JP2008515827A - Novel oxadiazinone derivatives and their use - Google Patents

Abstract

The present invention relates to novel 1,3,4-oxadiazin-5-one derivatives of general formula (I), processes for their preparation, their use for the treatment and / or prevention of diseases, and the treatment and / or treatment of diseases. It relates to their use for producing medicaments for use in prophylaxis, preferably for cardiovascular disorders, in particular for dyslipidemia and arteriosclerosis.
[Chemical 1]

Description

  The present invention provides novel 1,3,4-oxadiazin-5-one derivatives, methods for their production, their use for the treatment and / or prevention of diseases, and medicaments for the treatment and / or prevention of diseases. For their use, preferably for the treatment and / or prevention of cardiovascular disorders, in particular dyslipidemia and arteriosclerosis.

  Despite the numerous successful treatments, cardiovascular disorders remain a serious public health problem. Treatment with statins that inhibit HMG-CoA reductase has been very successful in reducing LDL cholesterol (LDL-C) plasma concentrations and mortality in patients at risk; however, the unfavorable HDL-C / Certain treatment strategies for the treatment of patients with LDL-C ratio and / or hypertriglyceridemia are still not available to date.

  Currently, in addition to niacin, fibrates are the only treatment option for patients in these risk groups. They reduce high triglyceride levels by 20-50%, reduce LDL-C by 10-15%, and change the LDL particle size of low density atherogenic LDL to normal density, low atherogenic LDL. And increase the HDL concentration by 10-15%.

Fibrates act as weak agonists of peroxisome proliferator activated receptor (PPAR) -alpha (Nature 1990, 347 , 645-50). PPAR-alpha is a nuclear receptor that regulates the expression of target genes by binding to DNA sequences [also called PPAR response elements (PPRE)] in the promoter region of these genes. PPRE has been identified in a number of genes encoding proteins that regulate lipid metabolism. PPAR-alpha is highly expressed in the liver and its activation leads, inter alia, to decreased VLDL production / secretion and decreased apolipoprotein CIII (ApoCIII) synthesis. In contrast, the synthesis of apolipoprotein A1 (ApoA1) is increased.

A drawback of the fibrates that have been recognized so far is that they only have weak interactions with the receptors (EC _{50 in the} μM range), which is due to the relatively small pharmacological effects described above. is there.

  The object of the present invention was to provide novel compounds suitable for use as PPAR-alpha modulators, in particular for the treatment and / or prevention of cardiovascular disorders.

  PPAR-alpha agonists having a 1,2,4-triazol-3-one partial structure are described in WO 02/38553. 1,3,4-oxadiazol-2-one derivatives as PPAR-alpha agonists are disclosed in WO 03/043997.

［式中、
ＹおよびＺは、相互に独立して、ＯまたはＳを表し、
ｍは、０、１または２の数を表し、
ｎは、１または２の数を表し、
Ｒ^１は、（Ｃ_６−Ｃ_１０）アリールまたは５員ないし１０員のヘテロアリールを表し、それらの各々は、ハロゲン、ニトロ、シアノ、（Ｃ_１−Ｃ_６）−アルキル（これは、ヒドロキシルにより置換されていてもよい）、（Ｃ_３−Ｃ_８）−シクロアルキル、フェニル、ヒドロキシル、（Ｃ_１−Ｃ_６）−アルコキシ、トリフルオロメチル、トリフルオロメトキシ、アミノ、モノ−およびジ−（Ｃ_１−Ｃ_６）−アルキルアミノ、Ｒ^８−Ｃ（Ｏ）−ＮＨ−、Ｒ^９−Ｃ（Ｏ）−、Ｒ^１０Ｒ^１１Ｎ−Ｃ（Ｏ）−ＮＨ−およびＲ^１２Ｒ^１３Ｎ−Ｃ（Ｏ）−からなる群から選択される４個までの同一かまたは異なる置換基により置換されていてもよく
｛式中、Ｒ^８は、水素、（Ｃ_１−Ｃ_６）−アルキル、（Ｃ_３−Ｃ_８）−シクロアルキル、フェニルまたは（Ｃ_１−Ｃ_６）−アルコキシを表し、
Ｒ^９は、水素、（Ｃ_１−Ｃ_６）−アルキル、（Ｃ_３−Ｃ_８）−シクロアルキル、フェニル、ヒドロキシルまたは（Ｃ_１−Ｃ_６）−アルコキシを表し、そして、
Ｒ^１０、Ｒ^１１、Ｒ^１２およびＲ^１３は、同一かまたは異なり、相互に独立して、水素、（Ｃ_１−Ｃ_６）−アルキル、（Ｃ_３−Ｃ_８）−シクロアルキルまたはフェニルを表す｝、
Ｒ^２は、水素、（Ｃ_６−Ｃ_１０）−アリール、（Ｃ_１−Ｃ_６）−アルキル、（Ｃ_２−Ｃ_６）−アルケニルまたは（Ｃ_２−Ｃ_６）−アルキニルを表し、ここで、アルキル、アルケニルおよびアルキニルは、トリフルオロメチル、（Ｃ_１−Ｃ_６）−アルコキシ、トリフルオロメトキシ、フッ素、シアノ、（Ｃ_６−Ｃ_１０）−アリールまたは５員または６員のヘテロアリールにより各々置換されていてもよく、ここで、言及される全てのアリールおよびヘテロアリール基は、各々、ハロゲン、ニトロ、シアノ、（Ｃ_１−Ｃ_６）−アルキル、ヒドロキシル、（Ｃ_１−Ｃ_６）−アルコキシ、トリフルオロメチルおよびトリフルオロメトキシからなる群から選択される３個までの同一かまたは異なる置換基により置換されていてもよく、
Ｒ^３およびＲ^４は、同一かまたは異なり、相互に独立して、水素、（Ｃ_１−Ｃ_６）−アルキル、（Ｃ_２−Ｃ_６）−アルケニル、（Ｃ_１−Ｃ_６）−アルコキシ、トリフルオロメチル、トリフルオロメトキシまたはハロゲンを表し、
Ｒ^５およびＲ^６は、同一かまたは異なり、相互に独立して、水素、（Ｃ_１−Ｃ_６）−アルキル、（Ｃ_１−Ｃ_６）−アルコキシまたはフェノキシを表すか、または、それらが結合している炭素原子と一体となって（Ｃ_３−Ｃ_８）−シクロアルキル環を形成しており、そして、
Ｒ^７は、式−ＮＨＲ^１４または−ＯＲ^１５の基を表す
｛式中、Ｒ^１４は、水素、（Ｃ_１−Ｃ_６）−アルキルまたは（Ｃ_１−Ｃ_６）−アルキルスルホニルを表し、そして、
Ｒ^１５は、水素を表すか、または対応するカルボン酸に変換され得る加水分解可能な基を表す｝］
の化合物、およびそれらの塩、溶媒和物および塩の溶媒和物を提供する。 The present invention relates to general formula (I)

[Where:
Y and Z independently of one another represent O or S;
m represents the number 0, 1 or 2;
n represents a number of 1 or 2,
R ¹ represents (C ₆ -C ₁₀ ) aryl or 5- to 10-membered heteroaryl, each of which is halogen, nitro, cyano, (C ₁ -C ₆ ) -alkyl (which depends on hydroxyl may be _{substituted), (C 3 -C 8)} - cycloalkyl, phenyl, _{hydroxyl, (C} 1 -C ₆₎ - alkoxy, trifluoromethyl, trifluoromethoxy, amino, mono- - and di - (C ₁ -C ₆₎ - ^{alkylamino, R 8 -C (O) -NH-} , R 9 -C (O) -, R 10 R 11 N-C (O) -NH- , and ^R 12 ^R 13 N-C Optionally substituted by up to 4 identical or different substituents selected from the group consisting of (O)-{wherein R ⁸ is hydrogen, (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₈₎ - cycloalkyl Alkyl, phenyl or _(C 1 -C ₆₎ - alkoxy,
R ⁹ represents hydrogen, (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₈ ) -cycloalkyl, phenyl, hydroxyl or (C ₁ -C ₆ ) -alkoxy, and
R ¹⁰ , R ¹¹ , R ¹² and R ¹³ are the same or different and independently of one another represent hydrogen, (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₈ ) -cycloalkyl or phenyl. },
R ² represents hydrogen, (C ₆ -C ₁₀ ) -aryl, (C ₁ -C ₆ ) -alkyl, (C ₂ -C ₆ ) -alkenyl or (C ₂ -C ₆ ) -alkynyl, wherein , Alkyl, alkenyl and alkynyl are each represented by trifluoromethyl, (C ₁ -C ₆ ) -alkoxy, trifluoromethoxy, fluorine, cyano, (C ₆ -C ₁₀ ) -aryl or 5- or 6-membered heteroaryl. may be substituted, where all aryl and heteroaryl groups referred are each halogen, nitro, _{cyano, (C} 1 -C ₆₎ - alkyl, _hydroxyl, (C 1 _-C 6) - Substituted with up to three identical or different substituents selected from the group consisting of alkoxy, trifluoromethyl and trifluoromethoxy Ku,
R ³ and R ⁴ are the same or different and independently of each other hydrogen, (C ₁ -C ₆ ) -alkyl, (C ₂ -C ₆ ) -alkenyl, (C ₁ -C ₆ ) -alkoxy, Represents trifluoromethyl, trifluoromethoxy or halogen;
R ⁵ and R ⁶ are the same or different and independently of each other represent hydrogen, (C ₁ -C ₆ ) -alkyl, (C ₁ -C ₆ ) -alkoxy or phenoxy, or they are bonded together with the carbon atoms you are (C 3 _-C 8) _- forms a cycloalkyl ring, and,
R ⁷ represents a group of formula —NHR ¹⁴ or —OR ¹⁵ wherein R ¹⁴ represents hydrogen, (C ₁ -C ₆ ) -alkyl or (C ₁ -C ₆ ) -alkylsulfonyl, and ,
R ¹⁵ represents hydrogen or represents a hydrolyzable group that can be converted to the corresponding carboxylic acid}]
And salts, solvates and solvates of the salts thereof.

In the context of the present invention, in the definition of R ¹⁵ , a hydrolyzable group designates a group in which, in the body, the —C (O) OR ¹⁵ group is converted into the corresponding carboxylic acid (R ¹⁵ = hydrogen). For example and preferably, such groups are in each case halogen, hydroxyl, amino, (C ₁ -C ₆ ) -alkoxy, carboxyl, (C ₁ -C ₆ ) -alkoxycarbonyl, (C ₁ -C ₆ ) -alkoxycarbonylamino and (C ₁ -C ₆ ) -benzyl, which may be mono- or polysubstituted by the same or different substituents from the group consisting of (C ₁ -C ₆ ) -alkanoyloxy, Alkyl or (C ₃ -C ₈ ) -cycloalkyl, especially halogen, hydroxyl, amino, (C ₁ -C ₄ ) -alkoxy, carboxyl, (C ₁ -C ₄ ) -alkoxycarbonyl, (C _1- C ₄₎ - alkoxycarbonylamino and _(C 1 -C ₄₎ - identical or different from the group consisting of alkanoyloxy (C ₁ -C ₄ ) -alkyl which may be mono- or poly-substituted by the above substituents.

  The compounds according to the invention are those of the formula (I) and their salts, solvents, provided that the compounds contained in the formula (I) mentioned below are not yet salts, solvates and solvates of salts. Solvates and solvates of salts, compounds included in formula (I) of the formulas mentioned below and their salts, solvates and solvates of salts, and the formulas mentioned below as examples ( The compounds included in I) and their salts, solvates and solvates of the salts.

Depending on their structure, the compounds according to the invention can exist in stereoisomeric forms (enantiomers, diastereomers). The present invention therefore includes the enantiomers or diastereomers and their respective mixtures. From a mixture of such enantiomers and / or diastereomers, it is possible to isolate stereoisomerically homogeneous constituents in a known manner.
If the compounds according to the invention can exist in tautomeric forms, the present invention includes all tautomeric forms.

In the context of the present invention, preferred salts are physiologically acceptable salts of the compounds according to the invention. The invention also includes salts that are not themselves suitable for pharmaceutical applications, but can be used, for example, for the isolation or purification of the compounds according to the invention.

  Physiologically acceptable salts of the compounds according to the invention include acid addition salts of inorganic acids, carboxylic acids and sulfonic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, Examples include toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid, and benzoic acid salts.

  Physiologically acceptable salts of the compounds according to the invention include the salts of conventional bases, such as, and preferably, alkali metal salts (for example sodium and potassium salts), alkaline earth metal salts (for example calcium and magnesium salts). Salt) as well as ammonia or organic amines having 1 to 16 carbon atoms (for example and preferably ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol). , Procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine).

In the context of the present invention, solvates are in the form of compounds according to the invention which form a complex by coordination with solvent molecules in the solid or liquid state. Hydrates are a special form of solvates whose coordination is with water. In the context of the present invention, the preferred solvate is a hydrate.

  The present invention further includes prodrugs of the compounds according to the invention. The term “prodrug” may itself be biologically active or inactive, but does not react with the compounds according to the invention (for example metabolically) during the time they remain in the body. Or compounds that are converted hydrolytically).

In the context of the present invention, unless otherwise indicated, the substituents have the following meanings:
In the context of the present invention, (C ₁ -C ₆ ) -alkyl and (C ₁ -C ₄ ) -alkyl are straight-chain or branched alkyl having 1 to 6 and 1 to 4 carbon atoms, respectively. Represents a radical. Preference is given to a straight-chain or branched alkyl radical having 1 to 4 carbon atoms. The following radicals may be mentioned by way of example and preferred: methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, 1-ethylpropyl, n-pentyl. And n-hexyl.

In the context of the present invention, (C ₂ -C ₆ ) -alkenyl and (C ₂ -C ₄ ) -alkenyl are straight-chain or branched alkenyl having 2 to 6 and 2 to 4 carbon atoms respectively. Represents a radical. Preference is given to a straight-chain or branched alkenyl radical having 2 to 4 carbon atoms. The following radicals may be mentioned by way of example and as preferred: vinyl, allyl, isopropenyl, n-but-2-en-1-yl and -2-methyl-2-propen-1-yl.

In the context of the present invention, (C ₂ -C ₆ ) -alkynyl and (C ₂ -C ₄ ) -alkynyl are straight-chain or branched alkynyl having 2 to 6 and 2 to 4 carbon atoms, respectively. Represents a radical. Preference is given to a straight-chain or branched alkynyl radical having 2 to 4 carbon atoms. The following radicals may be mentioned by way of example and preferred: ethynyl, n-prop-2-yn-1-yl, n-but-2-yn-1-yl and n-but-3-in- 1-yl.

In the context of the present invention, (C ₃ -C ₈ ) -cycloalkyl and (C ₃ -C ₆ ) -cycloalkyl are monocyclic cycloalkyls having 3 to 8 and 3 to 6 carbon atoms, respectively. To express. Preference is given to cycloalkyl radicals having 3 to 6 carbon atoms. The following radicals may be mentioned by way of example and preferred: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

In the context of the present invention, (C ₆ -C ₁₀ ) -aryl represents an aromatic radical, preferably having 6 to 10 carbon atoms. Preferred aryl radicals are phenyl and naphthyl.

In the context of the present invention, (C ₁ -C ₆ ) -alkoxy and (C ₁ -C ₄ ) -alkoxy are straight-chain or branched alkoxy having 1 to 6 and 1 to 4 carbon atoms, respectively. Represents a radical. Preference is given to a straight-chain or branched alkoxy radical having 1 to 4 carbon atoms. The following radicals may be mentioned by way of example and preferably: methoxy, ethoxy, n-propoxy, isopropoxy and tert-butoxy.

In the context of the present invention, (C ₁ -C ₆ ) -alkoxycarbonyl and (C ₁ -C ₄ ) -alkoxycarbonyl have 1 to 6 and 1 to 4 carbon atoms, respectively, via the carbonyl group Represents a linear or branched alkoxy radical bonded together. Preference is given to a straight-chain or branched alkoxycarbonyl radical having 1 to 4 carbon atoms in the alkoxy group. The following radicals may be mentioned by way of example and preferably: methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and tert-butoxycarbonyl.

In the context of the present invention, (C ₁ -C ₆ ) -alkylsulfonyl represents a straight-chain or branched alkylsulfonyl radical having 1 to 6 carbon atoms. Preference is given to a straight-chain or branched alkylsulfonyl radical having 1 to 4 carbon atoms. The following radicals may be mentioned by way of example and preferred: methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl and tert-butylsulfonyl.

In the context of the present invention, mono- (C ₁ -C ₆ ) -alkylamino and mono- (C ₁ -C ₄ ) -alkylamino are straight-chains having 1 to 6 and 1 to 4 carbon atoms, respectively. Or represents an amino group having a branched alkyl substituent. Preference is given to a straight-chain or branched monoalkylamino radical having 1 to 4 carbon atoms. The following radicals may be mentioned by way of example and as preferred: methylamino, ethylamino, n-propylamino, isopropylamino and tert-butylamino.

In the context of the present invention, di- (C ₁ -C ₆ ) -alkylamino and di- (C ₁ -C ₄ ) -alkylamino are two identical or different, 1 to 6 and 1 to 4 respectively. Represents an amino group having a linear or branched alkyl substituent having 1 carbon atom. Preference is given to a straight-chain or branched dialkylamino radical having 1 to 4 carbon atoms. The following radicals may be mentioned by way of example and preferred: N, N-dimethylamino, N, N-diethylamino, N-ethyl-N-methylamino, N-methyl-Nn-propylamino, N -Isopropyl-Nn-propylamino, N-tert-butyl-N-methylamino, N-ethyl-Nn-pentylamino and Nn-hexyl-N-methylamino.

In the context of the present invention, (C ₁ -C ₆ ) -alkoxycarbonylamino and (C ₁ -C ₄ ) -alkoxycarbonylamino have 1 to 6 and 1 to 4 carbon atoms, respectively, in the alkoxy radical. And an amino group having a linear or branched alkoxycarbonyl substituent bonded to the nitrogen atom via a carbonyl group. Preference is given to alkoxycarbonylamino radicals having 1 to 4 carbon atoms. The following radicals may be mentioned by way of example and preferably: methoxycarbonylamino, ethoxycarbonylamino, n-propoxycarbonylamino, isopropoxycarbonylamino and tert-butoxycarbonylamino.

In the context of the present invention, (C ₁ -C ₆ ) -alkanoyloxy and (C ₁ -C ₄ ) -alkanoyloxy have 1 to 6 and 1 to 4 carbon atoms, respectively, and Represents a linear or branched alkyl radical carrying a heavily bonded oxygen atom and bonded via an additional oxygen atom at the 1-position. Preference is given to alkanoyloxy radicals having 1 to 4 carbon atoms. The following radicals may be mentioned by way of example and preferably: acetoxy, propionoxy, n-butyloxy, isobutyloxy, pivaloyloxy and n-hexanoyloxy.

In the context of the present invention, a 5- to 10-membered heteroaryl is a monocyclic or, if appropriate, bicyclic aromatic having up to 4 identical or different heteroatoms from the group consisting of N, O and S A heterocycle (heteroaromatic), the radical of which is attached via a carbon atom of the heteroaromatic ring or, if appropriate, via a ring nitrogen atom. The following radicals may be mentioned by way of example: furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, benzofuranyl, benzofuranyl Thienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, indolyl, indazolyl, quinolinyl, isoquinolinyl, naphthyridinyl, quinazolinyl, quinoxalinyl. Preference is given to monocyclic 5- or 6-membered heteroaryl radicals having up to 3 heteroatoms from the group consisting of N, O and S, such as furyl, thienyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, Pyrazolyl, imidazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl.

In the context of the present invention, halogen includes fluorine, chlorine, bromine and iodine. Preference is given to chlorine or fluorine.

  If a radical in a compound according to the invention is substituted, the radical may be mono- or polysubstituted unless indicated otherwise. In the context of the present invention, the meanings of all radicals appearing more than once are independent of one another. Substitution with 1, 2 or 3 identical or different substituents is preferred. Very particular preference is given to substitution with one substituent.

For the present invention, preference is given to:
Y represents O,
Z represents S,
m represents the number 0, 1 or 2;
n represents the number 1 or 2,
R ¹ represents phenyl or 5- or 6-membered heteroaryl, each of which is halogen, nitro, cyano, (C ₁ -C ₄ ) -alkyl, which may be substituted by hydroxyl , _(C 3 -C ₆₎ - cycloalkyl, phenyl, _{hydroxy, (C} 1 -C ₄₎ - alkoxy, trifluoromethyl, trifluoromethoxy, amino, mono- - and di - _(C 1 -C ₄₎ - alkyl The group consisting of amino, R ⁸ —C (O) —NH—, R ⁹ —C (O) —, R ¹⁰ R ¹¹ N—C (O) —NH—, and R ¹² R ¹³ N—C (O) — And may be substituted with up to 4 identical or different substituents selected from: {wherein R ⁸ is hydrogen, (C ₁ -C ₄ ) -alkyl, (C ₃ -C ₆ )- Cycloalkyl, phenyl Other _(C 1 -C ₄₎ - alkoxy,
R ⁹ represents hydrogen, (C ₁ -C ₄ ) -alkyl, (C ₃ -C ₆ ) -cycloalkyl, phenyl, hydroxy or (C ₁ -C ₄ ) -alkoxy, and
R ¹⁰ , R ¹¹ , R ¹² and R ¹³ are the same or different and independently of one another represent hydrogen, (C ₁ -C ₄ ) -alkyl, (C ₃ -C ₆ ) -cycloalkyl or phenyl. },
R ² represents hydrogen, phenyl, (C ₁ -C ₄ ) -alkyl, (C ₂ -C ₄ ) -alkenyl or (C ₂ -C ₄ ) -alkynyl, wherein these alkyl, alkenyl and alkynyl are tri Each may be substituted by fluoromethyl, fluorine, cyano, (C ₁ -C ₄ ) -alkoxy, phenyl or 5- or 6-membered heteroaryl, where all phenyl and heteroaryl groups referred to are Up to 3 identical or selected from the group consisting of: halogen, nitro, cyano, (C ₁ -C ₄ ) -alkyl, hydroxyl, (C ₁ -C ₄ ) -alkoxy, trifluoromethyl and trifluoromethoxy May be substituted by different substituents,
R ³ and R ⁴ are the same or different and independently of each other represent hydrogen, (C ₁ -C ₄ ) -alkyl, (C ₁ -C ₄ ) -alkoxy, trifluoromethyl, trifluoromethoxy or halogen. Represent,
R ⁵ and R ⁶ are the same or different and independently of one another represent hydrogen, methyl, ethyl, methoxy, ethoxy or phenoxy, or together with the carbon atom to which they are attached (C ₃ -C ₆₎ - forms a cycloalkyl ring, and,
R ⁷ represents a group of formula —NHR ¹⁴ or —OR ¹⁵ wherein R ¹⁴ represents hydrogen or (C ₁ -C ₄ ) -alkyl, and
R ¹⁵ represents hydrogen or represents a hydrolyzable group that can be converted to the corresponding carboxylic acid},
Compounds of formula (I) and their salts, solvates and solvates of salts.

Particularly preferred in connection with the present invention is
Y represents O,
Z represents S,
m represents the number 0 or 1;
n represents the number 1 or 2,
R ¹ represents phenyl or pyridyl, each of which is mono- or di-substituted by the same or different substituents selected from the group consisting of fluorine, chlorine, nitro, methyl, methoxy, trifluoromethyl and trifluoromethoxy. May be replaced,
R ² represents hydrogen, propargyl or may be substituted by fluorine, cyano, (C ₁ -C ₄ ) -alkoxy, phenyl, furyl, thienyl, oxazolyl, thiazolyl, oxadiazolyl or thiadiazolyl (C _1- C ₄ ) -alkyl, where phenyl and all heteroaromatic rings referred to consist of fluorine, chlorine, methyl, ethyl, isopropyl, tert-butyl, methoxy, ethoxy, trifluoromethyl and trifluoromethoxy May be mono- or disubstituted by the same or different substituents selected from the group;
R ³ and R ⁴ are the same or different and independently of one another represent hydrogen, methyl, methoxy, fluorine or chlorine;
R ⁵ and R ⁶ are the same or different and represent hydrogen or methyl, and
R ⁷ represents —OH, —NH ₂ or —NHCH ₃ ,
Compounds of formula (I) and their salts, solvates and solvates of salts.

（式中、Ｒ^１、Ｒ^２、ｍおよびｎは、各々上記定義の通りである）
の化合物である。 Of particular importance is the formula (IA)

(Wherein R ¹ , R ² , m and n are each as defined above)
It is a compound of this.

Individual radical definitions given in each radical combination or preferred combination may be replaced by radical definitions in other combinations independent of the particular given radical combination.
Very particular preference is given to combinations of two or more of the above preferred ranges.

（式中、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６およびＺは、各々上記定義の通りであり、そして、
Ｔ^１は、（Ｃ_１−Ｃ_４）−アルキル、好ましくはｔｅｒｔ−ブチルを表すか、または、ベンジルを表す）
の化合物を、 The present invention further provides a process for the preparation of a compound of formula (I) or (IA) according to the present invention. It has the formula (II)

Wherein R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and Z are each as defined above, and
T ¹ represents (C ₁ -C ₄ ) -alkyl, preferably tert-butyl or benzyl)
A compound of

（式中、ｎは上記定義の通りであり、
Ｔ^２は、（Ｃ_１−Ｃ_４）−アルキル、好ましくはメチルまたはエチルを表し、そして、
Ｑ^１は、適する脱離基、例えば、ハロゲン、メシレート、トシレートまたはトリフレートを表す）
の化合物を用いて、 First, in the presence of a base in an inert solvent, the formula (III)

(Where n is as defined above,
T ² represents (C ₁ -C ₄ ) -alkyl, preferably methyl or ethyl, and
Q ¹ represents a suitable leaving group such as halogen, mesylate, tosylate or triflate)
Using the compound of

（式中、ｎ、Ｔ^１、Ｔ^２、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６およびＺは、各々上記定義の通りである）
の化合物に変換し、 Formula (IV)

(Wherein n, T ¹ , T ² , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and Z are as defined above)
Into the compound of

（式中、ｎ、Ｔ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６およびＺは、各々上記定義の通りである）
のカルボン酸に選択的に加水分解し、 Then, under suitable reaction conditions, the formula (V)

Wherein n, T ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and Z are as defined above.
Selectively hydrolyzed to the carboxylic acid of

（式中、Ｒ^１およびｍは、各々上記定義の通りである）
の化合物を用いて、式（ＶＩＩ）

（式中、ｍ、ｎ、Ｔ^１、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６およびＺは、各々上記定義の通りである）
の化合物に変換し、 Then, in the presence of a condensing agent and a base in an inert solvent, the formula (VI)

(Wherein R ¹ and m are each as defined above)
Using a compound of formula (VII)

(Wherein m, n, T ¹ , R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and Z are each as defined above)
Into the compound of

（式中、ｍ、ｎ、Ｔ^１、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６およびＺは、各々上記定義の通りである）
の化合物に環化して反応させ、 It is then converted to the formula (IB) in the presence of chloroacetyl chloride and a base.

(Wherein m, n, T ¹ , R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and Z are each as defined above)
Cyclize to react with

（式中、ｍ、ｎ、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６およびＺは、各々上記定義の通りである）
のカルボン酸に変換し、必要に応じて、続いて、文献から知られるエステル化またはアミド化の方法により、式（Ｉ）の化合物に変換し、
式（Ｉ）の化合物を、必要に応じて、適当な（ｉ）溶媒および／または（ｉｉ）塩基もしくは酸により、それらの溶媒和物、塩および／または塩の溶媒和物に変換する。 Subsequently, by basic or acidic hydrolysis, or when T ¹ is benzyl, and also hydrogenolytically, the compound of formula (IC)

(Wherein m, n, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and Z are as defined above)
To the carboxylic acid of the formula (I), optionally followed by the esterification or amidation method known from the literature,
Compounds of formula (I) are optionally converted to their solvates, salts and / or salt solvates with a suitable (i) solvent and / or (ii) a base or acid.

（式中、ｍ、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６、Ｒ^７およびＺは、各々上記定義の通りである）
の化合物は、式（ＩＩ）の化合物を、不活性溶媒中、塩基の存在下、式（ＶＩＩＩ）

（式中、ｍおよびＲ^１は、各々上記定義の通りであり、そして、
Ｑ^２は、適する脱離基、例えばハロゲンを表す）
の化合物を用いて変換し、 Formula (ID)

(Wherein m, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and Z are as defined above)
The compound of formula (II) is a compound of formula (VIII) in the presence of a base in an inert solvent.

Wherein m and R ¹ are each as defined above, and
Q ² represents a suitable leaving group, eg halogen)
Using the compound of

（式中、ｍ、Ｔ^１、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６およびＺは、各々上記定義の通りである）
の化合物を、続いて塩基性または酸性加水分解により、または、Ｔ^１がベンジルを表すならば、また水素化分解的に、式（Ｉ−Ｆ）

（式中、ｍ、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６およびＺは、各々上記定義の通りである）
のカルボン酸に変換し、次いで、必要に応じて、文献から知られるエステル化またはアミド化の方法により、式（Ｉ−Ｄ）の化合物に変換することにより製造できる。 And the formula (IE)

(Wherein m, T ¹ , R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and Z are as defined above)
Of the compound of formula (IF) by subsequent basic or acidic hydrolysis or, if T ¹ represents benzyl, also hydrolytically

(Wherein m, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and Z are as defined above)
And then optionally converted to a compound of formula (ID) by esterification or amidation methods known from the literature.

（式中、Ｒ^３およびＲ^４は、各々上記定義の通りである）
の化合物を、最初に、不活性溶媒中、硫化ナトリウムを用いて、式（Ｘ）

（式中、Ｒ^３およびＲ^４は、各々上記定義の通りである）
の化合物に変換し、 Compounds of formula (II) and their preparation are described in WO 02/28821 or they can be prepared analogously to the methods described therein. Compounds of formula (II) in which Z represents S are also represented by formula (IX)

(Wherein R ³ and R ⁴ are each as defined above)
The compound of formula (X) is first prepared using sodium sulfide in an inert solvent.

(Wherein R ³ and R ⁴ are each as defined above)
Into the compound of

（式中、Ｔ^１、Ｒ^５およびＲ^６は、各々上記定義の通りであり、そして、
Ｑ^３は、適する脱離基、例えば、ハロゲン、メシレート、トシレートまたはトリフレートを表す）
の化合物を用いて、式（ＸＩＩ）

（式中、Ｔ^１、Ｒ^３、Ｒ^４、Ｒ^５およびＲ^６は、各々上記定義の通りである）
の化合物に変換し、 These are then converted to formula (XI) with or without isolation of intermediates.

Wherein T ¹ , R ⁵ and R ⁶ are each as defined above, and
Q ³ represents a suitable leaving group such as halogen, mesylate, tosylate or triflate)
Using a compound of formula (XII)

(Wherein T ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ are each as defined above)
Into the compound of

（式中、Ｔ^１、Ｒ^３、Ｒ^４、Ｒ^５およびＲ^６は、各々上記定義の通りである）
の化合物に還元し、最後に、必要に応じて、これらを、塩基の存在下、式（ＸＩＩＩ）
Ｒ^２＊−Ｑ^４ （ＸＩＩＩ）
（式中、Ｒ^２＊は、上記Ｒ^２の意味を有するが、水素を表さず、そして、
Ｑ^４は、適する脱離基、例えば、ハロゲン、メシレート、トシレートまたはトリフレートを表す）
の化合物と反応させることによっても製造できる。 A suitable reducing agent such as, preferably, borane or a borane complex (eg diethylaniline, dimethyl sulfide or tetrahydrofuran complex) or sodium borohydride in combination with aluminum chloride is then used to formula (II-A)

(Wherein T ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ are each as defined above)
And, finally, if necessary, in the presence of a base, the compounds of formula (XIII)
R ^{2 *} -Q ⁴ (XIII)
(Wherein R ^{2 *} has the meaning of R ² above, but does not represent hydrogen, and
Q ⁴ represents a suitable leaving group such as halogen, mesylate, tosylate or triflate)
It can manufacture also by making it react with the compound of.

（式中、Ｑ^２は上記定義の通りである）
の化合物と反応させることにより製造できる。 The compound of formula (VIII) is obtained by converting the compound of formula (VI) into 2 equivalents of formula (XIV) in the presence of a base in an inert solvent.

(Wherein Q ² is as defined above)
It can manufacture by making it react with the compound of.

  Inert solvents for steps (II) + (III) → (IV), (II) + (VIII) → (IE) and (II-A) + (XIII) → (II) are, for example, dichloromethane , Halogenated hydrocarbons such as trichloromethane, carbon tetrachloride, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichloroethylene, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, benzene, xylene, toluene , Hydrocarbons such as hexane, cyclohexane or mineral oil fraction, or ethyl acetate, acetone, dimethylformamide, dimethyl sulfoxide, N, N′-dimethylpropyleneurea (DMPU), N-methylpyrrolidone (NMP), Other solvents such as lysine or acetonitrile. It is also possible to use mixtures of the solvents mentioned above. Preference is given to tetrahydrofuran and dimethylformamide.

Suitable bases for steps (II) + (III) → (IV), (II) + (VIII) → (IE) and (II-A) + (XIII) → (II) are conventional inorganic or organic It is a base. These preferably include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide or potassium hydroxide, alkali metal or alkaline earth metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate or Cesium carbonate, alkali metal alkoxides such as sodium methoxide or potassium methoxide, sodium ethoxide or potassium ethoxide or potassium tert-butoxide, alkali metal hydrides such as sodium hydride, amides such as sodium amide, lithium bis (trimethylsilyl) ) Amides or potassium bis (trimethylsilyl) amide or lithium diisopropylamide, or organic amines such as triethylamine, N-methylmorpholine, N-methyl Perijin, N, N- diisopropylethylamine, pyridine, 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), 1,4-diazabicyclo [2.2.2] octane (DABCO ^{(R )} ) Or 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU). Preference is given to N, N-diisopropylethylamine, triethylamine, sodium carbonate or cesium carbonate.

  In these steps, the base is used in each case in an amount of 1 to 5 mol, preferably 1 to 2.5 mol, based on 1 mol of the compound of formula (II) / (II-A) or its hydrochloride. In some cases, it has been found advantageous to carry out this reaction in the presence of an alkylation catalyst such as tetra-N-butylammonium bromide or iodide.

  This reaction is generally carried out in the temperature range of 0 ° C. to + 150 ° C., preferably + 20 ° C. to + 100 ° C. This reaction can be carried out at atmospheric pressure, elevated pressure or reduced pressure (eg 0.5 to 5 bar). In general, this reaction is carried out at atmospheric pressure.

  Hydrolysis of the carboxylic esters in steps (IV) → (V), (IB) → (IC) and (IE) → (IF) In a conventional manner by treatment with a base. Here, the initially formed salt is converted to the free carboxylic acid by acid treatment. In the case of tert-butyl esters, the ester cleavage is preferably carried out using an acid.

  Suitable inert solvents for the hydrolysis of carboxylic acids are water or organic solvents customary for ester cleavage. These preferably include alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, or ethers such as diethyl ether, tetrahydrofuran, dioxane or glycol dimethyl ether, or acetone, acetonitrile. , Other solvents such as dichloromethane, dimethylformamide or dimethyl sulfoxide. It is also possible to use mixtures of the solvents mentioned above. In the case of basic ester hydrolysis, preference is given to using a mixture of water and dioxane, tetrahydrofuran, methanol and / or ethanol. For reactions using trifluoroacetic acid, preference is given to using dichloromethane, and for reactions using hydrogen chloride, preference is given to using tetrahydrofuran, diethyl ether, dioxane or water.

  Suitable bases for ester hydrolysis are conventional inorganic bases. These preferably include alkali metal or alkaline earth metal hydroxides such as sodium hydroxide, lithium hydroxide, potassium hydroxide or barium hydroxide, or alkali metal or alkaline earth metal carbonates such as carbonate. Sodium, potassium carbonate or calcium carbonate is included. Particular preference is given to using sodium hydroxide or lithium hydroxide.

  Suitable acids for ester cleavage are generally sulfuric acid, hydrogen chloride / hydrochloric acid, hydrogen bromide / hydrobromic acid, phosphoric acid, acetic acid, trifluoroacetic acid, toluenesulfonic acid, methanesulfonic acid or trifluoromethanesulfonic acid, or their It is a mixture and water is added as needed. Preference is given to hydrogen chloride or trifluoroacetic acid in the case of tert-butyl esters and hydrochloric acid in the case of methyl esters.

  The ester cleavage is generally carried out in the temperature range of −20 ° C. to + 100 ° C., preferably 0 ° C. to + 50 ° C. This reaction can be carried out at atmospheric pressure, elevated pressure or reduced pressure (eg 0.5 to 5 bar). In general, this reaction is carried out at atmospheric pressure.

  Processes (IC) → (I), (IF) → (ID) and (V) + (VI) → (VII) are esterification or amidation (amide formation) of carboxylic acid known from literature ).

  Inert solvents for these processes include, for example, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or mineral oil fractions, dichloromethane , Halogenated hydrocarbons such as trichloromethane, carbon tetrachloride, 1,2-dichloroethane, trichloroethylene or chlorobenzene, or ethyl acetate, pyridine, dimethyl sulfoxide, dimethylformamide, N, N′-dimethylpropyleneurea (DMPU), Other solvents such as N-methylpyrrolidone (NMP), acetonitrile or acetone. It is also possible to use mixtures of the solvents mentioned above. Preference is given to dichloromethane, tetrahydrofuran, dimethylformamide or mixtures of these solvents.

  Suitable condensing agents for esterification or amide formation in steps (I-C) → (I), (IF) → (ID) and (V) + (VI) → (VII) are, for example, N, N′-diethyl-, N, N′-dipropyl-, N, N′-diisopropyl-, N, N′-dicyclohexylcarbodiimide (DCC), N- (3-dimethylaminoisopropyl) -N′-ethylcarbodiimide hydrochloride Carbodiimides such as (EDC), or phosgene derivatives such as N, N′-carbonyldiimidazole, or 2-ethyl-5-phenyl-1,2-oxazolium 3-sulfate or 2-tert-butyl-5-methyl -1,2-oxazolium compounds such as isoxazolium perchlorate, or acylates such as 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline Amino compounds, or isobutyl chloroformate, propanephosphonic anhydride, diethyl cyanophosphonate, bis (2-oxo-3-oxazolidinyl) phosphoryl chloride, benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate, benzo Triazol-1-yloxytris (pyrrolidino) phosphonium hexafluorophosphate (PyBOP), O- (benzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate (HBTU), 2- (2-oxo-1- (2H) -pyridyl) -1,1,3,3-tetramethyluronium tetrafluoroborate (TPTU), O- (7-azabenzotriazol-1-yl) -N , N, N ', N'-tetramethyl Uronium hexafluorophosphate (HATU) or O- (1H-6-chlorobenzotriazol-1-yl) -1,1,3,3-tetramethyluronium tetrafluoroborate (TCTU), as required Further adjuvants such as 1-hydroxybenzotriazole (HOBt) or N-hydroxysuccinimide (HOSu) and also as bases alkali metal carbonates such as sodium carbonate or potassium carbonate or sodium bicarbonate or potassium bicarbonate, Or in combination with an organic base, for example a trialkylamine such as triethylamine, N-methylmorpholine, N-methylpiperidine or N, N-diisopropylethylamine. Preference is given to HATU or TCTU in combination with N, N-diisopropylethylamine.

  Steps (IC) → (I), (IF) → (ID) and (V) + (VI) → (VII) are generally −20 ° C. to + 60 ° C., preferably − It is carried out in the temperature range from 10 ° C to + 40 ° C. This reaction can be carried out at atmospheric pressure, elevated pressure or reduced pressure (eg 0.5 to 5 bar). In general, this reaction is carried out at atmospheric pressure.

  In step (VII) → (IB), the reaction of the compound of formula (VII) with chloroacetyl chloride is preferably in DMF at 0 ° C. to + 30 ° C. or in chloroform at + 20 ° C. to + 70 ° C. carry out. The intermediate thus obtained is cyclized in the presence of a base, preferably potassium carbonate, in DMF or in an alcoholic solvent, in particular ethanol, at elevated temperatures, in particular in the temperature range of + 50 ° C. to + 80 ° C.

  Step (VI) + (XIV) → (VIII) is preferably performed at + 20 ° C. in DMF using the base N, N-diisopropylethylamine in a molar ratio of at least 3 based on the compound of formula (VI). Or in the temperature range of + 80 ° C.

  Compounds of formula (III), (VI), (IX), (XI), (XIII) and (XIV) are either commercially available, known from the literature or prepared analogously to methods known from the literature it can.

［ａ）：ＨＡＴＵまたはＴＣＴＵおよびＤＩＥＡをＴＨＦまたはＤＭＦ中で使用するカップリング反応；ｂ）：１．ＤＭＦまたはクロロホルム中のクロロアセチルクロリド、２．ＤＭＦまたはエタノール中の炭酸カリウム、７０℃；ｃ）：ジオキサン中の塩化水素］。 The preparation of the compounds according to the invention can be illustrated by the following synthetic scheme:
Scheme 1

[A): coupling reaction using HATU or TCTU and DIEA in THF or DMF; b): 1. 1. chloroacetyl chloride in DMF or chloroform; Potassium carbonate in DMF or ethanol, 70 ° C .; c): hydrogen chloride in dioxane].

［ａ）：トリエチルアミンをＤＭＦ中で使用するＮ−アルキル化（Ｘ＝ハロゲン）；ｂ）：ＤＭＦ中のＤＩＥＡ；ｃ）：トリエチルアミン、ＤＩＥＡおよびＴＢＡＩをＴＨＦ中で使用するＮ−アルキル化；ｄ）：ジオキサン中の塩化水素］。 Scheme 2

[A): N-alkylation using triethylamine in DMF (X = halogen); b): DIEA in DMF; c): N-alkylation using triethylamine, DIEA and TBAI in THF; d) : Hydrogen chloride in dioxane].

［ａ）：トリエチルアミンおよびＤＩＥＡをＴＨＦ中で使用するＮ−アルキル化；ｂ）：トリエチルアミン、ＤＩＥＡおよびＴＢＡＩをＴＨＦ中で使用するＮ−アルキル化（Ｘ＝ハロゲン）；ｃ）：ジオキサン中の塩化水素］。 Scheme 3

[A): N-alkylation using triethylamine and DIEA in THF; b): N-alkylation using triethylamine, DIEA and TBAI in THF (X = halogen); c): hydrogen chloride in dioxane ].

  The compounds according to the invention have useful pharmacological properties and can be used for the prevention and treatment of disorders in humans and animals.

  The compounds according to the invention are very effective PPAR-alpha modulators and are particularly suitable for the treatment of cardiovascular disorders. Such disorders include dyslipidemia (hypercholesterolemia, hypertriglyceridemia, hypoalphalipoproteinemia, mixed hyperlipidemia), arteriosclerosis and metabolic disorders (metabolic syndrome, non-insulin dependent diabetes mellitus) , Insulin-dependent diabetes mellitus, hyperinsulinemia, glucose intolerance, obesity, adiposity and diabetes sequelae such as retinopathy, nephropathy and neuropathy). Further independent risk factors for cardiovascular disorders that can be treated with the compounds according to the invention are hypertension, ischemia, myocardial infarction, elevated levels of fibrinogen and low density LDL, and plasminogen activator inhibitor 1 (PAI-1). ) Concentration. In addition, the compounds according to the invention can be used for cancer, disorders of the central nervous system (stroke, Alzheimer's disease, dementia), immune disorders (Crohn's disease, ulcerative colitis) and kidney disorders, thyroid disorders, liver fibrosis, It can also be used to treat or prevent psoriasis and osteoporosis.

The activity of the compounds according to the invention can be determined, for example, in vitro by the transactivation assay described in the experimental part.
The in vivo activity of the compounds according to the invention can be determined, for example, by the tests described in the experimental part.

The invention further provides the use of the compounds according to the invention for the treatment and / or prevention of disorders, in particular the disorders mentioned above.
The present invention also provides the use of a compound according to the invention for the manufacture of a medicament for the treatment and / or prevention of disorders, especially of the aforementioned disorders.
The present invention also provides a method for the treatment and / or prevention of disorders, in particular the disorders mentioned above, using an effective amount of at least one compound according to the invention.

  The compounds according to the invention can be used alone or, if necessary, in combination with other active compounds. The present invention further provides a medicament comprising at least one compound according to the invention and in particular at least one or more further active compounds for the treatment and / or prevention of the disorders mentioned above. Suitable active compounds for the combination include, for example and preferably: substances that modulate lipid metabolism (CETP inhibitors, inhibitors of HMG-CoA reductase, inhibitors of expression of HMG-CoA reductase, squalene synthesis inhibitors, ACAT inhibitors , Cholesterol absorption inhibitor, bile acid absorption inhibitor, MTP inhibitor, fibrates, niacin, lipase inhibitor, PPARγ- and / or PPAR-δ agonist), compound for hypertension (calcium antagonist, angiotensin II receptor antagonist) Substances that promote circulation (platelet aggregation inhibitors, anticoagulants), and also antidiabetics, antioxidants, thyroid hormones and / or thyroid mimetics, aldose reductase inhibitors and appetite-reducing drugs is there.

  The present invention further provides medicaments comprising at least one compound according to the invention, usually together with one or more inert, non-toxic pharmaceutically suitable auxiliaries, and their use for the purposes mentioned above. To do.

The compounds of the invention can act systemically and / or locally. For this purpose, they are adapted in a suitable manner, e.g. orally, parenterally, into the lung, into the nasal cavity, under the tongue, into the tongue, into the buccal side, into the rectum, into the skin, percutaneously, into the conjunctiva. It can be administered to the ear or as an implant or stent.
For these administration routes, the compounds according to the invention can be administered in suitable dosage forms.

  Suitable for oral administration works according to the prior art and releases the compounds according to the invention in a rapid and / or modified form, comprising the compounds according to the invention in crystalline and / or amorphous and / or dissolved form Ones, eg tablets (uncoated or coated tablets, eg enteric coatings, or those which have a delayed dissolving or insoluble coating which controls the release of the compounds according to the invention), or films / oblates In tablets, films / lyophilizers, capsules (eg hard or soft gelatin capsules), sugar-coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols or liquids that dissolve rapidly in the mouth is there.

  Parenteral administration avoids the absorption phase by the body (eg, intravenous, intraarterial, intracardiac, spinal or lumbar) or includes absorption by the body (eg, intramuscular, subcutaneous, skin Internal, percutaneous or intraperitoneal). Suitable dosage forms for parenteral administration are, inter alia, injection or infusion preparations in the form of solutions, suspensions, emulsions, lyophilizates or sterile powders.

  Suitable for other routes of administration are pharmaceutical forms for inhalation (among others, powder inhalers, nebulizers), nasal drops, liquids or sprays; tablets, films / oblates or capsules for tongue, sublingual or buccal administration, Suppositories, formulations for administration to the ears or eyes, vaginal capsules, aqueous suspensions (lotions, shaking mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (eg, plasters), Milk, paste, foam, irrigation powder, implant or stent.

Preference is given to oral or parenteral administration, in particular oral administration.
The compounds according to the invention can be converted into the stated administration forms. This can be done in a manner known per se by mixing with inert, non-toxic, pharmaceutically suitable auxiliaries. These adjuvants include, inter alia, carriers (eg microcrystalline cellulose, lactose, mannitol), solvents (eg liquid polyethylene glycol), emulsifiers and dispersants or wetting agents (eg sodium dodecyl sulfate, polyoxysorbitan oleate), binding Agents (eg polyvinylpyrrolidone), synthetic and natural polymers (eg albumin), stabilizers (eg antioxidants such as ascorbic acid), colorants (eg inorganic pigments such as iron oxide) and taste and / or odor masking agents Is included.

  In general, for parenteral administration, it is advantageous to obtain an effective result in an amount of about 0.001 to 1 mg / kg body weight, preferably about 0.01 to 0.5 mg / kg body weight. Was found. In the case of oral administration, the dose is about 0.01 to 100 mg / kg body weight, preferably about 0.01 to 20 mg / kg body weight, and particularly preferably 0.1 to 10 mg / body weight.

  Nevertheless, it may be necessary to deviate from the above-mentioned amounts, depending in particular on body weight, route of administration, individual response to the active compound, type of formulation and time or interval at which the administration takes place. Thus, it may be sufficient to administer less than the above-mentioned minimum amount, while in other cases the upper limit mentioned must be exceeded. When administered in relatively large amounts, it may be advantageous to divide them into multiple single doses that are administered over the course of the day.

The following examples illustrate the invention. The present invention is not limited to these examples.
The percentages in the following tests and examples are, unless indicated otherwise, percentages by weight; parts are parts by weight. The solvent ratio, dilution ratio and concentration of the liquid / liquid solution are in each case volume-based.

A. Example
Abbreviations:

LC / MS and HPLC methods:
Method 1 (LC / MS):
MS instrument type: Micromass ZQ; HPLC instrument type: HP 1100 Series; UV DAD; column: Phenomenex Synergi 2μ Hydro-RP Mercury 20 mm x 4 mm; mobile phase A: water 1 l + 0.5% 50% strength formic acid, mobile phase B: Gradient: 0.0 min 90% A → 2.5 min 30% A → 3.0 min 5% A → 4.5 min 5% A; flow rate: 0.0 min 1 ml /Min→2.5 min / 3.0 min / 4.5 min 2 ml / min; oven: 50 ° C .; UV detection: 210 nm.

Method 2 (LC / MS):
MS instrument type: Micromass ZQ; HPLC instrument type: Waters Alliance 2795; column: Phenomenex Synergi 2μ Hydro-RP Mercury 20 mm x 4 mm; mobile phase A: water 1 l + 50% strength formic acid 0.5 ml; mobile phase B: acetonitrile 1 l + 50% Strong formic acid 0.5 ml; Gradient: 0.0 min 90% A → 2.5 min 30% A → 3.0 min 5% A → 4.5 min 5% A; Flow rate: 0.0 min 1 ml / min → 2.5 min / 3.0 min / 4.5 min 2 ml / min; oven: 50 ° C .; UV detection: 210 nm.

Method 3 (LC / MS):
Equipment: Micromass Platform LCZ with HPLC Agilent Series 1100; Column: Phenomenex Synergi 2μ Hydro-RP Mercury 20 mm x 4 mm; Mobile Phase A: Water 1 l + 50% strength formic acid 0.5 ml; Mobile Phase B: acetonitrile 1 l + 50% strength formic acid 0 Gradient: 0.0 min 90% A → 2.5 min 30% A → 3.0 min 5% A → 4.5 min 5% A; flow rate: 0.0 min 1 ml / min → 2.5 Min / 3.0 min / 4.5 min 2 ml / min; oven: 50 ° C .; UV detection: 210 nm.

Method 4 (LC / MS):
Equipment: Micromass Quattro LCZ with HPLC Agilent Series 1100; Column: Phenomenex Synergi 2μ Hydro-RP Mercury 20 mm x 4 mm; Mobile Phase A: Water 1 l + 50% strength formic acid 0.5 ml, Mobile Phase B: acetonitrile 1 l + 50% strength formic acid 0 Gradient: 0.0 min 90% A → 2.5 min 30% A → 3.0 min 5% A → 4.5 min 5% A; flow rate: 0.0 min 1 ml / min → 2.5 Min / 3.0 min / 4.5 min 2 ml / min; oven: 50 ° C .; UV detection: 208-400 nm.

ｔｅｒｔ−ブチル２−［（４−｛［（２−フリルメチル）アミノ］メチル｝フェニル）チオ］−２−メチルプロピオネート塩酸塩（７.４６ｍｍｏｌ）［ＷＯ０２／２８８２１、実施例ＩＩ−３］３.００ｇを、ＤＭＦ３０ｍｌに懸濁し、炭酸セシウム４.８６ｇ（１４.９１ｍｍｏｌ）およびエチルブロモアセテート１.２５ｇ（７.４６ｍｍｏｌ）を添加する。反応混合物を室温で終夜撹拌する。水１００ｍｌを添加し、混合物をジクロロメタンで３回抽出する。合わせた有機相を硫酸ナトリウムで乾燥させ、ロータリーエバポレーターで溶媒を除去する。残渣をシリカゲルのクロマトグラフィー（移動相：シクロヘキサン／酢酸エチル１０：１）で精製する。これにより、表題化合物１.８７ｇ（理論値の５６％）を得る。
¹H-NMR (400 MHz, CDCl₃): δ = 1.26 (t, J = 7.2, 3H), 1.41 (s, 9H), 1.43 (s, 6H), 3.32 (s, 2H), 3.80 (s, 2H), 3.84 (s, 2H), 4.16 (q, J = 7.2, 2H), 6.19-6.20 (m, 1H), 6.31 (dd, J = 3.0, J = 1.9, 1H), 7.32-7.35 (m, 2H), 7.38 (dd, J = 1.9, J = 0.8, 1H), 7.44-7.47 (m, 2H).
LC/MS (方法 2): R_t = 3.06 分; MS (ESIpos): m/z = 448 [M+H]⁺ Starting materials and intermediates:
Example 1A
tert-Butyl 2-[(4-{[(2-furylmethyl) (2-ethoxy-2-oxoethyl) amino] methyl} phenyl) thio] -2-methylpropionate

tert-Butyl 2-[(4-{[(2-furylmethyl) amino] methyl} phenyl) thio] -2-methylpropionate hydrochloride (7.46 mmol) [WO 02/28821, Example II-3] 3.00 g is suspended in 30 ml DMF and 4.86 g (14.91 mmol) cesium carbonate and 1.25 g (7.46 mmol) ethyl bromoacetate are added. The reaction mixture is stirred at room temperature overnight. 100 ml of water are added and the mixture is extracted three times with dichloromethane. The combined organic phases are dried over sodium sulfate and the solvent is removed on a rotary evaporator. The residue is purified by chromatography on silica gel (mobile phase: cyclohexane / ethyl acetate 10: 1). This gives 1.87 g (56% of theory) of the title compound.
¹ H-NMR (400 MHz, CDCl ₃ ): δ = 1.26 (t, J = 7.2, 3H), 1.41 (s, 9H), 1.43 (s, 6H), 3.32 (s, 2H), 3.80 (s, 2H), 3.84 (s, 2H), 4.16 (q, J = 7.2, 2H), 6.19-6.20 (m, 1H), 6.31 (dd, J = 3.0, J = 1.9, 1H), 7.32-7.35 (m , 2H), 7.38 (dd, J = 1.9, J = 0.8, 1H), 7.44-7.47 (m, 2H).
LC / MS (Method 2): R _t = 3.06 min; MS (ESIpos): m / z = 448 [M + H] ⁺

実施例１Ａ由来の化合物１.００ｇ（２.２３ｍｍｏｌ）を、ジオキサン／水（２：１）７ｍｌに溶解し、１Ｎ水酸化ナトリウム水溶液３.３７ｍｌ（３.３７ｍｍｏｌ）を添加する。反応混合物を室温で１６時間撹拌する。２Ｎ塩酸を使用して混合物をｐＨ２に酸性化し、ジクロロメタンで３回抽出する。合わせた有機相を硫酸ナトリウムで乾燥させ、ロータリーエバポレーターで濃縮する。これにより表題化合物０.８３２ｇ（理論値の８９％）を得る。
ＬＣ／ＭＳ（方法１）：Ｒ_ｔ＝２.１８分；ＭＳ（ＥＳＩｐｏｓ）：ｍ／ｚ＝４２０［Ｍ＋Ｈ］^＋
1H-NMR (400 MHz, CDCl₃): δ [ppm] = 1.42 (s, 9H), 1.44 (s, 6H), 3.32 (s, 2H), 3.76 (s, 2H), 3.77 (s, 2H), 6.26-6.27 (m, 1H), 6.36 (m, 1H), 7.26-7.28 (m, 2H), 7.43-7.44 (m, 1H), 7.49-7.51 (m, 2H). Example 2A
N- {4-[(2-tert-butoxy-1,1-dimethyl-2-oxoethyl) thio] benzyl} -N- (2-furylmethyl) glycine

1.00 g (2.23 mmol) of the compound from Example 1A is dissolved in 7 ml of dioxane / water (2: 1) and 3.37 ml (3.37 mmol) of 1N aqueous sodium hydroxide solution is added. The reaction mixture is stirred at room temperature for 16 hours. Acidify the mixture to pH 2 using 2N hydrochloric acid and extract three times with dichloromethane. The combined organic phases are dried with sodium sulfate and concentrated on a rotary evaporator. This gives 0.832 g (89% of theory) of the title compound.
LC / MS (Method 1): R _t = 2.18 min; MS (ESIpos): m / z = 420 [M + H] ^+
1 H-NMR (400 MHz, CDCl ₃ ): δ [ppm] = 1.42 (s, 9H), 1.44 (s, 6H), 3.32 (s, 2H), 3.76 (s, 2H), 3.77 (s, 2H ), 6.26-6.27 (m, 1H), 6.36 (m, 1H), 7.26-7.28 (m, 2H), 7.43-7.44 (m, 1H), 7.49-7.51 (m, 2H).

実施例２Ａ由来の化合物１.００ｇ（２.３８ｍｍｏｌ）を、ＴＨＦ２０ｍｌに溶解し、ＴＣＴＵ９９７ｍｇ（２.８０ｍｍｏｌ）、ＤＩＥＡ０.８１ｍｌ（４.６７ｍｍｏｌ）および２,４−ジメチルフェニルヒドラジン４０３ｍｇ（２.３４ｍｍｏｌ）を添加する。混合物を室温で終夜撹拌する。混合物を濃縮し、残渣を水に取り、酢酸エチルで抽出する。有機相を飽和塩化ナトリウム溶液で洗浄し、硫酸ナトリウムを使用して乾燥させ、溶媒を減圧下で留去する。次いで、生成物をクロマトグラフィー（シリカゲル、シクロヘキサン／酢酸エチル１：１）で精製する。これにより、表題化合物１.０１ｇ（純度：ＬＣ／ＭＳによると９０％；理論値の７２％）を得る。これ以上の精製段階を経ず、この物質をさらに反応させる。
¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.34 (s, 9H), 1.38 (s, 6H), 2.12 (s, 3H), 2.15 (s, 3H), 3.18 (s, 2H), 3.73 (s, 2H), 3.76 (s, 2H), 6.36 (d, 1H), 6.42-6.51 (m, 2H), 6.72-6.89 (m, 3H), 7.45 (s*, 4H), 7.63 (dd, 1H), 9.60 (s, 1H).
LC/MS (方法 2): R_t = 2.96 分; MS (ESIpos): m/z = 538 [M+H]⁺ Example 3A
tert-butyl 2-[(4-{[{2- [2- (2,4-dimethylphenyl) hydrazino] -2-oxoethyl} (2-furylmethyl) amino] methyl} phenyl) thio] -2-methyl Propanoate

1.00 g (2.38 mmol) of the compound derived from Example 2A was dissolved in 20 ml of THF, and 997 mg (2.80 mmol) of TCTU, 0.81 ml (4.67 mmol) of DIEA and 403 mg (2.34 mmol) of 2,4-dimethylphenylhydrazine. Add. The mixture is stirred overnight at room temperature. The mixture is concentrated and the residue is taken up in water and extracted with ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried using sodium sulphate and the solvent is distilled off under reduced pressure. The product is then purified by chromatography (silica gel, cyclohexane / ethyl acetate 1: 1). This gives 1.01 g (purity: 90% according to LC / MS; 72% of theory) of the title compound. This material is further reacted without further purification steps.
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.34 (s, 9H), 1.38 (s, 6H), 2.12 (s, 3H), 2.15 (s, 3H), 3.18 (s , 2H), 3.73 (s, 2H), 3.76 (s, 2H), 6.36 (d, 1H), 6.42-6.51 (m, 2H), 6.72-6.89 (m, 3H), 7.45 (s *, 4H) , 7.63 (dd, 1H), 9.60 (s, 1H).
LC / MS (Method 2): R _t = 2.96 min; MS (ESIpos): m / z = 538 [M + H] ⁺

実施例３Ａ由来の化合物１.００ｇ（１.６７ｍｍｏｌ）を、無水ＤＭＦ２０ｍｌに溶解する。次いで、クロロアセチルクロリド２２７ｍｇ（０.１６ｍｌ、２.０１ｍｍｏｌ）を、無水ＤＭＦ５ｍｌ中の溶液として滴下して、３０分間かけて添加する。室温で３０分間の反応時間の後、炭酸カリウム５７８ｍｇ（４.１８ｍｍｏｌ）を添加し、混合物を７０℃で終夜撹拌する。溶媒を減圧下で留去し、残渣を水に取り、酢酸エチルで抽出する。硫酸ナトリウムで乾燥した後、溶媒を留去し、残渣を分取ＨＰＬＣ（移動相：０.１％ギ酸を含むアセトニトリル／水、グラジエント２０：８０→９５：５）で精製する。これにより、表題化合物７０ｍｇ（理論値の２５％）を得る。
¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.33 (s, 9H), 1.36 (s, 6H), 2.08 (s, 3H), 2.30 (s, 3H), 3.27 (s, 2H), 3.72 (s, 2H), 3.74 (s, 2H), 4.75 (s, 2H), 6.31 (d, 1H), 6.41 (dd, 1H), 7.04-7.14 (m, 3H), 7.36 (d, 2H), 7.42 (d, 2H), 7.6 (m, 1H).
MS (ESIpos): m/z = 578 [M+H]⁺ Example 4A
tert-butyl 2-[(4-{[{[4- (2,4-dimethylphenyl) -5-oxo-5,6-dihydro-4H-1,3,4-oxadiazin-2-yl] methyl} -(2-Furylmethyl) amino] methyl} phenyl) thio] -2-methylpropanoate

1.00 g (1.67 mmol) of the compound from Example 3A is dissolved in 20 ml of anhydrous DMF. Then 227 mg (0.16 ml, 2.01 mmol) chloroacetyl chloride are added dropwise as a solution in 5 ml anhydrous DMF and added over 30 minutes. After a reaction time of 30 minutes at room temperature, 578 mg (4.18 mmol) of potassium carbonate are added and the mixture is stirred at 70 ° C. overnight. The solvent is distilled off under reduced pressure, the residue is taken up in water and extracted with ethyl acetate. After drying over sodium sulfate, the solvent is distilled off and the residue is purified by preparative HPLC (mobile phase: acetonitrile / water with 0.1% formic acid, gradient 20: 80 → 95: 5). This gives 70 mg (25% of theory) of the title compound.
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.33 (s, 9H), 1.36 (s, 6H), 2.08 (s, 3H), 2.30 (s, 3H), 3.27 (s , 2H), 3.72 (s, 2H), 3.74 (s, 2H), 4.75 (s, 2H), 6.31 (d, 1H), 6.41 (dd, 1H), 7.04-7.14 (m, 3H), 7.36 ( d, 2H), 7.42 (d, 2H), 7.6 (m, 1H).
MS (ESIpos): m / z = 578 [M + H] ⁺

実施例２Ａ由来の化合物１.００ｇ（２.３８ｍｍｏｌ）、２−トリルヒドラジン塩酸塩３７８ｍｇ（２.３８ｍｍｏｌ）、ＨＯＢｔ３８７ｍｇ（２.８６ｍｍｏｌ）およびＥＤＣＩ９１３ｍｇ（４.７７ｍｍｏｌ）を、ＤＭＦ５ｍｌに溶解する。次いで、氷冷しながら、４−メチルモルホリン０.２６ｍｌ（２.３８ｍｍｏｌ）を滴下して添加する。混合物を室温で終夜撹拌する。混合物を冷却した１Ｎ塩酸に注ぎ、酢酸エチルで抽出する。有機相を飽和塩化ナトリウム溶液で洗浄し、硫酸ナトリウムで乾燥させ、溶媒を減圧下で留去する。次いで、生成物をカラムクロマトグラフィー（シリカゲル、ジクロロメタン→ジクロロメタン／イソプロパノール１０：１）により精製する。これにより、表題化合物９００ｍｇ（純度：ＬＣ／ＭＳによると８０％；理論値の５８％）を得る。これ以上の精製段階を経ず、この物質をさらに反応させる。
LC/MS (方法 3): R_t = 3.11 分; MS (ESIpos): m/z = 524 [M+H]⁺ Example 5A
tert-butyl 2-({4-[((2-furylmethyl) {2- [2- (2-methylphenyl) hydrazino] -2-oxoethyl} amino) methyl] phenyl} thio) -2-methylpropano Eate

1.00 g (2.38 mmol) of the compound from Example 2A, 378 mg (2.38 mmol) of 2-tolylhydrazine hydrochloride, 387 mg (2.86 mmol) of HOBt and 913 mg (4.77 mmol) of EDCI are dissolved in 5 ml of DMF. Then, 0.26 ml (2.38 mmol) of 4-methylmorpholine is added dropwise with ice cooling. The mixture is stirred overnight at room temperature. The mixture is poured into cold 1N hydrochloric acid and extracted with ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried over sodium sulphate and the solvent is distilled off under reduced pressure. The product is then purified by column chromatography (silica gel, dichloromethane → dichloromethane / isopropanol 10: 1). This gives 900 mg (purity: 80% according to LC / MS; 58% of theory) of the title compound. This material is further reacted without further purification steps.
LC / MS (Method 3): R _t = 3.11 min; MS (ESIpos): m / z = 524 [M + H] ⁺

実施例５Ａ由来の化合物３００ｍｇ（０.４７ｍｍｏｌ）を、クロロホルム１０ｍｌに溶解し、クロロアセチルクロリド１１６ｍｇ（０.０８ｍｌ、１.０３ｍｍｏｌ）を添加し、混合物を還流下で終夜加熱する。次いで、溶媒を留去し、残渣をエタノール１０ｍｌに取り、炭酸カリウム２８５ｍｇ（２.０６ｍｍｏｌ）を添加し、混合物を還流温度で終夜撹拌する。溶媒を減圧下で留去し、残渣を水に取り、酢酸エチルで抽出する。硫酸ナトリウムで乾燥後、溶媒を減圧下で留去し、残渣を分取ＨＰＬＣ（移動相：０.１％ギ酸を含むアセトニトリル／水、グラジエント２０：８０→９５：５）により精製する。これにより、表題化合物３６ｍｇ（理論値の１２％）を得る。
LC/MS (方法 4): R_t = 3.26 分; MS (ESIpos): m/z = 564 [M+H]⁺ Example 6A
tert-Butyl 2-({4-[((2-furylmethyl) {[4- (2-methylphenyl) -5-oxo-5,6-dihydro-4H-1,3,4-oxadiazine-2- Yl] methyl} amino) methyl] phenyl} thio) -2-methylpropanoate

300 mg (0.47 mmol) of the compound from Example 5A are dissolved in 10 ml of chloroform, 116 mg (0.08 ml, 1.03 mmol) of chloroacetyl chloride are added and the mixture is heated under reflux overnight. The solvent is then distilled off, the residue is taken up in 10 ml of ethanol, 285 mg (2.06 mmol) of potassium carbonate are added and the mixture is stirred at reflux temperature overnight. The solvent is distilled off under reduced pressure, the residue is taken up in water and extracted with ethyl acetate. After drying over sodium sulfate, the solvent is distilled off under reduced pressure and the residue is purified by preparative HPLC (mobile phase: acetonitrile / water with 0.1% formic acid, gradient 20: 80 → 95: 5). This gives 36 mg (12% of theory) of the title compound.
LC / MS (Method 4): R _t = 3.26 min; MS (ESIpos): m / z = 564 [M + H] ⁺

実施例２Ａ由来の化合物１.０６ｇ（２.５２ｍｍｏｌ）、３−トリルヒドラジン塩酸塩４００ｍｇ（２.５２ｍｍｏｌ）、ＨＯＢｔ４０８ｍｇ（３.０３ｍｍｏｌ）およびＥＤＣＩ９６６ｍｇ（５.０４ｍｍｏｌ）を、ＤＭＦ５ｍｌに溶解する。次いで、氷冷しながら、メチルモルホリン０.２８ｍｌ（２.５２ｍｍｏｌ）を、滴下して添加する。混合物を室温で終夜撹拌する。混合物を冷却した１Ｎ塩酸に注ぎ、酢酸エチルで抽出する。有機相を飽和塩化ナトリウム溶液で洗浄し、硫酸ナトリウムで乾燥させ、溶媒を減圧下で留去する。次いで、生成物をカラムクロマトグラフィー（シリカゲル、ジクロロメタン→ジクロロメタン／イソプロパノール２０：１）により精製する。これにより、表題化合物４８９ｍｇ（理論値の５８％）を得る。
¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.34 (s, 9H), 1.37 (s, 6H), 2.16 (s, 3H), 3.16 (s, 2H), 3.72 (s, 2H), 3.75 (s, 2H), 6.35 (d, 1H), 6.42-6.55 (m, 4H), 6.98 (t, 1H), 7.45 (s*, 4H), 7.58-7.66 (m, 2H), 9.58 (s, 1H).
LC/MS (方法 1): R_t = 3.07 分; MS (ESIpos): m/z = 524 [M+H]⁺ Example 7A
tert-Butyl 2-({4-[((2-furylmethyl) {2- [2- (3-methylphenyl) hydrazino] -2-oxoethyl} amino) methyl] -phenyl} thio) -2-methylprop Noate

1.06 g (2.52 mmol) of the compound from Example 2A, 400 mg (2.52 mmol) of 3-tolylhydrazine hydrochloride, 408 mg (3.03 mmol) of HOBt and 966 mg (5.04 mmol) of EDCI are dissolved in 5 ml of DMF. Then, 0.28 ml (2.52 mmol) of methylmorpholine is added dropwise with ice cooling. The mixture is stirred overnight at room temperature. The mixture is poured into cold 1N hydrochloric acid and extracted with ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried over sodium sulphate and the solvent is distilled off under reduced pressure. The product is then purified by column chromatography (silica gel, dichloromethane → dichloromethane / isopropanol 20: 1). This gives 489 mg (58% of theory) of the title compound.
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.34 (s, 9H), 1.37 (s, 6H), 2.16 (s, 3H), 3.16 (s, 2H), 3.72 (s , 2H), 3.75 (s, 2H), 6.35 (d, 1H), 6.42-6.55 (m, 4H), 6.98 (t, 1H), 7.45 (s *, 4H), 7.58-7.66 (m, 2H) , 9.58 (s, 1H).
LC / MS (Method 1): R _t = 3.07 min; MS (ESIpos): m / z = 524 [M + H] ⁺

実施例７Ａ由来の化合物２００ｍｇ（０.２９ｍｍｏｌ）を、クロロホルム１０ｍｌに溶解し、クロロアセチルクロリド８６ｍｇ（０.０６ｍｌ、０.７６ｍｍｏｌ）を添加し、混合物を還流下で終夜加熱する。次いで、溶媒を留去し、残渣をエタノール１０ｍｌに取り、炭酸カリウム２１１ｍｇ（１.５３ｍｍｏｌ）を添加し、混合物を還流温度で終夜撹拌する。溶媒を減圧下で留去し、残渣を水に取り、酢酸エチルで抽出する。硫酸ナトリウムで乾燥後、溶媒を留去し、残渣を分取ＨＰＬＣ（移動相：０.１％ギ酸を含むアセトニトリル／水、グラジエント２０：８０→９５：５）により精製する。これにより、表題化合物４０ｍｇ（理論値の１９％）を得る。
¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.33 (s, 9H), 1.36 (s, 6H), 2.33 (s, 3H), 3.76 (s, 2H), 3.77 (s, 2H), 4.74 (s, 2H), 6.34 (d, 1H), 6.42 (dd, 1H), 7.09 (d, 1H), 7.31-7.48 (m, 7H), 7.62 (m, 1H).
LC/MS (方法 4): R_t = 3.34 分; MS (ESIpos): m/z = 564 [M+H]⁺ Example 8A
tert-butyl 2-({4-[((2-furylmethyl) {[4- (3-methylphenyl) -5-oxo-5,6-dihydro-4H-1,3,4-oxadiazine-2- Yl] methyl} amino) methyl] phenyl} thio) -2-methylpropanoate

200 mg (0.29 mmol) of the compound from Example 7A are dissolved in 10 ml of chloroform, 86 mg (0.06 ml, 0.76 mmol) of chloroacetyl chloride are added and the mixture is heated under reflux overnight. The solvent is then distilled off, the residue is taken up in 10 ml of ethanol, 211 mg (1.53 mmol) of potassium carbonate are added and the mixture is stirred at reflux temperature overnight. The solvent is distilled off under reduced pressure, the residue is taken up in water and extracted with ethyl acetate. After drying over sodium sulfate, the solvent is distilled off and the residue is purified by preparative HPLC (mobile phase: acetonitrile / water with 0.1% formic acid, gradient 20: 80 → 95: 5). This gives 40 mg (19% of theory) of the title compound.
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.33 (s, 9H), 1.36 (s, 6H), 2.33 (s, 3H), 3.76 (s, 2H), 3.77 (s , 2H), 4.74 (s, 2H), 6.34 (d, 1H), 6.42 (dd, 1H), 7.09 (d, 1H), 7.31-7.48 (m, 7H), 7.62 (m, 1H).
LC / MS (Method 4): R _t = 3.34 min; MS (ESIpos): m / z = 564 [M + H] ⁺

実施例２Ａ由来の化合物１.００ｇ（２.３８ｍｍｏｌ）、４−トリルヒドラジン塩酸塩（２.３８ｍｍｏｌ）３７８ｍｇ、ＨＯＢｔ３８７ｍｇ（２.８６ｍｍｏｌ）およびＥＤＣＩ９１３ｍｇ（４.７７ｍｍｏｌ）を、ＤＭＦ５ｍｌ中で蒸留する。次いで、氷冷しながら、４−メチルモルホリン０.２６ｍｌ（２.３８ｍｍｏｌ）を滴下して添加する。混合物を室温で終夜撹拌する。混合物を冷却した１Ｎ塩酸に注ぎ、酢酸エチルで抽出する。有機相を飽和塩化ナトリウム溶液で洗浄し、硫酸ナトリウムで乾燥させ、溶媒を減圧下で留去する。次いで、生成物をカラムクロマトグラフィー（シリカゲル、ジクロロメタン→ジクロロメタン／イソプロパノール２０：１）により精製する。これにより、表題化合物５００ｍｇ（理論値の４０％、純度７５％）を得る。
LC/MS (方法 3): R_t = 3.08 分; MS (ESIpos): m/z = 524 [M+H]⁺ Example 9A
tert-Butyl 2-({4-[((2-furylmethyl) {2- [2- (4-methylphenyl) hydrazino] -2-oxoethyl} amino) methyl] -phenyl} thio) -2-methylprop Noate

1.00 g (2.38 mmol) of the compound from Example 2A, 378 mg of 4-tolylhydrazine hydrochloride (2.38 mmol), 387 mg of HOBt (2.86 mmol) and 913 mg of EDCI (4.77 mmol) are distilled in 5 ml of DMF. Then, 0.26 ml (2.38 mmol) of 4-methylmorpholine is added dropwise with ice cooling. The mixture is stirred overnight at room temperature. The mixture is poured into cold 1N hydrochloric acid and extracted with ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried over sodium sulphate and the solvent is distilled off under reduced pressure. The product is then purified by column chromatography (silica gel, dichloromethane → dichloromethane / isopropanol 20: 1). This gives 500 mg (40% of theory, purity 75%) of the title compound.
LC / MS (Method 3): R _t = 3.08 min; MS (ESIpos): m / z = 524 [M + H] ⁺

実施例９Ａ由来の化合物２００ｍｇ（０.２９ｍｍｏｌ）をクロロホルム１０ｍｌに溶解し、クロロアセチルクロリド６４ｍｇ（０.０５ｍｌ、０.５７ｍｍｏｌ）を添加し、混合物を還流下で終夜加熱する。次いで、溶媒を留去し、残渣をエタノール１０ｍｌに取り、炭酸カリウム１５８ｍｇ（１.１５ｍｍｏｌ）を添加し、混合物を還流温度で終夜撹拌する。溶媒を減圧下で留去し、残渣を水に取り、酢酸エチルで抽出する。硫酸ナトリウムで乾燥後、溶媒を留去し、残渣を分取ＨＰＬＣ（移動相：０.１％ギ酸を含むアセトニトリル／水、グラジエント２０：８０→９５：５）により精製する。これにより、表題化合物１１ｍｇ（理論値の６.４％）を得る。
LC/MS (方法 4): R_t = 3.33 分; MS (ESIpos): m/z = 564 [M+H]⁺ Example 10A
tert-butyl 2-({4-[((2-furylmethyl) {[4- (4-methylphenyl) -5-oxo-5,6-dihydro-4H-1,3,4-oxadiazine-2- Yl] methyl} amino) methyl] phenyl} thio) -2-methylpropanoate

Dissolve 200 mg (0.29 mmol) of the compound from Example 9A in 10 ml of chloroform, add 64 mg (0.05 ml, 0.57 mmol) of chloroacetyl chloride and heat the mixture under reflux overnight. The solvent is then distilled off, the residue is taken up in 10 ml of ethanol, 158 mg (1.15 mmol) of potassium carbonate are added and the mixture is stirred at reflux temperature overnight. The solvent is distilled off under reduced pressure, the residue is taken up in water and extracted with ethyl acetate. After drying over sodium sulfate, the solvent is distilled off and the residue is purified by preparative HPLC (mobile phase: acetonitrile / water with 0.1% formic acid, gradient 20: 80 → 95: 5). This gives 11 mg (6.4% of theory) of the title compound.
LC / MS (Method 4): R _t = 3.33 min; MS (ESIpos): m / z = 564 [M + H] ⁺

２６ｌのタンク中で、硫化ナトリウム（水を含有する）２４７３ｇ（１９.０１ｍｏｌ）を、ＮＭＰ１４.４ｌに懸濁する。次いで、溶媒５.１ｌを、１２５−１３０℃、１１０ｍｂａｒで留去する。次いで、内部温度１３０−１４０℃で、ＮＭＰ３.８４ｌ中の４−クロロベンゾニトリル２１１０ｇ（１５.３３ｍｏｌ）の溶液を、１時間かけて滴下して添加する。温度は１５５−１６０℃に上昇する。混合物を６時間撹拌する。４０−４５℃で、ｔｅｒｔ−ブチルブロモイソブチレート３７６１ｇ（１６.８６ｍｏｌ）を４５分間かけて量り入れる。次いで、９７℃、２４ｍｂａｒで、溶媒１３.０ｌを留去し、混合物を９０℃から冷却し、メチルシクロヘキサン５.８ｌを添加する。混合物を１５−２０℃に冷却し、水７.７０ｌおよび珪藻土２８８ｇを添加し、混合物を２０℃で１５分間撹拌する。次いで、Seitz フィルタープレート（Ｋ８００）を有する陶器製ヌッチェを通して混合物を濾過し、濾液を４０ｌの分液漏斗に移し、相を分離する。各回で水５.８ｌを用いて有機相（９.１ｌ）を２回撹拌し、有機相をロータリーエバポレーター中、５５−６０℃／１ｍｂａｒで濃縮する。得られる残渣は、油状物３７８８ｇ（理論値の８９％）であり、それは室温で保存中に凝固する（ＧＣによると、純度９３％）。残渣をこれ以上精製せずに、次の段階に使用する。
¹H-NMR (500 MHz, DMSO-d₆): δ = 1.37 (s, 9H), 1.45 (s, 6H), 7.60 (d, 2H), 7.85 (d, 2H). Example 11A
tert-Butyl 2- (4-cyanophenylsulfanyl) -2-methyl-propionate

In a 26 l tank, 2473 g (19.01 mol) of sodium sulfide (containing water) are suspended in 14.4 l of NMP. Then 5.1 l of solvent are distilled off at 125-130 ° C. and 110 mbar. A solution of 2110 g (15.33 mol) of 4-chlorobenzonitrile in 3.84 l of NMP is then added dropwise over 1 hour at an internal temperature of 130-140 ° C. The temperature rises to 155-160 ° C. The mixture is stirred for 6 hours. At 40-45 ° C., 3761 g (16.86 mol) of tert-butyl bromoisobutyrate are weighed in over 45 minutes. Then 13.0 l of solvent are distilled off at 97 ° C. and 24 mbar, the mixture is cooled from 90 ° C. and 5.8 l of methylcyclohexane are added. The mixture is cooled to 15-20 ° C., 7.70 l of water and 288 g of diatomaceous earth are added and the mixture is stirred at 20 ° C. for 15 minutes. The mixture is then filtered through a ceramic Nutsche with a Seitz filter plate (K800), the filtrate is transferred to a 40 l separatory funnel and the phases are separated. The organic phase (9.1 l) is stirred twice with 5.8 l of water each time and the organic phase is concentrated in a rotary evaporator at 55-60 ° C./1 mbar. The residue obtained is 3788 g (89% of theory) of an oil that solidifies upon storage at room temperature (purity 93% according to GC). The residue is used in the next step without further purification.
¹ H-NMR (500 MHz, DMSO-d ₆ ): δ = 1.37 (s, 9H), 1.45 (s, 6H), 7.60 (d, 2H), 7.85 (d, 2H).

２６ｌのタンク中、ボラン／Ｎ,Ｎ−ジエチルアニリン錯体２６２７ｇ（１６.１１ｍｏｌ）の溶液を、２時間かけて滴下して、７２℃で、ＴＨＦ５.５ｌ中のｔｅｒｔ−ブチル２−（４−シアノフェニルスルファニル）−２−メチルプロピオネート（実施例１１Ａ）３０００ｇ（１０.７４ｍｏｌ）の溶液に量り入れる。混合物を７２℃で１時間撹拌し、次いで、室温に冷却し、メタノール２.３３ｌを１時間かけて量り入れる。次いで、６Ｍ塩酸５.８１ｌを添加し、混合物を室温で終夜撹拌する。混合物を４０ｌの分液漏斗に移し、タンクを水３.８８ｌおよびメチルシクロヘキサン７.７５ｌですすぐ。有機相を、各回３.８ｌの水で２回撹拌する。合わせた水相を、メチルシクロヘキサン３.８８ｌで抽出し、次いで、濃水酸化ナトリウム水溶液を使用してｐＨ１０.５に合わせる（消費：２.５ｌ）。水性／油性相を各回３.８８ｌのメチルシクロヘキサンと２回撹拌し、合わせた有機相を水５.８１ｌで洗浄する。有機相（１４.５ｌ）をロータリーエバポレーター中、７５℃／４５ｍｂａｒで濃縮する。これにより、所望の生成物をジエチルアニリンとの混合物として含有する粗製溶液４.４５ｋｇを得る。 Example 12A
tert-Butyl 2- [4- (aminomethyl) phenylsulfanyl] -2-methylpropionate hydrochloride

In a 26 l tank, a solution of 2627 g (16.11 mol) of borane / N, N-diethylaniline complex was added dropwise over 2 hours and at 72 ° C., tert-butyl 2- (4-cyano in 5.5 l of THF. Weigh into a solution of 3000 g (10.74 mol) of phenylsulfanyl) -2-methylpropionate (Example 11A). The mixture is stirred at 72 ° C. for 1 hour, then cooled to room temperature and 2.33 l of methanol are weighed in over 1 hour. Then 5.81 l of 6M hydrochloric acid are added and the mixture is stirred at room temperature overnight. The mixture is transferred to a 40 l separatory funnel and the tank is rinsed with 3.88 l water and 7.75 l methylcyclohexane. The organic phase is stirred twice with 3.8 l of water each time. The combined aqueous phases are extracted with 3.88 l of methylcyclohexane and then adjusted to pH 10.5 using concentrated aqueous sodium hydroxide solution (consumption: 2.5 l). The aqueous / oil phase is stirred twice with 3.88 l of methylcyclohexane each time and the combined organic phases are washed with 5.81 l of water. The organic phase (14.5 l) is concentrated in a rotary evaporator at 75 ° C./45 mbar. This gives 4.45 kg of a crude solution containing the desired product as a mixture with diethylaniline.

This crude solution is combined with the same amount of the previous batch and most of the diethylaniline is distilled off in two stages on a thin layer evaporator (1. Distillation: product feed 458 g / hr, feed temperature 80-85 ° C., Pressure 2.7 mbar, head temperature 67 ° C., bottom temperature 37 ° C .; 2. filtration: 1.0 mbar, identical conditions). In a tank of enamel, the distillation residue (3664 g) is taken up in 7.8 l of MTBE and a 5-6 molar solution of hydrogen chloride in isopropanol is added dropwise over 20 minutes. During the addition, the internal temperature rises to 47 ° C. The suspension is cooled to room temperature and stirred for 2 hours. The mixture is filtered with suction through a Seitz filter plate and the filter cake is washed 4 times with 2.6 l MTBE each time. The wet product (5.33 kg) is dried at 40 ° C. under reduced pressure under a nitrogen stream until the mass is constant. The two combined batches form 2780 g (41% of theory) of the title compound as white crystals.
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 1.39 (m, 15H), 4.04 (s, 2H), 7.49 (m, 4H), 8.48 (sbr, 3H).
MS (DCI / NH ₃ ): m / z = 282 [M + H] ⁺ , 299 [M + NH ₄ ] ⁺

実施例１２Ａ由来の化合物５.００ｇ（１５.７３ｍｍｏｌ）を、最初にＤＭＦ１５ｍｌに入れ、２−ブロモエチルメチルエーテル１.９７ｇ（１４.１６ｍｍｏｌ）およびトリエチルアミン５.４８ｍｌ（３９.３２ｍｍｏｌ）を室温で添加する。混合物を室温で終夜撹拌し、次いでロータリーエバポレーターで濃縮する。水を残渣に添加し、混合物を酢酸エチルで２回抽出し、抽出物を硫酸ナトリウムで乾燥させ、溶媒を減圧下で留去する。シリカゲルのフラッシュクロマトグラフィー（移動相：ジクロロメタン／イソプロパノール５：１）により精製を実施する。これにより、表題化合物２.５６ｇ（理論値の４８％）を得る。
LC/MS (方法 2): R_t = 1.49 分; MS (ESIpos): m/z = 340 [M+H]⁺.
¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.38 (s*, 15H), 3.09 (t, 2H), 3.30 (s, 3H), 3.58 (t, 2H), 4.18 (s, 2H), 7.51 (s*, 4H), 8.92 (sbr, 1H). Example 13A
tert-Butyl 2-[(4-{[(2-methoxyethyl) amino] methyl} phenyl) thio] -2-methylpropanoate

5.00 g (15.73 mmol) of the compound from Example 12A is first placed in 15 ml of DMF, 1.97 g (14.16 mmol) of 2-bromoethyl methyl ether and 5.48 ml (39.32 mmol) of triethylamine are added at room temperature To do. The mixture is stirred at room temperature overnight and then concentrated on a rotary evaporator. Water is added to the residue, the mixture is extracted twice with ethyl acetate, the extract is dried over sodium sulphate and the solvent is distilled off under reduced pressure. Purification is carried out by flash chromatography on silica gel (mobile phase: dichloromethane / isopropanol 5: 1). This gives 2.56 g (48% of theory) of the title compound.
LC / MS (Method 2): R _t = 1.49 min; MS (ESIpos): m / z = 340 [M + H] ⁺ .
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.38 (s *, 15H), 3.09 (t, 2H), 3.30 (s, 3H), 3.58 (t, 2H), 4.18 ( s, 2H), 7.51 (s *, 4H), 8.92 (sbr, 1H).

３−メチルフェニルヒドラジン２.４６ｇ（２０.１４ｍｍｏｌ）および分子ふるい（４Å）１ｇを最初に無水ＤＭＦ３０ｍｌに入れる。次いで、クロロアセチルクロリド（２０.１４ｍｍｏｌ）１.６０ｍｌを無水ＤＭＦ１０ｍｌ中の溶液として、３０分間かけて滴下して添加する。反応完了後（分析ＨＰＬＣにより監視する）、さらなるクロロアセチルクロリド１当量を添加し、ＤＩＥＡ３.５１ｍｌ（２０.１４ｍｍｏｌ）を無水ＤＭＦ１０ｍｌ中の溶液として、約３０分間かけてゆっくりと滴下して添加する。もう一度ＨＰＬＣで確認した後、さらなるＤＩＥＡ７.０１ｍｌ（４０.２７ｍｍｏｌ）を添加する。次いで、混合物を７０℃で終夜撹拌する。冷却後、溶媒を減圧下で留去し、残渣を水に取り、酢酸エチルで３回抽出する。抽出物を水で洗浄し、硫酸ナトリウムで乾燥させ、次いで、溶媒をロータリーエバポレーターで除去する。シリカゲルのフラッシュクロマトグラフィー（移動相：シクロヘキサン／酢酸エチル５：１）により精製を実施する。これにより、表題化合物３.１１ｇ（理論値の６３％）を得る。
LC/MS (方法 4): R_t = 2.24 分; MS (ESIpos): m/z = 239 [M+H]^+
1H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 2.33 (s, 3H), 4.40 (s, 2H), 4.90 (s, 2H), 7.12 (m, 1H), 7.29-7.36 (m, 3H). Example 14A
2- (Chloromethyl) -4- (3-methylphenyl) -4H-1,3,4-oxadiazin-5 (6H) -one

2.46 g (20.14 mmol) of 3-methylphenylhydrazine and 1 g of molecular sieve (4Å) are initially placed in 30 ml of anhydrous DMF. Then 1.60 ml of chloroacetyl chloride (20.14 mmol) is added dropwise over 30 minutes as a solution in 10 ml of anhydrous DMF. After completion of the reaction (monitored by analytical HPLC), an additional 1 equivalent of chloroacetyl chloride is added and 3.51 ml (20.14 mmol) of DIEA is added slowly dropwise over about 30 minutes as a solution in 10 ml of anhydrous DMF. After another HPLC check, an additional 7.01 ml (40.27 mmol) of DIEA is added. The mixture is then stirred at 70 ° C. overnight. After cooling, the solvent is distilled off under reduced pressure, the residue is taken up in water and extracted three times with ethyl acetate. The extract is washed with water and dried over sodium sulfate, and then the solvent is removed on a rotary evaporator. Purification is carried out by flash chromatography on silica gel (mobile phase: cyclohexane / ethyl acetate 5: 1). This gives 3.11 g (63% of theory) of the title compound.
LC / MS (Method 4): R _t = 2.24 min; MS (ESIpos): m / z = 239 [M + H] ^+
1 H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 2.33 (s, 3H), 4.40 (s, 2H), 4.90 (s, 2H), 7.12 (m, 1H), 7.29-7.36 (m, 3H).

実施例１３Ａ由来の化合物１５０ｍｇ（０.４４ｍｍｏｌ）、実施例１４Ａ由来の化合物１１６ｍｇ（０.４９ｍｍｏｌ）、トリエチルアミン０.１５ｍｌ（１.１０ｍｍｏｌ）およびＴＢＡＩ３３ｍｇ（０.０９ｍｍｏｌ）を、ＴＨＦ３ｍｌに溶解し、圧力容器中、１００℃で終夜反応させる。次いで、溶媒を減圧下で除去し、残渣を水に取る。混合物を酢酸エチルで２回抽出した後、抽出物を硫酸ナトリウムで乾燥させ、溶媒をロータリーエバポレーターで除去する。分取ＨＰＬＣ（移動相：０.１％ギ酸を含むアセトニトリル／水、グラジエント２０：８０→９５：５）により精製を実施する。これにより、表題化合物１１６ｍｇ（理論値の４８％）を得る。
LC/MS (方法 2): R_t = 2.87 分; MS (ESIpos): m/z = 542 [M+H]⁺.
¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.34 (s, 9H), 1.36 (s, 6H), 2.33 (s, 3H), 2.76 (t, 2H), 3.21 (s, 3H), 3.39 (s, 2H), 3.44 (t, 2H), 3.80 (s, 2H), 4.76 (s, 2H), 7.09 (d, 1H), 7.25-7.45 (m, 7H). Example 15A
tert-Butyl 2-({4-[((2-methoxyethyl) {[4- (3-methylphenyl) -5-oxo-5,6-dihydro-4H-1,3,4-oxadiazine-2- Yl] methyl} amino) methyl] phenyl} thio) -2-methylpropanoate

150 mg (0.44 mmol) of the compound derived from Example 13A, 116 mg (0.49 mmol) of the compound derived from Example 14A, 0.15 ml (1.10 mmol) of triethylamine and 33 mg (0.09 mmol) of TBAI were dissolved in 3 ml of THF, and pressure React overnight at 100 ° C. in a container. The solvent is then removed under reduced pressure and the residue is taken up in water. After the mixture is extracted twice with ethyl acetate, the extract is dried over sodium sulfate and the solvent is removed on a rotary evaporator. Purification is carried out by preparative HPLC (mobile phase: acetonitrile / water with 0.1% formic acid, gradient 20: 80 → 95: 5). This gives 116 mg (48% of theory) of the title compound.
LC / MS (Method 2): R _t = 2.87 min; MS (ESIpos): m / z = 542 [M + H] ⁺ .
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.34 (s, 9H), 1.36 (s, 6H), 2.33 (s, 3H), 2.76 (t, 2H), 3.21 (s , 3H), 3.39 (s, 2H), 3.44 (t, 2H), 3.80 (s, 2H), 4.76 (s, 2H), 7.09 (d, 1H), 7.25-7.45 (m, 7H).

実施例１２Ａ由来の化合物１.３１ｇ（４.１１ｍｍｏｌ）を、最初にＴＨＦ２０ｍｌに入れ、ＤＩＥＡ０.７２ｍｌ（４.１１ｍｍｏｌ）を添加する。５分間撹拌した後、実施例１４Ａ由来の化合物１.００ｇ（４.１１ｍｍｏｌ）、トリエチルアミン０.８６ｍｌ（６.１６ｍｍｏｌ）およびＴＢＡＩ０.３０ｇ（０.８２ｍｍｏｌ）を添加し、反応混合物を室温で終夜撹拌する。次いで、混合物をロータリーエバポレーターで濃縮し、残渣を水に取る。混合物を酢酸エチルで２回抽出し、抽出物を硫酸ナトリウムで乾燥させ、溶媒を減圧下で留去する。シリカゲルのフラッシュクロマトグラフィー（移動相：シクロヘキサン／酢酸エチル１：１）により精製を実施する。これにより、表題化合物３５０ｍｇ（理論値の１８％）を得る。
LC/MS (方法 2): R_t = 1.78 分; MS (ESIpos): m/z = 484 [M+H]⁺.
¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.35 (s*, 15H), 2.33 (s, 3H), 2.68 (sbr, 1H), 3.35 (s, 2H), 3.79 (s, 2H), 4.76 (s, 2H), 7.09 (d, 1H), 7.29 (t, 1H), 7.33-7.43 (m, 6H). Example 16A
tert-butyl 2-methyl-2-({4-[({[4- (3-methylphenyl) -5-oxo-5,6-dihydro-4H-1,3,4-oxadiazin-2-yl] Methyl} amino) methyl] phenyl} thio) propanoate

1.31 g (4.11 mmol) of the compound from Example 12A is first placed in 20 ml of THF and 0.72 ml (4.11 mmol) of DIEA is added. After stirring for 5 minutes, 1.00 g (4.11 mmol) of the compound from Example 14A, 0.86 ml (6.16 mmol) of triethylamine and 0.30 g (0.82 mmol) of TBAI are added and the reaction mixture is stirred at room temperature overnight. To do. The mixture is then concentrated on a rotary evaporator and the residue is taken up in water. The mixture is extracted twice with ethyl acetate, the extract is dried over sodium sulfate and the solvent is distilled off under reduced pressure. Purification is carried out by flash chromatography on silica gel (mobile phase: cyclohexane / ethyl acetate 1: 1). This gives 350 mg (18% of theory) of the title compound.
LC / MS (Method 2): R _t = 1.78 min; MS (ESIpos): m / z = 484 [M + H] ⁺ .
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.35 (s *, 15H), 2.33 (s, 3H), 2.68 (sbr, 1H), 3.35 (s, 2H), 3.79 ( s, 2H), 4.76 (s, 2H), 7.09 (d, 1H), 7.29 (t, 1H), 7.33-7.43 (m, 6H).

実施例１６Ａ由来の化合物１３５ｍｇ（０.２８ｍｍｏｌ）、ヨウ化メチル０.０２ｍｌ（０.３３ｍｍｏｌ）、トリエチルアミン０.１０ｍｌ（０.７０ｍｍｏｌ）およびＤＩＥＡ０.０５ｍｌ（０.２８ｍｍｏｌ）を、ＴＨＦ４ｍｌ中で蒸留し、圧力容器中、１００℃で終夜反応させる。反応混合物をロータリーエバポレーターで濃縮し、残渣を水に取る。混合物を酢酸エチルで２回抽出し、抽出物を硫酸ナトリウムで乾燥させ、溶媒を減圧下で留去する。分取ＨＰＬＣ（移動相：０.１％ギ酸を含むアセトニトリル／水、グラジエント２０：８０→９５：５）により精製を実施する。これにより、表題化合物７３ｍｇ（理論値の５１％）を得る。
LC/MS (方法 2): R_t = 2.32 分; MS (ESIpos): m/z = 498 [M+H]⁺.
¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.34 (s, 9H), 1.36 (s, 6H), 2.26 (s, 3H), 2.33 (s, 3H), 3.28 (s, 2H), 3.66 (s, 2H), 4.80 (s, 2H), 7.09 (d, 1H), 7.24-7.38 (m, 5H), 7.42 (d, 2H). Example 17A
tert-butyl 2-methyl-2-({4-[(methyl {[4- (3-methylphenyl) -5-oxo-5,6-dihydro-4H-1,3,4-oxadiazin-2-yl ] Methyl} amino) methyl] phenyl} thio) propanoate

135 mg (0.28 mmol) of the compound from Example 16A, 0.02 ml (0.33 mmol) of methyl iodide, 0.10 ml (0.70 mmol) of triethylamine and 0.05 ml (0.28 mmol) of DIEA were distilled in 4 ml of THF. The reaction is allowed to proceed overnight at 100 ° C. in a pressure vessel. The reaction mixture is concentrated on a rotary evaporator and the residue is taken up in water. The mixture is extracted twice with ethyl acetate, the extract is dried over sodium sulfate and the solvent is distilled off under reduced pressure. Purification is carried out by preparative HPLC (mobile phase: acetonitrile / water with 0.1% formic acid, gradient 20: 80 → 95: 5). This gives 73 mg (51% of theory) of the title compound.
LC / MS (Method 2): R _t = 2.32 min; MS (ESIpos): m / z = 498 [M + H] ⁺ .
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.34 (s, 9H), 1.36 (s, 6H), 2.26 (s, 3H), 2.33 (s, 3H), 3.28 (s , 2H), 3.66 (s, 2H), 4.80 (s, 2H), 7.09 (d, 1H), 7.24-7.38 (m, 5H), 7.42 (d, 2H).

３−クロロフェニルヒドラジン１３.００ｇ（９１.１７ｍｍｏｌ）および分子ふるい５ｇ（４Å）を、最初に無水ＤＭＦ２００ｍｌに入れる。次いで、クロロアセチルクロリド７.２６ｍｌ（９１.１７ｍｍｏｌ）を無水ＤＭＦ１００ｍｌ中の溶液として、３０分間かけて滴下して添加する。反応完了後（分析ＨＰＬＣにより監視する）、さらに１当量のクロロアセチルクロリドを添加し、ＤＩＥＡ１５.８８ｍｌ（９１.１７ｍｍｏｌ）を無水ＤＭＦ１００ｍｌ中の溶液として、約３０分間かけてゆっくりと滴下して添加する。もう一度ＨＰＬＣで確認した後、さらなるＤＩＥＡ３１.７６ｍｌ（１８２.３４ｍｍｏｌ）を添加する。次いで、混合物を７０℃で終夜撹拌する。冷却後、溶媒を減圧下で留去し、残渣を水に取り、酢酸エチルで３回抽出する。抽出物を水で洗浄し、硫酸ナトリウムで乾燥させ、次いで、溶媒をロータリーエバポレーターで除去する。精製は、シリカゲルのフラッシュクロマトグラフィー（移動相：シクロヘキサン／酢酸エチル５：１）による。これにより、表題化合物１０.００ｇ（理論値の４２％）を得る。
LC/MS (方法 2): R_t = 2.16 分; MS (ESIpos): m/z = 259 [M+H]^+
1H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 4.43 (s, 2H), 4.92 (s, 2H), 7.37 (d, 1H), 7.47 (t, 1H), 7.59 (d, 1H), 7.67 (t, 1H). Example 18A
2- (Chloromethyl) -4- (3-chlorophenyl) -4H-1,3,4-oxadiazin-5 (6H) -one

13.00 g (91.17 mmol) of 3-chlorophenylhydrazine and 5 g (4 kg) of molecular sieve are initially placed in 200 ml of anhydrous DMF. Then 7.26 ml (91.17 mmol) of chloroacetyl chloride is added dropwise over 30 minutes as a solution in 100 ml of anhydrous DMF. After the reaction is complete (monitored by analytical HPLC), another 1 equivalent of chloroacetyl chloride is added and 15.88 ml (91.17 mmol) of DIEA is slowly added dropwise over about 30 minutes as a solution in 100 ml of anhydrous DMF. . After another HPLC check, an additional 31.76 ml (182.34 mmol) of DIEA is added. The mixture is then stirred at 70 ° C. overnight. After cooling, the solvent is distilled off under reduced pressure, the residue is taken up in water and extracted three times with ethyl acetate. The extract is washed with water and dried over sodium sulfate, and then the solvent is removed on a rotary evaporator. Purification is by flash chromatography on silica gel (mobile phase: cyclohexane / ethyl acetate 5: 1). This gives 10.00 g (42% of theory) of the title compound.
LC / MS (Method 2): R _t = 2.16 min; MS (ESIpos): m / z = 259 [M + H] ^+
1 H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 4.43 (s, 2H), 4.92 (s, 2H), 7.37 (d, 1H), 7.47 (t, 1H), 7.59 (d , 1H), 7.67 (t, 1H).

実施例１３Ａ由来の化合物２５０ｍｇ（０.７４ｍｍｏｌ）、実施例１８Ａ由来の化合物２０９ｍｇ（０.８１ｍｍｏｌ）、トリエチルアミン０.２６ｍｌ（１.８４ｍｍｏｌ）およびＴＢＡＩ５４ｍｇ（０.１５ｍｍｏｌ）を、ＴＨＦ３ｍｌに溶解し、圧力容器中、１００℃で終夜反応させる。次いで、溶媒を減圧下で除去し、残渣を水に取る。混合物を酢酸エチルで２回抽出し、抽出物を硫酸ナトリウムで乾燥させ、溶媒をロータリーエバポレーターで除去する。分取ＨＰＬＣ（移動相：０.１％ギ酸を含むアセトニトリル／水、グラジエント２０：８０→９５：５）により精製を実施する。これにより、表題化合物２７６ｍｇ（理論値の６７％）を得る。
LC/MS (方法 1): R_t = 3.17 分; MS (ESIpos): m/z = 562 [M+H]^+
1H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.33 (s, 9H), 1.35 (s, 6H), 2.77 (t, 2H), 3.21 (s, 3H), 3.41 (s, 2H), 3.45 (t, 2H), 3.81 (s, 2H), 4.79 (s, 2H), 7.31-7.50 (m, 6H), 7.61 (m, 1H), 7.68 (t, 1H). Example 19A
tert-butyl 2-({4-[((2-methoxyethyl) {[4- (3-chlorophenyl) -5-oxo-5,6-dihydro-4H-1,3,4-oxadiazin-2-yl ] Methyl} amino) methyl] phenyl} thio) -2-methylpropanoate

250 mg (0.74 mmol) of the compound derived from Example 13A, 209 mg (0.81 mmol) of the compound derived from Example 18A, 0.26 ml (1.84 mmol) of triethylamine and 54 mg (0.15 mmol) of TBAI were dissolved in 3 ml of THF, and pressure React overnight at 100 ° C. in a container. The solvent is then removed under reduced pressure and the residue is taken up in water. The mixture is extracted twice with ethyl acetate, the extract is dried over sodium sulfate and the solvent is removed on a rotary evaporator. Purification is carried out by preparative HPLC (mobile phase: acetonitrile / water with 0.1% formic acid, gradient 20: 80 → 95: 5). This gives 276 mg (67% of theory) of the title compound.
LC / MS (Method 1): R _t = 3.17 min; MS (ESIpos): m / z = 562 [M + H] ^+
1 H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.33 (s, 9H), 1.35 (s, 6H), 2.77 (t, 2H), 3.21 (s, 3H), 3.41 (s , 2H), 3.45 (t, 2H), 3.81 (s, 2H), 4.79 (s, 2H), 7.31-7.50 (m, 6H), 7.61 (m, 1H), 7.68 (t, 1H).

実施例１２Ａ由来の化合物５.００ｇ（１５.７３ｍｍｏｌ）を、最初にＤＭＦ５０ｍｌに入れ、ブロモアセトニトリル１.８９ｇ（１５.７３ｍｍｏｌ）およびトリエチルアミン５.４８ｍｌ（３９.３２ｍｍｏｌ）を室温で添加する。混合物を室温で終夜撹拌し、次いでロータリーエバポレーターで濃縮する。水を残渣に添加し、混合物を酢酸エチルで２回抽出し、抽出物を硫酸ナトリウムで乾燥させ、溶媒を減圧下で留去する。シリカゲルのフラッシュクロマトグラフィー（移動相：シクロヘキサン／酢酸エチル７：３）により精製を実施する。これにより、表題化合物４.５５ｇ（理論値の９０％）を得る。
LC/MS (方法 1): R_t = 2.55 分; MS (ESIpos): m/z = 641 [2M+H]⁺.
¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.36 (s*, 15H), 3.09 (dt, 1H), 3.58 (d, 2H), 3.77 (d, 2H), 7.34 (d, 2H), 7.42 (d, 2H). Example 20A
tert-Butyl 2-[(4-{[(cyanomethyl) amino] methyl} phenyl) thio] -2-methylpropanoate

5.00 g (15.73 mmol) of the compound from Example 12A is initially placed in 50 ml of DMF, and 1.89 g (15.73 mmol) of bromoacetonitrile and 5.48 ml (39.32 mmol) of triethylamine are added at room temperature. The mixture is stirred at room temperature overnight and then concentrated on a rotary evaporator. Water is added to the residue, the mixture is extracted twice with ethyl acetate, the extract is dried over sodium sulphate and the solvent is distilled off under reduced pressure. Purification is carried out by flash chromatography on silica gel (mobile phase: cyclohexane / ethyl acetate 7: 3). This gives 4.55 g (90% of theory) of the title compound.
LC / MS (Method 1): R _t = 2.55 min; MS (ESIpos): m / z = 641 [2M + H] ⁺ .
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.36 (s *, 15H), 3.09 (dt, 1H), 3.58 (d, 2H), 3.77 (d, 2H), 7.34 ( d, 2H), 7.42 (d, 2H).

実施例２０Ａ由来の化合物１５０ｍｇ（０.４７ｍｍｏｌ）、実施例１４Ａ由来の化合物１３４ｍｇ（０.３３ｍｍｏｌ）、トリエチルアミン０.１６ｍｌ（１.１７ｍｍｏｌ）およびＴＢＡＩ３５ｍｇ（０.０９ｍｍｏｌ）を、ＴＨＦ４ｍｌに溶解し、圧力容器中、１００℃で終夜反応させる。反応混合物をロータリーエバポレーターで濃縮し、残渣を水に取る。混合物を酢酸エチルで２回抽出し、抽出物を硫酸ナトリウムで乾燥させ、溶媒を減圧下で留去する。分取ＨＰＬＣ（移動相：０.１％ギ酸を含むアセトニトリル／水、グラジエント２０：８０→９５：５）により精製を実施する。これにより、表題化合物７０ｍｇ（理論値の２９％）を得る。
LC/MS (方法 4): R_t = 3.10 分; MS (ESIpos): m/z = 523 [M+H]^+
1H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.34 (s, 9H), 1.37 (s, 6H), 2.33 (s, 3H), 3.40 (s, 2H), 3.82 (s*, 4H), 4.79 (s, 2H), 7.10 (d, 1H), 7.27-7.41 (m, 5H), 7.45 (d, 2H). Example 21A
tert-butyl 2-({4-[((cyanomethyl) {[4- (3-methylphenyl) -5-oxo-5,6-dihydro-4H-1,3,4-oxadiazin-2-yl] methyl } Amino) methyl] phenyl} thio) -2-methylpropanoate

150 mg (0.47 mmol) of the compound derived from Example 20A, 134 mg (0.33 mmol) of the compound derived from Example 14A, 0.16 ml (1.17 mmol) of triethylamine and 35 mg (0.09 mmol) of TBAI were dissolved in 4 ml of THF, and pressure React overnight at 100 ° C. in a container. The reaction mixture is concentrated on a rotary evaporator and the residue is taken up in water. The mixture is extracted twice with ethyl acetate, the extract is dried over sodium sulfate and the solvent is distilled off under reduced pressure. Purification is carried out by preparative HPLC (mobile phase: acetonitrile / water with 0.1% formic acid, gradient 20: 80 → 95: 5). This gives 70 mg (29% of theory) of the title compound.
LC / MS (Method 4): R _t = 3.10 min; MS (ESIpos): m / z = 523 [M + H] ^+
1 H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.34 (s, 9H), 1.37 (s, 6H), 2.33 (s, 3H), 3.40 (s, 2H), 3.82 (s *, 4H), 4.79 (s, 2H), 7.10 (d, 1H), 7.27-7.41 (m, 5H), 7.45 (d, 2H).

実施例１２Ａ由来の化合物５.００ｇ（１５.７３ｍｍｏｌ）を、最初にＤＭＦ５０ｍｌに入れ、臭化プロパルギル１.８７ｇ（１５.７３ｍｍｏｌ）およびトリエチルアミン５.４８ｍｌ（３９.３２ｍｍｏｌ）を室温で添加する。混合物を室温で終夜撹拌し、次いで、ロータリーエバポレーターで濃縮する。残渣に水を添加し、混合物を酢酸エチルで２回抽出し、抽出物を硫酸ナトリウムで乾燥させ、溶媒を減圧下で留去する。シリカゲルのフラッシュクロマトグラフィー（移動相：シクロヘキサン／酢酸エチル６：４）により精製を実施する。これにより、表題化合物１.７０ｇ（理論値の３４％）を得る。
LC/MS (方法 4): R_t = 1.84 分; MS (ESIpos): m/z = 320 [M+H]^+
1H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.35 (s*, 15H), 2.56 (br. s, 1H), 3.09 (t, 1H), 3.26 (d, 2H), 3.75 (s, 2H), 7.33 (d, 2H), 7.40 (d, 2H). Example 22A
tert-Butyl 2-methyl-2-({4-[(prop-2-yn-1-ylamino) methyl] phenyl} thio) propanoate

5.00 g (15.73 mmol) of the compound from Example 12A is initially placed in 50 ml of DMF, and 1.87 g (15.73 mmol) of propargyl bromide and 5.48 ml (39.32 mmol) of triethylamine are added at room temperature. The mixture is stirred at room temperature overnight and then concentrated on a rotary evaporator. Water is added to the residue, the mixture is extracted twice with ethyl acetate, the extract is dried over sodium sulphate and the solvent is distilled off under reduced pressure. Purification is carried out by flash chromatography on silica gel (mobile phase: cyclohexane / ethyl acetate 6: 4). This gives 1.70 g (34% of theory) of the title compound.
LC / MS (Method 4): R _t = 1.84 min; MS (ESIpos): m / z = 320 [M + H] ^+
1 H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.35 (s *, 15H), 2.56 (br. S, 1H), 3.09 (t, 1H), 3.26 (d, 2H), 3.75 (s, 2H), 7.33 (d, 2H), 7.40 (d, 2H).

実施例２２Ａ由来の化合物１３４ｍｇ（０.４２ｍｍｏｌ）、実施例１４Ａ由来の化合物１２０ｍｇ（０.５０ｍｍｏｌ）、ＤＩＥＡ０.１８ｍｌ（１.０５ｍｍｏｌ）およびＴＢＡＩ３１ｍｇ（０.０８ｍｍｏｌ）を、ＴＨＦ２ｍｌに溶解し、圧力容器中、１００℃で終夜反応させる。反応混合物をロータリーエバポレーターで濃縮し、残渣を水に取る。混合物を酢酸エチルで２回抽出し、抽出物を硫酸ナトリウムで乾燥させ、溶媒を減圧下で留去する。分取ＨＰＬＣ（移動相：０.１％ギ酸を含むアセトニトリル／水、グラジエント２０：８０→９５：５）により精製を実施する。これにより、表題化合物１９３ｍｇ（理論値の８８％）を得る。
LC/MS (方法 1): R_t = 3.24 分; MS (ESIpos): m/z = 522 [M+H]^+
1H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.34 (s, 9H), 1.36 (s, 6H), 2.33 (s, 3H), 3.28 (t, 1H), 3.37 (s, 2H), 3.41 (d, 2H), 3.76 (s, 2H), 4.78 (s, 2H), 7.09 (d, 1H), 7.25-7.40 (m, 5H), 7.43 (d, 2H). Example 23A
tert-butyl 2-methyl-2-[(4-{[{[4- (3-methylphenyl) -5-oxo-5,6-dihydro-4H-1,3,4-oxadiazin-2-yl] Methyl} (prop-2-yn-1-yl) amino] methyl} phenyl) thio] propanoate

134 mg (0.42 mmol) of the compound derived from Example 22A, 120 mg (0.50 mmol) of the compound derived from Example 14A, 0.18 ml (1.05 mmol) of DIEA and 31 mg (0.08 mmol) of TBAI were dissolved in 2 ml of THF, and pressure vessel React overnight at 100 ° C. The reaction mixture is concentrated on a rotary evaporator and the residue is taken up in water. The mixture is extracted twice with ethyl acetate, the extract is dried over sodium sulfate and the solvent is distilled off under reduced pressure. Purification is carried out by preparative HPLC (mobile phase: acetonitrile / water with 0.1% formic acid, gradient 20: 80 → 95: 5). This gives 193 mg (88% of theory) of the title compound.
LC / MS (Method 1): R _t = 3.24 min; MS (ESIpos): m / z = 522 [M + H] ^+
1 H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.34 (s, 9H), 1.36 (s, 6H), 2.33 (s, 3H), 3.28 (t, 1H), 3.37 (s , 2H), 3.41 (d, 2H), 3.76 (s, 2H), 4.78 (s, 2H), 7.09 (d, 1H), 7.25-7.40 (m, 5H), 7.43 (d, 2H).

実施例１６Ａ由来の化合物１００ｍｇ（０.２１ｍｍｏｌ）、１−ブロモ−２−フルオロエタン４０ｍｇ（０.３１ｍｍｏｌ）、ＤＩＥＡ０.０９ｍｌ（０.５２ｍｍｏｌ）およびＴＢＡＩ１３ｍｇ（０.０４ｍｍｏｌ）を、ＴＨＦ１ｍｌに溶解し、圧力容器中、１００℃で終夜反応させる。反応混合物をロータリーエバポレーターで濃縮し、残渣を水に取る。混合物を酢酸エチルで２回抽出し、抽出物を硫酸ナトリウムで乾燥させ、溶媒を減圧下で留去する。分取ＨＰＬＣ（移動相：０.１％ギ酸を含むアセトニトリル／水、グラジエント２０：８０→９５：５）により精製を実施する。これにより、表題化合物８７ｍｇ（理論値の７９％）を得る。
LC/MS (方法 4): R_t = 3.19 分; MS (ESIpos): m/z = 530 [M+H]⁺ Example 24A
tert-butyl 2-({4-[((2-fluoroethyl) {[4- (3-methylphenyl) -5-oxo-5,6-dihydro-4H-1,3,4-oxadiazine-2- Yl] methyl} amino) methyl] phenyl} thio) -2-methylpropanoate

100 mg (0.21 mmol) of the compound derived from Example 16A, 40 mg (0.31 mmol) of 1-bromo-2-fluoroethane, 0.09 ml (0.52 mmol) of DIEA and 13 mg (0.04 mmol) of TBAI were dissolved in 1 ml of THF, The reaction is allowed to proceed overnight at 100 ° C. in a pressure vessel. The reaction mixture is concentrated on a rotary evaporator and the residue is taken up in water. The mixture is extracted twice with ethyl acetate, the extract is dried over sodium sulfate and the solvent is distilled off under reduced pressure. Purification is carried out by preparative HPLC (mobile phase: acetonitrile / water with 0.1% formic acid, gradient 20: 80 → 95: 5). This gives 87 mg (79% of theory) of the title compound.
LC / MS (Method 4): R _t = 3.19 min; MS (ESIpos): m / z = 530 [M + H] ⁺

４−トリフルオロメチルフェニルヒドラジン１.５５ｇ（８.８０ｍｍｏｌ）および分子ふるい（４Å）０.５ｇを、最初に無水ＤＭＦ２０ｍｌに入れる。次いで、クロロアセチルクロリド０.７ｍｌ（８.８０ｍｍｏｌ）を、無水ＤＭＦ１０ｍｌ中の溶液として、３０分間かけて滴下して添加する。反応完了後（分析ＨＰＬＣにより監視する）、さらに１当量のクロロアセチルクロリドを添加し、ＤＩＥＡ１.５ｍｌ（８.８０ｍｍｏｌ）を、無水ＤＭＦ１０ｍｌ中の溶液としてゆっくりと約３０分間かけて滴下して添加する。もう一度ＨＰＬＣで確認した後、さらなるＤＩＥＡ３.０ｍｌ（１７.６０ｍｍｏｌ）を添加する。次いで、混合物を７０℃で終夜撹拌する。冷却後、溶媒を減圧下で留去し、残渣を水に取り、混合物を酢酸エチルで３回抽出する。合わせた有機相を水で洗浄し、硫酸ナトリウムで乾燥させ、次いで、溶媒をロータリーエバポレーターで除去する。精製は、クロマトグラフィー（Biotage 40M、移動相：シクロヘキサン／ｔｅｒｔ−ブチルメチルエーテル３：１）を利用する。これにより、表題化合物０.５４ｇ（理論値の２０％）を得る。
MS (ESIpos): m/z = 310 [M+NH₄]^+
1H-NMR (400 MHz, CDCl₃): δ [ppm] = 4.19 (s, 2H), 4.83 (s, 2H), 7.66 (d, 2H), 7.82 (d, 2H). Example 25A
2- (Chloromethyl) -4- [4- (trifluoromethyl) phenyl] -4H-1,3,4-oxadiazin-5 (6H) -one

1.55 g (8.80 mmol) of 4-trifluoromethylphenylhydrazine and 0.5 g of molecular sieve (4 （) are initially placed in 20 ml of anhydrous DMF. Then 0.7 ml (8.80 mmol) of chloroacetyl chloride is added dropwise over 30 minutes as a solution in 10 ml of anhydrous DMF. After the reaction is complete (monitored by analytical HPLC), another 1 equivalent of chloroacetyl chloride is added and 1.5 ml (8.80 mmol) of DIEA is slowly added dropwise over about 30 minutes as a solution in 10 ml of anhydrous DMF. . After another HPLC check, an additional 3.0 ml (17.60 mmol) of DIEA is added. The mixture is then stirred at 70 ° C. overnight. After cooling, the solvent is distilled off under reduced pressure, the residue is taken up in water and the mixture is extracted three times with ethyl acetate. The combined organic phases are washed with water and dried over sodium sulfate, and then the solvent is removed on a rotary evaporator. Purification uses chromatography (Biotage 40M, mobile phase: cyclohexane / tert-butyl methyl ether 3: 1). This gives 0.54 g (20% of theory) of the title compound.
MS (ESIpos): m / z = 310 [M + NH ₄ ] ^+
1 H-NMR (400 MHz, CDCl ₃ ): δ [ppm] = 4.19 (s, 2H), 4.83 (s, 2H), 7.66 (d, 2H), 7.82 (d, 2H).

実施例１３Ａ由来の化合物５９７ｍｇ（１.７６ｍｍｏｌ）および実施例２５Ａ由来の化合物５１５ｍｇ（１.７６ｍｍｏｌ）を、最初に無水ＤＭＦ５.０ｍｌに入れ、炭酸カリウム４８６ｍｇ（３.５２ｍｍｏｌ）を添加する。混合物を９０℃で１時間撹拌する。水を添加し、反応混合物を酢酸エチルで抽出する。合わせた有機相を水で４回、飽和炭酸ナトリウム溶液で１回洗浄し、硫酸マグネシウムで乾燥させる。溶媒の除去後に得られる粗生成物をクロマトグラフィー（Biotage 40M、移動相：イソヘキサン／酢酸エチル６５：３５）で精製する。これにより、表題化合物６２３ｍｇ（理論値の５９％）を、無色油状物の形態で得る。
LC/MS (方法 1): R_t = 3.30 分; MS (ESIpos): m/z = 596 [M+H]⁺ Example 26A
tert-Butyl 2-[(4-{[(2-methoxyethyl) ({5-oxo-4- [4- (trifluoromethyl) phenyl] -5,6-dihydro-4H-1,3,4- Oxadiazin-2-yl} methyl) amino] methyl} phenyl) thio] -2-methylpropanoate

597 mg (1.76 mmol) of the compound from Example 13A and 515 mg (1.76 mmol) of the compound from Example 25A are first placed in 5.0 ml of anhydrous DMF and 486 mg (3.52 mmol) of potassium carbonate are added. The mixture is stirred at 90 ° C. for 1 hour. Water is added and the reaction mixture is extracted with ethyl acetate. The combined organic phases are washed 4 times with water and once with saturated sodium carbonate solution and dried over magnesium sulfate. The crude product obtained after removal of the solvent is purified by chromatography (Biotage 40M, mobile phase: isohexane / ethyl acetate 65:35). This gives 623 mg (59% of theory) of the title compound in the form of a colorless oil.
LC / MS (Method 1): R _t = 3.30 min; MS (ESIpos): m / z = 596 [M + H] ⁺

４−トリフルオロメトキシフェニルヒドラジン塩酸塩１.５０ｇ（６.５６ｍｍｏｌ）を、約３０％強度の水酸化ナトリウム水溶液６０.０ｍｌに溶解する。水相を酢酸エチルで４回抽出する。合わせた有機相を水および飽和塩化ナトリウム溶液で洗浄し、硫酸マグネシウムで乾燥させる。溶媒の除去後に、茶色がかった油状物の形態で得られる遊離塩基を、最初に無水ＤＭＦ２０.０ｍｌに入れる。次いで、クロロアセチルクロリド０.５ｍｌ（６.２８ｍｍｏｌ）を、無水ＤＭＦ１０ｍｌ中の溶液として、３０分間かけて滴下して添加する。反応完了後（ＨＰＬＣにより監視する）、さらに１当量のクロロアセチルクロリドを添加し、ＤＩＥＡ１.０ｍｌ（６.００ｍｍｏｌ）を、無水ＤＭＦ１０ｍｌ中の溶液として、約３０分間かけてゆっくりと滴下して添加する。もう一度ＨＰＬＣで確認した後、さらなるＤＩＥＡ２.０ｍｌ（１２.００ｍｍｏｌ）を添加する。次いで、混合物を７０℃で終夜撹拌する。冷却後、溶媒を減圧下で留去し、残渣を水に取り、酢酸エチルで３回抽出する。合わせた有機相を水で洗浄し、硫酸ナトリウムで乾燥させ、次いで溶媒をロータリーエバポレーターで除去する。クロマトグラフィー（Biotage 40M、移動相：シクロヘキサン／ｔｅｒｔ−ブチルメチルエーテル３：１）で精製を実施する。これにより、表題化合物０.５３ｇ（理論値の２９％）を得る。
LC/MS (方法 1): R_t = 2.60 分; MS (ESIpos): m/z = 309 [M+H]⁺.
¹H-NMR (400 MHz, CDCl₃): δ [ppm] = 4.17 (s, 2H), 4.82 (s, 2H), 7.26 (d, 2H), 7.67 (d, 2H). Example 27A
2- (Chloromethyl) -4- [4- (trifluoromethoxy) phenyl] -4H-1,3,4-oxadiazin-5 (6H) -one

1.50 g (6.56 mmol) of 4-trifluoromethoxyphenylhydrazine hydrochloride is dissolved in 60.0 ml of about 30% strength aqueous sodium hydroxide solution. The aqueous phase is extracted 4 times with ethyl acetate. The combined organic phases are washed with water and saturated sodium chloride solution and dried over magnesium sulphate. After removal of the solvent, the free base obtained in the form of a brownish oil is initially taken up in 20.0 ml of anhydrous DMF. Then 0.5 ml (6.28 mmol) of chloroacetyl chloride is added dropwise over 30 minutes as a solution in 10 ml of anhydrous DMF. After the reaction is complete (monitored by HPLC), another 1 equivalent of chloroacetyl chloride is added and 1.0 ml (6.00 mmol) of DIEA is slowly added dropwise over about 30 minutes as a solution in 10 ml of anhydrous DMF. . After another HPLC check, an additional 2.0 ml (12.00 mmol) of DIEA is added. The mixture is then stirred at 70 ° C. overnight. After cooling, the solvent is distilled off under reduced pressure, the residue is taken up in water and extracted three times with ethyl acetate. The combined organic phases are washed with water, dried over sodium sulfate and then the solvent is removed on a rotary evaporator. Purification is carried out by chromatography (Biotage 40M, mobile phase: cyclohexane / tert-butyl methyl ether 3: 1). This gives 0.53 g (29% of theory) of the title compound.
LC / MS (Method 1): R _t = 2.60 min; MS (ESIpos): m / z = 309 [M + H] ⁺ .
¹ H-NMR (400 MHz, CDCl ₃ ): δ [ppm] = 4.17 (s, 2H), 4.82 (s, 2H), 7.26 (d, 2H), 7.67 (d, 2H).

実施例１３Ａ由来の化合物５５１ｍｇ（１.６３ｍｍｏｌ）および実施例２７Ａ由来の化合物５０１ｍｇ（１.６３ｍｍｏｌ）を、最初に無水ＤＭＦ５.０ｍｌに入れ、炭酸カリウム４４９ｍｇ（３.２６ｍｍｏｌ）を添加する。混合物を９０℃で１時間撹拌する。水を添加し、反応混合物を酢酸エチルで抽出する。合わせた有機相を水で４回、飽和炭酸ナトリウム溶液で１回洗浄し、硫酸マグネシウムで乾燥させる。溶媒の除去後に得られる粗生成物を、クロマトグラフィー（Biotage 40M、移動相：イソヘキサン／酢酸エチル６５：３５）で精製する。これにより、表題化合物３７１ｍｇ（理論値の３７％）を、無色油状物の形態で得る。
LC/MS (方法 4): R_t = 3.25 分; MS (ESIpos): m/z = 612 [M+H]^+
1H-NMR (400 MHz, CDCl₃): δ [ppm] = 1.43 (sbr, 15H), 2.87 (t, 2H), 3.33 (s, 3H), 3.48 (s, 2H), 3.52 (t, 2H), 3.83 (s, 2H), 4.65 (s, 2H), 7.24 (d, 2H), 7.31 (d, 2H), 7.46 (d, 2H), 7.68 (d, 2H). Example 28A
tert-Butyl 2-[(4-{[(2-methoxyethyl) ({5-oxo-4- [4- (trifluoromethoxy) phenyl] -5,6-dihydro-4H-1,3,4- Oxadiazin-2-yl} methyl) amino] methyl} phenyl) thio] -2-methylpropanoate

551 mg (1.63 mmol) of the compound from Example 13A and 501 mg (1.63 mmol) of the compound from Example 27A are first placed in 5.0 ml of anhydrous DMF and 449 mg (3.26 mmol) of potassium carbonate are added. The mixture is stirred at 90 ° C. for 1 hour. Water is added and the reaction mixture is extracted with ethyl acetate. The combined organic phases are washed 4 times with water and once with saturated sodium carbonate solution and dried over magnesium sulfate. The crude product obtained after removal of the solvent is purified by chromatography (Biotage 40M, mobile phase: isohexane / ethyl acetate 65:35). This gives 371 mg (37% of theory) of the title compound in the form of a colorless oil.
LC / MS (Method 4): R _t = 3.25 min; MS (ESIpos): m / z = 612 [M + H] ^+
1 H-NMR (400 MHz, CDCl ₃ ): δ [ppm] = 1.43 (sbr, 15H), 2.87 (t, 2H), 3.33 (s, 3H), 3.48 (s, 2H), 3.52 (t, 2H ), 3.83 (s, 2H), 4.65 (s, 2H), 7.24 (d, 2H), 7.31 (d, 2H), 7.46 (d, 2H), 7.68 (d, 2H).

４−フルオロフェニルヒドラジン４.００ｇ（３１.７１ｍｍｏｌ）および分子ふるい２ｇ（４Å）を、最初に無水ＤＭＦ８０ｍｌに入れる。次いで、クロロアセチルクロリド３.５８ｍｌ（３１.７１ｍｍｏｌ）を、無水ＤＭＦ１５ｍｌ中の溶液として、３０分間かけて滴下して添加する。反応完了後（分析ＨＰＬＣにより監視する）、さらに１当量のクロロアセチルクロリドを添加し、ＤＩＥＡ５.５２ｍｌ（３１.１７ｍｍｏｌ）を無水ＤＭＦ１５ｍｌ中の溶液として、約３０分間かけてゆっくりと滴下して添加する。もう一度ＨＰＬＣで確認した後、さらなるＤＩＥＡ１１.０５ｍｌ（６３.４３ｍｍｏｌ）を添加する。次いで、混合物を７０℃で終夜撹拌する。冷却後、溶媒を減圧下で留去し、残渣を水に取り、酢酸エチルで３回抽出する。合わせた有機相を水で洗浄し、硫酸ナトリウムで乾燥させ、次いで、溶媒をロータリーエバポレーターで除去する。シリカゲルのフラッシュクロマトグラフィー（移動相：シクロヘキサン／酢酸エチル５：１）により精製を実施する。これにより、まだ環化されていない中間体６.５ｇを得、次いで、それを再度ＤＩＥＡ６.９ｍｌ（３７ｍｍｏｌ）と共に、ＤＭＦ５０ｍｌ中、７０℃で終夜撹拌する。同様の後処理により、表題化合物３.９７ｇ（理論値の４６％）を得る。
LC/MS (方法 4): R_t = 2.13 分; MS (ESIpos): m/z = 243 [M+H]^+
1H-NMR (400 MHz, CDCl₃): δ [ppm] = 4.2 (s, 2H), 4.85 (s, 2H), 7.1 (dd, 2H), 7.55 (m 2H). Example 29A
2- (Chloromethyl) -4- (4-fluorophenyl) -4H-1,3,4-oxadiazin-5 (6H) -one

4.00 g (31.71 mmol) of 4-fluorophenylhydrazine and 2 g (4 kg) of molecular sieve are initially placed in 80 ml of anhydrous DMF. Then, 3.58 ml (31.71 mmol) of chloroacetyl chloride is added dropwise over 30 minutes as a solution in 15 ml of anhydrous DMF. After the reaction is complete (monitored by analytical HPLC), another 1 equivalent of chloroacetyl chloride is added and 5.52 ml (31.17 mmol) of DIEA is added slowly dropwise over about 30 minutes as a solution in 15 ml of anhydrous DMF. . After another HPLC check, an additional 11.05 ml (63.43 mmol) of DIEA is added. The mixture is then stirred at 70 ° C. overnight. After cooling, the solvent is distilled off under reduced pressure, the residue is taken up in water and extracted three times with ethyl acetate. The combined organic phases are washed with water and dried over sodium sulfate, and then the solvent is removed on a rotary evaporator. Purification is carried out by flash chromatography on silica gel (mobile phase: cyclohexane / ethyl acetate 5: 1). This gives 6.5 g of an intermediate that has not yet been cyclized, which is then again stirred with 6.9 ml (37 mmol) of DIEA in 50 ml of DMF at 70 ° C. overnight. A similar workup gives 3.97 g (46% of theory) of the title compound.
LC / MS (Method 4): R _t = 2.13 min; MS (ESIpos): m / z = 243 [M + H] ^+
1 H-NMR (400 MHz, CDCl ₃ ): δ [ppm] = 4.2 (s, 2H), 4.85 (s, 2H), 7.1 (dd, 2H), 7.55 (m 2H).

ｔｅｒｔ−ブチル２−［（４−｛［（２−メトキシエチル）アミノ］メチル｝フェニル）チオ］−２−メチルプロパノエート（実施例１３Ａ）１００ｍｇ（０.２９ｍｍｏｌ）、２−（クロロメチル）−４−（４−フルオロフェニル）−４Ｈ−１,３,４−オキサジアジン−５（６Ｈ）−オン（実施例２９Ａ）７１ｍｇ（０.２９ｍｍｏｌ）および炭酸カリウム８２ｍｇを、ＤＭＦ１ｍｌに溶解し、１２０℃で終夜撹拌する。冷却した混合物を水に注ぐ。酢酸エチルで２回抽出した後、有機相を硫酸ナトリウムで乾燥させ、溶媒をロータリーエバポレーターで除去する。残渣を分取ＨＰＬＣにより精製する。これにより、表題化合物２８ｍｇ（理論値の１７％）を得る。
LC/MS (方法 4): R_t = 2.97 分; MS (ESIpos): m/z = 546 [M+H]^+
1H-NMR (400 MHz, CDCl₃): δ [ppm] = 1.45 (sbr, 15H), 2.75 (sbr, 2H), 3.3 (s, 3H), 3.45 (s, 2H), 3.5 (sbr, 2H), 3.85 (s, 2H), 4.7 (s, 2H), 7.1 (dd, 2H), 7.3 (d, 2H), 7.45 (d, 2H), 7.55 (dd, 2H). Example 30A
tert-butyl 2-({4-[((2-methoxyethyl) {[4- (4-fluorophenyl) -5-oxo-5,6-dihydro-4H-1,3,4-oxadiazine-2- Yl] methyl} amino) methyl] phenyl} thio) -2-methylpropanoate

tert-Butyl 2-[(4-{[(2-methoxyethyl) amino] methyl} phenyl) thio] -2-methylpropanoate (Example 13A) 100 mg (0.29 mmol), 2- (chloromethyl) 4- (4-Fluorophenyl) -4H-1,3,4-oxadiazin-5 (6H) -one (Example 29A) 71 mg (0.29 mmol) and potassium carbonate 82 mg were dissolved in 1 ml of DMF and dissolved at 120 ° C. Stir overnight. Pour the cooled mixture into water. After extraction twice with ethyl acetate, the organic phase is dried over sodium sulphate and the solvent is removed on a rotary evaporator. The residue is purified by preparative HPLC. This gives 28 mg (17% of theory) of the title compound.
LC / MS (Method 4): R _t = 2.97 min; MS (ESIpos): m / z = 546 [M + H] ^{+
1 H-NMR (400 MHz,} CDCl 3): δ [ppm] = 1.45 (sbr, 15H), 2.75 (sbr, 2H), 3.3 (s, 3H), 3.45 (s, 2H), 3.5 (sbr, 2H ), 3.85 (s, 2H), 4.7 (s, 2H), 7.1 (dd, 2H), 7.3 (d, 2H), 7.45 (d, 2H), 7.55 (dd, 2H).

４Ｍ塩化水素のジオキサン溶液５ｍｌを、実施例４Ａ由来の化合物１００ｍｇ（０.１７３ｍｍｏｌ）に添加し、混合物を室温で終夜撹拌する。次いで、溶媒を減圧下で留去し、残った塩酸塩をＬＣ／ＭＳにより特徴解析する。これにより、塩酸塩９０ｍｇ（理論値の９３％、純度９０％）を得る。
LC/MS (方法 4): R_t = 2.69 分; MS (ESIpos): m/z = 522 [M+H]⁺ (遊離塩基)
分取ＨＰＬＣ（移動相：０.１％ギ酸を含むアセトニトリル／水、グラジエント２０：８０→９５：５）によりさらに精製した後、表題化合物を得る。
¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.37 (s, 6H), 2.10 (s, 3H), 2.30 (s, 3H), 3.40 (s, 2H), 3.87 (s, 2H), 3.91 (s, 2H), 4.77 (s, 2H), 6.41 (m, 1H), 6.44 (m, 1H), 7.05-7.15 (m, 3H), 7.39 (d, 2H), 7.43 (d, 2H), 7.66 (s, 1H). Example:
Example 1
2-[(4-{[{[4- (2,4-Dimethylphenyl) -5-oxo-5,6-dihydro-4H-1,3,4-oxadiazin-2-yl] methyl} (2- Furylmethyl) amino] methyl} phenyl) thio] -2-methylpropanoic acid

5 ml of 4M hydrogen chloride in dioxane are added to 100 mg (0.173 mmol) of the compound from Example 4A and the mixture is stirred at room temperature overnight. The solvent is then distilled off under reduced pressure and the remaining hydrochloride salt is characterized by LC / MS. This gives 90 mg of hydrochloride (93% of theory, purity 90%).
LC / MS (Method 4): R _t = 2.69 min; MS (ESIpos): m / z = 522 [M + H] ⁺ (free base)
After further purification by preparative HPLC (mobile phase: acetonitrile / water with 0.1% formic acid, gradient 20: 80 → 95: 5), the title compound is obtained.
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.37 (s, 6H), 2.10 (s, 3H), 2.30 (s, 3H), 3.40 (s, 2H), 3.87 (s , 2H), 3.91 (s, 2H), 4.77 (s, 2H), 6.41 (m, 1H), 6.44 (m, 1H), 7.05-7.15 (m, 3H), 7.39 (d, 2H), 7.43 ( d, 2H), 7.66 (s, 1H).

４Ｍ塩化水素のジオキサン溶液５ｍｌを、実施例６Ａ由来の化合物３６ｍｇ（０.０６４ｍｍｏｌ）に添加し、混合物を室温で終夜撹拌する。次いで、溶媒を減圧下で留去し、残った塩酸塩をＬＣ／ＭＳにより特徴解析する。これにより、塩酸塩２５ｍｇ（理論値の９３％、純度８５％）を得る。
LC/MS (方法 2): R_t = 2.38 分; MS (ESIpos): m/z = 508 [M+H]⁺ (遊離塩基)
分取ＨＰＬＣ（移動相：０.１％ギ酸を含むアセトニトリル／水、グラジエント２０：８０→９５：５）によりさらに精製した後、表題化合物を得る。
¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.35 (s, 6H), 2.14 (s, 3H), 3.28 (s, 2H), 3.72 (s, 2H), 3.75 (s, 2H), 4.75 (s, 2H), 6.32 (d, 1H), 6.41 (dd, 1H), 7.21-7.45 (m, 8H), 7.62 (d, 1H). Example 2
2-[(4-{[{[4- (2-Methylphenyl) -5-oxo-5,6-dihydro-4H-1,3,4-oxadiazin-2-yl] methyl} (2-furylmethyl ) -Amino] methyl} phenyl) thio] -2-methylpropanoic acid

5 ml of 4M hydrogen chloride in dioxane are added to 36 mg (0.064 mmol) of the compound from Example 6A and the mixture is stirred at room temperature overnight. The solvent is then distilled off under reduced pressure and the remaining hydrochloride salt is characterized by LC / MS. This gives 25 mg (93% of theory, purity 85%) of the hydrochloride.
LC / MS (Method 2): R _t = 2.38 min; MS (ESIpos): m / z = 508 [M + H] ⁺ (free base)
After further purification by preparative HPLC (mobile phase: acetonitrile / water with 0.1% formic acid, gradient 20: 80 → 95: 5), the title compound is obtained.
^{1 H-NMR (400 MHz,} DMSO-d 6): δ [ppm] = 1.35 (s, 6H), 2.14 (s, 3H), 3.28 (s, 2H), 3.72 (s, 2H), 3.75 (s , 2H), 4.75 (s, 2H), 6.32 (d, 1H), 6.41 (dd, 1H), 7.21-7.45 (m, 8H), 7.62 (d, 1H).

４Ｍ塩化水素のジオキサン溶液１５ｍｌを、実施例８Ａ由来化合物９００ｍｇ（１.５６ｍｍｏｌ）に添加し、混合物を５０℃で３時間撹拌する。次いで、溶媒を減圧下で留去し、残渣を分取ＨＰＬＣ（移動相：０.１％ギ酸を含むアセトニトリル／水、グラジエント２０：８０→９５：５）により精製する。これにより、表題化合物５２０ｍｇ（理論値の６４％）を得る。
LC/MS (方法 2): R_t = 2.49 分; MS (ESIpos): m/z = 508 [M+H]^+
1H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.37 (s, 6H), 2.33 (s, 3H), 3.43 (s, 2H), 3.87 (s, 2H), 3.89 (s, 2H), 4.75 (s, 2H), 6.41 (d, 1H), 6.45 (dd, 1H), 7.10 (d, 1H), 7.27-7.48 (m, 7H) 7.66 (d, 1H). Example 3
2-[(4-{[{[4- (3-Methylphenyl) -5-oxo-5,6-dihydro-4H-1,3,4-oxadiazin-2-yl] methyl} (2-furylmethyl ) -Amino] methyl} phenyl) thio] -2-methylpropanoic acid

15 ml of 4M hydrogen chloride in dioxane is added to 900 mg (1.56 mmol) of the compound from Example 8A and the mixture is stirred at 50 ° C. for 3 hours. The solvent is then distilled off under reduced pressure and the residue is purified by preparative HPLC (mobile phase: acetonitrile / water with 0.1% formic acid, gradient 20: 80 → 95: 5). This gives 520 mg (64% of theory) of the title compound.
LC / MS (Method 2): R _t = 2.49 min; MS (ESIpos): m / z = 508 [M + H] ^+
1 H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.37 (s, 6H), 2.33 (s, 3H), 3.43 (s, 2H), 3.87 (s, 2H), 3.89 (s , 2H), 4.75 (s, 2H), 6.41 (d, 1H), 6.45 (dd, 1H), 7.10 (d, 1H), 7.27-7.48 (m, 7H) 7.66 (d, 1H).

４Ｍ塩化水素のジオキサン溶液３ｍｌを、実施例１０Ａ由来の化合物１１ｍｇ（０.０２０ｍｍｏｌ）に添加し、混合物を室温で終夜撹拌する。次いで、溶媒を減圧下で留去し、残った塩酸塩をＬＣ／ＭＳにより特徴解析する。これにより、塩酸塩９ｍｇ（理論値の７２％、純度８５％）を得る。
LC/MS (方法 4): R_t = 2.69 分; MS (ESIpos): m/z = 508 [M+H]⁺ (遊離塩基)
分取ＨＰＬＣ（移動相：０.１％ギ酸を含むアセトニトリル／水、グラジエント２０：８０→９５：５）によりさらに精製した後、遊離塩基を得る。
¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.36 (s, 6H), 2.31 (s, 3H), 3.31 (s, 2H), 3.75 (s, 2H), 3.77 (s, 2H), 4.72 (s, 2H), 6.34 (s*, 1H), 6.41 (s*, 1H), 7.22 (d, 2H), 7.33-7.45 (m, 6H), 7.62 (s, 1H), 12.59 (br. s, 1H). Example 4
2-[(4-{[{[4- (4-Methylphenyl) -5-oxo-5,6-dihydro-4H-1,3,4-oxadiazin-2-yl] methyl} (2-furylmethyl ) -Amino] methyl} phenyl) thio] -2-methylpropanoic acid

3 ml of 4M hydrogen chloride in dioxane are added to 11 mg (0.020 mmol) of the compound from Example 10A and the mixture is stirred at room temperature overnight. The solvent is then distilled off under reduced pressure and the remaining hydrochloride salt is characterized by LC / MS. This gives 9 mg of hydrochloride (72% of theory, purity 85%).
LC / MS (Method 4): R _t = 2.69 min; MS (ESIpos): m / z = 508 [M + H] ⁺ (free base)
The free base is obtained after further purification by preparative HPLC (mobile phase: acetonitrile / water with 0.1% formic acid, gradient 20: 80 → 95: 5).
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.36 (s, 6H), 2.31 (s, 3H), 3.31 (s, 2H), 3.75 (s, 2H), 3.77 (s , 2H), 4.72 (s, 2H), 6.34 (s *, 1H), 6.41 (s *, 1H), 7.22 (d, 2H), 7.33-7.45 (m, 6H), 7.62 (s, 1H), 12.59 (br.s, 1H).

４Ｍ塩化水素のジオキサン溶液５ｍｌを、実施例１５Ａ由来の化合物１１６ｍｇ（０.２１ｍｍｏｌ）に添加し、混合物を４０℃で３時間撹拌する。次いで、溶媒を減圧下で留去する。これにより、表題化合物１１５ｍｇ（理論値の９９％）を得る。
LC/MS (方法 2): R_t = 2.02 分; MS (ESIpos): m/z = 486 [M+H]⁺ (遊離塩基)
¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.39 (s, 6H), 2.35 (s, 3H), 3.27 (s, 3H), 3.44-3.75 (m, 4H), 3.95 (sbr, 2H), 4.43 (sbr, 2H), 4.88 (s, 2H), 7.13 (d, 1H), 7.28-7.42 (m, 3H), 7.44-7.53 (m, 2H), 7.54-7.66 (m, 2H). Example 5
2-({4-[((2-methoxyethyl) {[4- (3-methylphenyl) -5-oxo-5,6-dihydro-4H-1,3,4-oxadiazin-2-yl] methyl } Amino) methyl] phenyl} thio) -2-methylpropanoic acid hydrochloride

5 ml of 4M hydrogen chloride in dioxane are added to 116 mg (0.21 mmol) of the compound from Example 15A and the mixture is stirred at 40 ° C. for 3 hours. The solvent is then distilled off under reduced pressure. This gives 115 mg (99% of theory) of the title compound.
LC / MS (Method 2): R _t = 2.02 min; MS (ESIpos): m / z = 486 [M + H] ⁺ (free base)
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.39 (s, 6H), 2.35 (s, 3H), 3.27 (s, 3H), 3.44-3.75 (m, 4H), 3.95 (sbr, 2H), 4.43 (sbr, 2H), 4.88 (s, 2H), 7.13 (d, 1H), 7.28-7.42 (m, 3H), 7.44-7.53 (m, 2H), 7.54-7.66 (m , 2H).

４Ｍ塩化水素のジオキサン溶液５ｍｌを、実施例１６Ａ由来の化合物１００ｍｇ（０.２１ｍｍｏｌ）に添加し、混合物を４０℃で３時間撹拌する。次いで、溶媒を減圧下で留去する。これにより、表題化合物９０ｍｇ（理論値の９３％）を得る。
LC/MS (方法 2): R_t = 1.51 分; MS (ESIpos): m/z = 428 [M+H]⁺ (遊離塩基)
¹H-NMR (400 MHz, CDCl₃): δ [ppm] = 1.49 (s, 6H), 2.36 (s, 3H), 3.50-3.85 (m, 2H), 4.23 (sbr, 2H), 4.79 (s, 2H), 7.06 (d, 1H), 7.26 (1H), 7.35-7.64 (m, 6H), 10.22 (sbr, 1H). Example 6
2-methyl-2-({4-[({[4- (3-methylphenyl) -5-oxo-5,6-dihydro-4H-1,3,4-oxadiazin-2-yl] methyl} amino ) Methyl] phenyl} thio) propanoic acid hydrochloride

5 ml of 4M hydrogen chloride in dioxane is added to 100 mg (0.21 mmol) of the compound from Example 16A and the mixture is stirred at 40 ° C. for 3 hours. The solvent is then distilled off under reduced pressure. This gives 90 mg (93% of theory) of the title compound.
LC / MS (Method 2): R _t = 1.51 min; MS (ESIpos): m / z = 428 [M + H] ⁺ (free base)
¹ H-NMR (400 MHz, CDCl ₃ ): δ [ppm] = 1.49 (s, 6H), 2.36 (s, 3H), 3.50-3.85 (m, 2H), 4.23 (sbr, 2H), 4.79 (s , 2H), 7.06 (d, 1H), 7.26 (1H), 7.35-7.64 (m, 6H), 10.22 (sbr, 1H).

実施例１７Ａ由来の化合物１１.７７ｇ（０.２３ｍｍｏｌ）を、最初にジクロロメタン３０ｍｌに入れ、トリフルオロ酢酸３０ｍｌを０℃で添加する。室温で１時間撹拌した後、混合物を濃縮し、次いで、残渣を２０％強度酢酸ナトリウム溶液に取る。混合物を酢酸エチルで抽出し、合わせた有機相を水および濃塩化ナトリウム溶液で洗浄し、硫酸ナトリウムで乾燥させる。溶媒を減圧下で留去し、次いで、残渣を高真空下に乾燥させる。これにより、表題化合物９.５８ｇ（理論値の９２％）を得る。
LC/MS (方法 2): R_t = 1.58 分; MS (ESIpos): m/z = 442 [M+H]^+
1H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.37 (s, 6H), 2.26 (s, 3H), 2.33 (s, 3H), 3.29 (s, 2H), 3.66 (s, 2H), 4.80 (s, 2H), 7.10 (d, 1H), 7.27-7.38 (m, 5H), 7.41 (d, 2H), 12.49 (br. s, 1H). Example 7
2-methyl-2-({4-[(methyl {[4- (3-methylphenyl) -5-oxo-5,6-dihydro-4H-1,3,4-oxadiazin-2-yl] methyl} Amino) methyl] phenyl} thio) propanoic acid

11.77 g (0.23 mmol) of the compound from Example 17A are initially placed in 30 ml of dichloromethane and 30 ml of trifluoroacetic acid are added at 0 ° C. After stirring for 1 hour at room temperature, the mixture is concentrated and the residue is then taken up in 20% strength sodium acetate solution. The mixture is extracted with ethyl acetate and the combined organic phases are washed with water and concentrated sodium chloride solution and dried over sodium sulfate. The solvent is distilled off under reduced pressure and the residue is then dried under high vacuum. This gives 9.58 g (92% of theory) of the title compound.
LC / MS (Method 2): R _t = 1.58 min; MS (ESIpos): m / z = 442 [M + H] ^+
1 H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.37 (s, 6H), 2.26 (s, 3H), 2.33 (s, 3H), 3.29 (s, 2H), 3.66 (s , 2H), 4.80 (s, 2H), 7.10 (d, 1H), 7.27-7.38 (m, 5H), 7.41 (d, 2H), 12.49 (br.s, 1H).

４Ｍ塩化水素のジオキサン溶液１０ｍｌを、実施例１９Ａ由来の化合物２７６ｍｇ（０.４９ｍｍｏｌ）に添加し、混合物を４０℃で３時間撹拌する。次いで、溶媒を減圧下で留去する。これにより、表題化合物２４９ｍｇ（理論値の９４％）を得る。
LC/MS (方法 4): R_t = 2.33 分; MS (ESIpos): m/z = 506 [M+H]⁺ (遊離塩基)
¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.38 (s, 6H), 3.27 (s, 3H), 3.44-3.74 (m, 4H), 3.97 (sbr, 2H), 4.42 (sbr, 2H), 4.89 (s, 2H), 7.38 (d, 1H), 7.44-7.67 (m, 6H), 7.71 (t, 1H). Example 8
2-({4-[((2-methoxyethyl) {[4- (3-chlorophenyl) -5-oxo-5,6-dihydro-4H-1,3,4-oxadiazin-2-yl] methyl} -Amino) methyl] phenyl} thio) -2-methylpropanoic acid hydrochloride

10 ml of 4M hydrogen chloride in dioxane are added to 276 mg (0.49 mmol) of the compound from Example 19A and the mixture is stirred at 40 ° C. for 3 hours. The solvent is then distilled off under reduced pressure. This gives 249 mg (94% of theory) of the title compound.
LC / MS (Method 4): R _t = 2.33 min; MS (ESIpos): m / z = 506 [M + H] ⁺ (free base)
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.38 (s, 6H), 3.27 (s, 3H), 3.44-3.74 (m, 4H), 3.97 (sbr, 2H), 4.42 (sbr, 2H), 4.89 (s, 2H), 7.38 (d, 1H), 7.44-7.67 (m, 6H), 7.71 (t, 1H).

４Ｍ塩化水素のジオキサン溶液５ｍｌを、実施例２１Ａ由来の化合物７０ｍｇ（０.１３ｍｍｏｌ）に添加し、混合物を４０℃で３時間撹拌する。次いで、溶媒を減圧下で留去し、残渣を分取ＨＰＬＣ（移動相：０.１％ギ酸を含むアセトニトリル／水、グラジエント２０：８０→９５：５）により精製する。これにより、表題化合物４０ｍｇ（理論値の６４％）を得る。
LC/MS (方法 1): R_t = 2.51 分; MS (ESIpos): m/z = 467 [M+H]⁺.
¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.37 (s, 6H), 2.33 (s, 3H), 3.41 (s, 2H), 3.82 (s*, 4H), 4.79 (s, 2H), 7.10 (d, 1H), 7.27-7.39 (m, 5H), 7.44 (d, 2H). Example 9
2-({4-[((cyanomethyl) {[4- (3-methylphenyl) -5-oxo-5,6-dihydro-4H-1,3,4-oxadiazin-2-yl] methyl} amino) Methyl] phenyl} thio) -2-methylpropanoic acid

5 ml of 4M hydrogen chloride in dioxane are added to 70 mg (0.13 mmol) of the compound from Example 21A and the mixture is stirred at 40 ° C. for 3 hours. The solvent is then distilled off under reduced pressure and the residue is purified by preparative HPLC (mobile phase: acetonitrile / water with 0.1% formic acid, gradient 20: 80 → 95: 5). This gives 40 mg (64% of theory) of the title compound.
LC / MS (Method 1): R _t = 2.51 min; MS (ESIpos): m / z = 467 [M + H] ⁺ .
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.37 (s, 6H), 2.33 (s, 3H), 3.41 (s, 2H), 3.82 (s *, 4H), 4.79 ( s, 2H), 7.10 (d, 1H), 7.27-7.39 (m, 5H), 7.44 (d, 2H).

実施例２３Ａ由来の化合物１２０ｍｇ（０.２３ｍｍｏｌ）を、最初にジクロロメタン３ｍｌに入れ、トリフルオロ酢酸３ｍｌを０℃で添加する。室温で１時間撹拌した後、混合物を濃縮し、クロロホルムを残渣に添加し、溶媒を再度減圧下で留去する。残渣を分取ＨＰＬＣ（移動相：０.１％ギ酸を含むアセトニトリル／水、グラジエント２０：８０→９５：５）により精製する。これにより、表題化合物８０ｍｇ（理論値の７５％）を得る。
LC/MS (方法 4): R_t = 2.58 分; MS (ESIpos): m/z = 466 [M+H]^+
1H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.36 (s, 6H), 2.33 (s, 3H), 3.28 (t, 1H), 3.37 (s, 2H), 3.41 (d, 2H), 3.75 (s, 2H), 4.77 (s, 2H), 7.09 (d, 1H), 7.26-7.38 (m, 5H), 7.42 (d, 2H), 12.58 (br. s, 1H). Example 10
2-methyl-2-[(4-{[{[4- (3-methylphenyl) -5-oxo-5,6-dihydro-4H-1,3,4-oxadiazin-2-yl] methyl} ( Prop-2-yn-1-yl) amino] methyl} phenyl) thio] propanoic acid

120 mg (0.23 mmol) of the compound from Example 23A are initially placed in 3 ml of dichloromethane and 3 ml of trifluoroacetic acid are added at 0 ° C. After stirring for 1 hour at room temperature, the mixture is concentrated, chloroform is added to the residue and the solvent is again distilled off under reduced pressure. The residue is purified by preparative HPLC (mobile phase: acetonitrile / water with 0.1% formic acid, gradient 20: 80 → 95: 5). This gives 80 mg (75% of theory) of the title compound.
LC / MS (Method 4): R _t = 2.58 min; MS (ESIpos): m / z = 466 [M + H] ^+
1 H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.36 (s, 6H), 2.33 (s, 3H), 3.28 (t, 1H), 3.37 (s, 2H), 3.41 (d , 2H), 3.75 (s, 2H), 4.77 (s, 2H), 7.09 (d, 1H), 7.26-7.38 (m, 5H), 7.42 (d, 2H), 12.58 (br.s, 1H).

実施例２４Ａ由来の化合物８７ｍｇ（０.１６ｍｍｏｌ）を、最初にジクロロメタン３ｍｌに入れ、トリフルオロ酢酸３ｍｌを０℃で添加する。室温で１時間撹拌した後、混合物を濃縮し、残渣を飽和重炭酸ナトリウム溶液に取る。混合物をジクロロメタンで２回抽出し、有機相を合わせ、硫酸ナトリウムで乾燥させる。溶媒を減圧下で留去し、残渣を高真空下で乾燥させる。これにより、表題化合物７６ｍｇ（理論値の９８％）を得る。
LC/MS (方法 2): R_t = 2.35 分; MS (ESIpos): m/z = 474 [M+H]^+
1H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.36 (s, 6H), 2.33 (s, 3H), 2.94 (dt, 2H), 3.42 (s, 2H), 3.84 (s, 2H), 4.53 (dt, 2H), 4.75 (s, 2H), 7.09 (d, 1H), 7.27-7.43 (m, 7H), 12.57 (br. s, 1H). Example 11
2-({4-[((2-Fluoroethyl) {[4- (3-methylphenyl) -5-oxo-5,6-dihydro-4H-1,3,4-oxadiazin-2-yl] methyl } Amino) methyl] phenyl} thio) -2-methylpropanoic acid

87 mg (0.16 mmol) of the compound from Example 24A are initially placed in 3 ml of dichloromethane and 3 ml of trifluoroacetic acid are added at 0 ° C. After stirring for 1 hour at room temperature, the mixture is concentrated and the residue is taken up in saturated sodium bicarbonate solution. The mixture is extracted twice with dichloromethane and the organic phases are combined and dried over sodium sulfate. The solvent is distilled off under reduced pressure and the residue is dried under high vacuum. This gives 76 mg (98% of theory) of the title compound.
LC / MS (Method 2): R _t = 2.35 min; MS (ESIpos): m / z = 474 [M + H] ^+
1 H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.36 (s, 6H), 2.33 (s, 3H), 2.94 (dt, 2H), 3.42 (s, 2H), 3.84 (s , 2H), 4.53 (dt, 2H), 4.75 (s, 2H), 7.09 (d, 1H), 7.27-7.43 (m, 7H), 12.57 (br.s, 1H).

実施例７由来の化合物９.５８ｇ（２１.７０ｍｍｏｌ）を、必要量のジクロロメタンに溶解し、２Ｍ塩化水素のジエチルエーテル溶液１０.８５ｍｌ（２１.７０ｍｍｏｌ）を注意深く添加する。沈殿した塩酸塩を濾過し、固体をジエチルエーテルで洗浄する。高真空下で乾燥し、表題化合物８.８７ｇ（理論値の８６％）を得る。
LC/MS (方法 4): R_t = 1.79 分; MS (ESIpos): m/z = 442 [M+H]^+
1H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.40 (s, 6H), 2.35 (s, 3H), 2.79 (sbr, 3H), 4.04 (sbr, 2H), 4.40 (sbr, 1H), 4.55 (sbr, 1H), 4.91 (s, 2H), 7.13 (d, 1H), 7.29-7.44 (m, 3H), 7.50 (d, 2H), 7.55-7.64 (m, 2H), 11.11 (sbr, 1H), 12.70 (sbr, 1H). Example 12
2-methyl-2-({4-[(methyl {[4- (3-methylphenyl) -5-oxo-5,6-dihydro-4H-1,3,4-oxadiazin-2-yl] methyl} Amino) methyl] phenyl} thio) propanoic acid hydrochloride

9.58 g (21.70 mmol) of the compound from Example 7 are dissolved in the required amount of dichloromethane and 10.85 ml (21.70 mmol) of 2M hydrogen chloride in diethyl ether are carefully added. The precipitated hydrochloride is filtered and the solid is washed with diethyl ether. Dry under high vacuum to obtain 8.87 g (86% of theory) of the title compound.
LC / MS (Method 4): R _t = 1.79 min; MS (ESIpos): m / z = 442 [M + H] ^+
1 H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.40 (s, 6H), 2.35 (s, 3H), 2.79 (sbr, 3H), 4.04 (sbr, 2H), 4.40 (sbr , 1H), 4.55 (sbr, 1H), 4.91 (s, 2H), 7.13 (d, 1H), 7.29-7.44 (m, 3H), 7.50 (d, 2H), 7.55-7.64 (m, 2H), 11.11 (sbr, 1H), 12.70 (sbr, 1H).

実施例２６Ａ由来の化合物６２３ｍｇ（１.０５ｍｍｏｌ）を、最初にジクロロメタン６ｍｌに入れ、トリフルオロ酢酸３ｍｌを添加する。室温で１時間撹拌した後、混合物を濃縮し、残渣を酢酸エチルに取る。有機相を水、２０％強度酢酸ナトリウム溶液および飽和塩化ナトリウム溶液で洗浄し、硫酸マグネシウムで乾燥させる。溶媒を減圧下で留去し、残渣を高真空下で乾燥させる。粗生成物を分取ＨＰＬＣ（移動相：０.１％ギ酸を含むアセトニトリル／水、グラジエント２０：８０→９５：５）により精製する。これにより、表題化合物７２ｍｇ（理論値の１３％）を無色油状物の形態で得る。
LC/MS (方法 1): R_t = 2.59 分; MS (ESIpos): m/z = 540 [M+H]^+
1H-NMR (400 MHz, CDCl₃): δ [ppm] = 1.51 (s, 6H), 2.90 (t, 2H), 3.33 (s, 3H), 3.50 (s, 2H), 3.54 (t, 2H), 3.85 (s, 2H), 4.56 (s, 2H), 7.34 (d, 2H), 7.46 (d, 2H), 7.65 (d, 2H), 7.83 (d, 2H). Example 13
2-[(4-{[(2-methoxyethyl) ({5-oxo-4- [4- (trifluoromethyl) phenyl] -5,6-dihydro-4H-1,3,4-oxadiazine-2 -Yl} methyl) amino] methyl} phenyl) thio] -2-methylpropionic acid

623 mg (1.05 mmol) of the compound from Example 26A are initially placed in 6 ml of dichloromethane and 3 ml of trifluoroacetic acid are added. After stirring for 1 hour at room temperature, the mixture is concentrated and the residue is taken up in ethyl acetate. The organic phase is washed with water, 20% strength sodium acetate solution and saturated sodium chloride solution and dried over magnesium sulfate. The solvent is distilled off under reduced pressure and the residue is dried under high vacuum. The crude product is purified by preparative HPLC (mobile phase: acetonitrile / water with 0.1% formic acid, gradient 20: 80 → 95: 5). This gives 72 mg (13% of theory) of the title compound in the form of a colorless oil.
LC / MS (Method 1): R _t = 2.59 min; MS (ESIpos): m / z = 540 [M + H] ^+
1 H-NMR (400 MHz, CDCl ₃ ): δ [ppm] = 1.51 (s, 6H), 2.90 (t, 2H), 3.33 (s, 3H), 3.50 (s, 2H), 3.54 (t, 2H ), 3.85 (s, 2H), 4.56 (s, 2H), 7.34 (d, 2H), 7.46 (d, 2H), 7.65 (d, 2H), 7.83 (d, 2H).

実施例２８Ａ由来の化合物３６０ｍｇ（０.５９ｍｍｏｌ）を、最初にジクロロメタン３.４ｍｌに入れ、トリフルオロ酢酸１.７ｍｌを添加する。室温で１時間撹拌した後、混合物を濃縮し、残渣を酢酸エチルに取る。有機相を水、２０％強度酢酸ナトリウム溶液および飽和塩化ナトリウム溶液で洗浄し、硫酸マグネシウムで乾燥させる。溶媒を減圧下で留去し、残渣を高真空下で乾燥させる。粗生成物を分取ＨＰＬＣ（移動相：０.１％ギ酸を含むアセトニトリル／水、グラジエント２０：８０→９５：５）により精製する。これにより、表題化合物２０９ｍｇ（理論値の６４％）を、無色油状物の形態で得る。
LC/MS (方法 4): R_t = 2.44 分; MS (ESIpos): m/z = 556 [M+H]^+
1H-NMR (400 MHz, CDCl₃): δ [ppm] = 1.51 (s, 6H), 2.89 (t, 2H), 3.33 (s, 3H), 3.48 (s, 2H), 3.53 (t, 2H), 3.84 (s, 2H), 4.55 (s, 2H), 7.24 (d, 2H), 7.33 (d, 2H), 7.47 (d, 2H), 7.67 (d, 2H). Example 14
2-[(4-{[(2-methoxyethyl) ({5-oxo-4- [4- (trifluoromethoxy) phenyl] -5,6-dihydro-4H-1,3,4-oxadiazine-2 -Yl} methyl) amino] methyl} phenyl) thio] -2-methylpropionic acid

360 mg (0.59 mmol) of the compound from Example 28A are initially placed in 3.4 ml of dichloromethane and 1.7 ml of trifluoroacetic acid are added. After stirring for 1 hour at room temperature, the mixture is concentrated and the residue is taken up in ethyl acetate. The organic phase is washed with water, 20% strength sodium acetate solution and saturated sodium chloride solution and dried over magnesium sulfate. The solvent is distilled off under reduced pressure and the residue is dried under high vacuum. The crude product is purified by preparative HPLC (mobile phase: acetonitrile / water with 0.1% formic acid, gradient 20: 80 → 95: 5). This gives 209 mg (64% of theory) of the title compound in the form of a colorless oil.
LC / MS (Method 4): R _t = 2.44 min; MS (ESIpos): m / z = 556 [M + H] ^+
1 H-NMR (400 MHz, CDCl ₃ ): δ [ppm] = 1.51 (s, 6H), 2.89 (t, 2H), 3.33 (s, 3H), 3.48 (s, 2H), 3.53 (t, 2H ), 3.84 (s, 2H), 4.55 (s, 2H), 7.24 (d, 2H), 7.33 (d, 2H), 7.47 (d, 2H), 7.67 (d, 2H).

４Ｍ塩化水素のジオキサン溶液５ｍｌを実施例３０Ａ由来の化合物２５ｍｇ（０.０５ｍｍｏｌ）に添加し、混合物を室温で終夜撹拌する。次いで、溶媒を減圧下で留去し、残渣を真空で乾燥させる。これにより、表題化合物２４ｍｇ（理論値の９８％）を得る。
LC/MS (方法 2): R_t = 1.96 分; MS (ESIpos): m/z = 490 [M+H]^+
1H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.4 (s, 6H), 3.25 (s, 3H), 3.4-3.75 (m, 8H), 4.85 (s, 2H), 7.3 (t, 2H), 7.45 (m, 3H), 7.6 (dd, 2H), 7.7 (m, 1H). Example 15
2-({4-[((2-methoxyethyl) {[4- (4-fluorophenyl) -5-oxo-5,6-dihydro-4H-1,3,4-oxadiazin-2-yl] methyl } Amino) methyl] phenyl} thio)]-2-methylpropanoic acid hydrochloride

5 ml of 4M hydrogen chloride in dioxane is added to 25 mg (0.05 mmol) of the compound from Example 30A and the mixture is stirred at room temperature overnight. The solvent is then distilled off under reduced pressure and the residue is dried in vacuo. This gives 24 mg (98% of theory) of the title compound.
LC / MS (Method 2): R _t = 1.96 min; MS (ESIpos): m / z = 490 [M + H] ^+
1 H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.4 (s, 6H), 3.25 (s, 3H), 3.4-3.75 (m, 8H), 4.85 (s, 2H), 7.3 (t, 2H), 7.45 (m, 3H), 7.6 (dd, 2H), 7.7 (m, 1H).

B. Evaluation of Pharmacological Activity The pharmacological activity of the compounds according to the invention can be demonstrated by the following assay:
1. Cell transactivation assay :
a) Test principle:
A cellular assay is used to identify activators of peroxisome proliferator activated receptor alpha (PPAR-alpha).
Mammalian cells contain a variety of endogenous nuclear receptors that can complicate the unpredictable interpretation of results, so that the ligand binding domain of the human PPARα receptor is fused to the DNA binding domain of the yeast transcription factor GAL4. Use a chimeric system. The resulting GAL4-PPARα chimera is transfected together and stably expressed in CHO cells with the receptor construct.

b) Cloning:
The GAL4-PPARα expression construct contains the ligand binding domain of PPARα (amino acids 167-468) amplified by PCR and cloned into the vector pcDNA3.1. This vector already contains the GAL4 DNA binding domain (amino acids 1-147) of the vector pFC2-dbd (Stratagene). A reporter construct containing 5 copies of the GAL4 binding site upstream of the thymidine kinase promoter expresses firefly luciferase (Photinus pyralis) following activation and binding of GAL4-PPARα.

c) Transactivation assay (luciferase reporter):
CHO (Chinese Hamster Ovary) cells were 384-well plates (Greiner) at a cell density of 2 × 10 ³ cells / well in DMEM / F12 medium (BioWhittaker) supplemented with 10% fetal bovine serum and 1% penicillin / streptomycin (GIBCO). Sow. Cells were cultured for 48 hours at 37 ° C. and then stimulated. For this purpose, the substance to be tested is taken up in CHO-A-SFM medium (GIBCO) supplemented with 10% fetal calf serum and 1% penicillin / streptomycin (GIBCO) and added to the cells. After a 24 hour stimulation period, luciferase activity is measured using a video camera. The measured relative light unit gives a sigmoidal stimulation curve as a function of substance concentration. EC ₅₀ values are calculated using the computer program GraphPad PRISM (Version 3.02).
In this test, the compounds according to the invention exhibit EC ₅₀ values of 1 μM to 10 nM.

2. Fibrinogen measurement:
In order to determine the effect on plasma fibrinogen concentration, male Wistar rats or NMRI mice are treated for 4-9 days with the substance to be investigated, by gavage or by addition to food. Next, citrated blood is obtained by cardiac puncture under terminal anesthesia. Plasma fibrinogen concentration is determined by measuring thrombin time according to Clauss method [A. Clauss, Acta Haematol. 17 , 237-46 (1957)] using human fibrinogen as a standard.

3. Increase apoprotein A1 (ApoA1) and HDL cholesterol (HDL-C) concentrations in the serum of transgenic mice transfected with the human ApoA1 gene (hApoA1) and / or reduce serum triglycerides (TG), Test description to find pharmaceutically active substances:
A substance to be examined in vivo for HDL-C-increasing activity is orally administered to male transgenic hApoA1 mice. The day before the start of the experiment, animals are randomized into groups containing the same number (generally n = 7-10) of animals. Throughout the experiment, animals have free access to drinking water and food. The substance is administered orally once a day for 7 days. For this purpose, the test substances are dissolved in a solution of Solutol HS 15 + ethanol + brine (0.9%) (ratio 1 + 1 + 8) or in a solution of Solutol HS 15 + brine (0.9%) (ratio 2 + 8). Dissolved material is administered in a volume of 10 ml / kg body weight using a gastric tube. Animals treated in exactly the same way but given only the vehicle without test substance (10 ml / kg body weight) serve as a control group.

Prior to the first substance administration, blood samples are collected from each mouse by puncture of the retro-orbital venous plexus and ApoA1, serum cholesterol, HDL-C and serum triglycerides (TG) are measured (zero value). Subsequently, the test substance is administered to the animal for the first time using a gastric tube. 24 hours after the last substance administration (8 days after the start of treatment), a blood sample from each animal is again collected by puncture of the retroorbital venous plexus and the same parameters are measured. After centrifuging the blood sample and obtaining serum, each cassette (TRIGL, CHOL2, HDL-C and APOAT) can be removed using the Cobas Integra 400 Plus instrument (Cobas Integra, Roche Diagnostics GmbH, Mannheim, Germany). Used to measure TG, cholesterol, HDL-C and human ApoA1. Similar to the method of Garber et al. [J. Lipid Res. 41 , 1020-1026 (2000)], gel filtration and post-column derivatization using MEGA cholesterol reagent (Merck KGaA) can be used for HDL- C is measured.

  The effect of the test substance on the concentration of HDL-C, hApoA1 and TG is determined by subtracting the value measured in the first blood sample (zero value) from the value measured in the second blood sample (after treatment) To do. The average difference of all HDL-C, hApoA1 and TG values of the group is determined and compared to the average difference of the control group. After confirming the variance for homogeneity, statistical evaluation is performed using Student's t-test.

  HDL-C of treated animals is statistically significantly (p <0.05) increased by at least 20% compared to the control group, or TG is statistically significantly (p <0.05) by at least 25 Substances that decrease by% are considered pharmacologically effective.

C. Examples of pharmaceutical compositions The compounds according to the invention can be converted into pharmaceutical formulations in the following manner:
tablet:
composition:
100 mg of the compound according to the invention, 50 mg lactose (monohydrate), 50 mg corn starch, 10 mg polyvinylpyrrolidone (PVP 25) (from BASF, Ludwigshafen, Germany) and 2 mg magnesium stearate.
Tablet weight 222mg. Diameter 8mm, curvature radius 12mm.
Manufacturing:
A mixture of the compound according to the invention, lactose and starch is granulated with a 5% strength aqueous PVP solution (m / m). The granules are dried and then mixed with the magnesium stearate for 5 minutes. The mixture is tableted using a conventional tableting machine (see above for tablet shape). A tableting force of 15 kN is used as a guideline for tableting.

Suspension that can be administered orally
composition:
1000 mg of the compound according to the invention, 1000 mg of ethanol (96%), 400 mg of Rhodigel® ⁽ Xanthan gum from FMC, Pennsylvania, USA) and 99 g of water.
10 ml of oral suspension corresponds to a single dose of 100 mg of the compound according to the invention.
Manufacturing:
Rhodigel is suspended in ethanol and the compound according to the invention is added to the suspension. Add water with stirring. The mixture is stirred for about 6 hours until the Rhodigel swells.

Solution that can be administered orally:
Composition 500 mg of the compound according to the invention, 2.5 g of polysorbate and 97 g of polyethylene glycol 400. 20 g of oral solution corresponds to a single dose of 100 mg of the compound according to the invention.
Preparation The compounds of the invention are suspended in a mixture of polyethylene glycol and polysorbate with stirring. Stirring is continued until the compound of the invention is completely dissolved.

iv solution:
The compound according to the invention is dissolved in a physiologically acceptable solvent (for example isotonic saline, 5% glucose solution and / or 30% PEG 400 solution) at a concentration below saturation solubility. The solution is subjected to filter sterilization and filled into sterile pyrogen-free injection containers.

Claims (12)

Formula (I)

[Where:
Y and Z independently of one another represent O or S;
m represents the number 0, 1 or 2;
n represents a number of 1 or 2,
R ¹ represents (C ₆ -C ₁₀ ) aryl or 5- to 10-membered heteroaryl, each of which is halogen, nitro, cyano, (C ₁ -C ₆ ) -alkyl (which depends on hydroxyl may be _{substituted), (C 3 -C 8)} - cycloalkyl, phenyl, _{hydroxyl, (C} 1 -C ₆₎ - alkoxy, trifluoromethyl, trifluoromethoxy, amino, mono- - and di - (C ₁ -C ₆₎ - ^{alkylamino, R 8 -C (O) -NH-} , R 9 -C (O) -, R 10 R 11 N-C (O) -NH- , and ^R 12 ^R 13 N-C Optionally substituted by up to 4 identical or different substituents selected from the group consisting of (O)-{wherein R ⁸ is hydrogen, (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₈₎ - cycloalkyl Alkyl, phenyl or _(C 1 -C ₆₎ - alkoxy,
R ⁹ represents hydrogen, (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₈ ) -cycloalkyl, phenyl, hydroxyl or (C ₁ -C ₆ ) -alkoxy, and
R ¹⁰ , R ¹¹ , R ¹² and R ¹³ are the same or different and independently of one another represent hydrogen, (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₈ ) -cycloalkyl or phenyl. },
R ² represents hydrogen, (C ₆ -C ₁₀ ) -aryl, (C ₁ -C ₆ ) -alkyl, (C ₂ -C ₆ ) -alkenyl or (C ₂ -C ₆ ) -alkynyl, wherein , Alkyl, alkenyl and alkynyl are each represented by trifluoromethyl, (C ₁ -C ₆ ) -alkoxy, trifluoromethoxy, fluorine, cyano, (C ₆ -C ₁₀ ) -aryl or 5- or 6-membered heteroaryl. may be substituted, where all aryl and heteroaryl groups referred are each halogen, nitro, _{cyano, (C} 1 -C ₆₎ - alkyl, _hydroxyl, (C 1 _-C 6) - Substituted with up to three identical or different substituents selected from the group consisting of alkoxy, trifluoromethyl and trifluoromethoxy Ku,
R ³ and R ⁴ are the same or different and independently of each other hydrogen, (C ₁ -C ₆ ) -alkyl, (C ₂ -C ₆ ) -alkenyl, (C ₁ -C ₆ ) -alkoxy, Represents trifluoromethyl, trifluoromethoxy or halogen;
R ⁵ and R ⁶ are the same or different and independently of each other represent hydrogen, (C ₁ -C ₆ ) -alkyl, (C ₁ -C ₆ ) -alkoxy or phenoxy, or they are bonded together with the carbon atoms you are (C 3 _-C 8) _- forms a cycloalkyl ring, and,
R ⁷ represents a group of formula —NHR ¹⁴ or —OR ¹⁵ wherein R ¹⁴ represents hydrogen, (C ₁ -C ₆ ) -alkyl or (C ₁ -C ₆ ) -alkylsulfonyl, and ,
R ¹⁵ represents hydrogen or represents a hydrolyzable group that can be converted to the corresponding carboxylic acid}]
Or a salt, solvate or salt solvate thereof. Where
Y represents O,
Z represents S,
m represents the number 0, 1 or 2;
n represents the number 1 or 2,
R ¹ represents phenyl or 5- or 6-membered heteroaryl, each of which is halogen, nitro, cyano, (C ₁ -C ₄ ) -alkyl, which may be substituted by hydroxyl , _(C 3 -C ₆₎ - cycloalkyl, phenyl, _{hydroxy, (C} 1 -C ₄₎ - alkoxy, trifluoromethyl, trifluoromethoxy, amino, mono- - and di - _(C 1 -C ₄₎ - alkyl The group consisting of amino, R ⁸ —C (O) —NH—, R ⁹ —C (O) —, R ¹⁰ R ¹¹ N—C (O) —NH—, and R ¹² R ¹³ N—C (O) — Optionally substituted by up to 4 identical or different substituents selected from: {wherein R ⁸ is hydrogen, (C ₁ -C ₄ ) -alkyl, (C ₃ -C ₆ ) -cyclo Alkyl, phenyl or _(C 1 -C ₄₎ - alkoxy,
R ⁹ represents hydrogen, (C ₁ -C ₄ ) -alkyl, (C ₃ -C ₆ ) -cycloalkyl, phenyl, hydroxyl or (C ₁ -C ₄ ) -alkoxy, and
R ¹⁰ , R ¹¹ , R ¹² and R ¹³ are the same or different and independently of one another represent hydrogen, (C ₁ -C ₄ ) -alkyl, (C ₃ -C ₆ ) -cycloalkyl or phenyl. },
R ² represents hydrogen, phenyl, (C ₁ -C ₄ ) -alkyl, (C ₂ -C ₄ ) -alkenyl or (C ₂ -C ₄ ) -alkynyl, wherein alkyl, alkenyl and alkynyl are Trifluoromethyl, fluorine, cyano, (C ₁ -C ₄ ) -alkoxy, phenyl or 5- or 6-membered heteroaryl, each of which may be substituted, where all the phenyl and heteroaryl groups mentioned Is up to three identicals selected from the group consisting of halogen, nitro, cyano, (C ₁ -C ₄ ) -alkyl, hydroxyl, (C ₁ -C ₄ ) -alkoxy, trifluoromethyl and trifluoromethoxy Or may be substituted by different substituents,
R ³ and R ⁴ are the same or different and independently of each other represent hydrogen, (C ₁ -C ₄ ) -alkyl, (C ₁ -C ₄ ) -alkoxy, trifluoromethyl, trifluoromethoxy or halogen. Represent,
R ⁵ and R ⁶ are the same or different and independently of one another represent hydrogen, methyl, ethyl, methoxy, ethoxy or phenoxy, or together with the carbon atom to which they are attached (C ₃ -C ₆₎ - forms a cycloalkyl ring, and,
R ⁷ represents a group of formula —NHR ¹⁴ or —OR ¹⁵ wherein R ¹⁴ represents hydrogen or (C ₁ -C ₄ ) -alkyl, and
R ¹⁵ represents hydrogen or represents a hydrolyzable group that can be converted to the corresponding carboxylic acid},
A compound of formula (I) according to claim 1, or a salt, solvate or solvate of a salt thereof. Where
Y represents O,
Z represents S,
m represents the number 0 or 1;
n represents the number 1 or 2,
R ¹ represents phenyl or pyridyl, each of which is mono- or di-substituted by the same or different substituents selected from the group consisting of fluorine, chlorine, nitro, methyl, methoxy, trifluoromethyl and trifluoromethoxy. May be replaced,
R ² represents hydrogen, propargyl or may be substituted by fluorine, cyano, (C ₁ -C ₄ ) -alkoxy, phenyl, furyl, thienyl, oxazolyl, thiazolyl, oxadiazolyl or thiadiazolyl (C _1- C ₄ ) -alkyl, where phenyl and all heteroaromatic rings referred to consist of fluorine, chlorine, methyl, ethyl, isopropyl, tert-butyl, methoxy, ethoxy, trifluoromethyl and trifluoromethoxy May be mono- or disubstituted by the same or different substituents selected from the group;
R ³ and R ⁴ are the same or different and independently of one another represent hydrogen, methyl, methoxy, fluorine or chlorine;
R ⁵ and R ⁶ are the same or different and represent hydrogen or methyl, and
R ⁷ represents —OH, —NH ₂ or —NHCH ₃ ,
A compound of formula (I) according to claim 1 or claim 2, or a salt, solvate or solvate of a salt thereof. Formula (IA)

(Wherein R ¹ , R ² , m and n are as defined in any one of claims 1 to 3)
Or a salt, solvate or salt solvate thereof. A process for the preparation of a compound of formula (I) or (IA) as defined in any of claims 1 to 4, comprising the formula (II)

Wherein R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and Z are each as defined in any of claims 1 to 4 and
T ¹ represents (C ₁ -C ₄ ) -alkyl, preferably tert-butyl or benzyl)
Is first prepared in the presence of a base in an inert solvent of the formula (III)

Wherein n is as defined in any one of claims 1 to 4;
T ² represents (C ₁ -C ₄ ) -alkyl, preferably methyl or ethyl, and
Q ¹ represents a suitable leaving group such as halogen, mesylate, tosylate or triflate)
Using a compound of formula (IV)

(Wherein n, T ¹ , T ² , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and Z are as defined above)
And then under suitable reaction conditions, the compound of formula (V)

Wherein n, T ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and Z are as defined above.
Selectively hydrolyzed to the carboxylic acid of
Then, in the presence of a condensing agent and a base in an inert solvent, the formula (VI)

(Wherein R ¹ and m are each as defined in any one of claims 1 to 4).
Using a compound of formula (VII)

(Wherein m, n, T ¹ , R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and Z are each as defined above)
Which is then converted to a compound of formula (IB) in the presence of chloroacetyl chloride and a base.

(Wherein m, n, T ¹ , R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and Z are each as defined above)
The compound of formula (I-C) can be reacted by cyclization followed by basic or acidic hydrolysis, or when T ¹ is benzyl, and also hydrogenolytically.

(Wherein m, n, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and Z are as defined above)
The carboxylic acid of the formula
The compounds of formula (I) are then converted into their solvates, salts and / or solvates of salts, using appropriate (i) solvents and / or (ii) bases or acids, as appropriate. A method characterized by converting. Formula (ID)

Wherein m, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and Z are as defined in any one of claims 1 to 4.
A compound of formula (II) as defined in claim 5 is first prepared in the presence of a base in an inert solvent in the presence of a base (VIII).

Wherein m and R ¹ are each as defined in any of claims 1 to 4 and
Q ² represents a suitable leaving group, eg halogen)
Using a compound of formula (IE)

(Wherein m, T ¹ , R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and Z are as defined above)
The compound of formula (IF) by subsequent basic or acidic hydrolysis or, if T ¹ represents benzyl, also hydrolytically,

(Wherein m, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and Z are as defined above)
To the carboxylic acid of
And, if necessary, the method is converted to the compound of formula (ID) by a method of esterification or amidation subsequently known from literature.   A compound as defined in any of claims 1 to 4 for the treatment and / or prevention of diseases.   Use of a compound as defined in any of claims 1 to 4 for the manufacture of a medicament for the treatment and / or prevention of dyslipidemia and arteriosclerosis.   A medicament comprising a compound as defined in any of claims 1 to 4 in combination with an inert, non-toxic, pharmaceutically suitable adjuvant.   A compound as defined in any one of claims 1 to 4, comprising a CETP inhibitor, an HMG-CoA reductase inhibitor, a squalene synthesis inhibitor, an ACAT inhibitor, a cholesterol absorption inhibitor, an MTP inhibitor, fibrates, niacin, Lipase inhibitor, PPARγ- and / or PPAR-δ agonist, calcium antagonist, angiotensin II receptor antagonist, platelet aggregation inhibitor, anticoagulant, antidiabetic agent, antioxidant, thyroid hormone and / or thyroid hormone mimetic A medicament comprising in combination with a further active compound selected from the group consisting of an aldose reductase inhibitor and an anorectic agent.   The medicament according to claim 9 or 10, for the treatment and / or prevention of dyslipidemia and arteriosclerosis.   Dyslipidemia in humans and animals by administering an effective amount of at least one compound as defined in any of claims 1 to 4 or a medicament as defined in any of claims 9 to 11. And methods for treating and / or preventing arteriosclerosis.