CN1810802B - 3-substituted-4-pyrimidone derivatives - Google Patents

Abstract

其中R¹代表可被取代的C₁-C₁₂烷基；R代表例如下式(II)代表的基团：

其中R²和R³独立地代表氢原子或C₁-C₈烷基；R⁴代表可被取代的苯环、可被取代的萘环、可被取代的二氢化茚环、可被取代的四氢萘环、或具有1-4个选自氧原子、硫原子和氮原子的杂原子且总共具有5-10个构成环的原子的任选取代的杂环。A pyrimidinone derivative represented by formula (I) or its salt, or its solvate or its hydrate having the activity of inhibiting tau protein kinase 1:

Wherein R ¹ represents a C ₁ -C ₁₂ alkyl group that may be substituted; R represents, for example, a group represented by the following formula (II):

Wherein R ² and R ³ independently represent a hydrogen atom or a C ₁ -C ₈ alkyl group; R ⁴ represents a benzene ring that may be substituted, a naphthalene ring that may be substituted, an indane ring that may be substituted, or an indane ring that may be substituted A tetralin ring, or an optionally substituted heterocyclic ring having 1 to 4 heteroatoms selected from oxygen atoms, sulfur atoms, and nitrogen atoms and having a total of 5 to 10 atoms constituting the ring.

Description

3-substituted-4-pyrimidinone derivatives

This application is a divisional application of a patent application with the application number 02818469.6, the filing date being September 20, 2002, and the title "3-substituted-4-pyrimidinone derivatives".

technical field

The present invention relates to compounds useful as pharmaceutical active ingredients for the prevention and/or treatment of diseases mainly caused by abnormal activity of tau protein kinase 1, such as neurodegenerative diseases such as Alzheimer's disease.

Background technique

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

It is known that the occurrence of two characteristic pathological changes of Alzheimer's disease is highly correlated with the degree of mental retardation. Therefore, investigations of these two pathological components at the molecular level have been carried out since the early 1980s to reveal the etiology of this disease. Senile plaques accumulate extracellularly, and it has been clarified that amyloid β protein is its main component (abbreviated as "Aβ" hereinafter in this specification: Biochem. Biophys. Res. Commun., 120, 855 (1984); EMBO J., 4, 2757 (1985); Proc. Natl. Acad. Sci. USA, 82, 4245 (1985)). Another pathological change, that is, in neurofibrillary tangles, double-helical filamentous substances called paired helical filaments (hereinafter referred to as "PHF" in this specification) accumulate in cells, and tau protein (brain A microtubule-associated protein unique to the Department of Neuron) is its main component (Proc. Natl. Acad. Sci. USA, 85, 4506 (1988); Neuron, 1, 827 (1988)).

In addition, on the basis of genetic research, it was found that presenile genes (presenilins) 1 and 2 are the causative genes of familial Alzheimer's disease (Nature, 375, 754 (1995); Science, 269, 973 (1995) ; Nature. 376,775(1995)), and it has been found that the presence of progeria gene 1 and 2 variants promotes the secretion of Aβ (Neuron, 17, 1005(1996); Proc.Natl.Acad.Sci.USA, 94, 2025( 1997)). From these results, it is generally considered that in Alzheimer's disease, Aβ is abnormally aggregated and aggregated for some reason, which causes the formation of PHF and leads to the death of nerve cells. It is also generally believed that the outflow of glutamate and the activation of glutamate receptors in response to this outflow may be important factors in the early stages of neuronal cell death caused by cerebrovascular ischemic accidents (Latest Medicine [Latest Medicine] ], 49, 1506 (1994)).

It has been reported that kainic acid treatment, which stimulates the AMPA receptor, a glutamate receptor, increases the mRNA of amyloid precursor protein (hereinafter referred to simply as "APP" in this specification), which is a precursor of Aβ (Society for Neuroscience Abstracts, 17, 1445 (1991)), and also promote APP metabolism (TheJournal of Neuroscience, 10, 2400 (1990)). Therefore, it is certain that cell death caused by ischemic cerebrovascular disease is related to Aβ aggregation. Other diseases in which abnormal aggregation and aggregation of Aβ have been found include, for example, Down syndrome, cerebral hemorrhage due to isolated cerebral amyloid angiopathy, Lewy body disease (Nerve Advance, 34, 343 (1990); Protein Nucleic Acid, Enzyme, 41, 1476 (1996)) and the like. Furthermore, examples of diseases exhibiting neurofibrillary tangles due to aggregation of PHF include progressive supranuclear palsy, Parkinson's disease with subacute sclerosing panencephalitis, postencephalitic Parkinson's disease, punctal encephalitis, Guam (Guam) Parkinson's disease-dementia syndrome, leptospirosis, etc. 1991); Protein Nucleic Acid [Protein, Nucleic Acid, Enzyme], 41, 1476 (1996)).

Tau proteins generally consist of a group of related proteins with a molecular weight of 48-65 kDa that form several bands in SDS-polyacrylamide gel electrophoresis, and which promote microtubule formation. It has been demonstrated that tau protein bound to PHF is abnormally phosphorylated in brains with Alzheimer's disease compared with usual tau protein (J. Biochem., 99, 1807 (1986); Proc. Natl. Acad. Sci. USA, 83, 4913 (1986)). An enzyme catalyzing this abnormal phosphorylation has been isolated. The protein is named tau protein kinase 1 (abbreviated as "TPK1" hereinafter in this specification), and its physicochemical properties have been elucidated (Biochemistry [Biochemistry], 64, 308 (1992); J.Biol.Chem., 267 , 10897 (1992)). In addition, based on the partial amino acid sequence of TPK1, the cDNA of rat TPK1 has been cloned from the rat cerebral cortex cDNA library, and its nucleotide sequence and deduced amino acid sequence have been determined (Japanese Patent Unexamined Publication [Patent Laid-Open] ] No. 6-239893/1994). As a result, the initial structure of rat TPK1 was revealed to be consistent with an enzyme called rat GSK-3β (glycogen synthase kinase 3β, FEBS Lett., 325, 167 (1993)).

Aβ, a major component of senile plaques, has been reported to be neurotoxic (Science, 250, 279 (1990)). However, many theories have been proposed as to how Aβ causes cell death, but none of them have been confirmed yet. Takashima et al. found that Aβ treatment of the primary culture system of suckling rat hippocampus caused cell death, and thus found that the activity of TPK1 increased after Aβ treatment and the cell death caused by Aβ was inhibited by antisense TPK1 (Proc.Natl.Acad.Sci.USA , 90, 7789 (1993); Japanese Patent Unexamined Publication [Kokai] No. 6-329551/1994).

In summary, compounds that inhibit the activity of TPK1 may be able to inhibit the neurotoxicity of Aβ and the formation of PHF and inhibit the death of nerve cells in Alzheimer's disease, thereby terminating or delaying the progression of the disease. These compounds may also be used as drugs to treat ischemic cerebrovascular disease, Tewar syndrome, cerebral amyloid angiopathy, and cerebral hemorrhage caused by Leuter body disease by inhibiting the neurotoxicity of Aβ. In addition, these compounds may also be used as drugs to treat neurodegenerative diseases such as progressive supranuclear palsy, parkinsonism in subacute sclerosing panencephalitis, postencephalitic parkinsonism, boxer encephalitis, guam parkinsonism Dementia-dementia syndrome, Leptospirosis, Pick's disease, corticobulbar degeneration, frontotemporal dementia, vascular dementia, traumatic injuries, brain and spinal cord trauma, peripheral neuropathy, retinopathy, and glaucoma, and the following Other diseases: non-insulin-dependent diabetes mellitus, obesity, manic-depressive disorders, schizophrenia, alopecia, breast cancer, non-small cell lung cancer, thyroid cancer, T or B-cell leukemia, and several virally induced tumors.

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

Where R represents 2,6-dichlorobenzyl, 2-(2-chlorophenyl)ethylamino, 3-phenylpropylamino or 1-methyl-3-phenylpropylamino (WO98/24782) . The compound represented by formula (A) is characterized by having a 4-fluorophenyl group at the 5-position of the pyrimidine ring and a hydroxyl group at the 4-position, and is outside the scope of the present invention. And, the main pharmacological activity of the compound represented by formula (A) is an anti-inflammatory effect, and the compound of the present invention represented by formula (I) is used as a TPK1 inhibitor or a drug for clinical treatment of neurodegenerative diseases, therefore, their pharmacological The learning activities are completely different from each other.

Contents of the invention

The purpose to be achieved by the present invention

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

means of achieving this

In order to achieve the above object, the inventors of the present invention screened various compounds having the activity of inhibiting TPK1 phosphorylation. As a result, they found that compounds represented by the following formula (I) have desired activities and are useful as active ingredients of medicaments for the prevention and/or treatment of the above-mentioned diseases. The present invention was accomplished based on these findings.

Therefore the present invention provides the pyrimidinone derivative represented by formula (I) or its salt, or its solvate or its hydrate:

Wherein R ¹ represents a C ₁ -C ₁₂ alkyl group that may be substituted;

R represents any group represented by the following formulas (II)-(V):

Wherein R ² and R ³ independently represent a hydrogen atom or a C ₁ -C ₈ alkyl group;

R ⁴ represents a benzene ring that may be substituted, a naphthalene ring that may be substituted, an indane ring that may be substituted, a tetrahydronaphthalene ring that may be substituted, or 1-4 atoms selected from the group consisting of oxygen atoms, sulfur atoms and nitrogen Atoms of heteroatoms and optionally substituted heterocycles having a total of 5-10 atoms constituting the ring;

R ⁵ represents C ₁ -C ₈ alkyl that may be substituted, C ₃ -C ₈ cycloalkyl that may be substituted, benzene ring that may be substituted, naphthalene ring that may be substituted, indane ring that may be substituted , a tetralin ring that may be substituted or an optionally substituted heterocyclic ring having 1-4 heteroatoms selected from oxygen atoms, sulfur atoms and nitrogen atoms and having a total of 5-10 atoms constituting the ring;

R ⁶ represents a hydrogen atom, a C ₁ -C ₈ alkyl group that may be substituted, or a benzene ring that may be substituted;

Or R ^{and R} can be combined with each other to form an optionally substituted spirocarbocyclic ring together with the carbon connecting ^R and ^R , the ring having a total of 3-11 ring-forming atoms;

R ⁷ and R ⁸ independently represent a hydrogen atom or a C ₁ -C ₈ alkyl group, or R ⁷ and R ⁸ can be combined with each other to form a C ₂ -C ₆ alkylene group;

R ⁹ and R ¹⁰ represent C ₁ -C ₈ alkyl that may be substituted, C ₃ -C ₈ cycloalkyl that may be substituted, benzene ring that may be substituted, naphthalene ring that may be substituted, with 1-4 An optionally substituted heterocyclic ring which is a heteroatom selected from an oxygen atom, a sulfur atom, and a nitrogen atom and has a total of 5 to 10 atoms constituting the ring, or R ⁹ and R ¹⁰ represent -N(R ¹¹ )(R ¹² ), Wherein R ¹¹ represents a hydrogen atom, a C ₁ -C ₈ alkyl group; and R ¹² represents a C ₁ -C ₈ alkyl group, a benzene ring that may be substituted, a naphthalene ring that may be substituted, or 1-4 atoms selected from oxygen A heteroatom of atom, sulfur atom and nitrogen atom and an optionally substituted heterocyclic ring having a total of 5-10 atoms constituting the ring;

And X represents CH ₂ , O or NR ¹³ , wherein R ¹³ represents a hydrogen atom or a C ₁ -C ₈ alkyl group.

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

The aforementioned pyrimidinone derivatives or salts thereof, or solvates or hydrates thereof, wherein ^R is methyl;

The aforementioned pyrimidinone derivative or its salt, or its solvate or its hydrate, wherein R is a group represented by formula (II);

The aforementioned pyrimidinone derivative or a salt thereof, or a solvate or a hydrate thereof, wherein R ² and R ³ are each a hydrogen atom;

The aforementioned pyrimidinone derivative or its salt, or its solvate or its hydrate, wherein R is a group represented by formula (III);

The aforementioned pyrimidinone derivative or a salt thereof, or a solvate or a hydrate thereof, wherein ^R is a hydrogen atom;

The aforementioned pyrimidinone derivative or a salt thereof, or a solvate or a hydrate thereof, wherein R ⁷ and R ⁸ are each a hydrogen atom;

The aforementioned pyrimidinone derivative or a salt thereof, or a solvate or a hydrate thereof, wherein R ⁷ and R ⁸ are each methyl;

The aforementioned pyrimidinone derivative or its salt, or its solvate or its hydrate, wherein R is a group represented by formula (IV);

The aforementioned pyrimidinone derivative or its salt, or its solvate or its hydrate, wherein R ⁹ is a benzene ring that may be substituted;

The aforementioned pyrimidinone derivative or its salt, or its solvate or its hydrate, wherein X is CH ₂ ;

The aforementioned pyrimidinone derivative or its salt, or its solvate or its hydrate, wherein X is O;

The aforementioned pyrimidinone derivative or its salt, or its solvate or its hydrate, wherein R is a group represented by formula (V);

The aforementioned pyrimidone derivatives or salts thereof, or solvates or hydrates thereof, wherein R ¹⁰ is a benzene ring that may be substituted; and

The aforementioned pyrimidinone derivative or its salt, or its solvate or its hydrate, wherein R has ^1-4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom and has a total of 5-10 constituent rings atoms of the heterocycle.

According to another aspect, the present invention provides a drug comprising, as an active ingredient, a pyrimidone derivative represented by the aforementioned formula (I) and a salt thereof, a solvate thereof, and a hydrate thereof, and a drug selected from the aforementioned formula (I) Representative pyrimidinone derivatives and salts thereof, as well as solvates and hydrates thereof are tau protein kinase 1 inhibitors.

According to a preferred embodiment of the aforementioned medicament, the aforementioned medicament is provided, which is used for preventing and/or treating diseases caused by excessive activity of tau protein kinase 1;

The aforementioned drug, which is used for the prevention and/or treatment of neurodegenerative diseases;

The aforementioned drug, wherein the disease is selected from the group consisting of Alzheimer's disease, ischemic cerebrovascular accident, Teva syndrome, cerebral hemorrhage due to cerebral amyloid disease, progressive supranuclear palsy, subacute sclerosing general cerebral palsy Inflammatory Parkinson's disease, postencephalitic Parkinson's disease, pugilistic encephalitis, Guam Parkinson's disease-dementia syndrome, leptospirosis, Pick's disease, corticobulbar degeneration, frontotemporal dementia, vascular dementia , bruises, brain and spinal cord trauma, peripheral neuropathy, retinopathy and glaucoma, and

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

According to another aspect of the present invention, there is provided a method for preventing and/or treating diseases caused by excessive activity of tau protein kinase 1, the steps of which include an effective preventive and/or therapeutic amount selected from formula (I) 3-substituted-4-pyrimidinone derivatives and physiologically acceptable salts thereof, solvates and hydrates thereof are administered to patients; and 3-substituted-4-pyrimidinones selected from formula (I) Use of derivatives and physiologically acceptable salts thereof, solvates and hydrates thereof in the preparation of the aforementioned medicaments.

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

Wherein R ¹ represents a C ₁ -C ₁₂ alkyl group that may be substituted, and a pyrimidinone derivative represented by formula (VII) or a salt thereof, or a solvate or a hydrate thereof:

Wherein R ¹ represents a C ₁ -C ₁₂ alkyl group which may be substituted.

Detailed ways

Best Mode for Carrying Out the Invention

Alkyl groups as used herein may be linear or branched. The C ₁ -C ₁₂ alkyl represented by R ¹ can be, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, Isopentyl, neopentyl, 1,1-dimethylpropyl, n-hexyl, isohexyl, or linear or branched heptyl, octyl, nonyl, decyl, undecyl, or dodecyl alkyl. In this specification, when a functional group is defined as "it may be substituted" or "optionally substituted", the number and type of its substituents are not particularly limited, and when there are two or more substituents, they Can be the same or different.

When the C ₁ -C ₁₂ alkyl group represented by R ¹ has one or more substituents, the alkyl group may contain one or more substituents selected from the group consisting of: C ₁ -C ₅ alkoxy such as methoxy , ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy; amino, C ₁ -C ₃ alkylamino or C ₂ -C ₆ dialkylamino: C ₆ -C ₁₀ aryl such as phenyl, 1-naphthyl and 2-naphthyl;

The C ₁ -C ₈ alkyl represented by R ² or R ³ can be, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n- Pentyl, isopentyl, neopentyl, 1,1-dimethylpropyl, n-hexyl, isohexyl, or linear or branched heptyl or octyl.

When the benzene ring, naphthalene ring, indane ring, tetrahydronaphthalene ring or heterocycle represented by R ⁴ or R ⁵ has one or more substituents, these rings may contain one or more substituents selected from the following : C ₁ -C ₅ alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1, 1-Dimethylpropyl; C ₃ -C ₆ cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; C ₃ -C ₆ cycloalkoxy such as cyclopropoxy, cyclobutoxy base, cyclopentyloxy, cyclohexyloxy; C ₁ -C ₅ alkoxy such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butyl Oxygen, pentyloxy and isopentyloxy; C ₄ -C ₇ cycloalkylalkoxy such as cyclopropylmethoxy, cyclopentylmethoxy; C ₁ -C ₅ alkylthio such as methylthio , ethylthio, propylthio, butylthio and pentylthio; C ₁ -C ₅ alkylsulfonyl groups such as methylsulfonyl, ethylsulfonyl, propanesulfonyl, butylsulfonyl and pentylsulfonyl; halogen atoms such as Fluorine atom, chlorine atom, bromine atom and iodine atom; C ₁ -C ₅ haloalkyl such as trifluoromethyl; C ₁ -C ₅ haloalkoxy such as trifluoromethoxy, 2,2,2-trifluoroethoxy hydroxy; cyano; nitro; formyl; C ₂ -C ₆ alkylcarbonyl such as acetyl, propionyl, butyryl and pentanoyl; benzene rings that may be substituted, naphthalene rings that may be substituted, -4 optionally substituted heterocycles, optionally substituted phenoxy groups or substituted phenylamino groups, which are 4 heteroatoms selected from oxygen atoms, sulfur atoms and nitrogen atoms and have 5-10 atoms constituting the ring; Amino; C ₁ -C ₅ -alkylamino such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, tert-butylamino, pentylamino and isopentyl Amino; C ₂ -C ₁₀ dialkylamino such as dimethylamino, ethylmethylamino, diethylamino, methylpropylamino and diisopropylamino; C ₂ -C ₁₀ monoalkylaminomethyl Groups such as methylaminomethyl, ethylaminomethyl, propylaminomethyl, isopropylaminomethyl, butylaminomethyl, isobutylaminomethyl, tert-butylaminomethyl, pentylamino Methyl, isopentylaminomethyl; C ₃ -C ₁₁ dialkylaminomethyl such as dimethylaminomethyl, diethylaminomethyl, ethylmethylaminomethyl, methylpropylaminomethyl pyrrolidinylmethyl; piperidinylmethyl; morpholinomethyl; piperazinylmethyl; pyrrolylmethyl; imidazolylmethyl; pyrazolylmethyl and triazolylmethyl base.

When the benzene ring, naphthalene ring, indane ring, tetrahydronaphthalene ring or heterocycle has one or more substituents, the substituents may also have one or more substituents selected from the following: C ₁ -C ₅ alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1,1- Dimethylpropyl; C ₃ -C ₆ cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; C ₃ -C ₆ cycloalkoxy such as cyclopropoxy, cyclobutoxy, Cyclopentyloxy, cyclohexyloxy; C ₁ -C ₅ alkoxy such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy , pentyloxy and isopentyloxy; C ₄ -C ₇ cycloalkylalkoxy such as cyclopropylmethoxy, cyclopentylmethoxy; C ₁ -C ₅ alkylthio such as methylthio, ethyl Thio, propylthio, butylthio and pentylthio; C ₁ -C ₅ alkylsulfonyl groups such as methylsulfonyl, ethylsulfonyl, propanesulfonyl, butanesulfonyl and pentylsulfonyl; halogen atoms such as fluorine atoms , chlorine atom, bromine atom and iodine atom; C ₁ -C ₅ haloalkyl such as trifluoromethyl; C ₁ -C ₅ haloalkoxy such as trifluoromethoxy, 2,2,2-trifluoroethoxy; Hydroxyl; cyano; nitro; formyl; C ₂ -C ₆ alkylcarbonyl such as acetyl, propionyl, butyryl and pentanoyl; amino; C ₁ -C ₅ -alkylamino such as methylamino, ethyl Amino, propylamino, isopropylamino, butylamino, isobutylamino, tert-butylamino, pentylamino and isopentylamino; C ₂ -C ₁₀ dialkylamino such as dimethylamino, ethyl C ₂ -C ₁₀ -alkylaminomethyl such as methylaminomethyl, ethylaminomethyl, propylaminomethyl C ₃ -C ₁₁ Dialkyl Aminomethyl groups include dimethylaminomethyl, diethylaminomethyl, ethylmethylaminomethyl, methylpropylaminomethyl and the like.

The heterocyclic ring represented by R ⁴ or R ⁵ having 1-4 heteroatoms selected from oxygen atoms, sulfur atoms and nitrogen atoms and having 5-10 atoms constituting the ring may be, for example, a furan ring, a dihydrofuran ring , tetrahydrofuran ring, pyran ring, dihydropyran ring, tetrahydropyran ring, benzofuran ring, dihydrobenzofuran, isobenzofuran ring, benzodioxole ring, chromogen Alkene ring, chromane ring, isochromane ring, thiophene ring, benzothiophene ring, pyrrole ring, pyrroline ring, pyrrolidine ring, imidazole ring, imidazoline ring, imidazolidine ring, pyrazole ring, pyrazole Line 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 ring, isoindole ring, isoindoline ring, indazole ring, benzimidazole ring, benzotriazole ring, tetrahydroisoquinoline ring, benzothiazolinone ring, benzoxazolone ring, Purine ring, quinozine ring, quinoline ring, phthalazine ring, naphthyridine ring, quinoxaline ring, quinazoline ring, cinnoline ring, pteridine ring, oxazole ring, oxazolidine ring, isoxazole ring , isoxazolidine ring, diazole ring, thiazole ring, benzothiazole ring, thiazolidine ring, isothiazole ring, isothiazolidine ring, benzodioxolene ring, dioxane ring, benzodioxane ring, two Thiane ring, morpholine ring, thiomorpholine ring and phthalimide ring.

The C ₁ -C ₈ alkyl represented by R ⁵ , R ⁶ , R ⁷ or R ⁸ may be, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl , tert-butyl, n-pentyl, isopentyl, neopentyl, 1,1-dimethylpropyl, n-hexyl, isohexyl, or linear or branched heptyl or octyl.

The C ₃ -C ₈ cycloalkyl represented by R ⁵ may be, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.

The C ₁ -C ₈ alkyl or C ₃ -C ₈ cycloalkyl represented by R ⁵ , or the C ₁ -C ₈ alkyl represented by R ⁶ has one or more substituents, and the group may have one or One or more substituents selected from the following: halogen atom, C ₁ -C ₆ alkoxy group, C ₃ -C ₈ cycloalkyl group, benzene ring that may be substituted, naphthalene ring that may be substituted, phenoxy group that may be substituted or phenylamino that may be substituted; amino, C ₁ -C ₆ alkylamino, C ₂ -C ₁₂ dialkylamino, 1-pyrrolidinyl, 1-piperidinyl group, 1- Morpholinyl, 1-(tetrahydro-1,2,3,4-quinolinyl) group or 1-(tetrahydro-1,2,3,4-isoquinolinyl) group.

When the benzene ring represented by R has one or more substituents, the ring may have one or more substituents selected from the group consisting of: C ₁ ^-C ₅ alkyl such as methyl, ethyl, propyl, iso Propyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1,1-dimethylpropyl; C ₃ -C ₆ cycloalkyl such as cyclopropyl Cyclobutyl, cyclopentyl, cyclohexyl; C ₃ -C ₆ cycloalkoxy such as cyclopropoxy, cyclobutoxy, cyclopentyl, cyclohexyl; C ₁ -C ₅ alkoxy Groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy and isopentyloxy; C ₄ -C ₇ cycloalkane C ₁ -C ₅ alkylthio such as methylthio, ethylthio, propylthio, butylthio and pentylthio; C ₁ -C ₅ alkylsulfonyl groups such as methylsulfonyl, ethylsulfonyl, propanesulfonyl, butanesulfonyl and pentylsulfonyl; halogen atoms such as fluorine atom, chlorine atom, bromine atom and iodine atom; C ₁ -C ₅ haloalkyl Such as trifluoromethyl; C ₁ -C ₅ haloalkoxy such as trifluoromethoxy, 2,2,2-trifluoroethoxy; hydroxyl; cyano; nitro; formyl; C ₂ -C ₆ alkane Carbonyl groups such as acetyl, propionyl, butyryl and pentanoyl; benzene rings that may be substituted, naphthalene rings that may be substituted, have 1-4 heteroatoms selected from oxygen atoms, sulfur atoms and nitrogen atoms and have 5 - optionally substituted heterocycle, optionally substituted phenoxy or optionally substituted phenylamino; amino; C ₁ -C ₅ -alkylamino such as methylamino, ethylamino, with 10 ring-forming atoms , propylamino, isopropylamino, butylamino, isobutylamino, tert-butylamino, pentylamino and isopentylamino; C ₂ -C ₁₀ dialkylamino such as dimethylamino, ethyl Methylamino, diethylamino, methylpropylamino and diisopropylamino; C ₂ -C ₁₀ monoalkylaminomethyl such as methylaminomethyl, ethylaminomethyl, propylaminomethyl , isopropylaminomethyl, butylaminomethyl, isobutylaminomethyl, tert-butylaminomethyl, pentylaminomethyl, isopentylaminomethyl; C ₃ -C ₁₁ dialkylamino Methyl groups such as dimethylaminomethyl, diethylaminomethyl, ethylmethylaminomethyl, methylpropylaminomethyl; pyrrolidinylmethyl; piperidinylmethyl; morpholine Substituted methyl; piperazinylmethyl; pyrrolylmethyl; imidazolylmethyl; pyrazolylmethyl; triazolylmethyl.

When the benzene ^ring represented by R has one or more substituents, the substituent may also have one or more substituents selected from the group consisting of: C ₁ -C ₅ alkyl such as methyl, ethyl, propyl , isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1,1-dimethylpropyl; C ₃ -C ₆ cycloalkyl such as Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; C ₃ -C ₆ cycloalkoxy such as cyclopropoxy, cyclobutoxy, cyclopentyl, cyclohexyl; C ₁ -C ₅ Alkoxy such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy and isopentyloxy; C ₄ -C ₇ Cycloalkylalkoxy such as cyclopropylmethoxy, cyclopentylmethoxy; C ₁ -C ₅ alkylthio such as methylthio, ethylthio, propylthio, butylthio and pentylthio; C ₁ -C ₅ alkylsulfonyl groups such as methylsulfonyl, ethylsulfonyl, propanesulfonyl, butanesulfonyl and pentylsulfonyl; halogen atoms such as fluorine atom, chlorine atom, bromine atom and iodine atom; C ₁ -C ₅ Haloalkyl such as trifluoromethyl; C ₁ -C ₅ haloalkoxy such as trifluoromethoxy, 2,2,2-trifluoroethoxy; hydroxyl; cyano; nitro; formyl; C ₂ -C ₆ Alkylcarbonyl such as acetyl, propionyl, butyryl and valeryl; amino; C ₁ -C ₅ -alkylamino such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, Isobutylamino, tert-butylamino, pentylamino and isopentylamino; C ₂ -C ₁₀ dialkylamino such as dimethylamino, ethylmethylamino, diethylamino, methylpropylamino and diisopropylamino; C ₂ -C ₁₀ -alkylaminomethyl such as methylaminomethyl, ethylaminomethyl, propylaminomethyl, isopropylaminomethyl, butylaminomethyl, Isobutylaminomethyl, tert-butylaminomethyl, pentylaminomethyl, isopentylaminomethyl; C ₃ -C ₁₁ dialkylaminomethyl such as dimethylaminomethyl, diethylamino Methyl, ethylmethylaminomethyl, methylpropylaminomethyl.

When ^R5 and ^R6 combine with each other to form a spiro carbocycle together with the carbon atom connected to ^R5 and ^R6 , the carbocycle can be, for example, a cyclopropyl ring, a cyclobutyl ring, a cyclopentyl ring, a cyclohexyl ring , cycloheptyl ring, tetrahydrobenzocycloheptene ring, tetrahydronaphthalene ring, indane ring, bicyclo[4,2,0]octa-1,3,5-triene ring.

The C ₁ -C ₈ alkyl represented by R ⁹ , R ¹⁰ , R ¹¹ , R ¹² or R ¹³ may be, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, 1,1-dimethylpropyl, n-hexyl, isohexyl, or linear or branched heptyl or octyl.

The C ₃ -C ₈ cycloalkyl represented by R ⁹ or R ¹⁰ may be, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.

When the C ₁ -C ₈ alkyl or C ₃ -C ₈ cycloalkyl represented by R ⁹ or R ¹⁰ has one or more substituents, the group may have one or more substituents selected from the following: Halogen atoms, C ₃ -C ₈ cycloalkyl groups, benzene rings that may be substituted, naphthalene rings that may be substituted, have 1-4 heteroatoms selected from oxygen atoms, sulfur atoms and nitrogen atoms and have a total of 5-10 An optionally substituted heterocyclic ring of atoms constituting the ring.

When the benzene ring, naphthalene ring or heterocyclic ring represented by R ⁹ or R ¹⁰ has one or more substituents, the ring may have one or more substituents selected from the group consisting of: C ₁ -C ₅ alkyl such as methyl Base, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, neopentyl, _1,1 -dimethylpropyl; -C ₆ cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; C ₃ -C ₆ cycloalkoxy such as cyclopropyloxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy C ₁ -C ₅ alkoxy such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy and isopentyloxy C ₄ -C ₇ cycloalkylalkoxy such as cyclopropylmethoxy, cyclopentylmethoxy; C ₁ -C ₅ alkylthio such as methylthio, ethylthio, propylthio, butyl Thio group and pentylthio group; C ₁ -C ₅ alkylsulfonyl groups such as methylsulfonyl, ethylsulfonyl, propanesulfonyl, butanesulfonyl and pentylsulfonyl; halogen atoms such as fluorine atom, chlorine atom, bromine atom and iodine atom; C ₁ -C ₅ haloalkyl such as trifluoromethyl; C ₁ -C ₅ haloalkoxy such as trifluoromethoxy, 2,2,2-trifluoroethoxy; hydroxyl; cyano; nitro; Formyl; C ₂ -C ₆ alkylcarbonyl such as acetyl, propionyl, butyryl and pentanoyl; benzene ring that may be substituted, naphthalene ring that may be substituted, with 1-4 atoms selected from oxygen atoms and sulfur atoms Optionally substituted heterocyclic rings with heteroatoms of nitrogen and nitrogen atoms and having a total of 5-10 atoms constituting the ring; optionally substituted phenoxy; optionally substituted phenylamino; amino; C ₁ -C ₅ -alkane Amino groups such as methylamino, ethylamino, propylamino _, isopropylamino, butylamino, isobutylamino, tert-butylamino, pentylamino and _{isopentylamino} ; Amino groups such as dimethylamino, ethylmethylamino, diethylamino, methylpropylamino and diisopropylamino; C ₁ -C ₅ -alkylaminomethyl such as methylaminomethyl, ethyl Aminomethyl, propylaminomethyl, isopropylaminomethyl, butylaminomethyl, isobutylaminomethyl, tert-butylaminomethyl, pentylaminomethyl, isopentylaminomethyl ; C ₂ -C ₁₀ dialkylaminomethyl groups such as dimethylaminomethyl, diethylaminomethyl, ethylmethylaminomethyl, methylpropylaminomethyl; pyrrolidinylmethyl; piperazine morpholinomethyl; piperazinylmethyl; pyrrolylmethyl: imidazolylmethyl; pyrazolylmethyl and triazolylmethyl.

The heterocyclic heterocyclic ring represented by R ⁹ or R ¹⁰ having 1-4 heteroatoms selected from oxygen atoms, sulfur atoms and nitrogen atoms and having a total of 5-10 atoms constituting the ring may be, for example, a furan ring, a di Hydrofuran ring, tetrahydrofuran ring, pyran ring, dihydropyran ring, tetrahydropyran ring, benzofuran ring, dihydrobenzofuran, isobenzofuran ring, benzodioxole ring , chromene ring, chromane ring, isochromane 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, oxidized pyridine ring, piperidine ring, pyrazine ring, piperazine ring, pyrimidine ring, pyridazine ring, indole ring, di Indoline ring, isoindole ring, isoindoline ring, indazole ring, benzimidazole ring, benzotriazole ring, tetrahydroisoquinoline ring, benzothiazolinone ring, benzoxazoline Ketone ring, purine ring, quinoline ring, quinoline ring, phthalazine ring, naphthyridine ring, quinoxaline ring, quinazoline ring, cinnoline ring, pteridine ring, oxazole ring, oxazolidine ring, iso Oxazole ring, isoxazolidine ring, diazole ring, thiazole ring, benzothiazole ring, thiazolidine ring, isothiazole ring, isothiazolidine ring, benzodioxolene ring, dioxane ring, benzodioxane ring, dithiane ring, morpholine ring, thiomorpholine ring or phthalimide ring.

When the benzene ring, naphthalene ring or heterocyclic ring represented by R ¹² has one or more substituents, the ring may be substituted by one or more substituents selected from the group consisting of halogen atoms, C ₁ -C ₅ alkyl groups, C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ cycloalkoxy, C ₁ -C ₅ alkoxy, C ₄ -C ₇ cycloalkylalkoxy, C ₁ -C ₅ alkylthio, C ₁ -C ₅ alkylsulfonyl, C ₁ -C ₅ haloalkyl and benzene ring.

When the benzene ring, naphthalene ring or heterocycle has one or more substituents, the substituents may also have one or more substituents selected from the group consisting of: C ₁ -C ₅ alkyl such as methyl, ethyl , propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1,1-dimethylpropyl; C ₃ -C ₆ ring Alkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; C ₃ -C ₆ cycloalkoxy such as cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy; C ₁ -C ₅ alkoxy such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy and isopentyloxy; C ₄ -C ₇ cycloalkylalkoxy such as cyclopropylmethoxy, cyclopentylmethoxy; C ₁ -C ₅ alkylthio such as methylthio, ethylthio, propylthio, butylthio and pentylthio Thio group; C ₁ -C ₅ alkylsulfonyl group such as methylsulfonyl, ethylsulfonyl, propanesulfonyl, butylsulfonyl and pentylsulfonyl; halogen atom such as fluorine atom, chlorine atom, bromine atom and iodine atom; C ₁ -C ₅ haloalkyl such as trifluoromethyl; C ₁ -C ₅ haloalkoxy such as trifluoromethoxy, 2,2,2-trifluoroethoxy; hydroxyl; cyano; nitro; formyl; ₂ -C ₆ alkylcarbonyl such as acetyl, propionyl, butyryl, and valeryl; amino; C ₁ -C ₅ -alkylamino such as methylamino, ethylamino, propylamino, isopropylamino, Butylamino, isobutylamino, tert-butylamino, pentylamino and isopentylamino; C ₂ -C ₁₀ dialkylamino such as dimethylamino, ethylmethylamino, diethylamino, methylamino propylaminomethyl and diisopropylamino; C ₂ -C ₁₀ -alkylaminomethyl such as methylaminomethyl, ethylaminomethyl, propylaminomethyl, isopropylaminomethyl, butyl Aminomethyl, isobutylaminomethyl, tert-butylaminomethyl, pentylaminomethyl, isopentylaminomethyl; C ₃ -C ₁₁ dialkylaminomethyl such as dimethylaminomethyl, Diethylaminomethyl, ethylmethylaminomethyl, methylpropylaminomethyl, etc.

R ¹ may preferably be C ₁ -C ₃ alkyl, more preferably methyl.

R ² may preferably be a hydrogen atom.

R ³ may preferably be a hydrogen atom.

R ⁴ may preferably be a benzene ring which may be substituted.

R ⁵ may preferably be a benzene ring or a naphthalene ring which may be substituted.

R ⁶ may preferably be a hydrogen atom.

R ⁷ and R ⁸ may preferably be a hydrogen atom or a C ₁ -C ₃ alkyl group.

R ⁹ or R ¹⁰ may preferably be a benzene ring which may be substituted.

R ¹⁰ may preferably be an optionally substituted heterocyclic ring having 1 to 4 heteroatoms selected from oxygen atoms, sulfur atoms and nitrogen atoms and having a total of 5 to 10 atoms constituting the ring. Particularly preferred R ¹⁰ is an optionally substituted benzene ring, an optionally substituted 2,3-dihydroindole ring, or an optionally substituted 3,4-dihydro-2H-quinoline ring.

Particularly preferred X is _CH2 or O.

The compound represented by the aforementioned formula (I) may form a salt. Examples of such salts include, when acidic groups are present, with alkali and alkaline earth metals such as lithium, sodium, potassium, magnesium and calcium; with ammonium and amines such as methylamine, dimethylamine, trimethylamine, dimethylamine, Cyclohexylamine, tris(hydroxymethyl)aminomethane, N,N-bis(hydroxyethyl)piperazine, 2-amino-2-methyl-1-propanol, ethanolamine, N-methylglucamine and Salts with L-glucosamine; or salts with basic amino acids such as lysine, 8-hydroxylysine, and arginine. When a basic group is present, examples include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid, salts with organic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, acetic acid, Propionic, tartaric, fumaric, maleic, malic, oxalic, succinic, citric, benzoic, metadelic, cinnamic, lactic, glycolic, glucuronic, ascorbic, niacin and water Salts of sylic acid; or salts with acidic amino acids such as aspartic acid and glutamic acid.

In addition to the 3-substituted-4-pyrimidinone derivatives represented by the aforementioned formula (I) and their salts, their solvates and hydrates are also within the scope of the present invention. The 3-substituted-4-pyrimidinone derivatives represented by the aforementioned formula (I) may have one or more asymmetric carbon atoms. Regarding the stereochemistry of these asymmetric carbon atoms, they may be independently in (R) or (S) configuration, and the pyrimidinone derivative may exist in stereoisomers such as optical isomers or diastereomers. Any stereoisomers in pure form, any mixtures of stereoisomers, racemates, etc., are 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.

Compounds B288 and B289

·Measurement conditions

CHIRALPAK AD

Mobile phase: n-hexane: isopropanol = 80:20

Flow rate: 1.0ml/min

Temperature: 30°C

·keep time

B288: 18.1min

B289: 18.6min

Compounds C389 and C390

·Measurement conditions

CHIRALPAKAD

Mobile phase: n-hexane: isopropanol = 60:40

Flow rate: 1.0ml/min

Temperature: 30°C

·keep time

C389: 12.0min

C390: 14.7min

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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-pyrimidine-4- ketone;

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-pyrimidine- 4-keto;

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

(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-pyrimidine-4 -ketone;

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

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

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

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

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

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

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

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

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

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

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

2-[4-(3,4-Dihydro-2H-quinoline-1-carbonyl)-piperidin-1-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidine-4- Ketones; and

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

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

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

(In the above scheme, the definitions of R ¹ , R ² , R ³ and R ⁴ are the same as those already described.)

The 2-thiopyrimidinone represented by the above formula (XI) is readily prepared by modification of the method described in EP354,179. The reaction is carried out in the presence of bases such as sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium carbonate, sodium bicarbonate, potassium carbonate, triethylamine, diisopropylethyl In the case of amines and 1,8-diazabicyclo[5,4,0]undec-7-ene at suitable temperatures ranging from 0°C to 200°C in nitrogen and argon atmospheres or in normal air for 1-100 hours to obtain the desired compound (XI). Examples of the solvent used in this reaction include, for example, alcohol solvents such as methanol, ethanol, 1-propanol, isopropanol, t-butanol, ethylene glycol, propylene glycol; ether solvents such as diethyl ether, t-butyl methyl ether, tetrahydrofuran , isopropyl ether; hydrocarbon solvents such as benzene, toluene, xylene; halogenated hydrocarbon solvents such as dichloromethane, chloroform, dichloroethane; aprotic polar solvents such as formamide, N, N-dimethylformamide , N, N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, sulfolane, hexamethyl triamine phosphate, water, etc. Generally, a single solvent or a mixture of two or more solvents can be used to suit the base used.

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

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

Then the chloride derivative (XII) and amine (XIII) or its salt in the presence of a base such as sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium carbonate, sodium bicarbonate, potassium carbonate, In the case of triethylamine, diisopropylethylamine and 1,8-diazabicyclo[5,4,0]undec-7-ene at a suitable temperature ranging from 0°C to 200°C , in a nitrogen and argon environment or in normal air for 1-100 hours to obtain the desired compound (I). 4-Dimethylaminopyridine can be used as a catalyst.

Examples of the solvent used for this reaction include, for example, alcohol solvents such as methanol, ethanol, 1-propanol, isopropanol, t-butanol, ethylene glycol, propylene glycol; ether solvents such as diethyl ether, t-butyl methyl ether, Tetrahydrofuran, isopropyl ether; hydrocarbon solvents such as benzene, toluene, xylene; halogenated hydrocarbon solvents such as dichloromethane, chloroform, dichloroethane; aprotic polar solvents such as formamide, N,N-dimethylform Amide, N, N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, sulfolane, hexamethyl triamine phosphate, water, etc. Generally, a single solvent or a mixture of two or more solvents can be used to suit the base used.

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

(In the above schemes, the definitions of R ¹ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are the same as those already described.)

Chloride derivatives (XII) and amines (IVX) or their salts in the presence of bases such as sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium carbonate, sodium bicarbonate, potassium carbonate, triethyl In the case of amine, diisopropylethylamine and 1,8-diazabicyclo[5,4,0]undec-7-ene at a suitable temperature ranging from 0°C to 200°C, at Nitrogen and argon atmosphere or ordinary air for 1-100 hours to obtain the desired compound (I).

Examples of the solvent used for this reaction include, for example, alcohol solvents such as methanol, ethanol, 1-propanol, isopropanol, t-butanol, ethylene glycol, propylene glycol; ether solvents such as diethyl ether, t-butyl methyl ether, Tetrahydrofuran, isopropyl ether; hydrocarbon solvents such as benzene, toluene, xylene; halogenated hydrocarbon solvents such as dichloromethane, chloroform, dichloroethane; aprotic polar solvents such as formamide, N,N-dimethylform Amide, N, N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, sulfolane, hexamethyl triamine phosphate, water, etc. Generally, a single solvent or a mixture of two or more solvents can be used to suit the base used.

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

(In the above scheme, the definitions of R ¹ , R ⁹ and X are the same as those already described.)

The amine represented by the above formula (VX) can be improved by the method described in the literature (J.Med.Chem., 13, 1 (1970), J.Med.Chem., 41, 591 (1998)) or according to the present invention Prepared by methods known to those skilled in the art.

Then the chloride derivative (XII) and amine (VX) or its salt in the presence of alkali such as sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium carbonate, sodium bicarbonate, potassium carbonate, In the case of triethylamine, diisopropylethylamine and 1,8-diazabicyclo[5,4,0]undec-7-ene at a suitable temperature ranging from 0°C to 200°C , in a nitrogen and argon environment or in normal air for 1-100 hours to obtain the desired compound (I).

Examples of the solvent used for this reaction include, for example, alcohol solvents such as methanol, ethanol, 1-propanol, isopropanol, t-butanol, ethylene glycol, propylene glycol; ether solvents such as diethyl ether, t-butyl methyl ether, Tetrahydrofuran, isopropyl ether; hydrocarbon solvents such as benzene, toluene, xylene; halogenated hydrocarbon solvents such as dichloromethane, chloroform, dichloroethane; aprotic polar solvents such as formamide, N,N-dimethylform Amide, N, N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, sulfolane, hexamethyl triamine phosphate, water, etc. Generally, a single solvent or a mixture of two or more solvents can be used to suit the base used.

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

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

The amine represented by the above formula (VIX) is commercially available or can be obtained by the method described in the literature (J.Med.Chem., 13, 1(1970), J.Med.Chem., 41, 591(1998)) improved or prepared according to methods known to those skilled in the art.

Then the chlorinated derivative (XII) and amine (VIX) or its salt in the presence of alkali such as sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium carbonate, sodium bicarbonate, potassium carbonate, In the case of triethylamine, diisopropylethylamine and 1,8-diazabicyclo[5,4,0]undec-7-ene at a suitable temperature ranging from 0°C to 200°C , in a nitrogen and argon environment or in normal air for 1-100 hours to obtain the desired compound (I).

Examples of the solvent used for this reaction include, for example, alcohol solvents such as methanol, ethanol, 1-propanol, isopropanol, t-butanol, ethylene glycol, propylene glycol; ether solvents such as diethyl ether, t-butyl methyl ether, Tetrahydrofuran, isopropyl ether; hydrocarbon solvents such as benzene, toluene, xylene; halogenated hydrocarbon solvents such as dichloromethane, chloroform, dichloroethane; aprotic polar solvents such as formamide, N,N-dimethylform Amide, N, N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, sulfolane, hexamethyl triamine phosphate, water, etc. Generally, a single solvent or a mixture of two or more solvents can be used to suit the base used.

The compounds of the present invention have the activity of inhibiting TPK1, and they inhibit the activity of TPK1 in neurodegenerative diseases such as Alzheimer's disease, so they can inhibit the neurotoxicity of Aβ and the formation of PHF and inhibit the death of nerve cells. Accordingly, the compounds of the present invention are used as active ingredients of medicaments enabling fundamental prevention and/or treatment of Alzheimer's disease. In addition, the compound of the present invention can also be used as an active ingredient of a drug for the prevention and/or treatment of ischemic cerebrovascular accident, Tewar syndrome, cerebral hemorrhage caused by simple cerebral amyloid angiopathy, progressive supranuclear palsy, subacute Acute sclerosing panencephalitis, postencephalitic Parkinson's disease, pugilistic encephalitis, Guam Parkinson's disease-dementia syndrome, leptospirosis, Pick's disease, cortical degenerative frontotemporal dementia, vascular dementia, Traumatic injuries, brain and spinal cord injuries, peripheral neuropathy, retinopathy and glaucoma, non-insulin-dependent diabetes mellitus, obesity, manic-depressive disorders, schizophrenia, alopecia, breast cancer, non-small cell lung cancer, thyroid cancer, T or B-cell leukemia, and several viral-induced tumors.

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

The type of pharmaceutical composition is not particularly limited, and any formulation of the composition suitable for oral or parenteral administration can be provided. For example, the pharmaceutical composition can be formulated into, for example, dosage forms of pharmaceutical compositions suitable for oral administration such as granules, fine granules, powders, hard capsules, soft capsules, syrups, emulsions, suspensions, solutions, etc., or in a suitable Pharmaceutical dosage forms for parenteral administration include injections suitable for intravenous, intramuscular or subcutaneous administration, drip preparations, transdermal preparations, transmucosal preparations, nasal drops, inhalants, suppositories, etc. Injection or drip preparations can be prepared in powder form such as freeze-dried dosage form, and can be dissolved in suitable aqueous medium such as physiological saline before use. Delayed release formulations such as those coated with polymers can be administered directly in the brain.

The kinds of pharmaceutical additives used in the preparation of the pharmaceutical composition, the content of the pharmaceutical additives relative to the active ingredient, and the preparation method of the pharmaceutical composition can be appropriately selected by those skilled in the art. Inorganic or organic substances, or solid or liquid substances can be used as pharmaceutical additives. Usually, based on the weight of the active ingredient, the weight ratio of the blended pharmaceutical additives ranges from 1% to 90%.

Excipients used in the preparation of solid pharmaceutical compositions include, for example, lactose, sucrose, starch, talc, cellulose, dextrin, kaolin, calcium carbonate, and the like. For formulation of oral liquid compositions, conventional inert diluents such as water or vegetable oils may be employed. Besides inert diluents, liquid compositions can also contain adjuvants such as wetting agents, suspending agents, sweetening, flavoring, coloring and preservative agents. The liquid composition can be filled into capsules made of absorbable material such as gelatin. Examples of solvents or suspension media for composition formulations for parenteral administration, eg, injections, suppositories include water, propylene glycol, polyethylene glycol, benzyl alcohol, ethyl oleate, lecithin and the like. Examples of materials useful as suppository bases include, for example, cocoa butter, emulsified cocoa butter, lauryl butter, witepsol.

The dose and frequency of administration of the drug of the present invention are not particularly limited, and they can be appropriately selected depending on circumstances such as the purpose of prevention and/or treatment, type of disease, patient's body weight or age, disease severity, and the like. Usually, the oral daily dose for adults may be 0.01-1,000 mg (by weight of the active ingredient), and it may be administered once a day or several times a day in divided doses, or once a day. When an injection of the drug is used, it is preferably administered to an adult continuously or intermittently at a dose of 0.001-100 mg (weight of the active ingredient) per day.

Example

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

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

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

¹ H-NMR (DMSO-d ₆ ) δ: 3.58(s, 3H), 6.40(s, 1H), 7.72(dd, J=1.8, 4.5Hz, 2H), 8.73(dd, J=1.5, 4.8Hz , 2H), 12.92 (brd, 1H).

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

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

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

Example 3: 3-methyl-2-(2-oxa-2-phenylethylamino)-6-pyridin-4-yl-3H-pyrimidin-4-one (compound number A001 in Table-1 )Synthesis

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

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

MS[M ⁺ H] ⁺ :321.

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

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

¹ H-NMR (DMSO-d ₆ ) δ: 2.98-3.06 (m, 1H), 3.15-3.22 (m, 1H), 3.47 (s, 3H), 3.69-3.73 (m, 2H), 3.76 (s, 3H), 3.85-3.92(m, 1H), 4.04-4.08(m, 1H), 4.67-4.70(m, 1H), 6.95(d, J=8.5Hz, 2H), 7.10(s, 1H), 7.38 (d, J=8.5Hz, 2H), 8.49 (d, J=6.0Hz, 2H), 8.94 (d, J=6.0Hz, 2H).

MS[M ⁺ H] ⁺ :379.

Example 5: 2-[2,2-Dimethyl-6-(4-fluorophenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidine-4 -Synthesis of Ketone (Compound No. B214 in Table-1)

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

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

MS [M ⁺ H] ⁺ : 394.

Example 6: 2-(3-benzoylpiperidin-1-yl)-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one (compound number C001 in Table-1) synthesis

3-Benzoylpiperidine hydrochloride (109mg, 0.60mmol), 2-chloro-3-methyl-6-(4-pyridyl)-pyrimidin-4-one (118mg, 0.40mmol) and triethyl A solution of the amine (0.50 mL, 4.00 mmol) in THF (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 under vacuum. The residue was purified by silica gel column chromatography (ethyl acetate) to obtain the title compound (182 mg, 61%).

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

1-tert-butoxycarbonyl-3-piperidinecarboxylic acid (458mg, 2.00mmol), sodium hydride (88mg, 2.20mmol, 60% oil suspension), oxalyl chloride (0.22ml, 2.50mmol) and a catalytic amount of A solution of dimethylformamide (0.20ml) in dichloromethane (16ml) was stirred at 0°C. After stirring for 30 minutes, to the reaction mixture was added aniline (0.20ml, 2.20mmol) treated with n-butyllithium (1.45ml, 2.30mmol, 1.59M in methane) in tetrahydrofuran (4ml) at 0°C. After stirring for another 30 minutes, saturated ammonium chloride was added and the whole reaction mixture was extracted with ethyl acetate. _The organic phase was washed with brine, dried over _Na2SO4 and evaporated under vacuum. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 1-tert-butoxycarbonylpiperidine-3-carboxyaniline (437 mg, 71%).

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

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

Example 8: 2-(2-benzoylmorpholin-4-yl)-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one (compound number C101 in Table-1) synthesis

Grignard's reagent was prepared by reacting magnesium (932mg, 5.93mmol) with bromobenzene (144mg, 5.93mmol) in diethyl ether (20ml) at room temperature for 10 minutes. 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 followed by tetrahydrofuran (6.0 ml). The mixture was stirred at room temperature for 30 minutes. After decomposing with saturated aqueous sodium bicarbonate, the mixture was filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (n-hexane-ethyl acetate 3:1 to 2:1) to give the 2-benzoyl-4-benzylmorpholine (608 mg, 44%).

(CDCl ₃ ): 2.20-2.40 (m, 2H), 2.60-2.80 (m, 1H), 3.00-3.20 (m, 1H), 3.55 (dd, J=13.0, 27.8Hz, 2H), 3.70-3.90 ( m, 1H), 3.90-4.20 (m, 1H), 4.92 (dd, J=2.6, 9.9 Hz, 1H), 7.20-7.60 (m, 8H), 7.80-8.00 (m, 2H).

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

(DMSO-d ₆ ): 3.00-3.50 (m, 4H), 4.00-4.20 (m, 2H), 5.29 (dd, J=2.6, 10.1Hz, 1H), 7.50-8.10 (m, 5H), 9.40- 9.90 (brd, 2H).

2-Benzoylmorpholine hydrochloride (269mg, 1.17mmol), 2-chloro-3-methyl-6-(4-pyridyl)-pyrimidin-4-one (320mg, 1.41mmol) and triethyl A solution of the amine (0.49 mL, 3.51 mmol) in THF (10 mL) was refluxed for several hours. After cooling the precipitate was filtered off and the solvent was removed under vacuum. The residue was washed with refluxing ethyl acetate and diethyl ether to give the title compound (447 mg, by weight).

Example 9: 2-(4-benzoylpiperidin-1-yl)-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one (compound number D001 in Table-1) synthesis

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

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

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

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

Table 2

Compound number ¹ H-NMR (Solvent) δ: [M+H]+ A002 (CDCl ₃ ): 3.59(s, 3H), 5.00(dd, J=3.8, 3.8Hz, 2H), 6.19(brs, 1H), 6.50(s, 1H), 7.24-7.37(m, 2H), 7.67 (m, 1H), 7.78(d, J=5.1Hz, 2H), 8.04(m, 1H), 8.68(d, J=5.1Hz, 2H). 339

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

B012 (CDCl ₃ ): 3.10-3.33 (m, 2H), 3.50 (m, 1H), 3.71-4.20 (m, 6H), 6.70 (s, 1H), 6.89-7.03 (m, 3H), 7.24-7.36 ( m, 2H), 7.80(d, J=6.0Hz, 2H), 8.71(d, J=6.0Hz, 2H). 378 B027 (DMSO-d ₆ ): 3.01(m, 1H), 3.15(m, 1H), 3.47(s, 3H), 3.73(dd, J=13.5, 13.5Hz, 2H), 3.90(dd, J=10.9, 10.9Hz, 1H), 4.07(d, J=11.0Hz, 1H), 4.74(d, J=9.3Hz, 1H), 7.06(s, 1H), 7.30-7.47(m, 5H), 8.40(d, J=6.3Hz, 2H), 8.90(d, J=6.3Hz, 2H). 349

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

B038 (DMSO-d ₆ ): 3.07(m, 1H).3.24(m, 1H), 3.48(s, 3H), 3.69-4.10(m, 4H), 5.05(d, J=9.3Hz, 1H), 7.10 (s, 1H), 7.21-7.61(m, 4H), 8.49(d, J=6.3Hz, 2H), 8.94(d, J=6.3Hz, 2H). 367 B039 (DMSO-d ₆ ): 2.97(dd, J=11.0, 12.6Hz, 1H), 3.12-3.20(m, 1H), 3.45(s, 3H), 3.68-3.77(m, 2H), 3.85-3.92( m, 1H), 3.99-4.08(m, 1H), 4.73-4.76(m, 1H), 7.08(s, 1H), 7.42-7.49(m, 4H), 8.47(d, J=5.7Hz, 2H) , 8.93 (d, J=5.9Hz, 2H). 383 B042 (DMSO-d ₆ ): 3.02(dd, J=12.5, 10.9, 1H), 3.19(m, 1H), 3.48(s, 3H), 3.71-4.11(m, 4H), 4.78(d, J=8.9 Hz, 1H), 7.08(s, 1H), 7.38-7.53(m, 4H), 8.44(d, J=6.3Hz, 2H), 8.92(d, J=6.3Hz, 2H). 383 B045 (DMSO-d ₆ ): 2.93 (dd, J=12.8, 10.6, 1H), 3.23 (m, 1H), 3.39 (s, 3H), 3.69-4.15 (m, 4H), 5, 06 (d, J =9.0Hz, 1H), 7.14(s, 1H), 7.38-7.66(m, 4H), 8.56(d, J=6.3Hz, 2H), 8.98(d, J=6.3Hz, 2H). 383 B046 (DMSO-d ₆ ): 2.89(m, 1H), 3.35(m, 1H), 3.50(s, 3H), 3.68-4.14(m, 4H), 5, 06(m, 1H), 7.08(s, 1H), 7.39-7.64(m, 4H), 8.46(d, J=5.5Hz, 2H), 8.93(d, J=5.5Hz, 2H). 382 B048 □(DMSO-d ₆ ): 2.96 (1H, dd, J=10.7, 12.7Hz), 3.12-3.20 (1H, m), 3.45 (3H, s), 3.66-3.75 (2H, m), 3.86-3.93 (1H, m), 4.05-4.09 (1H, m), 4.75 (1H, d, J=8.9Hz), 6.85 (1H, s), 7.42 (2H, d, J=8.4Hz), 7.58 (2H, d, J=8.3Hz), 7.97 (2H, d, J=6.0Hz), 8.69 (2H, d, J=6.0Hz) [M+]=427 B051 (DMSO-d ₆ ): 2.94-3.02 (1H, m), 3.14-3.22 (1H, m), 3.46 (3H, s), 3.66-3.77 (2H, m), 3.87-3.94 (1H, m), 4.04-4.09(1H, m), 4.76(1H, d, J=9.5Hz), 6.85(1H, s), 7.33-7.38(1H, m), 7.46-7.48(1H, m), 7.52-7.55( 1H, m), 7.61-7.70 (1H, m), 7.97 (2H, d, J=5.7Hz), 8.68 (2H, d, J=5.7Hz) 427 B054 (DMSO-d ₆ ): 2.90 (dd, J=12.6, 10.5, 1H), 3.22 (m, 1H), 3.51 (s, 3H), 3.67-4.15 (m, 4H), 4.98 (d, J=9.0 Hz, 1H), 7.07(s, 1H), 7.29-7.68(m, 4H), 8.42(d, J=6.3Hz, 2H), 8.90(d, J=6.3Hz, 2H). 427 B057 (DMSO-d ₆ ): 3.00(dd, J=12.6, 10.5, 1H), 3.18(m, 1H), 3.47(s, 3H), 3.69-4.09(m, 4H), 4.70(d, J=9.3 Hz, 1H), 7.06(s, 1H), 7.20(d, J=7.8Hz, 2H), 7.34(d, J=7.8Hz, 2H), 8.41(d, J=6.3Hz, 2H), 8.91( d, J=6.3Hz, 2H). 363 B060 (DMSO-d ₆ ): 2.33(s, 3H), 2.97-3.05(m, 1H), 3.15-3.22(m, 1H), 3.48(s, 3H), 3.70-3.77(m, 1H), 3.86- 3.94(m, 1H), 4.05-4.09(m, 1H), 4.69-4.72(m, 1H), 7.07(s, 1H), 7.13-7.28(m, 4H), 8.43(d, J=6.0Hz, 2H), 8.92(d, J=6.3Hz, 2H). 363 B063 (CDCl ₃ ): 2.41(s, 3H), 3.08(m, 1H), 3.35(m, 1H), 3.54(m, 1H), 3.59(s, 3H), 3.66(m, 1H), 4.00(m , 1H), 4.21(m, 1H), 4.92(m, 1H), 6.69(s, 1H), 7.18-7.29(m, 3H), 7.55(m, 1H), 7.79(d, J=5.5Hz, 2H), 8.71(d, J=5.5Hz, 2H). 363

B064 (CDCl ₃ ): 2.41(s, 3H), 3.08(m, 1H), 3.35(m, 1H), 3.52-3.69(m, 2H), 3.60(s, 3H), 4.00(m, 1H), 4.21 (m, 1H), 4.92(m, 1H), 6.69(s, 1H), 7.18-7.29(m, 3H), 7.53(m, 1H), 7.79(d, J=6.3Hz, 2H), 8.70( d, J=6.0Hz, 2H). 362 B066 (DMSO-d ₆ ): 3.11(dd, J=10.8, 12.8Hz, 1H), 3.24-3.32(m, 1H), 3.47(s, 3H), 3.68-3.75(m, 2H), 3.90-3.98( m, 1H), 4.10-4.14(m, 1H), 4.96-4.99(m, 1H), 7.11(s, 1H), 7.60(t, J=7.4Hz, 1H), 7.77-7.79(m, 2H) , 7.90(d, J=8.0Hz, 1H), 8.48(d, J=6.0Hz, 2H), 8.94(d, J=6.1Hz, 2H). 417 B069 (DMSO-d ₆ ): 3.04(m, 1H), 3.19(m, 1H), 3.48(s, 3H), 3.50-4.15(m, 4H), 4.87(d, J=8.7Hz, 1H), 7.04 (s, 1H), 7.67(d, J=8.1Hz, 2H), 7.88(d, J=8.1Hz, 2H), 8.35(d, J=6.6Hz, 2H), 8.88(d, J=6.6Hz , 2H). 374 B072 (DMSO-d ₆ ): 3.02(m, 1H), 3.20(m, 1H), 3.49(s, 3H), 3.74(d, J=13.2Hz, 2H), 3.82(d, J=12.3Hz, 2H ), 3.94(m, 1H), 4.11(d, J=11.1Hz, 1H), 4.83(d, J=9.9Hz, 2H), 7.08(s, 1H), 7.62(t, J=7.8Hz, 1H ), 7.82(d, J=7.8Hz, 2H), 7.92(s, 1H), 8.43(d, J=5.7Hz, 2H), 8.92(d, J=5.7Hz, 2H). 374 B073 (DMSO-d ₆ ): 3.06(m, 1H), 3.12-3.85(m, 6H), 3.94(m, 1H), 4.11(d, J=9.9Hz, 1H), 4.83(d, J=9.0Hz , 1H), 7.00(s, 1H), 7.62(m, 1H), 7.83(d, J=7.8Hz, 2H), 7.92(s, 1H), 8.27(d, J=5.4Hz, 2H), 8.84 (d, J=5.4Hz, 2H). 373 B075 (DMSO-d ₆ ): 3.09(m, 1H), 3.19-3.33(m, 1H), 3.49(s, 3H), 3.69(d, J=12.6Hz, 1H), 3.83(d, J=12.6Hz , 1H), 3.97(m, 1H), 4.12(d, J=11.7Hz, 1H), 5.02(dd, J=2.4Hz, 10.5Hz, 1H), 6.86(s, 1H), 7.58(m, 1H ), 7.73-7.82(m, 2H), 7.90(d, J=7.5Hz, 1H), 7.99(dd, J=1.5Hz, 6.0Hz, 2H), 8.67(dd, J=1.5Hz, 6.0Hz, 2H). 373 B078 (DMSO-d ₆ ): 3.01(m, 1H), 3.18(m, 1H), 3.47(s, 3H), 3.68-3.73(m, 2H), 3.75(s, 3H), 3.88(m, 1H) , 4.06(m, 1H), 4.68(d, J=9.6Hz, 1H), 6.94(d, J=8.4Hz, 2H), 7.09(s, 1H), 7.37(d, J=8.4Hz, 2H) , 846(d, J=6.0Hz, 2H), 8.94(d, J=6.0Hz, 2H). 379 B080 (DMSO-d ₆ ): 2.95-3.03(m, 1H), 3.12-3.20(m, 1H), 3.45(s, 3H), 3.67-3.71(m, 2H), 3.73(s, 3H), 3.82- 3.90(m, 1H), 4.02-4.05(m, 1H), 4.64-4.67(m, 1H), 6.92(d, J=8.5Hz, 2H), 7.08(s, 1H), 7.35(d, J= 8.5Hz, 2H), 8.49(d, J=6.2Hz, 2H), 8.96(d, J=6.0Hz, 2H). 379 B081 (DMSO-d ₆ ): 3.02(m, 1H), 3.15(m, 1H), 3.48(s, 3H), 3.70-3.75(m, 2H), 3.77(s, 3H), 3.90(m, 1H) , 4.08(m, 1H), 4.73(d, J=9.6Hz, 1H), 6.89-7, 04(m, 3H), 7.10(s, 1H), 7.31(m, 1H), 8.47(d, J =5, 7Hz, 2H), 8.94(d, J=5.7Hz, 2H). 379

B082 (DMSO-d ₆ ): 2.99-3.06(m, 1H), 3.16-3.23(m, 1H), 3.48(s, 3H), 3.70-3.74(m, 2H), 3.77(s, 3H), 3.86- 3.94(m, 1H), 4.07-4.10(m, 1H), 4.71-4.74(m, 1H), 6.89-6.92(m, 1H), 7.01(s, 1H), 7.06(m, 2H), 7.31( t, J=7.8Hz, 1H), 8.45(d, J=5.9Hz, 2H), 8.93(d, J=5.9Hz, 2H). 378 B084 (DMSO-d ₆ ): 2.82(dd, J=10.2, 12.8Hz, 1H), 3.17-3.26(m, 1H), 3.50(s, 3H), 3.68-3.72(m, 1H), 3.83(s, 3H), 3.83-3.94(m, 2H), 4.09-4.13(m, 1H), 5.00-5.03(m, 1H), 6.98-7.07(m, 2H), 7.14(s, 1H), 7.29-7.35( m, 1H), 7.45(d, J=7.4Hz, 1H), 8.59(d, J=6.4Hz, 2H), 9.00(d, J=6.4Hz, 2H). 379 B085 (CDCl ₃ ): 2.83 (1H, dd, J = 10.2, 12.9Hz), 3..3-3.4 (1H, m), 3.5-3.6 (1H, m), 3.62 (3H, s), 3.8-3.9 (1H, m), 3.86 (3H, m), 4.0-4.1 (1H, m), 4.2-4.3 (1H, m), 5.08 (1H, dd, J=2.1, 10.2Hz), 6.69 (1H, s ), 7.0-7.1 (1H, m), 7.2-7.3 (1H, m), 7.53 (1H, dd, J = 1.5, 7.8Hz), 7.82 (1H, dd, J = 1.5, 4.5Hz), 8.71 ( 2H, dd, 1.5, 4.5Hz) 379 B087 (DMSO-d ₆ ): 1.30 (3H, t, J = 6.8Hz), 2.75 (1H, dd, J = 10.6, 12.5Hz), 3.17-3.25 (1H, m), 3.48 (3H, s), 3.66 -3.71(1H, m), 3.77-3.81(1H, m), 3.89-3.96(1H, m), 4.01-4.13(3H, m), 4.96(1H, d, J=9.3Hz), 6.84(1H , s), 6.95-7.03 (2H, m), 7.25-7.31 (1H, m), 7.42-7.44 (1H, m), 7.98 (2H, d, J = 5.1Hz), 8.68 (2H, d, J =5.3Hz) 393 B088 (CDCl ₃ ): 2.90(m, 1H), 3.35(m, 1H), 3.55(m, 1H), 3.62(s, 3H), 3.69(m, 1H), 4.03(m, 1H), 4.24(m , 1H), 5.05(m, 1H), 6.71(s, 1H), 7.26-7.40(m, 3H), 7.68(m, 1H), 7.80(d, J=6.0Hz, 2H), 8.71(d, J=6.0Hz, 2H). 433

B089 (CDCl ₃ ): 2.80(m, 1H), 3.37(m, 1H), 3.53-3.73(m, 2H), 3.60(s, 3H), 4.05(m, 1H), 4.21-4.58(m, 3H) , 5.08(m, 1H), 6.70(s, 1H), 6.86(d, 1H, J=8.2Hz), 7.14(m, 1H), 7.32(m, 1H), 7.59(m, 1H), 7.80( d, J=6.0Hz, 2H), 8.71(d, J=6.0Hz, 2H). 447 B090 (DMSO-d ₆ ): 2.82(dd, J=10.2, 12.8Hz, 1H), 3.19-3.26(m, 1H), 3.49(s, 3H), 3.67-3.71(m, 1H), 3.83(s, 3H), 3.81-3.94(m, 2H), 4.09-4.12(m, 1H), 4.98-5.01(m, 1H), 7.05-7.23(m, 4H), 8.51(d, J=5.4Hz, 2H) , 8.96 (d, J=6.4Hz, 2H). 397 B091 (DMSO-d ₆ ): 2.81(m, 1H), 3.20(m, 1H), 3.47(s, 3H), 3.56-3.91(m, 2H), 3.83(s, 3H), 4.08(m, 1H) , 4.95(d, J=9.3Hz, 1H), 6.78-6.98(m, 2H), 7.09(s, 1H), 7.43(m, 1H), 8.49(d, J=5.4Hz, 2H), 8.94( d, J=5.4Hz, 2H). 397 B092 (DMSO-d ₆ ): 2.94-3.01 (1H, m), 3.13-3.20 (1H, m), 3.46 (3H, s), 3.67-3.78 (2H, m), 3.88-3.95 (1H, m), 4.07-4.10(1H, m), 4.79(1H, d, J=9.8Hz), 6.86(1H, s), 7.47(1H, d, J=8.3Hz), 7.65-7.72(2H, m), 7.98 (2H, d, J=5.7Hz), 8.68 (2H, d, J=5.5Hz) 417

B093 (DMSO-d ₆ ): 2.78 (1H, dd, J=10.3, 12.7Hz), 3.16-3.24 (1H, m), 3.46 (3H, s), 3.62-3.66 (1H, m), 3.71 (3H, s), 3.78(3H, s), 3.83-4.11(2H, m), 4.97(1H, d, J=9.0Hz), 6.84(1H, s), 6.85-6.88(1H, m), 6.95-7.00 (2H, m), 7.99 (2H, d, J=5.6Hz), 8.69 (2H, d, J=5.9Hz) 409 B094 (DMSO-d ₆ ): 2.78-2.86 (m, 1H), 3.17-3.25 (m, 1H), 3.49 (s, 3H), 3.66-3.93 (m, 3H), 3.72 (s, 3H), 3.78 ( s, 3H), 4.09-4.13(m, 1H), 4.96-4.99(m, 1H), 6.85-7.09(m, 4H), 8.48(d, J=5.4Hz, 2H), 8.94(d, J= 6.0Hz, 2H). 408 B096 (CDCl ₃ ): 3.07(t, J=10.6Hz, 1H), 3.29(td, J=10.3, 3.2Hz, 1H), 3.53(d, J=12.2Hz, 1H), 3.58(s, 3H), 3.68(dt, J=13.1, 1.1Hz, 1H), 3.96(td, J=11.9, 2.3Hz, 1H), 4.19(dd, J=13.9, 2.3Hz, 1H), 4.75(dd, J=10.4, 1.1Hz, 2H), 6.72(s, 1H), 6.80(tt, J=8.9, 2.3Hz, 1H), 6.96(dd, J=6.0, 2.3Hz, 2H), 7.79(dd, J=4.6, 1.6 Hz, 2H), 8.73 (dd, J=4.5, 1.6Hz, 2H). 385 B097 (CDCl ₃ ): 2.78(dd, J=12.8, 10.4Hz, 1H), 3.32(td, J=12.2, 3.2Hz, 1H), 3.54(d, J=12.5Hz, 1H), 3.62(s, 3H ), 3.82 (dt, J = 12.9, 1.9Hz, 1H), 4.02 (td, J = 11.8, 2.3Hz, 1H), 4.23 (dd, J = 11.6, 2.2Hz, 1H), 5.02 (dd, J = 10.3, 1.9Hz, 2H), 6.71(s, 1H), 7.24(dd, J=6.9, 2.8Hz, 1H), 7.50(dd, J=11.2, 8.4Hz, 1H), 7.80(dd, J=4.6 , 1.5Hz, 2H), 8.70 (dd, J=4.5, 1.5Hz, 2H). 419 B098 (CDCl ₃ ): 2.78(dd, J=12.8, 10.4Hz, 1H), 3.32(td, J=12.2, 3.2Hz, 1H), 3.54(d, J=12.5Hz, 1H), 3.62(s, 3H ), 3.82 (dt, J = 12.9, 1.9Hz, 1H), 4.02 (td, J = 11.8, 2.3Hz, 1H), 4.23 (dd, J = 11.6, 2.2Hz, 1H), 5.02 (dd, J = 10.3, 1.9Hz, 2H), 6.71(s, 1H), 7.24(dd, J=6.9, 2.8Hz, 1H), 7.50(dd, J=11.2, 8.4Hz, 1H), 7.80(dd, J=4.6 , 1.5Hz, 2H), 8.70 (dd, J=4.5, 1.5Hz, 2H). 418 B100 (DMSO-d ₆ ): 2.90(dd, J=10.5Hz, 12.9Hz, 1H), 3.23(m, 1H), 3.51(s, 3H), 3.70(d, J=13.2Hz, 1H), 3.85( d, J=12.9Hz, 1H), 3.95(m, 1H), 4, 12(d, J=9.6Hz, 1H), 4.96(d, J=8.7Hz, 1H), 7.11(s, 1H), 7.37(m, 1H), 7.60-7.70(m, 2H), 8.50(d, J=6.3Hz, 2H), 8.95(d, J=6.6Hz, 2H). 446 B101 (DMSO-d ₆ ): 3.07(dd, J=12.8, 10.6, 1H), 3.24(m, 1H), 3.47(s, 3H), 3.67-4.09(m, 4H), 5.01(d, J=9.4 Hz, 1H), 7.06(s, 1H), 7.17(m, 1H), 7.32(m, 1H), 7.61(m, 1H), 8.41(d, J=6.3Hz, 2H), 8.90(d, J =6.3Hz, 2H). 384

B102 (DMSO-d ₆ ): 3.22(t, J=14.4Hz, 1H), 3.58(d, J=19.5Hz, 1H), 3.77(s, 3H), 3.26-4.04(m, 4H), 5.29(d , J=9.0Hz, 1H), 6.67(d, J=8.4Hz, 2H), 7.02(s, 1H), 7.27(t, J=8.4Hz, 1H), 8.44(d, J=5.7Hz, 2H ), 8.92 (d, J=5.7Hz, 2H). 408 B103 d(DMSO-d ₆ ): 3.22 (1H, t, J = 14.4Hz), 3.58 (1H, d, J = 19.5Hz), 3.77 (3H, s), 3.26-4.04 (4H, m), 5.29 ( 1H, d, J = 9.0Hz), 6.67 (2H, d, J = 8.4Hz), 7.02 (1H, s), 7.27 (1H, t, J = 8.4Hz), 8.44 (2H, d, J = 5.7 Hz), 8.92 (2H, d, J=5.7Hz). 409

B104 d(DMSO-d ₆ ): 3.22 (1H, t, J = 14.4Hz), 3.58 (1H, d, J = 19.5Hz), 3.77 (3H, s), 3.26-4.04 (4H, m), 5.29 ( 1H, d, J = 9.0Hz), 6.67 (2H, d, J = 8.4Hz), 7.02 (1H, s), 7.27 (1H, t, J = 8.4Hz), 8.44 (2H, d, J = 5.7 Hz), 8.92 (2H, d, J=5.7Hz). 409 B105 (DMSO-d ₆ ): 3.44-3.63 (m, 2H), 3.58 (s, 3H), 3.81 (m, 1H), 3.98 (m, 1H), 4.21 (m, 1H), 5.55 (dd, J= 2.7Hz, 11.1Hz, 1H), 6.69(s, 1H), 7.20(t, J=7.5Hz, 1H), 7.35(d, J=7.5Hz, 2H), 7.82(d, J=4.5Hz, 2H ), 8.70 (d, J=4.5Hz, 2H). 416 B106 (CDCl ₃ ): 3.44-3.55 (3H, m), 3.59 (3H, s), 3.82 (1H, dd, J=12.9, 10.8Hz), 3.98 (1H, m), 4.20 (1H, m), 5.55 (1H,dd,J=10.8,2.7Hz), 6.70(1H,s), 7.18-7.38(3H,m), 7.82(2H,dd,J=4.5,1.5Hz), 8.71(2H,dd,J =4.5, 1.8Hz). 417 B107 (CDCl ₃ ): 3.44-3.55 (3H, m), 3.59 (3H, s), 3.82 (1H, dd, J=12.9, 10.8Hz), 3.98 (1H, m), 4.20 (1H, m), 5.55 (1H,dd,J=10.8,2.7Hz), 6.70(1H,s), 7.18-7.38(3H,m), 7.82(2H,dd,J=4.5,1.5Hz), 8.71(2H,dd,J =4.5, 1.8Hz). 417 B108 (DMSO-d ₆ ): 3.03(t, J=12.6Hz, 1H), 3.20(t, J=11.1Hz, 1H), 3.48(s, 3H), 3.70-3.78(m, 2H), 3.90(m , 1H), 4.05(m, 1H), 4.73(d, J=10.2Hz), 7.03(m, 1H), 7.06(s, 1H), 7.18-7.25(m, 2H), 8.40(d, J= 5.7Hz, 2H), 8.90(d, J=5.7Hz, 2H). 396 B109 (CDCl ₃ ): 3.42-3.52 (2H, m), 3.57 (3H, s), 3.63-3.66 (2H, m), 3.67 (1H, m), 4.13 (1H, m), 5.24 (1H, dd, J=9.0, 1.8Hz), 6.70(1H, s), 6.95(2H, m), 7.32(1H, m), 7.82(2H, dd, J=4.5, 1.8Hz), 8.72(2H, dd, J =4.5, 1.8Hz). 410 B110 (CDCl ₃ ): 3.42-3.52 (2H, m), 3.57 (3H, s), 3.63-3.66 (2H, m), 3.67 (1H, m), 4.13 (1H, m), 5.24 (1H, dd, J=9.0, 1.8Hz), 6.70(1H, s), 6.95(2H, m), 7.32(1H, m), 7.82(2H, dd, J=4.5, 1.8Hz), 8.72(2H, dd, J =4.5, 1.8Hz). 385

B112 (CDCl ₃ ): 1.74-1.79(m, 4H), 2.50-2.53(m, 4H), 3.13(m, 1H), 3.32(m, 1H), 3.51-3.68(m, 2H), 3.64(s, 3H), 3.67(s, 2H), 4.00(m, 1H), 4.18(m, 1H), 4.72(m, 1H), 6.70(s, 1H), 7.33-7.44(m, 4H), 7.80(dd , J=4.8, 1.2Hz, 2H), 8.71 (dd, J=4.8, 1.2Hz, 2H). 432 B113 (CDCl ₃ ): 1.80-1.82 (4H, m), 2.56-5.58 (4H, m), 3.12 (1H, dd, J=13.2, 10.8Hz), 3.32 (1H, m), 3.54 (1H, m) , 3.58(3H, s), 3.64(1H, m), 3.68(2H, s), 3.98-4.21(2H, m), 4.73(1H, dd, J=10.5, 2.1Hz), 6.69(1H, s ), 7.35-7.42 (4H, m), 7.79 (2H, d, J=4.5, 1.5Hz), 8.71 (2H, d, J=4.5, 1.5Hz). 431 B115 (D ₂ O): 1.24-1.39 (1H, m), 1.46-1.67 (3H, m), 1.75-1.80 (2H, m), 2.78-2.86 (2H, m), 3.14-3.34 (4H, m) , 3.44(3H, s), 3.66-3.72(2H, m), 3.91-4.06(2H, m), 4.16(2H, s), 4.79(1H, d, J=10.4Hz), 6.83(1H, s ), 7.35-7.47 (4H, m), 8.44 (2H, d, J=6.5Hz), 8.72 (2H, d, J=6.6Hz) 446

B116 (D ₂ O): 1.81-1.96 (2H, m), 2.00-2.16 (2H, m), 3.03-3.15 (2H, m), 3.19-3.31 (2H, m), 3.39-3.47 (2H, m) , 3.50(3H, s), 3.70-3.78(2H, m), 3.95-4.11(2H, m), 4.31(2H, s), 4.85(2H, d, J=10.3Hz), 6.89(1H, s ), 7.41-7.56 (4H, m), 8.49 (2H, d, J=6.0Hz), 8.77 (2H, d, J=6.7Hz) 432 B117 (D ₂ O): 2.74 (6H, s), 3.17-3.34 (2H, m), 3.48 (3H, s), 3.68-3.76 (2H, m), 3.97-4.09 (2H, m), 4.23 (2H , s), 4.83(1H, d, J=9.9Hz), 6.87(1H, s), 7.39-7.52(4H, m), 8.46(2H, d, J=7.1Hz), 8.75(2H, d, J=6.6Hz) 406 B118 (D ₂ O): 3.11-3.25 (4H, m), 3.31-3.36 (2H, m), 3.48 (3H, s), 3.62-3.76 (4H, m), 3.98-4.06 (4H, m), 4.30 (2H, s), 4.83 (1H, d, J = 8.9Hz), 6.87 (1H, s), 7.41-7.52 (4H, m), 8.47 (2H, d, J = 6.8Hz), 8.76 (2H, d, J=6.6Hz) 448 B119 (CDCl ₃ ): 1.61-1.78 (4H, m), 2.34-2.48 (4H, m), 3.06 (1H, dd, J=10.5, 12.9Hz), 3.24-3.28 (1H, m), 3.35-3.45 ( 1H, m), 3.54 (3H, s), 3.68-3.81 (2H, m), 3.98-4.02 (1H, m), 4.03-4.20 (2H, m), 5.05 (1H, dd, J = 2.1, 10.2 Hz), 6.68(1H, s), 7.25-7.26(2H, m), 7.32-7.36(1H, m), 7.57-7.60(1H, m), 7.81(2H, d, J=6.3Hz), 8.72 (2H, d, J=6.0Hz) 431 B120 (CDCl ₃ ): 1.31 (3H, d, J=6.0Hz), 1.37 (3H, d, J=6.1Hz), 2.76 (1H, dd, J=10.1, 12.6Hz), 3..3-3.5( 1H, m), 3.5-3.7 (1H, m), 3.63 (3H, s), 3.7-3.8 (1H, m), 4.0-4.2 (1H, m), 4.2-4.3 (1H, m), 4.6- 4.7(1H, m), 5.02(1H, dd, J=2.0, 10.1Hz), 6.68(1H, s), 6.88(1H, d, J=8.3Hz), 6.98(1H, t, J=7.4Hz ), 7.2-7.3 (1H, m), 7.52 (1H, dd, J = 1.6, 7.6Hz), 7.81 (1H, dd, J = 1.6, 4.5Hz), 8.71 (2H, dd, 1.5, 4.5Hz) 407

B122 (CDCl ₃ ): 1.34 (6H, d, J = 6.0Hz), 3.13 (1H, dd, J = 10.8, 12.9Hz), 3.2-3.4 (1H, m), 3.5-3.7 (2H, m), 3.57 (3H, s), 3.9-4.0(1H, m), 4.1-4.2(1H, m), 4.5-4.6(1H, m), 4.66(1H, dd, J=2.1, 10.5Hz), 6.69(1H , s), 6.9-7.0 (2H, m), 7.3-7.4 (2H, m), 7.79 (2H, dd, J=1.8, 4.5Hz), 8.71 (2H, dd, J=1.8, 4.5Hz). 407 B126 (CDCl ₃ ): 0.3-0.4 (2H, m), 0.6-0.7 (2H, m), 1.2-1.3 (1H, m), 2.79 (1H, dd, J=10.2, 12.9Hz), 3..3 -3.5(1H,m), 3.6-3.7(1H,m), 3.65(3H,s), 3.7-4.0(3H,m), 4.0-4.1(1H,m), 4.2-4.3(1H,m) , 5.09 (1H, dd, J = 2.1, 10.2Hz), 6.68 (1H, s), 6.84 (2H, d, J = 8.1Hz), 7.03 (2H, t, J = 7.5Hz), 7.2-7.3 ( 1H, m), 7.53 (1H, dd, J=1.5, 7.5Hz), 7.81 (1H, dd, J=1.5, 4.5Hz), 8.71 (2H, dd, 1.5, 4.5Hz) 419

B128 (CDCl ₃ ): 0.3-04 (2H, m), 0.6-0.7 (2H, m), 1.2-1.3 (1H, m), 3.12 (1H, dd, J=10.8, 12.9Hz), 3.2-3.4 ( 1H, m), 3.5-3.7 (2H, m), 3.57 (3H, s), 3.82 (2H, d, J=6.9Hz), 3.9-4.0 (1H, m), 4.1-4.2 (1H, m) , 4.67 (1H, dd, J = 2.4, 10.8Hz), 6.69 (1H, s), 6.93 (2H, d, J = 8.7Hz), 7.32 (2H, d, J = 8.7Hz), 7.79 (2H, dd, J=1.8, 4.8Hz), 8.71 (2H, dd, J=1.8, 4.8Hz). 419

B130 (DMSO-d ₆ ): 2.98 (1H, dd, J=12.6, 14.4Hz), 3.18-3.24 (1H, m), 3.22 (3H, s), 3.46 (3H, s), 3.69 (1H, d, J=12.3Hz), 3.81(1H, d, J=12.9Hz), 3.89-3.96(1H, m), 4.10(1H, d, J=10.5Hz), 4.89(1H, d, J=9.0Hz) , 6.83(1H, s), 7.67(1H, t, J=7.8Hz), 7.80(1H, d, J=7.5Hz), 7.88(1H, d, J=6.9Hz), 7.96(2H, d, J=5.1Hz), 8.00(1H, s), 8.67(2H, d, J=5.1Hz) 427 B140 (CDCl ₃ ): 2.0-2.1 (4H, m), 3.16 (1H, dd, J=10.7, 12.8Hz), 3.2-3.4 (5H, m), 3.5-3.7 (2H, m), 3.56 (3H, s), 3.9-4.0(1H, m), 4.1-4.2(1H, m), 4.61(1H, dd, J=2.1, 10.7Hz), 6.57(2H, d, J=8.4Hz), 6.69(1H , s), 7.26 (2H, d, J = 8.7Hz), 7.80 (2H, dd, J = 1.4, 4.6Hz), 8.71 (2H, dd, J = 1.4, 4.6Hz) 418 B143 (CDCl ₃ ): 3.18 (1H, dd, J = 12.3, 10.1Hz), 3.35 (1H, m), 3.59 (1H, m), 3.60 (3H, s), 3.72 (1H, m), 3.98-4.23 (2H, m), 4.79 (1H, d, J=10.5), 6.70 (1H, s), 7.35-7.65 (9H, m), 7.80 (2H, d, J=5.7Hz), 8.72 (2H, d , J=5.7Hz). 425 B184 (DMSO-d ₆ ): 1.99-2.06 (2H, m), 2.82-2.89 (4H, m), 2.98 (1H, dd, J=10.7, 12.9Hz), 3.11-3.22 (1H, m), 3.45 ( 3H, s), 3.65-3.70 (2H, m), 3.84-3.92 (1H, m), 4.01-4.06 (1H, m), 4.79 (1H, d, J=8.7Hz), 6.83 (1H, s) , 7.17-7.23(2H, m), 7.29-7.32(1H, m), 7.96(2H, d, J=6.2Hz), 8.66(2H, d, J=6.0Hz) 389

B185 (DMSO-d ₆ ): 3.07 (1H, dd, J=10.9, 12.3Hz), 3.18-3.27 (1H, m), 3.49 (3H, s), 3.70-3.74 (1H, m), 3.81-3.86 ( 1H, m), 3.93-4.00(1H, m), 4.11-4.15(1H, m), 4.93(1H, d, J=9.5Hz), 6.86(1H, s), 7.51-7.56(2H, m) , 7.59-7.62 (1H, m), 7.91-7.99 (6H, m), 8.68 (2H, d, J=5.0Hz) 399 B186 (CDCl ₃ ): 3.21 (1H, dd, J=10.5, 13.2Hz), 3.31-3.41 (1H, m), 3.54-3.67 (1H, m), 3.61 (3H, s), 3.74-3.78 (1H, m), 4.01-4.10(1H, m), 4.23-4.28(1H, m), 4.92(1H, dd, J=2.1, 10.5Hz), 6.71(1H, s), 7.50-7.54(3H, m) , 7.80(2H, d, J=6.0Hz), 7.82-7.91(4H, m), 8.71(2H, d, J=6.0Hz) 398 B187 (DMSO-d ₆ ): 3.18 (dd, J=10.5, 12.9 Hz, 1H), 3.31-3.38 (m, 1H), 3.53 (s, 3H), 3.75-3.79 (m, 1H), 4.00-4.18 ( m, 3H), 5.52-5.55(m, 1H), 7.03(s, 1H), 7.51-8.30(m, 7H), 8.42(d, J=6.0Hz, 2H), 8.92(d, J=5.4Hz , 2H). 399 B188 (CDCl ₃ ): 3.09-3.33 (4H, m), 3.53-3.64 (2H, m), 3.57 (3H, s), 3.95-4.02 (1H, m), 4.13-4.20 (1H, m), 4.58 ( 2H, d, J = 8.7Hz), 4.65 (1H, dd, J = 2.1, 10.8Hz), 6.70 (1H, s), 6.78-6.81 (1H, m), 7.13-7.16 (1H, m), 7.25 -7.30(1H, m), 7.80(2H, d, J=6.0Hz), 8.71(2H, d, J=6.0Hz) 390 B189 (DMSO-d ₆ ): 3.07-3.27 (m, 2H), 3.48 (s, 3H), 3.77 (d, J=13.2Hz, 1H), 3.93-4.02 (m, 2H), 4.13 (d, J= 10.2Hz, 1H), 5.03(d, J=8.7Hz, 1H), 7.13(s, 1H), 8.05(m, 1H), 8.55(d, J=6.3Hz, 2H), 8.61(d, J= 8.1Hz, 1H), 8.90(d, J=5.4Hz, 2H), 8.97(d, J=5.4Hz, 2H). 388

B190 (DMSO-d ₆ ): 3.09-3.23 (m, 2H), 3.47 (s, 3H), 3.68 (d, J=12.6Hz, 1H), 3.87-3.94 (m, 2H), 4.03 (d, J= 11.8Hz, 1H), 5.05(D, J-8.4Hz, 1H), 7.05(m, 1H), 7.08(s, 1H), 7.17(d, J=3.3Hz, 1H), 7.53(d, J= 5.1Hz, 1H), 8.44(d, J=6.4Hz, 2H), 8.93(d, J=6.4Hz, 2H). 354 B191 (DMSO-d ₆ ): 3.03-3.22(m, 2H), 3.45(s, 3H), 3.69-4.04(m, 4H), 4.80(d, J=10.4Hz, 1H), 7.03(s, 1H) , 7.19(m, 1H), 7.52-7.55(m, 2H), 8.39(d, J=5.4Hz, 2H), 8.90(d, J=5.4Hz, 2H). 354 B194 (DMSO-d ₆ ): 3.18(m, 1H), 3.50(s, 3H), 3.73-4.17(m, 5H), 5.03(d, J=8.4Hz, 1H), 7.15(s, 1H), 7.65 (m, 1H), 7.82(d, J=7.8Hz, 1H), 8.20(t, J=7.8Hz, 1H), 8.57(d, J=6.6Hz, 2H), 8.72(d, J=4.5Hz , 1H), 8.98 (d, J=6.6Hz, 2H). 349 B195 (DMSO-d ₆ ): 3.07-3.27 (m, 2H), 3.48 (s, 3H), 3.77 (d, J=13.2Hz, 1H), 3.93-4.02 (m, 2H), 4.13 (d, J= 10.2Hz, 1H), 5.03(d, J=8.7Hz, 1H), 7.13(s, 1H), 8.05(m, 1H), 8.55(d, J=6.3Hz, 2H), 8.61(d, J= 8.1Hz, 1H), 8.90(d, J=5.4Hz, 1H), 8.90(d, J=5.4Hz, 1H), 8.97(d, J=6.3Hz, 2H). 349 B200 (DMSO-d ₆ ): 3.30(s, 3H), 3.36(m, 2H), 3.88(m, 2H), 4.01(m, 2H), 7.10(s, 1H), 7.22-7.42(m, 10H) , 8.46(d, J=6.4Hz, 2H), 8.93(d, J=6.3Hz, 2H). 425 B202 (DMSO-d ₆ ): 1.60-2.00(m, 3H), 2.62-2.76(m, 3H), 3.18-3.29(m, 2H), 3.48(s, 3H), 3.68-3.83(m, 3H), 4.10-4.17(m, 1H), 7.03(s, 1H), 7.10-7.24(m, 3H), 7.63-7.66(m, 1H), 8.38(d, J=6.1Hz, 2H), 8.89(d, J=6.0Hz, 2H). 388 B203 (CDCl ₃ ): 2.20-2.40(m, 1H), 2.60-2.70(m, 1H), 2.80-3.00(m, 1H), 3.00-3.20(m, 1H), 3.29-3.50(m, 4H), 3.59(s, 3H), 4.03-3.20(m, 2H), 6.70(s, 1H), 7.27-7.36(m, 3H), 7.49-7.51(m, 1H), 7.78(dd, J=1.5, 4.8 Hz, 2H), 8.70 (dd, J=1.8, 4.5Hz, 2H). 374 B205 (DMSO-d ₆ ): 1.30(s, 3H), 1.44(s, 3H), 2.80-2.95(m, 2H), 3.51(s, 3H), 3.63-3.80(m, 2H), 5.07(m, 1H), 7.03(s, 1H), 7.30-7.48(m, 5H), 8.35(br s, 2H), 8.89(br s, 2H). 377 B217 (CDCl ₃ ): 1.39(s, 3H), 1.52(s, 3H), 2.89-3.03(m, 2H), 3.39(m, 1H), 3.59(s, 3H), 3.63(m, 1H), 3.82 (s, 3H), 5.00 (m, 1H), 6.69 (s, 1H), 6.93 (d, J = 8.7Hz, 2H), 7.37 (d, J = 8.7Hz, 2H), 7.79 (d, J = 6.0Hz, 2H), 8.71(d, J=6.0Hz, 2H). 407 B219 2.97(1H, dd, J=10.5, 12.9Hz), 3.30-3.39(1H, m), 3.53-3.66(1H, m), 3.60(3H, s), 3.75-3.89(1H, m), 3.82( 3H, s), 3.95-4.03(1H, m), 4.18-4.23(1H, m), 5.07(1H, d, J=9.6Hz), 6.71(1H, s), 6.79-6.85(1H, m) , 6.97-7.04 (1H, m), 7.07-7.10 (1H, m), 7.82 (2H, d, J=6.0Hz), 8.72 (2H, d, J=6.0Hz) (CDCl ₃ ) 396

B220 2.79(1H,dd,J=10.1,12.7Hz), 3.29-3.38(1H,m), 3.54-3.59(1H,m), 3.61(3H,s), 3.79-3.83(1H,m), 3.84( 3H, s), 3.94 3.99 (1H, m), 4.19-4.23 (1H, m), 5.02 (1H, dd, J=2.1, 10.1Hz), 6.69 (1H, s), 6.77 (1H, d, J=8.8Hz), 7.40(1H,dd, J=2.6,8.7Hz), 7.66(1H,d,J=2.3Hz), 7.82(2H,d,J=6.1Hz), 8.71(2H,d, J=6.1Hz) (CDCl ₃ ) 457 B221 (DMSO-d ₆ ): 1.40-1.60(m, 1H), 1.80-2.20(m, 2H), 2.60-3.00(m, 5H), 3.00-3.20(m, 1H), 3.45(s, 3H), 3.50-3.70(m, 2H), 3.73(d, J=11.4Hz, 1H), 3.81(d, J=12.6Hz, 1H), 3.98(d, J=12.3Hz, 1H), 7.01(s, 1H ), 7.02-7.10(m, 4H), 8.38(dm, J=6.6Hz, 2H), 8.88-8.92(m, 2H). 402 B225 (CDCl ₃ ): 3.3-3.5 (2H, m), 3.63 (3H, s), 3.5-3.7 (1H, m), 4.0-4.2 (2H, m), 4.2-4.3 (1H, m), 5.20 ( 1H, dd, J=2.7, 9.8Hz), 6.73(1H, s), 7.4-7.6(2H, m), 7.80(1H, d, J=6.3Hz), 7.94(1H, d, J=7.9Hz ), 8.03 (1H, d, J=8.0Hz), 8.71 (1H, d, J=6.3Hz) 406 B234 (DMSO-d ₆ ); 3.01(m, 1H), 3.17(m, 1H), 3.46(s, 3H), 3.70(m, 2H), 3.89(m, 1H), 4.05(d, J=12.0Hz , 1H), 4.65(d, J=8.7Hz, 1H), 6.02(s, 2H), 6.89-6.96(m, 2H), 7.01(s, 2H), 8.34(d, J=6.6Hz, 2H) , 8.87 (d, J=6.6Hz, 2H). 393

B235 (DMSO-d ₆ ); 2.99(dd, J=10.8Hz, 12.9Hz, 1H), 3.12(m, 1H), 3.46(s, 3H), 3.69(d, J=12.9, 2H), 3.87(m , 1H), 4.04(d, J=11.7Hz, 1H), 4.24(s, 4H), 4.62(d, J=9.0Hz, 1H), 6.83-6.94(m, 3H), 7.05(s, 1H) , 8.41(d, J=6.6Hz, 2H), 8.91(d, J=6.6Hz, 2H). 407 B236 (DMSO-d ₆ ); 3.04(m, 1H), 3.19(m, 1H), 3.47(s, 3H), 3.69-4.09(m, 6H), 3.75(s, 3H), 3.77(s, 3H) , 4.67(d, J=9.0Hz, 1H), 6.93-7.05(m, 4H), 8.38(d, J=6.3Hz, 2H), 8.89(d, J=6.3Hz, 2H). 409 B237 (DMSO-d ₆ ): 2.5-2.6 (1H, m), 2.9-3.2 (6H, m), 3.44 (3H, s), 3.4-3.8 (4H, s), 3.9-4.0 (1H, m), 6.99(1H, s), 7.1-7.2(2H, m), 7.2-7.3(2H, m), 7.88(1H, d, J=6.9Hz), 8.31(2H, d, J=6.3Hz), 8.00 (1H, s), 8.88 (2H, d, J=6.5Hz) 389 B238 (DMSO): 3.05 (1H, dd, J = 10.8, 12.8Hz), 3.15-3.26 (1H, m), 3.45 (3H, s), 3.65 (1H, d, J = 13.4Hz), 3.73-3.91 ( 2H, m), 3.79(3H, s), 4.05(1H, d, J=13.6Hz), 4.95(1H, d, J=8.9Hz), 6.82-6.89(3H, m), 7.43-7.49(1H , m), 7.98 (2H, d, J=5.9Hz), 8.68 (2H, d, J=5.8Hz) 397 B239 (DMSO): 2.88 (1H, dd, J = 10.2, 13.0Hz), 3.19-3.27 (1H, m), 3.47 (3H, s), 3.66 (1H, d, J = 13.4Hz), 3.85 (1H, d, J = 13.4Hz), 3.93 (1H, t, J = 11.6Hz), 4.11 (1H, d, J = 9.6Hz), 5.03 (1H, d, J = 8.5Hz), 6.84 (1H, s) , 7.50-7.54(1H, m), 7.63-7.67(2H, m), 7.97(2H, d, J=6.0Hz), 8.67(2H, d, J=5.9Hz) 417

B240 (CDCl ₃ ): 3.00 (1H, dd, J=12.9, 10.5Hz), 3.21-3.41 (3H, m), 3.55 (1H, m), 3.59 (3H, s), 3.83-4.21 (3H, m) , 4.61(2H, m), 4.95(1H, d, J=8.4Hz), 6.69(1H, s), 6.91(1H, m), 7.16-7.31(2H, m), 7.84(2H, dd, J =4.5, 1.5Hz), 8.71 (2H, dd, J=4.5, 1.5Hz). 391

B241 (DMSO-d ₆ ): 2.80 (1H, dd, J = 10.2, 12.9Hz), 3.1-3.3 (1H, m), 3.46 (3H, s), 3.6-3.7 (1H, m), 3.77 (3H, s), 3.82(3H, s), 3.7-3.9(2H, m), 4.0-4.1(1H, m), 4.9-5.0(1H, m), 6.5-6.6(2H, m), 6.82(1H, s), 7.3-7.4 (1H, m), 7.79 (2H, dd, J=1.5, 4.5Hz), 8.69 (2H, dd, J=1.5, 4.5Hz). 409 B242 (DMSO-d ₆ ): 2.80 (1H, dd, J = 10.2, 12.9Hz), 3.1-3.3 (1H, m), 3.46 (3H, s), 3.6-3.7 (1H, m), 3.77 (3H, s), 3.82(3H, s), 3.7-3.9(2H, m), 4.0-4.1(1H, m), 4.9-5.0(1H, m), 6.5-6.6(2H, m), 6.82(1H, s), 7.3-7.4 (1H, m), 7.79 (2H, dd, J=1.5, 4.5Hz), 8.69 (2H, dd, J=1.5, 4.5Hz). 409 B243 (DMSO-d ₆ ): 2.7-2.9 (1H, m), 3.1-3.3 (1H, m), 3.46 (3H, s), 3.6-3.7 (1H, m), 3.89 (3H, s), 3.90 ( 3H, s), 3.7-3.9 (2H, m), 4.0-4.1 (1H, m), 4.9-5.0 (1H, m), 6.80 (1H, s), 6.83 (1H, s), 7.51 (1H, s), 7.9-8.0 (2H, m), 8.6-8.7 (2H, m) 488 B244 (DMSO-d ₆ ): 2.80 (1H, dd, J = 10.2, 12.9Hz), 3.1-3.3 (1H, m), 3.46 (3H, s), 3.6-3.7 (1H, m), 3.77 (3H, s), 3.82(3H, s), 3.7-3.9(2H, m), 4.0-4.1(1H, m), 4.9-5.0(1H, m), 6.5-6.6(2H, m), 6.82(1H, s), 7.3-7.4 (1H, m), 7.79 (2H, dd, J=1.5, 4.5Hz), 8.69 (2H, dd, J=1.5, 4.5Hz). 409 B245 (CDCl ₃ ): 2.80(1H,dd,J=12.6,10.4Hz), 3.33(1H,m), 3.55(1H,m), 3.62(3H,s), 3.77(1H,m), 3.85(3H , s), 4.01(1H, m), 4.21(1H, m), 5.02(1H, d, J=9.6Hz), 6.61-6.75(3H, m), 7.48(1H, m), 7.82(2H, d, J=5.7Hz), 8.71 (2H, d, J=5.7Hz). 397

B246 (CDCl ₃ ): 3.18 (1H, dd, J = 12.3, 10.1Hz), 3.35 (1H, m), 3.59 (1H, m), 3.60 (3H, s), 3.72 (1H, m), 3.98-4.23 (2H, m), 4.79 (1H, d, J=10.5), 6.71 (1H, s), 7.36-7.66 (9H, m), 7.80 (2H, d, J=5.7Hz), 8.72 (2H, d , J=5.7Hz). 425 B247 (CDCl ₃ ): 0.32-0.34 (2H, m), 0.62-0.67 (2H, m), 1.22 (1H, m), 2.76 (1H, dd, J=12.6, 10.2Hz), 3.37 (1H, m) , 3.60-4.25(7H, m), 3.65(3H, s), 5.02(1H, d, J=9.3Hz), 6.54-6.72(3H, m), 7.47(1H, dd, J=8.1, 7.2Hz ), 7.81 (2H, d, J=6.0Hz), 8.71 (2H, d, J=6.0Hz). 437 B248 (CDCl ₃ ): 1.33 (3H, d, J = 6.0Hz), 1.38 (3H, d, J = 6.0Hz), 2.72 (1H, dd, J = 12.6, 10.2Hz), 3.35 (1H, m), 3.57-3.72(5H, m), 4.03-4.25(2H, m), 4.57(1H, m), 4.95(1H, d, J=8.7Hz), 6.58-6.71(3H, m), 7.46(1H, dd, J=8.4, 7.2Hz), 7.80 (2H, d, J=6.0Hz), 8.71 (2H, d, J=6.0Hz). 425 B249 (DMSO): 2.98 (1H, dd, J = 10.5, 13.0Hz), 3.18-3.30 (1H, m), 3.47 (3H, s), 3.66 (1H, d, J = 12.5Hz), 3.80 (1H, d, J=13.0Hz), 3.84(3H,s), 3.92(1H,dd,J=9.5,11.7Hz), 4.18(1H,d,J=11.7Hz), 5.01(1H,dd,J=2.0 , 10.4Hz), 6.84(1H, s), 7.50(1H, d, J=2.6Hz), 7.67(1H, d, J=2.7Hz), 7.99(2H, d, J=6.2Hz), 8.69( 2H,d,J=6.1Hz) 447

B250 (DMSO): 3.01 (1H, dd, J=10.8, 12.9Hz), 3.14-3.18 (1H, m), 3.46 (3H, s), 3.66-3.76 (2H, m), 3.86-3.93 (1H, m ), 4.06 (1H, d, J = 11.7Hz), 4.74 (1H, d, J = 8.7Hz), 6.84 (1H, s), 6.98-7.04 (4H, m), 7.11-7.18 (1H, m) , 7.37-7.48 (4H, m), 7.97 (2H, d, J=6.3Hz), 8.69 (2H, d, J=6.0Hz) 441

B251 (CDCl ₃ ): 3.06 (1H, dd, J=12.9, 10.5Hz), 3.42 (1H, m), 3.60 (1H, m), 3.67 (3H, s), 4.07-4.32 (3H, m), 5.38 (1H, d, J = 10.2Hz), 6.73 (1H, s), 7.45-7.61 (2H, m), 7.82 (1H, d, J = 9.0Hz), 7.89 (2H, d, J = 6.0Hz) , 8.72 (2H, d, J=6.0Hz). 391 B252 (CDCl ₃ ): 3.3-3.7 (4H, m), 3.58 (3H, s), 3.96 (1H, t, J=11.7Hz), 4.17 (1H, dd, J=4.5, 8.3Hz), 6.70 (1H , s), 7.0-7.1 (1H, m), 7.2-74 (2H, m), 7.82 (2H, d, J=5.7Hz), 8.71 (2H, d, J=5.6Hz) 401 B253 (CDCl ₃ ): 2.81 (1H, dd, J=10.5, 12.8Hz), 3.3-3.4 (1H, m), 3.5-3.7 (2H, m), 3.63 (3H, s), 3.7-3.9 (1H, m), 4.03(1H, dt, J=2.2, 11.6Hz), 4.2-4.3(1H, m), 5.0-5.1(1H, m), 6.71(1H, s), 7.0-7.2(2H, m) , 7.63 (1H, dd, J=6.3, 8.7Hz), 7.80 (2H, d, J=6.0Hz), 8.71 (2H, d, J=5.6Hz). 401 B254 (DMSO): 2.89 (1H, dd, J = 10.2, 12.8Hz), 3.19-3.30 (1H, m), 3.49 (3H, s), 3.67 (1H, d, J = 13.0Hz), 3.86-3.95 ( 2H, m), 3.89 (3H, s), 4.13 (1H, d, J=9.8Hz), 5.07 (1H, d, J=8.4Hz), 6.84 (1H, s), 7.15 (1H, d, J =8.6Hz), 7.29-7.37(1H, m), 7.42-7.48(2H, m), 7.60-7.63(3H, m), 7.72(1H, d, J=2.3Hz), 8.00(2H, d, J=6.1Hz), 8.69 (2H, d, J=6.0Hz) 455 B255 (DMSO): 2.85 (1H, dd, J = 10.2, 12.9Hz), 3.19-3.28 (1H, m), 3.49 (3H, s), 3.67 (1H, d, J = 12.3Hz), 3.85-3.95 ( 2H, m), 3.88 (3H, s), 4.13 (1H, d, J=9.7Hz), 5.06 (1H, d, J=8.3Hz), 6.84 (1H, s), 7.14 (1H, d, J =8.6Hz), 7.21-7.30(2H, m), 7.57-7.70(4H, m), 8.00(2H, d, J=6.1Hz), 8.69(2H, d, J=6.1Hz) 473

B256 (DMSO): 2.93 (1H, dd, J = 10.3, 13.0Hz), 3.19-3.31 (1H, m), 3.49 (3H, s), 3.68 (1H, d, J = 12.6Hz), 3.86-3.95 ( 2H, m), 3.90 (3H, s9), 4.13 (1H, d, J=9.5Hz), 5.08 (1H, d, J=8.3Hz), 6.84 (1H, s), 7.20 (1H, d, J =8.6Hz), 7.41-7.50(1H, m), 7.66-7.70(1H, m), 7.76(1H, d, J=2.4Hz), 8.00(2H, d, J=6.2Hz), 8.00-8.04 (1H, m), 8.50-8.54 (1H, m), 8.69 (2H, d, J=6.1Hz), 8.85 (1H, d, J=2.0Hz) 456 B257 (DMSO): 2.99 (1H, dd, J=10.8, 12.9Hz), 3.10-3.21 (1H, m), 3.46 (3H, s), 3.66-3.77 (2H, m), 3.87-3.95 (1H, m ), 4.08(1H, d, J=11.7Hz), 4.76(1H, d, J=8.4Hz), 6.85(1H, s), 7.28-7.33(1H, m), 7.41-7.56(2H, m) , 7.96 (2H, d, J=6.0Hz), 8.69 (2H, d, J=6.0Hz) 385 B258 (DMSO): 2.99 (1H, dd, J = 10.7, 12.6Hz), 3.13-3.22 (1H, m), 3.46 (3H, s), 3.67-3.77 (2H, m), 3.87-3.95 (1H, m ), 4.08(1H, d, J=11.5Hz), 4.76(1H, d, J=9.2Hz), 6.86(1H, s), 7.41(1H, t, J=8.6Hz), 7.48-7.54(1H , m), 7.72-7.81 (1H, m), 7.98 (2H, d, J=5.9Hz), 8.69 (2H, d, J=5.9Hz) 445 B259 (DMSO-d ₆ ): 1.23 (6H, d, J=5.9Hz), 2.7-2.9 (1H, m), 3.1·3.3 (1H, m), 3.47 (3H, s), 3.6-3.7 (1H, m), 3.7-4.0(2H, m), 3.78(3H, s), 4.0-4.1(1H, m), 4.4-4.6(1H, m), 4.9-5.0(1H, m), 6.8-7.0( 4H, m), 8.00 (2H, d, J=5.3Hz), 8.69 (2H, d, J=5.6Hz) 437

B260 (DMSO-d ₆ ): 2.17(3H, s), 2.22(3H, s), 2.7-2.8(1H, m), 3.1-3.2(1H, m), 3.46(3H, s), 3.6-3.7( 1H, m), 3.7-3.9 (2H, m), 3.79 (3H, s), 4.0-4.1 (1H, m), 6.84 (2H, s), 7.19 (1H, s), 7.99 (2H, d, J=5.0Hz), 8.69 (2H, d, J=4.7Hz) 407 B261 (DMSO-d ₆ ): 1.27 (6H, d, J=5.1Hz), 2.7-2.9 (1H, m), 3.1-3.3 (1H, m), 3.46 (3H, s), 3.6-4.0 (3H, m), 3.84(3H, s), 4.0-4.1(1H, m), 4.6-4.7(1H, m), 4.9-5.0(1H, m), 6.5-6.6(2H, m), 6.84(1H, s), 7.2-7.3 (1H, m), 7.99 (2H, d, J=6.0Hz), 8.69 (2H, d, J=6.0Hz) 437 B262 (DMSO-d ₆ ): 2.7-2.9 (1H, m), 3.2-3.3 (1H, m), 3.47 (3H, s), 3.6-3.7 (1H, m), 3.8-4.0 (5H, m), 4.1-4.2(1H, m), 5.0-5.1(1H, m), 6.86(1H, s), 7.26(1H, d, J=8.5Hz), 7.78(1H, s), 7.84(1H, d, J=8.5Hz), 8.00(2H, d, J=5.7Hz), 8.70(2H, d, J=5.6Hz) 404 B263 (CDCl ₃ ): 1.40 (3H, t, J = 6.9Hz), 3.38-3.47 (3H, m), 3.86 (6H, s), 3.91-4.17 (5H, m), 5.44 (1H, dd, J = 10.8, 2.1Hz), 6.60 (1H, d, J = 8.4Hz), 6.67 (1H, s), 7.24-7.30 (2H, m), 7.84 (2H, d, J = 6.0Hz), 8.70 (2H, d, J=6.0Hz). 423 B264 (CDCl ₃ ): 0.95 (3H, t, J=7.2Hz), 1.77-1.86 (2H, m), 3.34-3.47 (2H, m), 3.89 (6H, s), 3.92-4.48 (5H, m) , 5.44 (1H, d, J = 8.4Hz), 6.60 (1H, d, J = 8.4Hz), 6.67 (1H, s), 7.24-7.30 (2H, m), 7.84 (2H, d, J = 6.0 Hz), 8.70 (2H, d, J=6.0Hz). 437

B265 (DMSO-d ₆ ): 1.30 (3H, t, J = 6.6Hz), 2.97-4.10 (8H, m), 4.78 (1H, d, J = 9.6Hz), 7.08 (1H, s), 7.19-7.25 (2H, m), 7.48-7.54 (2H, m), 8.35 (2H, d, J=6.0Hz), 8.88 (2H, d, J=6.0Hz). 381 B266 (DMSO-d ₆ ): 0.88(3H,t,J=7.2Hz), 1.69-1.77(2H,m), 1.26(1H,m), 3.00-3.26(2H,m), 3.59(2H,m) , 3.88-4.12(3H, m), 4.78(1H, d, J=9.6Hz), 7.08(1H, s), 7.20-7.26(2H, m), 7.49-7.54(2H, m), 8.36(2H , d, J=6.0Hz), 8.90(2H, d, J=6.0Hz). 395 B267 (CDCl ₃ ): 0.39-0.43 (2H, m), 0.53-0.58 (2H, m), 1.26 (1H, m), 3.09 (1H, dd, J=12.6, 10.8Hz), 3.29-3.51 (3H, m), 3.92(1H, m), 3.61(3H, s), 3.77(1H, m), 3.85(3H, s), 3.99(1H, m), 4.21(1H, m), 5.01(1H, dd , J = 9.9, 1.8Hz), 6.63 (1H, dd, J = 10.8, 2.4Hz), 6.69 (1H, s), 6.72 (1H, m), 7.48 (1H, dd, J = 8.4, 6.9Hz) , 7.82 (2H, dd, J=4.8, 1.8Hz), 8.71 (2H, dd, J=4.8, 1.8Hz). 407 B268 (CDCl ₃ ): 3.3-3.4 (1H, m), 3.5-3.6 (2H, m), 3.59 (3H, s), 3.83 (3H, s), 3.9-4.1 (2H, m), 4.1-4.2 ( 1H, m), 4.96 (1H, dd, J=2.4, 10.2Hz), 6.50 (1H, s), 6.73 (1H, s), 6.9-7.1 (1H, m), 7.2-7.3 (2H, m) , 7.81 (2H, dd, J=1.5, 4.5Hz), 8.74 (2H, dd, J=1.2, 4.5Hz) 420 B269 (DMSO-d ₆ ): 2.78 (1H, dd, J = 10.2, 12.8Hz), 3.1-3.3 (1H, m), 3.47 (3H, s), 3.6-3.7 (1H, m), 3.8-4.0 ( 5H, m), 4.0-4.1 (1H, m), 4.9-5.0 (1H, m), 6.84 (1H, s), 7.06 (1H, dd, J=2.0, 8.2Hz), 7.13 (1H, d, J = 2.0Hz), 7.44 (1H, d, J = 8.2Hz), 7.99 (2H, dd, J = 1.6, 4.7Hz), 8.69 (2H, dd, J = 1.6, 4.7Hz) 413

B270 (DMSO-d ₆ ): 3.1-3.3 (1H, m), 3.42 (3H, s), 3.5-3.6 (1H, m), 3.6-3.7 (2H, m), 3.7-3.9 (1H, m), 3.86(3H,s), 3.9-4.0(1H,m), 5.1-5.2(1H,m), 6.8-7.0(3H,m), 7.9-8.0(2H,m), 8.6-8.7(2H,m ) 415

B271 (CDCl ₃ ): 3.3-3.51H, m), 3.5-3.7(2H, m), 3.61(3H, s), 3.9-4.3(3H, m), 5.35(1H, dd, J=2.8, 9.8Hz ), 6.73(1H, s), 7.3-7.4(1H, m), 7.6-7.7(2H, m), 7.80(2H, dd, J=1.5, 4.7Hz), 7.96(1H, d, J=8.1 Hz), 8.71 (2H, dd, J=1.5, 4.7Hz) 390 B272 (DMSO-d ₆ ): 2.7-2.8 (1H, m), 3.2-3.3 (1H, m), 3.47 (3H, s), 3.6-3.7 (1H, m), 3.8-4.0 (5H, m), 4.1-4.2(1H, m), 5.0-5.1(1H, m), 6.84(1H, s), 7.48(1H, d, J=8.1Hz), 7.54(1H, s), 7.62(1H, d, J=8.1Hz), 7.99(2H, dd, J=1.2, 4.5Hz), 8.70(2H, d, J=1.2, 4.5Hz) 404 B273 (DMSO-d ₆ ): 2.8-2.9 (1H, m), 3.1-3.3 (1H, m), 3.49 (3H, s), 3.6-3.8 (1H, m), 3.8-4.0 (5H, m), 4.1-4.2(1H, m), 5.0-5.1(1H, m), 6.86(1H, s), 7.2-7.6(5H, m), 7.72(2H, d, J=7.5Hz), 8.01(2H, d, J=6.3Hz), 8.70 (2H, d, J=6.0Hz) 455 B274 (CDCl ₃ ): 1.9-2.1 (4H, m), 2.83 (1H, dd, J=10.2, 12.6Hz), 3.2-3.5 (5H, m), 3.5-3.7 (1H, m), 3.62 (3H, s), 3.79(3H, s), 3.8-3.9(1H, m), 3.9-4.1(1H, m), 4.2-4.3(1H, m), 5.0-5.1(1H, m), 6.49(1H, dd, J=3.0, 9.0Hz), 6.68(1H, s), 6.8-6.9(2H, m), 7.82(2H, d, J=6.0Hz), 8.71(2H, d, J=6.0Hz) 448 B275 (CDCl ₃ ): 1.9-2.1 (4H, m), 2.89 (1H, dd, J=10.3, 12.8Hz), 3.2-3.4 (5H, m), 3.5-3.6 (1H, m), 3.60 (3H, s), 3.75(3H, s), 3.7-3.8(1H, m), 3.9-4.1(1H, m), 4.1-4.3(1H, m), 4.99(1H, dd, J=2.1, 10.2Hz) , 6.08(1H, d, J=2.1Hz), 6.21(1H, dd, J=2.0, 8.5Hz), 6.68(1H, s), 7.31(1H, d, J=8.5Hz), 7.82(2H, dd, J=1.6, 4.6Hz), 8.71 (2H, dd, J=1.6, 4.6Hz) 448

B276 (DMSO): 2.84 (1H, dd, J = 10.5, 12.8Hz), 3.19-3.26 (1H, m), 3.49 (3H, s), 3.66 (1H, d, J = 12.7Hz). 3.88-3.94 ( 2H, m), 3.90(3H, s), 4.12(1H, d, J=10.3Hz), 5.06(1H, d, J=9.2Hz), 6.85(1H, s), 7.17(1H, d, J =8.6Hz), 7.26-7.33(2H, m), 7.36-7.40(1H, m), 7.48-7.53(2H, m), 7.63(1H, s), 8.01(2H, d, J=5.7Hz) , 8.69 (2H, d, J = 5.6Hz) 473 B277 (DMSO): 2.90 (1H, dd, J = 10.3, 12.8Hz), 3.26-3.29 (1H, m), 349 (3H, s), 3.67 (1H, d, J = 13.1Hz), 3.82 (3H, s), 3.85-3.94(2H, m), 3.89(3H, s), 4.14(1H, d, J=9.6Hz), 5.06(1H, d, J=8.7Hz), 6.85(1H, s), 6.90-6.93(1H, m), 7.12-7.19(3H, m), 7.34-7.39(1H, m), 7.60-7.64(1H, m), 7.71(1H, d, J=2.1Hz), 8.01( 2H, d, J=6.0Hz), 8.69 (2H, d, J=5.9Hz) 485 B278 DMSO): 2.84 (1H, dd, J = 10.5, 12.6Hz), 3.18-3.25 (1H, m), 3.48 (3H, s), 3.66 (1H, d, J = 13.2Hz), 3.86-3.93 (2H , m), 3.90 (3H,;), 4.10 (1H, d, J = 10.2Hz), 5.07 (1H, d, J = 9.0Hz), 6.85 (1H, s), 7.16 (1H, d, J = 8.7Hz), 7.39-7.45(2H, m), 7.50-7.52(2H, m), 7.72(1H, d, J=1.8Hz), 8.01(2H, d, J=5.4Hz), 8.70(2H, d, J=5.4Hz) 523

B279 DMSO): 1.52-1.71 (4H, m), 2.32-2.43 (4H, m), 2.76 (1H, dd, J=10.2, 12.9Hz), 3.18-3.25 (1H, m), 3.47 (3H, s) , 3.54(2H, d, J=3.9Hz), 3.65(1H, d, J=12.9Hz), 3.81-3.91(2H, m), 3.82(3H, s), 4.10(1H, d, J=9.9 Hz), 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), 6.00(2H, d, J=6.0Hz), 8.69(2H, d, J=6.0Hz) 462

B280 (DMSO): 3.11 (1H, dd, J = 10.3, 12.6Hz), 3.41-3.48 (1H, m), 3.67 (3H, s), 3.86 (1H, d, J = 12.7Hz), 4.03-4.13 ( 2H, m), 4.08(3H, s), 4.32(1H, d, J=11.0Hz), 5.25(1H, d, J=8.6Hz), 7.04(1H, s), 7.33-7.36(2H, m ), 7.60-7.70 (3H, m), 7.86 (1H, dd, J=2.4, 8.5Hz), 7.93 (1H, d, J=2.3Hz), 8.19 (2H, d, J=6.1Hz), 8.88 (2H, d, J=6.0Hz) 473 B281 (DMSO): 2.83 (1H, dd, J = 10.2, 12.9Hz), 3.14-3.25 (1H, m), 3.49 (3H, s), 3.66 (1H, d, J = 12.6Hz), 3.76 (3H, s), 3.84-3.93(2H, m), 3.87(3H, s), 4.10(1H, d, J=11.4Hz), 5.04(1H, d, J=8.7Hz), 6.85(1H, s), 6.98-7.03(1H, m), 7.07-7.11(2H, m), 7.25-7.34(2H, m), 7.41-7.47(1H, m), 7.53(1H, d, J=2.4Hz), 8.01( 2H, d, J=6.3Hz), 8.70 (2H, d, J=6.0Hz) 485 B282 (DMSO): 2.88 (1H, dd, J = 10.3, 12.9Hz), 3.18-3.28 (1H, m), 3.48 (3H, s), 3.67 (1H, d, J = 12.8Hz), 3.79 (3H, s), 3.85-3.94(2H, m), 3.87(3H, s), 4.13(1H, d, J=11.6Hz), 5.05(1H, d, J=8.4Hz), 6.85(1H, s), 7.01 (1H, d, J = 8.8Hz), 7.11 (1H, d, J = 8.7Hz), 7.53-7.56 (3H, m), 7.66 (1H, d, J = 2.3Hz), 8.00 (2H, d , J=6.1Hz), 8.69 (2H, d, J=6.0Hz) 485

B283 (DMSO): 2.77 (1H, dd, J = 10.2, 12.8Hz), 3.10-3.21 (1H, m), 3.47 (3H, s), 3.65 (1H, d, J = 12.9Hz), 3.80 (3H, s), 3.84-3.92 (2H, m), 4.04-4.10 (1H, m), 4.98 (1H, d, J=8.4Hz), 6.68-6.73 (1H, m), 6.85 (1H, s), 6.92 -6.98(3H, m), 7.01-7.08(1H, m), 7.14-7.20(2H, m), 7.23(1H, d, J=2.6Hz), 7.94(1H, s), 8.01(2H, d , J=6.1Hz), 8.69 (2H, d, J=6.1Hz) 470 B284 (CDCl ₃ ): 3.37-3.54 (3H, m), 3.59 (3H, s), 3.88 (1H, m), 4.03 (1H, m), 4.18 (1H, m), 4.99 (1H, dd, J = 10.2, 2.4Hz), 6.73(1H, s), 6.78(1H, s), 7.25-7.33(2H, m), 7.49-7.58(2H, m), 7.81(2H, dd, J=4.5, 1.8Hz ), 8.72 (dd, J=4.5, 1.8Hz). 389 B285 (CDCl ₃ ): 2.80(1H,dd,J=12.9,10.2Hz), 3.35(1H,m), 3.55(1H,m), 3.61(3H,s), 3.77(1H,m), 3.85(3H , s), 3.99(1H, m), 4.21(1H, m), 5.01(1H, dd, J=9.9, 1.8Hz), 6.63(1H, dd, J=10.8, 2.4Hz), 6.69(1H, s), 6.72 (1H, m), 7.48 (1H, dd, J = 8.4, 6.9Hz), 7.82 (2H, dd, J = 4.8, 1.8Hz), 8.71 (2H, dd, J = 4.8, 1.8Hz ). 397 B286 (CDCl ₃ ): 3.33-3.53 (3H, m), 3.58 (3H, s), 3.88 (1H, m), 3.98 (1H, m), 4.01 (3H, s), 4.18 (1H, m), 5.00 (1H, m), 6.72 (1H, s), 6.77 (1H, s), 6.82 (1H, m), 7.16-7.19 (2H, m), 7.83 (2H, d, J=6.0Hz), 8.72 ( 2H, d, J=6.0Hz). 419

B287 (DMSO-d ₆ ): 1.9-2.1 (4H, m), 2.9-3.2 (3H, m), 3.2-3.5 (3H, m), 3.51 (3H, s), 3.72 (1H, d, J=11.7 Hz), 3.90(3H, s), 3.8-4.1(2H, m), 4.14(1H, d, J=12.9Hz), 4.41(2H, d, J=5.4Hz), 5.08(1H, d, J =9.6Hz), 7.08(1H, s), 7.18(1H, d, J=8.7Hz), 7.4-7.6(1H, m), 7.6-7.8(2H, m), 7.79(1H, s), 7.96 (1H, s), 8.46 (2H, d, J=6.0Hz), 8.93 (2H, d, J=5.4Hz), 11.5 (1H, brd) 538

B288 (CDCl ₃ ): 1.9-2.1 (4H, m), 3.17 (1H, dd, J=10.5, 12.9Hz), 3.3-3.4 (5H, m), 3.5-3.6 (1H, m), 3.57 (3H, s), 3.7-3.8(1H, m), 3.9-4.1(1H, m), 4.1-4.2(1H, m), 4.69(1H, dd, J=2.1, 10.5Hz), 6.73(1H, s) , 6.54(1H, m), 6.60(1H, d, J=1.2Hz), 6.6-6.7(2H, m), 7.2-7.3(1H, m), 7.81(2H, dd, J=1.5, 4.5Hz) , 8.71 (2H, dd, J=1.8, 4.5Hz) 418 B289 (CDCl ₃ ): 1.9-2.1 (4H, m), 3.17 (1H, dd, J=10.5, 12.9Hz), 3.3-3.4 (5H, m), 3.5-3.6 (1H, m), 3.57 (3H, s), 3.7-3.8(1H, m), 3.9-4.1(1H, m), 4.1-4.2(1H, m), 4.69(1H, dd, J=2.1, 10.5Hz), 6.73(1H, s) , 6.54(1H, m), 6.60(1H, d, J=1.2Hz), 6.6-6.7(2H, m), 7.2-7.3(1H, m), 7.81(2H, dd, J=1.5, 4.5Hz) , 8.71 (2H, dd, J=1.8, 4.5Hz) 418 B290 (CDCl ₃ ): 2.87(1H, m), 3.38(1H, m), 3.58(1H, m), 3.64(3H, s), 3.84(1H, m), 3.91(3H, s), 4.03(1H , m), 4.22(1H, m), 5.11(1H, m), 6.70(1H, s), 7.08-7.46(6H, m), 7.60(1H, d, J=5.1Hz), 7.83(2H, d, J=6.0Hz), 8.72 (2H, d, J=6.0Hz). 473 B291 (CDCl ₃ ): 2.86(1H,dd,J=12.9,10.2Hz), 3.38(1H,m), 3.57(1H,m), 3.64(3H,s), 3.88(1H,m), 3.93(3H , s), 4.02(1H, m), 4.26(1H, m), 5.10(1H, m), 6.70(1H, s), 7.05-7.07(2H, m), 7.21-7.42(4H, m), 7.60(1H,d,J=4.8Hz), 7.83(2H,dd,J=4.5,1.2Hz), 8.72(2H,dd,J=4.5,1.2Hz). 473 B292 (CDCl ₃ ): 2.86(1H,dd,J=12.9,10.2Hz), 3.35(1H,m), 3.57(1H,m), 3.64(3H,s), 3.88(1H,m), 3.93(3H , s), 4.02(1H, m), 4.22(1H, m), 5.10(1H, m), 6.70(1H, s), 7.04(1H, s), 7.10-7.23(3H, m), 7.52- 7.60(3H, m), 7.83(2H, d, J=6.0Hz), 8.72(2H, d, J=6.0Hz). 473

B293 (DMSO): 2.86 (1H, dd, J = 10.2, 12.8Hz), 3.22-3.30 (1H, m), 3.49 (3H, S), 3.68 (1H, d, J = 12.1Hz), 3.87-3.96 ( 2H, m), 3.91 (3H, s), 4.16 (1H, d, J = 11.9Hz), 5.07 (1H, d, J = 8.7Hz), 6.85 (1H, s), 7.16 (1H, d, J =8.7Hz), 7.27-7.32(1H, m), 7.81-7.94(2H, m), 7.99-8.05(3H, m), 8.26(1H, d, J=2.3Hz), 8.63-8.65(1H, m), 8.69 (2H, d, J=6.0Hz) 456 B294 (DMSO): 2.90 (1H, dd, J = 10.5, 12.9Hz), 3.20-3.29 (1H, m), 3.49 (3H, s), 3.68 (1H, d, J = 12.3Hz), 3.84-3.92 ( 2H, m), 3.91(3H, s), 3.95(3H, s), 4.15(1H, d, J=12.0Hz), 5.07(1H, d, J=9.0Hz), 6.73(1H, d, J =8.1Hz), 6.85(1H, s), 7.17(1H, d, J=8.7Hz), 7.48(1H, d, J=7.5Hz), 7.76(1H, t, J=7.8Hz), 8.01( 2H, d, J = 6.0Hz), 8.07 (1H, dd, J = 2.1, 8.7Hz), 8.15 (1H, d, J = 2.1Hz), 8.69 (1H, d, J = 6.0Hz) 486 B295 (DMSO): 2.91 (1H, dd, J = 10.2, 12.8Hz), 3.21-3.28 (1H, m), 3.48 (3H, s), 3.67 (1H, d, J = 12.5Hz), 3.84-3.94 ( 2H, m), 3.88(3H, s), 3.89(3H, s), 4.12(1H, d, J=9.9Hz), 5.06(1H, d, J=8.5Hz), 6.85(1H, s), 6.90 (1H, d, J = 8.7Hz), 7.15 (1H, d, J = 8.6Hz), 7.58-7.63 (1H, m), 7.67 (1H, d, J = 2.4Hz, ), 7.94-7.98 ( 1H, m), 8.01 (2H, d, J=6.1Hz), 8.42 (1H, d, J=2.3Hz), 8.69 (2H, d, J=6.2Hz) 486

B296 (DMSO): 2.84 (1H, dd, J = 10.5, 12.6Hz), 3.18-3.25 (1H, m), 3.48 (3H, s), 3.62 (1H, d, J = 13.2Hz), 3.85·3.99 ( 2H, m), 3.87 (3H, s), 3.94 (6H, s), 4.11 (1H, d, J=10.2Hz), 5.04 (1H, d, J=9.6Hz), 6.85 (1H, s), 7.12 (1H, d, J = 8.7Hz), 7.46 (1H, d, J = 8.4Hz), 7.56 (1H, s), 8.00 (2H, d, J = 4.8Hz), 8.32 (1H, s), 8.70(2H, d, J=5.1Hz) 487 B297 (CDCl ₃ ): 2.2-2.4 (1H, m), 2.4-2.6 (1H, m), 3.3-3.4 (1H, m), 3.5-3.8 (3H, m), 3.58 (3H, s), 3.9- 4.1 (1H, m), 4.1-4.3 (2H, m), 4.5-4.6 (1H, m), 6.711H, 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 (2Hdd, J =1.8, 6.6Hz) 391 B298 (CDCl ₃ ): 1.8-2.0 (3H, m), 2.3-2.4 (1H, m), 3.2-3.4 (1H, m), 3.44 (3H, s) 3.5-3.6 (1H, m), 3.7-3.9 (3H, m), 4.1-4.2 (1H, m), 4.2-4.4 (2H, m), 6.66 (1H, s), 7.02 (1H, dd, J=1.2, 8.1Hz), 7.14 (1H, t , J=7.2Hz), 7.22 (1H, dd, J=1.8, 7.5Hz), 7.59 (1H, dd, J=1.8, 7.8Hz), 7.79 (2H, dd, J=1.5, 4.5Hz), 8.71 (2H, dd, J=1.5, 4.5Hz) 405 C001 (CDCl ₃ ): 1.79-1.95 (m, 3H), 2.14 (m, 1H), 3.08 (m, 1H), 3.26 (dd, J=12.6, 7.2Hz, 1H), 3.53 (s, 3H), 3.65 (m, 1H), 3.82-3.96(m, 2H), 6.65(s, 1H), 7.47(t, J=7.8Hz, 2H), 7.61(t, J=7.5Hz, 1H), 7.79(d, J=6.0Hz, 2H), 8.02(d, J=7.5Hz, 2H), 8.70(d, J=6.0Hz, 2H). 374

C002 (CDCl ₃ ): 1.81-1.92(m, 3H), 2.12(m, 1H), 3.08(m, 1H), 3.25(m, 1H), 3.52(s, 3H), 3.64(m, 1H), 3.75 -3.92(m, 2H), 6.65(s, 1H), 7.12(t, J=8.4Hz, 2H), 7.84(m, 1H), 8.03(dd, J=7.8, 5.7Hz, 2H), 8.76( m, 1H). 392 C005 (CDCl ₃ ): 1.65-1.93(m, 3H), 2.13(m, 1H), 3.08(m, 1H), 3.25(dd, J=12.9, 10.5Hz, 1H), 3.53(s, 3H), 3.65 (m, 1H), 3.88(s, 3H), 3.77-3.94(m, 2H), 6.65(s, 1H), 6.93(dd, J=9.6, 1.2Hz, 2H), 7.80(d, J=6.0 Hz, 2H), 8.00(dd, J=9.9, 1.2Hz, 2H), 8.70(d, J=6.0Hz, 2H). 405 C006 (CDCl ₃ ): 1.69-1.92(m, 3H), 2.12(m, 1H), 3.06(m, 1H), 3.21(dd, J=12.9, 10.2Hz, 1H), 3.50(s, 3H), 3.60 -3.83(m, 3H), 3.86(s, 3H), 6.66(s, 1H), 6.96-7.05(m, 2H), 7.45-7.57(m, 2H), 7.79(d, J=4.5Hz, 2H ), 8.69 (d, J=4.8Hz, 2H). 405 C067 (CDCl ₃ ): 1.83-2.14(m, 4H), 2.77(m, 1H), 3.06(m, 1H), 3.37(m, 1H), 3.45(s, 3H), 3.58(m, 1H), 3.90 (m, 1H), 6.64(s, 1H), 7.13(m, 1H), 7.33(m, 2H), 7.53(d, J=8.2Hz, 2H), 7.64(m, 1H), 7.79(d, J=5.8Hz, 2H), 8.70(d, J=5.7Hz, 2H). 390 C091 (CDCl ₃ ): 1.81-2.01 (6H, m), 2.70-2.75 (2H, m), 3.00 (1H, m), 3.25-3.92 (6H, m), 3.35 (3H, s), 6.61 (1H, s), 7.12-7.26(4H, m), 7.72(2H, d, J=6.0Hz), 8.69(2H, d, J=6.0Hz). 430 C092 (DMSO-d ₆ ): 1.48-1.89 (m, 10H), 2.92-3.07 (m, 4H), 3.41 (s, 3H), 3.42-3.72 (m, 5H), 6.97 (s, 1H), 8.38 ( d, J=5.1Hz, 2H), 8.92(d, J=5.1Hz, 2H). 382

C094 (CDCl ₃ ): 1.74-2.05(m, 4H), 3.08(m, 2H), 3.28(m, 1H), 3.51(s, 3H), 3.59-3.80(m, 10H), 6.63(s, 1H) , 7.76(d, J=4.8Hz, 2H), 8.71(d, J=4.8Hz, 2H). 384 C101 (CDCl ₃ ): 3.37-3.50(m, 3H), 3.57(s, 3H), 3.90-4.00(m, 2H), 4.10-4.19(m, 1H), 5.14(dd, J=2.7, 9.3Hz, 1H), 6.70(s, 1H), 7.48(t, J=7.8Hz, 2H), 7.63(t, J=7.5Hz, 1H), 7.79(dd, J=1.5, 4.8Hz, 2H), 8.06( dd, J=1.2, 7.2Hz, 2H), 8.73 (dd, J=1.8, 6.3Hz, 2H). 377 C102 (CDCl ₃ ): 3.30-3.50(m, 3H), 3.58(s, 3H), 3.85-4.17(m, 3H), 5.04(dd, J=2.7, 9.3Hz, 1H), 6.07(s, 1H) , 7.14(dd, J=7.2, 8.7Hz, 2H), 7.78(dd, J=1.5, 4.8Hz, 2H), 8.11(m, 2H), 8.73(dd, J=1.5, 4.5Hz, 2H). 395 C105 (CDCl ₃ ): 1.65-1.93 (3H, m), 2.13 (1H, m), 3.08 (1H, m), 3.25 (1H, dd, J=12.9, 10.5Hz), 3.53 (3H, s), 3.65 (1H, m), 3.88 (3H, s), 3.77-3.94 (2H, m), 6.65 (1H, s), 6.93 (2H, dd, J=9.6, 1.2Hz), 7.80 (2H, d, J =6.0Hz), 8.00(2H,dd,J=9.9,1.2Hz), 8.70(2H,d,J=6.0Hz). 405 C106 (CDCl ₃ ): 1.69-1.92 (3H, m), 2.12 (1H, m), 3.06 (1H, m), 3.21 (1H, dd, J=12.9, 10.2Hz), 3.50 (3H, s), 3.60 -3.83(3H, m), 3.86(3H, s), 6.66(1H, s), 6.96-7.05(2H, m), 7.45-7.57(2H, m), 7.79(2H, d, J=4.5Hz ), 8.69 (2H, d, J=4.8Hz). 405

C386 (CDCl ₃ ): 1.80-2.11 (4H, m), 3.07 (1H, m), 3.26 (1H, dd, J=13.1, 10.7Hz), 3.53 (3H, s), 3.59-3.66 (2H, m) , 3.88(1H, m), 6.65(1H, s), 6.95(1H, d, J=4.2Hz), 7.62(1H, d, J=4.2Hz), 7.78(2H, dd, J=4.5, 1.6 Hz), 8.71 (2H, dd, J=4.5, 1.6Hz). 415 C389 (CDCl ₃ ): 3.3-3.7 (3H, m), 3.57 (3H, s), 3.9-4.0 (2H, m), 4.1-4.2 (1H, m), 5.14 (1H, dd, J = 2.1, 9.0 Hz), 6.70(1H, s), 7.4-7.5(2H, m), 7.6-7.7(1H, m), 7.78(2H, dd, J=1.2, 4.5Hz), 8.05(2H, dd, J= 1.2, 7.2Hz), 8.73 (2H, dd, J=0.9, 4.5Hz) 377 C390 (CDCl ₃ ): 3.3-3.7 (3H, m), 3.57 (3H, s), 3.9-4.0 (2H, m), 4.1-4.2 (1H, m), 5.14 (1H, dd, J = 2.1, 9.0 Hz), 6.70(1H, s), 7.4-7.5(2H, m), 7.6-7.7(1H, m), 7.78(2H, dd, J=1.2, 4.5Hz), 8.05(2H, dd, J= 1.2, 7.2Hz), 8.73 (2H, dd, J=0.9, 4.5Hz) 377 D001 (CDCl ₃ ): 2.01-2.10(m, 4H), 3.16(m, 2H), 3.56(s+m, 3H+1H), 3.76(m, 2H), 6.69(s, 1H), 7.53(m, 2H), 7.63(m, 1H), 7.83(d, J=6.0Hz, 2H), 8.50(d, J=7.2Hz, 2H), 8.73(d, J=6.0Hz, 2H). 375 D002 (CDCl ₃ ): 1.93(m, 2H), 2.12(m, 2H), 3.12(m, 2H), 3.42(m, 1H), 3.53(s, 3H), 3.71(m, 2H), 6.68(s , 1H), 7.17(m, 1H), 7.28(m, 1H), 7.56(m, 1H), 7.80-7.86(m, 3H), 8.71(d, J=6.0Hz, 2H). 393 D003 (CDCl ₃ ): 1.94-2.10(m, 4H), 3.15(m, 2H), 3.49(m, 1H), 3.55(s, 3H), 3.75(m, 2H), 6.69(s, 1H), 7.31 (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). 393

D004 (CDCl ₃ ): 1.95-2.06 (m, 4H), 3.14 (m, 2H), 3.50 (m, 1H), 3.55 (s, 3H), 3.75 (m, 2H), 6.69 (s, 1H), 7.19 (t, J=8.6Hz, 2H), 7.82(d, J=6.0Hz, 2H), 8.02(m, 2H), 8.71(d, J=6.0Hz, 2H). 393

D005 (CDCl ₃ ): 1.89(m, 2H), 2.08(m, 2H), 3.06(m, 2H), 3.50(m, 1H), 3.53(s, 3H), 3.67(m, 2H), 3.93(s , 3H), 6.66(s, 1H), 6.98-7.06(m, 2H), 7.49(m, 1H), 7.61(m, 1H), 7.81(d, J=6.0Hz, 2H), 8.71(d, J=6.0Hz, 2H). 405 D006 (CDCl ₃ ): 1.94-2.10(m, 4H), 3.14(m, 2H), 3.50(m, 1H), 3.54(s, 3H), 3.74(m, 2H), 3.88(s, 3H), 6.68 (s, 1H), 7.15(m, 1H), 7.39-7.57(m, 3H), 7.82(d, J=6.3Hz, 2H), 8.71(d, J=6.3Hz, 2H). 405 D007 (CDCl ₃ ): 1.99-2.06(m, 4H), 3.13(m, 2H), 3.50(m, 1H), 3.55(s, 3H), 3.75(m, 2H), 3.90(s, 3H), 6.68 (s, 1H), 6.99 (d, J = 9.0Hz, 2H), 7.82 (d, J = 6.0Hz, 2H), 7.98 (d, J = 9.0Hz, 2H), 8.71 (d, J = 6.0Hz , 2H). 405 D008 (CDCl ₃ ): 1.94-2.06(m, 4H), 3.15(m, 2H), 3.49(m, 1H), 3.54(s, 3H), 3.75(m, 2H), 6.69(s, 1H), 7.44 -7.60(m, 2H), 7.81-7.93(m, 3H), 7.94(s, 1H), 8.71(d, J=5.7Hz, 2H). 409 D009 (CDCl ₃ ): 1.94-2.06 (m, 4H), 3.13 (m, 2H), 3.49 (m, 1H), 3.54 (s, 3H), 3.74 (m, 2H), 6.69 (s, 1H), 7.49 (d, J=8.4Hz, 2H), 7.81(d, J=6.0Hz, 2H), 7.92(d, J=8.4Hz, 2H), 8.71(d, J=6.0Hz, 2H). 409 D0010 (CDCl ₃ ): 1.95-2.06(m, 4H), 3.13(m, 2H), 348(m, 1H), 3.54(s, 3H), 3.74(m, 2H), 6.68(s, 1H), 7.66 (d, J=8.4Hz, 2H), 7.80-7.86(m, 4H), 8.71(d, J=6.0Hz, 2H). 454 D011 (CDCl ₃ ): 1.89(m, 2H), 2.08(m, 2H), 3.06(m, 2H), 3.38(m, 1H), 3.52(s, 3H), 3.67(m, 2H), 3.91(s , 3H), 3.92(s, 3H), 6.66(s, 1H), 7.02-7.16(m, 3H), 7.80(d, J=6.0Hz, 2H), 8.71(d, J=6.0Hz, 2H) . 435 D012 (CDCl ₃ ): 1.93(m, 2H), 2.10(m, 2H), 3.11(m, 2H), 3.38(m, 1H), 3.53(s, 3H), 3.72(m, 2H), 6.68(s , 1H), 6.88-7.04(m, 2H), 7.81(d, J=5Hz, 2H), 7.91(m, 1H), 8.71(d, J=5Hz, 2H). 411 D013 (CDCl3): 1.95-2.06 (m, 4H), 3.14 (m, 2H), 3.46 (m, 1H), 3.54 (s, 3H), 3.75 (m, 2H), 6.69 (s, 1H), 7.32 ( m, 1H), 7.75-7.86(m, 4H), 8.71(d, J=5.9Hz, 2H). 411 D014 (CDCl ₃ ): 2.06-2.08 (m, 4H), 3.12 (m, 2H), 3.38 (m, 1H), 3.55 (s, 3H), 3.76 (m, 2H), 6.69 (s, 1H), 7.19 (m, 1H), 7.71(d, J=5.2Hz, 2H), 7.79-7.83(m, 3H), 8.71(d, J=5.6Hz, 2H). 381 D015 (CDCl ₃ ): 1.95-2.07(m, 4H), 3.11(m, 2H), 3.37(m, 1H), 3.55(s, 3H), 3.75(m, 2H), 6.60(m, 1H), 6.68 (s, 1H), 7.29(m, 1H), 7.63(s, 1H), 7.82(d, J=6.0Hz, 2H), 8.71(d, J=6.0Hz, 2H). 365 D016 CDCl ₃ ): 1.95(m, 2H), 2.12(m, 2H), 3.18(m, 2H), 3.55(s, 3H), 3.76(m, 2H), 4.16(m, 1H), 6.67(s, 1H), 7.52(m, 1H), 7.82-7.91(m, 3H), 8.08(d, J=8.3Hz, 1H), 8.70-8.72(m, 3H). 376

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

Test Example: Inhibitory Activity of Drugs of the Present Invention on P-GS1 Phosphorylation Through Calf Brain TPK1

100mM MES-sodium hydroxide (pH6.5), 1mM magnesium acetate, 0.5mM EGTA, 5mM-mercaptoethanol, 0.02% Tween 20, 10% glycerol, 12μg/ml P-GS1, 41.7μM [γ ^-32 p] ATP (68 kBq/ml), calf brain TPK1 and a mixture of the compounds shown in the table (the final mixture contained 1.7% DMSO due to the presence of 10% DMSO when preparing the solutions of the test compounds) as the reaction system. The phosphorylation reaction was initiated by the addition of ATP, and the reaction was carried out at 25°C for 2 hours, and then terminated by the addition of 21% perchloric acid under ice-cooling. The reaction mixture was centrifuged at 12,000 rpm for 5 minutes and ice-adsorbed onto P81 paper (Whatmann), which was then washed 4 times with 75 mM phosphoric acid, 3 times with water and once with acetone. The paper was dried and the radioactivity of the residue was determined with a liquid scintillation counter. The results are shown in the table below. Test compounds significantly inhibited P-GS1 phosphorylation by TPK1. The results obviously suggest that the drug of the present invention inhibits the activity of TPK1, thereby inhibiting the neurotoxicity of Aβ and the formation of PHF, and that the drug of the present invention can effectively prevent and/or treat Alzheimer's disease and the diseases mentioned above.

Formulation example

(1) tablet

The following ingredients are mixed in a conventional manner and compressed using conventional equipment.

The compound of embodiment 1 30mg

Crystalline Cellulose 60mg

Corn starch 100mg

Lactose 200mg

Magnesium stearate 4mg

(2) soft capsules

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

The compound of Example 1 30mg

Olive oil 300mg

Lecithin 20mg

industrial application

The compound of the present invention has the activity of inhibiting TPK1 and is used as a pharmaceutical active ingredient to prevent and/or treat diseases due to abnormally high TPK1 activity such as neurodegenerative diseases (such as Alzheimer's disease) and the above-mentioned disease.

table 3

Compound No. IC ₅₀ (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 twenty one

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 twenty three B298 94 C001 2.1 C002 8.4 C005 45 C006 9 C067 72 C091 twenty three C092 63

C101 3.5 C102 20.4 C105 45 C106 9 C386 10 C389 34 C390 1.0 D001 9 D002 twenty three 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

Claims (11)

1. pyrimidone derivatives or its salt of a formula (I) representative:

R wherein ¹Represent C ₁-C ₃Alkyl;

R represents the group in the Formula Il:

R wherein ²And R ³Represent hydrogen atom or C independently ₁-C ₈Alkyl;

R ⁴Represent phenyl ring, naphthalene nucleus, hydrindene ring, tetrahydric naphthalene ring, cumarone ring, Dihydrobenzofuranes, thiphene ring, furan nucleus, pyridine ring, isoindoline ring, benzothiazole ring, tetrahydroisoquinoline ring, benzoglyoxaline ring, the luxuriant ring of Ben Bing Er Evil, benzo dioxane ring, indole ring, thiazole ring, diazole ring or thionaphthene ring, wherein each ring can have one or more and is selected from following substituting group: C ₁-C ₅Alkyl, C ₃-C ₆Cycloalkyl, C ₃-C ₆Cycloalkyloxy, C ₁-C ₅Alkoxyl group, C ₄-C ₇Cycloalkyl alkoxy, C ₁-C ₅Alkylthio, C ₁-C ₅Alkyl sulphonyl, C ₁-C ₅Haloalkyl, C ₁-C ₅Halogenated alkoxy, hydroxyl, cyano group, nitro, formyl radical, C ₂-C ₆Alkyl-carbonyl, phenyl ring, it can have one or more and be selected from C ₁-C ₅Alkyl, C ₁-C ₅The substituting group of alkoxy or halogen, naphthalene nucleus, pyrrolidine ring, can be by C ₁-C ₅The pyridine ring that alkoxyl group replaces, can be by C ₁-C ₅Pyrimidine ring, thiphene ring, furan nucleus, pyrazoline ring, phenoxy group, phenylamino, amino, C that alkoxyl group replaces ₁-C ₅One alkylamino, C ₂-C ₁₀Dialkyl amido, C ₂-C ₁₀One alkylamino methyl, C ₃-C ₁₁Dialkyl amino ylmethyl, pyrrolidyl methyl, piperidino methyl, morpholino methyl, piperazinyl methyl, pyrryl methyl, imidazolyl methyl, pyrazolyl methyl, triazolyl methyl and halogen.

2. pyrimidone derivatives as claimed in claim 1 or its salt, wherein R ¹It is methyl.

3. pyrimidone derivatives as claimed in claim 1 or its salt, wherein R ²And R ³Each is hydrogen atom naturally.

4. a pyrimidone derivatives or its salt, described pyrimidone derivatives is selected from:

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

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

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

3-methyl-2-(2-oxa--2-(3-chloro-phenyl-) ethylamino)-6-pyridin-4-yl-3H-pyrimidin-4-one and

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

5. medicine comprises with the pyrimidone derivatives that is selected from formula as claimed in claim 1 (I) representative or its salt as activeconstituents.

6. tau protein kinases 1 inhibitor combination, it comprises that compound is selected from pyrimidone derivatives or its salt of formula as claimed in claim 1 (I) representative.

7. medicine as claimed in claim 5, it is used to prevent and/or treat the disease that is caused by tau protein kinases 1 hyperactivity.

8. medicine as claimed in claim 5, it is used to prevent and/or treat neurodegenerative disease.

9. medicine as claimed in claim 8, wherein disease is selected from Parkinson's disease, boxing property encephalitis, Guam Parkinson's disease-dementia after the Parkinson's disease, encephalitis of cerebral hemorrhage due to Alzheimer's, ischemic cerebral vascular accident, special watt syndromes, the brain amyloid disease, stein-leventhal syndrome, subacute sclerosing panencephalitis, reins in tail corpusculum disease, Pick's disease, the degeneration of cortex oblongata, volume temporo dementia, vascular dementia, wound, brain and trauma of spinal cord, peripheral neuropathy, retinopathy and glaucoma.

10. medicine as claimed in claim 7, wherein disease is selected from: non-insulin-dependent diabetes mellitus (NIDDM), obesity, manic depressive illness, schizophrenia, alopecia, breast cancer, nonsmall-cell lung cancer, thyroid carcinoma, T or B-chronic myeloid leukemia and viral-induced tumour.

11. the pyrimidone derivatives of a formula (VII) representative:

R wherein ¹Represent C ₁-C ₃Alkyl.