# Patent

## Title
3-substituted-4-pyrimidone derivatives

## Abstract

A pyrimidone derivative represented by formula (I) or a salt thereof, or a solvate thereof or a hydrate thereof having inhibitory activity against tau protein kinase 1: wherein R1 represents a C1-C12 alkyl group which may be substituted; R represents, for example, a group represented by the following formula (II): wherein R2 and R3 independently represent a hydrogen atom or a C1-C8 alkyl group; R4 represents a benzene ring which may be substituted, a naphthalene ring which may be substituted, an indan ring which may be substituted, a tetrahydronaphthalene ring which may be substituted, or an optionally substituted heterocyclic ring having 1 to 4 hetero atoms selected from the group consisting of oxygen atom, sulfur atom and nitrogen atom, and having 5 to 10 ring-constituting atoms in total.

## Background
This application is a 371 of PCT/JP02/09685 filed Sep. 20, 2002.
TECHNICAL FIELD
The present invention relates to compounds that are useful as an active ingredient of a medicament for preventive and/or therapeutic treatment of diseases mainly caused by abnormal activity of tau protein kinase 1, such as neurodegenerative diseases (e.g. Alzheimer disease).
BACKGROUND ART
Alzheimer disease is progressive senile dementia, in which marked cerebral cortical atrophy is observed due to degeneration of nerve cells and decrease of nerve cell number. Pathologically, numerous senile plaques and neurofibrillary tangles are observed in brain. The number of patients has been increased with the increment of aged population, and the disease arises a serious social problem. Although various theories have been proposed, a cause of the disease has not yet been elucidated. Early resolution of the cause has been desired.
It has been known that the degree of appearance of two characteristic pathological changes of Alzheimer disease well correlates to the degree of intellectual dysfunction. Therefore, researches have been conducted from early 1980's to reveal the cause of the disease through molecular level investigations of components of the two pathological changes. Senile plaques accumulate extracellularly, and β amyloid protein has been elucidated as their main component (abbreviated as “A β” hereinafter in the specification: Biochem. Biophys. Res. Commun., 120, 855 (1984); EMBO J., 4, 2757 (1985); Proc. Natl. Acad. Sci. USA, 82, 4245 (1985)). In the other pathological change, i.e., the neurofibrillary tangles, a double-helical filamentous substance called paired helical filament (abbreviated as “PHF” hereinafter in the specification) accumulate intracellularly, and tau protein, which is a kind of microtubule-associated protein specific for brain, has been revealed as its main component (Proc. Natl. Acad. Sci. USA, 85, 4506 (1988); Neuron, 1, 827 (1988)).
Furthermore, on the basis of genetic investigations, presenilins 1 and 2 were found as causative genes of familial Alzheimer disease (Nature, 375, 754 (1995); Science, 269, 973 (1995); Nature. 376, 775 (1995)), and it has been revealed that presence of mutants of presenilins 1 and 2 promotes the secretion of A β (Neuron, 17, 1005 (1996); Proc. Natl. Acad. Sci. USA, 94, 2025 (1997)). From these results, it is considered that, in Alzheimer disease, A β abnormally accumulates and agglomerates due to a certain reason, which engages with the formation of PHF to cause death of nerve cells. It is also expected that extracellular outflow of glutamic acid and activation of glutamate receptor responding to the outflow may possibly be important factors in an early process of the nerve cell death caused by ischemic cerebrovascular accidents (Sai-shin Igaku [Latest Medicine], 49, 1506 (1994)).
It has been reported that kainic acid treatment that stimulates the AMPA receptor, one of glutamate receptor, increases mRNA of the amyloid precursor protein (abbreviated as “APP” hereinafter in the specification) as a precursor of A β (Society for Neuroscience Abstracts, 17, 1445 (1991)), and also promotes metabolism of APP (The Journal of Neuroscience, 10, 2400 (1990)). Therefore, it has been strongly suggested that the accumulation of A β is involved in cellular death due to ischemic cerebrovascular disorders. Other diseases in which abnormal accumulation and agglomeration of A β are observed include, for example, Down syndrome, cerebral bleeding due to solitary cerebral amyloid angiopathy, Lewy body disease (Shin-kei Shinpo [Nerve Advance], 34, 343 (1990); Tanpaku-shitu Kaku-san Koso [Protein, Nucleic Acid, Enzyme], 41, 1476 (1996)) and the like. Furthermore, as diseases showing neurofibrillary tangles due to the PHF accumulation, examples include progressive supranuclear palsy, subacute sclerosing panencephalitic parkinsonism, postencephalitic parkinsonism, pugilistic encephalitis, Guam parkinsonism-dementia complex, Lewy body disease and the like (Tanpakushitu Kakusan Koso [Protein, Nucleic Acid, Enzyme], 36, 2 (1991); Igaku no Ayumi [Progress of Medicine], 158, 511 (1991); Tanpakushitu Kakusan Koso [Protein, Nucleic Acid, Enzyme], 41, 1476 (1996)).
The tau protein is generally composed of a group of related proteins that forms several bands at molecular weights of 48-65 kDa in SDS-polyacrylamide gel electrophoresis, and it promotes the formation of microtubules. It has been verified that tau protein incorporated in the PHF in the brain suffering from Alzheimer disease is abnormally phosphorylated compared with usual tau protein (J. Biochem., 99, 1807 (1986); Proc. Natl. Acad. Sci. USA, 83, 4913 (1986)). An enzyme catalyzing the abnormal phosphorylation has been isolated. The protein was named as tau protein kinase 1 (abbreviated as “TPK1” hereinafter in the specification), and its physicochemical properties have been elucidated (Seikagaku [Biochemistry], 64, 308 (1992); J. Biol. Chem., 267, 10897 (1992)). Moreover, cDNA of rat TPK1 was cloned from a rat cerebral cortex cDNA library based on a partial amino acid sequence of TPK1, and its nucleotide sequence was determined and an amino acid sequence was deduced (Japanese Patent Un-examined Publication [Kokai] No. 6-239893/1994). As a result, it has been revealed that the primary structure of the rat TPK1 corresponds to that of the enzyme known as rat GSK-3β (glycogen synthase kinase 3β, FEBS Lett., 325, 167 (1993)).
It has been reported that A β the main component of senile plaques, is neurotoxic (Science, 250, 279 (1990)). However, various theories have been proposed as for the reason why A β causes the cell death, and any authentic theory has not yet been established. Takashima et al. observed that the cell death was caused by A β treatment of fetal rat hippocampus primary culture system, and then found that the TPK1 activity was increased by A β treatment and the cell death by A β was inhibited by antisense of TPK1 (Proc. Natl. Acad. Sci. USA, 90, 7789 (1993); Japanese Patent Un-examined Publication [Kokai] No. 6-329551/1994).
In view of the foregoing, compounds which inhibit the TPK1 activity may possibly suppress the neurotoxicity of A β and the formation of PHF and inhibit the nerve cell death in the Alzheimer disease, thereby cease or defer the progress of the disease. The compounds may also be possibly used as a medicament for therapeutic treatment of ischemic cerebrovascular disorder, Down syndrome, cerebral amyloid angiopathy, cerebral bleeding due to Lewy body disease and the like by suppressing the cytotoxicity of A β. Furthermore, the compounds may possibly be used as a medicament for therapeutic treatment of neurodegenerative diseases such as progressive supranuclear palsy, subacute sclerosing panencephalitic parkinsonism, postencephalitic parkinsonism, pugilistic encephalitis, Guam parkinsonism-dementia complex, Lewy body disease, Pick's disease, corticobasal degeneration, frontotemporal dementia, vascular dementia, traumatic injuries, brain and spinal cord trauma, peripheral neuropathies, retinopathies and glaucoma, as well as other diseases such as non-insulin dependent diabetes, obesity, manic depressive illness, schizophrenia, alopecia, breast cancer, non-small cell lung carcinoma, thyroid cancer, T or B-cell leukemia, and several virus-induced tumors.
As structurally similar compounds to the compounds of the present invention represented by formula (I) described later, compounds represented by the following formula (A) are known:




wherein R represents 2,6-dichlorobenzyl group, 2-(2-chlorophenyl)ethylamino group, 3-phenylpropylamino group, or 1 -methyl-3-phenylpropylamino group (WO98/24782). The compounds represented by formula (A) are characterized to have 4-fluorophenyl group at the 5-position of the pyrimidine ring and a hydroxy group at the 4-position, and not falling within the scope of the present invention. Moreover, main pharmacological activity of the compounds represented by formula (A) is anti-inflammatory effect, whereas the compounds of the present invention represented by formula (I) are useful as a TPK1 inhibitor or a medicament for therapeutic treatment of neurodegenerative diseases, and therefore, their pharmacological activities are totally different to each other.

OBJECT TO BE ACHIEVED BY THE INVENTION
An object of the present invention is to provide compounds useful as an active ingredient of a medicament for preventive and/or therapeutic treatment of diseases such as Alzheimer disease. More specifically, the object is to provide novel compounds useful as an active ingredient of a medicament that enables radical prevention and/or treatment of the neurodegenerative diseases such as Alzheimer disease by inhibiting the TPK1 activity to suppress the neurotoxicity of A β and the formation of the PHF and by inhibiting the death of nerve cells.
MEANS TO ACHIEVE THE OBJECT
In order to achieve the foregoing object, the inventors of the present invention conducted screenings of various compounds having inhibitory activity against the phosphorylation of TPK1. As a result, they found that compounds represented by the following formula (I) had the desired activity and were useful as an active ingredient of a medicament for preventive and/or therapeutic treatment of the aforementioned diseases. The present invention was achieved on the basis of these findings.
The present invention thus provide a pyrimidone derivative represented by formula (I) or a salt thereof, or a solvate thereof or a hydrate thereof:




wherein R1 represents a C1-C12 alkyl group which may be substituted;

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






wherein R2 and R3 independently represent a hydrogen atom or a C1-C8 alkyl group;

    R4 represents a benzene ring which may be substituted, a naphthalene ring which may be substituted, an indan ring which may be substituted, a tetrahydronaphthalene ring which may be substituted, or an optionally substituted heterocyclic ring having 1 to 4 hetero atoms selected from the group consisting of oxygen atom, sulfur atom and nitrogen atom, and having 5 to 10 ring-constituting atoms in total;
    R5 represents a C1-C8 alkyl group which may be substituted, a C3-C8 cycloalkyl group which may be substituted, a benzene ring which may be substituted, a naphthalene ring which may be substituted, an indan ring which may be substituted, a tetrahydronaphthalene ring which may be substituted, or an optionally substituted heterocyclic ring having 1 to 4 hetero atoms selected from the group consisting of oxygen atom, sulfur atom, and nitrogen atom, and having 5 to 10 ring-constituting atoms in total;
    R6 represents a hydrogen atom, a C1-C8 alkyl group which may be substituted, a benzene ring which may be substituted;
    or R5 and R6 may bind to each other to form together with the carbon to which R5 and R6 are attached an optionally substituted spiro carbocyclic ring having 3 to 11 ring-constituting atoms in total;
    R7 and R8 independently represent a hydrogen atom or a C1-C8 alkyl group, or R7 and
    R8 may combine to each other to form a C2-C6 alkylene group;
    R9 and R10 represent a C1-C8 alkyl group which may be substituted, a C3-C8 cycloalkyl group which may be substituted, a benzene ring which may be substituted, a naphthalene ring which may be substituted, an optionally substituted heterocyclic ring having 1 to 4 hetero atoms selected from the group consisting of oxygen atom, sulfur atom, and nitrogen atom, and having 5 to 10 ring-constituting atoms in total, or R9 and R10 represent —N(R11)(R12) wherein R11 represents a hydrogen atom, a C1-C8 alkyl group; and R12 represents a C1-C8 alkyl group, a benzene ring which may be substituted, a naphthalene ring which may be substituted, or an optionally substituted heterocyclic ring having 1 to 4 hetero atoms selected from the group consisting of oxygen atom, sulfur atom, and nitrogen atom, and having 5 to 10 ring-constituting atoms in total;
    and X represents CH2, O or NR13 wherein R13 represents a hydrogen atom or a C1-C8 alkyl group.


According to preferred embodiments of the present invention, provided are:

    
    
        the aforementioned pyrimidone derivative or the salt thereof, or the solvate thereof or the hydrate thereof, wherein R1 is methyl group;
        the aforementioned pyrimidone derivative or the salt thereof, or the solvate thereof or the hydrate thereof, wherein R is the group represented by formula (II);
        the aforementioned pyrimidone derivative or the salt thereof, or the solvate thereof or the hydrate thereof, wherein each of R2 and R3 is hydrogen atom;
        the aforementioned pyrimidone derivative or the salt thereof, or the solvate thereof or the hydrate thereof, wherein R is the group represented by formula (III);
        the aforementioned pyrimidone derivative or the salts thereof, or the solvate thereof or the hydrate thereof, wherein R6 is hydrogen atom;
        the aforementioned pyrimidone derivative or the salts thereof, or the solvate thereof or the hydrate thereof, wherein each of R7 and R8 is hydrogen atom;
        the aforementioned pyrimidone derivative or the salts thereof, or the solvate thereof or the hydrate thereof, wherein each of R7 and R8 is methyl group;
        the aforementioned pyrimidone derivative or the salt thereof, or the solvate thereof or the hydrate thereof, wherein R is the group represented by formula (IV);
        the aforementioned pyrimidone derivative or the salts thereof, or the solvate thereof or the hydrate thereof, wherein R9 is a benzene ring which may be substituted;
        the aforementioned pyrimidone derivative or the salts thereof, or the solvate thereof or the hydrate thereof, wherein X is CH2;
        the aforementioned pyrimidone derivative or the salts thereof, or the solvate thereof or the hydrate thereof, wherein X is O;
        the aforementioned pyrimidone derivative or the salt thereof, or the solvate thereof or the hydrate thereof, wherein R is the group represented by formula (V);
        the aforementioned pyrimidone derivative or the salts thereof, or the solvate thereof or the hydrate thereof, wherein R10 is a benzene ring which may be substituted; and
        the aforementioned pyrimidone derivative or the salts thereof, or the solvate thereof or the hydrate thereof, wherein R10 is a heterocyclic ring having 1 to 4 hetero atoms selected from the group consisting of oxygen atom, sulfur atom, and nitrogen atom, and having total ring-constituting atoms of 5 to 10 which may be substituted.
    
    


From another aspect, the present invention provides a medicament comprising as an active ingredient a substance selected from the group consisting of the pyrimidone derivative represented by the aforementioned formula (I) and a salt thereof, and a solvate thereof and a hydrate thereof, and a tau protein kinase 1 inhibitor selected from the group consisting of the pyrimidone derivative represented by the aforementioned formula (I) and a salt thereof, and a solvate thereof and a hydrate thereof.
According to preferred embodiments of the aforementioned medicament, provided are the aforementioned medicament which is used for preventive and/or therapeutic treatment of a disease caused by tau protein kinase 1 hyperactivity;

    
    
        the aforementioned medicament which is used for preventive and/or therapeutic treatment of a neurodegenerative disease;
        the aforementioned medicament, wherein the disease is selected from the group consisting of Alzheimer disease, ischemic cerebrovascular accidents, Down syndrome, cerebral bleeding due to cerebral amyloid angiopathy, progressive supranuclear palsy, subacute sclerosing panencephalitic parkinsonism, postencephalitic parkinsonism, pugilistic encephalitis, Guam parkinsonism-dementia complex, Lewy body disease, Pick's disease, corticobasal degeneration, frontotemporal dementia, vascular dementia, traumatic injuries, brain and spinal cord trauma, peripheral neuropathies, retinopathies and glaucoma; and
        the aforementioned medicament, wherein the disease is selected from the group consisting of non-insulin dependent diabetes, obesity, manic depressive illness, schizophrenia, alopecia, breast cancer, non-small cell lung carcinoma, thyroid cancer, T or B-cell leukemia, and a virus-induced tumor.
    
    


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




wherein R1 represents a C1-C12 alkyl group which may be substituted, and a pyrimidone derivative represented by formula (VII) or a salt thereof, or a solvate thereof or a hydrate thereof:





    
    
        wherein R1 represents a C1-C12 alkyl group which may be substituted.
    
    




BEST MODE FOR CARRYING OUT THE INVENTION
The alkyl group used herein may be either linear or branched. The C1-C12 alkyl group represented by R1 may be, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, isopentyl group, neopentyl group, 1,1-dimethylpropyl group, n-hexyl group, isohexyl group, or a linear or branched heptyl group, octyl group, nonyl group, decyl group, undecyl group or dodecyl group. In the specification, when a functional group is defined as “which may be substituted” or “optionally substituted”, the number of substituents as well as their types and substituting positions are not particularly limited, and when two or more substituents are present, they may be the same or different.
When the C1-C12 alkyl group represented by R1 has one or more substituents, the alkyl group may have one or more substituents selected from the group consisting of a C1-C5 alkoxyl group such as methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, tert-butoxy group; amino group, C1-C3 alkylamino group or C2-C6 dialkylamino group: a C6-C10 aryl group such as phenyl group, 1-naphthyl group, and 2-naphthyl group;
The C1-C8 alkyl group represented by R2 or R3 may be, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, isopentyl group, neopentyl group, 1,1-dimethylpropyl group, n-hexyl group, isohexyl group, or a linear or branched heptyl group or octyl group.
When the benzene ring, the naphthalene ring, the indan ring, the tetrahydronaphthalene ring, or the heterocyclic ring represented by R4 or R5 has one or more substituents, the rings may have one or more substituents selected from the groups consisting of a C1-C5 alkyl group such as methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group, 1,1-dimethylpropyl group; C3-C6 cycloalkyl group such as cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group; a C3-C6 cycloalkyloxy group such as cyclopropyloxy group, cyclobutyloxy group, cyclopentyloxy group, cyclohexyloxy group; a C1-C5 alkoxyl group such as methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, tert-butoxy group, pentyloxy group, and isopentyloxy group; a C4-C7 cycloalkylalkoxy group such as cyclopropylmethoxy group, cyclopentylmethoxy group; a C1-C5 alkylthio group such as methylthio group, ethylthio group, propylthio group, butylthio group, and pentylthio group; a C1-C5 alkylsulfonyl group such as methanesulfonyl group, ethanesulfonyl group, propanesulfonyl group, butanesulfonyl group, and pentanesulfonyl group; a halogen atom such as fluorine atom, chlorine atom, bromine atom, and iodine atom; a C1-C5 halogenated alkyl group such as trifluoromethyl group; a C1-C5 halogenated alkoxy group such as trifluoromethoxy group, 2,2,2-trifluoroethoxy group; hydroxyl group; cyano group; nitro group; formyl group; a C2-C6 alkylcarbonyl group such as acetyl group, propionyl group, butyryl group, and valeryl group; benzene ring which may be substituted, naphthalene ring which may be substituted, an optionally substituted heterocyclic ring having 1 to 4 hetero atoms selected from the group consisting of oxygen atom, sulfur atom and nitrogen atom, and having 5 to 10 ring-constituting atoms, phenoxy group which may be substituted or phenylamino group which may be substituted; amino group; a C1-C5 monoalkylamino group such as methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, tert-butylamino group, pentylamino group, and isopentylamino group; a C2-C10 dialkylamino group such as dimethylamino group, ethylmethylamino group, diethylamino group, methylpropylamino group, and diisopropylamino group; a C2-C10 monoalkylaminomethyl group such as methylaminomethyl group, ethylaminomethyl group, propylaminomethyl group, isopropylaminomethyl group, butylaminomethyl group, isobutylaminomethyl group, tert-butylaminomethyl group, pentylaminomethyl group, isopentylaminomethyl group; a C3-C11 dialkylaminomethyl group such as dimethylaminomethyl group, diethylaminomethyl group, ethylmethylaminomethyl group, methylpropylaminomethyl group; pyrrolidinylmethyl group; piperidinylmethyl group; morpholinomethyl group; piperazinylmethyl group; pyrrolylmethyl group; imidazolylmethyl group; pyrazolylmethyl group; and triazolylmethyl group.
When the benzene ring, the naphthalene ring, the indan ring, the tetrahydronaphthalene ring or the heterocyclic ring has one or more substituents, the substituent may further have one or more substituents selected from the group consisting of a C1-C5 alkyl group such as methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group, 1,1-dimethylpropyl group; C3-C6 cycloalkyl group such as cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group; a C3-C6 cycloalkyloxy group such as cyclopropyloxy group, cyclobutyloxy group, cyclopentyloxy group, cyclohexyloxy group; a C1-C5 alkoxy group such as methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, tert-butoxy group, pentyloxy group, and isopentyloxy group; a C4-C7 cycloalkylalkoxy group such as cyclopropylmethoxy group, cyclopentylmethoxy group; a C1-C5 alkylthio group such as methylthio group, ethylthio group, propylthio group, butylthio group, and pentylthio group; a C1-C5 alkylsulfonyl group such as methanesulfonyl group, ethanesulfonyl group, propanesulfonyl group, butanesulfonyl group, and pentanesulfonyl group; a halogen atom such as fluorine atom, chlorine atom, bromine atom, and iodine atom; a C1-C5 halogenated alkyl group such as trifluoromethyl group; a C1-C5 halogenated alkoxy group such as trifluoromethoxy group, 2,2,2-trifluoroethoxy group; hydroxyl group; cyano group; nitro group; formyl group; a C2-C6 alkylcarbonyl group such as acetyl group, propionyl group, butyryl group, and valeryl group; amino group; a C1-C5 monoalkylamino group such as methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, tert-butylamino group, pentylamino group, and isopentylamino group; a C2-C10 dialkylamino group such as dimethylamino group, ethylmethylamino group, diethylamino group, methylpropylamino group, and diisopropylamino group; a C2-C10 monoalkylaminomethyl group such as methylaminomethyl group, ethylaminomethyl group, propylaminomethyl group, isoproylaminomethyl group, butylaminomethyl group, isobutylaminomethyl group, tert-butylaminomethyl group, pentylaminomethyl group, isopentylaminomethyl group; a C3-C11 dialkylaminomethyl group such as dimethylaminomethyl group, diethylaminomethyl group, ethylmethylaminomethyl group, methylpropylaminomethyl group and the like.
The heterocyclic ring having 1 to 4 hetero atoms selected from the group consisting of oxygen atom, sulfur atom, and nitrogen atom, and having 5 to 10 ring-constituting atoms represented by R4 or R5 may be, for example, furan ring, dihydrofuran ring, tetrahydrofuran ring, pyran ring, dihydropyran ring, tetrahydropyran ring, benzofuran ring, dihydrobenzofuran, isobenzofuran ring, benzodioxole ring, chromene ring, chroman ring, isochroman ring, thiophene ring, benzothiophene ring, pyrrole ring, pyrroline ring, pyrrolidine ring, imidazole ring, imidazoline ring, imidazolidine ring, pyrazole ring, pyrazoline ring, pyrazolidine ring, triazole ring, tetrazole ring, pyridine ring, pyridine oxide ring, piperidine ring, pyrazine ring, piperazine ring, pyrimidine ring, pyridazine ring, indole ring, indoline ring, isoindole ring, isoindoline ring, indazole ring, benzimidazole ring, benzotriazole ring, tetrahydroisoquinoline ring, benzothiazolinone ring, benzoxazolinone ring, purine ring, quinolizine ring, quinoline ring, phthalazine ring, naphthyridine ring, quinoxaline ring, quinazoline ring, cinnoline ring, pteridine ring, oxazole ring, oxazolidine ring, isoxazole ring, isoxazolidine ring, oxadiazole ring, thiazole ring, benzothiazole ring, thiazylidine ring, isothiazole ring, isothiazolidine ring, benzodioxole ring, dioxane ring, benzodioxane ring, dithian ring, morpholine ring, thiomorpholine ring, and phthalimide ring.
The C1-C8 alkyl group represented by R5, R6, R7 or R8 may be, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, isopentyl group, neopentyl group, 1,1-dimethylpropyl group, n-hexyl group, isohexyl group, or a linear or branched heptyl group or octyl group.
The C3-C8 cycloalkyl group represented by R5 may be, for example, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group or cyclooctyl group.
When the C1-C8 alkyl group or C3-C8 cycloalkyl group represented by R5 or the C1-C8 alkyl group represented by R6 has one or more substituents, the group may have one or more substituents selected from the groups consisting of a halogen atom, a C1-C6 alkoxyl group, a C3-C8 cycloalkyl group, a benzene ring which may be substituted, a naphthalene ring which may be substituted, phenoxy group which may be substituted or phenylamino group which may be substituted; amino group, a C1-C6 alkylamino group, a C2-C12 dialkylamino group, 1-pyrrolidinyl group, 1-piperidinyl group, 1-morpholinyl group, 1-(tetrahydro-1,2,3,4-quinolinyl) group, or 1-(tetrahydro1,2,3 ,4-isoquinolinyl) group.
When the benzene ring represented by R6 has one or more substituents, the ring may have one or more substituents selected from the group consisting of a C1-C5 alkyl group such as methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group, 1,1-dimethylpropyl group; a C3-C6 cycloalkyl group such as cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group; a C3-C6 cycloalkyloxy group such as cyclopropyloxy group, cyclobutyloxy group, cyclopentyloxy group, cyclohexyloxy group; a C1-C5 alkoxyl group such as methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, tert-butoxy group, pentyloxy group, and isopentyloxy group; a C4-C7 cycloalkylalkoxyl group such as cyclopropylmethoxy group, cyclopentylmethoxy group; a C1-C5 alkylthio group such as methylthio group, ethylthio group, propylthio group, butylthio group, and pentylthio group; a C1-C5 alkylsulfonyl group such as methanesulfonyl group, ethanesulfonyl group, propanesulfonyl group, butanesulfonyl group, and pentanesulfonyl group; a halogen atom such as fluorine atom, chlorine atom, bromine atom, and iodine atom; a C1-C5 halogenated alkyl group such as trifluoromethyl group; a C1-C5 halogenated alkoxyl group such as trifluoromethoxy group, 2,2,2-trifluoroethoxy group; hydroxyl group; cyano group; nitro group; formyl group; a C2-C6 alkylcarbonyl group such as acetyl group, propionyl group, butyryl group, and valeryl group; a benzene ring which may be substituted, a naphthalene ring which may be substituted, an optionally substituted heterocyclic ring having 1 to 4 hetero atoms selected from the group consisting of oxygen atom, sulfur atom and nitrogen atom, and having 5 to 10 ring-constituting atoms, phenoxy group which may be substituted or phenylamino group which may be substituted; amino group; a C1-C5 monoalkylamino group such as methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, tert-butylamino group, pentylamino group, and isopentylamino group; a C2-C10 dialkylamino group such as dimethylamino group, ethylmethylamino group, diethylamino group, methyipropylamino group, and diisopropylamino group; a C2-C10 monoalkylaminomethyl group such as methylaminomethyl group, ethylaminomethyl group, propylaminomethyl group, isopropylaminomethyl group, butylaminomethyl group, isobutylaminomethyl group, tert-butylaminomethyl group, pentylaminomethyl group, isopentylaminomethyl group; a C3-C11 dialkylaminomethyl group such as dimethylaminomethyl group, diethylaminomethyl group, ethylmethylaminomethyl group, methylpropylaminomethyl group; pyrrolidinylmethyl group; piperidinylmethyl group; morpholinomethyl group; piperazinylmethyl group; pyrrolylmethyl group; imidazolylmethyl group; pyrazolylmethyl group; triazolylmethyl group.
When the benzene ring represented by R6 has one or more substituents, the substituent may further have one or more substituents selected from the groups consisting of a C1-C5 alkyl group such as methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group, 1,1-dimethylpropyl group; C8-C6 cycloalkyl group such as cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group; a C3-C6 cycloalkyloxy group such as cyclopropyloxy group, cyclobutyloxy group, cyclopentyloxy group, cyclohexyloxy group; a C1-C5 alkoxyl group such as methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, tert-butoxy group, pentyloxy group, and isopentyloxy group; a C4-C7 cycloalkylalkoxyl group such as cyclopropylmethoxy group, cyclopentylmethoxy group; a C1-C5 alkylthio group such as methylthio group, ethylthio group, propylthio group, butylthio group, and pentylthio group; a C1-C5 alkylsulfonyl group such as methanesulfonyl group, ethanesulfonyl group, propanesulfonyl group, butanesulfonyl group, and pentanesulfonyl group; a halogen atom such as fluorine atom, chlorine atom, bromine atom, and iodine atom; a C1-C5 halogenated alkyl group such as trifluoromethyl group; a C1-C5 halogenated alkoxyl group such as trifluoromethoxy group, 2,2,2-trifluoroethoxy group; hydroxyl group; cyano group; nitro group; formyl group; a C2-C6 alkylcarbonyl group such as acetyl group, propionyl group, butyryl group, and valeryl group; amino group; a C1-C5 monoalkylamino group such as methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, tert-butylamino group, pentylamino group, and isopentylamino group; a C2-C10 dialkylamino group such as dimethylamino group, ethylmethylamino group, diethylamino group, methylpropylamino group, and diisopropylamino group; a C2-C10 monoalkylaminomethyl group such as methylaminomethyl group, ethylaminomethyl group, propylaminomethyl group, isopropylaminomethyl group, butylaminomethyl group, isobutylaminomethyl group, tert-butylaminomethyl group, pentylaminomethyl group, isopentylaminomethyl group; a C3-C11 dialkylaminomethyl group such as dimethylaminomethyl group, diethylaminomethyl group, ethylmethylaminomethyl group, methylpropylaminomethyl group.
When R5 and R6 combine to each other to form a spiro carbocyclic ring, together with the carbon atom to which R5 and R6 bind, the carbocyclic ring may be, for example, cyclopropyl ring, cyclobutyl ring, cyclopentyl ring, cyclohexyl ring, cycloheptyl ring, tetrahydrobenzocycloheptene ring, tetrahydronaphthalene ring, indane ring, bicyclo[4,2,0]octa-1,3,5-triene ring.
The C1-C8 alkyl group represented by R9, R10, R11, R12 or R13 may be, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, isopentyl group, neopentyl group, 1,1-dimethylpropyl group, n-hexyl group, isohexyl group, or a linear or branched heptyl group or octyl group.
The C3-C8 cycloalkyl group represented by R9 or R10 may be, for example, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group or cyclooctyl group.
When the C1-C8 alkyl group or C3-C8 cycloalkyl group represented by R9 or R10 has one or more substituents, the group may have one or more substituents selected from, for example, the groups consisting of a halogen atom, C3-C8 cycloalkyl group, a benzene ring which may be substituted, a naphthalene ring which may be substituted, an optionally substituted heterocyclic ring having 1 to 4 hetero atoms selected from the group consisting of oxygen atom, sulfur atom and nitrogen atom, and having 5 to 10 ring-constituting atoms in total.
When the benzene ring, the naphthalene ring or the heterocyclic ring represented by R9 or R10 has one or more substituents, the ring may have one or more substituents selected form the group consisting of a C1-C5 alkyl group such as methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group, 1,1-dimethylpropyl group; C3-C6 cycloalkyl group such as cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group; a C3-C6 cycloalkyloxy group such as cyclopropyloxy group, cyclobutyloxy group, cyclopentyloxy group, cyclohexyloxy group; a C1-C5 alkoxy group such as methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, tert-butoxy group, pentyloxy group, and isopentyloxy group; a C4-C7 cycloalkylalkoxyl group such as cyclopropylmethoxy group, cyclopentylmethoxy group; a C1-C5 alkylthio group such as methylthio group, ethylthio group, propylthio group, butylthio group, and pentylthio group; a C1-C5 alkylsulfonyl group such as methanesulfonyl group, ethanesulfonyl group, propanesulfonyl group, butanesulfonyl group, and pentanesulfonyl group; a halogen atom such as fluorine atom, chlorine atom, bromine atom, and iodine atom; a C1-C5 halogenated alkyl group such as trifluoromethyl group; a C1-C5 halogenated alkoxyl group such as trifluoromethoxy group, 2,2,2-trifluoroethoxy group; hydroxyl group; cyano group; nitro group; formyl group; a C2-C6 alkylcarbonyl group such as acetyl group, propionyl group, butyryl group, and valeryl group; a benzene ring which may be substituted, a naphthalene ring which may be substituted, an optionally substituted heterocyclic ring having 1 to 4 hetero atoms selected from the group consisting of oxygen atom, sulfur atom and nitrogen atom, and having 5 to 10 ring-constituting atoms in total; a phenoxy group which may be substituted; a phenylamino group which may be substituted; an amino group; a C1-C5 monoalkylamino group such as methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, tert-butylamino group, pentylamino group, and isopentylamino group; a C2-C10 dialkylamino group such as dimethylamino group, ethylmethylamino group, diethylamino group, methylpropylamino group, and diisopropylamino group; a C1-C5 monoalkylaminomethyl group such as methylaminomethyl group, ethylaminomethyl group, propylaminomethyl group, isopropylaminomethyl group, butylaminomethyl group, isobutylaminomethyl group, tert-butylaminomethyl group, pentylaminomethyl group, isopentylaminomethyl group; a C2-C10 dialkylaminomethyl group such as dimethylaminomethyl group, diethylaminomethyl group, ethylmethylaminomethyl group, methylpropylaminomethyl group; pyrrolidinylmethyl group; piperidinylmethyl group; morpholinomethyl group; piperazinylmethyl group; pyrrolylmethyl group; imidazolylmethyl group; pyrazolylmethyl group; and triazolylmethyl group.
The heterocyclic ring having 1 to 4 hetero atoms selected from the group consisting of oxygen atom, sulfur atom, and nitrogen atom, and having 5 to 10 ring-constituting atoms in total represented by R9 or R10 may be, for example, furan ring, dihydrofuran ring, tetrahydrofuran ring, pyran ring, dihydropyran ring, tetrahydropyran ring, benzofuran ring, dihydrobenzofuran, isobenzofuran ring, benzodioxol ring, chromene ring, chroman ring, isochroman ring, thiophene ring, benzothiophene ring, pyrrole ring, pyrroline ring, pyrrolidine ring, imidazole ring, imidazoline ring, imidazolidine ring, pyrazole ring, pyrazoline ring, pyrazolidine ring, triazole ring, tetrazole ring, pyridine ring, pyridine oxide ring, piperidine ring, pyrazine ring, piperazine ring, pyrimidine ring, pyridazine ring, indole ring, indoline ring, isoindole ring, isoindoline ring, indazole ring, benzimidazole ring, benzotriazole ring, tetrahydroisoquinoline ring, benzothiazolinone ring, benzoxazolinone ring, purine ring, quinolizine ring, quinoline ring, phthalazine ring, naphthyridine ring, quinoxaline ring, quinazoline ring, cinnoline ring, pteridine ring, oxazole ring, oxazolidine ring, isoxazole ring, isoxazolidine ring, oxadiazole ring, thiazole ring, benzothiazole ring, thiazylidine ring, isothiazole ring, isothiazolidine ring, benzodioxole ring, dioxane ring, benzodioxane ring, dithian ring, morpholine ring, thiomorpholine ring, or phthalimide ring.
When the benzene ring, the naphthalene ring, or the heterocyclic ring represented by R12 has one or more substituents, the ring may be substituted by one or more substituents selected from the groups consisting of halogen atoms, a C1-C5 alkyl group, a C3-C6 cycloalkyl group, a C3-C6 cycloalkyloxy group, a C1-C5 alkoxy group, a C4-C7 cycloalkylalkoxy, a C1-C5 alkylthio group, a C1-C5 alkylsulfonyl group, a C1-C5 halogenated alkyl, and a benzene ring.
When the benzene ring, the naphthalene ring or the heterocyclic ring has one or more substituents, the substituent may further have one or more substituents selected from the group consisting of a C1-C5 alkyl group such as methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group, 1,1-dimethylpropyl group; C3-C6 cycloalkyl group such as cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group; a C3-C6 cycloalkyloxy group such as cyclopropyloxy group, cyclobutyloxy group, cyclopentyloxy group, cyclohexyloxy group; a C1-C5 alkoxy group such as methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, tert-butoxy group, pentyloxy group, and isopentyloxy group; a C4-C7 cycloalkylalkoxy group such as cyclopropylmethoxy group, cyclopentylmethoxy group; a C1-C5 alkylthio group such as methylthio group, ethylthio group, propylthio group, butylthio group, and pentylthio group; a C1-C5 alkylsulfonyl group such as methanesulfonyl group, ethanesulfonyl group, propanesulfonyl group, butanesulfonyl group, and pentanesulfonyl group; a halogen atom such as fluorine atom, chlorine atom, bromine atom, and iodine atom; a C1-C5 halogenated alkyl group such as trifluoromethyl group; a C1-C5 halogenated alkoxy group such as trifluoromethoxy group, 2,2,2-trifluoroethoxy group; hydroxyl group; cyano group; nitro group; formyl group; a C2-C6 alkylcarbonyl group such as acetyl group, propionyl group, butyryl group, and valeryl group; amino group; a C1-C5 monoalkylamino group such as methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, tert-butylamino group, pentylamino group, and isopentylamino group; a C2-C10 dialkylamino group such as dimethylamino group, ethylmethylamino group, diethylamino group, methylpropylamino group, and diisopropylamino group; a C2-C10 monoalkylaminomethyl group such as methylaminomethyl group, ethylaminomethyl group, propylaminomethyl group, isopropylaminomethyl group, butylaminomethyl group, isobutylaminomethyl group, tert-butylaminomethyl group, pentylaminomethyl group, isopentylaminomethyl group; a C3-C11 dialkylaminomethyl group such as dimethylaminomethyl group, diethylaminomethyl group, ethylmethylaminomethyl group, methylpropylaminomethyl group and the like.
R1 may preferably be a C1-C3 alkyl group, more preferably a methyl group.
R2 may preferably be a hydrogen atom.
R3 may preferably be a hydrogen atom.
R4 may preferably be a benzene ring which may be substituted.
R5 may preferably be a benzene ring or a naphthalene ring which may be substituted.
R6 may preferably be a hydrogen atom.
R7 and R8 may preferably be a hydrogen atom or a C1-C3 alkyl group.
R9 or R10 may preferably be a benzene ring which may be substituted.
R10 may preferably be a heterocyclic ring having 1-4 hetero atoms selected oxygen atom, sulfur atom and nitrogen atom, and having total ring-constituting atoms of 5-10 which may be substituted. Particularly preferred R10 is a benzene ring which may be substituted, a 2,3-dihydroindole ring which may be substituted, or 3,4-dihydro-2H-quinoline ring which may be substituted.
Particularly preferred X is CH2 or O.
The compounds represented by the aforementioned formula (I) may form a salt. Examples of the salt include, when an acidic group exists, salts of alkali metals and alkaline earth metals such as lithium, sodium, potassium, magnesium, and calcium; salts of ammonia and amines such as methylamine, dimethylamine, trimethylamine, dicyclohexylamine, tris(hydroxymethyl)aminomethane, N,N-bis(hydroxyethyl)piperazine, 2-amino-2-methyl-1-propanol, ethanolamine, N-methylglucamine, and L-glucamine; or salts with basic amino acids such as lysine, δ-hydroxylysine, and arginine. When a basic group exists, examples include salts with mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; salts with organic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, acetic acid, propionic acid, tartaric acid, fumaric acid, maleic acid, malic acid, oxalic acid, succinic acid, citric acid, benzoic acid, mandelic acid, cinnamic acid, lactic acid, glycolic acid, glucuronic acid, ascorbic acid, nicotinic acid, and salicylic acid; or salts with acidic amino acids such as aspartic acid, and glutamic acid.
In addition to the 3-substituted-4-pyrimidone derivatives represented by the aforementioned formula (I) and salts thereof, their solvates and hydrates also fall within the scope of the present invention. The 3-substituted-4-pyrimidone derivatives represented by the aforementioned formula (I) may have one or more asymmetric carbon atoms. As for the stereochemistry of such asymmetric carbon atoms, they may independently be in either (R) and (S) configuration, and the pyrimidone derivative may exist as stereoisomers such as optical isomers, or diastereoisomers. Any stereoisomers of pure form, any mixtures of stereoisomers, racemates and the like fall within the scope of the present invention.
Examples of preferred compounds of the present invention are shown in the table below. However, the scope of the present invention is not limited by the following compounds.











Com-



pound


No.
STRUCTURE







A001






 


A002






 


A003






 


A004






 


A005






 


A006






 


A007






 


A008






 


A009






 


A010






 


A011






 


A012






 


A013






 


A014






 


A015






 


A016






 


A017






 


A018






 


A019






 


A020






 


A021






 


A022






 


A023






 


A024






 


A025






 


A026






 


A027






 


A028






 


A029






 


A030






 


A031






 


A032






 


A033






 


A034






 


A035






 


A036






 


A037






 


A038






 


A039






 


A040






 


A041






 


A042






 


A043






 


A044






 


A045






 


A046






 


A047






 


A048






 


A049






 


A050






 


A051






 


A052






 


A053






 


A054






 


A055






 


A056






 


A057






 


A058






 


A059






 


A060






 


A061






 


A062






 


A063






 


A064






 


A065






 


A066






 


A067






 


A068






 


A069






 


A070






 


A071






 


A072






 


A073






 


A074






 


A075






 


A076






 


A077






 


A078






 


A079






 


A080






 


A081






 


A082






 


A083






 


A084






 


A085






 


A086






 


A087






 


A088






 


A089






 


A090






 


A091






 


A092






 


A093






 


A094






 


A095






 


A096






 


A097






 


A098






 


A099






 


A100






 


A101






 


A102






 


A103






 


A104






 


A105






 


A106






 


A107






 


A108






 


A109






 


A110






 


A111






 


A112






 


A113






 


A114






 


A115






 


A116






 


A117






 


A118






 


B001






 


B002






 


B003






 


B004






 


B005






 


B006






 


B007






 


B008






 


B009






 


B010






 


B011






 


B012






 


B013






 


B014






 


B015






 


B016






 


B017






 


B018






 


B019






 


B020






 


B021






 


B022






 


B023






 


B024






 


B025






 


B026






 


B027






 


B028






 


B029






 


B030






 


B031






 


B032






 


B033






 


B034






 


B035






 


B036






 


B037






 


B038






 


B039






 


B040






 


B041






 


B042






 


B043






 


B044






 


B045






 


B046






 


B047






 


B048






 


B049






 


B050






 


B051






 


B052






 


B053






 


B054






 


B055






 


B056






 


B057






 


B058






 


B059






 


B060






 


B061






 


B062






 


B063






 


B064






 


B065






 


B066






 


B067






 


B068






 


B069






 


B070






 


B071






 


B072






 


B073






 


B074






 


B075






 


B076






 


B077






 


B078






 


B079






 


B080






 


B081






 


B082






 


B083






 


B084






 


B085






 


B086






 


B087






 


B088






 


B089






 


B090






 


B091






 


B092






 


B093






 


B094






 


B095






 


B096






 


B097






 


B098






 


B099






 


B100






 


B101






 


B102






 


B103






 


B104






 


B105






 


B106






 


B107






 


B108






 


B109






 


B110






 


B111






 


B112






 


B113






 


B114






 


B115






 


B116






 


B117






 


B118






 


B119






 


B120






 


B121






 


B122






 


B123






 


B124






 


B125






 


B126






 


B127






 


B128






 


B129






 


B130






 


B131






 


B132






 


B133






 


B134






 


B135






 


B136






 


B137






 


B138






 


B139






 


B140
























Com-



pound


No.
STRUCTURE







B141






 


B142






 


B143






 


B144






 


B145






 


B146






 


B147






 


B148






 


B149






 


B150






 


B151






 


B152






 


B153






 


B154






 


B155






 


B156






 


B157






 


B158






 


B159






 


B160






 


B161






 


B162






 


B163






 


B164






 


B165






 


B166






 


B167






 


B168






 


B169






 


B170






 


B171






 


B172






 


B173






 


B174






 


B175






 


B176






 


B177






 


B178






 


B179






 


B180






 


B181






 


B182






 


B183






 


B184






 


B185






 


B186






 


B187






 


B188






 


B189






 


B190






 


B191






 


B192






 


B193






 


B194






 


B195






 


B196






 


B197






 


B198






 


B199






 


B200






 


B201






 


B202






 


B203






 


B205






 


B206






 


B207






 


B208






 


B209






 


B213






 


B214






 


B215






 


B216






 


B217






 


B218






 


B219






 


B220






 


B221






 


B222






 


B223






 


B224






 


B225






 


B226






 


B227






 


B228






 


B229






 


B230






 


B231






 


B232






 


B233






 


B234






 


B235






 


B236






 


B237






 


B238






 


B239






 


B240






 


B241






 


B242






 


B243






 


B244






 


B245






 


B246






 


B247






 


B248






 


B249






 


B250






 


B251






 


B252






 


B253






 


B254






 


B255






 


B256






 


B257






 


B258






 


B259






 


B260






 


B261






 


B262






 


B263






 


B264






 


B265






 


B266






 


B267






 


B268






 


B269






 


B270






 


B271






 


B272






 


B273






 


B274






 


B275






 


B276






 


B277






 


B278






 


B279






 


B280






 


B281






 


B282






 


B283






 


B284






 


B285






 


B286






 


B287






 


B288






 


B289






 


B290






 


B291






 


B292






 


B293






 


B294






 


B295






 


B296






 


B297






 


B298
























Com-



pound


No.
STRUCTURE







C001






 


C002






 


C003






 


C004






 


C005






 


C006






 


C007






 


C008






 


C009






 


C010






 


C011






 


C012






 


C013






 


C014






 


C015






 


C016






 


C017






 


C018






 


C019






 


C020






 


C021






 


C022






 


C023






 


C024






 


C025






 


C026






 


C027






 


C028






 


C029






 


C030






 


C031






 


C032






 


C033






 


C034






 


C035






 


C036






 


C037






 


C038






 


C039






 


C040






 


C041






 


C042






 


C043






 


C044






 


C045






 


C046






 


C047






 


C048






 


C049






 


C050






 


C051






 


C052






 


C053






 


C054






 


C055






 


C056






 


C057






 


C058






 


C059






 


C060






 


C061






 


C062






 


C063






 


C064






 


C065






 


C066






 


C067






 


C068






 


C069






 


C070






 


C071






 


C072






 


C073






 


C074






 


C075






 


C076






 


C077






 


C078






 


C079






 


C080






 


C081






 


C082






 


C083






 


C084






 


C085






 


C086






 


C087






 


C088






 


C089






 


C090






 


C091






 


C092






 


C093






 


C094






 


C095






 


C096






 


C097






 


C098






 


C099






 


C101






 


C102






 


C103






 


C104






 


C105






 


C106






 


C107






 


C108






 


C109






 


C110






 


C111






 


C112






 


C113






 


C114






 


C115






 


C116






 


C117






 


C118






 


C119






 


C120






 


C121






 


C122






 


C123






 


C124






 


C125






 


C126






 


C127






 


C128






 


C129






 


C130






 


C131






 


C132






 


C133






 


C134






 


C135






 


C136






 


C137






 


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Compound B288 and B289

Measurement condition

    
    
        CHIRALPAK AD
        Mobile phase: n-hexane: i-propanol=80:20
        Flow rate: 1.0 ml/min
        Temperature: 30° C.
    
    


Retention time

    
    
        B288:18.1 min
        B289:18.6 min

Compound C389 and C390

    
    


Measurement condition

    
    
        CHIRALPAK AD
        Mobile phase: n-hexane: i-propanol=60:40
        Flow rate: 1.0 ml/min
        Temperature: 30° C.
    
    


Retention time

    
    
        C389:12.0 min
        C390:14.7 min
    
    


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

    3-methyl-2-(2-oxo-2-phenylethylamino)-6-pyridin-4-yl-3H-pyrimidin-4-one;
    3-methyl-2-(2-oxo-2-(3-fluorophenyl)ethylamino)-6-pyridin-4-yl-3H-pyrimidin-4-one;
    3-methyl-2-(2-oxo-2-(4-fluorophenyl)ethylamino)-6-pyridin-4-yl-3H-pyrimidin-4-one;
    3-methyl-2-(2-oxo-2-(3-chlorophenyl)ethylamino)-6-pyridin-4-yl-3H-pyrimidin-4-one;
    3-methyl-2-(2-oxo-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;
    (S3-2-[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-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-Dim ethoxyphenyl)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-o ne;
    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)morpholine-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one;
    2-(2-Benzoylmorpholine-4-yl)-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one;
    2-[2-(2-Methoxybenzoyl)morpholine-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one;
    2-[2-(4-Methoxybenzoyl)morpholine-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-Dihydroindole-1-carbonyl)-piperidin-1-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one.


Salts of the aforementioned preferred compound, and solvates or hydrates of the aforementioned compounds and salts thereof are also preferred.
The 3-substituted-4-pyrimidone compounds represented by the aforementioned formula (I) wherein R is the group represented by formula (II) can be prepared, for example, according to the method explained below.




(In the above scheme, definitions of R1, R2, R3 and R4 are the same as those already described.).

The 2-thiopyrimidone represented by the above formula (XI) is prepared easily by a modification of the method 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 t-butoxide, sodium carbonate, sodium hydrogencarbonate, potassium carbonate, triethylamine, diisopropylethylamine, and 1,8-diazabicyclo[5,4,0]undec-7-en for 1 to 100 hours at a suitable temperature ranging from 0° C. to 200° C. under nitrogen or argon atmosphere or under ordinary air to afford the desired compound (XI). Examples of a solvent for the reactions include, for example, alcoholic solvent such as methanol, ethanol, 1-propanol, isopropanol, tert-butanol, ethylene glycol, propylene glycol; etheric solvents such as diethyl ether, tert-butyl methyl ether, tetrahydrofuran, isopropyl ether; hydrocarbonic solvents such as benzene, toluene, xylene; halogenated hydrocarbonic solvents such as dichloromethane, chloroform, dichloroethane; aprotic polar solvents such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, sulfolane, hexamethylphosphoric triamide, water and the like. Generally, a single solvent or a mixture of two or more solvents may be used so as to be suitable to a base used.
Then the 2-thiopyrimidone derivative (XI) is transformed into the 2-chloropyrimidone (XII) by a chlorinating agent. The reaction time and temperature depend on the chlorinating agent used. Examples of a chlorinating agent for the reactions include, for example, thionyl chloride, thionyl chloride and dimethylformamide, phosphorus oxychloride, phosphorus oxychloride and dimethylformamide, oxalyl chloride, phosphorous oxychloride and dimethylformamide, and phosphorus pentachloride.
The amine represented by the above formula (XIII) or salts thereof is may be prepared by a modification of the method described in the literature (Tetrahedron Lett., 30, 5285 (1989), Synthesis, 122 (1990)).
Then the chloride derivative (XII) is allowed to react with the amine (XIII) or salts thereof in the presence of a base such as sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium carbonate, sodium hydrogencarbonate, potassium carbonate, triethylamine, diisopropylethylamine, and 1,8-diazabicyclo[5,4,0]undec-7-en for 1 to 100 hours at a suitable temperature ranging from 0° C. to 200° C. under nitrogen or argon atmosphere or under ordinary air to afford the desired compound (I). 4-Dimethylaminopyridine may be used as a catalyst.
Examples of a solvent for the reactions include, for example, alcoholic solvent such as methanol, ethanol, 1-propanol, isopropanol, tert-butanol, ethylene glycol, propylene glycol; etheric solvents such as diethyl ether, tert-butyl methyl ether, tetrahydrofuran, isopropyl ether; hydrocarbonic solvents such as benzene, toluene, xylene; halogenated hydrocarbonic solvents such as dichloromethane, chloroform, dichloroethane; aprotic polar solvents such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, sulfolane, hexamethylphosphoric triamide, water and the like. Generally, a single solvent or a mixture of two or more solvents may be used so as to be suitable to a base used.
The 3-substituted-4-pyrimidone compounds represented by the aforementioned formula (I) wherein R is the group represented by formula (III) can be prepared, for example, according to the method explained below.




(In the above scheme, definitions of R1, R5, R6, R7 and R8 are the same as those already described.)

The chloride derivative (XII) is allowed to react with the amine (IVX) or salts thereof in the presence of a base such as sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium carbonate, sodium hydrogencarbonate, potassium carbonate, triethylamine, diisopropylethylamine, and 1,8-diazabicyclo[5,4,0]undec-7-en for 1 to 100 hours at a suitable temperature ranging from 0° C. to 200° C. under nitrogen or argon atmosphere or under ordinary air to afford the desired compound (I).
Examples of a solvent for the reactions include, for example, alcoholic solvent such as methanol, ethanol, 1-propanol, isopropanol, tert-butanol, ethylene glycol, propylene glycol; etheric solvents such as diethyl ether, tert-butyl methyl ether, tetrahydrofuran, isopropyl ether; hydrocarbonic solvents such as benzene, toluene, xylene; halogenated hydrocarbonic solvents such as dichloromethane, chloroform, dichloroethane; aprotic polar solvents such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, sulfolane, hexamethylphosphoric triamide, water and the like. Generally, a single solvent or a mixture of two or more solvents may be used so as to be suitable to a base used.
The 3-substituted-4-pyrimidone compounds represented by the aforementioned formula (I) wherein R is the group represented by formula (IV) can be prepared, for example, according to the method explained below.




(In the above scheme, definitions of R1, R9, and X are the same as those already described.)

The amine represented by the above formula (VX) may be prepared by a modification of the method described in the literature (J. Med. Chem., 13, 1 (1970), J. Med. Chem., 41, 591 (1998)) or according to well-known methods of one skilled in the art.
Then the chloride derivative (XII) is allowed to react with the amine (VX) or salts thereof in the presence of a base such as sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium carbonate, sodium hydrogencarbonate, potassium carbonate, triethylamine, diisopropylethylamine, and 1,8-diazabicyclo[5,4,0]undec-7-en for 1 to 100 hours at a suitable temperature ranging from 0° C. to 200° C. under nitrogen or argon atmosphere or under ordinary air to afford the desired compound (I).
Examples of a solvent for the reactions include, for example, alcoholic solvent such as methanol, ethanol, 1-propanol, isopropanol, tert-butanol, ethylene glycol, propylene glycol; etheric solvents such as diethyl ether, tert-butyl methyl ether, tetrahydrofuran, isopropyl ether; hydrocarbonic solvents such as benzene, toluene, xylene; halogenated hydrocarbonic solvents such as dichloromethane, chloroform, dichloroethane; aprotic polar solvents such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, sulfolane, hexamethylphosphoric triamide, water and the like. Generally, a single solvent or a mixture of two or more solvents may be used so as to be suitable to a base used.
The 3-substituted-4-pyrimidone compounds represented by the aforementioned formula (I) wherein R is the group represented by formula (V) can be prepared, for example, according to the method explained below.




(In the above scheme, definitions of R1 and R10 are the same as those already described.).

The amine represented by the above formula (VIX) is commercially available or may be prepared by a modification of the method described in the literature (J. Med. Chem., 13, 1 (1970), J. Med. Chem., 41, 591 (1998)) or according to well-known methods of one skilled in the art.
Then the chloride derivative (XII) is allowed to react with the amine (VIX) or salts thereof in the presence of a base such as sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium carbonate, sodium hydrogencarbonate, potassium carbonate, triethylamine, diisopropylethylamine, and 1,8-diazabicyclo[5,4,0]undec-7-en for 1 to 100 hours at a suitable temperature ranging from 0° C. to 200° C. under nitrogen or argon atmosphere or under ordinary air to afford the desired compound (I).
Examples of a solvent for the reactions include, for example, alcoholic solvent such as methanol, ethanol, 1-propanol, isopropanol, tert-butanol, ethylene glycol, propylene glycol; etheric solvents such as diethyl ether, tert-butyl methyl ether, tetrahydrofuran, isopropyl ether; hydrocarbonic solvents such as benzene, toluene, xylene; halogenated hydrocarbonic solvents such as dichloromethane, chloroform, dichloroethane; aprotic polar solvents such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, sulfolane, hexamethylphosphoric triamide, water and the like. Generally, a single solvent or a mixture of two or more solvents may be used so as to be suitable to A base used.
The compounds of the present invention have inhibitory activity against TPK1, and they inhibit TPK1 activity in neurodegenerative diseases such as Alzheimer disease, thereby suppress the neurotoxicity of A β and the formation of PHF and inhibit the nerve cell death. Accordingly, the compounds of the present invention are useful as an active ingredient of a medicament which radically enables preventive and/or therapeutic treatment of Alzheimer disease. In addition, the compounds of the present invention are also useful as an active ingredient of a medicament for preventive and/or therapeutic treatment of ischemic cerebrovascular accidents, Down syndrome, cerebral bleeding due to solitary cerebral amyloid angiopathy, progressive supranuclear palsy, subacute sclerosing panencephalitis, postencephalitic parkinsonism, pugilistic encephalosis, Guam parkinsonism-dementia complex, Lewy body disease, Pick's disease, corticobasal degeneration frontotemporal dementia, vascular dementia, traumatic injuries, brain and spinal cord trauma, peripheral neuropathies, retinopathies and glaucoma, non-insulin dependent diabetes, obesity, manic depressive illness, schizophrenia, alopecia, breast cancer, non-small cell lung carcinoma, thyroid cancer, T or B-cell leukemia, and several virus-induced tumors.
As the active ingredient of the medicament of the present invention, a substance may be used which is selected from the group consisting of the compound represented by the aforementioned formula (I) and pharmacologically acceptable salts thereof, and solvates thereof and hydrates thereof. The substance, per se, may be administered as the medicament of the present invention, however, it is desirable to administer the medicament in a form of a pharmaceutical composition which comprises the aforementioned substance as an active ingredient and one or more of pharmaceutical additives. As the active ingredient of the medicament of the present invention, two or more of the aforementioned substance may be used in combination. The above pharmaceutical composition may be supplemented with an active ingredient of other medicament for the treatment of Alzheimer disease and the above-mentioned diseases.
A type of the pharmaceutical composition is not particularly limited, and the composition may be provided as any formulation for oral or parenteral administration. For example, the pharmaceutical composition may be formulated, for example, in the form of pharmaceutical compositions for oral administration such as granules, fine granules, powders, hard capsules, soft capsules, syrups, emulsions, suspensions, solutions and the like, or in the form of pharmaceutical compositions for parenteral administrations such as injections for intravenous, intramuscular, or subcutaneous administration, drip infusions, transdermal preparations, transmucosal preparations, nasal drops, inhalants, suppositories and the like. Injections or drip infusions may be prepared as powdery preparations such as in the form of lyophilized preparations, and may be used by dissolving just before use in an appropriate aqueous medium such as physiological saline. Sustained-release preparations such as those coated with a polymer may be directly administered intracerebrally.
Types of pharmaceutical additives used for the manufacture of the pharmaceutical composition, content rations of the pharmaceutical additives relative to the active ingredient, and methods for preparing the pharmaceutical composition may be appropriately chosen 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 may be incorporated in a ratio ranging from 1% by weight to 90% by weight based on the weight of an active ingredient.
Examples of excipients used for the preparation of solid pharmaceutical compositions include, for example, lactose, sucrose, starch, talc, cellulose, dextrin, kaolin, calcium carbonate and the like. For the preparation of liquid compositions for oral administration, a conventional inert diluent such as water or a vegetable oil may be used. The liquid composition may contain, in addition to the inert diluent, auxiliaries such as moistening agents, suspension aids, sweeteners, aromatics, colorants, and preservatives. The liquid composition may be filled in capsules made of an absorbable material such as gelatin. Examples of solvents or suspension mediums used for the preparation of compositions for parenteral administration, e.g. injections, suppositories, include water, propylene glycol, polyethylene glycol, benzyl alcohol, ethyl oleate, lecithin and the like. Examples of base materials used for suppositories include, for example, cacao butter, emulsified cacao butter, lauric lipid, witepsol.
Dose and frequency of administration of the medicament of the present invention are not particularly limited, and they may be appropriately chosen depending on conditions such as a purpose of preventive and/or therapeutic treatment, a type of a disease, the body weight or age of a patient, severity of a disease and the like. Generally, a daily dose for oral administration to an adult may be 0.01 to 1,000 mg (the weight of an active ingredient), and the dose may be administered once a day or several times a day as divided portions, or once in several days. When the medicament is used as an injection, administrations may preferably be performed continuously or intermittently in a daily dose of 0.001 to 100 mg (the weight of an active ingredient) to an adult.
EXAMPLES
The present invention will be explained more specifically with reference to examples. However, the scope of the present invention is not limited to the following examples. The compound number in the examples corresponds to that in the table above.
Example 1
Synthesis of 2-mercapto-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one
A solution of ethyl 3-oxo-3-(4-pyridyl)propionate (29.0 g, 150 mmol), N-methyl thiourea (40.6 g, 450 mmol) and 1,8-diazabicyclo[5,4,0]-7-undecene (22.4 ml, 150 mmol) was refluxed for 4 hours and the solution of methanesulfonic acid (14.4 g, 150 mmol) in water (50 ml) was added after cooling by ice-water. The precipitate was washed with water, filtered and dried to give the title compound (23.7 g, 72%).
1H-NMR (DMSO-d6) δ: 3.58 (s, 3H), 6.40 (s, 1H), 7.72 (dd, J=1.8, 4.5 Hz, 2H), 8.73 (dd, J=1.5, 4.8 Hz, 2H), 12.92 (brd, 1H).
Example 2
Synthesis of 2-chloro-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one
Phosphorous oxychloride (26.11 g, 170 mmol) was added to dimethylformamide (180 ml) and stirred 20 min. 2-mercapto-3-methyl-6-(4-pyridyl)-pyrimidine-4-one (24.15 g, 110 mmol) was added to the solution and stirred 5 min and then stirred at 70° C. for 2 hours. Ethyl acetate (630 ml) was added to the ice-cooled solution and precipitate was collected by filtration after 20 minutes stirring. After drying, the precipitate was dissolved in water (400 ml) and pH was adjusted to 10 by aqueous sodium hydroxide. The precipitate was washed with water, filtered and dried to give the title compound (18.82 g, 77%).
1H-NMR (CDCl3) δ: 3.72 (s, 3H), 6.90 (s, 1H), 7.78 (dd, J=1.7, 4.5 Hz, 2H), 8.75 (dd, J=1.6, 4.5 Hz, 2H).
Example 3
Synthesis of 3-methyl-2-(2-oxo-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 (1.03 g, 6.00 mmol), 2-chloro-3-methyl-6-(4-pyridyl)-pyrimidine-4-one (0.665 g, 3.00 mmol), 4-dimethylaminopiridine (36.0 mg, 0.30 mmol) and triethylamine (0.80 ml, 6.00 mmol) in dimethylsulfoxide (15 ml) 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 (0.556 g, 68%).
1H-NMR (CDCl3) δ: 3.41 (s, 3H), 4.90 (d, J=5.1 Hz, 2H), 6.46 (s, 1H), 7.50-7.65 (m, 2H), 7.67-7.80 (m, 3H), 7.90 (t, J=5.1 Hz, 1H), 8.08 (m, 2H), 8.47 (dd, J=1.5 Hz, 4.8 Hz, 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 (1.02 g, 4.44 mmol), 2-chloro-3-methyl-6-(4-pyridyl)-pyrimidine-4-one (0.76 g, 3.42 mmol) and triethylamine (1.42 ml, 10.3 mmol) in tetrahydrofuran (20 ml) was refluxed for several hours. The precipitate was filtered off after cooling and solvent was removed in vacuo. The residue was washed with refluxing diethyl ether to give the title compound (1.22 g, 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=8.5 Hz, 2H), 7.10 (s, 1H), 7.38 (d, J=8.5 Hz, 2H), 8.49 (d, J=6.0 Hz, 2H), 8.94 (d, J=6.0 Hz, 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 (127 mg, 0.517 mmol), 2-chloro-3-methyl-6-(4-pyridyl)-pyrimidine-4-one (109 mg, 0.491 mmol) and triethylamine (0.180 ml, 1.29 mmol) in N,N-dimethylformamide (2 ml) 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 (166 mg, 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=6.0 Hz, 2H), 8.72 (d, J=6.0 Hz, 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 (109 mg, 0.60 mmol), 2-chloro-3-methyl-6-(4-pyridyl)-pyrimidine-4-one (118 mg, 0.40 mmol) and triethylamine (0.50 ml, 4.00 mmol) in tetrahydrofuran (6 ml) 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, dried over Na2SO4 and evaporated in vacuo. Purification of the residue by silica gel column chromatography (ethyl acetate) gave the title compound (182 mg, 61%).
Example 7
Synthesis of 1-(1-Methyl-6-oxo-4-pyridin-4-yl-1,6-dihydro-pyrimidine-2-yl)-piperidine-3-carboxanilide (Compound No. CO67 in Table-1)
A solution of 1-t-butoxycarbonyl-3-piperidinecarboxylic acid (458 mg, 2.00 mmol), sodium hydride (88 mg, 2.20 mmol, 60% oil suspension), oxalyl chloride (0.22 ml, 2.50 mmol) and catalytic amount of dimethylformamide (0.20 ml) in dichloromethane (16 ml) was stirred at 0° C. After stirring for 30 min, aniline (0.20 ml, 2.20 mmol) which was treated with n-butyl lithium (1.45 ml, 2.30 mmol, 1.59 M in hexane) in tetrahydrofuran (4 ml) was added to the reaction mixture at 0° C. After additional 30 min, saturated ammonium chloride was added and the whole reaction mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and evaporated in vacuo. Purification of the residue by silica gel column chromatography (hexane-ethyl acetate) gave 1-t-butoxycarbonylpiperidine-3-carboxanilide (437 mg, 71%).
A solution of 1-t-butoxycarbonyl-3-piperidinecarboxanilide (437 mg, 1.43 mmol) and hydrochloride (1 ml, 4.00 mmol, 4N ethyl acetate) was stirred for several hours. Filtration of the precipitate gave 3-piperidinecarboxanilide hydrochloride (187 mg, 55%).
A solution of 3-piperidinecarboxanilide hydrochloride (96.0 mg, 0.40 mmol), 2-chloro-3-methyl-6-(4-pyridyl)-pyrimidine-4-one (66.0 mg, 0.30 mmol) and triethylamine (0.33 ml, 2.50 mmol) in tetrahydrofuran (3 ml) was stirred at room temperature for 3 hours. The whole reaction mixture was evaporated in vacuo and the precipitate was washed with water and diethyl ether to give the title compound (107 mg, 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's reagent was prepared by reaction of magnesium (932 mg, 5.93 mmol) with bromobenzene (144 mg, 5.93 mmol) in diethyl ether (20 ml) at room temperature for 10 min. After cooling to 0° C., a solution of 2-cyano-4-benzyl-morpholine (1.00 g, 4.94 mmol) in diethyl ether (2.0 ml) was added and then tetrahydrofuran (6.0 ml) was added. The mixture was stirred at room temperature for 30 min. After decomposition with saturated aqueous sodium hydrogen carbonate, 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-benzylmorpholine (608 mg, 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, 27.8 Hz, 2H), 3.70-3.90 (m, 1H), 3.90-4.20 (m, 1H), 4.92 (dd, J=2.6, 9.9 Hz, 1H), 7.20-7.60 (m, 8H), 7.80-8.00 (m, 2H).
A solution of 2-benzoyl-4-benzylmorpholine (600 mg, 2.13 mmol) and chloroformic acid 1-chloromethyl ester (457 mg, 3.20 mmol) in 1,2-dichloroethane (8.0 ml) was refluxed for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in methanol (10 ml). The solution was refluxed for 1 h and concentrated under reduced pressure. The crude product was crystallized from ethyl acetate and filtrated to give 2-benzoylmorpholine hydrochloride (323 mg, 67%) as a colorless crystal.
(DMSO-d6): 3.00-3.50 (m, 4H), 4.00-4.20 (m, 2H), 5.29 (dd, J=2.6, 10.1 Hz, 1H), 7.50-8.10 (m, 5H), 9.40-9.90 (brd, 2H).
A solution of 2-benzoylmorpholine hydrochloride (269 mg, 1.17 mmol), 2-chloro-3-methyl-6-(4-pyridyl)-pyrimidine-4-one (320 mg, 1.41 mmol) and triethylamine (0.49 ml, 3.51 mmol) in tetrahydrofuran (10 ml) was refluxed for several hours. The precipitate was filtered off after cooling and solvent was removed in vacuo. The residue was washed with refluxing ethyl acetate and diethyl ether to give the title compound (447 mg, quant.).
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 (903 mg, 4.00 mmol), 2-chloro-3-methyl-6-(4-pyridyl)-pyrimidine-4-one (666 mg, 3.00 mmol) and triethylamine (2.0 ml, 15 mmol) in tetrahydrofuran (30 ml) 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 (1.00 g, 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 (55 mg, 0.226 mmol), 2-chloro-3-methyl-6-(4-pyridyl)-pyrimidine-4-one (50 mg, 0.226 mmol) and triethylamine (0.160 ml, 1.15 mmol) in N,N-dimethylformamide (1 ml) was stirred at 60° C. 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 (76 mg, 86%).
The compounds in the following table were prepared in the same manner as the methods described above. The compound numbers in the following table correspond to those shown in the above-described table of preferred compounds.









TABLE 2





Compound




No.
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),
339



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).


A003
(CDCl3): 3.60(s, 3H), 5.02(d, J=3.9Hz, 2H), 6.06(brs, 1H),
338



6.50(s, 1H), 7.26-7.88(m, 6H), 7.71(d, J=5.4Hz, 2H).


A004
(CDCl3): 3.41(s, 3H), 4.89(s, 2H), 6.48(s, 1H), 7.42(m, 2H),
339



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).


A006
(DMSO): 3.39(s, 3H), 4.88(d, J=5.1Hz, 2H), 6.46(s, 1H),
355



7.58-8.08(m, 6H), 7.67(m, 1H), 8.48(d, J=5.1Hz, 2H).


A012
(CDCl3): 2.48(s, 3H), 3.60(s, 3H), 5.01(d, J=3.9Hz, 2H),
335



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).


B008
(CDCl3): 0.99(s, 9H), 2.89(m, 1H), 3.10-3.65(m, 4H), 3.53(s,
328



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).


B009
(CDCl3): 2.74(dd, J=13.7, 7.4Hz, 1H), 2.87(dd, J=12.7,
363



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).


B010
(CDCl3): 1.81(m, 1H), 1.93(m, 1H), 2.76(m, 1H), 2.89(m, 1H),
377



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).


B011
(CDCl3): 1.49-1.90(m, 4H), 2.67(d, J=7.2Hz, 2H), 2.83(dd, J=12.8,
391



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).


B012
(CDCl3): 3.10-3.33(m, 2H), 3.50(m, 1H), 3.71-4.20(m, 6H),
378



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).


B027
(DMSO-d6): 3.01(m, 1H), 3.15(m, 1H), 3.47(s, 3H), 3.73(dd,
349



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).


B028
(DMSO-d6): 3.01(m, 1H), 3.15(m, 1H), 3.47(s, 3H), 3.73(dd,
349



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).


B029
(DMSO-d6): 3.02(m, 1H), 3.15(m, 1H), 3.47(s, 3H), 3.74(dd,
349



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).


B030
(DMSO-d6): 3.00(dd, J=12.9, 10.8, 1H), 3.18(m, 1H), 3.47(s,
367



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).


B031
(DMSO-d6): 3.01(dd, J=12.9, 10.8, 1H), 3.18(m, 1H), 3.47(s,
367



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).


B032
(DMSO-d6): 3.01(dd, J=12.9, 10.8, 1H), 3.19(m, 1H), 3.47(s,
367



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).


B033
(DMSO-d6): 3.00(m, 1H), 3.18(m, 1H), 3.47(s, 3H), 3.73-4.10
367



(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).


B036
(DMSO-d6): 3.06(m, 1H), 3.22(m, 1H), 3.47(s, 3H), 3.68-4.11
367



(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).


B037
(DMSO-d6): 3.04(m, 1H), 3.23(m, 1H), 3.46(s, 3H), 3.66-4.09
367



(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).


B038
(DMSO-d6): 3.07(m, 1H), 3.24(m, 1H), 3.48(s, 3H), 3.69-4.10
367



(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).


B039
(DMSO-d6): 2.97(dd, J=11.0, 12.6Hz, 1H), 3.12-3.20(m, 1H),
383



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).


B042
(DMSO-d6): 3.02(dd, J=12.5, 10.9, 1H), 3.19(m, 1H), 3.48(s,
383



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).


B045
(DMSO-d6): 2.93(dd, J=12.8, 10.6, 1H), 3.23(m, 1H), 3.39(s,
383



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).


B046
(DMSO-d6): 2.89(m, 1H), 3.35(m, 1H), 3.50(s, 3H),
382



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).


B048
□(DMSO-d6): 2.96(1H, dd, J=10.7, 12.7Hz), 3.12-3.20(1H, m),
[M+] = 427



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)


B051
(DMSO-d6): 2.94-3.02(1H, m), 3.14-3.22(1H, m), 3.46(3H, s),
427



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)


B054
(DMSO-d6): 2.90(dd, J=12.6, 10.5, 1H), 3.22(m, 1H), 3.51(s,
427



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).


B057
(DMSO-d6): 3.00(dd, J=12.6, 10.5, 1H), 3.18(m, 1H), 3.47(s,
363



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).


B060
(DMSO-d6): 2.33(s, 3H), 2.97-3.05(m, 1H), 3.15-3.22(m, 1H),
363



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).


B063
(CDCl3): 2.41(s, 3H), 3.08(m, 1H), 3.35(m, 1H), 3.54(m, 1H),
363



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).


B064
(CDCl3): 2.41(s, 3H), 3.08(m, 1H), 3.35(m, 1H), 3.52-3.69(m,
362



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).


B066
(DMSO-d6): 3.11(dd, J=10.8, 12.8Hz, 1H), 3.24-3.32(m, 1H),
417



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).


B069
(DMSO-d6): 3.04(m, 1H), 3.19(m, 1H), 3.48(s, 3H), 3.50-4.15(m,
374



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).


B072
(DMSO-d6): 3.02(m, 1H), 3.20(m, 1H), 3.49(s, 3H), 3.74(d,
374



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).


B073
(DMSO-d6): 3.06(m, 1H), 3.12-3.85(m, 6H), 3.94(m, 1H),
373



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).


B075
(DMSO-d6): 3.09(m, 1H), 3.19-3.33(m, 1H), 3.49(s, 3H), 3.69(d,
373



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).


B078
(DMSO-d6): 3.01(m, 1H), 3.18(m, 1H), 3.47(s, 3H),
379



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).


B080
(DMSO-d6): 2.95-3.03(m, 1H), 3.12-3.20(m, 1H), 3.45(s, 3H),
379



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).


B081
(DMSO-d6): 3.02(m, 1H), 3.15(m, 1H), 3.48(s, 3H),
379



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).


B082
(DMSO-d6): 2.99-3.06(m, 1H), 3.16-3.23(m, 1H), 3.48(s, 3H),
378



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).


B084
(DMSO-d6): 2.82(dd, J=10.2, 12.8Hz, 1H), 3.17-3.26(m, 1H),
379



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).


B085
(CDCl3): 2.83(1H, dd, J=10.2, 12.9Hz), 3..3-3.4(1H, m), 3.5-3.6(1H,
379



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)


B087
(DMSO-d6): 1.30(3H, t, J=6.8Hz), 2.75(1H, dd, J=10.6, 12.5Hz),
393



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)


B088
(CDCl3): 2.90(m, 1H), 3.35(m, 1H), 3.55(m, 1H), 3.62(s, 3H),
433



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).


B089
(CDCl3): 2.80(m, 1H), 3.37(m, 1H), 3.53-3.73(m, 2H), 3.60(s,
447



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).


B090
(DMSO-d6): 2.82(dd, J=10.2, 12.8Hz, 1H), 3.19-3.26(m, 1H),
397



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).


B091
(DMSO-d6): 2.81(m, 1H), 3.20(m, 1H), 3.47(s, 3H),
397



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).


B092
(DMSO-d6): 2.94-3.01(1H, m), 3.13-3.20(1H, m), 3.46(3H, s),
417



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)


B093
(DMSO-d6): 2.78(1H, dd, J=10.3, 12.7Hz), 3.16-3.24(1H, m),
409



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)


B094
(DMSO-d6): 2.78-2.86(m, 1H), 3.17-3.25(m, 1H), 3.49(s, 3H),
408



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).


B096
(CDCl3): 3.07(t, J=10.6Hz, 1H), 3.29(td, J=10.3, 3.2Hz,
385



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).


B097
(CDCl3): 2.78(dd, J=12.8, 10.4Hz, 1H), 3.32(td, J=12.2,
419



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).


B098
(CDCl3): 2.78(dd, J=12.8, 10.4Hz, 1H), 3.32(td, J=12.2,
418



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).


B100
(DMSO-d6): 2.90(dd, J=10.5Hz, 12.9Hz, 1H), 3.23(m, 1H),
446



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).


B101
(DMSO-d6): 3.07(dd, J=12.8, 10.6, 1H), 3.24(m, 1H), 3.47(s,
384



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).


B102
(DMSO-d6): 3.22(t, J=14.4Hz, 1H), 3.58(d, J=19.5Hz, 1H),
408



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).


B103
d(DMSO-d6): 3.22(1H, t, J=14.4Hz), 3.58(1H, d, J=19.5Hz),
409



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).


B104
d(DMSO-d6): 3.22(1H, t, J=14.4Hz), 3.58(1H, d, J=19.5Hz),
409



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).


B105
(DMSO-d6): 3.44-3.63(m, 2H), 3.58(s, 3H), 3.81(m, 1H), 3.98(m,
416



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).


B106
(CDCl3): 3.44-3.55(3H, m), 3.59(3H, s), 3.82(1H, dd, J=12.9,
417



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).


B107
(CDCl3): 3.44-3.55(3H, m), 3.59(3H, s), 3.82(1H, dd, J=12.9,
417



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).


B108
(DMSO-d6): 3.03(t, J=12.6Hz, 1H), 3.20(t, J=11.1Hz, 1H),
396



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).


B109
(CDCl3): 3.42-3.52(2H, m), 3.57(3H, s), 3.63-3.66(2H, m),
410



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).


B110
(CDCl3): 3.42-3.52(2H, m), 3.57(3H, s), 3.63-3.66(2H, m),
385



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).


B112
(CDCl3): 1.74-1.79(m, 4H), 2.50-2.53(m, 4H), 3.13(m, 1H),
432



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).


B113
(CDCl3): 1.80-1.82(4H, m), 2.56-5.58(4H, m), 3.12(1H, dd,
431



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).


B115
(D2O): 1.24-1.39(1H, m), 1.46-1.67(3H, m), 1.75-1.80(2H, m),
446



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)


B116
(D2O): 1.81-1.96(2H, m), 2.00-2.16(2H, m), 3.03-3.15(2H, m),
432



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)


B117
(D2O): 2.74(6H, s), 3.17-3.34(2H, m), 3.48(3H, s), 3.68-3.76(2H,
406



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)


B118
(D2O): 3.11-3.25(4H, m), 3.31-3.36(2H, m), 3.48(3H, s),
448



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)


B119
(CDCl3): 1.61-1.78(4H, m), 2.34-2.48(4H, m), 3.06(1H, dd,
431



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)


B120
(CDCl3): 1.31(3H, d, J=6.0Hz), 1.37(3H, d, J=6.1Hz), 2.76(1H, dd, J=10.1,
407



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)


B122
(CDCl3): 1.34(6H, d, J=6.0Hz), 3.13(1H, dd, J=10.8, 12.9Hz), 3.2-3.4
407



(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).


B126
(CDCl3): 0.3-0.4(2H, m), 0.6-0.7(2H, m), 1.2-1.3(1H, m), 2.79(1H, dd,
419



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)


B128
(CDCl3): 0.3-0.4(2H, m), 0.6-0.7(2H, m), 1.2-1.3(1H, m), 3.12(1H, dd,
419



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).


B130
(DMSO-d6): 2.98(1H, dd, J=12.6, 14.4Hz), 3.18-3.24(1H, m),
427



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=6.9Hz), 7.96(2H, d, J=5.1Hz),



8.00(1H, s), 8.67(2H, d, J=5.1Hz)


B140
(CDCl3): 2.0-2.1(4H, m), 3.16(1H, dd, J=10.7, 12.8Hz), 3.2-3.4(5H,
418



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)


B143
(CDCl3): 3.18(1H, dd, J=12.3, 10.1Hz), 3.35(1H, m), 3.59(1H,
425



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).


B184
(DMSO-d6): 1.99-2.06(2H, m), 2.82-2.89(4H, m), 2.98(1H, dd,
389



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)


B185
(DMSO-d6): 3.07(1H, dd, J=10.9, 12.3Hz), 3.18-3.27(1H, m),
399



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)


B186
(CDCl3): 3.21(1H, dd, J=10.5, 13.2Hz), 3.31-3.41(1H, m),
398



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)


B187
(DMSO-d6): 3.18(dd, J=10.5, 12.9Hz, 1H), 3.31-3.38(m, 1H),
399



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).


B188
(CDCl3): 3.09-3.33(4H, m), 3.53-3.64(2H, m), 3.57(3H, s),
390



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)


B189
(DMSO-d6): 3.07-3.27(m, 2H), 3.48(s, 3H), 3.77(d, J=13.2Hz,
388



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).


B190
(DMSO-d6): 3.09-3.23(m, 2H), 3.47(s, 3H), 3.68(d, J=12.6Hz,
354



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).


B191
(DMSO-d6): 3.03-3.22(m, 2H), 3.45(s, 3H), 3.69-4.04(m, 4H),
354



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).


B194
(DMSO-d6): 3.18(m, 1H), 3.50(s, 3H), 3.73-4.17(m, 5H),
349



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).


B195
(DMSO-d6): 3.07-3.27(m, 2H), 3.48(s, 3H), 3.77(d,
349



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).


B200
(DMSO-d6): 3.30(s, 3H), 3.36(m, 2H), 3.88(m, 2H), 4.01(m, 2H),
425



7.10(s, 1H), 7.22-7.42(m, 10H), 8.46(d, J=6.4Hz, 2H), 8.93(d,



J=6.3Hz, 2H).


B202
(DMSO-d6): 1.60-2.00(m, 3H), 2.62-2.76(m, 3H), 3.18-3.29(m,
388



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).


B203
(CDCl3): 2.20-2.40(m, 1H), 2.60-2.70(m, 1H), 2.80-3.00(m, 1H),
374



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), 7.49-7.51(m, 1H), 7.78(dd,



J=1.5, 4.8Hz, 2H), 8.70(dd, J=1.8, 4.5Hz, 2H).


B205
(DMSO-d6): 1.30(s, 3H), 1.44(s, 3H), 2.80-2.95(m, 2H), 3.51(s,
377



3H), 3.63-3.80(m, 2H), 5.07(m, 1H), 7.03(s, 1H), 7.30-7.48(m,



5H), 8.35(br s, 2H), 8.89(br s, 2H).


B217
(CDCl3): 1.39(s, 3H), 1.52(s, 3H), 2.89-3.03(m, 2H), 3.39(m,
407



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).


B219
2.97(1H, dd, J=10.5, 12.9Hz), 3.30-3.39(1H, m), 3.53-3.66(1H,
396



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)


B220
2.79(1H, dd, J=10.1, 12.7Hz), 3.29-3.38(1H, m), 3.54-3.59(1H,
457



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)


B221
(DMSO-d6): 1.40-1.60(m, 1H), 1.80-2.20(m, 2H), 2.60-3.00(m,
402



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).


B225
(CDCl3): 3.3-3.5(2H, m), 3.63(3H, s), 3.5-3.7(1H, m), 4.0-4.2(2H, m),
406



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)


B234
(DMSO-d6); 3.01(m, 1H), 3.17(m, 1H), 3.46(s, 3H), 3.70(m, 2H),
393



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).


B235
(DMSO-d6); 2.99(dd, J=10.8Hz, 12.9Hz, 1H), 3.12(m, 1H),
407



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).


B236
(DMSO-d6); 3.04(m, 1H), 3.19(m, 1H), 3.47(s, 3H), 3.69-4.09(m,
409



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).


B237
(DMSO-d6): 2.5-2.6(1H, m), 2.9-3.2(6H, m), 3.44(3H, s),
389



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)


B238
(DMSO): 3.05(1H, dd, J=10.8, 12.8Hz), 3.15-3.26(1H, m),
397



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)


B239
(DMSO): 2.88(1H, dd, J=10.2, 13.0Hz), 3.19-3.27(1H, m),
417



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)


B240
(CDCl3): 3.00(1H, dd, J=12.9, 10.5Hz), 3.21-3.41(3H, m),
391



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).


B241
(DMSO-d6): 2.80(1H, dd, J=10.2, 12.9Hz), 3.1-3.3(1H, m), 3.46(3H,
409



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).


B242
(DMSO-d6): 2.80(1H, dd, J=10.2, 12.9Hz), 3.1-3.3(1H, m), 3.46(3H,
409



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).


B243
(DMSO-d6): 2.7-2.9(1H, m), 3.1-3.3(1H, m), 3.46(3H, s), 3.6-3.7(1H,
488



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)


B244
(DMSO-d6): 2.80(1H, dd, J=10.2, 12.9Hz), 3.1-3.3(1H, m), 3.46(3H,
409



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).


B245
(CDCl3): 2.80(1H, dd, J=12.6, 10.4Hz), 3.33(1H, m), 3.55(1H,
397



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).


B246
(CDCl3): 3.18(1H, dd, J=12.3, 10.1Hz), 3.35(1H, m), 3.59(1H,
425



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).


B247
(CDCl3): 0.32-0.34(2H, m), 0.62-0.67(2H, m), 1.22(1H, m),
437



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).


B248
(CDCl3): 1.33(3H, d, J=6.0Hz), 1.38(3H, d, J=6.0Hz), 2.72(1H,
425



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).


B249
(DMSO): 2.98(1H, dd, J=10.5, 13.0Hz), 3.18-3.30(1H, m),
447



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)


B250
(DMSO): 3.01(1H, dd, J=10.8, 12.9Hz), 3.14-3.18(1H, m),
441



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)


B251
(CDCl3): 3.06(1H, dd, J=12.9, 10.5Hz), 3.42(1H, m), 3.60(1H,
391



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).


B252
(CDCl3): 3.3-3.7(4H, m), 3.58(3H, s), 3.96(1H, t, J=11.7Hz), 4.17(1H,
401



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)


B253
(CDCl3): 2.81(1H, dd, J=10.5, 12.8Hz), 3.3-3.4(1H, m), 3.5-3.7(2H,
401



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).


B254
(DMSO): 2.89(1H, dd, J=10.2, 12.8Hz), 3.19-3.30(1H, m),
455



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)


B255
(DMSO): 2.85(1H, dd, J=10.2, 12.9Hz), 3.19-3.28(1H, m),
473



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)


B256
(DMSO): 2.93(1H, dd, J=10.3, 13.0Hz), 3.19-3.31(1H, m),
456



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)


B257
(DMSO): 2.99(1H, dd, J=10.8, 12.9Hz), 3.10-3.21(1H, m),
385



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)


B258
(DMSO): 2.99(1H, dd, J=10.7, 12.6Hz), 3.13-3.22(1H, m),
445



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)


B259
(DMSO-d6): 1.23(6H, d, J=5.9Hz), 2.7-2.9(1H, m), 3.1-3.3(1H, m), 3.47
437



(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)


B260
(DMSO-d6): 2.17(3H, s), 2.22(3H, s), 2.7-2.8(1H, m), 3.1-3.2(1H, m),
407



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)


B261
(DMSO-d6): 1.27(6H, d, J=5.1Hz), 2.7-2.9(1H, m), 3.1-3.3(1H, m), 3.46
437



(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)


B262
(DMSO-d6): 2.7-2.9(1H, m), 3.2-3.3(1H, m), 3.47(3H, s), 3.6-3.7(1H,
404



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)


B263
(CDCl3): 1.40(3H, t, J=6.9Hz), 3.38-3.47(3H, m), 3.86(6H, s),
423



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).


B264
(CDCl3): 0.95(3H, t, J=7.2Hz), 1.77-1.86(2H, m), 3.34-3.47(2H,
437



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).


B265
(DMSO-d6): 1.30(3H, t, J=6.6Hz), 2.97-4.10(8H, m), 4.78(1H, d,
381



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).


B266
(DMSO-d6): 0.88(3H, t, J=7.2Hz), 1.69-1.77(2H, m), 1.26(1H,
395



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).


B267
(CDCl3): 0.39-0.43(2H, m), 0.53-0.58(2H, m), 1.26(1H, m),
407



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).


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
420



(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)


B269
(DMSO-d6): 2.78(1H, dd, J=10.2, 12.8Hz), 3.1-3.3(1H, m), 3.47(3H,
413



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)


B270
(DMSO-d6): 3.1-3.3(1H, m), 3.42(3H, s), 3.5-3.6(1H, m), 3.6-3.7(2H,
415



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)


B271
(CDCl3): 3.3-3.51H, m), 3.5-3.7(2H, m), 3.61(3H, s), 3.9-4.3(3H, m),
390



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)


B272
(DMSO-d6): 2.7-2.8(1H, m), 3.2-3.3(1H, m), 3.47(3H, s), 3.6-3.7(1H,
404



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)


B273
(DMSO-d6): 2.8-2.9(1H, m), 3.1-3.3(1H, m), 3.49(3H, s), 3.6-3.8(1H,
455



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)


B274
(CDCl3): 1.9-2.1(4H, m), 2.83(1H, dd, J=10.2, 12.6Hz), 3.2-3.5(5H,
448



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)


B275
(CDCl3): 1.9-2.1(4H, m), 2.89(1H, dd, J=10.3, 12.8Hz), 3.2-3.4(5H,
448



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)


B276
(DMSO): 2.84(1H, dd, J=10.5, 12.8Hz), 3.19-3.26(1H, m),
473



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)


B277
(DMSO): 2.90(1H, dd, J=10.3, 12.8Hz), 3.26-3.29(1H, m),
485



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)


B278
(DMSO): 2.84(1H, dd, J=10.5, 12.6Hz), 3.18-3.25(1H, m),
523



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)


B279
(DMSO): 1.52-1.71(4H, m), 2.32-2.43(4H, m), 2.76(1H, dd,
462



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)


B280
(DMSO): 3.11(1H, dd, J=10.3, 12.6Hz), 3.41-3.48(1H, m),
473



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)


B281
(DMSO): 2.83(1H, dd, J=10.2, 12.9Hz), 3.14-3.25(1H, m),
485



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)


B282
(DMSO): 2.88(1H, dd, J=10.3, 12.9Hz), 3.18-3.28(1H, m),
485



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)


B283
(DMSO): 2.77(1H, dd, J=10.2, 12.8Hz), 3.10-3.21(1H, m),
470



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)


B284
(CDCl3): 3.37-3.54(3H, m), 3.59(3H, s), 3.88(1H, m), 4.03(1H,
389



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).


B285
(CDCl3): 2.80(1H, dd, J=12.9, 10.2Hz), 3.35(1H, m), 3.55(1H,
397



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).


B286
(CDCl3): 3.33-3.53(3H, m), 3.58(3H, s), 3.88(1H, m), 3.98(1H,
419



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).


B287
(DMSO-d6): 1.9-2.1(4H, m), 2.9-3.2(3H, m), 3.2-3.5(3H, m), 3.51(3H,
538



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)


B288
(CDCl3): 1.9-2.1(4H, m), 3.17(1H, dd, J=10.5, 12.9Hz), 3.3-3.4(5H,
418



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)


B289
(CDCl3): 1.9-2.1(4H, m), 3.17(1H, dd, J=10.5, 12.9Hz), 3.3-3.4(5H,
418



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)


B290
(CDCl3): 2.87(1H, m), 3.38(1H, m), 3.58(1H, m), 3.64(3H, s),
473



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).


B291
(CDCl3): 2.86(1H, dd, J=12.9, 10.2Hz), 3.38(1H, m), 3.57(1H,
473



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).


B292
(CDCl3): 2.86(1H, dd, J=12.9, 10.2Hz), 3.35(1H, m), 3.57(1H,
473



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).


B293
(DMSO): 2.86(1H, dd, J=10.2, 12.8Hz), 3.22-3.30(1H, m),
456



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)


B294
(DMSO): 2.90(1H, dd, J=10.5, 12.9Hz), 3.20-3.29(1H, m),
486



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)


B295
(DMSO): 2.91(1H, dd, J=10.2, 12.8Hz), 3.21-3.28(1H, m),
486



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)


B296
(DMSO): 2.84(1H, dd, J=10.5, 12.6Hz), 3.18-3.25(1H, m),
487



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)


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,
391



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)


B298
(CDCl3): 1.8-2.0(3H, m), 2.3-2.4(1H, m), 3.2-3.4(1H, m), 3.44(3H, s)
405



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)


C001
(CDCl3): 1.79-1.95(m, 3H), 2.14(m, 1H), 3.08(m, 1H), 3.26(dd,
374



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).


C002
(CDCl3): 1.81-1.92(m, 3H), 2.12(m, 1H), 3.08(m, 1H), 3.25(m,
392



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).


C005
(CDCl3): 1.65-1.93(m, 3H), 2.13(m, 1H), 3.08(m, 1H), 3.25(dd,
405



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).


C006
(CDCl3): 1.69-1.92(m, 3H), 2.12(m, 1H), 3.06(m, 1H), 3.21(dd,
405



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).


C067
(CDCl3): 1.83-2.14(m, 4H), 2.77(m, 1H), 3.06(m, 1H), 3.37(m,
390



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).


C091
(CDCl3): 1.81-2.01(6H, m), 2.70-2.75(2H, m), 3.00(1H, m),
430



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).


C092
(DMSO-d6): 1.48-1.89(m, 10H), 2.92-3.07(m, 4H), 3.41(s, 3H),
382



3.42-3.72(m, 5H), 6.97(s, 1H), 8.38(d, J=5.1Hz, 2H), 8.92(d,



J=5.1Hz, 2H).


C094
(CDCl3): 1.74-2.05(m, 4H), 3.08(m, 2H), 3.28(m, 1H), 3.51(s,
384



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).


C101
(CDCl3): 3.37-3.50(m, 3H), 3.57(s, 3H), 3.90-4.00(m, 2H),
377



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).


C102
(CDCl3): 3.30-3.50(m, 3H), 3.58(s, 3H), 3.85-4.17(m, 3H),
395



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).


C105
(CDCl3): 1.65-1.93(3H, m), 2.13(1H, m), 3.08(1H, m), 3.25(1H,
405



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).


C106
(CDCl3): 1.69-1.92(3H, m), 2.12(1H, m), 3.06(1H, m), 3.21(1H,
405



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).


C386
(CDCl3): 1.80-2.11(4H, m), 3.07(1H, m), 3.26(1H, dd, J=13.1,
415



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).


C389
(CDCl3): 3.3-3.7(3H, m), 3.57(3H, s), 3.9-4.0(2H, m), 4.1-4.2( 1H, m),
377



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)


C390
(CDCl3): 3.3-3.7(3H, m), 3.57(3H, s), 3.9-4.0(2H, m), 4.1-4.2(1H, m),
377



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)


D001
(CDCl3): 2.01-2.10(m, 4H), 3.16(m, 2H), 3.56(s+m, 3H+1H),
375



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).


D002
(CDCl3): 1.93(m, 2H), 2.12(m, 2H), 3.12(m, 2H), 3.42(m, 1H),
393



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).


D003
(CDCl3): 1.94-2.10(m, 4H), 3.15(m, 2H), 3.49(m, 1H), 3.55(s,
393



3H), 3.75(m, 2H), 6.69(s, 1H), 7.31(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).


D004
(CDCl3): 1.95-2.06(m, 4H), 3.14(m, 2H), 3.50(m, 1H), 3.55(s,
393



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).


D005
(CDCl3): 1.89(m, 2H), 2.08(m, 2H), 3.06(m, 2H), 3.50(m, 1H),
405



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).


D006
(CDCl3): 1.94-2.10(m, 4H), 3.14(m, 2H), 3.50(m, 1H), 3.54(s,
405



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).


D007
(CDCl3): 1.99-2.06(m, 4H), 3.13(m, 2H), 3.50(m, 1H), 3.55(s,
405



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).


D008
(CDCl3): 1.94-2.06(m, 4H), 3.15(m, 2H), 3.49(m, 1H), 3.54(s,
409



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).


D009
(CDCl3): 1.94-2.06(m, 4H), 3.13(m, 2H), 3.49(m, 1H), 3.54(s,
409



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).


D0010
(CDCl3): 1.95-2.06(m, 4H), 3.13(m, 2H), 3.48(m, 1H), 3.54(s,
454



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).


D011
(CDCl3): 1.89(m, 2H), 2.08(m, 2H), 3.06(m, 2H), 3.38(m, 1H),
435



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).


D012
(CDCl3): 1.93(m, 2H), 2.10(m, 2H), 3.11(m, 2H), 3.38(m, 1H),
411



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).


D013
(CDCl3): 1.95-2.06(m, 4H), 3.14(m, 2H), 3.46(m, 1H), 3.54(s,
411



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).


D014
(CDCl3): 2.06-2.08(m, 4H), 3.12(m, 2H), 3.38(m, 1H), 3.55(s,
381



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).


D015
(CDCl3): 1.95-2.07(m, 4H), 3.11(m, 2H), 3.37(m, 1H), 3.55(s,
365



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).


D016
(CDCl3): 1.95(m, 2H), 2.12(m, 2H), 3.18(m, 2H), 3.55(s, 3H),
376



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).


D017
(CDCl3): 2.17-2.28(m, 4H), 3.16(m, 2H), 3.31(m, 1H), 3.57(s,
414



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).


D018
(CDCl3): 1.83(m, 2H), 1.95-2.18(m, 4H), 2.73(t, J=6.5Hz, 2H),
430



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).


D019
(CDCl3): 1.98-2.21(m, 4H), 2.76(m, 1H), 3.05(m, 2H), 3.25(t,
416



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).


D020
(CDCl3): 1.94-2.18(m, 4H), 2.81-3.08(m, 5H), 3.54(s, 3H),
430



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).


D021
(CDCl3): 2.02-2.09(m, 4H), 3.10(m, 2H), 3.29(m, 1H), 3.54(s,
415



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).


D022
(CDCl3): 1.98-2.10(m, 4H), 3.16(m, 2H), 3.55(s, 3H), 3.58(m,
451



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).


D023
(CDCl3): 1.57-1.77(m, 4H), 2.30(m, 1H), 2.59(m, 2H), 3.43(s,
451



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).


D024
(CDCl3): 1.97-2.12(m, 4H), 3.11(m, 2H), 3.50(m, 1H), 3.54(s,
425



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).


D025
(CDCl3): 1.89(m, 2H), 2.06(m, 2H), 3.06(m, 2H), 3.51(m, 1H),
423



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).









Test Example: Inhibitory activity of the medicament of the present invention against P-GS1 phosphorylation by bovine cerebral TPK1

A mixture containing 100 mM MES-sodium hydroxide (pH 6.5), 1 mM magnesium acetate, 0.5 mM EGTA, 5 mM β-mercaptoethanol, 0.02% Tween 20, 10% glycerol, 12 μg/ml P-GS1, 41.7 μM [Υ-32P] ATP (68 kBq/ml), bovine cerebral TPK1 and a compound shown in Table (a final mixture contained 1.7% DMSO deriving from a solution of a test compound prepared in the presence of 10% DMSO) was used as a reaction system. The phosphorylation was started by adding ATP, and the reaction was conducted at 25° C. for 2 hours, and then stopped by adding 21% perchloric acid on ice cooling. The reaction mixture was centrifuged at 12,000 rpm for 5 minutes and adsorbed on P81 paper (Whatmann), and then the paper was washed four times with 75 mM phosphoric acid, three times with water and once with acetone. The paper was dried, and the residual radioactivity was measured using a liquid scintillation counter. The results are shown in the table below. The test compound markedly inhibited the P-GS1 phosphorylation by TPK1. The results strongly suggest that the medicaments of the present invention inhibit the TPK1 activity, thereby suppress the A β neurotoxicity and the PHF formation, and that the medicaments of the present invention are effective for preventive and/or therapeutic treatment of Alzheimer disease and the above-mentioned diseases.










TABLE 3







Compound No.
IC50(nM)



















A001
8.9



A002
27



A003
25



A006
13



B010
6



B037
4.8



B046
8.3



B051
1.9



B054
4



B063
6



B079
3.3



B084
1.1



B085
1.4



B087
5



B088
6



B090
1.1



B091
1.2



B093
0.28



B094
1.2



B097
2.8



B100
4.7



B102
0.62



B103
0.36



B104
10.6



B105
1.6



B106
1.4



B107
50



B108
6.7



B109
7.7



B110
8.2



B112
4.7



B113
4.8



B120
54



B122
63



B128
30



B130
52.9



B140
8



B143
56



B184
8



B185
0.67



B186
1.9



B187
2



B189
5



B220
1.1



B217
70.3



B225
64



B234
30



B235
26.9



B236
11



B238
7.8



B239
17



B240
1.2



B241
0.9



B242
12



B243
0.906



B244
0.3



B245
0.44



B246
27



B247
72



B248
32



B249
10



B251
40



B252
5.2



B253
15



B254
3.9



B255
21



B256
1.1



B257
67



B258
12



B259
4.5



B260
0.76



B261
1.3



B262
1.1



B263
1.2



B264
15



B268
13



B269
1.5



B270
0.79



B271
3.2



B272
0.98



B273
1.9



B274
3.4



B275
2.1



B276
2.5



B277
8.1



B279
1.1



B280
9.3



B281
5.5



B282
17



B283
3.1



B284
9.8



B285
8.9



B286
17



B287
0.57



B288
40



B289
33



B290
2



B291
2



B292
1.5



B293
1.8



B294
1.2



B295
2.7



B296
2.5



B297
23



B298
94



C001
2.1



C002
8.4



C005
45



C006
9



C067
72



C091
23



C092
63



C101
3.5



C102
20.4



C105
45



C106
9



C386
10



C389
34



C390
1.0



D001
9



D002
23



D004
15



D007
18



D009
6



D011
11



D012
19



D013
19



D014
20



D017
10



D018
4.3



D019
8.1



D021
11



D022
7.8



D023
13



D024
19



D025
16










Formulation Example
(1) Tablets
The ingredients below were mixed by an ordinary method and compressed by using a conventional apparatus.
















Compound of Example 1
 30 mg



Crystalline cellulose
 60 mg



Corn starch
100 mg



Lactose
200 mg



Magnesium stearate
 4 mg










(2) Soft Capsules

The ingredients below were mixed by an ordinary method and filled in soft capsules.
















Compound of Example 1
 30 mg



Olive oil
300 mg



Lecithin
 20 mg










INDUSTRIAL APPLICABILITY
The compounds of the present invention have TPK1 inhibitory activity and are useful as an active ingredient of a medicament for preventive and/or therapeutic treatment of diseases caused by abnormal advance of TPK1 such as neurodegenerative diseases (e.g. Alzheimer disease) and the above-mentioned diseases.

## Claims

1. A pyrimidone compound represented by formula (I) or a salt thereof:



wherein R1 represents a C1-C12 alkyl group which may be substituted;
R represents any one of groups represented by the following formulas (II) to (V):




wherein R2 and R3 independently represent a hydrogen atom or a C1-C8 alkyl group; R4 represents a benzene ring which may be substituted, a naphthalene ring which may be substituted, an indan ring which may be substituted, a tetrahydronaphthalene ring which may be substituted, or an optionally substituted heterocyclic ring having 1 to 4 hetero atoms selected from the group consisting of oxygen atom, sulfur atom and nitrogen atom, and having 5 to 10 ring-constituting atoms in total;
R5 represents a C1-C8 alkyl group which may be substituted, a C3-C8 cycloalkyl group which may be substituted, a benzene ring which may be substituted, a naphthalene ring which may be substituted, an indan ring which may be substituted, a tetrahydronaphthalene ring which may be substituted, or an optionally substituted heterocyclic ring having 1 to 4 hetero atoms selected from the group consisting of oxygen atom, sulfur atom, and nitrogen atom, and having 5 to 10 ring-constituting atoms in total;
R6 represents a hydrogen atom, a C1-C8 alkyl group which may be substituted, a benzene ring which may be substituted;
or R5 and R6 may bind to each other to form together with the carbon to which R5 and R6 are attached an optionally substituted spiro carbocyclic ring having 3 to 11 ring-constituting atoms in total;
R7 and R8 independently represent a hydrogen atom or a C1-C8 alkyl group, or R7 and R8 may combine to each other to form a C2-C6 alkylene group;
R9 and R10 represent a C1-C8 alkyl group which may be substituted, a C3-C8 cycloalkyl group which may be substituted, a benzene ring which may be substituted, a naphthalene ring which may be substituted, an optionally substituted heterocyclic ring having 1 to 4 hetero atoms selected from the group consisting of oxygen atom, sulfur atom, and nitrogen atom, and having 5 to 10 ring-constituting atoms in total, or R9 and R10 represent —N(R11)(R12) wherein R11 represents a hydrogen atom, a C1-C8 alkyl group; and R12 represents a C1-C8 alkyl group, a benzene ring which may be substituted, a naphthalene ring which may be substituted, or an optionally substituted heterocyclic ring having 1 to 4 hetero atoms selected from the group consisting of oxygen atom, sulfur atom, and nitrogen atom, and having 5 to 10 ring-constituting atoms in total;
and X represents CH2, O or NR13 wherein R13 represents a hydrogen atom or a C1-C8 alkyl group.

2. The pyrimidone compound or the salt thereof according to claim 1, wherein R1 is methyl group.

3. The pyrimidone compound or the salt thereof according to claim 1, wherein R is the group represented by formula (II).

4. The pyrimidone compound or the salt thereof according to claim 3, wherein each of R2 and R3 is hydrogen atom.

5. A pyrimidone compound which is selected from the group consisting of:
3-methyl-2-(2-oxo-2-phenylethylamino)-6-pyridin-4-yl-3H-pyrimidin-4-one;
3-methyl-2-(2-oxo-2-(3-fluorophenyl)ethylamino)-6-pyridin-4-yl-3H-pyrimidin-4-one;
3-methyl-2-(2-oxo-2-(4-fluorophenyl)ethylamino)-6-pyridin-4-yl-3H-pyrimidin-4-one;
3-methyl-2-(2-oxo-2-(3-chlorophenyl)ethylamino)-6-pyridin-4-yl-3H-pyrimidin-4-one;
3-methyl-2-(2-oxo-2-(3-methylphenyl)ethylamino)-6-pyridin-4-yl-3H-pyrimidin-4-one;
or a salt thereof.

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

7. The pyrimidone compound or the salt thereof according to claim 6, wherein R6 is hydrogen atom.

8. The pyrimidone compound or the salt thereof according to claim 7, wherein each of R7 and R8 is hydrogen atom.

9. The pyrimidone compound or the salt thereof according to claim 7, wherein each of R7 and R8 is methyl group.

10. A pyrimidone compound which is selected from the group consisting of:
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-pyridin-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; and
(S)-2-[2-(Benzofuran-2-yl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one or a salt thereof.

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

12. The pyrimidone compound or the salt thereof according to claim 11, wherein R9 is a benzene ring which may be substituted.

13. The pyrimidone compound or the salt thereof according to claim 11, wherein X is CH2.

14. The pyrimidone compound or the salt thereof according to claim 11, wherein X is O.

15. A pyrimidone compound which is selected from the group consisting of:
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)morpholine-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one;
2-(2-Benzoylmorpholine-4-yl)-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one;
2-[2-(2-Methoxybenzoyl)morpholine-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one;
2-[2-(4-Methoxybenzoyl)morpholine-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one;
or a salt thereof.

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

17. The pyrimidone compound or the salt thereof, according to claim 16, wherein R10 is a benzene ring which may be substituted.

18. The pyrimidone compound or the salt thereof according to claim 16, wherein R10 is a heterocyclic ring having 1 to 4 hetero atoms selected oxygen atom, sulfur atom and nitrogen atom, and having total ring-constituting atoms of 5 to 10 which may be substituted.

19. A pyrimidone compound which is selected from the group consisting of:
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-Dihydroindole-1-carbonyl)-piperidin-1-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one,
or a salt thereof.

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

21. A method for therapeutic treatment of of at least one of Alzheimer disease, ischemic cerebrovascular accidents, progressive supranuclear palsy, Pick's disease, corticobasal degeneration, and frontotemporal dementia comprising administering to a patient a therapeutically effective amount of the medicament composition according to claim 20.

22. A method for therapeutic treatment of non-insulin dependent diabetes comprising administering to a patient a therapeutically effective amount of the medicament composition according to claim 20.

23. A pyrimidone compound represented by formula (VI) or a salt thereof:




wherein R1 represents a C1-C12 alkyl group which may be substituted.

24. A pyrimidone compound represented by formula (VII) or a salt thereof:




wherein R1 represents a C1-C12 alkyl group which may be substituted.