HK1069582A

HK1069582A - 3-substituted-4-pyrimidone derivatives

Info

Publication number: HK1069582A
Application number: HK05102605.8A
Authority: HK
Inventors: 上原史朗; 有友啓一; 照田文; 比企绅介; 奥山昌弘; 臼井义浩; 大泉充; 渡边和俊; 山越康一
Original assignee: 三菱制药株式会社; 沙诺费－辛芷拉保公司
Priority date: 2001-09-21
Filing date: 2002-09-20
Publication date: 2005-05-27

Description

3-substituted-4-pyrimidone derivatives

Technical Field

The present invention relates to a compound useful as a pharmaceutical active ingredient for the prophylaxis and/or treatment of diseases mainly caused by abnormal activity of tau protein kinase 1, such as neurodegenerative diseases (e.g. alzheimer's disease).

Background

Alzheimer's disease is a progressive senile dementia in which marked cerebral cortical atrophy is observed due to degeneration of nerve cells and reduction in the number of nerve cells. Pathologically, a large number of senile plaques and neurofibrillary tangles are visible in the brain. The number of patients has increased with the increasing population of the elderly, and a series of social problems are caused by the disease. Although many theories have been proposed, the etiology of the disease has not yet been elucidated. Early identification of the cause of the disease is still expected.

It is known that the degree of occurrence of two characteristic pathological changes of Alzheimer's disease is highly correlated with the degree of intellectual impairment. Therefore, the components of these two pathological changes have been investigated on a molecular level from the early 80 s of the 20 th century to reveal the cause of the disease. Senile plaques aggregate extracellularly, and amyloid beta protein has been elucidated as its main component (hereinafter, this specification is abbreviated as "A β": biochem. Biophys. Res. Commun. 120, 855 (1984); EMBO J., 4, 2757 (1985); Proc. Natl. Acad. Sci. USA, 82, 4245 (1985)). Another pathological change, namely, neurofibrillary tangles, the double-helical filamentous material called paired helical filament (hereinafter referred to simply as "PHF" in the present specification) is aggregated in cells, and it has been found that tau protein, a microtubule-associated protein unique to the brain, is its major component (Proc. Natl. Acad. Sci. USA, 85, 4506 (1988); Neuron, 1, 827 (1988)).

Furthermore, on the basis of gene studies, the presenilins genes (presenilins)1 and 2 were found to be causative genes of familial Alzheimer's disease (Nature, 375, 754 (1995); science, 269, 973 (1995); Nature. 376, 775(1995)), and the presence of the presenilin genes 1 and 2 variants has been found to promote the secretion of A β (Neuron, 17, 1005 (1996); Proc. Natl. Acad. Sci. USA, 94, 2025 (1997)). From these results, it is generally considered that in Alzheimer's disease, abnormal aggregation and aggregation of A β are caused for some reasons, leading to the formation of PHF and thus to the death of nerve cells. It is also generally believed that the efflux of glutamate out of the cell and the activation of glutamate receptors in response to such efflux may be important factors in the early stages of neuronal cell death caused by cerebrovascular ischemic accidents (Latest Medicine, 49, 1506 (1994)).

Carcinolic acid treatment, which stimulates AMPA receptors, a glutamate receptor, increases mRNA of amyloid precursor protein (hereinafter referred to as "APP" for short in the present specification) which is a precursor of A β (Society for Neuroscience Abstracts, 17, 1445(1991)), and also promotes APP metabolism (the journal of Neuroscience, 10, 2400 (1990)). Therefore, it is confirmed that cell death due to ischemic cerebrovascular disease is associated with A.beta.aggregation. Other diseases in which abnormal aggregation and aggregation of A.beta.have been found to occur include, for example, the Dewar (Down) syndrome, cerebral hemorrhage due to simple cerebral amyloid angiopathy, Lewy body disease (Nerve Advance, 34, 343 (1990)), Protein nucleases [ Protein, Nucleic Acid, Enzyme ], 41, 1476(1996)), and the like. In addition, examples of diseases exhibiting neurofibrillary tangles due to PHF aggregation include progressive supranuclear palsy, Parkinson's disease of subacute sclerosing panencephalitis, postencephalitic Parkinson's disease, pugilistic encephalitis, Guam Parkinson's disease-dementia syndrome, Leptongylosis, and the like (Protein nucleases [ Protein, Nucleic Acid, Enzyme ], 36, 2 (1991); medical Progress [ Progress of Medicine ], 158, 511 (1991); Protein nucleases [ Protein, Nucleic Acid, Enzyme ], 41, 1476 (1996)).

Tau proteins are usually composed of a group of related proteins with molecular weights of 48-65kDa, which form several bands in SDS-polyacrylamide gel electrophoresis, and which promote microtubule formation. PHF-binding tau proteins have been shown to be abnormally phosphorylated in brains with Alzheimer's disease compared to normal tau proteins (J.biochem., 99, 1807 (1986); Proc.Natl.Acad.Sci.USA, 83, 4913 (1986)). An enzyme that catalyzes the abnormal phosphorylation has been isolated. This protein is named tau protein kinase 1 (hereinafter abbreviated as "TPK 1" in the present specification), and its physicochemical properties have been elucidated (Biochemistry, 64, 308 (1992); J.biol.chem., 267, 10897 (1992)). In addition, a cDNA of rat TPK1 has been cloned from a rat cerebral cortex cDNA library on the basis of a partial amino acid sequence of TPK1, and its nucleotide sequence and amino acid sequence deduced have been determined (Japanese patent unexamined publication (KOKAI) No. 6-239893/1994). The results revealed that the initial structure of rat TPK1 is consistent with an enzyme called rat GSK-3 β (glycogen synthase kinase 3 β, FEBS Lett., 325, 167 (1993)).

The major component of senile plaques, a β, has been reported to be neurotoxic (science, 250, 279 (1990)). However, many theories have been proposed as to how a β causes cell death, but no reliable one has yet been established. Takashima et al found that treatment of A.beta.with the primary culture system of hippocampus of suckling mice caused cell death, and thus found that the activity of TPK1 was increased after A.beta.treatment and that cell death by A.beta.was inhibited by the antisense TPK1 (Proc. Natl. Acad. Sci. USA, 90, 7789 (1993); Japanese patent unexamined publication [ KOKAI ] No. 6-329551/1994).

Taken together, compounds that inhibit TPK1 activity may be capable of inhibiting the neurotoxicity of a β and PHF formation and inhibiting neuronal cell death in alzheimer's disease, thereby halting or delaying disease progression. These compounds may also be used as drugs for treating ischemic cerebrovascular diseases, twald syndrome, cerebral amyloid angiopathy, cerebral hemorrhage due to lewisdom disease, etc. by inhibiting neurotoxicity of a β. Furthermore, these compounds may be used as medicaments for the treatment of neurodegenerative diseases such as progressive supranuclear palsy, subacute sclerosing panencephalitic parkinsonism, postencephalitic parkinsonism, pugilistic encephalitis, guam parkinsonism-dementia complex, lepigone disease, pick's disease, corticobasal degeneration, frontotemporal dementia, vascular dementia, traumatic injury, brain and spinal cord trauma, peripheral neuropathy, retinopathy and glaucoma, as well as other diseases such as: non-insulin dependent diabetes mellitus, obesity, manic depressive illness, schizophrenia, alopecia, breast cancer, non-small cell lung cancer, thyroid cancer, T or B-cell leukemia and several virus-induced tumors.

The compounds having a structure similar to that of the compounds of the present invention represented by the following formula (I), the compounds represented by the following formula (A) are known:

wherein R represents 2, 6-dichlorobenzyl, 2- (2-chlorophenyl) ethylamino, 3-phenylpropylamino or 1-methyl-3-phenylpropylamino (WO 98/24782). The compound represented by the formula (A) is characterized by having a 4-fluorophenyl group at the 5-position and a monohydroxy group at the 4-position of the pyrimidine ring, and is out of the scope of the present invention. Further, the main pharmacological activity of the compound represented by the formula (a) is an anti-inflammatory effect, while the compound of the present invention represented by the formula (I) is useful as a TPK1 inhibitor or a drug for clinical treatment of neurodegenerative diseases, and therefore, their pharmacological activities are completely different from each other.

Disclosure of Invention

The purpose of the invention is achieved

The object of the present invention is to provide compounds useful as pharmaceutically active ingredients for the prevention and/or treatment of diseases such as Alzheimer's disease. More specifically, it is an object to provide novel compounds useful as pharmaceutically active ingredients which inhibit neurotoxicity of a β and PHF formation by inhibiting TPK1 activity and enable the fundamental prevention and/or treatment of neurodegenerative diseases such as alzheimer's disease by inhibiting neuronal apoptosis.

Means for achieving the object

In order to achieve the above object, the present inventors screened various compounds having an activity of inhibiting the phosphorylation of TPK 1. As a result, they have found that the compound represented by the following formula (I) has a desired activity and is useful as a pharmaceutically active ingredient for preventing and/or treating the above-mentioned diseases. The present invention has been completed based on these findings.

The present invention therefore provides a pyrimidone derivative represented by formula (I) or a salt thereof, or a solvate thereof or a hydrate thereof:

wherein R is¹Represents optionally substituted C₁-C₁₂An alkyl group;

r represents any one of groups represented by the following formulae (II) to (V):

wherein R is²And R³Independently represents a hydrogen atom or C₁-C₈An alkyl group;

R⁴represents a benzene ring which may be substituted, a naphthalene ring which may be substituted, an indan ring which may be substituted, a tetrahydronaphthalene ring which may be substituted, or an optionally substituted heterocyclic ring having 1 to 4 hetero atoms selected from an oxygen atom, a sulfur atom and a nitrogen atom and having 5 to 10 ring-constituting atoms in total;

R⁵represents optionally substituted C₁-C₈Alkyl, C which may be substituted₃-C₈Cycloalkyl, optionally substituted benzene ring, optionally substituted naphthalene ring, optionally substituted indane ringA tetrahydronaphthalene ring or an optionally substituted heterocyclic ring having 1 to 4 hetero atoms selected from an oxygen atom, a sulfur atom and a nitrogen atom and having 5 to 10 ring-constituting atoms in total;

R⁶represents a hydrogen atom, C which may be substituted₁-C₈Alkyl, optionally substituted benzene ring;

or R⁵And R⁶May be combined with each other to form⁵And R⁶The carbons attached together form an optionally substituted spirocarbocyclic ring having a total of 3 to 11 ring-forming atoms;

R⁷and R⁸Independently represents a hydrogen atom or C₁-C₈Alkyl, or R⁷And R⁸Can be combined with each other to form a C₂-C₆An alkylene group;

R⁹and R¹⁰Represents optionally substituted C₁-C₈Alkyl, C which may be substituted₃-C₈A cycloalkyl group, a benzene ring which may be substituted, a naphthalene ring which may be substituted, an optionally substituted heterocyclic ring having 1 to 4 hetero atoms selected from an oxygen atom, a sulfur atom and a nitrogen atom and having 5 to 10 ring-constituting atoms in total, or R⁹And R¹⁰represents-N (R)¹¹)(R¹²) Wherein R is¹¹Represents a hydrogen atom, C₁-C₈An alkyl group; and R is¹²Represents C₁-C₈An alkyl group, a benzene ring which may be substituted, a naphthalene ring which may be substituted, or an optionally substituted heterocyclic ring having 1 to 4 hetero atoms selected from an oxygen atom, a sulfur atom and a nitrogen atom and having 5 to 10 ring-constituting atoms in total;

and X represents CH₂O or NR¹³Wherein R is¹³Represents a hydrogen atom or C₁-C₈An alkyl group.

According to a preferred embodiment of the present invention, there is provided:

the foregoing pyrimidone derivative or salt thereof, or solvate thereof or hydrate thereof, wherein R¹Is methyl;

the foregoing pyrimidone derivative or a salt thereof, or a solvate thereof or a hydrate thereof, wherein R is a group represented by formula (II);

the foregoing pyrimidone derivative or salt thereof, or solvate thereof or hydrate thereof, wherein R²And R³Each is a hydrogen atom;

the foregoing pyrimidone derivative or a salt thereof, or a solvate thereof or a hydrate thereof, wherein R is a group represented by formula (III);

the foregoing pyrimidone derivative or salt thereof, or solvate thereof or hydrate thereof, wherein R⁶Is a hydrogen atom;

the foregoing pyrimidone derivative or salt thereof, or solvate thereof or hydrate thereof, wherein R⁷And R⁸Each is a hydrogen atom;

the foregoing pyrimidone derivative or salt thereof, or solvate thereof or hydrate thereof, wherein R⁷And R⁸Each is methyl;

the foregoing pyrimidone derivative or a salt thereof, or a solvate thereof or a hydrate thereof, wherein R is a group represented by formula (IV);

the foregoing pyrimidone derivative or salt thereof, or solvate thereof or hydrate thereof, wherein R⁹Is a benzene ring which may be substituted;

the foregoing pyrimidone derivative or salts thereof, or solvates thereof or hydrates thereof, wherein X is CH₂；

The foregoing pyrimidone derivative or salt thereof, or solvate thereof or hydrate thereof, wherein X is O;

the foregoing pyrimidone derivative or a salt thereof, or a solvate thereof or a hydrate thereof, wherein R is a group represented by formula (V);

the foregoing pyrimidone derivative or salt thereof, or solvate thereof or hydrate thereof, wherein R¹⁰Is a benzene ring which may be substituted; and

the foregoing pyrimidone derivative or salt thereof, or solvate thereof or hydrate thereof, wherein R¹⁰Is a heterocyclic ring having 1 to 4 hetero atoms selected from an oxygen atom, a sulfur atom and a nitrogen atom and having 5 to 10 ring-constituting atoms in total.

According to another aspect, the present invention provides a medicament comprising, as an active ingredient, a pyrimidone derivative represented by the aforementioned formula (I) and salts thereof, and solvates thereof and hydrates thereof, and a tau protein kinase 1 inhibitor selected from the pyrimidone derivative represented by the aforementioned formula (I) and salts thereof, and solvates thereof and hydrates thereof.

According to a preferred embodiment of the aforementioned medicament, there is provided the aforementioned medicament for use in the prevention and/or treatment of a disease caused by tau protein kinase 1 hyperactivity;

the aforementioned medicament for use in the prevention and/or treatment of neurodegenerative diseases;

the aforementioned medicament, wherein the disease is selected from the group consisting of Alzheimer's disease, ischemic cerebrovascular accident, Towa syndrome, cerebral hemorrhage due to cerebral amyloid disease, progressive supranuclear palsy, Parkinson's disease of subacute sclerosing panencephalitis, postencephalitic Parkinson's disease, pugilistic encephalitis, Guam Parkinson's disease-dementia syndrome, Leptongylosis, pick's disease, corticobasal degeneration, frontotemporal dementia, vascular dementia, traumatic injury, brain and spinal cord trauma, peripheral neuropathy, retinopathy and glaucoma, and

the aforementioned medicament, wherein the disease is selected from: non-insulin dependent diabetes mellitus, obesity, manic depressive illness, schizophrenia, alopecia, breast cancer, non-small cell lung cancer, thyroid cancer, T or B-cell leukemia, and virus-induced tumors.

According to another aspect of the present invention, there is provided a method for preventing and/or treating a disease caused by tau protein kinase 1 hyperactivity, which comprises the steps of administering to a patient a prophylactically and/or therapeutically effective amount of a substance selected from the group consisting of 3-substituted-4-pyrimidone derivatives of formula (I) and physiologically acceptable salts thereof, and solvates thereof and hydrates thereof; and the use of a substance selected from the group consisting of 3-substituted-4-pyrimidone derivatives of formula (I) and physiologically acceptable salts thereof, and solvates thereof and hydrates thereof for the preparation of the aforementioned medicaments.

According to another aspect of the present invention, there is provided a pyrimidone derivative represented by formula (VI) or a salt thereof, or a solvate thereof or a hydrate thereof:

wherein R is¹Represents optionally substituted C₁-C₁₂An alkyl group, and a pyrimidone derivative represented by formula (VII) or a salt thereof, or a solvate thereof or a hydrate thereof:

wherein R is¹Represents optionally substituted C₁-C₁₂An alkyl group.

Detailed Description

Best Mode for Carrying Out The Invention

Alkyl groups as used herein may be straight or branched chain. R¹C represents₁-C₁₂The alkyl group may be, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, 1-dimethylpropyl, n-hexyl, isohexyl, or a straight or branched heptyl, octyl, nonyl, decyl, undecyl, or dodecyl group. In the present specification, when a functional group is defined as "which may be substituted" or "optionally substituted", the number of substituents thereof and the type thereof are not particularly limited, and when two or more substituents are present, they may be the same or different.

When R is¹C represents₁-C₁₂When the alkyl group has one or more substituents, the alkyl group may have one or more substituents selected from the group consisting of: c₁-C₅Alkoxy such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy; amino group, C₁-C₃Alkylamino or C₂-C₆Dialkylamino group: c₆-C₁₀Aryl groups such as phenyl, 1-naphthyl and 2-naphthyl;

R²or R³C represents₁-C₈The alkyl group may be, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, 1-dimethylpropyl, n-hexyl, isohexyl, or a straight or branched heptyl or octyl group.

When R is⁴Or R⁵When the benzene ring, naphthalene ring, indane ring, tetrahydronaphthalene ring or heterocycle represented has one or more substituents, these rings may have one or more substituents selected from the following: c₁-C₅Alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-dimethylpropyl; c₃-C₆Cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; c₃-C₆Cycloalkoxy such as cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy; c₁-C₅Alkoxy groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, and isopentyloxy groups; c₄-C₇Cycloalkylalkoxy such as cyclopropylmethoxy, cyclopentylmethoxy; c₁-C₅Alkylthio groups such as methylthio, ethylthio, propylthio, butylthio and pentylthio; c₁-C₅Alkylsulfonyl such as methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl and pentylsulfonyl; a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom; c₁-C₅Haloalkyl such as trifluoromethyl;C₁-C₅haloalkoxy such as trifluoromethoxy, 2, 2, 2-trifluoroethoxy; a hydroxyl group; a cyano group; a nitro group; a formyl group; c₂-C₆Alkylcarbonyl such as acetyl, propionyl, butyryl and valeryl; a benzene ring which may be substituted, a naphthalene ring which may be substituted, an optionally substituted heterocyclic ring having 1 to 4 hetero atoms selected from an oxygen atom, a sulfur atom and a nitrogen atom and having 5 to 10 ring-constituting atoms, a phenoxy group which may be substituted or a phenylamino group which may be substituted; an amino group; c₁-C₅Monoalkylamino groups such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, tert-butylamino, pentylamino and isopentylamino; c₂-C₁₀Dialkylamino groups such as dimethylamino, ethylmethylamino, diethylamino, methylpropylamino and diisopropylamino; c₂-C₁₀Monoalkylaminomethyl such as methylaminomethyl, ethylaminomethyl, propylaminomethyl, isopropylaminomethyl, butylaminomethyl, isobutylaminomethyl, tert-butylaminomethyl, pentylaminomethyl, isopentylaminomethyl; c₃-C₁₁Dialkylaminomethyl groups such as dimethylaminomethyl groups, diethylaminomethyl groups, ethylmethylaminomethyl groups, methylpropylaminomethyl groups; pyrrolidinylmethyl; piperidino (piperidinyl) methyl; morpholinomethyl; a piperazinyl methyl group; a pyrrolylmethyl group; imidazolylmethyl; pyrazolylmethyl and triazolylmethyl.

When the benzene ring, the naphthalene ring, the indane ring, the tetrahydronaphthalene ring or the heterocycle has one or more substituents, the substituent may further have one or more substituents selected from the following: c₁-C₅Alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-dimethylpropyl; c₃-C₆Cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; c₃-C₆Cycloalkoxy such as cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy; c₁-C₅Alkoxy radicals such as methoxy, ethoxy, propoxy,Isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, and isopentyloxy; c₄-C₇Cycloalkylalkoxy such as cyclopropylmethoxy, cyclopentylmethoxy; c₁-C₅Alkylthio groups such as methylthio, ethylthio, propylthio, butylthio and pentylthio; c₁-C₅Alkylsulfonyl such as methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl and pentylsulfonyl; a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom; c₁-C₅Haloalkyl such as trifluoromethyl; c₁-C₅Haloalkoxy such as trifluoromethoxy, 2, 2, 2-trifluoroethoxy; a hydroxyl group; a cyano group; a nitro group; a formyl group; c₂-C₆Alkylcarbonyl such as acetyl, propionyl, butyryl and valeryl; an amino group; c₁-C₅Monoalkylamino groups such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, tert-butylamino, pentylamino and isopentylamino; c₂-C₁₀Dialkylamino groups such as dimethylamino, ethylmethylamino, diethylamino, methylpropylamino and diisopropylamino; c₂-C₁₀Monoalkylaminomethyl such as methylaminomethyl, ethylaminomethyl, propylaminomethyl, isopropylaminomethyl, butylaminomethyl, isobutylaminomethyl, tert-butylaminomethyl, pentylaminomethyl, isopentylaminomethyl; c₃-C₁₁Dialkylaminomethyl groups such as dimethylaminomethyl, diethylaminomethyl, ethylmethylaminomethyl, methylpropylaminomethyl, and the like.

R⁴Or R⁵The representative heterocyclic ring having 1 to 4 hetero atoms selected from an oxygen atom, a sulfur atom and a nitrogen atom and having 5 to 10 atoms constituting the ring 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, an isobenzofuran ring, a benzodioxole ring, a chromene ring, a chromane ring, an isochromane ring, a thiophene ring, a benzothiophene ring, a pyrrole ring, a pyrroline ring, a pyrrolidine ring, an imidazole ring, an imidazoline ring, an imidazole ringAn alkane ring, a pyrazole ring, a pyrazoline ring, a pyrazolidine ring, a triazole ring, a tetrazole ring, a pyridine oxide ring, a piperidine ring, a pyrazine ring, a piperazine ring, a pyrimidine ring, a pyridazine ring, an indole ring, an indoline ring, an isoindole ring, an isoindoline ring, an indazole ring, a benzimidazole ring, a benzotriazole ring, a tetrahydroisoquinoline ring, a benzothiazolone ring, a benzoxazolone ring, a purine ring, a quinoline ring, a phthalazine ring, a naphthyridine ring, a quinoxaline ring, a quinazoline ring, a cinnoline ring, a pteridine ring, an oxazole ring, an isoxazolidine ring, a diazole ring, a thiazole ring, a benzothiazole ring, a thiazolidine ring, an isothiazole ring, an isothiazoline ring, a benzodioxole ring, a dioxane ring, a benzodioxane ring, a dithiane ring, a morpholine ring, a thiomorpholine ring and a phthalimide ring.

R⁵、R⁶、R⁷Or R⁸C represents₁-C₈The alkyl group may be, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, 1-dimethylpropyl, n-hexyl, isohexyl, or a straight or branched heptyl or octyl group.

R⁵C represents₃-C₈Cycloalkyl groups may be, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.

R⁵C represents₁-C₈Alkyl or C₃-C₈Cycloalkyl, or R⁶C represents₁-C₈An alkyl group having one or more substituents, which may have one or more substituents selected from the group consisting of: halogen atom, C₁-C₆Alkoxy radical, C₃-C₈A cycloalkyl group, a benzene ring which may be substituted, a naphthalene ring which may be substituted, a phenoxy group which may be substituted, or a phenylamino group which may be substituted; amino group, C₁-C₆Alkylamino radical, C₂-C₁₂Dialkylamino, 1-pyrrolidinyl, 1-piperidino (pyridonyl), 1-morpholinyl, 1- (tetrahydro-1, 2, 3, 4-quinolyl) groups or1- (tetrahydro-1, 2, 3, 4-isoquinolinyl) group.

When R is⁶When the benzene ring represented by (a) has one or more substituents, the ring may have one or more substituents selected from the following: c₁-C₅Alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-dimethylpropyl; c₃-C₆Cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; c₃-C₆Cycloalkoxy such as cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy; c₁-C₅Alkoxy groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, and isopentyloxy groups; c₄-C₇Cycloalkylalkoxy such as cyclopropylmethoxy, cyclopentylmethoxy; c₁-C₅Alkylthio groups such as methylthio, ethylthio, propylthio, butylthio and pentylthio; c₁-C₅Alkylsulfonyl such as methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl and pentylsulfonyl; a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom; c₁-C₅Haloalkyl such as trifluoromethyl; c₁-C₅Haloalkoxy such as trifluoromethoxy, 2, 2, 2-trifluoroethoxy; a hydroxyl group; a cyano group; a nitro group; a formyl group; c₂-C₆Alkylcarbonyl such as acetyl, propionyl, butyryl and valeryl; a benzene ring which may be substituted, a naphthalene ring which may be substituted, an optionally substituted heterocyclic ring having 1 to 4 hetero atoms selected from an oxygen atom, a sulfur atom and a nitrogen atom and having 5 to 10 ring-constituting atoms, a phenoxy group which may be substituted or a phenylamino group which may be substituted; an amino group; c₁-C₅Monoalkylamino groups such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, tert-butylamino, pentylamino and isopentylamino; c₂-C₁₀Dialkylamino groups such as dimethylamino, ethylmethylamino, diethylamino, methylpropylamino and diisopropylamino; c₂-C₁₀Monoalkylaminomethyl radicals such as the methyl radicalAminomethyl, ethylaminomethyl, propylaminomethyl, isopropylaminomethyl, butylaminomethyl, isobutylaminomethyl, tert-butylaminomethyl, pentylaminomethyl, isopentylaminomethyl; c₃-C₁₁Dialkylaminomethyl groups such as dimethylaminomethyl groups, diethylaminomethyl groups, ethylmethylaminomethyl groups, methylpropylaminomethyl groups; pyrrolidinylmethyl; piperidinyl (piperidinyl) methyl; morpholinomethyl; a piperazinyl methyl group; a pyrrolylmethyl group; imidazolylmethyl; a pyrazolyl methyl group; a triazolylmethyl group.

When R is⁶When the benzene ring represented by (a) has one or more substituents, the substituents may have one or more substituents selected from the following: c₁-C₅Alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-dimethylpropyl; c₃-C₆Cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; c₃-C₆Cycloalkoxy such as cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy; c₁-C₅Alkoxy groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, and isopentyloxy groups; c₄-C₇Cycloalkylalkoxy such as cyclopropylmethoxy, cyclopentylmethoxy; c₁-C₅Alkylthio groups such as methylthio, ethylthio, propylthio, butylthio and pentylthio; c₁-C₅Alkylsulfonyl such as methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl and pentylsulfonyl; a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom; c₁-C₅Haloalkyl such as trifluoromethyl; c₁-C₅Haloalkoxy such as trifluoromethoxy, 2, 2, 2-trifluoroethoxy; a hydroxyl group; a cyano group; a nitro group; a formyl group; c₂-C₆Alkylcarbonyl such as acetyl, propionyl, butyryl and valeryl; an amino group; c₁-C₅Monoalkylamino groups such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, tert-butylaminoPhenyl, pentylamino, and isopentylamino; c₂-C₁₀Dialkylamino groups such as dimethylamino, ethylmethylamino, diethylamino, methylpropylamino and diisopropylamino; c₂-C₁₀Monoalkylaminomethyl such as methylaminomethyl, ethylaminomethyl, propylaminomethyl, isopropylaminomethyl, butylaminomethyl, isobutylaminomethyl, tert-butylaminomethyl, pentylaminomethyl, isopentylaminomethyl; c₃-C₁₁Dialkylaminomethyl groups such as dimethylaminomethyl, diethylaminomethyl, ethylmethylaminomethyl, methylpropylaminomethyl.

When R is⁵And R⁶Are bound to each other with R⁵And R⁶When the carbon atoms to which they are attached together form a spiro carbocyclic ring, the carbocyclic ring may be, for example, a cyclopropyl ring, cyclobutyl ring, cyclopentyl ring, cyclohexyl ring, cycloheptyl ring, tetrahydrobenzocycloheptene ring, tetrahydronaphthalene ring, indane ring, bicyclo [4, 2, 0] ring]An octa-1, 3, 5-triene ring.

R⁹、R¹⁰、R¹¹、R¹²Or R¹³C represents₁-C₈The alkyl group may be, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, 1-dimethylpropyl, n-hexyl, isohexyl, or a straight or branched heptyl or octyl group.

R⁹Or R¹⁰C represents₃-C₈Cycloalkyl groups may be, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.

When R is⁹Or R¹⁰C represents₁-C₈Alkyl or C₃-C₈When the cycloalkyl group has one or more substituents, the group may have one or more substituents selected from the following: halogen atom, C₃-C₈Cycloalkyl group, benzene ring which may be substituted, naphthalene ring which may be substituted, having 1 to 4 atoms selected from oxygen atom, sulfur atom and nitrogen atomOptionally substituted heterocyclic ring having 5 to 10 ring-constituting atoms in total.

When R is⁹Or R¹⁰When the benzene ring, naphthalene ring or heterocycle represented has one or more substituents, the ring may have one or more substituents selected from the group consisting of: c₁-C₅Alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-dimethylpropyl; c₃-C₆Cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; c₃-C₆Cycloalkoxy such as cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy; c₁-C₅Alkoxy groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, and isopentyloxy groups; c₄-C₇Cycloalkylalkoxy such as cyclopropylmethoxy, cyclopentylmethoxy; c₁-C₅Alkylthio groups such as methylthio, ethylthio, propylthio, butylthio and pentylthio; c₁-C₅Alkylsulfonyl such as methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl and pentylsulfonyl; a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom; c₁-C₅Haloalkyl such as trifluoromethyl; c₁-C₅Haloalkoxy such as trifluoromethoxy, 2, 2, 2-trifluoroethoxy; a hydroxyl group; a cyano group; a nitro group; a formyl group; c₂-C₆Alkylcarbonyl such as acetyl, propionyl, butyryl and valeryl; a benzene ring which may be substituted, a naphthalene ring which may be substituted, an optionally substituted heterocyclic ring having 1 to 4 hetero atoms selected from an oxygen atom, a sulfur atom and a nitrogen atom and having 5 to 10 ring-constituting atoms in total; a phenoxy group which may be substituted; a phenylamino group which may be substituted; an amino group; c₁-C₅Monoalkylamino groups such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, tert-butylamino, pentylamino and isopentylamino; c₂-C₁₀Dialkylamino groups such as dimethylamino, ethylmethylamino, diethylamino, methylpropylamino and diisopropylaminoAn amino group; c₁-C₅Monoalkylaminomethyl such as methylaminomethyl, ethylaminomethyl, propylaminomethyl, isopropylaminomethyl, butylaminomethyl, isobutylaminomethyl, tert-butylaminomethyl, pentylaminomethyl, isopentylaminomethyl; c₂-C₁₀Dialkylaminomethyl groups such as dimethylaminomethyl groups, diethylaminomethyl groups, ethylmethylaminomethyl groups, methylpropylaminomethyl groups; pyrrolidinylmethyl; piperidinomethyl; morpholinomethyl; a piperazinyl methyl group; a pyrrolylmethyl group; imidazolylmethyl; pyrazolylmethyl and triazolylmethyl.

R⁹Or R¹⁰The representative heterocyclic ring having 1 to 4 hetero atoms selected from an oxygen atom, a sulfur atom and a nitrogen atom and having 5 to 10 constituent ring atoms 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 benzodioxole ring, a chromene ring, a chromane ring, an isochromane ring, a thiophene ring, a benzothiophene ring, a pyrrole ring, a pyrroline ring, a pyrrolidine ring, an imidazole ring, an imidazoline ring, an imidazolidine ring, a pyrazole ring, a pyrazoline ring, a pyrazolidine ring, a triazole ring, a tetrazole ring, a pyridine ring, an oxidized pyridine ring, a piperidine ring, a pyrazine ring, a piperazine ring, a pyrimidine ring, a pyridazine ring, an indole ring, an indoline ring, an isoindoline ring, an indazole ring, a benzimidazole ring, a, A benzotriazole ring, a tetrahydroisoquinoline ring, a benzothiazolone ring, a benzoxazolone ring, a purine ring, a quinazoline ring, a quinoline ring, a phthalazine ring, a naphthyridine ring, a quinoxaline ring, a quinazoline ring, a cinnoline ring, a pteridine ring, an oxazole ring, an oxazolidine ring, an isoxazolidine ring, a diazole ring, a thiazole ring, a benzothiazole ring, a thiazolidine ring, an isothiazoline ring, an isothiazolidine ring, a benzodioxole ring, a dioxane ring, a benzodioxane ring, a dithiane ring, a morpholine ring, a thiomorpholine ring or a phthalimide ring.

When R is¹²When the benzene ring, naphthalene ring or heterocycle represented has one or more substituents, the ring may be substituted by one or more substituentsSubstituted with a substituent selected from: halogen atom, C₁-C₅Alkyl radical, C₃-C₆Cycloalkyl radical, C₃-C₆Cycloalkoxy, C₁-C₅Alkoxy radical, C₄-C₇Cycloalkylalkoxy radical, C₁-C₅Alkylthio radical, C₁-C₅Alkylsulfonyl radical, C₁-C₅Haloalkyl groups and benzene rings.

When the benzene ring, naphthalene ring or heterocycle has one or more substituents, the substituent may further have one or more substituents selected from the group consisting of: c₁-C₅Alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-dimethylpropyl; c₃-C₆Cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; c₃-C₆Cycloalkoxy such as cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy; c₁-C₅Alkoxy groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, and isopentyloxy groups; c₄-C₇Cycloalkylalkoxy such as cyclopropylmethoxy, cyclopentylmethoxy; c₁-C₅Alkylthio groups such as methylthio, ethylthio, propylthio, butylthio and pentylthio; c₁-C₅Alkylsulfonyl such as methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl and pentylsulfonyl; a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom; c₁-C₅Haloalkyl such as trifluoromethyl; c₁-C₅Haloalkoxy such as trifluoromethoxy, 2, 2, 2-trifluoroethoxy; a hydroxyl group; a cyano group; a nitro group; a formyl group; c₂-C₆Alkylcarbonyl such as acetyl, propionyl, butyryl, and valeryl; an amino group; c₁-C₅Monoalkylamino groups such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, tert-butylamino, pentylamino and isopentylamino; c₂-C₁₀Dialkylamino groups such as dimethylamino, ethylmethylamino, N-dimethylamino,Diethylamino, methylpropylamino and diisopropylamino; c₂-C₁₀Monoalkylaminomethyl such as methylaminomethyl, ethylaminomethyl, propylaminomethyl, isopropylaminomethyl, butylaminomethyl, isobutylaminomethyl, tert-butylaminomethyl, pentylaminomethyl, isopentylaminomethyl; c₃-C₁₁Dialkylaminomethyl groups such as dimethylaminomethyl, diethylaminomethyl, ethylmethylaminomethyl, methylpropylaminomethyl, and the like.

R¹May preferably be C₁-C₃Alkyl, more preferably methyl.

R²Hydrogen atoms may be preferred.

R³Hydrogen atoms may be preferred.

R⁴Benzene rings which may be substituted may be preferred.

R⁵A benzene ring or a naphthalene ring which may be substituted may be preferred.

R⁶Hydrogen atoms may be preferred.

R⁷And R⁸May preferably be a hydrogen atom or C₁-C₃An alkyl group.

R⁹Or R¹⁰Benzene rings which may be substituted may be preferred.

R¹⁰There may be preferably a heterocyclic ring which may be substituted, having 1 to 4 hetero atoms selected from an oxygen atom, a sulfur atom and a nitrogen atom, and having 5 to 10 ring-constituting atoms in total. Particularly preferred R¹⁰Is a benzene ring which may be substituted, a 2, 3-indoline ring which may be substituted, or a 3, 4-dihydro-2H-quinoline ring which may be substituted.

Particularly preferred X is CH₂Or O.

The compound represented by the aforementioned formula (I) may be salified. Examples of such salts include, when acidic groups are present, salts with alkali metals and alkaline earth metals such as lithium, sodium, potassium, magnesium and calcium; salts with ammonium and amines such as methylamine, dimethylamine, trimethylamine, dicyclohexylamine, tris (hydroxymethyl) aminomethane, N-bis (hydroxyethyl) piperazine, 2-amino-2-methyl-1-propanol, ethanolamine, N-methylglucamine and L-glucosamine; or salts with basic amino acids such as lysine, 8-hydroxylysine and arginine. When a basic group is present, examples include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and 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 derivative represented by the aforementioned formula (I) may have one or more asymmetric carbon atoms. With respect to the stereochemistry of these asymmetric carbon atoms, they may independently be in the (R) or (S) configuration, and the pyrimidone derivative may exist as stereoisomers such as optical isomers or diastereoisomers. Any stereoisomer in pure form, any mixture of stereoisomers, racemates and the like are within the scope of the present invention.

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

Compounds B288 and B289

Measurement conditions

Compounds C389 and C390

Measurement conditions

CHIRALPAK AD

Mobile phase: n-hexane to isopropanol 60: 40

Flow rate: 1.0ml/min

Temperature: 30 deg.C

Retention time

C389：12.0min

C390：14.7min

Particularly preferred compounds of the invention represented by formula (I) include:

3-methyl-2- (2-oxa-2-phenylethylamino) -6-pyridin-4-yl-3H-pyrimidin-4-one;

3-methyl-2- (2-oxa-2- (3-fluorophenyl) ethylamino) -6-pyridin-4-yl-3H-pyrimidin-4-one;

3-methyl-2- (2-oxa-2- (4-fluorophenyl) ethylamino) -6-pyridin-4-yl-3H-pyrimidin-4-one;

3-methyl-2- (2-oxa-2- (3-chlorophenyl) ethylamino) -6-pyridin-4-yl-3H-pyrimidin-4-one;

3-methyl-2- (2-oxa-2- (3-methylphenyl) ethylamino) -6-pyridin-4-yl-3H-pyrimidin-4-one;

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

(S) -2- [2- (4-fluorophenyl) morpholin-4-yl ] -3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one;

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

(S) -2- [2- (2-fluorophenyl) morpholin-4-yl ] -3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one;

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

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

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

(S) -2- [2- (2-chlorophenyl) morpholin-4-yl ] -3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one;

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

(S) -2- [2- (4-bromophenyl) morpholin-4-yl ] -3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one;

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

(S) -2- [2- (3-bromophenyl) morpholin-4-yl ] -3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one;

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

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

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

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

(S) -2- [2- (2-methylphenyl) morpholin-4-yl ] -3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one;

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

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

(S) -2- [2- (3-cyanophenyl) morpholin-4-yl ] -3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one;

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

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

(S) -2- [2- (4-methoxyphenyl) morpholin-4-yl ] -3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one;

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

(S) -2- [2- (3-methoxyphenyl) morpholin-4-yl ] -3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one;

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

(S) -2- [2- (2-methoxyphenyl) morpholin-4-yl ] -3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one;

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

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

2- [2- (5-fluoro-2-methoxyphenyl) morpholin-4-yl ] -3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one;

2- [2- (4-fluoro-2-methoxyphenyl) morpholin-4-yl ] -3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one;

(S) -2- [2- (4-fluoro-2-methoxyphenyl) morpholin-4-yl ] -3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one;

2- [2- (2, 5-dimethoxyphenyl) morpholin-4-yl ] -3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one;

(S) -2- [2- (2, 5-dimethoxyphenyl) morpholin-4-yl ] -3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one;

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

(S) -2- [2- (2-chloro-4, 5-difluorophenyl) morpholin-4-yl ] -3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one;

2- [2- (2-bromo-4-fluorophenyl) morpholin-4-yl ] -3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one;

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

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

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

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

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

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

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

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

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

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

2- [2- (2-chloro-6-fluorophenyl) morpholin-4-yl ] -3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one;

(S) -2- [2- (2-chloro-6-fluorophenyl) morpholin-4-yl ] -3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one;

2- [2- (4-fluoro-3-methoxyphenyl) morpholin-4-yl ] -3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one;

2- [2- (5-cyano-2-methoxyphenyl) morpholin-4-yl ] -3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one;

(S) -2- [2- (5-cyano-2-methoxyphenyl) morpholin-4-yl ] -3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one;

2- [2- (4-cyano-2-methoxyphenyl) morpholin-4-yl ] -3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one;

(S) -2- [2- (4-cyano-2-methoxyphenyl) morpholin-4-yl ] -3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one;

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

(S) -2- [2- (2, 4-difluoro-6-methoxyphenyl) morpholin-4-yl ] -3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one;

2- [2- (4- (pyrrolidin-1-yl-methyl) phenyl) morpholino-4-yl ] -3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one;

(S) -2- [2- (4- (pyrrolidin-1-yl-methyl) phenyl) morpholino-4-yl ] -3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one;

2- [2- (1-naphthyl) morpholin-4-yl ] -3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one;

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

(S) -2- [2- (2-naphthyl) morpholin-4-yl ] -3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one;

2- [2- (2, 3-dihydrobenzofuran-7-yl) morpholin-4-yl ] -3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one;

(S) -2- [2- (2, 3-dihydrobenzofuran-7-yl) morpholin-4-yl ] -3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one;

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

(S) -2- [2- (benzofuran-2-yl) morpholin-4-yl ] -3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one;

2- [3- (4-fluorobenzoyl) piperidin-1-yl ] -3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one;

2- (3-benzoylpiperidin-1-yl) -3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one;

2- [3- (2-methoxybenzoyl) piperidin-1-yl ] -3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one;

2- [3- (4-methoxybenzoyl) piperidin-1-yl ] -3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one;

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

2- (2-benzoylmorpholin-4-yl) -3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one;

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

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

2- [4- (4-chlorobenzoyl) piperidin-1-yl ] -3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one;

2- [4- (3, 4-dihydro-2H-quinoline-1-carbonyl) -piperidin-1-yl ] -3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; and

2- [4- (2, 3-indoline-1-carbonyl) -piperidin-1-yl ] -3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one.

Salts of the aforementioned preferred compounds, and solvates or hydrates of the aforementioned compounds and salts thereof are also preferred.

The 3-substituted-4-pyrimidone compound represented by the aforementioned formula (I), wherein R is a group represented by the formula (II), can be produced, for example, according to the method described below.

(in the above scheme, R¹、R²、R³And R⁴Are the same as those already described. )

The 2-thiopyrimidinone represented by the above formula (XI) is easily prepared by modification of the process described in EP 354,179. The reaction is 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, 8-diazabicyclo [5, 4, 0] undec-7-ene at an appropriate temperature in the range of from 0 ℃ to 200 ℃ under a nitrogen and argon atmosphere or ordinary air for 1 to 100 hours to obtain the desired compound (XI). Examples of the solvent for the reaction include, for example, alcohol solvents such as methanol, ethanol, 1-propanol, isopropanol, t-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-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, sulfolane, hexamethylphosphoric triamide, water and the like. In general, a single solvent or a mixture of two or more solvents may be employed to suit the base employed.

The 2-thiopyrimidone derivative (XI) is then converted to 2-chloropyrimidinone (XII) by means of a chlorinating agent. The reaction time and temperature depend on the chlorinating agent used. Examples of the chlorinating agent used in these reactions include, for example, thionyl chloride and dimethylformamide, phosphorus oxychloride and dimethylformamide, oxalyl chloride, phosphorus oxychloride and dimethylformamide, phosphorus pentachloride.

The amine represented by the above formula (XIII) or a salt thereof can be produced by modification of the method described in the literature (Tetrahedron Lett., 30, 5285(1989), Synthesis, 122 (1990)).

The chloride derivative (XII) is then reacted with an amine (XIII) or a salt thereof in the presence of a base such as sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium carbonate, sodium bicarbonate, potassium carbonate, triethylamine, diisopropylethylamine, and 1, 8-diazabicyclo [5, 4, 0] undec-7-ene at an appropriate temperature in the range of from 0 ℃ to 200 ℃ in a nitrogen and argon atmosphere or in ordinary air for 1 to 100 hours to give the desired compound (I). 4-dimethylaminopyridine may be used as catalyst.

Examples of the solvent used for the reaction include, for example, alcohol solvents such as methanol, ethanol, 1-propanol, isopropanol, t-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-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, sulfolane, hexamethylphosphoric triamide, water and the like. In general, a single solvent or a mixture of two or more solvents may be employed to suit the base employed.

The 3-substituted-4-pyrimidone compound represented by the aforementioned formula (I), wherein R is a group represented by the formula (III), can be produced, for example, according to the method described below.

(in the above scheme, R¹、R⁵、R⁶、R⁷And R⁸Are in accordance with those already describedThe same is true. )

The chloride derivative (XII) is reacted with an amine (IVX) or a salt thereof in the presence of a base such as sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium carbonate, sodium bicarbonate, potassium carbonate, triethylamine, diisopropylethylamine, and 1, 8-diazabicyclo [5, 4, 0] undec-7-ene at an appropriate temperature ranging from 0 ℃ to 200 ℃ in a nitrogen and argon atmosphere or in ordinary air for 1 to 100 hours to obtain the desired compound (I).

The 3-substituted-4-pyrimidone compound represented by the aforementioned formula (I), wherein R is a group represented by the formula (IV), can be produced, for example, according to the method described below.

(in the above scheme, R¹、R⁹And X are as defined as those already described. )

The amines represented by formula (VX) above can be prepared by modifications of the methods described in the literature (j.med. chem., 13, 1(1970), j.med. chem., 41, 591(1998)) or according to methods well known to those skilled in the art.

The chloride derivative (XII) is then reacted with an amine (VX) or a salt thereof in the presence of a base such as sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, triethylamine, diisopropylethylamine and 1, 8-diazabicyclo [5, 4, 0] undec-7-ene at an appropriate temperature in the range of from 0 ℃ to 200 ℃ in a nitrogen and argon atmosphere or in ordinary air for 1 to 100 hours to give the desired compound (I).

The 3-substituted-4-pyrimidone compound represented by the aforementioned formula (I), wherein R is a group represented by the formula (V), can be produced, for example, according to the method described below.

(in the above scheme, R¹And R¹⁰Are the same as those already described. )

The amines represented by formula (VIX) above are commercially available or can be prepared by modifications of the methods described in the literature (j.med.chem., 13, 1(1970), j.med.chem., 41, 591(1998)) or according to methods well known to those skilled in the art.

The chlorinated derivative (XII) is then reacted with an amine (VIX) or a salt thereof in the presence of a base such as sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium carbonate, sodium bicarbonate, potassium carbonate, triethylamine, diisopropylethylamine and 1, 8-diazabicyclo [5, 4, 0] undec-7-ene at an appropriate temperature ranging from 0 ℃ to 200 ℃ in a nitrogen and argon atmosphere or in ordinary air for 1 to 100 hours to obtain the desired compound (I).

The compounds of the present invention have the activity of inhibiting TPK1, and they inhibit the activity of TPK1 in neurodegenerative diseases such as alzheimer's disease, and thus inhibit the neurotoxicity of a β and the formation of PHF and inhibit neuronal cell death. Accordingly, the use of the compounds of the present invention as active ingredients of medicaments makes it possible to fundamentally prevent and/or treat Alzheimer's disease. In addition, the compounds of the present invention can be used as active ingredients of medicaments for the prevention and/or treatment of ischemic cerebrovascular accidents, teva syndrome, cerebral hemorrhage due to cerebral amyloid angiopathy alone, progressive supranuclear palsy, subacute sclerosing panencephalitis, postencephalitic parkinsonism, pugilistic encephalitis, guam parkinsonism-dementia syndrome, leptospirosis, pick's disease, corticobasal dementia, vascular dementia, traumatic injury, brain and spinal cord trauma, peripheral neuropathy, retinopathy and glaucoma, non-insulin-dependent diabetes mellitus, obesity, manic-depressive illness, schizophrenia, alopecia, breast cancer, non-small cell lung cancer, thyroid cancer, T-or B-cell leukemia, and several virus-induced tumors.

As for the active ingredient of the medicament of the present invention, substances which can be used are selected from a group consisting of the compounds represented by the aforementioned formula (I) and pharmacologically acceptable salts thereof, and solvates thereof and hydrates thereof. The substance itself may be administered as a medicament according to the invention, however it is generally desirable to administer the medicament in the form of a pharmaceutical composition comprising the substance as an active ingredient together with one or more pharmaceutical additives. As the active ingredient of the medicament of the present invention, two or more of the above-mentioned substances may be used in combination. The above pharmaceutical composition may be supplemented with other pharmaceutically active ingredients useful for the treatment of Alzheimer's disease and the above-mentioned diseases.

The type of pharmaceutical composition is not particularly limited, and any formulation of the composition suitable for oral or parenteral administration may be provided. For example, the pharmaceutical composition may be formulated, for example, in a pharmaceutical composition form suitable for oral administration such as granules, fine particles, powders, hard capsules, soft capsules, syrups, emulsions, suspensions, solutions and the like, or in a pharmaceutical form suitable for parenteral administration such as injections, instillations, transdermal preparations, transmucosal preparations, nasal drops, inhalants, suppositories and the like, suitable for intravenous, intramuscular or subcutaneous administration. The injection or instillation preparation may be prepared as a powdered preparation such as a freeze-dried formulation, and may be dissolved in a suitable aqueous medium such as physiological saline before use. Extended release formulations such as those coated with polymers may be administered directly intracerebrally.

The kind of the pharmaceutical additive used for preparing the pharmaceutical composition, the content ratio of the pharmaceutical additive with respect to the active ingredient, and the preparation method of the pharmaceutical composition may be appropriately selected by those skilled in the art. Inorganic or organic substances, or solid or liquid substances may be used as pharmaceutical additives. Generally, the pharmaceutical additives are incorporated in a weight ratio ranging from 1% to 90% by weight of the active ingredient.

Excipients used in the preparation of solid pharmaceutical compositions include, for example, lactose, sucrose, starch, talc, cellulose, dextrin, kaolin, calcium carbonate and the like. For oral liquid composition preparations, conventional inert diluents such as water or vegetable oils may be employed. In addition to inert diluents, the liquid compositions can also contain adjuvants such as wetting agents, suspending agents, sweetening, flavoring, coloring and preserving agents. The liquid composition may be filled into capsules made of an absorbable material such as gelatin. Examples of solvent or suspension media for parenteral administration of the composition preparation, for example, injection, suppository, include water, propylene glycol, polyethylene glycol, benzyl alcohol, ethyl oleate, lecithin, etc. Examples of materials useful as suppository base include, for example, cocoa butter, emulsified cocoa butter, lauryl butter, witepsol (witepsol).

The dose and frequency of administration of the medicament of the present invention are not particularly limited, and they may be appropriately selected depending on the circumstances such as the purpose of prevention and/or treatment, the type of disease, the body weight or age of the patient, the severity of the disease, and the like. In general, the daily dose orally administered to an adult may be 0.01 to 1,000mg (weight of active ingredient), and may be administered once a day or several times a day in divided doses, or once a few days. When an injection of the drug is used, administration to an adult may be preferably carried out continuously or intermittently at a dose of 0.001 to 100mg (weight of active ingredient) per day.

Examples

The present invention will be described in more detail with reference to examples. However, the scope of the present invention is not limited by the following examples. The compound numbers in the examples correspond to the above tables.

Example 1: synthesis of 2-mercapto-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one

A solution of ethyl 3-oxa-3- (4-pyridyl) propionate (29.0g, 150mmol), N-methylthiourea (40.6g, 450mmol) and 1, 8-diazabicyclo [5, 4, 0] -7-undecene (22.4ml, 150mmol) was refluxed for 4 hours and, after cooling with ice water, a solution of methanesulfonic acid (14.4g, 150mmol) in water (50ml) was added. The precipitate was washed with water, filtered and dried to give the title compound (23.7g, 72%).

¹H-NMR(DMSO-d₆)δ：3.58(s，3H)，6.40(s，1H)，7.72(dd，J＝1.8，4.5Hz，2H)，8.73(dd，J＝1.5，4.8Hz，2H)，12.92(brd，1H)。

Example 2: synthesis of 2-chloro-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one

Phosphoryl chloride (26.11g, 170mmol) was added to dimethylformamide (180ml) and stirred for 20 minutes. To the solution was added 2-mercapto-3-methyl-6- (4-pyridyl) -pyrimidin-4-one (24.15g, 110mmol) and stirred for 5 minutes, then stirred at 70 ℃ for 2 hours. To the ice-cooled solution was added ethyl acetate (630ml) and after stirring for 20 minutes the precipitate was collected by filtration. After drying, the precipitate was dissolved in water (400ml) and the pH was adjusted to 10 with aqueous sodium hydroxide solution. The precipitate was washed with water, filtered and dried to give the title compound (18.82g, 77%).

¹H-NMR(CDCl₃)δ：3.72(s，3H)，6.90(s，1H)，7.78(dd，J＝1.7，4.5Hz，2H)，8.75(dd，J＝1.6，4.5Hz，2H)。

Example 3: synthesis of 3-methyl-2- (2-oxa-2-phenylethylamino) -6-pyridin-4-yl-3H-pyrimidin-4-one (Compound No. A001 in Table-1)

A solution of 2-amino-1-phenyl-ethanone hydrochloride (1.03g, 6.00mmol), 2-chloro-3-methyl-6- (4-pyridyl) -pyrimidin-4-one (0.665g, 3.00mmol), 4-dimethylaminopyridine (36.0mg, 0.30mmol) and triethylamine (0.80ml, 6.00mmol) in dimethylsulfoxide (15ml) was stirred at room temperature. After stirring for several hours, water was added to the reaction mixture. The precipitate was filtered and washed with refluxing diethyl ether to give the title compound (0.556g, 68%).

¹H-NMR(CDCl₃)δ：3.41(s，3H)，4.90(d，J＝5.1Hz，2H)，6.46(s，1H)，7.50-7.65(m，2H)，7.67-7.80(m，3H)，7.90(t，J＝5.1Hz，1H)，8.08(m，2H)，8.47(dd，J＝1.5Hz，4.8Hz，2H)。

MS[M⁺H]⁺：321。

Example 4: synthesis of (S) -2- [2- (4-methoxyphenyl) morpholin-4-yl ] -3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one (Compound No. B079 in Table-1)

A solution of (S) -2- (4-methoxyphenyl) morpholine hydrochloride (1.02g, 4.44mmol), 2-chloro-3-methyl-6- (4-pyridinyl) -pyrimidin-4-one (0.76g, 3.42mmol) and triethylamine (1.42ml, 10.3mmol) in tetrahydrofuran (20ml) was refluxed for several hours, after cooling the precipitate was filtered off and the solvent was removed in vacuo. The residue was washed with refluxing diethyl ether to give the title compound (1.22g, 95%).

¹H-NMR(DMSO-d₆)δ：2.98-3.06(m，1H)，3.15-3.22(m，1H)，3.47(s，3H)，3.69-3.73(m，2H)，3.76(s，3H)，3.85-3.92(m，1H)，4.04-4.08(m，1H)，4.67-4.70(m，1H)，6.95(d，J＝8.5Hz，2H)，7.10(s，1H)，7.38(d，J＝8.5Hz，2H)，8.49(d，J＝6.0Hz，2H)，8.94(d，J＝6.0Hz，2H)。

MS[M⁺H]⁺：379。

Example 5: synthesis of 2- [2, 2-dimethyl-6- (4-fluorophenyl) morpholin-4-yl ] -3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one (Compound No. B214 in Table-1)

A solution of 2, 2-dimethyl-6- (4-fluorophenyl) morpholine hydrochloride (127mg, 0.517mmol), 2-chloro-3-methyl-6- (4-pyridyl) -pyrimidin-4-one (109mg, 0.491mmol) and triethylamine (0.180ml, 1.29mmol) in N, N-dimethylformamide (2ml) was stirred at room temperature. After stirring for several hours, water was added to the reaction mixture. The precipitate was filtered, washed with water and dried to give the title compound (166mg, 81%).

¹H-NMR(CDCl₃)δ：1.39(s，3H)，1.51(s，3H)，2.86-3.02(m，2H)，3.39(m，1H)，3.60(s，3H)，3.65(m，1H)，5.04(m，1H)，6.69(s，1H)，7.09(m，2H)，7.42(m，2H)，7.79(d，J＝6.0Hz，2H)，8.72(d，J＝6.0Hz，2H)。

MS[M⁺H]⁺：394。

Example 6: synthesis of 2- (3-benzoylpiperidin-1-yl) -3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one (Compound No. C001 in Table-1)

A solution of 3-benzoylpiperidine hydrochloride (109mg, 0.60mmol), 2-chloro-3-methyl-6- (4-pyridyl) -pyrimidin-4-one (118mg, 0.40mmol) and triethylamine (0.50ml, 4.00mmol) in tetrahydrofuran (6ml) was stirred at room temperature for several hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, over Na₂SO₄Dried and evaporated under vacuum. The residue was purified by silica gel column chromatography (ethyl acetate) to give the title compound (182mg, 61%).

Example 7: synthesis of 1- (1-methyl-6-oxa-4-pyridin-4-yl-1, 6-dihydro-pyrimidin-2-yl) -piperidine-3-carboxyaniline (Compound No. C067 in Table-1)

A solution of 1-tert-butoxycarbonyl-3-piperidinecarboxylic acid (458mg, 2.00mmol), sodium hydride (88mg, 2.20mmol, 60% oil suspension), oxalyl chloride (0.22ml, 2.50mmol) and a catalytic amount of dimethylformamide (0.20ml) in dichloromethane (16ml) was stirred at 0 ℃. After stirring for 30 min, aniline (0.20ml, 2.20mmol) treated with n-butyllithium (1.45ml, 2.30mmol, 1.59M in methane) in tetrahydrofuran (4ml) was added to the reaction mixture at 0 ℃. After stirring for a further 30 minutes, saturated ammonium chloride was added and the entire reaction mixture was extracted with ethyl acetate. The organic phase was washed with brine and washed with Na₂SO₄Dried and evaporated under vacuum. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 1-tert-butoxycarbonylpiperidine-3-carboxyaniline (437mg, 71%).

A solution of 1-tert-butoxycarbonyl-3-piperidinecarboxanilide (437mg, 1.43mmol) and hydrochloric acid (1ml, 4.00mmol, 4N ethyl acetate) was stirred for several hours. The precipitate was filtered off to give 3-piperidinecarboxanilide hydrochloride (187mg, 55%).

A solution of 3-piperidinecarboxanilide hydrochloride (96.0mg, 0.40mmol), 2-chloro-3-methyl-6- (4-pyridyl) -pyrimidin-4-one (66.0mg, 0.30mmol) and triethylamine (0.33ml, 2.50mmol) in tetrahydrofuran (3ml) was stirred at room temperature for 3 hours. The entire reaction mixture was evaporated in vacuo and the residue was washed with water and diethyl ether to give the title compound (107mg, 92%).

Example 8: synthesis of 2- (2-benzoylmorpholin-4-yl) -3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one (Compound No. C101 in Table-1)

Grignard reagent was prepared by reacting magnesium (932mg, 5.93mmol) with bromobenzene (144mg, 5.93mmol) in diethyl ether (20ml) at room temperature for 10 min. After cooling to 0 ℃ a solution of 2-cyano-4-benzyl-morpholine (1.00g, 4.94mmol) in diethyl ether (2.0ml) was added followed by tetrahydrofuran (6.0 ml). The mixture was stirred at room temperature for 30 minutes. After decomposition with saturated aqueous sodium bicarbonate, the mixture was filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (n-hexane-ethyl acetate 3: 1 to 2: 1) to give the 2-benzoyl-4-benzyl morpholine (608mg, 44%).

(CDCl₃)：2.20-2.40(m，2H)，2.60-2.80(m，1H)，3.00-3.20(m，1H)，3.55(dd，J＝13.0，27.8Hz，2H)，3.70-3.90(m，1H)，3.90-4.20(m，1H)，4.92(dd，J＝2.6，9.9Hz，1H)，7.20-7.60(m，8H)，7.80-8.00(m，2H)。

A solution of 2-benzoyl-4-benzylmorpholine (600mg, 2.13mmol) and 1-chloromethyl chloroformate (457mg, 3.20mmol) in 1, 2-dichloroethane (8.0ml) was refluxed for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in methanol (10 ml). The solution was refluxed for 1 hour and concentrated under reduced pressure. The crude product was crystallized from ethyl acetate and filtered to give 2-benzoylmorpholine hydrochloride (323mg, 67%) as colorless crystals.

(DMSO-d₆)：3.00-3.50(m，4H)，4.00-4.20(m，2H)，5.29(dd，J＝2.6，10.1Hz，1H)，7.50-8.10(m，5H)，9.40-9.90(brd，2H)。

A solution of 2-benzoylmorpholine hydrochloride (269mg, 1.17mmol), 2-chloro-3-methyl-6- (4-pyridyl) -pyrimidin-4-one (320mg, 1.41mmol) and triethylamine (0.49ml, 3.51mmol) in tetrahydrofuran (10ml) was refluxed for several hours. After cooling the precipitate was filtered off and the solvent was removed in vacuo. The residue was washed with refluxing ethyl acetate and diethyl ether to give the title compound (447mg, wt).

Example 9: synthesis of 2- (4-benzoylpiperidin-1-yl) -3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one (Compound No. D001 in Table-1)

A solution of 4-benzoylpiperidine hydrochloride (903mg, 4.00mmol), 2-chloro-3-methyl-6- (4-pyridyl) -pyrimidin-4-one (666mg, 3.00mmol) and triethylamine (2.0ml, 15mmol) in tetrahydrofuran (30ml) was refluxed for several hours. After cooling, water was added to the reaction mixture. The precipitate was filtered, washed with water and dried to give the title compound (1.00g, 81%).

Example 10: synthesis of 2- [4- (4-chlorobenzoyl) piperidin-1-yl ] -3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one (Compound No. D009 in Table-1)

A solution of (4-chlorobenzoyl) piperidine hydrochloride (550mg, 0.226mmol), 2-chloro-3-methyl-6- (4-pyridyl) -pyrimidin-4-one (50mg, 0.226mmol) and triethylamine (0.160ml, 1.15mmol) in N, N-dimethylformamide (1ml) was stirred at 60 ℃. After stirring for several hours, water was added to the reaction mixture. The precipitate was filtered off, washed with water and dried to give the title compound (76mg, 86%).

The compounds in the following table were prepared in the same manner as the above-described method. The compound numbers in the compounds of the following table correspond to those shown in the preferred compounds of the above table.

TABLE 2

Compound numbering	¹H-NMR(Solvent)δ：	[M+H]+
Compound numbering	¹H-NMR(Solvent)δ：	[M+H]+	A002	(CDCl₃)：3.59(s，3H)，5.00(dd，J＝3.8，3.8Hz，2H)，6.19(brs，1H)，6.50(s，1H)，7.24-7.37(m，2H)，7.67(m，1H)，7.78(d，J＝5.1Hz，2H)，8.04(m，1H)，8.68(d，J＝5.1Hz，2H).	339
A003	(CDCl₃)：3.60(s，3H)，5.02(d，J＝3.9Hz，2H)，6.06(brs，1H)，6.50(s，1H)，7.26-7.88(m，6H)，7.71(d，J＝5.4Hz，2H).	338	A002		339
A003		338	A004	(CDCl₃)：3.41(s，3H)，4.89(s，2H)，6.48(s，1H)，7.42(m，2H)，7.70(dd，J＝1.5Hz，4.5Hz，2H)，7.92(br，1H)，8.18(m，2H)，8.49(dd，J＝1.5Hz，4.5Hz，2H).	339
A006	(DMSO)：3.39(s，3H)，4.88(d，J＝5.1Hz，2H)，6.46(s，1H)，7.58-8.08(m，6H)，7.67(m，1H)，8.48(d，J＝5.1Hz，2H).	355	A004		339
A006		355	A012	(CDCl₃)：2.48(s，3H)，3.60(s，3H)，5.01(d，J＝3.9Hz，2H)，6.22(brs，1H)，6.48(s，1H)，7.43-7.49(m，2H)，7.79(dd，J＝4.5，1.8Hz，2H)，7.86-7.89(m，2H)，8.67(dd，J＝4.5，1.8Hz，2H).	335
B008	(CDCl₃)：0.99(s，9H)，2.89(m，1H)，3.10-3.65(m，4H)，3.53(s，3H)，3.76(m，1H)，4.04(m，1H)，6.68(s，1H)，7.80(d，J＝6.0Hz，2H)，8.72(d，J＝6.0Hz，2H).	328	A012		335
B008		328	B009	(CDCl₃)：2.74(dd，J＝13.7，7.4Hz，1H)，2.87(dd，J＝12.7，10.4Hz，1H)，3.02(dd，J＝13.7，6.2Hz，1H)，3.24(td，J＝12.2，3.0Hz，1H)，3.39(s，3H)，3.48(dd，J＝15.1，1.6Hz，2H)，3.77(td，J＝11.7，2.4Hz，2H)，3.91(m，1H)，4.03(dd，J＝11.6，2.0Hz，1H)，6.65(s，1H)，7.24-7.37(m，5H)，7.71(dd，J＝6.0，1.5Hz，2H)，8.70(dd，J＝6.0，1.5Hz，2H).	363
B010	(CDCl₃)：1.81(m，1H)，1.93(m，1H)，2.76(m，1H)，2.89(m，1H)，3.19(td，J＝11.6，3.1Hz，1H)，3.44(m，2H)，3.49(s，3H)，3.65(m，1H)，3.81(td，J＝11.5，2.0Hz，1H)，4.06(dt，J＝10.7，1.1Hz，1H)，6.68(s，1H)，7.21-7.34(m，5H)，7.77(dd，J＝4.6，1.5Hz，2H)，8.73(dd，J＝4.6，1.5Hz，2H).	377	B009		363
B010		377	B011	(CDCl₃)：1.49-1.90(m，4H)，2.67(d，J＝7.2Hz，2H)，2.83(dd，J＝12.8，10.5Hz，1H)，3.15(td，J＝11.9，2.8Hz，1H)，3.45(d，J＝12.8Hz，2H)，3.52(s，3H)，3.65(m，1H)，3.79(dd，J＝11.4，2.1Hz，1H)，4.01(dd，J＝11.1，1.5Hz，1H)，6.68(s，1H)，7.18-7.33(m，5H)，7.79(dd，J＝4.5，1.5Hz，2H)，8.71(dd，J＝4.8，1.5Hz，2H).	391

B012	(CDCl₃)：3.10-3.33(m，2H)，3.50(m，1H)，3.71-4.20(m，6H)，6.70(s，1H)，6.89-7.03(m，3H)，7.24-7.36(m，2H)，7.80(d，J＝6.0Hz，2H)，8.71(d，J＝6.0Hz，2H).	378
B012		378	B027	(DMSO-d₆)：3.01(m，1H)，3.15(m，1H)，3.47(s，3H)，3.73(dd，J＝13.5，13.5Hz，2H)，3.90(dd，J＝10.9，10.9Hz，1H)，4.07(d，J＝11.0Hz，1H)，4.74(d，J＝9.3Hz，1H)，7.06(s，1H)，7.30-7.47(m，5H)，8.40(d，J＝6.3Hz，2H)，8.90(d，J＝6.3Hz，2H).	349
B028	(DMSO-d₆)：3.01(m，1H)，3.15(m，1H)，3.47(s，3H)，3.73(dd，J＝13.4，13.4Hz，2H)，3.90(dd，J＝11.6，11.6Hz，1H)，4.07(d，J＝10.1Hz，1H)，4.74(d，J＝9.3Hz，1H)，7.07(s，1H)，7.30-7.46(m，5H)，8.43(d，J＝6.3Hz，2H)，8.92(d，J＝6.3Hz，2H).	349	B027		349
B028		349	B029	(DMSO-d₆)：3.02(m，1H)，3.15(m，1H)，3.47(s，3H)，3.74(dd，J＝13.4，13.4Hz，2H)，3.90(dd，J＝11.7，11.7Hz，1H)，4.07(d，J＝11.2Hz，1H)，4.74(d，J＝9.3Hz，1H)，7.07(s，1H)，7.30-7.47(m，5H)，8.44(d，J＝6.3Hz，2H)，8.92(d，J＝6.3Hz，2H).	349
B030	(DMSO-d₆)：3.00(dd，J＝12.9，10.8，1H)，3.18(m，1H)，3.47(s，3H)，3.73(dd，J＝12.3，12.3Hz，2H)，3.89(dd，J＝9.9，9.9Hz，1H)，4.07(d，J＝11.2Hz，1H)，4.75(d，J＝9.3Hz，1H)，7.04(s，1H)，7.18-7.24(m，2H)，7.47-7.52(m，2H)，8.40(d，J＝6.6Hz，2H)，8.90(d，J＝6.6Hz，2H).	367	B029		349
B030		367	B031	(DMSO-d₆)：3.01(dd，J＝12.9，10.8，1H)，3.18(m，1H)，3.47(s，3H)，3.74(dd，J＝12.0，12.0Hz，2H)，3.91(dd，J＝11.7，11.7Hz，1H)，4.08(d，J＝10.5Hz，1H)，4.75(d，J＝9.3Hz，1H)，7.05(s，1H)，7.19-7.26(m，2H)，7.48-7.54(m，2H)，8.38(d，J＝6.3Hz，2H)，8.90(d，J＝6.3Hz，2H).	367
B032	(DMSO-d₆)：3.01(dd，J＝12.9，10.8，1H)，3.19(m，1H)，3.47(s，3H)，3.73(dd，J＝11，4，11，4Hz，2H)，3.91(dd，J＝11.4，11.4Hz，1H)，4.08(d，J＝11，4Hz，1H)，4.75(d，J＝9.3Hz，1H)，7.04(s，1H)，7.19-7.26(m，2H)，7.48-7.54(m，2H)，8.36(d，J＝6.3Hz，2H)，8.89(d，J＝6.3Hz，2H).	367	B031		367
B032		367	B033	(DMSO-d₆)：3.00(m，1H)，3.18(m，1H)，3.47(s，3H)，3.73-4.10(m，4H)，4.77(d，J＝9.4Hz，1H)，7.05(s，1H)，7.13-7.48(m，4H)，8.38(d，J＝6.0Hz，2H)，8.89(d，J＝6.0Hz，2H).	367
B036	(DMSO-d₆)：3.06(m，1H)，3.22(m，1H)，3.47(s，3H)，3.68-4.11(m，4H)，5.05(d，J＝9.3Hz，1H)，7.06(s，1H)，7.22-7.61(m，4H)，8.40(d，J＝6.3Hz，2H)，8.90(d，J ＝ 6.3Hz，2H).	367	B033		367
B036		367	B037	(DMSO-d₆)：3.04(m，1H)，3.23(m，1H)，3.46(s，3H)，3.66-4.09(m，4H)，5.04(d，J＝9.6Hz，1H)，7.05(s，1H)，7.20-7.59(m，4H)，8.39(d，J＝6.0Hz，2H)，8.88(d，J＝6.0Hz，2H).	367

B038	(DMSO-d₆)：3.07(m，1H)，3.24(m，1H)，3.48(s，3H)，3.69-4.10(m，4H)，5.05(d，J＝9.3Hz，1H)，7.10(s，1H)，7.21-7.61(m，4H)，8.49(d，J＝6.3Hz，2H)，8.94(d，J＝6.3Hz，2H).	367
B038		367	B039	(DMSO-d₆)：2.97(dd，J＝11.0，12.6Hz，1H)，3.12-3.20(m，1H)，3.45(s，3H)，3.68-3.77(m，2H)，3.85-3.92(m，1H)，3.99-4.08(m，1H)，4.73-4.76(m，1H)，7.08(s，1H)，7.42-7.49(m，4H)，8.47(d，J＝5.7Hz，2H)，8.93(d，J＝5.9Hz，2H).	383
B042	(DMSO-d₆)：3.02(dd，J＝12.5，10.9，1H)，3.19(m，1H)，3.48(s，3H)，3.71-4.11(m，4H)，4.78(d，J＝8.9Hz，1H)，7.08(s，1H)，7.38-7.53(m，4H)，8.44(d，J＝6.3Hz，2H)，8.92(d，J＝6.3Hz，2H).	383	B039		383
B042		383	B045	(DMSO-d₆)：2.93(dd，J＝12.8，10.6，1H)，3.23(m，1H)，3.39(s，3H)，3.69-4.15(m，4H)，5,06(d，J＝9.0Hz，1H)，7.14(s，1H)，7.38-7.66(m，4H)，8.56(d，J＝6.3Hz，2H)，8.98(d，J＝6.3Hz，2H).	383
B046	(DMSO-d₆)：2.89(m，1H)，3.35(m，1H)，3.50(s，3H)，3.68-4.14(m，4H)，5,06(m，1H)，7.08(s，1H)，7.39-7.64(m，4H)，8.46(d，J＝5.5Hz，2H)，8.93(d，J＝5.5Hz，2H).	382	B045		383
B046		382	B048	□(DMSO-d₆)：2.96(1H，dd，J＝10.7，12.7Hz)，3.12-3.20(1H，m)，3.45(3H，s)，3.66-3.75(2H，m)，3.86-3.93(1H，m)，4.05-4.09(1H，m)，4.75(1H，d，J＝8.9Hz)，6.85(1H，s)，7.42(2H，d，J＝8.4Hz)，7.58(2H，d，J＝8.3Hz)，7.97(2H，d，J＝6.0Hz)，8.69(2H，d，J＝6.0Hz)	[M+]＝427
B051	(DMSO-d₆)：2.94-3.02(1H，m)，3.14-3.22(1H，m)，3.46(3H，s)，3.66-3.77(2H，m)，3.87-3.94(1H，m)，4.04-4.09(1H，m)，4.76(1H，d，J＝9.5Hz)，6.85(1H，s)，7.33-7.38(1H，m)，7.46-7.48(1H，m)，7.52-7.55(1H，m)，7.61-7.70(1H，m)，7.97(2H，d，J＝5.7Hz)，8.68(2H，d，J＝5.7Hz)	427	B048		[M+]＝427
B051		427	B054	(DMSO-d₆)：2.90(dd，J＝12.6，10.5，1H)，3.22(m，1H)，3.51(s，3H)，3.67-4.15(m，4H)，4.98(d，J＝9.0Hz，1H)，7.07(s，1H)，7.29-7.68(m，4H)，8.42(d，J＝6.3Hz，2H)，8.90(d，J＝6.3Hz，2H).	427
B057	(DMSO-d₆)：3.00(dd，J＝12.6，10.5，1H)，3.18(m，1H)，3.47(s，3H)，3.69-4.09(m，4H)，4.70(d，J＝9.3Hz，1H)，7.06(s，1H)，7.20(d，J＝7.8Hz，2H)，7.34(d，J＝7.8Hz，2H)，8.41(d，J＝6.3Hz，2H)，8.91(d，J＝6.3Hz，2H).	363	B054		427
B057		363	B060	(DMSO-d₆)：2.33(s，3H)，2.97-3.05(m，1H)，3.15-3.22(m，1H)，3.48(s，3H)，3.70-3.77(m，1H)，3.86-3.94(m，1H)，4.05-4.09(m，1H)，4.69-4.72(m，1H)，7.07(s，1H)，7.13-7.28(m，4H)，8.43(d，J＝6.0Hz，2H)，8.92(d，J＝6.3Hz，2H).	363
B063	(CDCl₃)：2.41(s，3H)，3.08(m，1H)，3.35(m，1H)，3.54(m，1H)，3.59(s，3H)，3.66(m，1H)，4.00(m，1H)，4.21(m，1H)，4.92(m，1H)，6.69(s，1H)，7.18-7.29(m，3H)，7.55(m，1H)，7.79(d，J＝5.5Hz，2H)，8.71(d，J＝5.5Hz，2H).	363	B060		363

B064	(CDCl₃)：2.41(s，3H)，3.08(m，1H)，3.35(m，1H)，3.52-3.69(m，2H)，3.60(s，3H)，4.00(m，1H)，4.21(m，1H)，4.92(m，1H)，6.69(s，1H)，7.18-7.29(m，3H)，7.53(m，1H)，7.79(d，J＝6.3Hz，2H)，8.70(d，J＝6.0Hz，2H).	362
B064		362	B066	(DMSO-d₆)：3.11(dd，J＝10.8，12.8Hz，1H)，3.24-3.32(m，1H)，3.47(s，3H)，3.68-3.75(m，2H)，3.90-3.98(m，1H)，4.10-4.14(m，1H)，4.96-4.99(m，1H)，7.11(s，1H)，7.60(t，J＝7.4Hz，1H)，7.77-7.79(m，2H)，7.90(d，J＝8.0Hz，1H)，8.48(d，J＝6.0Hz，2H)，8.94(d，J＝6.1Hz，2H).	417
B069	(DMSO-d₆)：3.04(m，1H)，3.19(m，1H)，3.48(s，3H)，3.50-4.15(m，4H)，4.87(d，J＝8.7Hz，1H)，7.04(s，1H)，7.67(d，J＝8.1Hz，2H)，7.88(d，J＝8.1Hz，2H)，8.35(d，J＝6.6Hz，2H)，8.88(d，J＝6.6Hz，2H).	374	B066		417
B069		374	B072	(DMSO-d₆)：3.02(m，1H)，3.20(m，1H)，3.49(s，3H)，3.74(d，J＝13.2Hz，2H)，3.82(d，J＝12.3Hz，2H)，3.94(m，1H)，4.11(d，J＝11.1Hz，1H)，4.83(d，J＝9.9Hz，2H)，7.08(s，1H)，7.62(t，J＝7.8Hz，1H)，7.82(d，J＝7.8Hz，2H)，7.92(s，1H)，8.43(d，J＝5.7Hz，2H)，8.92(d，J＝5.7Hz，2H).	374
B073	(DMSO-d₆)：3.06(m，1H)，3.12-3.85(m，6H)，3.94(m，1H)，4.11(d，J＝9.9Hz，1H)，4.83(d，J＝9.0Hz，1H)，7.00(s，1H)，7.62(m，1H)，7.83(d，J＝7.8Hz，2H)，7.92(s，1H)，8.27(d，J＝5.4Hz，2H)，8.84(d，J＝5.4Hz，2H).	373	B072		374
B073		373	B075	(DMSO-d₆)：3.09(m，1H)，3.19-3.33(m，1H)，3.49(s，3H)，3.69(d，J＝12.6Hz，1H)，3.83(d，J＝12.6Hz，1H)，3.97(m，1H)，4.12(d，J＝11.7Hz，1H)，5.02(dd，J＝2.4Hz，10.5Hz，1H)，6.86(s，1H)，7.58(m，1H)，7.73-7.82(m，2H)，7.90(d，J＝7.5Hz，1H)，7.99(dd，J＝1.5Hz，6.0Hz，2H)，8.67(dd，J＝1.5Hz，6.0Hz，2H).	373
B078	(DMSO-d₆)：3.01(m，1H)，3.18(m，1H)，3.47(s，3H)，3.68-3.73(m，2H)，3.75(s，3H)，3.88(m，1H)，4.06(m，1H)，4.68(d，J＝9.6Hz，1H)，6.94(d，J＝8.4Hz，2H)，7.09(s，1H)，7.37(d，J＝8.4Hz，2H)，8.46(d，J＝6.0Hz，2H)，8.94(d，J＝6.0Hz，2H).	379	B075		373
B078		379	B080	(DMSO-d₆)：2.95-3.03(m，1H)，3.12-3.20(m，1H)，3.45(s，3H)，3.67-3.71(m，2H)，3.73(s，3H)，3.82-3.90(m，1H)，4.02-4.05(m，1H)，4.64-4.67(m，1H)，6.92(d，J＝8.5Hz，2H)，7.08(s，1H)，7.35(d，J＝8.5Hz，2H)，8.49(d，J＝6.2Hz，2H)，8.96(d，J＝6.0Hz，2H).	379
B081	(DMSO-d₆)：3.02(m，1H)，3.15(m，1H)，3.48(s，3H)，3.70-3.75(m，2H)，3.77(s，3H)，3.90(m，1H)，4.08(m，1H)，4.73(d，J＝9.6Hz，1H)，6.89-7,04(m，3H)，7.10(s，1H)，7.31(m，1H)，8.47(d，J＝5,7Hz，2H)，8.94(d，J＝5.7Hz，2H).	379	B080		379

B082	(DMSO-d₆)：2.99-3.06(m，1H)，3.16-3.23(m，1H)，3.48(s，3H)，3.70-3.74(m，2H)，3.77(s，3H)，3.86-3.94(m，1H)，4.07-4.10(m，1H)，4.71-4.74(m，1H)，6.89-6.92(m，1H)，7.01(s，1H)，7.06(m，2H)，7.31(t，J＝7.8Hz，1H)，8.45(d，J＝5.9Hz，2H)，8.93(d，J＝5.9Hz，2H).	378
B082		378	B084	(DMSO-d₆)：2.82(dd，J＝10.2，12.8Hz，1H)，3.17-3.26(m，1H)，3.50(s，3H)，3.68-3.72(m，1H)，3.83(s，3H)，3.83-3.94(m，2H)，4.09-4.13(m，1H)，5.00-5.03(m，1H)，6.98-7.07(m，2H)，7.14(s，1H)，7.29-7.35(m，1H)，7.45(d，J＝7.4Hz，1H)，8.59(d，J＝6.4Hz，2H)，9.00(d，J＝6.4Hz，2H).	379
B085	(CDCl₃)：2.83(1H，dd，J＝10.2，12.9Hz)，3..3-3.4(1H，m)，3.5-3.6(1H，m)，3.62(3H，s)，3.8-3.9(1H，m)，3.86(3H，m)，4.0-4.1(1H，m)，4.2-4.3(1H，m)，5.08(1H，dd，J＝2.1，10.2Hz)，6.69(1H，s)，7.0-7.1(1H，m)，7.2-7.3(1H，m)，7.53(1H，dd，J＝1.5，7.8Hz)，7.82(1H，dd，J＝1.5，4.5Hz)，8.71(2H，dd，1.5，4.5Hz)	379	B084		379
B085		379	B087	(DMSO-d₆)：1.30(3H，t，J＝6.8Hz)，2.75(1H，dd，J＝10.6，12.5Hz)，3.17-3.25(1H，m)，3.48(3H，s)，3.66-3.71(1H，m)，3.77-3.81(1H，m)，3.89-3.96(1H，m)，4.01-4.13(3H，m)，4.96(1H，d，J＝9.3Hz)，6.84(1H，s)，6.95-7.03(2H，m)，7.25-7.31(1H，m)，7.42-7.44(1H，m)，7.98(2H，d，J＝5.1Hz)，8.68(2H，d，J＝5.3Hz)	393
B088	(CDCl₃)：2.90(m，1H)，3.35(m，1H)，3.55(m，1H)，3.62(s，3H)，3.69(m，1H)，4.03(m，1H)，4.24(m，1H)，5.05(m，1H)，6.71(s，1H)，7.26-7.40(m，3H)，7.68(m，1H)，7.80(d，J＝6.0Hz，2H)，8.71(d，J＝6.0Hz，2H).	433	B087		393
B088		433	B089	(CDCl₃)：2.80(m，1H)，3.37(m，1H)，3.53-3.73(m，2H)，3.60(s，3H)，4.05(m，1H)，4.21-4.58(m，3H)，5.08(m，1H)，6.70(s，1H)，6.86(d，1H，J＝8.2Hz)，7.14(m，1H)，7.32(m，1H)，7.59(m，1H)，7.80(d，J＝6.0Hz，2H)，8.71(d，J＝6.0Hz，2H).	447
B090	(DMSO-d₆)：2.82(dd，J＝10.2，12.8Hz，1H)，3.19-3.26(m，1H)，3.49(s，3H)，3.67-3.71(m，1H)，3.83(s，3H)，3.81-3.94(m，2H)，4.09-4.12(m，1H)，4.98-5.01(m，1H)，7.05-7.23(m，4H)，8.51(d，J＝5.4Hz，2H)，8.96(d，J＝6.4Hz，2H).	397	B089		447
B090		397	B091	(DMSO-d₆)：2.81(m，1H)，3.20(m，1H)，3.47(s，3H)，3.56-3.91(m，2H)，3.83(s，3H)，4.08(m，1H)，4.95(d，J＝9.3Hz，1H)，6.78-6.98(m，2H)，7.09(s，1H)，7.43(m，1H)，8.49(d，J＝5.4Hz，2H)，8.94(d，J＝5.4Hz，2H).	397
B092	(DMSO-d₆)：2.94-3.01(1H，m)，3.13-3.20(1H，m)，3.46(3H，s)，3.67-3.78(2H，m)，3.88-3.95(1H，m)，4.07-4.10(1H，m)，4.79(1H，d，J＝9.8Hz)，6.86(1H，s)，7.47(1H，d，J＝8.3Hz)，7.65-7.72(2H，m)，7.98(2H，d，J＝5.7Hz)，8.68(2H，d，J＝5.5Hz)	417	B091		397

B093	(DMSO-d₆)：2.78(1H，dd，J＝10.3，12.7Hz)，3.16-3.24(1H，m)，3.46(3H，s)，3.62-3.66(1H，m)，3.71(3H，s)，3.78(3H，s)，3.83-4.11(2H，m)，4.97(1H，d，J＝9.0Hz)，6.84(1H，s)，6.85-6.88(1H，m)，6.95-7.00(2H，m)，7.99(2H，d，J＝5.6Hz)，8.69(2H，d，J＝5.9Hz)	409
B093		409	B094	(DMSO-d₆)：2.78-2.86(m，1H)，3.17-3.25(m，1H)，3.49(s，3H)，3.66-3.93(m，3H)，3.72(s，3H)，3.78(s，3H)，4.09-4.13(m，1H)，4.96-4.99(m，1H)，6.85-7.09(m，4H)，8.48(d，J＝5.4Hz，2H)，8.94(d，J＝6.0Hz，2H).	408
B096	(CDCl₃)：3.07(t，J＝10.6Hz，1H)，3.29(td，J＝10.3，3.2Hz，1H)，3.53(d，J＝12.2Hz，1H)，3.58(s，3H)，3.68(dt，J＝13.1，1.1Hz，1H)，3.96(td，J＝11.9，2.3Hz，1H)，4.19(dd，J＝13.9，2.3Hz，1H)，4.75(dd，J＝10.4，1.1Hz，2H)，6.72(s，1H)，6.80(tt，J＝8.9，2.3Hz，1H)，6.96(dd，J＝6.0，2.3Hz，2H)，7.79(dd，J＝4.6，1.6Hz，2H)，8.73(dd，J＝4.5，1.6Hz，2H).	385	B094		408
B096		385	B097	(CDCl₃)：2.78(dd，J＝12.8，10.4Hz，1H)，3.32(td，J＝12.2，3.2Hz，1H)，3.54(d，J＝12.5Hz，1H)，3.62(s，3H)，3.82(dt，J＝12.9，1.9Hz，1H)，4.02(td，J＝11.8，2.3Hz，1H)，4.23(dd，J＝11.6，2.2Hz，1H)，5.02(dd，J＝10.3，1.9Hz，2H)，6.71(s，1H)，7.24(dd，J＝6.9，2.8Hz，1H)，7.50(dd，J＝11.2，8.4Hz，1H)，7.80(dd，J＝4.6，1.5Hz，2H)，8.70(dd，J＝4.5，1.5Hz，2H).	419
B098	(CDCl₃)：2.78(dd，J＝12.8，10.4Hz，1H)，3.32(td，J＝12.2，3.2Hz，1H)，3.54(d，J＝12.5Hz，1H)，3.62(s，3H)，3.82(dt，J＝12.9，1.9Hz，1H)，4.02(td，J＝11.8，2.3Hz，1H)，4.23(dd，J＝11.6，2.2Hz，1H)，5.02(dd，J＝10.3，1.9Hz，2H)，6.71(s，1H)，7.24(dd，J＝6.9，2.8Hz，1H)，7.50(dd，J＝11.2，8.4Hz，1H)，7.80(dd，J＝4.6，1.5Hz，2H)，8.70(dd，J＝4.5，1.5Hz，2H).	418	B097		419
B098		418	B100	(DMSO-d₆)：2.90(dd，J＝10.5Hz，12.9Hz，1H)，3.23(m，1H)，3.51(s，3H)，3.70(d，J＝13.2Hz，1H)，3.85(d，J＝12.9Hz，1H)，3.95(m，1H)，4，12(d，J＝9.6Hz，1H)，4.96(d，J＝8.7Hz，1H)，7.11(s，1H)，7.37(m，1H)，7.60-7.70(m，2H)，8.50(d，J＝6.3Hz，2H)，8.95(d，J＝6.6Hz，2H).	446
B101	(DMSO-d₆)：3.07(dd，J＝12.8，10.6，1H)，3.24(m，1H)，3.47(s，3H)，3.67-4.09(m，4H)，5.01(d，J＝9.4Hz，1H)，7.06(s，1H)，7.17(m，1H)，7.32(m，1H)，7.61(m，1H)，8.41(d，J＝6.3Hz，2H)，8.90(d，J＝6.3Hz，2H).	384	B100		446
B101		384	B102	(DMSO-d₆)：3.22(t，J＝14.4Hz，1H)，3.58(d，J＝19.5Hz，1H)，3.77(s，3H)，3.26-4.04(m，4H)，5.29(d，J＝9.0Hz，1H)，6.67(d，J＝8.4Hz，2H)，7.02(s，1H)，7.27(t，J＝8.4Hz，1H)，8.44(d，J＝5.7Hz，2H)，8.92(d，J＝5.7Hz，2H).	408
B103	d(DMSO-d₆)：3.22(1H，t，J＝14.4Hz)，3.58(1H，d，J＝19.5Hz)，3.77(3H，s)，3.26-4.04(4H，m)，5.29(1H，d，J＝9.0Hz)，6.67(2H，d，J＝8.4Hz)，7.02(1H，s)，7.27(1H，t，J＝8.4Hz)，8.44(2H，d，J＝5.7Hz)，8.92(2H，d，J＝5.7Hz).	409	B102		408

B104	d(DMSO-d₆)：3.22(1H，t，J＝14.4Hz)，3.58(1H，d，J＝19.5Hz)，3.77(3H，s)，3.26-4.04(4H，m)，5.29(1H，d，J＝9.0Hz)，6.67(2H，d，J＝8.4Hz)，7.02(1H，s)，7.27(1H，t，J＝8.4Hz)，8.44(2H，d，J＝5.7Hz)，8.92(2H，d，J＝5.7Hz).	409
B104		409	B105	(DMSO-d₆)：3.44-3.63(m，2H)，3.58(s，3H)，3.81(m，1H)，3.98(m，1H)，4.21(m，1H)，5.55(dd，J＝2.7Hz，11.1Hz，1H)，6.69(s，1H)，7.20(t，J＝7.5Hz，1H)，7.35(d，J＝7.5Hz，2H)，7.82(d，J＝4.5Hz，2H)，8.70(d，J＝4.5Hz，2H).	416
B106	(CDCl₃)：3.44-3.55(3H，m)，3.59(3H，s)，3.82(1H，dd，J＝12.9，10.8Hz)，3.98(1H，m)，4.20(1H，m)，5.55(1H，dd，J＝10.8，2.7Hz)，6.70(1H，s)，7.18-7.38(3H，m)，7.82(2H，dd，J＝4.5，1.5Hz)，8.71(2H，dd，J＝4.5，1.8Hz).	417	B105		416
B106		417	B107	(CDCl₃)：3.44-3.55(3H，m)，3.59(3H，s)，3.82(1H，dd，J＝12.9，10.8Hz)，3.98(1H，m)，4.20(1H，m)，5.55(1H，dd，J＝10.8，2.7Hz)，6.70(1H，s)，7.18-7.38(3H，m)，7.82(2H，dd，J＝4.5，1.5Hz)，8.71(2H，dd，J＝4.5，1.8Hz).	417
B108	(DMSO-d₆)：3.03(t，J＝12.6Hz，1H)，3.20(t，J＝11.1Hz，1H)，3.48(s，3H)，3.70-3.78(m，2H)，3.90(m，1H)，4.05(m，1H)，4.73(d，J＝10.2Hz)，7.03(m，1H)，7.06(s，1H)，7.18-7.25(m，2H)，8.40(d，J＝5.7Hz，2H)，8.90(d，J＝5.7Hz，2H).	396	B107		417
B108		396	B109	(CDCl₃)：3.42-3.52(2H，m)，3.57(3H，s)，3.63-3.66(2H，m)，3.67(1H，m)，4.13(1H，m)，5.24(1H，dd，J＝9.0，1.8Hz)，6.70(1H，s)，6.95(2H，m)，7.32(1H，m)，7.82(2H，dd，J＝4.5，1.8Hz)，8.72(2H，dd，J＝4.5，1.8Hz).	410
B110	(CDCl₃)：3.42-3.52(2H，m)，3.57(3H，s)，3.63-3.66(2H，m)，3.67(1H，m)，4.13(1H，m)，5.24(1H，dd，J＝9.0，1.8Hz)，6.70(1H，s)，6.95(2H，m)，7.32(1H，m)，7.82(2H，dd，J＝4.5，1.8Hz)，8.72(2H，dd，J＝4.5，1.8Hz).	385	B109		410
B110		385	B112	(CDCl₃)：1.74-1.79(m，4H)，2.50-2.53(m，4H)，3.13(m，1H)，3.32(m，1H)，3.51-3.68(m，2H)，3.64(s，3H)，3.67(s，2H)，4.00(m，1H)，4.18(m，1H)，4.72(m，1H)，6.70(s，1H)，7.33-7.44(m，4H)，7.80(dd，J＝4.8，1.2Hz，2H)，8.71(dd，J＝4.8，1.2Hz，2H).	432
B113	(CDCl₃)：1.80-1.82(4H，m)，2.56-5.58(4H，m)，3.12(1H，dd，J＝13.2，10.8Hz)，3.32(1H，m)，3.54(1H，m)，3.58(3H，s)，3.64(1H，m)，3.68(2H，s)，3.98-4.21(2H，m)，4.73(1H，dd，J＝10.5，2.1Hz)，6.69(1H，s)，7.35-7.42(4H，m)，7.79(2H，d，J＝4.5，1.5Hz)，8.71(2H，d，J＝4.5，1.5Hz).	431	B112		432
B113		431	B115	(D₂O)：1.24-1.39(1H，m)，1.46-1.67(3H，m)，1.75-1.80(2H，m)，2.78-2.86(2H，m)，3.14-3.34(4H，m)，3.44(3H，s)，3.66-3.72(2H，m)，3.91-4.06(2H，m)，4.16(2H，s)，4.79(1H，d，J＝10.4Hz)，6.83(1H，s)，7.35-7.47(4H，m)，8.44(2H，d，J＝6.5Hz)，8.72(2H，d，J＝6.6Hz)	446

B116	(D₂O)：1.81-1.96(2H，m)，2.00-2.16(2H，m)，3.03-3.15(2H，m)，3.19-3.31(2H，m)，3.39-3.47(2H，m)，3.50(3H，s)，3.70-3.78(2H，m)，3.95-4.11(2H，m)，4.31(2H，s)，4.85(2H，d，J＝10.3Hz)，6.89(1H，s)，7.41-7.56(4H，m)，8.49(2H，d，J＝6.0Hz)，8.77(2H，d，J＝6.7Hz)	432
B116		432	B117	(D₂O)：2.74(6H，s)，3.17-3.34(2H，m)，3.48(3H，s)，3.68-3.76(2H，m)，3.97-4.09(2H，m)，4.23(2H，s)，4.83(1H，d，J＝9.9Hz)，6.87(1H，s)，7.39-7.52(4H，m)，8.46(2H，d，J＝7.1Hz)，8.75(2H，d，J＝6.6Hz)	406
B118	(D₂O)：3.11-3.25(4H，m)，3.31-3.36(2H，m)，3.48(3H，s)，3.62-3.76(4H，m)，3.98-4.06(4H，m)，4.30(2H，s)，4.83(1H，d，J＝8.9Hz)，6.87(1H，s)，7.41-7.52(4H，m)，8.47(2H，d，J＝6.8Hz)，8.76(2H，d，J＝6.6Hz)	448	B117		406
B118		448	B119	(CDCl₃)：1.61-1.78(4H，m)，2.34-2.48(4H，m)，3.06(1H，dd，J＝10.5，12.9Hz)，3.24-3.28(1H，m)，3.35-3.45(1H，m)，3.54(3H，s)，3.68-3.81(2H，m)，3.98-4.02(1H，m)，4.03-4.20(2H，m)，5.05(1H，dd，J＝2.1，10.2Hz)，6.68(1H，s)，7.25-7.26(2H，m)，7.32-7.36(1H，m)，7.57-7.60(1H，m)，7.81(2H，d，J＝6.3Hz)，8.72(2H，d，J＝6.0Hz)	431
B120	(CDCl₃)：1.31(3H，d，J＝6.0Hz)，1.37(3H，d，J＝6.1Hz)，2.76(1H，dd，J＝10.1，12.6Hz)，3..3-3.5(1H，m)，3.5-3.7(1H，m)，3.63(3H，s)，3.7-3.8(1H，m)，4.0-4.2(1H，m)，4.2-4.3(1H，m)，4.6-4.7(1H，m)，5.02(1H，dd，J＝2.0，10.1Hz)，6.68(1H，s)，6.88(1H，d，J＝8.3Hz)，6.98(1H，t，J＝7.4Hz)，7.2-7.3(1H，m)，7.52(1H，dd，J＝1.6，7.6Hz)，7.81(1H，dd，J＝1.6，4.5Hz)，8.71(2H，dd，1.5，4.5Hz)	407	B119		431
B120		407	B122	(CDCl₃)：1.34(6H，d，J＝6.0Hz)，3.13(1H，dd，J＝10.8，12.9Hz)，3.2-3.4(1H，m)，3.5-3.7(2H，m)，3.57(3H，s)，3.9-4.0(1H，m)，4.1-4.2(1H，m)，4.5-4.6(1H，m)，4.66(1H，dd，J＝2.1，10.5Hz)，6.69(1H，s)，6.9-7.0(2H，m)，7.3-7.4(2H，m)，7.79(2H，dd，J＝1.8，4.5Hz)，8.71(2H，dd，J＝1.8，4.5Hz).	407
B126	(CDCl₃)：0.3-0.4(2H，m)，0.6-0.7(2H，m)，1.2-1.3(1H，m)，2.79(1H，dd，J＝10.2，12.9Hz)，3..3-3.5(1H，m)，3.6-3.7(1H，m)，3.65(3H，s)，3.7-4.0(3H，m)，4.0-4.1(1H，m)，4.2-4.3(1H，m)，5.09(1H，dd，J＝2.1，10.2Hz)，6.68(1H，s)，6.84(2H，d，J＝8.1Hz)，7.03(2H，t，J＝7.5Hz)，7.2-7.3(1H，m)，7.53(1H，dd，J＝1.5，7.5Hz)，7.81(1H，dd，J＝1.5，4.5Hz)，8.71(2H，dd，1.5，4.5Hz)	419	B122		407
B126		419	B128	(CDCl₃)：0.3-0.4(2H，m)，0.6-0.7(2H，m)，1.2-1.3(1H，m)，3.12(1H，dd，J＝10.8，12.9Hz)，3.2-3.4(1H，m)，3.5-3.7(2H，m)，3.57(3H，s)，3.82(2H，d，J＝6.9Hz)，3.9-4.0(1H，m)，4.1-4.2(1H，m)，4.67(1H，dd，J＝2.4，10.8Hz)，6.69(1H，s)，6.93(2H，d，J＝8.7Hz)，7.32(2H，d，J＝8.7Hz)，7.79(2H，dd，J＝1.8，4.8Hz)，8.71(2H，dd，J＝1.8，4.8Hz).	419

B130	(DMSO-d₆)：2.98(1H，dd，J＝12.6，14.4Hz)，3.18-3.24(1H，m)，3.22(3H，s)，.3.46(3H，s)，3.69(1H，d，J＝12.3Hz)，3.81(1H，d，J＝12.9Hz)，3.89-3.96(1H，m)，4.10(1H，d，J＝10.5Hz)，4.89(1H，d，J＝9.0Hz)，6.83(1H，s)，7.67(1H，t，J＝7.8Hz)，7.80(1H，d，J＝7.5Hz)，7.88(1H，d，J＝6.9 Hz)，7.96(2H，d，J＝5.1Hz)，8.00(1H，s)，8.67(2H，d，J＝5.1Hz)	427
B130		427	B140	(CDCl₃)：2.0-2.1(4H，m)，3.16(1H，dd，J＝10.7，12.8Hz)，3.2-3.4(5H，m)，3.5-3.7(2H，m)，3.56(3H，s)，3.9-4.0(1H，m)，4.1-4.2(1H，m)，4.61(1H，dd，J＝2.1，10.7Hz)，6.57(2H，d，J＝8.4Hz)，6.69(1H，s)，7.26(2H，d，J＝8.7Hz)，7.80(2H，dd，J＝1.4，4.6Hz)，8.71(2H，dd，J＝1.4，4.6Hz)	418
B143	(CDCl₃)：3.18(1H，dd，J＝12.3，10.1Hz)，3.35(1H，m)，3.59(1H，m)，3.60(3H，s)，3.72(1H，m)，3.98-4.23(2H，m)，4.79(1H，d，J＝10.5)，6.70(1H，s)，7.35-7.65(9H，m)，7.80(2H，d，J＝5.7Hz)，8.72(2H，d，J＝5.7Hz).	425	B140		418
B143		425	B184	(DMSO-d₆)：1.99-2.06(2H，m)，2.82-2.89(4H，m)，2.98(1H，dd，J＝10.7，12.9Hz)，3.11-3.22(1H，m)，3.45(3H，s)，3.65-3.70(2H，m)，3.84-3.92(1H，m)，4.01-4.06(1H，m)，4.79(1H，d，J＝8.7Hz)，6.83(1H，s)，7.17-7.23(2H，m)，7.29-7.32(1H，m)，7.96(2H，d，J＝6.2Hz)，8.66(2H，d，J＝6.0Hz)	389
B185	(DMSO-d₆)：3.07(1H，dd，J＝10.9，12.3Hz)，3.18-3.27(1H，m)，3.49(3H，s)，3.70-3.74(1H，m)，3.81-3.86(1H，m)，3.93-4.00(1H，m)，4.11-4.15(1H，m)，4.93(1H，d，J＝9.5Hz)，6.86(1H，s)，7.51-7.56(2H，m)，7.59-7.62(1H，m)，7.91-7.99(6H，m)，8.68(2H，d，J＝5.0Hz)	399	B184		389
B185		399	B186	(CDCl₃)：3.21(1H，dd，J＝10.5，13.2Hz)，3.31-3.41(1H，m)，3.54-3.67(1H，m)，3.61(3H，s)，3.74-3.78(1H，m)，4.01-4.10(1H，m)，4.23-4.28(1H，m)，4.92(1H，dd，J＝2.1，10.5Hz)，6.71(1H，s)，7.50-7.54(3H，m)，7.80(2H，d，J＝6.0Hz)，7.82-7.91(4H，m)，8.71(2H，d，J＝6.0Hz)	398
B187	(DMSO-d₆)：3.18(dd，J＝10.5，12.9Hz，1H)，3.31-3.38(m，1H)，3.53(s，3H)，3.75-3.79(m，1H)，4.00-4.18(m，3H)，5.52-5.55(m，1H)，7.03(s，1H)，7.51-8.30(m，7H)，8.42(d，J＝6.0Hz，2H)，8.92(d，J＝5.4Hz，2H).	399	B186		398
B187		399	B188	(CDCl₃)：3.09-3.33(4H，m)，3.53-3.64(2H，m)，3.57(3H，s)，3.95-4.02(1H，m)，4.13-4.20(1H，m)，4.58(2H，d，J＝8.7Hz)，4.65(1H，dd，J＝2.1，10.8Hz)，6.70(1H，s)，6.78-6.81(1H，m)，7.13-7.16(1H，m)，7.25-7.30(1H，m)，7.80(2H，d，J＝6.0Hz)，8.71(2H，d，J＝6.0Hz)	390
B189	(DMSO-d₆)：3.07-3.27(m，2H)，3.48(s，3H)，3.77(d，J＝13.2Hz，1H)，3.93-4.02(m，2H)，4.13(d，J＝10.2Hz，1H)，5.03(d，J＝8.7Hz，1H)，7.13(s，1H)，8.05(m，1H)，8.55(d，J＝6.3Hz，2H)，8.61(d，J＝8.1Hz，1H)，8.90(d，J＝5.4Hz，2H)，8.97(d，J＝5.4Hz，2H).	388	B188		390

B190	(DMSO-d₆)：3.09-3.23(m，2H)，3.47(s，3H)，3.68(d，J＝12.6Hz，1H)，3.87-3.94(m，2H)，4.03(d，J＝11.8Hz，1H)，5.05(D，J-8.4Hz，1H)，7.05(m，1H)，7.08(s，1H)，7.17(d，J＝3.3Hz，1H)，7.53(d，J＝5.1Hz，1H)，8.44(d，J＝6.4Hz，2H)，8.93(d，J＝6.4Hz，2H).	354
B190		354	B191	(DMSO-d₆)：3.03-3.22(m，2H)，3.45(s，3H)，3.69-4.04(m，4H)，4.80(d，J＝10.4Hz，1H)，7.03(s，1H)，7.19(m，1H)，7.52-7.55(m，2H)，8.39(d，J＝5.4Hz，2H)，8.90(d，J＝5.4Hz，2H).	354
B194	(DMSO-d₆)：3.18(m，1H)，3.50(s，3H)，3.73-4.17(m，5H)，5.03(d，J＝8.4Hz，1H)，7.15(s，1H)，7.65(m，1H)，7.82(d，J＝7.8Hz，1H)，8.20(t，J＝7.8Hz，1H)，8.57(d，J＝6.6Hz，2H)，8.72(d，J＝4.5Hz，1H)，8.98(d，J＝6.6Hz，2H).	349	B191		354
B194		349	B195	(DMSO-d₆)：3.07-3.27(m，2H)，3.48(s，3H)，3.77(d，J＝13.2Hz，1H)，3.93-4.02(m，2H)，4.13(d，J＝10.2Hz，1H)，5.03(d，J＝8.7Hz，1H)，7.13(s，1H)，8.05(m，1H)，8.55(d，J＝6.3Hz，2H)，8.61(d，J＝8.1Hz，1H)，8.90(d，J＝5.4Hz，1H)，8.90(d，J＝5.4Hz，1H)，8.97(d，J＝6.3Hz，2H).	349
B200	(DMSO-d₆)：3.30(s，3H)，3.36(m，2H)，3.88(m，2H)，4.01(m，2H)，7.10(s，1H)，7.22-7.42(m，10H)，8.46(d，J＝6.4Hz，2H)，8.93(d，J＝6.3Hz，2H).	425	B195		349
B200		425	B202	(DMSO-d₆)：1.60-2.00(m，3H)，2.62-2.76(m，3H)，3.18-3.29(m，2H)，3.48(s，3H)，3.68-3.83(m，3H)，4.10-4.17(m，1H)，7.03(s，1H)，7.10-7.24(m，3H)，7.63-7.66(m，1H)，8.38(d，J＝6.1Hz，2H)，8.89(d，J＝6.0Hz，2H).	388
B203	(CDCl₃)：2.20-2.40(m，1H)，2.60-2.70(m，1H)，2.80-3.00(m，1H)，3.00-3.20(m，1H)，3.29-3.50(m，4H)，3.59(s，3H)，4.03-3.20(m，2H)，6.70(s，1H)，7.27-7.36(m，3H)，7.49-7.5 1(m，1H)，7.78(dd，J＝1.5，4.8Hz，2H)，8.70(dd，J＝1.8，4.5Hz，2H).	374	B202		388
B203		374	B205	(DMSO-d₆)：1.30(s，3H)，1.44(s，3H)，2.80-2.95(m，2H)，3.51(s，3H)，3.63-3.80(m，2H)，5.07(m，1H)，7.03(s，1H)，7.30-7.48(m，5H)，8.35(brs，2H)，8.89(brs，2H).	377
B217	(CDCl₃)：1.39(s，3H)，1.52(s，3H)，2.89-3.03(m，2H)，3.39(m，1H)，3.59(s，3H)，3.63(m，1H)，3.82(s，3H)，5.00(m，1H)，6.69(s，1H)，6.93(d，J＝8.7Hz，2H)，7.37(d，J＝8.7Hz，2H)，7.79(d，J＝6.0Hz，2H)，8.71(d，J＝6.0Hz，2H).	407	B205		377
B217		407	B219	2.97(1H，dd，J＝10.5，12.9Hz)，3.30-3.39(1H，m)，3.53-3.66(1H，m)，3.60(3H，s)，3.75-3.89(1H，m)，3.82(3H，s)，3.95-4.03(1H，m)，4.18-4.23(1H，m)，5.07(1H，d，J＝9.6Hz)，6.71(1H，s)，6.79-6.85(1H，m)，6.97-7.04(1H，m)，7.07-7.10(1H，m)，7.82(2H，d，J＝6.0Hz)，8.72(2H，d，J＝6.0Hz)(CDCl₃)	396

B220	2.79(1H，dd，J＝10.1，12.7Hz)，3.29-3.38(1H，m)，3.54-3.59(1H，m)，3.61(3H，.s)，3.79-3.83(1H，m)，3.84(3H，s)，3.94-3.99(1H，m)，4.19-4.23(1H，m)，5.02(1H，dd，J＝2.1，10.1Hz)，6.69(1H，s)，6.77(1H，d，J＝8.8Hz)，7.40(1H，dd，J＝2.6，8.7Hz)，7.66(1H，d，J＝2.3Hz)，7.82(2H，d，J＝6.1Hz)，8.71(2H，d，J＝6.1Hz)(CDCl₃)	457
B220		457	B221	(DMSO-d₆)：1.40-1.60(m，1H)，1.80-2.20(m，2H)，2.60-3.00(m，5H)，3.00-3.20(m，1H)，3.45(s，3H)，3.50-3.70(m，2H)，3.73(d，J＝11.4Hz，1H)，3.81(d，J＝12.6Hz，1H)，3.98(d，J＝12.3Hz，1H)，7.01(s，1H)，7.02-7.10(m，4H)，8.38(dm，J＝6.6Hz，2H)，8.88-8.92(m，2H).	402
B225	(CDCl₃)：3.3-3.5(2H，m)，3.63(3H，s)，3.5-3.7(1H，m)，4.0-4.2(2H，m)，4.2-4.3(1H，m)，5.20(1H，dd，J＝2.7，9.8Hz)，6.73(1H，s)，7.4-7.6(2H，m)，7.80(1H，d，J＝6.3Hz)，7.94(1H，d，J＝7.9Hz)，8.03(1H，d，J＝8.0Hz)，8.71(1H，d，J＝6.3Hz)	406	B221		402
B225		406	B234	(DMSO-d₆)；3.01(m，1H)，3.17(m，1H)，3.46(s，3H)，3.70(m，2H)，3.89(m，1H)，4.05(d，J＝12.0Hz，1H)，4.65(d，J＝8.7Hz，1H)，6.02(s，2H)，6.89-6.96(m，2H)，7.01(s，2H)，8.34(d，J＝6.6Hz，2H)，8.87(d，J＝6.6Hz，2H).	393
B235	(DMSO-d₆)；2.99(dd，J＝10.8Hz，12.9Hz，1H)，3.12(m，1H)，3.46(s，3H)，3.69(d，J＝12.9，2H)，3.87(m，1H)，4.04(d，J＝11.7Hz，1H)，4.24(s，4H)，4.62(d，J＝9.0Hz，1H)，6.83-6.94(m，3H)，7.05(s，1H)，8.41(d，J＝6.6Hz，2H)，8.91(d，J＝6.6Hz，2H).	407	B234		393
B235		407	B236	(DMSO-d₆)；3.04(m，1H)，3.19(m，1H)，3.47(s，3H)，3.69-4.09(m，6H)，3.75(s，3H)，3.77(s，3H)，4.67(d，J＝9.0Hz，1H)，6.93-7.05(m，4H)，8.38(d，J＝6.3Hz，2H)，8.89(d，J＝6.3Hz，2H).	409
B237	(DMSO-d₆)：2.5-2.6(1H，m)，2.9-3.2(6H，m)，3.44(3H，s)，3.4-3.8(4H，s)，3.9-4.0(1H，m)，6.99(1H，s)，7.1-7.2(2H，m)，7.2-7.3(2H，m)，7.88(1H，d，J＝6.9Hz)，8.31(2H，d，J＝6.3Hz)，8.00(1H，s)，8.88(2H，d，J＝6.5Hz)	389	B236		409
B237		389	B238	(DMSO)：3.05(1H，dd，J＝10.8，12.8Hz)，3.15-3.26(1H，m)，3.45(3H，s)，3.65(1H，d，J＝13.4Hz)，3.73-3.91(2H，m)，3.79(3H，s)，4.05(1H，d，J＝13.6Hz)，4.95(1H，d，J＝8.9Hz)，6.82-6.89(3H，m)，7.43-7.49(1H，m)，7.98(2H，d，J＝5.9Hz)，8.68(2H，d，J＝5.8Hz)	397
B239	(DMSO)：2.88(1H，dd，J＝10.2，13.0Hz)，3.19-3.27(1H，m)，3.47(3H，s)，3.66(1H，d，J＝13.4Hz)，3.85(1H，d，J＝13.4Hz)，3.93(1H，t，J＝11.6Hz)，4.11(1H，d，J＝9.6Hz)，5.03(1H，d，J＝8.5Hz)，6.84(1H，s)，7.50-7.54(1H，m)，7.63-7.67(2H，m)，7.97(2H，d，J＝6.0Hz)，8.67(2H，d，J＝5.9Hz)	417	B238		397
B239		417	B240	(CDCl₃)：3.00(1H，dd，J＝12.9，10.5Hz)，3.21-3.41(3H，m)，3.55(1H，m)，3.59(3H，s)，3.83-4.21(3H，m)，4.61(2H，m)，4.95(1H，d，J＝8.4Hz)，6.69(1H，s)，6.91(1H，m)，7.16-7.31(2H，m)，7.84(2H，dd，J＝4.5，1.5Hz)，8.71(2H，dd，J＝4.5，1.5Hz).	391

B241	(DMSO-d₆)：2.80(1H，dd，J＝10.2，12.9Hz)，3.1-3.3(1H，m)，3.46(3H，s)，3.6-3.7(1H，m)，3.77(3H，s)，3.82(3H，s)，3.7-3.9(2H，m)，4.0-4.1(1H，m)，4.9-5.0(1H，m)，6.5-6.6(2H，m)，6.82(1H，s)，7.3-7.4(1H，m)，7.79(2H，dd，J＝1.5，4.5Hz)，8.69(2H，dd，J＝1.5，4.5Hz).	409
B241		409	B242	(DMSO-d₆)：2.80(1H，dd，J＝10.2，12.9Hz)，3.1-3.3(1H，m)，3.46(3H，s)，3.6-3.7(1H，m)，3.77(3H，s)，3.82(3H，s)，3.7-3.9(2H，m)，4.0-4.1(1H，m)，4.9-5.0(1H，m)，6.5-6.6(2H，m)，6.82(1H，s)，7.3-7.4(1H，m)，7.79(2H，dd，J＝1.5，4.5Hz)，8.69(2H，dd，J＝1.5，4.5Hz).	409
B243	(DMSO-d₆)：2.7-2.9(1H，m)，3.1-3.3(1H，m)，3.46(3H，s)，3.6-3.7(1H，m)，3.89(3H，s)，3.90(3H，s)，3.7-3.9(2H，m)，4.0-4.1(1H，m)，4.9-5.0(1H，m)，6.80(1H，s)，6.83(1H，s)，7.51(1H，s)，7.9-8.0(2H，m)，8.6-8.7(2H，m)	488	B242		409
B243		488	B244	(DMSO-d₆)：2.80(1H，dd，J＝10.2，12.9Hz)，3.1-3.3(1H，m)，3.46(3H，s)，3.6-3.7(1H，m)，3.77(3H，s)，3.82(3H，s)，3.7-3.9(2H，m)，4.0-4.1(1H，m)，4.9-5.0(1H，m)，6.5-6.6(2H，m)，6.82(1H，s)，7.3-7.4(1H，m)，7.79(2H，dd，J＝1.5，4.5Hz)，8.69(2H，dd，J＝1.5，4.5Hz).	409
B245	(CDCl₃)：2.80(1H，dd，J＝12.6，10.4Hz)，3.33(1H，m)，3.55(1H，m)，3.62(3H，s)，3.77(1H，m)，3.85(3H，s)，4.01(1H，m)，4.21(1H，m)，5.02(1H，d，J＝9.6Hz)，6.61-6.75(3H，m)，7.48(1H，m)，7.82(2H，d，J＝5.7Hz)，8.71(2H，d，J＝5.7Hz).	397	B244		409
B245		397	B246	(CDCl₃)：3.18(1H，dd，J＝12.3，10.1Hz)，3.35(1H，m)，3.59(1H，m)，3.60(3H，s)，3.72(1H，m)，3.98-4.23(2H，m)，4.79(1H，d，J＝10.5)，6.71(1H，s)，7.36-7.66(9H，m)，7.80(2H，d，J＝5.7Hz)，8.72(2H，d，J＝5.7Hz).	425
B247	(CDCl₃)：0.32-0.34(2H，m)，0.62-0.67(2H，m)，1.22(1H，m)，2.76(1H，dd，J＝12.6，10.2Hz)，3.37(1H，m)，3.60-4.25(7H，m)，3.65(3H，s)，5.02(1H，d，J＝9.3Hz)，6.54-6.72(3H，m)，7.47(1H，dd，J＝8.1，7.2Hz)，7.81(2H，d，J＝6.0Hz)，8.71(2H，d，J＝6.0Hz).	437	B246		425
B247		437	B248	(CDCl₃)：1.33(3H，d，J＝6.0Hz)，1.38(3H，d，J＝6.0Hz)，2.72(1H，dd，J＝12.6，10.2Hz)，3.35(1H，m)，3.57-3.72(5H，m)，4.03-4.25(2H，m)，4.57(1H，m)，4.95(1H，d，J＝8.7Hz)，6.58-6.71(3H，m)，7.46(1H，dd，J＝8.4，7.2Hz)，7.80(2H，d，J＝6.0Hz)，8.71(2H，d，J＝6.0Hz).	425
B249	(DMSO)：2.98(1H，dd，J＝10.5，13.0Hz)，3.18-3.30(1H，m)，3.47(3H，s)，3.66(1H，d，J＝12.5Hz)，3.80(1H，d，J＝13.0Hz)，3.84(3H，s)，3.92(1H，dd，J＝9.5，11.7Hz)，4.18(1H，d，J＝11.7Hz)，5.01(1H，dd，J＝2.0，10.4Hz)，6.84(1H，s)，7.50(1H，d，J＝2.6Hz)，7.67(1H，d，J＝2.7Hz)，7.99(2H，d，J＝6.2Hz)，8.69(2H，d，J＝6.1Hz)	447	B248		425
B249		447	B250	(DMSO)：3.01(1H，dd，J＝10.8，12.9Hz)，3.14-3.18(1H，m)，3.46(3H，s)，3.66-3.76(2H，m)，3.86-3.93(1H，m)，4.06(1H，d，J＝11.7Hz)，4.74(1H，d，J＝8.7Hz)，6.84(1H，s)，6.98-7.04(4H，m)，7.11-7.18(1H，m)，7.37-7.48(4H，m)，7.97(2H，d，J＝6.3Hz)，8.69(2H，d，J＝6.0Hz)	441

B251	(CDCl₃)：3.06(1H，dd，J＝12.9，10.5Hz)，3.42(1H，m)，3.60(1H，m)，3.67(3H，s)，4.07-4.32(3H，m)，5.38(1H，d，J＝10.2Hz)，6.73(1H，s)，7.45-7.61(2H，m)，7.82(1H，d，J＝9.0Hz)，7.89(2H，d，J＝6.0Hz)，8.72(2H，d，J＝6.0Hz).	391
B251		391	B252	(CDCl₃)：3.3-3.7(4H，m)，3.58(3H，s)，3.96(1H，t，J＝11.7Hz)，4.17(1H，dd，J＝4.5，8.3Hz)，6.70(1H，s)，7.0-7.1(1H，m)，7.2-7.4(2H，m)，7.82(2H，d，J＝5.7Hz)，8.71(2H，d，J＝5.6Hz)	401
B253	(CDCl₃)：2.81(1H，dd，J＝10.5，12.8Hz)，3.3-3.4(1H，m)，3.5-3.7(2H，m)，3.63(3H，s)，3.7-3.9(1H，m)，4.03(1H，dt，J＝2.2，11.6Hz)，4.2-4.3(1H，m)，5.0-5.1(1H，m)，6.71(1H，s)，7.0-7.2(2H，m)，7.63(1H，dd，J＝6.3，8.7Hz)，7.80(2H，d，J＝6.0Hz)，8.71(2H，d，J＝5.6Hz).	401	B252		401
B253		401	B254	(DMSO)：2.89(1H，dd，J＝10.2，12.8Hz)，3.19-3.30(1H，m)，3.49(3H，s)，3.67(1H，d，J＝13.0Hz)，3.86-3.95(2H，m)，3.89(3H，s)，4.13(1H，d，J＝9.8Hz)，5.07(1H，d，J＝8.4Hz)，6.84(1H，s)，7.15(1H，d，J＝8.6Hz)，7.29-7.37(1H，m)，7.42-7.48(2H，m)，7.60-7.63(3H，m)，7.72(1H，d，J＝2.3Hz)，8.00(2H，d，J＝6.1Hz)，8.69(2H，d，J＝6.0Hz)	455
B255	(DMSO)：2.85(1H，dd，J＝10.2，12.9Hz)，3.19-3.28(1H，m)，3.49(3H，s)，3.67(1H，d，J＝12.3Hz)，3.85-3.95(2H，m)，3.88(3H，s)，4.13(1H，d，J＝9.7Hz)，5.06(1H，d，J＝8.3Hz)，6.84(1H，s)，7.14(1H，d，J＝8.6Hz)，7.21-7.30(2H，m)，7.57-7.70(4H，m)，8.00(2H，d，J＝6.1Hz)，8.69(2H，d，J＝6.1Hz)	473	B254		455
B255		473	B256	(DMSO)：2.93(1H，dd，J＝10.3，13.0Hz)，3.19-3.31(1H，m)，3.49(3H，s)，3.68(1H，d，J＝12.6Hz)，3.86-3.95(2H，m)，3.90(3H，s9)，4.13(1H，d，J＝9.5Hz)，5.08(1H，d，J＝8.3Hz)，6.84(1H，s)，7.20(1H，d，J＝8.6Hz)，7.41-7.50(1H，m)，7.66-7.70(1H，m)，7.76(1H，d，J＝2.4Hz)，8.00(2H，d，J＝6.2Hz)，8.00-8.04(1H，m)，8.50-8.54(1H，m)，8.69(2H，d，J＝6.1Hz)，8.85(1H，d，J＝2.0Hz)	456
B257	(DMSO)：2.99(1H，dd，J＝10.8，12.9Hz)，3.10-3.21(1H，m)，3.46(3H，s)，3.66-3.77(2H，m)，3.87-3.95(1H，m)，4.08(1H，d，J＝11.7Hz)，4.76(1H，d，J＝8.4Hz)，6.85(1H，s)，7.28-7.33(1H，m)，7.41-7.56(2H，m)，7.96(2H，d，J＝6.0Hz)，8.69(2H，d，J＝6.0Hz)	385	B256		456
B257		385	B258	(DMSO)：2.99(1H，dd，J＝10.7，12.6Hz)，3.13-3.22(1H，m)，3.46(3H，s)，3.67-3.77(2H，m)，3.87-3.95(1H，m)，4.08(1H，d，J＝11.5Hz)，4.76(1H，d，J＝9.2Hz)，6.86(1H，s)，7.41(1H，t，J＝8.6Hz)，7.48-7.54(1H，m)，7.72-7.81(1H，m)，7.98(2H，d，J＝5.9Hz)，8.69(2H，d，J＝5.9Hz)	445
B259	(DMSO-d₆)：1.23(6H，d，J＝5.9Hz)，2.7-2.9(1H，m)，3.1-3.3(1H，m)，3.47(3H，s)，3.6-3.7(1H，m)，3.7-4.0(2H，m)，3.78(3H，s)，4.0-4.1(1H，m)，4.4-4.6(1H，m)，4.9-5.0(1H，m)，6.8-7.0(4H，m)，8.00(2H，d，J＝5.3Hz)，8.69(2H，d，J＝5.6Hz)	437	B258		445

B260	(DMSO-d₆)：2.17(3H，s)，2.22(3H，s)，2.7-2.8(1H，m)，3.1-3.2(1H，m)，3.46(3H，s)，3.6-3.7(1H，m)，3.7-3.9(2H，m)，3.79(3H，s)，4.0-4.1(1H，m)，6.84(2H，s)，7.19(1H，s)，7.99(2H，d，J＝5.0Hz)，8.69(2H，d，J＝4.7Hz)	407
B260		407	B261	(DMSO-d₆)：1.27(6H，d，J＝5.1Hz)，2.7-2.9(1H，m)，3.1-3.3(1H，m)，3.46(3H，s)，3.6-4.0(3H，m)，3.84(3H，s)，4.0-4.1(1H，m)，4.6-4.7(1H，m)，4.9-5.0(1H，m)，6.5-6.6(2H，m)，6.84(1H，s)，7.2-7.3(1H，m)，7.99(2H，d，J＝6.0Hz)，8.69(2H，d，J＝6.0Hz)	437
B262	(DMSO-d₆)：2.7-2.9(1H，m)，3.2-3.3(1H，m)，3.47(3H，s)，3.6-3.7(1H，m)，3.8-4.0(5H，m)，4.1-4.2(1H，m)，5.0-5.1(1H，m)，6.86(1H，s)，7.26(1H，d，J＝8.5Hz)，7.78(1H，s)，7.84(1H，d，J＝8.5Hz)，8.00(2H，d，J＝5.7Hz)，8.70(2H，d，J＝5.6Hz)	404	B261		437
B262		404	B263	(CDCl₃)：1.40(3H，t，J＝6.9Hz)，3.38-3.47(3H，m)，3.86(6H，s)，3.91-4.17(5H，m)，5.44(1H，dd，J＝10.8，2.1Hz)，6.60(1H，d，J＝8.4Hz)，6.67(1H，s)，7.24-7.30(2H，m)，7.84(2H，d，J＝6.0Hz)，8.70(2H，d，J＝6.0Hz).	423
B264	(CDCl₃)：0.95(3H，t，J＝7.2Hz)，1.77-1.86(2H，m)，3.34-3.47(2H，m)，3.89(6H，s)，3.92-4.48(5H，m)，5.44(1H，d，J＝8.4Hz)，6.60(1H，d，J＝8.4Hz)，6.67(1H，s)，7.24-7.30(2H，m)，7.84(2H，d，J＝6.0Hz)，8.70(2H，d，J＝6.0Hz).	437	B263		423
B264		437	B265	(DMSO-d₆)：1.30(3H，t，J＝6.6Hz)，2.97-4.10(8H，m)，4.78(1H，d，J＝9.6Hz)，7.08(1H，s)，7.19-7.25(2H，m)，7.48-7.54(2H，m)，8.35(2H，d，J＝6.0Hz)，8.88(2H，d，J＝6.0Hz).	381
B266	(DMSO-d₆)：0.88(3H，t，J＝7.2Hz)，1.69-1.77(2H，m)，1.26(1H，m)，3.00-3.26(2H，m)，3.59(2H，m)，3.88-4.12(3H，m)，4.78(1H，d，J＝9.6Hz)，7.08(1H，s)，7.20-7.26(2H，m)，7.49-7.54(2H，m)，8.36(2H，d，J＝6.0Hz)，8.90(2H，d，J＝6.0Hz).	395	B265		381
B266		395	B267	(CDCl₃)：0.39-0.43(2H，m)，0.53-0.58(2H，m)，1.26(1H，m)，3.09(1H，dd，J＝12.6，10.8Hz)，3.29-3.51(3H，m)，3.92(1H，m)，3.61(3H，s)，3.77(1H，m)，3.85(3H，s)，3.99(1H，m)，4.21(1H，m)，5.01(1H，dd，J＝9.9，1.8Hz)，6.63(1H，dd，J＝10.8，2.4Hz)，6.69(1H，s)，6.72(1H，m)，7.48(1H，dd，J＝8.4，6.9Hz)，7.82(2H，dd，J＝4.8，1.8Hz)，8.71(2H，dd，J＝4.8，1.8Hz).	407
B268	(CDCl₃)：3.3-3.4(1H，m)，3.5-3.6(2H，m)，3.59(3H，s)，3.83(3H，s)，3.9-4.1(2H，m)，4.1-4.2(1H，m)，4.96(1H，dd，J＝2.4，10.2Hz)，6.50(1H，s)，6.73(1H，s)，6.9-7.1(1H，m)，7.2-7.3(2H，m)，7.81(2H，dd，J＝1.5，4.5Hz)，8.74(2H，dd，J＝1.2，4.5Hz)	420	B267		407
B268		420	B269	(DMSO-d₆)：2.78(1H，dd，J＝10.2，12.8Hz)，3.1-3.3(1H，m)，3.47(3H，s)，3.6-3.7(1H，m)，3.8-4.0(5H，m)，4.0-4.1(1H，m)，4.9-5.0(1H，m)，6.84(1H，s)，7.06(1H，dd，J＝2.0，8.2Hz)，7.13(1H，d，J＝2.0Hz)，7.44(1H，d，J＝8.2Hz)，7.99(2H，dd，J＝1.6，4.7Hz)，8.69(2H，dd，J＝1.6，4.7Hz)	413
B270	(DMSO-d₆)：3.1-3.3(1H，m)，3.42(3H，s)，3.5-3.6(1H，m)，3.6-3.7(2H，m)，3.7-3.9(1H，m)，3.86(3H，s)，3.9-4.0(1H，m)，5.1-5.2(1H，m)，6.8-7.0(3H，m)，7.9-8.0(2H，m)，8.6-8.7(2H，m)	415	B269		413

B271	(CDCl₃)：3.3-3.51H，m)，3.5-3.7(2H，m)，3.61(3H，s)，3.9-4.3(3H，m)，5.35(1H，dd，J＝2.8，9.8Hz)，6.73(1H，s)，7.3-7.4(1H，m)，7.6-7.7(2H，m)，7.80(2H，dd，J＝1.5，4.7Hz)，7.96(1H，d，J＝8.1Hz)，8.71(2H，dd，J＝1.5，4.7Hz)	390
B271		390	B272	(DMSO-d₆)：2.7-2.8(1H，m)，3.2-3.3(1H，m)，3.47(3H，s)，3.6-3.7(1H，m)，3.8-4.0(5H，m)，4.1-4.2(1H，m)，5.0-5.1(1H，m)，6.84(1H，s)，7.48(1H，d，J＝8.1Hz)，7.54(1H，s)，7.62(1H，d，J＝8.1Hz)，7.99(2H，dd，J＝1.2，4.5Hz)，8.70(2H，d，J＝1.2，4.5Hz)	404
B273	(DMSO-d₆)：2.8-2.9(1H，m)，3.1-3.3(1H，m)，3.49(3H，s)，3.6-3.8(1H，m)，3.8-4.0(5H，m)，4.1-4.2(1H，m)，5.0-5.1(1H，m)，6.86(1H，s)，7.2-7.6(5H，m)，7.72(2H，d，J＝7.5Hz)，8.01(2H，d，J＝6.3Hz)，8.70(2H，d，J＝6.0Hz)	455	B272		404
B273		455	B274	(CDCl₃)：1.9-2.1(4H，m)，2.83(1H，dd，J＝10.2，12.6Hz)，3.2-3.5(5H，m)，3.5-3.7(1H，m)，3.62(3H，s)，3.79(3H，s)，3.8-3.9(1H，m)，3.9-4.1(1H，m)，4.2-4.3(1H，m)，5.0-5.1(1H，m)，6.49(1H，dd，J＝3.0，9.0Hz)，6.68(1H，s)，6.8-6.9(2H，m)，7.82(2H，d，J＝6.0Hz)，8.71(2H，d，J＝6.0Hz)	448
B275	(CDCl₃)：1.9-2.1(4H，m)，2.89(1H，dd，J＝10.3，12.8Hz)，3.2-3.4(5H，m)，3.5-3.6(1H，m)，3.60(3H，s)，3.75(3H，s)，3.7-3.8(1H，m)，3.9-4.1(1H，m)，4.1-4.3(1H，m)，4.99(1H，dd，J＝2.1，10.2Hz)，6.08(1H，d，J＝2.1Hz)，6.21(1H，dd，J＝2.0，8.5Hz)，6.68(1H，s)，7.31(1H，d，J＝8.5Hz)，7.82(2H，dd，J＝1.6，4.6Hz)，8.71(2H，dd，J＝1.6，4.6Hz)	448	B274		448
B275		448	B276	(DMSO)：2.84(1H，dd，J＝10.5，12.8Hz)，3.19-3.26(1H，m)，3.49(3H，s)，3.66(1H，d，J＝12.7Hz)，3.88-3.94(2H，m)，3.90(3H，s)，4.12(1H，d，J＝10.3Hz)，5.06(1H，d，J＝9.2Hz)，6.85(1H，s)，7.17(1H，d，J＝8.6Hz)，7.26-7.33(2H，m)，7.36-7.40(1H，m)，7.48-7.53(2H，m)，7.63(1H，s)，8.01(2H，d，J＝5.7Hz)，8.69(2H，d，J＝5.6Hz)	473
B277	(DMSO)：2.90(1H，dd，J＝10.3，12.8Hz)，3.26-3.29(1H，m)，3.49(3H，s)，3.67(1H，d，J＝13.1Hz)，3.82(3H，s)，3.85-3.94(2H，m)，3.89(3H，s)，4.14(1H，d，J＝9.6Hz)，5.06(1H，d，J＝8.7Hz)，6.85(1H，s)，6.90-6.93(1H，m)，7.12-7.19(3H，m)，7.34-7.39(1H，m)，7.60-7.64(1H，m)，7.71(1H，d，J＝2.1Hz)，8.01(2H，d，J＝6.0Hz)，8.69(2H，d，J＝5.9Hz)	485	B276		473
B277		485	B278	(DMSO)：2.84(1H，dd，J＝10.5，12.6Hz)，3.18-3.25(1H，m)，3.48(3H，s)，3.66(1H，d，J＝13.2Hz)，3.86-3.93(2H，m)，3.90(3H，s)，4.10(1H，d，J＝10.2Hz)，5.07(1H，d，J＝9.0Hz)，6.85(1H，s)，7.16(1H，d，J＝8.7Hz)，7.39-7.45(2H，m)，7.50-7.52(2H，m)，7.72(1H，d，J＝1.8Hz)，8.01(2H，d，J＝5.4Hz)，8.70(2H，d，J＝5.4Hz)	523
B279	(DMSO)：1.52-1.71(4H，m)，2.32-2.43(4H，m)，2.76(1H，dd，J＝10.2，12.9Hz)，3.18-3.25(1H，m)，3.47(3H，s)，3.54(2H，d，J＝3.9Hz)，3.65(1H，d，J＝12.9Hz)，3.81-3.91(2H，m)，3.82(3H，s)，4.10(1H，d，J＝9.9Hz)，4.99(1H，d，J＝8.7Hz)，6.84(1H，s)，6.97(1H，d，J＝8.4Hz)，7.17-7.23(1H，m)，7.39(1H，d，J＝1.8Hz)，8.00(2H，d，J＝6.0Hz)，8.69(2H，d，J＝6.0Hz)	462	B278		523

B280	(DMSO)：3.11(1H，dd，J＝10.3，12.6Hz)，3.41-3.48(1H，m)，3.67(3H，s)，3.86(1H，d，J＝12.7Hz)，4.03-4.13(2H，m)，4.08(3H，s)，4.32(1H，d，J＝11.0Hz)，5.25(1H，d，J＝8.6Hz)，7.04(1H，s)，7.33-7.36(2H，m)，7.60-7.70(3H，m)，7.86(1H，dd，J＝2.4，8.5Hz)，7.93(1H，d，J＝2.3Hz)，8.19(2H，d，J＝6.1Hz)，8.88(2H，d，J＝6.0Hz)	473
B280		473	B281	(DMSO)：2.83(1H，dd，J＝10.2，12.9Hz)，3.14-3.25(1H，m)，3.49(3H，s)，3.66(1H，d，J＝12.6Hz)，3.76(3H，s)，3.84-3.93(2H，m)，3.87(3H，s)，4.10(1H，d，J＝11.4Hz)，5.04(1H，d，J＝8.7Hz)，6.85(1H，s)，6.98-7.03(1H，m)，7.07-7.11(2H，m)，7.25-7.34(2H，m)，7.41-7.47(1H，m)，7.53(1H，d，J＝2.4Hz)，8.01(2H，d，J＝6.3Hz)，8.70(2H，d，J＝6.0Hz)	485
B282	(DMSO)：2.88(1H，dd，J＝10.3，12.9Hz)，3.18-3.28(1H，m)，3.48(3H，s)，3.67(1H，d，J＝12.8Hz)，3.79(3H，s)，3.85-3.94(2H，m)，3.87(3H，s)，4.13(1H，d，J＝11.6Hz)，5.05(1H，d，J＝8.4Hz)，6.85(1H，s)，7.01(1H，d，J＝8.8Hz)，7.11(1H，d，J＝8.7Hz)，7.53-7.56(3H，m)，7.66(1H，d，J＝2.3Hz)，8.00(2H，d，J＝6.1Hz)，8.69(2H，d，J＝6.0Hz)	485	B281		485
B282		485	B283	(DMSO)：2.77(1H，dd，J＝10.2，12.8Hz)，3.10-3.21(1H，m)，3.47(3H，s)，3.65(1H，d，J＝12.9Hz)，3.80(3H，s)，3.84-3.92(2H，m)，4.04-4.10(1H，m)，4.98(1H，d，J＝8.4Hz)，6.68-6.73(1H，m)，6.85(1H，s)，6.92-6.98(3H，m)，7.01-7.08(1H，m)，7.14-7.20(2H，m)，7.23(1H，d，J＝2.6Hz)，7.94(1H，s)，8.01(2H，d，J＝6.1Hz)，8.69(2H，d，J＝6.1Hz)	470
B284	(CDCl₃)：3.37-3.54(3H，m)，3.59(3H，s)，3.88(1H，m)，4.03(1H，m)，4.18(1H，m)，4.99(1H，dd，J＝10.2，2.4Hz)，6.73(1H，s)，6.78(1H，s)，7.25-7.33(2H，m)，7.49-7.58(2H，m)，7.81(2H，dd，J＝4.5，1.8Hz)，8.72(dd，J＝4.5，1.8Hz).	389	B283		470
B284		389	B285	(CDCl₃)：2.80(1H，dd，J＝12.9，10.2Hz)，3.35(1H，m)，3.55(1H，m)，3.61(3H，s)，3.77(1H，m)，3.85(3H，s)，3.99(1H，m)，4.21(1H，m)，5.01(1H，dd，J＝9.9，1.8Hz)，6.63(1H，dd，J＝10.8，2.4Hz)，6.69(1H，s)，6.72(1H，m)，7.48(1H，dd，J＝8.4，6.9Hz)，7.82(2H，dd，J＝4.8，1.8Hz)，8.71(2H，dd，J＝4.8，1.8Hz).	397
B286	(CDCL₃)：3.33-3.53(3H，m)，3.58(3H，s)，3.88(1H，m)，3.98(1H，m)，4.01(3H，s)，4.18(1H，m)，5.00(1H，m)，6.72(1H，s)，6.77(1H，s)，6.82(1H，m)，7.16-7.19(2H，m)，7.83(2H，d，J＝6.0Hz)，8.72(2H，d，J＝6.0Hz).	419	B285		397
B286		419	B287	(DMSO-d₆)：1.9-2.1(4H，m)，2.9-3.2(3H，m)，3.2-3.5(3H，m)，3.51(3H，s)，3.72(1H，d，J＝11.7Hz)，3.90(3H，s)，3.8-4.1(2H，m)，4.14(1H，d，J＝12.9Hz)，4.41(2H，d，J＝5.4Hz)，5.08(1H，d，J＝9.6Hz)，7.08(1H，s)，7.18(1H，d，J＝8.7Hz)，7.4-7.6(1H，m)，7.6-7.8(2H，m)，7.79(1H，s)，7.96(1H，s)，8.46(2H，d，J＝6.0Hz)，8.93(2H，d，J＝5.4Hz)，11.5(1H，brd)	538

B288	(CDCl₃)：1.9-2.1(4H，m)，3.17(1H，dd，J＝10.5，12.9Hz)，3.3-3.4(5H，m)，3.5-3.6(1H，m)，3.57(3H，s)，3.7-3.8(1H，m)，3.9-4.1(1H，m)，4.1-4.2(1H，m)，4.69(1H，dd，J＝2.1，10.5Hz)，6.73(1H，s)，6.54(1H，m)，6.60(1H，d，J＝1.2Hz)，6.6-6.7(2H，m)，7.2-7.3(1H，m)7.81(2H，dd，J＝1.5，4.5Hz)，8.71(2H，dd，J＝1.8，4.5Hz)	418
B288		418	B289	(CDCl₃)：1.9-2.1(4H，m)，3.17(1H，dd，J＝10.5，12.9Hz)，3.3-3.4(5H，m)，3.5-3.6(1H，m)，3.57(3H，s)，3.7-3.8(1H，m)，3.9-4.1(1H，m)，4.1-4.2(1H，m)，4.69(1H，dd，J＝2.1，10.5Hz)，6.73(1H，s)，6.54(1H，m)，6.60(1H，d，J＝1.2Hz)，6.6-6.7(2H，m)，7.2-7.3(1H，m)7.81(2H，dd，J＝1.5，4.5Hz)，8.71(2H，dd，J＝1.8，4.5Hz)	418
B290	(CDCl₃)：2.87(1H，m)，3.38(1H，m)，3.58(1H，m)，3.64(3H，s)，3.84(1H，m)，3.91(3H，s)，4.03(1H，m)，4.22(1H，m)，5.11(1H，m)，6.70(1H，s)，7.08-7.46(6H，m)，7.60(1H，d，J＝5.1Hz)，7.83(2H，d，J＝6.0Hz)，8.72(2H，d，J＝6.0Hz).	473	B289		418
B290		473	B291	(CDCl₃)：2.86(1H，dd，J＝12.9，10.2Hz)，3.38(1H，m)，3.57(1H，m)，3.64(3H，s)，3.88(1H，m)，3.93(3H，s)，4.02(1H，m)，4.26(1H，m)，5.10(1H，m)，6.70(1H，s)，7.05-7.07(2H，m)，7.21-7.42(4H，m)，7.60(1H，d，J＝4.8Hz)，7.83(2H，dd，J＝4.5，1.2Hz)，8.72(2H，dd，J＝4.5，1.2Hz).	473
B292	(CDCl₃)：2.86(1H，dd，J＝12.9，10.2Hz)，3.35(1H，m)，3.57(1H，m)，3.64(3H，s)，3.88(1H，m)，3.93(3H，s)，4.02(1H，m)，4.22(1H，m)，5.10(1H，m)，6.70(1H，s)，7.04(1H，s)，7.10-7.23(3H，m)，7.52-7.60(3H，m)，7.83(2H，d，J＝6.0Hz)，8.72(2H，d，J＝6.0Hz).	473	B291		473
B292		473	B293	(DMSO)：2.86(1H，dd，J＝10.2，12.8Hz)，3.22-3.30(1H，m)，3.49(3H，S)，3.68(1H，d，J＝12.1Hz)，3.87-3.96(2H，m)，3.91(3H，s)，4.16(1H，d，J＝11.9Hz)，5.07(1H，d，J＝8.7Hz)，6.85(1H，s)，7.16(1H，d，J＝8.7Hz)，7.27-7.32(1H，m)，7.81-7.94(2H，m)，7.99-8.05(3H，m)，8.26(1H，d，J＝2.3Hz)，8.63-8.65(1H，m)，8.69(2H，d，J＝6.0Hz)	456
B294	(DMSO)：2.90(1H，dd，J＝10.5，12.9Hz)，3.20-3.29(1H，m)，3.49(3H，s)，3.68(1H，d，J＝12.3Hz)，3.84-3.92(2H，m)，3.91(3H，s)，3.95(3H，s)，4.15(1H，d，J＝12.0Hz)，5.07(1H，d，J＝9.0Hz)，6.73(1H，d，J＝8.1Hz)，6.85(1H，s)，7.17(1H，d，J＝8.7Hz)，7.48(1H，d，J＝7.5Hz)，7.76(1H，t，J＝7.8Hz)，8.01(2H，d，J＝6.0Hz)，8.07(1H，dd，J＝2.1，8.7Hz)，8.15(1H，d，J＝2.1Hz)，8.69(1H，d，J＝6.0Hz)	486	B293		456
B294		486	B295	(DMSO)：2.91(1H，dd，J＝10.2，12.8Hz)，3.21-3.28(1H，m)，3.48(3H，s)，3.67(1H，d，J＝12.5Hz)，3.84-3.94(2H，m)，3.88(3H，s)，3.89(3H，s)，4.12(1H，d，J＝9.9Hz)，5.06(1H，d，J＝8.5Hz)，6.85(1H，s)，6.90(1H，d，J＝8.7Hz)，7.15(1H，d，J＝8.6Hz)，7.58-7.63(1H，m)，7.67(1H，d，J＝2.4Hz，)，7.94-7.98(1H，m)，8.01(2H，d，J＝6.1Hz)，8.42(1H，d，J＝2.3Hz)，8.69(2H，d，J＝6.2Hz)	486

B296	(DMSO)：2.84(1H，dd，J＝10.5，12.6Hz)，3.18-3.25(1H，m)，3.48(3H，s)，3.62(1H，d，J＝13.2Hz)，3.85-3.99(2H，m)，3.87(3H，s)，3.94(6H，s)，4.11(1H，d，J＝10.2Hz)，5.04(1H，d，J＝9.6Hz)，6.85(1H，s)，7.12(1H，d，J＝8.7Hz)，7.46(1H，d，J＝8.4Hz)，7.56(1H，s)，8.00(2H，d，J＝4.8Hz)，8.32(1H，s)，8.70(2H，d，J＝5.1Hz)	487
B296		487	B297	(CDCl₃)：2.2-2.4(1H，m)，2.4-2.6(1H，m)，3.3-3.4(1H，m)，3.5-3.8(3H，m)，3.58(3H，s)，3.9-4.1(1H，m)，4.1-4.3(2H，m)，4.5-4.6(1H，m)，6.71(1H，s)，6.87(1H，d，J＝8.4Hz)，7.00(1H，t，J＝7.8Hz)，7.25(1H，t，J＝8.4Hz)，7.62(1H，dd，J＝1.5，8.1Hz)，7.78(2H，dd，J＝1.5，4.5Hz)，8.71(2H，dd，J＝1.8，6.6Hz)	391
B298	(CDCl₃)：1.8-2.0(3H，m)，2.3-2.4(1H，m)，3.2-3.4(1H，m)，3.44(3H，s)3.5-3.6(1H，m)，3.7-3.9(3H，m)，4.1-4.2(1H，m)，4.2-4.4(2H，m)，6.66(1H，s)，7.02(1H，dd，J＝1.2，8.1Hz)，7.14(1H，t，J＝7.2Hz)，7.22(1H，dd，J＝1.8，7.5Hz)，7.59(1H，dd，J＝1.8，7.8Hz)，7.79(2H，dd，J＝1.5，4.5Hz)，8.71(2H，dd，J＝1.5，4.5Hz)	405	B297		391
B298		405	C001	(CDCl₃)：1.79-1.95(m，3H)，2.14(m，1H)，3.08(m，1H)，3.26(dd，J＝12.6，7.2Hz，1H)，3.53(s，3H)，3.65(m，1H)，3.82-3.96(m，2H)，6.65(s，1H)，7.47(t，J＝7.8Hz，2H)，7.61(t，J＝7.5Hz，1H)，7.79(d，J＝6.0Hz，2H)，8.02(d，J＝7.5Hz，2H)，8.70(d，J＝6.0Hz，2H).	374
C002	(CDCl₃)：1.81-1.92(m，3H)，2.12(m，1H)，3.08(m，1H)，3.25(m，1H)，3.52(s，3H)，3.64(m，1H)，3.75-3.92(m，2H)，6.65(s，1H)，7.12(t，J＝8.4Hz，2H)，7.84(m，1H)，8.03(dd，J＝7.8，5.7Hz，2H)，8.76(m，1H).	392	C001		374
C002		392	C005	(CDCl₃)：1.65-1.93(m，3H)，2.13(m，1H)，3.08(m，1H)，3.25(dd，J＝12.9，10.5Hz，1H)，3.53(s，3H)，3.65(m，1H)，3.88(s，3H)，3.77-3.94(m，2H)，6.65(s，1H)，6.93(dd，J＝9.6，1.2Hz，2H)，7.80(d，J＝6.0Hz，2H)，8.00(dd，J＝9.9，1.2Hz，2H)，8.70(d，J＝6.0Hz，2H).	405
C006	(CDCl₃)：1.69-1.92(m，3H)，2.12(m，1H)，3.06(m，1H)，3.21(dd，J＝12.9，10.2Hz，1H)，3.50(s，3H)，3.60-3.83(m，3H)，3.86(s，3H)，6.66(s，1H)，6.96-7.05(m，2H)，7.45-7.57(m，2H)，7.79(d，J＝4.5Hz，2H)，8.69(d，J＝4.8Hz，2H).	405	C005		405
C006		405	C067	(CDCl₃)：1.83-2.14(m，4H)，2.77(m，1H)，3.06(m，1H)，3.37(m，1H)，3.45(s，3H)，3.58(m，1H)，3.90(m，1H)，6.64(s，1H)，7.13(m，1H)，7.33(m，2H)，7.53(d，J＝8.2Hz，2H)，7.64(m，1H)，7.79(d，J＝5.8Hz，2H)，8.70(d，J＝5.7Hz，2H).	390
C091	(CDCl₃)：1.81-2.01(6H，m)，2.70-2.75(2H，m)，3.00(1H，m)，3.25-3.92(6H，m)，3.35(3H，s)，6.61(1H，s)，7.12-7.26(4H，m)，7.72(2H，d，J＝6.0Hz)，8.69(2H，d，J＝6.0Hz).	430	C067		390
C091		430	C092	(DMSO-d₆)：1.48-1.89(m，10H)，2.92-3.07(m，4H)，3.41(s，3H)，3.42-3.72(m，5H)，6.97(s，1H)，8.38(d，J＝5.1Hz，2H)，8.92(d，J＝5.1Hz，2H).	382

C094	(CDCl₃)：1.74-2.05(m，4H)，3.08(m，2H)，3.28(m，1H)，3.51(s，3H)，3.59-3.80(m，10H)，6.63(s，1H)，7.76(d，J＝4.8Hz，2H)，8.71(d，J＝4.8Hz，2H).	384
C094		384	C101	(CDCl₃)：3.37-3.50(m，3H)，3.57(s，3H)，3.90-4.00(m，2H)，4.10-4.19(m，1H)，5.14(dd，J＝2.7，9.3Hz，1H)，6.70(s，1H)，7.48(t，J＝7.8Hz，2H)，7.63(t，J＝7.5Hz，1H)，7.79(dd，J＝1.5，4.8Hz，2H)，8.06(dd，J＝1.2，7.2Hz，2H)，8.73(dd，J＝1.8，6.3Hz，2H).	377
C102	(CDCl₃)：3.30-3.50(m，3H)，3.58(s，3H)，3.85-4.17(m，3H)，5.04(dd，J＝2.7，9.3Hz，1H)，6.07(s，1H)，7.14(dd，J＝7.2，8.7Hz，2H)，7.78(dd，J＝1.5，4.8Hz，2H)，8.11(m，2H)，8.73(dd，J＝1.5，4.5Hz，2H).	395	C101		377
C102		395	C105	(CDCl₃)：1.65-1.93(3H，m)，2.13(1H，m)，3.08(1H，m)，3.25(1H，dd，J＝12.9，10.5Hz)，3.53(3H，s)，3.65(1H，m)，3.88(3H，s)，3.77-3.94(2H，m)，6.65(1H，s)，6.93(2H，dd，J＝9.6，1.2Hz)，7.80(2H，d，J＝6.0Hz)，8.00(2H，dd，J＝9.9，1.2Hz)，8.70(2H，d，J＝6.0Hz).	405
C106	(CDCl₃)：1.69-1.92(3H，m)，2.12(1H，m)，3.06(1H，m)，3.21(1H，dd，J＝12.9，10.2Hz)，3.50(3H，s)，3.60-3.83(3H，m)，3.86(3H，s)，6.66(1H，s)，6.96-7.05(2H，m)，7.45-7.57(2H，m)，7.79(2H，d，J＝4.5Hz)，8.69(2H，d，J＝4.8Hz).	405	C105		405
C106		405	C386	(CDCl₃)：1.80-2.11(4H，m)，3.07(1H，m)，3.26(1H，dd，J＝13.1，10.7Hz)，3.53(3H，s)，3.59-3.66(2H，m)，3.88(1H，m)，6.65(1H，s)，6.95(1H，d，J＝4.2Hz)，7.62(1H，d，J＝4.2Hz)，7.78(2H，dd，J＝4.5，1.6Hz)，8.71(2H，dd，J＝4.5，1.6Hz).	415
C389	(CDCl₃)：3.3-3.7(3H，m)，3.57(3H，s)，3.9-4.0(2H，m)，4.1-4.2(1H，m)，5.14(1H，dd，J＝2.1，9.0Hz)，6.70(1H，s)，7.4-7.5(2H，m)，7.6-7.7(1H，m)，7.78(2H，dd，J＝1.2，4.5Hz)，8.05(2H，dd，J＝1.2，7.2Hz)，8.73(2H，dd，J＝0.9，4.5Hz)	377	C386		415
C389		377	C390	(CDCl₃)：3.3-3.7(3H，m)，3.57(3H，s)，3.9-4.0(2H，m)，4.1-4.2(1H，m)，5.14(1H，dd，J＝2.1，9.0Hz)，6.70(1H，s)，7.4-7.5(2H，m)，7.6-7.7(1H，m)，7.78(2H，dd，J＝1.2，4.5Hz)，8.05(2H，dd，J＝1.2，7.2Hz)，8.73(2H，dd，J＝0.9，4.5Hz)	377
D001	(CDCl₃)：2.01-2.10(m，4H)，3.16(m，2H)，3.56(s+m，3H+1H)，3.76(m，2H)，6.69(s，1H)，7.53(m，2H)，7.63(m，1H)，7.83(d，J＝6.0Hz，2H)，8.50(d，J＝7.2Hz，2H)，8.73(d，J＝6.0Hz，2H).	375	C390		377
D001		375	D002	(CDCl₃)：1.93(m，2H)，2.12(m，2H)，3.12(m，2H)，3.42(m，1H)，3.53(s，3H)，3.71(m，2H)，6.68(s，1H)，7.17(m，1H)，7.28(m，1H)，7.56(m，1H)，7.80-7.86(m，3H)，8.71(d，J＝6.0Hz，2H).	393
D003	(CDCl₃)：1.94-2.10(m，4H)，3.15(m，2H)，3.49(m，1H)，3.55(s，3H)，3.75(m，2H)，6.69(s，1H)，7.3 1(m，1H)，7.50(m，1H)，7.65(m，1H)，7.76(d，J＝7.8Hz，1H)，7.82(d，J＝6.0Hz，2H)，8.72(d，J＝6.0Hz，2H).	393	D002		393

D004	(CDCl₃)：1.95-2.06(m，4H)，3.14(m，2H)，3.50(m，1H)，3.55(s，3H)，3.75(m，2H)，6.69(s，1H)，7.19(t，J＝8.6Hz，2H)，7.82(d，J＝6.0Hz，2H)，8.02(m，2H)，8.71(d，J＝6.0Hz，2H).	393
D004		393	D005	(CDCl₃)：1.89(m，2H)，2.08(m，2H)，3.06(m，2H)，3.50(m，1H)，3.53(s，3H)，3.67(m，2H)，3.93(s，3H)，6.66(s，1H)，6.98-7.06(m，2H)，7.49(m，1H)，7.61(m，1H)，7.81(d，J＝6.0Hz，2H)，8.71(d，J＝6.0Hz，2H).	405
D006	(CDCl₃)：1.94-2.10(m，4H)，3.14(m，2H)，3.50(m，1H)，3.54(s，3H)，3.74(m，2H)，3.88(s，3H)，6.68(s，1H)，7.15(m，1H)，7.39-7.57(m，3H)，7.82(d，J＝6.3Hz，2H)，8.71(d，J＝6.3Hz，2H).	405	D005		405
D006		405	D007	(CDCl₃)：1.99-2.06(m，4H)，3.13(m，2H)，3.50(m，1H)，3.55(s，3H)，3.75(m，2H)，3.90(s，3H)，6.68(s，1H)，6.99(d，J＝9.0Hz，2H)，7.82(d，J＝6.0Hz，2H)，7.98(d，J＝9.0Hz，2H)，8.71(d，J＝6.0Hz，2H).	405
D008	(CDCl₃)：1.94-2.06(m，4H)，3.15(m，2H)，3.49(m，1H)，3.54(s，3H)，3.75(m，2H)，6.69(s，1H)，7.44-7.60(m，2H)，7.81-7.93(m，3H)，7.94(s，1H)，8.71(d，J＝5.7Hz，2H).	409	D007		405
D008		409	D009	(CDCl₃)：1.94-2.06(m，4H)，3.13(m，2H)，3.49(m，1H)，3.54(s，3H)，3.74(m，2H)，6.69(s，1H)，7.49(d，J＝8.4Hz，2H)，7.81(d，J＝6.0Hz，2H)，7.92(d，J＝8.4Hz，2H)，8.71(d，J＝6.0Hz，2H).	409
D0010	(CDCl₃)：1.95-2.06(m，4H)，3.13(m，2H)，3.48(m，1H)，3.54(s，3H)，3.74(m，2H)，6.68(s，1H)，7.66(d，J＝8.4Hz，2H)，7.80-7.86(m，4H)，8.71(d，J＝6.0Hz，2H).	454	D009		409
D0010		454	D011	(CDCl₃)：1.89(m，2H)，2.08(m，2H)，3.06(m，2H)，3.38(m，1H)，3.52(s，3H)，3.67(m，2H)，3.91(s，3H)，3.92(s，3H)，6.66(s，1H)，7.02-7.16(m，3H)，7.80(d，J＝6.0Hz，2H)，8.71(d，J＝6.0Hz，2H).	435
D012	(CDCl₃)：1.93(m，2H)，2.10(m，2H)，3.11(m，2H)，3.38(m，1H)，3.53(s，3H)，3.72(m，2H)，6.68(s，1H)，6.88-7.04(m，2H)，7.81(d，J＝5Hz，2H)，7.91(m，1H)，8.71(d，J＝5Hz，2H).	411	D011		435
D012		411	D013	(CDCl₃)：1.95-2.06(m，4H)，3.14(m，2H)，3.46(m，1H)，3.54(s，3H)，3.75(m，2H)，6.69(s，1H)，7.32(m，1H)，7.75-7.86(m，4H)，8.71(d，J＝5.9Hz，2H).	411
D014	(CDCl₃)：2.06-2.08(m，4H)，3.12(m，2H)，3.38(m，1H)，3.55(s，3H)，3.76(m，2H)，6.69(s，1H)，7.19(m，1H)，7.71(d，J＝5.2Hz，2H)，7.79-7.83(m，3H)，8.71(d，J＝5.6Hz，2H).	381	D013		411
D014		381	D015	(CDCl₃)：1.95-2.07(m，4H)，3.11(m，2H)，3.37(m，1H)，3.55(s，3H)，3.75(m，2H)，6.60(m，1H)，6.68(s，1H)，7.29(m，1H)，7.63(s，1H)，7.82(d，J＝6.0Hz，2H)，8.71(d，J＝6.0Hz，2H).	365
D016	(CDCl₃)：1.95(m，2H)，2.12(m，2H)，3.18(m，2H)，3.55(s，3H)，3.76(m，2H)，4.16(m，1H)，6.67(s，1H)，7.52(m，1H)，7.82-7.91(m，3H)，8.08(d，J＝8.3Hz，1H)，8.70-8.72(m，3H).	376	D015		365

D017	(CDCl₃)：2.17-2.28(m，4H)，3.16(m，2H)，3.31(m，1H)，3.57(s，3H)，3.80(m，2H)，6.70(s，1H)，6.72(d，J＝3.7Hz，1H)，7.28-7.42(m，2H)，7.52(d，J＝3.7Hz，1H)，7.60(d，J＝7.7Hz，1H)，7.82(d，J＝6.0Hz，2H)，8.49(d，J＝8.1Hz，1H)，8.72(d，J＝6.0Hz，2H).	414
D017		414	D018	(CDCl₃)：1.83(m，2H)，1.95-2.18(m，4H)，2.73(t，J＝6.5Hz，2H)，2.86(m，2H)，3.13(m，1H)，3.52(s，3H)，3.65(m，2H)，3.82(t，J＝6.8Hz，2H)，6.65(s，1H)，7.21-7.26(m，4H)，7.78(d，J＝6.0Hz，2H)，8.69(d，J＝6.0Hz，2H).	430
D019	(CDCl₃)：1.98-2.21(m，4H)，2.76(m，1H)，3.05(m，2H)，3.25(t，J＝8.3Hz，2H)，3.55(s，3H)，3.77(m，2H)，4.20(t，J＝8.3Hz，2H)，6.68(s，1H)，7.05(m，1H)，7.20-7.27(m，2H)，7.82(d，J＝5.9Hz，2H)，8.26(d，J＝8.2Hz，1H)，8.71(d，J＝5.9Hz，2H).	416	D018		430
D019		416	D020	(CDCl₃)：1.94-2.18(m，4H)，2.81-3.08(m，5H)，3.54(s，3H)，3.71-3.89(m，4H)，4.72-4.77(m，2H)，6.67(s，1H)，7.19-7.26(m，4H)，7.81(d，J＝6.0Hz，2H)，8.71(d，J＝6.0Hz，2H).	430
D021	(CDCl₃)：2.02-2.09(m，4H)，3.10(m，2H)，3.29(m，1H)，3.54(s，3H)，3.75(m，2H)，6.69(s，1H)，7.01(d，J＝3.9Hz，1H)，7.57(d，J＝3.9Hz，1H)，7.81(d，J＝6.2Hz，2H)，8.71(d，J＝6.2Hz，2H).	415	D020		430
D021		415	D022	(CDCl₃)：1.98-2.10(m，4H)，3.16(m，2H)，3.55(s，3H)，3.58(m，1H)，3.76(m，2H)，6.69(s，1H)，7.40-7.52(m，3H)，7.64(d，J＝7.8Hz，2H)，7.73(d，J＝8.4Hz，1H)，7.82(d，J＝6.0Hz，2H)，8.06(d，J＝8.4Hz，2H)，8.72(d，J＝6.0Hz，2H).	451
D023	(CDCl₃)：1.57-1.77(m，4H)，2.30(m，1H)，2.59(m，2H)，3.43(s，3H)，3.49(m，2H)，6.62(s，1H)，7.35-7.53(m，8H)，7.57(m，1H)，7.74(d，J＝5.9Hz，2H)，8.69(d，J＝5.9Hz，2H).	451	D022		451
D023		451	D024	(CDCl₃)：1.97-2.12(m，4H)，3.11(m，2H)，3.50(m，1H)，3.54(s，3H)，3.73(m，2H)，6.68(s，1H)，7.51-7.61(m，3H)，7.80-7.82(m，3H)，7.92(m，1H)，8.02(d，J＝8.4Hz，1H)，8.34(d，J＝7.5Hz，1H)，8.71(d，J＝6.0Hz，2H).	425
D025	(CDCl₃)：1.89(m，2H)，2.06(m，2H)，3.06(m，2H)，3.51(m，1H)，3.53(s，3H)，3.68(m，2H)，3.94(s，3H)，6.70(s，1H)，6.68-6.78(m，2H)，7.70(dd，J＝8.7，6.9Hz，1H)，7.81(d，J＝6.0Hz，2H)，8.71(d，J＝6.0Hz，2H).	423	D024		425

Test examples: the drug of the invention has the inhibition activity on P-GS1 phosphorylation of calf brain TPK1

Using a mixture containing 100mM MES-sodium hydroxide (pH 6.5), 1mM magnesium acetate, 0.5mM EGTA, 5mM mercaptoethanol, 0.02% Tween 20, 10% glycerol, 12. mu.g/ml P-GS1, 41.7. mu.M [ gamma. ]^-32P]ATP (68kBq/ml), calf brain TPK1 and the mixture of compounds as shown in the table (final mixture contains 1.7% DMSO due to the presence of 10% DMSO when preparing the solution of test compound) were used as reaction systems. The phosphorylation reaction was initiated by adding ATP and was carried out at 25C for 2 hours, then stopped by adding 21% perchloric acid under ice bath cooling. The reaction mixture was centrifuged at 12,000rpm for 5 minutes with ice adsorbed on P81 paper (Whatmann) which was then washed 4 times with 75 mM phosphoric acid, 3 times with water and once with acetone. The paper was dried and the radioactivity of the residue was measured with a liquid scintillation counter. The results are shown in the following table. The test compound significantly inhibited P-GS1 phosphorylation by TPK 1. This result clearly suggests that the present drug inhibits the activity of TPK1, and thus the neurotoxicity of a β and PHF formation, and that the present drug is effective in preventing and/or treating alzheimer's disease and the above-mentioned diseases.

Formulation examples

(1) Tablet formulation

The following ingredients were mixed in a conventional manner and tableted using conventional equipment.

Compound of example 1 30mg

Crystalline cellulose 60mg

Corn starch 100mg

Lactose 200mg

Magnesium stearate 4mg

(2) Soft capsule

The following ingredients were mixed and filled into soft capsules in a conventional manner.

Compound of example 1 30mg

Olive oil 300mg

Lecithin 20mg

Industrial applications

The compound of the present invention has an activity of inhibiting TPK1 and is useful as a pharmaceutically active ingredient for the prevention and/or treatment of diseases due to abnormally high TPK1 activity such as neurodegenerative diseases (e.g., alzheimer's disease) and the above-mentioned diseases.

TABLE 3

Compound No.	IC₅₀(nM)
Compound No.	IC₅₀(nM)	A001	8.9
A002	27	A001	8.9
A002	27	A003	25
A006	13	A003	25
A006	13	B010	6
B037	4.8	B010	6
B037	4.8	B046	8.3
B051	1.9	B046	8.3
B051	1.9	B054	4
B063	6	B054	4
B063	6	B079	3.3
B084	1.1	B079	3.3
B084	1.1	B085	1.4
B087	5	B085	1.4
B087	5	B088	6
B090	1.1	B088	6
B090	1.1	B091	1.2
B093	0.28	B091	1.2
B093	0.28	B094	1.2
B097	2.8	B094	1.2
B097	2.8	B100	4.7
B102	0.62	B100	4.7
B102	0.62	B103	0.36
B104	10.6	B103	0.36
B104	10.6	B105	1.6
B106	1.4	B105	1.6
B106	1.4	B107	50
B108	6.7	B107	50
B108	6.7	B109	7.7
B110	8.2	B109	7.7
B110	8.2	B112	4.7
B113	4.8	B112	4.7
B113	4.8	B120	54
B122	63	B120	54
B122	63	B128	30
B130	52.9	B128	30
B130	52.9	B140	8
B143	56	B140	8
B143	56	B184	8
B185	0.67	B184	8
B185	0.67	B186	1.9
B187	2	B186	1.9
B187	2	B189	5
B220	1.1	B189	5
B220	1.1	B217	70.3
B225	64	B217	70.3

B234	30
B234	30	B235	26.9
B236	11	B235	26.9
B236	11	B238	7.8
B239	17	B238	7.8
B239	17	B240	1.2
B241	0.9	B240	1.2
B241	0.9	B242	12
B243	0.906	B242	12
B243	0.906	B244	0.3
B245	0.44	B244	0.3
B245	0.44	B246	27
B247	72	B246	27
B247	72	B248	32
B249	10	B248	32
B249	10	B251	40
B252	5.2	B251	40
B252	5.2	B253	15
B254	3.9	B253	15
B254	3.9	B255	21
B256	1.1	B255	21
B256	1.1	B257	67
B258	12	B257	67
B258	12	B259	4.5
B260	0.76	B259	4.5
B260	0.76	B261	1.3
B262	1.1	B261	1.3
B262	1.1	B263	1.2
B264	15	B263	1.2
B264	15	B268	13
B269	1.5	B268	13
B269	1.5	B270	0.79
B271	3.2	B270	0.79
B271	3.2	B272	0.98
B273	1.9	B272	0.98
B273	1.9	B274	3.4
B275	2.1	B274	3.4
B275	2.1	B276	2.5
B277	8.1	B276	2.5
B277	8.1	B279	1.1
B280	9.3	B279	1.1
B280	9.3	B281	5.5
B282	17	B281	5.5
B282	17	B283	3.1
B284	9.8	B283	3.1
B284	9.8	B285	8.9
B286	17	B285	8.9
B286	17	B287	0.57
B288	40	B287	0.57
B288	40	B289	33
B290	2	B289	33

B291	2
B291	2	B292	1.5
B293	1.8	B292	1.5
B293	1.8	B294	1.2
B295	2.7	B294	1.2
B295	2.7	B296	2.5
B297	23	B296	2.5
B297	23	B298	94
C001	2.1	B298	94
C001	2.1	C002	8.4
C005	45	C002	8.4
C005	45	C006	9
C067	72	C006	9
C067	72	C091	23
C092	63	C091	23
C092	63	C101	3.5
C102	20.4	C101	3.5
C102	20.4	C105	45
C106	9	C105	45
C106	9	C386	10
C389	34	C386	10
C389	34	C390	1.0
D001	9	C390	1.0
D001	9	D002	23
D004	15	D002	23
D004	15	D007	18
D009	6	D007	18
D009	6	D011	11
D012	19	D011	11
D012	19	D013	19
D014	20	D013	19
D014	20	D017	10
D018	4.3	D017	10
D018	4.3	D019	8.1
D021	11	D019	8.1
D021	11	D022	7.8
D023	13	D022	7.8
D023	13	D024	19
D025	16	D024	19

Claims

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

wherein R is¹Represents optionally substituted C₁-C₁₂An alkyl group;

r represents any one of the following formulae (II) to (V):

R⁵represents optionally substituted C₁-C₈Alkyl, C which may be substituted₃-C₈A cycloalkyl group, a benzene ring which may be substituted, a naphthalene ring which may be substituted, an indan ring which may be substituted, a tetrahydronaphthalene ring which may be substituted, or an optionally substituted heterocyclic ring having 1 to 4 hetero atoms selected from an oxygen atom, a sulfur atom and a nitrogen atom and having 5 to 10 ring-constituting atoms in total;

R⁹and R¹⁰Represents optionally substituted C₁-C₈Alkyl, C which may be substituted₃-C₈A cycloalkyl group, a benzene ring which may be substituted, a naphthalene ring which may be substituted, an optionally substituted heterocyclic ring having 1 to 4 hetero atoms selected from an oxygen atom, a sulfur atom and a nitrogen atom and having 5 to 10 ring-constituting atoms in total, or R⁹And R¹⁰represents-N (R)¹¹)(R¹²) Wherein R is¹¹Represents a hydrogen atom, C₁-C₈An alkyl group; and R is¹²Represents C₁-C₈Alkyl, optionally substituted benzene ring, optionally substitutedA substituted naphthalene ring, or an optionally substituted heterocyclic ring having 1 to 4 hetero atoms selected from an oxygen atom, a sulfur atom and a nitrogen atom and having 5 to 10 ring-constituting atoms in total;

2. The pyrimidone derivative or the salts thereof, or the solvate thereof or the hydrate thereof according to claim 1, wherein R¹Is methyl.

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

4. The pyrimidone derivative or the salts thereof, or the solvate thereof or the hydrate thereof according to claim 3, wherein R²And R³Each is a hydrogen atom.

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

3-methyl-2- (2-oxa-2-phenylethylamino) -6-pyridin-4-yl-3H-pyrimidin-4-one;

3-methyl-2- (2-oxa-2- (3-methylphenyl) ethylamino) -6-pyridin-4-yl-3H-pyrimidin-4-one.

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

7. The pyrimidone derivative or the salts thereof, or the solvate thereof or the hydrate thereof according to claim 6, wherein R⁶Is a hydrogen atom.

8. The pyrimidone derivative or the salts thereof, or the solvate thereof or the hydrate thereof according to claim 7, wherein R⁷And R⁸Each is a hydrogen atom.

9. The pyrimidone derivative or the salts thereof, or the solvate thereof or the hydrate thereof according to claim 7, wherein R⁷And R⁸Each is methyl.

10. A pyrimidone derivative or a salt thereof, or a solvate thereof or a hydrate thereof, selected from the group consisting of:

(S) -2- [2- (benzofuran-2-yl) morpholin-4-yl ] -3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one.

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

12. The pyrimidone derivative or the salts thereof, or the solvate thereof or the hydrate thereof according to claim 11, wherein R⁹Is a benzene ring which may be substituted.

13. The pyrimidone derivative or the salts thereof, or the solvate thereof or the hydrate thereof according to claim 11, wherein X is CH₂。

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

15. A pyrimidone derivative or a salt thereof, or a solvate thereof or a hydrate thereof, selected from the group consisting of:

2- (3-benzoylpiperidin-1-yl) -3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one;

2- (2-benzoylmorpholin-4-yl) -3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one;

2- [2- (4-methoxybenzoyl) morpholin-4-yl ] -3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one.

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

17. The pyrimidone derivative or the salts thereof, or the solvate thereof or the hydrate thereof according to claim 16, wherein R¹⁰Is a benzene ring which may be substituted.

18. The pyrimidone derivative or the salts thereof, or the solvate thereof or the hydrate thereof according to claim 16, wherein R¹⁰Is a heterocyclic ring having 1 to 4 hetero atoms selected from an oxygen atom, a sulfur atom and a nitrogen atom and having 5 to 10 ring-constituting atoms in total.

19. A pyrimidone derivative or a salt thereof, or a solvate thereof or a hydrate thereof, selected from the group consisting of:

2- [4- (3, 4-dihydro-2H-quinoline-1-carbonyl) -piperidin-1-yl ] -3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one;

20. A medicament comprising, as an active ingredient, a compound selected from the group consisting of pyrimidone derivatives represented by formula (I) and salts thereof, and solvates and hydrates thereof according to claim 1.

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

22. A medicament according to claim 20 for the prophylaxis and/or treatment of diseases which are caused by tau protein kinase 1 hyperactivity.

23. The medicament according to claim 20, which is used for the prophylaxis and/or treatment of neurodegenerative diseases.

24. The medicament of claim 23, wherein the disease is selected from the group consisting of alzheimer's disease, ischemic cerebrovascular accident, tware syndrome, cerebral hemorrhage due to cerebral amyloid disease, progressive supranuclear palsy, subacute sclerosing panencephalitic parkinsonism, postencephalitic parkinsonism, pugilistic encephalitis, guam parkinsonism-dementia syndrome, lewy body disease, pick's disease, corticobasal degeneration, frontotemporal dementia, vascular dementia, traumatic injury, brain and spinal cord trauma, peripheral neuropathy, retinopathy and glaucoma.

25. The medicament of claim 20, wherein the disease is selected from the group consisting of: non-insulin dependent diabetes mellitus, obesity, manic depressive illness, schizophrenia, alopecia, breast cancer, non-small cell lung cancer, thyroid cancer, T or B-cell leukemia, and virus-induced tumors.

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

wherein R is¹Represents optionally substituted C₁-C₁₂An alkyl group.

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

wherein R is¹Represents optionally substituted C₁-C₁₂An alkyl group.