MXPA05010323A - 2, 3, 6-trisubstituted-4-pyrimidone derivatives - Google Patents

Abstract

A pyrimidone derivative having tau protein kinase 1 inhibitory activity which is represented by formula (I) or a salt thereof, or a solvate thereof or a hydrate thereof;useful for prventive and/or therapeutic treatment of diseass such as neurodegenerative diseases (e.g. Alzheimer disease);wherein Q represents CH or nitrogen atom;R represents a C1-C12 alkyl group;the ring of Formula (I):represents piperazine ring or piperidine ring;each X independently represents a C1-C8 alkyl group, an optionally partially hydrogenated C6-C10 aryl ring, an indan ring or the like;m represents an integer of 1 to 3;each Y independently represents a halogen atom, a hydroxy group, a cyano group, a C1-C6 alkyl group or the like;n represents an integer of 0 to 8;when X and Y or two Y groups are attached on the same carbon atom, they may combine to each other to form a C2-C6 alkylene group.

Description

DESCRIPTIVE MEMORY DERIVATIVES OF 4-PYRIMIDONE 2, 3, 6-TRISUSTITUIDE Technical Field The present invention relates to compounds that are useful as an active ingredient of a medicament for the preventive and / or therapeutic treatment of diseases caused mainly by the abnormal activity of the drug. tau protein kinase 1, such as neurodegenerative diseases (for example Alzheimer's disease).

Art Background Alzheimer's disease is a progressive senile dementia, in which a marked cerebral cortical atrophy is observed due to the degeneration of nerve cells and the decrease in the number of nerve cells. Pathologically, numerous senile plaques and neurofibrillary tangles are observed in the brain. The number of patients has increased with the increase of the elderly population, and the disease gives rise to a serious social problem. Although different theories have been proposed, a cause of the disease has not yet been elucidated. The early resolution of the cause has been desired.

It has been known that the level of appearance of two pathological changes characteristic of Alzheimer's disease correlates well with the level of intellectual dysfunction. As a result, research has been conducted since the early 1980s to reveal the cause of the disease through investigations at the molecular level of the components of the two pathological changes. Senile plaques accumulate extracellularly, and the ß amyloid protein has been elucidated as the main component (abbreviated as "A ß" hereinafter in the specification: Biochem Biophys, Res. Común., 120, 855 (1984); EMBO J., 4, 2757 (1985); Proc. Nati Acad. Sci. USA, 82, 4245 (1985)). In the other pathological change, ie, the neurofibrillary tangles, a double helical filamentous substance called helical filament in pair (abbreviated as WPHF "hereafter in the descriptive memory) accumulate intracellularly, and the tau protein, which is a class of protein associated with microtubules specific to the brain, it has been revealed as its main component (Proc. Nati, Acad. Sci. USA, 85, 4506 (1988), Neurona, 1, 827 (1988)).

Furthermore, on the basis of genetic research, presenilins 1 and 2 were found as the genes that cause Alzheimer's disease in the family (Nature, 375, 754 (1995), Science, 269, 973 (1995); 376, 775 (1995)), and it has been revealed that the presence of mutants of presenilins 1 and 2 promotes the secretion of Aβ (Neurona, 17, 1005 (1996); Proc. Nati. Acad. Sci. USA, 94, 2025 (1997)). From these results, it is considered that, in Alzheimer's disease, Aß accumulates and agglomerates abnormally due to a certain reason, which is related to the formation of HPF to produce the death of nerve cells. It is also expected that the flow of glutamic acid and the activation of the glutamate receptor that responds to the flow may possibly be important factors in an early process of nerve cell death caused by ischemic serebrovascular events (Sai-shin Igaku [Most Current Medicine] , 49, 1506 (1994)).

It has been reported that the cainic acid treatment that stimulates the AMPA receptor, one of the glutamate receptors, increases the mRNA of the amyloid precursor protein (abbreviated as "APP" hereinafter in the specification) as a precursor of Aβ (Society for Neuroscientific Abstracts, 17, 1445, (1991)), and also promotes APP metabolism (The Jorunal of Neuroscience, 10, 2400 (1990)). Consequently, it has been strongly suggested that the accumulation of Aβ is involved in cell death due to ischemic cerebrovascular disorders.

Other diseases in which abnormal accumulation and agglomeration of Aß was observed include, for example, Down syndrome, cerebral bleeding due to solitary cerebral amyloid angiopathy, Lewi's body disease (Shin-kei Shinpo [Advancement of Nerves], 34 343 (190); Tanpaku-shitu Kaku-san Koso [Protein, Nucleic Acid, Enzyme], 41, 1476 (1996)) and the like. Moreover, as diseases presenting neurofibrillary tangles due to the accumulation of PHF, some examples include progressive supranuclear palsy, subacute sclerosing panelenic 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)).

Tau protein is generally composed of a group of related proteins that form several bands at molecular weights of 48-65 kDa in SDS-polyacrylamide gel electrophoresis and promotes the formation of microtubules. It has been verified that the tau protein incorporated in the PHF in the brain suffering from Alzheimer's disease is abnormally phosphorylated compared to the usual tau protein (J. Biochem., 99, 1807 (1986); Proc. Nati. Acad. Sci. USA, 83, 4913 (1986)). An enzyme that catalyzes abnormal phosphorylation has been isolated. The protein was designated tau protein kinase 1 (abbreviated as "TPKl" hereinafter in the specification), and its physicochemical properties have been elucidated (Seikagaku [Biochemistry], 64, 308 (1992); J. Biol. Chem., 267 , 10897 (1992)). Moreover, the rat TPKl cDNA was cloned from a cDNA library of the rat cerebral cortex based on a partial amino acid sequence of TPKl, and its nucleotide sequence was determined and an amino acid sequence was deduced (Patent Publication). Japanese Unexamined [Kokai] No. 6-239893 / 1994). As a result, it has been revealed that the main structure of the rat TPK1 corresponds to that of the enzyme called rat GSK-3β (glycogen synthase 3β, FEBS Lett., 325, 167 (1993)).

It has been reported that Aß, the main component of senile plaques, is neurotoxic (Science, 250, 279 (1990)). However, different theories have been proposed as to why Aß produces cell death, and no real theory has yet been established. Takashima et al observed that cell death was produced by treatment with Aβ from the main hippocampus culture system of fetal rats, and then found that the activity of TPK1 was increased by treatment with Aβ and cell death by A ß was inhibited by the contradictory of TPKl (Proc. Nati, Acad. Sci. USA, 90, 7789 (1993), Japanese Unexamined Patent Publication [Kokai] No. 6-329551 / 1994).

In view of the foregoing, compounds that inhibit the activity of TPKl can possibly eliminate the neurotoxicity of Aβ and the formation of PHF and inhibit the death of nerve cells in Alzheimer's disease, thus stopping or deferring the progress of the disease. The compounds can also possibly be used as a medicament for the therapeutic treatment of ischemic cerebrovascular disorder, Down syndrome, cerebral amyloid angiopathy, cerebral bleeding due to Lewy body disease and the like by eliminating A ß cytotoxicity. Moreover, the compounds can possibly be used as a medicament for the therapeutic treatment of neurodegenerative diseases such as progressive supranuclear palsy, subacute sclerosing panelenic sclerosing parkinsonism, postencephalitic parkinsonism, pugilistic encephalitis, Guam parkinsonism-dementia complex, Lewy body disease, disease of Pick, cortisobasal degeneration, frontotemporal dementia, vascular dementia, acute attack and traumatic injuries, brain and spinal cord trauma, peripheral neuropathies1, retinopathies and glaucoma; non-insulin dependent diabetes (such as type II diabetes), and obesity, manic depressive illness, schizophrenia, alopecia, cancers such as breast cancer, non-small cell lung carcinoma, thyroid cancer, T or B cell leukemia and various tumors induced by viruses.

As compounds structurally similar to the compounds of the present invention represented by the formula (I) described below, the compounds represented by the following Formula (A) are known: wherein R represents the 2, 6-dichlorobenzyl group, the 2- (2-chlorophenyl) ethylamino group, the 3-phenylpropylamino group, or the 1-methyl-3-phenylpro-ylamino group (W098 / 24782). The compounds represented by the formula (A) are characterized in that they have the 4-fluorophenyl group in the 5-position of the pyrimidine ring and a hydroxy group in the 4-position., and are not within the scope of the present invention. Moreover, the main pharmacological activity of the compounds represented by the formula (A) is the anti-inflammatory effect, while the compounds of the present invention represented by the formula (I) are useful as an inhibitor of the TPKl or a drug for the therapeutic treatment of neurodegenerative diseases, and consequently, their pharmacological activities are totally different from each other.

Patent Document 1: WO 00/18758 Patent Document 2: WO 01/70728 Patent Document 3: WO 01/70729 Description of the invention An object of the present invention is to provide useful compounds as an active ingredient of a medicament for the preventive and / or therapeutic treatment of diseases such as Alzheimer's disease. More specifically, the aim is to provide novel useful compounds as an active ingredient of a medicament that allows the radical prevention and / or treatment of neurodegenerative diseases such as Alzheimer's disease by inhibiting the activity of TPKl to eliminate neurotoxicity of A ß and the formation of PHF and the inhibition of nerve cell death.

To achieve the above objective, the inventors of the present invention performed evaluations of different compounds that have inhibitory activity against the phosphorylation of TPKl. As a result, they found that the compounds represented by the following formula (I) had the desired activity and were useful as an active ingredient of a medicament for the preventive and / or therapeutic treatment of the aforementioned diseases. The present invention was achieved on the basis of these findings.

The present invention then provides 3-substituted 4-pyrimidone derivatives represented by Formula (I) or salts thereof, or solvates thereof or hydrates thereof: wherein Q represents CH or a nitrogen atom; R represents an alkyl group of C? -C? 2 which can be substituted; The ring of: represents a piperazine ring or a piperidine ring; each X independently represents X1-X2, wherein X1 represents an oxo group; an alkyl group of C? -C8 which can be substituted; a C3-C8 cycloalkyl group that can be substituted; a partially hydrogenated C6-C? aryl ring in an optional form that can be substituted; an indane ring that can be substituted; an optionally substituted heterocyclic ring having from 1 to 4 heteroatoms which are selected from the group consisting of an oxygen atom, a sulfur atom, and a nitrogen atom, and having from 5 to 10 atoms constituting the ring in total; an aralkyloxy group; a group represented -N (Ra) (Rb) wherein Ra and Rb are the same or different and each is hydrogen, an alkyl group of C? -C4 that can be substituted, an aralkyl group that can be substituted, a cycloalkyl group of C3-C8 which may be substituted, an aryl group which may be substituted, a C 1 -C 7 alkylcarbonyl group which may be substituted, a C 3 -C 8 cycloalkylcarbonyl group which may be substituted, an aralkylcarbonyl group which may be substituted, a a C6-C10 arylcarbonyl group which may be substituted, an alkylsulfonyl group of L-CS which may be substituted, a C3-C8 cycloalkylsulfonyl group which may be substituted, an aralkylsulfonyl group which may be substituted, a C6-C10 arylsulfonyl group which can be substituted, an alkyloxycarbonyl group of L-CS which can be substituted, a C3-C8 cycloalkyloxycarbonyl group which can be substituted, an aralkyloxycarbonyl group which can be substituted, a C6-C6 aryloxycarbonyl group which can be substituted, if it is substituted, aminocarbonyl, a C-C8 N-alkylaminocarbonyl group which can be substituted, a N, N'-dialkylaminocarbonyl group of C? -C8 which can be substituted, an N-alkyl group of C? -C8- N'-C3-C8-cycloalkylaminocarbonyl which may be substituted, a C-C8-N'-aralkylaminocarbonyl N-alkyl group which may be substituted, a C-C8-N'-arylaminocarbonyl C6-alkyl group -C? 0 which can be substituted, a C3-C8 cycloalkylaminocarbonyl group which can be substituted, a C3-C8 N, N '-dicycloalkylaminocarbonyl group which can be substituted, a C3-C8-N'N-cycloalkyl group -aralkylaminocarbonyl which can be substituted, a N-cycloalkyl group of C3-C8-N'-arylaminocarbonyl of C6-C10 which can be substituted, an aralkylaminocarbonyl group which can be substituted, a N, N'-diaralkylaminocarbonyl group which can be substituted, a C6-C? N-aralkyl-N'-arylaminocarbonyl group which can be substituted, a C6-C10 arylaminocarbonyl group which may be substituted, a N, N'-diarylaminocarbonyl group of C6-C? or which may be substituted, or an optionally substituted heterocyclic ring having from 1 to 4 heteroatoms which are selected from the group consisting of an oxygen atom, a atom of sulfur and a nitrogen atom, and that has from 5 to 10 atoms that constitute the ring in total; or Ra and Rb together with the adjacent nitrogen atom form a 4- to 7-membered heterocyclic ring which may further contain from 1 to 4 groups which are selected from an oxygen atom, a sulfur atom, N-Rc (wherein Rc represents a hydrogen atom, a C 1 -C 4 alkyl group that can be substituted, an aralkyl group that can be substituted, a C 3 -C 8 cycloalkyl group that can be substituted or an aryl group that can be substituted, an alkylcarbonyl group of Cx-Cs which can be substituted, a C3-C8 cycloalkylcarbonyl group which can be substituted, an aralkylcarbonyl group which can be substituted, a C6-C10 arylcarbonyl group which can be substituted, an alkylsulfonyl group of C? -C8 which it can be substituted, a C3-C8 cycloalkylsulfonyl group which can be substituted, an aralkylsulfonyl group which can be substituted, a C6-C6-alkylsulfonyl group which can be substituted, a C? -C8 alkyloxycarbonyl group which can be substituted , a C3-C8 cycloalkyloxycarbonyl group which may be substituted, an aralkyloxycarbonyl group which may be substituted, a C6-C10 aryloxycarbonyl group which may be substituted, aminocarbonyl, an N-alkylaminocarbonyl group of L-CS which may be substituted, a N group , N'-dialkylaminocarbonyl of Ci-C8 which may be substituted, an N-alkyl group of C3-C8-Cs-N'-cycloalkylaminocarbonyl which may be substituted, an N-alkyl group of Cx-Cs-N '- aralkylaminocarbonyl which can be substituted, a C-C8-N'-arylaminocarbonyl Cs-Cio alkyl group which can be substituted, a C3-C8 cycloalkylaminocarbonyl group which can be substituted, a N, N '-dicycloalkylaminocarbonyl group of C3-C8 which may be substituted, a N-cycloalkyl group of C3-C8-N '-aralkylaminocarbonyl which may be substituted, a C3-C8-N'-arylaminocarbonyl C6-Cao N-cycloalkyl group which may be substituted , an aralkylaminocarbonyl group that can be substituted, a group N, N '-di aralkylaminocarbonyl which can be substituted, a N-aralkyl-N'-arylaminocarbonyl group of C 6 -C 0 which can be substituted, a C 6 -C 0 arylaminocarbonyl group which can be substituted, a N, N'-diarylaminocarbonyl group of C 1 -C 0 which can be substituted, or an optionally substituted heterocyclic ring having from 1 to 4 heteroatoms which are selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom, and having from 5 to 10 atoms constituting the ring in total), a carbonyl group, a sulfinyl group or a sulfonyl group in the ring and said 4- to 7-membered heterocyclic ring can optionally be fused with an aryl group which can be substituted; X2 represents a bond, a carbonyl group, a sulfinyl group, a sulfonyl group, an oxygen atom, a sulfur atom, an alkylene group of C? -C4 that can be substituted or N-Rd (Rd represents a hydrogen atom , an alkyl group of C? -C4 that can be substituted, an aralkyl group that can be substituted, a C3-C8 cycloalkyl group that can be substituted or an aryl group that can be substituted, an alkylcarbonyl group of C? -C8 which may be substituted, a C3-C8 cycloalkylcarbonyl group which may be substituted, an aralkylcarbonyl group which may be substituted, a C6-C6 arylcarbonyl group or which may be substituted, an alkylsulfonyl group of C? -C8 which may be substituted, a C3-C8 cycloalkylsulfonyl group which may be substituted, an aralkylsulfonyl group which may be substituted, a C6-C ar arylsulfonyl group or which may be substituted, a C?-C8 alkyloxycarbonyl group which may be substituted, a Cycloalkyloxycarbonyl group of C3 -C8 which can be substituted, an aralkyloxycarbonyl group which can be substituted, a C6-C6-aryloxycarbonyl group which can be substituted, aminocarbonyl, a C-C8 N-alkylaminocarbonyl group which can be substituted, a N group, N'-dialkylaminocarbonyl of Ci-C8 which can be substituted, a C-C8-N'-cycloalkylaminocarbonyl C3-C8 alkyl group which can be substituted, a C-C8-N'-aralkylaminocarbonyl N-alkyl group which can be substituted, an N-alkyl group of Ca-C8-N'-arylaminocarbonyl of Ce-Cxo which may be substituted, a C3-C8 cycloalkylaminocarbonyl group which may be substituted, a C3-C8 N, N '-dicycloalkylaminocarbonyl group which may be substituted, a N group -C3-C8-N'-aralkylaminocarbonyl cycloalkyl which can be substituted, a N-cycloalkyl group of C3-C8-N'-arylaminocarbonyl of C6-C10 which can be substituted, an aralkylaminocarbonyl group which can be substituted, a group N , N'-diaralkylaminocarbonyl which may be substituted, a C6-C10 N-aralkyl-N'-arylaminocarbonyl group which may be substituted, a C6-C6 arylaminocarbonyl group which may be substituted, a group N, N '- C6-C-diarylaminocarbonyl or which can be substituted, or an optionally substituted heterocyclic ring having from 1 to 4 heteroatoms that are selected from the group consisting of an oxygen atom, a sulfur atom, and a nitrogen atom, and having from 5 to 10 atoms constituting the ring in total); m represents an integer from 1 to 3; each Y independently represents a halogen atom, a hydroxy group, a cyano group, Y1-Y3 wherein Y1 represents a C? -C8 alkyl group which can be substituted, a C3-C8 cycloalkyl group which can be substituted or a C6-C10 aryl ring that can be substituted; Y3 represents a carbonyl group, a sulfinyl group, a sulfonyl group, an oxygen atom, a sulfur atom, an alkylene group of Cx-C that can be substituted or N-Re (Re represents a hydrogen atom, an alkyl group of C? -C which may be substituted, an aralkyl group which may be substituted, a C3-C8 cycloalguyl group which may be substituted or an aryl group which may be substituted, a C? -C8 alkylcarbonyl group which may be substituted , a C3-C8 cycloalkylcarbonyl group that can be substituted, an aralkylcarbonyl group that can be substituted, a C6-C6-arylcarbonyl group that can be substituted, a C? -C8 alkylsulfonyl group that can be substituted, a group C6-Cao cycloalkylsulphonyl which can be substituted, an aralkylsulphonyl group which can be substituted, a C6-C?-arylsulfonyl group which can be substituted, a C?-C8 alkyloxycarbonyl group which can be substituted, a C3 cycloalkyloxycarboonyl group -C8 that can to be substituted, an aralkyloxycarbonyl group which can be substituted, a C 6 -C 0 aryloxycarbonyl group which can be substituted, aminocarbonyl, an N-alkylaminocarbonyl group of L-CS which can be substituted, a N, N'-dialkylaminocarbonyl group of Ci-C8 which can be substituted, a C-C8-N'-cycloalkylaminocarbonyl C3-C8 alkyl group which can be substituted, an N-alkyl group of L-CS-N 'aralkylaminocarbonyl which can be substituted, a C-C8-N'-arylaminocarbonyl group of C6-C? or which can be substituted, a C3-C8 cycloalkyminosarbonyl group which can be substituted, a C3-C8 N, N '-dicycloalkylaminocarbonyl group which may be substituted, a N-cycloalkyl group of C3-C8-N'-aralkylaminosarbonyl which may be substituted, a N-cycloalkyl group of C3-C8-N'-arylaminocarbonyl of C6-C10 which may be substituted, an aralkylaminocarbonyl group which can be substituted, a N, N'-diaralkylaminocarbonyl group which can be substituted, a N-aralkyl-N'-arylaminocarbonyl group of C 6 -C 0 which can be substituted, a C 6 -C 0 arylaminocarbonyl group which can be substituted, a N, N '-arylaminocarbonyl group of C 6 -C 6 or to be substituted, or an optionally substituted heterocyclic ring having from 1 to 4 heteroatoms which are selected from the group consisting of an oxygen atom, a sulfur atom, and a nitrogen atom, and having from 5 to 10 atoms constituting the ring in total); n represents an integer from 0 to 8; when X and Y or two groups Y are joined in the same carbon atom, they can be combined with one another to form an alkylene group of C2-Ce; and when m is 1, n is 0, and X is Xx-C0-, (1) X does not bind to the 3-position of the unsubstituted 1-piperazinyl group or does not bind to the 3-position of a 4-alkyl group - 1-piperazinyl; or (2) X does not bind to the 3-position or the 4-position of the unsubstituted 1-piperidinyl group.

According to another aspect of the present invention, there is provided a medicament comprising as active ingredient a substance which is selected from the group consisting of the 3-substituted 4-pyrimidone derivatives represented by the formula (I) and the physiologically acceptable salts of they, and the solvates of them and the hydrates of them. As preferred embodiments of the medicament, said medicament is provided which is used for the preventive and / or therapeutic treatment of diseases produced by the hyperactivity of tau protein kinase 1 and the aforementioned medicament which is used for the preventive and / or therapeutic treatment of neurodegenerative diseases.

As other preferred embodiments of the present invention, the aforementioned medicament is provided wherein the diseases are selected from the group consisting of Alzheimer's disease, ischemic strokes, Down syndrome, cerebral bleeding due to cerebral amyloid angiopathy, progressive supranuclear palsy, parkinsonism subacute sclerosing panencephalitis, postencephalitic parkinsonism, pugilistic encephalitis, Guam parkinsonism-dementia complex, Lewy body disease, Pick disease, corticobasal degeneration and frontotemporal dementia, vascular dementia, acute attack and traumatic injuries, brain and spinal cord trauma, peripheral neuropathies, retinopathies and glaucoma, non-insulin dependent diabetes (such as type II diabetes) and obesity, manic depressive illness, schizophrenia, alopecia, cancers such as breast cancer, non-small cell lung carcinoma, thyroid cancer, leukemia T or B cells, and various cancers induced by viruses and the aforementioned medicament in the form of a pharmaceutical composition containing the preceding substance as an active ingredient together with one or more pharmaceutical additives.

The present invention further provides a tau protein kinase 1 inhibitor comprising as active ingredient a substance selected from the group consisting of 3-substituted 4-pyrimidone derivatives of the formula (I) and the salts thereof, and the solvates of them and their hydrates.

According to other aspects of the present invention, a method is provided for the preventive and / or therapeutic treatment of diseases produced by the hyperactivity of tau protein kinase 1, which comprises the step of administering to a patient a preventive amount and / or Therapeutically effective of a substance selected from the group consisting of the 3-substituted 4-pyrimidone derivatives of the formula (I) and the physiologically acceptable salts thereof, and the solvates thereof and the hydrates thereof; and a use of a substance selected from the group consisting of the 3-substituted 4-pyrimidone derivatives of the formula (I) and the physiologically acceptable salts thereof and the solvates thereof and the hydrates thereof for the manufacture of the medication mentioned.

Best Way to Carry Out the Invention In the present descriptive memory, each group has the following definitions: The alkyl group used herein may be linear or branched.

The C-C12 alkyl group represented by R can be, for example, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, an n-pentyl group, an isopentyl group, a neopentyl group, a 1, 1-dimethylpropyl group, an n-hexyl group, an isohexyl group, or a linear or branched heptyl group, an octyl group, a nonyl group, a decyl group, an undecyl group or a dodecyl group. R particularly preferred is the methyl group.

In the specification, when a functional group is defined as "that can be substituted" or "optionally substituted", the number of substituents as well as their types and substitution positions are not particularly limited, and when two or more substituents are present, They can be the same or different.

When the C? -C12 alkyl group represented by R has one or more substituents, the alkyl group may have one or more substituents which are selected from, for example, the groups formed by a C3-C8 cycloalkyl group such as a group cyclopropyl, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group; an alkoxy group of Ca-C5 such as a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a tert-butoxy group; an alkylamino group of C? -C3 or a dialkylamino group of C2-C6; a C6-C10 aryl group such as a phenyl group, a 1-naphthyl group, and a 2-naphthyl group.

The C? -C8 alkyl group can be, for example, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a group tert-butyl, an n-pentyl group, an isopentyl group, a neopentyl group, a 1, 1-dimethylpropyl group, an n-hexyl group, an isohexyl group, or a linear or branched heptyl group or an octyl group.

The C?-C 4 alkyl group can be for example a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group or a tert-butyl group. butyl.

The C3-C8 cycloalkyl group can be for example a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group or a cyclooctyl group.

The partially hydrogenated C6-C10 aryl ring may optionally be, for example, a benzene ring, a naphthalene ring, an indane ring or a 1,2,3,4-tetrahydronaphthalene ring.

The heterocyclic ring having 1 to 4 heteroatoms which are selected from the group consisting of an oxygen atom, a sulfur atom, and a nitrogen atom, and having from 5 to 10 atoms constituting the ring in total may be, for example, a furan ring, a dihydrofuran ring, a tetrahydrofuran ring, a pyran ring, a dihydropyran ring, a tetrahydropyran ring, a benzofuran ring, a dihydrobenzofuran ring, an isobenzofuran ring, a ring of benzodioxole, a chromene ring, a chroman ring, an isochroman ring, a thiophene ring, a benzothiophene ring, a pyrrole ring, a pyrroline ring, a pyrrolidine ring, a 2-oxopyrrolidine ring, a imidazole ring, an imidazoline ring, a pyrazole ring, a pyrazoline ring, a pyrazolidine ring, a triazole ring, a tetrazole ring, a pyridine ring, a piperidine ring, a 4-oxopiperidine ring , a pyrazine ring, a piperazine ring, a homopiperazine ring, a pyrimidine ring, a pyridazine ring, an indole ring, an indoline ring, an isoindol ring, an isoindoline ring, an indazole ring, an benzimidazole ring, a benzotriazole ring, a tetrahydroisoquinoline ring, a benzothiazolinone ring, a benzoxazolinone ring, a purine ring, a quinolizine ring, a quinoline ring, a phthalazine ring, a naphthyridine ring, a quinoxaline ring, a quinazoline ring, a cinolin ring, a pteridine ring, an oxazole ring, an oxazolidine ring, an isoxazole ring, an isoxazolidine ring, an oxadiazole ring, a thiazole ring, a benzothiazole ring, a thiazilidine ring, an isothiazole ring, an isothiazolidine ring, a benzodioxole ring, a dioxane ring, a benzodioxane ring, a dithiano ring, a morpholine ring, a thiomorph ring ina, or a phthalimide ring. The aralkyl group can be for example a benzyl group, a 2-phenylethyl group, a 3-phenylpropyl group or a 4-phenylbutyl group.

The alkylene group of C? -C4 can be, for example, methylene, ethylene, trimethylene or tetramethylene.

The 4- to 7-membered heterocyclic ring may further contain from 1 to 4 groups which may be, for example, pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, homopiperazine, 2-oxopyrrolidine, pyrrole, imidazoline, imidazole, pyrazole, pyrroline, pyrrolidine. , imidazolidine, imidazolone, succinimide or glutarimide.

The C6-C10 aryl ring can be, for example, a benzene ring or a naphthalene ring, and the aryl group or the C6-C10 aryl group can be for example a phenyl group or a naphthyl group.

When the ring represented by X or X1 has one or more substituents, the ring may have one or more substituents that are selected from the group consisting of a C3-C5 alkyl group such as a methyl group, an ethyl group, a propyl group , an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, an isopentyl group, a neopentyl group, a 1,1-dimethylpropyl group, a C3 cycloalkyl group -C6 such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a C3-C6 cycloalkyl group of C? -C4 alkyl such as cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl; a hydroxyalkyl group of C? -C4 such as hydroxymethyl, hydroxyethyl, hydroxypropyl; a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom; a halogenated C1-C5 alkyl group such as a trifluoromethyl group; a hydroxyl group; a cyano group; a nitro group; a formyl group; a benzene ring that can be substituted; a naphthalene ring that can be substituted; an optionally substituted heterocyclic ring having from 1 to 4 heteroatoms which are selected from the group consisting of oxygen atom, sulfur atom and nitrogen atom and having from 5 to 10 atoms constituting the ring in total (the same as defined above) ); an amino group; a N-cycloalkyl group of C3-C6-N-alkylaminoalkyl of C? -C4 wherein said alkyl group of C-? - C4 can be substituted by a hydroxy group or a C? -C4 alkoxy group which can be substituted, a N-cyclopropyl-N-methylaminomethyl group, an N-cislohexyl-N-methylaminomethyl group; a C 1 -C 5 monoalkylaminomethyl group such as a methylaminomethyl group, an ethylaminomethyl group, a propylaminomethyl group, an isopropylaminomethyl group, a butylaminomethyl group, an isobutylaminomethyl group, a tert-butylaminomethyl group, a pentylaminomethyl group, an isopentylaminomethyl group; a dialkylminomethyl group of C2-C? 0 such as a dimethylaminomethyl group, a diethylaminomethyl group, an ethylmethylaminomethyl group, a methylpropylaminomethyl group; a pyrrolidinylmethyl group; a piperidinylmethyl group; a morpholinomethyl group; a piperazinyl methyl group; a pyrrolylmethyl group; an imidazolylmethyl group; a pyrazolylmethyl group; a triazolylmethyl group; and a group of the formula -E-Rf wherein E represents O, S, SO, S02, CO or N (R4) and Rf represents an alkyl group of Cx-C5 (as above), a cycloalkyl group of C- C7 (as above), a cycloalkylalkyl group of C4-C7 (same as above), a hydroxyalkyl group of Q1-C5 (as above), a bensen ring that can be substituted, a naphthalene ring that can be substituted , an optionally substituted heterocyclic ring having from 1 to 4 heteroatoms which are selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom and having from 5 to 10 atoms constituting the ring in total (same as above), a C3-C6-N-alkylamino group of C? -C4 N-cycloalkyl (as above), a C1-C5 monoalkylamino group (as above), a dialkylaminoalkyl group of C2-C? (same as above), a pyrrolidinylmethyl group, a piperidinylmethyl group, a morph group olinomethyl, a piperazinylmethyl group, a pyrrolylmethyl group, an imidazolylmethyl group, a pyrazolylmethyl group or a triazolylmethyl group; a C 1 -C 8 alkylcarbonyl group which can be substituted, a C 3 -C 8 cycloalkylcarbonyl group which can be substituted, an aralkylcarbonyl group which can be substituted, a C 6 -C 0 arylcarbonyl group which can be substituted, an alkylsulfonyl group of C? -C8 which can be substituted, a C3-C8 cycloalkylsulfonyl group which may be substituted, an aralkylsulfonyl group which may be substituted, a C6-C6-alkylsulfonyl group which may be substituted, an alkyloxycarbonyl group of Ci-Cs which may be substituted, a cycloalkyloxycarbonyl group of C 3 -C 8 which may be substituted, an aralkyloxycarbonyl group which may be substituted, a C 6 -C 0 aryloxycarbonyl group which may be substituted, aminocarbonyl, a C 1 -C 8 N-alkylaminocarbonyl group which may be substituted, a group N, N'-dialkylaminocarbonyl of Ca-C8 which may be substituted, a C-C8-N'-cycloalkylaminocarbonyl C3-C8 alkyl group which may be substituted, an N-alkyl group of Cx-Cs-N '-aralkylaminocarbonyl which can be substituted, an N-alkyl group of C? -C8-N' -arylaminocarbonyl of Ce-C? 0 which can be substituted, a C3-C8 cycloalkylaminocarbonyl group which can be substituted, a group N, N'-dicycloalkylaminocarbonyl of C3-C8 which can be substituted, a group N-cycloalkyl of C3-Ca-N'-aralkylaminocarbonyl which can be substituted, a C3-C8-N'-arylaminosarbonyl N-cisloalkyl group of C6-C6 which can be substituted, an aralkylaminocarbonyl group which can be substituted, a N, N'-diaralkylaminocarbonyl group which can be substituted, a N-aralkyl-N'-arylaminocarbonyl group of C 6 -C 0 which can be substituted, a C 6 -C 0 arylaminocarbonyl group which can be substituted, a group N, N'-C6-C10aryl aminocarbonyl which can be substituted, and R4 represents a hydrogen atom, a C? -C alkyl group which can be substituted, an aralkyl group which can be substituted, a C3-cycloalkyl group C8 which may be substituted, or an aryl group which may be substituted, an alkylcarbonyl group of i -Cs which may be substituted, a C3-C8 cycloalkylcarbonyl group which may be substituted, an aralkylcarbonyl group which may be substituted, an arylcarbonyl group of C6-C? 0 that can be replaced, a group alquilsu Cx-Cs lfonyl which may be substituted, a C3-C8 cycloalkylsulfonyl group which may be substituted, an aralkylsulfonyl group which may be substituted, a C6-C10 aryisulfonyl group which may be substituted, an alkyloxysarbonyl group of L-C8 which can be substituted, a C3-C8 cycloalkyloxycarbonyl group which can be substituted, an aralkyloxycarbonyl group which can be substituted, a C6-C6-aryloxycarbonyl group which can be substituted, aminocarbonyl, a C-C8 N-alkylaminocarbonyl group which can be substituted, a N, N'-dialkylaminocarbonyl group of Ci-C8 which can be substituted, a C-C8-N'-cis-alkoxycarbonyl group of C3-C8 which can be substituted, a N group -C-C8-N'-aralkylaminocarbonyl alkyl which can be substituted, an N-C-C8-N'-arylaminocarbonyl group of Ce-Cio which can be substituted, a C3-C8 cycloalkyminosarbonyl group which can be substituted, replaced, a N, N '-dicycloalkylaminocarbonyl group of C3-C8 which can be substituted, a C3-C8-N'-aralkylaminocarbonyl N-cycloalkyl group which can be substituted, a C3-C8-N'-arylaminocarbonyl C6-C? 0 -cycloalkyl group which can be substituted substituted, an aralkylaminocarbonyl group that can be substituted, a N, N'-diaralkylaminocarbonyl group that can be substituted, a C6-C10 N-aralkyl-N'-arylaminocarbonyl group that can be substituted, a C6-C arylaminocarbonyl group? 0 that can be substituted, a C, N, N'-diarylaminocarbonyl group or that can be substituted, or an optionally substituted heterocyclic ring having from 1 to 4 heteroatom which is selected from the group consisting of an oxygen atom, a sulfur atom, and a nitrogen atom, and having 5 to 10 atoms that make up the ring in total.

When the C6-C? Aryl ring represented by Y1 has one or more substituents, the ring can be substituted by one or more substituents which are selected from the groups formed by halogen atoms, an alkyl group of C?-C5 , a C3-C6 cycloalkyl group, a C3-C6 cycloalkyloxy group, a C1-C5 alkoxy group, a C4-C7 cycloalkylalkoxy group, a C1-C5 alkylthio group, a C1-C5 alkylsulfonyl group, a C1-C5 halogenated alkyl group and a benzene ring.

When the ring represented by X, X1 or Y1 has one or more substituents, the substituent may further have one or more substituents that are selected from the group consisting of a C1-C5 alkyl group such as a methyl group, an ethyl group, an propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, an isopentyl group, a neopentyl group, a 1,1-dimethylpropyl group, a cycloalkyl group of C3-C6 such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group; a C3-C6 cisloalkyloxy group such as a cyclopropyloxy group, a cyclobutyloxy group, a cyclopentyloxy group, a cyclohexyloxy group; a hydroxyalkyl group of C? ~ C4 such as a hydroxymethyl group, a hydroxyethyl group, a hydroxypropyl group, a hydroxybutyl group; a C! -C5 alkoxy group such as a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a tert-butoxy group, a pentyloxy group, and an isopentyloxy group; a cycloalkyloxy group of C-C7 such as a cyclopropylmethoxy group, a cyclopentylmethoxy group; an alkylthio group of 1.-C5 such as a methylthio group, an ethylthio group, a propylthio group, a butylthio group, and a pentylthio group; a C1-C5 alkylsulfonyl group such as a methanesulfonyl group, an ethanesulfonyl group, a propanesulfonyl group, a butanesulfonyl group, and a pentanesulfonyl group; a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom, an iodine atom; a halogenated C1-C5 alkyl group such as a trifluorosulfonyl group; a halogenated C1-C5 alkoxy group such as a trifluoromethoxy group, a 2,2,2-trifluoromethoxy group; a hydroxyl group; a cyano group; a nitro group; a formyl group; a C2-C6 alkylcarbonyl group such as an acetyl group, a propionyl group, a butyryl group, and a valeryl group; an amino group; a C1-C5 monoalkylamino group such as a methylamino group, an ethylamino group, a propylamino group, an isopropylamino group, a butylamino group, an isobutylamino group, a tert-butylamino group, a pentylamino group, and an isopentylamino group; a dialkylamino group of C2-C? 0 such as a dimethylamino group, an ethylmethylamino group, a diethylamino group, a methylpropylamino group, and a diisopropylamino group; a cyclic amino group such as a pyrrolidinyl group, a piperidino group, a morpholino group; a C2-C10 monoalkylaminomethyl group such as a methylaminomethyl group, an ethylaminomethyl group, a propylaminomethyl group, an isopropylaminomethyl group, a butylaminomethyl group, an isobutylaminomethyl group, a tert-butylaminomethyl group, a pentylaminomethyl group, an isopentylaminomethyl group, a dialkylaminomethyl group of C3-Cn such as a dimethylaminomethyl group, a diethylaminomethyl group, an ethylmethylaminomethyl group, a methylpropylaminomethyl group; a phenyl group; an aralkyloxy group such as benzyloxy, 2-phenylethyloxy, 3-phenylpropyloxy; an aralkyloxycarbonyl group such as benzyloxycarbonyl, 2-phenyloxycarbonyl; a C2-C4 alkanoyloxy-C4-C4 alkyl group such as acetyloxymethyl, 2-methyloxyethyl, 2-propionyloxyethyl; an alkanoylamino group such as acetylamino, propionylamino, butyrylamino; an N-C 1 -C 4 -N-alkanoylamino group such as N-methyl-N-acetylamino, N-ethyl-N-acetylamino, N-methyl-N-propionylamino, N-methyl-N-butyrylamino; a heterocyclic ring amino such as pyridylamino, pyrimidinylamino, thienylamino, furylamino; an N-alkyl group of C!-C4-N-heterocyclic amino ring such as N-methyl-N-pyridylamino, N-methyl-N-pyridinylamino, N-methyl-N-thienylamino, N-methyl-N-furylamino; an amino group of a diheterocyclic ring such as dipyridylamino, dipyrimidinylamino, dithienylamino, difurylamino, and the like.R may preferably be a C 1 -C 3 alkyl group, more preferably a methyl group or an ethyl group. The substituent of the alkyl group may preferably be a C3-C8 alkyl group.

X may preferably be a benzene ring which may be substituted, a benzyl group which may be substituted, a naphthyl group which may be substituted, a ring of benzofuran which may be substituted, a ring of dihydrobenzofuran which may be substituted, a ring of benzoxazole that can be substituted, a benzisoxazole ring that can be substituted, a benzothiophene ring that can be substituted, a benzothiazole ring that can be substituted, a benzisothiazole ring that can be substituted, and a benzopyrazole ring that can be substituted replaced; more preferably a benzene ring which can be substituted, a benzyl group which can be substituted. The substituent of X can preferably be selected from the group consisting of a halogen atom, a C 1 -C 4 alkyl group, a C 1 -C alkoxy group, a hydroxy group, a nitro group, a cyano group, a C x alkyl group Perhalogenated C4, a carboxyl group, a C 1 -C 4 alkoxycarbonyl group, an C 1 -C 4 alkylthio group, an C 1 -C 4 alkoxysulfonyl group, an amino group which can be substituted by an C x C 4 alkyl group , a benzene ring that can be substituted and a cyclic amino group that can be substituted.

The compounds represented by the aforementioned formula (I) can form a salt. Examples of the salt include, when there is an acid group, alkali metal and alkaline earth metal salts such as lithium, sodium, potassium, magnesium, and calcium; ammonium salts 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-glusamine; or salts with basic amino acids such as lysine, d-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 are also 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 stoichiometry of such asymmetric carbon atoms, they can be independently in the (R) and (S) configuration, and the pyrimidone derivative can exist as stereoisomers such as optical isomers, or diastereomers. Any stereoisomer in pure form, any mixture of stereoisomers, racemates and the like is within the scope of the present invention.

The preferred compounds of the present invention are represented by the formula (II): where Q, R, X, Y are the same as those defined above; p is 0 or 1; q is 0 or 1; r is an integer from 0 to 6; p + q is 1 or 2; and Z represents N or CZ1 where Z1 represents a hydrogen atom or Y.

Examples of more preferred classes of compounds represented by formula (II) include: (1) those wherein R represents an alkyl group of C? -C3 which can be substituted by a C3-C8 cycloalkyl group; (2) the compounds of item (1) above wherein R is a methyl group or an ethyl group; And it is in position 3, 4 or 5 of the piperazine ring or the piperidine ring; p + q is 1; and r is an integer from 0 to 3; (3) the compounds of item (2) above wherein X is an alkyl group of C?-C8 which may be substituted or the Cß-Cio ar aryl ring which may be substituted; And it is an alguyl group of Ci-Cß that can be substituted; p is 1; q is 0; r is an integer from 0 to 3; and Z is N or CH; (4) the compounds of item (3) above wherein X is a benzene ring that can be substituted, a benzyl ring that can be substituted; And it's a methyl group that can be substituted; Z is N and r is 0 or 1; (5) the compounds of item (2) above wherein X is a benzene ring that can be substituted, a benzyl group that can be substituted, a benzoyl group that can be substituted, or a benzisothiazole group that can be substituted; and it is a methyl group that can be substituted; Z is N and p is 0; (6) the compounds of item (2) above wherein X is a Cx-C8 alkyl group substituted by a benzene ring that can be substituted or a benzene ring that can be substituted; Y is a hydroxy group, a cyano group, or a Y1-C0- group wherein Y1 is an alkyl group of C? -C8; Z is CH or C-Y and r is 0 or 1; Y (7) the compounds of item (6) above wherein X is a benzyl group that can be substituted or a benzene ring that can be substituted; And it is a hydroxy group, a cyano group, or an acetyl group; Z is CH or C-Y and r is 0 or 1.

Examples of particularly preferred classes of compounds represented by formula (II) include: (1) those in which R is a methyl group, Y is a group CH30-C0- or a group CH3CH20-C0-, Z is N, p is 0, q is 1, r is 0 or 1 and Y is in position 3 of the piperazine ring; (2) those in which R is a methyl group, Y is a methyl group, a benzyl group or an acetyl group, Z is N, p is 1, q is 0, r is 0 or 1 and Y is in position 4 of the piperazine ring; (3) those where R is a methyl group, Y is a methyl group, Z is N, p is 1, q is 0, r is from 1 to 3 and Y is in position 3, 4 or 5 of the ring piperazine; (4) those in which R is a methyl group, Y is a hydroxyl group or a cyano group, Z is CH, p is 1, q is 0, r is 0 or 1 and X and Y are joined in the same atom carbon; (5) those in which R is a methyl group, Y is a hydroxyl group, a cyano group or an acetyl group, Z is C-Y, p is 0, q is 1 and r is 1.

Examples of preferred embodiments of the present invention are shown in the following tables. However, the scope of the present invention is not limited to the following compounds.

ZL is 831 Table 2 S?:.

Table-4 Particularly preferred compounds of the present invention represented by the formula (I) include: 2- (3-Phenylpiperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (4-Fluorophenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (3-fluorophenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin -one; 2- (3- (2-fluorophenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (4-chlorophenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; . { S) -2- (3- (4-chlorophenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; (R) -2- (3- (4-chlorophenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (3-chlorophenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (2-chlorophenyl) -piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (4-bromophenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (3-bromophenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (2-bromophenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (4-methylphenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (3-methylphenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (2-methylphenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3h-pyrimidin-4-one; 2- (3- (4-cyanophenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (3-cyanophenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (2-cyanophenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (4-methoxyphenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (3-methoxyphenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (2-methoxyphenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (2-ethoxyphenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (5-fluoro-2-methoxyphenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (4-fluoro-3-methoxyphenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (4-fluoro-2-methoxyphenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; (S) -2- (2- (4-fluoro-2-methoxyphenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; (R) -2- (3- (4-Fluoro-2-methoxyphenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (4-chloro-2-methoxyphenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (4-fluoro-2-methylphenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (2-fluoro-6-methoxyphenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (5-Bromo-2-methoxyphenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (2-bromo-4-fluorophenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (2-chloro-6-fluorophenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (2,4-difluorophenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (2,6-difluorophenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (2,6-dichlorophenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (2, 4-dimethoxyphenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (3, 4-dimethoxyphenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (2, 5-dimethoxyphenyl) iperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (2,6-dimethoxyphenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidinone -one; 2- (3- (2,4-difluoro-6-methoxyphenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (5-cyano-2-methoxyphenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (4-cyano-2-methoxyphenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (l-naphthyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (2-naphthyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (2,3-dihydrobenzofuran-7-yl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (benzofuran-2-yl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; (S) -2- (3- (Benzofuran-2-yl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (4- (pyrrolidin-1-yl-methyl) phenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (4- (pyrrolidin-1-yl) phenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (2-methoxy-4- (pyrrolidin-1-yl) phenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (2-methoxy-5- (pyrrolidin-1-yl) phenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (4- (phenyl) phenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (4- (4-fluorophenyl) phenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (4- (4-methoxyphenyl) phenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (4- (2-methoxyphenyl) phenyl) piperazin-1-yl-3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (4- ( morpholin-4-yl) phenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (4- (4-methyl-piperazin-1- il) phenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (4-phenylpiperazin-1-yl) -3-methyl-6- ( 4-pyridyl) -3H-pyrimidin-4-one; 2- (4-benzylpiperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (4-benzoylpiperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (4- (1, 2-benzisothiazol-3-yl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (4-methyl-3-phenylpiperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyridin-4-one; 2- (3- (4-fluoro-2-methoxyphenyl) -4-methylpiperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; (S) -2- (3- (4-fluoro-2-methoxyphenyl) -4-methylpiperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; (R) -2- (3- (4-Fluoro-2-methoxyphenyl) -4-methylpiperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (4-acetyl-3- (4-fluoro-2-methoxyphenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (4-benzyl-3- (4-fluoro-2-methoxyphenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (4-benzyl-3- (ethoxycarbonyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (4-methyl) -3- (1-naphthyl) piperazin-1-yl) -3-methyl-6 (4-pyridyl) -3H-pyrimidin-4-one; 2- (5,5-Dimethyl-3- (2-methoxyphenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3-phenylpiperidin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (4-fluorophenyl) piperidin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (3-fluorophenyl) piperdin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (2-fluorophenyl) piperidin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (4-chlorophenyl) piperidin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (4-bromophenyl) piperidin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (4-methoxyphenyl) piperidin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (3-methoxyphenyl) piperidin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (2-methoxyphenyl) piperidin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (4- ((Pyrrolidin-1-yl) methyl) phenyl) piperidin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; (S) -2- (3- (4- (pyrrolidin-1-yl-methyl) phenyl) piperidin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; (R) -2- (3- (4- (pyrrolidin-1-yl-methyl) phenyl) piperidin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3-hydroxy-3-phenylpiperidin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3-phenylpiperazin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; 2- (3- (4-fluorophenyl) piperazin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; 2- (3- (3-fluorophenyl) piperazin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; 2- (3- (2-fluorophenyl) piperazin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; 2- (3- (4-chlorophenyl) piperazin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; 2- (3- (3-chlorophenyl) piperazin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; 2- (3- (2-chlorophenyl) piperazin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; 2- (3- (4-bromophenyl) piperazin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; 2- (3- (3-bromophenyl) piperazin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; 2- (3- (2-bromophenyl) piperazin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; 2- (3- (4-cyanophenyl) piperazin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; 2- (3- (3-cyanophenyl) piperazin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; 2- (3- (2-cyanophenyl) piperazin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; 2- (3- (4-methoxyphenyl) piperazin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; 2- (3- (3-methoxyphenyl) piperazin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; 2- (3- (2-methoxyphenyl) piperazin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; 2- (3- (2-ethoxyphenyl) piperazin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; 2- (3- (6-fluoro-2-methoxyphenyl) piperazin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; 2- (3- (5-fluoro-2-methoxyphenyl) piperazin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; 2- (3- (4-fluoro-2-methoxyphenyl) piperazin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; (S) -2- (3- (4-fluoro-2-methoxyphenyl) piperazin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; (R) -2- (3- (4-Fluoro-2-methoxyphenyl) piperazin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; 2- (3- (4-chloro-2-methoxyphenyl) piperazin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one, 2- (3- (5-bromine -2-methoxyphenyl) piperazin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; 2- (3- (2,6-dichlorophenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (2,4-dimethoxyphenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (3, 4-dimethoxyphenyl) piperazin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; 2- (3- (2, 5-dimethoxyphenyl) piperazin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; 2- (3- (2,6-dimethoxyphenyl) iperazin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin -one; 2- (3- (2,4-difluoro-6-methoxyphenyl) piperazin-1-yl) -3-tnethyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; 2- (3- (1-naphthyl) piperazin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; 2- (3- (2-naphthyl) piperazin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; 2- (3- (2,3-dihydrobenzofuran-7-yl) piperazin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; 2- (3-benzofuran-2-yl) piperazin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; 2- (3- (4-pyrrolidin-1-yl-methyl) phenyl) piperazin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; 2- (3- (4-pyrrolidin-1-yl) phenyl) piperazin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; 2- (3- (2-methoxy-4- (pyrrolidin-1-yl) phenyl) piperazin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; 2- (3- (2-methoxy-5- (pyrimidin-1-yl) phenyl) piperazin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; 2- (3- (4- (phenyl) phenyl) piperazin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; 2- (3- (4- (4-fluorophenyl) phenyl) piperazin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; 2- (3- (4- (4-methoxyphenyl) phenyl) piperazin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; 2- (3- (4- (2-methoxyphenyl) phenyl) piperazin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one, 2- (3- (4- morpholin-4-yl) phenyl) piperazin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; 2- (3- (4- (4-methyl-piperazin-1-yl) -phenyl) -piperazin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrmidin-4-one; 2- (3- (4-fluoro-2-methoxyphenyl) -4-methylpiperazin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; (S) -2- (3- (4-fluoro-2-methoxyphenyl) -4-methylpiperazin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; (R) -2- (3- (4-Fluoro-2-methoxyphenyl) -4-methylpiperazin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; 2- (4-acetyl-3- (4-fluoro-2-methoxyphenyl) piperazin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; 2- (4-Benzyl-3- (4-fluoro-2-methoxyphenyl) piperazin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; 2- (4- (4-fluorophenyl) piperidin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; 2- (4-cyano-4-phenylpiperidin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; 2- (4- (6-fluorobenzofuran-3-yl) piperidin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; 2- (3-benzoisoxazol-3-yl) piperidin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; (S) -2- (3- (Benzoisoxazol-3-yl) piperidin-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; (R) -2- (3- (Benzoisoxazol-3-yl) piperidin-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; 2- (3- (6-fluorobenzisoxazol-3-yl) piperidin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; 2- (4- (6-fluorobenzisoxazol-3-yl) piperidin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; 2- (4- (5-methylbenzofuran-3-yl) piperidin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; and 2- (4- (6-fluorobenzothiophene-3-yl) piperidin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one.

Also preferred are the salts of the aforementioned preferred compound, and the solvates or hydrates of the aforementioned compounds and salts thereof.

The 3-substituted-pyrimidone compounds represented by the aforementioned formula (I) can be prepared, for example, according to the method explained below.

(In the preceding scheme, the definitions of Q, R, X and Y are the same as those already described.) The 2-thiopyrimidone represented by the above formula (III) is easily prepared by a modification of the method described in EP 354,179. The reaction can be carried out in the presence of a base such as sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium carbonate, sodium hydrogencarbonate, potassium carbonate, triethylamine, diisopropylethylamine, and 1,6-diazabicyclo [5.4.0] undec-7-ene for 1 to 100 hours at a suitable temperature in the range of 0 ° C to 100 ° C under a nitrogen or argon atmosphere or under air ordinary to give the desired compound (III). Examples of a solvent for the reactions include, for example, alcohol solvent such as methanol, ethanol, 1-propanol, isopropanol, tert-butanol, ethylene glycol, propylene glycol; ether solvents such as diethyl ether, tert-butyl methyl ether, tetrahydrofuran, isopropyl ether; hydrocarbon solvents such as benzene, toluene, xylene; halogenated hydrocarbon solvents such as dichloromethane, chloroform, dichloroethane; aprotic polar solvents such as formamide, N, N-dimethylformamide, N, N-dimethylacetamide, irmethylpyrrolidone, dimethyl sulfoxide, sulfolane, hexamethylphosphoric triamide, water and the like. In general, a single solvent or a mixture of two or more solvents may be used in a manner that is suitable for a base used.

Then, the derivative of 2-thiopyrimidone (III) is transformed into 2-chloropyrimidone (IV) with a chlorinating agent. The time and temperature of the reaction depend on the chlorinating agent used. Examples of a chlorinating agent for the reactions include, for example, thionyl chloride, thionyl chloride and dimethylformamide, phosphorus oxychloride, phosphorus oxychloride and dimethylformamide, oxalyl chloride, phosphorus oxychloride and dimethylformamide, and phosphorus pentachloride.

The amine represented by the above formula (V) can be prepared by a modification of the method described in Japanese Unexamined Patent Publication [Kokai] No. 52-139085 / 1977 or according to methods known to one skilled in the art. .

The chloride (IV) derivative is then allowed to react with the amine (V) or salts thereof in the presence of a base such as sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium carbonate, sodium hydrogencarbonate, potassium carbonate, triethylamine, diisopropylethylamine, and 1,8-diazabicyclo [5, 4, 0] undec-7-ene for 0.1 to 100 hours at a suitable temperature in the range of 0 ° C to 200 ° C under a nitrogen or argon atmosphere or under ordinary air to obtain the desired compound (II).

Examples of a solvent for the reactions include, for example, an alcohol solvent such as methanol, ethanol, 1-propanol, isopropanol, tert-butanol, ethylene glycol, propylene glycol; ether solvents such as diethyl ether, tert-butyl methyl ether, tetrahydrofuran, isopropyl ether; hydrocarbon solvents such as benzene, toluene, xylene; halogenated hydrocarbon solvents such as dichloromethane, chloroform, dichloroethane; polar aprotic solvents such as formamide, N, -dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, sulfolane, hexamethylphosphoric triamine, water and the like. In general, a single solvent or a mixture of two or more solvents may be used in a manner that is suitable for a base used.

The compounds of the present invention have inhibitory activity against TPK1, and inhibit the activity of TPK1 in neurodegenerative diseases such as Alzheimer's disease, and thereby eliminate the neurotoxicity of Aβ and the formation of PHF and inhibit cell death. Nervous Accordingly, the compounds of the present invention are useful as an active ingredient of a medicament that radically allows the preventive and / or therapeutic treatment of Alzheimer's disease. In addition, the compounds of the present invention are also useful as an active ingredient of a medicament for the preventive and / or therapeutic treatment of ischemic strokes, Down syndrome, cerebral bleeding due to solitary cerebral amyloid angiopathy, progressive supranuclear palsy, sclerosing panencephalitis subacute, postencephalitic parkinsonism, pugilistic encephalosis, Guam parkinsonism-dementia complex, Lewy body disease, Pick's disease, corticobasal degeneration, frontotemporal dementia, vascular dementia, acute attack and traumatic injuries, brain and spinal cord trauma, neuropathies peripheral, retinopathy and glaucoma, non-insulin-dependent diabetes (such as diabetes type .11) and obesity, manic depressive illness, schizophrenia, alopecia, cancers such as breast cancer, non-small cell lung carcinoma, thyroid cancer, leukemia of the T or B cells, and various s tumors induced by viruses.

As the active ingredient of the medicament of the present invention, a substance selected from the group consisting of the compound represented by the aforementioned formula (I) and pharmacologically acceptable salts thereof and solvates thereof and hydrates thereof can be used. The substance, per se, can be administered as the medicament of the present invention, although it is desirable to administer the medicament in a form of a composition comprising the substance mentioned as the active ingredient and one or more pharmaceutical additives. As the active ingredient of the medicament of the present invention, two or more of the aforementioned substance may be used in combination. The above pharmaceutical composition can be supplemented with an active ingredient of the other medicament for the treatment of, for example, Alzheimer's disease, vascular dementia, acute attack and traumatic injuries, brain and spinal cord trauma, peripheral neuropathies, retinopathies and glaucoma, non-insulin dependent diabetes (such as type II diabetes) and obesity, manic depressive illness, schizophrenia, alopecia, cancers such as breast cancer, non-small cell lung carcinoma, T or B cell leukemia, various virus-induced tumors.

A type of pharmaceutical composition is not particularly limited, and the composition can be provided as any formulation for oral or parenteral administration. For example, the pharmaceutical composition can be formulated, for example, in the form of pharmaceutical compositions for oral administration, such as granules, fine granules, powders, hard capsules, soft capsules, syrups, emulsions, suspensions., solutions and the like, or in the form of pharmaceutical compositions for parenteral administrations such as injections for intravenous, intramuscular, or subcutaneous administration, infusions for drip, transdermal preparations, transmucosal preparations, nasal drops, inhalants, suppositories and the like. Drip injections or infusions can be prepared as powder preparations such as in the form of lyophilized preparations, and can be used by dissolving them immediately before use in an appropriate aqueous medium such as physiological saline. Sustained release preparations such as those cd with a polymer can be administered directly intracerebrally.

The types of pharmaceutical additives used for the manufacture of the pharmaceutical composition, the rations of content of the pharmaceutical additives in relation to the active ingredient, and the methods for preparing the pharmaceutical composition can be chosen appropriately by the person skilled in the art. Inorganic or organic substances, or solid or liquid substances can be used as pharmaceutical additives. In general, pharmaceutical additives can be incorporated in a ratio in the range of 1% by weight to 90% by weight based on the weight of an active ingredient.

Examples of excipients used for 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 liquid compositions for oral administration, a conventional inert diluent such as water or a vegetable oil can be used. The liquid composition may contain, in addition to the inert diluent auxiliaries such as wetting agents, suspension aids, sweeteners, aromatics, colorants and preservatives. With the liquid composition, capsules made of an absorbable material such as gelatin can be filled. Examples of solvents or suspending media that are used for the preparation of compositions for parenteral administration, for example, injections, suppositories, include water, propylene glycol, polyethylene glycol, benzyl alcohol, ethyl oleate, lecithin and the like. Examples of base materials that are used for suppositories include, for example, cocoa butter, emulsified cocoa butter, lauric lipid, witepsol.

The dose and frequency of administration of the medicament of the present invention are not particularly limited, and may be appropriately chosen according to conditions such as a purpose of preventive and / or therapeutic treatment, a type of disease, the body weight or the age of the patient. , the severity of a disease or similar. In general, a daily dose for oral administration to an adult may be from 0.01 to 1,000 mg (the weight of an active ingredient), and the dose may be administered once per day or several times per day as divided portions, or once in several days. When the medicament is used as an injection, administrations may preferably be performed continuously or intermittently in a daily dose of 0.001 to 100 mg (the weight of an active ingredient) to an adult.

Examples The present invention will be explained more specifically with reference to examples. However, the scope of the present invention is not limited to the following examples. The numbers of the compounds of the examples correspond to those of the preceding table.

Reference Example 1: Synthesis of 2-mercapto-3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one A solution of ethyl 3-oxo-3- (4-pyridyl) pripionate (29.0 g, 150 mmol), N-methyl thiourea (40.6 g, 450 mmol) and 1,8-diazabicyclo [5.4 , 0] -7-undecene (22.4 ml, 150 mmol) was refluxed for 4 hours and the solution of methanesulfonic acid (14.4 g, 150 mmol) in water was added after cooling with ice water. The precipitate was washed with water, filtered and dried to give the title compound (23.7 g, 72%). aH-NMR (DMSO-d6) d: 3.58 (s, 3H), 6.40 (s, ÍH), 7.72 (dd, J = 1, 8, 4.5 Hz, 2H), 8, 73 (dd, J = 1, 5, 4.8 Hz, 2H), 12.92 (brd, ÍH).

Reference Example 2: Synthesis of 2-chloro-3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one Phosphorus oxychloride (26.11 g, 170 mmol) was added to dimethylformamide (180 ml) and stirred for 20 minutes. 2- ercapto-3-methyl-6- (4-pyridyl) -pyrimidin-4-one (24.15 g, 110 mmol) was added to the solution and stirred for 5 minutes and then stirred at 70 ° C for 2 hours. Ethyl acetate (630 ml) was added to the ice-cooled solution and the precipitate was collected by filtration after stirring for 20 minutes. After stirring, the precipitate was dissolved in water (400 ml) and the pH was adjusted to 10 using aqueous sodium hydroxide. The precipitate was washed with water, filtered and dried to give the title compound (18.82 g, 77%). ^ - MR (CDC13) d: 3.72 (s, 3H), 6.90 (s, ÍH), 7.78 (dd, J = l, 7, 4.5 Hz, 2H), 8.75 ( dd, J = 1, 6, 4.5 Hz, 2H).

Reference Example 3: Synthesis of 2-mercapto-3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one A solution of ethyl 3-oxo-3- (4-pyrimidyl) pripionate (34.1 g, 176 mmol), N-methyl thiourea (47.5 g, 27 mmol) and 1,8-diazabicyclo [5.4 , 0] -7-undecene (26.3 ml, 176 mmol) in ethanol (340 ml) was refluxed for 2 hours and the solution of methanesulfonic acid (16.9 g, 176 mmol) in water (70 ml) was added after cooling with ice water. The precipitate was washed with water, filtered and dried to give the title compound (30.2 g, 78%). aH-MR (DMS0-d6) d: 3.56 (s, 3H), 6.88 (s, ÍH), 8.24 (dd, J = 1, 2, 5, 4 Hz, 2H), 9, 05 (dd, J = 5.4 Hz, ÍH), 11.94 (s, 1H).

Reference Example 4: Synthesis of 2-chloro-3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one Phosphorus oxychloride (4.80 g, 30 mmol) was added to dimethylformamide (32 ml) and stirred for 20 minutes at 0 ° C. 2-Mercapto-3-methyl-6- (4-pyrimidyl) -pyrimidin-4-one (4.40 g, 20 mmol) was added to the solution and stirred for 5 minutes and then stirred at 70 ° C for 2 hours. The reaction mixture was poured into ice water, neutralized with solid potassium carbonate, and extracted with ethyl acetate. The organic layer was washed with saline, dried over sodium sulfate, and evaporated under reduced pressure. Purification of the residue by silica gel chromatography (ethyl acetate) gave the title compound (1.20 g, 27%).

^ - MR (CDCI3) d: 3.74 (s, 3H), 7.56 (s, ÍH), 8.18 (d, J = 5.1 Hz, ÍH), 8.92 (d, J = 5, l Hz, ÍH), 9.30 (s, ÍH). MS [M + H] +: 228 Example 1: Synthesis of 2- (2- (4-fluoro-2-methoxyphenyl) piperazin-4-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one dihydrochloride (No. XA468) A solution of 2-bromo-5-fluoroanisole (11.8 g, 57.6 mmol) in tetrahydrofuran (60 ml) was added dropwise to magnesium (1.40 g, 57.6 mmol) in tetrahydrofuran (32 g). ml) containing a small amount of 1,2-dibromoethane and refluxed for 15 minutes. After adding tetrahydrofuran (50 ml), the solution was cooled to -78 ° C and diethyl oxalate (7.41 g, 50.7 mmol) in diethyl ether (50 ml) was dropped into the solution. After stirring at the same temperature for 30 minutes, the solution was warmed to -10 ° C and aqueous hydrogen chloride was added. (50 ml) and water. The organic layer was extracted with diethyl ether, washed with saline and dried over magnesium sulfate. After removal of the solvent under reduced pressure, purification of the residue by silica gel column chromatography (eluent: hexane / ethyl acetate = 5/2) gave 2- (4-fluoro-2-methoxyphenyl) -2- ethyl oxoacetate (6.80 g, 59%).

-NMR (CDCI3) d: 1.40 (3H, t, J = 7, l Hz), 3.87 (3H, s), 4.89 (2H, q, J = 7, l Hz), 6, 68 (1H, d, J = 10.5 Hz), 6.77-6.81 (1H, m), 7.91-7.95 (1H, m).

Ethylenediamine (0.60 g, 10.0 mmol) was added to a solution of ethyl 2- (4-fluoro-3-methoxyphenyl) -2-oxoacetate (2.26 g, 10.0 mmol) in ethanol (30 mL). ml) and refluxed for 4 h. After removal of the solvent under reduced pressure, the residue was washed with ethanol-diethyl ether to give 5,6-dihydro-3- (4-fluoro-2-methoxyphenyl) pyrazinone (1.76 g, 79%). XH-NMR (CDCl 3) d: 3.50-3.56 (2H, m), 3.81 (3H, s), 3.88-3.92 (2H, m), 6.65 (1H, d) , J = 11.0 Hz), 6.70-6.76 (HH, m), 6.89 (HH, bs), 7.36-7.40 (1H, m). ,6-Dihydro-3- (4-fluoro-2-methoxyphenyl) irazinone was added to the solution of lithium aluminum hydride (0.46 g, 12 mmol) in diethyl ether (25 ml) and refluxed for 6 hours. h. Water (0.48 ml), 15% sodium hydroxide solution (0.48 ml) and again water (1.21 ml) were added to the ice-cooled solution and the precipitate was filtered and washed with dichloromethane. The combined organic layer was evaporated to give 2- (4-fluoro-2-methoxyphenyl) iperazine (0.83 g, 99%).

XH ~ NMR (CDCl 3) d: 2.02 (2H, s), 2.57-2.63 (HH, m), 2.80-2.89 (HH, m), 2.92-2.99 (2H, m), 3.06-3.12 (2H, m), 3.80 (3H, s), 4.06 (IH, d, J = 10.0 Hz), 6.56-6, 65 (2H, m), 7.40 (H, t, J = 7.8 Hz). 2-Chloro-3-methyl-6- (4-pyridyl) -pyrimidin-4-one (222 mg, 1.0 mmol) was added to an ice-cooled solution of 2- (4-fluoro-2-methoxyphenyl) piperazine (210 mg, 1.0 mmol), triethylamine (0.15 mL, 1.1 mmol) in N, N-dimethylformamide (10 ml) and stirred at that temperature for 1 hour and then at room temperature for 2 hours. The next day, the reaction was cooled with ice water and the filtrate was washed with water and dried to give 2- (3- (4-fluoro-2-methoxyphenyl) piperazin-4-yl) -3-methyl-6- (4-pyridyl) -pyrimidin-4-one (246 mg, 62%). XH-NMR (CDC13) d: 2.89-2.96 (HI, m), 3.19-3.31 (3H, m), 3.59 (3H, s), 3.62-3.74 (2H, m), 3.85 (3H, s), 4.39-4.44 (HH, m), 6.63-6.71 (2H, m), 6.67 (HH, s), 7.51-7.55 (HH, m), 7.81 (2H, dd, J = 1.7, 4.6 Hz), 8.71 (2H, dd, J = 1.7, 4.6 Hz).

Hydrogen chloride 4N in 1, -dioxane (0.4 ml) was added to the solution of 2- (2- (4-fluoro-2-methoxyphenyl) piperazin-4-yl) -3-methyl-6- (4 -pyridyl) -pyrimidin-4-one (217 mg, 0.6 mmol) in dichloromethane (5 ml) and stirred for 15 minutes. After adding diethyl ether, filtration and washing with diethyl ether and drying gave the title compound (260 mg, quant.) Example 2: Synthesis of 2- (2- (4-methoxyphenyl) -piperazin-4-yl) -3-methyl-6- (4-pyridyl) pyrimidin-4-one dihydrochloride (No. XA393) A solution in demethyl sulfoxide (50 ml) of 4-methoxyphenylbromide (9.94 g, 43.4 mmol) and water (1.6 ml, 88.8 mmol) were stirred at 50 ° C for 2.5 hours. Water was added and the solution was extracted with ethyl acetate 3 times and washed with saline and then dried over sodium sulfate. Removal of the solvent gave 4-methoxyphenylglyoxal (8.30, g, quant.) 2H-NMR (DMSO) d: 3.84 (3H, s), 6.60-6.69 (1H, m), 7, 04 (2H, d, J = 8.8 Hz), 8.05 (2H, d, J = 9, 1 Hz).

A solution in methanol (5 ml) of ethylenediamine (3.74 g, 62.29 mmol) was added to the ice-cooled solution of 4-methoxyphenylglyoxal (8.30 g, 45.5 mmol) in methanol (100 ml). and tetrahydrofuran (50 ml) and stirred for 10 minutes. After cooling to 0 ° C, tetrahydroborate (6.14 g, 162.2 mmol) and additional methanol (50 mL) was added and stirred overnight. After removal of the solvent, aqueous sodium hydroxide was added and extracted with dichloromethane three times and washed with saline and dried over sodium sulfate. After removal of the solvent, purification of the residue by silica gel column chromatography (eluent, dichloromethane / ethanol / diethylamine = 20/2/1) gave 2- (4-methoxyphenyl) -piperazine (3.96 g, Four. Five%). ^ -NR (CDC13) d: 2.69 (ÍH, dd, J = 10.3, 11.9 Hz), 2.80-3.01 (4H, m), 3.07-3.11 (H) , m), 3.68-3.73 (1H, m), 3.79 (3H, s), 6.84-6.88 (2H, m), 7.27-7.32 (2H, m ).

A solution of triethylamine (697 mg, 6.9 mmol), 2- (4-methoxyphenyl) -piperazine (430 mg), tetrahydrofuran (10 ml) was stirred at room temperature for 30 minutes and at 50 ° C for 3 hours. The solvent was removed under reduced pressure, and a 1% aqueous sodium hydroxide solution was added. The residue was extracted with dichloromethane three times and washed with saline and dried over sodium sulfate. After removal of the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent: dichloromethane / ethanol = 10/1) to give 2- (2- (-methoxyphenyl) -piperazin-4-yl. ) -3-methyl-6- (4-pyridyl) pyrimidin-4-one (594 mg, 76%). aH-? MR (CDCI3) d: 3.02 (ΔH, dd, J = 10.8, 12.7 Hz), 3.18-3.25 (3H, m), 3.55 (3H, s) , 3.57-3.67 (2H, m), 3.82 (3H, s), 3.98 (HH, dd, J = 2.7 10.8 Hz), 6.67 (HH, s) , 6.92 (2H, d, J = 8.7 Hz), 7.37 (2H, d, J = 8.7 Hz), 7.80 (2H, d, J = 6.0 Hz), 8 , 71 (2H, d, J = 6.0 Hz). 4N Hydrogen chloride in ethyl acetate (5 ml) was added to the solution of 2- (2- (4-methoxyphenyl) -piperazin-4-yl) -3-methyl-6- (4-pyridyl) pyrimidine-4 -one (594 mg, 1.6 mmol) in dichloromethane (5 ml) and stirred for 1 hour. Washing with ethyl acetate after removal of the solvent and drying gave the title compound (683 mg, 96%).

Example 3: Synthesis of 2- (2- (4-dichlorophenyl) -piperazin-4-yl) -3-methyl-6- (4-pyridyl) pyrimidin-4-one hydrochloride (No. XA371) The mixture of methyl (4-chlorophenyl) acetate (5.10 g, 27.6 mmol) and N-bromosuccinimide (5.16 g, 29 mmol) in carbon tetrachloride was treated with a Hg lamp. After filtration, the solvent was removed under reduced pressure and the residue was dissolved in methanol. Ethylenediamine (2.03 ml, 30.4 mmol) and triethylamine (2.06 ml, 14.8 mmol) and di-tert-butyldicarbonate (3.10 ml, 13.5 mmol) were added to the solution of 3- (4-chlorophenyl) piperazin-2-one (2.60 g, 12.3 mmol) in dichloromethane (100 ml) and stirred. The reaction mixture was washed with IN aqueous hydrogen chloride, water, saline and then dried. After removing the solvent under reduced pressure, the residue was purified by silica gel column chromatography to give 4- (tert-butoxycarbonyl) -3- (4-chlorophenyl) -piperazin-2-one. ^ -NMR (CDC13) d: 1.44 (9H, s), 3.21-3.32 (2H, m), 3.48 (ÍH, brs), 4.04 (ÍH, brs), 5, 66 (1H, brs), 7.10 (1H, brs), 7.30-7.38 (4H, m).A solution of 4- (tert-butoxycarbonyl) -3- (4-chlorophenyl) -piperazin-2-one (500 mg, 1.6 mmol) and acetic acid (929 μl, 16 mmol) were added to a refluxed solution of Sodium borohydride (608 mg, 16 mmol), in 1,4-dioxane (5 ml) and reflux was continued. The reaction was quenched with water and extracted with dichloromethane and washed with saline and dried. After removal of the solvent, the residue was purified by silica gel column chromatography to give 4- (tert-butoxycarbonyl) -3- (4-chlorophenyl) piperazine (330 mg, 69%). XH-NMR (CDC13) d: 1.46 (9H, s), 2.76-2.99 (3H, m), 3.13 (1H, dd, J = 13.0 Hz, 4.3 Hz) , 3.45-3.49 (2H, m), 3.92 (HH, m), 5.15 (HH, s), 7.27-7.33 (4H, m).

A solution of 4- (tert-butoxycarbonyl) -3- (4-chlorophenyl) piperazine (330 mg, 1.1 mmol), 2-chloro-3-methyl-6- (4-pyridyl) pyrimidin-4-one ( 246 mg, 1.1 mmol) and triethylamine (170 μL, 1.22 mmol) in tetrahydrofuran were refluxed. The usual work-up and purification by silica gel chromatography gave 2- (1- (tert-butoxy-carbonyl) -2- (4-chlorophenyl) -piperazin-4-yl) -3-methyl-6- (4- pyridyl) pyrimidin-4-one (500 mg, 93%). ^ -NMR (CDC13) d: 1.45 (9H, s), 3.09 (ÍH, m), 3.35 (3H, s), 3.40-3.63 (4H, m), 3, 96-4.19 (2H,), 5.43 (HH, s), 6.68 (HH, s), 7.23 (2H, d, J = 8.3 Hz), 7.32 (2H, d, J = 8.3 Hz), 7.78 (2H, d, J = 5.9 Hz), 8.72 (2H, d, J = 5.9 Hz). 4N Hydrogen chloride in ethyl acetate was added to the solution of 2- (1-tert-butoxycarbonyl) -2- (4-chlorophenyl) -piperazin-4-yl) -3-methyl-6- (4-pyridyl) pyrimidin-4-one (500 mg, 1.0 mmol) in ethyl acetate and stirred. Filtration and successive drying gave the title compound (373 mg, 79%).

Example 4: Synthesis of 3-methyl-2- (3- (4- ((1-pyrrolidinyl) methyl) phenyl) pyridin-1-yl) -6- (4-pyridyl) pyrimidin-4-one fumarate (N ° XB43) Tetrakis (triphenylphosphine) palladium (0.65 g, 0.56 mmol), 4-formylphenylboronic acid (2.81 g, 18.7 mmol), 2M aqueous sodium carbonate (18.7 mL, 37.4 mmol) and Ethanol were added to the saturated solution with nitrogen of 3-bromopyridine (2.66 g, 16.8 mmol) in toluene and refluxed under nitrogen for 8 hours. Water was added to the solution and extracted with ethyl acetate, washed with water and saline and dried. The solvents were removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent; hexane / ethyl acetate = 1 / 1.5) to give 4- (3-pyridyl) benzaldehyde (0.78 g. , 25%).

Methyl iodide (0.8 mL, 12.9 mmol) was added to a solution of 4- (3-pyridyl) benzaldehyde (0.78 g, 4.3 mmol) in dichloromethane and stirred for 2 days. Additional methyl iodide (0.8 ml, 12.9 mmol) was added and stirred for 3 hours. After removal of the solvent, methanol was added to the residue and cooled with ice. Sodium tetrahydroborate (6.4 g, 17.0 mmol) was added to the solution and stirred for 1.5 hours while warming to room temperature. The organic solvents were removed under reduced pressure after adding water and extracted with ethyl acetate, washed with water and saline and dried over sodium sulfate. After removal of the solvent under reduced pressure, the residue was purified by silica gel chromatography (eluent ethyl acetate to methanol) to give 3- (4-hydroxymethylphenyl) -1-methyl-1, 2,3,5, 6-tetrahydropyridine (0.63 g, 72%).

Triethylamine (1.29 ml, 9.2 mmol), acetic anhydride (0.35 ml, 3.7 mmol) were added to a solution of 4- (hydroxymethyl) phenyl-1-methyl-1, 2, 5, 6 -tetrahydropyridine (0.63 g, 3.1 mmol) in dichloromethane and stirred overnight. The organic solvents were removed under reduced pressure after adding water and extracted with ethyl acetate, washed with water and saline and dried over sodium sulfate. Removal of the solvent under reduced pressure gave 3- (4-methyloxymethyl-phenyl) -1-methyl-1,2,5,6-tetrahydropyridine (0.67 g, 89%).

A solution of 3- (4-acetoxymethylphenyl) -1-methyl-1,2,5,6-tetrahydropyridine (0, 67 g, 2.7 mmol) and 1-chloroethyl chloroformate (0.36 mL, 3.3 mmol) in dichloromethane was refluxed for 2 hours. The organic solvents were removed under reduced pressure after adding water and extracted with ethyl acetate, washed with water and saline and dried over sodium sulfate. After removal of the solvent, methanol was added and refluxed for 1.5 hours. Tetrahydrofuran and water were added to the residue after removal of the solvent under reduced pressure and triethylamine (1.9 ml, 13.6 mmol) and di-tert-butyl dicarbonate (0.66 g, 3.0 mmol) were added. and they stirred. The organic solvents were removed under reduced pressure after adding water and extracted with ethyl acetate, washed with water and saline and dried over sodium sulfate. Removal of the solvent under reduced pressure and the residue was purified by silica gel chromatography to give 3- (4-acetoxymethylphenyl) -1- (tert-butoxycarbonyl) -1, 2,5,6-tetrahydropyridine (0.71 g , 78%). Pdium on charcoal was added to the solution of 3- (4-acetoxy-methylphenyl) -1- (tert-butoxycarbonyl) -1,2,5,6-tetrahydropyridine (0.71 g, 2.1 mmol) in acetate of ethyl and stirred under a hydrogen atmosphere. After filtering with celite and removing the solvent under reduced pressure, methanol and IN aqueous sodium hydroxide were added and stirred. The organic solvents were removed under reduced pressure after adding water and extracted with ethyl acetate, washed with water and saline and dried over sodium sulfate. Solvent was removed under reduced pressure and the residue was purified by silica gel chromatography (eluent; hexane / ethyl acetate = 3/1) to give 3- (4-hydroxymethylphenyl) -1- (tert-butoxycarbonyl) pyridine (0.39 g, 62%).

Triethylamine (0.47 g, 3.4 mmol) and methanesulfonyl chloride (0.12 mL, 1.6 mmol) were added to an ice-cold solution of 3- (4-hydroxymethylphenyl) -1- (tert-butoxycarbonyl) pyridine (0.39 g, 1.34 mmol) in dichloromethane and stirred for 7.5 hours. Pyrrolidine (1.0 ml, 12 mmol) was added to the solution and stirred overnight. The organic solvents were removed under reduced pressure after adding water and extracted with ethyl acetate, washed with water and saline and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography (eluent: ethyl acetate to ethyl acetate / methanol 1/1, then methanol only) to give 3- (4- (l-pyrrolidinyl) ethyl-phenyl) -1- (tert-butoxycarbonyl) piperidine (0.26 g, 56%). 4N Hydrogen chloride in ethyl acetate was added to 3- (4- (1-pyrrolidinyl) -methylphenyl) -1- (tert-butoxycarbonyl) piperidine (0.26 g, 0.75 mmol) and stirred overnight . After filtering and drying, triethylamine (0.5 ml, 3.6 mmol), 2-chloro-3-methyl-6- (4-pyridyl) -pyrimidin-4-one (0.14 g, 0, 63 mmol) and tetrahydrofuran and stirred at 70 ° C. The organic solvents were removed under reduced pressure after adding water and extracted with ethyl acetate, washed with water and saline and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate. A solution of fumaric acid (0.095 g, 0.82 mmol) in acetone was added and the resulting precipitate was filtered and dried to give the title compound (0.29 g, 76%).

Example 5: Synthesis of (R) -2- (2- (4-chlorophenyl) piperidin-4-yl) -3-methyl-6- (4-pyridyl) -pyrimidin-4-one (N ° XA372) To a solution of (S) -2-methyl-CBS-oxazoborolidine (27.6 ml, 1.0 M solution in toluene, 27.6 mmol) was added a complex of borane-tetrahydrofuran (166 ml, solution 1.0 M in tetrahydrofuran, 166 mmol) at -40 ° C. To the resulting solution was added a solution of 4 '-chlorophenacyl bromide (32.25 g, 138.1 mmol) in tetrahydrofuran (200 mL) through a dropping funnel for 1 hour at -40 ° C. After stirring for 3 hours below 0 ° C, methanol (50 ml) was added dropwise. After stirring the resulting solution for another 30 minutes at room temperature, the solvent was removed under reduced pressure. The residue, dissolved in ethyl acetate, was treated with 1N hydrochloric acid to form a white precipitate, which was filtered. The layers of the filtrate were separated and the organic layer was washed with hydrochloric acid and saline successively, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was used for the next reaction without further purification.

The residue was dissolved in ether (250 ml) and stirred vigorously with potassium hydroxide (15.5 g, 276 mmol) in water (250 ml). After this material was consumed, the layers separated.

The organic layer was washed with saline, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was used for the next reaction without further purification.

The residue was heated with benzylamine (37.7 ml, 345 mmol) at 80 ° C for 4.5 hours. After cooling to room temperature, the resulting white crystals were washed with ether / hexane and collected to obtain (S) -2-benzylamino-1- (4-chlorophenyl) -ethanol (23.8 g, 65.8%) . The excess benzylamine in the filtrate was distilled at 120 ° C under reduced pressure. From the residue, another (S) -2-benzylamino-1- (4-chlorophenyl) ethanol (2.41 g, 6.7%) was obtained. XH-NMR (CDC13) d: 2.68 (ΔI, dd, J = 12.3, 8.9 Hz), 2.92 (1H, dd, J = 12.3, 3.7 Hz), 3, 80 (1H, d, J = 11, 9 Hz), 3.86 (HH, d, J = 11, 9 Hz), 4.68 (HH, dd, J = 8.9 Hz, 3.7 Hz) 7.30 (9H, m).

To a suspension of (S) -2-benzylamino-1- (4-chlorophenyl) ethanol (15.76 g, 60.21 mmol) and triethylamine (33.6 mL, 241 mmol) in dichloromethane (300 mL) was added a thionyl chloride solution (4, 83 mL, 66.2 mmol) in dichloromethane (20 mL) at -78 ° C for 20 minutes. The resulting suspension was stirred at -78 ° C for 20 minutes and at 0 ° C for another 20 minutes. The reaction mixture was partitioned between ether and water, and the organic layer was washed with saline, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 10% -20% ethyl acetate-hexane) to give 2-oxide (2R, 5S) -3-benzyl-5- (4-chlorophenyl) -1, 2, 3-oxathiazolidine (16.2 g, 87.4%) as a pale yellow solid. The resulting product was obtained as a mixture of two diastereoisomers due to the S-oxide. Major isomer: ^ -NMR (CDC13) d: 3.31 (ÍH, dd, J = 10.5, 9.9 Hz), 3.55 (ÍH, dd, J = 9.0, 6.3 Hz) , 3.88 (HH, d, J = 13.2 Hz), 4.37 (HH, d, J = 13.2 Hz), 5.49 (HH, dd, J = 10.5, 6.3 Hz), 7.22-7.43 (9H, m). Minor isomer: XH-NMR (CDC13) d: 3.21 (ΔI, dd, J = 13.5, 4.5 Hz), 3.77 (ΔI, dd, J = 13.5, 11.4 Hz) , 4.05 (HH, d, J = 13.5 Hz), 4.38 (1H, d, J = 13.5 Hz), 5.99 (HH, dd, J = 11, 4, 4.5 Hz), 7.22-7.43 (9H, m).

A solution of (2R, 5S) -3-benzyl-5- (4-chlorophenyl) -1,2,3-oxathiazolidine 2-oxide (16.2 g, 52.6 mmol) and sodium azide (17, 11 g, 263.2 mmol) in N, N-dimethylformamide (100 ml) was heated at 70 ° C for 24 hours. The reaction mixture was partitioned between ether and water, and the organic layer was washed with water and saline successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: 10% -20% ethyl acetate-hexane) to give (R) -N-benzyl-2-azido-2- (4-chlorophenyl) ethylamine (12, 7 g, 83.8%) as a yellow oil. XH-NMR (CDC13) d: 2.81 (ΔI, dd, J = 12.5, 5.1 Hz), 2.89 (ΔI, dd, J = 12.5, 8.5 Hz), 3, 82 (2H, s), 4.64 (1H, dd, J = 8.5, 5.1 Hz), 7.23-7.36 (9H,).

A solution of (R) -N-benzyl-2-azido-2- (4-chlorophenyl) ethylamine (12.7 g, 44.1 mmol) in tetrahydrofuran (176 ml) was treated with triphenylphosphine (13.9 g, 52.9 mmol) at room temperature.

After adding water (20 ml), the reaction mixture was heated at 60 ° C for 1 hour. The reaction mixture was condensed, and partitioned between ether and 1 N hydrochloric acid. The aqueous layer was treated with a 1 N aqueous sodium hydroxide solution until the solution became basic. The resulting solution was extracted with dichloromethane completely. The combined organic layer was washed with water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was used for the next reaction without further purification.

The residue was heated with diethyl oxalate (18 ml, 132 mmol) at 120 ° C for 1.5 hour. The resulting white precipitate was washed with ether and collected to give (R) -l-benzyl-5- (4-chlorophenyl) -2,3-dioxopiperazine (11.4 g, 82.2%). ^? - NMR (CDC13) d: 3.46 (1H, dd, J = 12.9, 8.1 Hz), 3.60 (1H, dd, J = 12.9, 3.8 Hz), 4 , 48 (HH, d, J = 14.7 Hz), 4.79 (HH, d, J = 14.7 Hz), 4.80 (HH, dd, J = 8.9, 3.8 Hz) , 6.83 (HH, s), 7.13 (4H, m), 7.27 (5H, m).

To a solution of (R) -l-benzyl-5- (4-chlorophenyl) -2,3-dioxo-iperazine (11.4 g, 36.3 mmol) in tetrahydrofuran (300 mL) was added a borane- tetrahydrofuran (181 ml, 1.0 M solution in tetrahydrofuran, 181 mmol) at room temperature. After stirring for 24 hours, the reaction mixture was quenched with methanol (50 ml) at 0 ° C, and concentrated under reduced pressure. The residue was treated with a 10% aqueous sodium hydroxide solution (300 ml) and heated at 100 ° C for 2 hours. After cooling to room temperature, the mixture was extracted with dichloromethane completely. The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was used for the next reaction without further purification.

To a solution of the residue and triethylamine (7.58 ml, 54.4 mmol) in dichloromethane (150 ml) was added di-tert-butyl dicarbonate (9.49 g, 43.5 mmol) at room temperature. After stirring for 45 minutes, the resulting mixture was partitioned between dichloromethane and water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 10% -20% ethyl acetate-hexane) to obtain (R) -l-benzyl-4- (tert-butoxycarbonyl) -3- (4-chlorophenyl) piperazine (11.6 g, 82.8 %) as an oil. aH-NMR (CDC13) d: 1.43 (9H, s), 2.16 (1H, dt, J = 4, 4, 11.7 Hz), 2.40 (1H, dd, J = 4.4 , 11.7 Hz), 2.78 (ΔI, dd, J = 4, 4, 11.7 Hz), 2.98 (HH, dt, J = 4.4, 11.7Hz), 3.20 (HH, d, J = 12.8Hz), 3.42 (HH, d, J = 12.9Hz), 3, 57 (HH, d, J = 12.9 Hz), 3.89 (1H, d, J = 12.8 Hz), 5.17 (HH, s), 7.24-7.36 (9H,) .

To a solution of (R) -l-benzyl-4- (tert-butoxycarbonyl) -3- (4-chlorophenyl) piperazine (11.6 g, 30.1 mmol) in 1,2-dichloroethane (80 ml) was added 1-chloroethyl chloroformate (4.91 ml, 45.1 mmol) at room temperature. When the initial material disappeared, the reaction mixture was concentrated under reduced pressure. The residue was then dissolved in methanol (100 ml) and refluxed for 30 minutes. The resulting white precipitate was filtered and washed with methanol to give (R) -2- (4-chlorophenyl) piperazine dihydrochloride, a solution of aqueous sodium hydroxide, and extracted with dichloromethane to give (R) -2- (4-chlorophenyl) piperazine (3.04 g, 51.4%) as a white solid. ^ -NR (CDC13) d: 2.65 (H, dd, J = 12.0, 10.5 Hz), 2.82-3.04 (4H, m), 3.09 (H, d, J) = 12.6 Hz), 3.73 (1H, dd, J = 10, 1, 2.7 Hz), 7.29 (4H, m).

The filtrate was concentrated under pressure and partitioned between ether and 1N hydrochloric acid. The aqueous layer was neutralized with a 1N aqueous sodium hydroxide solution, and extracted with dichloromethane completely. The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified after Boc protection (BocO, Et3N, CH2C12 to give (R) -1,4-di (tert-butoxycarbonyl) -2- (4-chlorophenyl) piperazine (2.70 g, 22.6 %) as a pale yellow solid, XH-NMR (CDCl 3) d: 1.43 (9H, s), 1.46 (9H, s), 2.96 (2H, m), 3.32 (1H, dd) , J = 13.8, 4.2 Hz), 3.74 (HH, m), 3.94 (HH, m), 3.94 (HH, d, J = 11, 4 Hz), 4.40 (ÍH, d, J = 13.2 Hz), 5.23 (1H, s), 7.25 (2H, m).

To a suspension of (R) -2- (4-chlorophenyl) piperazine dihydrochloride (1.09 g, 4.05 mmol) in tetrahydrofuran (24 mL) was added to triethylamine (2.82 mL, 20.3 mmol) . After stirring for 15 minutes at room temperature, 2-chloro-3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one (748 mg, 3.38 mmol) was added in portions. When the chloropyrimidone disappeared, the reaction mixture condensed under reduced pressure. The residue was partitioned between a solution of saturated aqueous sodium bicarbonate and dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a pale yellow solid, which was recrystallized from ethanol to give (R) -2- (2- (4-chlorophenyl) piperazine-4 -yl) -3-methyl-6- (4-pyridyl) -pyrimidin-4-one (998 mg, 77.4%) as white crystals. The excess of enantiomer was determined by HPLC. { > 99%). The crystals were converted to the dihydrochloride salt.

^ -NMR (CDC13) d: 3.40 (3H, m), 3.46 (3H, s), 3.62 (1H, dd, J = 12.0, 13.2 Hz), 3.72 (HH, m), 3.92 (HH, t, J = 15.5 Hz), 4.68 (ÍH, t, J = 10, l Hz), 7.18 (lH, s), 7.58 (2H, d, J = 8.6 Hz), 7.83 (2H, d, J = 8, 6 Hz), 8, 57 (2H, d, J = 6, 6 Hz), 9, 01 (2H, d, J = 6, 6 Hz), 10, 20 (H) , d, J = 7, 8 Hz), 10, 76 (1H, br s). MS: 382 (M + H) [a] d 24 = +62, 2 ° (c 1, 00, H20) Example 6: Synthesis of (S) -2- (2- (4-chlorophenyl) piperazin-4-yl ) -3-methyl-6- (4-pyridyl) -pyrimidin-4-one (N ° XA373) The (S) isomer was prepared in the same manner as the previous one using (R) -2-methyl-CBS-oxazaborolidine in place of (S) -2-methyl-CBS-oxazaborolidine. aH-NMR (CDC13) d: 3.40 (3H, m), 3.45 (3H, s), 3.58-3.96 (3H, m), 4.68 (1H, t, J = 13 , 5 Hz), 7.10 (ÍH, s), 7.60 (2H, d, J = 8.3 Hz), 7.76 (2H, d, J = 8.3 Hz), 8.38 ( ÍH, br s), 8.91 (HH, d, J = 4.8 Hz), 9.88 (HH, br s), 10.31 (HH, br s). MS: 382 (M + H) [a] d 24 = -63.3 ° (c 1.00, H20) Example 7: Synthesis of 2- (2- (4-fluoro-2-methoxyphenyl) piperazin-4-yl) -3-methyl-6- (4-pyrimidyl) -pyrimidin-4-one (No. YA0366) A solution of 2-bromo-5-fluoroanisole (11.8 g, 57.6 mmol) in tetrahydrofuran (60 ml) was dripped into magnesium (1.40 g, 57.6 mmol) in refluxed tetrahydrofuran (32 ml). which contained a small amount of 1,2-dibromoethane and refluxed for 15 minutes. After adding tetrahydrofuran (50 ml), the solution was cooled to -78 ° C and diethyl oxalate (7.41 g, 50.7 mmol) in diethyl ether (50 ml) was added dropwise in the solution. After stirring at the same temperature for 30 minutes, the solution was warmed to -10 ° C and IN aqueous hydrogen chloride (50 ml) and water were added. The organic layer was extracted with diethyl ether, washed with saline and dried over magnesium sulfate. After removing the solvent under reduced pressure, purification of the residue by silica gel column chromatography (eluent: hexane / vinyl acetate = 5/2) gave 2- (4-fluoro-2-methoxyphenyl) -2-oxoacetate. of ethyl (6.80 g, 59%). XH-NMR (CDC13) d: 1.40 (3H, t, J = 7, 1 Hz), 3.87 (3H, s), 4.89 (2H, q, J = 7, 1 Hz), 6 , 68 (1H, d, J = 10.5 Hz), 6.77-6.81 (1H, m), 7.91-7.95 (1H, m) Ethylenediamine (0.60g, 10mg) was added. , 0 mmol) was added to a solution of ethyl 2- (4-fluoro-2-methoxyphenyl) -2-oxoacetate (2.26 g, 10.0 mmol) in ethanol (30 ml) and refluxed for 4 hours. After removing the solvent under reduced pressure, the residue was washed with ethanol-diethyl ether to give 5,6-dihydro-3- (4-fluoro-2-methoxyphenyl) pyrazinone (1.76 g, 79%). XH-NMR (CDCl 3) d: 3.50-3.56 (2H, m), 3.81 (3H, s), 3.88-3.92 (2H, m), 6.65 (1H, d) , J = 11.0 Hz), 6.70-6.76 (HH, m), 6.89 (HH, bs), 7.36-7.40 (HH, m) ,6-Dihydro-3- (4-fluoro-2-methoxyphenyl) pyrazinone was added to the solution of lithium aluminum hydride (0.46 g, 12 mmol) in diethyl ether (25 ml) and refluxed for 6 hours. hours. Water (0.48 ml), a 15% sodium hydroxide solution (0.48 ml) and again water (1.21 ml) were added to the ice-cooled solution and the precipitate was filtered and washed with dichloromethane. . The combined organic layer was evaporated to give 2- (4-fluoro-2-methoxyphenyl) piperazine (0.83 g, 99%). XH-NMR (CDC13) d: 2.02 (2H, s), 2.57-2.63 (1H, m), 2.80-2.89 (IN, m), 2.92-2.99 (2H, m), 3.06-3.12 (2H, m), 3.80 (3H, s), 4.06 (IH, d, J = 10.0 Hz), 6.56-6, 65 (2H, m), 7.40 (ÍH, t, J = 7.8 Hz) 2-Chloro-3-methyl-6- (4-pyrimidyl) -pyrimidin-4-one (223 mg, 1.0 mmol) was added to an ice-cooled solution of 2- (4-fluoro-3-methoxyphenyl) piperazine (210 mg, 1.0 mmol), triethylamine (0.15 mL, 1.1 mmol) in N, N-dimethylformamide (10 mL) and stirred at that temperature for 0.5 hour and then at room temperature during 3 hours . The reaction was quenched with ice water and the filtrate was washed with water and dried to give 2- (2- (4-fluoro-2-methoxyphenyl) piperazin-4-yl) -3-methyl-6- (4-pyrimidyl) ) -pyrimidin-4-one (262 mg, 66%). XH-NMR (CDC13) d: 2.89-2.98 (1H, m), 3.22-3.31 (3H, m), 3.60 (3H, s), 3.62-3.71 (2H, m), 3.86 (3H, s), 4.39-4.44 (HH,), 6.43-6.73 (2H, m), 7.33 (HH, s), 7 , 52-7.56 (HH, m), 8.19 (HH, d, J = 5, Hz Hz), 8.87 (HH, d, J = 5.2 Hz), 9.28 (HH, d, J = 1, 2 Hz). 4N hydrogen chloride in 1,4-dioxane (0.2 ml) was added to the solution of 2- (2- (4-fluoro-2-methoxyphenyl) piperazin-4-yl) -3-methyl-6- ( 4-pyrimidyl) -pyrimidin-4-one (238 mg, 0.6 mmol) in dichloromethane (5 ml) and stirred for 15 minutes. Washing with methanol and ethyl acetate after removal of the solvent and drying gave the title compound (223 mg, 86%).

Example 8: Synthesis of 2- (2- (4-chlorophenyl) -piperazin-4-yl) -3-methyl-6- (4-pyrimidyl) pyrimidin-4-one (No. YA0269) A solution in dimethyl sulfoxide (60 ml) of 4-chlorophenacyl bromide (11.11 g, 65.9 mmol) and water (1.7 ml) were stirred.

The solution was extracted with ethyl acetate three times and washed with water twice and saline and then dried over sodium sulfate. After removal of the solvent, the residue was washed with hexane-ethyl acetate and dried to give 4-chlorophenylglyoxal (4.43 g, 50%). XH-NMR (CDC13) d: 4.02-4.16 (2H, m), 5.90-5.95 (1H,), 7.45-7.53 (2H, m), 8.05- 8.11 (2H, m).

A solution in methanol (10 ml) of ethylenediamine (1.90 g, 31.6 mmol) was added to the ice-cooled solution of 4-chlorophenylglyoxal (4.43 g, 26.3 mmol) in methanol (100 ml). and tetrahydrofuran (30 ml) and stirred for 10 minutes. After adding sodium tetrahydroborate (3.26 g, 86.3 mmol), additional methanol (50 mL) was added and stirred overnight. After removing the solvent, dilute hydrochloric acid was added and extracted with ether twice. After adding sodium hydroxide, the basic aqueous layer was extracted with dichloromethane three times and washed with saline and dried over sodium sulfate. After removing the solvent by filtration, purification of the residue by column chromatography on silica gel (eluent: dichloromethane / ethanol = 10/1 to dichloromethane / ethanol / diethylamine = 20/2/1) to give 2- (4- chlorophenyl) -piperazine (0.43 g, 9%). aH-NMR (CDC13) d: 2.67 (1H, dd, J = 10.5, 12.0 Hz), 2.87-3.03 (4H, m), 3.07-3.13 (1H) , m), 3.77 (ΔI, dd, J = 2.7, 10.2 Hz), 7.27-7.36 (4H, m).

Triethylamine (528 mg, 5.2 mmol) was added to a solution of 4- (chlorophenyl) piperazine (216 mg, 1.1 mmol) and 2-chloro-3-methyl-6- (4-pyrimidyl) pyrimidine-4. -one and stirred at 50 ° C for 2 hours. The solvent was removed under reduced pressure, and a solution of aqueous sodium hydroxide IN was added to the residue and extracted by dichloromethane. After washing with saline and drying with sodium sulfate, the solvent was removed under reduced pressure, and the residue was purified using ISOLUTE® SI (International Solvent Technology, United Kingdom) (eluent; dichloromethane / ethanol = 10/1) to give the title compound (396 mg, 95%).

Example 9: Synthesis of 2- (2- (4-chlorophenyl) -6,6-dimethyl-piperazin-4-yl) -3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one dihydrochloride (No. XA1986) A solution of 4'-chloro-2-bromoacetophenone (25.0 g, 107 mmol), water (1.92 mL, 107 mmol) and 47% hydrobromic acid (0.20 mL) in sulfoxide of dimethyl (160 ml) was stirred at 80 ° C for 5 hours. After the reaction mixture was poured into water, the precipitate was filtered, washed with diethyl ether and dried, yielding 4'-chloro-2,2-dihydroxyacetophenone (14.0 g, 70%). aH-NMR (300 MHz, CDC13) d: 5.92 (OH, s), 7.45-7.52 (2H, m), 8.05-8.20 (2H, m) 2, 2-Dimethyl-ethylenediamine (2.10 ml, 20.0 mmol) was added to a solution of 4'-chloro-2,2-dihydroxyacetophenone (3.70 g, 20.0 mmol) in methanol (120 ml. ) and tetrahydrofuran (30 ml) at room temperature. After 2 hours, sodium borohydride (1.50 g, 40.0 mmol) was added to the reaction mixture at 0 ° C. The reaction mixture was stirred overnight, then cooled with IN hydrochloric acid and evaporated in vacuo. The acid solution was extracted with ethyl acetate, then basified to pH 11 using 15% aqueous sodium hydroxide and extracted with dichloromethane. The extract was dried over sodium sulfate and concentrated in vacuo. Di-t-butyldicarbonate (6.40 mL, 27.9 mmol) was added to the solution of the residue in IN aqueous sodium hydroxide (40 mL) and tetrahydrofuran (60 mL). The resulting suspension was heated at 40 ° C for 8 hours, then diluted with ethyl acetate and water. The organic layer was further ethyl acetate, dried and concentrated in vacuo. The crude product was purified by flash column chromatography to give 2- (4-chlorophenyl) -4-t-butoxycarbonyl-6,6-dimethyl-piperazine (1.69 g, 28%, 2 steps). ^? - NMR (300 MHz, CDCl3) d: 1.15 (3H, s), 1.21 (3H, s), 2.47-2.70 (2H, m), 3.72-4.16 (3H, m), 7.26-7.37 (4H, m) 4M Hydrogen chloride in ethyl acetate (5.0 mL, 20.0 mmol) was added to a solution of 2- (4-chlorophenyl) -4-t-butoxycarbonyl-6,6-dimethyl-piperazine (1.69 g, 5.2 mmol). After 12 hours, removing the solvent, filtering and washing the precipitate with diethyl acetate gave 2- (4-chlorophenyl) -6,6-dimethyl-piperazine dihydrochloride (1.43 g, 95%).

XH-NMR (300 MHz, DMS0-d6) d: 1.40 (3H, s), 1.58 (3H, s), 3.24-3.99 (4H, m), 4.73 (1H, m), 7.69 (2H, d, J = 8.4 Hz), 7.79 (2H,), 9.99-10.12 (2H, m) A solution of 2- (4-chlorophenyl) -6,6-dimethyl-piperazine hydrochloride (155 mg, 0.52 mmol), 2-chloro-3-methyl-6- (4-pyridyl) -pyrimidin-4- ona (111 mg, 0.50 mmol) and triethylamine (0.42 ml, 2.50 mmol) in tetrahydrofuran (5 ml) was stirred at room temperature for 6 hours. All was evaporated in vacuo and the residue was extracted with dichloromethane. The organic layer was washed with water, dried and concentrated in vacuo. The residue was dissolved in methanol (5 ml) and treated with 4M hydrogen chloride in ethyl acetate (0.50 ml, 2.0 mmol) for 20 minutes. After removing the solvent, filtering and washing the precipitate with ethanol gave 2- (2- (4-chlorophenyl) -6,6-dimethyl-piperazin-4-yl) -3-methyl-6-pyridine dihydrochloride. 4-yl-3H-pyrimidin-4-one (235 mg, 97%).

Example 10: Synthesis of 2- (2S- (4-bromophenyl) -piperazin-1-yl) -3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one (No. XA2051) Benzyl chloroformate (2.40 ml, 15.0 mmol) was added to a solution of 2S- (4-bromophenyl) -piperazine dihydrochloride in IN sodium aqueous hydroxide (30 ml) and dichloromethane (60 ml). The resulting suspension was stirred at room temperature for 1.5 hour. After partitioning between ethyl acetate, the organic layer was extracted with additional ethyl acetate, dried and concentrated in vacuo. The precipitate was washed with ether, to give 2S- (4-bromophenyl) - - bnecyloxycarbonyl - piperazine (2.92 g, 57%). XH-NMR (300 MHz, CDCl 3) d: 2.87-3.01 (2H, m), 3.47 (2H, m), 3.93-3.97 (1H, m), 4.20 ( 2H, m), 5.16 (2H, s), 7.36 (5H, m), 7.42-7.61 (4H, m) A solution of 2S- (4-bromophenyl) - -benzyloxycarbonyl-piperazine (788 mg, 2.10 mmol), 2-chloro-3-methyl-6- (4-pyridyl) -pyrimidin-4-one (444 mg, 2.00 mmol) and diisopropylethylamine (0.70 mL, 4, 00 mmol) in dimethylformamide (20 ml) was stirred at 80 ° C for 3 hours. The reaction mixture was poured into water and all was extracted with ethyl acetate. The organic layer was washed with saline, dried and concentrated in vacuo. Chromatographic purification of the residue provided 2- (2S- (4-bromophenyl) -4-benzyloxycarbonyl-piperazin-1-yl)) - 3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one (601 mg, 54%). XH-NMR (300 MHz, CDCl 3) d: 3.05 (1H, m), 3.30-3.48 (3H, m), 3.64 (3H, s), 4.08-4.22 (2H, m), 4.68 (HH, m), 5.15 (1H, d, J = 12.3 Hz), 5.21 (HH, d, J = 12.6 Hz), 6.63 (HH, s), 7.21 (2H, d, J = 8.4 Hz), 7.28-7, 39 (7H,), 7.59 (2H, d, J = 6.3 Hz), 8.68 (2H, d, J = 6.3 Hz).

Potassium hydroxide (168 mg, 3.0 mmol) was added to a solution of 2- (2S- (4-bromophenyl) -4-benzyloxycarbonyl-piperazin-1-yl) -3-methyl-6-pyridin-4- il-3H-pyrimidin-4-one in ethanol (2.0 ml). After stirring for 8 hours at room temperature, purification by preparative HPLC gave 2- (2S- (4-bromophenyl) -piperazin-1-yl) -3-methyl-6-pyridin-4-yl-3H-pyrimidin-4- ona (40 mg, 26%).

Example 11: Synthesis of (S) -3-methyl-6- (4-pyridyl) -2- (3- (4- (3- (pyrimidin-1-yl) -pyrrolidin-1-yl) phenyl) piperazine- 1-yl) pyrimidin-4-one (No. XA2032) A suspension of (S) -2- (4-bromophenyl) -1,4-di (t-butoxycarbonyl) piperazine (1.33 g, 3.00 mmol ), (R) -3-pyrrolidinol (520 mg, 4.20 mmol), palladium acetate (27 mg, 0.12 mmol), 2- (di-t-butylphosphino) biphenyl (72 mg, 0.24 mmol ), and sodium t-butoxide (808 mg, 8.41 mmol) in tert-butanol (20 ml) was heated at 90 ° C for 3.5 hours. After dissolution with ethyl acetate, the resulting mixture was passed through a Celite column. The filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography eluting with 10% -50% ethyl acetate-hexane to give (S) -1,4-di- (t-butoxycarbonyl) 2- (4- ((R) -3-hydroxypyrrolidino) phenyl) piperazine (733 mg, 54.5%) as a yellow foam. To a solution of (S) -1,4-di (t-butoxycarbonyl) -2- (4- ((R) -8-hydroxy-pyrrolidino) phenyl) piperazine (733 mg, 1.64 mmol) and triethylamine ( , 34 mL, 2.46 mmol) in dichloromethane (20 mL) was added methanesulfonyl chloride (0.152 mL, 1.97 mmol) at 0 ° C. After stirring for 20 minutes, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with saline, dried over anhydrous sodium sulfate and concentrated in vacuo to give (S) -1,4-di (t-butoxycarbonyl) -2- (4- ((R) -3- (methanesulfonyloxy) pyrrolidin-1-yl) phenyl) piperazine (877 mg, quant.) as a brown solid. To a solution of (S) -1,4-di (t-butoxycarbonyl) -2- (4- ((R) -3-methanesulfonyloxy-pyrrolidino) phenyl) piperazine (877 mg, 1.64 mmol) in toluene ( 10 ml) was added pyrrolidine (0.64 ml, 8.19 mmol) and the resulting solution was heated at 90 ° C for 8 hours. After verifying the consumption of the starting material with TLC, the reaction mixture was partitioned between ethyl acetate and an aqueous solution of saturated sodium bicarbonate. The organic layer was washed with saline, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 80% -100% ethyl acetate-hexane and then with 3% -10% methanol-ethyl acetate to give (S) -1,4-di. (t-butoxycarbonyl) -2- (4- ((S) -3- (pyrrolidin-1-yl) pyrrolidin-1-yl) phenyl) piperazine (479 mg, 58%) as a pale yellow powder. To a solution of (S) -1,4-di (t-butoxycarbonyl) -2 - (4- ((S) -3- (pyrrolidin-1-yl) pyrrolidin-1-yl) phenyl) piperazine (479 mg , 0.957 mmol) in dichloromethane (4 ml) was added to 4N hydrogen chloride in ethyl acetate (4 ml) at room temperature. After stirring for 3 hours, the resulting precipitate was collected and dried in vacuo to give (S) -2- (4- ((S) -3- (pyrrolidin-1-yl) pyrrolidin-1-yl tetrachlorohydrate) phenyl) piperazine (370 mg, 87%) as a white solid. To a suspension of (S) -2- (4- ((S) -3- (pyrrolidin-1-yl) pyrrolidin-1-yl) phenyl) piperazine tetrahydrochloride (98 mg, 0.22 mmol) in tetrahydrofuran ( 5 ml) triethylamine (0.20 ml, 1.40 mmol) and 2-chloro-3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one (44 mg, 0.20 mmol) at room temperature. After stirring for 24 hours, the reaction mixture was concentrated in vacuo. The residue was dissolved in dichloromethane and an aqueous solution of sodium bicarbonate and the solution was passed through CHEM ELUT CE1010 (manufactured by VARIAN). The filtrate was concentrated and the resulting crystals were washed in a mixture of diisopropyl ether and ethanol to give (S) -2- (3- (4- (3- (pyrrolidin-1-yl) pyrrolidin-1-yl) phenyl ) piperazin-1-yl) -3-methyl-6- (4-pyridyl) pyrimidin-4-one (80 mg, 82%) as a pale yellow solid.

Example 12: Synthesis of (S) -3-methyl-6- (4-pyrimidinyl) -2- (3- (pyrrolidin-1-yl) -pyrrolidin-1-yl) phenyl) piperazin-1-yl) pyrimidine- 4-one (No. YA1577) To a suspension of (S) -2- (4- ((S) -3- (pyrrolidin-1-yl) pyrrolidin-1-yl) phenyl) piperazine tetrachlorohydrate (99 mg, 0.22 mmol) in tetrahydrofuran (5 ml) was added triethylamine (0.20 ml, 1.40 mmol) and 2-chloro-3-methyl-6- (4-pyrimidinyl) -3H-pyrimidin-4-one. (45 mg, 0.20 mmol) at room temperature. After stirring for 24 hours, the reaction mixture was concentrated in vacuo. The residue was dissolved in dichloromethane and an aqueous solution of sodium bicarbonate and the solution was passed through CHEM ELUT CE1010 (manufactured by VARIAN). The filtrate was concentrated, and the resulting crystals were washed in a mixture of diisopropyl ether and ethanol to give (S) -3-methyl-6- (4-pyrimidinyl) -2- (3- (4- (3- ( pyrrolidin-1-yl) pyrrolidin-1-yl) phenyl) piperazin-1-yl) -pyrimidin-4-one (65 mg, 66%) as a pale yellow solid.

Example 13: Synthesis of (S) -2- (3- (4- (β-cyclohexyl-β-methylamino) phenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -pyrimidin-4 -one (? ° XA1999) A suspension of (S) -2- (4-bromophenyl) -1,4-di (t-butoxycarbonyl) piperazine (1.21 g, 2.75 mmol),? -methylcyclohexylamine (0) , 43 mL, 3.30 mmol), palladium acetate (25 mg, 0.11 mmol), 2- (di-t-butoxyphosphino) biphenyl. { 66 mg, 0.22 mmol) and sodium t-butoxide (370 mg, 3.85 mmol) in t-butanol (15 ml) was heated at 80 ° C for 8 hours. The resulting solution was partitioned between ethyl acetate and water. The organic layer was washed with saline, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 10% -15% ethyl acetate-hexane to give (S) -1,4-di (t-butoxycarbonyl) -2- (4- (N- cyclohexyl-N-methylamino) phenyl) piperazine (917 mg) as white crystals. To a solution of (S) -1,4-di (t-butoxycarbonyl) -2- (4- (N-cyclohexyl-N-methylamino) phenyl) piperazine in dichloromethane (4 ml) was added 4N hydrogen chloride in acetate of ethyl (4 ml). After stirring for 40 minutes, the white precipitate, which included the impurities, was collected. The mixture was purified by reverse phase chromatography eluting with 0.06% TFA in water-acetonitrile to give (S) -2- (4- (N-cyclohexyl-N-methylamino) phenyl) piperazine (59 mg, 8% 2 steps) as a transparent oil. To a solution of (S) -2- (4- (N-cyclohexyl-N-methylamino) phenyl) piperazine (50 mg, 0.183 mmol) and triethylamine (0.077 mL, 0.55 mmol) was added 2-chloro-3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one (37 mg, 0.17 mmol) at room temperature.

After stirring for 4.5 hours, the reaction mixture was concentrated in vacuo. The residue was partitioned between dichloromethane and an aqueous solution of saturated sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by reverse phase chromatography eluting with 0.05% TFA in water-acetonitrile to give (S) -2- (3- (4- (N-cyclohexyl-N-methylamino) phenyl) piperazin-1-yl. ) -3-methyl-6- (4-pyridyl) pyrimidin-4-one (67-g, 88%) as an oil, which was dissolved in ethyl acetate and treated with 4N hydrogen chloride in ethyl acetate give trichlorhydrate.

Example 14: Synthesis of (S) -2- (3- (4- (N) trichlorohydrate, N-dimethylamino) phenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) pyrimidin-4-one (N ° XA2017) A suspension of (S) -2- (4-bromophenyl) - 1,4-di (t-butoxycarbonyl) piperazine (1.14 g, 2.59 mmol), N, N-dimethylamine hydrochloride (422 mg, 5.17 mmol), palladium acetate (23 mg, 0.10 mmol), 2- (di-t-butylphosphino) biphenyl (62 mg, 0.21 mmol) and sodium t-butoxide (845 mg, 8.80 mmol) in t-butanol (15 ml) was heated to 90 °. C for 3 hours. After diluting with ethyl acetate, the resulting solution was passed through a Celite column. The filtrate was concentrated, and the residue was purified by silica gel column chromatography eluting with 10% -20% ethyl acetate-hexane to give (S) -1,4-di (t-butoxycarbonyl) -2- (4- (N, N-dimethylamino) phenyl) piperazine (556 mg, 53%) as white crystals. To a solution of (S) -1,4-di (t-butoxycarbonyl) -2- (4- (N, N-dimethylamino) phenyl) piperazine (556 mg, 1.37 mmol) in dichloromethane (4 ml) was added 4 N hydrogen chloride in ethyl acetate (4 ml). After stirring for 8.5 hours, the white precipitate was collected and dried to give (S) -2- (4- (N, -dimethylamino) phenyl) piperazine trichlorohydrate (413 mg, 96%) as white crystals. To a suspension of (S) -2- (4- (N, N-dimethylamino) phenyl) piperazine trichlorohydrate (115 mg, 0.365 mmol) in tetrahydrofuran (5 ml) was added triethylamine (0.28 ml, 2.0 mmol) and then 2-chloro-3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one (74 mg, 0.33 mmol) at room temperature. After stirring for 10 hours, the resulting mixture was concentrated in vacuo. The residue was dissolved in dichloromethane and an aqueous solution of saturated sodium bicarbonate, and the solution was passed through CHEM ELUT CE1010 (manufactured by VARIAN). The filtrate was concentrated in vacuo to give crystals, which were washed with diisopropyl ether. After the crystals were dissolved in ethyl acetate, the solution was treated with 4N hydrogen chloride in ethyl acetate. The white precipitate was collected and dried in vacuo to give (S) -2- (3- (4- (N, N-dimethylamino) phenyl) piperazin-1-yl) -3-methyl-6- (4-trichlorohydrate. pyridyl) pyrimidin-4-one (135 mg, 81%).

Example 15: Synthesis of (S) -2- (3- (4-methoxybifen-4-yl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) pyrimidin-4-one (No. XA1991 ) A mixture of (S) -2- (4-bromophenyl) -1,4-di (t-butoxycarbonyl) piperazine (1.82 mg, 4.11 mmol), 4-methoxyphenylboronic acid (937 mg, 6.17 g) mmol), sodium carbonate (2.18 g, 20.6 mmol) and tetrakis (triphenylphosphino) palladium (0) (238 mg, 0.206 mmol) was dissolved in dimethoxyethane (20 ml) and water (20 ml) and the solution The resultant was refluxed for 3 hours. After cooling to room temperature, the mixture was partitioned between ethyl acetate and water. The organic layer was washed with saline, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting solid was washed with ethyl acetate to give (S) -1,4-di (t-butoxycarbonyl) 2- (4'-methoxybifen-4-yl) piperazine (1.46 g, 75.9%) as a white solid. To a solution of (S) -1,4-di (t-butoxycarbonyl) -2- (4'-methoxybifen-4-yl) piperazine (1.46 g, 3.12 mmol) in dichloromethane (8 ml) was added to 4N hydrogen chloride in ethyl acetate (8 ml) at room temperature. After stirring for 1 hour, the precipitate was collected and dried under vacuum to give (S) -2- (4'-methoxybifen-4-yl) piperazine dihydrochloride (1.00 g, 94%) as a white solid .

To a suspension of (S) -2- (4'-methoxybifen-4-yl) -piperazine dihydrochloride (237 mg, 0.694 mmol) in tetrahydrofuran (5 ml) was added triethylamine (0.40 ml, 2.9 mmol ) and then 2-chloro-3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one (128 mg, 0.579 mmol) at room temperature. After stirring for 28 hours, the resulting mixture was concentrated in vacuo. The residue was partitioned between dichloromethane and an aqueous solution of saturated sodium bicarbonate, and the organic layer was dried over anhydrous sodium sulfate and then concentrated in vacuo. The resulting solid was washed with hot ethanol to give (S) -2- (3- (4-meoxybiphenyl) -yl piperazin-lyl) -3-methyl-6- (4-pyridyl) pyrimidin-4-one ( 252 mg, 96%) which was treated with 4N hydrogen chloride in ethyl acetate to give its dihydrochloride salt (252 mg) as pale yellow crystals.

Example 16: Synthesis of (S) -2- (3-benzylpiperazin-1-yl) -3-methyl-6- (4-pyridyl) pyrimidin-4-one (No. XA2004) To a solution of ethyl ester hydrochloride of L-phenylalanine (3.875 g, 16.87 mmol), Boc-glycine (2.815 g, 16.07 mmol) in dichloromethane (100 mL) was added triethylamine (2.85 mL, 16.87 mmol) and then chloroformate. 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (3.23 g, 16.87 mmol) at room temperature. After the resulting mixture was stirred for 2.5 hours, it was partitioned between ethyl acetate and water. The organic layer was washed with 1N hydrochloric acid, saline, and then an aqueous saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated in vacuo to give Boc-glycylphenylalanine ethyl ester (5.96 g. ). To a solution of ethyl ester of Boc-glycylphenylalanine (5.96 g) in dichloromethane (20 ml) was added trifluoroacetic acid (20 ml) at room temperature. After stirring for 1.5 h, the resulting solution was concentrated in vacuo. The residue was dissolved in water, where sodium bicarbonate was added until the pH was 9. After the solution was stirred for several hours, the resulting white crystals were collected and dried in vacuo to give (S) -3 -bencil-2, 5-dioxopiperazine (2.29 g, 70% in 2 steps) as a white powder. To a suspension of (S) -3-benzyl-2,5-dioxopiperazine (2.244 g, 11.18 mmol) in tetrahydrofuran (20 ml) was added a borane-tetrahydrofuran complex (49 ml, 1.0 M solution in THF, 49 mmol) at room temperature. The resulting mixture was refluxed for several hours before cooling with methanol at 0 ° C. After concentration in vacuo, the residue was treated with a 10% sodium hydroxide solution, which was thoroughly examined with dichloromethane. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo to give white crystals, which were washed with ether to give (S) -2-benzylpiperazine (795 mg, 40.3%).

To a solution of (S) -2-benzylpiperazine (48 mg, 0.27 mmol) in tetrahydrofuran (5 ml) was added triethylamine (0.10 ml, 0.74 mmol) and then 2-chloro-3-methyl- 6- (4-pyridyl) -3H-pyrimidin-4-one (55 mg, 0.248 mmol) at room temperature. After refluxing for 24 hours, the resulting mixture was concentrated in vacuo. The residue was partitioned between dichloromethane and an aqueous solution of saturated sodium bicarbonate, and the organic layer was dried over anhydrous sodium sulfate and then concentrated in vacuo. The residue was purified by inverted phase chromatography eluting with 0.05% TFA in water-acetonitrile to give (S) -2- (3-benzylpiperazin-1-yl) -3-methyl-6- (4-pyridyl) pyrimidine. -4-one (73 mg, 81%), which was treated with 4 N hydrogen chloride in ethyl acetate to give its dihydrochloride salt as a yellow powder.

Example 17: Synthesis of (S) -3-methyl-2- (3- (4- (1, 2, 4-oxadiazol-3-yl) phenyl) piperazin-1-yl) -6- (4-pyridyl) pyrimidine- 4-one (No. XA2039) To a solution of 4-cyanoacetophenone (11.32 g, 77.98 mmol) in dichloromethane (200 ml) was added bromine (4.00 ml, 78.0 mmol) dropwise to room temperature . After stirring for several minutes, the reaction mixture was washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo to give 4-cyanophenacyl bromide (17.73 g) as a white solid. A solution of 4-cyanophenacyl bromide (11.20 g, 49.99 mmol) in dimethyl sulfoxide (83 ml) was treated with water (0.90 ml, 49.99 mmol). After stirring for 24 hours at room temperature, it was poured into ice water, and extracted with ether. The organic layer was washed with water and then with saline, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 20% -50% ethyl acetate in hexane to give 4-cyanophenylglyoxal (5.10 g, 64.1%) as a yellow solid. To a solution of 4-cyanophenylglyoxal (2.21 g, 12.5 mmol) in methanol (30 ml) and tetrahydrofuran (10 ml) was added ethylene diamine (1.00 ml, 14.96 mmol) at room temperature. After the mixture was stirred at room temperature for 1 hour, sodium borohydride (943 mg, 24.92 mmol) was added at 0 ° C. The solution was warmed to room temperature and stirred for another 2 hours before cooling with 1N hydrochloric acid. After concentration in vacuo, the mixture was partitioned between ether and water. The aqueous layer was alkalized with sodium hydroxide and extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate, and then concentrated in vacuo to give a reddish oil (1.69 g). The oil was dissolved in dichloromethane (80 ml), where triethylamine (3.82 ml, 27.41 mmol) and di-tert-butyl dicarbonate (5.98 g, 27.41 mmol) were added at room temperature. The reaction mixture was stirred for several hours before partitioning between ethyl acetate and water. The organic layer was dried over anhydrous sodium sulfate and then concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 5% -20% ethyl acetate in hexane to give 1,4-di (t-butoxycarbonyl) -2- (4-cyanophenyl) piperazine (2.46 g, 50.9%) as white crystals. A solution of 1,4-di (t-butoxycarbonyl) -2- (4-cyanophenyl) piperazine (558 mg, 1.44 mmol), hydroxylamine hydrochloride (300 mg, 4.23 mmol) and sodium carbonate (763) mg, 7.20 mmol) in ethanol (3 ml) and water (3 ml) was heated at 80 ° C for 2.5 hours before being partitioned between dichloromethane and water. The aqueous layer was extracted with dichloromethane. The combined organic layer was dried over sodium sulfate, and concentrated in vacuo to give a white foam (680 mg), which was dissolved in toluene (5 ml) and treated with triethyl orthoformate (2.4 ml, 14.4 mmol) and p-toluenesulfonic acid (27 mg, 0.14 mmol). The solution was heated at 90 ° C for 1 hour before it was partitioned between dichloromethane and an aqueous solution of saturated sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate, and concentrated in vacuum. The resulting white crystals were washed with ethyl acetate, and dried in vacuo to give 1,4-di (t-butoxycarbonyl) -2- (4- (1, 2,4-oxadiazol-3-yl) phenyl) piperazine (464 mg, 75% in 2 steps). To a solution of 1,4-di (t-butoxycarbonyl) 2- (4- (1, 2, 4-oxadiazol-3-yl) phenyl) piperazine (464 mg, 1.08 mmol) in dichloromethane (2 ml) 4N hydrogen chloride in ethyl acetate (3 ml) was added at room temperature. After stirring for 1.5 h, the precipitate was collected and dried under vacuum to give 2- (4- (1, 2, 4-oxadiazol-3-yl) phenyl) piperazine dihydrochloride (321 mg, 98%) like a white powder. To a suspension of 2- (4- (1, 2, -oxadiazol-3-yl) phenyl) piperazine dihydrochloride (102 mg, 0.34 mmol) in tetrahydrofuran (6 mL) was added triethylamine (0.23 mL, 1.65 mmdl) and then 2-chloro-3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one (73 mg, 0.33 mmol) at room temperature. After stirring for 24 hours, the resulting mixture was concentrated in vacuo. The residue was dissolved in dichloromethane and saturated aqueous sodium bicarbonate solution, and the solution was passed through CHEM ELUT CE1010 (manufactured by VARIAN). The filtrate was concentrated in vacuo to give crystals, which were washed with diisopropyl ether and ethanol to give (S) -2- (3- (4- (1, 2, 4-oxadiazol-3-yl) phenyl) piperazine- 1-yl) -3-methyl-6- (4-pyridyl) pyrimidin-4-one (102 mg, 74%) as a white powder.

Example 18: Synthesis of. 2- [4- (2-methoxyphenylamino) -piperidin-1-yl] -3-methyl-6- (pyridin-4-yl) -3H-pyrimidin-4-one (N ° XB276) To a solution of anisidine ( 3.1 g, 25.2 mmol) and 4-oxo-piperidine-l-carboxylic acid tert-butyl ester (5.0 g, 25.1 mmol) in methanol (100 ml) was added triacetoxyborohydride (13, 4 g, 63.2 mmol) at room temperature. After stirring for 6 hours, the resulting suspension was partitioned between ethyl acetate and 1N sodium hydroxide. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with saline, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 10% -20% ethyl acetate in hexane to provide 4- (2-methoxyphenylamino) -piperidine-1-carboxylic acid tert-butyl ester (2.7 g. 8.8 mmol, 35%) as a pale yellow oil. To a solution of 4- (2-methoxyphenylamino) -piperidine-1-carboxylic acid tert-butyl ester (2.7 g, 8.8 mmol) in methanol (30 mL) was added 4N hydrochloric acid in ethyl acetate (20 ml) at room temperature. After stirring for 1 hour, the resulting suspension was concentrated in vacuo. The residue was partitioned between chloroform and 1N sodium hydroxide. The aqueous layer was extracted with chloroform. The combined organic layer was washed with saline, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 10% -20% methanol in chloroform to provide 4- (2-methoxyphenylamino) -piperidine (1.8 g, 8.7 mmol, 99%) as white crystals. To a solution of 4- (2-methoxyphenylamino) -piperidine (0.8 g, 3.87 mmol) and triethylamine (1.3 g, 12.8 mmol) in tetrahydrofuran (20 mL) was added 2-chloro-3 methyl-6- (pyridin-4-yl) -3H-pyrimidin-4-one (0.8 g, 3.61 mmol) per portions. After stirring for 12 hours, the resulting suspension was partitioned between chloroform and IN sodium hydroxide. The aqueous layer was extracted with chloroform. The combined organic layer was washed with saline, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 5% -10% methanol in chloroform to provide 2- (4- (2-methoxyphenylamino) -piperidin-1-yl) -3-methyl-6- (pyridine). 4-yl) -3H-pyrimidin-4-one (1.2 g, 3.07 mmol, 85%) as white crystals.

Example 19: Synthesis of 3-methyl-2- (3- (4- (4-methylpiperidin-1-yl) -phenyl) -piperidin-1-yl) -6- (pyridin-4-yl) -3H- pyrimidin-4-one (No. XB278) A solution of (4-bromo-phenyl) -acetic acid ethyl ester (2.31 g, 9.50 mmol) in dimethyl sulfoxide (6 ml) was added to . the suspension of sodium hydride (407 mg, 60% in oil, 10.17 mmol) and stirred for 3 minutes. A solution of tert-butyl ester of (3-bromo-propyl) -carbamic acid (2.03 g, 8.52 mmol) in dimethyl sulfoxide (6 ml) was added to the solution and stirred at 50 ° C. for 30 minutes. The resulting solution is partitioned between ethyl acetate and saturated aqueous ammonium chloride. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water and saline, dried by passing through a Celite column, and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with ethyl acetate / hexane (4/1 to 8/1, v / v) to give 3- (4-bromo-phenyl) -6-tert. -acetic acid ethyl ester. butoxycarbonylamino-hexanoic acid (2.43 g, 74%). To a solution of 3- (4-bromo-phenyl) -6-tert-butoxycarbonylamino-hexanoic acid ethyl ester (2.43 g, 6.32 mmol) in ethyl acetate (3 mL) was added 4N hydrogen chloride in ethyl acetate (6 ml) at room temperature. Removal of the solvent in vacuo after stirring for 30 minutes gave 6-amino-3- (4-bromo-phenyl) -hexanoic acid ethyl ester hydrochloride which was used in the next step without further purification. A solution of 6-amino-3- (4-bromo-phenyl) -hexanoic acid ethyl ester hydrochloride solution, potassium carbonate (1039 mg, 7.52 mmol) in ethanol (50 ml) was refluxed for 20 hours. The solvent was removed in vacuo after adding dilute hydrochloric acid and water was added to the residue. Filtration, washing with water and drying gave 3- (4-bromo-phenyl) -piperidin-2-one (1387 mg, 86%, 2 steps). To a ice-cold solution of 3- (4-bromo-phenyl) -piperidin-2-one (37.97 g, 149 mmol) in tetrahydrofuran (250 mL) was added a borane-tetrahydrofuran complex (335 mL, solution 1.0 M in THF, 335 mmol). The solution was stirred overnight at room temperature and then refluxed for 1.5 hour after adding 10% hydrochloric acid. The solvents were removed in vacuo, and the residue was partitioned between dichloromethane and IN sodium hydroxide. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed with water and saline, dried over sodium sulfate and concentrated in vacuo. The residue was dissolved in water (100 ml) and concentrated hydrochloric acid (100 ml) and refluxed for 3 hours. Sodium hydroxide was added to the solution and the resulting solution was extracted with dichloromethane. The organic layer was washed with water and saline, dried over sodium sulfate. Concentration in vacuo gave 3- (4-bromophenyl) -piperidine (32.18 g, 90%). To a suspension of 3- (4-bromophenyl) -piperidine (25.2 g, 105 mmol), and triethylamine (13 g, 128 mmol) in tetrahydrofuran (250 mL) was added di-tert-butyl-dicarbonate (25, 2 g, 105 mmol) at room temperature. After stirring for 1 hour, the resulting suspension was partitioned between ethyl acetate and 1N sodium hydroxide. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with saline, dried over magnesium sulfate, and concentrated in vacuo. The residue was washed with hexane to provide 3- (4-bromophenyl) -piperidine-1-carboxylic acid tert-butyl ester (35.7 g, 105 mmol, 100%) as white crystals. To a suspension of 3- (4-bromophenyl) -piperidine-1-carboxylic acid tert-butyl ester (3.0 g, 8.8 mmol), palladium acetate (80 mg, 0.36 mmol), 2 - (di-t-butyl phosphino) biphenyl (210 mg, 0.70 mmol) and sodium t-butoxide (1.2 g, 125 mmol) in toluene (30 ml) was added N-methylpiperazine (1.3 g , 13.0 mmol) at room temperature. After heating at 90 ° C for 5 hours, the resulting suspension was passed through a Celite column. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography eluting with 5% -25% ethyl acetate in hexane to give 3- (4- (4-methylpiperazine) tert-butyl ester. -l-yl) -phenyl) -piperidine-1-carboxylic acid (2.0 g, 5.56 mmol, 63%) as white crystals. To a solution of 3- (4- (4-methyl-piperazin-1-yl) -phenyl) -piperidine-1-carboxylic acid tert-butyl ester (2.0 g, 5.56 mmol) in methanol (20 ml. ) 4N hydrochloric acid in ethyl acetate (20 ml) was added at room temperature. After stirring for 1 hour, the resulting suspension was concentrated in vacuo. The residue was washed with ethyl acetate to provide 3- (4- (4-methyl-piperazin-1-yl) -phenyl) -piperidine trichlorohydrate (1.84 g, 4.99 mmol) as white crystals. To a solution of 3- (4- (4-methylpiperazin-1-yl) -phenyl) -piperidine hydrochloride salt (0.4 g, 1.08 mmol) and triethylamine (0.6 g, 5.93 mmol ) in tetrahydrofuran (10 ml) was added 2-chloro-3-methyl-6- (pyridin-4-yl) -3H-pyrimidin-4-one (0.22 g, 0.99 mmol) in portions. After stirring for 12 hours, the resulting suspension was partitioned between chloroform and IN sodium hydroxide. The aqueous layer was extracted with chloroform. The combined organic layer was washed with saline, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 5% -10% methanol in chloroform to provide 3-methyl-2- (3- (4- (4-methylpiperazin-1-yl) -phenyl) -piperidin-1. -yl) -6- (pyridin-4-yl) -3H-pyrimidin-4-one (0.31 g, 0.70 mmol, 71%) as white crystals.

Example 20: Synthesis of 2- (3- (4-cyclohexylaminophenyl) -piperidin-1-yl) -3-methyl-6- (pyridin-4-yl) -3H-pyrimidin-4-one (No. XB301) A a suspension of 3- (4-bromophenyl) -piperidine-1-carboxylic acid tert-butyl ester (8.0 g, 23.5 mmol), palladium acetate (210 mg, 0.94 mmol), 2- (di-t-butyl phosphino) biphenyl (560 mg, 1.88 mmol) and sodium t-butoxide (3.2 g, 33.3 mmol) in toluene (80 ml) were added cyclohexylamine (2.8 g, 28.2 mmol) at room temperature. After heating at 90 ° C for 5 hours, the resulting suspension was passed through a Celite column. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography eluting with 5% -25% ethyl acetate in hexane to give 3- (4-cyclohexylaminophenyl) tert-butyl ester. piperidine-1-carboxylic acid (6.74 g, 18.8 mmol, 80%) as white crystals. To a solution of 3- (4-cyclohexylaminophenyl) -piperidine-1-carboxylic acid tert-butyl ester (6.74 g, 18.8 mmol) in methanol (50 ml) was added 4N hydrochloride in ethyl acetate (40 ml) at room temperature. After stirring for 1 hour, the resulting suspension was concentrated in vacuo. The residue was washed with ethyl acetate to provide 3- (4-cyclohexylaminophenyl) -piperidine dihydrochloride (5.84 g, 17.6 mmol, 94%) as white crystals. To a solution of the hydrochloride salt of 3- (4-cyclohexylaminophenyl) -piperidine (1.0 g, 3.02 mmol) and triethylamine (1.5 g, 14.8 mmol) in tetrahydrofuran (20 ml) was added 2-Chloro-3-methyl-6- (pyridin-4-yl) -3H-pyrimidin-4-one (0.64 g, 2.89 mmol) in portions. After stirring for 12 hours, the resulting suspension was partitioned between chloroform and IN sodium hydroxide. The aqueous layer was extracted with chloroform. The combined organic layer was washed with saline, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography eluting 5% -10% methanol in chloroform to provide 2- (3- (4-cyclohexylaminophenyl) -piperidin-1-yl) -3-methyl-6- (pyridin-4-) il) -3H-pyrimidin-4-one (1.23 g, 2.77 mmol, 96%) as white crystals.

Example 21: Synthesis of 2- (4- (4-bromophenyl) -piperidin-1-yl) -3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one (N ° XB267) A mixture of 4-bromobenzaldehyde (22.40 g, 121.1 mmol), dimethyl malonate (19.37 g, 146.6 mmol), acetic acid cat. and piperidine cat. in toluene (100 ml) was refluxed for 6 hours with azeotropic removal of water. The resulting solution was partitioned between ethyl acetate and water. The water layer was extracted with ethyl acetate. The combined organic layer was washed with water, saturated aqueous sodium bicarbonate and saline, dried over sodium sulfate. Concentration of the organic solvent in vacuo gave 2- (4-bromo-benzylidene) -malonic acid diethyl ester as an oil which was used in the next step without further purification. To an ice cooled solution of dimethyl malonate (19.35 g, 146.5 mmol) and sodium methoxide (30.12 g in a solution of 28% methanol, 156.1 mmol) in methanol (300 mL) 2- (4-bromo-benzylidene) -malonic acid diethyl ester in methanol was added (50 ml). After stirring for 3 hours, the solvent was removed in vacuo and the residue was partitioned between ethyl acetate and dilute hydrochloric acid. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with saline, dried over sodium sulfate. Concentration of the organic solvent in vacuo gave 3- (4-bromo-phenyl) -2,4-bis-ethoxycarbonyl-pentanedioic acid diethyl ester as an oil which was used in the next step without further purification. A solution of 3- (4-bromo-phenyl-9-2,4-bis-ethoxycarbonyl-pentanedioic acid diethyl ester in concentrated hydrochloric acid (100 ml) and acetic acid (100 ml) was refluxed for 8 hours. Removal of the solvent in vacuo and recrystallization of the residue from acetonitrile gave 3- (4-bromo-phenyl) -pentanedioic acid (22), 84 g in the harvest Ia, 65%, 3.84 g in the 2nd harvest, 11.05% from 4-bromobenzaldehyde). A solution of 3- (4-bromo-phenyl) -pentanedioic acid (26.68 g, 92.9 mmol) in acetic anhydride (100 mL) was refluxed for 1.5 h. Removal of the solvent in vacuo, and the remaining solvent were removed azeotropically using toluene. Tetrahydrofuran (200 ml) and aqueous ammonia (28%, 50 ml) were added to the residue and stirred overnight. After removal of the solvent in vacuo, acetic anhydride (100 ml) was added and refluxed for 4 hours. After removal of the solvent in vacuo and azeotropic distillation with toluene, the residue was partitioned between ethyl ether and water. Filtration of the suspension and drying gave 4- (4-bromo-phenyl) -piperidin-2,6-dione (12.53 g, 50%) as a solid. To an ice cooled solution of lithium tetrahydroborate (4.13 g, 189.6 mmol) in tetrahydrofuran (200 mL) was added chlorotrimethylsilane (41.52 g, 382.2 mmol). After stirring for 5 minutes, a solution of 4- (4-bromo-phenyl) -piperidine-2,6-dione (12.53 g, 46.7 mmol) was added and stirred overnight. The resulting solution was concentrated in vacuo after adding 10% aqueous hydrochloric acid. The residue was dissolved in a solution of aqueous sodium hydroxide and methanol, and a solution of di-tert-butyl dicarbonate (11.45 g, 52.5 mmol) in methanol (10 ml) was added and stirred for 6 hours. hours. After removal of the solvent in vacuo, concentrated hydrochloric acid was added and stirred overnight. After extraction of the solution with diethyl ether, sodium hydroxide was added to the aqueous layer to make it basic, and extracted with dichloromethane. The organic layer was washed with saline, dried over sodium sulfate. The residue of diethyl ether and dichloromethane after removal of the solvents under reduced pressure was mixed and dissolved in tetrahydrofuran (200 ml). A solution of di-tert-butyl dicarbonate (7.45 g, 34.1 mmol) in tetrahydrofuran (10 ml) and triethylamine were added and stirred overnight. The resulting solution was concentrated in vacuo. Purification of the residue by silica gel chromatography eluting hexane / ethyl acetate (5/1 v / v) provided 4- (4-bromo-phenyl) -piperidine-1-carboxylic acid tert-butyl ester (14, 4 g, 91%) as a solid. To a solution of the 4- (4-bromophenyl) -piperidine-1-carboxylic acid tert-butyl ester provided (1114 mg, 3.27 mmol) in ethyl acetate (1 mL) was added 4N hydrogen chloride in ethyl acetate. ethyl (2 mL) at room temperature. After stirring for 5 hours, the solvent was removed in vacuo and the resulting solid was washed with ethyl acetate and dried under vacuum to give (4- (4-bromophenyl) -piperidine hydrochloride (884 mg, 98%) as a white solid.

A solution of (4- (4-bromo-phenyl) -piperidine hydrochloride (279 mg, 1.01 mmol) in triethylamine (554 mg, 5.47 mmol), 2-chloro-3-methyl-6- (pyridine-4) -yl) -3H-pyrimidin-4-one (206 mg, 0.929 mmol) in tetrahydrofuran (20 ml) was stirred for 3 hours.The resulting solution was diluted with tetrahydrofuran and filtered, after removal of the solvents under pressure reduced and the purification of the resulting residue by CHEM ELUT CE1010 (manufactured by VARIAN) eluting with dichloromethane / ethanol (15/1, v / v) and washing with ethyl acetate gave 2- (4- (4- (bromophenyl) -piperidin-1-yl) -3-methyl- 6-pyridin-4-yl-3H-pyrimidin-4-one (368 mg, 93%) as a solid.

Example 22: Synthesis of 3-methyl-6-pyridin-4-yl-2- [4- (4-pyrrolidin-1-yl-phenyl) -piperidin-1-yl] -3H-pyrimidin-4-one (N ° XB269) A suspension of 4- (4-bromophenyl) -piperidine-1-carboxylic acid tert-butyl ester (1.97 g, 5.79 mmol), palladium acetate (54 mg, 0.24 mmol) , 2- (di-t-butylphosphino) biphenyl (154 mg, 0.52 mmol), and sodium t-butoxide (846 mg, 8.80 mmol), pyrrolidine (587 mg, 8.25 mmol) in toluene ( 80 ml) was heated at 90 ° C for 3 hours under a nitrogen atmosphere. The resulting suspension was passed through a Celite column and partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with saline, dried over sodium sulfate, and concentrated in vacuo. Purification of the residue by HPLC gave 4- (4-pyrrolidin-1-yl-phenyl) -piperidine-1-carboxylic acid tert-butyl ester as a solid which was used in the next step without further purification. To a solution of 4- (4-pyrrolidin-1-yl-phenyl) -piperidine-1-carboxylic acid tert-butyl ester in ethyl acetate (5 ml) was added 4N hydrogen chloride in ethyl acetate (10 ml). ml) at room temperature. After stirring for 3 hours, the solvent was removed in vacuo, and the resulting solid was purified by HPLC. Sodium hydroxide was added to the resulting fractions and the aqueous layer was extracted by dichloromethane. The organic layer was washed with saline, and passed through Celite. Removal of the solvent under reduced pressure gave 4- (4-pyrrolidin-1-yl-phenyl) -piperidine (1.01 g, 76%). A solution of 4- (4-pyrrolidin-1-yl-phenyl) -piperdine (215 mg, 0.933 mmol) and triethylamine (391 mg, 3.86 mmol), 2-chloro-3-methyl-6- (pyridine) 4-yl) -3H-pyrimidin-4-one (187 mg, 0.844 mmol) in tetrahydrofuran (10 ml) was refluxed for 5 hours. The resulting solution was diluted with tetrahydrofuran and filtered. After removal of the solvents under reduced pressure and purification of the resulting residue by CHEM ELUT CE1010 (manufactured by VARIAN) eluting dichloromethane / ethanol (15/1, v / v) and washing with ethyl acetate gave 3-methyl-6-pyridin-4-yl-2- (4- (4-pyrrolidin-l- il-phenyl) -piperidin-1-yl) -3H-pyrimidin-4-one (284 mg, 81%) as a solid.

Example 23: Synthesis of 2- (4- (6-fluorobenzo [b] thiophen-3-yl) iperidin-1-yl) -1-methyl-lH- [4,4 '] bipyrimidinyl-6-one (No. YB253) The key intermediate compound 4- (6-fluorobenzo [b] thiophen-3-yl) piperidine hydrochloride of 2- [4- (6-fluorobenzo [b] thiophen-3-yl) piperidin-1-yl] - 1-methyl-1H- [4, '] bipyrimidinyl-6-one was synthesized from 1-acetylpiperidine-4-carboxylic acid which was prepared according to the method reported by Watanabe (J. Heterocyclic Chem., 30, 445 (1993)). To a solution of l-benzoylpiperidine-4-carboxylic acid (66 g, 285 mmol) in dichloromethane (160 ml) was added thionyl chloride (26 ml, 388 mmol). After stirring at 60 ° C for 1 hour, the mixture was added portionwise to a stirred suspension of 2,4-difluorobenzene (45 g, 397 mmol) and anhydrous aluminum chloride (88 g, 666 mmol) in dichloromethane (245 g). ml) and the reaction mixture was refluxed for 5 hours. The reaction mixture was poured into a mixture of ice and concentrated hydrochloric acid and extracted with chloroform. The organic layer was dried over sodium sulfate and the solvent was evaporated under reduced pressure. Recrystallization from benzene gave l-benzoyl-4- (2, 4-difluorobenzoyl) piperidine (46 g, 50%) as colorless crystals. A solution of l-benzoyl-4- (2,4-difluorobenzoyl) piperidine (40 g, 120 mmol), methyl thioglycolate (12 mL, 130 mmol) in dimethylformamide (500 mL) was stirred at room temperature for 12 hours. The solvent was evaporated in vacuo and the residue treated with water and ethyl acetate. The organic layer was dried over sodium sulfate and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography eluting hexane / ethyl acetate to give 3- (l-benzoylpiperidin-4-yl) -6-fluorobenzo [b] thiophene-2-carboxylic acid (11.8 g , 26%) as an oil. 3- (l-Benzoylpiperidin-4-yl) -6-fluorobenzo [b] thiophene-2-carboxylic acid (10 g, 26 mmol) was suspended in quinoline (100 ml) and copper powder (0.5 g) was added. ). After stirring at 100 ° C for 1 hour, the mixture was cooled to room temperature and partitioned between ethyl acetate and water. The organic layer was dried over magnesium sulfate and suspended. The obtained residue was purified by silica gel column chromatography eluting hexane / ethyl acetate to give (4- (6-fluorobenzo [b] thiophen-3-yl) piperidin-1-yl) phenylmethanone (5.0 g, 48%) as yellow crystals. A solution of (4- (6-fluorobenzo [b] thiophen-3-yl) piperidin-1-yl) phenylmethanone (6.5 g, 19 mmol) in acetic acid (100 ml) and concentrated hydrochloric acid (100 ml) it was stirred at 90 ° C for 10 hours. To a solution of the reaction mixture was added ethyl acetate. The precipitated crystals were collected by filtration and washed with ethyl acetate to give 4- (6-fluorobenzo [b] thiophen-3-yl) piperidine hydrochloride (4.8 g, 89%) as yellow crystals. To a solution of 4- (6-fluorobenzo [b] thiophen-3-piperazine hydrochloride (200 mg, 0.74 mmol) and 2-chloro-1-methyl-1H- [4,4 '] ipyrimidinyl-6 one (160 mg, 0.70 mmol) in tetrahydrofuran (10 ml) was added triethylamine (212 mg, 2.1 mmol) The mixture was stirred at 90 ° C for 6 hours.The solvent was evaporated in vacuo and the residue it was treated with water and chloroform.The organic layer was dried over sodium sulfate and the solvent was evaporated under reduced pressure.Recrystallization from ethyl acetate gave 2- [4- (6-fluorobenzo [b] thiophen-3-yl) piperidin-1-yl] -1-methyl-lH- [4,4 '] bipyrimidinyl-6-one (220 mg, 96%) as colorless crystals.

Example 24: Synthesis of 2- (4- (biphenyl-2-yl) piperidin-1-yl) -1-methyl-lH- [4,4 '] bipyrimidinyl-6-one (N ° YA1552) To a solution of 1-biphenyl-2-yl-piperidine dihydrochloride (311 mg, 1.0 mmol) and 2-chloro-l-methyl-lH- [4, 4 '] bipyrimidinyl-6-one (202 mg, 0.91 mmol ) in tetrahydrofuran (20 ml) was added triethylamine (404 mg, 4.0 mmol). The mixture was stirred at 90 ° C for 4 hours. The solvent was evaporated in vacuo and the residue was treated with water and chloroform. The organic layer was dried over sodium sulfate and the solvent was evaporated under reduced pressure. Recrystallization from ethyl acetate gave 2- [4- (biphenyl-2-yl) iperazin-1-yl] -1-methyl-lH- [4,4 '] bipyrimidinyl-6-one (250 mg, 65%) as colorless crystals.

The compounds of the following table were prepared in the same manner as the methods described above. The numbers of the compounds of the following table correspond to those indicated in the table described above of the preferred compounds.

Table 5 Test Example: Inhibitory activity of the medicament of the present invention against phosphorylation of P-GSl by bovine cerebral TPKl A mixture containing 100 mM MES-sodium hydroxide (pH 6.5), 1 mM magnesium acetate, 0.5 mM EGTA, 5 mM β-mercaptoethanol, 0.02% Tween 20, 10% glycerol, 12 μg / ml of P-GSl, 41.7 μM [? "32P] ATP (68 kBq / ml), bovine cerebral TPKl and a compound shown in the Table (a final mixture contained 1.7% DMSO derived from a solution of a test compound prepared in the presence of 10% DMSO) was used as the reaction system Phosphorylation was initiated by adding ATP and the reaction was carried out at 25 ° C for 2 hours, and then stopped by adding 21% perchloric acid When cooling with ice, the reaction mixture was centrifuged at 12,000 rpm for 5 minutes and absorbed on P81 paper (hatmann), and then the paper was washed four times with 75 M phosphoric acid, three times with water and once with water. The paper was dried, and the residual radioactivity was measured using a liquid scintillation counter.The results are shown in the following table. The test compound markedly inhibited phosphorylation of P-GSl by TPKl. The results strongly suggest that the medicaments of the present invention inhibit the activity of TPKl, thereby eliminating the neurotoxicity of Aβ and the formation of PHF, and that the medicaments of the present invention are effective for the preventive and / or therapeutic treatment of Alzheimer's disease and the diseases mentioned above.

Table 6 Formulation Examples (1) Tablets The following ingredients were mixed by an ordinary method and compressed using a conventional apparatus: Compound of Example 1 30 mg Crystalline cellulose 60 mg Corn starch 100 mg Lactose 200 mg Magnesium stearate 4 mg (2) Soft capsules The following ingredients were mixed by an ordinary method and filled with soft capsules.

Compound of Example 1 30 mg Olive oil 300 mg Lecithin 20 mg Industrial Applicability The compounds of the present invention have inhibitory activity of TPKl and are useful as an active ingredient of a medicament for the preventive and / or therapeutic treatment of diseases caused by abnormal progression of TPK1 such as neurodegenerative diseases (eg. Alzheimer's) and the diseases mentioned above.

Claims (16)

1. A pyrimidone derivative represented by the formula (I) or a salt thereof, or a solvate thereof or a hydrate thereof: wherein Q represents CH or a nitrogen atom; R represents an alkyl group of C? -C12 which can be substituted; The ring of: represents a piperazine ring or a piperidine ring; each X independently represents X x -X, wherein X 1 represents an oxo group; an alkyl group of C? -C8 which can be substituted; a C3-C8 cycloalkyl group that can be substituted; a partially hydrogenated C6-C? aryl ring in an optional form that can be substituted; an indane ring that can be substituted; an optionally substituted heterocyclic ring having from 1 to 4 heteroatoms which are selected from the group consisting of an oxygen atom, a sulfur atom, and a nitrogen atom, and having from 5 to 10 atoms constituting the ring in total; an aralkyloxy group; a group represented -N (Ra) (Rb) wherein Ra and Rb are the same or different and each is hydrogen, an alkyl group of C? -C4 that can be substituted, an aralkyl group that can be substituted, a cycloalkyl group of C3-C8 which may be substituted, an aryl group which may be substituted, a C 1 -C 8 alkylcarbonyl group which may be substituted, a C 3 -C 8 cycloalkylcarbonyl group which may be substituted, an aralkylcarbonyl group which may be substituted, a C6-C ar arylcarbonyl group which may be substituted, an alkylsulfonyl group of L-C8 which may be substituted, a C3-C8 cycloalkylsulfonyl group which may be substituted, an aralkylsulfonyl group which may be substituted, an arylsulfonyl group of C6-C? Which can be substituted, an alkyloxycarbonyl group of L-C8 which can be substituted, a C3-C8 cycloalkyloxycarbonyl group which can be substituted, an aralkyloxycarbonyl group which can be substituted, a C6-C? Aryloxycarbonyl group? 0 that can to be substituted, aminocarbonyl, a C-C8 N-alkylaminocarbonyl group which can be substituted, a N, N'-dialkylaminocarbonyl group of L-CS which can be substituted, an N-C-C8-N 'alkyl group -C3-C8-cycloalkylaminocarbonyl which can be substituted, a C-C8-N'-aralkylaminocarbonyl N-alkyl group that can be substituted, a C-C8-N'-arylaminocarbonyl C-C6-C alkyl group 0 that can be substituted, a C3-C8 cycloalkylaminocarbonyl group that can be substituted, a C3-C8 N, N '-dicycloalkylaminocarbonyl group that can be substituted, a C3-C8-N'-aralkylaminocarbonyl N-cycloalkyl group which can be substituted, a N-cycloalkyl group of C3-C8-N'-arylaminocarbonyl of C6-C? which can be substituted, an aralkylaminocarbonyl group which can be substituted, a N, N'-diaralkylaminocarbonyl group which can be substituted , an N-aralkyl-N'-arylaminocarbonyl group of C6-C? 0 which can be substituted, a C6-C6-arylaminocarbonyl group which can be substituted, a N, N'-diarylaminecarbonyl group of Ce-Cio which can be substituted, or an optionally substituted heterocyclic ring having from 1 to 4 heteroatoms which are selected from the group consisting of an oxygen atom, an sulfur and a nitrogen atom, and having 5 to 10 atoms constituting the ring in total; or Ra and Rb together with the adjacent nitrogen atom form a 4- to 7-membered heterocyclic ring which may further contain from 1 to 4 groups which are selected from an oxygen atom, a sulfur atom, N-Rc (wherein Rc represents a hydrogen atom, a C 1 -C 4 alkyl group that can be substituted, an aralkyl group that can be substituted, a C 3 -C 8 cycloalkyl group that can be substituted or an aryl group that can be substituted, an alkylcarbonyl group of C? -C8 which may be substituted, a C3-C8 cycloalkylcarbonyl group which may be substituted, an aralkylcarbonyl group which may be substituted, a C6-C6-C6-arylcarbonyl group which may be substituted, an alkylsulfonyl group of Cx- Cs that can be substituted, a C3-C8 cycloalkylsulfonyl group which can be substituted, an aralkylsulphonyl group which can be substituted, a C6-C6 alkylsulfonyl group which can be substituted, a C? -C8 alkyloxycarbonyl group which can be substituted, a group C3-C8 cycloalkyloxycarbonyl which may be substituted, an aralkyloxycarbonyl group which may be substituted, a C6-C6 aryloxycarbonyl group which may be substituted, aminocarbonyl, a C-C8 N-alkylaminocarbonyl group which may be substituted, an N, N'-dialkylaminocarbonyl group of Ci-C8 which can be substituted, a C-C8-N'-cycloalkylaminocarbonyl C3-C8 alkyl group which can be substituted, a C-C8 N-alkyl group -N'-aralkylaminocarbonyl which can be substituted, a C-C8-N'-arylaminocarbonyl N-alkyl group of Ce-Cio which can be substituted, a C3-C8 cycloalkylaminocarbonyl group which can be substituted, a N group, N'-dicycloalkylaminocarbonyl of C3-C8 which can be substituted, a group C3-C8-N'-aralkylaminocarbonyl N-cycloalkyl which can be substituted, a N-cycloalkyl group of C3-C8-N'-arylaminocarbonyl of C6-C? Which can be substituted, an aralkylaminocarbonyl group which can be substituted, a N, N'-diaralkylaminocarbonyl group which may be substituted, a N-aralkyl-N'-arylaminocarbonyl group of C 6 -C 0 which may be substituted, a C 6 -C 0 arylaminocarbonyl group which may be substituted, a group N, N'-C6-C-arylaminocarbonyl or which may be substituted, or an optionally substituted heterocyclic ring having from 1 to 4 heteroatoms which are selected from the group consisting of an oxygen atom, a sulfur atom and a sulfur atom. nitrogen, and having 5 to 10 atoms constituting the ring in total), a carbonyl group, a sulfinyl group or a sulfonyl group in the ring and said 4- to 7-membered heterocyclic ring can optionally be fused with an aryl group which can be substituted; X2 represents a bond, a carbonyl group, a sulfinyl group, a sulfonyl group, an oxygen atom, a sulfur atom, an alkylene group of C? -C4 that can be substituted or N-Rd (Rd represents a hydrogen atom , an alkyl group of Ci-C4 which may be substituted, an aralkyl group which may be substituted, a C3-C8 cycloalkyl group which may be substituted or an aryl group which may be substituted, an alkylcarbonyl group of C? -C8 which it can be substituted, a C3-C8 cycloalkylcarbonyl group which can be substituted, an aralkylcarbonyl group which can be substituted, a C6-C10 arylcarbonyl group which can be substituted, a C? -C8 alkylsulfonyl group which can be substituted, an C3-C8 cycloalkylsulfonyl group which may be substituted, an aralkylsulfonyl group which may be substituted, a C6-C6-arylsulfonyl group which may be substituted, a C-C8 alkyloxycarbonyl group which may be substituted, a cycloalkyloxycarbonyl group of C3 -C8 which may be substituted, an aralkyloxycarbonyl group which may be substituted, a C6-C aryloxycarbonyl group or which may be substituted, aminocarbonyl, a C-C8 N-alkylaminocarbonyl group which may be substituted, a N group, N'-dialkylaminocarbonyl of Ci-C8 which can be substituted, an N-alkyl group of Ca-C8-N '-cycloalkylaminocarbonyl of C3-C8 which can be substituted, an N-alkyl group of C? -C8-N' - aralkylaminocarbonyl which can be substituted, a C-Cs-N'-arylaminocarbonyl N-alkyl group of C6-C or can be substituted, a C3-C8 cycloalkylaminocarbonyl group which can be substituted, a N, N'- group C3-C8 dicycloalkylaminocarbonyl which can be substituted, a N-cycloalkyl group of C3-C8-N'-aralkylaminocarbonyl which can be substituted, a C3-C8-N'-arylaminocarbonyl C-Cio-cycloalkyl group which can be substituted substituted, an aralkylaminocarbonyl group that can be substituted, a N, N'-diaralkylaminocarbonyl group that can be substituted and to be substituted, a N-aralkyl-N'-arylaminocarbonyl group of C6-C? 0 which can be "substituted, a C6-C10 arylaminocarbonyl group which can be substituted, a N, N '-arylaminocarbonyl group of C6-C 0 which can be substituted, or an optionally substituted heterocyclic ring having from 1 to 4 heteroatoms which are selected from the group consisting of an oxygen atom, a sulfur atom, and a nitrogen atom, and having from 5 to 10 atoms that make up the ring in total); m represents an integer from 1 to 3; each Y independently represents a halogen atom, a hydroxy group, a cyano group, Y1-Y3 wherein Y1 represents a C? -C8 alkyl group which can be substituted, a C3-C3 cycloalkyl group which can be substituted or a C6-C? 0 aryl ring that can be substituted; Y3 represents a carbonyl group, a sulfinyl group, a sulfonyl group, an oxygen atom, a sulfur atom, an alkylene group of C? -C4 which can be substituted or N-Re (Re represents a hydrogen atom, a group C? -C4 alkyl which can be substituted, an aralkyl group which can be substituted, a C3-C8 cycloalkyl group which can be substituted or an aryl group which can be substituted, a C? -C8 alkylcarbonyl group which can be substituted, substituted, a C3-C8 cycloalkylcarbonyl group which may be substituted, an aralkylcarbonyl group which may be substituted, a C6-C10 arylcarbonyl group which may be substituted, a C? -C8 alkylsulfonyl group which may be substituted, a cycloalkylsulfonyl group of C6-C10 which may be substituted, an aralkylsulphonyl group which may be substituted, a C6-C?-arylsulfonyl group which may be substituted, a C?-C8 alkyloxycarbonyl group which may be substituted, a C3-cycloalkyloxycarboonyl group C8 that can and to be substituted, an aralkyloxycarbonyl group which may be substituted, a C6-C10 aryloxycarbonyl group which may be substituted, aminocarbonyl, a C-C8 N-alkylaminocarbonyl group which may be substituted, a N, N '-dialkylaminocarbonyl group of Cx-C8 which can be substituted, a C-C8-N'-cycloalkylaminocarbonyl C3-C8 alkyl group which can be substituted, an N-alkyl group of C- C8-N'-aralkylaminocarbonyl which can be substituted, a C-C8-N'-arylaminocarbonyl N-alkyl group which can be substituted, a C3-C8 cycloalkylaminocarbonyl group which can be substituted, a N group, C3-C8-N-cycloalkylaminocarbonyl which can be substituted, a C3-C8-N'-aralkylaminocarbonyl N-cycloalkyl group which can be substituted, a C3-C8-N'-arylaminocarbonyl C6-C10 N-cycloalkyl group which may be substituted, an aralkylaminocarbonyl group which may be substituted, a N, N'-diaralkylaminocarbonyl group which may be substituted, an N-aralkyl-N'-arylaminocarbonyl group of C 6 -C 0 which may be substituted, an arylaminocarbonyl group of C6-C10 which may be substituted, a N, N'-dialkylaminocarbonyl group of Ce-Cio which may be substituted, or an optionally substituted heterocyclic ring having from 1 to 4 heteroatoms which are selected from the group consisting of an oxygen atom, a sulfur atom, and a nitrogen atom, and having from 5 to 10 atoms constituting the ring in total); n represents an integer from 0 to 8; when X and Y or two groups Y are joined in the same carbon atom, they can be combined with one another to form a C2-C6 alkylene group; and when m is 1, n is 0, and X is X2-C0-, (1) X does not bind to position 3 of the unsubstituted 1-piperazinyl group or does not bind to position 3 of a 4-alguil group - 1-piperazinyl; or (2) X does not bind to the 3-position or the 4-position of the unsubstituted 1-piperidinyl group.

2. The pyrimidone derivative or salts thereof, or the solvate thereof or the hydrate thereof according to claim 1, having the following formula (II) wherein Q, R, X, Y are the same as those defined in claim 1; p is 0 or 1; q is 0 or 1; r is an integer from 0 to 6; p + q is 1 O 2; and Z represents N or CZ1 where Z1 represents a hydrogen atom or Y.

3. The pyrimidone derivative or the salt thereof, or the solvate thereof, or the hydrate thereof according to claim 2, wherein R is an alkyl group of C? -C3 which can be substituted by a cycloalkyl group of C3 -C8

4. The pyrimidone derivative or the salt thereof, or the solvate thereof or the hydrate thereof according to claim 3, wherein R is a methyl group or an ethyl group; And it is in position 3, 4 or 5 of the piperazine ring or the piperidine ring; p + q is 1; and r is an integer from 0 to 3.

5. The pyrimidone derivative or the salt thereof, or the solvate thereof or the hydrate thereof according to claim 4, wherein X is a C? -C8 alkyl group which may be substituted or a C6 aryl ring -C? 0 that can be substituted; Y is an alkyl group of C? -C6 which can be substituted; p is 1; q is 0; r is an integer from 0 to 3; and Z is N or CH.

6. The pyrimidone derivative or the salt thereof, or the solvate thereof or the hydrate thereof according to claim 5, wherein X is a benzene ring which may be substituted, a benzyl group which may be substituted; And it's a methyl group that can be substituted; Z is N and r is O or l.

7. The pyrimidone derivative or the salt thereof, or the solvate thereof or the hydrate thereof according to claim 4, wherein X is a benzene ring which may be substituted, a benzyl group which may be substituted, a group benzoyl that can be substituted, or a benzisothiazole ring that can be substituted; And it's a methyl group that can be substituted; Z is N and p is 0.

8. The pyrimidone derivative or the salt thereof, or the solvate thereof or the hydrate thereof according to claim 4, wherein X is a C? -C8 alkyl group which can be substituted by a benzene ring which can be to be replaced or a benzene ring that can be substituted; Y is a hydroxy group, a cyano group or Y1-C0- wherein Y1 is an alkyl group of C? -C8; Z is CH or C-Y and r is 0 or 1.

9. The pyrimidone derivative or the salt thereof, or the solvate thereof or the hydrate thereof according to claim 8, wherein X is a benzyl group which may be substituted or a benzene ring which may be substituted; And it is a hydroxy group, a cyano group or an acetyl group; Z is CH or C-Y and r is 0 or 1.

10. A pyrimidone derivative selected from the group consisting of: 2- (3-Phenylpiperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (4-Fluorophenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pi imidin-4-one; 2- (3- (3-fluorophenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (2-fluorophenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (4-chlorophenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin -one; (S) -2- (3- (4-chlorophenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; (R) -2- (3- (4-chlorophenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (3-chlorophenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (2-chlorophenyl) -piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (4-bromophenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (3-bromophenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (2-bromophenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (4-methylphenyl) -piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (3-methylphenyl) -piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (2-methylphenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3h-pyrimidin -one; 2- (3- (4-cyanophenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (3-cyanophenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin -one; 2- (3- (2-cyanophenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (4-methoxyphenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin -one; 2- (3- (3-methoxyphenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (2-methoxyphenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (2-ethoxyphenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (5-fluoro-2-methoxyphenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (4-fluoro-3-methoxyphenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (4-fluoro-2-methoxyphenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; (S) -2- (3- (4-Fluoro-2-methoxyphenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; (R) -2- (3- (4-Fluoro-2-methoxyphenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (4-chloro-2-methoxyphenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (4-fluoro-2-methylphenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (2-fluoro-6-methoxyphenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (5-Bromo-2-methoxyphenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (2-bromo-4-fluorophenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (2-chloro-6-fluorophenyl) iperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (2,4-difluorophenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (2,6-difluorophenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (2,6-dichlorophenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (2,4-dimethoxyphenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (3, -dimethoxyphenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (2, 5-dimethoxyphenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (2,6-dimethoxyphenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (2,4-difluoro-6-methoxyphenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (5-cyano-2-methoxyphenyl) iperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (4-cyano-2-methoxyphenyl) iperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (l-naphthyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (2-naphthyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (2, 3-dihydrobenzofuran-7-yl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (benzofuran-2-yl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin -one; (S) -2- (3- (Benzofuran-2-yl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (4- (pyrrolidin-1-yl-methyl) phenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (4- (pyrrolidin-1-yl) phenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (2-methoxy-4- (pyrrolidin-1-yl) phenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (2-methoxy-5- (pyrrolidin-1-yl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; - (4- (phenyl) phenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (4- (4-fluorophenyl) phenyl) ) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (4- (4-methoxyphenyl) phenyl) piperazin-1-yl) - 3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (4- (2-methoxyphenyl) phenyl) piperazin-1-yl-3-methyl-6- (4- pyridyl) -3H-pyrimidin-4-one; • 2- (3- (4- (morpholin-4-yl) phenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H- pyrimidin-4-one; 2- (3- (4- (4-methylpiperazin-1-yl) phenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidine-4- ona; 2- (4-phenylpiperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (4-benzylpiperazin-1-yl) -3-methyl- 6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (4-benzoyl-piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; (4- (1, 2-benzisothiazol-3-yl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (4-methyl-3-) phenylpiperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (4-fluoro-2-methoxyphenyl) -4-methylpiperazin-1-yl) -3-methyl-6- (-pyridyl) -3H-pyrimidin-4-one; (S) -2- (3- (4-Fluoro-2-methoxyphenyl) -4-methylpiperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; (R) -2- (3- (4-Fluoro-2-methoxyphenyl) -4-methylpiperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (4-acetyl-3- (4-fluoro-2-methoxyphenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (4-benzyl-3- (4-fluoro-2-methoxyphenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (4-benzyl-3- (ethoxycarbonyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (4-methyl) -3- (1-naphthyl) iperazin-1-yl) -3-methyl-6 (4-pyridyl) -3H-pyrimidin-4-one; 2- (5,5-dimethyl-3- (2-methoxyphenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3-phenylpiperidin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (4-fluorophenyl) piperidin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (3-fluorophenyl) piperdin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (2-fluorophenyl) piperidin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (4-chlorophenyl) piperidin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (4-bromophenyl) piperidin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (4-methoxyphenyl) piperidin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (3-methoxyphenyl) piperidin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (2-methoxyphenyl) piperidin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (4- ((Pyrrolidin-1-yl) methyl) phenyl) piperidin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; (S) -2- (3- (4- (pyrrolidin-1-yl-methyl) phenyl) piperidin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; (R) -2- (3- (4- (pyrrolidin-1-yl-methyl) phenyl) piperidin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3-hydroxy-3-phenylpiperidin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3-phenylpiperazin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; 2- (3- (4-fluorophenyl) piperazin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; 2- (3- (3-fluorophenyl) piperazin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; 2- (3- (2-fluorophenyl) piperazin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; 2- (3- (4-chlorophenyl) piperazin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; 2- (3- (3-chlorophenyl) piperazin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; 2- (3- (2-chlorophenyl) piperazin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; 2- (3- (4-bromophenyl) piperazin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; 2- (3- (3-bromophenyl) piperazin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; 2- (3- (2-bromophenyl) piperazin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; 2- (3- (4-cyanophenyl) piperazin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; 2- (3- (3-cyanophenyl) piperazin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; 2- (3- (2-cyanophenyl) piperazin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; 2- (3- (4-methoxyphenyl) piperazin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; 2- (3- (3-methoxyphenyl) piperazin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; 2- (3- (2-methoxyphenyl) piperazin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; 2- (3- (2-ethoxyphenyl) piperazin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; 2- (3- (6-fluoro-2-methoxyphenyl) piperazin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; 2- (3- (5-fluoro-2-methoxyphenyl) piperazin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; 2- (3- (4-fluoro-2-methoxyphenyl) piperazin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; (S) -2- (3- (4-fluoro-2-methoxyphenyl) piperazin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; (R) -2- (3- (4-Fluoro-2-methoxyphenyl) piperazin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; 2- (3- (4-chloro-2-methoxyphenyl) piperazin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one, 2- (3- (5-bromine -2-methoxyphenyl) piperazin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; 2- (3- (2,6-dichlorophenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (2,4-dimethoxyphenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (3,4-dimethoxyphenyl) piperazin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; 2- (3- (2, 5-dimethoxyphenyl) piperazin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; 2- (3- (2,6-dimethoxyphenyl) piperazin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; 2- (3- (2, -difluoro-6-methoxyphenyl) piperazin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; 2- (3- (1-naphthyl) piperazin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; 2- (3- (2-naphthyl) piperazin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin -one; 2- (3- (2,3-dihydrobenzofuran-7-yl) piperazin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; 2- (3-benzofuran-2-yl) piperazin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; 2- (3- (4-pyrrolidin-1-yl-methyl) phenyl) piperazin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; 2- (3- (4-pyrrolidin-1-yl) phenyl) piperazin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (3- (2-methoxy-4- (pyrrolidin-1-yl) phenyl) piperazin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; 2- (3- (2-methoxy-5- (pyrimidin-1-yl) phenyl) piperazin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; 2- (3- (4- (phenyl) phenyl) piperazin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; 2- (3- (4- (4-fluorophenyl) phenyl) piperazin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; 2- (3- (4- (4-methoxyphenyl) phenyl) piperazin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; 2- (3- (4- (2-methoxyphenyl) phenyl) iperazin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one, 2- (3- (4- morpholin-4-yl) phenyl) piperazin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; 2- (3- (4- (4-methyl-piperazin-1-yl) -phenyl) -piperazin-1-yl) -3-methyl-6- (-pyrimidyl) -3H-pyrmidin-4-one; 2- (3- (4-fluoro-2-methoxyphenyl) -4-methylpiperazin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; (S) -2- (3- (4-Fluoro-2-methoxyphenyl) -4-methylpiperazin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; (R) -2- (3- (4-Fluoro-2-methoxyphenyl) -4-methylpiperazin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; 2- (4-acetyl-3- (4-fluoro-2-methoxyphenyl) piperazin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; 2- (4-Benzyl-3- (4-fluoro-2-methoxyphenyl) piperazin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; 2- (4- (4-fluorophenyl) piperidin'-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; 2- (4-cyano-4-phenylpiperidin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; 2- (4- (6-fluorobenzofuran-3-yl) piperidin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; 2- (3-Benzoisoxazol-3-yl) piperidin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; (S) -2- (3- (Benzoisoxazol-3-yl) piperidin-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; (R) -2- (3- (benzoisoxazol-3-yl) piperidin-i, 1) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; 2- (3- (6-fluorobenzoisoxazol-3-yl) piperidin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; 2- (4- (6-fluorobenzisoxazol-3-yl) piperidin-1-yl) -3-methyl-6- (4-pyridyl) -3H-pyrimidin-4-one; 2- (4- (5-methylbenzofuran-3-yl) piperidin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one; and 2- (4- (6-fluorobenzothiophene-3-yl) piperidin-1-yl) -3-methyl-6- (4-pyrimidyl) -3H-pyrimidin-4-one or a salt thereof, or a solvate of them, or a hydrate of them.

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

12. An inhibitor of the tau protein cyanase 1 which is selected from the group consisting of the pyrimidone derivative represented by the formula (I) and a salt thereof, and a solvate thereof and a hydrate thereof according to claim 1.

13. The medicament according to claim 11 which is used for the preventive and / or therapeutic treatment of a disease caused by the hyperactivity of tau protein kinase 1.

14. The medicament according to claim 11, which is used for the preventive and / or therapeutic treatment of a neurodegenerative disease.

15. The medicament according to claim 14, wherein the neurodegenerative disease is selected from the group consisting of Alzheimer's disease, ischemic strokes, Down syndrome, cerebral bleeding due to cerebral amyloid angiopathy, progressive supranuclear palsy, subacute sclerosing panencephalitis parkinsonism, postencephalitic parkinsonism, pugilistic encephalitis, parkinsonism-dementia complex of Guam, Lewy body disease, Pick disease, corticobasal degeneration, frontotemporal dementia, vascular dementia, traumatic injuries, brain and spinal cord trauma, peripheral neuropathies, retinopathies and glaucoma.

16. The medicament according to claim 11, wherein the disease is selected from the group consisting of non-insulin-dependent diabetes, obesity, manic depressive illness, schizophrenia, allergy, breast cancer, non-small cell lung carcinoma, T-cell leukemia. or B and a tumor induced by virus.