyrazine ring, piperazine ring, pyrimidine ring, pyridazine ring, indole ring, indoline ring, isoindole ring, isoindoline ring, indazole ring, benzimidazole ring, benzotriazole ring, tetrahydroisoquinoline ring, benzothiazolinone ring, benzoxazolinone ring, purine ring, quinolizine ring, quinoline ring, phthalazine ring, naphthyridine ring, quinoxaline ring, quinazoline ring, cinnoline ring, pteridine ring, oxazole ring, oxazolidine ring, isoxazole ring, isoxazolidine ring, oxadiazole ring, thiazole ring, benzothiazole ring, thiazylidine ring, isothiazole ring, isothiazolidine ring, benzodioxole ring, dioxane ring, benzodioxane ring, dithian ring, morpholine ring, thiomorpholine ring, or phthalimide ring.

When the benzene ring, the naphthalene ring, or the heterocyclic ring represented by R12 has one or more substituents, the ring may be substituted by one or more substituents selected from the groups consisting of halogen atoms, a C1-Cs alkyl group, a C3-Cs cycloalkyl group, a Cs-Cs cycloalkyloxy group, a C1-Cs alkoxy group, a C4-C7 cycloalkylalkoxy, a C1-Cs alkylthio group, a C1-Cs alkylsulfonyl group, a C1-Cs halogenated alkyl, and a benzene ring.

When the benzene ring, the naphthalene ring or the heterocyclic ring has one or more substituents, the substituent may further have one or more substituents selected from the group consisting of a C1-Cs alkyl group such as methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopenty! group, neopentyl group, 1,1-dimethylpropyl group; Cs-Ce cycloalkyl group such as cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group; a C3-Cs cycloalkyloxy group such as cyclopropyloxy group, ~ cyclobutyloxy group, cyclopentyloxy group, cyclohexyloxy group; a C1-Cs alkoxy group such as methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, tert-butoxy group, pentyloxy group, and isopentyloxy group; a C4-C cycloalkylalkoxy group such as cyclopropylmethoxy group, cyclopentylmethoxy group; a C1-Cs alkylthio group such as methylthio group, ethylthio group, propylthio group, butylthio group, and pentylthio group; a C1-Cs alkylsulfonyl group such as methanesulfonyl group, ethanesulfonyl group, propanesulfonyl group, butanesulfonyl group, and pentanesulfonyl group; a halogen atom such as fluorine atom, chlorine atom, bromine atom, and iodine atom; a C1-Cs halogenated alkyl group such as trifluoromethyl group; a C1-Cs halogenated alkoxy group such as triflnoromethoxy ~~ group, 2,2,2-trifluoroethoxy group; hydroxyl group; cyano group; nitro group; formyl group; a C2-Cs alkylcarbonyl group such as acetyl group, propionyl group, butyryl group, and valeryl group; amino group; a C1-Cs monoalkylamino group such as methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, tert-butylamine group, pentylamino group, and isopentylamino group; a C2-C1o dialkylamino group such as dimethylamino group, ethylmethylamino group, diethylamino group, methylpropylamino group, and diisopropylamino group; a C2-Ci0 monoalkylaminomethyl group such as methylaminomethyl group, ethylaminomethyl group, propylaminomethyl group, isopropylaminomethyl group, butylaminomethyl group, isobutylaminomethyl group, tert-butylaminomethyl group, pentylaminomethyl group, isopentylaminomethyl group; a C3-Cn dialkylaminomethyl group such as dimethylaminomethyl group, diethylaminomethyl group, ethylmethylaminomethyl group, methylpropylaminomethyl group and the like.

R! may preferably be a C1-Cs alkyl group, more preferably a methyl group.

R2 may preferably be a hydrogen atom.

R3 may preferably be a hydrogen atom.

R4 may preferably be a benzene ring which may be substituted.

R5 may preferably be a benzene ring or a naphthalene ring which may be substituted.

RS may preferably be a hydrogen atom.

R7 and R8 may preferably be a hydrogen atom or a C1-Cs alkyl group.

R9 or R10 may preferably be a benzene ring which may be substituted.

R10 may preferably be a heterocyclic ring having 1-4 hetero atoms selected oxygen atom, sulfur atom and nitrogen atom, and having total ring-constituting atoms of 5-10 which may be substituted. Particularly preferred R10 is a benzene ring which may be substituted, a 2,3-dihydroindole ring which may be substituted, or 3,4-dihydro-2H-quinoline ring which may be substituted.

Particularly preferred X is CHz or O.

The compounds represented by the aforementioned formula (I) may form a salt. Examples of the salt include, when an acidic group exists, salts of alkali metals and alkaline earth metals such as lithium, sodium, potassium, magnesium, and calcium; salts of ammonia and amines such as methylamine, dimethylamine, trimethylamine, dicyclohexylamine, tris(hydroxymethyl)aminomethane, :

N,N-bis(hydroxyethyl)piperazine, 2-amino-2-methyl-1-propanol, ethanolamine,

N-methylglucamine, and L-glucamine; or salts with basic amino acids such as lysine, 8 -hydroxylysine, and arginine. When a basic group exists, examples include salts with mineral 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.

In addition to the 3-substituted-4-pyrimidone derivatives represented by the aforementioned formula (I) and salts thereof, their solvates and hydrates also fall within the scope of the present invention. The 3-substituted-4-pyrimidone ’ derivatives represented by the aforementioned formula (I) may have one or more asymmetric carbon atoms. As for the stereochemistry of such asymmetric carbon atoms, they may independently be in either (R) and (S) configuration, and the pyrimidone derivative may exist as stereoisomers such as optical isomers, or diastereoisomers. Any stereoisomers of pure form, any mixtures of stereoisomers, racemates and the like fall within the scope of the present invention

Examples of preferred compounds of the present invention are shown in the table below. However, the scope of the present invention is not limited by the following compounds.

0. No.

N N

AN N

) Ll . NN cl ; AN

Nn o a ° * 0 H | [o}

N N

~~ = @! @

ZZ LZ

F NTS Br ; ~

EN Aue [o] i o

N

" 3

N N

F =z

OL | ISOS

A Br N N (o}

N” NT To Ho

Poa : . N N

N EN

=N pi!

F ; SN A128 Br n N

Ako AL [o} o H

N N

N ND

=N ® re JC. 1 \ = ro oe lo} o

N N x x ® (2) cl ol

A124 EN A130 NS ’ Ny 0 on [o] 3H o "

STRUCTURE STRUCTURE

No. No.

N N

(1) [1

ZN

A131 NT A136 NT

AN AA So

H | H | . o 0

N N

=» [1 [1 - > i» - POUR i ye "O00 h 0 °

N N

~ =N =N o Ns

RX

A133 | = Ne A138 | NS iL

LL ] yn

H I [o] o}

N No = [ ) (1) = F ZZ

F

A134 AO N EN A139 F ; SN yn 0 no 6) [o] | Fo) H

N N

3 F N _N aN _N

A135 N ~ A140 ° NTS

An 0 . 0 ~_° ° | [lo] H

Claims

1. A pyrimidone derivative represented by formula (I) or a salt thereof, or a . solvate thereof or a hydrate thereof: NA \ CN =|=/ I NOX (1) ] RN 0 ) R? wherein R! represents a C1-C12 alkyl group which may be substituted; R represents any one of groups represented by the following formulas (II) to v): RS R3 R2 REY NT 4 (Im R oN (In I < 0) R7 RS RO NT i. v XA (0) wherein R2 and R3 independently represent a hydrogen atom or a C1-Cs alkyl group; R¢ represents a benzene ring which may be substituted, a naphthalene ring which may be substituted, an indan ring which may be substituted, a tetrahydronaphthalene ring which may be substituted, or an optionally substituted heterocyclic ring having 1 to 4 hetero atoms selected from the group consisting of

\ Gg oxygen atom, sulfur atom and nitrogen atom, and having 5 to 10 ring-constituting atoms in total; RS represents a C1-Cs alkyl group which may be substituted, a Cs-Cs cycloalkyl group which may be substituted, a benzene ring which may be substituted, a naphthalene ring which may be substituted, an indan ring which may be substituted, a tetrahydronaphthalene ring which may be substituted, or an optionally substituted heterocyclic ring having 1 to 4 hetero atoms selected from the group consisting of oxygen atom, sulfur atom, and nitrogen atom, and having 5 to 10 ring-constituting atoms in total; RS represents a hydrogen atom, a C1-Cs alkyl group which may be substituted, a benzene ring which may be substituted; or R5 and R6 may bind to each other to form together with the carbon to which R? and RS are attached an optionally substituted spiro carbocyclic ring having 3 to 11 ring-constituting atoms in total; R7 and R8 independently represent a hydrogen atom or a C1-Cs alkyl group, or R7and R8 may combine to each other to form a C2-Ce alkylene group; R? and R10 represent a C1-Cs alkyl group which may be substituted, a Cs-Cs cycloalkyl group which may be substituted, a benzene ring which may be substituted, a naphthalene ring which may be substituted, an optionally substituted heterocyclic ring having 1 to 4 hetero atoms selected from the group consisting of oxygen atom, sulfur atom, and nitrogen atom, and having 5 to 10 ring-constituting atoms in total, or R9 and R!® represent -N(R11)(R12) wherein R!! represents a hydrogen atom, a C1-Cs : alkyl group; and R12 represents a C1-Cs alkyl group, a benzene ring which may be substituted, a naphthalene ring which may be substituted, or an optionally substituted heterocyclic ring having 1 to 4 hetero atoms selected from the group consisting of oxygen atom, sulfur atom, and nitrogen atom, and having 5 to 10 ring-constituting atoms in total;

and X represents CHa, O or NR13 wherein R13 represents a hydrogen atom or a C1-Cs alkyl group.

2. The pyrimidone derivative or the salt thereof, or the solvate thereof or the hydrate thereof according to claim 1, wherein R! is a methyl group.

3. The pyrimidone derivative or the salt thereof, or the solvate thereof or the hydrate thereof according to claim 1 or 2, wherein R is the group represented by formula (ID).

4. The pyrimidone derivative or the salt thereof, or the solvate thereof or the hydrate thereof according to claim 3, wherein each of R2 and R? is a hydrogen atom.

5. A pyrimidone derivative which is selected from the group consisting of: 3-methyl-2-(2-0x0-2-phenylethylamino)-6-pyrimidin-4-yl-3 H-pyrimidin-4-one; : 3-methyl-2-(2-0x0-2-(3-fluorophenyl)ethylamino)-6-pyrimidin-4-yl-3 H-pyrimidin-4-one; 3-methyl-2-(2-0x0-2-(4-fluorophenyl)ethylamino)-6-pyrimidin-4-yl-3 H-pyrimidin-4-one; 3-methyl-2-(2-020-2-(3-chlorophenyl)ethylamino)-6-pyrimidin-4-yl-3 H-pyrimidin-4- one and 3-methyl-2-(2-0x0-2-(3-methylphenyl)ethylamino)-6-pyrimidin-4-yl-3 H-pyrimidin-4- one or a salt thereof, or a solvate thereof or a hydrate thereof.

6. The pyrimidone derivative or the salt thereof, or the solvate thereof or the hydrate thereof according to claim 1 or 2, wherein R is the group represented by formula (III).

7. The pyrimidone derivative or the salts thereof, or the solvate thereof or the hydrate thereof according to claim 6, wherein RS is’ a hydrogen atom.

8. The pyrimidone derivative or the salts thereof, or the solvate thereof or the hydrate thereof according to claim 7, wherein each of R” and R%1s a hydrogen atom.

§. The pyrimidone derivative or the salts thereof, or the solvate thereof or the hydrate thereof according to claim 7, wherein each of R? and R¥ is a methyl group. 124 Amended Sheet — 4-04-2005

10. A pyrimidone derivative which is selected from the group consisting of: 2-(2-(4-Fluorophenyl)morpholin-4-yl}-3-methyl-6-pyrimidin-4-yl-3 H-pyrimidin-4-one; (9)-2-[2 -(4-Fluorophenyl)morpholin-4-yl}-3-methyl-6-pyrimidin-4-yl-3 H-pyrimidin-4- one; 2-[2-(2-Fluorophenyl)morpholin-4-yl]-3-methyl-6-pyrimidin-4-yl-3 H-pyrimidin-4-one; ( S)-2-[2-(2-Fluorophenyl)morpholin-4-yl}-3-methyl-6-pyrimidin-4 -yl-3 H-pyrimidin-4- one; 2-[2-(4-Chlorophenyl)morpholin-4-yl]-3-methyl-6-pyrimidin-4-yl-3 H-pyrimidin-4-one; 2-[2-(3-Chlorophenyl)morpholin-4-yl}-3-methyl-6-pyrimidin-4-yl-3 H-pyrimidin-4-one; 2-[2-(2-Chlorophenyl)morpholin-4-yl]-3-methyl-6-pyrimidin-4-yl-3 H-pyrimidin-4-one; (S)-2-[2-(2-C hlorophenyl)morpholin-4-yl]-3-methyl-6-pyrimidin-4-yl-3 H-pyrimidin-4- one; 2-[2-(4-Bromophenyl)morpholin-4-yl]-3 -methyl-6-pyrimidin-4-yl-3 H-pyrimidin-4-one; (S)-2-[2-(4-B romophenyl)morpholin-4-yl}-3-methyl-6-pyrimidin-4-yl-3 H-pyrimidin-4- one; 2-[2-(3-Bromophenyl)morpholin-4-y1}-3 -methyl-6-pyrimidin-4-yl-3 H-pyrimidin-4-one; (5)-2-[2-(3-Bromophenyl)morpholin-4-yl]-3-methyl-6-pyrimidin-4-yl-3 H-pyrimidin-4- one; 2-[2-( 2-Bromophenyl)morpholin-4-yl]-3-methyl-6-pyrimidin-4-yl-3 H-pyrimidin-4-one; 2-[2-( 4-Methylphenyl)morpholin-4-yl}-3-methyl-6-pyrimidin-4-yl-3 H-pyrimidin-4-one; 2-[2-(3-Methylphenyl)morpholin-4-yl}-3-methyl-6-pyrimidin-4-yl-3 H-pyrimidin-4-one; 2-[2-(2-Methylphenyl)morpholin-4-yl]-3-methyl-6-pyrimidin-4-yl-3 H-pyrimidin-4-one; (8)-2-[2-(2-Methylphenyl)morpholin-4-yl]-3-methyl-6-pyrimidin-4-yl-3 H-pyrimidin-4- one; 2-[2-(4-Cyanophenyl)morpholin-4-yl]-3 -methyl-6-pyrimidin-4-yl-3 H-pyrimidin-4-one; 2-[2-(3-Cyanophenyl)morpholin-4-yl}-3-methyl-6-pyrimidin-4-yl-3 H-pyrimidin-4-one; (S)-2-[2-(3-Cyanophenyl)morpholin-4-yl}-3-methyl-6-pyrimidin-4-yl-3 H-pyrimidin-4-

one; 2-[2-(2-Cyanophenyl)morpholin-4-yl]-3-methyl-6-pyrimidin-4-y1-3 H-pyrimidin-4-one; 2-{2-(4-Methoxyphenylmorpholin-4-yl]-3-methyl-6-pyrimidin-4-y1-3 H-pyrimidin-4- ) one; : ( 5)-2-[2-(4-Methoxyphenyl)morpholin-4-yl}-3-methyl-6-pyrimidin-4-yl-3 H-pyrimidin-4- ' one; 2-[2-(3-Methoxyphenyl)morpholin-4-yl}-3-methyl-6-pyrimidin-4-yl-3 H-pyrimidin-4- one; (5)-2-[2-(3-Methoxyphenyl)morpholin-4-yl]-3-methyl-6-pyrimidin-4-yl-3 H-pyrimidin-4- one 2-[2-(2-Methoxyphenyl)morpholin-4-yl]-3-methyl-6-pyrimidin-4-yl-3 H-pyrimidin-4- one; (S)-2-[2-(2-Methoxyphenyl)morpholin-4-yl}-3-methyl-6-pyrimidin-4-yl-3 H-pyrimidin-4- one; 2-[2-(2-Ethoxyphenyl)morpholin-4-yl]-3-methyl-6-pyrimidin-4-yl-3 H-pyrimidin-4-one; 2-[2-(2-Trifluoromethoxyphenyl)morpholin-4-yl}-3-methyl-6-pyrimidin-4-yl-3 H- pyrimidin-4-one; 2-[2-(5-Fluoro-2-methoxyphenyl)morpholin-4-yl]-3-methyl-6-pyrimidin-4-yl-3 H- pyrimidin-4-one; 2-[2-(4-Fluoro-2-methoxyphenyl)morpholin-4-y1)-3-methyl-6-pyrimidin-4-yl-3 H- pyrimidin-4-one; (S)-2-[2-(4-Fluoro-2-methoxyphenyl)morpholin-4-yl}-3-methyl-6-pyrimidin-4-yl-3 H- pyrimidin-4-one; 2-[2-(2 ,5-Dimethoxyphenyl)morpholin-4-yl}-3-methyl-6-pyrimidin-4-yl-3 H-pyrimidin- 4-one; (9)-2-[2-(2,5-Dimethoxyphenyl)morpholin-4-yl]-3-methyl-6-pyrimidin-4-yl-3 H- pyrimidin-4-one;

2-[2-(2-Chloro-4,5 -difluorophenyl)morpholin-4-yl)-3 -methyl-6-pyrimidin-4-yl-3 H- pyrimidin-4-one;

(S)-2-[2-(2-Chloro-4 ,5-difluorophenyl)morpholin-4-yl}-3-methyl-6-pyrimidin-4-yl-3 H- ) pyrimidin-4-one; ‘ 2-[2-(2-Bromo-4-fluorophenyl)morpholin-4-y1]-3-m ethyl-6-pyrimidin-4-yl-3 H- pyrimidin-4-one;

2-[2-(2,4-Difluorophenyl)morpholin-4-yl]-3-methyl-6-pyrimidin-4-yl-3 H-pyrimidin-4- one;

(5)-2-[2-(2,4-Difluorophenyl)morpholin-4-yl1}-3 -methyl-6-pyrimidin-4-yl-3 H-pyrimidin-

4-one;

2-[2< 2,6-Dimethoxyphenyl)morpholin-4-yl]-3-methyl-6-pyrimidin-4-yl-3 H-pyrimidin-

4-one; (5)-2-[2-(2,6-Dimethoxyphenyl)morpholin-4 -yl1-3-methyl-6-pyrimidin-4-yl-3 H-pyrimidi n-4-one; :

2-[2-(2,4-Dimethoxyphenyl)morpholin-4-yl}-3-methyl-6-pyrimidin-4-yl-3 H-pyrimidin- :

4-one;

(S)-2-[2-(2 ,+4-Dimethoxyphenyl)morpholin-4-y1]-3-methyl-6-pyrim idin-4-yl-3 H-

pyrimidin-4-one;

2-[2-(2,6-Dichloropheny! )morpholin-4-yl]-3-methyl-6-pyrimidin-4-yl-3 H-pyrimidin-4-

one;

(8)-2-[2-(2,6-Dichlorophenyl)morpholin-4-yl}-3-methyl-6-pyrimidin-4 yl-3 H-pyrimidin-

4-one;

'2-{2-(2,6-Difluorophenyl)morpholin-4-yl]-3-methyl-6-pyrimidin-4-yl-3 H-pyrimidin-4-

one;

(9-2-[2-(2,6-Difluorophenyl)morpholin-4-yl}-3-methyl-6-pyrimidin-4-yl-3 H-pyrimidin- ‘ 4-one; 2-[2-(2-Chloro-6-fluorophenyl)morpholin-4-yl]-3-methyl-6-pyrimidin-4-yl-3 H-pyrimidi n-4-one; (S)-2-[2-(2-Chloro-6-fluorophenyl)m orpholin-4-yl]-3-methyl-6-pyrimidin-4-yl-3 H- pyrimidin-4-one; 2-[2-(4-Fluoro-3-methoxyphenyl)morpholin-4-yl)-3-methyl-6-pyrimidin-4-yl-3 H- pyrimidin-4-one; * 2-[2-(5-C yano-2-methoxyphenyl)morpholin-4-yl]-3-methyl-6-pyrimidin-4-yl-3 H- pyrimidin-4-one; : ( S)-2-[2-(5-Cyano-2-methoxyphenyl)morpholin-4-yl]-3 -methyl-6-pyrimidin-4-yl-3 H- pyrimidin-4-one; 2-[2-(4-C yano-2-methoxyphenyl)morpholin-4-yl]-3-methyl-6-pyrimidin-4-yl-3 H- pyrimidin-4-one; (5)-2-(2-(4-Cyano-2-methoxyphenyl)morpholin-4-yll-3-methyl-6-pyrimidin-4-y1-3 H- pyrimidin-4-one; 2-[2-(2,4-Difluoro-6-m ethoxyphenyl)morpholin-4-y1]-3 -methyl-6-pyrimidin-4-yl-3 H- pyrimidin-4-one; (5)-2-[2-(2,4-Difluoro-6-methoxyphenyl)morpholin-4-y1}-3 -methyl-6-pyrimidin-4-yl-3 H- pyrimidin-4-one; 2-{2-(4-(Pyrrolidin-1-yl-methyl)phenyl)morpholino-4-yl]-3-methyl-6-pyrimidin-4-yl- 3 H-pyrimidin-4-one; (85)-2-[2-(4-(Pyrrolidin-1-yl-m ethyl)phenyl)morpholino-4-yl]-3-methyl-6-pyrimidin-4- yl-3 H-pyrimidin-4-one; 2-[2+( 1-Naphthyl)morpholin-4-yl]-3-methyl-6-pyrimidin-4-yl-3 H-pyrimidin-4-one; 2-[2-(2-N aphthylmorpholin-4-yl]-3-methyl-6-pyrimidin-4-yl-3 H-pyrimidin-4-one; (5)-2-[2-(2-Naphthyl)morpholin-4-yl]-3-methyl-6-pyrimidin-4-yl-3 H-pyrimidin-4-one; 2-{2-(2,3-dihydrobenzofuran-7-ylmorpholin-4-yl}-3-methyl-6-pyrimidin-4-y1-3 H- pyrimidin-4-one; (8)-2-[2-(2,3-dihydrobenzofuran-7-yl)morpholin-4-yl}-3-m ethyl-6-pyrimidin-4-yl-3 H-

pyrimidin-4-one; 2-(2-(Benzofuran-2-yl)morpholin-4-yl}-3-methyl-6-pyrimidin-4-yl-3 H-pyrimidin-4-one; and (5)-2-[2-(Benzofuran-2 -ylmorpholin-4-yl}-3-methyl-6-pyrimidin-4-yl-3 H-pyrimidin-4- ‘ one or a salt thereof, or a solvate thereof or a hydrate thereof.

11. The pyrimidone derivative or the salt thereof, or the solvate thereof or the hydrate thereof according to claim 1 or 2, wherein R is the group represented by formula (IV).

12. The pyrimidone derivative or the salts thereof, or the solvate thereof or the hydrate thereof according to claim 11, wherein R? is a benzene ring which may be substituted.

13. The pyrimidone derivative or the salts thereof, or the solvate thereof or the hydrate thereof according to claim 11, wherein X is CHa.

14. The pyrimidone derivative or the salts thereof, or the solvate thereof or the hydrate thereof according to claim 11, wherein X is O.

15. A pyrimidone derivative which is selected from the group consisting of: 2-[3-(4-Fluorobenzoyl)piperidin-1-yl]-3-methyl-6-pyrimidin-4-yl-3 H-pyrimidin-4-one; 2-(3-Benzoylpiperidin-1-yl)-3 -methyl-6-pyrimidin-4-yl-3 H-pyrimidin-4-one; 2-[3-(2-Methoxybenzoyl)piperidin-1-yl}-3-methyl-6-pyrimidin-4-yl-3 H-pyrimidin-4-one; 2-[3-(4-Methoxybenzoyl)piperidin-1-yl}-3-methyl-6-pyrimidin-4-yl-3 H-pyrimidin-4-one; 2-[2-(4-Fluorobenzoyl)morpholine-4-yl]-3-methyl-6-pyrimidin-4-yl-3 H-pyrimidin-4- one; 2-(2-Benzoylmorpholine-4-yl)-3-methyl-6-pyrimidin-4-yl-3 H-pyrimidin-4-one; 2-[2-(2-M ethoxybenzoyl)morpholine-4-yl}-3-methyl-6-pyrimidin-4-yl-3 H pyrimidin-4-one; and 2-[2-(4-Methoxybenzoyl)morpholine-4-yl]-3-methyl-6-pyrimidin-4-yl-3 E-

pyrimidin-4-one; : or a salt thereof, or a solvate thereof or a hydrate thereof.

16. The pyrimidone derivative or the salt thereof, or the solvate thereof or the hydrate thereof according to claim 1 or 2, wherein R is the group represented by formula (V).

17. The pyrimidone derivative or the salts thereof, or the solvate thereof or the hydrate thereof according to claim 16, wherein R10 is a benzene ring which may be substituted.

18. The pyrimidone derivative or the salts thereof, or the solvate thereof or the hydrate thereof according to claim 16, wherein R1° is a heterocyclic ring having 1 to 4 hetero atoms selected oxygen atom, sulfur atom and nitrogen atom, and having total ring-constituting atoms of § te 10 which may be substituted,

19. A pyrimidone derivative which is selected from the group consisting of: 2-[4-(4-Chlorobenzoyl)piperidin-1-yl]-3-methyl-6-pyrimidin-4-yl-3H-pyrimidin-4-one; or a salt thereof, or a solvate thereof or a hydrate thereof.

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

21. A tau protein kinase 1 inhibitor selected from the group consisting of the pyrimidone derivative represented by formula (I) and a salt thereof, and a solvate thereof and a hydrate thereof according to claim 1.

22. The medicament according to claim 20 which is used for preventive and/or therapeutic treatment of a disease caused by tau protein kinase 1 hyperactivity.

23. The medicament according to claim 20 which is used for preventive and/or therapeutic treatment of a neurodegenerative disease.

24. The medicament according to claim 23, wherein the disease is selected from the group consisting of Alzheimer disease, ischemic cerebrovascular accidents,

Down syndrome, cerebral! bleeding due to cerebral amyloid angiopathy, progressive supranuclear palsy, subacute sclerosing panencephalitic parkinsonism, postencephalitic parkinsonism, pugilistic encephalitis, Guam parkinsonism-dementia complex, Lewy body disease, Picks disease, corticobasal degeneration, frontotemporal dementia, vascular dementia, traumatic injuries, brain and spinal cord trauma, peripheral neuropathies, retinopathies and glaucoma.

25. The medicament according to claim 20, which is used for preventive and/or therapeutic treatment of a disease selected from the group consisting of non- insulin dependent diabetes, obesity, manic depressive illness, schizophrenia, alopecia, breast cancer, non-small cell lung carcinoma, thyroid cancer, T or B-cell leukemia, and a virus-induced tumor.

26. A pyrimidone derivative represented by formula (VI) or a salt thereof, or a solvate thereof or a hydrate thereof: : oo PAR oh ={=/ vn NT A HS N 0 = wherein R! represents a Ci-Ci2 alkyl group which may be substituted.

27. A pyrimidone derivative represented by formula (VII) or a salt thereof, or a solvate thereof or a hydrate thereof: 131 Amended Sheet — 4-04-2005

BP

\.# = ARR { N =|=/ : Ji NT vin . d cl Ax 0

R' . wherein R! represents a C1-Ciz alkyl group which may be substituted. J 1"