HK1166498A - Carbinol compound having heterocyclic linker - Google Patents

Description

Carbinol compounds having a heterocyclic linker

Technical Field

The present invention relates to a novel LXR β agonist, a methanol compound having a heterocyclic linker, useful as a prophylactic and/or therapeutic agent for atherosclerosis, arteriosclerosis such as arteriosclerosis due to diabetes, dyslipidemia, hypercholesterolemia, a blood lipid-related disease, an inflammatory disease such as a disease caused by an inflammatory cytokine, a skin disease such as an allergic skin disease, diabetes, or alzheimer's disease.

Background

Liver X Receptor (LXR) is a nuclear receptor, and has been cloned as an orphan receptor whose ligand and function are unknown, and studies have reported that a part of oxysterols represented by 22-R-hydroxycholesterol act as a ligand (non-patent documents 1 to 3). LXRs form heterodimers with other nuclear receptors, Retinol X Receptor (RXRs), ligand-dependently regulating transcription of target genes.

As the LXR subtype, two LXR genes (α and β) are known to exist in mammals. LXR α and LXR β recognize the same sequence on DNA and activate transcription of nearby target genes, but their expression profiles are greatly different between the two genes, and LXR α is specifically expressed in tissues related to cholesterol metabolism such as liver, small intestine and adipose tissue, while LXR β is generally expressed in almost all tissues under study (non-patent documents 4 and 5).

Most of the genomes identified as target genes of LXRs are genes (ApoE, CETP, and LPL) involved in Reverse Cholesterol Transport (RCT) represented by ABC transporters (ABCA1, ABCG1, ABCG5, ABCG 8). Therefore, it is expected that activation of LXR increases the expression of these genes and activates the reverse cholesterol transport pathway, thereby increasing cholesterol efflux from the periphery, increasing HDL cholesterol, and reducing the cholesterol content in the arteriosclerotic lesion site (non-patent document 6).

Furthermore, it has been reported that LXR plays an important role in the regulation of the expression of inflammatory mediators such as NO synthase, cyclooxygenase-2 (COX-2), and interleukin-6 (IL-6) by inhibiting NF-. kappa.B (non-patent document 7). Inflammation is known to be important in arteriosclerotic lesions, and it is expected that the exacerbation of arteriosclerosis due to the expression of macrophage inflammatory mediators in lesion sites is suppressed by LXR ligands or LXR agonists (non-patent documents 6 and 8).

Further, it has been reported that when high-cholesterol feeds are administered to LXR α and β -deficient mice, the mice show symptoms such as fatty liver, increased LDL cholesterol concentration in blood, and decreased HDL cholesterol concentration, as compared to when high-cholesterol feeds are administered to normal mice (non-patent documents 9 and 10). Namely, it is strongly suggested that LXR plays an important role in cholesterol metabolism. Further, analysis of symptoms of an arteriosclerosis model mouse having normal LXR α and β functions in the liver, small intestine, etc. and lacking LXR α and β in macrophages has revealed that LXR α and β activities in macrophages have a strong influence on the incidence of arteriosclerosis (non-patent document 11). Therefore, in particular in macrophages, the reverse cholesterol transport is activated by activating LXR, which is important for the treatment of arteriosclerosis.

As applications of LXR modulators or LXR agonists disclosed in the prior art, applications to diseases such as hypercholesterolemia and atherosclerosis have been reported (patent documents 1 and 2). In addition, it has been reported that in LDL receptor-deficient mice loaded with a high-fat diet to which LXR ligands are administered, HDL cholesterol is increased, VLDL and LDL cholesterol are decreased, and the area of arteriosclerotic lesion sites is decreased (non-patent document 12).

In addition, LXR ligands or LXR agonists are expected to control sugar metabolism in the liver and adipose tissue, and improve diabetes (non-patent documents 6 and 8). In recent years, it has been reported that administration of LXR agonists to diabetic model animals improves insulin sensitivity and blood glucose level (non-patent documents 13 and 14). In addition, the possibility of being a therapeutic drug for alzheimer's disease, inflammatory diseases, and skin diseases has been studied (non-patent document 15).

However, LXR agonists have been reported to increase LDL cholesterol in animal species having Cholesteryl Ester Transfer Protein (CETP) (non-patent document 16). In addition, it has been observed in animal experiments that when LXR is activated by administering an LXR agonist, the synthesis of fatty acids and triglycerides is accelerated through transcriptional activation of enzymes important in fatty acid synthesis, such as Fatty Acid Synthase (FAS) or stearoyl-CoA desaturase (SCD-1) (non-patent document 17). It should be noted that, among LXR modulators, LXR ligands, LXR agonists and the like disclosed in the prior art, no disclosure is made of the selectivity for LXR α/β.

Therefore, there is a need for an ideal synthetic LXR-binding compound that retains the activation of reverse cholesterol transport by ABC transporter and the agonist activity of increased cholesterol efflux from macrophages, and does not exert an effect of worsening dyslipidemia through a high synthesis of fatty acids and triglycerides. As one of the methods for solving the problems, it is considered that a compound which selectively activates LXR β is a compound having desirable characteristics such that it can inhibit activation of LXR α highly expressed in the liver and inhibit increase in synthesis of fatty acids and triglycerides which are likely to be side effects, as compared with LXR modulators disclosed in the prior art (non-patent documents 6, 8, 15, 18, and 19). However, since LXR α and β have high homology at ligand binding sites, it is not easy to create a compound having a difference in action between LXR α and β.

Actually, compounds having LXR agonist action, such as benzofuran-5-acetic acid derivatives (patent document 3), 2-aminoquinazolin-4-one derivatives (patent document 4), tetrahydroquinoline derivatives (patent document 5), tetrahydrocarbazole derivatives (patent document 6), isoquinolinone derivatives (patent document 7), and naphthalene derivatives (patent document 8), GW3965 as an aromatic amino alcohol derivative (example 16 of patent document 9), and T0901317 as a benzenesulfonamide derivative (example 12 of patent document 10), have been reported, but agonists having high LXR β selectivity have not been reported so far, and compounds having high LXR β selectivity have been demanded.

On the other hand, LXR agonists having quinoline skeleton have been reported (patent document 11 and non-patent documents 20 to 22). For example, it has been reported that a quinoline derivative WAY-254011 (Compound 4 of non-patent document 22) has selective binding ability (α/β ratio of 5 times) for LXR β, and a compound having a binding ability α/β ratio of at most 50 times has also been reported in non-patent document 22. However, in the case of agonist action, even when the transcription promoting activity of Gal4 was measured, selectivity of α/β ratio of at most about 2.7 times was confirmed, and although selective binding to LXR β was confirmed, it was suggested that the effect of expressing LXR target gene was weak. Therefore, there is still a strong demand for compounds having an effect of expressing a target gene selectively to LXR β.

[ patent document 1] Japanese Kokai publication No. 2002-539155

[ patent document 2] Japanese Kokai publication No. 2004-509161

[ patent document 3] WO2003/82192 pamphlet

[ patent document 4] pamphlet of International publication WO2004/24161

[ patent document 5] WO2004/72046 pamphlet

[ patent document 6] U.S. Pat. No. 2005/215577 publication

[ patent document 7] WO2004/58717 pamphlet

[ patent document 8] WO2005/23188 pamphlet

[ patent document 9] International publication WO2002/24632 pamphlet

[ patent document 10] WO2000/54759 pamphlet

[ patent document 11] WO2005/58834 pamphlet

[ non-patent document 1] Janowski et al, Nature, 383, pp.728-731, 1996

[ Nonpatent document 2] Lehmann et al, J. biol. chem., 272, pp.3137-3140, 1997

[ Nonpatent document 3] Fu et al, J.biol. chem., 276, pp.38378-38387, 2001

[ non-patent document 4] Auboeuf et al, Diabetes, 46, pp.1319-1327, 1997

[ Nonpatent document 5] Lu et al, J. biol. chem., 276, pp.37735-37738, 2001

[ Nonpatent document 6] Zelcer et al, J. Clin. invest, 116, pp.607-614, 2006

[ non-patent document 7] Mangelsdorf et al, nat. Med., 9, pp.213-219, 2003

[ Nonpatent document 8] Geyeregger et al, cell. mol. Life Sci.63, pp.524-539, 2006

[ non-patent document 9] Peet et al, Cell, 93, pp.693-704, 1998

[ Nonpatent document 10] Alberti et al, J. Clin. invest, 107, pp.565-573, 2001

[ Nonpatent document 11] Tangirala et al, Proc. Natl. Acad. Sci. USA, 99, pp.11896-11901, 2002

[ Nonpatent document 12] Terasaka et al, FEBS Lett.,536, pp.6-11, 2003

[ Nonpatent document 13] Cao et al, J. biol. chem., 278, pp.1131-1136, 2003

[ Nonpatent document 14] Laffitte et al, Proc. Natl. Acad. Sci. USA, 100, pp.5419-5424, 2003

[ non-patent document 15] Lala et al, curr, Opin, Investig, Drugs, 6, pp.934-943, 2005

[ Nonpatent document 16] Pieter et al, J.lipid Res., 46, pp.2182-2191, 2005

[ Nonpatent document 17] Schultz et al, Genes Dev., 14, pp.2831-2838, 2000

[ non-patent document 18] Lund et al, Arterioscler.Thromb.Vasc.biol., 23, pp.1169-1177, 2003

[ Nonpatent document 19] Bradley et al, Drug Discov. Today ther. Strateg.2, pp.97-103, 2005

[ Nonpatent document 20] Hu et al, J. Med. chem., 49, pp.6151-6154, 2006

[ Nonpatent document 21] Hu et al, bioorg. Med. chem., 15, pp.3321-3333, 2007

Non-patent document 22 Hu et al, bioorg. med. chem. lett., 18, pp.54-59, 2008.

Disclosure of Invention

It is therefore an object of the present invention to create novel compounds that exhibit highly selective agonist activity towards LXR β.

The present inventors have intensively studied to achieve the above object and, as a result, have found that: the present inventors have completed the present invention by finding that a compound having a structure in which a methanol skeleton and an imidazolidine-2, 4-dione skeleton are bonded via a heterocyclic linker, that is, a compound represented by the following general formula (I), has highly selective agonist activity for LXR β.

Namely, the present invention relates to the following:

[1] a methanol compound represented by the following general formula (I):

[ solution 1]

Wherein V, W independently represent N or C-R⁷，

X, Y each independently represent CH₂、CH（C_1-8Alkyl group), C (C)_1-8Alkyl radical)₂C ═ O or SO₂，

Z represents a group of atoms selected from the group consisting of CH and N,

R¹、R²、R⁷each independently represents a hydrogen atom, a halogen atom, or C which may have a substituent_1-8Alkyl or C_2-8An alkenyl group, which is a radical of an alkenyl group,

R³is represented by C_1-8An alkyl group, a carboxyl group,

R⁴represents optionally substituted C_6-10Aryl or 5-to 11-membered substitutable groupA heterocyclic group,

R⁵represents a hydrogen atom or C_1-8An alkyl group, a carboxyl group,

R⁶represents a hydrogen atom, C_1-8Alkoxy radical C_1-8Alkyl or C which may have a substituent_6-10Aryl radical C_1-8An alkyl group, a carboxyl group,

l represents C which may be substituted by oxo or sulfonyl_1-8An alkyl chain is arranged on the base,

n represents an arbitrary integer of 0 to 2 ].

[2] A pharmaceutical agent comprising the methanol compound according to [1], a salt thereof or a solvate of the compound or the salt as an active ingredient.

[3] The medicament according to [2] above, which is a prophylactic and/or therapeutic agent for atherosclerosis, arteriosclerosis due to diabetes, dyslipidemia, hypercholesterolemia, a blood lipid-related disease, an inflammatory disease which is a disease caused by an inflammatory cytokine, a skin disease, diabetes or Alzheimer's disease.

[4] An LXR modulator comprising the methanol compound according to [1], a salt thereof or a solvate of the compound or the salt as an active ingredient.

[5] A pharmaceutical composition comprising the methanol compound according to [1], a salt thereof or a solvate of the compound or the salt and a pharmaceutically acceptable carrier.

[6] A method for preventing and/or treating atherosclerosis, arteriosclerosis due to diabetes, dyslipidemia, hypercholesterolemia, a blood-lipid related disease, an inflammatory disease which is a disease caused by an inflammatory cytokine, a skin disease, diabetes or Alzheimer's disease, characterized by comprising: administering an effective amount of the methanol compound described in the above [1], or a salt thereof or a solvate of either thereof to a patient in need of treatment.

[7] Use of the methanol compound according to [1] above, or a salt or solvate thereof for the production of a preparation for the prevention and/or treatment of atherosclerosis, arteriosclerosis due to diabetes, dyslipidemia, hypercholesterolemia, a blood lipid-related disease, an inflammatory disease which is a disease caused by an inflammatory cytokine, a skin disease, diabetes, or alzheimer's disease.

Detailed Description

The terms in the present invention are defined as follows.

In the present invention, examples of the "halogen" atom include a fluorine atom, a chlorine atom, a bromine atom, an iodine atom and the like.

In the present invention, "C_1-8The "alkyl group" means a straight-chain or branched alkyl group having 1 to 8 carbon atoms. Examples thereof include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, n-pentyl group, isopentyl group, neopentyl group, 2-methylbutyl group, 2-dimethylpropyl group, n-hexyl group, isohexyl group, n-heptyl group, and n-octyl group.

In the present invention, "C_2-8The alkenyl group means a straight-chain or branched alkenyl group having 2 to 8 carbon atoms and having a carbon-carbon double bond at any one or more positions on the alkyl chain. Examples thereof include vinyl, prop-1-en-1-yl, prop-2-en-1-yl, prop-1-en-2-yl, but-1-en-1-yl, but-2-en-1-yl, but-3-en-1-yl, but-1-en-2-yl, but-3-en-2-yl, pent-1-en-1-yl, pent-4-en-1-yl, pent-1-en-2-yl, pent-4-en-2-yl, 3-methyl-but-1-en-1-yl, hex-1-en-1-yl, and, Hex-5-en-1-yl, hept-1-en-1-yl, hept-6-en-1-yl, oct-1-en-1-yl, oct-7-en-1-yl, and the like.

"C" of the invention_1-8Specific examples of the alkoxy group "include: methoxy, ethoxy, n-propoxy, 1-methylethoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, isopentoxy, neopentoxy, 1-methylbutoxy, 1-ethylpropoxy, n-hexoxy, isohexoxy, 3-methylpentoxy, 2-methylpentoxy, 1-methylpentoxy, 3-dimethylbutoxy, 2-dimethylbutoxyButoxy, 1-dimethylbutoxy, 1, 2-dimethylbutoxy, 1, 3-dimethylbutoxy, 2, 3-dimethylbutoxy, 1-ethylbutoxy, 2-ethylbutoxy and the like. In addition, "C_1-8Alkoxy radical C_1-8Alkyl "represents" C_1-8Alkoxy "with C above_1-8Examples of the alkyl group-bonded group include a methoxymethyl group, a methoxyethyl group, an ethoxymethyl group, and an ethoxyethyl group.

Further, the "C" of the present invention_3-8As the cycloalkoxy group "are specifically mentioned: cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, cyclooctyloxy, and the like.

In the present invention, "C_1-8Examples of the "acyl group" include an alkylcarbonyl group such as a formyl group, an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, a valeryl group, an isovaleryl group, and a pivaloyl group, an alkenylcarbonyl group such as an acryloyl group, and an arylcarbonyl group such as a benzoyl group. In addition, "C_1-8Examples of the "acyloxy group" include an alkylcarbonyloxy group such as a formyloxy group, an acetyloxy group, a propionyloxy group, a butyryloxy group, an isobutyryloxy group, a valeryloxy group, an isovaleryloxy group, a pivaloyloxy group and the like, an alkenylcarbonyloxy group such as an acryloyloxy group and the like, and an arylcarbonyloxy group such as a benzoyloxy group and the like.

In the present invention, "C_6-10The aryl group means a monocyclic or polycyclic aryl group having 6 to 10 carbon atoms. In the case of polycyclic aromatic radicals, in addition to being completely unsaturated, they also contain partially saturated radicals. Examples thereof include phenyl, naphthyl, azulenyl, indenyl, indanyl and tetrahydronaphthyl.

In the present invention, "C_6-10Aryl radical C_1-8Alkyl "refers to the following C_6-10Aryl radicals with the above-mentioned radicals C_1-8An alkyl-bonded group. Examples thereof include benzyl, phenethyl, 3-phenyl-n-propyl, 4-phenyl-n-butyl, 5-phenyl-n-pentyl, 8-phenyl-n-octyl, and naphthylmethyl.

In the present invention, "5-to 11-membered heterocyclic group" means: the ring-constituting atoms include, in addition to carbon atoms, atoms selected from nitrogen and oxygen5-7 membered aromatic heterocycle, saturated heterocycle, unsaturated heterocycle having 1-4 hetero atoms of atom and sulfur atom or condensed heterocycle obtained by condensing these heterocycles with benzene ring. Examples thereof include: 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, pyrrol-1-yl, pyrrol-2-yl, pyrrol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrazin-2-yl, pyrazin-3-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrimidin-6-yl, pyridazin-3-yl, pyridazin-4-yl, 1, 3-benzodioxol-5-yl, 1, 4-benzodioxolEn-5-yl, 1, 4-benzodiIN-6-YL, 3, 4-DIHYDRO-2H-1, 5-BENZODIOXANE-6-yl, 3, 4-dihydro-2H-1, 5-benzodioxan-7-yl, 2, 3-dihydrobenzofuran-4-yl, 2, 3-dihydrobenzofuran-5-yl, 2, 3-dihydrobenzofuran-6-yl, 2, 3-dihydrobenzofuran-7-yl, benzofuran-2-yl, benzofuran-3-yl, benzofuran-4-yl, benzofuran-5-yl, benzofuran-6-yl, benzofuran-7-yl, benzothien-2-yl, benzothien-3-yl, benzothien-4-yl, benzothien-5-yl, benzothien-6-yl, benzothien-7-yl, quinoxalin-2-yl, quinoxalin-5-yl, quinoxalin-3-yl, quinoxalin-4-yl, quinoxalin-5-yl, quinoxalin-3-yl, quinoxalin-4-yl, quinoxalin, Quinoxalin-5-yl, quinoxalin-6-yl, indol-1-yl, indol-2-yl, indol-3-yl, indol-4-yl, indol-5-yl, indol-6-yl, indol-7-yl, isoindol-1-yl, isoindol-2-yl, isoindol-4-yl, isoindol-5-yl, isoindol-6-yl, isoindol-7-yl, isobenzofuran-1-yl, isobenzofuran-4-yl, isobenzofuran-5-yl, isobenzofuran-6-yl, isobenzofuran-7-yl, chromen-2-yl, chromen-3-yl, chromen-2-yl, indo-3-yl, indo-4-yl, isoindol-5-, Chromen-4-yl, chromen-5-yl, chromen-6-yl, chromen-7-yl, chromen-8-yl, imidazol-1-yl,Imidazol-2-yl, imidazol-4-yl, imidazol-5-yl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, and mixtures thereof,An oxazol-2-yl group,An oxazol-4-yl group,Azol-5-yl, isoAzol-3-yl isoAzol-4-yl isoAzol-5-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, benzimidazol-1-yl, benzimidazol-2-yl, benzimidazol-4-yl, benzimidazol-5-yl, benzothiazol-2-yl, benzothiazol-4-yl, benzothiazol-5-ylAzol-2-yl, benzoAzol-4-yl, benzoOxazol-5-yl, quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, quinolin-8-yl, isoquinolin-1-yl, isoquinolin-3-yl, isoquinolin-4-yl, isoquinolin-5-yl, isoquinolin-6-yl, isoquinolin-7-yl, isoquinolin-8-yl, 1,3, 4-thiadiazol-2-yl, morpholino, 1,2, 3-triazol-1-yl, 1,2, 3-triazol-4-yl, 1,2, 3-triazol-5-yl, 1,2, 4-triazol-1-yl, 1,2, 4-triazol-3-yl, 1,2, 4-triazol-5-ylTetrazol-1-yl, tetrazol-2-yl, indolin-4-yl, indolin-5-yl, indolin-6-yl, indolin-7-yl, 1,2,3, 4-tetrahydroquinolin-5-yl, 1,2,3, 4-tetrahydroquinolin-6-yl, 1,2,3, 4-tetrahydroquinolin-7-yl, 1,2,3, 4-tetrahydroquinolin-8-yl, 1,2,3, 4-tetrahydroisoquinolin-5-yl, 1,2,3, 4-tetrahydroisoquinolin-6-yl, 1,2,3, 4-tetrahydroisoquinolin-7-yl, 1,2,3, 4-tetrahydroisoquinolin-8-yl, and the like.

In the present invention, "C_1-8The alkyl chain "means a linear or branched 2-valent hydrocarbon chain having 1 to 8 carbon atoms, and examples thereof include a methylene chain, a1, 2-ethylene chain, a1, 3-propylene chain, a methyl 1, 2-ethylene chain, a1, 4-butylene chain, a1, 2-dimethyl 1, 2-ethylene chain, a1, 5-pentylene chain, a 1-methyl 1, 4-butylene chain, a 2-methyl 1, 4-butylene chain, a1, 6-hexylene chain, a1, 7-heptylene chain, and a1, 8-octylene chain.

In the present invention, the "optionally substituted C" may be_1-8Alkyl group "," C which may have a substituent group_6-10Aryl group, optionally substituted 5-to 11-membered heterocyclic group, optionally substituted C_6-10Aryl radical C_1-8Examples of the "substituent" in the alkyl group include the following groups.

Halogen atom, C_1-8Alkyl, halo C_1-8Alkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, C_3-8Cycloalkyl, cyano, nitro, hydroxy, amino, mono C_1-8Alkylamino, di-C_1-8Alkylamino radical, C_1-8Alkoxy, halo C_1-8Alkoxy radical, C_1-8Acyl, carboxyl, C_1-8Acyloxy, C_1-8Alkoxycarbonyl, carbamoyl, C_6-10Aryl, 5-11 membered heteroaryl, C_6-10Aryl radical C_1-8Alkoxy radical, C_1-8Alkylthio radical, C_1-8Alkylsulfinyl radical, C_1-8Alkylsulfonyl radical, C_6-10Arylthio radical, C_6-10Arylsulfinyl radical, C_6-10Arylsulfonyl radical, C_3-8Cycloalkylthio radical, C_3-8Cycloalkoxy, and the like.

As described aboveIn the substituents, "halogen atom", "C_1-8Alkyl group "," C_2-8Alkenyl group "," C_1-8Alkoxy group "," C_1-8Acyl "and" C_6-10Aryl "is as defined above.

Among the above substituents, "halogeno C_1-8Alkyl "means C_1-8The alkyl group is preferably bonded with 1 to 9 halogen atoms, and examples thereof include trifluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 3-fluoropropyl, 3-chloropropyl, 4-fluorobutyl, 4-chlorobutyl, 2,2, 2-trifluoroethyl, 3,3, 3-trifluoropropyl, pentafluoroethyl, 2,2, 2-trifluoro-1-trifluoromethylethyl and the like.

Among the above substituents, "halogeno C_1-8Alkoxy "means a halo C as defined above_1-8Examples of the group in which an alkyl group is bonded to an oxygen atom include: trifluoromethoxy group, 2-fluoroethoxy group, 2-chloroethoxy group, 2-bromoethoxy group, 3-fluoropropoxy group, 3-chloropropoxy group, 4-fluorobutoxy group, 4-chlorobutoxy group, 2,2, 2-trifluoroethoxy group, 3,3, 3-trifluoropropoxy group, pentafluoroethoxy group, 2,2, 2-trifluoro-1-trifluoromethylethoxy group and the like.

In the above substituents, "C_2-8The alkynyl group "means a straight-chain or branched alkynyl group having 2 to 8 carbon atoms and having a carbon-carbon triple bond at any one or more positions in the alkyl chain, and examples thereof include ethynyl, prop-1-yn-1-yl, prop-2-yn-1-yl, but-1-yn-1-yl, but-3-yn-1-yl, 1-methylpropan-2-yn-1-yl, pent-1-yn-1-yl, pent-4-yn-1-yl, hex-1-yn-1-yl, and hex-5-yn-1-yl.

In the above substituents, "C_3-8Cycloalkyl groups "include, for example: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.

In the above substituents, "mono C_1-8As the alkylamino group ", for example, there can be mentioned: methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, sec-butylamino, tert-butylamino, n-pentylamino, isopentylamino, neopentylamino, 1-methylbutylamino, 1-ethylpropylamino, n-hexylaminoA group such as isohexylamino, 3-methylpentylamino, 2-methylpentylamino, 1-methylpentylamino, 3-dimethylbutylamino, 2-dimethylbutylamino, 1-dimethylbutylamino, 1, 2-dimethylbutylamino, 1, 3-dimethylbutylamino, 2, 3-dimethylbutylamino, 1-ethylbutylamino, 2-ethylbutylamino, etc.

In the above substituents, "di C_1-8As the alkylamino group ", for example, dimethylamino group, methylethylamino group, diethylamino group, methyl-n-propylamino group, ethyl-n-propylamino group, di-n-propylamino group, methylisopropylamino group, ethylisopropylamino group, diisopropylamino group, methyl-n-butylamino group, ethyl-n-butylamino group, n-propyl-n-butylamino group, di-sec-butylamino group, di-tert-butylamino group, dipentylamino group, dihexylamino group and the like are mentioned.

In the above substituents, "C_1-8Examples of the "acyloxy" include acetoxy, propionyloxy, butyryloxy, isobutyryloxy, valeryloxy, isovaleryloxy, pivaloyloxy and the like.

In the above substituents, "C_1-8Examples of the alkoxycarbonyl group "include: methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, 1-methylethoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, n-pentoxycarbonyl, isopentoxycarbonyl, neopentoxycarbonyl, 1-methylbutoxycarbonyl, 1-ethylpropoxycarbonyl, n-hexyloxycarbonyl, isohexyloxycarbonyl, 3-methylpentyloxycarbonyl, 2-methylpentyloxycarbonyl, 1-methylpentyloxycarbonyl, 3-dimethylbutoxycarbonyl, 2-dimethylbutoxycarbonyl, 1-dimethylbutoxycarbonyl, 1, 2-dimethylbutoxycarbonyl, 1, 3-dimethylbutoxycarbonyl, 2, 3-dimethylbutoxycarbonyl, 1-ethylbutoxycarbonyl, 2-ethylbutoxycarbonyl and the like.

In the above substituents, "5-to 11-membered heteroaryl" means: the ring-constituting atoms include 1 to 4 hetero atoms selected from nitrogen atoms, oxygen atoms and sulfur atoms in addition to carbon atoms5-7 membered aromatic heterocycle, saturated heterocycle, unsaturated heterocycle, or condensed heterocycle obtained by condensing these heterocycles with benzene ring. Examples thereof include: 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, pyrrol-1-yl, pyrrol-2-yl, pyrrol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrazin-2-yl, pyrazin-3-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrimidin-6-yl, pyridazin-3-yl, pyridazin-4-yl, 1, 3-benzodioxol-5-yl, 1, 4-benzodioxolAlk-5-yl, 1, 4-benzodiAlk-6-yl, 3, 4-dihydro-2H-1, 5-benzodioxan-6-yl, 3, 4-dihydro-2H-1, 5-benzodioxan-7-yl, 1, 4-dihydrobenzodiEn-5-yl, 1, 4-dihydrobenzodiOn-6-yl, 2, 3-dihydrobenzofuran-4-yl, 2, 3-dihydrobenzofuran-5-yl, 2, 3-dihydrobenzofuran-6-yl, 2, 3-dihydrobenzofuran-7-yl, benzofuran-2-yl, benzofuran-3-yl, benzofuran-4-yl, benzofuran-5-yl, benzofuran-6-yl, benzofuran-7-yl, benzothien-2-yl, benzothien-3-yl, benzothien-4-yl, benzothien-5-yl, benzothien-6-yl, benzothien-7-yl, quinoxalin-2-yl, quinoxalin-5-yl, quinoxalin-3-yl, quinoxalin-2-yl, quinoxalin-3-yl, quinoxalin, Fluoropyridin-2-yl, fluoropyridin-3-yl, fluoropyridin-4-yl, fluoropyridin-5-yl, fluoropyridin-6-yl, fluoropyridin-7-yl, 2, 3-dihydrofluoropyridin-2-yl, 2, 3-dihydrofluoropyridin-3-yl, 23-dihydropyridin-4-yl, 2, 3-dihydropyridin-5-yl, 2, 3-dihydropyridin-6-yl, 2, 3-dihydropyridin-7-yl, 2, 3-dihydro-1, 4-dioxin-5-yl, 2, 3-dihydro-1, 4-dioxin-6-yl, 2, 3-dihydro-1, 4-dioxin-pyridin-7-yl, 2, 3-dihydro-1, 4-dioxin-pyridin-8-yl and the like.

In the above substituents, "C_6-10Aryl radical C_1-8Alkoxy "means" C "as defined above_6-10Aryl radical C_1-8Alkyl "a group bonded to an oxygen atom. Examples thereof include a benzyloxy group, a phenethyloxy group, and a naphthylmethyloxy group.

In the above substituents, "C_1-8Examples of the alkylthio group "include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio, n-pentylthio, isopentylthio, neopentylthio, 1-methylbutylthio, 1-ethylpropylthio, n-hexylthio, isohexylthio, 3-methylpentylthio, 2-methylpentylthio, 1-methylpentylthio, 3-dimethylbutylthio, 2-dimethylbutylthio, 1-dimethylbutylthio, 1, 2-dimethylbutylthio, 1, 3-dimethylbutylthio, 2, 3-dimethylbutylthio, 1-ethylbutylthio, and 2-ethylbutylthio.

In the above substituents, "C_1-8Alkylsulfinyl "includes, for example: methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, isopropylsulfinyl, n-butylsulfinyl, isobutylsulfinyl, sec-butylsulfinyl, tert-butylsulfinyl, n-pentylsulfinyl, isopentylsulfinyl, neopentylsulfinyl, 1-methylbutylsulfinyl, 1-ethylpropylsulfinyl, n-hexylsulfinyl, isohexylsulfinyl, 3-methylpentylsulfinyl, 2-methylpentylsulfinyl, 1-methylpentylsulfinyl, 3-dimethylbutylsulfinyl, 2-dimethylbutylsulfinyl, 1-dimethylbutylsulfinyl, 1, 2-dimethylbutylsulfinyl, 1, 3-dimethylbutylsulfinyl, 2, 3-dimethylbutylsulfinyl, a, 1-ethylbutylsulfinyl group, 2-ethylbutylsulfinyl group, and the like.

In the above substituents, "C_1-8Examples of the alkylsulfonyl group "include: methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl, n-pentylsulfonyl, isopentylsulfonyl, neopentylsulfonyl, 1-methylbutylsulfonyl, 1-ethylpropylsulfonyl, n-hexylsulfonyl group, isohexylsulfonyl group, 3-methylpentylsulfonyl group, 2-methylpentylsulfonyl group, 1-methylpentylsulfonyl group, 3-dimethylbutylsulfonyl group, 2-dimethylbutylsulfonyl group, 1-dimethylbutylsulfonyl group, 1, 2-dimethylbutylsulfonyl group, 1, 3-dimethylbutylsulfonyl group, 2, 3-dimethylbutylsulfonyl group, 1-ethylbutylsulfonyl group, 2-ethylbutylsulfonyl group and the like.

In the above substituents, "C_6-10The "arylthio group" includes, for example: phenylthio, naphthylthio, azulenylthio and the like.

In the above substituents, "C_6-10Arylsulfinyl "includes, for example: benzenesulfinyl, p-toluenesulfonyl, p-chlorobenzenesulfinyl, naphthalen-1-ylsulfinyl, naphthalen-2-ylsulfinyl, and the like.

In the above substituents, "C_6-10Arylsulfonyl "includes, for example: benzenesulfonyl, p-toluenesulfonyl, p-chlorobenzenesulfonyl, naphthalen-1-yl-sulfonyl, naphthalen-2-yl-sulfonyl and the like.

In the above substituents, "C_3-8Examples of the cycloalkylthio group "include: cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio, cycloheptylthio, cyclooctylthio and the like.

In the above substituents, "C_3-8Examples of the cycloalkoxy group "include: cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, cyclooctyloxy, and the like.

Otherwise, the groups not defined here follow the usual definitions.

Preferred embodiments of the present invention include the following.

In the general formula (I), as R¹、R²、R⁷C which may have a substituent(s) in (1)_1-8Alkyl, preferably C_1-4Alkyl, more preferably n-propyl.

In the general formula (I), as R¹、R²、R⁷C in (1)_2-8Alkenyl, preferably C_2-4Alkenyl, more preferably prop-2-en-1-yl.

In the general formula (I), as R³C in (1)_1-8Alkyl, preferably C_1-4Alkyl, more preferably methyl.

In the general formula (I), R⁴C in (1)_6-10Aryl is preferably phenyl. The phenyl group preferably has a substituent, and the substituent is preferably C such as 1-methylethoxy_1-8C of alkoxy, cyclopropoxy, or the like_3-8C of cycloalkoxy, cyclopropylthio, etc_3-8Cycloalkylthio groups, and the like.

In the general formula (I), as R⁴The 5-to 11-membered heterocyclic group in (1) is preferably a 5-to 7-membered aromatic heterocyclic ring containing 1 to 2 hetero atoms selected from a nitrogen atom and an oxygen atom in addition to carbon atoms as ring-constituting atoms, an unsaturated heterocyclic ring or a condensed heterocyclic ring obtained by condensing these heterocyclic rings with a benzene ring or a pyridine ring, and more preferably a pyridyl group, a1, 3-benzodioxolyl group, a1, 4-benzodioxinyl group, a 2, 3-dihydrobenzofuranyl group, a benzofuranyl group, a fluoropyridinyl group, a 2, 3-dihydrofluoropyridinyl group, a 2, 3-dihydro-1, 4-dioxin pyridinyl group. These 5-to 11-membered heterocyclic groups may have 1 to the maximum number of substitutable substituents, and the substituent is preferably C such as methyl_1-8C of alkyl, methoxy, 1-methylethoxy, etc_1-8C of alkoxy, cyclopropoxy, or the like_3-8A cycloalkoxy group.

In the general formula (I), R⁵Preferably a hydrogen atom.

In the general formula (I), as R⁶C in (1)_1-8Alkoxy radical C_1-8The alkyl group is preferably a methoxymethyl group, an ethoxyethyl group or the like.

In the general formula (I), as R⁶C which may have a substituent(s) in (1)_6-10Aryl radical C_1-8Alkyl groups are preferably benzyl, p-methoxybenzyl and the like.

In the formula (I), X, Y represents CH (C)_1-8Alkyl group), C (C)_1-8Alkyl radical)₂The "alkyl" moiety in (1) is preferably methyl or ethyl.

In the general formula (I), C which may be substituted by oxo in L_1-8Alkyl chains, preferably 1, 2-ethylene, 1-oxo-1, 2-ethylene, 1, 2-propylene chains.

In the general formula (I), C which may be substituted by a sulfonyl group in L_1-8The "alkyl chain" in the alkyl chain is preferably a methylene chain or a1, 2-ethylene chain.

In the general formula (I), n is preferably an integer of 0 to 2, more preferably an integer of 1 or 2.

Examples of addition salts of a methanol compound represented by the general formula (I) include: alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, organic base salts such as ammonium salts and trialkylamine salts, inorganic acid salts such as hydrochloride and sulfate, organic acid salts such as acetate, and the like, and any pharmaceutically acceptable salts are not particularly limited.

The solvate of the methanol compound represented by the general formula (I) includes a hydrate.

When the compounds of the present invention exist as geometric isomers or optical isomers, these isomers are also included in the scope of the present invention.

The compound (I) can be produced by various known methods, and is not particularly limited, and can be produced, for example, by the following reaction procedure. That is, compound (I) can be produced by reacting an imidazolidine-2, 4-dione compound represented by general formula (III) with a derivative represented by general formula (II). The reaction scheme is represented by the following chemical reaction formula.

[ solution 2]

(in the formula, R¹、R²、R³、R⁴、R⁵、R⁶X, Y, Z, V, W, L and n represent the same groups as described above, and M represents a leaving residue such as a halogen atom or a hydroxyl group. )

When M is a halogen atom, the target compound (I) can be prepared by reacting a derivative represented by the general formula (II) with an imidazolidine-2, 4-dione compound (III) in a solvent, in the presence or absence of a base. The solvent is not particularly limited, and may be, for example, tetrahydrofuran, toluene or dioxaneAlkyl, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile, propionitrile, acetone, methyl ethyl ketone, water and the like are used alone or in combination. The base is not particularly limited, and for example, alkali metal hydrides such as lithium hydride, sodium hydride, potassium hydride and the like; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, etc.; alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, and the like; metal salts of alcohols such as sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, etc.; lithium diisopropylamide, sodium diisopropylamide, potassium diisopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, n-butyllithium, sec-butyllithium, tert-butyllithium, and the like. Through the reaction conditions: reacting at-80-150 deg.C, preferably 0-100 deg.C for 1 min-5 days, preferably 1 hr-3 days to obtain the target product.

When M is a hydroxyl group, compound (I) can be produced by a mitsunobu reaction which is general practiceThe reaction is carried out by dissolving the derivative represented by the general formula (II), the imidazolidine-2, 4-dione compound represented by the general formula (III) and a phosphine reagent in a reaction solvent, adding an azo reagent or a succinic acid reagent thereto, and reacting the resulting mixture at 0 to 100 ℃ and preferably at room temperature to 80 ℃ for 2 hours to 1 day under an argon or nitrogen atmosphere. As the solvent used in the reaction, N-dimethylformamide, tetrahydrofuran and dioxane can be usedAlkyl, acetonitrile, nitromethane, acetone, ethyl acetate, benzene, chlorobenzene, toluene, chloroform, dichloromethane and the like, wherein N, N-dimethylformamide, tetrahydrofuran, and bis (methyl) are preferableAlkanes and acetonitrile, and N, N-dimethylformamide and tetrahydrofuran are particularly preferable. Examples of phosphine reagents include: trialkylphosphines such as trimethylphosphine, triethylphosphine, tripropylphosphine, triisopropylphosphine, tributylphosphine, triisobutylphosphine and tricyclohexylphosphine, and triarylphosphines such as triphenylphosphine and diphenylphosphino polystyrene, and among them, trimethylphosphine, tributylphosphine and triphenylphosphine are preferable. Examples of the azo reagent include: diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), di-tert-butyl azodicarboxylate (DBAD), 1 ' -azobis (N, N-dimethylformamide) (TMAD), 1 ' - (azodicarbonyl) dipiperidine (ADDP), 1 ' -azobis (N, N-diisopropylformamide) (TIPA), 1, 6-dimethyl-1, 5, 7-hexahydro-1, 4,6, 7-tetraazacyclooctatetra-ene (テトラゾシン) -2, 5-dione (DHTD), etc., with diethyl azodicarboxylate being particularly preferable.

In addition, when the functional group to be reacted with the imidazolidine-2, 4-dione compound represented by the general formula (III) is other than the above, it can be protected by a conventionally used method (Protective Groups in Organic Synthesis Third Edition, John Wiley & Sons, Inc.) and then deprotected at an appropriate stage, thereby obtaining the target compound.

The derivatives of the general formula (II) can be prepared by the following reaction scheme.

[ solution 3]

(in the formula, R¹、R²、R⁶X, Y, Z, V, W, L, M and n represent the same groups as above, R⁸Represents a group convertible into a carboxyl group, R⁹Represents a halogen atom or a leaving residue. )

The reaction from the general formula (IV) to the general formula (V) is carried out by reacting the substituents R⁸The step of converting into a carboxyl group may be carried out by various known carboxyl group-forming reactions such as oxidation of a methyl group, a hydroxymethyl group or an aldehyde group, hydrolysis of an ester, an amide or a nitrile, conversion of a halogenated group into a Grignard reagent, and reaction with carbon dioxide.

The derivative of the carboxylic acid compound (V) obtained by the above-mentioned method to the hexafluorocarbinol compound (VII) can be produced by a method described in publicly known literature (Tetrahedron, 61 (2005) 1813-1819), that is, by converting the carboxylic acid compound (V) to an acid halide, an acid anhydride or an ester (VI) by a conventionally used method (John Wiley & Sons, Inc.), and then using (trifluoromethyl) trimethylsilane and tetramethylammonium fluoride to obtain the hexafluorocarbinol compound (VII).

In the literature, (trifluoromethyl) trimethylsilane is used as the trifluoromethyl source, but the present invention is not limited thereto, and triethyl (trifluoromethyl) silane, triisopropyl (trifluoromethyl) silane, methyldiphenyl (trifluoromethyl) silane, dimethyl (diphenyl) trifluoromethylsilane and the like can be used. Furthermore, if perfluoroalkyl silanes such as (pentafluoroethyl) trimethylsilane and (heptafluoropropyl) trimethylsilane are used, then the perfluoroalkyl group can be formed. Further, tetramethylammonium fluoride is used as the fluorine compound, but the fluorine compound is not limited thereto, and tetraethylammonium fluoride and tetrabutylammonium fluoride may be usedTetraalkylammonium salts such as ammonium, and metal salts such as lithium fluoride, sodium fluoride, potassium fluoride, and cesium fluoride. The solvent can be tetrahydrofuran, toluene, or dioxane, except dimethoxyethaneAlkyl, N-dimethylformamide, N-methylpyrrolidone, tetramethylurea, dimethyl sulfoxide, acetonitrile, propionitrile, acetone, methyl ethyl ketone, and the like are used singly or in combination.

Examples of the ester include an ester with an aliphatic alcohol such as methanol and an ester with an aromatic alcohol such as pentafluorophenol. The acid anhydride includes acid anhydrides of aliphatic carboxylic acids such as acetic acid and acid anhydrides of aromatic carboxylic acids such as benzoic acid.

Reacting R in a solvent, in the presence or absence of a base⁶The halide of (4) is reacted with the obtained hexafluorocarbinol compound (VII), whereby the objective compound (II) can be produced. The solvent is not particularly limited, and may be, for example, tetrahydrofuran, toluene or dioxaneAlkyl, N-dimethylformamide, N-methylpyrrolidone, tetramethylurea, dimethyl sulfoxide, acetonitrile, propionitrile, acetone, methyl ethyl ketone, water, and the like are used singly or in combination. The base is not particularly limited, and for example, alkali metal hydrides such as lithium hydride, sodium hydride, potassium hydride and the like; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, etc.; alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, and the like; metal salts of alcohols such as sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, etc.; examples of the organometallic compound include lithium diisopropylamide, sodium diisopropylamide, potassium diisopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, n-butyllithium, sec-butyllithium, and tert-butyllithium.

When M is a hydroxyl group, each reaction may be carried out while protecting the hydroxyl group in order to avoid side reactions. As the protection and deprotection conditions, it can be carried out by a conventionally used method (Protective Groups in Organic Synthesis Third Edition, John Wiley & Sons, Inc.).

The derivative represented by the general formula (IV) can be produced by the following reaction scheme.

[ solution 4]

(in the formula, R¹、R²、R⁸X, Y, Z, V, W, Z, L, M and n represent the same groups as above, R¹⁰Represents an aldehyde group, a functional group convertible into an aldehyde group or a halogen atom, R¹¹Represents a halogen atom or a hydroxyl group).

R¹¹In the case of a halogen atom, the target product (XII) can be produced by reacting a derivative represented by the general formula (VIII) with the general formula (IX) in a solvent, in the presence or absence of a base, in the presence or absence of a metal catalyst. The solvent is not particularly limited, and may be, for example, tetrahydrofuran, toluene or dioxaneAlkyl, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile, propionitrile, acetone, methyl ethyl ketone, water and the like are used alone or in combination. The base is not particularly limited, and for example, alkali metal hydrides such as lithium hydride, sodium hydride, potassium hydride and the like; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, etc.; alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, and the like; metal salts of alcohols such as sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, etc.; lithium diisopropylamide, sodium diisopropylamide, potassium diisopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, and hexamethylPotassium disilylamido, n-butyllithium, sec-butyllithium, tert-butyllithium and the like. The metal catalyst is not particularly limited, and a palladium catalyst, a nickel catalyst, a copper oxide, a copper salt, or the like can be used. Tetrakis (triphenylphosphine) palladium (O) may be preferably used. Through the reaction conditions: reacting at-80-150 ℃, preferably 0-100 ℃ for 1 min-5 days, preferably 30 min-3 days to obtain the target product. If necessary, the reaction may be carried out under microwave irradiation.

When R is¹¹In the case of a hydroxyl group, the derivative represented by the general formula (VIII) is derivatized to a leaving group such as a sulfonyl group, and reacted with the general formula (IX) in a solvent, in the presence or absence of a base, in the presence or absence of a metal catalyst, whereby the target product (XII) can be produced. The solvent for the reaction of derivatizing the leaving group such as sulfonyl group is not particularly limited, and examples thereof include tetrahydrofuran, toluene, and bisAlkyl, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile, propionitrile, acetone, methyl ethyl ketone, water and the like are used alone or in combination. The base is not particularly limited, and for example, alkali metal hydrides such as lithium hydride, sodium hydride, and potassium hydride; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, and potassium hydroxide; alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, and cesium carbonate; metal salts of alcohols such as sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium tert-butoxide, and potassium tert-butoxide; lithium diisopropylamide, sodium diisopropylamide, potassium diisopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, n-butyllithium, sec-butyllithium, tert-butyllithium, and the like. The metal catalyst is not particularly limited, and a palladium catalyst, a nickel catalyst, a copper oxide, a copper salt, or the like can be used. Tetrakis (triphenylphosphine) palladium (O) may be preferably used. Through the reaction conditions: reacting at-80-150 ℃, preferably 0-100 ℃ for 1 min-5 days, preferably 30 min-3 days to obtain the target product. In addition, R may be substituted¹¹By conversion of hydroxy groups to halogen atomsThe target product (XII) is produced through the above reaction.

R¹⁰In the case of a halogen atom, the derivative of the general formula (IV) can be obtained as the target product by reacting the derivative of the general formula (XII) obtained in the above-mentioned method with a boric acid derivative in a solvent in the presence of a base and a metal catalyst. The solvent is not particularly limited, and may be, for example, methylene chloride, chloroform, carbon tetrachloride, tetrahydrofuran, toluene or dioxaneAlkane, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile, propionitrile and the like are used alone or in combination. The base is not particularly limited, and for example, organic amines such as pyridine and triethylamine; alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, and cesium carbonate; cesium fluoride, and the like. The metal catalyst is not particularly limited, and a palladium catalyst, a nickel catalyst, a copper oxide, a copper salt, or the like can be used. Tetrakis (triphenylphosphine) palladium (O) may be preferably used. Through the reaction conditions: the reaction is carried out at-80 to 150 ℃, preferably 0 to 100 ℃, for 1 minute to 5 days, preferably 1 hour to 3 days, to obtain the target product, the derivative of the general formula (IV).

When R is¹⁰In the case where the derivative is an aldehyde group or a functional group which can be converted to an aldehyde group, the derivative represented by the general formula (XII) obtained by the above-mentioned method is reacted with a Wittig reagent or Horner-Wadsworth-Emmons reagent in a solvent in the presence or absence of a base, whereby the derivative represented by the general formula (IV) is obtained as a target product. The solvent is not particularly limited, and may be, for example, methylene chloride, chloroform, carbon tetrachloride, tetrahydrofuran, toluene or dioxaneAlkanes and the like are used alone or in combination. The base is not particularly limited, and for example, organic amines such as pyridine and triethylamine; alkyl lithium such as butyl lithium; alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, and cesium carbonate; cesium fluoride, and the like. By reaction conditions: the reaction is carried out at-80 to 150 ℃, preferably 0 to 100 ℃, for 1 minute to 5 days, preferably 1 hour to 3 days, to obtain the target product, the derivative of the general formula (IV).

In the derivative represented by the general formula (VIII), when either V or W is N, the compound can be produced, for example, by the following reaction procedure.

[ solution 5]

(in the formula, R¹、R⁸、R¹⁰、R¹¹V and W represent the same groups as described above. R¹²Represents a halogen atom or a hydroxyl group).

The derivative represented by the general formula (XV) can be obtained by using, for example, a reaction of substitution into an amino group, which is known as a chihibabin reaction. The step is a reaction in which the reaction is carried out in a solvent in the presence of an alkali metal amide (アルカリ metal アミド), wherein the solvent is not particularly limited, and for example, methylene chloride, chloroform, carbon tetrachloride, tetrahydrofuran, toluene, and dioxane can be usedAlkane, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile, propionitrile and the like are used alone or in combination. The alkali metal amide is not particularly limited, and lithium amide, sodium amide, potassium amide, and the like can be used. Through the reaction conditions: the reaction is carried out at-80 to 150 ℃, preferably 0 to 120 ℃, for 1 minute to 5 days, preferably 1 hour to 3 days, to obtain the target product, the derivative of the general formula (XV).

The derivative of the general formula (XVI) can be obtained by reacting the general formula (XV) obtained in the above-mentioned method with a halogenating agent in a solvent. The halogenating agent used is not particularly limited, and examples thereof include chlorine, bromine, iodine, and the like,Tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, carbon tetrabromide, and the like. Alternatively, a halide salt such as potassium bromide, potassium iodide, sodium bromide, or sodium iodide may be oxidized with an oxidizing agent such as hydrogen peroxide water or sodium hypochlorite water to generate a halogenating agent in the system, and the reaction may be carried out. The solvent is not particularly limited, and may be, for example, methylene chloride, chloroform, carbon tetrachloride, tetrahydrofuran, toluene or dioxaneAlkane, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile, propionitrile and the like are used alone or in combination. Through the reaction conditions: the reaction is carried out at-80 to 150 ℃ and preferably 0 to 120 ℃ for 1 minute to 5 days, preferably 1 minute to 1 day, to obtain the derivative of the general formula (XVI) as the target product.

The halogenated aromatic ring compound (XVII) can be derived by diazotizing the compound (XVI) to obtain a diazonium salt, and thermally decomposing the diazonium salt in an acidic aqueous solution. The acid used is not particularly limited, and p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, acetic acid, formic acid, hydrochloric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid and the like can be used, but not limited thereto. The solvent is not particularly limited, and may be, for example, tetrahydrofuran, toluene or dioxaneAlkyl, N-dimethylformamide, N-methylpyrrolidone, tetramethylurea, dimethyl sulfoxide, acetonitrile, propionitrile, acetone, methyl ethyl ketone, water, and the like are used singly or in combination.

The halogen atom or hydroxyl group of the general formula (XVII) obtained in the above-mentioned method can be converted into a group convertible into a carboxyl group by referring to a conventionally used method (Comprehensive Organic Transformations Second Edition, John Wiley & Sons, Inc.). That is, the general formula (XVII) can be derived to the general formula (VIII) by reacting with carbon monoxide, N-dimethylformamide, or the like in a solvent under basic conditions. Further, the general formula (VIII) can be derived by reacting the general formula (XVII) with a cyanating agent in a solvent, in the presence or absence of a metal reagent.

Further, the derivative represented by the general formula (II) can be produced by the following reaction scheme.

[ solution 6]

(in the formula, R¹、R²、R⁶X, Y, Z, V, W, L, M and n have the same meanings as described above, R¹³Represents a protecting group, R¹⁴Represents a halogen atom or a hydroxyl group).

R¹³The protecting group shown may be any protecting group conventionally used, and as the deprotection conditions from the general formula (XVIII) to the general formula (XIX), for example, reference may be made to the literature (Protective Groups in Organic Synthesis Third Edition, John Wiley&Sons, Inc.).

When R is¹⁴In the case of a halogen atom, the target product (II) can be produced by reacting a derivative represented by the general formula (XIX) with the general formula (XX) in a solvent in the presence or absence of a base. The solvent is not particularly limited, and may be, for example, tetrahydrofuran, toluene or dioxaneAlkyl, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile, propionitrile, acetone, methyl ethyl ketone, water and the like are used alone or in combination. The base is not particularly limited, and for example, alkali metal hydrides such as lithium hydride, sodium hydride, and potassium hydride; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, and potassium hydroxide; alkali gold such as lithium carbonate, sodium carbonate, potassium carbonate, and cesium carbonateBelong to carbonates; metal salts of alcohols such as sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium tert-butoxide, and potassium tert-butoxide; lithium diisopropylamide, sodium diisopropylamide, potassium diisopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, n-butyllithium, sec-butyllithium, tert-butyllithium, and the like. Through the reaction conditions: reacting at-80-150 ℃, preferably 0-100 ℃ for 1 min-5 days, preferably 1 h-3 days to obtain the target product.

When R is¹⁴In the case of a hydroxyl group, the compound (I) can be produced by a mitsunobu reaction in which a derivative represented by the general formula (XIX) and a derivative represented by the general formula (XX) are dissolved in a reaction solvent, and an azo reagent or an oxalic acid reagent is added thereto and reacted at 0 to 100 ℃ and preferably at room temperature to 80 ℃ for 2 hours to 1 day under an argon or nitrogen atmosphere. As the solvent used in the reaction, N-dimethylformamide, tetrahydrofuran and dioxane can be usedAlkyl, acetonitrile, nitromethane, acetone, ethyl acetate, benzene, chlorobenzene, toluene, chloroform, dichloromethane and the like, wherein N, N-dimethylformamide, tetrahydrofuran, and dimethylformamide are preferredAlkanes and acetonitrile, and N, N-dimethylformamide and tetrahydrofuran are particularly preferable. Examples of phosphine reagents include: trialkylphosphines such as trimethylphosphine, triethylphosphine, tripropylphosphine, triisopropylphosphine, tributylphosphine, triisobutylphosphine and tricyclohexylphosphine, and triarylphosphines such as triphenylphosphine and diphenylphosphino polystyrene, and among them, trimethylphosphine, tributylphosphine and triphenylphosphine are preferable. Examples of the azo reagent include: diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate, 1 ' -azobis (N, N-dimethylformamide) (TMAD), 1 ' - (azodicarbonyl) dipiperidine (ADDP), 1 ' -azobis (N, N-diisopropylformamide) (TIPA), 1, 6-dimethyl-1, 5, 7-hexahydro-1, 4,6, 7-tetraazacyclooctatetra-2, 5-dione (DHTD), etc., with diethyl azodicarboxylate being particularly preferable。

When L-R¹⁴In the case of a carboxylic acid, the compound (II) can be produced by dissolving the derivative represented by the general formula (XIX) and the derivative represented by the general formula (XX) in a reaction solvent, adding a commonly used condensing agent thereto, and reacting the resulting mixture at 0 to 100 ℃, preferably at room temperature to 80 ℃ for 2 hours to 1 day in an argon or nitrogen atmosphere. As the solvent used in the reaction, N-dimethylformamide, tetrahydrofuran and dioxane can be usedThe organic solvent is selected from the group consisting of alkyl, acetonitrile, nitromethane, acetone, ethyl acetate, benzene, chlorobenzene, toluene, chloroform, and dichloromethane. Examples of the condensation reagent include carbodiimide-based reagents such as Dicyclohexylcarbodiimide (DCC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC) and diisopropylcarbodiimide (DIPCDI), and (1H-benzotriazol-1-yloxy) tris (dimethylamino) phosphoniumAnd phosphonium salt type guanidine salt type reagents such as hexafluorophosphate (BOP), benzotriazole-1, 1,3, 3-tetramethyluronium Hexafluorophosphate (HBTU), benzotriazole-1, 1,3, 3-tetramethyluronium tetrafluoroborate (TBTU), 6-chlorobenzotriazole-1, 1,3, 3-tetramethyluronium Hexafluorophosphate (HCTU), 6-chlorobenzotriazole-1, 1,3, 3-tetramethyluronium tetrafluoroborate (TCTU), and Dicyclohexylcarbodiimide (DCC) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC) are preferable. Examples of the additive include 1-hydroxybenzotriazole (HOBt), 6-chloro-1-hydroxybenzotriazole (6-Cl-HOBt), 3, 4-dihydro-3-hydroxy-4-oxo-1, 2, 3-benzotriazine (HOOBt), and 1-hydroxy-7-azabenzotriazole (HOAt).

The derivative represented by the general formula (XVIII) can be produced by the reaction route in which the derivative represented by the general formula (XXI) obtained in the above-described method is reacted according to the above-described procedure for producing (IV) from the general formula (XII).

[ solution 7]

(in the formula, R¹、R²、R⁶、R¹⁰、R¹³X, Y, Z, V, W and n have the same meanings as described above).

The derivative represented by the general formula (XXI) can be produced by the following reaction scheme.

[ solution 8]

(in the formula, R¹、R⁶、R⁸、R⁹、R¹⁰、R¹¹、R¹³X, Y, Z, V, W and n have the same meanings as described above).

The reaction of formula (XXII) through (XXIII) and (XXIV) to give formula (XXV) can be carried out according to the above-mentioned steps of formula (IV) through (V) and (VI) to give formula (VII).

The reaction for obtaining formula (XXVII) from formula (XXV) may be carried out according to the procedure for producing formula (XII) from formula (VIII) described above.

The reaction for obtaining formula (XXI) from formula (XXVII) may be carried out according to the procedure for producing formula (II) from formula (VII) described above.

The process for the preparation of imidazolidine-2, 4-dione derivatives (III) is described in German patent No. 335993, to which reference is made for the preparation of various imidazolidine-2, 4-dione derivatives.

The methanol compound represented by the general formula (I) of the present invention can be obtained by the above-mentioned method, and can be further purified by a conventional purification method such as recrystallization and column chromatography, if necessary. Further, the above-mentioned desired salt or solvate can be prepared by a conventional method as required.

The methanol compound represented by the general formula (I), a salt thereof, or a solvate thereof (hereinafter, sometimes collectively referred to as "the compound represented by the general formula (I)") thus obtained exhibits an excellent LXR β agonist activity, and is useful as an active ingredient of a prophylactic and/or therapeutic agent for diseases caused by abnormal cholesterol metabolism, such as atherosclerosis, arteriosclerosis including arteriosclerosis caused by diabetes, dyslipidemia, hypercholesterolemia, a blood lipid-related disease, an inflammatory disease including a disease caused by an inflammatory cytokine, a skin disease such as an allergic skin disease, diabetes, alzheimer's disease, and the like in animals including humans.

The pharmaceutical composition of the present invention contains a methanol compound represented by the general formula (I), a salt thereof or a solvate of either, and can be used alone, usually in combination with a pharmaceutically acceptable carrier, additive or the like. The mode of administration of the pharmaceutical composition is not particularly limited, and may be appropriately selected depending on the purpose of treatment. For example, it may be in any form of oral preparation, injection, suppository, ointment, inhalant, eye drop, nasal drop, patch, etc. Pharmaceutical compositions suitable for these modes of administration may be prepared according to well-known formulation methods.

When preparing a solid preparation for oral administration, the methanol compound represented by the general formula (I) may be added with an excipient, and further, if necessary, a binder, a disintegrant, a lubricant, a coloring agent, a corrigent, etc., followed by preparing a tablet, a coated tablet, a granule, a powder, a capsule, etc. according to a conventional method. The additive may be an additive conventionally used in this field. Examples of the excipient include lactose, white sugar, sodium chloride, glucose, starch, calcium carbonate, kaolin, microcrystalline cellulose, silicic acid, and the like. Examples of the binder include water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, hydroxypropyl starch, methyl cellulose, ethyl cellulose, shellac, calcium phosphate, and polyvinyl pyrrolidone. Examples of the disintegrating agent include dried starch, sodium alginate, agar powder, sodium bicarbonate, calcium carbonate, sodium lauryl sulfate, glyceryl monostearate, and lactose. The lubricant may be purified talc, stearate, borax, polyethylene glycol, or the like. Examples of the taste-improving agent include white sugar, orange peel, citric acid, tartaric acid, and the like.

When preparing a liquid preparation for oral administration, a corrigent, a buffer, a stabilizer, a corrigent, etc. may be added to the methanol compound represented by the general formula (I) to prepare a liquid preparation for oral administration, a syrup, an elixir, etc. according to a conventional method. Examples of the taste-imparting agent include the above-mentioned ones, examples of the buffer include sodium citrate, and examples of the stabilizer include tragacanth, gum arabic and gelatin.

When preparing an injection, a methanol compound represented by the general formula (I) may be added with a pH adjuster, a buffer, a stabilizer, an isotonic agent, a local anesthetic, etc. to prepare subcutaneous, intramuscular, and intravenous injections according to a conventional method. Examples of the pH adjusting agent and the buffering agent include sodium citrate, sodium acetate, sodium phosphate and the like. Examples of the stabilizer include sodium pyrosulfite, EDTA, thioglycolic acid, and thiolactic acid. Examples of the local anesthetic include procaine hydrochloride and lidocaine hydrochloride. Examples of isotonic agents include sodium chloride and glucose.

When preparing suppositories, known suppository carriers such as polyethylene glycol, lanolin, cacao butter, fatty acid triglyceride and the like may be added to the methanol compound represented by the general formula (I), and if necessary, a surfactant such as ツイ - ン (registered trademark) may be further added to prepare the suppositories according to a conventional method.

When preparing an ointment, a conventionally used base, stabilizer, humectant, preservative and the like may be added to the methanol compound represented by the general formula (I) as required, and the mixture may be mixed by a conventional method to prepare a preparation. Examples of the base include liquid paraffin, white vaseline, white beeswax, octyl dodecyl alcohol, and paraffin. Examples of the preservative include methyl parahydroxybenzoate, ethyl parahydroxybenzoate, and propyl parahydroxybenzoate.

The methanol compound represented by the general formula (I) can be prepared into inhalants, eye drops and nose drops according to a conventional method.

The amount of the methanol compound represented by the general formula (I) to be administered varies depending on age, body weight, symptoms, administration manner, administration frequency, etc., and it is generally preferable that 1 to 1000mg of the methanol compound represented by the general formula (I) is administered orally or parenterally in one or a plurality of divided doses per day for an adult.

Examples

The present invention will be further described with reference to the following examples, but the present invention is not limited to these examples.

Example 1: production of 3- (2- {4- [5- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -4-propylpyridin-2-yl ] piperazin-1-yl } ethyl) -5- [4- (1-methylethoxy) phenyl ] -5-methylimidazolidine-2, 4-dione:

[ solution 9]

a) Production of 6-chloro-N-methylnicotinamide:

2-Chloronicotinyl chloride (5.65 g, 32.1 mol) was dissolved in tetrahydrofuran (64 mL), and triethylamine (5.59 mL, 40.1 mol) and a tetrahydrofuran solution of methylamine (20.1 mL, 40.1 mol) were added in this order under ice cooling, followed by stirring at room temperature for 3.5 hours. The reaction mixture was concentrated under reduced pressure and recrystallized (ethyl acetate/hexane) to obtain 5.06g (yield 92%) of the title compound as pale brown crystals.

¹H-NMR (CDCl₃) δ：3.05 (3H, d, J =4.6 Hz), 6.14 (1H, brs), 7.42 (1H, d, J = 8.3 Hz), 8.09 (1H, dd, J= 2.4, 8.3 Hz), 8.72 (1H, d, J = 2.4 Hz)。

b) Production of 6-chloro-N-methyl-4-propylnicotinamide:

6-chloro-N-methylnicotinamide (2.00 g, 11.7 mol) was dissolved in tetrahydrofuran (59 mL), propylmagnesium bromide (46.9 mL, 46.9 mol) was added under ice cooling, and the mixture was stirred at room temperature for 4.5 hours. Then, propylmagnesium bromide (46.9 mL, 46.9 mol) was added under ice cooling, and the mixture was further stirred at room temperature for 9 hours. Methanol (140 mL) and ammonium chloride (7.5 g) were added to the reaction mixture under ice cooling, and the mixture was stirred at room temperature for 30 minutes. DDQ (3.19 g, 14.1 mmol) was added to the reaction solution under ice cooling, and the mixture was stirred at room temperature for 2 hours. T-butyl methyl ether was added to the reaction solution, filtered through celite, and concentrated under reduced pressure. Extraction was performed with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform/methanol) to give the title compound as pale brown crystals 1.88g (yield 75%).

¹H-NMR (CDCl₃) δ：0.96 (3H, t, J= 7.3 Hz), 1.64 (2H, qt, J = 7.3, 7.8 Hz), 2.76 (2H, t, J = 7.8 Hz), 3.01 (3H, d, J = 4.9 Hz), 6.14 (1H, brs), 7.21 (1H, s), 8.30 (1H, s)。

c) Production of 6- [4- (2-hydroxyethyl) piperazin-1-yl ] -N-methyl-4-propylnicotinamide:

6-chloro-N-methyl-4-propylnicotinamide (123 mg, 0.578 mol) was dissolved in tetrahydrofuran (2 mL), 1-piperazineethanol (355. mu.L, 2.89 mol) was added at room temperature, and the mixture was stirred at 100 ℃ for 18 hours. The reaction solution was purified by silica gel column chromatography (chloroform/methanol) to give the title compound as yellow crystals (177 mg (> 99% yield).

¹H-NMR (CD₃OD) δ：0.93 (3H, t, J= 7.3 Hz), 1.59 (2H, qt, J = 7.3, 7.6 Hz), 2.58 (2H, t, J = 5.8 Hz), 2.63 (4H, t, J = 4.9 Hz), 2.74 (2H, t, J = 7.6 Hz), 2.86 (3H, s), 3.60 (4H, t, J = 4.9 Hz), 3.72 (2H, t, J = 5.8 Hz), 6.65 (1H, s), 8.09 (1H, s)。

d) Production of 6- [4- (2-acetoxyethyl) piperazin-1-yl ] -N-methyl-4-propylnicotinamide:

6- [4- (2-hydroxyethyl) piperazin-1-yl ] -N-methyl-4-propylnicotinamide (477 mg, 1.56 mol) was dissolved in acetic anhydride (1.5mL), and sulfuric acid (50. mu.L) was added under ice cooling, followed by stirring at room temperature for 10 minutes. The reaction solution was concentrated under reduced pressure, extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 496mg of the title compound as a yellow oil (yield 91%).

¹H-NMR (CDCl₃) δ：0.95 (3H, t, J= 7.3 Hz), 1.61 (2H, qt, J = 7.3, 7.6 Hz), 2.08 (3H, s), 2.60 (4H, t, J= 4.9 Hz), 2.68 (2H, t, J = 5.7 Hz), 2.76 (2H, t, J = 7.6 Hz), 2.97 (3H, d, J = 4.9 Hz), 3.60 (4H, t, J = 4.9 Hz),4.24 (2H, t, J= 5.7 Hz),5.73 (1H, brs), 6.44 (1H, s), 8.18 (1H, s)。

e) Production of tert-butyl 6- [4- (2-acetoxyethyl) piperazin-1-yl ] -4-propylnicotinoyl (methyl) carbamate:

reacting 6- [4- (2-acetoxyethyl) piperazin-1-yl]-N-methyl-4-propylnicotinamide (496 mg, 1.42 mol) was dissolved in acetonitrile (7.0 mL), and N, N '-dimethylaminopyridine (35mg, 0.284 mmol), di-tert-butyl dicarbonate (Boc) and N, N' -dimethylaminopyridine (35mg, 0.284 mmol) were added under ice cooling₂O), stirred at room temperature overnight. The reaction solution was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound 754m as a crude productg。

¹H-NMR (CDCl₃) δ：0.97 (3H, t, J= 7.3 Hz), 1.23 (9H, s), 1.48 (2H, qt, J = 7.3, 7.6 Hz), 2.09 (3H, s), 2.60 (4H, t, J = 4.9 Hz), 2.66-2.71 (4H, m), 3.29 (3H, s), 3.61 (4H, t, J= 4.9 Hz),4.24 (2H, t, J = 5.7 Hz), 6.45 (1H, s), 8.03 (1H, s)。

f) Production of methyl 6- [4- (2-hydroxyethyl) piperazin-1-yl ] -4-propylnicotinate:

sodium hydride (341 mg, 7.10 mmol) was added to methanol (7.5 mL) under ice-cooling, and a solution of tert-butyl 6- [4- (2-acetoxyethyl) piperazin-1-yl ] -4-propylnicotinoyl (methyl) carbamate (754 mg) in methanol (1.5mL) was added at room temperature, followed by stirring at room temperature for 1.5 hours. The reaction solution was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform/methanol) to give the title compound 441mg as a yellow oil (yield > 99%).

¹H-NMR (CDCl₃) δ：0.98 (3H, t, J= 7.3 Hz), 1.59 (2H, qt, J = 7.3, 7.6 Hz), 2.59-2.63 (6H, m), 2.89 (2H, t, J = 7.6 Hz), 3.65-3.69 (7H, m), 3.84 (3H, s), 6.39 (1H, s), 8.74 (1H, s)。

g) Production of 1,1,1,3,3, 3-hexafluoro-2- {6- [4- (2-hydroxyethyl) piperazin-1-yl ] -4-propylpyridin-3-yl } propan-2-ol:

methyl 6- [4- (2-hydroxyethyl) piperazin-1-yl ] -4-propylnicotinate (441 mg, 1.43 mmol) was dried under a vacuum pump and dissolved in ethylene glycol dimethyl ether (7.2 mL). (trifluoromethyl) trimethylsilane (2.11mL, 14.3mmol) and tetramethylammonium fluoride (1.20g, 12.9mmol) were added sequentially at-78 deg.C, the temperature was slowly raised to room temperature, and the mixture was stirred overnight. To the reaction mixture was added a 5% aqueous hydrochloric acid solution under ice cooling, followed by extraction with chloroform, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform/methanol) to give the title compound 296mg as brown crystals (yield 50%).

¹H-NMR (CDCl₃) δ：0.98 (3H, t, J= 7.3 Hz), 1.64 (2H, qt, J = 7.3, 7.8 Hz), 2.59-2.65 (6H, m), 2.67 (1H, s), 2.84 (2H, t, J = 7.8 Hz), 3.60 (4H, t, J = 5.1 Hz), 3.64 (1H, s), 3.67 (2H, t, J = 5.4 Hz), 6.48 (1H, s), 8.30 (1H, s)。

h) Production of 2- {4- [5- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -4-propylpyridin-2-yl ] piperazin-1-yl } ethyl acetate:

1,1,1,3,3, 3-hexafluoro-2- {6- [4- (2-hydroxyethyl) piperazin-1-yl ] -4-propylpyridin-3-yl } propan-2-ol (208 mg, 0.501 mol) was dissolved in dichloromethane (2.5 mL), pyridine (121. mu.L, 1.50 mmol) and acetic anhydride (142. mu.L, 1.50 mmol) were added under ice cooling, and the mixture was stirred at room temperature for 3 hours. Methanol was added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, extracted with chloroform, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 247mg of the title compound as a reddish brown oil.

¹H-NMR (CDCl₃) δ：0.97 (3H, t, J= 7.3 Hz), 1.64 (2H, qt, J = 7.3, 7.8 Hz), 2.08 (3H, s), 2.64 (4H, t, J= 4.6 Hz), 2.71 (2H, t, J = 5.7 Hz), 2.84 (2H, t, J = 7.8 Hz), 3.61 (4H, t, J = 4.6 Hz), 3.62 (1H, s), 4.25 (2H, t, J = 5.7 Hz), 6.47 (1H, s), 8.30 (1H, s)。

i) Production of 2- (4- {5- [1,1,1,3,3, 3-hexafluoro-2- (4-methoxybenzyloxy) propan-2-yl ] -4-propylpyridin-2-yl } piperazin-1-yl) acetic acid ethyl ester:

acetic acid 2- {4- [5- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -4-propylpyridin-2-yl ] piperazin-1-yl } ethyl ester (211 mg, 0.461 mol) was dissolved in N, N-dimethylformamide (2.3 mL), and potassium carbonate (191mg, 1.38mmol) was added at room temperature. Methoxybenzylchloride (125. mu.L, 0.923 mmol) was added under ice cooling, and the mixture was stirred at room temperature for one night. Then, potassium carbonate (96mg, 0.690mmol) was further added at room temperature, and methoxybenzyl chloride (63. mu.L, 0.462 mmol) was added under ice cooling, followed by stirring at room temperature for 8 hours. Water was added to the reaction solution, followed by extraction with chloroform, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 479mg of the title compound as a reddish brown oil.

¹H-NMR (CDCl₃) δ：0.79 (3H, t, J= 7.3 Hz), 1.54 (2H, qt, J = 7.3, 8.3 Hz), 2.08 (3H, s), 2.62 (4H, t, J= 4.9 Hz), 2.69 (2H, t, J = 5.8 Hz), 2.77 (2H, t, J = 8.3 Hz), 3.62 (4H, t, J = 4.9 Hz), 3.81 (3H, s), 4.24 (2H, t, J = 5.8 Hz), 4.53 (2H, s), 6.57 (1H, s), 6.90 (2H, d, J = 8.6 Hz), 7.27 (2H, d, J= 8.6 Hz), 8.30 (1H, s)。

j) Production of 2- (4- {5- [1,1,1,3,3, 3-hexafluoro-2- (4-methoxybenzyloxy) propan-2-yl ] -4-propylpyridin-2-yl } piperazin-1-yl) ethanol:

acetic acid 2- (4- {5- [1,1,1,3,3, 3-hexafluoro-2- (4-methoxybenzyloxy) propan-2-yl ] -4-propylpyridin-2-yl } piperazin-1-yl) ethyl ester (479 mg) was dissolved in methanol (2.3 mL), and potassium carbonate (127mg, 0.722mmol) was added, followed by stirring at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform/methanol) to give the title compound 117mg (yield 47%) as a yellow oil.

¹H-NMR (CDCl₃) δ：0.79 (3H, t, J= 7.3 Hz), 1.54 (2H, qt, J = 7.3, 8.3 Hz), 2.62 (2H, t, J = 5.2 Hz), 2.66 (4H, t, J = 5.1 Hz), 2.77 (2H, t, J = 8.3 Hz), 3.11 (1H, s), 3.65 (4H, t, J = 5.1 Hz), 3.70 (2H, t, J = 5.2 Hz), 3.82 (3H, s), 4.53 (2H, s), 6.58 (1H, s), 6.90 (2H, d, J = 8.8 Hz), 7.27 (2H, d, J = 8.8 Hz), 8.31 (1H, s)。

k) Production of 1- [4- (1-methylethoxy) phenyl ] ethanone:

15.0g (110 mmol) of 1- (4-hydroxyphenyl) ethanone was dissolved in 125 mL of acetone, and 30.4 g (220 mmol) of potassium carbonate and 16.5 mL (165 mmol) of 1-methylethyl iodide were sequentially added thereto, followed by stirring at 70 ℃ for 8 hours. The reaction solution was filtered, washed with acetone, and concentrated under reduced pressure. To the resulting residue were added water and ethyl acetate, followed by extraction with ethyl acetate, washing of the organic layer with a 1N aqueous solution of sodium hydroxide and saturated brine, drying over anhydrous sodium sulfate, and concentration under reduced pressure to obtain 18.2 g (yield 93%) of 1- [4- (1-methylethoxy) phenyl ] ethanone as white crystals.

¹H-NMR (CDCl₃) δ：1.37 (6H, d, J = 5.9 Hz), 2.56 (3H, s), 4.65 (1H, quint, J = 5.9 Hz), 6.90 (2H, d, J = 8.9 Hz). 7.92 (2H, d, J = 8.9 Hz)。

l) production of 5-methyl-5- (4- (1-methylethoxy) phenyl) imidazolidine-2, 4-dione:

35.2g (196 mmol) of 1- [4- (1-methylethoxy) phenyl ] ethanone was dissolved in 200mL of ethanol and 200mL of water, and sodium cyanide (14.4g, 294mmol) and ammonium carbonate (226g, 9.41mol) were added thereto, followed by stirring at 70 ℃ for 13 hours. The reaction mixture was filtered, washed with water, hexane/ethyl acetate and dried to obtain 35.1g (yield: 72%) of the title compound as white crystals.

¹H-NMR (CDCl₃) δ：1.28 (6H, d, J = 5.9 Hz), 1.72 (3H, s), 4.59 (1H, quint, J = 5.9 Hz), 6.89 (2H, d, J = 8.6 Hz), 7.38 (2H, d, J = 8.6 Hz)。

m) production of 3- [2- (4- {5- [1,1,1,3,3, 3-hexafluoro-2- (4-methoxybenzyloxy) propan-2-yl ] -4-propylpyridin-2-yl } piperazin-1-yl) ethyl ] -5- [4- (1-methylethoxy) phenyl ] -5-methylimidazolidine-2, 4-dione:

2- (4- {5- [1,1,1,3,3, 3-hexafluoro-2- (4-methoxybenzyloxy) propan-2-yl ] -4-propylpyridin-2-yl } piperazin-1-yl) ethanol (20 mg, 0.0373 mmol), 5-methyl-5- (4- (1-methylethoxy) phenyl) imidazolidine-2, 4-dione (34.3 mg,0.138 mmol), triphenylphosphine (34.5 mg,0.132 mmol) were dried with a vacuum pump, dissolved in N, N-dimethylformamide (3mL), DEAD (51. mu.L, 0.111 mmol) was added under ice cooling, and stirred at room temperature for 1 hour. Water (1.0mL) and a 2N aqueous hydrochloric acid solution (1.0mL) were added to the reaction mixture under ice cooling, extraction was performed with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/acetone) to give the title compound as a yellow oil 30mg (yield 99%).

¹H-NMR (CDCl₃) δ：0.79 (3H, t, J= 7.3 Hz), 1.26 (6H, d, J = 6.1 Hz), 1.53 (2H, qt, J = 7.3, 8.3 Hz), 1.81 (3H, s), 2.55-2.60 (4H, m), 2.64 (2H, t, J = 6.1 Hz), 2.76 (2H, t, J = 8.3 Hz), 3.45-3.49 (4H, m), 3.69 (2H, t, J = 6.1 Hz), 3.81 (3H, s), 4.49 (1H, q, J = 6.1 Hz), 4.52 (2H, s), 6.02 (1H, brs), 6.53 (1H, s), 6.85 (2H, d, J = 8.8 Hz), 6.90 (2H, d, J = 8.6 Hz), 7.27 (2H, d, J = 8.6 Hz), 7.40 (2H, d, J = 8.8 Hz), 8.29 (1H, s)。

n) production of 3- (2- {4- [5- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -4-propylpyridin-2-yl ] piperazin-1-yl } ethyl) -5- [4- (1-methylethoxy) phenyl ] -5-methylimidazolidine-2, 4-dione:

3- [2- (4- {5- [1,1,1,3,3, 3-hexafluoro-2- (4-methoxybenzyloxy) propan-2-yl ] -4-propylpyridin-2-yl } piperazin-1-yl) ethyl ] -5- [4- (1-methylethoxy) phenyl ] -5-methylimidazolidine-2, 4-dione (10mg, 0.0131 mmol) was dissolved in ethyl acetate (2 mL), palladium on carbon (1.0mg) was added, hydrogenation was performed, and stirring was performed at room temperature for 6 hours. The reaction mixture was filtered through celite, and concentrated under reduced pressure to give 7.3mg (yield 86%) of the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：0.97 (3H, t, J= 7.3 Hz), 1.27 (6H, d, J = 6.1 Hz), 1.62 (2H, qt, J = 7.3, 7.8 Hz), 1.81 (3H, s), 2.52-2.59 (4H, m), 2.64 (2H, t, J = 6.1 Hz), 2.80 (2H, t, J = 7.8 Hz), 3.42-3.46 (5H, m), 3.68 (2H, t, J = 6.1 Hz), 4.48 (1H, q, J = 6.1 Hz),5.82 (1H, brs), 6.42 (1H, s), 6.85 (2H, d, J= 8.8 Hz), 7.39 (2H, d, J = 8.8 Hz), 8.28 (1H, s)。

Example 2: production of 3- (2- {4- [5- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -4-propylpyridin-2-yl ] piperazin-1-yl } ethyl) -5- (6-methoxypyridin-3-yl) -5-methylimidazolidine-2, 4-dione:

[ solution 10]

a) Production of 5- (6-methoxypyridin-3-yl) -5-methylimidazolidine-2, 4-dione:

using 1- (6-methoxypyridin-3-yl) ethanone, the reaction and treatment were carried out in the same manner as in example 1-l) to obtain the title compound as white crystals.

¹H-NMR (CDCl₃) δ：1.74 (3H, s), 3.90 (3H, s), 6.81 (1H, d, J = 8.6 Hz), 7.81 (1H, dd, J = 2.7, 8.6 Hz), 8.23 (1H, d, J = 2.7 Hz)。

b) Production of 3- (2- {4- [5- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -4-propylpyridin-2-yl ] piperazin-1-yl } ethyl) -5- (6-methoxypyridin-3-yl) -5-methylimidazolidine-2, 4-dione:

the reaction and the treatment were carried out in the same manner as in example 1 using 5- (6-methoxypyridin-3-yl) -5-methylimidazolidine-2, 4-dione to give the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：0.91 (3H, t, J = 7.3 Hz), 1.55 (2H, qt, J = 7.3, 7.6 Hz), 1.76 (3H, s), 2.50-2.58 (6H, m), 2.74 (2H, t, J = 7.6 Hz), 3.31-3.42 (5H, m), 3.61-3.65 (2H, m), 3.77 (3H, s),5.89 (1H, brs), 6.36 (1H, s), 6.65 (1H, d, J = 8.8 Hz), 7.66 (1H, dd, J = 2.2, 8.8 Hz), 8.21 (1H, s), 8.24 (1H, d, J = 2.2 Hz)。

Example 3: production of 5- (2, 3-dihydrobenzofuran-5-yl) -3- (2- {4- [5- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -4-propylpyridin-2-yl ] piperazin-1-yl } ethyl) -5-methylimidazolidine-2, 4-dione:

[ solution 11]

a) Production of 5- (2, 3-dihydrobenzofuran-5-yl) -5-methylimidazolidine-2, 4-dione:

2, 3-dihydrobenzofuran (10g, 83.2 mmol) was dissolved in dichloromethane (400 mL), acetyl chloride (11.8mL, 167mmol) and aluminum chloride (33.3g, 250mmol) were added in this order at-10 ℃ and stirred at-10 ℃ for 30 minutes. To the reaction mixture was added a 5% aqueous hydrochloric acid solution, followed by extraction with ethyl acetate, washing of the organic layer with a saturated aqueous sodium bicarbonate solution and a saturated brine, drying over anhydrous sodium sulfate, and concentration under reduced pressure to obtain 13.4g of 1- (2, 3-dihydrobenzofuran-5-yl) ethanone as a colorless oil (yield 99%).

¹H-NMR (CDCl₃) δ：2.55 (3H, s), 3.25 (2H, t, J = 8.6 Hz), 4.67 (2H, t, J = 8.6 Hz), 6.80 (1H, d, J= 8.1 Hz), 7.80 (1H, dd, J = 1.9, 8.1 Hz), 7.85 (1H, d, J = 1.9 Hz)。

Using 1- (2, 3-dihydrobenzofuran-5-yl) ethanone, the reaction and treatment were carried out in the same manner as in example 1-l) to obtain the title compound as white crystals.

¹H-NMR (CDCl₃) δ：2.62 (3H, s), 3.32 (2H, t, J = 8.6 Hz), 4.74 (2H, t, J = 8.6 Hz), 6.87 (1H, d, J= 8.8 Hz), 7.22 (1H, dd, J = 2.2, 8.8 Hz), 7.34 (1H, d, J = 2.2 Hz)。

b) Production of 5- (2, 3-dihydrobenzofuran-5-yl) -3- (2- {4- [5- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -4-propylpyridin-2-yl ] piperazin-1-yl } ethyl) -5-methylimidazolidine-2, 4-dione:

the reaction and the treatment were carried out in the same manner as in example 1 using 5- (2, 3-dihydrobenzofuran-5-yl) -5-methylimidazolidine-2, 4-dione to obtain the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：0.98 (3H, t, J= 7.3 Hz), 1.63 (2H, qt, J = 7.3, 8.0 Hz), 1.81 (3H, s), 2.53-2.59 (4H, m), 2.64 (2H, t, J = 6.1 Hz), 2.81 (2H, t, J = 8.0 Hz), 3.14 (2H, t, J = 8.8 Hz), 3.41-3.44 (4H, m), 3.46 (1H, s), 3.69 (2H, t, J = 6.1 Hz), 4.49 (2H, t, J = 8.8 Hz),5.57 (1H, s), 6.42 (1H, s), 6.74 (1H, d, J = 8.6 Hz), 7.22 (1H, dd, J = 2.0. 8.6 Hz), 7.33 (1H, d, J= 2.0 Hz), 8.28 (1H, s)。

Example 4: production of 3- (2- {4- [4- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -2-propylphenyl ] piperazin-1-yl } ethyl) -5- [4- (1-methylethoxy) phenyl ] -5-methylimidazolidine-2, 4-dione:

[ solution 12]

a) Production of methyl 3-bromo-4-fluorobenzoate:

3-bromo-4-fluorobenzoic acid (3.33 g, 15.2 mmol) was dissolved in methanol (30 mL), acetyl chloride (4.3mL, 60.8mmol) was added under ice cooling, and the mixture was stirred at room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound as a colorless oil 3.2g (yield 90%).

¹H-NMR (CDCl₃) δ：3.92 (3H, s), 7.18 (1H, dd, J = 8.0, 8.2 Hz), 7.99 (1H, ddd, J = 1.9, 4.9, 8.0 Hz), 8.27 (1H, dd, J = 1.9, 6.5 Hz)。

b) Production of methyl 3-bromo-4- [4- (2-hydroxyethyl) piperazin-1-yl ] benzoate:

methyl 3-bromo-4-fluorobenzoate (1.39 g,5.96 mmol) was dissolved in N, N-dimethylformamide (12 mL), 1-piperazineethanol (3.88g, 29.8mmol) and potassium carbonate (2.47g, 17.9mmol) were added, and the mixture was stirred at 100 ℃ for 30 minutes under microwave irradiation. Water was added to the reaction solution at room temperature, extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/acetone) to give the title compound as a yellow oil 730mg (yield 36%).

¹H-NMR (CDCl₃) δ：2.64 (2H, t, J= 5.1 Hz), 2.71-2.75 (5H, m), 3.15-3.19 (4H, m), 3.67 (2H, t, J = 5.1 Hz), 3.89 (3H, s), 7.03 (1H, d, J = 8.6 Hz), 7.94 (1H, dd, J = 1.6, 8.6 Hz), 8.22 (1H, d, J = 1.6 Hz)。

c) Preparation of methyl 4- {4- [2- (benzyloxy) ethyl ] piperazin-1-yl } -3-bromobenzoate:

methyl 3-bromo-4- [4- (2-hydroxyethyl) piperazin-1-yl ] benzoate (100mg, 0.291 mmol) was dried with a vacuum pump and dissolved in N, N-dimethylformamide (2.9 mL). Sodium hydride (15.2mg, 0.350mmol) and benzyl bromide (38. mu.L, 0.320mmol) were added successively under ice cooling, and the mixture was stirred at room temperature for 15 hours. Water was added to the reaction solution under ice-cooling, extraction was performed with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/acetone) to give the title compound 43mg as a yellow oil (yield 34.3%).

¹H-NMR (CDCl₃) δ：2.70-2.73 (6H, m), 3.11-3.65 (4H, m), 3.63 (2H, t, J = 5.6 Hz), 3.86 (3H, s), 4.56 (2H, s), 7.03 (1H, d, J = 8.6 Hz), 7.28-7.42 (5H, m), 7.93 (1H, dd, J = 1.9, 8.6 Hz), 8.22 (1H, d, J = 1.9 Hz)。

d) Production of methyl (Z) -4- {4- [2- (benzyloxy) ethyl ] piperazin-1-yl } -3- (prop-1-en-1-yl) benzoate:

methyl 4- {4- [2- (benzyloxy) ethyl ] piperazin-1-yl } -3-bromobenzoate (78 mg, 0.180 mmol) was dissolved in N, N-dimethylformamide: water = 3: 1 (1.8 mL). (Z) -Propenylboronic acid (containing about 10% of E-form, the same material was used hereinafter) (37mg, 0.433mmol), tetrakis (triphenylphosphine) palladium (10mg, 0.00902mmol) and sodium carbonate (76mg, 0.722mmol) were added in this order at room temperature, and the mixture was stirred at 80 ℃ for 1 hour under microwave irradiation. The reaction solution was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/acetone) to give the title compound 61mg as a yellow oil (yield 86%).

¹H-NMR (CDCl₃) δ：1.89 (3H, dd, J= 1.7, 7.1 Hz), 2.63-2.65 (4H, m), 2.69 (2H, t, J = 5.6 Hz), 3.09-3.11 (4H, m), 3.62 (2H, t, J = 5.6 Hz), 3.88 (3H, s), 4.56 (2H, s),5.80 (1H, qd, J = 7.1, 11.4 Hz), 6.41 (1H, dd, J = 1.7, 11.4 Hz), 6.95 (1H, d, J = 8.5 Hz), 7.27-7.44 (5H, m), 7.87 (1H, dd, J = 1.9, 8.5 Hz), 7.92 (1H, d, J = 1.9 Hz)。

e) Production of (Z) -4- {4- [2- (benzyloxy) ethyl ] piperazin-1-yl } -3- (prop-1-en-1-yl) benzoic acid:

methyl (Z) -4- {4- [2- (benzyloxy) ethyl ] piperazin-1-yl } -3- (prop-1-en-1-yl) benzoate (20 mg, 0.0507 mmol) was dissolved in methanol (1.0 mL). Under ice-cooling, a 4N-sodium hydroxide aqueous solution (50. mu.L) was added thereto, and the mixture was stirred at 50 ℃ overnight. To the reaction solution was added a 4N-hydrochloric acid aqueous solution under ice cooling, extraction was performed with chloroform, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/acetone) to give the title compound 13mg (yield 65%) as a yellow oil.

¹H-NMR (CDCl₃) δ：1.89 (3H, dd, J= 1.4, 7.1 Hz), 2.75-2.83 (6H, m), 3.14-3.17 (4H, m), 3.71 (2H, t, J = 5.4 Hz), 4.54 (2H, s), 4.71 (1H, s),5.81 (1H, qd, J = 7.1, 11.4 Hz), 6.41 (1H, dd, J = 1.4, 11.4 Hz), 6.96 (1H, d, J = 8.5 Hz), 7.27-7.38 (5H, m), 7.91 (1H, dd, J = 2.0, 8.5 Hz), 7.96 (1H, d, J = 2.0 Hz)。

f) Production of perfluorophenyl (Z) -4- {4- [2- (benzyloxy) ethyl ] piperazin-1-yl } -3- (prop-1-en-1-yl) benzoate:

(Z) -4- {4- [2- (benzyloxy) ethyl ] piperazin-1-yl } -3- (prop-1-en-1-yl) benzoic acid (13 mg, 0.0331 mmol) was dissolved in ethyl acetate (3.3 mL). Pentafluorophenol (7.3mg, 0.0397mmol) and N, N' -dicyclohexylcarbodiimide (8.2mg, 0.0397mmol) were added in this order at room temperature, and the mixture was stirred at room temperature for 14 hours. Water was added to the reaction solution, extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/acetone) to give the title compound as pale yellow crystals 16mg (yield 86%).

¹H-NMR (CDCl₃) δ：1.91 (3H, dd, J= 1.7, 7.1 Hz), 2.66-2.68 (4H, m), 2.71 (2H, t, J = 5.6 Hz), 3.17-3.19 (4H, m), 3.63 (2H, t, J = 5.6 Hz), 4.56 (2H, s),5.86 (1H, qd, J= 7.1, 11.4 Hz), 6.40 (1H, dd, J = 1.7, 11.4 Hz), 7.02 (1H, d, J= 9.3 Hz), 7.27-7.38 (5H, m), 8.01-8.04 (2H, m)。

g) Production of (Z) -2- (4- {4- [2- (benzyloxy) ethyl ] piperazin-1-yl } -3- (prop-1-en-1-yl) phenyl) -1,1,1,3,3, 3-hexafluoropropan-2-ol:

perfluorophenyl (Z) -4- {4- [2- (benzyloxy) ethyl ] piperazin-1-yl } -3- (prop-1-en-1-yl) benzoate (60 mg, 0.110 mmol) was dried with a vacuum pump and dissolved in ethylene glycol dimethyl ether (2.2 mL). (trifluoromethyl) trimethylsilane (162. mu.L, 1.10mmol) and tetramethylammonium fluoride (102mg, 1.10mmol) were added sequentially at-78 ℃ and the mixture was slowly warmed to room temperature and stirred for 12 hours. Water was added to the reaction solution under ice-cooling, extraction was performed with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/acetone) to give the title compound as an orange oil 40mg (yield 73%).

¹H-NMR (CDCl₃) δ：1.83 (3H, dd, J= 1.7, 7.1 Hz), 2.68-2.71 (4H, m), 2.74 (2H, t, J = 5.6 Hz), 3.02-3.05 (4H, m), 3.65 (2H, t, J = 5.6 Hz), 4.07 (1H, brs), 4.54 (2H, s),5.80 (1H, qd, J = 7.1, 11.4 Hz), 6.44 (1H, dd, J = 1.7, 11.4 Hz), 6.99 (1H, d, J = 9.3 Hz), 7.27-7.37 (5H, m), 7.54-7.56 (2H, m)。

h) Production of (Z) -1- [2- (benzyloxy) ethyl ] -4- {4- [1,1,1,3,3, 3-hexafluoro-2- (methoxymethoxy) propan-2-yl ] -2- (prop-1-en-1-yl) phenyl } piperazine:

(Z) -2- (4- {4- [2- (benzyloxy) ethyl ] piperazin-1-yl } -3- (prop-1-en-1-yl) phenyl) -1,1,1,3,3, 3-hexafluoropropan-2-ol (40 mg, 0.0796 mmol) was dried with a vacuum pump and dissolved in dichloromethane (796. mu.L). Diisopropylethylamine (42. mu.L, 0.239mmol) and chloromethyl methyl ether (6.6. mu.L, 0.0876mmol) were added in this order under ice cooling, and the mixture was stirred at room temperature for 20 hours. Diisopropylethylamine (84. mu.L, 0.478mmol) and chloromethyl methyl ether (26. mu.L, 0.350mmol) were further added successively under ice cooling, and the mixture was stirred at room temperature overnight. Water was added to the reaction solution under ice-cooling, extraction was performed with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/acetone) to give the title compound as a pale yellow oil 32mg (yield 73%).

¹H-NMR (CDCl₃) δ：1.84 (3H, dd, J= 1.7, 7.1 Hz), 2.67-2.69 (4H, m), 2.72 (2H, t, J = 5.6 Hz), 3.07-3.09 (4H, m), 3.54 (3H, s), 3.64 (2H, t, J = 5.6 Hz), 4.54 (2H, s), 4.85 (2H, s),5.81 (1H, qd, J = 7.1, 11.4 Hz), 6.45 (1H, dd, J = 1.7, 11.4 Hz), 6.99 (1H, d, J = 8.5 Hz), 7.27-7.37 (5H, m), 7.43 (1H, dd, J= 2.0, 8.5 Hz), 7.47 (1H, d, J = 2.0 Hz)。

i) Production of 2- (4- {4- [1,1,1,3,3, 3-hexafluoro-2- (methoxymethyloxy) propan-2-yl ] -2-propylphenyl } piperazin-1-yl) ethanol:

(Z) -1- [2- (benzyloxy) ethyl ] -4- {4- [1,1,1,3,3, 3-hexafluoro-2- (methoxymethoxy) propan-2-yl ] -2- (prop-1-en-1-yl) phenyl } piperazine (33 mg, 0.0604 mmol) was dissolved in methanol (4mL), palladium on carbon (3.3mg) was added, hydrogenation was performed, and stirring was performed at room temperature for 12 hours. The reaction solution was filtered through celite, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/acetone) to give the title compound 7.8mg (yield 24%) as a yellow oil.

¹H-NMR (CDCl₃) δ：0.96 (3H, t, J= 7.3 Hz), 1.65 (2H, qt, J = 7.3, 7.6 Hz), 2.62-2.71 (9H, m), 2.96 (4H, t, J = 4.6 Hz), 3.55 (3H, s), 3.67 (2H, t, J = 5.4 Hz), 4.83 (2H, s), 7.09 (1H, d, J = 8.3 Hz), 7.37-7.41 (2H, m)。

j) Production of 3- [2- (4- {4- [1,1,1,3,3, 3-hexafluoro-2- (methoxymethyloxy) propan-2-yl ] -2-propylphenyl } piperazin-1-yl) ethyl ] -5- [4- (1-methylethoxy) phenyl ] -5-methylimidazolidine-2, 4-dione:

2- (4- {4- [1,1,1,3,3, 3-hexafluoro-2- (methoxymethoxy) propan-2-yl ] -2-propylphenyl } piperazin-1-yl) ethanol (7.8 mg, 0.0170 mmol), 5-methyl-5- (4- (1-methylethoxy) phenyl) imidazolidine-2, 4-dione (15.6 mg, 0.0631 mmol), triphenylphosphine (15.8 mg, 0.0601 mmol) were dried with a vacuum pump, dissolved in N, N-dimethylformamide (284. mu.L), DEAD (23. mu.L, 0.0167 mmol) was added under ice cooling, and stirred at room temperature for 1 hour. Water (1.0mL) and a 2N aqueous hydrochloric acid solution (1.0mL) were added to the reaction mixture under ice cooling, extraction was performed with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/acetone) to give the title compound as a yellow oil, 3.1mg (yield 26%).

¹H-NMR (CDCl₃) δ：0.94 (3H, t, J= 7.3 Hz), 1.30 (6H, d, J = 6.1 Hz), 1.62 (2H, qt, J = 7.3, 7.6 Hz), 1.83 (3H, s), 2.58-2.71 (8H, m), 2.78-2.80 (4H, m), 3.55 (3H, s), 3.65-3.73 (2H, m), 4.51 (1H, q, J = 6.1 Hz), 4.82 (2H, s), 4.57 (1H, s), 6.87 (2H, d, J = 8.8 Hz), 7.00 (1H, dd, J = 8.3 Hz), 7.35 (1H, dd, J = 2.2, 8.3 Hz), 7.38 (1H, d, J = 2.2 Hz), 7.42 (2H, d, J= 8.8 Hz)。

k) Production of 3- (2- {4- [4- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -2-propylphenyl ] piperazin-1-yl } ethyl) -5- [4- (1-methylethoxyphenyl) ] -5-methylimidazolidine-2, 4-dione:

3- [2- (4- {4- [1,1,1,3,3, 3-hexafluoro-2- (methoxymethoxy) propan-2-yl ] -2-propylphenyl } piperazin-1-yl) ethyl ] -5- [4- (1-methylethoxy) phenyl ] -5-methylimidazolidine-2, 4-dione (3.1mg, 0.00450 mmol) was dissolved in methanol (1mL), and 4N-aqueous hydrochloric acid (50. mu.L) was added and stirred at 50 ℃ for 1.5 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the obtained residue, and a saturated aqueous sodium bicarbonate solution was added under ice cooling. Extraction was performed with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/acetone) to give the title compound as a yellow oil, 3.0mg (yield 99%).

¹H-NMR (CDCl₃) δ：0.95 (3H, t, J= 7.3 Hz), 1.29 (6H, d, J = 6.1 Hz), 1.64 (2H, qt, J = 7.3, 7.6 Hz), 1.83 (3H, s), 2.59-2.72 (8H, m), 2.76-2.82 (4H, m), 3.39 (1H, s), 3.64-3.71 (2H, m), 4.51 (1H, q, J = 6.1 Hz),5.56 (1H, s), 6.87 (2H, d, J= 8.8 Hz), 7.00 (1H, dd, J = 8.6 Hz), 7.42 (2H, d, J = 8.3 Hz), 7.44 (1H, dd, J = 2.2, 8.6 Hz), 7.48 (1H, d, J = 2.2 Hz)。

Example 5: production of 5- (benzo [ d ] [1,3] dioxol-5-yl) -3- (2- {4- [4- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -2-propylphenyl ] piperazin-1-yl } ethyl) -5-methylimidazolidine-2, 4-dione:

[ solution 13]

a) Production of 5- (benzo [ d ] [1,3] dioxol-5-yl) -5-methylimidazolidine-2, 4-dione:

using 5- (benzo [ d ] [1,3] dioxol-5-yl) ethanone, the reaction and treatment were carried out in the same manner as in example 1-l) to obtain the title compound as white crystals.

¹H-NMR (CDCl₃) δ：1.83 (3H, s),5.99 (2H, s), 6.81 (1H, d, J = 8.3 Hz), 6.95 (1H, dd, J = 2.2, 8.3 Hz), 6.99 (1H, d, J = 2.2 Hz)。

b) Production of 5- (benzo [ d ] [1,3] dioxol-5-yl) -3- (2- {4- [4- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -2-propylphenyl ] piperazin-1-yl } ethyl) -5-methylimidazolidine-2, 4-dione:

the reaction and treatment were carried out in the same manner as in example 4 using 5- (benzo [ d ] [1,3] dioxol-5-yl) -5-methylimidazolidine-2, 4-dione to obtain the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：0.94 (3H, t, J= 7.3 Hz), 1.64 (2H, qt, J = 7.3, 7.6 Hz), 1.81 (3H, s), 2.59-2.73 (8H, m), 2.77-2.79 (4H, m), 3.62-3.76 (3H, m),5.66 (1H, s),5.89 (2H, s), 6.80 (1H, d, J = 8.0 Hz), 6.98 (1H, dd, J = 1.9, 8.0 Hz), 7.01 (1H, d, J= 8.3 Hz), 7.05 (1H, d, J = 1.9 Hz), 7.44 (1H, dd, J = 2.0, 8.3 Hz), 7.48 (1H, d, J = 2.0 Hz)。

Example 6: production of 3- (2- {4- [4- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -2-propylphenyl ] piperazin-1-yl } -2-oxoethyl) -5- [5- (1-methylethoxy) pyridin-2-yl ] -5-methylimidazolidine-2, 4-dione:

[ solution 14]

a) Production of methyl 4-fluoro-3-nitrobenzoate:

3-Nitro-4-fluorobenzoic acid (25.6 g, 138 mmol) was dissolved in methanol (300 mL), thionyl chloride (18.4mL, 258mmol) was added at-78 deg.C, and after stirring at-78 deg.C for 10 minutes, stirring was carried out at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain 29.6g of the title compound as white crystals (yield > 99%).

¹H-NMR (CDCl₃) δ：3.98 (3H, s), 7.39 (1H, dd, J = 8.8, 10.3 Hz), 8.32 (1H, ddd, J = 2.4, 4.3, 8.8 Hz), 8.75 (1H, dd, J = 2.4, 7.2 Hz)。

b) Production of tert-butyl 4- [4- (methoxycarbonyl) -2-nitrophenyl ] piperazine-1-carboxylate:

to a solution of methyl 4-fluoro-3-nitrobenzoate (2.50g, 12.6 mmol) in tetrahydrofuran (75 mL) were added tert-butyl piperazine-1-carboxylate (4.67 g, 25.2 mmol) and potassium carbonate (4.34 g, 25.2 mmol) in this order under ice cooling, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution under ice cooling, extraction was performed with ethyl acetate, and then the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate) to obtain 4.83g (yield 100%) of the title compound as yellow crystals.

¹H-NMR (CDCl₃) δ：1.48 (9H, s), 3.15 (4H, t, J = 4.3 Hz), 3.61 (4H, t, J = 4.3 Hz), 3.92 (3H, s), 7.08 (1H, d, J = 8.6 Hz), 8.09 (1H, dd, J = 2.2, 8.6 Hz), 8.47 (1H, d, J = 2.2 Hz)。

c) Preparation of tert-butyl 4- [ 2-amino-4- (methoxycarbonyl) phenyl ] piperazine-1-carboxylate

In 4- [4- (methoxycarbonyl) -2-nitrophenyl]Piperazine-1-carboxylic acid tert-butyl ester (200 mg,0.547 mmol) in 1, 4-bisTo a solution of alkane-water (2:1) (6.0 mL) were added iron powder (76mg, 1.37 mmol) and acetic acid (1mL) under ice cooling, and the mixture was stirred at room temperature overnight. Water and a saturated aqueous sodium bicarbonate solution were added to the reaction mixture under ice cooling, the mixture was filtered through celite, extracted with ethyl acetate, and then the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/acetone) to give the title compound as a yellow oil 83mg (yield 45%).

¹H-NMR (CDCl₃) δ：1.49 (9H, s), 2.91 (4H, t, J = 4.6 Hz), 3.58 (4H, t, J = 4.6 Hz), 3.87 (3H, s), 4.42 (2H, brs), 6.95 (1H, d, J = 7.8 Hz), 7.41 (1H, d, J = 7.9 Hz), 7.45 (1H, dd, J = 1.9, 7.8 Hz)。

d) Preparation of tert-butyl 4- [ 2-iodo-4- (methoxycarbonyl) phenyl ] piperazine-1-carboxylate

To a solution of tert-butyl 4- [ 2-amino-4- (methoxycarbonyl) phenyl ] piperazine-1-carboxylate (231 mg, 0.657 mmol) in acetonitrile (6.6 mL) was added p-toluenesulfonic acid monohydrate (375 mg, 1.97 mmol) under ice cooling, and then a mixed solution of sodium nitrite (91mg, 1.31mmol) and potassium iodide (273mg, 1.64mmol) was added under ice cooling, and the mixture was stirred at room temperature overnight. Water and an aqueous solution of sodium thiosulfate were added to the reaction mixture under ice cooling, followed by extraction with ethyl acetate, and then the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/acetone) to give the title compound 127mg (yield 43%) as white crystals.

¹H-NMR (CDCl₃) δ：1.49 (9H, s), 3.01 (4H, t, J = 4.9 Hz), 3.64 (4H, t, J = 4.9 Hz), 3.89 (3H, s),6.98 (1H, d, J = 8.4 Hz), 7.79 (1H, dd, J = 2.0, 8.4 Hz), 8.51 (1H, d, J = 2.0 Hz)。

e) Production of tert-butyl (Z) -4- [4- (methoxycarbonyl) -2- (prop-1-en-1-yl) phenyl ] piperazine-1-carboxylate:

tert-butyl 4- (2-iodo-4- (methoxycarbonyl) phenyl) piperazine-1-carboxylate (127mg, 0.285 mmol) was dissolved in N, N-dimethylformamide: water = 3: 1 (2.8 mL). (Z) -Propenylboronic acid (59mg, 0.684mmol), tetrakis (triphenylphosphine) palladium (16mg, 0.0143mmol) and sodium carbonate (121mg, 1.14 mmol) were added in this order at room temperature, and the mixture was stirred at 80 ℃ for 1 hour under microwave irradiation. The reaction solution was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/acetone) to give the title compound as yellow crystals 96mg (yield 94%).

¹H-NMR (CDCl₃) δ：1.48 (9H, s), 1.89 (3H, dd, J = 1.9, 7.2 Hz), 2.99 (4H, t, J = 4.9 Hz), 3.54 (4H, t, J = 4.9 Hz), 3.89 (3H, s),5.84 (1H, qd, J = 7.2, 11.6 Hz), 6.43 (1H, dd, J = 1.9, 11.6 Hz), 6.94 (1H, d, J = 8.4 Hz), 7.88 (1H, dd, J = 2.2, 8.4 Hz), 7.93 (1H, d, J = 2.2 Hz)。

f) Production of (Z) -4- [4- (tert-butoxycarbonyl) piperazin-1-yl ] -3- (prop-1-en-1-yl) benzoic acid:

tert-butyl (Z) -4- [4- (methoxycarbonyl) -2- (prop-1-en-1-yl) phenyl ] piperazine-1-carboxylate (96mg, 0.267 mmol) was dissolved in methanol (3.0 mL). Under ice-cooling, a 4N-aqueous sodium hydroxide solution (334. mu.L) was added thereto, and the mixture was stirred at 50 ℃ overnight. Then, a 4N-aqueous sodium hydroxide solution (668. mu.L) was further added thereto under ice-cooling, and the mixture was stirred at 50 ℃ overnight. To the reaction solution was added a 4N-hydrochloric acid aqueous solution under ice cooling, extraction was performed with chloroform, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/acetone) to obtain 108mg of the title compound as white crystals (yield > 99%).

¹H-NMR (CD₃OD) δ：1.47 (9H, s), 1.87 (3H, dd, J = 2.0, 7.1 Hz), 2.98 (4H, t, J = 4.6 Hz), 3.55 (4H, t, J = 4.6 Hz),5.85 (1H, qd, J = 7.1, 11.6 Hz), 6.50 (1H, dd, J= 2.0, 11.6 Hz), 7.03 (1H, d, J = 8.4 Hz), 7.86 (1H, dd, J = 2.2, 8.4 Hz) , 7.90 (1H, d, J = 2.2 Hz)。

g) Production of tert-butyl (Z) -4- {4- [ (perfluorophenoxy) carbonyl ] -2- (prop-1-en-1-yl) phenyl } piperazine-1-carboxylate:

(Z) -4- [4- (tert-butoxycarbonyl) piperazin-1-yl ] -3- (prop-1-en-1-yl) benzoic acid (108 mg, 0.267 mmol) was dissolved in ethyl acetate: acetone = 4:1 (5.7 mL). Pentafluorophenol (59mg, 0.320mmol) and N, N' -dicyclohexylcarbodiimide (66mg, 0.320mmol) were added in this order at room temperature, and the mixture was stirred at room temperature for 10 hours. Water was added to the reaction solution, extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/acetone) to obtain the title compound as white crystals 129mg (yield 95%).

¹H-NMR (CDCl₃) δ：1.49 (9H, s), 1.91 (3H, dd, J = 2.0, 7.1 Hz), 3.07 (4H, t, J = 4.6 Hz), 3.57 (4H, t, J = 4.6 Hz),5.89 (1H, qd, J = 7.1, 11.6 Hz), 6.43 (1H, dd, J= 2.0, 11.6 Hz), 7.01 (1H, d, J = 8.8 Hz), 8.03-8.06 (2H, m)。

h) Production of tert-butyl (Z) -4- [4- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -2- (prop-1-en-1-yl) phenyl ] piperazine-1-carboxylate:

tert-butyl (Z) -4- {4- [ (perfluorophenoxy) carbonyl ] -2- (prop-1-en-1-yl) phenyl } piperazine-1-carboxylate (129 mg, 0.252 mmol) was dried with a vacuum pump and dissolved in ethylene glycol dimethyl ether (5.0 mL). (trifluoromethyl) trimethylsilane (186. mu.L, 1.26mmol) and tetramethylammonium fluoride (118mg, 1.26mmol) were added sequentially at-78 ℃ and slowly warmed to room temperature, followed by stirring for 14 hours. Water was added to the reaction solution under ice-cooling, extraction was performed with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/acetone) to give the title compound as yellow crystals 85mg (yield 72%).

¹H-NMR (CDCl₃) δ：1.48 (9H, s), 1.86 (3H, dd, J = 1.7, 7.1 Hz), 2.95 (4H, t, J = 4.9 Hz), 3.54 (4H, t, J = 4.9 Hz), 3.55 (1H, s),5.84 (1H, qd, J = 7.11, 11.3 Hz), 6.49 (1H, dd, J = 1.7, 11.3 Hz), 6.99 (1H, d, J = 8.4 Hz), 7.54 (1H, dd, J = 1.7, 8.4 Hz), 7.58 (1H, d, J = 1.7 Hz)。

i) Production of tert-butyl (Z) -4- {4- [2- (benzyloxy) -1,1,1,3,3, 3-hexafluoropropan-2-yl ] -2- (prop-1-en-1-yl) phenyl } piperazine-1-carboxylate:

tert-butyl (Z) -4- [4- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -2- (prop-1-en-1-yl) phenyl ] piperazine-1-carboxylate (85 mg, 0.181 mmol) was dissolved in N, N-dimethylformamide (1.8 mL), and sodium hydride (9.5mg, 217mmol) and benzyl bromide (23 μ L, 0.190 mmol) were added under ice cooling, and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/acetone) to give the title compound as a yellow oil, 67 mg.

¹H-NMR (CDCl₃) δ：1.48 (9H, s), 1.73 (3H, dd, J = 1.7, 7.1 Hz), 2.96 (4H, t, J = 4.9 Hz), 3.54 (4H, t, J = 4.9 Hz), 4.67 (2H, s),5.80 (1H, qd, J = 7.1, 11.6 Hz), 6.47 (1H, dd, J = 1.7, 11.6 Hz), 6.89 (1H, d, J = 8.6 Hz), 7.31-7.39 (5H, m), 7.44 (1H, dd, J = 1.7, 8.6 Hz), 7.50 (1H, d, J = 1.7 Hz)。

j) Production of (Z) -1- {4- [2- (benzyloxy) -1,1,1,3,3, 3-hexafluoropropan-2-yl ] -2- (prop-1-en-1-yl) phenyl } piperazine:

tert-butyl (Z) -4- {4- [2- (benzyloxy) -1,1,1,3,3, 3-hexafluoropropan-2-yl ] -2- (prop-1-en-1-yl) phenyl } piperazine-1-carboxylate (67 mg, 0.119 mmol) was dissolved in dichloromethane (2.0 mL). Trifluoroacetic acid (200. mu.L) was added thereto under ice cooling, and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added a saturated aqueous sodium bicarbonate solution under ice cooling, extraction was performed with chloroform, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform) to obtain the title compound 77mg as a white peach-colored oil (yield > 99%).

¹H-NMR (CDCl₃) δ：1.70 (3H, dd, J= 2.0, 7.1 Hz), 3.30 (4H, t, J = 4.9 Hz), 3.78 (4H, t, J = 4.9 Hz), 4.67 (2H, s),5.88 (1H, qd, J = 7.1, 11.1 Hz), 6.43 (1H, dd, J= 2.0, 11.1 Hz), 7.05 (1H, d, J = 8.3 Hz), 7.34-7.40 (5H, m), 7.49 (1H, dd, J = 1.7, 8.3 Hz), 7.53 (1H, d, J = 1.7 Hz)。

k) Production of (Z) -1- (4- {4- [2- (benzyloxy) -1,1,1,3,3, 3-hexafluoropropan-2-yl ] -2- (prop-1-en-1-yl) phenyl } piperazin-1-yl) -2-bromoethanone:

(Z) -1- {4- [2- (benzyloxy) -1,1,1,3,3, 3-hexafluoropropan-2-yl ] -2- (prop-1-en-1-yl) phenyl } piperazine (38 mg, 0.0595 mmol) was dissolved in dichloromethane (1.0 mL). N, N' -dimethylaniline (9.0. mu.L, 0.0714mmol) and bromoacetyl bromide (5.5. mu.L, 0.0625mmol) were added under ice cooling, and the mixture was stirred for 30 minutes under ice cooling. Then, N' -dimethylaniline (9.0. mu.L, 0.0714mmol) and bromoacetyl bromide (5.5. mu.L, 0.0625mmol) were added under ice cooling, and stirred for 30 minutes under ice cooling. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane/acetone) to give the title compound 16mg as a yellow oil (yield 47%).

¹H-NMR (CDCl₃) δ：1.74 (3H, dd, J = 1.7, 7.1 Hz), 3.02 (2H, t, J = 4.6 Hz), 3.09 (2H, t, J = 4.6 Hz), 3.64 (2H, t, J= 4.6 Hz), 3.76 (2H, t, J = 4.6 Hz),5.84 (1H, qd, J = 7.1, 11.13 Hz), 6.84 (1H, dd, J = 1.7, 11.7 Hz), 7.00 (1H, d, J = 8.8 Hz), 7.49 (1H, dd, J = 2.0, 8.8 Hz), 7.52 (1H, d, J = 2.0 Hz)。

l) production of 5- [5- (1-methylethoxy) pyridin-2-yl ] -5-methylimidazolidine-2, 4-dione:

5-hydroxy-2-methylpyridine (11.0 g, 100 mmol) was dissolved in N, N-dimethylformamide (100mL), and sodium hydride (7.2g, 150mmol) and iodo-1-methylethane (12mL, 121mmol) were added under ice cooling, followed by stirring at room temperature overnight. Iodo 1-methylethane (4mL) was then added and stirred at 60 ℃ for 4 hours. Water was added to the reaction solution, extracted with diethyl ether, and the organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give 12.7g (yield 84%) of 5- (1-methylethoxy) -2-methylpyridine as a yellow oil.

¹H-NMR (CDCl₃) δ：1.34 (6H, d, J = 6.0 Hz), 2.48 (3H, s), 4.52 (1H, quint, J = 6.0 Hz), 7.03-7.10 (2H, m), 8.17 (1H, d, J = 2.4 Hz)。

5- (1-Methylethoxy) -2-methylpyridine (227 mg, 0.661 mmol) was dissolved in dichloromethane (7.5 mL), 3-chloroperoxybenzoic acid (408mg, 0.733mmol) was added under ice cooling, and the mixture was stirred at 0 ℃ for 45 minutes. Ethyl acetate, a saturated aqueous sodium metabisulfite solution and an aqueous sodium bicarbonate solution were added to the reaction mixture, extraction was performed with ethyl acetate, and the organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate) to give 240mg of 5- (1-methylethoxy) -2-methylpyridine 1-oxide (yield 6%) as a colorless oil.

¹H-NMR (CDCl₃) δ：1.35 (6H, d, J = 6.2 Hz), 2.46 (3H, s), 4.47 (1H, quint, J = 6.2 Hz), 6.82 (1H, dd, J = 2.2, 8.9 Hz), 7.11 (1H, d, J = 8.9 Hz), 8.05 (1H, d, J = 2.2 Hz)。

5- (1-Methylethoxy) -2-methylpyridine 1-oxide (234mg, 1.40 mmol) was dissolved in acetic anhydride (3.0 mL) and stirred at 140 ℃ for 1 h. Methanol was added to the reaction mixture at room temperature, followed by stirring and concentration under reduced pressure. The organic layer was washed with an aqueous sodium hydrogencarbonate solution and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give 209mg (yield 71%) of [5- (1-methylethoxy) pyridin-2-yl ] methyl acetate as a yellow oil.

¹H-NMR (CDCl₃) δ：1.36 (6H, d, J = 6.2 Hz), 2.13 (3H, s), 4.58 (1H, quint, J = 6.2 Hz),5.13 (2H, s), 7.17 (1H, dd, J = 2.4, 8.1 Hz), 7.26-7.30 (1H, m), 8.27 (1H, d, J = 2.4 Hz)。

[5- (1-Methylethoxy) pyridin-2-yl ] methyl acetate (209 mg) was dissolved in methanol (2.0mL), potassium carbonate (276mg, 2.0mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, water was added to the reaction mixture, extraction was performed with ethyl acetate, and the organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give 137mg of [5- (1-methylethoxy) pyridin-2-yl ] methanol as a yellow oil (yield 83%).

¹H-NMR (CDCl₃) δ：1.36 (6H, d, J = 6.0 Hz), 4.57 (1H, quint, J = 6.0 Hz), 4.69 (2H, s), 7.15-7.22 (2H, m), 8.23 (1H, s)。

[5- (1-Methylethoxy) pyridin-2-yl ] methanol (30mg, 0.198 mmol) was dissolved in acetone (2.0mL), and 2,2,6, 6-tetramethylpiperidine 1-oxide (3.1mg, 0.020mmol) and trichloroisocyanuric acid (50mg, 0.218mmol) were added under ice cooling, followed by stirring at 0 ℃ for 5 minutes. The reaction mixture was concentrated under reduced pressure, an aqueous sodium hydrogencarbonate solution was added to the reaction mixture, extraction was performed with ethyl acetate, and the organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give 25mg of 5- (1-methylethoxy) pyridinecarboxaldehyde as a yellow oil (yield 85%).

¹H-NMR (CDCl₃) δ：1.41 (6H, d, J = 6.4 Hz), 4.71 (1H, quint, J = 6.4 Hz), 7.25-7.27 (1H, m), 7.95 (1H, d, J = 8.4 Hz), 8.39 (1H, d, J = 2.8 Hz), 9.98 (1H, s)。

5- (1-Methylethoxy) pyridinecarboxaldehyde (24 mg, 0.145 mmol) was dissolved in tetrahydrofuran (1.5mL), methylmagnesium bromide (230. mu.L, 0.218mmol) was added under ice cooling, and the mixture was stirred at 0 ℃ for 30 minutes. Further stirred at room temperature for 30 minutes. To the reaction mixture were added 1N-hydrochloric acid aqueous solution and sodium hydrogen carbonate aqueous solution, followed by extraction with ethyl acetate, and the organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give 27mg of 1- [5- (1-methylethoxy) pyridin-2-yl ] ethanol as a brown oil (yield 98%).

¹H-NMR (CDCl₃) δ：1.36 (6H, d, J = 6.0 Hz), 1.48 (3H, d, J = 6.4 Hz), 4.57 (1H, quint, J = 6.0 Hz), 4.85 (1H, q, 6.4 Hz), 7.17-7.21 (2H, m), 8.19-8.20 (1H, m)。

1- [5- (1-Methylethoxy) pyridin-2-yl ] ethanol (22 mg, 0.119 mmol) was dissolved in acetone (1.2 mL), and 2,2,6, 6-tetramethylpiperidine 1-oxide (2.0mg, 0.012mmol) and trichloroisocyanuric acid (30mg, 0.131mmol) were added under ice cooling, followed by stirring at 0 ℃ for 10 minutes. The reaction mixture was concentrated under reduced pressure, an aqueous sodium hydrogencarbonate solution was added to the reaction mixture, extraction was performed with ethyl acetate, and the organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give 20mg of 1- [5- (1-methylethoxy) pyridin-2-yl ] ethanone as a yellow oil (yield 94%).

¹H-NMR (CDCl₃) δ：1.40 (6H, d, J = 6.2 Hz), 2.68 (3H, s), 4.68 (1H, quint, J = 6.2 Hz), 7.22 (1H, dd, J = 2.7, 8.6 Hz), 8.03 (1H, d, J = 8.6 Hz), 8.28 (1H, d, J = 2.7 Hz)。

Using 1- [5- (1-methylethoxy) pyridin-2-yl ] ethanone, the reaction and treatment were carried out in the same manner as in example 1-l) to obtain the title compound as white crystals.

¹H-NMR (CDCl₃) δ：1.33 (6H, d, J = 6.2 Hz), 1.79 (3H, s), 4.67 (1H, quint, J = 6.2 Hz), 7.36 (1H, dd, J = 2.7, 8.9 Hz), 7.46 (1H, d, J = 8.9 Hz), 8.18 (1H, d, J = 2.7 Hz)。

m) (preparation of Z) -3- [2- (4- {4- [2- (benzyloxy) -1,1,1,3,3, 3-hexafluoropropan-2-yl ] -2- (prop-1-en-1-yl) phenyl } piperazin-1-yl) -2-oxoethyl ] -5- [5- (1-methylethoxy) pyridin-2-yl ] -5-methylimidazolidine-2, 4-dione:

5-methyl-5- [5- (1-methylethoxy) pyridin-2-yl ] imidazolidine-2, 4-dione (7.7 mg, 0.0309 mmol) was dissolved in N, N-dimethylformamide (2.8 mL), and potassium carbonate (9.3 mg,0.0674 mmol) was added under ice cooling to stir at room temperature for 5 minutes. Then, 1- (4- {4- [2- (benzyloxy) -1,1,1,3,3, 3-hexafluoropropan-2-yl ] -2- (prop-1-en-1-yl) phenyl } piperazin-1-yl) -2-bromoethanone (16mg, 0.0281 mmol) was added under ice cooling, and stirred at room temperature overnight. Then, the mixture was stirred at 60 ℃ for 10 hours. Water was added to the reaction solution under ice-cooling, extraction was performed with ethyl acetate, and the organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/acetone) to give the title compound as a yellow oil 17mg (yield 80%).

¹H-NMR (CDCl₃) δ：1.35 (6H, d, J = 6.1 Hz), 1.73 (3H, dd, J = 1.7, 7.1 Hz), 1.86 (3H, s), 3.00 (2H, t, J = 4.6 Hz), 3.07 (2H, t, J = 4.6 Hz), 3.59 (2H, t, J = 4.6 Hz), 3.73 (2H, t, J = 4.6 Hz), 4.36 (2H, s), 4.56 (1H, q , J = 6.1 Hz), 4.67 (2H, s),5.84 (1H, qd, J= 7.1, 11.13 Hz), 4.33 (1H, s), 6.47 (1H, dd, J = 1.7, 7.1 Hz), 6.99 (1H, dd, J = 2.4,8.8 Hz), 7.18 (1H, dd, J = 2.4, 8.8 Hz), 7.31-7.39 (5H, m), 7.46 (1H, dd, J = 2.0, 8.6 Hz), 7.52 (1H, d, J= 2.0 Hz), 7.62 (1H, d, J = 8.8 Hz), 8.20 (1H, d, J = 2.4 Hz)。

n) production of 3- (2- {4- [4- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -2-propylphenyl ] piperazin-1-yl } -2-oxoethyl) -5- [5- (1-methylethoxy) pyridin-2-yl ] -5-methylimidazolidine-2, 4-dione

(Z) -3- [2- (4- {4- [2- (benzyloxy) -1,1,1,3,3, 3-hexafluoropropan-2-yl ] -2- (prop-1-en-1-yl) phenyl } piperazin-1-yl) -2-oxoethyl ] -5- [5- (1-methylethoxy) pyridin-2-yl ] -5-methylimidazolidine-2, 4-dione (17 mg, 0.0225 mmol) was dissolved in methanol (2.0mL), and palladium hydroxide (6.0mg) was added to conduct hydrogenation, followed by stirring at room temperature for 12 hours. The reaction solution was filtered through celite, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform) to give the title compound 10mg as a pale yellow oil (yield 67%).

¹H-NMR (CDCl₃) δ：0.96 (3H, t, J = 7.3 Hz), 1.35 (6H, d, J = 5.6 Hz), 1.67 (2H, qt, J = 7.3, 7.8 Hz), 1.87 (3H, s), 2.66 (2H, t, J = 7.8 Hz), 2.89 (2H, t, J = 4.6 Hz), 2.96 (2H, t, J = 4.6 Hz), 3.58 (1H, s), 3.62 (2H, t, J = 4.6 Hz), 3.75 (2H, t, J = 4.6 Hz), 4.38 (2H, s), 4.56 (1H, q, J = 5.6 Hz), 6.41 (1H, brs), 7.07 (1H, d, J= 8.3 Hz), 7.18 (1H, dd, J = 2.4, 8.8 Hz), 7.50 (1H, dd, J = 2.0, 8.3 Hz), 7.54 (1H, d, J = 2.0 Hz), 87.63 (1H, d, J = 8.8 Hz), 8.20 (1H, d, J = 2.4 Hz)。

Example 7: production of 3- (2- {4- [4- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -2-propylphenyl ] piperazin-1-yl } -2-oxoethyl) -5- [4- (1-methylethoxy) phenyl ] -5-methylimidazolidine-2, 4-dione

[ solution 15]

The reaction and the treatment were carried out in the same manner as in example 6 using 5- [4- (1-methylethoxy) phenyl ] -5-methylimidazolidine-2, 4-dione to give the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ： 0.96 (3H, t, J = 7.3 Hz), 1.32 (6H, d, J = 6.1 Hz), 1.66 (2H, qt, J = 7.3, 8.0 Hz), 1.90 (3H, s), 2.66 (2H, t,J = 8.0 Hz), 2.88 (2H, t, J = 4.6 Hz), 2.96 (2H, t, J = 4.6 Hz), 3.60 (2H, t, J = 4.6 Hz), 3.74 (2H, t, J = 4.6 Hz), 3.75 (1H, s), 4.31-4.40 (2H, m), 4.54 (1H, q, J = 6.1 Hz),5.84 (1H, brs), 6.90 (2H, d, J = 8.8 Hz), 7.06 (1H, d, J = 8.6 Hz), 7.45 (2H, d, J= 8.8 Hz), 7.50 (1H, dd, J = 2.0, 8.8 Hz), 7.53 (1H, d, J = 2.0 Hz)。

Example 8: production of 5- (2, 3-dihydrobenzofuran-5-yl) -3- (2- {4- [4- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -2-propylphenyl ] piperazin-1-yl } -2-oxoethyl) -5-methylimidazolidine-2, 4-dione:

[ solution 16]

The reaction and the treatment were carried out in the same manner as in example 6 using 5- (2, 3-dihydrobenzofuran-5-yl) -5-methylimidazolidine-2, 4-dione to obtain the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：0.96 (3H, t, J = 7.3 Hz), 1.66 (2H, qt, J = 7.3, 8.0 Hz), 1.89 (3H, s), 2.65 (2H, t, J= 8.0 Hz), 2.87 (2H, t, J = 4.6 Hz), 2.96 (2H, t, J = 4.6 Hz), 3.21 (2H, t, J = 8.6 Hz), 3.48 (1H, s), 3.60 (2H, t, J = 4.6 Hz), 3.74 (2H, t, J = 4.6 Hz), 4.35 (2H, dd, J = 4.4, 20.5 Hz), 4.57 (2H, t, J = 8.6 Hz),5.99 (1H, brs), 6.78 (1H, d, J = 8.5 Hz), 7.05 (1H, J = 8.5 Hz), 7.29 (1H, dd, J = 4.9, 8.5 Hz), 7.41 (1H, d, J = 4.9 Hz ), 7.50 (1H, dd, J = 2.0, 8.5 Hz), 7.99 (1H, d, J = 2.0 Hz)。

Example 9: production of 5- (benzo [ d ] [1,3] dioxol-5-yl) -3- (2- {4- [4- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -2-propylphenyl ] piperazin-1-yl } -2-oxoethyl) -5-methylimidazolidine-2, 4-dione

[ solution 17]

The reaction and treatment were carried out in the same manner as in example 6 using 5- (benzo [ d ] [1,3] dioxol-5-yl) -5-methylimidazolidine-2, 4-dione to obtain the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：0.97 (3H, t, J= 7.3 Hz), 1.67 (2H, qt, J = 7.3, 7.8 Hz), 1.89 (3H, s), 2.66 (2H, t, J= 7.8 Hz), 2.89 (2H, t, J = 4.6 Hz), 2.96 (2H, t, J = 4.6 Hz), 3.61 (2H, t, J = 4.6 Hz), 3.65 (1H, s), 3.76 (2H, t, J = 4.6 Hz), 4.31-4.40 (2H, m),5.73 (1H, s),5.97 (2H, s), 6.82 (1H, d, J = 8.3 Hz), 7.03 (1H, dd, J = 2.0, 8.3 Hz), 7.06-7.09 (2H, m), 7.49-7.53 (2H, m)。

Example 10: production of 5- (2, 3-dihydrobenzofuran-5-yl) -3- (2- {4- [6- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -4-propylpyridin-3-yl ] piperazin-1-yl } -2-oxoethyl) -5-methylimidazolidine-2, 4-dione:

[ solution 18]

a) Production of 4-propylpyridin-2-amine:

to a solution of 4-propylpyridine (10.0 g, 82.5 mmol) in toluene (170 mL) was added sodium amide (6.4g, 165mmol) at room temperature, and the mixture was stirred at 140 ℃ for 2 days. To the reaction mixture was added 6N-aqueous hydrochloric acid (30 mL) under ice cooling, extraction was performed with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate/1% triethylamine) to give the title compound 5.70g (yield 51%) as a reddish brown solid.

¹H-NMR (CDCl₃) δ：0.94 (3H, t, J = 7.3 Hz), 1.57-1.66 (2H, m), 2.46 (2H, J = 7.8 Hz), 4.32 (2H, br), 6.32 (1H, s), 6.49 (1H, d, J = 4.2 Hz), 7.95 (1H, d, J =, 4.2 Hz)。

b) Production of 5-bromo-4-propylpyridin-2-amine:

to a solution of 4-propylpyridin-2-amine (5.70 g, 41.8 mmol) in ethanol (210 mL) was added an ethanol solution of bromine (2.38 mL/50 mL of ethanol) under ice cooling, and the mixture was stirred for 30 minutes under ice cooling. An aqueous sodium hydrogencarbonate solution was added to the reaction mixture under ice cooling, and the mixture was concentrated under reduced pressure. Extraction with ethyl acetate was performed, and then the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain 4.34g (yield 48%) of the title compound as a brown oil.

¹H-NMR (CDCl₃) δ：0.99 (3H, t, J = 7.6 Hz), 1.58-1.70 (2H, m), 2.54-2.60 (2H, m), 4.36 (2H, br), 6.38 (1H, s), 8.08 (1H, s)。

c) Production of 2, 5-dibromo-4-propylpyridine:

to 5-bromo-4-propylpyridin-2-amine (5.67 g, 26.3 mmol) was added 48% hydrogen bromide (21 mL) at 10 ℃. Bromine (4.0mL) was added thereto under ice cooling, and an aqueous solution (4.5 mL) of sodium nitrite (4.54 g) was added dropwise at-10 ℃. After stirring at-10 ℃ for 30 minutes, a 1N-aqueous sodium hydroxide solution (10mL) was added and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution. Extraction was performed with diethyl ether, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (diethyl ether) to give the title compound as a brown oil 6.96g (yield 95%).

¹H-NMR (CDCl₃) δ：1.01 (3H, t, J = 7.3 Hz), 1.62-1.69 (2H, m), 2.66 (2H, t, J = 7.8 Hz), 7.33 (1H, s), 8.40 (1H, s)。

d) Production of 5-bromo-4-propylpyridinecarbonitrile:

to a solution of 2, 5-dibromo-4-propylpyridine (100mg, 0.444 mmol) in N, N-dimethylformamide (0.9 mL) were added zinc dinitrile (57mg, 0.449mmol) and tetrakis (triphenylphosphine) palladium (25mg,0.0222mmol) at room temperature, and the mixture was stirred for 20 minutes at 100 ℃ under microwave irradiation. To the reaction mixture was added saturated aqueous sodium bicarbonate solution, extracted with hexane/ethyl acetate (4/1), and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound as colorless crystals 60mg (yield 60%).

¹H-NMR (CDCl₃) δ：1.02 (3H, t, J = 7.6 Hz), 1.66-1.72 (2H, m), 2.75 (2H, t, J = 7.6 Hz), 7.53 (1H, s), 8.74 (1H, s)。

e) Production of methyl 5-bromo-4-propylpicolinate:

to a solution of 5-bromo-4-propylpyridinenitrile (15 mg, 0.0670mmol) in methanol (1.3 mL) was added sulfuric acid (180. mu.L, 0.0670mmol) under ice cooling, and the mixture was stirred at 80 ℃ overnight. To the reaction mixture were added a 1N-sodium hydroxide aqueous solution and a saturated sodium bicarbonate aqueous solution under ice cooling, and the mixture was concentrated under reduced pressure with methanol. Extraction with ethyl acetate, washing of the organic layer with saturated brine, drying over anhydrous sodium sulfate, and concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound as brown crystals (11 mg, yield 62%).

¹H-NMR (CDCl₃) δ：1.02 (3H, t, J = 7.3 Hz), 1.66-1.75 (2H, m), 2.74-2.80 (2H, m), 4.01 (3H, s), 8.00 (1H, s), 8.75 (1H, s)。

f) Production of tert-butyl 4- [6- (methoxycarbonyl) -4-propylpyridin-3-yl ] piperazine-1-carboxylate:

to a solution of methyl 5-bromo-4-propylpicolinate (100mg, 0.387 mmol) in toluene (1.94 mL) were added 1-tert-butoxycarbonylpiperazine (84mg, 0.453mmol), tris (dibenzylideneacetone) dipalladium (8.3mg, 0.00902mmol), BINAP (11.2mg, 0.0180mmol), and cesium carbonate (295mg, 0.906mmol), and the mixture was stirred at 110 ℃ for 14 hours. Water was added to the reaction mixture, which was extracted with chloroform, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate) to obtain the title compound as pale yellow crystals 70mg (yield 49%).

¹H-NMR (CDCl₃) δ：0.99 (3H, t, J= 7.0 Hz), 1.49 (9H, s), 1.73 (2H, qt, J = 7.0, 7.6 Hz), 2.66 (2H, t, J= 7.6 Hz), 2.99 (4H, t, J = 5.1 Hz), 3.60 (4H, t, J = 5.1 Hz), 3.98 (3H, s), 7.99 (1H, s), 8.33 (1H, s)。

g) Production of 5- [4- (tert-butoxycarbonyl) piperazin-1-yl ] -4-propylpicolinic acid:

to a solution of tert-butyl 4- [6- (methoxycarbonyl) -4-propylpyridin-3-yl ] piperazine-1-carboxylate (111 mg, 0.307 mmol) in methanol (3.0 mL) was added a 4N-aqueous sodium hydroxide solution (383. mu.L, 1.53mmol) under ice cooling, and the mixture was stirred at room temperature overnight. To the reaction mixture was added a 4N-hydrochloric acid aqueous solution under ice cooling, followed by extraction with chloroform, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform) to obtain 134mg of the title compound as yellow crystals (yield > 99%).

¹H-NMR (CDCl₃) δ：1.01 (3H, t, J= 7.3 Hz), 1.49 (9H, s), 1.77 (2H, qt, J = 7.3, 7.6 Hz), 2.79 (2H, t, J= 7.6 Hz), 3.03 (4H, t, J = 5.1 Hz), 3.61 (4H, t, J = 5.1 Hz), 4.90 (1H, brs), 8.06 (1H, s), 8.28 (1H, s)。

h) Production of tert-butyl 4- {6- [ (perfluorophenoxy) carbonyl ] -4-propylpyridin-3-yl } piperazine-1-carboxylate:

5- [4- (tert-butoxycarbonyl) piperazin-1-yl ] -4-propylpicolinic acid (134 mg, 0.307 mmol) was dissolved in ethyl acetate (6.2 mL). Pentafluorophenol (68mg, 0.368mmol) and N, N' -dicyclohexylcarbodiimide (76mg, 0.368mmol) were added in this order at room temperature, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture under ice cooling, extraction was performed with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain 189mg (yield >99%) of the title compound as tan colored crystals.

¹H-NMR (CDCl₃) δ：1.03 (3H, t, J= 7.2 Hz), 1.50 (9H, s), 1.78 (2H, qt, J = 7.2, 8.0 Hz), 2.71 (2H, t, J= 8.0 Hz), 3.06 (4H, t, J = 5.2 Hz), 3.63 (4H, t, J = 5.2 Hz), 8.13 (1H, s), 8.42 (1H, s)。

i) Production of tert-butyl 4- [6- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -4-propylpyridin-3-yl ] piperazine-1-carboxylate:

tert-butyl 4- {6- [ (perfluorophenoxy) carbonyl ] -4-propylpyridin-3-yl } piperazine-1-carboxylate (189 mg, 0.307 mmol) was dried with a vacuum pump and dissolved in ethylene glycol dimethyl ether (6.2 mL). (trifluoromethyl) trimethylsilane (227. mu.L, 1.53mmol) and tetramethylammonium fluoride (143mg, 1.53mmol) were added successively at-78 ℃ and slowly warmed to room temperature, followed by stirring overnight. Water was added to the reaction mixture under ice-cooling, extraction was performed with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound as a yellow oil 60mg (yield 41%).

¹H-NMR (CDCl₃) δ：1.00 (3H, t, J= 7.3 Hz), 1.50 (9H, s), 1.71 (2H, qt, J = 7.3, 7.6 Hz), 2.70 (2H, t, J = 7.6 Hz), 2.97 (4H, t, J = 4.9 Hz), 3.60 (4H, t, J = 4.9 Hz), 3.90 (1H, brs), 7.53 (1H, s), 8.25 (1H, s)。

j) Production of tert-butyl 4- {6- [2- (benzyloxy) -1,1,1,3,3, 3-hexafluoropropan-2-yl ] -4-propylpyridin-3-yl } piperazine-1-carboxylate:

tert-butyl 4- [6- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -4-propylpyridin-3-yl ] piperazine-1-carboxylate (60 mg, 0.126 mmol) was dried with a vacuum pump and dissolved in N, N-dimethylformamide (2.5 mL). Sodium hydride (7.3mg,0.152mmol) and benzyl bromide (17. mu.L, 0.139mmol) were added successively under ice cooling, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture under ice cooling, extraction was performed with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/acetone) to give the title compound 54mg (yield 76%) as a yellow oil.

¹H-NMR (CDCl₃) δ： 0.91 (3H, t, J= 7.2 Hz), 1.49 (9H, s), 1.56 (2H, qt, J = 7.2, 7.6 Hz), 2.61 (2H, t, J= 7.6 Hz), 2.96 (4H, t, J = 4.8 Hz), 3.58 (4H, t, J = 4.8 Hz), 4.68 (2H, s), 7.32-7.41 (5H, m), 7.46 (1H, s), 8.39 (1H, s)。

k) Preparation of 1- {6- [2- (benzyloxy) -1,1,1,3,3, 3-hexafluoropropan-2-yl ] -4-propylpyridin-3-yl } piperazine:

tert-butyl 4- {6- [2- (benzyloxy) -1,1,1,3,3, 3-hexafluoropropan-2-yl ] -4-propylpyridin-3-yl } piperazine-1-carboxylate (32 mg, 0.0563 mmol) was dissolved in dichloromethane (10 mL). Trifluoroacetic acid (43 μ L, 0.563mmol) was added under ice cooling, and stirred at room temperature for 30 minutes. To the reaction mixture was added saturated aqueous sodium bicarbonate under ice-cooling, followed by extraction with chloroform, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform) to obtain the title compound 27mg as a yellow oil (yield > 99%).

¹H-NMR (CDCl₃) δ：0.91 (3H, t, J= 7.2 Hz), 1.56 (2H, qt, J = 7.3, 7.6 Hz), 2.61 (2H, t, J = 7.6 Hz), 2.99-3.05 (8H, m), 3.58 (1H, s), 4.68 (2H, s), 7.32-7.41 (5H, m), 7.46 (1H, s), 8.41 (1H, s)。

l) preparation of 1- (4- {6- [2- (benzyloxy) -1,1,1,3,3, 3-hexafluoropropan-2-yl ] -4-propylpyridin-3-yl } piperazin-1-yl) -2-bromoethanone:

1- {6- [2- (benzyloxy) -1,1,1,3,3, 3-hexafluoropropan-2-yl ] -4-propylpyridin-3-yl } piperazine (27mg, 0.0563 mmol) was dissolved in dichloromethane (1.0 mL). N, N-dimethylaniline (15. mu.L, 0.118mmol) and bromoacetyl bromide (5.1. mu.L, 0.0591mmol) were added under ice cooling, and the mixture was stirred under ice cooling for 20 minutes. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane/acetone) to give the title compound 25mg (yield 78%) as a yellow oil.

¹H-NMR (CDCl₃) δ：0.92 (3H, t, J= 7.2 Hz), 1.57 (2H, qt, J = 7.2, 7.6 Hz), 2.63 (2H, t, J = 7.6 Hz), 3.02 (2H, t, J = 4.8 Hz), 3.10 (2H, t, J = 4.8 Hz), 3.69 (2H, t, J = 4.8 Hz), 3.80 (2H, t, J = 4.8 Hz), 3.92 (2H, s), 4.69 (2H, s), 7.33-7.41 (5H, m), 7.48 (1H, s), 8.41 (1H, s)。

m) preparation of 3- [2- (4- {6- [2- (benzyloxy) -1,1,1,3,3, 3-hexafluoropropane-2-yl ] -4-propylpyridin-3-yl } piperazin-1-yl) -2-oxoethyl ] -5- (2, 3-dihydrobenzofuran-5-yl) -5-methylimidazolidine-2, 4-dione:

5- (2, 3-Dihydrobenzofuran-5-yl) -5-methylimidazolidine-2, 4-dione (5.6 mg, 0.0240 mmol) was dissolved in N, N-dimethylformamide (500. mu.L), and potassium carbonate (7.5 mg,0.0545 mmol) was added under ice cooling, followed by stirring at room temperature for 5 minutes. Then, 1- (4- {6- [2- (benzyloxy) -1,1,1,3,3, 3-hexafluoropropan-2-yl ] -4-propylpyridin-3-yl } piperazin-1-yl) -2-bromoethanone (13 mg, 0.0218 mmol) was added under ice-cooling, and stirred at room temperature for 18 hours. Water was added to the reaction mixture under ice-cooling, extraction was performed with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/acetone) to give the title compound as a yellow oil 13mg (yield 78%).

¹H-NMR (CDCl₃) δ：0.91 (3H, t, J= 7.3 Hz), 1.56 (2H, qt, J = 7.3, 8.0 Hz), 1.90 (3H, s), 2.62 (2H, t, J= 8.0 Hz), 3.00 (2H, t, J = 4.8 Hz), 3.08 (2H, t, J = 4.8 Hz), 3.22 (2H, t, J = 8.8 Hz), 3.63 (2H, t, J = 4.8 Hz), 3.77 (2H, t, J= 4.8 Hz), 4.31-4.41 (2H, m), 4.58 (2H, t, J = 8.8 Hz), 4.68 (2H, s),5.75 (1H, s), 6.78 (1H, d, J = 8.3 Hz), 7.29 (1H, dd, J = 2.0, 8.3 Hz), 7.33-7.41 (6H, m), 7.48 (1H, s), 8.40 (1H, s)。

n) production of 5- (2, 3-dihydrobenzofuran-5-yl) -3- (2- {4- [6- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -4-propylpyridin-3-yl ] piperazin-1-yl } -2-oxoethyl) -5-methylimidazolidine-2, 4-dione:

3- [2- (4- {6- [2- (benzyloxy) -1,1,1,3,3, 3-hexafluoropropane-2-yl ] -4-propylpyridin-3-yl } piperazin-1-yl) -2-oxoethyl ] -5- (2, 3-dihydrobenzofuran-5-yl) -5-methylimidazolidine-2, 4-dione (13 mg, 0.0170 mmol) was dissolved in methanol (1.5mL), and palladium on carbon (2.0mg) was added to conduct hydrogenation, followed by stirring at room temperature for 2 hours. The reaction solution was filtered through celite, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane/acetone) to give the title compound 7.3mg (yield 80%) as a yellow oil.

¹H-NMR (CDCl₃) δ：1.00 (3H, t, J= 7.3 Hz), 1.72 (2H, qt, J = 7.3, 7.6 Hz), 1.90 (3H, s), 2.71 (2H, t, J= 7.6 Hz), 3.01 (2H, t, J = 4.6 Hz), 3.09 (2H, t, J = 4.6 Hz), 3.22 (2H, t, J = 8.8 Hz), 3.65 (2H, t, J = 4.6 Hz), 3.76 (1H, s), 3.80 (2H, t, J = 4.6 Hz), 4.32-4.41 (2H, m), 4.58 (2H, t, J = 8.8 Hz),5.59 (1H, s), 6.79 (1H, d, J = 8.3 Hz), 7.30 (1H, dd, J = 2.0, 8.3 Hz), 7.40 (1H, d, J = 2.0 Hz), 7.55 (1H, s), 8.27 (1H, s)。

Example 11: production of 3- (2- {4- [6- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -4-propylpyridin-3-yl ] piperazin-1-yl } -2-oxoethyl) -5- [4- (1-methylethoxy) phenyl ] -5-methylimidazolidine-2, 4-dione:

[ solution 19]

The reaction and the treatment were carried out in the same manner as in example 10 using 5- [4- (1-methylethoxy) phenyl ] -5-methylimidazolidine-2, 4-dione to give the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：1.00 (3H, t, J= 7.3 Hz), 1.33 (6H, d, J = 6.1 Hz), 1.72 (2H, qt, J = 7.3, 7.6 Hz), 1.91 (3H, s), 2.71 (2H, t, J = 7.6 Hz), 3.01 (2H, t, J = 4.9 Hz), 3.09 (2H, t, J = 4.9 Hz), 3.65 (2H, t, J = 4.9 Hz), 3.75 (1H, s), 3.79 (2H, t, J = 4.9 Hz), 4.32-4.41 (2H, m), 4.54 (1H, t, J= 6.1 Hz),5.70 (1H, s), 6.90 (2H, d, J = 8.8 Hz), 7.45 (2H, d, J= 8.8 Hz), 7.54 (1H, s), 8.27 (1H, s)。

Example 12: production of (R) -3- (2- {4- [4- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -2-propylphenyl ] -3-methylpiperazin-1-yl } -2-oxoethyl) -5- [4- (1-methylethoxy) phenyl ] -5-methylimidazolidine-2, 4-dione:

[ solution 20]

a) Production of (R) -4- [4- (methoxycarbonyl) -2-nitrophenyl ] -3-methylpiperazine-1-carboxylic acid tert-butyl ester:

the reaction and the treatment were carried out in the same manner as in example 6-b) except for using (R) -3-methyl-1-tert-butoxycarbonylpiperazine instead of 1-tert-butoxycarbonylpiperazine to obtain the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：1.04 (3H, d, J= 6.8 Hz), 1.48 (9H, s), 2.83-2.92 (1H, m), 3.34-3.51 (6H, m), 3.92 (3H, s), 7.14 (1H, d, J = 8.6 Hz), 8.10 (1H, dd, J = 1.9, 8.6 Hz), 8.39 (1H, d, J = 1.9 Hz)。

b) Production of (R) -4- [ 2-amino-4- (methoxycarbonyl) phenyl ] -3-methylpiperazine-1-carboxylic acid tert-butyl ester:

the reaction and the treatment were carried out in the same manner as in example 6-c) to give 7.3mg (yield: 80%) of the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：0.86 (3H, d, J= 5.9 Hz), 1.49 (9H, s), 2.56-2.66 (1H, m), 2.82-3.2 (6H, m), 3.87 (3H, s), 4.18 (2H, brs), 7.02 (1H, d, J = 8.6 Hz), 7.39-7.42 (2H, m)。

c) Production of tert-butyl (R) -4- [ 2-iodo-4- (methoxycarbonyl) phenyl ] -3-methylpiperazine-1-carboxylate

The reaction and the treatment were carried out in the same manner as in example 6-d) to give 7.3mg (yield: 80%) of the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：1.00 (3H, t, J= 7.3 Hz), 1.33 (6H, d, J = 6.1 Hz), 1.72 (2H, qt, J = 7.3, 7.6 Hz), 1.91 (3H, s), 2.71 (2H, t, J = 7.6 Hz), 3.01 (2H, t, J = 4.9 Hz), 3.09 (2H, t, J = 4.9 Hz), 3.65 (2H, t, J = 4.9 Hz)。

d) Production of (R, Z) -4- [4- (methoxycarbonyl) -2- (prop-1-en-1-yl) phenyl ] -3-methylpiperazine-1-carboxylic acid tert-butyl ester

The reaction and the treatment were carried out in the same manner as in example 6-e) to give the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：0.91 (3H, d, J= 6.2 Hz), 1.48 (9H, s), 1.88 (3H, d, J = 6.8 Hz), 2.70-2.78 (1H, m), 3.10-3.55 (6H, m), 3.89 (3H, s),5.76-5.88 (1H, m), 6.49 (1H, d, J = 11.6 Hz), 6.96 (1H, d, J = 8.6 Hz), 7.87 (1H, dd, J = 1.9, 8.6 Hz), 7.94 (1H, d, J = 1.9 Hz)。

e) Production of (R, Z) -4- [4- (tert-butoxycarbonyl) -2-methylpiperazin-1-yl ] -3- (prop-1-en-1-yl) benzoic acid

The reaction and the treatment were carried out in the same manner as in example 6-f) to give the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：0.93 (3H, d, J= 6.2 Hz), 1.48 (9H, s), 1.89 (3H, d, J = 6.2 Hz), 2.72-2.80 (1H, m), 3.19-3.57 (6H, m),5.75-5.90 (1H, m), 6.47 (1H, d, J = 10.8 Hz), 6.97 (1H, d, J = 8.4 Hz), 7.93 (1H, d, J = 8.4 Hz), 8.00 (1H, s)。

f) Production of tert-butyl (R, Z) -3-methyl-4- {4- [ (perfluorophenoxy) carbonyl ] -2- (prop-1-en-1-yl) phenyl } piperazine-1-carboxylate

The reaction and the treatment were carried out in the same manner as in example 6-g) to obtain the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：0.97 (3H, d, J= 6.5 Hz), 1.49 (9H, s), 1.90 (3H, d, J = 7.0 Hz), 2.80-2.90 (1H, m), 3.20-3.70 (6H, m),5.81-5.93 (1H, m), 6.46 (1H, d, J = 11.0 Hz), 7.02 (1H, d, J = 8.1 Hz), 8.04 (1H, d, J = 8.1 Hz), 8.06 (1H, s)。

g) Production of (R, Z) -4- [4- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -2- (prop-1-en-1-yl) phenyl ] -3-methylpiperazine-1-carboxylic acid tert-butyl ester

The reaction and the treatment were carried out in the same manner as in example 6-h) to give the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：0.90 (3H, d, J= 6.2 Hz), 1.48 (9H, s), 1.83 (3H, d, J = 6.8 Hz), 2.65-2.73 (1H, m), 3.08-3.18 (1H, m), 3.25-3.68 (5H, m),5.76-5.88 (1H, m), 6.56 (1H, d, J= 13.2 Hz), 7.02 (1H, d, J = 8.4 Hz), 7.53 (1H, d, J = 8.4 Hz), 7.59 (1H, s)。

h) Production of (R, Z) -1,1,1,3,3, 3-hexafluoro-2- [4- (2-methylpiperazin-1-yl) -3- (prop-1-en-1-yl) phenyl ] propan-2-ol

The reaction and the treatment were carried out in the same manner as in example 6-j) to give the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：0.96 (3H, d, J= 6.2 Hz), 1.81 (3H, d, J = 6.8 Hz), 2.76-2.85 (2H, m), 3.08-3.29 (4H, m), 3.45-3.55 (1H, m),5.78-5.90 (1H, m), 6.59 (1H, d, J = 13.2 Hz), 7.14 (1H, d, J = 8.9 Hz), 7.61 (1H, d, J = 8.9 Hz), 7.62 (1H, s)。

i) Preparation of (R, Z) -1- {4- [1,1,1,3,3, 3-hexafluoro-2- (methoxymethyloxy) propan-2-yl ] -2- (prop-1-en-1-yl) phenyl } -2-methylpiperazine

The reaction and the treatment were carried out in the same manner as in example 6-i) except for using methoxymethyl ether chloride instead of the benzyl bromide to obtain 7.3mg (yield: 90%) of the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：0.94 (3H, d, J= 5.9 Hz), 1.82 (3H, d, J = 6.5 Hz), 2.70-2.76 (3H, m), 2.95-3.18 (3H, m), 3.35-3.49 (1H, m), 3.55 (3H, s), 4.87 (2H, s),5.76-5.89 (1H, m), 6.58 (1H, d, J = 11.3 Hz), 7.08 (1H, d, J = 8.4 Hz), 7.44 (1H, d, J= 8.4 Hz), 7.51 (1H, s)。

j) Production of (R, Z) -2-bromo-1- (4- {4- [1,1,1,3,3, 3-hexafluoro-2- (methoxymethyloxy) propan-2-yl ] -2- (prop-1-en-1-yl) phenyl } -3-methylpiperazin-1-yl) ethanone

The reaction and the treatment were carried out in the same manner as in example 6-k) to obtain the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：0.94 (3H, d, J= 5.9 Hz), 1.82 (3H, d, J = 7.0 Hz), 2.75-2.87 (2H, m), 3.11-3.39 (2H, m), 3.49-3.81 (3H, m), 3.55 (3H, s), 3.89 (1H, d, J = 10.0 Hz), 3.92 (1H, d, J = 10.0 Hz), 4.87 (2H, s),5.79-5.82 (1H, m), 6.56 (1H, d, J= 11.9 Hz), 7.03 (1H, d, J = 7.3 Hz), 7.45 (1H, d, J = 7.3 Hz), 7.52 (1H, s)。

k) Production of (R) -3- (2- {4- [4- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -2-propylphenyl ] -3-methylpiperazin-1-yl } -2-oxoethyl) -5- [4- (1-methylethoxy) phenyl ] -5-methylimidazolidine-2, 4-dione

5- [4- (1-Methylethoxy) phenyl ] -5-methylimidazolidine-2, 4-dione (7.7 mg, 0.0311 mmol) was dissolved in N, N-dimethylformamide (500. mu.L), and potassium carbonate (8.6 mg, 0.0622 mmol) was added under ice cooling, followed by stirring at room temperature for 5 minutes. Then, (R, Z) -2-bromo-1- (4- {4- [1,1,1,3,3, 3-hexafluoro-2- (methoxymethoxy) propan-2-yl ] -2- (prop-1-en-1-yl) phenyl } -3-methylpiperazin-1-yl) ethanone (17 mg, 0.0311 mmol) was added under ice-cooling, and stirred at room temperature for 18 hours. Water was added to the reaction mixture under ice cooling, extraction was performed with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was dissolved in ethyl acetate (1.0mL), and a 4N-hydrochloric acid-ethyl acetate solution (1.0mg) was added thereto and stirred at room temperature for 1 hour. Water and a saturated aqueous sodium bicarbonate solution were added to the reaction mixture under ice cooling, extraction was performed with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give (R, Z) -3- (2- {4- [4- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -2- (prop-1-en-1-yl) phenyl ] -3-methylpiperazin-1-yl } -2-oxoethyl) -5- [4- (1-methylethoxy) phenyl ] -5-methylimidazolidine-2, 4-dione 17.4mg as a yellow oil (yield 83%).

¹H-NMR (CDCl₃) δ：0.87-0.96 (3H, m), 1.32 (6H, d, J = 5.9 Hz), 1.83 (3H, dd, J = 6.5, 7.3 Hz), 1.90 (3H, s). 2.67-2.80 (1H, m), 3.08-4.05 (7H, m), 4.25-4.42 (2H, m), 4.53 (1H, q, J= 5.9 Hz),5.84 (1H, qd, J = 7.3, 11.5 Hz),5.96 (1H, brs), 6.67 (1H, dd, J = 6.5, 11.5 Hz), 6.89 (2H, d, J = 8.6 Hz), 7.02 (1H, d, J= 8.1 Hz), 7.45 (2H, d, J = 8.6 Hz), 7.56 (1H, dd, J = 2.0, 8.1 Hz), 7.61 (1H, d, J = 2.0 Hz)。

The reaction and treatment were carried out in the same manner as in example 6-m) and n) using (R, Z) -3- (2- {4- [4- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -2- (prop-1-en-1-yl) phenyl ] -3-methylpiperazin-1-yl } -2-oxoethyl) -5- [4- (1-methylethoxy) phenyl ] -5-methylimidazolidine-2, 4-dione, whereby the title compound was obtained as a yellow oil.

¹H-NMR (CDCl₃) δ：0.79-0.86 (3H, m), 0.95 (3H, t, J = 7.3 Hz), 1.32 (6H, d, J = 5.9 Hz), 1.62 (2H, qt, J= 7.3, 7.6 Hz), 1.90 (3H, s), 2.70-2.80 (2H, m), 2.89-3.46 (3H, m), 3.63-3.70 (2H, m), 3.95-4.05 (2H, m), 4.26-4.43 (2H, m), 4.54 (1H, q, J = 5.9 Hz),5.94 (1H, s), 6.89 (2H, d, J = 8.6 Hz), 7.10-7.15 (1H, m), 7.46 (2H, d, J= 8.6 Hz), 7.49-7.53 (1H, m), 7.53 (1H, d, J = 2.0 Hz)。

Example 13: production of (S) -3- (2- {4- [4- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -2-propylphenyl ] -3-methylpiperazin-1-yl } -2-oxoethyl) -5- [4- (1-methylethoxy) phenyl ] -5-methylimidazolidine-2, 4-dione:

[ solution 21]

The reaction was carried out in the same manner as in example 12 using (S) -3-methyl-1-tert-butoxycarbonylpiperazine instead of (R) -3-methyl-1-tert-butoxycarbonylpiperazine, so as to obtain the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：0.79-0.86 (3H, m), 0.95 (3H, t, J = 7.3 Hz), 1.32 (6H, d, J = 6.2 Hz), 1.62 (2H, qt, J= 7.3, 7.6 Hz), 1.91 (3H, s), 2.60-2.80 (2H, m), 2.90-3.49 (3H, m), 3.63-3.70 (2H, m), 4.20-4.25 (2H, m), 4.25-4.43 (2H, m), 4.54 (1H, q, J = 6.2 Hz),5.86 (1H, s), 6.99 (2H, d, J = 8.6 Hz), 7.10-7.14 (1H, m), 7.46 (2H, d, J= 8.6 Hz), 7.49-7.53 (1H, m), 7.53 (1H, d, J 2.0 Hz)。

Example 14-1: production of (2R,5S, Z) -3- (2- {4- [4- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -2- (prop-1-en-1-yl) phenyl ] -2, 5-dimethylpiperazin-1-yl } -2-oxoethyl) -5- [4- (1-methylethoxy) phenyl ] -5-methylimidazolidine-2, 4-dione:

[ solution 22]

a-1) preparation of tert-butyl trans-2, 5-dimethylpiperazine-1-carboxylate

To a solution of trans-2, 5-dimethylpiperazine (100mg, 0.876mmol) in dichloromethane (3mL) were added triethylamine (245. mu.L, 1.75mmol) and di-tert-butyl dicarbonate (201. mu.L, 0.876mmol) in this order under ice cooling, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture under ice-cooling, extraction was performed with chloroform, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform/methanol) to give the title compound 111mg (yield 59%) as a colorless oil.

¹H-NMR (CDCl₃) δ：1.16 (3H, d, J= 6.6 Hz), 1.21 (3H, d, J = 6.6 Hz), 1.46 (9H, s), 2.48 (1H, d, J= 12.8 Hz), 3.09-3.16 (1H, m), 3.18-3.24 (2H, m), 3.54 (1H, d, J = 13.4 Hz), 4.15-4.30 (1H, m),5.68 (1H, brs)。

a-2-1) production of (2R,5S) -tert-butyl 2, 5-dimethylpiperazine-1-carboxylate:

production of (S) -methyl-a-2-1-1) 2- (benzylamino) propanoate:

l-alanine methyl ester hydrochloride (15.0g,107mmol) was dissolved in N, N' -dimethylformamide (150mL), potassium carbonate (32.5g,235mmol) and benzyl bromide (18.4g,107mmol) were added, and the mixture was stirred at 80 ℃ overnight. Then, the reaction solution was cooled to room temperature, filtered through celite, extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (12.7g,61%) as a colorless oil.

¹H-NMR (CDCl₃) δ：1.32 (3H, d, J = 7.1 Hz), 3.40 (1H, q, J = 7.1 Hz), 3.69 (1H, d, J = 12.7 Hz), 3.73 (3H, s), 3.80 (1H, d, J = 12.7 Hz), 7.25-7.36 (5H, m)。

Production of (S) -methyl a-2-1-2) 2- { (R) -N-benzyl-2- [ (tert-butoxycarbonyl) amino ] propionamide } propanoate:

Boc-D-alanine (10g,52.9mmol) was added to a solution of (S) -methyl 2- (benzylamino) propionate (9.28g, 48.1mmol) in dichloromethane (100mL), and then 4-dimethylaminopyridine (587mg,4.81mmol) and EDCI (11g,57.7mmol) were added under ice cooling, followed by stirring at room temperature overnight. The reaction solution was extracted with chloroform, washed with a 5% citric acid aqueous solution, water, and a saturated sodium bicarbonate aqueous solution, dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (9.34g,53%) as a colorless oil.

¹H-NMR (CDCl₃) δ：1.24 (3H, d, J = 6.8 Hz), 1.38 (3H, d, J= 7.1 Hz), 1.43 (9H, s), 3.67 (3H, s), 4.20 (1H, q, J = 7.1 Hz), 4.59 (1H, d, J = 16.8 Hz), 4.61-4.73 (1H, m), 4.77 (1H, d, J= 16.8 Hz),5.31 (1H, d, J = 7.8 Hz), 7.22-7.39 (5H, m)。

Production of a-2-1-3) (3R,6S) -1-benzyl-3, 6-dimethylpiperazine-2, 5-dione:

to a solution of (S) -methyl 2- { (R) -N-benzyl-2- [ (tert-butoxycarbonyl) amino ] propionamide } propanoate (9.34g, 25.6mmol) in dichloromethane (100mL) was added trifluoroacetic acid (14.6g, 128mmol) under ice cooling, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, methanol (40mL) was added, and a saturated aqueous sodium bicarbonate solution (added to pH =8) was added under ice cooling, followed by stirring at 80 ℃ overnight. The reaction solution was concentrated under reduced pressure, extracted with ethyl acetate, washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate) to give the title compound (4.05g, 68%) as a colorless oil.

¹H-NMR (CDCl₃) δ：1.42 (3H, d, J = 7.1 Hz), 1.54 (3H, d, J = 6.8 Hz), 3.87 (1H, q, J = 7.1 Hz), 4.09 (1H, d, J= 14.9 Hz), 4.16 (1H, q, J = 6.8 Hz),5.17 (1H, d, J = 14.9 Hz), 6.51 (1H, s), 7.23-7.36 (5H, m)。

Production of a-2-1-4) (2R,5S) -1-benzyl-2, 5-dimethylpiperazine:

lithium aluminum hydride (993mg, 26.2mmol) was added to a solution of (3R,6S) -1-benzyl-3, 6-dimethylpiperazine-2, 5-dione (4.05g,17.4mmol) in tetrahydrofuran (70mL) under an argon atmosphere under ice cooling, and the mixture was stirred at room temperature for 10 minutes and then at 80 ℃ for 4 hours. Then, lithium aluminum hydride (331mg,8,72mmol) was added to the reaction solution under ice cooling, and stirred at 80 ℃ for 1.5 hours. Then, tetrahydrofuran and water were added to the reaction solution under ice cooling, and the mixture was stirred at room temperature overnight.

The reaction solution was filtered through celite, washed with ethyl acetate and water, dried over sodium sulfate, and concentrated under reduced pressure to give the title compound (3.52g, 99%) as a yellow oil.

¹H-NMR (CDCl₃) δ：0.93 (3H, d, J = 6.3 Hz), 1.14 (3H, d, J = 6.1 Hz), 1.63 (1H, dd, J = 10.2, 11.2 Hz), 2.18-2.26 (1H, m), 2.63 (1H, dd, J = 10.5, 12.2 Hz), 2.68 (1H, dd, J = 2.7, 11.2 Hz), 2.75-2.83 (1H, m), 2.91 (1H, dd, J = 2.9, 12.2 Hz), 3.09 (1H, d, J = 13.4 Hz), 4.10 (1H, d, J = 13.4 Hz), 7.22-7.32 (5H, m)。

a-2-1-5) preparation of (2R,5S) -tert-butyl 4-benzyl-2, 5-dimethylpiperazine-1-carboxylate:

to a solution of (2R,5S) -1-benzyl-2, 5-dimethylpiperazine (3.52g,17.2mmol) in tetrahydrofuran (50mL) were added trimethylamine (2.12g,20.9mmol) and di-tert-butyl carbonate (4.56g,20.9mmol) under ice cooling, and the mixture was stirred for 15 minutes. Then, the mixture was stirred at room temperature for 5.5 hours. Water was added to the reaction solution, which was extracted with ethyl acetate, washed with saturated brine, dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (3.16g, 60%) as a pale yellow oil.

¹H-NMR (CDCl₃) δ：0.98 (3H, d, J = 6.6 Hz), 1.23 (3H, d, J = 6.6 Hz), 1.46 (9H, s), 2.19 (1H, d, J = 12.2 Hz), 2.70 (1H, dd, J = 4.4, 12,2 Hz), 2.91-2.98 (1H, m), 3.31 (1H, dd, J= 3.6, 12.9 Hz), 3.46 (1H, d, J = 13.5 Hz), 3.62 (1H, d, J = 13.5 Hz), 3.65 (1H, d, J = 12.9 Hz), 4.17-4.25 (1H, m), 7.22-7.37 (5H, m)。

a-2-1-6) production of (2R,5S) -tert-butyl 2, 5-dimethylpiperazine-1-carboxylate:

under an argon atmosphere, (2R,5S) -tert-butyl 4-benzyl-2, 5-dimethylpiperazine-1-carboxylate (2.0g, 6.57mmol) was dissolved in methanol (60mL), and 10% palladium on carbon (670mg) and formic acid (1.5g, 32.9mmol) were added. Stirred at room temperature for 2 hours. Then, the reaction solution was subjected to celite filtration and concentrated under reduced pressure. To the obtained residue were added chloroform and a saturated aqueous solution of sodium hydrogencarbonate, followed by extraction with chloroform, drying over sodium sulfate and concentration under reduced pressure to obtain the title compound (1.56g, >100%) as a yellow oil.

¹H-NMR (CDCl₃) δ：1.17 (3H, d, J = 6.6 Hz), 1.21 (3H, d, J = 6.8 Hz), 1.46 (9H, s), 2.48 (1H, dd, J = 2.9, 13.0 Hz), 3.03-3.15 (1H, m), 3.18-3.23 (2H, m), 3.54 (1H, dd, J = 2.0, 13.4 Hz), 4.08-4.14 (1H, m)。

a-2-2) production of (2S,5R) -tert-butyl 2, 5-dimethylpiperazine-1-carboxylate:

the reaction and the treatment were carried out in the same manner as in examples 14-1-a-2-1-1) to 14-1-a-2-1-6) using D-alanine methyl ester hydrochloride instead of L-alanine methyl ester hydrochloride to obtain the title compound as a colorless oil.

a-3-1) preparation of (2S,5R) -tert-butyl 2, 5-dimethylpiperazine-1-carboxylate:

a-3-1-1) preparation of racemic trans-1-benzyl-2, 5-dimethylpiperazine:

trans-2, 5-dimethylpiperazine (25g,219mmol) was dissolved in cyclohexane (250mL) -water (35 mL), and tetrabutylammonium chloride (2.2g,15.5mmol), an aqueous sodium hydroxide solution (23mL), and benzyl chloride (26.5g,208mmol) were added at room temperature. Stirred at 40 ℃ for 18 hours. Then, the temperature was returned to room temperature, and the reaction solution was extracted with cyclohexane. To the organic layer was added 37% aqueous hydrochloric acid solution, and the mixture was stirred. 2-methyltetrahydrofuran and a 50% aqueous solution of sodium hydroxide were added to the aqueous layer obtained by the extraction operation, and extraction was performed with 2-methyltetrahydrofuran. The obtained organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 34g of the title compound as a colorless oil (yield 76%).

¹H-NMR (CDCl₃) δ： 0.93 (3H, d, J = 6.3 Hz), 1.14 (3H, d, J = 6.1 Hz), 1.63 (1H, dd, J = 10.2, 11.2 Hz), 2.18-2.26 (1H, m), 2.63 (1H, dd, J = 10.5, 12.2 Hz), 2.68 (1H, dd, J = 2.7, 11.2 Hz), 2.75-2.83 (1H, m), 2.91 (1H, dd, J = 2.9, 12.2 Hz), 3.09 (1H, d, J = 13.4 Hz), 4.10 (1H, d, J = 13.4 Hz), 7.22-7.32 (5H, m)。

Production of a-3-1-2) (2S,5R) -1-benzyl-2, 5-dimethylpiperazine-2-tartrate:

racemic trans-1-benzyl-2, 5-dimethylpiperazine (2.35g, 11.5mmol) was dissolved in methanol (14 mL), and D- (-) -tartaric acid (3.45g, 23.0mmol) was added and allowed to stand at 5 ℃ for 20 hours. Filtration through methanol and drying under reduced pressure gave 2.66g (yield 44%) of the title compound as white crystals. The obtained white crystals were further dissolved in methanol (27 mL) and recrystallized to obtain 1.7g of the title compound as white crystals (yield 28%, 99.9% ee).

¹H-NMR (D₂O) δ：1.18 (3H, d, J= 6.5 Hz), 1.51 (3H, d, J = 6.3 Hz), 1.92 (1H, bs), 2.89 (1H, t, J = 12.9 Hz), 3.18 (1H, t, J = 13.8 Hz), 3.29 (1H, dd. J = 3.0, 13.8 Hz), 3.47 (1H, m), 3.53 (1H, m), 3.62 (1H, dd, J = 3.0, 12.9 Hz), 3.98 (1H, d, J = 13.1 Hz), 4.41 (4H, s), 4.71 (1H, d, J = 13.1 Hz), 7.39-7.48 (5H, m)。

a-3-1-3) preparation of (2S,5R) -tert-butyl 4-benzyl-2, 5-dimethylpiperazine-1-carboxylate:

(2S,5R) -1-benzyl-2, 5-dimethylpiperazine-2-tartrate (5.0g, 9.91mmol) was dissolved in 2-methyltetrahydrofuran (30 mL), and a solution of an aqueous solution of sodium hydroxide (sodium hydroxide: 2.62g, 65.4mmol, water: 18mL) and di-tert-butyl dicarbonate (2.2g, 9.91mmol) in 2-methyltetrahydrofuran was added under ice cooling, followed by stirring at room temperature overnight. Then, the reaction solution was extracted with 2-methyltetrahydrofuran, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 3.11g of the title compound as white crystals (yield > 100%).

¹H-NMR (CDCl₃) δ：0.98 (3H, d, J = 6.2 Hz), 1.23 (3H, d, J = 6.5 Hz), 1.46 (9H, s), 2.19 (1H, dd, J = 1.6, 11.9 Hz), 2.69 (1H, dd, J = 4.3, 11.9 Hz), 2.92-3.00 (1H, m), 3.31 (1H, dd, J = 3.5, 12.4 Hz), 3.46 (1H, d, J= 13.5 Hz), 3.62 (1H, d, J = 13.5 Hz), 3.66 (1H, dd, J = 2.4, 12.4 Hz), 4.15-4.23 (1H, m), 7.20-7.37 (5H, m)。

a-3-1-4) production of (2S,5R) -tert-butyl 2, 5-dimethylpiperazine-1-carboxylate:

4-benzyl-2, 5-dimethylpiperazine-1-carboxylic acid (2S,5R) -tert-butyl ester (3.11g, 10.2mmol) was dissolved in methanol (19mL), palladium on carbon (156mg) was added under an argon atmosphere, and formic acid (2.4g,51.1mmol) was added under ice cooling. Return to room temperature and stir overnight. Then, the reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. To the resulting residue were added water and hexane, followed by extraction, and an aqueous sodium hydroxide solution was added to the aqueous layer, followed by extraction with 2-methyltetrahydrofuran, drying over anhydrous sodium sulfate, and concentration under reduced pressure to obtain 2.21g of the title compound as a colorless oil (yield > 100%).

¹H-NMR (CDCl₃) δ：1.16 (3H, d, J= 6.6 Hz), 1.21 (3H, d, J = 6.6 Hz), 1.46 (9H, s), 2.48 (1H, d, J= 12.8 Hz), 3.09-3.16 (1H, m), 3.18-3.24 (2H, m), 3.54 (1H, d, J = 13.4 Hz), 4.15-4.30 (1H, m),5.68 (1H, brs)。

a-3-2) production of (2R,5S) -tert-butyl 2, 5-dimethylpiperazine-1-carboxylate:

the reaction and the treatment were carried out in the same manner as in example 14-1-a-3-1-2) below using L- (+) -tartaric acid instead of D- (-) -tartaric acid, whereby the title compound was obtained as a colorless oil.

b) Production of tert-butyl (2R,5S) -4- [4- (methoxycarbonyl) -2-nitrophenyl ] -2, 5-dimethylpiperazine-1-carboxylate:

the reaction and the treatment were carried out in the same manner as in example 6-b) using (2R,5S) -tert-butyl 2, 5-dimethylpiperazine-1-carboxylate instead of tert-butyl piperazine-1-carboxylate to obtain the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：1.09 (3H, d, J= 6.3 Hz), 1.26 (3H, d, J = 6.3 Hz), 1.48 (9H, s), 2.75 (1H, d, J= 11.7 Hz), 3.54-3.68 (4H, m), 3.91 (3H, s), 4.35-4.42 (1H, m), 7.03 (1H, d, J= 8.6 Hz), 8.06 (1H, dd, J = 1.9, 8.6 Hz), 8.45 (1H, d, J = 1.9 Hz)。

c) Production of tert-butyl (2R,5S) -4- [ 2-amino-4- (methoxycarbonyl) phenyl ] -2, 5-dimethylpiperazine-1-carboxylate:

the reaction and the treatment were carried out in the same manner as in example 6-c) using tert-butyl (2R,5S) -4- [4- (methoxycarbonyl) -2-nitrophenyl ] -2, 5-dimethylpiperazine-1-carboxylate to obtain the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：0.92 (3H, d, J= 6.6 Hz), 1.30 (3H, d, J = 6.8 Hz), 1.49 (9H, s), 2.55 (1H, d, J= 11.9 Hz), 3.41-3.45 (1H, m), 3.59-3.63 (2H, m), 3.78 (1H, d, J = 13.4 Hz), 3.87 (3H, s), 3.93 (1H, brs), 4.40-4.47 (1H, m), 6.84 (1H, d, J = 8.3 Hz), 7.40 (1H, dd, J = 1.9, 8.3 Hz), 7.43 (1H, d, J = 1.9 Hz)。

d) Preparation of tert-butyl (2R,5S) -4- [ 2-iodo-4- (methoxycarbonyl) phenyl ] -2, 5-dimethylpiperazine-1-carboxylate

The reaction and the treatment were carried out in the same manner as in example 6-d) using tert-butyl (2R,5S) -4- [ 2-amino-4- (methoxycarbonyl) phenyl ] -2, 5-dimethylpiperazine-1-carboxylate to obtain the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：0.93 (3H, d, J= 6.6 Hz), 1.35 (3H, d, J = 6.8 Hz), 1.49 (9H, s), 2.56 (1H, d, J= 11.2 Hz), 3.61-3.65 (2H, m), 3.77-3.80 (2H, m), 3.89 (3H, s), 4.41-4.46 (1H, m), 6.86 (1H, d, J = 8.3 Hz), 7.96 (1H, dd, J = 2.0, 8.3 Hz), 8.50 (1H, d, J = 2.0 Hz)。

e) Preparation of tert-butyl (2R,5S, Z) -4- [4- (methoxycarbonyl) -2- (prop-1-en-1-yl) phenyl ] -2, 5-dimethylpiperazine-1-carboxylate

The reaction and the treatment were carried out in the same manner as in example 6-e) using tert-butyl (2R,5S) -4- [ 2-iodo-4- (methoxycarbonyl) phenyl ] -2, 5-dimethylpiperazine-1-carboxylate to obtain the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：0.90 (3H, d, J= 6.3 Hz), 1.28 (3H, d, J = 6.6 Hz), 1.48 (9H, s), 1.90-1.92 (3H, m), 2.73 (1H, d, J = 11.7 Hz), 3.41-3.44 (1H, m), 3.53-3.58 (1H, m), 3.69-3.72 (2H, m), 3.89 (3H, s), 4.41-4.46 (1H, m),5.79-5.88 (1H, m), 6.45 (1H, d, J = 11.5 Hz), 6.84 (1H, d, J = 8.6 Hz), 7.86 (1H, dd, J= 2.0, 8.6 Hz), 7.93 (1H, d, J = 2.0 Hz)。

f) Production of (2R,5S, Z) -4- [4- (tert-butoxycarbonyl) -2, 5-dimethylpiperazin-1-yl ] -3- (prop-1-en-1-yl) benzoic acid

The reaction and the treatment were carried out in the same manner as in example 6-f) using tert-butyl (2R,5S, Z) -4- [4- (methoxycarbonyl) -2- (prop-1-en-1-yl) phenyl ] -2, 5-dimethylpiperazine-1-carboxylate to obtain the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：0.92 (3H, d, J= 5.9 Hz), 1.27 (3H, d, J = 6.6 Hz), 1.48 (9H, s), 1.91-1.93 (3H, m), 2.77 (1H, d, J = 11.7 Hz), 3.43-3.76 (4H, m), 4.12-4.21 (1H, m), 4.42-4.49 (1H, m),5.81-5.89 (1H, m), 6.44 (1H, d, J = 10.5 Hz), 6.87 (1H, d, J = 8.5 Hz), 7.93 (1H, dd, J = 2.0, 8.5 Hz), 7.99 (1H, d, J = 2.0 Hz)。

g) Production of tert-butyl (2R,5S, Z) -2, 5-dimethyl-4- {4- [ (perfluorophenoxy) carbonyl ] -2- (prop-1-en-1-yl) phenyl } piperazine-1-carboxylate

The reaction and the treatment were carried out in the same manner as in example 6-g) using (2R,5S, Z) -4- [4- (tert-butoxycarbonyl) -2, 5-dimethylpiperazin-1-yl ] -3- (prop-1-en-1-yl) benzoic acid to give the title compound 7.3mg (yield 80%) as a yellow oil.

¹H-NMR (CDCl₃) δ：0.96 (3H, d, J= 6.6 Hz), 1.29 (3H, d, J = 6.8 Hz), 1.49 (9H, s), 1.92-1.94 (3H, m), 2.82 (1H, d, J = 11.0 Hz), 3.43-3.87 (4H, m), 4.42-4.49 (1H, m),5.85-5.93 (1H, m), 6.44 (1H, d, J = 11.7 Hz), 6.92 (1H, d, J = 8.5 Hz), 8.03 (1H, dd, J = 2.0, 8.5 Hz), 8.05 (1H, d, J = 2.0 Hz)。

h) Production of (2R,5S) -tert-butyl 4- [4- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -2- ((Z) -prop-1-en-1-yl) phenyl ] -2, 5-dimethylpiperazine-1-carboxylate

The reaction and the treatment were carried out in the same manner as in example 6-h) using tert-butyl (2R,5S, Z) -2, 5-dimethyl-4- {4- [ (perfluorophenoxy) carbonyl ] -2- (prop-1-en-1-yl) phenyl } piperazine-1-carboxylate to obtain the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：0.89 (3H, d, J= 6.5 Hz), 1.29 (3H, d, J = 6.5 Hz), 1.48 (9H, s), 1.87 (3H, dd, J= 1.6, 7.0 Hz), 2.67 (1H, d, J = 11.6 Hz), 3.38-3.74 (4H, m), 4.37-4.46 (1H, m),5.77-5.90 (1H, m), 6.51 (1H, dd, J = 1.6, 11.7 Hz), 6.88 (1H, d, J = 8.6 Hz), 7.37 (1H, dd, J = 2.0, 8.6 Hz), 7.57 (1H, d, J= 2.0 Hz)。

i) Production of (2R,5S, Z) -2- [4- (2, 5-dimethylpiperazin-1-yl) -3- (prop-1-en-1-yl) phenyl ] -1,1,1,3,3, 3-hexafluoropropan-2-ol

The reaction and the treatment were carried out in the same manner as in example 6-j) using (2R,5S) -tert-butyl 4- [4- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -2- ((Z) -prop-1-en-1-yl) phenyl ] -2, 5-dimethylpiperazine-1-carboxylate to obtain the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：0.85 (3H, d, J= 6.2 Hz), 1.07 (3H, d, J = 6.2 Hz), 1.82 (3H, dd, J = 1.6, 7.3 Hz), 2.26-3.20 (8H, m),5.82 (1H, qd, J = 7.3, 11.6 Hz), 6.69 (1H, dd, J= 1.6, 11.6 Hz), 7.19 (1H, d, J = 8.1 Hz), 7.61-7.66 (2H, m)。

j) Preparation of (2R,5S, Z) -1- {4- [1,1,1,3,3, 3-hexafluoro-2- (methoxymethyloxy) propan-2-yl ] -2- (prop-1-en-1-yl) phenyl } -2, 5-dimethylpiperazine

The reaction and treatment were carried out in the same manner as in example 12-i) using (2R,5S, Z) -2- [4- (2, 5-dimethylpiperazin-1-yl) -3- (prop-1-en-1-yl) phenyl ] -1,1,1,3,3, 3-hexafluoropropan-2-ol to give the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：0.88 (3H, d, J= 5.9 Hz), 1.14 (3H, d, J = 6.2 Hz), 1.81 (3H, dd, J = 1.6, 7.2 Hz), 2.32-2.45 (1H, m), 2.67-2.96 (2H, m), 3.05-3.29 (4H, m), 3.55 (3H, s), 4.87 (2H, s),5.77-5.90 (1H, m), 6.66 (1H, dd, J = 1.6, 11.9 Hz), 7.18 (1H, d, J = 8.4 Hz), 7.46 (1H, dd, J = 2.0, 8.4 Hz), 7.55 (1H, d, J = 2.0 Hz)。

k) Production of (2R,5S, Z) -2-bromo-1- (4- {4- [1,1,1,3,3, 3-hexafluoro-2- (methoxymethyloxy) propan-2-yl ] -2- (prop-1-en-1-yl) phenyl } -2, 5-dimethylpiperazin-1-yl) ethanone

The reaction and the treatment were carried out in the same manner as in example 6-k) using (2R,5S, Z) -1- {4- [1,1,1,3,3, 3-hexafluoro-2- (methoxymethoxy) propan-2-yl ] -2- (prop-1-en-1-yl) phenyl } -2, 5-dimethylpiperazine to give the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：0.89-0.99 (3H, m), 1.31-1.50 (3H, m), 1.87 (3H, dd, 1.6, 7.2 Hz), 2.74-2.81 (1H, m), 3.28-3.46 (2H, m), 3.55 (3H, s), 3.67-3.98 (4H, m), 4.16-4.28 (1H, m), 4.86 (2H, s),5.86 (1H, qd, J = 7.2, 11.3 Hz), 6.50 (1H, dd, J = 1.6, 11.3 Hz), 6.89 (1H, d, J = 8.6 Hz), 7.43 (1H, dd, J = 2.0, 8.6 Hz), 7.49 (1H, d, J = 2.0 Hz)。

l) (production of 2R,5S, Z) -3- (2- {4- [4- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -2- (prop-1-en-1-yl) phenyl ] -2, 5-dimethylpiperazin-1-yl } -2-oxoethyl) -5- [4- (1-methylethoxy) phenyl ] -5-methylimidazolidine-2, 4-dione:

5- [4- (1-Methylethoxy) phenyl ] -5-methylimidazolidine-2, 4-dione (7.7 mg, 0.0311 mmol) was dissolved in N, N-dimethylformamide (500. mu.L), and potassium carbonate (8.6 mg, 0.0622 mmol) was added under ice cooling, followed by stirring at room temperature for 5 minutes. Then, (2R,5S, Z) -2-bromo-1- (4- {4- [1,1,1,3,3, 3-hexafluoro-2- (methoxymethoxy) propan-2-yl ] -2- (prop-1-en-1-yl) phenyl } -2, 5-dimethylpiperazin-1-yl) ethanone (17 mg, 0.0311 mmol) was added under ice-cooling, and stirred at room temperature for 18 hours. Water was added to the reaction solution under ice cooling, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate (1.0mL), and a 4N-hydrochloric acid-ethyl acetate solution (1.0mg) was added thereto and stirred at room temperature for 1 hour. Water and a saturated aqueous sodium bicarbonate solution were added to the reaction mixture under ice cooling, extraction was performed with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound 17.4mg (yield 83%) as a yellow oil.

¹H-NMR (CDCl₃) δ：0.88-1.05 (3H, m), 1.26-1.34 (9H, m), 1.83-1.90 (6H, m), 2.68-2.80 (1H, m), 3.30-3.85 (4H, m), 4.05-4.34 (3H, m), 4.54 (1H, q, J = 6.1 Hz), 4.87 (1H, s),5.83-5.96 (2H, m), 6.53-6.58 (1H, m), 6.86-6.91 (3H, m), 7.36-7.59 (4H, m)。

Example 14-2: production of (2S,5R, Z) -3- (2- {4- [4- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -2- (prop-1-en-1-yl) phenyl ] -2, 5-dimethylpiperazin-1-yl } -2-oxoethyl) -5- [4- (1-methylethoxy) phenyl ] -5-methylimidazolidine-2, 4-dione:

(2R,5S, Z) -3- (2- {4- [4- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -2- (prop-1-en-1-yl) phenyl ] -2, 5-dimethylpiperazin-1-yl } -2-oxoethyl) -5- [4- (1-methylethoxy) phenyl ] -5-methylimidazolidine-2 in example 14-1 using (2S,5R) -tert-butyl 2, 5-dimethylpiperazine-1-carboxylate instead of (2R,5S) -tert-butyl 2, 5-dimethylpiperazine-1-carboxylate, production of 4-diketone the title compound was obtained as a yellow oil by performing the same reaction and treatment.

Example 15-1: production of (2R,5S) -3- (2- {4- [4- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -2-propylphenyl ] -2, 5-dimethylpiperazin-1-yl } -2-oxoethyl) -5- [4- (1-methylethoxy) phenyl ] -5-methylimidazolidine-2, 4-dione:

[ solution 23]

(2R,5S, Z) -3- (2- {4- [4- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -2- (prop-1-en-1-yl) phenyl ] -2, 5-dimethylpiperazin-1-yl } -2-oxoethyl) -5- [4- (1-methylethoxy) phenyl ] -5-methylimidazolidine-2, 4-dione (example 14-1) (6.0mg,0.0088mmol) was dissolved in methanol (1.0mL), and palladium on carbon (5.0mg) was added to conduct hydrogenation, followed by stirring at room temperature for 1 hour. The reaction solution was filtered through celite, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound 4.7mg (yield 78%) as a yellow oil.

¹H-NMR (CDCl₃) δ：0.95-1.00 (6H, m), 1.26-1.33 (9H, m), 1.68 (2H, qt, J = 7.0, 7.6 Hz), 1.90 (3H, s), 2.46-2.64 (2H, m), 2.77-2.89 (1H, m), 3.39-3.90 (5H, m), 4.20-4.30 (2H, m), 4.54 (1H, q, J = 5.9 Hz), 4.84 (1H, s),5.99 (1H, s), 6.88-6.94 (3H, m), 7.36-7.52 (4H, m)。

Example 15-2: production of (2S,5R) -3- (2- {4- [4- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -2-propylphenyl ] -2, 5-dimethylpiperazin-1-yl } -2-oxoethyl) -5- [4- (1-methylethoxy) phenyl ] -5-methylimidazolidine-2, 4-dione:

(2S, 5S, Z) -3- (2- {4- [4- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -2- (prop-1-en-1-yl) phenyl ] -2, 5-dimethylpiperazin-1-yl } -2-oxoethyl) -5- [4- (1-methylethoxy) phenyl ] -5-methylimidazolidine-2, 4-dione (example 14-2) was used instead of (2R,5S, Z) -3- (2- {4- [4- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -2- (prop-1-en-1-yl) ) Phenyl ] -2, 5-dimethylpiperazin-1-yl } -2-oxoethyl) -5- [4- (1-methylethoxy) phenyl ] -5-methylimidazolidine-2, 4-dione (example 14-1) was reacted and treated in the same manner as in the production of example 15-1 to obtain the title compound as a yellow oily substance.

Example 16: production of (R) -5- (2, 3-dihydrobenzofuran-5-yl) -3- (2- {4- [4- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -2-propylphenyl ] -3-methylpiperazin-1-yl } -2-oxoethyl) -5-methylimidazolidine-2, 4-dione:

[ solution 24]

The reaction and the treatment were carried out in the same manner as in example 12 using 5- (2, 3-dihydrobenzofuran-5-yl) -5-methylimidazolidine-2, 4-dione to obtain the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：0.79-0.86 (3H, m), 0.95 (3H, t, J = 7.3 Hz), 1.62 (2H, qt, J = 7.3, 7.6 Hz), 1.96 (3H, s), 2.60-2.80 (2H, m), 2.94-3.49 (3H, m), 3.22 (2H, t, J = 8.4 Hz), 3.63-3.70 (2H, m), 3.91-3.95 (2H, m), 4.27-4.46 (2H, m), 4.58 (2H, t, J= 8.4 Hz),5.90 (1H, s), 6.78 (1H, d, J = 8.4 Hz), 7.10-7.15 (1H, m), 7.26-7.31 (1H, m), 7.41 (1H, s), 7.49-7.54 (1H, m), 7.54 (1H, s)。

Example 17: production of (S) -5- (2, 3-dihydrobenzofuran-5-yl) -3- (2- {4- [4- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -2-propylphenyl ] -3-methylpiperazin-1-yl } -2-oxoethyl) -5-methylimidazolidine-2, 4-dione:

[ solution 25]

The title compound was obtained as a yellow oil by performing the reaction in the same manner as in example 12 using (S) -2-methyl-1-tert-butoxycarbonylpiperazine instead of (R) -2-methyl-1-tert-butoxycarbonylpiperazine and 5- (2, 3-dihydrobenzofuran-5-yl) -5-methylimidazolidine-2, 4-dione.

¹H-NMR (CDCl₃) δ：0.79-0.86 (3H, m), 0.95 (3H, t, J = 7.3 Hz), 1.62 (2H, qt, J = 7.3, 7.6 Hz), 1.90 (3H, s), 2.60-2.80 (2H, m), 2.90-3.48 (3H, m), 3.22 (2H, t, J = 8.6 Hz), 3.64-3.74 (2H, m), 3.97-4.00 (2H, m), 4.27-4.44 (2H, m), 4.58 (2H, t, J= 8.6 Hz),5.90 (1H, s), 6.79 (1H, d, J = 8.6 Hz), 7.10-7.15 (1H, m), 7.26-7.30 (1H, m), 7.41 (1H, s), 7.49-7.54 (1H, m), 7.54 (1H, s)。

Example 18-1: production of (2R,5S, Z) -5- (2, 3-dihydrobenzofuran-5-yl) -3- (2- {4- [4- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -2- (prop-1-en-1-yl) phenyl ] -2, 5-dimethylpiperazin-1-yl } -2-oxoethyl) -5-methylimidazolidine-2, 4-dione:

[ solution 26]

Using 5- (2, 3-dihydrobenzofuran-5-yl) -5-methylimidazolidine-2, 4-dione, a reaction and treatment were carried out in the same manner as in example 14-1 to obtain the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：0.88-1.01 (3H, m), 1.49-1.71 (3H, m), 1.86-1.95 (6H, m), 3.22 (2H, t, J = 8.6 Hz), 3.28-3.84 (6H, m), 4.08-4.24 (2H, m), 4.58 (2H, t, J = 8.6 Hz),4.88 (1H, s),5.75-5.90 (2H, m), 6.49-6.53 (1H, m), 6.78 (1H, dd, J = 4.9, 8.2 Hz), 6.88 (1H, d, J = 8.6 Hz), 7.29 (1H, d, J = 8.2 Hz), 7.41 (1H, d, J = 4.9 Hz), 7.53 (1H, dd, J = 2.0, 8.6 Hz), 7.58 (1H, d, J = 2.0 Hz)。

Example 18-2: production of (2S,5R, Z) -5- (2, 3-dihydrobenzofuran-5-yl) -3- (2- {4- [4- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -2- (prop-1-en-1-yl) phenyl ] -2, 5-dimethylpiperazin-1-yl } -2-oxoethyl) -5-methylimidazolidine-2, 4-dione:

the reaction and the treatment were carried out in the same manner as in example 18-1 to give the title compound as a yellow oil.

Example 19-1: production of (2R,5S) -5- (2, 3-dihydrobenzofuran-5-yl) -3- (2- {4- [4- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -2-propylphenyl ] -2, 5-dimethylpiperazin-1-yl } -2-oxoethyl) -5-methylimidazolidine-2, 4-dione:

[ solution 27]

Using 5- (2, 3-dihydrobenzofuran-5-yl) -5-methylimidazolidine-2, 4-dione, a reaction was carried out in the same manner as in examples 14-1 and 15-1, and then the title compound was obtained as a yellow oil.

¹H-NMR (CDCl₃) δ：0.95-1.00 (6H, m), 1.35-1.50 (3H, m), 1.64-1.75 (2H, m), 1.90 (3H, s), 2.46-2.63 (2H, m), 2.74-2.89 (1H, m), 3.22 (2H, t, J = 8.6 Hz), 3.38-3.95 (5H, m), 4.20-4.34 (2H, m), 4.58 (2H, t, J = 8.6 Hz), 4.86 (1H, s),5.81 (1H, s), 6.78 (1H, dd, J = 2.2, 8.6 Hz), 6.92 (1H, d, J = 8.1 Hz), 7.28-7.31 (1H, m), 7.40-7.48 (2H, m), 7.52 (1H, d, J = 2.0 Hz)。

Example 19-2: production of (2S,5R) -5- (2, 3-dihydrobenzofuran-5-yl) -3- (2- {4- [4- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -2-propylphenyl ] -2, 5-dimethylpiperazin-1-yl } -2-oxoethyl) -5-methylimidazolidine-2, 4-dione:

the reaction and the treatment were carried out in the same manner as in example 19-1 to give the title compound as a yellow oil.

Example 20: (R) -5- (2, 3-dihydrobenzo [ b ]][1,4]IIOn-6-yl) -3- (2- {4- [4- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -2-propylphenyl]Production of (E) -3-methylpiperazin-1-yl } -2-oxoethyl) -5-methylimidazolidine-2, 4-dione:

[ solution 28]

a)5- (2, 3-dihydrobenzo [ b ]][1,4]IIProduction of in-6-yl) -5-methylimidazolidine-2, 4-dione:

using 1- (2, 3-dihydrobenzo [ b ]][1,4]IIEn-6-yl) ethanone, reacted and treated in the same manner as in example 1-l), to give the title compound as white crystals.

¹H-NMR (CDCl₃) δ：1.69 (3H, s), 4.21 (4H, s), 6.81 (1H, d, J = 8.1 Hz), 6.93 (1H, dd, J = 2.2, 8.1 Hz), 6.95 (1H, d, J = 2.2 Hz)。

b) Using 5- (2, 3-dihydrobenzo [ b ]][1,4]IIIn-6-yl) -5-methylimidazolidine-2, 4-dione was reacted and treated in the same manner as in example 12 to give the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：0.79-0.85 (3H, m), 0.95 (3H, t, J = 7.3 Hz), 1.62 (2H, qt, J = 7.3, 7.6 Hz), 1.88 (3H, s), 2.60-2.80 (2H, m), 2.89-3.50 (3H, m), 3.63-3.70 (2H, m), 4.00-4.02 (2H, m), 4.24 (4H, s), 4.30-4.45 (2H, m),5.96 (1H, s), 6.88 (1H, d, J = 8.6 Hz), 7.03 (1H, dd, J = 2.2, 8.6 Hz), 7.08 (1H, d, J = 2.2 Hz), 7.10-7.15 (1H, m), 7.49-7.53 (1H, m), 7.53 (1H, s)。

Example 21: (S) -5- (2, 3-dihydrobenzo [ b ]][1,4]IIOn-6-yl) -3- (2- {4- [4- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -2-propylphenyl]Production of (E) -3-methylpiperazin-1-yl } -2-oxoethyl) -5-methylimidazolidine-2, 4-dione:

[ solution 29]

(S) -2-methyl-1-tert-butoxycarbonylpiperazine was used instead of (R) -2-methyl-1-tert-butoxycarbonylpiperazine, and 5- (2, 3-dihydrobenzo [ b ] was used][1,4]IIFurther, a reaction and treatment were carried out in the same manner as in example 12 using in-6-yl) -5-methylimidazolidine-2, 4-dione to obtain the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：0.79-0.86 (3H, m), 0.95 (3H, t, J = 7.3 Hz), 1.62 (2H, qt, J = 7.3, 7.6 Hz), 1.88 (3H, s), 2.60-2.80 (2H, m), 2.89-3.47 (3H, m), 3.63-3.70 (2H, m), 3.90-3.95 (2H, m), 4.24 (4H, s), 4.24-4.40 (2H, m),5.86 (1H, s), 6.88 (1H, d, J = 8.6 Hz), 7.03 (1H, dd, J = 2.4, 8.6 Hz), 7.08 (1H, d, J = 2.4 Hz), 7.10-7.14 (1H, m), 7.49-7.54 (1H, m), 7.54 (1H, s)。

Example 22: production of (R) -5- (2, 2-dimethyl-2, 3-dihydrobenzofuran-5-yl) -3- (2- {4- [4- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -2-propylphenyl ] -3-methylpiperazin-1-yl } -2-oxoethyl) -5-methylimidazolidine-2, 4-dione:

[ solution 30]

a) Production of 5- (2, 2-dimethyl-2, 3-dihydrobenzofuran-5-yl) -5-methylimidazolidine-2, 4-dione:

1- (4-hydroxyphenyl) ethanone (1.36g, 10mmol) was dissolved in acetone (50mL), tetrabutylammonium iodide (370mg, 1.0mmol), potassium carbonate (2.76g, 20mmol), and 3-chloro-2-methyl-1-propene (1.5mL, 15mmol) were added in this order, and the mixture was stirred at 70 ℃ overnight. The reaction mixture was filtered, washed with acetone, and concentrated under reduced pressure. To the resulting residue were added water and ethyl acetate, followed by extraction with ethyl acetate, and the organic layer was washed with a 1N-aqueous sodium hydroxide solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 1.71g (yield 90%) of 1- (4- (2-methylallyloxy) phenyl) ethanone as a colorless oil.

¹H-NMR (CDCl₃) δ：1.84 (3H, s), 2.56 (3H., s), 4.50 (2H, s),5.06 (2H, d, J= 20.8 Hz), 6.95 (2H, d, J = 8.9 Hz), 7.93 (2H, d, J = 8.9 Hz)。

1- (4- (2-methylallyloxy) phenyl) ethanone (85 mg, 0.450 mmol) was dissolved in PEG400 (0.3 mL) and stirred under microwave irradiation at 250 ℃ for 2 hours. Water was added to the reaction solution, which was extracted with ethyl acetate, washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give 42mg of 1- (2, 2-dimethyl-2, 3-dihydrobenzofuran-5-yl) ethanone as a yellow oil (yield 50%).

¹H-NMR (CDCl₃) δ：1.50 (6H, s), 2.54 (3H, s), 3.04 (2H, s), 6.74 (1H, d, J= 9.2 Hz), 7.78-7.81 (2H, m)。

Using 1- (2, 2-dimethyl-2, 3-dihydrobenzofuran-5-yl) ethanone, the reaction and treatment were carried out in the same manner as in example 1-l) to obtain the title compound as white crystals.

¹H-NMR (CDCl₃) δ：1.43 (6H, s), 1.72 (3H, s), 3.02 (2H, s), 6.64 (1H, d, J= 8.4 Hz), 7.21 (1H, d, J = 8.4 Hz), 7.28 (1H, s)。

b) The reaction and the treatment were carried out in the same manner as in example 12 using 5- (2, 2-dimethyl-2, 3-dihydrobenzofuran-5-yl) -5-methylimidazolidine-2, 4-dione to obtain the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：0.80-0.87 (3H, m), 0.95 (3H, t, J = 7.3 Hz), 1.46 (6H, s), 1.62 (2H, qt, J = 7.3, 7.6 Hz), 1.90 (3H, s), 2.60-2.80 (2H, m), 2.90-3.48 (3H, m), 3.02 (2H, s), 3.64-3.70 (2H, m), 3.90-3.94 (2H, m), 4.27-4.44 (2H, m),5.86 (1H, s), 6.72 (1H, d, J = 8.4 Hz), 7.10-7.15 (1H, m), 7.26-7.30 (1H, m), 7.34 (1H, s), 7.49-7.54 (1H, m), 7.54 (1H, s)。

Example 23: production of (S) -5- (2, 2-dimethyl-2, 3-dihydrobenzofuran-5-yl) -3- (2- {4- [4- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -2-propylphenyl ] -3-methylpiperazin-1-yl } -2-oxoethyl) -5-methylimidazolidine-2, 4-dione:

[ solution 31]

The title compound was obtained as a yellow oil by performing the reaction and treatment in the same manner as in example 12 using (S) -2-methyl-1-tert-butoxycarbonylpiperazine instead of (R) -2-methyl-1-tert-butoxycarbonylpiperazine and 5- (2, 2-dimethyl-2, 3-dihydrobenzofuran-5-yl) -5-methylimidazolidine-2, 4-dione.

¹H-NMR (CDCl₃) δ：0.80-0.87 (3H, m), 0.95 (3H, t, J = 7.3 Hz), 1.46 (6H, s), 1.62 (2H, qt, J = 7.3, 7.6 Hz), 1.96 (3H, s), 2.68-2.76 (2H, m), 2.95-3.48 (3H, m), 3.02 (2H, s), 3.64-3.70 (2H, m), 3.90-4.00 (2H, m), 4.27-4.40 (2H, m),5.85 (1H, s), 6.72 (1H, d, J = 8.4 Hz), 7.10-7.15 (1H, m), 7.29-7.32 (1H, m), 7.34 (1H, s), 7.49-7.54 (1H, m), 7.54 (1H, s)。

Example 24-1: production of (2R,5S, Z) -3- (2- {4- [4- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -2- (prop-1-en-1-yl) phenyl ] -2, 5-dimethylpiperazin-1-yl } -2-oxoethyl) -5- [5- (1-methylethoxy) pyridin-2-yl ] -5-methylimidazolidine-2, 4-dione:

[ solution 32]

The reaction and the treatment were carried out in the same manner as in example 14-1 using 5- (5- (1-methylethoxy) pyridin-2-yl) -5-methylimidazolidine-2, 4-dione to obtain the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：0.89-1.00 (3H, m), 1.34-1.36 (9H, m), 1.82-1.93 (6H, m), 2.68-2.80 (1H, m), 3.28-3.85 (5H, m), 4.08-4.33 (2H, m), 4.57 (1H, q, J = 5.9 Hz), 4.86 (1H, s),5.83-5.90 (1H, m), 6.33 (1H, s), 6.49-6.65 (1H, m), 6.88 (1H, d, J = 8.6 Hz), 7.19 (1H, dd, J = 3.0, 8.6 Hz), 7.52-7.70 (3H, m), 8.19 (1H, d, J = 3.0 Hz)。

Example 24-2: production of (2S,5R, Z) -3- (2- {4- [4- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -2- (prop-1-en-1-yl) phenyl ] -2, 5-dimethylpiperazin-1-yl } -2-oxoethyl) -5- [5- (1-methylethoxy) pyridin-2-yl ] -5-methylimidazolidine-2, 4-dione:

the reaction and the treatment were carried out in the same manner as in example 24-1 to give the title compound as a yellow oil.

Example 25-1: production of (2R,5S) -3- (2- {4- [4- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -2-propylphenyl ] -2, 5-dimethylpiperazin-1-yl } -2-oxoethyl) -5- [5- (1-methylethoxy) pyridin-2-yl ] -5-methylimidazolidine-2, 4-dione:

[ solution 33]

Using 5- [5- (1-methylethoxy) pyridin-2-yl ] -5-methylimidazolidine-2, 4-dione, a reaction was carried out in the same manner as in examples 14-1 and 15-1 to obtain the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：0.95-1.00 (6H, m), 1.34-1.50 (9H, m), 1.68 (2H, qt, J = 7.0, 7.3 Hz), 1.93 (3H, s), 2.47-2.60 (2H, m), 2.77-2.89 (1H, m), 3.29-3.95 (5H, m), 4.27-4.33 (2H, m), 4.57 (1H, q, J = 5.9 Hz),5.86 (1H, s), 6.43 (1H, s), 6.93 (1H, d, J = 8.6 Hz), 7.20 (1H, dt, J = 2.7, 6.2 Hz), 7.47 (1H, dd, J = 2.0, 8.6 Hz), 7.53 (1H, d, J = 2.0 Hz), 7.64 (1H, dd , J = 5.9, 8.8 Hz), 8.19 (1H, d, J= 2.7 Hz)。

Example 25-2: production of (2S,5R) -3- (2- {4- [4- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -2-propylphenyl ] -2, 5-dimethylpiperazin-1-yl } -2-oxoethyl) -5- [5- (1-methylethoxy) pyridin-2-yl ] -5-methylimidazolidine-2, 4-dione:

the reaction and the treatment were carried out in the same manner as in example 25-1 to give the title compound as a yellow oil.

Example 26-1: production of (2R,5S, Z) -3- (2- {4- [4- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -2- (prop-1-en-1-yl) phenyl ] -2, 5-dimethylpiperazin-1-yl } -2-oxoethyl) -5- [3- (1-methylethoxy) phenyl ] -5-methylimidazolidine-2, 4-dione:

[ chemical 34]

a) Production of 5- [3- (1-methylethoxy) phenyl ] -5-methylimidazolidine-2, 4-dione:

1- (3-hydroxyphenyl) ethanone (1.36g, 10mmol) was dissolved in acetone (50mL), and potassium carbonate (2.76g, 20mmol) and 1-methylethyl iodide (1.5mL, 15mmol) were added in that order, followed by stirring at 70 ℃ overnight. The reaction mixture was filtered, washed with acetone, and concentrated under reduced pressure. To the resulting residue were added water and ethyl acetate, followed by extraction with ethyl acetate, and the organic layer was washed with a 1N-aqueous sodium hydroxide solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 1.67g of 1- (3- (1-methylethoxy) phenyl) ethanone as a yellow oil (yield 94%).

¹H-NMR (CDCl₃) δ：1.35 (6H, d, J = 6.0 Hz), 2.55 (3H, s), 4.63 (1H, quint, J = 6.0 Hz), 7.09 (1H, dd, J = 2.4, 8.3 Hz). 7.35 (1H, t, J = 8.0 Hz), 7.48-7.52 (2H, m)。

Using 1- [3- (1-methylethoxy) phenyl ] ethanone, the reaction and treatment were carried out in the same manner as in example 1-l) to obtain the title compound as white crystals.

¹H-NMR (CDCl₃) δ：1.30 (6H, d, J = 6.0 Hz), 1.73 (3H, s), 4.60 (1H, quint, J = 6.0 Hz), 6.85 (1H, dd, J = 1.6, 8.3 Hz), 7.03-7.10 (2H, m), 7.27 (1H, t, J = 8.3 Hz)。

b) The reaction and the treatment were carried out in the same manner as in example 14-1 using 5- (3- (1-methylethoxy) phenyl) -5-methylimidazolidine-2, 4-dione to give the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：0.85-0.99 (3H, m), 1.31-1.34 (9H, m), 1.86-1.95 (6H, m), 2.68-2.82 (1H, m), 3.28-3.85 (5H, m), 4.16-4.31 (2H, m), 4.59 (1H, q, J = 5.9 Hz), 4.85 (1H, s),5.79-5.90 (2H, m), 6.48-6.66 (1H, m), 6.84-6.89 (2H, m), 7.08-7.12 (2H, m), 7.26-7.33 (1H, m), 7.52-7.58 (2H, m)。

Example 26-2: production of (2S,5R, Z) -3- (2- {4- [4- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -2- (prop-1-en-1-yl) phenyl ] -2, 5-dimethylpiperazin-1-yl } -2-oxoethyl) -5- [3- (1-methylethoxy) phenyl ] -5-methylimidazolidine-2, 4-dione:

the reaction and the treatment were carried out in the same manner as in example 26-1 to give the title compound as a yellow oil.

Example 27-1: production of (2R,5S) -3- (2- {4- [4- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -2-propylphenyl ] -2, 5-dimethylpiperazin-1-yl } -2-oxoethyl) -5- [3- (1-methylethoxy) phenyl ] -5-methylimidazolidine-2, 4-dione:

[ solution 35]

Using 5- (3- (1-methylethoxy) phenyl) -5-methylimidazolidine-2, 4-dione, a reaction was carried out in the same manner as in examples 14-1 and 15-1, and the title compound was obtained as a yellow oil.

¹H-NMR (CDCl₃) δ：0.95-1.00 (6H, m), 1.31-1.45 (9H, m), 1.68 (2H, qt, J = 7.3, 7.6 Hz), 1.91 (3H, s), 2.46-2.61 (3H, m), 2.77-2.88 (1H, m), 3.36-3.43 (2H, m), 3.58-3.62 (2H, m), 4.24-4.32 (2H, m), 4.59 (1H, q, J = 6.5 Hz),5.83 (1H, s),5.79 (1H, s), 6.85 (1H, d, J = 7.0 Hz), 6.92 (1H, d, J= 8.6 Hz), 7.10 (2H, dd, J = 5.0,5.4 Hz), 7.27-7.33 (1H, m), 7.45 (1H, dd, J= 2.0, 7.8 Hz), 7.52 (1H, d, J = 2.0 Hz)。

Example 27-2: production of (2S,5R) -3- (2- {4- [4- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -2-propylphenyl ] -2, 5-dimethylpiperazin-1-yl } -2-oxoethyl) -5- [3- (1-methylethoxy) phenyl ] -5-methylimidazolidine-2, 4-dione:

the reaction and the treatment were carried out in the same manner as in example 27-1 to give the title compound as a yellow oil.

Example 28-1: production of (2R,5S, Z) -5- [4- (cyclopropylthio) phenyl ] -3- (2- {4- [4- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -2- (prop-1-en-1-yl) phenyl ] -2, 5-dimethylpiperazin-1-yl } -2-oxoethyl) -5-methylimidazolidine-2, 4-dione:

[ solution 36]

a) Production of 5- (4- (cyclopropylthio) phenyl) -5-methylimidazolidine-2, 4-dione:

acetyl chloride (189. mu.L, 2.66mmol) and aluminum chloride (267mg, 2.0mmol) were added to dichloromethane (6.7mL) in this order at 0 ℃ and stirred at 0 ℃ for 10 minutes. Then, a solution of cyclopropyl (phenyl) sulfane (200 mg,1.33 mmol) in dichloromethane (890. mu.L) was added, and the mixture was stirred at 0 ℃ for 30 minutes. To the reaction solution was added 5% aqueous hydrochloric acid solution, extraction was performed with ethyl acetate, and the organic layer was washed with saturated aqueous sodium bicarbonate solution, saturated brine, and dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give 181mg of 1- (4- (cyclopropylthio) phenyl) ethanone as a colorless oil (yield 71%).

¹H-NMR (CDCl₃) δ：0.69-0.75 (2H, m), 1.12-1.19 (2H, m), 2.16-2.25 (1H, m), 2.58 (3H, s), 7.41 (2H, d, J = 8.9 Hz), 7.87 (2H, d, J = 8.9 Hz)。

Using 1- (4- (cyclopropylthio) phenyl) ethanone, the reaction and treatment were carried out in the same manner as in example 1-l) to give the title compound as white crystals.

¹H-NMR (CDCl₃) δ：0.56-0.62 (2H, m), 1.05-1.12 (2H, m), 1.74 (1H, m), 2.18-2.26 (1H, m), 7.34-7.44 (4H, m)。

b) The reaction and the treatment were carried out in the same manner as in example 14-1 using 5- (4- (cyclopropylthio) phenyl) -5-methylimidazolidine-2, 4-dione to give the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：0.65-0.70 (3H, m), 0.88-1.45 (7H, m), 1.86-1.95 (6H, m), 2.14-2.21 (1H, m), 2.67-2.82 (1H, m), 3.28-3.86 (5H, m), 4.23-4.29 (2H, m), 4.86 (1H, s),5.84-5.96 (2H, m), 6.49-6.65 (1H, m), 6.88 (1H, d, J = 8.6 Hz), 7.36-7.58 (6H, m)。

Example 28-2: production of (2S,5R, Z) -5- [4- (cyclopropylthio) phenyl ] -3- (2- {4- [4- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -2- (prop-1-en-1-yl) phenyl ] -2, 5-dimethylpiperazin-1-yl } -2-oxoethyl) -5-methylimidazolidine-2, 4-dione:

the reaction and the treatment were carried out in the same manner as in example 28-1 to give the title compound as a yellow oil.

Example 29: production of 3- (2- { (R) -4- [4- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -2-propylphenyl ] -2-methylpiperazin-1-yl } -2-oxoethyl) -5- [4- (1-methylethoxy) phenyl ] -5-methylimidazolidine-2, 4-dione:

[ solution 37]

a) Production of methyl (R) -4- (4-benzyl-3-methylpiperazin-1-yl) -3-nitrobenzoate

The reaction and the treatment were carried out in the same manner as in example 6-b) except for using (R) -2-methyl-1-benzylpiperazine instead of tert-butyl piperazine-1-carboxylate to obtain the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：1.20 (3H, d, J= 5.9 Hz), 2.28-2.37 (1H, m), 2.67-2.80 (2H, m), 2.89-2.97 (1H, m), 3.03-3.25 (3H, m), 3.23 (1H, d, J = 13.2 Hz), 3.90 (3H, s), 4.07 (1H, d, J= 13.2 Hz), 7.04 (1H, d, J = 8.9 Hz), 7.26-7.34 (5H, m), 8.04 (1H, dd, J= 2.2, 8.9 Hz), 8.42 (1H, d, J = 2.2 Hz)。

b) Production of methyl (R) -3-amino-4- (4-benzyl-3-methylpiperazin-1-yl) benzoate

The reaction and the treatment were carried out in the same manner as in example 6-c) to give the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：1.23 (3H, d, J= 5.7 Hz), 2.28-2.38 (1H, m), 2.59-2.71 (2H, m), 2.77-2.86 (2H, m), 2.99-3.11 (2H, m), 3.26 (1H, d, J = 13.2 Hz), 3.86 (3H, s), 3.94 (2H, s), 4.19 (1H, d, J = 13.2 Hz), 6.95 (1H, d, J = 8.1 Hz), 7.26-7.35 (5H, m), 7.38 (1H, d, J = 1.9 Hz), 7.43 (1H, dd, J = 1.9, 8.1 Hz)。

c) Production of methyl (R) -4- (4-benzyl-3-methylpiperazin-1-yl) -3-iodobenzoate

The reaction and the treatment were carried out in the same manner as in example 6-d) to give the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：1.23 (3H, d, J= 6.1 Hz), 2.39-2.45 (1H, m), 2.66-2.92 (4H, m), 3.13-3.16 (1H, m), 3.22-3.29 (2H, m), 3.88 (3H, s), 4.11 (1H, d, J = 13.7 Hz), 6.98 (1H, d, J= 8.3 Hz), 7.24-7.37 (5H, m), 7.96 (1H, dd, J = 2.0, 8.3 Hz), 8.49 (1H, d, J = 2.0 Hz)。

d) Production of methyl (R) -4- (4-benzyl-3-methylpiperazin-1-yl) -3- (prop-1-en-1-yl) benzoate

The reaction and the treatment were carried out in the same manner as in example 6-e) to give the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：1.21 (3H, d, J= 5.9 Hz), 1.88 (3H, d, J = 7.0 Hz), 2.27-2.34 (1H, m), 2.63-2.88 (4H, m), 3.15-3.25 (2H, m), 3.23 (1H, d, J = 12.4 Hz), 3.88 (3H, s), 4.09 (1H, d, J = 12.4 Hz),5.79 (1H, qd, J= 7.0, 9.7 Hz), 6.41 (1H, d, J = 9.7 Hz), 6.92 (1H, d, J = 8.1 Hz), 7.29-7.35 (5H, m), 7.86 (1H, dd, J = 2.4, 8.1 Hz), 7.90 (1H, d, J= 2.4 Hz)。

e) Production of (R) -4- (4-benzyl-3-methylpiperazin-1-yl) -3- (prop-1-en-1-yl) benzoic acid

The reaction and the treatment were carried out in the same manner as in example 6-f) to give the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：1.22 (3H, d, J= 6.2 Hz), 1.89 (3H, d, J = 7.0 Hz), 2.25-2.40 (1H, m), 2.60-2.90 (4H, m), 3.17-3.27 (2H, m), 3.25 (1H, d, J = 13.0 Hz), 4.10 (1H, d, J= 13.0 Hz),5.80 (1H, qd, J = 7.0, 12.2 Hz), 6.40 (1H, d, J = 12.2 Hz), 6.94 (1H, d, J = 8.1 Hz), 7.29-7.35 (5H, m), 7.91 (1H, d, J = 8.1 Hz), 7.94 (1H, s)。

f) Production of pentafluorophenyl (R) -4- (4-benzyl-3-methylpiperazin-1-yl) -3- (prop-1-en-1-yl) benzoate

The reaction and the treatment were carried out in the same manner as in example 6-g) to obtain the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：1.23 (3H, d, J= 5.9 Hz), 1.89 (3H, dd, J = 1.9, 7.3 Hz), 2.26-2.39 (1H, m), 2.61-2.96 (4H, m), 3.23-3.33 (3H, m), 3.25 (1H, d, J = 13.2 Hz),5.80-5.91 (1H, m), 6.37-6.44 (1H, m), 6.98 (1H, d, J = 9.2 Hz), 7.32-7.36 (5H, m), 8.00-8.03 (2H, m)。

g) Production of (R) -2- [4- (4-benzyl-3-methylpiperazin-1-yl) -3- (prop-1-en-1-yl) phenyl ] -1,1,1,3,3, 3-hexafluoropropan-2-ol

The reaction and the treatment were carried out in the same manner as in example 6-h) to give the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：1.22 (3H, d, J= 6.2 Hz), 1.84 (3H, d, J = 6.8 Hz), 2.25-2.36 (1H, m), 2.61-2.87 (4H, m), 3.07-3.28 (3H, m), 4.09 (1H, d, J = 11.6 Hz),5.75-5.85 (1H, m), 6.43-6.48 (1H, m), 6.98 (1H, d, J = 8.4 Hz), 7.27-7.35 (5H, m), 7.51 (1H, d, J = 8.4 Hz), 7.54 (1H, s)。

h) Preparation of (R) -1-benzyl-4- {4- [1,1,1,3,3, 3-hexafluoro-2- (methoxymethyloxy) propan-2-yl ] -2- (prop-1-en-1-yl) phenyl } -2-methylpiperazine

Using methoxymethyl ether chloride instead of benzyl bromide, the reaction and treatment were carried out in the same manner as in example 6-i) to obtain the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：1.21 (3H, d, J= 5.7 Hz), 1.83 (3H, d, J = 7.0 Hz), 2.26-2.35 (1H, m), 2.62-2.88 (4H, m), 3.08-3.21 (2H, m), 3.23 (1H, d, J = 13.2 Hz), 3.54 (3H, s), 4.08 (1H, d, J = 13.2 Hz), 4.85 (2H, s),5.80 (1H, qd, J = 7.0, 11.3 Hz), 6.46 (1H, d, J = 11.3 Hz), 6.96 (1H, d, J = 8.6 Hz), 7.26-7.34 (5H, m), 7.41 (1H, d, J = 8.6 Hz), 7.45 (1H, s)。

i) Preparation of (R) -1- {4- [1,1,1,3,3, 3-hexafluoro-2- (methoxymethyloxy) propan-2-yl ] -2-propylphenyl } -3-methylpiperazine

The reaction and the treatment were carried out in the same manner as in example 6-j) to give the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：0.96 (3H, t, J= 7.6 Hz), 1.10 (3H, d, J = 6.2 Hz), 1.65 (2H, qt, J = 7.6, 7.8 Hz), 2.36-2.44 (1H, m), 2.64 (2H, t, J = 7.8 Hz), 2.71-2.78 (1H, m), 2.96-3.09 (5H, m), 3.55 (3H, s), 4.83 (2H, s), 7.07 (1H, d, J = 8.1 Hz), 7.37 (1H, d, J = 8.1 Hz), 7.39 (1H, s)。

j) Preparation of (R) -2-bromo-1- (4- {4- [1,1,1,3,3, 3-hexafluoro-2- (methoxymethyloxy) propan-2-yl ] -2-propylphenyl } -2-methylpiperazin-1-yl) ethanone

The reaction and the treatment were carried out in the same manner as in example 6-k) to obtain the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：0.98 (3H, t, J = 7.3 Hz), 1.42 (3H, d, J = 6.5 Hz), 1.59-1.73 (2H, m), 2.70 (2H, t, J= 7.3 Hz), 2.86-3.10 (4H, m), 3.55 (3H, s), 3.65-3.75 (1H, m), 3.89 (2H, s), 4.10-4.20 (1H, m), 4.45-4.55 (1H, m), 4.83 (2H, s), 7.08 (1H, d, J = 8.4 Hz), 7.41 (1H, d, J = 8.4 Hz), 7.43 (1H, s)。

Also, in step a) of this example, (S) -2-bromo-1- (4- {4- [1,1,1,3, 3-hexafluoro-2- (methoxymethoxy) propan-2-yl ] -2-propylphenyl } -2-methylpiperazin-1-yl) ethanone was obtained as a yellow oil by using (S) -2-methyl-1-benzylpiperazine instead of (R) -2-methyl-1-benzylpiperazine.

k) The reaction and treatment were carried out in the same manner as in examples 14-1 and 15-1 using (R) -2-bromo-1- (4- {4- [1,1,1,3,3, 3-hexafluoro-2- (methoxymethoxy) propan-2-yl ] -2-propylphenyl } -2-methylpiperazin-1-yl) ethanone and 5- (3- (1-methylethoxy) phenyl) -5-methylimidazolidine-2, 4-dione to give the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：0.98 (3H, t, J= 7.6 Hz), 1.32 (6H, d, J = 6.2 Hz), 1.59-1.73 (5H, m), 1.91 (3H, s), 2.70 (2H, t, J = 7.6 Hz), 2.80-3.05 (4H, m), 3.55-3.65 (1H, m), 4.00-4.80 (4H, m), 4.47-4.60 (1H, m),5.68 (1H, s), 6.90 (2H, d, J = 8.9 Hz), 7.07 (1H, d, J = 8.4 Hz), 7.44-7.48 (2H, m), 7.50 (1H, d, J= 8.4 Hz), 7.52 (1H, s)。

Example 30: 5- (2, 3-dihydrobenzo [ b ]][1,4]IIEn-6-yl) -3- (2- { (R) -4- [4- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -2-propylphenyl]Production of (E) -2-methylpiperazin-1-yl } -2-oxoethyl) -5-methylimidazolidine-2, 4-dione:

[ solution 38]

Using (R) -2-bromo-1- (4- {4- [1,1,1,3,3, 3-hexafluoro-2-)(methoxymethoxy) propan-2-yl]-2-propylphenyl } -2-methylpiperazin-1-yl) ethanone and 5- (2, 3-dihydrobenzo [ b ]][1,4]IIEn-6-yl) -5-methylimidazolidine-2, 4-dione was reacted and treated in the same manner as in examples 14-1 and 15-1 to give the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：0.97 (3H, t, J= 7.3 Hz), 1.60-1.73 (5H, m), 1.88 (3H, s), 2.69 (2H, t, J = 7.6 Hz), 2.89-3.05 (4H, m), 3.53-3.70 (1H, m), 4.00-4.80 (4H, m), 4.25 (4H, s),5.73 (1H, s), 6.88 (1H, d, J = 8.6 Hz), 7.00-7.09 (3H, m), 7.50 (1H, d, J= 8.6 Hz), 7.52 (1H, s)。

Example 31: production of 5- (2, 3-dihydrobenzofuran-5-yl) -3- (2- [ (R) -4- {4- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -2-propylphenyl } -2-methylpiperazin-1-yl ] -2-oxoethyl) -5-methylimidazolidine-2, 4-dione:

[ solution 39]

The reaction and treatment were carried out in the same manner as in examples 14-1 and 15-1 using (R) -2-bromo-1- (4- {4- [1,1,1,3,3, 3-hexafluoro-2- (methoxymethoxy) propan-2-yl ] -2-propylphenyl } -2-methylpiperazin-1-yl) ethanone and 5- (2, 3-dihydrobenzofuran-5-yl) -5-methylimidazolidine-2, 4-dione to obtain the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：0.97 (3H, t, J= 7.3 Hz), 1.58-1.71 (5H, m), 1.90 (3H, s), 2.69 (2H, t, J = 7.3 Hz), 2.89-3.05 (4H, m), 3.22 (2H, t, J = 8.6 Hz), 3.55-3.65 (1H, m), 4.05-4.77 (4H, m), 4.58 (2H, t, J = 8.6 Hz),5.79 (1H, s), 6.78 (1H, d, J= 8.6 Hz), 7.07 (1H, d, J = 8.4 Hz), 7.25-7.32 (1H, m), 7.41 (1H, s), 7.50 (1H, d, J = 8.4 Hz), 7.52 (1H, s)。

Example 32: production of 3- (2- [ (R) -4- {4- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -2-propylphenyl } -2-methylpiperazin-1-yl ] -2-oxoethyl) -5- [5- (1-methylethoxy) pyridin-2-yl ] -5-methylimidazolidine-2, 4-dione:

[ solution 40]

The reaction and treatment were carried out in the same manner as in examples 14-1 and 15-1 using (R) -2-bromo-1- (4- {4- [1,1,1,3,3, 3-hexafluoro-2- (methoxymethoxy) propan-2-yl ] -2-propylphenyl } -2-methylpiperazin-1-yl) ethanone and 5- [5- (1-methylethoxy) pyridin-2-yl ] -5-methylimidazolidine-2, 4-dione to obtain the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：0.98 (3H, t, J= 7.3 Hz), 1.35 (6H, d, J = 5.9 Hz), 1.60-1.71 (5H, m), 1.87 (3H, s), 2.70 (2H, t, J = 7.6 Hz), 2.89-3.05 (4H, m), 3.62-3.69 (1H, m), 4.05-4.75 (4H, m), 4.52-4.61 (1H, m), 6.33 (1H, s), 7.07 (1H, d, J = 8.4 Hz), 7.19 (1H, dd, J = 2.7, 8.6 Hz), 7.50 (1H, d, J = 8.4 Hz), 7.52 (1H, s), 7.61-7.65 (1H, m), 8.19 (1H, d, J = 2.7 Hz)。

Example 33: production of 3- (2- { (S) -4- [4- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -2-propylphenyl ] -2-methylpiperazin-1-yl } -2-oxoethyl) -5- [4- (1-methylethoxy) phenyl ] -5-methylimidazolidine-2, 4-dione:

[ solution 41]

The reaction and treatment were carried out in the same manner as in examples 14-1 and 15-1 using (S) -2-bromo-1- (4- {4- [1,1,1,3,3, 3-hexafluoro-2- (methoxymethoxy) propan-2-yl ] -2-propylphenyl } -2-methylpiperazin-1-yl) ethanone and 5- (3- (1-methylethoxy) phenyl) -5-methylimidazolidine-2, 4-dione to give the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：0.98 (3H, t, J= 7.3 Hz), 1.32 (6H, d, J = 6.2 Hz), 1.59-1.73 (5H, m), 1.91 (3H, s), 2.70 (2H, t, J = 7.3 Hz), 2.80-3.05 (4H, m), 3.55-3.65 (1H, m), 4.00-4.80 (4H, m), 4.47-4.60 (1H, m),5.69 (1H, s), 6.90 (2H, d, J = 8.9 Hz), 7.07 (1H, d, J = 8.1 Hz), 7.44-7.48 (2H, m), 7.50 (1H, d, J= 8.1 Hz), 7.52 (1H, s)。

Example 34: 5- (2, 3-dihydrobenzo [ b ]][1,4]IIEn-6-yl) -3- (2- { (S) -4- [4- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -2-propylphenyl]Production of (E) -2-methylpiperazin-1-yl } -2-oxoethyl) -5-methylimidazolidine-2, 4-dione:

[ solution 42]

Using (S) -2-bromo-1- (4- {4- [1,1,1,3,3, 3-hexafluoro-2- (methoxymethyloxy) propan-2-yl]-2-propylphenyl } -2-methylpiperazin-1-yl) ethanone and 5- (2, 3-dihydrobenzo [ b ]][1,4]IIEn-6-yl) -5-methylimidazolidine-2, 4-dione was reacted and treated in the same manner as in examples 14-1 and 15-1Thus, the title compound was obtained as a yellow oil.

¹H-NMR (CDCl₃) δ：0.97 (3H, t, J= 7.3 Hz), 1.60-1.73 (5H, m), 1.88 (3H, s), 2.69 (2H, t, J = 7.6 Hz), 2.89-3.05 (4H, m), 3.53-3.70 (1H, m), 4.00-4.80 (4H, m), 4.25 (4H, s),5.71 (1H, s), 6.88 (1H, d, J = 8.6 Hz), 7.00-7.09 (3H, m), 7.50 (1H, d, J= 8.6 Hz), 7.52 (1H, s)。

Example 35: production of 5- (2, 3-dihydrobenzofuran-5-yl) -3- (2- { (S) -4- [4- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -2-propylphenyl ] -2-methylpiperazin-1-yl } -2-oxoethyl) -5-methylimidazolidine-2, 4-dione:

[ solution 43]

The reaction and treatment were carried out in the same manner as in examples 14-1 and 15-1 using (S) -2-bromo-1- (4- {4- [1,1,1,3,3, 3-hexafluoro-2- (methoxymethoxy) propan-2-yl ] -2-propylphenyl } -2-methylpiperazin-1-yl) ethanone and 5- (2, 3-dihydrobenzofuran-5-yl) -5-methylimidazolidine-2, 4-dione to obtain the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：0.98 (3H, t, J= 7.3 Hz), 1.58-1.71 (5H, m), 1.91 (3H, s), 2.69 (2H, t, J = 7.6 Hz), 2.89-3.05 (4H, m), 3.22 (2H, t, J = 8.9 Hz), 3.55-3.65 (1H, m), 4.05-4.77 (4H, m), 4.58 (2H, t, J = 8.9 Hz),5.73 (1H, s), 6.78 (1H, d, J= 8.1 Hz), 7.07 (1H, d, J = 8.6 Hz), 7.25-7.32 (1H, m), 7.41 (1H, s), 7.50 (1H, d, J = 8.6 Hz), 7.52 (1H, s)。

Example 36: production of 3- (2- { (S) -4- [4- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -2-propylphenyl ] -2-methylpiperazin-1-yl } -2-oxoethyl) -5- [5- (1-methylethoxy) pyridin-2-yl ] -5-methylimidazolidine-2, 4-dione:

[ solution 44]

The reaction and treatment were carried out in the same manner as in examples 14-1 and 15-1 using (S) -2-bromo-1- (4- {4- [1,1,1,3,3, 3-hexafluoro-2- (methoxymethoxy) propan-2-yl ] -2-propylphenyl } -2-methylpiperazin-1-yl) ethanone and 5- [5- (1-methylethoxy) pyridin-2-yl ] -5-methylimidazolidine-2, 4-dione to obtain the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：0.98 (3H, t, J= 7.3 Hz), 1.35 (6H, d, J = 5.9 Hz), 1.60-1.71 (5H, m), 1.87 (3H, s), 2.70 (2H, t, J = 7.8 Hz), 2.89-3.05 (4H, m), 3.62-3.69 (1H, m), 4.05-4.75 (4H, m), 4.52-4.61 (1H, m), 6.31 (1H, s), 7.08 (1H, d, J = 8.1 Hz), 7.19 (1H, dd, J = 2.7, 8.6 Hz), 7.50 (1H, d, J = 8.1 Hz), 7.52 (1H, s), 7.61-7.65 (1H, m), 8.19 (1H, d, J = 2.7 Hz)。

Example 37: production of 3- (2- {4- [4- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -2-propylphenyl ] -1, 4-diazepan-1-yl } -2-oxoethyl) -5- [4- (1-methylethoxy) phenyl ] -5-methylimidazolidine-2, 4-dione:

[ solution 45]

a) Production of tert-butyl 4- [4- (methoxycarbonyl) -2-nitrophenyl ] -1, 4-diazepan-1-carboxylate:

the reaction and treatment were carried out in the same manner as in example 6-b) except for using 1-tert-butyl-1, 4-diazepan-1-carboxylic acid instead of tert-butyl piperazine-1-carboxylate to obtain the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：1.30 (9H, s), 1.95-2.01 (2H, m), 3.24-3.28 (1H, m), 3.41-3.65 (7H, m), 3.90 (3H, s), 7.06 (1H, d, J = 8.3 Hz), 7.99 (1H, d, J = 8.3 Hz), 8.36 (1H, s)。

b) Production of tert-butyl 4- [ 2-amino-4- (methoxycarbonyl) phenyl ] -1, 4-diazepan-1-carboxylate:

the reaction and the treatment were carried out in the same manner as in example 6-c) to give the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：1.48 (9H, s), 1.87-2.01 (2H, m), 3.04-3.14 (4H, m), 3.52-3.64 (4H, m), 3.86 (3H, s), 4.00 (2H, s), 6.99 (1H, d, J = 7.8 Hz), 7.38-7.42 (2H, m)。

c) Production of tert-butyl 4- [ 2-iodo-4- (methoxycarbonyl) phenyl ] -1, 4-diazepan-1-carboxylate:

the reaction and the treatment were carried out in the same manner as in example 6-d) to give the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：1.49 (9H, s), 2.04-2.13 (2H, m), 3.12-3.20 (4H, m), 3.57-3.71 (4H, m), 3.89 (3H, s), 7.06 (1H, d, J = 8.6 Hz), 7.94 (1H, dd, J = 1.9, 8.6 Hz), 8.50 (1H, d, J = 1.9 Hz)。

d) Production of tert-butyl 4- [4- (methoxycarbonyl) -2- (prop-1-en-1-yl) phenyl ] -1, 4-diazepan-1-carboxylate:

the reaction and the treatment were carried out in the same manner as in example 6-e) to give the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：1.47 (9H, s), 1.85 (3H, d, J = 7.0 Hz), 1.90-2.00 (2H, m), 3.21-3.35 (4H, m), 3.47-3.61 (4H, m), 3.88 (3H, s),5.81 (1H, qd, J = 7.0, 10.5 Hz), 6.40 (1H, d, J = 10.5 Hz), 6.97 (1H, d, J = 8.4 Hz), 7.83 (1H, d, J = 8.4 Hz), 7.85 (1H, s)。

e) Production of tert-butyl 4- [ 4-carboxy-2- (prop-1-en-1-yl) phenyl ] -1, 4-diazepan-1-carboxylate:

the reaction and the treatment were carried out in the same manner as in example 6-f) to give the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：1.22 (3H, d, J= 6.2 Hz), 1.89 (3H, d, J = 7.0 Hz), 2.25-2.40 (1H, m), 2.60-2.90 (4H, m), 3.17-3.27 (2H, m), 3.25 (1H, d, J = 13.0 Hz), 4.10 (1H, d, J= 13.0 Hz),5.80 (1H, dq, J = 7.0, 12.2 Hz), 6.40 (1H, d, J = 12.2 Hz), 6.94 (1H, d, J = 8.1 Hz), 7.29-7.35 (5H, m), 7.91 (1H, d, J= 8.1 Hz), 7.94 (1H, s)。

f) Production of tert-butyl 4- {4- [ (perfluorophenoxy) carbonyl ] -2- (prop-1-en-1-yl) phenyl } -1, 4-diazepan-1-carboxylate:

the reaction and the treatment were carried out in the same manner as in example 6-g) to obtain the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：1.47 (9H, s), 1.86 (3H, d, J = 7.0 Hz), 1.90-2.05 (2H, m), 3.38-3.62 (8H, m),5.85 (1H, qd, J = 7.0, 10.5 Hz), 6.39 (1H, d, J = 10.5 Hz), 7.01 (1H, d, J = 8.9 Hz), 7.95 (1H, s), 7.97 (1H, d, J = 8.9 Hz)。

g) Production of tert-butyl 4- [4- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -2- (prop-1-en-1-yl) phenyl ] -1, 4-diazepan-1-carboxylate:

the reaction and the treatment were carried out in the same manner as in example 6-h) to give the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ： 1.47 (9H, s), 1.82 (3H, d, J = 7.0 Hz), 1.88-1.98 (2H, m), 3.14-3.25 (4H, m), 3.50-3.61 (4H, m),5.82 (1H, qd, J = 7.0, 11.1 Hz), 6.46 (1H, d, J = 11.1 Hz), 7.03 (1H, d, J = 8.6 Hz), 7.48 (1H, d, J= 8.6 Hz), 7.51 (1H, s)。

h) Production of 2- [4- (1, 4-diazepan-1-yl) -3- (prop-1-en-1-yl) phenyl ] -1,1,1,3,3, 3-hexafluoropropan-2-ol:

the reaction and the treatment were carried out in the same manner as in example 12-h) to give the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：1.79 (3H, d, J= 7.0 Hz), 2.12-2.22 (2H, m), 3.28-3.40 (8H, m),5.86 (1H, qd, J = 7.0, 11.4 Hz), 6.47 (1H, d, J = 11.4 Hz), 7.06 (1H, d, J = 8.9 Hz), 7.53 (1H, d, J = 8.9 Hz), 7.55 (1H, s)。

i) Production of 1- {4- [1,1,1,3,3, 3-hexafluoro-2- (methoxymethyloxy) propan-2-yl ] -2- (prop-1-en-1-yl) phenyl } -1, 4-diazepan:

the reaction and the treatment were carried out in the same manner as in example 12-i) to give the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：1.79 (3H, d, J= 7.3 Hz), 2.19-2.29 (2H, m), 3.29-3.48 (8H, m), 3.55 (3H, s), 4.85 (2H, s),5.87 (1H, qd, J = 7.3, 11.1 Hz), 6.48 (1H, d, J = 11.1 Hz), 7.07 (1H, d, J = 8.9 Hz), 7.43 (1H, d, J = 8.9 Hz), 7.45 (1H, s)。

j) Production of 1- {4- [1,1,1,3,3, 3-hexafluoro-2- (methoxymethyloxy) propan-2-yl ] -2-propylphenyl } -1, 4-diazepan:

the reaction and the treatment were carried out in the same manner as in example 6-j) to give the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：0.98 (3H, d, J= 7.3 Hz), 1.61 (2H, qt, J = 7.3, 7.6 Hz), 2.13-2.33 (2H, m), 2.66 (2H, t, J = 7.6 Hz), 3.17-3.21 (2H, m), 3.37-3.52 (6H, m), 3.55 (3H, s), 4.83 (2H, s), 7.16 (1H, d, J = 8.4 Hz), 7.41 (1H, d, J = 8.4 Hz), 7.42 (1H, s)。

k) Production of 2-bromo-1- (4- {4- [1,1,1,3,3, 3-hexafluoro-2- (methoxymethoxy) propan-2-yl ] -2-propylphenyl } -1, 4-diazepan-1-yl) ethanone:

the reaction and the treatment were carried out in the same manner as in example 6-k) to obtain the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：0.97 (3H, d, J= 7.6 Hz), 1.64 (2H, qt, J = 7.6, 7.6 Hz), 2.05-2.15 (2H, m), 2.65 (2H, t, J = 7.6 Hz), 3.06-3.28 (4H, m), 3.55 (3H, s), 3.69-3.85 (4H, m), 3.93 (2H, s), 4.83 (2H, s), 7.10 (1H, d, J = 8.4 Hz), 7.37 (1H, d, J = 8.4 Hz), 7.39 (1H, s)。

l) Using 2-bromo-1- (4- {4- [1,1,1,3,3, 3-hexafluoro-2- (methoxymethoxy) propan-2-yl ] -2-propylphenyl } -1, 4-diazepan-1-yl) ethanone and 5- (3- (1-methylethoxy) phenyl) -5-methylimidazolidine-2, 4-dione, the reaction and treatment were carried out in the same manner as in examples 14-1 and 15-1 to obtain the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：0.96 (3H, t, J= 7.3 Hz), 1.32 (6H, d, J = 6.2 Hz), 1.60-1.70 (2H, m), 1.90 (3H, s), 2.01-2.10 (2H, m), 2.65 (2H, t, J = 7.6 Hz), 3.08-3.15 (2H, m), 3.29-3.37 (1H, m), 3.53-3.78 (5H, m), 4.30-4.40 (2H, m), 4.49-4.58 (1H, m),5.75 (1H, s), 6.89 (2H, d, J = 8.6 Hz), 7.08 (1H, d, J = 8.4 Hz), 7.40-7.47 (4H, m)。

Example 38: 5- (2, 3-dihydrobenzo [ b ]][1,4]IIOn-6-yl) -3- (2- {4- [4- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -2-propylphenyl]Production of 1, 4-diazepan-1-yl } -2-oxoethyl) -5-methylimidazolidine-2, 4-dione:

[ solution 46]

2-bromo-1- (4- {4- [1,1,1,3,3, 3-hexafluoro-2- (methoxymethyloxy) propan-2-yl) was used]-2-propylphenyl } -1, 4-diazepan-1-yl) ethanone and 5- (2, 3-dihydrobenzo [ b][1,4]IIEn-6-yl) -5-methylimidazolidine-2, 4-dione was reacted and treated in the same manner as in examples 14-1 and 15-1 to give the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：0.96 (3H, t, J= 7.3 Hz), 1.60-1.70 (2H, m), 1.88 (3H, s), 2.00-2.15 (2H, m), 2.65 (2H, t, J= 7.6 Hz), 3.10-3.15 (2H, m), 3.28-3.35 (1H, m), 3.53-3.78 (5H, m), 4.24 (4H, s), 4.25-4.40 (2H, m),5.70 (1H, s), 6.88 (1H, d, J = 8.6 Hz), 6.99-7.13 (3H, m), 7.45 (1H, d, J = 8.4 Hz), 7.48 (1H, s)。

Example 39: production of 5- (2, 3-dihydrobenzofuran-5-yl) -3- (2- {4- [4- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -2-propylphenyl ] -1, 4-diazepan-1-yl } -2-oxoethyl) -5-methylimidazolidine-2, 4-dione:

[ solution 47]

The reaction and treatment were carried out in the same manner as in examples 14-1 and 15-1 using 2-bromo-1- (4- {4- [1,1,1,3,3, 3-hexafluoro-2- (methoxymethoxy) propan-2-yl ] -2-propylphenyl } -1, 4-diazepan-1-yl) ethanone and 5- (2, 3-dihydrobenzofuran-5-yl) -5-methylimidazolidine-2, 4-dione to obtain the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：0.96 (3H, t, J= 7.6 Hz), 1.57-1.70 (2H, m), 1.90 (3H, s), 2.05-2.15 (2H, m), 2.65 (2H, t, J= 7.8 Hz), 3.08-3.14 (2H, m), 3.21 (2H, t, J = 8.4 Hz), 3.28-3.35 (1H, m), 3.55-3.80 (5H, m), 4.25-4.42 (2H, m), 4.57 (2H, t, J = 8.4 Hz),5.75 (1H, s), 6.78 (1H, d, J = 8.4 Hz), 7.08 (1H, d, J = 8.4 Hz), 7.40-7.48 (3H, m), 7.48 (1H, s)。

Example 40: production of 3- (2- {4- [4- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -2-propylphenyl ] -1, 4-diazepan-1-yl } -2-oxoethyl) -5- [5- (1-methylethoxy) pyridin-2-yl ] -5-methylimidazolidine-2, 4-dione:

[ solution 48]

The reaction and treatment were carried out in the same manner as in examples 14-1 and 15-1 using 2-bromo-1- (4- {4- [1,1,1,3,3, 3-hexafluoro-2- (methoxymethoxy) propan-2-yl ] -2-propylphenyl } -1, 4-diazepan-1-yl) ethanone and 5- [5- (1-methylethoxy) pyridin-2-yl ] -5-methylimidazolidine-2, 4-dione to obtain the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：0.96 (3H, t, J = 7.3 Hz), 1.35 (6H, d, J = 6.5 Hz), 1.60-1.71 (2H, m), 1.87 (3H, s), 2.02-2.15 (2H, m), 2.65 (2H, t, J = 7.6 Hz), 3.08-3.18 (2H, m), 3.30-3.40 (1H, m), 3.53-3.78 (5H, m), 4.35-4.45 (2H,m), 4.52-4.60 (1H, m), 6.30 (1H, s), 7.09 (1H, d, J = 8.6 Hz), 7.16 (1H, dd, J = 2.4, 8.9 Hz), 7.45 (1H, d, J = 8.6 Hz), 7.48 (1H, s), 7.63 (1H, d, J = 8.9 Hz), 8.19 (1H, d, J = 2.4 Hz)。

Example 41: production of 5- (5-Cyclopropoxypyridin-2-yl) -3- (2- {4- [4- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -2-propylphenyl ] -1, 4-diazepan-1-yl } -2-oxoethyl) -5-methylimidazolidine-2, 4-dione:

[ solution 49]

a) Production of 2-methyl-5- [1- (phenylthio) cyclopropoxy ] pyridine:

cyclopropylphenyl sulfide (5.0g, 33.3mmol) was dissolved in tetrahydrofuran (50mL), and n-butyllithium (25.1mL, 39.9mmol) was added dropwise at 0 ℃ for 5 minutes under an argon atmosphere. A solution of N-iodosuccinimide (8.99g, 39.9mmol) in tetrahydrofuran (100mL) is then added dropwise at-78 deg.C. Stir overnight and slowly warm to room temperature. To the reaction mixture was added a saturated aqueous sodium bicarbonate solution, and extraction was performed with hexane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (hexane) to obtain 5.64g of a crude product ((1-iodocyclopropyl) (phenyl) sulfane: cyclopropylphenyl sulfide ═ 2.4: 1).

Subsequently, 5-hydroxy-2-methylpyridine (1.82 g, 16.7 mmol) was dissolved in toluene (150mL), and silver carbonate (9.19g, 33.3mmol), (1-iodocyclopropyl) (phenyl) sulfane: a mixture of cyclopropylphenyl sulfide (═ 2.4:1) (5.64g, 16.7mmol (calculated as 1-iodocyclopropyl) (phenyl) sulfane)) was stirred at room temperature overnight. Then, acetic acid (200mL) was added and the mixture was stirred for 10 minutes. The reaction solution was filtered through celite, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound 1.88g (yield 44%) as a yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ：1.34-1.37 (2H, m), 1.44-1.50 (2H, m), 2.51 (3H, s), 7.09 (1H, d, J = 8.6 Hz), 7.22-7.35 (4H, m), 7.46-7.52 (2H, m), 8.31 (1H, d, J = 2.9 Hz)。

c) Production of 2-methyl-5- [1- (phenylsulfonyl) cyclopropoxy ] pyridine:

2-methyl-5- [1- (phenylthio) cyclopropoxy ] pyridine (2.04 g, 7.93 mmol) was dissolved in chloroform (15mL), and alumina (5.0g) and oxone (3.79g, 6.18mmol) were added and stirred at 80 ℃ for 1 hour. Further potassium hydrogen persulfate (1.36g, 2.22mmol) was added thereto, and the mixture was stirred for 1 hour. The reaction solution was filtered through celite, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound 542mg as a yellow oil (yield 24%).

¹H-NMR (400 MHz, CD₃OD) δ：1.42-1.46 (2H, m), 1.91-1.94 (2H, m), 2.47 (3H, s), 7.22 (1H, d, J = 8.6 Hz), 7.55 (1H, dd, J = 2.8, 8.6 Hz), 7.64 (2H, tt, J = 1.7, 7.0 Hz), 7.76 (1H, tt, J = 1.7, 7.0 Hz), 7.88 (2H, td, J = 1.7, 7.0 Hz), 8.16 (1H, d, J = 2.8 Hz)。

d) Production of 5-Cyclopropoxy-2-methylpyridine:

2-methyl-5- [1- (phenylsulfonyl) cyclopropoxy ] pyridine (540 mg, 1.87 mmol) was dissolved in methanol (5.5mL), and sodium phosphite (671mg,5.598mmol) was added thereto, and sodium amalgam (3.58g, 7.47mmol) was added thereto under ice cooling, followed by stirring at the same temperature for 30 minutes and then at room temperature for 3 hours. Saturated aqueous sodium bicarbonate was added to the reaction solution, and extraction was performed with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by distillation to obtain the title compound as a yellow oil (240 mg, yield 86%).

¹H-NMR (400 MHz, CDCl₃) δ：0.77-0.83 (4H, m), 2.49 (3H, s), 3.76 (1H, tt, J = 3.0,5.7 Hz), 7.06 (1H, d, J= 8.3 Hz), 7.25 (1H, dd, J = 2.9, 8.6 Hz), 8.31 (1H, d, J = 2.9 Hz)。

e) Production of 5-cyclopropoxy-2-methylpyridine 1-oxide:

using 5-cyclopropoxy-2-methylpyridine, the reaction and the treatment were carried out in the same manner as in example 6-l), so as to obtain the title compound as white crystals.

¹H-NMR (400 MHz, CDCl₃) δ：0.77-0.86 (4H, m), 2.47 (3H, s), 3.74 (1H, tt, J = 3.0,5.7 Hz), 6.91 (1H, dd, J= 2.2, 8.8 Hz), 7.12 (1H, d, J = 8.8 Hz), 8.27 (1H, d, J = 2.2 Hz)。

f) Production of (5-Cyclopropoxypyridin-2-yl) methanol:

using 5-cyclopropoxy-2-methylpyridine 1-oxide, the reaction and treatment were carried out in the same manner as in example 6-l) to obtain the title compound as white crystals.

¹H-NMR (400 MHz, CDCl₃) δ：0.80-0.83 (4H, m), 3.39 (1H, br s), 3.80 (1H, tt, J = 3.0,5.9 Hz), 4.71 (2H, s), 7.18 (1H, d, J = 8.5 Hz), 7.36 (1H, dd, J = 2.7, 8.5 Hz), 8.37 (1H, d, J = 2.7 Hz)。

g) Production of 5-Cyclopropoxypyridine Formaldehyde:

the reaction and treatment were carried out in the same manner as in example 6-l) using (5-cyclopropyloxypyridin-2-yl) methanol to obtain the title compound as white crystals.

¹H-NMR (270 MHz, CDCl₃) δ：0.82-0.92 (4H, m), 3.89 (1H, tt, J = 3.0,5.8 Hz), 7.50 (1H, dd, J = 2.8, 8.8 Hz), 7.98 (1H, d, J = 8.8 Hz), 8.53 (1H, d, J = 2.8 Hz), 10.00 (1H, s)。

h) Production of 1- (5-Cyclopropoxypyridin-2-yl) ethanol:

using 5-Cyclopropoxypyridine carbaldehyde, the reaction and treatment were carried out in the same manner as in example 6-l) to obtain the title compound as white crystals.

¹H-NMR (400 MHz, CDCl₃) δ：0.79-0.83 (4H, m), 1.49 (3H, d, J = 6.6 Hz), 3.79 (1H, tt, J = 3.0,5.6 Hz), 3.94 (1H, d, J = 4.4 Hz), 4.85 (1H, dq, J = 4.4, 6.6 Hz), 7.20 (1H, d, J = 8.6 Hz), 7.36 (1H, dd, J = 2.8, 8.6 Hz), 8.34 (1H, d, J = 2.8 Hz)。

i) Production of 1- (5-Cyclopropoxypyridin-2-yl) ethanone:

the reaction and the treatment were carried out in the same manner as in example 6-l) using 1- (5-cyclopropyloxypyridin-2-yl) ethanol to obtain the title compound as white crystals.

¹H-NMR (400 MHz, CDCl₃) δ：0.81-0.91 (4H, m), 2.68 (3H, s), 3.86 (1H, tt, J = 3.0, 6.0 Hz), 7.44 (1H, dd, J= 2.7, 8.8 Hz), 8.05 (1H, d, J = 8.8 Hz), 8.42 (1H, d, J = 2.7 Hz)。

j) Production of 5- (5-Cyclopropoxypyridin-2-yl) -5-methylimidazolidine-2, 4-dione:

using 1- (5-Cyclopropoxypyridin-2-yl) ethanone, the reaction and treatment were carried out in the same manner as in example 1-l) to obtain the title compound as white crystals.

¹H-NMR (400 MHz, CDCl₃) δ：0.79-0.84 (4H, m), 1.80 (3H, s), 3.80 (1H, tt, J = 3.0,5.9 Hz), 6.27 (1H, br s), 7.38 (1H, dd, J = 2.9, 8.8 Hz), 7.51 (1H, br s), 7.58 (1H, d, J = 8.8 Hz), 8.35 (1H, d, J = 2.9 Hz)。

The reaction and treatment were carried out in the same manner as in examples 14-1 and 15-1 using 2-bromo-1- (4- {4- [1,1,1,3,3, 3-hexafluoro-2- (methoxymethoxy) propan-2-yl ] -2-propylphenyl } -1, 4-diazepan-1-yl) ethanone and 5- (5-cyclopropoxypyridin-2-yl) -5-methylimidazolidine-2, 4-dione to give the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：0.78-1.00 (7H, m), 1.60-1.70 (2H, m), 1.87 (3H, s), 2.00-2.11 (2H, m), 2.65 (2H, t, J = 7.8 Hz), 3.07-3.16 (2H, m), 3.28-3.40 (1H, m), 3.54-3.81 (6H, m), 4.35-4.42 (2H, m), 6.34 (1H, s), 7.08 (1H, d, J = 8.4 Hz), 7.38 (1H, dd, J = 2.4, 8.9 Hz), 7.46 (1H, d, J = 8.4 Hz), 7.48 (1H, s), 7.66 (1H, d, J= 8.9 Hz), 8.33 (1H, d, J = 2.4 Hz)。

Example 42: production of 5- (2, 3-dihydrobenzofuran-6-yl) -3- (2- {4- [4- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -2-propylphenyl ] -1, 4-diazepan-1-yl } -2-oxoethyl) -5-methylimidazolidine-2, 4-dione:

[ solution 50]

a) Production of 1-bromo-3- (2, 2-diethoxyethoxy) benzene:

to a solution of 3-bromophenol (1.68 g, 9.77 mmol) in N, N' -dimethylformamide (32mL) was added sodium hydride (50% pure) (516mg, 10.7mmol) under ice cooling, and bromoacetaldehyde diethyl acetal (1.76mL, 11.7mmol) was added at 0 ℃ and stirred at 120 ℃ overnight. Water was added to the reaction solution at room temperature, followed by extraction with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (hexane) to obtain 2.69g of the title compound as a yellow oil (yield > 100%).

¹H-NMR (CDCl₃) δ：1.25 (6H, t, J = 7.2 Hz), 3.57-3.70 (2H, m), 3.72-3.80 (2H, m), 3.98 (2H, d, J = 5.2 Hz), 4.82 (1H, t, J = 5.2 Hz), 6.84-6.87 (1H, m), 7.07-7.15 (3H, m)。

b) Production of 6-bromobenzofuran:

PPA (5.0mL) was added to a solution of 1-bromo-3- (2, 2-diethoxyethoxy) benzene (2.3 g, 8.35 mmol) in toluene (28mL), and the mixture was stirred under reflux overnight. Water was added to the reaction solution at room temperature, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (hexane) to give the title compound 1.2g (yield 68%, mixture with 7-bromobenzofuran) as a yellow oil.

¹H-NMR (CDCl₃) δ：6.75 (1H, d, J = 2.4 Hz), 7.36 (1H, d, J = 8.1 Hz), 7.46 (1H, d, J = 8.1 Hz), 7.60 (1H, d, J = 2.4 Hz), 7.68 (1H, s)。

c) Production of 1- (benzofuran-6-yl) ethanone:

to a solution of a mixture of 6-bromobenzofuran and 7-bromobenzofuran (1.12 g,5.68 mmol) in toluene (19mL) was added tetrakis (triphenylphosphine) palladium (650mg, 0.57mmol) and tributyl (1-ethoxyvinyl) tin (2.11mL, 6.25mmol), and the mixture was stirred at 100 ℃ overnight. Water was added to the reaction solution at room temperature, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (hexane) to give the title compound (280mg) as yellow crystals.

¹H-NMR (CDCl₃) δ：2.67 (3H, s), 6.83 (1H, d, J = 1.9 Hz), 7.65 (1H, d, J = 8.4 Hz), 7.78 (1H, d, J = 1.9 Hz), 7.89 (1H, d, J = 8.4 Hz), 8.12 (1H, s)。

d) Production of 5- (benzofuran-6-yl) -5-methylimidazolidine-2, 4-dione:

using 1- (benzofuran-6-yl) ethanone, the reaction and treatment were carried out in the same manner as in example 1-l) to obtain the title compound as white crystals.

¹H-NMR (CDCl₃) δ：1.82 (3H, s), 6.83 (1H, d, J = 2.2 Hz), 7.32 (1H, d, J = 8.4 Hz), 7.63 (1H, d, J = 8.4 Hz), 7.67 (1H, s), 7.78 (1H, d, J = 2.2 Hz)。

e) Production of 5- (2, 3-dihydrobenzofuran-6-yl) -5-methylimidazolidine-2, 4-dione:

using 5- (benzofuran-6-yl) -5-methylimidazolidine-2, 4-dione, a reaction was carried out in the same manner as in example 1-l), and then the title compound was obtained as white crystals.

¹H-NMR (CD₃OD) δ：1.75 (3H, s), 3.18 (2H, t, J = 8.6 Hz), 4.57 (2H, t, J = 8.6 Hz), 7.00 (1H, s), 7.04 (1H, d, J = 7.8 Hz), 7.20 (1H, d, J = 7.8 Hz)。

The reaction and treatment were carried out in the same manner as in examples 14-1 and 15-1 using 2-bromo-1- (4- {4- [1,1,1,3,3, 3-hexafluoro-2- (methoxymethoxy) propan-2-yl ] -2-propylphenyl } -1, 4-diazepan-1-yl) ethanone and 5- (2, 3-dihydrobenzofuran-6-yl) -5-methylimidazolidine-2, 4-dione to obtain the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：0.96 (3H, t, J= 7.3 Hz), 1.58-1.70 (2H, m), 1.90 (3H, s), 2.00-2.11 (2H, m), 2.65 (2H, t, J= 7.3 Hz), 3.07-3.15 (2H, m), 3.18 (2H, t, J = 8.6 Hz), 3.28-3.38 (1H, m), 3.53-3.80 (5H, m), 4.28-4.40 (2H, m), 4.57 (2H, t, J = 8.6 Hz),5.74 (1H, s), 6.96-7.05 (2H, m), 7.08 (1H, d, J = 8.1 Hz), 7.20 (1H, d, J= 7.3 Hz), 7.45 (1H, d, J = 8.1 Hz), 7.48 (1H, s)。

Example 43: production of 3- [2- (4- {4- [2- (benzyloxy) -1,1,1,3,3, 3-hexafluoropropane-2-yl ] -2- (prop-1-en-1-yl) phenyl } piperazin-1-yl) -2-oxoethyl ] -5- (2, 3-dihydrobenzofuran-6-yl) -5-methylimidazolidine-2, 4-dione:

[ solution 51]

a) Production of 1,1,1,3,3, 3-hexafluoro-2- (4-fluoro-3-nitrophenyl) propan-2-ol:

4-fluoro-3-nitrobenzoic acid (1.5g, 8.10mmol) was dissolved in N, N-dimethylformamide (1.0mL), and thionyl chloride (16.6mL) was added and heated under reflux for 2 hours. Then, the reaction solution was concentrated under reduced pressure to obtain a crude product (3.57 g). Subsequently, trimethylsilyltrifluoromethane (3.0mL. 20.26mmol) and tetramethylammonium fluoride (1.89g. 20.26mmol) were added to a solution of the crude product (3.57g) in ethylene glycol dimethyl ether (81mL) under argon atmosphere under ice cooling, and the mixture was stirred at the same temperature for 20 minutes. Then, the mixture was further stirred at room temperature for 12 hours. Water was added to the reaction mixture under ice cooling, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (hexane) to give the title compound 2.99g as a yellow oil (yield > 100%).

¹H-NMR (CDCl₃) δ：7.42 (1H, dd, J= 8.6, 10.3 Hz), 8.37 (1H, ddd, J = 2.4, 4.3, 8.6 Hz), 8.81 (1H, dd, J= 2.4, 7.3 Hz)。

b) Production of tert-butyl 4- [4- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -2-nitrophenyl ] piperazine-1-carboxylate:

the reaction and the treatment were carried out in the same manner as in example 6-b) using 1,1,1,3,3, 3-hexafluoro-2- (4-fluoro-3-nitrophenyl) propan-2-ol and tert-butyl piperazine-1-carboxylate to obtain the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：1.48 (9H, s), 3.07-3.12 (4H, m), 3.58-3.61 (4H, m), 3.87 (1H, brs), 7.15 (1H, d, J = 8.9 Hz), 7.77 (1H, dd, J = 2.4, 8.9 Hz), 8.18 (1H, d, J = 2.4 Hz)。

c) Production of tert-butyl 4- {4- [2- (benzyloxy) -1,1,1,3,3, 3-hexafluoropropan-2-yl ] -2-nitrophenyl } piperazine-1-carboxylate:

the reaction and the treatment were carried out in the same manner as in example 6-i) using tert-butyl 4- [4- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -2-nitrophenyl ] piperazine-1-carboxylate to obtain the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：1.48 (9H, s), 3.10-3.13 (4H, m), 3.59-3.62 (4H, m), 4.64 (2H, s), 7.16 (1H, d, J = 8.9 Hz), 7.36-7.43 (5H, m), 7.69 (1H, dd, J = 2.4, 8.9 Hz), 8.07 (1H, d, J= 2.4 Hz)。

d) Production of tert-butyl 4- { 2-amino-4- [2- (benzyloxy) -1,1,1,3,3, 3-hexafluoropropan-2-yl ] phenyl } piperazine-1-carboxylate:

using tert-butyl 4- {4- [2- (benzyloxy) -1,1,1,3,3, 3-hexafluoropropan-2-yl ] -2-nitrophenyl } piperazine-1-carboxylate, the reaction and treatment were carried out in the same manner as in example 6-c) to obtain the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：1.49 (9H, s), 2.88-2.90 (4H, m), 3.54-3.60 (4H, m), 4.65 (2H, s), 6.94-7.00 (3H, m), 7.33-7.41 (5H, m)。

e) Preparation of tert-butyl 4- {4- [2- (benzyloxy) -1,1,1,3,3, 3-hexafluoropropan-2-yl ] -2-iodophenyl } piperazine-1-carboxylate:

using tert-butyl 4- { 2-amino-4- [2- (benzyloxy) -1,1,1,3,3, 3-hexafluoropropan-2-yl ] phenyl } piperazine-1-carboxylate, the reaction and treatment were carried out in the same manner as in example 6-d) to obtain the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：1.49 (9H, s), 2.98-3.02 (4H, m), 3.62-3.66 (4H, m), 4.62 (2H, s), 7.03 (1H, d, J = 8.4 Hz), 7.34-7.45 (5H, m), 7.56 (1H, dd, J = 1.6, 8.4 Hz), 8.07 (1H, d, J= 1.6 Hz)。

f) Production of tert-butyl 4- {4- [2- (benzyloxy) -1,1,1,3,3, 3-hexafluoropropan-2-yl ] -2- (prop-1-en-1-yl) phenyl } piperazine-1-carboxylate:

using tert-butyl 4- {4- [2- (benzyloxy) -1,1,1,3,3, 3-hexafluoropropan-2-yl ] -2-iodophenyl } piperazine-1-carboxylate, the reaction and treatment were carried out in the same manner as in example 6-e) to obtain the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：1.48 (9H, s), 1.73 (3H, dd, J = 1.6, 6.8 Hz), 2.94-2.98 (4H, m), 3.52-3.56 (4H, m), 4.67 (2H, s),5.80 (1H, qd, J = 6.8, 11.1 Hz), 6.46 (1H, qd, J = 1.6, 11.1 Hz), 6.98 (1H, d, J = 8.6 Hz), 7.32-7.46 (6H, m), 7.50 (1H, s)。

g) Production of (Z) -1- {4- [2- (benzyloxy) -1,1,1,3,3, 3-hexafluoropropan-2-yl ] -2- (prop-1-en-1-yl) phenyl } piperazine:

the reaction and the treatment were carried out in the same manner as in example 6-j) using tert-butyl 4- {4- [2- (benzyloxy) -1,1,1,3,3, 3-hexafluoropropan-2-yl ] -2- (prop-1-en-1-yl) phenyl } piperazine-1-carboxylate to obtain the title compound as a yellow oily substance.

¹H-NMR (CDCl₃) δ：1.70 (3H, dd, J= 2.0, 7.1 Hz), 3.30 (4H, t, J = 4.9 Hz), 3.78 (4H, t, J = 4.9 Hz), 4.67 (2H, s),5.88 (1H, qd, J = 7.1, 11.1 Hz), 6.43 (1H, dd, J= 2.0, 11.1 Hz), 7.05 (1H, d, J = 8.3 Hz), 7.34-7.40 (5H, m), 7.49 (1H, dd, J = 1.7, 8.3 Hz), 7.53 (1H, d, J = 1.7 Hz)。

h) Production of (Z) -1- (4- {4- [2- (benzyloxy) -1,1,1,3,3, 3-hexafluoropropan-2-yl ] -2- (prop-1-en-1-yl) phenyl } piperazin-1-yl) -2-bromoethanone:

using (Z) -1- {4- [2- (benzyloxy) -1,1,1,3,3, 3-hexafluoropropan-2-yl ] -2- (prop-1-en-1-yl) phenyl } piperazine, the reaction and treatment were carried out in the same manner as in example 6-k) to obtain the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：1.74 (3H, dd, J = 1.6, 7.0 Hz), 3.00-3.11 (4H, m), 3.63-3.78 (4H, m), 3.90 (2H, s), 4.67 (2H, s),5.84 (1H, qd, J = 2.0, 11.6 Hz), 6.48 (1H, qd, J = 1.6, 11.6 Hz), 7.00 (1H, d, J= 8.4 Hz), 7.31-7.39 (5H, m), 7.46 (1H, d, J = 8.4 Hz), 7.52 (1H, s)。

i) Production of 3- [2- (4- {4- [2- (benzyloxy) -1,1,1,3,3, 3-hexafluoropropane-2-yl ] -2- (prop-1-en-1-yl) phenyl } piperazin-1-yl) -2-oxoethyl ] -5- (2, 3-dihydrobenzofuran-6-yl) -5-methylimidazolidine-2, 4-dione:

the reaction and the treatment were carried out in the same manner as in example 14-1 using (Z) -1- (4- {4- [2- (benzyloxy) -1,1,1,3,3, 3-hexafluoropropan-2-yl ] -2- (prop-1-en-1-yl) phenyl } piperazin-1-yl) -2-bromoethanone and 5- (2, 3-dihydrobenzofuran-6-yl) -5-methylimidazolidine-2, 4-dione to obtain the title compound as a yellow oily substance.

¹H-NMR (CDCl₃) δ：1.73 (3H, dd, J= 1.7, 7.1 Hz), 1.90 (3H, s), 2.98-3.07 (4H, m), 3.18 (2H, t, J = 8.6 Hz), 3.57-3.74 (4H, m), 4.32 (1H, d, J = 16.1 Hz), 4.34 (1H, d, J= 16.1 Hz), 4.57 (2H, t, J = 8.6 Hz), 4.67 (2H, s),5.81 (1H, s),5.83 (1H, qd, J = 7.1, 11.7 Hz), 6.47 (1H, qd, J = 1.7, 11.7 Hz), 6.99 (1H, d, J = 8.3 Hz), 7.00 (1H, d, J = 1.7 Hz), 7.04 (1H, dd, J= 1.7, 7.8 Hz), 7.20 (1H, d, J = 7.8 Hz), 7.32-7.42 (5H, m), 7.46 (1H, d, J = 8.3 Hz), 7.51 (1H, s)。

Example 44: production of 5- (2, 3-dihydrobenzofuran-6-yl) -3- (2- {4- [4- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -2-propylphenyl ] piperazin-1-yl } -2-oxoethyl) -5-methylimidazolidine-2, 4-dione:

[ solution 52]

The reaction and treatment were carried out in the same manner as in example 15-1 using 3- [2- (4- {4- [2- (benzyloxy) -1,1,1,3,3, 3-hexafluoropropane-2-yl ] -2- (prop-1-en-1-yl) phenyl } piperazin-1-yl) -2-oxoethyl ] -5- (2, 3-dihydrobenzofuran-6-yl) -5-methylimidazolidine-2, 4-dione to give the title compound as a yellow oily substance.

¹H-NMR (CDCl₃) δ：0.96 (3H, t, J= 7.3 Hz), 1.65 (2H, qt, J = 7.3, 7.6 Hz), 1.90 (3H, s), 2.66 (2H, t, J= 7.6 Hz), 2.87-2.97 (4H, m), 3.17 (2H, t, J = 8.8 Hz), 3.59-3.76 (4H, m), 4.34 (1H, d, J = 15.9 Hz), 4.36 (1H, d, J = 15.9 Hz), 4.58 (2H, t, J = 8.8 Hz),5.81 (1H, brs), 6.99 (1H, s), 7.04 (1H, d, J= 8.8 Hz), 7.07 (1H, d, J = 7.8 Hz), 7.20 (1H, d, J = 7.8 Hz), 7.50 (1H, d, J = 8.8 Hz), 7.53 (1H, s)。

Example 45: production of 3- [2- (4- {4- [2- (benzyloxy) -1,1,1,3,3, 3-hexafluoropropan-2-yl ] -2- (prop-1-en-1-yl) phenyl } piperazin-1-yl) -2-oxoethyl ] -5- (2, 3-dihydro- [1,4] dioxin [2,3-b ] pyridin-7-yl) -5-methylimidazolidine-2, 4-dione:

[ Hua 53]

a) Production of 7-bromo-2, 3-dihydro- [1,4] dioxin [2,3-b ] pyridine:

2, 3-hydroxy-5-bromopyridine (100mg, 0.53mmol) was dissolved in N, N' -dimethylformamide (5 mL), and sodium hydride (30mg, 0.63mmol) was added under ice cooling under an argon atmosphere. After 5 minutes, a solution of 1, 2-dibromoethane (50. mu.L, 0.58mmol) in N, N' -dimethylformamide (5 mL) was added at the same temperature and stirred at 110 ℃ for 14 hours. The reaction solution was returned to room temperature, and after adding water, it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by preparative thin layer chromatography (n-hexane/ethyl acetate: 2/1) to give the title compound 20mg as a white solid (yield 17%).

¹H-NMR (CDCl₃) δ： 4.25-4.27 (2H, m), 4.42-4.44 (2H, m), 7.33 (1H, d J = 2.4 Hz), 7.87 (1H, d, J = 2.4 Hz)。

b) Production of 1- (2, 3-dihydro- [1,4] dioxin [2,3-b ] pyridin-7-yl) ethanone:

7-bromo-2, 3-dihydro- [1,4] dioxin [2,3-b ] pyridine (65mg, 0.30mmol) was dissolved in toluene (1.5mL) under an argon atmosphere, and tetrakis (triphenylphosphine) palladium (35mg, 0.03mmol) and 1-ethoxyvinyltri-n-butyltin (112. mu.L, 0.33mmol) were added, followed by stirring at 100 ℃ overnight. The reaction solution was returned to room temperature, and 1N hydrochloric acid was added. The reaction solution was filtered through celite, and ethyl acetate was added to the reaction solution to conduct extraction. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by preparative thin layer chromatography (n-hexane/ethyl acetate: 1/1) to give the title compound 37mg as a white solid (yield 69%).

¹H-NMR (CDCl₃) δ：2.57 (3H, s), 4.27-4.31 (2H, m), 4.50-4.52 (2H, m), 7.44 (1H, d, J = 2.4 Hz), 8.44 (1H, d, J = 2.4 Hz)。

c) Production of 5- (2, 3-dihydro- [1,4] dioxin [2,3-b ] pyridin-7-yl) -5-methylimidazolidine-2, 4-dione:

using 1- (2, 3-dihydro- [1,4] dioxin [2,3-b ] pyridin-7-yl) ethanone, the reaction and treatment were carried out in the same manner as in example 1-l) to obtain the title compound as a white crystal.

¹H-NMR (CDCl₃) δ：1.73 (3H, s), 4.26-4.29 (2H, m), 4.43-4.46 (2H, m), 7.43 (1H, d, J = 2.4 Hz), 7.83 (1H, d, J = 2.4 Hz)。

d) Production of 3- [2- (4- {4- [2- (benzyloxy) -1,1,1,3,3, 3-hexafluoropropan-2-yl ] -2- (prop-1-en-1-yl) phenyl } piperazin-1-yl) -2-oxoethyl ] -5- (2, 3-dihydro- [1,4] dioxin [2,3-b ] pyridin-7-yl) -5-methylimidazolidine-2, 4-dione:

the reaction and treatment were carried out in the same manner as in example 14-1 using (Z) -1- (4- {4- [2- (benzyloxy) -1,1,1,3,3, 3-hexafluoropropan-2-yl ] -2- (prop-1-en-1-yl) phenyl } piperazin-1-yl) -2-bromoethanone and 5- (2, 3-dihydro- [1,4] dioxin [2,3-b ] pyridin-7-yl) -5-methylimidazolidine-2, 4-dione to give the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：1.73 (3H, dd, J= 2.2, 7.1 Hz), 1.90 (3H, s), 2.99-3.08 (4H, m), 3.57-3.74 (4H, m), 4.24-4.26 (2H, m), 4.34 (1H, d, J = 15.8 Hz), 4.35 (1H, d, J = 15.8 Hz), 4.42-4.43 (2H, m), 4.67 (2H, s),5.84 (1H, qd, J = 7.1, 12.0 Hz), 6.23 (1H, s), 6.47 (1H, qd, J = 2.2, 12.0 Hz), 6.99 (1H, d, J = 8.8 Hz), 7.31-7.43 (5H, m), 7.46 (1H, d, J= 8.8 Hz), 7.47 (1H, d, J = 2.2 Hz), 7.51 (1H, s), 7.98 (1H, d, J= 2.2 Hz)。

Example 46: production of 5- (2, 3-dihydro- [1,4] dioxin [2,3-b ] pyridin-7-yl) -3- (2- {4- [4- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -2-propylphenyl ] piperazin-1-yl } -2-oxoethyl) -5-methylimidazolidine-2, 4-dione:

[ solution 54]

The reaction and treatment were carried out in the same manner as in example 15-1 using 3- [2- (4- {4- [2- (benzyloxy) -1,1,1,3,3, 3-hexafluoropropane-2-yl ] -2- (prop-1-en-1-yl) phenyl } piperazin-1-yl) -2-oxoethyl ] -5- (2, 3-dihydro- [1,4] dioxin [2,3-b ] pyridin-7-yl) -5-methylimidazolidine-2, 4-dione to obtain the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：0.96 (3H, t, J= 7.3 Hz), 1.66 (2H, qt, J = 7.3, 7.6 Hz), 1.90 (3H, s), 2.66 (2H, t, J= 7.6 Hz), 2.87-2.97 (4H, m), 3.61-3.75 (4H, m), 4.23-4.25 (2H, m), 4.35 (1H, d, J = 16.4 Hz), 4.37 (1H, d, J = 16.4 Hz), 4.41-4.43 (2H, m), 6.30 (1H, brs), 7.07 (1H, d, J = 8.5 Hz), 7.47 (1H, d, J = 2.2 Hz), 7.51 (1H, d, J = 8.5 Hz), 7.54 (1H, s), 7.96 (1H, d, J = 2.2 Hz)。

Example 47: production of 3- [2- ((S) -4- {4- [2- (benzyloxy) -1,1,1,3,3, 3-hexafluoropropan-2-yl ] -2- (prop-1-en-1-yl) phenyl } -3-methylpiperazin-1-yl) -2-oxoethyl ] -5- (2, 3-dihydrobenzofuran-6-yl) -5-methylimidazolidine-2, 4-dione:

[ solution 55]

a) Production of (S) -4- [4- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -2- (prop-1-en-1-yl) phenyl ] -3-methylpiperazine-1-carboxylic acid tert-butyl ester:

the title compound was obtained as a yellow oily substance by carrying out the reaction and treatment in the same manner as in example 6-b) and then in the same manner as in examples 12-b) to g) after carrying out the reaction and treatment in the same manner as in example 6-b) using (S) -3-methyl-1-tert-butoxycarbonylpiperazine instead of 1-tert-butoxycarbonylpiperazine.

¹H-NMR (CDCl₃) δ：0.90 (3H, d, J= 6.2 Hz), 1.48 (9H, s), 1.83 (3H, d, J = 6.8 Hz), 2.65-2.73 (1H, m), 3.08-3.18 (1H, m), 3.25-3.68 (5H, m),5.76-5.88 (1H, m), 6.56 (1H, d, J= 13.2 Hz), 7.02 (1H, d, J = 8.4 Hz), 7.53 (1H, d, J = 8.4 Hz), 7.59 (1H, s)。

b) Production of (S) -4- {4- [2- (benzyloxy) -1,1,1,3,3, 3-hexafluoropropan-2-yl ] -2- (prop-1-en-1-yl) phenyl } -3-methylpiperazine-1-carboxylic acid tert-butyl ester:

the reaction and the treatment were carried out in the same manner as in example 6-i) using tert-butyl (S) -4- [4- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -2- (prop-1-en-1-yl) phenyl ] -3-methylpiperazine-1-carboxylate to obtain the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：0.91 (3H, d, J= 6.2 Hz), 1.48 (9H, s), 1.71 (3H, dd, J = 1.6, 7.0 Hz), 2.64-2.73 (1H, m), 3.09-3.78 (6H, m), 4.67 (2H, s),5.72-5.86 (1H, m), 6.47-6.52 (1H, m), 7.02 (1H, d, J = 8.6 Hz), 7.31-7.44 (6H, m), 7.52 (1H, s)。

c) Production of (S) -1- {4- [2- (benzyloxy) -1,1,1,3,3, 3-hexafluoropropan-2-yl ] -2- (prop-1-en-1-yl) phenyl } -2-methylpiperazine:

the reaction and the treatment were carried out in the same manner as in example 6-j) using tert-butyl (S) -4- {4- [2- (benzyloxy) -1,1,1,3,3, 3-hexafluoropropan-2-yl ] -2- (prop-1-en-1-yl) phenyl } -3-methylpiperazine-1-carboxylate to obtain the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：0.96 (3H, d, J= 5.9 Hz), 1.71 (3H, d, J = 7.0 Hz), 2.78-2.87 (1H, m), 3.19-3.29 (1H, m), 3.48-3.99 (5H, m), 4.68 (2H, s),5.77-5.89 (1H, m), 6.51-6.57 (1H, m), 7.03 (1H, d, J = 8.4 Hz), 7.33-7.39 (5H, m), 7.46 (1H, d, J = 8.4 Hz), 7.54 (1H, s)。

d) Production of (S) -1- (4- {4- [2- (benzyloxy) -1,1,1,3,3, 3-hexafluoropropan-2-yl ] -2- (prop-1-en-1-yl) phenyl } -3-methylpiperazin-1-yl) -2-bromoethanone:

the reaction and the treatment were carried out in the same manner as in example 6-k) using (S) -1- {4- [2- (benzyloxy) -1,1,1,3,3, 3-hexafluoropropan-2-yl ] -2- (prop-1-en-1-yl) phenyl } -2-methylpiperazine to obtain the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：0.99 (3H, d, J= 6.5 Hz), 1.72 (3H, dd, J = 1.6, 7.0 Hz), 2.75-2.84 (1H, m), 3.11-3.79 (6H, m), 3.92 (2H, s), 4.67 (2H, s),5.76-5.88 (1H, m), 6.53-6.57 (1H, m), 7.03 (1H, d, J = 8.6 Hz), 7.32-7.43 (6H, m), 7.54 (1H, s)。

e) Production of 3- [2- ((S) -4- {4- [2- (benzyloxy) -1,1,1,3,3, 3-hexafluoropropan-2-yl ] -2- (prop-1-en-1-yl) phenyl } -3-methylpiperazin-1-yl) -2-oxoethyl ] -5- (2, 3-dihydrobenzofuran-6-yl) -5-methylimidazolidine-2, 4-dione:

the reaction and treatment were carried out in the same manner as in example 14-1 using (S) -1- (4- {4- [2- (benzyloxy) -1,1,1,3,3, 3-hexafluoropropan-2-yl ] -2- (prop-1-en-1-yl) phenyl } -3-methylpiperazin-1-yl) -2-bromoethanone and 5- (2, 3-dihydrobenzofuran-6-yl) -5-methylimidazolidine-2, 4-dione to obtain the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：0.98 (3H, d, J = 6.1 Hz), 1.71 (3H, d, J = 7.1 Hz), 1.90 (3H, s), 2.71-2.82 (1H, m), 3.19 (2H, t, J = 8.8 Hz), 3.28-3.90 (6H, m), 4.29-4.34 (2H, m), 4.58 (2H, t, J = 8.8 Hz), 4.68 (2H, s),5.67 (1H, s),5.77-5.87 (1H, m), 6.53-6.58 (1H, m), 6.99 (1H, s), 7.03-7.05 (2H, m), 7.21 (1H, d, J = 7.1 Hz), 7.33-7.40 (5H, m), 7.45 (1H, d, J = 8.3 Hz), 7.54 (1H, s)。

Example 48: production of 5- (2, 3-dihydrobenzofuran-6-yl) -3- (2- ((S) -4- (4- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -2-propylphenyl) -3-methylpiperazin-1-yl) -2-oxoethyl) -5-methylimidazolidine-2, 4-dione:

[ solution 56]

The reaction and treatment were carried out in the same manner as in example 15-1 using 3- [2- ((S) -4- {4- [2- (benzyloxy) -1,1,1,3,3, 3-hexafluoropropan-2-yl ] -2- (prop-1-en-1-yl) phenyl } -3-methylpiperazin-1-yl) -2-oxoethyl ] -5- (2, 3-dihydrobenzofuran-6-yl) -5-methylimidazolidine-2, 4-dione to obtain the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：0.84-0.96 (6H, m), 1.56-1.59 (2H, m), 1.91 (3H, s), 2.61-3.41 (8H, m), 3.19 (2H, t, J = 5.1 Hz), 3.62-3.73 (1H, m), 4.30-4.40 (2H, m), 4.58 (2H, t, J = 5.1 Hz),5.84 (1H, s), 7.00-7.05 (2H, m), 7.15-7.21 (2H, m), 7.37-7.45 (2H, m)。

Example 49: production of 3- [2- ((S) -4- {4- [2- (benzyloxy) -1,1,1,3,3, 3-hexafluoropropan-2-yl ] -2- (prop-1-en-1-yl) phenyl } -3-methylpiperazin-1-yl) -2-oxoethyl ] -5- (2, 3-dihydro- [1,4] dioxin [2,3-b ] pyridin-7-yl) -5-methylimidazolidine-2, 4-dione:

[ solution 57]

Using (S) -1- (4- {4- [2- (benzyloxy) -1,1,1,3,3, 3-hexafluoropropan-2-yl ] -2- (prop-1-en-1-yl) phenyl } -3-methylpiperazin-1-yl) -2-bromoethanone, 5- (2, 3-dihydrobenzofuran-6-yl) -5-methylimidazolidine-2, 4-dione and 5- (2, 3-dihydro- [1,4] dioxin [2,3-b ] pyridin-7-yl) -5-methylimidazolidine-2, 4-dione, a reaction was carried out in the same manner as in example 14-1, Work-up gave the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：0.99 (3H, d, J = 6.0 Hz), 1.71 (3H, d, J = 7.1 Hz), 1.91 (3H, s), 2.73-2.82 (1H, m), 3.17-3.89 (6H, m), 4.24-4.26 (2H, m), 4.31-4.37 (2H, m), 4.42-4.44 (2H, m), 4.67 (1H, d, J = 11.0 Hz), 4.69 (1H, d, J= 11.0 Hz),5.78-5.86 (1H, m), 6.07 (1H, s), 6.52-6.58 (1H, m), 7.00-7.05 (1H, m), 7.30-7.47 (7H, m), 7.54 (1H, s), 7.98 (1H, s)。

Example 50: production of 5- (2, 3-dihydro- [1,4] dioxin [2,3-b ] pyridin-7-yl) -3- (2- { (S) -4- [4- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -2-propylphenyl ] -3-methylpiperazin-1-yl } -2-oxoethyl) -5-methylimidazolidine-2, 4-dione:

[ solution 58]

The reaction and treatment were carried out in the same manner as in example 15-1 using 3- [2- ((S) -4- {4- [2- (benzyloxy) -1,1,1,3,3, 3-hexafluoropropan-2-yl ] -2- (prop-1-en-1-yl) phenyl } -3-methylpiperazin-1-yl) -2-oxoethyl ] -5- (2, 3-dihydro- [1,4] dioxin [2,3-b ] pyridin-7-yl) -5-methylimidazolidine-2, 4-dione to give the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：0.87 (3H, d, J = 6.1 Hz), 0.95 (3H, t, J = 7.3 Hz), 1.62 (2H, qt, J = 7.3, 7.3 Hz), 1.90 (3H, s), 2.63-3.21 (8H, m), 3.64-3.71 (1H, m), 4.23-4.26 (2H, m), 4.32-4.39 (2H, m), 4.41-4.45 (2H, m), 6.36 (1H, brs), 7.11-7.16 (1H, m), 7.48 (1H, d, J = 2.0 Hz), 7.52 (1H, d, J= 9.0 Hz), 7.55 (1H, s), 7.97 (1H, d, J = 2.0 Hz)。

Example 51: production of 3- [2- ((S) -4- {4- [2- (benzyloxy) -1,1,1,3,3, 3-hexafluoropropan-2-yl ] -2- (prop-1-en-1-yl) phenyl } -3-methylpiperazin-1-yl) -2-oxoethyl ] -5- [5- (1-methylethoxy) pyridin-2-yl ] -5-methylimidazolidine-2, 4-dione:

[ chemical 59]

Using (S) -1- (4- {4- [2- (benzyloxy) -1,1,1,3,3, 3-hexafluoropropan-2-yl ] -2- (prop-1-en-1-yl) phenyl } -3-methylpiperazin-1-yl) -2-bromoethanone and 5- (2, 3-dihydrobenzofuran-6-yl) -5-methylimidazolidine-2, 4-dione and 5- [5- (1-methylethoxy) pyridin-2-yl ] -5-methylimidazolidine-2, 4-dione, the reaction and the treatment were carried out in the same manner as in example 14-1 to give the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：0.99 (3H, d, J= 6.5 Hz), 1.35 (6H, d, J = 5.9 Hz), 1.71 (3H, d, J = 7.0 Hz), 1.86 (3H, s), 2.72-2.85 (1H, m), 3.13-3.91 (6H, m), 4.37 (2H, s), 4.50-4.63 (1H, m), 4.68 (2H, s),5.76-5.87 (1H, m), 6.28 (1H, s), 6.52-6.60 (1H, m), 7.01 (1H, d, J = 8.1 Hz), 7.19 (1H, d, J = 8.9 Hz), 7.31-7.39 (5H, m), 7.45 (1H, d, J = 8.1 Hz), 7.53 (1H, s), 7.62 (1H, dd, J = 2.4, 8.9 Hz), 8.19 (1H, d, J = 2.4 Hz)。

Example 52: production of 3- (2- { (S) -4- [4- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -2-propylphenyl ] -3-methylpiperazin-1-yl } -2-oxoethyl) -5- [5- (1-methylethoxy) pyridin-2-yl ] -5-methylimidazolidine-2, 4-dione:

[ solution 60]

The reaction and treatment were carried out in the same manner as in example 15-1 using 3- (2- ((S) -4- (4- (2- (benzyloxy) -1,1,1,3,3, 3-hexafluoropropan-2-yl) -2- (prop-1-en-1-yl) phenyl) -3-methylpiperazin-1-yl) -2-oxoethyl) -5- [5- (1-methylethoxy) pyridin-2-yl ] -5-methylimidazolidine-2, 4-dione to obtain the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：0.95 (3H, t, J= 7.3 Hz), 1.35 (6H, d, J = 5.9 Hz), 1.63 (2H, qt, J = 7.3, 7.3 Hz), 1.87 (3H, s), 2.64-3.20 (7H, m), 3.45-3.72 (2H, m), 4.36-4.42 (2H, m), 4.52-4.61 (1H, m), 6.30 (1H, s), 7.15 (1H, d, J = 8.9 Hz), 7.19 (1H, dd, J = 2.2, 8.9 Hz), 7.52 (1H, d, J = 8.9 Hz), 7.54 (1H, s), 7.63 (1H, d, J = 8.9 Hz), 8.19 (1H, d, J = 2.2 Hz)。

Example 53: production of 3- [2- (4- {4- [2- (benzyloxy) -1,1,1,3,3, 3-hexafluoropropan-2-yl ] -2- (prop-1-en-1-yl) phenyl } piperazin-1-yl) -2-oxoethyl ] -5- (2, 3-dihydro- [1,4] dioxin [2,3-c ] pyridin-7-yl) -5-methylimidazolidine-2, 4-dione:

[ solution 61]

a) Production of 5- (methoxymethoxy) -2-methylpyridine:

using 2-methyl-5-hydroxypyridine, the reaction and the treatment were carried out in the same manner as in example 4-h), so as to obtain the title compound as a colorless oil.

¹H-NMR (CDCl₃) δ：2.50 (3H, s), 3.48 (3H, s),5.17 (2H, s), 7.07 (1H, d, J = 8.4 Hz), 7.27 (1H, dd, J = 3.0, 8.4 Hz), 8.29 (1H, d, J = 3.0 Hz)。

b) Production of 5- (methoxymethoxy) -2-methylpyridin-4-ylboronic acid:

to a solution of 5-methoxymethyloxy-2-methylpyridine (3.0 g, 19.6 mmol) in tetrahydrofuran (100mL) was added n-butyllithium (18.4mL, 29.4mmol) at-78 ℃ and the mixture was stirred at-78 ℃ for 40 minutes. Isopropoxybutyrate (6.8mL, 29.4mmol) was then added and the mixture was stirred at-78 ℃ for 45 minutes. After adding a 1N aqueous hydrochloric acid solution to the reaction mixture, the temperature was raised. The reaction solution was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The obtained residue was washed with diethyl ether and filtered to obtain 2.08g of the title compound as white crystals (yield: 54%).

¹H-NMR (CDCl₃) δ：2.53 (3H, s), 3.52 (3H, s),5.31 (2H, s),5.80 (2H, s), 7.54 (1H, s), 8.41 (1H, s)。

c) Production of 5- (methoxymethoxy) -2-methylpyridin-4 (1H) -one:

to a solution of 5- (methoxymethoxy) -2-methylpyridin-4-ylboronic acid (500 mg, 2.54 mmol) in tetrahydrofuran (12.7mL) was added an aqueous hydrogen peroxide solution (purity 30%) (2.9mL, 25.4mmol) at room temperature, and the mixture was stirred at room temperature for 4 hours. After a saturated aqueous solution of sodium persulfate was added to the reaction mixture, the mixture was concentrated under reduced pressure. The obtained residue was washed with chloroform/methanol and filtered to obtain 440mg of the title compound as a yellow amorphous substance (yield > 100%).

¹H-NMR (CDCl₃) δ：2.37 (3H, s), 3.44 (3H, s),5.11 (2H, s), 6.40 (1H, s), 7.66 (1H, s)。

d) Production of 2- (5- (methoxymethoxy) -2-methylpyridin-4-yloxy) ethanol:

to a solution of 5- (methoxymethoxy) -2-methylpyridin-4 (1H) -one (1.28g, 7.56mmol) in N, N' -dimethylformamide (19mL) were added potassium carbonate (2.10g, 15.1mmol) and 2-bromoethanol (804. mu.L, 11.3mmol) in this order, and the mixture was stirred at 90 ℃ overnight. After the reaction, the reaction solution was concentrated under reduced pressure. The resulting residue was dissolved in chloroform/methanol, the solid was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (hexane/acetone) to give 2- (5- (methoxymethoxy) -2-methylpyridin-4-yloxy) ethanol (900mg, yield 56%) as an orange oil.

¹H-NMR (CDCl₃) δ：2.48 (3H, s), 3.54 (3H, s), 3.99 (2H, t, J = 4.4 Hz), 4.16 (2H, t, J = 4.4 Hz),5.16 (2H, s), 6.70 (1H, s), 8.21 (1H, s)。

e) Production of 4- (2-hydroxyethoxy) -6-methylpyridin-3-ol:

2- (5- (methoxymethoxy) -2-methylpyridin-4-yloxy) ethanol (900mg, 4.22mmol) was dissolved in ethyl acetate (10mL), and a 4N hydrochloric acid-ethyl acetate solution (10mL) was added to stir at room temperature for 5 hours. After completion of the reaction, the reaction solution was adjusted to pH =8 using a 4N aqueous sodium hydroxide solution under ice cooling. The reaction solution was concentrated under reduced pressure. The resulting residue was washed with chloroform/methanol and dried to give 4- (2-hydroxyethoxy) -6-methylpyridin-3-ol (1.2g) as a crude product as a white solid.

¹H-NMR (CDCl₃) δ：1.96 (1H, s), 2.44 (3H, s), 3.93 (2H, t, J = 4.4 Hz), 4.18 (2H, s), 6.95 (1H, s), 7.76 (1H, s)。

f) Production of 7-methyl-2, 3-dihydro- [1,4] dioxin [2,3-c ] pyridine:

after 4- (2-hydroxyethoxy) -6-methylpyridin-3-ol (714 mg, 4.22mmol) and triphenylphosphine (1.66 g, 6.33 mmol) were dried by a vacuum pump, they were dissolved in tetrahydrofuran (42 mL), and di-tert-butyl azodicarboxylate (DBAD) (1.46 g, 6.33 mmol) was added thereto under ice cooling, followed by stirring at room temperature overnight. Water was added to the reaction mixture under ice cooling, extraction was performed with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified using silica gel column chromatography (hexane/acetone, chloroform/methanol) to give the title compound as a white solid 1.74g as a crude product (yield > 100%).

¹H-NMR (CDCl₃) δ：2.42 (3H, s), 4.23-4.31 (4H, m), 6.64 (1H, s), 8.04 (1H, s)。

g) Production of 7-methyl-2, 3-dihydro- [1,4] dioxin [2,3-c ] pyridine 6-oxide:

using 7-methyl-2, 3-dihydro- [1,4] dioxin [2,3-c ] pyridine, the reaction and treatment were carried out in the same manner as in example 6-l) to obtain the title compound as a colorless oil.

¹H-NMR (CDCl₃) δ：2.45 (3H, s), 4.28-4.35 (4H, m), 6.75 (1H, s), 8.09 (1H, s)。

h) Production of methyl (2, 3-dihydro- [1,4] dioxin [2,3-c ] pyridin-7-yl) acetate:

using 7-methyl-2, 3-dihydro- [1,4] dioxin [2,3-c ] pyridine 6-oxide, the reaction and treatment were carried out in the same manner as in example 6-l) to obtain the title compound as a colorless oil.

¹H-NMR (CDCl₃) δ：2.14 (3H, s), 4.29-4.35 (4H, m),5.09 (2H, s), 6.88 (1H, s), 8.16 (1H, s)。

i) Production of (2, 3-dihydro- [1,4] dioxin [2,3-c ] pyridin-7-yl) methanol:

the reaction and treatment were carried out in the same manner as in example 6-l) using methyl acetate (2, 3-dihydro- [1,4] dioxin [2,3-c ] pyridin-7-yl) to give the title compound as a colorless oil.

¹H-NMR (CDCl₃) δ：4.29-4.35 (4H, m), 4.62 (2H, s), 6.76 (1H, s), 8.12 (1H, s)。

j) Production of 2, 3-dihydro- [1,4] dioxin [2,3-c ] pyridine-7-carbaldehyde:

using (2, 3-dihydro- [1,4] dioxin [2,3-c ] pyridin-7-yl) methanol, the reaction and treatment were carried out in the same manner as in example 6-l) to obtain the title compound as a colorless oil.

¹H-NMR (CDCl₃) δ：4.39 (4H, s), 7.51 (1H, s), 8.31 (1H, s), 9.93 (1H, s)。

k) Production of 1- (2, 3-dihydro- [1,4] dioxin [2,3-c ] pyridin-7-yl) ethanol:

using 2, 3-dihydro- [1,4] dioxin [2,3-c ] pyridine-7-carbaldehyde, the reaction and treatment were carried out in the same manner as in example 6-l) to obtain the title compound as a colorless oil.

¹H-NMR (CDCl₃) δ：1.45 (3H, d, J = 6.2 Hz), 4.28-4.35 (4H, m), 4.77 (1H, q, 6.2 Hz), 6.77 (1H, s), 8.09 (1H, s)。

l) production of 1- (2, 3-dihydro- [1,4] dioxin [2,3-c ] pyridin-7-yl) ethanone:

the reaction and treatment were carried out in the same manner as in example 6-l) using 1- (2, 3-dihydro- [1,4] dioxin [2,3-c ] pyridin-7-yl) ethanol to give the title compound as a colorless oil.

¹H-NMR (CDCl₃) δ：2.66 (3H, s), 4.36 (4H, s), 7.60 (1H, s), 8.20 (1H, s)。

m) production of 5- (2, 3-dihydro- [1,4] dioxin [2,3-c ] pyridin-7-yl) -5-methylimidazolidine-2, 4-dione:

using 1- (2, 3-dihydro- [1,4] dioxin [2,3-c ] pyridin-7-yl) ethanone, the reaction and treatment were carried out in the same manner as in example 1-l) to obtain the title compound as a colorless oil.

¹H-NMR (CDCl₃) δ：1.73 (3H, s), 4.29-4.37 (4H, m), 7.06 (1H, s), 8.05 (1H, s)。

n) Using (Z) -1- (4- {4- [2- (benzyloxy) -1,1,1,3,3, 3-hexafluoropropan-2-yl ] -2- (prop-1-en-1-yl) phenyl } piperazin-1-yl) -2-bromoethanone and 5- (2, 3-dihydro- [1,4] dioxin [2,3-c ] pyridin-7-yl) -5-methylimidazolidine-2, 4-dione, the reaction and treatment were carried out in the same manner as in example 14-1 to obtain the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：1.73 (3H, dd, J= 1.9, 7.0 Hz), 1.83 (3H, s), 2.96-3.08 (4H, m), 3.57-3.75 (4H, m), 4.26-4.37 (6H, m), 4.67 (2H, s),5.84 (1H, qd, J = 7.0, 11.3 Hz), 6.41 (1H, s), 6.47 (1H, qd, J = 1.9, 11.3 Hz), 6.99 (1H, d, J = 8.4 Hz), 7.33-7.47 (6H, m), 7.51 (1H, s), 8.09 (1H, s)。

Example 54: production of 5- (2, 3-dihydro- [1,4] dioxin [2,3-c ] pyridin-7-yl) -3- (2- {4- [4- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -2-propylphenyl ] piperazin-1-yl } -2-oxoethyl) -5-methylimidazolidine-2, 4-dione:

[ solution 62]

The reaction and treatment were carried out in the same manner as in example 15-1 using 3- [2- (4- {4- [2- (benzyloxy) -1,1,1,3,3, 3-hexafluoropropane-2-yl ] -2- (prop-1-en-1-yl) phenyl } piperazin-1-yl) -2-oxoethyl ] -5- (2, 3-dihydro- [1,4] dioxin [2,3-c ] pyridin-7-yl) -5-methylimidazolidine-2, 4-dione to obtain the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：0.97 (3H, t, J= 7.0 Hz), 1.67 (2H, qt, J = 7.0, 7.3 Hz), 1.83 (3H, s), 2.66 (2H, t, J= 7.3 Hz), 2.94-2.98 (4H, m), 3.59-3.77 (4H, m), 4.26-4.37 (6H, m), 6.41 (1H, s), 7.07 (1H, d, J = 8.1 Hz), 7.51 (1H, d, J = 8.1 Hz), 7.53 (1H, s), 8.09 (1H, s)。

Example 55: production of 3- [2- (4- {4- [2- (benzyloxy) -1,1,1,3,3, 3-hexafluoropropan-2-yl) -2- (prop-1-en-1-yl) phenyl } piperazin-1-yl) -2-oxoethyl ] -5- (2, 3-dihydro- [1,4] dioxin [2,3-b ] pyridin-6-yl) -5-methylimidazolidine-2, 4-dione:

[ solution 63]

a) Production of 5- (2, 3-dihydro- [1,4] dioxin [2,3-b ] pyridin-6-yl) -5-methylimidazolidine-2, 4-dione:

a-1) production of 2, 3-dihydro- [1,4] dioxin [2,3-b ] pyridine:

2, 3-dihydroxypyridine (2.22g, 20.0mmol) was dissolved in N, N' -dimethylformamide (100mL), and potassium carbonate (5.52g, 40.0mmol) was added at room temperature. After 5 minutes, 1, 2-dibromoethane (2.6mL, 30.0mmol) was added at the same temperature and stirred at 90 ℃ overnight. The reaction mixture was returned to room temperature, filtered, and the obtained filtrate was concentrated under reduced pressure. Then, ethyl acetate was added to the resulting residue. The suspension was collected by filtration, washed with ethyl acetate, and dried under reduced pressure to give the title compound as a colorless oil (157 mg, yield 5.7%).

¹H-NMR (CDCl₃) δ： 4.26-4.28 (2H, m), 4.42-4.44 (2H, m), 6.94 (1H, dd, J = 5.6, 7.6 Hz), 7.28 (1H, dd, J = 1.2, 7.6 Hz), 7.69 (1H, dd, J = 1.2,5.6 Hz)。

a-2) production of 2, 3-dihydro- [1,4] dioxin [2,3-b ] pyridine 5-oxide:

2, 3-dihydro- [1,4] Dioxin [2,3-b ] pyridine (121mg, 790. mu. mol) was dissolved in dichloromethane (4.0mL), 3-chloroperoxybenzoic acid (234mg, 950. mu. mol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform/methanol) to obtain 102mg (yield 84%) of the title compound as a white solid.

¹H-NMR (CDCl₃) δ：4.33-4.36 (2H, m), 4.59-4.62 (2H, m), 6.81 (1H, dd, J = 6.8, 8.4 Hz), 6.95 (1H, dd, J = 1.4, 8.4 Hz), 7.95 (1H, dd, J = 1.4, 6.8 Hz)。

a-3) production of 2, 3-dihydro- [1,4] dioxin [2,3-b ] pyridine-6-carbonitrile:

2, 3-dihydro- [1,4] dioxin [2,3-b ] pyridine 5-oxide (102mg, 666. mu. mol) was dissolved in acetonitrile (700. mu.L) under an argon atmosphere, triethylamine (202mg, 2.00mmol) and trimethylsilylnitrile (529mg,5.33mmol) were added at room temperature, and the mixture was stirred at 100 ℃ overnight. Water was added thereto under ice cooling, and the reaction solution was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform/methanol) to obtain the title compound 105mg (yield 97%) as a tan solid.

¹H-NMR (CDCl₃) δ： 4.33-4.36 (2H, m), 4.48-4.51 (2H, m), 7.24 (1H, d, J = 8.1 Hz), 7.32 (1H, d, J = 8.1 Hz)。

a-4) production of 1- (2, 3-dihydro- [1,4] dioxin [2,3-b ] pyridin-6-yl) ethanone:

2, 3-dihydro- [1,4] dioxin [2,3-b ] pyridine-6-carbonitrile (16mg, 99. mu. mol) was dissolved in tetrahydrofuran (500. mu.L) under an argon atmosphere, methyllithium (150. mu.L (1.04M in THF solution), 148. mu. mol) was added under ice cooling, and stirred at the same temperature for 5 minutes. 1M sulfuric acid (2.0mL) was added to the reaction solution, and the mixture was stirred at room temperature for 3 hours. A saturated aqueous sodium bicarbonate solution was added to the reaction solution under ice cooling (pH =8 was confirmed). The reaction solution was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound as a yellow oil (8.3mg, yield 47%).

¹H-NMR (CDCl₃) δ：2.64 (3H, s), 4.33-4.35 (2H, m), 4.49-4.51 (2H, m), 7.27 (1H, d, J = 8.4 Hz), 7.21 (1H, d, J= 8.4 Hz)。

a-5) production of 5- (2, 3-dihydro- [1,4] dioxin [2,3-b ] pyridin-6-yl) -5-methylimidazolidine-2, 4-dione:

using 1- (2, 3-dihydro- [1,4] dioxin [2,3-b ] pyridin-6-yl) ethanone, the reaction and treatment were carried out in the same manner as in example 1-l) to obtain the title compound as a white crystal.

¹H-NMR (CDCl₃) δ：1.75 (3H, s), 4.24-4.26 (2H, m), 4.41-4.43 (2H, m), 7.09 (1H, d, J = 8.0 Hz), 7.25 (1H, d, J= 8.0 Hz)。

b) Production of 3- [2- (4- {4- [2- (benzyloxy) -1,1,1,3,3, 3-hexafluoropropan-2-yl ] -2- (prop-1-en-1-yl) phenyl ] piperazin-1-yl ] -2-oxoethyl ] -5- (2, 3-dihydro- [1,4] dioxin [2,3-b ] pyridin-6-yl) -5-methylimidazolidine-2, 4-dione:

the reaction and treatment were carried out in the same manner as in example 14-1 using (Z) -1- (4- {4- [2- (benzyloxy) -1,1,1,3,3, 3-hexafluoropropan-2-yl ] -2- (prop-1-en-1-yl) phenyl } piperazin-1-yl) -2-bromoethanone and 5- (2, 3-dihydro- [1,4] dioxin [2,3-b ] pyridin-6-yl) -5-methylimidazolidine-2, 4-dione to give the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：1.73 (3H, dd, J= 1.6, 7.0 Hz), 1.84 (3H, s), 2.99-3.08 (4H, m), 3.57-3.75 (4H, m), 4.24-4.27 (2H, m), 4.36 (2H, s), 4.43-4.46 (2H, m), 4.67 (2H, s),5.84 (1H, qd, J= 7.0, 11.3 Hz), 6.20 (1H, s), 6.47 (1H, qd, J = 1.6, 11.3 Hz), 7.20 (1H, d, J = 7.8 Hz), 7.26-7.51 (9H, m)。

Example 56: production of 5- (2, 3-dihydro- [1,4] dioxin [2,3-b ] pyridin-6-yl) -3- (2- {4- [4- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -2-propylphenyl ] piperazin-1-yl } -2-oxoethyl) -5-methylimidazolidine-2, 4-dione:

[ solution 64]

The reaction and treatment were carried out in the same manner as in example 15-1 using 3- [2- (4- {4- [2- (benzyloxy) -1,1,1,3,3, 3-hexafluoropropane-2-yl ] -2- (prop-1-en-1-yl) phenyl } piperazin-1-yl } -2-oxoethyl } -5- (2, 3-dihydro- [1,4] dioxin [2,3-b ] pyridin-6-yl) -5-methylimidazolidine-2, 4-dione to obtain the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：0.96 (3H, t, J= 7.6 Hz), 1.66 (2H, qt, J = 7.6, 7.6 Hz), 1.85 (3H, s), 2.66 (2H, t, J= 7.6 Hz), 2.86-2.98 (4H, m), 3.59-3.76 (4H, m), 4.25-4.27 (2H, m), 4.38 (2H, s), 4.43-4.46 (2H, m), 6.25 (1H, s), 7.06 (1H, d, J = 8.1 Hz), 7.20 (1H, d, J = 7.8 Hz), 7.28 (1H, d, J = 7.8 Hz), 7.50 (1H, d, J = 8.1 Hz), 7.53 (1H, s)。

Example 57: production of 5- (benzofuran-6-yl) -3- (2- {4- [4- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -2-propylphenyl ] piperazin-1-yl } -2-oxoethyl) -5-methylimidazolidine-2, 4-dione:

[ solution 65]

In example 6, 5- (benzofuran-6-yl) -5-methylimidazolidine-2, 4-dione was used in place of 5- [5- (1-methylethoxy) pyridin-2-yl ] 5-methylimidazolidine-2, 4-dione, and the reaction and treatment were carried out in the same manner to obtain the title compound as a yellow oily substance.

¹H-NMR (CDCl₃) δ：0.96 (3H, t, J= 7.3 Hz), 1.66 (2H, qt, J = 7.3, 7.6 Hz), 1.99 (3H, s), 2.66 (2H, t, J= 7.6 Hz), 2.88-2.96 (4H, m), 3.60-3.75 (4H, m), 4.13 (1H, brs), 4.36 (1H, d, J = 16.1 Hz), 4.38 (1H, d, J = 16.1 Hz), 6.02 (1H, brs), 6.76 (1H, d, J = 2.2 Hz), 7.06 (1H, d, J = 8.3 Hz), 7.48 (1H, dd, J = 2.2, 8.3 Hz), 7.50 (1H, d, J = 8.3 Hz), 7.54 (1H, s), 7.63 (1H, d, J = 8.3 Hz), 7.65 (1H, d, J = 2.2 Hz), 8.00 (1H, d, J = 2.2 Hz)。

Example 58: production of 5- (benzofuran-5-yl) -3- (2- {4- [4- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -2-propylphenyl ] piperazin-1-yl } -2-oxoethyl) -5-methylimidazolidine-2, 4-dione:

[ solution 66]

a) Production of 5- (benzofuran-5-yl) -5-methylimidazolidine-2, 4-dione:

a-1) production of 1- (4- (2, 2-diethoxyethoxy) phenyl) ethanone:

to a solution of 1- (4-hydroxyphenyl) ethanone (1.00 g, 7.34 mmol) in N, N' -dimethylformamide (24mL) were added sodium hydride (purity 50%) (380mg, 8.07mmol) and bromoacetaldehyde diethyl acetal (1.30mL, 8.81mmol) under ice-cooling, and the mixture was stirred at 120 ℃ overnight. Water was added to the reaction mixture under ice cooling, followed by extraction with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain 2.47g of the title compound as a yellow oil (yield > 100%).

¹H-NMR (CDCl₃) δ：1.24 (6H, t, J = 7.3 Hz), 2.56 (3H, s), 3.56-3.81 (4H, m), 4.06 (2H, d, J = 5.1 Hz), 4.85 (1H, t, J = 5.1 Hz), 6.95 (2H, d, J = 7.0 Hz), 7.92 (2H, d, J = 7.0 Hz)。

a-2) production of 1- (benzofuran-5-yl) ethanone:

PPA (2.50g) was added to a solution of 1- (4- (2, 2-diethoxyethoxy) phenyl) ethanone (2.46 g, 7.34 mmol) in toluene (25mL), and the mixture was stirred under reflux for 1 hour. Water was added to the reaction mixture under ice cooling, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound 44mg (yield 3.7%) as a white solid.

¹H-NMR (CDCl₃) δ：2.68 (3H, s), 6.86-6.87 (1H, m), 7.54 (1H, d, J = 8.6 Hz), 7.70 (1H, d, J = 2.4 Hz), 7.97 (1H, dd, J = 2.4, 8.6 Hz), 8.26 (1H, d, J = 1.6 Hz)。

a-3) production of 5- (benzofuran-5-yl) -5-methylimidazolidine-2, 4-dione:

using 1- (benzofuran-5-yl) ethanone, the reaction and treatment were carried out in the same manner as in example 1-l) to obtain the title compound as white crystals.

¹H-NMR (CDCl₃) δ：1.82 (3H, s), 6.86 (1H, d, J = 1.2 Hz), 7.46 (1H, dd, J = 2.0, 8.4 Hz), 7.51 (1H, d, J = 8.4 Hz), 7.77 (1H, d, J = 2.0 Hz), 7.78 (1H, d, J = 1.2 Hz)。

b) 5- (benzofuran-5-yl) -3- (2- {4- [4- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -2-propylphenyl ] piperazin-1-yl } -2-oxoethyl) -5-methylimidazolidine-2, 4-dione

In example 6, 5- (benzofuran-5-yl) -5-methylimidazolidine-2, 4-dione was used in place of 5- [5- (1-methylethoxy) pyridin-2-yl ] 5-methylimidazolidine-2, 4-dione, and the reaction and treatment were carried out in the same manner to obtain the title compound as a yellow oily substance.

¹H-NMR (CDCl₃) δ：0.96 (3H, t, J= 7.6 Hz), 1.66 (2H, qt, J = 7.6, 7.6 Hz), 1.99 (3H, s), 2.65 (2H, t, J= 7.6 Hz), 2.88-2.95 (4H, m), 3.60-3.74 (4H, m), 4.36 (1H, d, J = 16.1 Hz), 4.38 (1H, d, J = 16.1 Hz), 6.79 (1H, d, J = 2.2 Hz), 7.05 (1H, d, J = 8.5 Hz), 7.46-7.54 (4H, m), 7.64 (1H, d, J = 2.2 Hz), 7.82 (1H, d, J = 2.2 Hz)。

Example 59: production of 5- (furo [2,3-c ] pyridin-5-yl) -3- (2- {4- [4- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -2-propylphenyl ] piperazin-1-yl } -2-oxoethyl) -5-methylimidazolidine-2, 4-dione:

[ solution 66]

a) Production of 5- (furo [2,3-c ] pyridin-5-yl) -5-methylimidazolidine-2, 4-dione:

a-1) production of 2- (hydroxymethyl) -5- [ (4-methoxybenzyl) oxy ] -4H-pyran-4-one:

5-hydroxy-2-hydroxymethyl-4H-4-pyrone (5.0g, 35.2mmol) was dissolved in N, N' -dimethylformamide (70mL), and potassium tert-butoxide (4.0g, 35.2mmol) was added under ice cooling under an argon atmosphere. After 5 minutes 4-methoxybenzyl chloride (6.06g, 38.7mmol) was added at the same temperature and stirred at 50 ℃ for 21 hours. Then, the reaction solution was concentrated under reduced pressure. Water and a 1N aqueous sodium hydroxide solution were added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. Diethyl ether was added to the obtained residue, and the mixture was purified by recrystallization to obtain 4.80g (yield: 52%) of the title compound as brown powdery crystals.

¹H-NMR (CDCl₃) δ： 3.76 (3H, s), 4.28 (2H, s), 4.86 (2H, s), 6.31 (1H, s), 6.94 (2H, d, J = 8.4 Hz), 7.34 (2H, d, J = 8.4 Hz), 8.14 (1H, s)。

a-2) production of 2- (hydroxymethyl) -5- [ (4-methoxybenzyl) oxy ] pyridin-4 (1H) -one:

2- (hydroxymethyl) -5- [ (4-methoxybenzyl) oxy ] -4H-pyran-4-one (1.2g, 4.56mmol) was dissolved in ethanol (3.0 mL), and an aqueous ammonia solution (9.0mL) was added, sealed, and stirred at 100 ℃ for 6 hours. This operation was carried out in 4 batches and summarized immediately before being processed. The reaction mixture was concentrated under reduced pressure. After diethyl ether was added, the reaction solution was ice-cooled. The precipitated solid was collected by filtration, washed with diethyl ether, and dried under reduced pressure to obtain 4.0g (yield: 84%) of the title compound as a brown powdery crystal.

¹H-NMR (CDCl₃) δ：3.78 (3H, s), 4.56 (2H, s),5.01 (2H, s), 6.42 (1H, s), 6.90 (2H, d, J = 8.4 Hz), 7.36 (2H, d, J= 8.4 Hz), 7.41 (1H, s)。

a-3) production of acetic acid {5- [ (4-methoxybenzyl) oxy ] -4-oxo-1, 4-dihydropyridin-2-yl } methyl ester:

2- (hydroxymethyl) -5- [ (4-methoxybenzyl) oxy ] pyridin-4 (1H) -one (3.21g, 12.2mmol) was dissolved in pyridine (60mL), and acetyl chloride (1.44g, 18.3mmol) was added under ice cooling, and the mixture was stirred at 60 ℃ overnight. Then, the reaction solution was concentrated under reduced pressure. After water was added under ice cooling, the mixture was stirred at room temperature for 30 minutes. The precipitated solid was collected by filtration, washed with ice water and diethyl ether, and dried under reduced pressure to obtain 3.56g (yield: 96%) of the title compound as brown powdery crystals.

¹H-NMR (CDCl₃) δ： 2.11 (3H, s), 4.99 (2H, s), 3.78 (3H, s),5.01 (2H, s), 6.52 (1H, s), 6.89 (2H, d, J = 8.4 Hz), 7.35 (2H, d, J = 8.4 Hz), 7.49 (1H, s)。

a-4) preparation of (5- [ (4-methoxybenzyl) oxy ] -4- { [ (trifluoromethyl) sulfonyl ] oxy } pyridin-2-yl) methyl acetate:

acetic acid {5- [ (4-methoxybenzyl) oxy ] -4-oxo-1, 4-dihydropyridin-2-yl } methyl ester (3.56g, 11.7mmol) was dissolved in methylene chloride (60mL), and triethylamine (3.55g, 35.1mmol) and trifluoromethanesulfonic anhydride (6.60g, 23.4mmol) were added under ice cooling under argon atmosphere, followed by stirring at 0 ℃ for 15 minutes. After adding water and a saturated aqueous sodium bicarbonate solution to the reaction mixture, extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound as a yellow oil 4.84g (yield 95%).

¹H-NMR (CDCl₃) δ： 2.15 (3H, s), 3.82 (3H, s),5.16 (2H, s),5.20 (2H, s), 6.92 (2H, d, J = 8.9 Hz), 7.25 (1H, s), 7.36 (2H, d, J = 8.9 Hz), 8.45 (1H, s)。

a-5) production of {5- [ (4-methoxybenzyl) oxy ] -4- [ (trimethylsilyl) ethynyl ] pyridin-2-yl } methyl acetate:

acetic acid (5- [ (4-methoxybenzyl) oxy ] -4- { [ (trifluoromethyl) sulfonyl ] oxy } pyridin-2-yl) methyl ester (1.2g, 2.78mmol) was dissolved in acetonitrile (9.3 mL), and copper iodide (53mg, 278. mu. mol), bis (triphenylphosphine) palladium (II) dichloride (98mg, 139. mu. mol), triethylamine (8.0mL), and trimethylsilylacetylene (819mg, 8.34mmol) were added under ice cooling under argon atmosphere, and stirred at 45 ℃ overnight. This operation was divided into 4 batches and summarized immediately prior to processing. After water was added to the reaction mixture, the mixture was filtered through celite. The obtained filtrate was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product (5.38g) of the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ： 0.26 (9H, s), 2.14 (3H, s), 3.82 (3H, s),5.11 (2H, s),5.18 (2H, s), 6.91 (2H, d, J = 8.8 Hz), 7.36-7.41 (3H, m), 8.28 (1H, s)。

a-6) production of { 5-hydroxy-4- [ (trimethylsilyl) ethynyl ] pyridin-2-yl } methyl acetate:

acetic acid (5- ((4-methoxybenzyl) oxy) -4- ((trimethylsilyl) ethynyl) pyridin-2-yl) methyl ester (5.38g, 11.1mmol) as a crude product was dissolved in dichloromethane (55 mL), trimethylsilane (1.9mL,35.1mmol), trifluoroacetic acid (5.5mL) were added at room temperature, and stirred at room temperature overnight. To the reaction solution, a saturated aqueous sodium bicarbonate solution (pH =8 was confirmed) was added under ice cooling, and the reaction solution was filtered through celite. The obtained filtrate was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound 1.54g as a yellow oil (yield 53%).

¹H-NMR (CDCl₃) δ： 0.26 (9H, s), 2.14 (3H, s),5.11 (2H, s), 7.29 (1H, s), 8.35 (1H, s)。

a-7) production of furo [2,3-c ] pyridin-5-ylmethyl acetate:

acetic acid (5-hydroxy-4- ((trimethylsilyl) ethynyl) pyridin-2-yl) methyl ester (1.47g,5.59mmol) was dissolved in pyridine (28mL), copper iodide (1.28g, 6.71mmol) was added at room temperature, and the mixture was stirred under reflux for 5 hours. The reaction solution was returned to room temperature, concentrated under reduced pressure, and then filtered through celite. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound 345mg (yield 32%) as an orange oil.

¹H-NMR (CDCl₃) δ： 2.16 (3H, s),5.31 (2H, s), 6.81 (1H, d, J = 2.4 Hz), 7.63 (1H, s), 7.78 (1H, d, J= 2.4 Hz), 8.87 (1H, s)。

a-8) preparation of furo [2,3-c ] pyridin-5-ylmethanol:

furo [2,3-c ] pyridin-5-ylmethyl acetate (722mg, 3.78mmol) was dissolved in methanol (19mL), potassium carbonate (1.04g, 7.56mmol) was added at room temperature, and the mixture was stirred at room temperature overnight. To the reaction mixture, 1N-hydrochloric acid aqueous solution was added under ice cooling, extraction was performed with chloroform, and the organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound 521mg (yield 92%) as a yellow oil.

¹H-NMR (CDCl₃) δ： 3.68 (1H, s), 4.85 (2H, s), 6.79 (1H, s), 7.54 (1H, s), 7.79 (1H, s), 8.83 (1H, s)。

a-9) preparation of furo [2,3-c ] pyridine-5-carbaldehyde:

furo [2,3-c ] pyridin-5-ylmethanol (521mg, 3.49mmol) was dissolved in acetone (17 mL), and 2,2,6, 6-tetramethylpiperidine 1-oxide (27mg, 170. mu. mol) was added at room temperature. Then, 1,3, 5-trichloro-2, 4, 6-triazinetrione (892mg, 3.84mmol) was added to the reaction mixture under ice cooling, and the mixture was stirred at the same temperature for 5 minutes. The reaction solution was concentrated under reduced pressure, water and a saturated aqueous sodium bicarbonate solution were added under ice cooling, extraction was performed with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain 488mg (yield 95%) of the title compound as a yellow solid.

¹H-NMR (CDCl₃) δ： 6.98 (1H, dd, J = 0.8, 2.2 Hz), 7.88 (1H, d, J = 2.2 Hz), 8.32 (1H, d, J = 0.8 Hz), 9.03 (1H, s), 10.18 (1H, s)。

a-10) production of 1- (furo [2,3-c ] pyridin-5-yl) ethanol:

furo [2,3-c ] pyridine-5-carbaldehyde (488mg, 3.31mmol) was dissolved in tetrahydrofuran (11 mL) under an argon atmosphere, and methylmagnesium bromide (5.5mL (1.0M in THF), 4.97mmol) was added under ice cooling. Then, the mixture was stirred at room temperature for 1.5 hours. To the reaction solution, 1N-hydrochloric acid aqueous solution was added under ice cooling, and then saturated sodium bicarbonate aqueous solution was added. The reaction solution was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound 356mg as a yellow solid (yield 66%).

¹H-NMR (CDCl₃) δ：1.56 (3H, d, J = 6.2 Hz),5.00 (1H, q, J = 6.2 Hz), 6.80 (1H, d, J = 2.2 Hz), 7.53 (1H, s), 7.78 (1H, d, J = 2.2 Hz), 8.80 (1H, s)。

a-11) production of 1- (furo [2,3-c ] pyridin-5-yl) ethanone:

1- (furo [2,3-c ] pyridin-5-yl) ethanol (356mg, 2.19mmol) was dissolved in acetone (11 mL), and 2,2,6, 6-tetramethylpiperidine 1-oxide (34mg, 220. mu. mol) was added at room temperature. Then, 1,3, 5-trichloro-2, 4, 6-triazinetrione (560mg, 2.41mmol) was added to the reaction solution under ice cooling, and stirred at the same temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, water and a saturated aqueous sodium bicarbonate solution were added under ice cooling, extraction was performed with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound as a yellow solid in an amount of 119mg (yield 34%).

¹H-NMR (CDCl₃) δ：2.79 (3H, s), 6.93-6.94 (1H, m), 7.83 (1H, d, J= 2.0 Hz), 8.39 (1H, d, J = 0.8 Hz), 8.91 (1H, s)。

a-12) production of 5- (furo [2,3-c ] pyridin-5-yl) -5-methylimidazolidine-2, 4-dione:

using 1- (furo [2,3-c ] pyridin-5-yl) ethanone, the reaction and treatment were carried out in the same manner as in example 1-l) to obtain the title compound as white crystals.

¹H-NMR (CDCl₃) δ：1.88 (3H, s), 6.99-7.00 (1H, m), 7.89 (1H, d, J= 1.2 Hz), 8.02 (1H, d, J = 2.0 Hz), 8.82 (1H, s)。

b) Production of 5- (furo [2,3-c ] pyridin-5-yl) -3- (2- {4- [4- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -2-propylphenyl ] piperazin-1-yl } -2-oxoethyl) -5-methylimidazolidine-2, 4-dione:

in example 6, 5- (furo [2,3-c ] pyridin-5-yl) -5-methylimidazolidine-2, 4-dione was used in place of 5- [5- (1-methylethoxy) pyridin-2-yl ] 5-methylimidazolidine-2, 4-dione, and the reaction and treatment were carried out in the same manner to obtain the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：0.96 (3H, t, J= 7.3 Hz), 1.67 (2H, qt, J = 7.3, 7.6 Hz), 1.93 (3H, s), 2.66 (2H, t, J= 7.6 Hz), 2.89-2.96 (4H, m), 3.62-3.75 (4H, m), 4.19 (1H, s), 4.41 (2H, s), 6.57 (1H, s), 6.83 (1H, d, J = 2.2 Hz), 7.07 (1H, d, J = 8.5 Hz), 7.51 (1H, d, J = 8.5 Hz), 7.54 (1H, s), 7.78 (1H, d, J = 2.2 Hz), 8.01 (1H, d, J = 1.0 Hz), 8.81 (1H, d, J= 1.0 Hz)。

Example 60: production of 5- (benzofuran-6-yl) -3- (2- { (S) -4- [4- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -2-propylphenyl ] -3-methylpiperazin-1-yl } -2-oxoethyl) -5-methylimidazolidine-2, 4-dione:

[ solution 67]

The reaction and treatment were carried out in the same manner as in example 12 using (S) -2-methyl-1-tert-butoxycarbonylpiperazine instead of (R) -2-methyl-1-tert-butoxycarbonylpiperazine and 5- (benzofuran-6-yl) -5-methylimidazolidine-2, 4-dione to obtain the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：0.85 (3H, d, J= 6.0 Hz), 0.95 (3H, t, J = 7.3 Hz), 1.62 (2H, qt, J = 7.3, 7.3 Hz), 2.00 (3H, s), 2.62-3.23 (6H, m), 3.47-3.79 (3H, m), 4.35 (1H, d, J= 16.3 Hz), 4.37 (1H, d, J = 16.3 Hz),5.98 (1H, s), 6.76 (1H, d, J= 2.2 Hz), 7.14 (1H, d, J = 8.6 Hz), 7.48 (1H, d, J = 8.3 Hz), 7.51 (1H, d, J = 8.6 Hz), 7.54 (1H, s), 7.63 (1H, d, J = 8.3 Hz), 7.65 (1H, d, J = 2.2 Hz), 7.75 (1H, s)。

Example 61: production of 5- (benzofuran-5-yl) -3- (2- { (S) -4- [4- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -2-propylphenyl ] -3-methylpiperazin-1-yl } -2-oxoethyl) -5-methylimidazolidine-2, 4-dione:

[ solution 68]

The reaction and treatment were carried out in the same manner as in example 12 using (S) -2-methyl-1-tert-butoxycarbonylpiperazine instead of (R) -2-methyl-1-tert-butoxycarbonylpiperazine and 5- (benzofuran-5-yl) -5-methylimidazolidine-2, 4-dione to obtain the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：0.85 (3H, d, J= 6.3 Hz), 0.95 (3H, t, J = 7.3 Hz), 1.62 (2H, qt, J = 7.3, 7.3 Hz), 2.00 (3H, s), 2.62-3.20 (6H, m), 3.44-3.81 (3H, m), 4.36 (1H, d, J= 15.6 Hz), 4.40 (1H, d, J = 15.6 Hz),5.98 (1H, s), 6.80 (1H, d, J= 2.2 Hz), 7.14 (1H, d, J = 8.8 Hz), 7.46-7.54 (4H, m), 7.65 (1H, d, J= 2.2 Hz), 7.82 (1H, s)。

Example 62: production of 5- (furo [2,3-c ] pyridin-5-yl) -3- (2- { (S) -4- [4- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -2-propylphenyl ] -3-methylpiperazin-1-yl } -2-oxoethyl) -5-methylimidazolidine-2, 4-dione:

[ solution 69]

The reaction and treatment were carried out in the same manner as in example 12 using (S) -2-methyl-1-tert-butoxycarbonylpiperazine instead of (R) -2-methyl-1-tert-butoxycarbonylpiperazine and 5- (furo [2,3-c ] pyridin-5-yl) -5-methylimidazolidine-2, 4-dione to give the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：0.87 (3H, d, J= 6.1 Hz), 0.95 (3H, t, J = 7.3 Hz), 1.62 (2H, qt, J = 7.3, 7.3 Hz), 1.93 (3H, s), 2.62-3.18 (6H, m), 3.46-3.96 (3H, m), 4.37 (1H, d, J= 15.8 Hz), 4.42 (1H, d, J = 15.8 Hz), 6.56 (1H, s), 6.83 (1H, d, J= 2.2 Hz), 7.14 (1H, d, J = 8.4 Hz), 7.51 (1H, d, J = 8.3 Hz), 7.55 (1H, s), 7.78 (1H, d, J = 2.2 Hz), 8.02 (1H, s), 8.81 (1H, s)。

Example 63: (2S,5R, Z) -3- [2- (4- {4- [2- (benzyloxy) -1,1,1,3,3, 3-hexafluoropropan-2-yl)]-2- (prop-1-en-1-yl) phenyl } -2, 5-dimethylpiperazin-1-yl) -2-oxoethyl]-5- (2, 3-dihydrobenzo [ b ]][1,4]IIProduction of in-6-yl) -5-methylimidazolidine-2, 4-dione:

[ solution 70]

a) Production of (2S,5R) -4- [4- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -2-nitrophenyl ] -2, 5-dimethylpiperazine-1-carboxylic acid tert-butyl ester:

the reaction and treatment were carried out in the same manner as in example 43-b) except for using (2S,5R) -tert-butyl 2, 5-dimethylpiperazine-1-carboxylate obtained in example 14-1-a-2-2) instead of using 1,1,1,3,3, 3-hexafluoro-2- (4-fluoro-3-nitrophenyl) propan-2-ol and tert-butyl piperazine-1-carboxylate obtained in example 43-a), so as to obtain the title compound as a yellow oily substance.

¹H-NMR (CDCl₃) δ：1.07 (3H, d, J= 6.8 Hz), 1.28 (3H, d, J = 6.5 Hz), 1.48 (9H, s), 2.70-2.74 (1H, m), 3.52-3.70 (4H, m), 4.35-4.44 (1H, m), 7.07 (1H, d, J = 9.2 Hz), 7.73 (1H, dd, J = 1.9, 9.2 Hz), 8.15 (1H, d, J = 1.9 Hz)。

b) Production of (2S,5R) -4- {4- [2- (benzyloxy) -1,1,1,3,3, 3-hexafluoropropan-2-yl ] -2-nitrophenyl } -2, 5-dimethylpiperazine-1-carboxylic acid tert-butyl ester:

the reaction and the treatment were carried out in the same manner as in example 43-c) using tert-butyl (2S,5R) -4- [4- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -2-nitrophenyl ] -2, 5-dimethylpiperazine-1-carboxylate to obtain the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：1.09 (3H, d, J= 6.5 Hz), 1.29 (3H, d, J = 6.8 Hz), 1.48 (9H, s), 2.70-2.75 (1H, m), 3.52-3.70 (4H, m), 4.37-4.46 (1H, m), 4.66 (2H, s), 7.08 (1H, d, J = 8.9 Hz), 7.31-7.45 (5H, m), 7.65 (1H, d, J = 8.9 Hz), 8.04 (1H, s)。

c) Production of (2S,5R) -4- { 2-amino-4- [2- (benzyloxy) -1,1,1,3,3, 3-hexafluoropropan-2-yl ] phenyl } -2, 5-dimethylpiperazine-1-carboxylic acid tert-butyl ester:

the reaction and the treatment were carried out in the same manner as in example 43-d) using tert-butyl (2S,5R) -4- {4- [2- (benzyloxy) -1,1,1,3,3, 3-hexafluoropropan-2-yl ] -2-nitrophenyl } -2, 5-dimethylpiperazine-1-carboxylate to give the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：0.95 (3H, d, J= 6.2 Hz), 1.31 (3H, d, J = 6.8 Hz), 1.48 (9H, s), 2.52 (1H, d, J= 11.6 Hz), 3.39-3.96 (4H, m), 4.40-4.50 (1H, m), 4.66 (2H, s), 6.86 (1H, d, J= 8.6 Hz), 6.94-6.98 (2H, m), 7.30-7.41 (5H, m)。

d) Production of (2S,5R) -4- {4- [2- (benzyloxy) -1,1,1,3,3, 3-hexafluoropropan-2-yl ] -2-iodophenyl } -2, 5-dimethylpiperazine-1-carboxylic acid tert-butyl ester:

the reaction and the treatment were carried out in the same manner as in example 43-e) using tert-butyl (2S,5R) -4- { 2-amino-4- [2- (benzyloxy) -1,1,1,3,3, 3-hexafluoropropan-2-yl ] phenyl } -2, 5-dimethylpiperazine-1-carboxylate to obtain the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：0.95 (3H, d, J= 6.5 Hz), 1.36 (3H, d, J = 6.5 Hz), 1.49 (9H, s), 2.53 (1H, d, J= 10.8 Hz), 3.59-3.82 (4H, m), 4.40-4.50 (1H, m), 4.63 (2H, s), 6.91 (1H, d, J= 8.4 Hz), 7.36-7.43 (5H, m), 7.54 (1H, d, J = 8.4 Hz), 8.06 (1H, s)。

e) Production of (2S,5R) -4- {4- [2- (benzyloxy) -1,1,1,3,3, 3-hexafluoropropan-2-yl ] -2- (prop-1-en-1-yl) phenyl } -2, 5-dimethylpiperazine-1-carboxylic acid tert-butyl ester:

the reaction and the treatment were carried out in the same manner as in example 43-f) using tert-butyl (2S,5R) -4- {4- [2- (benzyloxy) -1,1,1,3,3, 3-hexafluoropropan-2-yl ] -2-iodophenyl } -2, 5-dimethylpiperazine-1-carboxylate to give the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：0.91 (3H, d, J= 6.5 Hz), 1.29 (3H, d, J = 6.8 Hz), 1.48 (9H, s), 1.74 (3H, dd, J= 1.9, 7.0 Hz), 2.68 (1H, d, J = 11.1 Hz), 3.39-3.73 (4H, m), 4.36-4.46 (1H, m), 4.68 (2H, s),5.80 (1H, qd, J = 7.0, 11.3 Hz), 6.48 (1H, qd, J= 1.9, 11.3 Hz), 6.88 (1H, d, J = 8.9 Hz), 7.30-7.42 (6H, m), 7.49 (1H, s)。

f) Preparation of (2S,5R) -1- {4- [2- (benzyloxy) -1,1,1,3,3, 3-hexafluoropropan-2-yl ] -2- (prop-1-en-1-yl) phenyl } -trans-2, 5-dimethylpiperazine:

the reaction and the treatment were carried out in the same manner as in example 43-g) using tert-butyl (2S,5R) -4- {4- [2- (benzyloxy) -1,1,1,3,3, 3-hexafluoropropan-2-yl ] -2- (prop-1-en-1-yl) phenyl } -2, 5-dimethylpiperazine-1-carboxylate to obtain the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：0.96 (3H, d, J = 5.9 Hz), 1.45 (3H, d, J = 6.8 Hz), 1.69 (3H, d, J= 6.9 Hz), 3.03-2.82 (3H, m), 3.41-3.47 (2H, m), 3.58-3.69 (1H, m), 4.67 (2H, s),5.83 (1H, qd, J = 6.9, 11.4 Hz), 6.60 (1H, d, J = 11.4 Hz), 7.25 (1H, d, J = 9.1 Hz), 7.31-7.41 (5H, m), 7.49 (1H, dd, J = 2.2, 9.1 Hz), 7.59 (1H, d, J = 2.2 Hz)。

g) Production of 1- ((2S,5R) -4- (4- (2- (benzyloxy) -1,1,1,3,3, 3-hexafluoropropan-2-yl) -2- (prop-1-en-1-yl) phenyl) -2, 5-dimethylpiperazin-1-yl) -2-bromoethanone:

the reaction and the treatment were carried out in the same manner as in example 43-h) using (2S,5R) -1- {4- [2- (benzyloxy) -1,1,1,3,3, 3-hexafluoropropan-2-yl ] -2- (prop-1-en-1-yl) phenyl } -2, 5-dimethylpiperazine to give the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：0.99 (3H, d, J= 6.5 Hz), 1.50 (3H, d, J = 6.8 Hz), 1.75 (3H, dd, J = 1.9, 7.0 Hz), 2.74-2.81 (1H, m), 3.29-4.27 (6H, m), 4.68 (2H, s), 4.83-4.92 (1H, m),5.84 (1H, qd, J = 7.0, 11.3 Hz), 6.50 (1H, qd, J = 1.9, 11.3 Hz), 6.91 (1H, d, J = 8.6 Hz), 7.30-7.45 (6H, m), 7.51 (1H, s)。

h) (2R,5S, Z) -3- [2- (4- {4- [2- (benzyloxy) -1,1,1,3,3, 3-hexafluoropropan-2-yl)]-2- (prop-1-en-1-yl) phenyl } -2, 5-dimethylpiperazin-1-yl) -2-oxoethyl]-5- (2, 3-dihydrobenzo [ b ]][1,4]IIProduction of in-6-yl) -5-methylimidazolidine-2, 4-dione:

1- ((2S,5R) -4- {4- [2- (benzyloxy) -1,1,1,3,3, 3-hexafluoropropan-2-yl) is used]-2- (prop-1-en-1-yl) phenyl } -2, 5-dimethylpiperazin-1-yl) -2-bromoethanone and 5- (2, 3-dihydrobenzo [ b ]][1,4]IIEn-6-yl) -5-methylimidazolidine-2, 4-dione was reacted and treated in the same manner as in example 14-1 to give the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：0.88-1.00 (3H, m), 1.32-1.49 (3H, m), 1.74 (3H, d, J = 7.1 Hz), 1.87 (3H, s), 2.70-2.80 (1H, m), 3.29-3.82 (4H, m), 4.06-4.83 (6H, m), 4.65 (1H, d, J = 11.0 Hz), 4.69 (1H, d, J = 11.0 Hz), 4.82-4.90 (1H, m),5.83 (1H, qd, J= 7.1, 11.7 Hz), 6.49 (1H, d, J = 11.7 Hz), 6.86-6.89 (2H, m), 7.01-7.09 (2H, m), 7.33-7.44 (6H, m), 7.51 (1H, s)。

Example 64: (2S,5R) -5- (2, 3-dihydrobenzo [ b ]][1,4]IIProduction of in-6-yl) -3- (2- (-4- (4- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -2-propylphenyl) -2, 5-dimethylpiperazin-1-yl) -2-oxoethyl) -5-methylimidazolidine-2, 4-dione:

[ solution 71]

Using (2S,5R, Z) -3- [2- (4- {4- [2- (benzyloxy) -1,1,1,3,3, 3-hexafluoropropan-2-yl)]-2- (prop-1-en-1-yl) phenyl } -2, 5-dimethylpiperazin-1-yl) -2-oxoethyl]-5- (2, 3-dihydrobenzo [ b ]][1,4]IIEn-6-yl) -5-methylimidazolidine-2, 4-dione was reacted and treated in the same manner as in example 15-1 to give the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：0.90-1.10 (9H, m), 1.60-1.75 (2H, m), 1.88 (3H, s), 2.54-3.41 (7H, m), 4.04-4.25 (7H, m), 6.89-7.10 (4H, m), 7.47-7.53 (1H, m), 7.53 (1H, s)。

Example 65: production of (2S,5R, Z) -3- (2- (4- (4- (2- (benzyloxy) -1,1,1,3,3, 3-hexafluoropropan-2-yl) -2- (prop-1-en-1-yl) phenyl) -2, 5-dimethylpiperazin-1-yl) -2-oxoethyl) -5- (furo [2,3-c ] pyridin-5-yl) -5-methylimidazolidine-2, 4-dione:

[ chemical formula 72]

The reaction and treatment were carried out in the same manner as in example 14-1 using [ (2S,5R, Z) -1- (4- {4- [2- (benzyloxy) -1,1,1,3,3, 3-hexafluoropropan-2-yl ] -2- (prop-1-en-1-yl) phenyl } -2, 5-dimethylpiperazin-1-yl) ] -2-bromoethanone and 5- (furo [2,3-c ] pyridin-5-yl) -5-methylimidazolidine-2, 4-dione to give the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：0.90-1.02 (3H, m), 1.34-1.50 (3H, m), 1.74 (3H, d, J = 7.1 Hz), 1.92 (3H, s), 2.70-2.73 (1H, m), 3.33-3.85 (4H, m), 4.29-4.34 (2H, m), 4.66 (1H, d, J = 12.7 Hz), 4.69 (1H, d, J = 12.7 Hz), 4.85-4.91 (1H, m),5.84 (1H, qd, J= 2.1, 12.4 Hz), 6.49 (1H, s), 6.49 (1H, d, J = 12.4 Hz), 6.83 (1H, d, J= 2.2 Hz), 6.89 (1H, d, J = 8.5 Hz), 7.30-7.44 (6H, m), 7.51 (1H, s), 7.78 (1H, d, J = 2.2 Hz), 8.00 (1H, s), 8.81 (1H, s)。

Example 66: production of (2S,5R) -5- (2, 3-dihydrofuro [2,3-c ] pyridin-5-yl) -3- (2- (4- (4- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) -2-propylphenyl) -2, 5-dimethylpiperazin-1-yl) -2-oxoethyl) -5-methylimidazolidine-2, 4-dione:

[ solution 73]

The reaction and treatment were carried out in the same manner as in example 15-1 using (2S,5R, Z) -3- (2- (4- (2- (benzyloxy) -1,1,1,3,3, 3-hexafluoropropan-2-yl) -2- (prop-1-en-1-yl) phenyl) -2, 5-dimethylpiperazin-1-yl) -2-oxoethyl) -5- (furo [2,3-c ] pyridin-5-yl) -5-methylimidazolidine-2, 4-dione to give the title compound as a yellow oil.

¹H-NMR (CDCl₃) δ：0.88-0.99 (9H, m), 1.63-1.72 (2H, m), 1.92 (3H, s), 2.51-2.89 (3H, m), 3.20-3.89 (8H, m), 4.25-4.83 (3H, m), 6.91-6.95 (1H, m), 7.29-7.37 (2H, m), 7.72-7.76 (1H, m), 8.03-8.13 (1H, m).

Test example 1: transcription promotion assay

< construction of plasmid >

Expression constructs were prepared by inserting the Ligand Binding Domains (LBDs) of the human LXR α and LXR β cDNAs adjacently into the yeast GAL4 transcription factor DNA Binding Domain (DBD) of the mammalian expression vector pBIND (Promega), and pBIND-LXR α/GAL4 and pBIND-LXR β/GAL4 were prepared, respectively. The GAL 4-responsive reporter construct, pG5luc, is a well-known vector available from Promega, containing 5 copies of the GAL 4-responsive element and luciferase reporter gene located adjacent to the promoter.

< determination >

At 5% CO₂Will stably express LXR alpha/GAL 4 or LXR beta/GAL 4 heterozygote and GAL4 responsive reporter vector p at 37 ℃ in a humid atmosphereThe G5luc CHOK-1 cells were seeded at 20,000 cells/well in a 96-well plate to which HAM-F12 medium containing 10% inactivated fetal bovine serum, 100 units/ml penicillin G and 100. mu.g/ml streptomycin sulfate was added. After 24 hours, a medium prepared by dissolving the test compound in the test concentration range (0.01. mu.M, 0.1. mu.M, 1. mu.M, 10. mu.M) was added, and the cells were incubated for 24 hours. The effect of the test compound on the transcriptional activation of luciferase via LBD of LXR. alpha. or. beta. was determined by measuring the luminescence intensity with a luminometer LB960 (Berthold Technologies) using Bright-glo (Promega) as a substrate for luciferase assay. T0901317 (the compound of example 12 of the WO 2000/54759) was also evaluated as a comparative compound. The results of luciferase activity are shown in Table 1 as the emission intensity at 10. mu.M of T0901317 as 100, and the activity value (% eff) of the test compound at each concentration at that time. The activity data of the compound having a dimethylpiperazine structure was obtained using a mixture of the (2R,5S) form and the (2S,5R) form.

< results >

As shown in table 1, it was experimentally confirmed that the methanol compound of the present invention has LXR agonists with higher selectivity for LXR β than T0901317, which is a control drug.

[ Table 1]

[ Table 2]

Industrial applicability

The methanol compound represented by the general formula (I) of the present invention has an LXR β agonist action and is useful as an agent for arteriosclerosis such as atherosclerosis and arteriosclerosis caused by diabetes; dyslipidemia; hypercholesterolemia; blood lipid related diseases; inflammatory diseases caused by inflammatory cytokines such as rheumatoid arthritis, osteoarthritis, allergic diseases, asthma, sepsis, psoriasis, and osteoporosis; autoimmune diseases such as systemic lupus erythematosus, ulcerative colitis, Crohn's disease, etc.; cardiovascular diseases such as ischemic heart disease and myocardial failure; cerebrovascular diseases; renal disease; diabetes mellitus; diabetic complications such as retinopathy, nephropathy, neuropathy, and coronary artery disease; skin diseases such as allergic skin diseases; obesity; nephritis; hepatitis; cancer; or an agent for preventing and/or treating Alzheimer's disease, and is preferably used as an agent for preventing and/or treating atherosclerosis, arteriosclerosis caused by diabetes, or the like; dyslipidemia; hypercholesterolemia; blood lipid related diseases; diseases caused by inflammatory cytokines-inflammatory diseases; skin diseases such as allergic skin diseases; diabetes mellitus; or an agent for preventing and/or treating Alzheimer's disease.

Claims (7)

1. A methanol compound represented by the following general formula (I), a salt thereof or a solvate of either thereof,

[ solution 1]

Wherein V, W independently represent N or C-R⁷，

X, Y each independently represent CH₂、CH（C_1-8Alkyl group), C (C)_1-8Alkyl radical)₂C ═ O or SO₂，

Z represents a group of atoms selected from the group consisting of CH and N,

R¹、R²、R⁷each independently represents a hydrogen atom, a halogen atom, or C which may have a substituent_1-8Alkyl or C_2-8An alkenyl group, which is a radical of an alkenyl group,

R³is represented by C_1-8An alkyl group, a carboxyl group,

R⁴represents optionally substituted C_6-10An aryl group or a 5-to 11-membered heterocyclic group which may have a substituent,

R⁵represents a hydrogen atom or C_1-8An alkyl group, a carboxyl group,

R⁶represents a hydrogen atom, C_1-8Alkoxy radical C_1-8Alkyl or C which may have a substituent_6-10Aryl radical C_1-8An alkyl group, a carboxyl group,

l represents C which may be substituted by oxo or sulfonyl_1-8An alkyl chain is arranged on the base,

n represents an arbitrary integer of 0 to 2 ].

2. A pharmaceutical agent comprising the methanol compound according to claim 1, or a salt or solvate thereof as an active ingredient.

3. The pharmaceutical agent according to claim 2, which is a prophylactic and/or therapeutic agent for atherosclerosis, arteriosclerosis due to diabetes, dyslipidemia, hypercholesterolemia, a blood lipid-related disease, an inflammatory disease which is a disease caused by an inflammatory cytokine, a skin disease, diabetes, or alzheimer's disease.

A LXR modulator comprising the methanol compound according to claim 1, or a salt or solvate thereof as an active ingredient.

5. A pharmaceutical composition comprising the methanol compound according to claim 1, or a salt thereof or a solvate of either thereof, and a pharmaceutically acceptable carrier.

6. A method for preventing and/or treating atherosclerosis, arteriosclerosis due to diabetes, dyslipidemia, hypercholesterolemia, a blood-lipid related disease, an inflammatory disease which is a disease caused by an inflammatory cytokine, a skin disease, diabetes or Alzheimer's disease, characterized by comprising: administering an effective amount of the methanol compound or a salt thereof or a solvate thereof according to claim 1 to a patient in need of treatment.

7. Use of the methanol compound or a salt thereof or a solvate of either thereof according to claim 1 for the manufacture of a preparation for the prevention and/or treatment of atherosclerosis, arteriosclerosis due to diabetes, dyslipidemia, hypercholesterolemia, a blood lipid-related disease, an inflammatory disease which is a disease induced by an inflammatory cytokine, a skin disease, diabetes or alzheimer's disease.