JP2013530139A - Hydroxyalkylbenzylpyrazoles and uses thereof - Google Patents

Abstract

The present invention relates to novel 1- [3- (hydroxyalkyl) benzyl] -1H-pyrazole derivatives, methods for their production, use for the treatment and / or prevention of diseases, and diseases, more specifically, It relates to the treatment and / or prevention of proliferative and angiogenic diseases and their use for the manufacture of a medicament for the treatment and / or prevention of diseases resulting from metabolic adaptation to hypoxic conditions. Such therapeutic agents can be administered as monotherapy or in combination with other medicaments or with other therapeutic means.

Description

  The present application relates to novel 1- [3- (hydroxyalkyl) benzyl] -1H-pyrazole derivatives, methods for their preparation, use for treatment and / or prevention of diseases, and treatment and / or prevention of diseases More specifically, they relate to their use for the manufacture of a medicament for the treatment and / or prevention of hyperproliferative and angiogenic diseases and diseases resulting from metabolic adaptation to hypoxic conditions. Such treatment can be performed in the form of a monotherapy or in combination with other medications or even other therapeutic means.

  Cancer is the result of uncontrollable cell growth in a wide variety of tissues. In many cases, new cells penetrate existing tissues (invasive growth) or they metastasize to distant organs. Cancer occurs in a wide variety of organs and often progresses in a tissue-specific manner. The term “cancer” as a general term thus means a large group of defined diseases of various organs, tissues and cell types.

  In 2002, 4.4 million people worldwide were diagnosed with breast, small intestine, ovary, lung or prostate tumors. That same year, approximately 2.5 million people are believed to have died as a result of these diseases (Globocan 2002 Report). In the United States alone, in 2005, more than 1.25 million new cases and more than 500,000 deaths were predicted to be due to cancer. Most of these new cases are associated with cancers of the small intestine (~ 100000), lungs (~ 170,000), breast (~ 210000) and prostate (~ 230000). Over the next 10 years, an estimated 15% increase in cancer is predicted (American Cancer Society, Cancer Facts and Figures 2005).

  Some early stage tumors can be removed by surgical and radiotherapeutic means. Metastatic tumors are generally only temporarily overcome by chemotherapeutic agents. The aim here is to achieve an optimal combination of quality of life improvement and life extension.

  Chemotherapeutic agents consist of a combination of cytotoxic drugs. Most of these substances are compounds that bind to tubulin as their mechanism of action or interact with nucleic acid formation and processing. In recent years, these also include enzyme inhibitors that inhibit epigenetic DNA modification or cell cycle progression (eg, histone deacetylase inhibitors, Aurora kinase inhibitors). Due to the toxicity of such treatments, in recent years there has been an increasing focus on targeted therapies in which certain steps in the cell are inhibited without a high level of cytotoxic burden. These include in particular kinase inhibitors that inhibit the phosphorylation of receptors and signaling molecules. One example is imatinib, which has been used very effectively in the treatment of chronic myelogenous leukemia (CML) and gastrointestinal stromal tumors (GIST). Further examples are substances that inhibit EGFR kinase and HER2, such as erlotinib, and VEGFR kinase inhibitors such as renal cell carcinoma, liver cancer and advanced stage GIST such as sorafenib and sunitinib.

  Antibodies to VEGF may be used to prolong colorectal cancer patients. Bevacizumab inhibits vascular growth, which impedes rapid tumor growth because the tumor requires connection to the vasculature in order for the supply and disposal to function continuously.

  One stimulator of angiogenesis is hypoxia, which occurs repeatedly in solid tumors because of uncontrolled growth and poor blood supply. In the absence of oxygen, cells change their metabolism from oxidative phosphorylation to glycolysis to stabilize ATP levels in the cell. This process is controlled by transcription factors that are upregulated depending on the oxygen content in the cell. This transcription factor, called the “hypoxia-inducing factor” (HIF), is usually post-translationally removed by rapid degradation, preventing transport to the nucleus. This is done by the hydroxylation of two proline units in the oxygen-degrading domain (ODD) and one asparagine unit adjacent to the C-terminus by the enzymes prolyl dehydrogenase and FIH (“HIF inhibitor”). After modification of the proline unit, HIF is degraded by the Hippel-Lindau protein (part of the ubiquitin-E3-ligase complex) via the proteasome organ (Maxwell, Wiesener et al., 1999). In the case of hypoxia, degradation does not occur and the protein is up-regulated, leading to the transcription or inhibition of transcription of many (more than 100) other proteins (Semenza and Wang, 1992; Wang and Semenza, 1995).

  The transcription factor HIF is formed by a regulated α-subunit and a structurally present β-subunit (ARNT, aryl hydrocarbon receptor nuclear transporter). There are three different species of α-subunits, 1α, 2α and 3α, the latter being considered rather inhibitory (Makino, Cao et al., 2001). The HIF subunit is a bHLH (basic helix loop helix) protein that dimerizes via HLH and PAS (Per-Arnt-Sim) domains that initiate transcriptional activity (Jiang, Rue et al., 1996).

  In the most important tumor entities, overexpression of HIF1α protein is associated with increased vascular density and high VEGF expression (Hirota and Semenza, 2006). At the same time, glucose metabolism is transferred to glycolysis and the Krebs cycle is reduced to benefit the production of cell units. This also suggests changes in lipid metabolism. Such changes appear to ensure tumor survival. On the other hand, if the activity of HIF is inhibited, tumor growth will be suppressed as a result. This has already been observed with various test models (Chen, Zhao et al., 2003; Stoeltzing, McCarty et al., 2004; Li, Lin et al., 2005; Mizukami, Jo et al., 2005; Li, Shi et al., 2006). Therefore, specific inhibitors of HIF-controlled metabolism should be suitable as tumor therapeutic agents.

  WO 2004 / 089303-A2 discloses diaryl-substituted pyrazoles as mGluR5 modulators for the treatment of psychiatric disorders. WO 2010 / 072352-A1 and WO 2010 / 085584-A1 describe 3-phenyl-5- (1H-pyrazole- as a sphingosine-1-phosphate agonist for the treatment of autoimmunity and vascular disorders. 4-yl) -1,2,4-oxadiazole derivatives are disclosed.

  WO 2005 / 030121-A2 and WO 2007 / 065010-A2 disclose the possibility of using certain pyrazole derivatives for the inhibition of expression of HIF and HIF-regulated genes in tumor cells. WO 2008 / 141731-A2 discloses heteroaryl-substituted N-benzylpyrazoles as HIF regulatory pathway inhibitors for the treatment of cancer. However, many of these compounds do not have sufficient inhibitory activity, etc., or based on the pharmacokinetic properties in animal models, a considerable amount of substances can accumulate in the human body after repeated daily administration It was found to be expected to have a long, long half-life (> 48 hours).

  Therefore, the present invention allows for repeated once-daily administration that acts primarily as a potent inhibitor of transactivation of the transcription factor HIF and second, without the concurrent occurrence of clinically relevant accumulation The object was to develop and provide a novel compound having the following pharmacokinetic profile. Such properties as a whole can broaden the clinical applicability of these HIF inhibitors, and more specifically promote their combined use with other active ingredients such as conventional tumor chemotherapeutic agents.

  This object is achieved by the inventive compounds described herein. From a structural point of view, a new group of N-benzylpyrazole derivatives is characterized by a hydroxyalkyl substituent at the 3-position of the benzyl head group, which surprisingly leads to an improved profile of the compound properties.

（式中
Aは、式

｛式中
*は、ヒドロキシル基との結合点を表し、
**は、フェニル環との結合点を表し、
R^1AおよびR^1B は、それぞれ独立して、水素、重水素、メチル、ヒドロキシメチルまたはトリフルオロメチルを表し、
または
互いに一体となって、それらが結合する炭素原子と一緒に、シクロプロパン-1,1-ジイル、シクロブタン-1,1-ジイル、オキセタン-3,3-ジイルまたはテトラヒドロ-2H-ピラン-4,4-ジイル環を形成し、
R^2AおよびR^2B は、それぞれ独立して水素、重水素、メチルまたはトリフルオロメチルを表し、
R^3AおよびR^3B は、それぞれ独立して水素、フッ素、メチル、ヒドロキシメチルまたはトリフルオロメチルを表し、
または
互いに一体となって、それらが結合する炭素原子と一緒に、シクロプロパン-1,1-ジイル、シクロブタン-1,1-ジイル、オキセタン-3,3-ジイルまたはテトラヒドロ-2H-ピラン-4,4-ジイル環を形成するものを表す。｝
の基であり、
R⁴ は、トリフルオロメトキシ、トリフルオロメチルスルファニル、トリフルオロメチルスルホニル、ペンタフルオロスルファニル、トリメチルシリルまたは式

｛式中、#はフェニル環との結合点を表し、
R^5AおよびR^5B はそれぞれ独立して、水素、フッ素、メチル、エチル、n-プロピルまたはイソプロピルを表すか
または
互いに一体となって、それらが結合する炭素原子と一緒に、シクロプロパン-1,1-ジイル、シクロブタン-1,1-ジイル、シクロペンタン-1,1-ジイル、シクロヘキサン-1,1-ジイル、オキセタン-3,3-ジイルまたはテトラヒドロ-2H-ピラン-4,4-ジイル環を形成し、R⁶は、水素、フッ素、メチル、トリフルオロメチル、メトキシメチルまたはエトキシメチルを表す。｝
の基を表し、
R⁷は、水素、フッ素またはメチルを表す。）
の化合物およびそれらの塩類、溶媒和物および塩類の溶媒和物に関する。 Specifically, the present invention relates to general formula (I)

(In the formula
A is the formula

{In formula
* Represents the point of attachment to the hydroxyl group,
** represents the point of attachment to the phenyl ring,
R ^1A and R ^1B each independently represent hydrogen, deuterium, methyl, hydroxymethyl or trifluoromethyl;
Or together, together with the carbon atom to which they are attached, cyclopropane-1,1-diyl, cyclobutane-1,1-diyl, oxetane-3,3-diyl or tetrahydro-2H-pyran-4, Forming a 4-diyl ring,
R ^2A and R ^2B each independently represent hydrogen, deuterium, methyl or trifluoromethyl,
R ^3A and R ^3B each independently represent hydrogen, fluorine, methyl, hydroxymethyl or trifluoromethyl;
Or together, together with the carbon atom to which they are attached, cyclopropane-1,1-diyl, cyclobutane-1,1-diyl, oxetane-3,3-diyl or tetrahydro-2H-pyran-4, Represents a 4-diyl ring. }
The basis of
R ⁴ is trifluoromethoxy, trifluoromethylsulfanyl, trifluoromethylsulfonyl, pentafluorosulfanyl, trimethylsilyl or the formula

{Wherein # represents the point of attachment to the phenyl ring
R ^5A and R ^5B each independently represent hydrogen, fluorine, methyl, ethyl, n-propyl or isopropyl, or together, together with the carbon atom to which they are attached, together with cyclopropane-1,1 -Diyl, cyclobutane-1,1-diyl, cyclopentane-1,1-diyl, cyclohexane-1,1-diyl, oxetane-3,3-diyl or tetrahydro-2H-pyran-4,4-diyl ring R ⁶ represents hydrogen, fluorine, methyl, trifluoromethyl, methoxymethyl or ethoxymethyl. }
Represents the group of
R ⁷ represents hydrogen, fluorine or methyl. )
And their salts, solvates and solvates of salts.

｛式中
*は、ヒドロキシル基との結合点を表し、
**は、フェニル環との結合点を表し、
R^2AおよびR^2B は、いずれも水素または重水素を表す｝
の基を表し、
R⁴は、トリフルオロメチル、トリフルオロメトキシ、トリフルオロメチルスルファニル、ペンタフルオロスルファニル、トリメチルシリルまたは式

｛式中、
#は、フェニル環との結合点を表し、
R^5AおよびR^5B は、いずれもメチルまたは一緒になって、それらが結合する炭素原子と一緒に、シクロプロパン-1,1-ジイルまたはテトラヒドロ-2H-ピラン-4,4-ジイル環を形成し、
R⁶ は、フッ素、メチルまたはトリフルオロメチルを表す｝
の基を表し、
R⁷ は、水素またはメチルを表す。）
の化合物およびそれらの塩類、溶媒和物および塩類の溶媒和物に関する。 In the context of the present invention, preferably the formula (I)
(Where
A is the formula

{In formula
* Represents the point of attachment to the hydroxyl group,
** represents the point of attachment to the phenyl ring,
R ^2A and R ^2B both represent hydrogen or deuterium}
Represents the group of
R ⁴ is trifluoromethyl, trifluoromethoxy, trifluoromethylsulfanyl, pentafluorosulfanyl, trimethylsilyl or the formula

{Where,
# Represents the point of attachment to the phenyl ring,
R ^5A and R ^5B are both methyl or taken together with the carbon atom to which they are attached to form a cyclopropane-1,1-diyl or tetrahydro-2H-pyran-4,4-diyl ring. ,
R ⁶ represents fluorine, methyl or trifluoromethyl}
Represents the group of
R ⁷ represents hydrogen or methyl. )
And their salts, solvates and solvates of salts.

｛式中
*は、ヒドロキシル基との結合点を表し、
**は、フェニル環との結合点を表す。｝
の基を表し、
R⁴ はトリフルオロメトキシ、トリフルオロメチルスルファニルまたは式

｛式中
#は、フェニル環との結合点を表す｝
の基を表し、
R⁷ は、水素を表す。）
の化合物およびそれらの塩類、溶媒和物および塩類の溶媒和物が特に好ましい。
更なる局面としては、本発明はまた特定の式(I)の化合物のプロドラッグに関する。一般に用語「プロドラッグ」は、ここでは、それ自体生物学的に活性または不活性であるが、体内において存在している間に、例えば代謝または加水分解経路により式(I)の化合物に変換される式(I)の化合物の共有結合誘導体を言う。 In the context of the present invention, the formula (I)
(In the formula
A is the formula

{In formula
* Represents the point of attachment to the hydroxyl group,
** represents a point of attachment to the phenyl ring. }
Represents the group of
R ⁴ is trifluoromethoxy, trifluoromethylsulfanyl or the formula

{In formula
# Represents the point of attachment to the phenyl ring}
Represents the group of
R ⁷ represents hydrogen. )
And the salts, solvates and solvates of the salts thereof are particularly preferred.
In a further aspect, the present invention also relates to prodrugs of certain compounds of formula (I). In general, the term “prodrug” here is biologically active or inactive per se, but is converted to a compound of formula (I), for example by metabolic or hydrolysis pathways, while present in the body. A covalent derivative of a compound of formula (I).

（式中、
A、R⁴およびR⁷ はそれぞれ上述の意味を表し、
R^PD は、式

｛式中、
#は、酸素原子との結合点を表し、
R⁸ は、水素または(C₁-C₄)-アルキルを表し、
R^9AおよびR^9B はそれぞれ独立して水素またはメチルを表す。｝
のプロドラッグ基を表す。）
の化合物およびそれらの塩類、溶媒和物および塩類の溶媒和物をも表す。
本発明の情況においては、式(I-PD)
（式中、
R^PD は、式

｛式中
#は、酸素原子との結合点を表し、
R⁸ はメチル、イソプロピル、イソブチルまたはsec-ブチルを表す。｝
のプロドラッグ基を表す。）
の化合物およびそれらの塩類、溶媒和物および塩類の溶媒和物に関する。 Accordingly, the present invention also provides a compound of formula (I-PD)

(Where
A, R ⁴ and R ⁷ each represent the above meaning,
R ^PD is the formula

{Where,
# Represents the point of attachment to the oxygen atom,
R ⁸ represents hydrogen or (C ₁ -C ₄ ) -alkyl,
R ^9A and R ^9B each independently represent hydrogen or methyl. }
Represents a prodrug group. )
And their salts, solvates and solvates of the salts.
In the context of the present invention, the formula (I-PD)
(Where
R ^PD is the formula

{In formula
# Represents the point of attachment to the oxygen atom,
R ⁸ represents methyl, isopropyl, isobutyl or sec-butyl. }
Represents a prodrug group. )
And their salts, solvates and solvates of salts.

Compounds of formula (I-PD) are prodrugs of compounds of formula (I) that exhibit good solubility in aqueous or other physiologically compatible media; in addition they further enhance solubility It offers the possibility of forming salts with suitable bases or acids that can be increased. Accordingly, compounds of formula (I-PD) and their salts are particularly suitable for intravenous dosage forms. This opens up additional therapeutic applications for these compounds.
The compounds of the present invention are therefore encompassed by the compounds of formula (I) and (I-PD) and their salts, solvates and solvates of salts, formulas (I) and (I-PD) And the salts, solvates and solvates of the salts, and the compounds included in formulas (I) and (I-PD), identified below as working examples and These salts, solvates and solvates of salts are included.

Depending on the structure, the compounds of the invention may be in different stereoisomeric forms, i.e. configurational isomers or, where appropriate, conformational isomers (atropisomers). Enantiomers and / or diastereomers). The present invention therefore includes the enantiomers or diastereomers and mixtures thereof. Single constituents as stereoisomers can be isolated from mixtures of enantiomers and / or diastereomers in a known manner; it is preferred to use chromatographic methods, in particular HPLC chromatography with achiral or chiral phases. .
Where the compounds in the present invention can occur in tautomeric forms, the present invention includes all tautomeric forms.

The invention also includes all suitable isotope compounds of the compounds of the invention. In the isotopic compound of the present invention, at least one element in the compound of the present invention is an atom having the same element number, but is replaced with an atom having an atomic mass different from that which is naturally or predominantly present in nature. Means that. Examples of isotopes incorporated into the compounds of the present invention are hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine such as ² H (deuterium), ³ H (tritium), ¹³ C , ¹⁴ C, ¹⁵ N, ¹⁷ O, ¹⁸ O, ³² P, ³³ P, ³³ S, ³⁴ S, ³⁵ S, ³⁶ S, ¹⁸ F, ³⁶ Cl, ⁸² Br, ¹²³ I, ¹²⁴ I, ¹²⁹ I and ¹³¹ I. In particular, certain isotopic compounds of the compounds of the invention that incorporate one or more radioisotopes may be useful, for example, for testing the mechanism of action or active compound distribution in the body; For purposes of preparation and detectability, compounds labeled with ³ H or ¹⁴ C isotopes are particularly suitable for this purpose. In addition, incorporation of isotopes, such as deuterium, can result in certain therapeutic benefits, such as increased half-life in the body or decreased effective dose, as a result of the greater metabolic stability of the compound; Such modifications of the compounds therefore also constitute preferred embodiments of the invention in some cases. Isotope compounds of the compounds of the present invention are produced using processes generally known to those skilled in the art. For example, a specific reagent and / or starting material isotope isotope by the method described in the methods and working examples described later. This is done using the replacement.

Preferred salts in the context of the present invention are physiologically acceptable salts of the compounds of the invention. Also encompassed are salts that are not themselves suitable for pharmaceutical applications, but may be used, for example, in the isolation, purification or storage of the compounds of the invention.
Physiologically acceptable salts of the compounds of the present invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid. , 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 of the present invention also include salts with commonly used bases, such as -examples and preferred are -alkali metal salts (for example, sodium and potassium salts), alkaline earth metals Salts (e.g. calcium and magnesium salts) and ammonium or ammonium salts derived from organic amines having 1 to 16 carbon atoms, e.g. -examples and preferred are -ethylamine, diethylamine, triethylamine, N, N-diisopropyl There are ethylamine, monoethanolamine, diethanolamine, triethanolamine, dimethylaminoethanol, diethylaminoethanol, procaine, dicyclohexylamine, dibenzylamine, N-methylpiperidine, N-methylmorpholine, arginine, lysine and 1,2-ethylenediamine.
In the context of the present invention, a solvate is a form of a compound of the present invention that forms a complex in the solid or liquid state by coordination of solvent molecules. Hydrates are one specific form of solvates that are coordinated with water. Preferred solvates in the context of the present invention are hydrates.

In the context of this invention, unless otherwise specified, substituents have the following definitions.
In the context of this invention (C ₁ -C ₄ ) -alkyl is a straight-chain or branched alkyl having 1 to 4 carbon atoms. Preferred examples are: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl.
In the context of the present invention, all groups which occur more than once are independent of one another. When a group of a compound of the invention is substituted, the group may be mono- or polysubstituted unless otherwise indicated. It is preferably substituted by one, two or three identical or different substituents. Most preferably, it is substituted by one substituent.
The individual groups defined for each group combination or preferred combination are independent of each particular group combination, and are optionally replaced by other combination group definitions.
Highly preferred is a combination of two or more of the preferred ranges described above.

（式中、R⁴およびR⁷ は、上に示した意味を有する。）
のN’-ヒドロキシアミジンを式(III)

のピラゾールカルボン酸と縮合させ、式(IV)

（式中、R⁴およびR⁷ は上に示した意味を有する。）
の1,2,4-オキサジアゾール誘導体を得て、
続いて、化合物(IV)を塩基の存在下、式(V)

（式中、Aは上に示した意味を有し、
Xは、脱離基、例えば、塩素、臭素、ヨウ素、メシレート、トリフレートまたはトシフレートを表し、
R¹⁰は、水素または慣用されているヒドロキシル保護基、例えば、アセチル、テトラヒドロピラニル、トリメチルシリル、トリイソプロピルシリル、tert-ブチルジメチルシリルまたはtert-ブチル(ジフェニル)シリルを表す。）
の化合物と反応させて、式(VI)

（式中、A、R⁴、R⁷およびR¹⁰ はそれぞれ上に示した意味を有する。）
の化合物を得て、
ヒドロキシル保護基 R¹⁰ を、続いて-存在する場合には-慣用されている方法により除去し、そして生成した式(I)

（式中、A、R⁴およびR⁷ は上に示した意味を有する。）
化合物を、最後に、所望の場合、式(VII)

の化合物またはこの化合物の活性化形態（式中、R^PDは上に示した意味を有する。）
を用いて式(I-PD)

（式中、A、R^PD、R⁴およびR⁷ はそれぞれ上に示した意味を有する。）
のプロドラッグ化合物に変換し、
そして生成した式(I)または(I-PD)の化合物を、場合により、エナンチオマーおよび/またはジアステレオマーに分割しおよび/または適当な(i)溶媒および/または(ii)塩基または酸を用いてそれらの溶媒和物、塩類および/または塩類の溶媒和物に変換することにより特徴付けられる、方法を提供する。 Furthermore, the present invention provides a process for producing the compounds of formula (I) and (I-PD),
First, the formula (II)

(Wherein R ⁴ and R ⁷ have the meanings indicated above.)
N'-hydroxyamidine of formula (III)

With a pyrazole carboxylic acid of formula (IV)

(Wherein R ⁴ and R ⁷ have the meanings indicated above.)
To obtain a 1,2,4-oxadiazole derivative of
Subsequently, compound (IV) is converted to formula (V) in the presence of a base.

(Wherein A has the meaning indicated above,
X represents a leaving group such as chlorine, bromine, iodine, mesylate, triflate or tosiflate,
R ¹⁰ represents hydrogen or a conventional hydroxyl protecting group such as acetyl, tetrahydropyranyl, trimethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl or tert-butyl (diphenyl) silyl. )
Is reacted with a compound of formula (VI)

(In the formula, A, R ⁴ , R ⁷ and R ¹⁰ each have the meaning shown above.)
To obtain a compound of
The hydroxyl protecting group R ¹⁰ is subsequently removed—if present—by conventional methods and the resulting formula (I)

(Wherein A, R ⁴ and R ⁷ have the meanings indicated above.)
The compound is finally, if desired, the formula (VII)

Or an activated form of this compound wherein R ^PD has the meaning indicated above.
To formula (I-PD)

(In the formula, A, R ^PD , R ⁴ and R ⁷ each have the meaning shown above.)
Into a prodrug compound of
The resulting compound of formula (I) or (I-PD) is then optionally separated into enantiomers and / or diastereomers and / or using appropriate (i) solvents and / or (ii) bases or acids. To a solvate, salt and / or salt solvate thereof.

The condensation reaction (II) + (III) → (IV) is preferably carried out using carbodiimide, for example N ′-(3-dimethylaminopropyl) -N-ethylcarbodiimide (EDC), as the active ester component. Phosgene derivatives such as 1,1′-carbonyldiimidazole (CDI) ) Is used.
The first coupling step of this reaction is generally carried out in the temperature range of 0 ° C. to + 50 ° C .; cyclization to 1,2,4-oxadiazole is followed by the reaction mixture at + 100 ° C. to + 150 ° C. Heat with The reaction can also be carried out at atmospheric pressure, elevated pressure or reduced pressure (eg 0.5-5 bar); in general, the reaction is carried out at atmospheric pressure.

Inert solvents in the production process (IV) + (V) → (VI) are, for example, halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, trichloroethylene or chlorobenzene, ethers such as diethyl ether, diisopropyl ether, Methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane or bis (2-methoxyethyl) ether, hydrocarbons such as benzene, toluene, xylene, pentane, hexane, cyclohexane or mineral oil fractions, Or dipolar aprotic solvents such as acetone, methyl ethyl ketone, ethyl acetate, acetonitrile, N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), N, N ' -Dimethylpropylene urea (DMPU), N-methylpyrrolidinone (NMP ) Or pyridine. It is equally possible to use mixtures of the solvents mentioned. Preferably, tetrahydrofuran or 1,4-dioxane is used.
Suitable bases for reaction (IV) + (V) → (VI) are the customary inorganic or organic bases. These preferably include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide or potassium hydroxide, alkali metal alkoxides such as sodium methoxide or potassium methoxide, sodium ethoxide or potassium ethoxide or sodium or Potassium tert-butoxide, alkali metal hydrides such as sodium hydride or potassium hydride, or amides such as sodium amide, lithium bis (trimethylsilyl) amide or potassium bis (trimethylsilyl) amide or lithium diisopropylamide are included. Preferably potassium tert-butoxide is used. If appropriate, it may be advantageous to add alkylation catalysts such as lithium bromide, sodium iodide, potassium iodide, tetra-n-butylammonium bromide or benzyltriethylammonium chloride.

This reaction is generally performed at a temperature of -20 ° C to + 100 ° C, preferably 0 ° C to + 60 ° C. The reaction can also be carried out at atmospheric pressure, elevated pressure or reduced pressure (eg 0.5-5 bar); in general, the reaction is carried out at atmospheric pressure.
Conventional methods for removal of the hydroxyl protecting group R ¹⁰ include, for example, in the case of ester derivatives, hydrolysis with a base or acid or reaction with an organometallic compound (for example methylmagnesium bromide or ethylmagnesium bromide), In the case of tetrahydropyranyl ether, it is hydrolysis by acid, and in the case of silyl ether, there is a similar hydrolysis or reaction with fluoride (eg potassium fluoride or tetra-n-butylammonium fluoride) [eg TW Greene and PGM Wuts, Protective Groups in Organic Synthesis, Wiley, New York, 1999].

Activated forms of compound (VII) suitable for introduction of the prodrug group R ^PD [transform (I) → (I-PD)] include, for example, anhydrides, including chloride or mixed anhydrides, or other specific There are ester or amide derivatives. Other hydroxyl or amino groups present in the ^RPD group are present in a temporarily protected form and are subsequently removed at the end of the series of reactions by conventional methods. In this step, the protecting group used for the hydroxyl group is preferably benzyl, which is removed by hydrogenolysis and the preferred amino protecting group is tert-butoxycarbonyl, which is a strong acid such as hydrochloric acid or trifluoroacetic acid. [For example, M. Bodanszky and A. Bodanszky, The Practice of Peptide Synthesis, Springer-Verlag, Berlin, 1984; M. Bodanszky, Principles of Peptide Synthesis, Springer-Verlag, Berlin, 1993; TWGreene and PGM Wuts, Protective Groups in Organic Synthesis, Wiley, New York, 1999; see also Reaction Scheme 8-10 below].

（式中、Xは上に示した意味であり、
および、
Zは、一般的に、続く化学変換により、上に定義したヒドロキシアルキル基HO-A-の導入または構築を可能とする置換基または官能基を表す。）
の化合物を反応させて、式(IX)

（式中、R⁴、R⁷およびZは上に示した意味を有する。）
の化合物を生成し、
続いて、これを文献公知の方法を用いて、Z基を変換することにより、式(I)の化合物とすることによっても製造できる。 Alternatively, or alternatively, the compound of formula (I) of the present invention is first prepared in the presence of a base with the compound of formula (IV) described above and formula (VIII)

(In the formula, X has the meaning shown above,
and,
Z generally represents a substituent or functional group that allows the introduction or construction of the hydroxyalkyl group HO-A- defined above by subsequent chemical transformations. )
Is reacted with a compound of formula (IX)

(Wherein R ⁴ , R ⁷ and Z have the meanings indicated above.)
Produces a compound of
Subsequently, this can also be produced by converting the Z group using methods known in the literature to obtain a compound of formula (I).

Reaction (IV) + (VIII) → (IX) is carried out under similar reaction conditions to steps (IV) + (V) → (VI) shown above with respect to solvent, base and temperature.
Examples of substituents or functional groups Z in formula (VIII) in which the hydroxyalkyl group HO-A- as defined above can be introduced or constructed are firstly halides, such as bromide or iodide, and secondly carbonyl groups. For example, alkoxycarbonyl, alkoxycarbonylalkyl, hydroxycarbonyl, hydroxycarbonylalkyl, formyl, alkylcarbonyl or alkylcarbonylalkyl. The transformation is performed by a known method commonly used by those skilled in the art, for example, metal hydride complex, 1,2-addition of an organometallic compound (for example, Grignard compound) to a carbonyl compound, hydroxylation, C-alkyl And the introduction and removal of temporary protecting groups [see also reaction schemes 1-7 below and the preparation in the working examples detailed in the experimental section].
Compounds of formula (II), (III), (V), (VII) and (VIII) are either commercially available, as such are described in the literature or similar to published literature methods. Depending on the method, it can be produced by methods apparent to those skilled in the art. Numerous explanations and literature information for the preparation of starting materials can be found in the section on starting compounds and intermediates in the experimental section.

スキーム2

The preparation of the compounds of the invention is illustrated by an exemplary method according to the following reaction scheme:
Scheme 1

Scheme 2

Scheme 3

Scheme 4

Scheme 5

Scheme 6

スキーム8

[R＝フェニルまたはベンジル]。 Scheme 7

Scheme 8

[R = phenyl or benzyl].

[Y.Watanabe et al.、Tetrahedron Lett.1990、31 (2)、255-256参照]。
スキーム10

Scheme 9

[See Y. Watanabe et al., Tetrahedron Lett. 1990, 31 (2), 255-256].
Scheme 10

Inventive compounds have valuable pharmacological properties and can be used for the prevention and treatment of diseases in humans and animals.
The compound is a very potent inhibitor of the regulatory HIF pathway. In addition, the compounds of the invention have advantageous pharmacokinetic properties with regard to their volume of distribution and / or their clearance and the half-life obtained therefrom, and are suitable for repeated once-daily administration.
Based on the profile of action, the compounds of the invention are particularly suitable for the treatment of hyperproliferative diseases in general, especially in humans and mammals. The compounds can inhibit, block, reduce or reduce cell proliferation and cell division and secondarily increase apoptosis.

  Hyperproliferative diseases in which the compounds of the invention can be used for the treatment are inter alia psoriasis, keloids, scar formation and other proliferative diseases of the skin, benign diseases such as benign prostatic hyperplasia (BPH), and especially tumors Includes disease group. In the context of the present invention, it will be understood that these mean in particular but not limited to the following: breast and breast tumors (including glandular and lobular cancers, as well as carcinoma in situ), breathing Tumors of ducts (poor and non-poor cell carcinomas, bronchial cancers), brain tumors (eg brainstem and hypothalamus, astrocytoma, medulloblastoma, ependymoma and neuroectodermal and pineal tumors), digestion Organ tumors (esophagus, stomach, gallbladder, small intestine, large intestine, rectum), liver tumors (especially hepatocellular carcinoma, cholangiocellular carcinoma and mixed hepatocellular and cholangiocellular carcinoma), head and neck tumors (larynx, hypopharynx, nasopharynx) , Oropharynx, lips and oral cavity), skin tumors (squamous cell carcinoma, Kaposi sarcoma, malignant melanoma, Merkel skin cancer and non-melanoma skin cancer), soft tissue tumors (especially soft tissue sarcoma, osteosarcoma, malignant fibrosis) Histiocytoma, lymphosarcoma and rhabdomyosarcoma), eye tumor (removal Intraocular melanoma and retinoblastoma), endocrine and exocrine gland tumors (e.g. thyroid and parathyroid glands, pancreas and salivary glands), urinary tract tumors (bladder, penis, kidney, renal pelvis and ureteral tumors) and genital Tumors (endometrial, cervical, ovarian, vaginal, vulvar and uterine carcinomas in women and prostate and testicular carcinomas in men). They are also proliferative blood diseases in solid form and as circulating blood cells such as lymphoma, leukemia and myeloproliferative diseases such as acute myeloid, acute lymphoblastic, chronic lymphatic, chronic myelogenous and hairy Cellular leukemia and AIDS-related lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, cutaneous T-cell lymphoma, Burkitt lymphoma and lymphoma in the central nervous system.

These well-documented human diseases can occur in other mammals with similar etiology and can be treated with the compounds of the present invention.
In the context of the present invention, the term “treatment” or “treating” is intended to eradicate, reduce, alleviate or ameliorate a disease or health disorder, and by these diseases, for example, a quality of・ Used in the meaning and meaning of the practice of caring for, nursing and nursing patients for the purpose of improving life.
The compounds of the present invention act as modulators of the HIF regulatory pathway and are therefore suitable for the treatment of diseases associated with deleterious expression of HIF transcription factors. This applies in particular to the transcription factors HIF-1α and HIF-2α. The term “detrimental expression of HIF” here means the presence of an abnormal physiological HIF protein. This can be caused by the synthesis of excess protein (mRNA- or translation-related), by reduced degradation or by inappropriate reverse regulation in the function of transcription factors.

  HIF-1α and HIF-2α regulate more than 100 genes. It plays a role in angiogenesis, and therefore directly to tumor-related proteins, and also to proteins that affect glucose, amino acid and lipid metabolism, and cell migration, metastasis and DNA repair, or of tumor cell survival by inhibiting apoptosis It also applies to improvements. Others act more indirectly through inhibition of immune responses and upregulation of angiogenic factors in inflammatory cells. HIF also plays an important role in stem cells, and tumor stem cells reported here as having particularly elevated HIF levels. Therefore, inhibition of the HIF regulatory pathway by the compounds of the invention does not have a high growth rate and therefore also has a therapeutic effect on tumor stem cells that are not adequately affected by cytotoxic agents (Semenza, 2007; Weidemann and Johnson, 2008). reference).

  Changes in cell metabolism by HIF are not limited to tumors, but also occur in other chronic or transient hypoxic pathophysiological processes. HIF inhibitors—for example compounds of the invention—can cause further damage, for example due to adaptation of the cells to hypoxia, because damaged cells can cause further damage if they do not function as intended. Is also therapeutically effective. One example of this is the formation of epileptic lesions in tissues that are partially destroyed after a stroke. Similar conditions are seen in cases of cardiovascular disease if the process of ischemia occurs in the heart or brain as a result of thromboembolic events, inflammation, wounds, addiction or other causes. These can cause disorders such as local delayed action potentials, which in turn can lead to arrhythmias or chronic heart failure. In transient forms, such as those that occur as a result of apnea syndrome, essential hypertension may exist under certain circumstances, which can lead to known sequelae such as stroke and myocardial infarction.

Inhibition of the HIF regulatory pathway, as achieved by the compounds of the present invention, is therefore e.g. heart failure, arrhythmia, myocardial infarction, apnea syndrome-induced hypertension, pulmonary hypertension, transplant ischemia, reperfusion injury, stroke and macular It is also effective in diseases such as degeneration, as well as restoration of neurological function after traumatic injury or amputation.
Since HIF is one of the factors that control the epithelial to mesenchymal cell type transition that is important in the lungs and kidneys in particular, the inventive compounds also prevent fibrosis in the lungs and kidneys associated with HIF or It can also be used for control.
Further diseases for which the compounds of the invention can be used for the treatment are inflammatory joint diseases such as various forms of arthritis and inflammatory small intestinal diseases such as Crohn's disease.
Chubash erythrocytosis is erythropoiesis mediated by HIF-2α activity, which occurs in a number of organs, particularly in the spleen. The inventive compounds as inhibitors of the HIF regulatory pathway are therefore suitable here for the suppression of excessive erythropoiesis and are therefore effective in reducing this disease.

The compounds of the present invention can also be used to treat diseases associated with excessive or abnormal angiogenesis. These include, among others, diabetic retinopathy, ischemic retinal vein occlusion and retinopathy of prematurity (see Aiello et al., 1994; Peer et al., 1995), age-related macular degeneration (AMD; Lopex et al. , 1996), neovascular glaucoma, psoriasis, post-lens fibroproliferation, angiofibroma, inflammation, rheumatoid arthritis (RA), restenosis, in-stent restenosis and post-vascular implantation restenosis.
Increased blood supply is further associated with cancerous, neoplastic tissue where it accelerates tumor growth. In addition, the growth of new blood vessels and lymph vessels promotes metastasis, ie tumor spread. New lymph vessels and blood vessels are detrimental to immune privileged tissues, such as ocular allografts, and increase susceptibility to rejection, for example. The compounds of the invention can therefore also be used for the treatment of one of the aforementioned diseases, for example by inhibiting the growth of blood vessels or reducing the number of blood vessels. This is achieved by inhibition of endothelial cell proliferation or other mechanisms that inhibit or attenuate angiogenesis and by reduction of neoplastic cells by apoptosis.

In the case of obesity, HIF-1α is abundant in adipose tissue and catabolism causes a HIF-mediated shift in the glycolytic direction so that increased amounts of glucose are consumed. This simultaneously leads to a decrease in lipid metabolism and thus tissue lipid storage. The substances according to the invention are therefore also suitable for the treatment of HIF-1α-mediated lipid enrichment in tissues, especially in obese cases.
The present invention further provides the use of the compounds of the invention for the treatment and / or prevention of diseases, in particular the diseases mentioned above.
The present invention further provides the use of a compound of the present invention for the manufacture of a medicament for the treatment and / or prevention of diseases, in particular those mentioned above.
The present invention further provides the use of the compounds of the invention in a method for the treatment and / or prevention of diseases, in particular the diseases mentioned above.
The present invention further provides a method for the treatment and / or prevention of diseases, particularly the diseases mentioned above, using an effective amount of at least one compound of the present invention.

Inventive compounds can be used alone or, if necessary, in combination with one or more pharmacologically active substances as long as the combination is not desired and does not cause unacceptable side effects. The invention therefore further provides a medicament comprising at least one compound according to the invention and one or more further active compounds for the treatment and / or prevention of the diseases mentioned above.
For example, the compounds of the present invention can be combined with known anti-hyperproliferative, cytostatic or cytotoxic agents for the treatment of cancer diseases. The hypoxic region of the tumor responds only weakly to the conventional treatments described, whereas the compounds of the present invention are particularly active there, so that the compounds of the present invention and other substances commonly used in cancer treatment Alternatively, a combination with radiation therapy is particularly suggested.

Suitable active compounds for the combination, which may be mentioned by way of example, are:
Aldesleukin, Alendronate, Alphaferon, Alitretinoin, Allopurinol, Alloprim, Alloxy, Altretamine, Aminoglutethimide, Amifostine, Amrubicin, Amsacrine, Anastrozole, Anzumet, Aranesp, Algravin, Arsenic trioxide, Aromasin, 5- Azacitidine, azathioprine, BCG or THYS-BCG, bestatin, betamethasone acetate, betamethasone sodium phosphate, bexarotene, bleomycin sulfate, broxuridine, bortezomib, busulfan, calcitonin, campus, capecitabine, carboplatin, casodex, cephison, cermoleukin, servidin Chlorambucil, cisplatin, cladribine, clodronic acid, cyclophosphamide, cytarabine, dacarba , Dactinomycin, daunoxome, decadron, decadron phosphate, derestrogens, denileukin diftitox, depomedrol, deslorelin, dexrazoxane, diethylstilbestrol, diflucan, docetaxel, doxyfluridine, doxorubicin, dronabinol, DW-166HC, guard Elitec, Elens, Emend, Epirubicin, Epoetin alfa, Epogen, Eptaplatin, Ergamizole, Estracol, Estradiol, Estramustine phosphate sodium, Ethinyl estradiol, Ethiol, Etidronate, Etopofos, Etoposide, Fadrozole, Farston, Filgrastim, Finasteride, frigrastim, floxuridine, fluconazole, fludarabine, 5-fu Orodeoxyuridine monophosphate, 5-fluorouracil (5-FU), fluoxymesterone, flutamide, formestane, fostearbin, hotemustine, fulvestrant, gamma guard, gemcitabine, gemtuzumab, gleevec, gliadel, goserelin, granisetron hydrochloride , Histrelin, hicamtine, hydrocorton, erythro-hydroxynonyladenine, hydroxyurea, ibritumomab tiuxetan, idarubicin, ifosfamide, interferon-alpha, interferon-alpha-2, interferon-alpha-2α, interferon-alpha-2β, interferon -Alpha-n1, interferon-alpha-n3, interferon-beta, interferon-gamma-1α, interleukin-2, Ntron A, Iressa, Irinotecan, Kaitril, Lentinan Phosphate, Letrozole, Leucovorin, Leuprolide, Leuprolide Acetate, Levamisole, Levophoric Acid Calcium Salt, Levotiloid, Levoxil, Lomustine, Lonidamine, Marinol, Mechloretamine, Mecobalamin, Medroxyprogesterone Acetate Megestrol, melphalan, menest, 6-mercaptopurine, mesna, methotrexate, methobix, miltefosine, minocycline, mitomycin C, mitotane, mitoxantrone, modalrenal, myoset, nedaplatin, neurasta, neumega, neupogen, nilutamide, norbadex, NSC -631570, OCT-43, octreotide, ondansetron hydrochloride, olapred, oxaliplatin, paclitaxel , Pediapled, Pegaspargase, Pegasis, Pentostatin, Pisibanil, Pilocarpine hydrochloride, Pirarubicin, Prikamycin, Sodium porfimer, Prednisomine, Prednisolone, Prednisone, Premarin, Procarbazine, Procrit, Raltitrexed, Levif, Rhenium-186 etidribate , Roferon-A, Romultide, Salagen, Sandstatin, Sargramostim, Semustine, Schizophyllan, Sobuzoxan, Solemedol, Streptozocin, Sotrontium-89 Chloride, Scintiloid, Tamoxifen, Tamsulosin, Tasonermine, Tastolactone, Taxotere, Teselomidte, Tezeloimide , Testosterone propionate, testred, thioguanine Thiotepa, thiotropin, tiludronic acid, topotecan, toremifene, tositumomab, trastuzumab, teosulfan, tretinoin, trexal, trimethylmelamine, trimethrexate, triptorelin acetate, triptorelin pamoate, UFT, uridine, valrubicin, vestinolinone, vestinirin Vindesine, vinorelbine, virulidine, ginecardo, dinostatin stimamarer, zofuran; ABI-007, acolbifene, actimimun, affinitac, aminopterin, arzoxifene, asoplicinyl, atamestan, atrasentan, abastin, CCI-779, CDC-501 , Celebrex, Cetuximab, Crisnatol, Cyproterone acetate, Decitabine, DN-101, Doxorubicin-MTC, dSLIM, Dutasteri Edotecarin, eflornithine, exatecan, fenretinide, histamine dihydrochloride, histrelin hydrogel implant, holmium-166 DOTMP, ibandronic acid, interferon-gamma, intron-PEG, ixabepilone, keyhole limpet hemocyanin, L-651582, lanreotide , Lasofoxifene, Libra, Lonafarnib, Miproxyfen, Minodronate, MS-209, Liposome MTP-PE, MX-6, Nafarelin, Nemorubicin, Neobastat, Noratrexed, Obrimersen, Onco-TCS, Osidem , Paclitaxel polyglutamate, disodium pamidronate, PN-401, QS-21, quazepam, R-1549, raloxifene, lampirnase, regorafenib, 13-cis-retinoic acid, satraplatin, seocalcito , Sorafenib, T-138067, Tarceva, taxoplexin, thymosin-alpha-1, thiazofurin, tipifarnib, tirapazamine, TLK-286, toremifene, trans-MID-107R, valspodal, bapreotide, bataranib, verteporfin, vinfluron, Z-100, zoledrone Acids and combinations thereof.

In a preferred embodiment, the compounds of the invention may be combined with an anti-hyperproliferative agent, as an example-although this list is not final-
Aminoglutethimide, L-asparaginase, azathioprine, 5-azacytidine, bleomycin, busulfan, camptothecin, carboplatin, carmustine, chlorambucil, cisplatin, cholaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, diethylstilbestrol 2 ', 2'-difluorodeoxycytidine, docetaxel, doxorubicin (adriamycin), epirubicin, epothilone and its derivatives, erythro-hydroxynonyladenine, ethinylestradiol, etoposide, fludarabine phosphate, 5-fluorodeoxyuridine, 5-fluorodeoxy Uridine monophosphate, 5-fluorouracil, fluoxymesterone, flutamide, hexamethylmelamine, hydroxyurea , Hydroxyprogesterone caprylate, idarubicin, ifosfamide, interferon, irinotecan, leucovorin, lomustine, mechlorethamine, medroxyprogesterone acetate, megestrol acetate, melphalan, 6-mercaptopurine, mesna, methotrexate, mitomycin C, mitoxantrone , Paclitaxel, pentostatin, N-phosphonoacetyl L-aspartate (PALA), pricamycin, prednisolone, prednisone, procarbazine, raloxifene, semustine, streptozocin, tamoxifen, teniposide, testosterone propionate, thioguanine, thiotepa, topotecan, tripotamine Uridine, vinblastine, vincristine, vindesine and vinorelbine Yeah.

The compounds of the present invention are also very promising with biological therapeutic agents such as antibodies (eg, Avastin, Rituxan, Erbitux, Herceptin) and recombinant proteins that promote additive or synergistic effects of inhibiting the HIF signaling pathway Can be combined in various ways.
HIF regulatory pathway inhibitors, such as compounds of the present invention, can achieve favorable effects in combination with other therapeutic agents for angiogenesis, such as Avastin, actinitib, resentin, regorafenib, sorafenib or sunitinib. Combinations of proteasome and mTOR inhibitors and antihormonal agents and steroidal metabolic enzyme inhibitors are particularly suitable due to their favorable profile of their side effects.

In general, the compounds of the present invention can achieve the following objectives in combination with other cytostatic or cytotoxic active agents:
Improved effect on tumor growth delay, size reduction or their complete disappearance compared to treatment with individual active ingredients;
The possibility of using chemotherapeutic agents at lower doses than in monotherapy;
The possibility of a more tolerable treatment with fewer side effects compared to individual administration;
More extensive tumor treatment possibilities;
Achieving a high response rate to treatment;
Longer patient survival compared to current standard treatment.
In addition, the compounds of the invention can also be used in conjunction with radiation therapy and / or surgical intervention.

The present invention further provides a medicament comprising at least one compound of the present invention, typically together with one or more inert, non-toxic, pharmaceutically suitable auxiliaries, and uses thereof for the aforementioned purposes .
The compounds of the invention can act systemically and / or locally. For this purpose,
It can be administered by oral, parenteral, pulmonary, nasal, sublingual, buccal, buccal, rectal, subcutaneous, transdermal, transconjunctival, transotic route, or by implant or stent.

The compound of the present invention can be administered in an appropriate dosage form for these administration routes.
Suitable forms for oral administration are those which work according to the prior art, release the compounds of the invention rapidly and / or in a modified manner, and contain the compounds of the invention in crystalline and / or amorphous and / or dissolved form For example, tablets (uncoated tablets or tablets coated with a gastric juice resistant or slow dissolving or insoluble coating that controls the release of the compounds of the invention), tablets or films / oblates that disintegrate rapidly in the oral cavity, Film / lyophilized formulations or capsules (eg hard or soft gelatin capsules), dragees, granules, pills, powders, emulsions, suspensions, aerosols or solutions.
Parenteral administration bypasses the absorption process (e.g., intravenous, intraarterial, intracardiac, intrathecal, or lumbar), but also involves absorption (e.g., intramuscular, subcutaneous, intradermal, transdermal) (Skin or intraperitoneal administration). Suitable dosage forms for parenteral administration are solutions, suspensions, emulsions, lyophilized formulations or sterile powders.
Other routes of administration include, for example, inhalation formulations (including powder inhalation formulations and nebulizers), nasal drops, solutions or sprays, electuary, sublingual or buccal tablets, films / oblates or capsules, Suppository, ear or eye preparation, vaginal capsule, aqueous suspension (lotion, shaking mixture), lipophilic suspension, ointment, cream, transdermal therapeutic system (e.g., plaster), emulsion, Plasters, foams, sprinkling powders, implants or stents are suitable.
Oral or parenteral administration is preferred, especially oral and intravenous administration.

The compounds of 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 additives include carriers (e.g., microcrystalline cellulose, lactose, mannitol), solvents (e.g., liquid polyethylene glycol), emulsifiers and dispersants or wetting agents (e.g., sodium dodecyl sulfate, polyoxysorbitan oleate), binding Agents (e.g. polyvinylpyrrolidone), synthetic and natural polymers (e.g. albumin), stabilizers (e.g. antioxidants, e.g. ascorbic acid), colorants (e.g. inorganic pigments e.g. iron oxide) and flavors and Contains a flavoring agent.
In general, it has been found advantageous to administer an amount of about 0.001 to 1 mg / kg body weight, preferably about 0.01 to 0.5 mg / kg body weight, in order to obtain beneficial results with parenteral administration. For oral administration, the dosage is 0.01 to 100 mg / kg body weight, preferably 0.01 to 20 mg / kg, very preferably 0.1 to 10 mg / kg body weight.

  Nevertheless, it may be appropriate to deviate from the dosage, particularly depending on body weight, route of administration, individual response to the active substance, the nature of the formulation and the time or interval at which the administration takes place. Therefore, in some cases a lower dose than the aforementioned minimum dose may be sufficient, while in other cases the upper limit mentioned must be exceeded. If large doses are administered, it may be advisable to divide them into several doses throughout the day.

The invention is illustrated in the following working examples. The present invention is not limited to the examples.
Unless otherwise stated, the proportions in the following tests and examples are percentages by weight and parts are parts by weight. Solvent ratio, dilution ratio and liquid / liquid solution concentration values are each based on volume.

A. Examples
Abbreviations and acronyms:
abs. anhydrous
Ac Acetyl
AIBN 2,2'-azobis (isobutyronitrile)
aq. Aqueous
Ex. Examples
Bu Butyl
approx.
CDI 1,1'-carbonyldiimidazole
CI chemical ionization (in MS)
d Doublet (by NMR)
d days
DAST diethylaminosulfur trifluoride
TLC thin layer chromatography
DCI direct chemical ionization (in MS)
dd doublet doublet (by NMR)
DMAP 4-N, N-dimethylaminopyridine
DME 1,2-dimethoxyethane
DMF N, N-dimethylformamide
DMSO Dimethyl sulfoxide
dt triplet doublet (by NMR)
EDC N '-(3-Dimethylaminopropyl) -N-ethylcarbodiimide hydrochloride
ee Enantiomeric excess
EI electron impact ionization (with MS)
eq. equivalent
ESI electrospray ionization (with MS)
Et ethyl
GC gas chromatography
h hours
HOBt 1-hydroxy-1H-benzotriazole hydrate
HPLC High pressure, high performance liquid chromatography
ⁱ Pr Isopropyl
LC-MS liquid chromatography-binding mass spectrometry
LiHMDS lithium hexamethyldisilazide
lit. Literature (reference)
m Multiplet (by NMR)
mCPBA meta-chloroperbenzoic acid
Me methyl
min minutes
MPLC medium pressure liquid chromatography (on silica gel; also called “flash chromatography”)
Ms Methanesulfonyl (mesyl)
MS mass spectrometry
NBS N-Bromosuccinimide
NMP N-methyl-2-pyrrolidinone
NMR nuclear magnetic resonance spectroscopy
Pd / C Palladium on activated carbon
PEG polyethylene glycol
Pr propyl
quart quartet (by NMR)
quint quintet (by NMR)
R _f retention index (in TLC)
RT Room temperature
_Rt retention time (by HPLC)
s Singlet (by NMR)
sept septet (by NMR)
t triplet (by NMR)
TBAF Tetra-n-butylammonium fluoride
^t Bu tert-Butyl
Tf trifluoromethylsulfonyl (trifuryl)
TFA trifluoroacetic acid
THF tetrahydrofuran
TIPS Triisopropylsilyl
UV UV spectroscopy
v / v volume ratio (of solution)
tog.

HPLC, LC / MS and GC / MS methods:
Method 1 (LC / MS):
MS instrument type: Micromass ZQ; instrument HPLC: HP 1100 series; UV DAD; column: Phenomenex Gemini 3μ, 30 mm x 3.00 mm; mobile phase A: water 1 l + 50% formic acid 0.5 ml, mobile phase B: acetonitrile 1 l + 50 % 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 2 (LC / MS):
Instrument: Micromass Quattro Micro MS combined with HPLC Agilent Series 1100; Column: Thermo Hypersil GOLD 3μ, 20 mm x 4 mm; Mobile phase A: Water 1 l + 50% formic acid 0.5 ml, Mobile phase B: Acetonitrile 1 l + 50% formic acid 0.5 ml Gradient: 0.0 min 100% A → 3.0 min 10% A → 4.0 min 10% A → 4.01 min 100% A (flow rate 2.5 ml / min) → 5.00 min 100% A; oven: 50 ° C; flow rate: 2 ml / Minute; UV detection: 210 nm

Method 3 (LC / MS):
MS instrument type: Micromass ZQ; instrument HPLC: Waters Alliance 2795; column: Phenomenex Synergi 2.5μ MAX-RP 100A Mercury 20 mm x 4 mm; mobile phase A: water 1 l + 0.5% 50% formic acid, mobile phase B: acetonitrile 1 l + 50% formic acid 0.5 ml; gradient: 0.0 min 90% A → 0.1 min 90% A → 3.0 min 5% A → 4.0 min 5% A → 4.01 min 90% A; flow rate: 2 ml / min; oven: 50 ° C UV detection: 210 nm
Method 4 (LC / MS):
Apparatus: Micromass Quattro Premier with Waters UPLC Acquity; Column: Thermo Hypersil GOLD 1.9μ, 50 mm x 1 mm; Mobile phase A: Water 1 l + 50% formic acid 0.5 ml, Mobile phase B: Acetonitrile 1 l + 50% formic acid 0.5 ml; Gradient: 0.0 min 90% A → 0.1 min 90% A → 1.5 min 10% A → 2.2 min 10% A; flow rate: 0.33 ml / min; oven: 50 ° C; UV detection: 210 nm
Method 5 (LC / MS):
Equipment: Micromass Quattro LCZ combined with HPLC Agilent series 1100; Column: Phenomenex Synergi 2.5μ MAX-RP 100A Mercury 20 mm x 4 mm; Mobile phase A: Water 1 l + 50% formic acid 0.5 ml, Mobile phase B: Acetonitrile 1 l + 50% Formic acid 0.5 ml; gradient: 0.0 minutes 90% A → 0.1 minutes 90% A → 3.0 minutes 5% A → 4.0 minutes 5% A → 4.1 minutes 90% A; flow rate: 2 ml / min; oven: 50 ° C; UV detection : 208-400 nm.

Method 6 (LC / MS):
Apparatus: Waters Acquity SQD UPLC System; Column: Waters Acquity UPLC HSS T3 1.8μ 50 mm x 1 mm; Mobile phase A: Water 1 l + 99% formic acid 0.25 ml, Mobile phase B: Acetonitrile 1 l + 99% formic acid 0.25 ml; Gradient: 0.0 Min 90% A → 1.2 min 5% A → 2.0 min 5% A; flow rate: 0.40 ml / min; oven: 50 ° C .; UV detection: 210-400 nm.
Method 7 (LC / MS):
MS instrument type: Waters ZQ; instrument HPLC: Agilent 1100 Series; UV DAD; column: Thermo Hypersil GOLD 3μ, 20 mm x 4 mm; mobile phase A: water 1 l + 0.5% 50% formic acid, mobile phase B: acetonitrile 1 l + 50% formic acid 0.5 ml; gradient: 0.0 min 100% A → 3.0 min 10% A → 4.0 min 10% A → 4.1 min 100% A (flow rate 2.5 ml / min); oven: 55 ° C; flow rate: 2 ml / min UV detection: 210 nm
Method 8 (LC / MS):
MS instrument type: Micromass ZQ; instrument HPLC: HP 1100 series; UV DAD; column: Phenomenex Gemini 3μ, 30 mm x 3.00 mm; mobile phase A: water 1 l + 50% formic acid 0.5 ml, mobile phase B: acetonitrile 1 l + 50 % 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 9 (LC / MS):
Instrument: Micromass GCT, GC 6890; Column: Restek RTX-35, 15 mx 200 μm x 0.33 μm; Constant flow rate aerated with helium: 0.88 ml / min; Oven: 70 ° C; Input: 250 ° C; Gradient: 70 ° C 30 ℃ / min → 310 ℃ (maintained for 3 minutes).
Method 10 (Analytical HPLC):
Equipment: HP 1100 combined with DAD detection; Column: Kromasil 100 RP-18, 60 mm x 2.1 mm, 3.5 μm; Mobile phase A: Perchloric acid (70% concentration) 5 ml / l water, mobile phase B: Acetonitrile; Gradient: 0 min 2% B → 0.5 min 2% B → 4.5 min 90% B → 6.5 min 90% B → 6.7 min 2% B → 7.5 min 2% B; Flow rate: 0.75 ml / min; Column temperature: 30 ° C; UV detection: 210 nm
Method 11 (preparative HPLC):
Column: GROM-SIL 120 ODS-4 HE, 10 μm, 250 mm x 30 mm; mobile phase and gradient program: acetonitrile / 0.1% formic acid aqueous solution 10:90 (0-3 minutes), acetonitrile / 0.1% formic acid aqueous solution 10: 90 → 95: 5 (3-27 min), acetonitrile / 0.1% formic acid aqueous solution 95: 5 (27-34 min), acetonitrile / 0.1% formic acid aqueous solution 10:90 (34-38 min); flow rate: 50 ml / min , Temperature: 22 ° C; UV detection: 254 nm

Method 12 (preparative HPLC):
Column: Daiso C18 Bio Spring column, 10 μm, 300 mm x 100 mm; mobile phase and gradient program: water / methanol 80:20 (0-6 min), water / methanol 80:20 → 20:80 (6-60 Min), water / methanol 20:80 (60-95 min), water / methanol 10:90 (95-105 min), water / methanol 80:20 (105-113 min); flow rate: 250 ml / min, temperature : 25 ° C; UV detection: 240 nm
Method 13 (preparative HPLC):
Column: Reprosil-Pur C18, 10 μm, 250 mm x 30 mm; mobile phase and gradient program: acetonitrile / 0.1% formic acid in water 10:90 (0-3 min), acetonitrile / 0.1% formic acid in water 10:90 → 95: 5 (3-27 min), acetonitrile / 0.1% formic acid aqueous solution 95: 5 (27-34 min), acetonitrile / 0.1% formic acid aqueous solution 10:90 (34-38 min); flow rate: 50 ml / min, temperature: 22 ° C; UV detection: 254 nm
Method 14 (preparative HPLC):
Column: YMC-ODS-AQ, C18, 10 μm, 30 mm x 250 mm; mobile phase and gradient program: methanol / 0.1% aqueous TFA solution 50:50 (0: 004: 25 min) → 70:30 (4:25 -4: 50 minutes) → 90:10 (4: 50-11: 50 minutes) → 100: 0 (11: 50-12: 00 minutes) → 100: 0 (12: 00-14: 50 minutes); flow rate : 50 ml / min, temperature: 22 ° C; UV detection: 210 nm

Method 15 (preparative HPLC):
Column: YMC-ODS-AQ, C18, 10 μm, 30 mm x 250 mm; mobile phase and gradient program: methanol / 0.1% aqueous TFA solution 60:40 (0: 00-4: 25 min) → 80:20 (4 : 25-4: 50 min) → 100: 0 (4: 50-11: 50 min) → 100: 0 (11: 50-14: 50 min); flow rate: 50 ml / min, temperature: 22 ° C; UV Detection: 210 nm
Method 16 (preparative HPLC):
Column: Sunfire C18 OBD 5 μm, 20 mm x 250 mm; mobile phase: water / methanol / 1% aqueous TFA solution 20: 75: 5 (0: 00-7: 00 min); flow rate: 25 ml / min, temperature: 40 ° C; UV detection: 210 nm
Method 17 (HPLC for preparative):
Column: Reprosil C18, 10 μm, 250 mm x 30 mm; mobile phase and gradient program: acetonitrile / 0.1% aqueous ammonia 20:80 (0-3 min), acetonitrile / 0.1% aqueous ammonia 20:80 → 98: 2 ( 3-35 min), acetonitrile / 0.1% aqueous ammonia 98: 2 (35-40 min); flow rate: 50 ml / min, temperature: 22 ° C .; UV detection: 210 nm
Method 18 (HPLC for preparative):
Column: Sunfire C18 OBD 5 μm, 20 mm x 250 mm; mobile phase: water / acetonitrile / 1% aqueous TFA solution 24:70:06 (0: 00-14: 00 min); flow rate: 25 ml / min, temperature: 40 ° C; UV detection: 210 nm
Method 19 (LC / MS):
Equipment: Thermo DFS, Trace GC Ultra; Column: Restek RTX-35, 15 mx 200 μm x 0.33 μm; Constant flow rate aerated with helium: 1.20 ml / min; Oven: 60 ° C; Input: 220 ° C; Gradient: 60 ° C , 30 ℃ / min → 300 ℃ (maintain 3.33 minutes).

  For all reactants or reagents whose preparation is not explicitly described below, they were obtained commercially from publicly available sources. In the following, all other reactants or reagents obtained from where the preparations are also not clearly shown and are not commercially available or generally accessible are referenced in the published literature describing their preparation. .

工程1： 2-(4-ブロモフェニル)-1,1,1-トリフルオロプロパン-2-オール

ジクロロ(ジメチル)チタニウムのヘプタン/ジクロロメタン混合物の懸濁液を、最初に以下の通り調製した： 1 M四塩化チタンのジクロロメタン溶液100 ml(100 mmol)を-30℃に冷却し、1 Mジメチル亜鉛のヘプタン溶液100 ml(100 mmol)を滴下し、混合物を続いて-30℃で30分撹拌した。続いてこの懸濁液を-40℃に冷却し、1-(4-ブロモフェニル)-2,2,2-トリフルオロエタノン10 g(39.5 mmol)のジクロロメタン溶液50 mlを加えた。続いて混合物を-40℃で5分撹拌し、続いて温度を室温に戻し、混合物を室温でさらに2時間撹拌した。氷冷下、水50 mlをゆっくり加え、続いて混合物をさらに水300 mlで希釈した。ジクロロメタンで2回抽出し、合わせたジクロロメタン相を水で1回洗浄し、無水硫酸マグネシウムで乾燥させ、濾過し、溶媒をロータリーエバポレーターで除去した。残渣をシリカゲルカラムクロマトグラフィーで精製した(移動相：シクロヘキサン/酢酸エチル 85:15)。¹H NMRによるとなお溶媒が残留している表題化合物10.5 g(理論値の100%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：7.52 (d、2H)、7.47 (d、2H)、1.76 (s、3H)。
LC/MS (方法1、ESIpos)：R_t＝2.27分；m/z＝268 [M+H]⁺; Starting materials and intermediates:
Example 1A
N'-hydroxy-4- (1,1,1-trifluoro-2-methylpropan-2-yl) benzenecarboximidamide

Step 1: 2- (4-Bromophenyl) -1,1,1-trifluoropropan-2-ol

A suspension of a dichloro (dimethyl) titanium heptane / dichloromethane mixture was first prepared as follows: 100 ml (100 mmol) of 1 M titanium tetrachloride in dichloromethane was cooled to −30 ° C. and 1 M dimethylzinc Of heptane in 100 ml (100 mmol) was added dropwise and the mixture was subsequently stirred at −30 ° C. for 30 minutes. Subsequently, the suspension was cooled to −40 ° C., and 50 ml of a dichloromethane solution of 10 g (39.5 mmol) of 1- (4-bromophenyl) -2,2,2-trifluoroethanone was added. The mixture was subsequently stirred at −40 ° C. for 5 minutes, then the temperature was allowed to return to room temperature and the mixture was stirred at room temperature for a further 2 hours. Under ice cooling, 50 ml of water was slowly added, and then the mixture was further diluted with 300 ml of water. Extracted twice with dichloromethane and the combined dichloromethane phases were washed once with water, dried over anhydrous magnesium sulfate, filtered and the solvent removed on a rotary evaporator. The residue was purified by silica gel column chromatography (mobile phase: cyclohexane / ethyl acetate 85:15). 10.5 g (100% of theory) of the title compound, which still had a solvent remaining by ¹ H NMR.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 7.52 (d, 2H), 7.47 (d, 2H), 1.76 (s, 3H).
LC / MS (Method 1, ESIpos): R _t = 2.27 min; m / z = 268 [M + H] ⁺ ;

アルゴン下、水素化ナトリウム3.12 g(78.05 mmol、60%鉱油中)をTHF45 mlに加え、実施例1A/工程1で得られた化合物10.5 g(39.03 mmol)のTHF溶液20 mlを室温で加えた。混合物を室温で1時間および40℃で30分撹拌した後、メタンスルホニルクロライド8.94 g(78.05 mmol)のTHF溶液45 mlを滴下し、反応混合物をさらに40℃で60分撹拌した。続いて混合物に水50 mlをゆっくり滴下し、混合物を飽和重炭酸ナトリウム水溶液で希釈し、酢酸エチルで2回抽出した。合わせた酢酸エチル相を無水硫酸マグネシウムで乾燥させ、濾過し、溶媒をロータリーエバポレーターで除去した。残渣をヘキサン中で撹拌し、得られた固体を濾過し、真空下乾燥させた。これにより表題化合物12.4 g(理論値の92%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：7.58 (d、2H)、7.43 (d、2H)、3.16 (s、3H)、2.28 (s、3H)。
LC/MS (方法2、ESIpos)：R_t＝2.32分、m/z＝364 [M+NH₄]⁺。 Step 2: 2- (4-Bromophenyl) -1,1,1-trifluoropropan-2-ylmethanesulfonate

Under argon, 3.12 g (78.05 mmol, 60% in mineral oil) of sodium hydride was added to 45 ml of THF, and 20 ml of a THF solution of compound 10.5 g (39.03 mmol) obtained in Example 1A / Step 1 was added at room temperature. . After the mixture was stirred at room temperature for 1 hour and at 40 ° C. for 30 minutes, 45 ml of a THF solution of 8.94 g (78.05 mmol) of methanesulfonyl chloride was added dropwise, and the reaction mixture was further stirred at 40 ° C. for 60 minutes. Subsequently, 50 ml of water was slowly added dropwise to the mixture, and the mixture was diluted with a saturated aqueous sodium bicarbonate solution and extracted twice with ethyl acetate. The combined ethyl acetate phases were dried over anhydrous magnesium sulfate, filtered and the solvent was removed on a rotary evaporator. The residue was stirred in hexane and the resulting solid was filtered and dried under vacuum. This gave 12.4 g (92% of theory) of the title compound.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 7.58 (d, 2H), 7.43 (d, 2H), 3.16 (s, 3H), 2.28 (s, 3H).
LC / MS (Method 2, ESIpos): R _t = 2.32 min, m / z = 364 [M + NH ₄ ] ⁺ .

実施例1A/工程2で得られた化合物12.4 g(35.72 mmol)をまずジクロロメタン250 ml中に加え、混合物を0℃に冷却した。撹拌下、0℃で、2 Mトリメチルアルミニウム溶液35.7 ml(71.44 mmol)をゆっくり加え、混合物を室温に戻し、続いて室温でさらに1.5時間撹拌した。混合物に飽和重炭酸ナトリウム水溶液120 mlをゆっくり滴下し、続いて飽和塩化ナトリウム水溶液40 mlを加えた。混合物をkieselguhrで濾過し、kieselguhrをジクロロメタンで2回洗浄した。合わせたジクロロメタン相を飽和塩化ナトリウム水溶液で1回洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒をロータリーエバポレーターで除去した。これにより表題化合物8.69 g(理論値の87%)を純度95%で得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：7.49 (d、2H)、7.33 (d、2H)、1.55 (s、6H)。
LC/MS (方法3、ESIpos)：R_t＝2.54分、イオン化しない
GC/MS (方法9、ESIpos)：R_t＝3.48分、m/z＝266 [M]⁺。 Step 3: 1-Bromo-4- (1,1,1-trifluoro-2-methylpropan-2-yl) benzene

12.4 g (35.72 mmol) of the compound obtained in Example 1A / Step 2 was first added into 250 ml of dichloromethane and the mixture was cooled to 0 ° C. Under stirring at 0 ° C., 35.7 ml (71.44 mmol) of 2 M trimethylaluminum solution was slowly added and the mixture was allowed to warm to room temperature, followed by further stirring at room temperature for 1.5 hours. To the mixture was slowly added dropwise 120 ml of saturated aqueous sodium bicarbonate solution, followed by 40 ml of saturated aqueous sodium chloride solution. The mixture was filtered through kieselguhr and kieselguhr was washed twice with dichloromethane. The combined dichloromethane phases were washed once with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed on a rotary evaporator. This gave 8.69 g (87% of theory) of the title compound with a purity of 95%.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 7.49 (d, 2H), 7.33 (d, 2H), 1.55 (s, 6H).
LC / MS (Method 3, ESIpos): R _t = 2.54 min, not ionized
GC / MS (Method 9, ESIpos): R _t = 3.48 min, m / z = 266 [M] ⁺ .

最初に、アルゴン下、実施例1A/工程3で得られた化合物3.34 g(12.50 mmol)を脱気したDMF2.5 mlに加え、シアン化亜鉛881 mg(7.50 mmol)およびテトラキス(トリフェニルホスフィン)パラジウム(0)867 mg(0.75 mmol)を加え、混合物を80℃で一夜撹拌した。室温に冷却した後、反応混合物を酢酸エチルで希釈し、固体成分を濾過した。濾液を2 N アンモニア水溶液で2回および飽和塩化ナトリウム水溶液で1回洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒をロータリーエバポレーターで除去した。残渣をシリカゲルカラムクロマトグラフィーで精製した(移動相：シクロヘキサン/酢酸エチル 85:15)。これにより表題化合物2.08 g(理論値の78%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：7.68 (d、2H)、7.62 (d、2H)、1.60 (s、6H)。
GC/MS (方法9、ESIpos)：R_t＝3.83分、m/z＝213 [M]⁺。 Step 4: 4- (1,1,1-trifluoro-2-methylpropan-2-yl) benzenecarbonitrile

First, under argon, 3.34 g (12.50 mmol) of the compound obtained in Example 1A / Step 3 was added to 2.5 ml of degassed DMF, 881 mg (7.50 mmol) of zinc cyanide and tetrakis (triphenylphosphine). Palladium (0) 867 mg (0.75 mmol) was added and the mixture was stirred at 80 ° C. overnight. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and the solid component was filtered. The filtrate was washed twice with 2 N aqueous ammonia and once with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and the solvent was removed on a rotary evaporator. The residue was purified by silica gel column chromatography (mobile phase: cyclohexane / ethyl acetate 85:15). This gave 2.08 g (78% of theory) of the title compound.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 7.68 (d, 2H), 7.62 (d, 2H), 1.60 (s, 6H).
GC / MS (Method 9, ESIpos): R _t = 3.83 min, m / z = 213 [M] ⁺ .

実施例1A/工程4からの化合物2.40 g(11.26 mmol)、ヒドロキシルアミンヒドロクロライド1.72 g(24.77 mmol)およびトリエチルアミン3.45 ml(24.77 mmol)のエタノール60 ml中の混合物を還流下1時間撹拌した。室温に冷却した後、溶媒をロータリーエバポレーターで除去した。残渣に酢酸エチルを加え、存在する固体を濾過した。酢酸エチル 溶液を水および続いて飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、濾過した。溶媒を除去した後、得られた油状物を石油エーテルで摩砕した。生成した固体を吸引濾過した後、高真空下乾燥させ、表題化合物2.65 g(理論値の96%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：8.0 (s、broad、1H)、7.62 (d、2H)、7.52 (d、2H)、4.88 (s、broad、2H)、1.60 (s、6H)。
LC/MS (方法2、ESIpos)：R_t＝1.34分；m/z＝247 [M+H]⁺; Step 5: N'-hydroxy-4- (1,1,1-trifluoro-2-methylpropan-2-yl) benzenecarboximidamide

A mixture of 2.40 g (11.26 mmol) of the compound from Example 1A / Step 4, 1.72 g (24.77 mmol) of hydroxylamine hydrochloride and 3.45 ml (24.77 mmol) of triethylamine in 60 ml of ethanol was stirred under reflux for 1 hour. After cooling to room temperature, the solvent was removed on a rotary evaporator. Ethyl acetate was added to the residue and the solid present was filtered. The ethyl acetate solution was washed with water followed by saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. After removing the solvent, the resulting oil was triturated with petroleum ether. The produced solid was subjected to suction filtration and then dried under high vacuum to obtain 2.65 g (96% of theory) of the title compound.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 8.0 (s, broad, 1H), 7.62 (d, 2H), 7.52 (d, 2H), 4.88 (s, broad, 2H), 1.60 (s 6H).
LC / MS (Method 2, ESIpos): R _t = 1.34 min; m / z = 247 [M + H] ⁺ ;

工程1： 4-(2-フルオロプロパン-2-イル)ベンゼンカルボニトリル

0℃で、ジエチルアミノサルファートリフルオライド(DAST)1.20 g(7.44 mmol)を4-(2-ヒドロキシプロパン-2-イル)ベンゼンカルボニトリル [J.L.Tucker et al.、Synth.Comm.2006、36 (15)、2145-2155に従い、4-(プロパン-2-イル)ベンゼンカルボニトリルから得られる] 1.00 g(6.20 mmol)のジクロロメタン溶液20 mlに加えた。反応混合物は、室温で2時間撹拌し、続いて水で希釈し、ジクロロメタンで抽出した。有機層を水で洗浄し、無水硫酸マグネシウムで乾燥させ、濾過した。溶媒をロータリーエバポレーターで除去した後、残渣をMPLCで精製した(シリカゲル、移動相：シクロヘキサン/酢酸エチル 95:5)。これにより表題化合物675 mg(理論値の67%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：7.57 (d、2H)、7.48 (d、2H)、1.72 (s、3H)、1.68 (s、3H)。
LC/MS (方法2、ESIpos)：R_t＝2.12分；m/z＝163 [M+H]⁺; Example 2A
4- (2-Fluoropropan-2-yl) -N'-hydroxybenzenecarboximidamide

Process 1: 4- (2-fluoropropan-2-yl) benzenecarbonitrile

At 0 ° C., diethylaminosulfur trifluoride (DAST) 1.20 g (7.44 mmol) was converted to 4- (2-hydroxypropan-2-yl) benzenecarbonitrile [JLTucker et al., Synth. Comm. 2006, 36 (15), According to 2145-2155, obtained from 4- (propan-2-yl) benzenecarbonitrile] was added to 20 ml of a solution of 1.00 g (6.20 mmol) in dichloromethane. The reaction mixture was stirred at room temperature for 2 hours, subsequently diluted with water and extracted with dichloromethane. The organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered. After removing the solvent on a rotary evaporator, the residue was purified by MPLC (silica gel, mobile phase: cyclohexane / ethyl acetate 95: 5). This gave 675 mg (67% of theory) of the title compound.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 7.57 (d, 2H), 7.48 (d, 2H), 1.72 (s, 3H), 1.68 (s, 3H).
LC / MS (Method 2, ESIpos): R _t = 2.12 min; m / z = 163 [M + H] ⁺ ;

実施例1A/工程5に記載した工程により、実施例2A/工程1の化合物675 mg(4.14 mmol)から表題化合物756 mg(理論値の93%)が得られた。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：7.62 (d、2H)、7.41 (d、2H)、4.89 (s、broad、2H)、1.72 (s、3H)、1.68 (s、3H)。
LC/MS (方法2、ESIpos)：R_t＝1.04分；m/z＝197 [M+H]⁺; Step 2: 4- (2-Fluoropropan-2-yl) -N'-hydroxybenzenecarboximidamide

By the steps described in Example 1A / Step 5, 675 mg (4.14 mmol) of the compound of Example 2A / Step 1 yielded 756 mg of the title compound (93% of theory).
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 7.62 (d, 2H), 7.41 (d, 2H), 4.89 (s, broad, 2H), 1.72 (s, 3H), 1.68 (s, 3H ).
LC / MS (Method 2, ESIpos): R _t = 1.04 min; m / z = 197 [M + H] ⁺ ;

実施例1A/工程5に記載した工程により、4-[(トリフルオロメチル)スルホニル]ベンゼンカルボニトリル [W.Su、Tetrahedron.Lett.1994、35 (28)、4955-4958] 4.60 g(19.56 mmol)から表題化合物5.08 g(理論値の97%)が得られた。
¹H NMR (400 MHz、DMSO-d₆、δ/ppm)：10.26 (s、1H)、8.13 (dd、4H)、6.12 (s、2H)。
LC/MS (方法2、ESIpos)：R_t＝1.57分；m/z＝269 [M+H]⁺; Example 3A
N'-hydroxy-4-[(trifluoromethyl) sulfonyl] benzenecarboximidamide

According to the process described in Example 1A / Process 5, 4-[(trifluoromethyl) sulfonyl] benzenecarbonitrile [W. Su, Tetrahedron. Lett. 1994, 35 (28), 4955-4958] 4.60 g (19.56 mmol) ) Gave 5.08 g (97% of theory) of the title compound.
¹ H NMR (400 MHz, DMSO-d ₆ , δ / ppm): 10.26 (s, 1H), 8.13 (dd, 4H), 6.12 (s, 2H).
LC / MS (Method 2, ESIpos): R _t = 1.57 min; m / z = 269 [M + H] ⁺ ;

工程1： 4-(3-ヒドロキシオキセタン-3-イル)ベンゼンカルボニトリル

不活性条件下、40℃で2 Mイソプロピルマグネシウムクロライドのジエチルエーテル溶液11 ml(21.8 mmol)を4-ヨードベンゾニトリル5.0 g(21.8 mmol)の無水THF溶液100 mlに滴下した。混合物を同一の温度で1.5時間撹拌した後、これを-78℃に冷却し、溶液に、同様に-78℃に冷却した3-オキソオキセタン [G. Wuitschik et al.、Angew. Chem. Int. Ed. Engl. 2006、45 (46)、7736-7739] 2.95 g(32.7 mmol、80%ジクロロメタン中)の無水THF溶液100 mlを、カニューレを用いてゆっくり滴下した。添加が終わると、反応混合物を最初に-78℃で10分、続いて0℃で2時間、最後に室温で30分撹拌した。続いて飽和塩化ナトリウム水溶液数mlを加えた。続いて、溶媒を大部分ロータリーエバポレーターで除去した。得られた残渣を水200 mlで希釈し、各回酢酸エチル約200 mlで3回抽出した。合わせた有機層抽出物を水、続いて飽和塩化ナトリウム溶液で洗浄した。無水硫酸マグネシウムで乾燥させた後、混合物を濾過し、溶媒をロータリーエバポレーターで除去した。得られた粗成生物をシクロヘキサン/酢酸エチル10:1からの結晶化により精製した。これにより表題化合物2.42 g(理論値の63%)を得た。
¹H NMR (400 MHz、DMSO-d₆、δ/ppm)：7.88 (d、2H)、7.80 (d、2H)、6.63 (s、1H)、4.79 (d、2H)、4.65 (d、2H)。
HPLC (方法10)：R_t＝3.09分
MS (DCI、NH₃)：m/z＝193 [M+NH₄]⁺。 Example 4A
4- (3-Fluorooxetane-3-yl) -N'-hydroxybenzenecarboximidamide

Step 1: 4- (3-Hydroxyoxetane-3-yl) benzenecarbonitrile

Under inert conditions, 11 ml (21.8 mmol) of diethyl ether solution of 2 M isopropylmagnesium chloride was added dropwise at 40 ° C. to 100 ml of anhydrous THF solution of 5.0 g (21.8 mmol) of 4-iodobenzonitrile. After the mixture was stirred at the same temperature for 1.5 hours, it was cooled to −78 ° C., and the solution was 3-oxooxetane (G. Wuitschik et al., Angew. Chem. Int. Ed. Engl. 2006, 45 (46), 7936-7739] 100 ml of an anhydrous THF solution of 2.95 g (32.7 mmol, 80% in dichloromethane) was slowly added dropwise using a cannula. When the addition was complete, the reaction mixture was first stirred at −78 ° C. for 10 minutes, then at 0 ° C. for 2 hours and finally at room temperature for 30 minutes. Subsequently, several ml of saturated aqueous sodium chloride solution was added. Subsequently, the solvent was largely removed on a rotary evaporator. The obtained residue was diluted with 200 ml of water and extracted three times with about 200 ml of ethyl acetate each time. The combined organic extracts were washed with water followed by saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, the mixture was filtered and the solvent was removed on a rotary evaporator. The resulting crude product was purified by crystallization from cyclohexane / ethyl acetate 10: 1. This gave 2.42 g (63% of theory) of the title compound.
¹ H NMR (400 MHz, DMSO-d ₆ , δ / ppm): 7.88 (d, 2H), 7.80 (d, 2H), 6.63 (s, 1H), 4.79 (d, 2H), 4.65 (d, 2H ).
HPLC (Method 10): R _t = 3.09 min
_{MS (DCI, NH 3):} m / z = 193 [M + NH 4] +.

不活性条件下、-78℃で、ジエチルアミノサルファートリフルオライド(DAST)662 mg(4.11 mmol)のジクロロメタン溶液5 mlを実施例4A/工程1からの化合物600 mg(3.43 mmol)のジクロロメタン懸濁液55 mlに滴下した。-78℃で30分後、反応混合物を、氷/水浴を用いて非常に急速に-20℃とした。約30秒後、1 M 水酸化ナトリウム溶液20 mlを加え、混合物を室温に戻した。水150 mlで希釈した後、混合物を各回約50 mlのジエチルエーテルで3回抽出した。合わせた有機層抽出物を無水硫酸マグネシウムで乾燥させた。濾過した後、溶媒をロータリーエバポレーターで除去した。粗成生物を、MPLC(シリカゲル、移動相：シクロヘキサン/酢酸エチル 8:1)により精製した。これにより表題化合物495 mg(理論値の82%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：7.76 (d、2H)、7.73 (d、2H)、5.15 (dd、2H)、4.81 (dd、2H)。
LC/MS (方法2、ESIpos)：R_t＝1.59分；m/z＝178 [M+H]⁺;
工程3： 4-(3-フルオロオキセタン-3-イル)-N’-ヒドロキシベンゼンカルボキシミドアミド

実施例1A/工程5に記載した工程により、実施例4A/工程2からの化合物450 mg(2.54 mmol)から、表題化合物470 mg(理論値の86%)が得られた。
¹H NMR (400 MHz、DMSO-d₆、δ/ppm)：9.71 (s、1H)、7.77 (d、2H)、7.54 (d、2H)、5.87 (broad s、2H)、4.97 (dd、2H)、4.91 (dd、2H)。
HPLC (方法10)：R_t＝2.64分
MS (DCI、NH₃)：m/z＝211 [M+H]⁺。
LC/MS (方法2、ESIpos)：R_t＝0.80分；m/z＝211 [M+H]⁺; Process 2: 4- (3-fluorooxetane-3-yl) benzenecarbonitrile

Under inert conditions at −78 ° C., 5 ml of a solution of 662 mg (4.11 mmol) of diethylaminosulfur trifluoride (DAST) in dichloromethane was suspended in a dichloromethane suspension of 600 mg (3.43 mmol) of the compound from Example 4A / Step 1. Added dropwise to ml. After 30 minutes at -78 ° C, the reaction mixture was brought to -20 ° C very rapidly using an ice / water bath. After about 30 seconds, 20 ml of 1 M sodium hydroxide solution was added and the mixture was allowed to warm to room temperature. After dilution with 150 ml of water, the mixture was extracted three times with about 50 ml of diethyl ether each time. The combined organic layer extracts were dried over anhydrous magnesium sulfate. After filtration, the solvent was removed on a rotary evaporator. The crude product was purified by MPLC (silica gel, mobile phase: cyclohexane / ethyl acetate 8: 1). This gave 495 mg (82% of theory) of the title compound.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 7.76 (d, 2H), 7.73 (d, 2H), 5.15 (dd, 2H), 4.81 (dd, 2H).
LC / MS (method _{2, ESIpos): R t =} 1.59 min; m / z = 178 [M + H] +;
Step 3: 4- (3-Fluorooxetane-3-yl) -N'-hydroxybenzenecarboximidamide

The process described in Example 1A / Step 5 gave 470 mg (86% of theory) of the title compound from 450 mg (2.54 mmol) of the compound from Example 4A / Step 2.
¹ H NMR (400 MHz, DMSO-d ₆ , δ / ppm): 9.71 (s, 1H), 7.77 (d, 2H), 7.54 (d, 2H), 5.87 (broad s, 2H), 4.97 (dd, 2H), 4.91 (dd, 2H).
HPLC (Method 10): R _t = 2.64 min
_{MS (DCI, NH 3):} m / z = 211 [M + H] +.
LC / MS (Method 2, ESIpos): R _t = 0.80 min; m / z = 211 [M + H] ⁺ ;

工程1： 4-(4-ヒドロキシテトラヒドロ-2H-ピラン-4-イル)ベンゼンカルボニトリル

実施例4A/工程1に記載した工程により、4-ヨードベンゾニトリル25.0 g(109 mmol)をテトラヒドロ-4H-ピラン-4-オン16.4 g(164 mmol)と反応させ、表題化合物7.56 g(理論値の34%)を得た。
¹H NMR (400 MHz、DMSO-d₆、δ/ppm)：7.80 (d、2H)、7.70 (d、2H)、5.30 (s、1H)、3.81-3.70 (m、4H)、2.02-1.94 (m、2H)、1.51-1.48 (m、2H)。
HPLC (方法10)：R_t＝3.35分
MS (DCI、NH₃)：m/z＝204 [M+H]⁺、221 [M+NH₄]⁺。 Example 5A
4- (4-Fluorotetrahydro-2H-pyran-4-yl) -N'-hydroxybenzenecarboximidamide

Step 1: 4- (4-Hydroxytetrahydro-2H-pyran-4-yl) benzenecarbonitrile

According to the process described in Example 4A / Step 1, 25.0 g (109 mmol) of 4-iodobenzonitrile was reacted with 16.4 g (164 mmol) of tetrahydro-4H-pyran-4-one to give 7.56 g (theoretical value) of the title compound. Of 34%).
¹ H NMR (400 MHz, DMSO-d ₆ , δ / ppm): 7.80 (d, 2H), 7.70 (d, 2H), 5.30 (s, 1H), 3.81-3.70 (m, 4H), 2.02-1.94 (m, 2H), 1.51-1.48 (m, 2H).
HPLC (Method 10): R _t = 3.35 min
_{MS (DCI, NH 3):} m / z = 204 [M + H] +, 221 [M + NH 4] +.

実施例4A/工程2に記載した工程により、実施例5A/工程1からの化合物6.5 g(31.98 mmol)を反応させ、表題化合物3.73 g(理論値の57%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：7.68 (d、2H)、7.50 (d、2H)、3.98-3.83 (m、4H)、2.23-2.05 (m、2H)、1.91-1.85 (m、2H)。
HPLC (方法10)：R_t＝4.04分
MS (DCI、NH₃)：m/z＝223 [M+NH₄]⁺。 Step 2: 4- (4-Fluorotetrahydro-2H-pyran-4-yl) benzenecarbonitrile

The process described in Example 4A / Step 2 was reacted with 6.5 g (31.98 mmol) of the compound from Example 5A / Step 1 to give 3.73 g (57% of theory) of the title compound.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 7.68 (d, 2H), 7.50 (d, 2H), 3.98-3.83 (m, 4H), 2.23-2.05 (m, 2H), 1.91-1.85 (m, 2H).
HPLC (Method 10): R _t = 4.04 min
_{MS (DCI, NH 3):} m / z = 223 [M + NH 4] +.

実施例1A/工程5に記載した工程により、実施例5A/工程2からの化合物3.5 g(17.05 mmol)から表題化合物3.57 g(理論値の88%)を得た。
¹H NMR (500 MHz、DMSO-d₆、δ/ppm)：9.64 (s、1H)、7.70 (d、2H)、7.44 (d、2H)、5.81 (s、2H)、3.88-3.83 (m、2H)、3.73-3.67 (m、2H)、2.23-2.06 (m、2H)、1.87-1.81 (m、2H)。
HPLC (方法10)：R_t＝3.06分
MS (DCI、NH₃)：m/z＝239 [M+H]⁺。
LC/MS (方法4、ESIpos)：R_t＝0.40分；m/z＝239 [M+H]⁺; Step 3: 4- (4-Fluorotetrahydro-2H-pyran-4-yl) -N'-hydroxybenzenecarboximidamide

The steps described in Example 1A / Step 5 gave 3.57 g (88% of theory) of the title compound from 3.5 g (17.05 mmol) of the compound from Example 5A / Step 2.
¹ H NMR (500 MHz, DMSO-d ₆ , δ / ppm): 9.64 (s, 1H), 7.70 (d, 2H), 7.44 (d, 2H), 5.81 (s, 2H), 3.88-3.83 (m , 2H), 3.73-3.67 (m, 2H), 2.23-2.06 (m, 2H), 1.87-1.81 (m, 2H).
HPLC (Method 10): R _t = 3.06 min
_{MS (DCI, NH 3):} m / z = 239 [M + H] +.
LC / MS (Method 4, ESIpos): R _t = 0.40 min; m / z = 239 [M + H] ⁺ ;

実施例1A/工程5に記載した方法に準じて、4-シクロヘキシルベンゼンカルボニトリル [E. Riguet et al.、J. Organomet. Chem. 2001、624 (1-2)、376-379] 240 mg(1.29 mmol)から表題化合物252 mg(理論値の89%)を得た。
¹H NMR (400 MHz、DMSO-d₆、δ/ppm)：9.51 (s、1H)、7.56 (d、2H)、7.20 (d、2H)、5.72 (s、broad、2H)、2.52-2.48 (m、1H)、1.81-1.74 (m、4H)、1.73-1.67 (m、1H)、1.45-1.31 (m、4H)、1.28-1.19 (m、1H)。
LC/MS (方法5、ESIpos)：R_t＝1.24分、m/z＝219 [M+H]⁺。 Example 6A
4-Cyclohexyl-N'-hydroxybenzenecarboximidamide

According to the method described in Example 1A / Step 5, 4-cyclohexylbenzenecarbonitrile [E. Riguet et al., J. Organomet. Chem. 2001, 624 (1-2), 376-379] 240 mg ( 1.29 mmol) gave 252 mg (89% of theory) of the title compound.
¹ H NMR (400 MHz, DMSO-d ₆ , δ / ppm): 9.51 (s, 1H), 7.56 (d, 2H), 7.20 (d, 2H), 5.72 (s, broad, 2H), 2.52-2.48 (m, 1H), 1.81-1.74 (m, 4H), 1.73-1.67 (m, 1H), 1.45-1.31 (m, 4H), 1.28-1.19 (m, 1H).
LC / MS (Method _{5, ESIpos): R t =} 1.24 min, m / z = 219 [M + H] +.

実施例1A/工程5に記載した方法に準じて、4-(ペンタフルオロ-λ⁶-スルファニル)ベンゼンカルボニトリル [P.J. Crowley et al.、Chimia 2004、58 (3)、138-142] 5.00 g(21.8 mmol)から表題化合物5.50 g(理論値の96%)を得た。
¹H NMR (400 MHz、DMSO-d₆、δ/ppm)：9.99 (s、1H)、7.94-7.85 (m、4H)、6.00 (s、2H)。
LC/MS (方法2、ESIpos)：R_t＝1.49分、m/z＝263 [M+H]⁺。 Example 7A
N'-hydroxy-4- (pentafluoro-λ ⁶ -sulfanyl) benzenecarboximidamide

According to the method described in Example 1A / Step 5, 4- (pentafluoro-λ ⁶ -sulfanyl) benzenecarbonitrile [PJ Crowley et al., Chimia 2004, 58 (3), 138-142] 5.00 g ( 21.8 mmol) gave 5.50 g (96% of theory) of the title compound.
¹ H NMR (400 MHz, DMSO-d ₆ , δ / ppm): 9.99 (s, 1H), 7.94-7.85 (m, 4H), 6.00 (s, 2H).
LC / MS (method _{2, ESIpos): R t =} 1.49 min, m / z = 263 [M + H] +.

実施例1A/工程5に記載した方法に準じて、4-[(トリフルオロメチル)スルファニル]ベンゼンカルボニトリル5.20 g(25.6 mmol)から表題化合物5.98 g(理論値の97%)を得た。
¹H NMR (400 MHz、DMSO-d₆、δ/ppm)：9.90 (s、1H)、7.80 (d、2H)、7.72 (d、2H)、5.94 (s、2H)。
LC/MS (方法2、ESIpos)：R_t＝1.42分、m/z＝237 [M+H]⁺。 Example 8A
N'-hydroxy-4-[(trifluoromethyl) sulfanyl] benzenecarboximidamide

According to the method described in Example 1A / Step 5, 4.98 g (25.6 mmol) of 4-[(trifluoromethyl) sulfanyl] benzenecarbonitrile gave 5.98 g (97% of theory) of the title compound.
¹ H NMR (400 MHz, DMSO-d ₆ , δ / ppm): 9.90 (s, 1H), 7.80 (d, 2H), 7.72 (d, 2H), 5.94 (s, 2H).
LC / MS (Method 2, ESIpos): R _t = 1.42 min, m / z = 237 [M + H] ⁺ .

実施例1A/工程5に記載した方法に準じて、4-(トリメチルシリル)ベンゼンカルボニトリル [P. di Raddo et al.、J.Chem.Soc.Chem. Commun. 1984、(3)、159-160] 2.10 g(11.9 mmol)から表題化合物2.20 g(91%純度、理論値の80%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：7.95 (s、broad、1H)、7.60 (d、2H)、7.55 (d、2H)、4.86 (s、broad、2H)、0.27 (s、9H)。
LC/MS (方法6、ESIpos)：R_t＝0.75分、m/z＝209 [M+H]⁺。 Example 9A
N'-hydroxy-4- (trimethylsilyl) benzenecarboximidamide

According to the method described in Example 1A / Step 5, 4- (trimethylsilyl) benzenecarbonitrile [P. di Raddo et al., J. Chem. Soc. Chem. Commun. 1984, (3), 159-160 The title compound 2.20 g (91% purity, 80% of theory) was obtained from 2.10 g (11.9 mmol).
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 7.95 (s, broad, 1H), 7.60 (d, 2H), 7.55 (d, 2H), 4.86 (s, broad, 2H), 0.27 (s 9H).
LC / MS (Method 6, ESIpos): R _t = 0.75 min, m / z = 209 [M + H] ⁺ .

工程1： 4-(1-ヒドロキシシクロブチル)ベンゼンカルボニトリル

実施例4A/工程1に記載した方法に準じて、4-ヨードベンゾニトリル15.00 g(65.5 mmol)、イソプロピルマグネシウムクロライド溶液(2 Mジエチルエーテル中)34.4 ml(68.8 mmol)およびシクロブタノン7.4 ml(98.2 mmol)から、表題化合物9.47 g(理論値の83%)を得た。生成物の精製は、MPLCにより行った(シリカゲル、移動相：シクロヘキサン/酢酸エチル 10:1 → 4:1)。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：7.67 (d、2H)、7.62 (d、2H)、2.58-2.51 (m、2H)、2.44-2.37 (m、2H)、2.23-2.04 (m、2H)、1.83-1.72 (m、1H)。
HPLC (方法10)：R_t＝3.47分
MS (DCI、NH₃)：m/z＝191 [M+NH₄]⁺。 Example 10A
4- (1-Fluorocyclobutyl) -N'-hydroxybenzenecarboximide

Process 1: 4- (1-hydroxycyclobutyl) benzenecarbonitrile

In accordance with the method described in Example 4A / Step 1, 15.00 g (65.5 mmol) of 4-iodobenzonitrile, 34.4 ml (68.8 mmol) of isopropylmagnesium chloride solution (in 2 M diethyl ether) and 7.4 ml (98.2 mmol) of cyclobutanone. ) To give 9.47 g (83% of theory) of the title compound. The product was purified by MPLC (silica gel, mobile phase: cyclohexane / ethyl acetate 10: 1 → 4: 1).
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 7.67 (d, 2H), 7.62 (d, 2H), 2.58-2.51 (m, 2H), 2.44-2.37 (m, 2H), 2.23-2.04 (m, 2H), 1.83-1.72 (m, 1H).
HPLC (Method 10): R _t = 3.47 min
_{MS (DCI, NH 3):} m / z = 191 [M + NH 4] +.

実施例4A/工程2に記載した方法に準じて、実施例10A/工程1からの化合物2.00 g(11.5 mmol)およびジエチルアミノサルファートリフルオライド(DAST)1.8 ml(13.9 mmol)から表題化合物1.39 g(理論値の69%)を得た。生成物の精製は、MPLCにより行った(シリカゲル、移動相：シクロヘキサン/酢酸エチル 10:1 → 5:1)。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：7.69 (d、2H)、7.57 (d、2H)、2.78-2.62 (m、2H)、2.58-2.48 (m、2H)、2.20-2.09 (m、1H)、1.87-1.75 (m、1H)。
GC/MS (方法9、EIpos)：R_t＝4.71分、m/z＝155 [M-HF]⁺。
工程3： 4-(1-フルオロシクロブチル)-N’-ヒドロキシベンゼンカルボキシミドアミド

実施例1A/工程5に記載した方法に準じて、実施例10A/工程2からの化合物1.25 g(7.13 mmol)から出発して表題化合物(理論値の78%)1.16 gを得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：7.67 (d、2H)、7.50 (d、2H)、4.87 (s、broad、2H)、2.72-2.52 (m、5H)、2.16-2.05 (m、1H)、1.82-1.71 (m、1H)。
HPLC (方法10)：R_t＝3.17分
MS (DCI、NH₃)：m/z＝209 [M+H]⁺。 Process 2: 4- (1-fluorocyclobutyl) benzenecarbonitrile

According to the method described in Example 4A / Step 2, from 2.00 g (11.5 mmol) of the compound from Example 10A / Step 1 and 1.39 g (13.9 mmol) of the title compound from 1.8 ml (13.9 mmol) of diethylaminosulfur trifluoride (DAST) 69% of the value) was obtained. The product was purified by MPLC (silica gel, mobile phase: cyclohexane / ethyl acetate 10: 1 → 5: 1).
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 7.69 (d, 2H), 7.57 (d, 2H), 2.78-2.62 (m, 2H), 2.58-2.48 (m, 2H), 2.20-2.09 (m, 1H), 1.87-1.75 (m, 1H).
GC / MS (Method 9, EIpos): R _t = 4.71 min, m / z = 155 [M-HF] ⁺ .
Step 3: 4- (1-Fluorocyclobutyl) -N'-hydroxybenzenecarboximidamide

According to the method described in Example 1A / Step 5, starting from 1.25 g (7.13 mmol) of the compound from Example 10A / Step 2, 1.16 g of the title compound (78% of theory) was obtained.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 7.67 (d, 2H), 7.50 (d, 2H), 4.87 (s, broad, 2H), 2.72-2.52 (m, 5H), 2.16-2.05 (m, 1H), 1.82-1.71 (m, 1H).
HPLC (Method 10): R _t = 3.17 min
_{MS (DCI, NH 3):} m / z = 209 [M + H] +.

工程1： 4-(テトラヒドロ-2H-ピラン-4-イル)ベンゾニトリル

ヨウ化ニッケル(II)186 mg(0.594 mmol)、トランス-2-アミノシクロヘキサノール ヒドロクロライド90 mg(0.594 mmol)およびナトリウム ヘキサメチルジシラジド3.63 g(19.8 mmol)を4-シアノフェニルボロン酸 [M. Nishimura et al.、Tetrahedron 2002、58 (29)、5779-5788] 2.91 g(19.8 mmol)のイソプロパノール溶液20 mlに加えた。こうして得られた懸濁液をアルゴン雰囲気下室温で5分撹拌した。4-ヨードテトラヒドロピラン [Heuberger et al.、J.Chem.Soc.1952、910] 2.1 g(9.90 mmol)を加えた。反応混合物を75℃で15時間撹拌した後、室温に冷却し、ジクロロメタンを用いてシリカゲル約50 gで濾過し、大部分の無機塩類を除去した。粗成生物をMPLC(シリカゲル、移動相：ジクロロメタン)により精製した。これにより表題化合物986 mg(理論値の53%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：7.60 (d、2H)、7.32 (d、2H)、4.12-4.07 (m、2H)、3.56-3.50 (m、2H)、2.87-2.79 (m、1H)、1.86-1.73 (m、4H)。
GC/MS (方法9、EIpos)：R_t＝5.97分、m/z＝187 [M]⁺。
工程2： N’-ヒドロキシ-4-(テトラヒドロ-2H-ピラン-4-イル)ベンゼンカルボキシミドアミド

実施例1A/工程5に記載した方法に準じて、実施例11A/工程1からの化合物480 mg(2.56 mmol)を反応させ表題化合物525 mg(理論値の93%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：7.58 (d、2H)、7.26 (d、2H)、6.79 (broad、1H)、4.82 (s、broad、2H)、4.11-4.05 (m、2H)、3.57-3.50 (m、2H)、2.83-2.74 (m、1H)、1.87-1.73 (m、4H)。
LC/MS (方法2、ESIpos)：R_t＝0.92分；m/z＝221 [M+H]⁺; Example 11A
N'-hydroxy-4- (tetrahydro-2H-pyran-4-yl) benzenecarboximidamide

Step 1: 4- (Tetrahydro-2H-pyran-4-yl) benzonitrile

Nickel (II) iodide 186 mg (0.594 mmol), trans-2-aminocyclohexanol hydrochloride 90 mg (0.594 mmol) and sodium hexamethyldisilazide 3.63 g (19.8 mmol) were added to 4-cyanophenylboronic acid [M Nishimura et al., Tetrahedron 2002, 58 (29), 5779-5788] was added to 20 ml of 2.91 g (19.8 mmol) isopropanol solution. The suspension thus obtained was stirred for 5 minutes at room temperature under an argon atmosphere. 2.1 g (9.90 mmol) of 4-iodotetrahydropyran [Heuberger et al., J. Chem. Soc. 1952, 910] was added. The reaction mixture was stirred at 75 ° C. for 15 hours, then cooled to room temperature and filtered through about 50 g of silica gel with dichloromethane to remove most of the inorganic salts. The crude product was purified by MPLC (silica gel, mobile phase: dichloromethane). This gave 986 mg (53% of theory) of the title compound.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 7.60 (d, 2H), 7.32 (d, 2H), 4.12-4.07 (m, 2H), 3.56-3.50 (m, 2H), 2.87-2.79 (m, 1H), 1.86-1.73 (m, 4H).
GC / MS (Method 9, EIpos): R _t = 5.97 min, m / z = 187 [M] ⁺ .
Step 2: N'-Hydroxy-4- (tetrahydro-2H-pyran-4-yl) benzenecarboximidamide

According to the method described in Example 1A / Step 5, 480 mg (2.56 mmol) of the compound from Example 11A / Step 1 was reacted to obtain 525 mg (93% of theory) of the title compound.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 7.58 (d, 2H), 7.26 (d, 2H), 6.79 (broad, 1H), 4.82 (s, broad, 2H), 4.11-4.05 (m , 2H), 3.57-3.50 (m, 2H), 2.83-2.74 (m, 1H), 1.87-1.73 (m, 4H).
LC / MS (Method 2, ESIpos): R _t = 0.92 min; m / z = 221 [M + H] ⁺ ;

工程1： 4-イソブチルベンゼンニトリル

不活性な、無酸素条件下、1-ブロモ-4-イソブチルベンゼン5.0 g(23.5 mmol)、シアン化亜鉛3.14 g(26.7 mmol)、ジシクロヘキシル-(2’,6’-ジメトキシビフェニル-2-イル)ホスファン963 mg(2.35 mmol)およびトリス(ジベンジリデンアセトン)ジパラジウム 1.08 g(1.17 mmol)のDMF/水(99:1)230 mlを120℃で1時間加熱した。室温に冷却した後、混合物を水約1000 mlで希釈し、各回約150 mlの酢酸エチルで3回抽出した。合わせた有機層抽出物を水、続いて飽和塩化ナトリウム溶液で洗浄した。無水硫酸マグネシウムで乾燥させた後、混合物を濾過し、濾液からロータリーエバポレーターにより溶媒を除去した。得られた残渣を10:1のシクロヘキサン/酢酸エチルを移動相として用いてシリカゲルで吸引濾過により精製した。これにより表題化合物3.04 g(理論値の81%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：7.56 (d、2H)、7.23 (d、2H)、2.53 (d、2H)、1.94-1.83 (m、1H)、0.90 (d、6H)。
GC/MS (方法9、EIpos)：R_t＝4.05分、m/z＝159 [M]⁺。 Example 12A
N'-hydroxy-4-isobutylbenzenecarboximide

Process 1: 4-isobutylbenzene nitrile

Inert, oxygen-free conditions, 1-bromo-4-isobutylbenzene 5.0 g (23.5 mmol), zinc cyanide 3.14 g (26.7 mmol), dicyclohexyl- (2 ', 6'-dimethoxybiphenyl-2-yl) 230 ml of DMF / water (99: 1) of 963 mg (2.35 mmol) of phosphane and 1.08 g (1.17 mmol) of tris (dibenzylideneacetone) dipalladium was heated at 120 ° C. for 1 hour. After cooling to room temperature, the mixture was diluted with about 1000 ml of water and extracted three times with about 150 ml of ethyl acetate each time. The combined organic extracts were washed with water followed by saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, the mixture was filtered, and the solvent was removed from the filtrate by a rotary evaporator. The resulting residue was purified by suction filtration on silica gel using 10: 1 cyclohexane / ethyl acetate as mobile phase. This gave 3.04 g (81% of theory) of the title compound.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 7.56 (d, 2H), 7.23 (d, 2H), 2.53 (d, 2H), 1.94-1.83 (m, 1H), 0.90 (d, 6H ).
GC / MS (Method 9, EIpos): R _t = 4.05 min, m / z = 159 [M] ⁺ .

実施例1A/工程5に記載した方法に準じて、実施例12A/工程1からの化合物3.03 g(19.0 mmol)を反応させ、表題化合物3.39 g(理論値の93%)を得た。
¹H NMR (400 MHz、DMSO-d₆、δ/ppm)：9.53 (s、1H)、7.57 (d、2H)、7.14 (d、2H)、5.74 (broad、2H)、2.46 (d、2H)、1.89-1.79 (m、1H)、0.87 (d、6H)。
LC/MS (方法6、ESIpos)：R_t＝0.68分、m/z＝193 [M+H]⁺。 Process 2: N'-hydroxy-4-isobutylbenzenecarboximide amide

In a manner similar to that described in Example 1A / Step 5, compound 3.03 g (19.0 mmol) from Example 12A / Step 1 was reacted to give 3.39 g (93% of theory) of the title compound.
¹ H NMR (400 MHz, DMSO-d ₆ , δ / ppm): 9.53 (s, 1H), 7.57 (d, 2H), 7.14 (d, 2H), 5.74 (broad, 2H), 2.46 (d, 2H ), 1.89-1.79 (m, 1H), 0.87 (d, 6H).
LC / MS (Method 6, ESIpos): R _t = 0.68 min, m / z = 193 [M + H] ⁺ .

実施例1A/工程5に記載した方法に準じて、4-イソプロピルベンゼンニトリル5.00 g(34.4 mmol)から表題化合物4.65 g(94% 純度、理論値の71%)を得た。
¹H NMR (400 MHz、DMSO-d₆、δ/ppm)：9.53 (s、1H)、7.58 (d、2H)、7.23 (d、2H)、5.74 (s、broad、2H)、2.89 (sept、1H)、1.20 (d、6H)。
LC/MS (方法4、ESIpos)：R_t＝0.64分、m/z＝179 [M+H]⁺。 Example 13A
N'-hydroxy-4-isopropylbenzenecarboximidamide

In accordance with the method described in Example 1A / Step 5, 5.00 g (34.4 mmol) of 4-isopropylbenzenenitrile gave 4.65 g (94% purity, 71% of theory) of the title compound.
¹ H NMR (400 MHz, DMSO-d ₆ , δ / ppm): 9.53 (s, 1H), 7.58 (d, 2H), 7.23 (d, 2H), 5.74 (s, broad, 2H), 2.89 (sept , 1H), 1.20 (d, 6H).
LC / MS (Method 4, ESIpos): R _t = 0.64 min, m / z = 179 [M + H] ⁺ .

工程1： エチル 1-(4-ブロモフェニル)シクロブタンカルボキシレート

1 Mリチウム ヘキサメチルジシラジドのTHF溶液45 ml(45.2 mmol)を4-ブロモフェニル酢酸 エチル エステル10.0 g(41.1 mmol)の無水THF溶液250 mlに0℃で加えた。15分後、1,3-ジブロモプロパン5.4 ml(53.5 mmol)を加えた。反応混合物を室温に戻し、続いてこの温度で1時間撹拌した。これを続いて再び0℃に冷却し、さらにリチウム ヘキサメチルジシラジド(1 M THF溶液)溶液 45 ml(45.2 mmol)を加えた。その後、混合物を室温に戻した。1時間後、飽和塩化ナトリウム水溶液約10 mlを加えて反応を終了させた。大部分のTHFをロータリーエバポレーターで除去した。残渣を水で希釈し、酢酸エチルで抽出した。有機抽出物を水、続いて飽和塩化ナトリウム溶液で洗浄した。無水硫酸マグネシウムで乾燥させた後、混合物を濾過し、ロータリーエバポレーターにより濾液から溶媒を除去した。こうして得られた粗生成物は、移動相としてシクロヘキサン/酢酸エチル3:1を用いてシリカゲル約300 gで吸引濾過して、粗く精製した。表題化合物7.1 g(理論値の44%、純度73%)が得られ、この形態でさらに反応させた。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：7.44 (d、2H)、7.17 (d、2H)、4.10 (quart、2H)、2.85-2.79 (m、2H)、2.49-2.41 (m、2H)、2.10-1.98 (m、1H)、1.91-1.81 (m、1H)、1.18 (t、3H)。
MS (DCI、NH₃)：m/z＝300/302 [M+NH₄]⁺。
LC/MS (方法2、ESIpos)：R_t＝2.70分、m/z＝283/285 [M+H]⁺。 Example 14A
N'-hydroxy-4- [1- (methoxymethyl) cyclobutyl] benzenecarboximidamide

Step 1: Ethyl 1- (4-bromophenyl) cyclobutanecarboxylate

45 ml (45.2 mmol) of a THF solution of 1 M lithium hexamethyldisilazide was added to 250 ml of an anhydrous THF solution of 10.0 g (41.1 mmol) of 4-bromophenylacetic acid ethyl ester at 0 ° C. After 15 minutes, 5.4 ml (53.5 mmol) of 1,3-dibromopropane was added. The reaction mixture was allowed to return to room temperature and subsequently stirred at this temperature for 1 hour. This was subsequently cooled again to 0 ° C., and 45 ml (45.2 mmol) of a lithium hexamethyldisilazide (1 M THF solution) solution was further added. The mixture was then returned to room temperature. After 1 hour, about 10 ml of saturated aqueous sodium chloride solution was added to terminate the reaction. Most of the THF was removed on a rotary evaporator. The residue was diluted with water and extracted with ethyl acetate. The organic extract was washed with water followed by saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, the mixture was filtered and the solvent was removed from the filtrate by rotary evaporator. The crude product thus obtained was roughly purified by suction filtration on about 300 g of silica gel using cyclohexane / ethyl acetate 3: 1 as mobile phase. 7.1 g (44% of theory, purity 73%) of the title compound was obtained and reacted further in this form.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 7.44 (d, 2H), 7.17 (d, 2H), 4.10 (quart, 2H), 2.85-2.79 (m, 2H), 2.49-2.41 (m 2H), 2.10-1.98 (m, 1H), 1.91-1.81 (m, 1H), 1.18 (t, 3H).
_{MS (DCI, NH 3):} m / z = 300/302 [M + NH 4] +.
LC / MS (Method 2, ESIpos): R _t = 2.70 min, m / z = 283/285 [M + H] ⁺ .

実施例14A/工程1からの化合物17.20 g(25.4 mmol)を無水THF150 mlに溶解させ、1 Mリチウムアルミニウムハイドライド25 ml(25 mmol)のTHF溶液を0℃で滴下した。添加が終わると、氷/水浴を外し、室温で撹拌を続けた。1時間後、-最初は注意深く-飽和塩化ナトリウム水溶液約450 mlを加え、反応を終了させた。続いて酢酸エチルで抽出した。無水硫酸マグネシウムで有機抽出物を乾燥させた後、続いて濾過し、溶媒をロータリーエバポレーターで除去した。表題化合物6.04 g(理論値の88%、90%純度)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：7.43 (d、2H)、7.02 (d、2H)、3.72 (d、2H)、2.33-2.20 (m、4H)、2.13-2.01 (m、1H)、1.93-1.83 (m、1H)。
MS (DCI、NH₃)：m/z＝258/260 [M+NH₄]⁺。
GC/MS (方法9、ESIpos)：R_t＝5.77分、m/z＝240/242 [M]⁺。
工程3： 1-ブロモ-4-[1-(メトキシメチル)シクロブチル]ベンゼン

水素化ナトリウムの60%鉱油中懸濁液1.28 g(31.9 mmol)を、実施例14A/工程2からの化合物7.0 g(29.0 mmol)の無水DMF溶液120 mlに約5℃で加えた。混合物をこの温度で1時間撹拌した後、ヨウ化メチル2.2 ml(34.8 mmol)を加えた。反応混合物を室温に戻し、撹拌を15時間続けた。続いて反応混合物をロータリーエバポレーターにより約20 mlまで濃縮した。水約500 mlを加え、混合物を各回約200 mlのジエチルエーテルで3回抽出した。合わせた有機層抽出物を飽和塩化ナトリウム溶液で洗浄し、無水硫酸マグネシウムで乾燥させた。濾過した後、溶媒をロータリーエバポレーターで除去し、粗成生物を、シリカゲル約200 gで移動相としてシクロヘキサン/酢酸エチル50:1を用いて吸引濾過して精製した。これにより表題化合物4.92 g(理論値の66%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：7.41 (d、2H)、7.04 (d、2H)、3.48 (s、2H)、3.27 (s、3H)、2.32-2.22 (m、4H)、2.12-2.00 (m、1H)、1.90-1.80 (m、1H)。
MS (DCI、NH₃)：m/z＝272/274 [M+NH₄]⁺。
GC/MS (方法9、ESIpos)：R_t＝5.25分、m/z＝254/256 [M]⁺。 Step 2: [1- (4-Bromophenyl) cyclobutyl] methanol

17.14 g (25.4 mmol) of the compound from Example 14A / Step 1 was dissolved in 150 ml of anhydrous THF, and a THF solution of 25 ml (25 mmol) of 1 M lithium aluminum hydride was added dropwise at 0 ° C. When the addition was complete, the ice / water bath was removed and stirring was continued at room temperature. After 1 hour-initially carefully-about 450 ml of saturated aqueous sodium chloride solution was added to terminate the reaction. Subsequently, extraction was performed with ethyl acetate. The organic extract was dried over anhydrous magnesium sulfate and then filtered, and the solvent was removed on a rotary evaporator. This gave 6.04 g (88% of theory, 90% purity) of the title compound.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 7.43 (d, 2H), 7.02 (d, 2H), 3.72 (d, 2H), 2.33-2.20 (m, 4H), 2.13-2.01 (m , 1H), 1.93-1.83 (m, 1H).
_{MS (DCI, NH 3):} m / z = 258/260 [M + NH 4] +.
GC / MS (Method 9, ESIpos): R _t = 5.77 min, m / z = 240/242 [M] ⁺ .
Step 3: 1-Bromo-4- [1- (methoxymethyl) cyclobutyl] benzene

A suspension of sodium hydride in 60% mineral oil 1.28 g (31.9 mmol) was added to 120 ml of an anhydrous DMF solution of 7.0 g (29.0 mmol) of the compound from Example 14A / Step 2 at about 5 ° C. After the mixture was stirred at this temperature for 1 hour, 2.2 ml (34.8 mmol) of methyl iodide was added. The reaction mixture was allowed to return to room temperature and stirring was continued for 15 hours. Subsequently, the reaction mixture was concentrated to about 20 ml on a rotary evaporator. About 500 ml of water was added and the mixture was extracted three times with about 200 ml of diethyl ether each time. The combined organic layer extracts were washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After filtration, the solvent was removed on a rotary evaporator and the crude product was purified by suction filtration using about 200 g of silica gel with cyclohexane / ethyl acetate 50: 1 as mobile phase. This gave 4.92 g (66% of theory) of the title compound.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 7.41 (d, 2H), 7.04 (d, 2H), 3.48 (s, 2H), 3.27 (s, 3H), 2.32-2.22 (m, 4H ), 2.12-2.00 (m, 1H), 1.90-1.80 (m, 1H).
_{MS (DCI, NH 3):} m / z = 272/274 [M + NH 4] +.
GC / MS (Method 9, ESIpos): R _t = 5.25 min, m / z = 254/256 [M] ⁺ .

実施例12A/工程1に記載した方法に準じて、実施例14A/工程3からの化合物4.80 g(18.8 mmol)から、表題化合物1.82 g(理論値の48%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：7.58 (d、2H)、7.24 (d、2H)、3.52 (s、2H)、3.26 (s、3H)、2.34-2.24 (m、4H)、2.16-2.03 (m、1H)、1.92-1.83 (m、1H)。
LC/MS (方法4、ESIpos)：R_t＝1.22分；m/z＝202 [M+H]⁺;
工程5： N’-ヒドロキシ-4-[1-(メトキシメチル)シクロブチル]ベンゼンカルボキシミドアミド

実施例1A/工程5に記載した方法に準じて、実施例14A/工程4からの化合物1.82 g(9.04 mmol)から、表題化合物2.04 g(理論値の96%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：7.55 (d、2H)、7.20 (d、2H)、7.10 (broad、1H)、4.83 (broad、2H)、3.51 (s、2H)、3.27 (s、3H)、2.36-2.25 (m、4H)、2.12-2.01 (m、1H)、1.90-1.81 (m、1H)。
LC/MS (方法6、ESIpos)：R_t＝0.61分；m/z＝235 [M+H]⁺; Step 4: 4- [1- (Methoxymethyl) cyclobutyl] benzonitrile

According to the method described in Example 12A / Step 1, 1.82 g (48% of theory) of the title compound was obtained from 4.80 g (18.8 mmol) of the compound from Example 14A / Step 3.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 7.58 (d, 2H), 7.24 (d, 2H), 3.52 (s, 2H), 3.26 (s, 3H), 2.34-2.24 (m, 4H ), 2.16-2.03 (m, 1H), 1.92-1.83 (m, 1H).
LC / MS (Method 4, ESIpos): R _t = 1.22 min; m / z = 202 [M + H] ⁺ ;
Step 5: N'-Hydroxy-4- [1- (methoxymethyl) cyclobutyl] benzenecarboximidamide

According to the method described in Example 1A / Step 5, from the compound 1.82 g (9.04 mmol) from Example 14A / Step 4, 2.04 g (96% of theory) of the title compound was obtained.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 7.55 (d, 2H), 7.20 (d, 2H), 7.10 (broad, 1H), 4.83 (broad, 2H), 3.51 (s, 2H), 3.27 (s, 3H), 2.36-2.25 (m, 4H), 2.12-2.01 (m, 1H), 1.90-1.81 (m, 1H).
LC / MS (Method 6, ESIpos): R _t = 0.61 min; m / z = 235 [M + H] ⁺ ;

工程1： 1-ブロモ-4-[1-(トリフルオロメチル)シクロプロピル]ベンゼン

モンモリロナイトで活性化した臭化亜鉛を最初に以下の通り調製した：臭化亜鉛7.0 g(31.1 mmol)をまず、メタノール225 mlの入った1リットルフラスコに加え、K10 モンモリロナイト28.2 gを加えた。続いて懸濁液を室温で1時間撹拌した。続いて混合物をロータリーエバポレーターで乾燥するまで濃縮した。残った粉末を温度200℃の砂浴において緩やかな真空下(約500 mbar)1時間加熱し、アルゴン下冷却した。
続いて表題化合物は以下の通り調製した：1-フェニル-1-(トリフルオロメチル)シクロプロパン49.63 g(267 mmol)をまずペンタン1.25リットルに加え、上述したモンモリロナイトで活性化した臭化亜鉛を加えた。続いて、光の入射を減らすため、反応容器の外部をアルミニウムで包んだ。臭素137 ml(2.67 mol)を撹拌下、滴下した。続いて、反応混合物を暗室で、室温で16時間撹拌した。続いて、氷冷下、飽和亜硫酸ナトリウム水溶液1リットルを滴下した。固体を吸引濾過し、ペンタンで2回洗浄した。相分離後、濾液を各回1リットルのペンタンで2回抽出した。合わせた有機層抽出物を無水硫酸ナトリウムで乾燥させ、濾過し、溶媒を緩やかな真空下ロータリーエバポレーターで除去した。これにより表題化合物77.18 g(92%純度、理論値の100%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：7.47 (d、2H)、7.33 (s、2H)、1.37-1.34 (m、2H)、1.03-0.98 (m、2H)。
GC/MS (方法9、ESIpos)：R_t＝3.43分、m/z＝264/266 [M]⁺。 Example 15A
N'-hydroxy-4- [1- (trifluoromethyl) cyclopropyl] benzenecarboximidamide

Step 1: 1-Bromo-4- [1- (trifluoromethyl) cyclopropyl] benzene

Zinc bromide activated with montmorillonite was first prepared as follows: 7.0 g (31.1 mmol) of zinc bromide was first added to a 1 liter flask containing 225 ml of methanol and 28.2 g of K10 montmorillonite. The suspension was subsequently stirred at room temperature for 1 hour. The mixture was subsequently concentrated to dryness on a rotary evaporator. The remaining powder was heated in a sand bath at a temperature of 200 ° C. under gentle vacuum (about 500 mbar) for 1 hour and cooled under argon.
Subsequently, the title compound was prepared as follows: 49.63 g (267 mmol) of 1-phenyl-1- (trifluoromethyl) cyclopropane was first added to 1.25 liters of pentane, followed by zinc bromide activated with montmorillonite as described above. It was. Subsequently, in order to reduce the incidence of light, the outside of the reaction vessel was wrapped with aluminum. Bromine 137 ml (2.67 mol) was added dropwise with stirring. Subsequently, the reaction mixture was stirred in the dark at room temperature for 16 hours. Subsequently, 1 liter of a saturated aqueous sodium sulfite solution was added dropwise under ice cooling. The solid was filtered off with suction and washed twice with pentane. After phase separation, the filtrate was extracted twice with 1 liter of pentane each time. The combined organic layer extracts were dried over anhydrous sodium sulfate, filtered and the solvent was removed on a rotary evaporator under mild vacuum. This gave 77.18 g (92% purity, 100% of theory) of the title compound.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 7.47 (d, 2H), 7.33 (s, 2H), 1.37-1.34 (m, 2H), 1.03-0.98 (m, 2H).
GC / MS (Method 9, ESIpos): R _t = 3.43 min, m / z = 264/266 [M] ⁺ .

実施例15A/工程1からの化合物75.0 g(283 mmol)のDMF990 mlおよび水10 ml溶液の混合物にアルゴンを注入し、緩やかな吸引を繰り返すことにより酸素を除去した。続いてシアン化亜鉛37.87 g(322 mmol)およびテトラキス(トリフェニルホスフィン)パラジウム(0)32.69 g(28.3 mmol)を加えた。反応混合物を続いて120℃で5時間加熱した。室温に冷却した後、不溶物を濾過し、残渣を少量のDMFで洗浄した。濾液を続いてロータリーエバポレーターにより溶媒を除去した。得られた粗生成物を酢酸エチル1.5リットルに溶解し、混合物を各回500 mlの飽和塩化アンモニウム溶液で2回および飽和塩化ナトリウム溶液500 mlで1回洗浄した。有機相を無水硫酸マグネシウムで乾燥させた後、混合物を濾過し、濾液をロータリーエバポレーターで濃縮した。得られた油状物を、シクロヘキサン/酢酸エチル40:1を溶離剤としてシリカゲル175 gで吸引濾過により精製した。生成物分画の濃縮及び高真空下における乾燥により、表題化合物49.7 g(理論値の83%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：7.65 (d、2H)、7.57 (d、2H)、1.46-1.42 (m、2H)、1.09-1.03 (m、2H)。
GC/MS (方法9、ESIpos)：R_t＝3.79分、m/z＝211 [M]⁺。
工程3： N’-ヒドロキシ-4-[1-(トリフルオロメチル)シクロプロピル]ベンゼンカルボキシミドアミド

塩化ヒドロキシルアンモニウム14.48 g(208 mmol)およびトリエチルアミン29 ml(208 mmol)を実施例15A/工程2からの化合物20.0 g(94.7 mmol)のエタノール溶液500 mlに加えた。反応混合物を還流下2時間加熱した。続いて、約半分の溶媒をロータリーエバポレーターで除去した。残りの混合物に水1.5リットルを加え、得られた懸濁液を室温で20分撹拌した。続いて固体を吸引濾過し、少量の冷水で洗浄し、高真空下乾燥させた。更なる精製として、これをペンタン120 mlおよびジクロロメタン30 ml中で撹拌した。固体を再び吸引濾過し、表題化合物15.79 g(理論値の68%)を得た。
¹H NMR (400 MHz、DMSO-d₆、δ/ppm)：9.68 (s、1H)、7.67 (d、2H)、7.46 (d、2H)、5.83 (s、broad、2H)、1.36-1.32 (m、2H)、1.15-1.11 (m、2H)。
LC/MS (方法4、ESIpos)：R_t＝0.80分、m/z＝245 [M+H]⁺。 Step 2: 4- [1- (Trifluoromethyl) cyclopropyl] benzonitrile

Example 15A / Oxygen was removed by injecting argon into a mixture of 75.0 g (283 mmol) of the compound from Step 1 in 990 ml of DMF and 10 ml of water and repeating gentle suction. Subsequently, 37.87 g (322 mmol) of zinc cyanide and 32.69 g (28.3 mmol) of tetrakis (triphenylphosphine) palladium (0) were added. The reaction mixture was subsequently heated at 120 ° C. for 5 hours. After cooling to room temperature, the insoluble material was filtered and the residue was washed with a small amount of DMF. The filtrate was subsequently removed by a rotary evaporator. The resulting crude product was dissolved in 1.5 liters of ethyl acetate and the mixture was washed twice with 500 ml saturated ammonium chloride solution and once with 500 ml saturated sodium chloride solution. After drying the organic phase over anhydrous magnesium sulfate, the mixture was filtered and the filtrate was concentrated on a rotary evaporator. The oil obtained was purified by suction filtration over 175 g of silica gel with cyclohexane / ethyl acetate 40: 1 as eluent. Concentration of the product fraction and drying under high vacuum gave 49.7 g (83% of theory) of the title compound.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 7.65 (d, 2H), 7.57 (d, 2H), 1.46-1.42 (m, 2H), 1.09-1.03 (m, 2H).
GC / MS (Method 9, ESIpos): R _t = 3.79 min, m / z = 211 [M] ⁺ .
Step 3: N'-hydroxy-4- [1- (trifluoromethyl) cyclopropyl] benzenecarboximidamide

14.48 g (208 mmol) of hydroxylammonium chloride and 29 ml (208 mmol) of triethylamine were added to 500 ml of an ethanol solution of 20.0 g (94.7 mmol) of the compound from Example 15A / Step 2. The reaction mixture was heated under reflux for 2 hours. Subsequently, about half of the solvent was removed on a rotary evaporator. 1.5 liters of water was added to the remaining mixture and the resulting suspension was stirred at room temperature for 20 minutes. Subsequently, the solid was filtered off with suction, washed with a small amount of cold water and dried under high vacuum. For further purification, it was stirred in 120 ml pentane and 30 ml dichloromethane. The solid was again filtered off with suction to give 15.79 g (68% of theory) of the title compound.
¹ H NMR (400 MHz, DMSO-d ₆ , δ / ppm): 9.68 (s, 1H), 7.67 (d, 2H), 7.46 (d, 2H), 5.83 (s, broad, 2H), 1.36-1.32 (m, 2H), 1.15-1.11 (m, 2H).
LC / MS (Method 4, ESIpos): R _t = 0.80 min, m / z = 245 [M + H] ⁺ .

実施例1A/工程5、5.0 g(23.9 mmol)に記載した方法に準じて、3-フルオロ-4-(トリフルオロメトキシ)ベンゾニトリルから表題化合物5.7 g(理論値の99%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：7.53-7.49 (dd、1H)、7.45-7.41 (m、1H)、7.37-7.31 (t、1H)、4.87 (s、broad、2H)。
LC/MS (方法6、ESIpos)：R_t＝0.74分；m/z＝239 [M+H]⁺; Example 16A
3-Fluoro-N'-hydroxy-4- (trifluoromethoxy) benzenecarboximidamide

According to the method described in Example 1A / Step 5, 5.0 g (23.9 mmol), 5.7 g (99% of theory) of the title compound was obtained from 3-fluoro-4- (trifluoromethoxy) benzonitrile.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 7.53-7.49 (dd, 1H), 7.45-7.41 (m, 1H), 7.37-7.31 (t, 1H), 4.87 (s, broad, 2H) .
LC / MS (Method 6, ESIpos): R _t = 0.74 min; m / z = 239 [M + H] ⁺ ;

工程1： 3-メチル-4-(トリフルオロメトキシ)ベンゾニトリル

実施例12A/工程1に記載した方法に準じて、3-メチル-4-(トリフルオロメトキシ)ブロモベンゼン5.00 g(19.6 mmol)から表題化合物3.55 g(90%純度、理論値の81%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：7.59 (d、1H)、7.53 (dd、1H)、7.31 (d、1H)、2.36 (s、3H)。
GC/MS (方法9、DCI/NH₃)：R_t＝2.58分、m/z＝201 [M]⁺。
工程2： N’-ヒドロキシ-3-メチル-4-(トリフルオロメトキシ)ベンゼンカルボキシミドアミド

実施例1A/工程5に記載した方法に準じて、実施例17A/工程1からの化合物2.50 g(12.4 mmol)から表題化合物2.36 g(87%純度、理論値の70%)を得た。
LC/MS (方法6、ESIpos)：R_t＝0.67分、m/z＝235 [M+H]⁺。 Example 17A
N'-hydroxy-3-methyl-4- (trifluoromethoxy) benzenecarboximidamide

Step 1: 3-Methyl-4- (trifluoromethoxy) benzonitrile

According to the method described in Example 12A / Step 1, from 5.00 g (19.6 mmol) of 3-methyl-4- (trifluoromethoxy) bromobenzene to 3.55 g (90% purity, 81% of theory) of the title compound. Obtained.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 7.59 (d, 1H), 7.53 (dd, 1H), 7.31 (d, 1H), 2.36 (s, 3H).
GC / MS (Method 9, DCI / NH ₃ ): R _t = 2.58 min, m / z = 201 [M] ⁺ .
Step 2: N'-hydroxy-3-methyl-4- (trifluoromethoxy) benzenecarboximidamide

According to the method described in Example 1A / Step 5, 2.36 g (87% purity, 70% of theory) of the title compound was obtained from 2.50 g (12.4 mmol) of the compound from Example 17A / Step 1.
LC / MS (Method 6, ESIpos): R _t = 0.67 min, m / z = 235 [M + H] ⁺ .

工程1： 1-ブロモ-4-[1-(エトキシメチル)シクロブチル]ベンゼン

実施例14A/工程3に記載した方法に準じて、実施例14A/工程2からの化合物1.50 g(6.22 mmol)およびブロモエタン557 μl(7.46 mmol)から表題化合物1.28 g(理論値の77%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：7.40 (d、2H)、7.05 (d、2H)、3.51 (s、2H)、3.38 (quart、2H)、2.29-2.24 (m、4H)、2.11-2.00 (m、1H)、1.89-1.79 (m、1H)、1.10 (t、3H)。
GC/MS (方法9、ESIpos)：R_t＝5.37分、m/z＝268/270 [M]⁺。
工程2： 4-[1-(エトキシメチル)シクロブチル]ベンゾニトリル

実施例12A/工程1に記載した方法に準じて、実施例18A/工程1からの化合物1.15 g(4.29 mmol)から表題化合物0.64 g(理論値の69%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：7.59 (d、2H)、7.27 (d、2H)、3.54 (s、2H)、3.37 (quart、2H)、2.31-2.27 (m、4H)、2.16-2.03 (m、1H)、1.91-1.82 (m、1H)、1.08 (t、3H)。
LC/MS (方法6、ESIpos)：R_t＝1.18分、m/z＝216 [M+H]⁺。
工程3： 4-[1-(エトキシメチル)シクロブチル]-N’-ヒドロキシベンゼンカルボキシミドアミド

実施例1A/工程5に記載した方法に準じて、実施例18A/工程2からの化合物635 mg(2.95 mmol)から表題化合物725 mg(90%純度、理論値の90%)を得た。
¹H NMR (400 MHz、DMSO-d₆、δ/ppm)：9.55 (s、1H)、7.58 (d、2H)、7.14 (d、2H)、5.79 (broad、2H)、3.50 (s、2H)、3.35 (quart、2H)、2.23-2.20 (m、4H)、2.08-1.97 (m、1H)、1.82-1.73 (m、1H)、1.03 (t、3H)。
LC/MS (方法6、ESIpos)：R_t＝0.67分、m/z＝249 [M+H]⁺。 Example 18A
4- [1- (Ethoxymethyl) cyclobutyl] -N'-hydroxybenzenecarboximidamide

Step 1: 1-Bromo-4- [1- (ethoxymethyl) cyclobutyl] benzene

According to the method described in Example 14A / Step 3, 1.50 g (6.22 mmol) of the compound from Example 14A / Step 2 and 1.28 g (77% of theory) of the title compound from 557 μl (7.46 mmol) of bromoethane. Obtained.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 7.40 (d, 2H), 7.05 (d, 2H), 3.51 (s, 2H), 3.38 (quart, 2H), 2.29-2.24 (m, 4H ), 2.11-2.00 (m, 1H), 1.89-1.79 (m, 1H), 1.10 (t, 3H).
GC / MS (Method 9, ESIpos): R _t = 5.37 min, m / z = 268/270 [M] ⁺ .
Step 2: 4- [1- (Ethoxymethyl) cyclobutyl] benzonitrile

According to the method described in Example 12A / Step 1, 0.64 g (69% of theory) of the title compound was obtained from 1.15 g (4.29 mmol) of the compound from Example 18A / Step 1.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 7.59 (d, 2H), 7.27 (d, 2H), 3.54 (s, 2H), 3.37 (quart, 2H), 2.31-2.27 (m, 4H ), 2.16-2.03 (m, 1H), 1.91-1.82 (m, 1H), 1.08 (t, 3H).
LC / MS (Method _{6, ESIpos): R t =} 1.18 min, m / z = 216 [M + H] +.
Step 3: 4- [1- (Ethoxymethyl) cyclobutyl] -N'-hydroxybenzenecarboximidamide

The title compound 725 mg (90% purity, 90% of theory) was obtained from 635 mg (2.95 mmol) of the compound from Example 18A / Step 2 according to the method described in Example 1A / Step 5.
¹ H NMR (400 MHz, DMSO-d ₆ , δ / ppm): 9.55 (s, 1H), 7.58 (d, 2H), 7.14 (d, 2H), 5.79 (broad, 2H), 3.50 (s, 2H ), 3.35 (quart, 2H), 2.23-2.20 (m, 4H), 2.08-1.97 (m, 1H), 1.82-1.73 (m, 1H), 1.03 (t, 3H).
LC / MS (Method 6, ESIpos): R _t = 0.67 min, m / z = 249 [M + H] ⁺ .

工程1： エチル 1-(4-ブロモフェニル)シクロペンタンカルボキシレート

実施例14A/工程1に記載した方法に準じて、エチル(4-ブロモフェニル)アセテート75.0 g(308 mmol)および1,4-ジブロモブタン47.5 ml(401 mmol)から表題化合物100 g(理論値の98%、約90%純度)を得、これをこの形態でさらに反応させた。
GC/MS (方法9、EIpos)：R_t＝6.22分、m/z＝296/298 [M]⁺。
工程2： [1-(4-ブロモフェニル)シクロペンチル]メタノール

実施例19A/工程1からの化合物100.0 g(336 mmol)を無水THF1800 mlに溶解し、1 MリチウムアルミニウムハイドライドのTHF溶液337 ml(337 mmol)を0℃で滴下した。添加が終わると、氷/水浴を外し、室温で撹拌を続けた。1時間後、-最初は注意深く-飽和塩化ナトリウム水溶液約100 mlを加えて反応を終了させた。続いてほとんどのTHFをロータリーエバポレーターで除去した。得られた残渣を各1.5リットルの2 M塩酸および酢酸エチルに分配した。相分離後、有機抽出物を無水硫酸マグネシウムで乾燥させた。濾過した後、溶媒をロータリーエバポレーターで除去した。得られた残渣をシクロヘキサン/酢酸エチル 95:5 → 80:20を移動相として、シリカゲル1.5 kgによりクロマトグラフィーにかけた。これにより表題化合物45.7 g(理論値の53%)を得た。
¹H NMR (400 MHz、DMSO-d₆、δ/ppm)：7.44 (d、2H)、7.23 (d、2H)、4.62 (t、1H)、3.33 (d、2H)、1.97-1.90 (m、2H)、1.72-1.56 (m、6H)。
MS (DCI、NH₃)：m/z＝272/274 [M+NH₄]⁺。
GC/MS (方法9、EIpos)：R_t＝6.34分、m/z＝254/256 [M]⁺。 Example 19A
N'-hydroxy-4- [1- (methoxymethyl) cyclopentyl] benzenecarboximidamide

Step 1: Ethyl 1- (4-bromophenyl) cyclopentanecarboxylate

According to the method described in Example 14A / Step 1, from 75.0 g (308 mmol) of ethyl (4-bromophenyl) acetate and 47.5 ml (401 mmol) of 1,4-dibromobutane (100 g of the theoretical value) 98%, about 90% purity), which was further reacted in this form.
GC / MS (Method 9, EIpos): R _t = 6.22 min, m / z = 296/298 [M] ⁺ .
Step 2: [1- (4-Bromophenyl) cyclopentyl] methanol

100.0 g (336 mmol) of the compound from Example 19A / Step 1 was dissolved in 1800 ml of anhydrous THF, and 337 ml (337 mmol) of 1 M lithium aluminum hydride in THF was added dropwise at 0 ° C. When the addition was complete, the ice / water bath was removed and stirring was continued at room temperature. After 1 hour-initially carefully-about 100 ml of saturated aqueous sodium chloride solution was added to terminate the reaction. Subsequently, most of the THF was removed with a rotary evaporator. The resulting residue was partitioned between 1.5 liters of 2 M hydrochloric acid and ethyl acetate. After phase separation, the organic extract was dried over anhydrous magnesium sulfate. After filtration, the solvent was removed on a rotary evaporator. The residue obtained was chromatographed on 1.5 kg of silica gel with cyclohexane / ethyl acetate 95: 5 → 80: 20 as mobile phase. This gave 45.7 g (53% of theory) of the title compound.
¹ H NMR (400 MHz, DMSO-d ₆ , δ / ppm): 7.44 (d, 2H), 7.23 (d, 2H), 4.62 (t, 1H), 3.33 (d, 2H), 1.97-1.90 (m , 2H), 1.72-1.56 (m, 6H).
_{MS (DCI, NH 3):} m / z = 272/274 [M + NH 4] +.
GC / MS (Method 9, EIpos): R _t = 6.34 min, m / z = 254/256 [M] ⁺ .

実施例14A/工程3に記載した方法に準じて、実施例19A/工程2からの化合物10.0 g(39.1 mmol)およびヨードメタン2.9 ml(43.1 mmol)から表題化合物9.52 g(理論値の90%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：7.40 (d、2H)、7.19 (d、2H)、3.33 (s、2H)、3.22 (s、3H)、2.00-1.94 (m、2H)、1.87-1.79 (m、2H)、1.76-1.66 (m、4H)。
GC/MS (方法9、EIpos)：R_t＝5.78分、m/z＝268/270 [M]⁺。
工程4： 4-[1-(メトキシメチル)シクロペンチル]ベンゾニトリル

実施例12A/工程1に記載した方法に準じて、実施例19A/工程3からの化合物5.00 g(18.6 mmol)から表題化合物2.21 g(理論値の55%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：7.58 (d、2H)、7.42 (d、2H)、3.35 (s、2H)、3.22 (s、3H)、2.05-1.99 (m、2H)、1.88-1.70 (m、6H)。
LC/MS (方法4、ESIpos)：R_t＝1.31分、m/z＝216 [M+H]⁺。
工程5： N’-ヒドロキシ- 4-[1-(メトキシメチル)シクロペンチル]ベンゼンカルボキシミドアミド

実施例1A/工程5に記載した方法に準じて、実施例19A/工程4からの化合物2.17 g(10.1 mmol)から表題化合物2.32 g(理論値の93%)を得た。
¹H NMR (400 MHz、DMSO-d₆、δ/ppm)：9.53 (s、1H)、7.56 (d、2H)、7.29 (d、2H)、5.73 (broad、2H)、3.32 (s、2H)、3.12 (s、3H)、1.97-1.90 (m、2H)、1.82-1.75 (m、2H)、1.73-1.58 (m、4H)。
LC/MS (方法6、ESIpos)：R_t＝0.69分、m/z＝249 [M+H]⁺。 Step 3: 1-Bromo-4- [1- (methoxymethyl) cyclopentyl] benzene

According to the method described in Example 14A / Step 3, 10.0 g (39.1 mmol) of the compound from Example 19A / Step 2 and 9.52 g (90% of theory) of the title compound from 2.9 ml (43.1 mmol) of iodomethane. Obtained.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 7.40 (d, 2H), 7.19 (d, 2H), 3.33 (s, 2H), 3.22 (s, 3H), 2.00-1.94 (m, 2H ), 1.87-1.79 (m, 2H), 1.76-1.66 (m, 4H).
GC / MS (Method 9, EIpos): R _t = 5.78 min, m / z = 268/270 [M] ⁺ .
Step 4: 4- [1- (Methoxymethyl) cyclopentyl] benzonitrile

According to the method described in Example 12A / Step 1, the title compound 2.21 g (55% of theory) was obtained from 5.00 g (18.6 mmol) of the compound from Example 19A / Step 3.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 7.58 (d, 2H), 7.42 (d, 2H), 3.35 (s, 2H), 3.22 (s, 3H), 2.05-1.99 (m, 2H) ), 1.88-1.70 (m, 6H).
LC / MS (Method 4, ESIpos): R _t = 1.31 min, m / z = 216 [M + H] ⁺ .
Step 5: N'-Hydroxy-4- [1- (methoxymethyl) cyclopentyl] benzenecarboximidamide

According to the method described in Example 1A / Step 5, 2.32 g (10.1 mmol) of the compound from Example 19A / Step 4 gave 2.32 g (93% of theory) of the title compound.
¹ H NMR (400 MHz, DMSO-d ₆ , δ / ppm): 9.53 (s, 1H), 7.56 (d, 2H), 7.29 (d, 2H), 5.73 (broad, 2H), 3.32 (s, 2H ), 3.12 (s, 3H), 1.97-1.90 (m, 2H), 1.82-1.75 (m, 2H), 1.73-1.58 (m, 4H).
LC / MS (Method 6, ESIpos): R _t = 0.69 min, m / z = 249 [M + H] ⁺ .

工程1： エチル(4-ブロモ-2-フルオロフェニル)アセテート

4-ブロモ-2-フルオロフェニル酢酸50.0 g(0.215 mol)のエタノール溶液500 mlに濃硫酸100 μlを加え、続いて混合物を還流下16時間加熱した。室温に冷却した後、ほとんどの溶媒をロータリーエバポレーターで除去した。得られた残渣を酢酸エチル500 mlに取り込み、飽和重炭酸ナトリウム水溶液250 mlで洗浄した。無水硫酸マグネシウムで乾燥させた後、混合物を濾過し、濾液を蒸発乾固した。表題化合物53.2 g(理論値の90%、95%純度)を得た。
GC/MS (方法9、EIpos)：R_t＝4.74分、m/z＝260/262 [M]⁺。 Example 20A
3-Fluoro-N'-hydroxy-4- [1- (methoxymethyl) cyclobutyl] benzenecarboximidamide

Step 1: Ethyl (4-bromo-2-fluorophenyl) acetate

To 500 ml of ethanol solution of 50.0 g (0.215 mol) of 4-bromo-2-fluorophenylacetic acid was added 100 μl of concentrated sulfuric acid, and the mixture was subsequently heated under reflux for 16 hours. After cooling to room temperature, most of the solvent was removed on a rotary evaporator. The resulting residue was taken up in 500 ml ethyl acetate and washed with 250 ml saturated aqueous sodium bicarbonate. After drying over anhydrous magnesium sulfate, the mixture was filtered and the filtrate was evaporated to dryness. This gave 53.2 g (90% of theory, 95% purity) of the title compound.
GC / MS (Method 9, EIpos): R _t = 4.74 min, m / z = 260/262 [M] ⁺ .

実施例14A/工程1に記載した方法に準じて、実施例20A/工程1からの化合物53.0 g(0.202 mol)および1,3-ジブロモプロパン26.8 ml(0.264 mol)から、表題化合物67.6 g(75%純度、理論値の82%)を得て、これをこの形態でさらに反応させた。
LC/MS (方法6、ESIpos)：Rt＝1.31分、m/z＝301/303 [M+H]+。
工程3： [1-(4-ブロモ-2-フルオロフェニル)シクロブチル]メタノール

実施例14A/工程2に記載した方法に準じて、実施例20A/工程2からの化合物67.6 g(0.150 mol)から表題化合物23.9 g(85%純度、理論値の50%)を製造した。ここでは実施例14A/工程2の記載と異なり、後処理において飽和塩化アンモニウム溶液を加えた後、透明な水相が得られるまで、より多くの2 M 塩酸を加える必要があった。
¹H NMR (400 MHz、DMSO-d₆、δ/ppm)：7.38 (dd、1H)、7.32 (dd、1H)、7.02 (t、1H)、4.80 (t、1H)、3.57 (d、2H)、2.24-2.19 (m、4H)、2.07-1.95 (m、1H)、1.83-1.74 (m、1H)。
工程4： 4-ブロモ-2-フルオロ-1-[1-(メトキシメチル)シクロブチル]ベンゼン

実施例14A/工程3に記載した方法に準じて、実施例20A/工程3からの化合物12.8 g(49.4 mmol)およびヨウ化メチル3.7 ml(59.3 mmol)から表題化合物12.6 g(理論値の93%)を得た。
¹H NMR (400 MHz、DMSO-d₆、δ/ppm)：7.39 (dd、1H)、7.33 (dd、1H)、7.06 (t、1H)、3.53 (s、2H)、3.18 (s、3H)、2.32-2.17 (m、4H)、2.12-2.01 (m、1H)、1.85-1.75 (m、1H)。
GC/MS (方法9、EIpos)：R_t＝5.04分、m/z＝272/274 [M]⁺。 Step 2: Ethyl 1- (4-bromo-2-fluorophenyl) cyclobutanecarboxylate

According to the method described in Example 14A / Step 1, from 53.0 g (0.202 mol) of the compound from Example 20A / Step 1 and 26.8 ml (0.264 mol) of 1,3-dibromopropane, the title compound 67.6 g (75 % Purity, 82% of theory) was obtained and this was further reacted in this form.
LC / MS (Method 6, ESIpos): Rt = 1.31 min, m / z = 301/303 [M + H] +.
Step 3: [1- (4-Bromo-2-fluorophenyl) cyclobutyl] methanol

According to the method described in Example 14A / Step 2, 23.9 g (85% purity, 50% of theory) of the title compound was prepared from 67.6 g (0.150 mol) of the compound from Example 20A / Step 2. Here, unlike the description in Example 14A / Step 2, it was necessary to add more 2 M hydrochloric acid after the addition of saturated ammonium chloride solution in the post-treatment until a clear aqueous phase was obtained.
¹ H NMR (400 MHz, DMSO-d ₆ , δ / ppm): 7.38 (dd, 1H), 7.32 (dd, 1H), 7.02 (t, 1H), 4.80 (t, 1H), 3.57 (d, 2H ), 2.24-2.19 (m, 4H), 2.07-1.95 (m, 1H), 1.83-1.74 (m, 1H).
Step 4: 4-Bromo-2-fluoro-1- [1- (methoxymethyl) cyclobutyl] benzene

According to the method described in Example 14A / Step 3, from 12.8 g (49.4 mmol) of the compound from Example 20A / Step 3 and 3.7 ml (59.3 mmol) of methyl iodide to 12.6 g (93% of theory) of the title compound. )
¹ H NMR (400 MHz, DMSO-d ₆ , δ / ppm): 7.39 (dd, 1H), 7.33 (dd, 1H), 7.06 (t, 1H), 3.53 (s, 2H), 3.18 (s, 3H ), 2.32-2.17 (m, 4H), 2.12-2.01 (m, 1H), 1.85-1.75 (m, 1H).
GC / MS (Method 9, EIpos): R _t = 5.04 min, m / z = 272/274 [M] ⁺ .

実施例12A/工程1に記載した方法に準じて、実施例20A/工程4からの化合物12.60 g(46.1 mmol)から表題化合物7.01 g(理論値の63%)を得た。
¹H NMR (400 MHz、DMSO-d₆、δ/ppm)：7.72 (dd、1H)、7.62 (dd、1H)、7.30 (t、1H)、3.59 (s、2H)、3.18 (s、3H)、2.36-2.20 (m、4H)、2.15-2.03 (m、1H)、1.86-1.77 (m、1H)。
工程6： 3-フルオロ-N’-ヒドロキシ-4-[1-(メトキシメチル)シクロブチル]ベンゼンカルボキシミドアミド

実施例1A/工程5に記載した方法に準じて、実施例20A/工程5からの化合物5.00 g(22.8 mmol)から表題化合物2.04 g(90%純度、理論値の86%)を得た。
¹H NMR (400 MHz、DMSO-d₆、δ/ppm)：9.69 (s、1H)、7.43 (dd、1H)、7.33 (dd、1H)、7.10 (t、1H)、5.83 (s、broad、2H)、3.55 (s、2H)、3.18 (s、3H)、2.34-2.19 (m、4H)、2.12-2.01 (m、1H)、1.84-1.77 (m、1H)。
LC/MS (方法6、ESIpos)：R_t＝0.70分、m/z＝253 [M+H]⁺。 Step 5: 3-Fluoro-4- [1- (methoxymethyl) cyclobutyl] benzonitrile

According to the method described in Example 12A / Step 1, the title compound 7.01 g (63% of theory) was obtained from 12.60 g (46.1 mmol) of the compound from Example 20A / Step 4.
¹ H NMR (400 MHz, DMSO-d ₆ , δ / ppm): 7.72 (dd, 1H), 7.62 (dd, 1H), 7.30 (t, 1H), 3.59 (s, 2H), 3.18 (s, 3H ), 2.36-2.20 (m, 4H), 2.15-2.03 (m, 1H), 1.86-1.77 (m, 1H).
Step 6: 3-Fluoro-N'-hydroxy-4- [1- (methoxymethyl) cyclobutyl] benzenecarboximidamide

According to the method described in Example 1A / Step 5, 2.04 g (90% purity, 86% of theory) of the title compound was obtained from 5.00 g (22.8 mmol) of the compound from Example 20A / Step 5.
¹ H NMR (400 MHz, DMSO-d ₆ , δ / ppm): 9.69 (s, 1H), 7.43 (dd, 1H), 7.33 (dd, 1H), 7.10 (t, 1H), 5.83 (s, broad , 2H), 3.55 (s, 2H), 3.18 (s, 3H), 2.34-2.19 (m, 4H), 2.12-2.01 (m, 1H), 1.84-1.77 (m, 1H).
LC / MS (Method 6, ESIpos): R _t = 0.70 min, m / z = 253 [M + H] ⁺ .

工程1： 1-[4-ブロモ-2-フルオロ-3-(トリメチルシリル)フェニル]-2,2,2-トリフルオロエタノン

アルゴン下、浴槽温度-20℃で、1.6 M n-ブチルリチウムのヘキサン溶液78 ml(125 mmol)を2,2,6,6-テトラメチルピペリジン17.60 g(124 mmol)のTHF溶液110 mlにゆっくりと滴下した。-20℃で30分撹拌した後、混合物をさらに浴槽温度-70℃に冷却し、(2-ブロモ-6-フルオロフェニル)(トリメチル)シラン [S.Lulinski et al.、J.Org.Chem.2003、68 (24)、9384-9388に従い、1-ブロモ-3-フルオロベンゼンおよびクロロ(トリメチル)シランから得た] 28.0 g(113 mmol)のTHF溶液30 mlを加えた。浴槽温度-70℃で1時間撹拌した後、トリフルオロ酢酸エチル17.70 g(124.6 mmol)を-70℃で滴下した。続いて混合物をゆっくりと室温に戻し、さらに1時間撹拌した。続いて飽和塩化ナトリウム水溶液を加え、混合物を酢酸エチルで2回抽出した。合わせた酢酸エチル相を塩化ナトリウム溶液で1回洗浄し、硫酸マグネシウムで乾燥させ、濾過し、濃縮した。これにより表題化合物42.0 g(82%純度、理論値の89%)を得た。
GC/MS (方法9、EIpos)：R_t＝3.92分、m/z＝342/344 [M]⁺。 Example 21A
3-Fluoro-N'-hydroxy-4- (1,1,1-trifluoro-2-methylpropan-2-yl) benzenecarboximidamide

Step 1: 1- [4-Bromo-2-fluoro-3- (trimethylsilyl) phenyl] -2,2,2-trifluoroethanone

Under argon, at a bath temperature of -20 ° C, slowly add 78 ml (125 mmol) of a 1.6 M n-butyllithium hexane solution to 110 ml of a THF solution of 17.60 g (124 mmol) of 2,2,6,6-tetramethylpiperidine. And dripped. After stirring at −20 ° C. for 30 minutes, the mixture was further cooled to a bath temperature of −70 ° C. and (2-bromo-6-fluorophenyl) (trimethyl) silane (S. Lulinski et al., J. Org. Chem. 2003, 68 (24), 9384-9388, obtained from 1-bromo-3-fluorobenzene and chloro (trimethyl) silane] 30 ml of a 28.0 g (113 mmol) THF solution was added. After stirring at a bath temperature of -70 ° C for 1 hour, 17.70 g (124.6 mmol) of ethyl trifluoroacetate was added dropwise at -70 ° C. Subsequently, the mixture was slowly returned to room temperature and stirred for an additional hour. Subsequently, a saturated aqueous sodium chloride solution was added, and the mixture was extracted twice with ethyl acetate. The combined ethyl acetate phases were washed once with sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. This gave 42.0 g (82% purity, 89% of theory) of the title compound.
GC / MS (Method 9, EIpos): R _t = 3.92 min, m / z = 342/344 [M] ⁺ .

室温で、1 Mテトラ-n-ブチルアンモニウムフルオライドのTHF溶液120 ml(120 mmol)を実施例21A/工程1からの化合物42.0 g(100 mmol、純度82%)のTHF溶液140 mlに加えた。30分室温で撹拌した後、混合物を酢酸エチルで希釈し、水で1回洗浄した。水相を酢酸エチルで再抽出した。続いて合わせた有機相を飽和塩化ナトリウム溶液で1回洗浄し、硫酸マグネシウムで乾燥させ、濾過し、濃縮した。得られた残渣をフラッシュクロマトグラフィーにより精製した(シリカゲル、移動相：シクロヘキサン → シクロヘキサン/酢酸エチル 95:5)。溶媒を除去して表題化合物18.90 g(92%純度、理論値の64%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：7.78 (t、1H)、7.49 (dd、1H)、7.45 (dd、1H)。
GC/MS (方法9、EIpos)：R_t＝2.63分、m/z＝270/272 [M]⁺。
工程3： 2-(4-ブロモ-2-フルオロフェニル)-1,1,1-トリフルオロプロパン-2-オール

最初にジクロロ(ジメチル)チタニウムのヘプタン/ジクロロメタン混合物の懸濁液を以下の通り調製した：1 M 四塩化チタンのジクロロメタン溶液160 ml(160 mmol)を-30℃に冷却し、続いて1 Mジメチル亜鉛のヘプタン溶液160 ml(160 mmol)を滴下し、続いて混合物を-30℃で30分撹拌した。続いて懸濁液を-40℃に冷却し、実施例21A/工程2からの化合物19.4 g(65.9 mmol、純度92%)のクロロメタン80 ml溶液を加えた。混合物を-40℃で5分撹拌し、続いて浴槽温度を室温に戻し、混合物を室温でさらに2時間撹拌した。氷冷下、水80 mlをゆっくり滴下し、続いて混合物をさらに水250 mlで希釈した。混合物を各回250 mlのジクロロメタンで2回抽出し、合わせたジクロロメタン相を水350 mlで1回洗浄し、無水硫酸マグネシウムで乾燥させ、濾過し、溶媒をロータリーエバポレーターで除去した。これにより表題化合物を¹H NMRにおいて純度92%で含む23.7 g(＞理論値の100%)を得、この形態で反応させた。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：7.52 (t、1H)、7.34 (dd、1H)、7.29 (dd、1H)、3.06-2.99 (m、1H)、1.86 (s、3H)。
LC/MS (方法6、ESIpos)：R_t＝1.08分、m/z＝331/333 [M-H+HCO₂H]。
GC/MS (方法19、EIpos)：R_t＝3.61分、m/z＝286/288 [M]⁺。 Step 2: 1- (4-Bromo-2-fluorophenyl) -2,2,2-trifluoroethanone

At room temperature, 120 ml (120 mmol) of 1 M tetra-n-butylammonium fluoride in THF was added to 140 ml of a THF solution of 42.0 g (100 mmol, purity 82%) of the compound from Example 21A / Step 1. . After stirring for 30 minutes at room temperature, the mixture was diluted with ethyl acetate and washed once with water. The aqueous phase was re-extracted with ethyl acetate. The combined organic phases were subsequently washed once with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The resulting residue was purified by flash chromatography (silica gel, mobile phase: cyclohexane → cyclohexane / ethyl acetate 95: 5). Removal of the solvent gave 18.90 g (92% purity, 64% of theory) of the title compound.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 7.78 (t, 1H), 7.49 (dd, 1H), 7.45 (dd, 1H).
GC / MS (Method 9, EIpos): R _t = 2.63 min, m / z = 270/272 [M] ⁺ .
Step 3: 2- (4-Bromo-2-fluorophenyl) -1,1,1-trifluoropropan-2-ol

First, a suspension of a dichloro (dimethyl) titanium heptane / dichloromethane mixture was prepared as follows: 160 ml (160 mmol) of 1 M titanium tetrachloride in dichloromethane was cooled to −30 ° C., followed by 1 M dimethyl 160 ml (160 mmol) of a heptane solution of zinc was added dropwise and the mixture was subsequently stirred at −30 ° C. for 30 minutes. The suspension was subsequently cooled to −40 ° C. and a solution of 19.4 g (65.9 mmol, purity 92%) of the compound from Example 21A / Step 2 in 80 ml of chloromethane was added. The mixture was stirred at −40 ° C. for 5 minutes, followed by returning the bath temperature to room temperature, and the mixture was stirred at room temperature for an additional 2 hours. Under ice cooling, 80 ml of water was slowly added dropwise, and the mixture was further diluted with 250 ml of water. The mixture was extracted twice with 250 ml of dichloromethane each time and the combined dichloromethane phases were washed once with 350 ml of water, dried over anhydrous magnesium sulfate, filtered and the solvent was removed on a rotary evaporator. This gave 23.7 g (> 100% of theory) containing the title compound in 92% purity in ¹ H NMR and reacted in this form.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 7.52 (t, 1H), 7.34 (dd, 1H), 7.29 (dd, 1H), 3.06-2.99 (m, 1H), 1.86 (s, 3H ).
LC / MS (Method _{6, ESIpos): R t =} 1.08 min, m / z = 331/333 [M-H + HCO 2 H].
GC / MS (Method 19, EIpos): R _t = 3.61 min, m / z = 286/288 [M] ⁺ .

室温で、実施例21A/工程3からの化合物23.7 g(75.9 mmol、純度92%)のTHF溶液40 mlを、水素化ナトリウム 6.08 g(60%鉱油中、152 mmol)のTHF懸濁液90 mlに滴下した。1時間室温で撹拌した後、さらに30分40℃で攪拌し、メタンスルホニルクロライド 11.8 ml(151.91 mmol)のTHF溶液90 mlを滴下し、続いて混合物を40℃で1時間攪拌した。続いて水100 mlをゆっくり滴下した。続いて反応混合物を飽和重炭酸ナトリウム水溶液で希釈し、酢酸エチルで2回抽出した。合わせた有機相を硫酸マグネシウムで乾燥させ、濾過し、濃縮した。このように得られた残渣をペンタンで摩砕した。固体を濾過し、ペンタンで1回洗浄し、空気乾燥させた。これにより表題化合物25.6 g(理論値の92%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：7.42 (t、1H)、7.37 (dd、1H)、7.32 (dd、1H)、3.19 (s、3H)、2.33 (s、3H)。
LC/MS (方法4、ESIpos)：R_t＝1.34分、m/z＝382/384 [M+NH₄]⁺。
工程5： 4-ブロモ-2-フルオロ-1-(1,1,1-トリフルオロ-2-メチルプロパン-2-イル)ベンゼン

0℃で、2 Mトリメチルアルミニウム70 ml(140 mmol)のヘプタン溶液を、攪拌下ゆっくりと実施例21A/工程4からの化合物25.6 g(70.1 mmol)のジクロロメタン溶液480 mlに加えた。浴槽温度を室温に戻し、混合物を室温でさらに1時間攪拌した。続いて飽和重炭酸ナトリウム水溶液230 mlおよび飽和塩化ナトリウム水溶液75 mlをゆっくりと加えた。混合物をkieselguhrで濾過し、残渣をジクロロメタンで2回洗浄した。濾液を洗液と合わせ飽和塩化ナトリウム水溶液で1回洗浄し、硫酸マグネシウムで乾燥させ、濾過し、濃縮した。これにより表題化合物18.77 g(理論値の94%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：7.32-7.24 (m、3H)、1.63 (s、6H)。
GC/MS (方法9、EIpos)：R_t＝2.99分、m/z＝283/285 [M]⁺。 Step 4: 2- (4-Bromo-2-fluorophenyl) -1,1,1-trifluoropropan-2-ylmethanesulfonate

At room temperature, 40 ml of a THF solution of 23.7 g (75.9 mmol, purity 92%) of the compound from Example 21A / step 3 was added to a THF suspension of 6.08 g of sodium hydride (152 mmol in 60% mineral oil) 90 ml. It was dripped in. After stirring at room temperature for 1 hour, the mixture was further stirred at 40 ° C. for 30 minutes, 90 ml of a THF solution of 11.8 ml (151.91 mmol) of methanesulfonyl chloride was added dropwise, and then the mixture was stirred at 40 ° C. for 1 hour. Subsequently, 100 ml of water was slowly added dropwise. The reaction mixture was subsequently diluted with saturated aqueous sodium bicarbonate solution and extracted twice with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue thus obtained was triturated with pentane. The solid was filtered, washed once with pentane and air dried. This gave 25.6 g (92% of theory) of the title compound.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 7.42 (t, 1H), 7.37 (dd, 1H), 7.32 (dd, 1H), 3.19 (s, 3H), 2.33 (s, 3H).
LC / MS (method _{4, ESIpos): R t =} 1.34 min, m / z = 382/384 [M + NH 4] +.
Step 5: 4-Bromo-2-fluoro-1- (1,1,1-trifluoro-2-methylpropan-2-yl) benzene

At 0 ° C., 70 ml (140 mmol) of 2M trimethylaluminum in heptane was slowly added with stirring to 480 ml of a dichloromethane solution of 25.6 g (70.1 mmol) of the compound from Example 21A / Step 4. The bath temperature was returned to room temperature and the mixture was stirred for an additional hour at room temperature. Subsequently, 230 ml of saturated aqueous sodium bicarbonate solution and 75 ml of saturated aqueous sodium chloride solution were slowly added. The mixture was filtered through kieselguhr and the residue was washed twice with dichloromethane. The filtrate was combined with the washings, washed once with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. This gave 18.77 g (94% of theory) of the title compound.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 7.32-7.24 (m, 3H), 1.63 (s, 6H).
GC / MS (Method 9, EIpos): R _t = 2.99 min, m / z = 283/285 [M] ⁺ .

アルゴン下、シアン化亜鉛2.47 g(21 mmol)およびテトラキス(トリフェニルホスフィン)パラジウム(0)2.43 g(2.10 mmol)を、実施例21A/工程5からの化合物10.0 g(35.1 mmol)のDMF溶液50 mlに加えた。混合物は80℃で一夜攪拌した。室温に冷却した後、存在した固体を濾過し少量のDMFで洗浄した。濾液および洗液を合わせ、濃縮した。残渣をカラムクロマトグラフィー(シリカゲル、移動相：シクロヘキサン/酢酸エチル 95:5)により精製した。これにより表題化合物5.40 g(理論値の67%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：7.57 (t、1H)、7.45 (dd、1H)、7.38 (dd、1H)、1.67 (s、6H)。
GC/MS (方法9、EIpos)：R_t＝3.22分、m/z＝231 [M]⁺。
工程7： 3-フルオロ-N’-ヒドロキシ-4-(1,1,1-トリフルオロ-2-メチルプロパン-2-イル)ベンゼンカルボキシミドアミド

実施例1A/工程5に記載した方法に準じて、実施例21A/工程6からの化合物5.40 g(23.36 mmol)から、表題化合物5.81 g(理論値の94%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：7.46 (t、1H)、7.41-7.31 (m、2H)、4.84 (s、broad、2H)、1.65 (s、6H)。
LC/MS (方法6、ESIpos)：R_t＝0.77分、m/z＝265 [M+H]⁺。 Step 6: 3-Fluoro-4- (1,1,1-trifluoro-2-methylpropan-2-yl) benzonitrile

Under argon, 2.47 g (21 mmol) of zinc cyanide and 2.43 g (2.10 mmol) of tetrakis (triphenylphosphine) palladium (0) were added to a solution of 10.0 g (35.1 mmol) of the compound from Example 21A / Step 5 in 50 ml of DMF. added to ml. The mixture was stirred at 80 ° C. overnight. After cooling to room temperature, the solid present was filtered and washed with a small amount of DMF. The filtrate and washings were combined and concentrated. The residue was purified by column chromatography (silica gel, mobile phase: cyclohexane / ethyl acetate 95: 5). This gave 5.40 g (67% of theory) of the title compound.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 7.57 (t, 1H), 7.45 (dd, 1H), 7.38 (dd, 1H), 1.67 (s, 6H).
GC / MS (Method 9, EIpos): R _t = 3.22 min, m / z = 231 [M] ⁺ .
Step 7: 3-Fluoro-N'-hydroxy-4- (1,1,1-trifluoro-2-methylpropan-2-yl) benzenecarboximidamide

According to the method described in Example 1A / Step 5, 5.81 g (94.3% of theory) of the title compound was obtained from 5.40 g (23.36 mmol) of the compound from Example 21A / Step 6.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 7.46 (t, 1H), 7.41-7.31 (m, 2H), 4.84 (s, broad, 2H), 1.65 (s, 6H).
LC / MS (Method 6, ESIpos): R _t = 0.77 min, m / z = 265 [M + H] ⁺ .

方法A:
室温で、EDC23.3 g(0.121 mol)、HOBt16.4 g(0.121 mol)およびN’-ヒドロキシ-4-(トリフルオロメトキシ)ベンゼンカルボキシミドアミド26.7 g(0.121 mol)を順に5-メチル-1H-ピラゾール-3-カルボン酸15.3g(0.121 mol)の無水DMF溶液600 mlに加えた。混合物を最初に室温で2時間、続いて140℃5時間撹拌した。冷却した後、混合物を水2リットルで希釈し、各回1リットルの酢酸エチルで3回抽出した。合わせた有機層抽出物を水、続いて飽和塩化ナトリウム溶液で洗浄した。無水硫酸マグネシウムで乾燥させた後、混合物を濾過し、溶媒をロータリーエバポレーターで除去した。得られた粗成生物を、シリカゲル(移動相：シクロヘキサン/酢酸エチル 5:1 → 1:1)を充てんした吸引フィルターで吸引濾過して精製した。生成物分画を合わせ、生成物がちょうど沈殿し始めるまで、溶媒をロータリーエバポレーターで除去した。沈殿を室温で完了させた。母液を濾過し、さらに濃縮して、2つの固体の分画を得、これを合わせて高真空下乾燥させた。合わせて表題化合物19.7 g(理論値の52%)を得た。 Example 22A
5- (5-Methyl-1H-pyrazol-3-yl) -3- [4- (trifluoromethoxy) phenyl] -1,2,4-oxadiazole

Method A:
At room temperature, 23.3 g (0.121 mol) of EDC, 16.4 g (0.121 mol) of HOBt, and 26.7 g (0.121 mol) of N'-hydroxy-4- (trifluoromethoxy) benzenecarboximidamide were sequentially added to 5-methyl-1H. -It was added to 600 ml of anhydrous DMF solution of 15.3 g (0.121 mol) of pyrazole-3-carboxylic acid. The mixture was first stirred at room temperature for 2 hours, followed by 140 ° C. for 5 hours. After cooling, the mixture was diluted with 2 liters of water and extracted 3 times with 1 liter of ethyl acetate each time. The combined organic extracts were washed with water followed by saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, the mixture was filtered and the solvent was removed on a rotary evaporator. The obtained crude product was purified by suction filtration with a suction filter filled with silica gel (mobile phase: cyclohexane / ethyl acetate 5: 1 → 1: 1). The product fractions were combined and the solvent was removed on a rotary evaporator until the product just started to precipitate. Precipitation was completed at room temperature. The mother liquor was filtered and further concentrated to give two solid fractions that were combined and dried under high vacuum. Together, 19.7 g (52% of theory) of the title compound were obtained.

Method B:
To 75 ml of an anhydrous DMF suspension of 20.25 g (125 mmol) of 1,1′-carbonyldiimidazole (CDI), 15.0 g (119 of 5-methyl-1H-pyrazole-3-carboxylic acid was added within 15 minutes at room temperature. mmol) in anhydrous DMF was added dropwise. After the mixture was stirred at room temperature for 1 hour 45 minutes, 26.19 g (119 mmol) of N′-hydroxy-4- (trifluoromethoxy) benzenecarboximidamide was added. Subsequently, the reaction mixture was heated at 110 ° C. for 4 hours. After cooling, most of the solvent was removed on a rotary evaporator. 800 ml of water was added to the residue and this was stirred for several minutes. The insoluble material was filtered off with suction and washed with diethyl ether. The ether phase was removed from the filtrate and the aqueous phase was extracted once more with diethyl ether. 25 ml of methanol was added to the combined ether extract, and the product suspended therein was filtered with suction. After stirring for a few minutes, the mixture was filtered and again filtered off with suction. The residue was dried under high vacuum to give the first fraction of the title compound (8.79 g). The same amount of water was added to the filtrate and extracted by infiltration. After phase separation, the organic phase was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and finally the solvent was removed by a rotary evaporator. The residue was dried under high vacuum, thus obtaining a second fraction (24.43 g) of the title compound. Together, 33.32 g (90% of theory) of the title compound were obtained.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 10.64 (broad, 1H), 8.23 (d, 2H), 7.34 (d, 2H), 6.82 (s, 1H), 2.46 (s, 3H).
HPLC (Method 10): R _t = 4.72 min
_{MS (DCI, NH 3):} m / z = 311 [M + H] +.
LC / MS (Method 4, ESIpos): R _t = 1.28 min; m / z = 311 [M + H] ⁺ ;

実施例22A(方法A)に記載した方法に準じて、5-メチル-1H-ピラゾール-3-カルボン酸7.57 g(60.0 mmol)および実施例1Aからの化合物14.8 g(60.0 mmol)から表題化合物14.7 g(理論値の73%)を得た。ここでは、反応終了後、後処理として、撹拌下氷水を反応混合物に加えることにより行い生成物を沈殿させ、吸引濾過し、続いて水で洗浄し、高真空下乾燥させた。
¹H NMR (400 MHz、DMSO-d₆、δ/ppm)：11.80 (s、broad、1H)、8.17 (d、2H)、7.63 (d、2H)、6.83 (s、1H)、2.46 (s、3H)、1.63 (s、6H)。
LC/MS (方法4、ESIpos)：R_t＝1.34分、m/z＝337 [M+H]⁺。 Example 23A
5- (5-Methyl-1H-pyrazol-3-yl) -3- [4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenyl] -1,2,4-oxa Diazole

According to the method described in Example 22A (Method A), 7.57 g (60.0 mmol) of 5-methyl-1H-pyrazole-3-carboxylic acid and 14.8 g (60.0 mmol) of the compound from Example 1A were used to obtain the title compound 14.7. g (73% of theory) was obtained. Here, after completion of the reaction, as a post-treatment, the product was precipitated by adding ice water to the reaction mixture with stirring, suction filtered, subsequently washed with water and dried under high vacuum.
¹ H NMR (400 MHz, DMSO-d ₆ , δ / ppm): 11.80 (s, broad, 1H), 8.17 (d, 2H), 7.63 (d, 2H), 6.83 (s, 1H), 2.46 (s , 3H), 1.63 (s, 6H).
LC / MS (method _{4, ESIpos): R t =} 1.34 min, m / z = 337 [M + H] +.

実施例22A(方法A)に記載した方法に準じて、5-メチル-1H-ピラゾール-3-カルボン酸3.15 g(25.0 mmol)および実施例2Aからの化合物 4.91 g(25.0 mmol)から表題化合物5.0 g(理論値の68%)を得た。ここでは、反応終了後、後処理として、撹拌下氷水を反応混合物に加えることにより行い生成物を沈殿させ、吸引濾過し、続いて水で洗浄し、高真空下乾燥させた。
¹H NMR (400 MHz、DMSO-d₆、δ/ppm)：13.54 (s、broad、1H)、8.08 (d、2H)、7.62 (d、2H)、6.81 (s、1H)、2.33 (s、3H)、1.72 (s、3H)、1.68 (s、3H)。
LC/MS (方法2、ESIpos)：R_t＝2.19分、m/z＝287 [M+H]⁺。 Example 24A
3- [4- (2-Fluoropropan-2-yl) phenyl] -5- (5-methyl-1H-pyrazol-3-yl) -1,2,4-oxadiazole

According to the method described in Example 22A (Method A), 5-methyl-1H-pyrazole-3-carboxylic acid 3.15 g (25.0 mmol) and the compound from Example 2A 4.91 g (25.0 mmol) to the title compound 5.0 g (68% of theory) was obtained. Here, after completion of the reaction, as a post-treatment, the product was precipitated by adding ice water to the reaction mixture with stirring, suction filtered, subsequently washed with water and dried under high vacuum.
¹ H NMR (400 MHz, DMSO-d ₆ , δ / ppm): 13.54 (s, broad, 1H), 8.08 (d, 2H), 7.62 (d, 2H), 6.81 (s, 1H), 2.33 (s , 3H), 1.72 (s, 3H), 1.68 (s, 3H).
LC / MS (Method 2, ESIpos): R _t = 2.19 min, m / z = 287 [M + H] ⁺ .

実施例22A(方法A)に記載した方法に準じて、5-メチル-1H-ピラゾール-3-カルボン酸2.37 g(18.7 mmol)および実施例3Aからの化合物5.03 g(18.7 mmol)から表題化合物3.4 g(理論値の51%)を得た。
¹H NMR (400 MHz、DMSO-d₆、δ/ppm)：13.62 (s、broad、1H)、8.49 (d、2H)、8.38 (d、2H)、6.83 (s、1H)、2.34 (s、3H)。
LC/MS (方法4、ESIpos)：R_t＝1.25分、m/z＝359 [M+H]⁺。 Example 25A
5- (5-Methyl-1H-pyrazol-3-yl) -3- {4-[(trifluoromethyl) sulfonyl] phenyl} -1,2,4-oxadiazole

According to the method described in Example 22A (Method A), from 2.37 g (18.7 mmol) of 5-methyl-1H-pyrazole-3-carboxylic acid and 5.03 g (18.7 mmol) of the compound from Example 3A to the title compound 3.4. g (51% of theory) was obtained.
¹ H NMR (400 MHz, DMSO-d ₆ , δ / ppm): 13.62 (s, broad, 1H), 8.49 (d, 2H), 8.38 (d, 2H), 6.83 (s, 1H), 2.34 (s 3H).
LC / MS (Method 4, ESIpos): R _t = 1.25 min, m / z = 359 [M + H] ⁺ .

実施例22A(方法A)に記載した方法に準じて、5-メチル-1H-ピラゾール-3-カルボン酸2.52 g(20.0 mmol)および実施例9Aからの化合物 4.63 g(20.0 mmol、90%純度)から表題化合物4.67 g(理論値の78%)を得た。ここでは、反応終了後、後処理として、撹拌下氷水を反応混合物に加えることにより行い生成物を沈殿させ、吸引濾過し、続いて水で洗浄し、高真空下乾燥させた。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：11.3 (s、broad、1H)、8.12 (d、2H)、7.63 (d、2H)、6.81 (s、1H)、2.43 (s、3H)、0.31 (s、9H)。
LC/MS (方法3、ESIpos)：R_t＝2.39分、m/z＝299 [M+H]⁺。 Example 26A
5- (5-Methyl-1H-pyrazol-3-yl) -3- [4- (trimethylsilyl) phenyl] -1,2,4-oxadiazole

According to the method described in Example 22A (Method A), 2.52 g (20.0 mmol) of 5-methyl-1H-pyrazole-3-carboxylic acid and 4.63 g (20.0 mmol, 90% purity) of the compound from Example 9A. Gave 4.67 g (78% of theory) of the title compound. Here, after completion of the reaction, as a post-treatment, the product was precipitated by adding ice water to the reaction mixture with stirring, suction filtered, subsequently washed with water and dried under high vacuum.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 11.3 (s, broad, 1H), 8.12 (d, 2H), 7.63 (d, 2H), 6.81 (s, 1H), 2.43 (s, 3H ), 0.31 (s, 9H).
LC / MS (Method 3, ESIpos): R _t = 2.39 min, m / z = 299 [M + H] ⁺ .

実施例22A(方法A)に記載した方法に準じて、5-メチル-1H-ピラゾール-3-カルボン酸2.40 g(19.0 mmol)およびN’-ヒドロキシ-4-(トリフルオロメチル)ベンゼンカルボキシミドアミド3.88 g(19.0 mmol)から表題化合物3.95 g(理論値の71%)を得た。ここでは、反応終了後、後処理として、撹拌下氷水を反応混合物に加えることにより行い生成物を沈殿させ、吸引濾過し、続いて水で洗浄し、高真空下乾燥させた。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：10.52 (broad、1H)、8.32 (d、2H)、7.77 (d、2H)、6.82 (s、1H)、2.63 (s、3H)。
LC/MS (方法6、ESIpos)：R_t＝1.11分、m/z＝295 [M+H]⁺。 Example 27A
5- (5-Methyl-1H-pyrazol-3-yl) -3- [4- (trifluoromethyl) phenyl] -1,2,4-oxadiazole

According to the method described in Example 22A (Method A), 2.40 g (19.0 mmol) of 5-methyl-1H-pyrazole-3-carboxylic acid and N′-hydroxy-4- (trifluoromethyl) benzenecarboximidamide The title compound 3.95 g (71% of theory) was obtained from 3.88 g (19.0 mmol). Here, after completion of the reaction, as a post-treatment, the product was precipitated by adding ice water to the reaction mixture with stirring, suction filtered, subsequently washed with water and dried under high vacuum.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 10.52 (broad, 1H), 8.32 (d, 2H), 7.77 (d, 2H), 6.82 (s, 1H), 2.63 (s, 3H).
LC / MS (Method 6, ESIpos): R _t = 1.11 min, m / z = 295 [M + H] ⁺ .

実施例22A(方法A)に記載した方法に準じて、5-メチル-1H-ピラゾール-3-カルボン酸469 mg(3.72 mmol)および実施例11Aからの化合物820 mg(3.72 mmol)から、アセトニトリル中撹拌することによる粗成生物の抽出により表題化合物450 mgを得、さらに母液を分取用HPLC(方法11)により精製し、表題化合物97 mg(収量は合わせて理論値の47 %)を得た。
¹H NMR (400 MHz、DMSO-d₆、δ/ppm)：13.52 (s、1H)、8.01 (d、2H)、7.49 (d、2H)、6.79 (s、1H)、3.99-3.95 (m、2H)、3.49-3.42 (m、2H)、2.92-2.84 (m、1H)、2.34 (s、3H)、1.77-1.65 (m、4H)。
LC/MS (方法6、ESIpos)：R_t＝0.98分、m/z＝311 [M+H]⁺。 Example 28A
5- (5-Methyl-1H-pyrazol-3-yl) -3- [4- (tetrahydro-2H-pyran-4-yl) phenyl] -1,2,4-oxadiazole

According to the method described in Example 22A (Method A), from 469 mg (3.72 mmol) of 5-methyl-1H-pyrazole-3-carboxylic acid and 820 mg (3.72 mmol) of the compound from Example 11A in acetonitrile. Extraction of the crude product by stirring gave 450 mg of the title compound, and the mother liquor was further purified by preparative HPLC (Method 11) to give 97 mg of the title compound (a combined yield of 47% of theory). .
¹ H NMR (400 MHz, DMSO-d ₆ , δ / ppm): 13.52 (s, 1H), 8.01 (d, 2H), 7.49 (d, 2H), 6.79 (s, 1H), 3.99-3.95 (m 2H), 3.49-3.42 (m, 2H), 2.92-2.84 (m, 1H), 2.34 (s, 3H), 1.77-1.65 (m, 4H).
LC / MS (Method 6, ESIpos): R _t = 0.98 min, m / z = 311 [M + H] ⁺ .

実施例22A(方法A)に記載した方法に準じて、5-メチル-1H-ピラゾール-3-カルボン酸2.0 g(15.9 mmol)および実施例16Aからの化合物3.78 g(15.9 mmol)から表題化合物3.15 g(92%純度、理論値の56%)を得た。この場合、生成物は、クロマトグラフィーで精製せず、粗成生物を水およびペンタンで洗浄し、続いて減圧下乾燥することにより得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：12.0-9.5 (broad、1H)、8.10-7.97 (m、2H)、7.46-7.41 (t、1H)、6.81 (s、1H)、2.47 (s、3H)。
LC/MS (方法6、ESIpos)：R_t＝1.16分、m/z＝329 [M+H]⁺。 Example 29A
3- [3-Fluoro-4- (trifluoromethoxy) phenyl] -5- (5-methyl-1H-pyrazol-3-yl) -1,2,4-oxadiazole

According to the method described in Example 22A (Method A), 2.0 g (15.9 mmol) of 5-methyl-1H-pyrazole-3-carboxylic acid and 3.78 g (15.9 mmol) of the compound from Example 16A were used to obtain the title compound 3.15. g (92% purity, 56% of theory) was obtained. In this case, the product was not purified by chromatography and was obtained by washing the crude product with water and pentane followed by drying under reduced pressure.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 12.0-9.5 (broad, 1H), 8.10-7.97 (m, 2H), 7.46-7.41 (t, 1H), 6.81 (s, 1H), 2.47 (s, 3H).
LC / MS (Method _{6, ESIpos): R t =} 1.16 min, m / z = 329 [M + H] +.

方法A:
実施例22A(方法A)に記載した方法に準じて、5-メチル-1H-ピラゾール-3-カルボン酸1.19 g(9.42 mmol)および実施例15Aからの化合物2.30 g(9.42 mmol)から表題化合物1.05 g(理論値の62%)を得た。ここでは、粗成生物の精製は、分取用HPLC(方法13)により行った。
方法B:
1,1’-カルボニルジイミダゾール(CDI)6.75 g(41.6 mmol)の無水DMF懸濁液25 mlに、室温で15分以内で、5-メチル-1H-ピラゾール-3-カルボン酸5.0 g(36.6 mmol)の無水DMF溶液25 mlを滴下した。混合物を室温で1時間45分撹拌した後、実施例15Aからの化合物9.68 g(39.6 mmol)を加えた。続いて、反応混合物を110℃で2.5時間撹拌した。室温に冷却した後、激しく撹拌している中、水800 mlをゆっくりと加えると、生成物の沈殿が析出した。固体を吸引濾過し、少量の冷水で洗浄した。まだ湿潤している粗成生物をエタノール300 mlおよび水350 mlの沸騰混合物から再結晶した。これにより表題化合物11.03 g(理論値の83%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：11.04 (s、broad、1H)、8.16 (d、2H)、7.60 (d、2H)、6.82 (s、1H)、2.45 (s、3H)、1.43-1.40 (m、2H)、1.11-1.07 (m、2H)。
LC/MS (方法6、ESIpos)：R_t＝1.14分、m/z＝335 [M+H]⁺。 Example 30A
5- (5-Methyl-1H-pyrazol-3-yl) -3- {4- [1- (trifluoromethyl) cyclopropyl] phenyl} -1,2,4-oxadiazole

Method A:
According to the method described in Example 22A (Method A), 1.19 g (9.42 mmol) of 5-methyl-1H-pyrazole-3-carboxylic acid and 2.30 g (9.42 mmol) of compound from Example 15A were used to obtain the title compound 1.05. g (62% of theory) was obtained. Here, the crude product was purified by preparative HPLC (Method 13).
Method B:
To 25 ml of an anhydrous DMF suspension of 6.75 g (41.6 mmol) of 1,1′-carbonyldiimidazole (CDI), 5.0 g (36.6 g) of 5-methyl-1H-pyrazole-3-carboxylic acid was added within 15 minutes at room temperature. mmol) in 25 ml of anhydrous DMF was added dropwise. After the mixture was stirred at room temperature for 1 hour 45 minutes, 9.68 g (39.6 mmol) of the compound from Example 15A was added. The reaction mixture was subsequently stirred at 110 ° C. for 2.5 hours. After cooling to room temperature, 800 ml of water was slowly added while stirring vigorously, resulting in the precipitation of the product. The solid was filtered off with suction and washed with a small amount of cold water. The still wet crude product was recrystallized from a boiling mixture of 300 ml ethanol and 350 ml water. This gave 11.03 g (83% of theory) of the title compound.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 11.04 (s, broad, 1H), 8.16 (d, 2H), 7.60 (d, 2H), 6.82 (s, 1H), 2.45 (s, 3H ), 1.43-1.40 (m, 2H), 1.11-1.07 (m, 2H).
LC / MS (Method _{6, ESIpos): R t =} 1.14 min, m / z = 335 [M + H] +.

実施例22A(方法A)に記載した方法に準じて、5-メチル-1H-ピラゾール-3-カルボン酸2.50 g(19.8 mmol)および実施例20Aからの化合物5.0 g(19.8 mmol)から表題化合物2.07 g(理論値の30%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：10.80 (broad、1H)、7.91 (dd、1H)、7.80 (dd、1H)、7.24 (t、1H)、6.80 (s、1H)、3.67 (s、2H)、3.29 (s、3H)、2.45 (s、3H)、2.48-2.31 (m、4H)、2.19-2.07 (m、1H)、1.95-1.86 (m、1H)。
LC/MS (方法4、ESIpos)：R_t＝1.34分、m/z＝343 [M+H]⁺。 Example 31A
3- {3-Fluoro-4- [1- (methoxymethyl) cyclobutyl] phenyl} -5- (5-methyl-1H-pyrazol-3-yl) -1,2,4-oxadiazole

According to the method described in Example 22A (Method A), the title compound 2.07 was obtained from 2.50 g (19.8 mmol) of 5-methyl-1H-pyrazole-3-carboxylic acid and 5.0 g (19.8 mmol) of the compound from Example 20A. g (30% of theory) was obtained.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 10.80 (broad, 1H), 7.91 (dd, 1H), 7.80 (dd, 1H), 7.24 (t, 1H), 6.80 (s, 1H), 3.67 (s, 2H), 3.29 (s, 3H), 2.45 (s, 3H), 2.48-2.31 (m, 4H), 2.19-2.07 (m, 1H), 1.95-1.86 (m, 1H).
LC / MS (method _{4, ESIpos): R t =} 1.34 min, m / z = 343 [M + H] +.

実施例22A(方法A)に記載した方法に準じて、5-メチル-1H-ピラゾール-3-カルボン酸368 mg(2.92 mmol)および実施例18Aからの化合物725 mg(2.92 mmol)から表題化合物608 mg(理論値の60%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：11.13 (broad、1H)、8.10 (d、2H)、7.30 (d、2H)、6.81 (s、1H)、3.58 (s、2H)、3.39 (quart、2H)、2.45 (s、3H)、2.41-2.29 (m、4H)、2.15-2.04 (m、1H)、1.92-1.83 (m、1H)、1.10 (t、3H)。
LC/MS (方法2、ESIpos)：R_t＝2.52分、m/z＝339 [M+H]⁺。 Example 32A
3- {4- [1- (Ethoxymethyl) cyclobutyl] phenyl} -5- (5-methyl-1H-pyrazol-3-yl) -1,2,4-oxadiazole

According to the method described in Example 22A (Method A), 368 mg (2.92 mmol) of 5-methyl-1H-pyrazole-3-carboxylic acid and 725 mg (2.92 mmol) of the compound from Example 18A were used for the title compound 608. mg (60% of theory) was obtained.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 11.13 (broad, 1H), 8.10 (d, 2H), 7.30 (d, 2H), 6.81 (s, 1H), 3.58 (s, 2H), 3.39 (quart, 2H), 2.45 (s, 3H), 2.41-2.29 (m, 4H), 2.15-2.04 (m, 1H), 1.92-1.83 (m, 1H), 1.10 (t, 3H).
LC / MS (Method 2, ESIpos): R _t = 2.52 min, m / z = 339 [M + H] ⁺ .

実施例22A(方法A)に記載した方法に準じて、5-メチル-1H-ピラゾール-3-カルボン酸1.18 g(9.34 mmol)および実施例19Aからの化合物2.32 g(9.34 mmol)から、表題化合物1.31 g(理論値の41%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：10.82 (broad、1H)、8.10 (d、2H)、7.46 (d、2H)、6.80 (s、1H)、3.41 (s、2H)、3.23 (s、3H)、2.43 (s、3H)、2.07-2.00 (m、2H)、1.97-1.89 (m、2H)、1.78-1.71 (m、4H)。
LC/MS (方法6、ESIpos)：R_t＝1.19分、m/z＝339 [M+H]⁺。 Example 33A
3- {4- [1- (methoxymethyl) cyclopentyl] phenyl} -5- (5-methyl-1H-pyrazol-3-yl) -1,2,4-oxadiazole

According to the method described in Example 22A (Method A), the title compound was obtained from 1.18 g (9.34 mmol) of 5-methyl-1H-pyrazole-3-carboxylic acid and 2.32 g (9.34 mmol) of the compound from Example 19A. 1.31 g (41% of theory) was obtained.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 10.82 (broad, 1H), 8.10 (d, 2H), 7.46 (d, 2H), 6.80 (s, 1H), 3.41 (s, 2H), 3.23 (s, 3H), 2.43 (s, 3H), 2.07-2.00 (m, 2H), 1.97-1.89 (m, 2H), 1.78-1.71 (m, 4H).
LC / MS (Method _{6, ESIpos): R t =} 1.19 min, m / z = 339 [M + H] +.

実施例22A(方法A)に記載した方法に準じて、5-メチル-1H-ピラゾール-3-カルボン酸1.50 g(11.9 mmol)および実施例17Aからの化合物2.79 g(11.9 mmol)から表題化合物1.81 g(94%純度、理論値の44%)を得た。
¹H NMR (400 MHz、DMSO-d₆、δ/ppm)：13.56 (broad、1H)、8.12 (s、1H)、8.02 (d、1H)、7.54 (d、1H)、6.81 (s、1H)、2.39 (s、3H)、2.35 (s、3H)。
LC/MS (方法6、ESIpos)：R_t＝1.17分、m/z＝325 [M+H]⁺。 Example 34A
5- (5-Methyl-1H-pyrazol-3-yl) -3- [3-methyl-4- (trifluoromethoxy) phenyl] -1,2,4-oxadiazole

According to the method described in Example 22A (Method A), the title compound 1.81 was obtained from 1.50 g (11.9 mmol) of 5-methyl-1H-pyrazole-3-carboxylic acid and 2.79 g (11.9 mmol) of the compound from Example 17A. g (94% purity, 44% of theory) was obtained.
¹ H NMR (400 MHz, DMSO-d ₆ , δ / ppm): 13.56 (broad, 1H), 8.12 (s, 1H), 8.02 (d, 1H), 7.54 (d, 1H), 6.81 (s, 1H ), 2.39 (s, 3H), 2.35 (s, 3H).
LC / MS (Method _{6, ESIpos): R t =} 1.17 min, m / z = 325 [M + H] +.

実施例22A(方法A)に記載した方法に準じて、5-メチル-1H-ピラゾール-3-カルボン酸300 mg(2.38 mmol)および実施例4Aからの化合物500 mg(2.38 mmol)から表題化合物204 mg(理論値の28%)を得た。この場合、粗成生物はクロマトグラフィーではなくエタノールからの結晶化により精製した。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：8.27 (d、2H)、7.72 (d、2H)、6.81 (s、1H)、5.05 (dd、2H)、5.01 (dd、2H)、2.47 (s、3H)。
LC/MS (方法2、ESIpos)：R_t＝1.93分、m/z＝301 [M+H]⁺。 Example 35A
3- [4- (3-Fluorooxetane-3-yl) phenyl] -5- (5-methyl-1H-pyrazol-3-yl) -1,2,4-oxadiazole

According to the method described in Example 22A (Method A), the title compound 204 was obtained from 300 mg (2.38 mmol) of 5-methyl-1H-pyrazole-3-carboxylic acid and 500 mg (2.38 mmol) of the compound from Example 4A. mg (28% of theory) was obtained. In this case, the crude product was purified by crystallization from ethanol rather than chromatography.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 8.27 (d, 2H), 7.72 (d, 2H), 6.81 (s, 1H), 5.05 (dd, 2H), 5.01 (dd, 2H), 2.47 (s, 3H).
LC / MS (Method 2, ESIpos): R _t = 1.93 min, m / z = 301 [M + H] ⁺ .

実施例22A(方法A)に記載した方法に準じて、5-メチル-1H-ピラゾール-3-カルボン酸600 mg(4.76 mmol)および実施例8Aからの化合物1.12 g(4.76 mmol)から表題化合物485 mg(理論値の31%)を得た。この場合、粗成生物はクロマトグラフィーではなくエタノールからの結晶化により精製した。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：10.60 (broad、1H)、8.23 (d、2H)、7.79 (d、2H)、6.81 (s、1H)、2.47 (s、3H)。
LC/MS (方法6、ESIpos)：R_t＝1.17分、m/z＝327 [M+H]⁺。 Example 36A
5- (5-Methyl-1H-pyrazol-3-yl) -3- {4-[(trifluoromethyl) sulfanyl] phenyl} -1,2,4-oxadiazole

According to the method described in Example 22A (Method A), the title compound 485 was obtained from 600 mg (4.76 mmol) of 5-methyl-1H-pyrazole-3-carboxylic acid and 1.12 g (4.76 mmol) of the compound from Example 8A. mg (31% of theory) was obtained. In this case, the crude product was purified by crystallization from ethanol rather than chromatography.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 10.60 (broad, 1H), 8.23 (d, 2H), 7.79 (d, 2H), 6.81 (s, 1H), 2.47 (s, 3H).
LC / MS (Method _{6, ESIpos): R t =} 1.17 min, m / z = 327 [M + H] +.

実施例22A(方法A)に記載した方法に準じて、5-メチル-1H-ピラゾール-3-カルボン酸6.66 g(52.8 mmol)および実施例6Aからの化合物11.54 g(52.8 mmol)から表題化合物9.02 g(理論値の55%)を得た。粗成生物はクロマトグラフィーではなくエタノールからの結晶化により精製した。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：10.91 (s、broad、1H)、8.09 (d、2H)、7.33 (d、2H)、6.81 (s、1H)、2.61-2.52 (m、1H)、2.45 (s、3H)、1.95-1.82 (m、4H)、1.80-1.73 (m、1H)、1.52-1.34 (m、4H)、1.33-1.21 (m、1H)。
LC/MS (方法6、ESIpos)：R_t＝1.31分、m/z＝309 [M+H]⁺。 Example 37A
3- (4-Cyclohexylphenyl) -5- (5-methyl-1H-pyrazol-3-yl) -1,2,4-oxadiazole

According to the method described in Example 22A (Method A), the title compound 9.02 was obtained from 6.66 g (52.8 mmol) of 5-methyl-1H-pyrazole-3-carboxylic acid and 11.54 g (52.8 mmol) of the compound from Example 6A. g (55% of theory) was obtained. The crude product was purified by crystallization from ethanol rather than chromatography.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 10.91 (s, broad, 1H), 8.09 (d, 2H), 7.33 (d, 2H), 6.81 (s, 1H), 2.61-2.52 (m 1H), 2.45 (s, 3H), 1.95-1.82 (m, 4H), 1.80-1.73 (m, 1H), 1.52-1.34 (m, 4H), 1.33-1.21 (m, 1H).
LC / MS (Method 6, ESIpos): R _t = 1.31 min, m / z = 309 [M + H] ⁺ .

実施例22A(方法A)に記載した方法に準じて、5-メチル-1H-ピラゾール-3-カルボン酸1.58 g(12.5 mmol)および実施例7Aからの化合物3.28 g(12.5 mmol)から表題化合物2.87 g(理論値の65%)を得た。ここでは、反応終了後、生成物の後処理として、撹拌下、反応混合物に氷水を加えることにより生成物を沈殿させ、吸引濾過し、続いて水で洗浄し、高真空下乾燥させた。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：11.0 (s、broad、1H)、8.29 (d、2H)、7.89 (d、2H)、6.82 (s、1H)、2.46 (s、3H)。
LC/MS (方法6、ESIpos)：R_t＝1.13分、m/z＝353 [M+H]⁺。 Example 38A
5- (5-Methyl-1H-pyrazol-3-yl) -3- [4- (pentafluoro-λ ⁶ -sulfanyl) phenyl] -1,2,4-oxadiazole

According to the method described in Example 22A (Method A), 1.58 g (12.5 mmol) of 5-methyl-1H-pyrazole-3-carboxylic acid and 3.28 g (12.5 mmol) of compound from Example 7A were used to obtain the title compound 2.87. g (65% of theory) was obtained. Here, after completion of the reaction, as a workup of the product, the product was precipitated by adding ice water to the reaction mixture under stirring, suction filtered, subsequently washed with water and dried under high vacuum.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 11.0 (s, broad, 1H), 8.29 (d, 2H), 7.89 (d, 2H), 6.82 (s, 1H), 2.46 (s, 3H ).
LC / MS (Method _{6, ESIpos): R t =} 1.13 min, m / z = 353 [M + H] +.

EDC3.19 g(16.7 mmol)、HOBt2.55 g(16.7 mmol)および実施例12Aからの化合物3.35 g(17.4 mmol)を、順に5-メチル-1H-ピラゾール-3-カルボン酸2.0 g(15.9 mmol)の無水DMF溶液80 mlに加えた。混合物を室温で1時間撹拌し、続いて140℃で30分加熱した。室温に冷却した後、ほとんどの溶媒をロータリーエバポレーターで除去した。水約500 mlを残渣に加え、混合物を各回200 mlのジエチルエーテルで3回抽出した。合わせた有機層抽出物を水、続いて飽和塩化ナトリウム溶液で洗浄した。無水硫酸マグネシウムで乾燥させた後、混合物を濾過し、濾液をロータリーエバポレーターで除去した。得られた残渣をMPLCにより精製した(シリカゲル、移動相：シクロヘキサン/酢酸エチル 2:1)。最後に、約50 mlのペンタンで摩砕し、表題化合物1.7 g(理論値の38%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：10.84 (broad、1H)、8.08 (d、2H)、7.27 (d、2H)、6.81 (s、1H)、2.54 (d、2H)、2.44 (s、3H)、1.97-1.87 (m、1H)、0.93 (d、6H)。
LC/MS (方法7、ESIpos)：R_t＝2.59分、m/z＝283 [M+H]⁺。 Example 39A
3- (4-Isobutylphenyl) -5- (5-methyl-1H-pyrazol-3-yl) -1,2,4-oxadiazole

EDC 3.19 g (16.7 mmol), HOBt 2.55 g (16.7 mmol) and 3.35 g (17.4 mmol) of the compound from Example 12A were added in turn to 2.0 g (15.9 mmol) of 5-methyl-1H-pyrazole-3-carboxylic acid. ) In anhydrous DMF solution (80 ml). The mixture was stirred at room temperature for 1 hour followed by heating at 140 ° C. for 30 minutes. After cooling to room temperature, most of the solvent was removed on a rotary evaporator. About 500 ml of water was added to the residue and the mixture was extracted 3 times with 200 ml of diethyl ether each time. The combined organic extracts were washed with water followed by saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, the mixture was filtered and the filtrate was removed on a rotary evaporator. The resulting residue was purified by MPLC (silica gel, mobile phase: cyclohexane / ethyl acetate 2: 1). Finally, trituration with about 50 ml of pentane gave 1.7 g (38% of theory) of the title compound.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 10.84 (broad, 1H), 8.08 (d, 2H), 7.27 (d, 2H), 6.81 (s, 1H), 2.54 (d, 2H), 2.44 (s, 3H), 1.97-1.87 (m, 1H), 0.93 (d, 6H).
LC / MS (Method 7, ESIpos): R _t = 2.59 min, m / z = 283 [M + H] ⁺ .

実施例39Aに記載した方法に準じて、5-メチル-1H-ピラゾール-3-カルボン酸1.08 g(8.52 mmol)および実施例14Aからの化合物2.0 g(8.52 mmol)から表題化合物1.87 g(理論値の46%)を得た。粗生成物のMPLC精製には、シクロヘキサン/酢酸エチル(5:1 → 1:1)移動相勾配を用いた。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：11.57 (broad、1H)、8.10 (d、2H)、7.30 (d、2H)、6.81 (s、1H)、3.57 (s、2H)、3.29 (s、3H)、2.45 (s、3H)、2.41-2.28 (m、4H)、2.15-2.03 (m、1H)、1.93-1.84 (m、1H)。
LC/MS (方法4、ESIpos)：R_t＝1.28分、m/z＝325 [M+H]⁺。 Example 40A
3- {4- [1- (methoxymethyl) cyclobutyl] phenyl} -5- (5-methyl-1H-pyrazol-3-yl) -1,2,4-oxadiazole

According to the method described in Example 39A, 1.08 g (8.52 mmol) of 5-methyl-1H-pyrazole-3-carboxylic acid and 2.0 g (8.52 mmol) of the compound from Example 14A to 1.87 g (theoretical value) 46%). A mobile phase gradient of cyclohexane / ethyl acetate (5: 1 → 1: 1) was used for MPLC purification of the crude product.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 11.57 (broad, 1H), 8.10 (d, 2H), 7.30 (d, 2H), 6.81 (s, 1H), 3.57 (s, 2H), 3.29 (s, 3H), 2.45 (s, 3H), 2.41-2.28 (m, 4H), 2.15-2.03 (m, 1H), 1.93-1.84 (m, 1H).
LC / MS (method _{4, ESIpos): R t =} 1.28 min, m / z = 325 [M + H] +.

実施例39Aに記載した方法に準じて、5-メチル-1H-ピラゾール-3-カルボン酸2.0 g(15.9 mmol)および実施例13Aからの化合物 3.11 g(17.4 mmol)から表題化合物2.20 g(理論値の52%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：8.10 (d、2H)、7.36 (d、2H)、6.81 (s、1H)、2.97 (sept、1H)、2.43 (s、3H)、1.29 (d、6H)。
LC/MS (方法7、ESIpos)：R_t＝2.42分、m/z＝269 [M+H]⁺。 Example 41A
3- (4-Isopropylphenyl) -5- (5-methyl-1H-pyrazol-3-yl) -1,2,4-oxadiazole

According to the method described in Example 39A, 2.0 g (15.9 mmol) of 5-methyl-1H-pyrazole-3-carboxylic acid and 3.11 g (17.4 mmol) of the compound from Example 13A to 2.20 g (theoretical value) Of 52%).
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 8.10 (d, 2H), 7.36 (d, 2H), 6.81 (s, 1H), 2.97 (sept, 1H), 2.43 (s, 3H), 1.29 (d, 6H).
LC / MS (Method 7, ESIpos): R _t = 2.42 min, m / z = 269 [M + H] ⁺ .

実施例39Aに記載した方法に準じて、5-メチル-1H-ピラゾール-3-カルボン酸2.50 g(19.8 mmol)および4-tert-ブチル-N’-ヒドロキシベンゼンカルボキシミドアミド4.19 g(21.8 mmol)から表題化合物2.60 g(理論値の46%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：11.08 (s、broad、1H)、8.10 (d、2H)、7.51 (d、2H)、6.81 (s、1H)、2.46 (s、3H)、1.37 (s、9H)。
LC/MS (方法6、ESIpos)：R_t＝1.21分、m/z＝283 [M+H]⁺。 Example 42A
3- (4-tert-Butylphenyl) -5- (5-methyl-1H-pyrazol-3-yl) -1,2,4-oxadiazole

According to the method described in Example 39A, 2.50 g (19.8 mmol) of 5-methyl-1H-pyrazole-3-carboxylic acid and 4.19 g (21.8 mmol) of 4-tert-butyl-N′-hydroxybenzenecarboxamide amide Gave 2.60 g (46% of theory) of the title compound.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 11.08 (s, broad, 1H), 8.10 (d, 2H), 7.51 (d, 2H), 6.81 (s, 1H), 2.46 (s, 3H ), 1.37 (s, 9H).
LC / MS (Method 6, ESIpos): R _t = 1.21 min, m / z = 283 [M + H] ⁺ .

室温で、5-メチル-1H-ピラゾール-3-カルボン酸4.30 g(34.1 mmol)の無水DMF溶液20 mlを約15分かけて1,1’-カルボニルジイミダゾール5.81 g(35.8 mmol)の無水DMF懸濁液25 mlに滴下した。混合物を室温で105分撹拌した後、実施例5Aからの化合物8.12 g(34.1 mmol)を加えた。続いて反応混合物は110℃で5時間加熱した。室温に冷却した後、混合物をゆっくり水800 mlに加えた。沈殿した生成物を吸引濾過し、水で洗浄した。湿潤した粗生成物を続いてエタノール430 mlから再結晶した。結晶分画を濾過した後、乾燥させ、表題化合物8.31 g(理論値の74%)を得た。母液を濃縮することによりさらなる分画を得た(1.69 g、85%純度、理論値の13%)。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：10.73 (broad、1H)、8.20 (d、2H)、7.52 (d、2H)、6.81 (s、1H)、4.00-3.88 (m、4H)、2.45 (s、3H)、2.30-2.11 (m、2H)、1.98-1.91 (m、2H)。
LC/MS (方法8、ESIpos)：R_t＝4.24分、m/z＝329 [M+H]⁺。 Example 43A
3- [4- (4-Fluorotetrahydro-2H-pyran-4-yl) phenyl] -5- (5-methyl-1H-pyrazol-3-yl) -1,2,4-oxadiazole

At room temperature, 20 ml of an anhydrous DMF solution of 5.30 g (34.1 mmol) of 5-methyl-1H-pyrazole-3-carboxylic acid was added to 5.81 g (35.8 mmol) of anhydrous DMF over about 15 minutes. It was added dropwise to 25 ml of the suspension. After the mixture was stirred at room temperature for 105 minutes, 8.12 g (34.1 mmol) of the compound from Example 5A was added. The reaction mixture was subsequently heated at 110 ° C. for 5 hours. After cooling to room temperature, the mixture was slowly added to 800 ml of water. The precipitated product was filtered off with suction and washed with water. The wet crude product was subsequently recrystallized from 430 ml of ethanol. The crystalline fraction was filtered and dried to give 8.31 g (74% of theory) of the title compound. Further fractions were obtained by concentrating the mother liquor (1.69 g, 85% purity, 13% of theory).
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 10.73 (broad, 1H), 8.20 (d, 2H), 7.52 (d, 2H), 6.81 (s, 1H), 4.00-3.88 (m, 4H) ), 2.45 (s, 3H), 2.30-2.11 (m, 2H), 1.98-1.91 (m, 2H).
LC / MS (Method 8, ESIpos): R _t = 4.24 min, m / z = 329 [M + H] ⁺ .

実施例43Aに記載した方法に準じて、5-メチル-1H-ピラゾール-3-カルボン酸2.50 g(19.8 mmol)および実施例10Aからの化合物4.13 g(19.8 mmol)から表題化合物4.41 g(理論値の75%)を得た。反応混合物に撹拌下、水を加え、続いて各回約200 mlの酢酸エチルで3回抽出した。合わせた有機層抽出物を飽和塩化ナトリウム溶液で洗浄し、無水硫酸マグネシウムで乾燥させた。濾過した後、溶媒を蒸発させ、粗成生物をエタノールからの結晶化により精製した。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：11.36 (broad、1H)、8.20 (d、2H)、7.60 (d、2H)、6.82 (s、1H)、2.77-2.54 (m、4H)、2.47 (s、3H)、2.19-2.08 (m、1H)、1.87-1.77 (m、1H)。
LC/MS (方法6、ESIpos)：R_t＝1.07分、m/z＝299 [M+H]⁺。 Example 44A
3- [4- (1-Fluorocyclobutyl) phenyl] -5- (5-methyl-1H-pyrazol-3-yl) -1,2,4-oxadiazole

According to the method described in Example 43A, 2.50 g (19.8 mmol) of 5-methyl-1H-pyrazole-3-carboxylic acid and 4.13 g (19.8 mmol) of the compound from Example 10A to 4.41 g (theoretical value) Of 75%). Water was added to the reaction mixture with stirring, followed by extraction three times with about 200 ml of ethyl acetate each time. The combined organic layer extracts were washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated and the crude product was purified by crystallization from ethanol.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 11.36 (broad, 1H), 8.20 (d, 2H), 7.60 (d, 2H), 6.82 (s, 1H), 2.77-2.54 (m, 4H) ), 2.47 (s, 3H), 2.19-2.08 (m, 1H), 1.87-1.77 (m, 1H).
LC / MS (Method 6, ESIpos): R _t = 1.07 min, m / z = 299 [M + H] ⁺ .

実施例39Aに記載した方法に準じて、5-メチル-1H-ピラゾール-3-カルボン酸2.71 g(21.5 mmol)および実施例21Aからの化合物5.68 g(21.5 mmol)から表題化合物4.36 g(95%純度、理論値の54%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：7.94 (d、1H)、7.88 (d、1H)、7.57 (t、1H)、6.81 (s、1H)、2.45 (s、3H)、1.69 (s、6H)。
LC/MS (方法6、ESIpos)：R_t＝1.16分、m/z＝355 [M+H]⁺。 Example 45A
3- [3-Fluoro-4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenyl] -5- (5-methyl-1H-pyrazol-3-yl) -1,2 , 4-Oxadiazole

According to the method described in Example 39A, 2.71 g (21.5 mmol) of 5-methyl-1H-pyrazole-3-carboxylic acid and 5.68 g (21.5 mmol) of the compound from Example 21A to 4.36 g (95% Purity, 54% of theory).
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 7.94 (d, 1H), 7.88 (d, 1H), 7.57 (t, 1H), 6.81 (s, 1H), 2.45 (s, 3H), 1.69 (s, 6H).
LC / MS (Method _{6, ESIpos): R t =} 1.16 min, m / z = 355 [M + H] +.

工程1： 2-[3-(ヒドロキシメチル)フェニル]プロパン-2-オール

2.4 MリチウムアルミニウムハイドライドのTHF溶液1.5 ml(3.47 mmol)をゆっくりと3-(2-ヒドロキシプロパン-2-イル)安息香酸500 mg(2.78 mmol)のTHF懸濁液10 mlに加えた。続いて混合物を浴槽温度80℃で2時間加熱した。室温に冷却した後、1 N 塩酸50 mlを加え、混合物を各回30 mlのtert-ブチルメチルエーテルで3回抽出した。合わせた有機相を硫酸ナトリウムで乾燥させ、濾過し、濃縮した。残渣を真空下乾燥させ、表題化合物455 mg(97%純度、理論値の99%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：7.51 (s、1H)、7.42 (d、1H)、7.34 (t、1H)、7.25 (d、1H)、4.71 (s、2H)、1.59 (s、6H)。
LC/MS (方法6、ESIpos)：R_t＝0.57分、m/z＝149 [M+H-H₂O]⁺。
工程2： 3-(2-ヒドロキシプロパン-2-イル)ベンジル メタンスルホネート

アルゴン下、トリエチルアミン1.1 ml(7.88 mmol)を室温で、続いてメタンスルホン酸無水物1.01 g(5.78 mmol)を0℃で、実施例46A/工程1からの化合物873 mg(5.25 mmol)のジクロロメタン溶液50 mlに加えた。1時間室温で撹拌した後、混合物を塩化アンモニウム水溶液100 mlおよび塩化ナトリウム溶液100 mlで続いて洗浄した。有機相を硫酸マグネシウムで乾燥させ、濾過し、濃縮した。減圧下、残渣を乾燥させ、表題化合物1.13 g(理論値の88%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：7.56 (s、1H)、7.51 (d、1H)、7.39 (t、1H)、7.32 (d、1H)、5.25 (s、2H)、2.94 (s、3H)、1.59 (s、6H)。
LC/MS (方法6、ESIpos)：R_t＝0.74分、m/z＝227 [M+H-H₂O]⁺。 Example 46A
3- (2-Hydroxypropan-2-yl) benzyl methanesulfonate

Step 1: 2- [3- (hydroxymethyl) phenyl] propan-2-ol

1.5 ml (3.47 mmol) of a THF solution of 2.4 M lithium aluminum hydride was slowly added to 10 ml of a THF suspension of 500 mg (2.78 mmol) of 3- (2-hydroxypropan-2-yl) benzoic acid. Subsequently, the mixture was heated at a bath temperature of 80 ° C. for 2 hours. After cooling to room temperature, 50 ml of 1N hydrochloric acid was added and the mixture was extracted 3 times with 30 ml of tert-butyl methyl ether each time. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was dried under vacuum to give 455 mg (97% purity, 99% of theory) of the title compound.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 7.51 (s, 1H), 7.42 (d, 1H), 7.34 (t, 1H), 7.25 (d, 1H), 4.71 (s, 2H), 1.59 (s, 6H).
LC / MS (Method 6, ESIpos): R _t = 0.57 min, m / z = 149 [M + HH ₂ O] ⁺ .
Step 2: 3- (2-Hydroxypropan-2-yl) benzyl methanesulfonate

Under argon, 1.1 ml (7.88 mmol) of triethylamine at room temperature, followed by 1.01 g (5.78 mmol) of methanesulfonic anhydride at 0 ° C., a solution of 873 mg (5.25 mmol) of the compound from Example 46A / Step 1 in dichloromethane. Added to 50 ml. After stirring for 1 hour at room temperature, the mixture was subsequently washed with 100 ml of aqueous ammonium chloride solution and 100 ml of sodium chloride solution. The organic phase was dried over magnesium sulfate, filtered and concentrated. The residue was dried under reduced pressure to give 1.13 g (88% of theory) of the title compound.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 7.56 (s, 1H), 7.51 (d, 1H), 7.39 (t, 1H), 7.32 (d, 1H), 5.25 (s, 2H), 2.94 (s, 3H), 1.59 (s, 6H).
LC / MS (Method 6, ESIpos): R _t = 0.74 min, m / z = 227 [M + HH ₂ O] ⁺ .

工程1： 1-[3-({[tert-ブチル(ジメチル)シリル]オキシ}メチル)フェニル]シクロプロパノール

溶液 Aの調製：メタノール60 mlおよび1滴の濃塩酸を[(1-エトキシシクロプロピル)オキシ](トリメチル)シラン12.32 g(70.7 mmol)に加え、混合物を室温で一夜撹拌した。続いて溶媒を、ロータリーエバポレーターにより室温で、および30 mbar以上の減圧下で除去した。これによりTHF80 mlに溶解した1-エトキシシクロプロパノール6.26 g(61.27 mmol)を得た。アルゴン下、続いて、この溶液を-70℃に冷却し、2 MエチルマグネシウムクロライドのTHF溶液30.6 ml(61.27 mmol)を加えた。続いて冷却浴を外し、溶液を内部温度が0℃に達するまで、冷却せずに撹拌した。
溶液 Bの調製：アルゴン下、-40℃で、1.3 M イソプロピルマグネシウムクロライド/リチウムクロライド複合体のTHF溶液47.1 ml(61.27 mmol)を、tert-ブチル[(3-ヨードベンジル)オキシ]ジメチルシラン19.40 g(55.70 mmol)のTHF溶液280 mlに加え、混合物は-40℃で1時間撹拌した。
2つの溶液を調製すると、溶液 Aを溶液 Bに0℃で加えた。続いて反応混合物を還流下、1時間加熱した。室温に冷却した後、飽和塩化ナトリウム水溶液を加え、混合物をtert-ブチルメチルエーテルで抽出した。合わせた有機相を飽和塩化ナトリウム溶液で1回洗浄し、硫酸マグネシウムで乾燥させ、濾過し、濃縮した。残渣をフラッシュクロマトグラフィー(シリカゲル、移動相：シクロヘキサン → シクロヘキサン/酢酸エチル 85:15)により精製した。溶媒を除去して表題化合物9.55 g(理論値の60%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：7.32-7.24 (m、2H)、7.22-7.16 (m、2H)、4.74 (s、2H)、2.36 (s、1H)、1.26 (dd、2H)、1.06 (dd、2H)、0.94 (s、9H)、0.11 (s、6H)。
MS (DCI、NH₃)：m/z＝296 [M+NH₄]⁺。 Example 47A
1- (3-{[(Methylsulfonyl) oxy] methyl} phenyl) cyclopropyl acetate

Step 1: 1- [3-({[tert-Butyl (dimethyl) silyl] oxy} methyl) phenyl] cyclopropanol

Preparation of solution A: 60 ml of methanol and 1 drop of concentrated hydrochloric acid were added to 12.32 g (70.7 mmol) of [(1-ethoxycyclopropyl) oxy] (trimethyl) silane and the mixture was stirred at room temperature overnight. Subsequently, the solvent was removed on a rotary evaporator at room temperature and under reduced pressure above 30 mbar. As a result, 6.26 g (61.27 mmol) of 1-ethoxycyclopropanol dissolved in 80 ml of THF was obtained. Under argon, the solution was subsequently cooled to −70 ° C. and 30.6 ml (61.27 mmol) of 2M ethylmagnesium chloride in THF was added. Subsequently, the cooling bath was removed and the solution was stirred without cooling until the internal temperature reached 0 ° C.
Preparation of solution B: Under argon at -40 ° C., 47.1 ml (61.27 mmol) of a THF solution of 1.3 M isopropylmagnesium chloride / lithium chloride complex was added to 19.40 g of tert-butyl [(3-iodobenzyl) oxy] dimethylsilane. (55.70 mmol) in THF solution (280 ml) and the mixture was stirred at −40 ° C. for 1 hour.
Once two solutions were prepared, Solution A was added to Solution B at 0 ° C. The reaction mixture was subsequently heated under reflux for 1 hour. After cooling to room temperature, saturated aqueous sodium chloride solution was added and the mixture was extracted with tert-butyl methyl ether. The combined organic phases were washed once with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography (silica gel, mobile phase: cyclohexane → cyclohexane / ethyl acetate 85:15). Removal of the solvent gave 9.55 g (60% of theory) of the title compound.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 7.32-7.24 (m, 2H), 7.22-7.16 (m, 2H), 4.74 (s, 2H), 2.36 (s, 1H), 1.26 (dd , 2H), 1.06 (dd, 2H), 0.94 (s, 9H), 0.11 (s, 6H).
_{MS (DCI, NH 3):} m / z = 296 [M + NH 4] +.

室温で、2 M エチルマグネシウムクロライドのTHF溶液21.4 ml(42.87 mmol)、直後にアセチルクロライド3.0 ml(42.87 mmol)を、実施例47A/工程1からの化合物9.55 g(34.3 mmol)のTHF溶液100 mlに加えた。5分室温で撹拌した後、飽和塩化ナトリウム水溶液を加え、混合物を酢酸エチルで2回洗浄した。合わせた有機相を硫酸マグネシウムで乾燥させ、濾過し、濃縮した。これにより表題化合物11.25 g(94%純度、理論値の96%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：7.30-7.24 (m、2H)、7.20-7.13 (m、2H)、4.72 (s、2H)、2.04 (s、3H)、1.31-1.25 (m、2H)、1.24-1.18 (m、2H)、0.94 (s、9H)、0.09 (s、6H)。
MS (DCI、NH₃)：m/z＝338 [M+NH₄]⁺。 Step 2: 1- [3-({[tert-Butyl (dimethyl) silyl] oxy} methyl) phenyl] cyclopropyl acetate

At room temperature, 21.4 ml (42.87 mmol) of 2 M ethylmagnesium chloride in THF, followed immediately by 3.0 ml (42.87 mmol) of acetyl chloride, 100 ml of THF solution of compound 9.55 g (34.3 mmol) from Example 47A / Step 1. Added to. After stirring for 5 minutes at room temperature, saturated aqueous sodium chloride solution was added and the mixture was washed twice with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated. This gave 11.25 g (94% purity, 96% of theory) of the title compound.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 7.30-7.24 (m, 2H), 7.20-7.13 (m, 2H), 4.72 (s, 2H), 2.04 (s, 3H), 1.31-1.25 (m, 2H), 1.24-1.18 (m, 2H), 0.94 (s, 9H), 0.09 (s, 6H).
_{MS (DCI, NH 3):} m / z = 338 [M + NH 4] +.

室温で、1 M テトラ-n-ブチルアンモニウム フルオライドのTHF溶液65.6 ml(65.6 mmol)を、実施例47A/工程2からの化合物11.25 g(32.82 mmol、純度94%)の溶液に加えた。混合物を室温で30分撹拌し、続いて酢酸エチルで希釈し、水で1回洗浄した。水相を酢酸エチルで1回再抽出した。合わせた有機相を飽和塩化ナトリウム溶液で1回洗浄し、硫酸マグネシウムで乾燥させ、濃縮した。これにより表題化合物8.0 g(80%純度、理論値の95%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：7.24-7.12 (m、5H)、4.58 (s、2H)、1.95 (s、3H)、1.22-1.17 (m、2H)、1.16-1.10 (m、2H)。
工程4： 1-(3-{[(メチルスルホニル)オキシ]メチル}フェニル)シクロプロピルアセテート

0℃で、メタンスルホニルクロライド2.8 ml(37.24 mmol)を、実施例47A/工程3からの化合物8.0 g(31.03 mmol、純度80%)およびトリエチルアミン5.6 ml(40.34 mmol)のTHF溶液90 mlに滴下した。続いて混合物をゆっくりと室温に戻し、室温で次の10分撹拌し、続いて酢酸エチルで希釈した。混合物を水で1回洗浄し、水相を酢酸エチルで再抽出した。合わせた有機相を飽和塩化ナトリウム溶液で1回洗浄し、硫酸マグネシウムで乾燥させ、濃縮した。得られた残渣を、フラッシュクロマトグラフィー(シリカゲル、移動相：シクロヘキサン/酢酸エチル 95:5 → 70:30)により精製した。溶媒を除去し残渣を減圧下乾燥させ、表題化合物8.45 g(95%純度、理論値の91%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：7.39-7.27 (m、4H)、5.22 (s、2H)、2.90 (s、3H)、2.06 (s、3H)、1.35-1.28 (m、2H)、1.27-1.20 (m、2H)。
LC/MS (方法4、ESIpos)：R_t＝1.02分、m/z＝285 [M+H]⁺。 Step 3: 1- [3- (Hydroxymethyl) phenyl] cyclopropyl acetate

At room temperature, 65.6 ml (65.6 mmol) of 1 M tetra-n-butylammonium fluoride in THF was added to a solution of 11.25 g (32.82 mmol, purity 94%) of the compound from Example 47A / Step 2. The mixture was stirred at room temperature for 30 minutes, then diluted with ethyl acetate and washed once with water. The aqueous phase was re-extracted once with ethyl acetate. The combined organic phases were washed once with saturated sodium chloride solution, dried over magnesium sulfate and concentrated. This gave 8.0 g (80% purity, 95% of theory) of the title compound.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 7.24-7.12 (m, 5H), 4.58 (s, 2H), 1.95 (s, 3H), 1.22-1.17 (m, 2H), 1.16-1.10 (m, 2H).
Step 4: 1- (3-{[(Methylsulfonyl) oxy] methyl} phenyl) cyclopropyl acetate

At 0 ° C., 2.8 ml (37.24 mmol) of methanesulfonyl chloride was added dropwise to 90 ml of a THF solution of 8.0 g (31.03 mmol, purity 80%) of the compound from Example 47A / Step 3 and 5.6 ml (40.34 mmol) of triethylamine. . The mixture was then slowly allowed to warm to room temperature and stirred at room temperature for the next 10 minutes, followed by dilution with ethyl acetate. The mixture was washed once with water and the aqueous phase was re-extracted with ethyl acetate. The combined organic phases were washed once with saturated sodium chloride solution, dried over magnesium sulfate and concentrated. The resulting residue was purified by flash chromatography (silica gel, mobile phase: cyclohexane / ethyl acetate 95: 5 → 70: 30). The solvent was removed and the residue was dried under reduced pressure to give 8.45 g (95% purity, 91% of theory) of the title compound.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 7.39-7.27 (m, 4H), 5.22 (s, 2H), 2.90 (s, 3H), 2.06 (s, 3H), 1.35-1.28 (m , 2H), 1.27-1.20 (m, 2H).
LC / MS (Method 4, ESIpos): R _t = 1.02 min, m / z = 285 [M + H] ⁺ .

工程1： 1-(3-ブロモフェニル)-2-メチルプロパン-2-オール

0℃で、3 M メチルマグネシウムクロライドのTHF溶液55 ml(164 mmol)を、メチル(3-ブロモフェニル)アセテート15.0 g(65.5 mmol)の無水THF溶液600 mlに滴下した。添加終了後、0℃で1時間撹拌した。続いて氷/水浴を外し、室温で一夜撹拌した。続いて飽和塩化ナトリウム水溶液約1.2リットルを加え、混合物を各回約200 mlの酢酸エチルで抽出した。合わせた有機層抽出物を飽和塩化ナトリウム溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、濾過し、最後に溶媒を減圧下除去した。得られた残渣は、シクロヘキサン/酢酸エチル10:1 → 1:1の移動相を用いたシリカゲルで、吸引濾過により精製した。これにより表題化合物8.04 g(理論値の53%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：7.41-7.37 (m、2H)、7.20-7.13 (m、2H)、2.73 (s、2H)、1.32 (s、1H)、1.23 (s、6H)。
GC/MS (方法9、EIpos)：R_t＝4.56分、m/z＝210/212 [M-H₂O]⁺。 Example 48A
3- (2-hydroxy-2-methylpropyl) benzyl methanesulfonate

Step 1: 1- (3-Bromophenyl) -2-methylpropan-2-ol

At 0 ° C., 55 ml (164 mmol) of a THF solution of 3 M methylmagnesium chloride was added dropwise to 600 ml of an anhydrous THF solution of 15.0 g (65.5 mmol) of methyl (3-bromophenyl) acetate. After completion of the addition, the mixture was stirred at 0 ° C. for 1 hour. Subsequently, the ice / water bath was removed and the mixture was stirred overnight at room temperature. Subsequently, about 1.2 liters of saturated aqueous sodium chloride solution was added and the mixture was extracted with about 200 ml of ethyl acetate each time. The combined organic layer extracts were washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and finally the solvent was removed under reduced pressure. The resulting residue was purified by suction filtration on silica gel using a mobile phase of cyclohexane / ethyl acetate 10: 1 → 1: 1. This gave 8.04 g (53% of theory) of the title compound.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 7.41-7.37 (m, 2H), 7.20-7.13 (m, 2H), 2.73 (s, 2H), 1.32 (s, 1H), 1.23 (s 6H).
GC / MS (Method 9, EIpos): R _t = 4.56 min, m / z = 210/212 [MH ₂ O] ⁺ .

-78℃で、n-ブチルリチウム13.7 ml(21.8 mmol)溶液(1.6 Mヘキサン溶液)を実施例48A/工程1からの化合物2.50 g(10.9 mmol)の無水THF溶液100 mlに滴下した。滴下終了後、混合物を-78℃でさらに30分撹拌し、続いて、また-78℃で、無水N,N-ジメチルホルムアミド2.6 ml(32.8 mmol)を加えた。続いて冷却浴を外し、室温で一夜撹拌した。続いて飽和塩化ナトリウム水溶液約100 mlを加え、混合物を各回約100 mlの酢酸エチルで3回抽出した。合わせた有機層抽出物を水、続いて飽和塩化ナトリウム溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、濾過し、最後に溶媒を減圧下除去した。こうして得られた粗生成物をMPLCにより精製した(シリカゲル、移動相：シクロヘキサン/酢酸エチル 2:1)。これにより表題化合物1.15 g(理論値の59%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：10.01 (s、1H)、7.79-7.74 (m、2H)、7.53-7.47 (m、2H)、2.86 (s、2H)、1.25 (s、6H)。
GC/MS (方法9、EIpos)：R_t＝4.76分、m/z＝160 [M-H₂O]⁺。
工程3： 1-[3-(ヒドロキシメチル)フェニル]-2-メチルプロパン-2-オール

0℃で、リチウムアルミニウムハイドライド溶液(1.0 M THF溶液)6.0 ml(6.00 mmol)を、実施例48A/工程2からの化合物1.07 g(6.00 mmol)の無水THF溶液30 mlに滴下した。添加終了後、室温で1時間撹拌した。注意深く、飽和塩化ナトリウム水溶液1-2 mlおよび続いて約30 mlの酢酸エチルを加えた。水相を完全に取り込むのに必要な量の無水硫酸マグネシウムを加えた。濾過した後、ロータリーエバポレーターにより濾液から溶媒を除去し、残渣を高真空下乾燥させた。これにより表題化合物1.09 g(理論値の100%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：7.31 (t、1H)、7.25 (dd、1H)、7.22 (dd、1H)、7.14 (dd、1H)、4.69 (s、broad、2H)、2.78 (s、2H)、1.79 (broad、1H)、1.41 (s、broad、1H)、1.23 (s、6H)。
GC/MS (方法9、EIpos)：R_t＝5.00分、m/z＝162 [M-H₂O]⁺。
工程4： 3-(2-ヒドロキシ-2-メチルプロピル)ベンジル メタンスルホネート

0℃で、メタンスルホン酸無水物1.12 g(6.41 mmol)を、実施例48A/工程3からの化合物1.05 g(5.83 mmol)およびトリエチルアミン1.2 ml(8.74 mmol)の無水ジクロロメタン溶液60 mlに加えた。続いて混合物を室温でさらに1時間撹拌した。続いて反応混合物を分液漏斗に移し、準-飽和塩化ナトリウム水溶液、続いて水で素早く洗浄した。無水硫酸マグネシウムで乾燥させた後、混合物を濾過し、ロータリーエバポレーターにより濾液から溶媒を除去した。これにより表題化合物1.5 g(理論値の99%)を得た。
MS (DCI、NH₃)：m/z＝276 [M+NH₄]⁺。 Process 2: 3- (2-hydroxy-2-methylpropyl) benzaldehyde

At −78 ° C., a solution of 13.7 ml (21.8 mmol) of n-butyllithium (1.6 M in hexane) was added dropwise to 100 ml of an anhydrous THF solution of the compound 2.50 g (10.9 mmol) from Example 48A / Step 1. After the addition was complete, the mixture was stirred at −78 ° C. for a further 30 minutes, followed by the addition of 2.6 ml (32.8 mmol) of anhydrous N, N-dimethylformamide again at −78 ° C. Subsequently, the cooling bath was removed and the mixture was stirred overnight at room temperature. Subsequently, about 100 ml of saturated aqueous sodium chloride solution was added, and the mixture was extracted three times with about 100 ml of ethyl acetate each time. The combined organic layer extracts were washed with water followed by saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and finally the solvent was removed under reduced pressure. The crude product thus obtained was purified by MPLC (silica gel, mobile phase: cyclohexane / ethyl acetate 2: 1). This gave 1.15 g (59% of theory) of the title compound.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 10.01 (s, 1H), 7.79-7.74 (m, 2H), 7.53-7.47 (m, 2H), 2.86 (s, 2H), 1.25 (s 6H).
GC / MS (Method 9, EIpos): R _t = 4.76 min, m / z = 160 [MH ₂ O] ⁺ .
Step 3: 1- [3- (Hydroxymethyl) phenyl] -2-methylpropan-2-ol

At 0 ° C., 6.0 ml (6.00 mmol) of lithium aluminum hydride solution (1.0 M THF solution) was added dropwise to 30 ml of an anhydrous THF solution of 1.07 g (6.00 mmol) of the compound from Example 48A / Step 2. After completion of addition, the mixture was stirred at room temperature for 1 hour. Carefully, 1-2 ml of saturated aqueous sodium chloride solution was added followed by about 30 ml of ethyl acetate. An amount of anhydrous magnesium sulfate required to completely take up the aqueous phase was added. After filtration, the solvent was removed from the filtrate by a rotary evaporator, and the residue was dried under high vacuum. This gave 1.09 g (100% of theory) of the title compound.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 7.31 (t, 1H), 7.25 (dd, 1H), 7.22 (dd, 1H), 7.14 (dd, 1H), 4.69 (s, broad, 2H ), 2.78 (s, 2H), 1.79 (broad, 1H), 1.41 (s, broad, 1H), 1.23 (s, 6H).
GC / MS (Method 9, EIpos): R _t = 5.00 min, m / z = 162 [MH ₂ O] ⁺ .
Step 4: 3- (2-hydroxy-2-methylpropyl) benzyl methanesulfonate

At 0 ° C., 1.12 g (6.41 mmol) of methanesulfonic anhydride was added to 60 ml of anhydrous dichloromethane in 1.048 g (5.83 mmol) of the compound from Example 48A / Step 3 and 1.2 ml (8.74 mmol) of triethylamine. The mixture was subsequently stirred at room temperature for a further hour. The reaction mixture was then transferred to a separatory funnel and washed quickly with a semi-saturated aqueous sodium chloride solution followed by water. After drying over anhydrous magnesium sulfate, the mixture was filtered and the solvent was removed from the filtrate by rotary evaporator. This gave 1.5 g (99% of theory) of the title compound.
_{MS (DCI, NH 3):} m / z = 276 [M + NH 4] +.

工程1： エチル 2-メチル-2-(3-メチルフェニル)プロパノエート

エチルm-トリルアセテート10.0 g(56.1 mmol)およびヨウ化メチル15.9 g(112 mmol)を無水THF300 mlに加え、約-70℃に冷却した。カリウムtert-ブトキシド6.93 g(61.7 mmol)を加え、混合物はさらなる冷却なしに1時間撹拌した。続いて混合物を再び約-70℃に冷却し、さらなるカリウムtert-ブトキシド6.93 g(61.7 mmol)を加え、混合物をさらに1時間冷却せずに撹拌した。続いて混合物を酢酸エチルで希釈し、水および飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、濾過した。ロータリーエバポレーターにより濾液から溶媒を除去した。これにより表題化合物9.7 g(理論値の76%)を得た。
GC/MS (方法9、EIpos)：R_t＝4.23分、m/z＝206 [M]⁺。
工程2： エチル 2-[3-(ブロモメチル)フェニル]-2-メチルプロパノエート

最初に実施例49A/工程1からの化合物3.70 g(17.9 mmol)をアセトニトリル55 mlに加え、N-ブロモスクシンイミド3.19 g(17.9 mmol)および2,2’-アゾビス-2-メチルプロパンニトリル(AIBN)29 mg(0.18 mmol)を加えて、混合物を還流下、一夜加熱した。続いて混合物は、ロータリーエバポレーターにより溶媒を除去し、残渣をペンタンに懸濁させ、固体を濾過により分離した。ロータリーエバポレーターにより濾液から溶媒を除去した。得られた残渣は黄色油状物で、出発物質をいまだ含んでいたが、さらなる精製なしに直接次の反応を行った。
収量：4.64 g(理論値の64%、GC/MSにより71%純度)
GC/MS (方法9、EIpos)：R_t＝5.71分、m/z＝284/286 [M]⁺。 Example 49A
Ethyl 2- [3- (bromomethyl) phenyl] -2-methylpropanoate

Step 1: Ethyl 2-methyl-2- (3-methylphenyl) propanoate

Ethyl m-tolyl acetate 10.0 g (56.1 mmol) and methyl iodide 15.9 g (112 mmol) were added to anhydrous THF 300 ml and cooled to about -70 ° C. Potassium tert-butoxide 6.93 g (61.7 mmol) was added and the mixture was stirred for 1 h without further cooling. The mixture was subsequently cooled again to about −70 ° C., an additional 6.93 g (61.7 mmol) of potassium tert-butoxide was added and the mixture was stirred without cooling for an additional hour. The mixture was subsequently diluted with ethyl acetate, washed with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. The solvent was removed from the filtrate by rotary evaporator. This gave 9.7 g (76% of theory) of the title compound.
GC / MS (Method 9, EIpos): R _t = 4.23 min, m / z = 206 [M] ⁺ .
Step 2: Ethyl 2- [3- (bromomethyl) phenyl] -2-methylpropanoate

First, 3.70 g (17.9 mmol) of the compound from Example 49A / Step 1 was added to 55 ml of acetonitrile, and 3.19 g (17.9 mmol) of N-bromosuccinimide and 2,2′-azobis-2-methylpropanenitrile (AIBN) 29 mg (0.18 mmol) was added and the mixture was heated under reflux overnight. Subsequently, the solvent was removed from the mixture by a rotary evaporator, the residue was suspended in pentane, and the solid was separated by filtration. The solvent was removed from the filtrate by rotary evaporator. The resulting residue was a yellow oil and still contained starting material, but the next reaction was performed directly without further purification.
Yield: 4.64 g (64% of theory, 71% purity by GC / MS)
GC / MS (Method 9, EIpos): R _t = 5.71 min, m / z = 284/286 [M] ⁺ .

工程1： メチル 1-(3-ブロモフェニル)シクロプロパンカルボキシレート

0℃で、1 Mリチウムヘキサメチルジシラジド(LiHMDS)のTHF溶液48 ml(48.0 mmol)をメチル(3-ブロモフェニル)アセテート10.0 g(43.6 mmol)の無水THF溶液250 mlに加えた。15分0℃で撹拌した後、1,2-ジブロモエタン4.9 ml(56.7 mmol)を加えた。氷/水浴を外し、混合物を室温でさらに1時間撹拌した。続いて混合物をもう一度0℃に冷却し、さらにLiHMDS溶液48 ml(48.0 mmol)を加えた。添加終了後、撹拌を室温で63時間続けた。続いて飽和塩化ナトリウム水溶液約250 mlを加え、反応混合物は各回約200 mlの酢酸エチルで3回抽出した。合わせた有機層抽出物を水、続いて飽和塩化ナトリウム溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、濾過し、最後に溶媒を減圧下除去した。得られた残渣をシクロヘキサン/酢酸エチル20:1を移動相として用いたシリカゲルで吸引濾過により精製した 。これにより表題化合物6.24 g(理論値の56%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：7.50 (m、1H)、7.39 (m、1H)、7.27 (m、1H)、7.19 (m、1H)、3.63 (s、3H)、1.62-1.60 (m、2H)、1.20-1.17 (m、2H)。
GC/MS (方法9、EIpos)：R_t＝5.27分、m/z＝254/256 [M]⁺。 Example 50A
3- (1-{[(Triisopropylsilyl) oxy] methyl} cyclopropyl) benzyl methanesulfonate

Step 1: Methyl 1- (3-bromophenyl) cyclopropanecarboxylate

At 0 ° C., 48 ml (48.0 mmol) of 1 M lithium hexamethyldisilazide (LiHMDS) in THF was added to 250 ml of anhydrous THF solution of 10.0 g (43.6 mmol) of methyl (3-bromophenyl) acetate. After stirring at 0 ° C. for 15 minutes, 4.9 ml (56.7 mmol) of 1,2-dibromoethane was added. The ice / water bath was removed and the mixture was stirred at room temperature for an additional hour. Subsequently, the mixture was once again cooled to 0 ° C., and 48 ml (48.0 mmol) of LiHMDS solution was further added. After the addition was complete, stirring was continued for 63 hours at room temperature. Subsequently, about 250 ml of saturated aqueous sodium chloride solution was added, and the reaction mixture was extracted three times with about 200 ml of ethyl acetate each time. The combined organic layer extracts were washed with water followed by saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and finally the solvent was removed under reduced pressure. The resulting residue was purified by suction filtration over silica gel using cyclohexane / ethyl acetate 20: 1 as the mobile phase. This gave 6.24 g (56% of theory) of the title compound.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 7.50 (m, 1H), 7.39 (m, 1H), 7.27 (m, 1H), 7.19 (m, 1H), 3.63 (s, 3H), 1.62-1.60 (m, 2H), 1.20-1.17 (m, 2H).
GC / MS (Method 9, EIpos): R _t = 5.27 min, m / z = 254/256 [M] ⁺ .

-78℃で、1 M リチウムアルミニウムハイドライドのTHF溶液13.7 ml(13.7 mmol)を実施例50A/工程1からの化合物3.50 g(13.7 mmol)の無水THF溶液70 mlに加えた。1時間撹拌した後、約3 mlの飽和塩化ナトリウム水溶液を加え、反応混合物を室温に戻した。続いて混合物を酢酸エチル約80 mlで希釈し、続いて、水相が完全に取り込まれる量の無水硫酸マグネシウムを加えた。濾過した後、濾液を濃縮し、残渣をMPLCで精製した(シリカゲル；移動相：シクロヘキサン → シクロヘキサン/酢酸エチル 5:1)。これにより表題化合物1.37 g(理論値の44%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：7.52 (s、1H)、7.36 (d、1H)、7.29 (d、1H)、7.18 (t、1H)、3.66 (d、2H)、1.44 (t、1H)、0.91-0.84 (m、4H)。
GC/MS (方法9、EIpos)：R_t＝5.26分、m/z＝226/228 [M]⁺。
工程3： {[1-(3-ブロモフェニル)シクロプロピル]メトキシ}(トリイソプロピル)シラン

約-50℃で、トリイソプロピルシリルトリフレート1.55 ml(6.19 mmol)を、実施例50A/工程2からの化合物1.34 g(5.90 mmol)および2,6-ルチジン948 mg(8.85 mmol)の無水ジクロロメタン溶液25 mlに加えた。30分後、冷却浴を外し、室温で1時間撹拌した。続いて水約50 mlを加え、混合物を各回約50 mlの酢酸エチルで抽出した。合わせた有機層抽出物を飽和塩化ナトリウム溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、濾過し、最後に溶媒を減圧下除去した。得られた残渣をMPLCにより精製した(シリカゲル、移動相：シクロヘキサン/酢酸エチル 5:1)。これにより表題化合物1.93 g(理論値の85%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：7.52 (s、1H)、7.31 (d、1H)、7.27 (d、1H)、7.13 (t、1H)、3.74 (s、2H)、1.02 (m、3H)、0.99 (d、18H)、0.91-0.89 (m、2H)、0.78-0.75 (m、2H)。
GC/MS (方法9、EIpos)：R_t＝6.87分、m/z＝339/341 [M-ⁱPr]⁺。
工程4： 3-(1-{[(トリイソプロピルシリル)オキシ]メチル}シクロプロピル)ベンズアルデヒド

実施例48A/工程2に記載した方法に準じて、実施例50A/工程3からの化合物1.92 g(5.01 mmol)および対応する量のn-ブチルリチウムおよびN,N-ジメチルホルムアミドから表題化合物1.48 g(理論値の88%)を、MPLC精製(シリカゲル、移動相：シクロヘキサン/酢酸エチル 10:1)により得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：10.00 (s、1H)、7.89 (s、1H)、7.72 (d、1H)、7.65 (d、1H)、7.43 (t、1H)、3.79 (s、2H)、1.01 (sept、3H)、0.98 (d、18H)、0.96-0.94 (m、2H)、0.83-0.81 (m、2H)。
GC/MS (方法9、EIpos)：R_t＝7.00分、m/z＝289 [M-ⁱPr]⁺。 Step 2: [1- (3-Bromophenyl) cyclopropyl] methanol

At −78 ° C., 13.7 ml (13.7 mmol) of 1 M lithium aluminum hydride in THF was added to 70 ml of anhydrous THF solution of 3.50 g (13.7 mmol) of the compound from Example 50A / Step 1. After stirring for 1 hour, about 3 ml of saturated aqueous sodium chloride solution was added and the reaction mixture was allowed to warm to room temperature. The mixture was subsequently diluted with about 80 ml of ethyl acetate, followed by the addition of anhydrous magnesium sulfate in an amount that completely incorporated the aqueous phase. After filtration, the filtrate was concentrated and the residue was purified by MPLC (silica gel; mobile phase: cyclohexane → cyclohexane / ethyl acetate 5: 1). This gave 1.37 g (44% of theory) of the title compound.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 7.52 (s, 1H), 7.36 (d, 1H), 7.29 (d, 1H), 7.18 (t, 1H), 3.66 (d, 2H), 1.44 (t, 1H), 0.91-0.84 (m, 4H).
GC / MS (Method 9, EIpos): R _t = 5.26 min, m / z = 226/228 [M] ⁺ .
Step 3: {[1- (3-Bromophenyl) cyclopropyl] methoxy} (triisopropyl) silane

At about −50 ° C., 1.55 ml (6.19 mmol) of triisopropylsilyl triflate was added to 1.34 g (5.90 mmol) of the compound from Example 50A / Step 2 and 948 mg (8.85 mmol) of 2,6-lutidine in anhydrous dichloromethane. Added to 25 ml. After 30 minutes, the cooling bath was removed and the mixture was stirred at room temperature for 1 hour. Subsequently, about 50 ml of water was added and the mixture was extracted with about 50 ml of ethyl acetate each time. The combined organic layer extracts were washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and finally the solvent was removed under reduced pressure. The resulting residue was purified by MPLC (silica gel, mobile phase: cyclohexane / ethyl acetate 5: 1). This gave 1.93 g (85% of theory) of the title compound.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 7.52 (s, 1H), 7.31 (d, 1H), 7.27 (d, 1H), 7.13 (t, 1H), 3.74 (s, 2H), 1.02 (m, 3H), 0.99 (d, 18H), 0.91-0.89 (m, 2H), 0.78-0.75 (m, 2H).
GC / MS (Method 9, EIpos): R _t = 6.87 min, m / z = 339/341 [M− ⁱ Pr] ⁺ .
Step 4: 3- (1-{[(Triisopropylsilyl) oxy] methyl} cyclopropyl) benzaldehyde

According to the procedure described in Example 48A / Step 2, 1.92 g (5.01 mmol) of the compound from Example 50A / Step 3 and the corresponding amount of the title compound 1.48 g from n-butyllithium and N, N-dimethylformamide. (88% of theory) was obtained by MPLC purification (silica gel, mobile phase: cyclohexane / ethyl acetate 10: 1).
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 10.00 (s, 1H), 7.89 (s, 1H), 7.72 (d, 1H), 7.65 (d, 1H), 7.43 (t, 1H), 3.79 (s, 2H), 1.01 (sept, 3H), 0.98 (d, 18H), 0.96-0.94 (m, 2H), 0.83-0.81 (m, 2H).
GC / MS (Method 9, EIpos): R _t = 7.00 min, m / z = 289 [M− ⁱ Pr] ⁺ .

実施例50A/工程2に記載した方法に準じて、実施例50A/工程4からの化合物1.40 g(4.21 mmol)および対応する量のリチウムアルミニウムハイドライドから、表題化合物1.10 g(理論値の78%)を得た。ここでは、生成物のクロマトグラフィー精製は省いた。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：7.38 (s、1H)、7.31-7.25 (m、2H)、7.20 (d、1H)、4.67 (d、2H)、3.79 (s、2H)、1.60 (t、1H)、1.02 (sept、3H)、1.00 (d、18H)、0.93-0.90 (m、2H)、0.77-0.75 (m、2H)。
GC/MS (方法9、EIpos)：R_t＝7.18分、m/z＝291 [M-ⁱPr]⁺。
工程6： 3-(1-{[(トリイソプロピルシリル)オキシ]メチル}シクロプロピル)ベンジル メタンスルホネート

実施例48A/工程4に記載した方法に準じて、実施例50A/工程5からの化合物820 mg(2.45 mmol)および対応する量のトリエチルアミンおよびメタンスルホン酸無水物から表題化合物1.01 g(理論値の100%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：7.42 (s、1H)、7.40 (d、1H)、7.32 (t、1H)、7.25 (d、1H)、5.21 (s、2H)、3.77 (s、2H)、2.91 (s、3H)、1.02 (sept、3H)、0.98 (d、18H)、0.93-0.91 (m、2H)、0.79-0.76 (m、2H)。
LC/MS (方法6、ESIpos)：R_t＝1.59分、m/z＝413 [M+H]⁺。
MS (DCI、NH₃)：m/z＝430 [M+NH₄]⁺。 Step 5: [3- (1-{[(Triisopropylsilyl) oxy] methyl} cyclopropyl) phenyl] methanol

According to the method described in Example 50A / Step 2, from 1.40 g (4.21 mmol) of the compound from Example 50A / Step 4 and the corresponding amount of lithium aluminum hydride, 1.10 g (78% of theory) of the title compound. Got. Here, chromatographic purification of the product was omitted.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 7.38 (s, 1H), 7.31-7.25 (m, 2H), 7.20 (d, 1H), 4.67 (d, 2H), 3.79 (s, 2H ), 1.60 (t, 1H), 1.02 (sept, 3H), 1.00 (d, 18H), 0.93-0.90 (m, 2H), 0.77-0.75 (m, 2H).
GC / MS (method _{9, EIpos): R t =} 7.18 min, m / z = 291 [M- i Pr] +.
Step 6: 3- (1-{[(Triisopropylsilyl) oxy] methyl} cyclopropyl) benzyl methanesulfonate

According to the method described in Example 48A / Step 4, 820 mg (2.45 mmol) of the compound from Example 50A / Step 5 and the corresponding amount of triethylamine and methanesulfonic anhydride from the title compound 1.01 g (theoretical 100%).
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 7.42 (s, 1H), 7.40 (d, 1H), 7.32 (t, 1H), 7.25 (d, 1H), 5.21 (s, 2H), 3.77 (s, 2H), 2.91 (s, 3H), 1.02 (sept, 3H), 0.98 (d, 18H), 0.93-0.91 (m, 2H), 0.79-0.76 (m, 2H).
LC / MS (Method _{6, ESIpos): R t =} 1.59 min, m / z = 413 [M + H] +.
_{MS (DCI, NH 3):} m / z = 430 [M + NH 4] +.

工程1： [1-(3-ブロモフェニル)シクロプロピル]-1,1-ジジュウテロメタノール

実施例50A/工程2に記載した方法に準じて、実施例50A/工程1からの化合物3.50 g(13.7 mmol)をリチウムアルミニウムデューテライド(リチウムアルミニウムハイドライドの代わりに)と反応させ、表題化合物1.39 g(理論値の44%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：7.51 (s、1H)、7.36 (d、1H)、7.29 (d、1H)、7.18 (t、1H)、1.43 (s、1H)、0.90-0.86 (m、4H)。
GC/MS (方法9、EIpos)：R_t＝5.26分、m/z＝228/230 [M]⁺。
工程2： ({[1-(3-ブロモフェニル)シクロプロピル]-1,1-ジジュウテロメチル}オキシ)(トリイソプロピル)シラン

実施例50A/工程3に記載した方法に準じて、実施例51A/工程1からの化合物1.38 g(6.02 mmol)をトリイソプロピルシリルトリフレートと反応させ、表題化合物2.03 g(理論値の88%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：7.52 (s、1H)、7.31 (d、1H)、7.27 (d、1H)、7.13 (t、1H)、1.03 (m、3H)、1.00 (d、18H)、0.91-0.88 (m、2H)、0.78-0.75 (m、2H)。
GC/MS (方法9、EIpos)：R_t＝6.86分、m/z＝341/343 [M-ⁱPr]⁺。 Example 51A
3- (1- {dideutero [(triisopropylsilyl) oxy] methyl} cyclopropyl) benzyl methanesulfonate

Step 1: [1- (3-Bromophenyl) cyclopropyl] -1,1-dideuteromethanol

According to the method described in Example 50A / Step 2, 3.50 g (13.7 mmol) of the compound from Example 50A / Step 1 was reacted with lithium aluminum deuteride (in place of lithium aluminum hydride) to give 1.39 g of the title compound. (44% of theory) was obtained.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 7.51 (s, 1H), 7.36 (d, 1H), 7.29 (d, 1H), 7.18 (t, 1H), 1.43 (s, 1H), 0.90-0.86 (m, 4H).
GC / MS (Method 9, EIpos): R _t = 5.26 min, m / z = 228/230 [M] ⁺ .
Step 2: ({[1- (3-Bromophenyl) cyclopropyl] -1,1-dideuteromethyl} oxy) (triisopropyl) silane

According to the method described in Example 50A / Step 3, 1.38 g (6.02 mmol) of the compound from Example 51A / Step 1 was reacted with triisopropylsilyl triflate to give 2.03 g (88% of theory) of the title compound. Got.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 7.52 (s, 1H), 7.31 (d, 1H), 7.27 (d, 1H), 7.13 (t, 1H), 1.03 (m, 3H), 1.00 (d, 18H), 0.91-0.88 (m, 2H), 0.78-0.75 (m, 2H).
GC / MS (Method 9, EIpos): R _t = 6.86 min, m / z = 341/343 [M− ⁱ Pr] ⁺ .

実施例48A/工程2に記載した方法に準じて、実施例51A/工程2からの化合物2.01 g(5.23 mmol)および対応する量のn-ブチルリチウムおよびN,N-ジメチルホルムアミドから表題化合物1.75 g(理論値の100%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：10.00 (s、1H)、7.89 (s、1H)、7.72 (d、1H)、7.64 (d、1H)、7.43 (t、1H)、1.01 (sept、3H)、0.98 (d、18H)、0.97-0.93 (m、2H)、0.83-0.81 (m、2H)。
GC/MS (方法9、EIpos)：R_t＝7.00分、m/z＝291 [M-ⁱPr]⁺。
工程4： [3-(1-{[(トリイソプロピルシリル)オキシ]ジジュウテロメチル}シクロプロピル)フェニル]メタノール

実施例50A/工程2に記載した方法に準じて、実施例51A/工程3からの化合物1.74 g(5.21 mmol)および対応する量のリチウムアルミニウムハイドライドから、表題化合物1.45 g(理論値の83%)を、MPLC精製により得た(シリカゲル、移動相：シクロヘキサン/酢酸エチル 10:1)。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：7.37 (s、1H)、7.30-7.25 (m、2H)、7.20 (d、1H)、4.67 (d、2H)、1.60 (t、1H)、1.02 (sept、3H)、1.00 (d、18H)、0.93-0.90 (m、2H)、0.77-0.75 (m、2H)。
GC/MS (方法9、EIpos)：R_t＝7.18分、m/z＝293 [M-ⁱPr]⁺。
工程5： 3-(1-{[(トリイソプロピルシリル)オキシ]ジジュウテロメチル}シクロプロピル)ベンジル メタンスルホネート

実施例48A/工程4に記載した方法に準じて、実施例51A/工程4からの化合物1.18 g(3.51 mmol)および対応する量のトリエチルアミンおよびメタンスルホン酸無水物から表題化合物1.46 g(理論値の100%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：7.42 (s、1H)、7.40 (d、1H)、7.32 (t、1H)、7.25 (d、1H)、5.21 (s、2H)、2.91 (s、3H)、1.02 (sept、3H)、0.98 (d、18H)、0.93-0.90 (m、2H)、0.79-0.76 (m、2H)。
LC/MS (方法6、ESIpos)：R_t＝1.59分、m/z＝415 [M+H]⁺。
MS (DCI、NH₃)：m/z＝432 [M+NH₄]⁺。 Step 3: 3- (1-{[(Triisopropylsilyl) oxy] dideuteromethyl} cyclopropyl) benzaldehyde

According to the method described in Example 48A / Step 2, the title compound 1.75 g (5.23 mmol) from Example 51A / Step 2 and the corresponding amounts of n-butyllithium and N, N-dimethylformamide. (100% of theory) was obtained.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 10.00 (s, 1H), 7.89 (s, 1H), 7.72 (d, 1H), 7.64 (d, 1H), 7.43 (t, 1H), 1.01 (sept, 3H), 0.98 (d, 18H), 0.97-0.93 (m, 2H), 0.83-0.81 (m, 2H).
GC / MS (Method 9, EIpos): R _t = 7.00 min, m / z = 291 [M− ⁱ Pr] ⁺ .
Step 4: [3- (1-{[(Triisopropylsilyl) oxy] dideuteromethyl} cyclopropyl) phenyl] methanol

According to the method described in Example 50A / Step 2, from 1.74 g (5.21 mmol) of the compound from Example 51A / Step 3 and the corresponding amount of lithium aluminum hydride, 1.45 g (83% of theory) of the title compound. Was obtained by MPLC purification (silica gel, mobile phase: cyclohexane / ethyl acetate 10: 1).
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 7.37 (s, 1H), 7.30-7.25 (m, 2H), 7.20 (d, 1H), 4.67 (d, 2H), 1.60 (t, 1H ), 1.02 (sept, 3H), 1.00 (d, 18H), 0.93-0.90 (m, 2H), 0.77-0.75 (m, 2H).
GC / MS (Method 9, EIpos): R _t = 7.18 min, m / z = 293 [M− ⁱ Pr] ⁺ .
Step 5: 3- (1-{[(Triisopropylsilyl) oxy] dideuteromethyl} cyclopropyl) benzyl methanesulfonate

According to the method described in Example 48A / Step 4, 1.46 g (3.51 mmol) of the compound from Example 51A / Step 4 and the corresponding amount of triethylamine and methanesulfonic anhydride to 1.46 g (theoretical 100%).
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 7.42 (s, 1H), 7.40 (d, 1H), 7.32 (t, 1H), 7.25 (d, 1H), 5.21 (s, 2H), 2.91 (s, 3H), 1.02 (sept, 3H), 0.98 (d, 18H), 0.93-0.90 (m, 2H), 0.79-0.76 (m, 2H).
LC / MS (Method _{6, ESIpos): R t =} 1.59 min, m / z = 415 [M + H] +.
_{MS (DCI, NH 3):} m / z = 432 [M + NH 4] +.

工程1： エチル ジフルオロ(3-メチルフェニル)アセテート

アルゴン下、室温で、エチルブロモ(ジフルオロ)アセテート25.0 g(123 mmol)および青銅(90/10 銅/錫合金)41.0 g(225 mmol)を、3-ヨードトルエン23.35 g(107 mmol)のDMSO溶液110 mlに加えた。続いて反応混合物を50℃で16時間撹拌した。室温に冷却した後、混合物を1 N 塩酸200 mlに注ぎ、酢酸エチル100 mlを加えた。存在したあらゆる固体を濾過し、濾液を各回50 mlの1 N 塩酸および50 mlの酢酸エチルで2回抽出した。合わせた有機相を各回200 mlの水および200 mlの飽和塩化ナトリウム溶液で1回洗浄し、硫酸ナトリウムで乾燥させ、濾過し、濃縮した。残渣は、カラムクロマトグラフィー(シリカゲル、移動相：イソヘキサン/酢酸エチル 98:2 → 90:10)により精製した。溶媒を除去して、表題化合物21.41 g(理論値の54%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：7.43-7.38 (m、2H)、7.37-7.21 (m、2H)、4.30 (quart、2H)、2.40 (s、3H)、1.31 (t、3H)。
GC/MS (方法9、EIpos)：R_t＝3.72分、m/z＝214 [M]⁺。
工程2： 2,2-ジフルオロ-2-(3-メチルフェニル)エタノール

アルゴン下、室温で、水素化ホウ素ナトリウム1.51 g(40 mmol)をゆっくりと実施例52A/工程1からの化合物8.57 g(40.0 mmol)のエタノール溶液70 mlに加えた。30分室温で攪拌した後、tert-ブチルメチルエーテル300 mlおよび1 N 塩酸300 mlをゆっくりと反応混合物に加えた。続いて水相をtert-ブチルメチルエーテル200 mlで1回再抽出した。合わせた有機相を硫酸ナトリウムで乾燥させ、濾過し、室温で、ほどよく減圧されたロータリーエバポレーターを用いて濃縮した。これにより標的化合物および残溶媒も含む残渣7.17 g(理論値の＞100%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：7.35-7.24 (m、3H)、3.96 (t、2H)、2.40 (s、3H)。
GC/MS (方法9、EIpos)：R_t＝3.32分、m/z＝172 [M]⁺。 Example 52A
2- [3- (Bromomethyl) phenyl] -2,2-difluoroethanol

Step 1: Ethyl difluoro (3-methylphenyl) acetate

At room temperature under argon, 25.0 g (123 mmol) of ethyl bromo (difluoro) acetate and 41.0 g (225 mmol) of bronze (90/10 copper / tin alloy) were mixed with DMSO solution of 23.35 g (107 mmol) of 3-iodotoluene. added to ml. The reaction mixture was subsequently stirred at 50 ° C. for 16 hours. After cooling to room temperature, the mixture was poured into 200 ml of 1N hydrochloric acid and 100 ml of ethyl acetate was added. Any solids present were filtered and the filtrate was extracted twice with 50 ml of 1 N hydrochloric acid and 50 ml of ethyl acetate each time. The combined organic phases were washed once with 200 ml water and 200 ml saturated sodium chloride solution each time, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel, mobile phase: isohexane / ethyl acetate 98: 2 → 90: 10). Removal of the solvent gave 21.41 g (54% of theory) of the title compound.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 7.43-7.38 (m, 2H), 7.37-7.21 (m, 2H), 4.30 (quart, 2H), 2.40 (s, 3H), 1.31 (t 3H).
GC / MS (Method 9, EIpos): R _t = 3.72 min, m / z = 214 [M] ⁺ .
Step 2: 2,2-difluoro-2- (3-methylphenyl) ethanol

At room temperature under argon, 1.51 g (40 mmol) of sodium borohydride was slowly added to 70 ml of an ethanol solution of the compound from Example 52A / Step 1 8.57 g (40.0 mmol). After stirring for 30 minutes at room temperature, 300 ml of tert-butyl methyl ether and 300 ml of 1 N hydrochloric acid were slowly added to the reaction mixture. Subsequently, the aqueous phase was re-extracted once with 200 ml of tert-butyl methyl ether. The combined organic phases were dried over sodium sulfate, filtered and concentrated using a rotary evaporator under moderate pressure at room temperature. This gave 7.17 g (> 100% of theory) of a residue which also contained the target compound and residual solvent.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 7.35-7.24 (m, 3H), 3.96 (t, 2H), 2.40 (s, 3H).
GC / MS (Method 9, EIpos): R _t = 3.32 min, m / z = 172 [M] ⁺ .

室温で、N-ブロモスクシンイミド7.47 g(42.0 mmol)および2,2’-アゾビス-2-メチルプロパンニトリル(AIBN)328 mg(2.00 mmol)を実施例52A/工程2からの化合物6.88 g(約40 mmol)のアセトニトリル溶液150 mlに加えた。混合物を浴槽温度80℃で6時間加熱した。室温に冷却した後、溶媒を除去しおよび残渣をペンタン100 mlおよび酢酸エチル50 mlの混合物で摩砕した。固体を吸引濾過し、ペンタンおよび酢酸エチルの2:1混合物15 mlで洗浄した。濾液および洗液を合わせ、各場合200 mlの飽和亜硫酸ナトリウム水溶液および200 mlの飽和塩化ナトリウム水溶液で1回洗浄し、硫酸ナトリウムで乾燥させ、濾過し、濃縮した。これにより表題化合物9.72 g(70%純度、理論値の68%)を得、これをこの形態でさらに反応させた。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：7.56-7.42 (m、4H)、4.51 (s、2H)、3.98 (m、2H)。
GC/MS (方法9、EIpos)：R_t＝5.06分、m/z＝250 [M]⁺。 Step 3: 2- [3- (Bromomethyl) phenyl] -2,2-difluoroethanol

At room temperature, 7.47 g (42.0 mmol) of N-bromosuccinimide and 328 mg (2.00 mmol) of 2,2′-azobis-2-methylpropanenitrile (AIBN) were combined with 6.88 g (about 40) of the compound from Example 52A / Step 2. mmol) in 150 ml of acetonitrile. The mixture was heated at a bath temperature of 80 ° C. for 6 hours. After cooling to room temperature, the solvent was removed and the residue was triturated with a mixture of 100 ml pentane and 50 ml ethyl acetate. The solid was filtered off with suction and washed with 15 ml of a 2: 1 mixture of pentane and ethyl acetate. The filtrate and washings were combined and washed once with 200 ml saturated aqueous sodium sulfite and 200 ml saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. This gave 9.72 g (70% purity, 68% of theory) of the title compound, which was further reacted in this form.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 7.56-7.42 (m, 4H), 4.51 (s, 2H), 3.98 (m, 2H).
GC / MS (Method 9, EIpos): R _t = 5.06 min, m / z = 250 [M] ⁺ .

N-ブロモスクシンイミド4.05 g(22.74 mmol)および2,2’-アゾビス-2-メチルプロパンニトリル(AIBN)178 mg(1.08 mmol)を実施例52A/工程1からの化合物4.64 g(21.7 mmol)のアセトニトリル溶液110 mlに加えた。混合物を浴槽温度80℃で2.5時間加熱した。室温に冷却した後、溶媒を除去し、残渣を30 mlの酢酸エチルおよび60 mlのペンタンで摩砕した。固体を濾過し、各回10 mlのペンタンで2回洗浄した。濾液を洗液と合わせ、10% チオ硫酸ナトリウム水溶液100 ml、水100 mlおよび飽和塩化ナトリウム溶液100 mlで洗浄し、硫酸ナトリウムで乾燥させ、濃縮した。これにより表題化合物5.56 g(70%純度、理論値の62%)を得て、これをこの形態でさらに反応させた。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：7.64 (s、1H)、7.58-7.28 (m、3H)、4.51 (s、2H)、4.31 (quart、2H)、1.31 (t、3H)。
GC/MS (方法9、EIpos)：R_t＝5.24分、m/z＝282 [M]⁺。 Example 53A
Ethyl [3- (bromomethyl) phenyl] (difluoro) acetate

4.05 g (22.74 mmol) of N-bromosuccinimide and 178 mg (1.08 mmol) of 2,2′-azobis-2-methylpropanenitrile (AIBN) were added to 4.64 g (21.7 mmol) of acetonitrile from Example 52A / Step 1. Added to 110 ml of solution. The mixture was heated at a bath temperature of 80 ° C. for 2.5 hours. After cooling to room temperature, the solvent was removed and the residue was triturated with 30 ml ethyl acetate and 60 ml pentane. The solid was filtered and washed twice with 10 ml pentane each time. The filtrate was combined with the washings, washed with 100 ml 10% aqueous sodium thiosulfate, 100 ml water and 100 ml saturated sodium chloride solution, dried over sodium sulfate and concentrated. This gave 5.56 g (70% purity, 62% of theory) of the title compound, which was further reacted in this form.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 7.64 (s, 1H), 7.58-7.28 (m, 3H), 4.51 (s, 2H), 4.31 (quart, 2H), 1.31 (t, 3H) ).
GC / MS (Method 9, EIpos): R _t = 5.24 min, m / z = 282 [M] ⁺ .

方法A:
実施例23Aからの化合物1.0 g(2.97 mmol)およびメチル 3-ブロモメチルベンゾエート0.82 g(3.56 mmol)無水THF30 mlに、カリウムtert-ブトキシド0.37 g(3.27 mmol)を、氷浴で冷却し、混合物を室温で一夜攪拌した。続いて水を加え、混合物を各回50 mlの酢酸エチルで3回抽出した。合わせた有機層抽出物を飽和塩化ナトリウム溶液で洗浄した。無水硫酸マグネシウムで乾燥させた後、混合物を濾過し、濾液をロータリーエバポレーターで濃縮した。残渣をシリカゲルクロマトグラフィーに付した(移動相：シクロヘキサン/酢酸エチル 4:1)。これにより表題化合物0.74 g(理論値の51%)を得た。
方法B:
0℃で、固体カリウムtert-ブトキシド3.67 g(32.7 mmol)を、実施例23Aからの化合物10.0 g(29.7 mmol)およびメチル 3-ブロモメチルベンゾエート8.86 g(38.6 mmol)の無水1,4-ジオキサン溶液300 mlに加え、続いて混合物を室温で15時間攪拌した。続いて水約600 mlを加え、混合物を各回約250 mlの酢酸エチルで3回抽出した。合わせた有機層抽出物を飽和塩化ナトリウム溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、濾過し、最後にロータリーエバポレーターにより溶媒を除去した。室温で、粗成生物をペンタン50 mlおよびジイソプロピルエーテル5 mlの混合物で30分摩砕した。固体を濾過し、濾液を捨て、残渣をもう1回上述のペンタン/ジイソプロピルエーテルで摩砕した。もう1回残渣を濾過し、高真空下乾燥させ、表題化合物11.0 g(理論値の72%、95%純度)を得た。
¹H NMR (400 MHz、DMSO-d₆、δ/ppm)：8.10 (d、2H)、7.91 (d、1H)、7.84 (s、1H)、7.77 (d、2H)、7.55 (t、1H)、7.47 (d、1H)、6.96 (s、1H)、5.61 (s、2H)、3.85 (s、3H)、2.34 (s、3H)、1.61 (s、6H)。
LC/MS (方法6、ESIpos)：R_t＝1.38分、m/z＝485 [M+H]⁺。 Example 54A
Methyl 3-[(5-methyl-3- {3- [4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenyl] -1,2,4-oxadiazole-5 -Il} -1H-pyrazol-1-yl) methyl] benzoate

Method A:
To 30 ml of anhydrous THF, 1.0 g (2.97 mmol) of the compound from Example 23A and 0.82 g (3.56 mmol) of methyl 3-bromomethylbenzoate, 0.37 g (3.27 mmol) of potassium tert-butoxide was cooled in an ice bath, and the mixture was cooled. Stir overnight at room temperature. Subsequently, water was added and the mixture was extracted three times with 50 ml of ethyl acetate each time. The combined organic layer extracts were washed with saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, the mixture was filtered and the filtrate was concentrated on a rotary evaporator. The residue was chromatographed on silica gel (mobile phase: cyclohexane / ethyl acetate 4: 1). This gave 0.74 g (51% of theory) of the title compound.
Method B:
At 0 ° C., 3.67 g (32.7 mmol) of solid potassium tert-butoxide was added to 10.0 g (29.7 mmol) of the compound from Example 23A and 8.86 g (38.6 mmol) of methyl 3-bromomethylbenzoate in anhydrous 1,4-dioxane. 300 ml was added followed by stirring the mixture at room temperature for 15 hours. Subsequently, about 600 ml of water was added and the mixture was extracted three times with about 250 ml of ethyl acetate each time. The combined organic layer extracts were washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and finally the solvent was removed by rotary evaporator. At room temperature, the crude product was triturated with a mixture of 50 ml pentane and 5 ml diisopropyl ether for 30 minutes. The solid was filtered, the filtrate was discarded and the residue was triturated once more with the above pentane / diisopropyl ether. The residue was filtered once more and dried under high vacuum to give 11.0 g (72% of theory, 95% purity) of the title compound.
¹ H NMR (400 MHz, DMSO-d ₆ , δ / ppm): 8.10 (d, 2H), 7.91 (d, 1H), 7.84 (s, 1H), 7.77 (d, 2H), 7.55 (t, 1H ), 7.47 (d, 1H), 6.96 (s, 1H), 5.61 (s, 2H), 3.85 (s, 3H), 2.34 (s, 3H), 1.61 (s, 6H).
LC / MS (Method _{6, ESIpos): R t =} 1.38 min, m / z = 485 [M + H] +.

-20℃で、1.3 Mイソプロピルマグネシウムクロライド/リチウムクロライド複合体THF溶液2.6 ml(3.42 mmol)を、実施例81Aからの化合物600 mg(1.14 mmol)の無水THF溶液25 mlに急速に加えた。4分後、反応混合物を約-40℃まで冷却し、続いてトリフルオロ酢酸無水物644 μl(4.56 mmol)を一度に加えた。反応混合物を-40℃で10分攪拌し、続いて飽和塩化ナトリウム水溶液1 mlを加え、混合物を室温まで温めた。続いて、水約100 mlを加え、混合物を各回約50 mlの酢酸エチルで3回抽出した。合わせた有機層抽出物を飽和塩化ナトリウム溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、濾過し、最後にロータリーエバポレーターにより溶媒を除去した。得られた残渣を最初にMPLC(シリカゲル約50 g、移動相：シクロヘキサン/酢酸エチル 4:1)で精製した。生成物分画を蒸発させた後、残渣をペンタン25 mlおよびジクロロメタン1 ml混合物で摩砕した。生成物を吸引濾過し、続いて高真空下乾燥させた。これにより表題化合物233 mg(理論値の39%、95%純度)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：8.25 (d、2H)、8.02 (d、1H)、7.90 (s、1H)、7.55 (t、1H)、7.50 (d、1H)、7.33 (d、2H)、6.86 (s、1H)、5.53 (s、2H)、2.32 (s、3H)。
LC/MS (方法6、ESIpos)：R_t＝1.22分、イオン化しない。 Example 55A
2,2,2-trifluoro-1- {3-[(5-methyl-3- {3- [4- (trifluoromethoxy) phenyl] -1,2,4-oxadiazol-5-yl} -1H-pyrazol-1-yl) methyl] phenyl} ethanone

At −20 ° C., 2.6 ml (3.42 mmol) of 1.3 M isopropylmagnesium chloride / lithium chloride complex THF solution was rapidly added to 25 ml of anhydrous THF solution of 600 mg (1.14 mmol) of the compound from Example 81A. After 4 minutes, the reaction mixture was cooled to about −40 ° C., followed by the addition of 644 μl (4.56 mmol) trifluoroacetic anhydride in one portion. The reaction mixture was stirred at −40 ° C. for 10 minutes, followed by addition of 1 ml of saturated aqueous sodium chloride solution and the mixture was allowed to warm to room temperature. Subsequently, about 100 ml of water was added and the mixture was extracted three times with about 50 ml of ethyl acetate each time. The combined organic layer extracts were washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and finally the solvent was removed by rotary evaporator. The resulting residue was first purified by MPLC (silica gel about 50 g, mobile phase: cyclohexane / ethyl acetate 4: 1). After evaporating the product fractions, the residue was triturated with a mixture of 25 ml pentane and 1 ml dichloromethane. The product was filtered off with suction and subsequently dried under high vacuum. This gave 233 mg (39% of theory, 95% purity) of the title compound.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 8.25 (d, 2H), 8.02 (d, 1H), 7.90 (s, 1H), 7.55 (t, 1H), 7.50 (d, 1H), 7.33 (d, 2H), 6.86 (s, 1H), 5.53 (s, 2H), 2.32 (s, 3H).
LC / MS (Method 6, ESIpos): R _t = 1.22 min, no ionization.

0℃で、固体カリウムtert-ブトキシド70 mg(0.620 mmol)を、実施例28Aからの化合物175 mg(0.564 mmol)およびメチル 3-ブロモメチルベンゾエート168 mg(0.733 mmol)の無水THF溶液6 mlに加え、続いて混合物を室温で4時間攪拌した。続いて反応を、2滴の水で終了させ、メタノールを、ちょうど全ての固体成分が溶解するまで加えた。続いてこの溶液を直接分取用HPLC(方法11)により精製した。これにより表題化合物208 mg(理論値の80%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：8.15 (d、2H)、7.98 (d、1H)、7.89 (s、1H)、7.42 (t、1H)、7.34 (d、2H)、7.33 (d、1H)、6.82 (s、1H)、5.50 (s、2H)、4.13-4.08 (m、2H)、3.91 (s、3H)、3.54 (dt、2H)、2.87-2.79 (m、1H)、2.28 (s、3H)、1.92-1.78 (m、4H)。
LC/MS (方法6、ESIpos)：R_t＝1.24分、m/z＝459 [M+H]⁺。 Example 56A
Methyl 3-[(5-methyl-3- {3- [4- (tetrahydro-2H-pyran-4-yl) phenyl] -1,2,4-oxadiazol-5-yl} -1H-pyrazole- 1-yl) methyl] benzoate

At 0 ° C., 70 mg (0.620 mmol) of solid potassium tert-butoxide is added to 6 ml of an anhydrous THF solution of 175 mg (0.564 mmol) of the compound from Example 28A and 168 mg (0.733 mmol) of methyl 3-bromomethylbenzoate. Subsequently, the mixture was stirred at room temperature for 4 hours. The reaction was then terminated with 2 drops of water and methanol was added until all the solid components were dissolved. This solution was then purified directly by preparative HPLC (Method 11). This gave 208 mg (80% of theory) of the title compound.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 8.15 (d, 2H), 7.98 (d, 1H), 7.89 (s, 1H), 7.42 (t, 1H), 7.34 (d, 2H), 7.33 (d, 1H), 6.82 (s, 1H), 5.50 (s, 2H), 4.13-4.08 (m, 2H), 3.91 (s, 3H), 3.54 (dt, 2H), 2.87-2.79 (m, 1H), 2.28 (s, 3H), 1.92-1.78 (m, 4H).
LC / MS (Method _{6, ESIpos): R t =} 1.24 min, m / z = 459 [M + H] +.

0℃で、固体カリウムtert-ブトキシド298 mg(2.66 mmol)を、実施例42Aからの化合物500 mg(1.77 mmol)およびメチル 3-ブロモメチルベンゾエート811 mg(3.54 mmol)の無水THF溶液15 mlに加え、続いて混合物を室温で15時間攪拌した。続いて水約45 mlを加え、混合物を各回約20 mlの酢酸エチルで3回抽出した。合わせた有機層抽出物を飽和塩化ナトリウム溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、濾過し、最後にロータリーエバポレーターにより溶媒を除去した。粗成生物のMPLC(シリカゲル、移動相：シクロヘキサン/酢酸エチル 5:1)により表題化合物493 mg(理論値の64%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：8.13 (d、2H)、7.98 (d、1H)、7.89 (s、1H)、7.50 (d、2H)、7.42 (t、1H)、7.33 (d、1H)、6.83 (s、1H)、5.50 (s、2H)、3.91 (s、3H)、2.28 (s、3H)、1.37 (s、9H)。
LC/MS (方法6、ESIpos)：R_t＝1.41分、m/z＝431 [M+H]⁺。 Example 57A
Methyl 3-({3- [3- (4-tert-butylphenyl) -1,2,4-oxadiazol-5-yl] -5-methyl-1H-pyrazol-1-yl} methyl) benzoate

At 0 ° C., 298 mg (2.66 mmol) of solid potassium tert-butoxide is added to 15 ml of an anhydrous THF solution of compound 500 mg (1.77 mmol) from Example 42A and 811 mg (3.54 mmol) of methyl 3-bromomethylbenzoate. Subsequently, the mixture was stirred at room temperature for 15 hours. Subsequently, about 45 ml of water was added and the mixture was extracted three times with about 20 ml of ethyl acetate each time. The combined organic layer extracts were washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and finally the solvent was removed by rotary evaporator. Crude product MPLC (silica gel, mobile phase: cyclohexane / ethyl acetate 5: 1) gave 493 mg (64% of theory) of the title compound.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 8.13 (d, 2H), 7.98 (d, 1H), 7.89 (s, 1H), 7.50 (d, 2H), 7.42 (t, 1H), 7.33 (d, 1H), 6.83 (s, 1H), 5.50 (s, 2H), 3.91 (s, 3H), 2.28 (s, 3H), 1.37 (s, 9H).
LC / MS (Method 6, ESIpos): R _t = 1.41 min, m / z = 431 [M + H] ⁺ .

実施例57Aに記載した方法に準じて、実施例40Aからの化合物325 mg(1.00 mmol)およびメチル 3-ブロモメチルベンゾエートから表題化合物206 mg(理論値の44%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：8.14 (d、2H)、7.98 (d、1H)、7.90 (s、1H)、7.42 (t、1H)、7.33 (d、1H)、7.30 (d、2H)、6.83 (s、1H)、5.50 (s、2H)、3.91 (s、3H)、3.55 (s、2H)、3.28 (s、3H)、2.43-2.28 (m、4H)、2.28 (s、3H)、2.15-2.03 (m、1H)、1.93-1.83 (m、1H)。
LC/MS (方法6、ESIpos)：R_t＝1.38分、m/z＝473 [M+H]⁺。 Example 58A
Methyl 3-{[3- (3- {4- [1- (methoxymethyl) cyclobutyl] phenyl} -1,2,4-oxadiazol-5-yl) -5-methyl-1H-pyrazole-1- Il] methyl} benzoate

According to the method described in Example 57A, 325 mg (1.00 mmol) of the compound from Example 40A and 206 mg (44% of theory) of the title compound were obtained from methyl 3-bromomethylbenzoate.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 8.14 (d, 2H), 7.98 (d, 1H), 7.90 (s, 1H), 7.42 (t, 1H), 7.33 (d, 1H), 7.30 (d, 2H), 6.83 (s, 1H), 5.50 (s, 2H), 3.91 (s, 3H), 3.55 (s, 2H), 3.28 (s, 3H), 2.43-2.28 (m, 4H) 2.28 (s, 3H), 2.15-2.03 (m, 1H), 1.93-1.83 (m, 1H).
LC / MS (Method _{6, ESIpos): R t =} 1.38 min, m / z = 473 [M + H] +.

実施例57Aに記載した方法に準じて、実施例31Aからの化合物350 mg(1.02 mmol)およびメチル 3-ブロモメチルベンゾエートから、表題化合物233 mg(理論値の46%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：7.99 (d、1H)、7.93 (dd、1H)、7.89 (s、1H)、7.83 (dd、1H)、7.43 (t、1H)、7.33 (d、1H)、7.23 (d、1H)、6.83 (s、1H)、5.51 (s、2H)、3.91 (s、3H)、3.67 (s、2H)、3.28 (s、3H)、2.48-2.40 (m、2H)、2.37-2.30 (m、2H)、2.28 (s、3H)、2.19-2.07 (m、1H)、1.94-1.85 (m、1H)。
LC/MS (方法6、ESIpos)：R_t＝1.42分、m/z＝491 [M+H]⁺。
実施例60A
メチル 3-{[3-(3-{4-[1-(メトキシメチル)シクロペンチル]フェニル}-1,2,4-オキサジアゾール-5-イル)-5-メチル-1H-ピラゾール-1-イル]メチル}ベンゾエート

実施例57Aに記載した方法に準じて、実施例33Aからの化合物350 mg(1.03 mmol)およびメチル 3-ブロモメチルベンゾエートから、表題化合物174 mg(理論値の35%)を得た。この場合、生成物はMPLCではなく分取用HPLCにより単離した(方法11)。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：8.12 (d、2H)、7.99 (d、1H)、7.90 (s、1H)、7.45 (d、2H)、7.42 (t、1H)、7.33 (d、1H)、6.83 (s、1H)、5.50 (s、2H)、3.91 (s、3H)、3.41 (s、2H)、3.23 (s、3H)、2.28 (s、3H)、2.07-2.00 (m、2H)、1.96-1.88 (m、2H)、1.79-1.70 (m、4H)。
LC/MS (方法6、ESIpos)：R_t＝1.43分、m/z＝487 [M+H]⁺。 Example 59A
Methyl 3-{[3- (3- {3-fluoro-4- [1- (methoxymethyl) cyclobutyl] phenyl} -1,2,4-oxadiazol-5-yl) -5-methyl-1H- Pyrazol-1-yl] methyl} benzoate

In a manner similar to that described in Example 57A, 350 mg (1.02 mmol) of the compound from Example 31A and 233 mg (46% of theory) of the title compound were obtained from methyl 3-bromomethylbenzoate.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 7.99 (d, 1H), 7.93 (dd, 1H), 7.89 (s, 1H), 7.83 (dd, 1H), 7.43 (t, 1H), 7.33 (d, 1H), 7.23 (d, 1H), 6.83 (s, 1H), 5.51 (s, 2H), 3.91 (s, 3H), 3.67 (s, 2H), 3.28 (s, 3H), 2.48 -2.40 (m, 2H), 2.37-2.30 (m, 2H), 2.28 (s, 3H), 2.19-2.07 (m, 1H), 1.94-1.85 (m, 1H).
LC / MS (Method 6, ESIpos): R _t = 1.42 min, m / z = 491 [M + H] ⁺ .
Example 60A
Methyl 3-{[3- (3- {4- [1- (methoxymethyl) cyclopentyl] phenyl} -1,2,4-oxadiazol-5-yl) -5-methyl-1H-pyrazole-1- Il] methyl} benzoate

In a manner similar to that described in Example 57A, 350 mg (1.03 mmol) of the compound from Example 33A and 174 mg (35% of theory) of the title compound were obtained from methyl 3-bromomethylbenzoate. In this case, the product was isolated by preparative HPLC rather than MPLC (Method 11).
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 8.12 (d, 2H), 7.99 (d, 1H), 7.90 (s, 1H), 7.45 (d, 2H), 7.42 (t, 1H), 7.33 (d, 1H), 6.83 (s, 1H), 5.50 (s, 2H), 3.91 (s, 3H), 3.41 (s, 2H), 3.23 (s, 3H), 2.28 (s, 3H), 2.07 -2.00 (m, 2H), 1.96-1.88 (m, 2H), 1.79-1.70 (m, 4H).
LC / MS (Method 6, ESIpos): R _t = 1.43 min, m / z = 487 [M + H] ⁺ .

実施例56Aに記載した方法に準じて、実施例32Aからの化合物150 mg(0.443 mmol)およびメチル 3-ブロモメチルベンゾエートから、表題化合物43 mg(理論値の19%)を得た。加えて、対応する安息香酸85 mg(理論値の41%)が単離された。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：8.13 (d、2H)、7.98 (d、1H)、7.90 (s、1H)、7.43 (t、1H)、7.33 (d、1H)、7.30 (d、2H)、6.83 (s、1H)、5.50 (s、2H)、3.91 (s、3H)、3.57 (s、2H)、3.38 (quart、2H)、2.40-2.30 (m、4H)、2.27 (s、3H)、2.15-2.03 (m、1H)、1.92-1.83 (m、1H)、1.09 (t、3H)。
LC/MS (方法6、ESIpos)：R_t＝1.45分、m/z＝487 [M+H]⁺。 Example 61A
Methyl 3-{[3- (3- {4- [1- (ethoxymethyl) cyclobutyl] phenyl} -1,2,4-oxadiazol-5-yl) -5-methyl-1H-pyrazole-1- Il] methyl} benzoate

According to the method described in Example 56A, 150 mg (0.443 mmol) of the compound from Example 32A and 43 mg (19% of theory) of the title compound were obtained from methyl 3-bromomethylbenzoate. In addition, the corresponding 85 mg (41% of theory) of benzoic acid was isolated.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 8.13 (d, 2H), 7.98 (d, 1H), 7.90 (s, 1H), 7.43 (t, 1H), 7.33 (d, 1H), 7.30 (d, 2H), 6.83 (s, 1H), 5.50 (s, 2H), 3.91 (s, 3H), 3.57 (s, 2H), 3.38 (quart, 2H), 2.40-2.30 (m, 4H) 2.27 (s, 3H), 2.15-2.03 (m, 1H), 1.92-1.83 (m, 1H), 1.09 (t, 3H).
LC / MS (Method _{6, ESIpos): R t =} 1.45 min, m / z = 487 [M + H] +.

0℃で、固体カリウムtert-ブトキシド112 mg(0.996 mmol)を、実施例36Aからの化合物250 mg(0.766 mmol)およびメチル 3-ブロモメチルベンゾエート211 mg(0.919 mmol)の無水1,4-ジオキサン溶液7.5 mlに加え、続いて混合物を室温で15時間攪拌した。続いて水約25 mlを加え、混合物を各回約20 mlの酢酸エチルで3回抽出した。合わせた有機層抽出物を飽和塩化ナトリウム溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、濾過し、最後にロータリーエバポレーターにより溶媒を除去した。粗成生物のMPLC(シリカゲル、移動相：シクロヘキサン/酢酸エチル 10:1 → 5:1)により表題化合物268 mg(理論値の74%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：8.27 (d、2H)、7.99 (d、1H)、7.89 (s、1H)、7.78 (d、2H)、7.43 (t、1H)、7.34 (d、1H)、6.83 (s、1H)、5.51 (s、2H)、3.91 (s、3H)、2.29 (s、3H)。
LC/MS (方法6、ESIpos)：R_t＝1.39分、m/z＝475 [M+H]⁺。 Example 62A
Methyl 3-{[5-methyl-3- (3- {4-[(trifluoromethyl) sulfanyl] phenyl} -1,2,4-oxadiazol-5-yl) -1H-pyrazol-1-yl ] Methyl} benzoate

At 0 ° C., solid potassium tert-butoxide 112 mg (0.996 mmol), 250 mg (0.766 mmol) of the compound from Example 36A and 211 mg (0.919 mmol) of methyl 3-bromomethylbenzoate in anhydrous 1,4-dioxane solution 7.5 ml was added and the mixture was subsequently stirred at room temperature for 15 hours. Subsequently, about 25 ml of water was added and the mixture was extracted three times with about 20 ml of ethyl acetate each time. The combined organic layer extracts were washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and finally the solvent was removed by rotary evaporator. Crude product MPLC (silica gel, mobile phase: cyclohexane / ethyl acetate 10: 1 → 5: 1) gave 268 mg (74% of theory) of the title compound.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 8.27 (d, 2H), 7.99 (d, 1H), 7.89 (s, 1H), 7.78 (d, 2H), 7.43 (t, 1H), 7.34 (d, 1H), 6.83 (s, 1H), 5.51 (s, 2H), 3.91 (s, 3H), 2.29 (s, 3H).
LC / MS (Method 6, ESIpos): R _t = 1.39 min, m / z = 475 [M + H] ⁺ .

実施例62に記載した方法に準じてA、実施例43Aからの化合物500 mg(1.52 mmol)およびメチル 3-ブロモメチルベンゾエートから表題化合物434 mg(理論値の60%)を得た。この場合、生成物はMPLCではなく分取用HPLCにより単離した(方法11)。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：8.12 (d、2H)、7.99 (d、1H)、7.90 (s、1H)、7.52 (d、2H)、7.42 (t、1H)、7.34 (d、1H)、6.84 (s、1H)、5.51 (s、2H)、4.00-3.87 (m、4H)、3.91 (s、3H)、2.29 (s、3H)、2.29-2.12 (m、2H)、1.98-1.92 (m、2H)。
LC/MS (方法6、ESIpos)：R_t＝1.23分、m/z＝477 [M+H]⁺。 Example 63A
Methyl 3-[(3- {3- [4- (4-Fluorotetrahydro-2H-pyran-4-yl) phenyl] -1,2,4-oxadiazol-5-yl} -5-methyl-1H -Pyrazol-1-yl) methyl] benzoate

The title compound 434 mg (60% of theory) was obtained from A, 500 mg (1.52 mmol) of the compound from Example 43A and methyl 3-bromomethylbenzoate according to the method described in Example 62. In this case, the product was isolated by preparative HPLC rather than MPLC (Method 11).
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 8.12 (d, 2H), 7.99 (d, 1H), 7.90 (s, 1H), 7.52 (d, 2H), 7.42 (t, 1H), 7.34 (d, 1H), 6.84 (s, 1H), 5.51 (s, 2H), 4.00-3.87 (m, 4H), 3.91 (s, 3H), 2.29 (s, 3H), 2.29-2.12 (m, 2H), 1.98-1.92 (m, 2H).
LC / MS (Method 6, ESIpos): R _t = 1.23 min, m / z = 477 [M + H] ⁺ .

実施例54A(方法A)に記載した方法に準じて、実施例22Aからの化合物300 mg(0.97 mmol)およびメチル 3-ブロモメチルベンゾエートから表題化合物430 mg(理論値の89%)を得た。
¹H NMR (400 MHz、DMSO-d₆、δ/ppm)：8.20 (d、2H)、7.91 (d、1H)、7.84 (s、1H)、7.59 (d、2H)、7.55 (t、1H)、7.48 (d、1H)、6.96 (s、1H)、5.61 (s、2H)、3.85 (s、3H)、2.34 (s、3H)。
LC/MS (方法4、ESIpos)：R_t＝1.54分、m/z＝459 [M+H]⁺。 Example 64A
Methyl 3-[(5-methyl-3- {3- [4- (trifluoromethoxy) phenyl] -1,2,4-oxadiazol-5-yl} -1H-pyrazol-1-yl) methyl] Benzoate

Following the method described in Example 54A (Method A), 300 mg (0.97 mmol) of the compound from Example 22A and 430 mg (89% of theory) of the title compound were obtained from methyl 3-bromomethylbenzoate.
¹ H NMR (400 MHz, DMSO-d ₆ , δ / ppm): 8.20 (d, 2H), 7.91 (d, 1H), 7.84 (s, 1H), 7.59 (d, 2H), 7.55 (t, 1H ), 7.48 (d, 1H), 6.96 (s, 1H), 5.61 (s, 2H), 3.85 (s, 3H), 2.34 (s, 3H).
LC / MS (Method 4, ESIpos): R _t = 1.54 min, m / z = 459 [M + H] ⁺ .

実施例54A(方法A)実施例44に記載した方法に準じてAからの化合物200 mg(0.67 mmol)およびメチル 3-ブロモメチルベンゾエートから表題化合物210 mg(理論値の68%)を得た。この場合、生成物を分取用HPLCにより単離した(方法17)。
¹H NMR (400 MHz、DMSO-d₆、δ/ppm)：8.12 (d、2H)、7.91 (d、1H)、7.84 (s、1H)、7.70 (d、2H)、7.55 (t、1H)、7.47 (d、1H)、6.96 (s、1H)、5.61 (s、2H)、3.85 (s、3H)、2.64 (t、2H)、2.59 (t、2H)、2.35 (s、3H)、2.07 (m、1H)、1.77 (m、1H)。
LC/MS (方法6、ESIpos)：R_t＝1.37分、m/z＝447 [M+H]⁺。 Example 65A
Methyl 3-[(3- {3- [4- (1-fluorocyclobutyl) phenyl] -1,2,4-oxadiazol-5-yl} -5-methyl-1H-pyrazol-1-yl) Methyl] benzoate

Example 54A (Method A) According to the method described in Example 44, 200 mg (0.67 mmol) of the compound from A and 210 mg (68% of theory) of the title compound were obtained from methyl 3-bromomethylbenzoate. In this case, the product was isolated by preparative HPLC (Method 17).
¹ H NMR (400 MHz, DMSO-d ₆ , δ / ppm): 8.12 (d, 2H), 7.91 (d, 1H), 7.84 (s, 1H), 7.70 (d, 2H), 7.55 (t, 1H ), 7.47 (d, 1H), 6.96 (s, 1H), 5.61 (s, 2H), 3.85 (s, 3H), 2.64 (t, 2H), 2.59 (t, 2H), 2.35 (s, 3H) 2.07 (m, 1H), 1.77 (m, 1H).
LC / MS (Method 6, ESIpos): R _t = 1.37 min, m / z = 447 [M + H] ⁺ .

0℃で、カリウムtert-ブトキシド103 mg(0.92 mmol)を、実施例42Aからの化合物200 mg(0.71 mmol)および実施例47Aからの化合物232 mg(0.78 mmol、純度95%)のTHF溶液5 mlに加えた。続いて反応混合物を室温で1時間攪拌した。酢酸エチルで希釈した後、混合物を水で1回洗浄し、水相を酢酸エチルで1回再抽出した。合わせた有機相を飽和塩化ナトリウム溶液で1回洗浄し、硫酸マグネシウムで乾燥させ、濾過し、濃縮した。これにより表題化合物350 mg(80%純度、理論値の84%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：8.13 (d、2H)、7.51 (d、2H)、7.30-7.24 (m、1H)、7.18 (d、1H)、7.10 (s、1H)、7.01 (d、1H)、6.81 (s、1H)、5.44 (s、2H)、2.26 (s、3H)、2.01 (s、3H)、1.36 (s、9H)、1.31-1.24 (m、2H)、1.21-1.15 (m、2H)。
LC/MS (方法4、ESIpos)：R_t＝1.64分、m/z＝471 [M+H]⁺。 Example 66A
1- [3-({3- [3- (4-tert-butylphenyl) -1,2,4-oxadiazol-5-yl] -5-methyl-1H-pyrazol-1-yl} methyl) Phenyl] cyclopropyl acetate

At 0 ° C., potassium tert-butoxide 103 mg (0.92 mmol) was added to a solution of compound 200 mg (0.71 mmol) from example 42A and compound 232 mg (0.78 mmol, purity 95%) from example 42A in 5 ml THF. Added to. The reaction mixture was subsequently stirred at room temperature for 1 hour. After dilution with ethyl acetate, the mixture was washed once with water and the aqueous phase was re-extracted once with ethyl acetate. The combined organic phases were washed once with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. This gave 350 mg (80% purity, 84% of theory) of the title compound.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 8.13 (d, 2H), 7.51 (d, 2H), 7.30-7.24 (m, 1H), 7.18 (d, 1H), 7.10 (s, 1H ), 7.01 (d, 1H), 6.81 (s, 1H), 5.44 (s, 2H), 2.26 (s, 3H), 2.01 (s, 3H), 1.36 (s, 9H), 1.31-1.24 (m, 2H), 1.21-1.15 (m, 2H).
LC / MS (method _{4, ESIpos): R t =} 1.64 min, m / z = 471 [M + H] +.

0℃で、カリウムtert-ブトキシド65 mg(0.58 mmol)を、実施例28Aからの化合物139 mg(0.45 mmol)および実施例47Aからの化合物147 mg(0.49 mmol、純度95%)のTHF溶液3.5 mlに加えた。室温に戻し、混合物を室温でさらに1時間攪拌した。酢酸エチルで希釈した後、混合物を水で1回洗浄し、水相は酢酸エチルで再抽出した。合わせた有機相を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、濾過し、濃縮した。残渣をカラムクロマトグラフィー(シリカゲル、移動相：シクロヘキサン/酢酸エチル 7:3)により精製した。溶媒を除去し、表題化合物164 mg(79%純度、理論値の58%)を得た。
LC/MS (方法6、ESIpos)：R_t＝1.27分、m/z＝499 [M+H]⁺。 Example 67A
1- {3-[(5-Methyl-3- {3- [4- (tetrahydro-2H-pyran-4-yl) phenyl] -1,2,4-oxadiazol-5-yl} -1H- Pyrazol-1-yl) methyl] phenyl} cyclopropyl acetate

At 0 ° C., 65 mg (0.58 mmol) of potassium tert-butoxide was added to a solution of 139 mg (0.45 mmol) of the compound from Example 28A and 147 mg (0.49 mmol, purity 95%) of the compound from Example 47A in 3.5 ml of THF. Added to. The mixture was allowed to return to room temperature, and the mixture was further stirred at room temperature for 1 hour. After dilution with ethyl acetate, the mixture was washed once with water and the aqueous phase was re-extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel, mobile phase: cyclohexane / ethyl acetate 7: 3). The solvent was removed to give 164 mg (79% purity, 58% of theory) of the title compound.
LC / MS (Method _{6, ESIpos): R t =} 1.27 min, m / z = 499 [M + H] +.

実施例67Aに記載した方法に準じて、実施例26Aからの化合物211 mg(0.71 mmol)および実施例47Aからの化合物232 mg(0.78 mmol、純度95%)から表題化合物231 mg(90%純度、理論値の60%)を得た。ここでは、移動相としてシクロヘキサン/酢酸エチル 4:1を用いてクロマトグラフィーによる生成物の精製を行った。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：8.17 (d、2H)、7.64 (d、2H)、7.30-7.26 (m、1H)、7.18 (d、1H)、7.10 (s、1H)、7.01 (d、1H)、6.81 (s、1H)、5.44 (s、2H)、2.26 (s、3H)、2.01 (s、3H)、1.31-1.15 (m、4H)、0.31 (s、9H)。
LC/MS (方法6、ESIpos)：R_t＝1.49分、m/z＝487 [M+H]⁺。 Example 68A
1- {3-[(5-Methyl-3- {3- [4- (trimethylsilyl) phenyl] -1,2,4-oxadiazol-5-yl} -1H-pyrazol-1-yl) methyl] Phenyl} cyclopropyl acetate

According to the method described in Example 67A, 211 mg (0.71 mmol) of compound from Example 26A and 232 mg (0.78 mmol, purity 95%) of compound from Example 47A to 231 mg (90% purity, 60% of theory) was obtained. Here, the product was purified by chromatography using cyclohexane / ethyl acetate 4: 1 as mobile phase.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 8.17 (d, 2H), 7.64 (d, 2H), 7.30-7.26 (m, 1H), 7.18 (d, 1H), 7.10 (s, 1H ), 7.01 (d, 1H), 6.81 (s, 1H), 5.44 (s, 2H), 2.26 (s, 3H), 2.01 (s, 3H), 1.31-1.15 (m, 4H), 0.31 (s, 9H).
LC / MS (Method _{6, ESIpos): R t =} 1.49 min, m / z = 487 [M + H] +.

実施例67Aに記載した方法に準じて、実施例23Aからの化合物238 mg(0.71 mmol)および実施例47Aからの化合物232 mg(0.78 mmol、純度95%)から、表題化合物286 mg(88%純度、理論値の68%)を得た。ここでは、移動相としてシクロヘキサン/酢酸エチル 3:1を用いて、クロマトグラフィーによる生成物の精製を行った。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：8.20 (d、2H)、7.62 (d、2H)、7.30-7.26 (m、1H)、7.21-7.17 (d、1H)、7.10 (s、1H)、7.01 (d、1H)、6.82 (s、1H)、5.44 (s、2H)、2.27 (s、3H)、2.01 (s、3H)、1.62 (s、6H)、1.33-1.15 (m、4H)。
LC/MS (方法6、ESIpos)：R_t＝1.40分、m/z＝525 [M+H]⁺。 Example 69A
1- {3-[(5-Methyl-3- {3- [4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenyl] -1,2,4-oxadiazole -5-yl} -1H-pyrazol-1-yl) methyl] phenyl} cyclopropyl acetate

According to the method described in Example 67A, from the compound 238 mg (0.71 mmol) from Example 23A and the compound 232 mg (0.78 mmol, purity 95%) from Example 47A, the title compound 286 mg (88% purity). 68% of the theoretical value). Here, the product was purified by chromatography using cyclohexane / ethyl acetate 3: 1 as the mobile phase.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 8.20 (d, 2H), 7.62 (d, 2H), 7.30-7.26 (m, 1H), 7.21-7.17 (d, 1H), 7.10 (s , 1H), 7.01 (d, 1H), 6.82 (s, 1H), 5.44 (s, 2H), 2.27 (s, 3H), 2.01 (s, 3H), 1.62 (s, 6H), 1.33-1.15 ( m, 4H).
LC / MS (Method _{6, ESIpos): R t =} 1.40 min, m / z = 525 [M + H] +.

実施例66Aに記載した方法に準じて、実施例41Aからの化合物190 mg(0.71 mmol)および実施例47Aからの化合物232 mg(0.78 mmol、純度95%)から、表題化合物359 mg(69%純度、理論値の76%)を得た。
LC/MS (方法6、ESIpos)：R_t＝1.41分、m/z＝457 [M+H]⁺。 Example 70A
1- [3-({3- [3- (4-Isopropylphenyl) -1,2,4-oxadiazol-5-yl] -5-methyl-1H-pyrazol-1-yl} methyl) phenyl] Cyclopropyl acetate

According to the method described in Example 66A, from the compound 190 mg (0.71 mmol) from Example 41A and the compound 232 mg (0.78 mmol, purity 95%) from Example 47A, the title compound 359 mg (69% purity) was obtained. 76% of the theoretical value).
LC / MS (Method 6, ESIpos): R _t = 1.41 min, m / z = 457 [M + H] ⁺ .

実施例66Aに記載した方法に準じて、実施例39Aからの化合物200 mg(0.71 mmol)および実施例47Aからの化合物232 mg(0.78 mmol、純度95%)から、表題化合物381 mg(72%純度、理論値の82%)を得た。
LC/MS (方法6、ESIpos)：R_t＝1.47分、m/z＝471 [M+H]⁺。 Example 71A
1- [3-({3- [3- (4-Isobutylphenyl) -1,2,4-oxadiazol-5-yl] -5-methyl-1H-pyrazol-1-yl} methyl) phenyl] Cyclopropyl acetate

According to the method described in Example 66A, from the compound 200 mg (0.71 mmol) from Example 39A and the compound 232 mg (0.78 mmol, purity 95%) from Example 47A, the title compound 381 mg (72% purity). 82% of the theoretical value).
LC / MS (Method 6, ESIpos): R _t = 1.47 min, m / z = 471 [M + H] ⁺ .

実施例66Aに記載した方法に準じて、実施例30Aからの化合物237 mg(0.71 mmol)および実施例47Aからの化合物232 mg(0.78 mmol、純度95%)から、表題化合物408 mg(70%純度、理論値の77%)を得た。
LC/MS (方法6、ESIpos)：R_t＝1.40分、m/z＝523 [M+H]⁺。 Example 72A
1- (3-{[5-methyl-3- (3- {4- [1- (trifluoromethyl) cyclopropyl] phenyl} -1,2,4-oxadiazol-5-yl) -1H- Pyrazol-1-yl] methyl} phenyl) cyclopropyl acetate

According to the method described in Example 66A, from the compound 237 mg (0.71 mmol) from Example 30A and the compound 232 mg (0.78 mmol, purity 95%) from Example 47A, the title compound 408 mg (70% purity). Obtained 77% of the theoretical value).
LC / MS (Method _{6, ESIpos): R t =} 1.40 min, m / z = 523 [M + H] +.

実施例66Aに記載した方法に準じて、実施例38Aからの化合物275 mg(0.71 mmol)および実施例47Aからの化合物232 mg(0.78 mmol、純度95%)から、表題化合物423 mg(75%純度、理論値の75%)を得た。この場合、反応時間は室温で4時間であった。
LC/MS (方法6、ESIpos)：R_t＝1.39分、m/z＝541 [M+H]⁺。 Example 73A
1- {3-[(5-Methyl-3- {3- [4- (pentafluoro-λ ⁶ -sulfanyl) phenyl] -1,2,4-oxadiazol-5-yl} -1H-pyrazole- 1-yl) methyl] phenyl} cyclopropyl acetate

According to the method described in Example 66A, from the compound 275 mg (0.71 mmol) from Example 38A and the compound 232 mg (0.78 mmol, purity 95%) from Example 47A, the title compound 423 mg (75% purity). 75% of the theoretical value). In this case, the reaction time was 4 hours at room temperature.
LC / MS (Method _{6, ESIpos): R t =} 1.39 min, m / z = 541 [M + H] +.

実施例66Aに記載した方法に準じて、実施例24Aからの化合物223 mg(0.78 mmol)および実施例47Aからの化合物255 mg(0.86 mmol、純度95%)から、表題化合物406 mg(75%純度、理論値の82%)を得た。この場合、反応時間は室温で4時間であった。
LC/MS (方法6、ESIpos)：R_t＝1.34分、m/z＝475 [M+H]⁺。 Example 74A
1- {3-[(3- {3- [4- (2-fluoropropan-2-yl) phenyl] -1,2,4-oxadiazol-5-yl} -5-methyl-1H-pyrazole -1-yl) methyl] phenyl} cyclopropyl acetate

According to the method described in Example 66A, from the compound 223 mg (0.78 mmol) from Example 24A and 255 mg (0.86 mmol, purity 95%) from Example 47A, the title compound 406 mg (75% purity). 82% of the theoretical value). In this case, the reaction time was 4 hours at room temperature.
LC / MS (Method _{6, ESIpos): R t =} 1.34 min, m / z = 475 [M + H] +.

実施例66Aに記載した方法に準じて、実施例27Aからの化合物230 mg(0.78 mmol)および実施例47Aからの化合物255 mg(0.86 mmol、純度95%)から、表題化合物375 mg(74%純度、理論値の74%)を得た。この場合、反応時間は室温で16時間であった。
LC/MS (方法6、ESIpos)：R_t＝1.55分、m/z＝483 [M+H]⁺。 Example 75A
1- {3-[(5-methyl-3- {3- [4- (trifluoromethyl) phenyl] -1,2,4-oxadiazol-5-yl} -1H-pyrazol-1-yl) Methyl] phenyl} cyclopropylacetate

According to the method described in Example 66A, from the compound 230 mg (0.78 mmol) from Example 27A and the compound 255 mg (0.86 mmol, purity 95%) from Example 47A, the title compound 375 mg (74% purity). 74% of the theoretical value). In this case, the reaction time was 16 hours at room temperature.
LC / MS (Method 6, ESIpos): R _t = 1.55 min, m / z = 483 [M + H] ⁺ .

実施例66Aに記載した方法に準じて、実施例27Aからの化合物256 mg(0.78 mmol)および実施例47Aからの化合物255 mg(0.86 mmol、純度95%)から、表題化合物415 mg(65%純度、理論値の67%)を得た。この場合、反応時間は室温で16時間であった。
LC/MS (方法4、ESIpos)：R_t＝1.44分、m/z＝517 [M+H]⁺。 Example 76A
1- {3-[(3- {3- [4- (4-Fluorotetrahydro-2H-pyran-4-yl) phenyl] -1,2,4-oxadiazol-5-yl} -5-methyl -1H-pyrazol-1-yl) methyl] phenyl} cyclopropyl acetate

According to the method described in Example 66A, from the compound 256 mg (0.78 mmol) from Example 27A and 255 mg (0.86 mmol, purity 95%) from Example 47A, the title compound 415 mg (65% purity). 67% of the theoretical value) was obtained. In this case, the reaction time was 16 hours at room temperature.
LC / MS (method _{4, ESIpos): R t =} 1.44 min, m / z = 517 [M + H] +.

実施例66Aに記載した方法に準じて、実施例37Aからの化合物195 mg(0.63 mmol)および実施例47Aからの化合物207 mg(0.70 mmol、純度95%)から、表題化合物318 mg(42%純度、理論値の43%)を得た。この場合、反応時間は室温で4時間であった。
LC/MS (方法6、ESIpos)：R_t＝1.59分、m/z＝497 [M+H]⁺。 Example 77A
1- [3-({3- [3- (4-cyclohexylphenyl) -1,2,4-oxadiazol-5-yl] -5-methyl-1H-pyrazol-1-yl} methyl) phenyl] Cyclopropyl acetate

According to the method described in Example 66A, from the compound 195 mg (0.63 mmol) from Example 37A and the compound 207 mg (0.70 mmol, purity 95%) from Example 47A, the title compound 318 mg (42% purity) 43% of the theoretical value). In this case, the reaction time was 4 hours at room temperature.
LC / MS (Method _{6, ESIpos): R t =} 1.59 min, m / z = 497 [M + H] +.

実施例66Aに記載した方法に準じて、実施例36Aからの化合物254 mg(0.78 mmol)および実施例47Aからの化合物255 mg(0.86 mmol、純度95%)から、表題化合物396 mg(72%純度、理論値の70%)を得た。この場合、反応時間は室温で4時間であった。
LC/MS (方法6、ESIpos)：R_t＝1.25分、m/z＝441 [M+H]⁺。 Example 78A
1- (3-{[5-methyl-3- (3- {4-[(trifluoromethyl) sulfanyl] phenyl} -1,2,4-oxadiazol-5-yl) -1H-pyrazole-1 -Il] methyl} phenyl) cyclopropyl acetate

According to the method described in Example 66A, from the compound 254 mg (0.78 mmol) from Example 36A and the compound 255 mg (0.86 mmol, purity 95%) from Example 47A, the title compound 396 mg (72% purity). 70% of the theoretical value). In this case, the reaction time was 4 hours at room temperature.
LC / MS (Method 6, ESIpos): R _t = 1.25 min, m / z = 441 [M + H] ⁺ .

0℃で、カリウムtert-ブトキシド113 mg(1.01 mmol)を、実施例36Aからの化合物233 mg(0.78 mmol)および実施例47Aからの化合物255 mg(0.86 mmol、純度95%)のTHF溶液5.5 mlに加えた。室温に戻し、混合物を室温でさらに4時間攪拌した。酢酸エチルで希釈した後、混合物を水で1回洗浄し、水相をで酢酸エチル1回再抽出した。合わせた有機相を飽和塩化ナトリウム溶液で1回洗浄し、硫酸マグネシウムで乾燥させ、濾過し、濃縮した。残渣は分取用HPLC(方法15)により精製した。きれいな生成物を含有する分画を合わせ、飽和重炭酸ナトリウム水溶液を加え、混合物を水相の残容積まで再濃縮した。混合物を酢酸エチルで2回抽出した。合わせた有機相を硫酸マグネシウムで乾燥させ、濾過し、濃縮した。これにより表題化合物187 mg(62%純度、理論値の30%)を得た。
LC/MS (方法6、ESIpos)：R_t＝1.37分、m/z＝487 [M+H]⁺。 Example 79A
1- {3-[(3- {3- [4- (1-Fluorocyclobutyl) phenyl] -1,2,4-oxadiazol-5-yl} -5-methyl-1H-pyrazole-1- Yl) methyl] phenyl} cyclopropylacetate

At 0 ° C., potassium tert-butoxide 113 mg (1.01 mmol) was added to a THF solution 5.5 ml of compound 233 mg (0.78 mmol) from example 36A and 255 mg (0.86 mmol, purity 95%) from example 47A. Added to. The mixture was allowed to return to room temperature, and the mixture was further stirred at room temperature for 4 hours. After dilution with ethyl acetate, the mixture was washed once with water and the aqueous phase was re-extracted once with ethyl acetate. The combined organic phases were washed once with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (Method 15). Fractions containing clean product were combined, saturated aqueous sodium bicarbonate was added and the mixture was reconcentrated to the remaining volume of the aqueous phase. The mixture was extracted twice with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated. This gave 187 mg (62% purity, 30% of theory) of the title compound.
LC / MS (Method _{6, ESIpos): R t =} 1.37 min, m / z = 487 [M + H] +.

実施例66Aに記載した方法に準じて、実施例45Aからの化合物200 mg(0.54 mmol、純度95%)および実施例47Aからの化合物176 mg(0.59 mmol、純度96%)から、表題化合物192 mg(69%純度、理論値の46%)を得た。この場合、反応時間は室温で4時間であった。粗成生物を、方法15に従い、分取用HPLCにより精製した。
LC/MS (方法6、ESIpos)：R_t＝1.45分、m/z＝543 [M+H]⁺。 Example 80A
1- {3-[(3- {3- [3-Fluoro-4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenyl] -1,2,4-oxadiazole -5-yl} -5-methyl-1H-pyrazol-1-yl) methyl] phenyl} cyclopropyl acetate

According to the method described in Example 66A, from the compound from Example 45A 200 mg (0.54 mmol, purity 95%) and the compound from Example 47A 176 mg (0.59 mmol, purity 96%), the title compound 192 mg (69% purity, 46% of theory) was obtained. In this case, the reaction time was 4 hours at room temperature. The crude product was purified by preparative HPLC according to Method 15.
LC / MS (Method _{6, ESIpos): R t =} 1.45 min, m / z = 543 [M + H] +.

実施例54A(方法A)に記載した方法に準じて、実施例22Aからの化合物500 mg(1.61 mmol)および3-ヨード臭化ベンジル570 mg(1.93 mmol)を反応させ、表題化合物690 mg(理論値の78%)を得た。ここでは、生成物を分取用HPLC(方法17)により単離した。
¹H NMR (400 MHz、DMSO-d₆、δ/ppm)：8.20 (d、2H)、7.69 (m、1H)、7.63 (s、1H)、7.59 (d、2H)、7.18 (d、2H)、6.94 (s、1H)、5.49 (s、2H)、2.35 (s、3H)。
LC/MS (方法2、ESIpos)：R_t＝3.05分、m/z＝527 [M+H]⁺。 Example 81A
5- [1- (3-Iodobenzyl) -5-methyl-1H-pyrazol-3-yl] -3- [4- (trifluoromethoxy) phenyl] -1,2,4-oxadiazole

According to the method described in Example 54A (Method A), 500 mg (1.61 mmol) of the compound from Example 22A and 570 mg (1.93 mmol) of 3-iodobenzyl bromide were reacted to give 690 mg (theoretical) 78% of the value) was obtained. Here, the product was isolated by preparative HPLC (Method 17).
¹ H NMR (400 MHz, DMSO-d ₆ , δ / ppm): 8.20 (d, 2H), 7.69 (m, 1H), 7.63 (s, 1H), 7.59 (d, 2H), 7.18 (d, 2H ), 6.94 (s, 1H), 5.49 (s, 2H), 2.35 (s, 3H).
LC / MS (Method 2, ESIpos): R _t = 3.05 min, m / z = 527 [M + H] ⁺ .

実施例54A(方法A)に記載した方法に準じて、実施例23Aからの化合物0.50 g(1.49 mmol)およびエチル [3-(ブロモメチル)フェニル]アセテート [lit.S.R.Kasibhatla et al.、J.Med.Chem.2000、43 (8)、1508-1518] 0.50 g(1.93 mmol)から、表題化合物0.47 g(理論値の62%)を得た。ここでは、生成物を分取用HPLC(方法17)により単離した 。
¹H NMR (400 MHz、DMSO-d₆、δ/ppm)：8.09 (d、2H)、7.77 (d、2H)、7.33 (t、1H)、7.21 (d、1H)、7.10 (d、2H)、6.94 (s、1H)、5.50 (s、2H)、4.04 (quart、2H)、3.65 (s、2H)、2.33 (s、3H)、1.61 (s、6H)、1.14 (t、3H)。
LC/MS (方法6、ESIpos)：R_t＝1.43分、m/z＝513 [M+H]⁺。 Example 82A
Ethyl {3-[(5-methyl-3- {3- [4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenyl] -1,2,4-oxadiazole- 5-yl} -1H-pyrazol-1-yl) methyl] phenyl} acetate

In analogy to the method described in Example 54A (Method A), 0.50 g (1.49 mmol) of the compound from Example 23A and ethyl [3- (bromomethyl) phenyl] acetate [lit.SRKasibhatla et al., J. Med. Chem. 2000, 43 (8), 1508-1518] From 0.50 g (1.93 mmol), 0.47 g (62% of theory) of the title compound was obtained. Here, the product was isolated by preparative HPLC (Method 17).
¹ H NMR (400 MHz, DMSO-d ₆ , δ / ppm): 8.09 (d, 2H), 7.77 (d, 2H), 7.33 (t, 1H), 7.21 (d, 1H), 7.10 (d, 2H ), 6.94 (s, 1H), 5.50 (s, 2H), 4.04 (quart, 2H), 3.65 (s, 2H), 2.33 (s, 3H), 1.61 (s, 6H), 1.14 (t, 3H) .
LC / MS (Method 6, ESIpos): R _t = 1.43 min, m / z = 513 [M + H] ⁺ .

カリウムtert-ブトキシド15.5 g(138 mmol)を実施例22Aからの化合物39.0 g(126 mmol)の無水THF溶液1リットルに加えた。続いて、約5℃(氷/水浴)で、エチル [3-(ブロモメチル)フェニル]アセテート [lit.：S.R.Kasibhatla et al.、J.Med.Chem.2000、43 (8)、1508-1518] 38.8 g(151 mmol)の無水THF溶液700 mlを滴下した。反応混合物を室温で40時間攪拌した後、混合物を1リットルの酢酸エチルで希釈した。約100 gの無水硫酸マグネシウムを加え、不均一混合物を激しく攪拌した。続いて混合物を濾過し、ロータリーエバポレーターにより濾液から溶媒を除去した。粗成生物を移動相としてシクロヘキサン/酢酸エチル 勾配 [9:1(5リットル)→ 8:2(4リットル)→ 7:3(4リットル)→ 6:4(4リットル)→ 1:1(4リットル)]を用いたシリカゲル(粒子サイズ0.06-0.2 mm)約2 kgで吸引濾過により精製した。これにより表題化合物33.8 g(理論値の48%、87%純度)を得た。
¹H NMR (400 MHz、DMSO-d₆、δ/ppm)：8.20 (d、2H)、7.60 (d、2H)、7.33 (t、1H)、7.21 (d、1H)、7.11 (s、1H)、7.10 (d、1H)、6.93 (s、1H)、5.49 (s、2H)、4.05 (quart、2H)、3.65 (s、2H)、2.34 (s、3H)、1.14 (t、3H)。
LC/MS (方法6、ESIpos)：R_t＝1.37分、m/z＝487 [M+H]⁺。 Example 83A
Ethyl {3-[(5-methyl-3- {3- [4- (trifluoromethoxy) phenyl] -1,2,4-oxadiazol-5-yl} -1H-pyrazol-1-yl) methyl ] Phenyl} acetate

15.5 g (138 mmol) of potassium tert-butoxide was added to 1 liter of an anhydrous THF solution of 39.0 g (126 mmol) of the compound from Example 22A. Subsequently, at about 5 ° C. (ice / water bath), ethyl [3- (bromomethyl) phenyl] acetate [lit .: SRKasibhatla et al., J. Med. Chem. 2000, 43 (8), 1508-1518] 38.8 700 ml of anhydrous THF solution of g (151 mmol) was added dropwise. After the reaction mixture was stirred at room temperature for 40 hours, the mixture was diluted with 1 liter of ethyl acetate. About 100 g of anhydrous magnesium sulfate was added and the heterogeneous mixture was stirred vigorously. Subsequently, the mixture was filtered, and the solvent was removed from the filtrate by a rotary evaporator. Cyclohexane / ethyl acetate gradient (9: 1 (5 liters) → 8: 2 (4 liters) → 7: 3 (4 liters) → 6: 4 (4 liters) → 1: 1 (4 Liters)] with about 2 kg of silica gel (particle size 0.06-0.2 mm). This gave 33.8 g (48% of theory, 87% purity) of the title compound.
¹ H NMR (400 MHz, DMSO-d ₆ , δ / ppm): 8.20 (d, 2H), 7.60 (d, 2H), 7.33 (t, 1H), 7.21 (d, 1H), 7.11 (s, 1H ), 7.10 (d, 1H), 6.93 (s, 1H), 5.49 (s, 2H), 4.05 (quart, 2H), 3.65 (s, 2H), 2.34 (s, 3H), 1.14 (t, 3H) .
LC / MS (Method _{6, ESIpos): R t =} 1.37 min, m / z = 487 [M + H] +.

0℃で、メチルマグネシウムブロマイド溶液(3 Mジエチルエーテル溶液)50.5 ml(152 mmol)を、実施例83Aからの化合物33.5 g(68.9 mmol)の無水THF溶液700 mlに滴下した。添加が終わると、氷/水浴を外し、室温で撹拌を続けた。2時間後、飽和塩化ナトリウム水溶液50 mlを注意深く加えて反応を終了させた。続いて反応液を、酢酸エチル700 mlで希釈し、無水硫酸マグネシウム100 gを加えた。簡単に撹拌した後、混合物を濾過し、ロータリーエバポレーターにより濾液から溶媒を除去した。得られた残渣を、移動相としてシクロヘキサン/酢酸エチル 勾配 [8:2(8リットル)→ 7:3(8リットル)→ 6:4(8リットル)→ 1:1(4リットル)]を用いたシリカゲル(粒子サイズ 0.06-0.2 mm)770 gで吸引濾過により精製した。溶媒を蒸発させ、表題化合物に加え、主として化合物 2-メチル-1-{3-[(5-メチル-3-{3-[4-(トリフルオロメトキシ)フェニル]-1,2,4-オキサジアゾール-5-イル}-1H-ピラゾール-1-イル)メチル]フェニル}プロパン-2-オール(実施例43参照)を含む、粗生成物22.5 gを得た。
この粗生成物7.6 gを沸騰ジイソプロピルエーテル61 mlから再結晶した。得られた結晶を室温で吸引濾過し、各回5 mlの冷ジイソプロピルエーテルで2回洗浄した。こうして得られた物質は、2-メチル-1-{3-[(5-メチル-3-{3-[4-(トリフルオロメトキシ)フェニル]-1,2,4-オキサジアゾール-5-イル}-1H-ピラゾール-1-イル)メチル]フェニル}プロパン-2-オールから構成される(実施例43参照)。母液からロータリーエバポレーターにより溶媒を除去し、残渣を分取用HPLC(方法12)によりその構成物に分離した。これにより表題化合物540 mg、およびさらに2-メチル-1-{3-[(5-メチル-3-{3-[4-(トリフルオロメトキシ)フェニル]-1,2,4-オキサジアゾール-5-イル}-1H-ピラゾール-1-イル)メチル]フェニル}プロパン-2-オール(実施例43参照)2.85 gを得た。表題化合物540 mgを最後にジイソプロピルエーテル5 mlから再結晶した。高真空下乾燥させ、表題化合物373 mgを純粋な形態で得た(理論値の3.5%、更なる加工に付した粗生成物7.6 gに基づく)。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：8.25 (d、2H)、7.33 (d、2H)、7.31 (t、1H)、7.14 (d、1H)、7.07 (d、1H)、7.01 (s、1H)、6.82 (s、1H)、5.43 (s、2H)、3.69 (s、2H)、2.29 (s、3H)、2.14 (s、3H)。
LC/MS (方法6、ESIpos)：R_t＝1.31分、m/z＝457 [M+H]⁺。 Example 84A
1- {3-[(5-methyl-3- {3- [4- (trifluoromethoxy) phenyl] -1,2,4-oxadiazol-5-yl} -1H-pyrazol-1-yl) Methyl] phenyl} acetone

At 0 ° C., 50.5 ml (152 mmol) of methylmagnesium bromide solution (3 M diethyl ether solution) was added dropwise to 700 ml of anhydrous THF solution of 33.5 g (68.9 mmol) of the compound from Example 83A. When the addition was complete, the ice / water bath was removed and stirring was continued at room temperature. After 2 hours, 50 ml of a saturated aqueous sodium chloride solution was carefully added to terminate the reaction. Subsequently, the reaction solution was diluted with 700 ml of ethyl acetate, and 100 g of anhydrous magnesium sulfate was added. After briefly stirring, the mixture was filtered and the solvent was removed from the filtrate by rotary evaporator. The resulting residue was used as mobile phase with a cyclohexane / ethyl acetate gradient [8: 2 (8 liters) → 7: 3 (8 liters) → 6: 4 (8 liters) → 1: 1 (4 liters)] Purification by suction filtration over 770 g of silica gel (particle size 0.06-0.2 mm). The solvent is evaporated and added to the title compound, mainly the compound 2-methyl-1- {3-[(5-methyl-3- {3- [4- (trifluoromethoxy) phenyl] -1,2,4-oxa 22.5 g of crude product was obtained containing diazol-5-yl} -1H-pyrazol-1-yl) methyl] phenyl} propan-2-ol (see Example 43).
7.6 g of this crude product was recrystallized from 61 ml of boiling diisopropyl ether. The obtained crystals were suction filtered at room temperature and washed twice with 5 ml of cold diisopropyl ether each time. The substance thus obtained is 2-methyl-1- {3-[(5-methyl-3- {3- [4- (trifluoromethoxy) phenyl] -1,2,4-oxadiazole-5- IL} -1H-pyrazol-1-yl) methyl] phenyl} propan-2-ol (see Example 43). The solvent was removed from the mother liquor with a rotary evaporator and the residue was separated into its constituents by preparative HPLC (Method 12). This gave 540 mg of the title compound, and further 2-methyl-1- {3-[(5-methyl-3- {3- [4- (trifluoromethoxy) phenyl] -1,2,4-oxadiazole- There was obtained 2.85 g of 5-yl} -1H-pyrazol-1-yl) methyl] phenyl} propan-2-ol (see Example 43). 540 mg of the title compound was finally recrystallized from 5 ml of diisopropyl ether. Drying under high vacuum yielded 373 mg of the title compound in pure form (3.5% of theory, based on 7.6 g of crude product subjected to further processing).
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 8.25 (d, 2H), 7.33 (d, 2H), 7.31 (t, 1H), 7.14 (d, 1H), 7.07 (d, 1H), 7.01 (s, 1H), 6.82 (s, 1H), 5.43 (s, 2H), 3.69 (s, 2H), 2.29 (s, 3H), 2.14 (s, 3H).
LC / MS (Method 6, ESIpos): R _t = 1.31 min, m / z = 457 [M + H] ⁺ .

0℃で、カリウムtert-ブトキシド99 mg(0.88 mmol)を、実施例30Aからの化合物227 mg(0.68 mmol)および実施例49Aからの化合物300 mg(0.75 mmol、純度71%)のTHF溶液5 mlに加えた。混合物を室温に戻し、続いて一夜室温で攪拌した。酢酸エチルおよび水を加えた後、水相を酢酸エチルで1回抽出した。合わせた有機相を飽和塩化ナトリウム溶液で1回洗浄し、硫酸マグネシウムで乾燥させ、濾過し、濃縮した。残渣を分取用HPLC(方法15)により精製した。きれいな生成物分画を合わせ、水相の残容量まで濃縮した。飽和重炭酸ナトリウム水溶液を加えた後、混合物を酢酸エチルで2回抽出した。合わせた有機相を硫酸マグネシウムで乾燥させ、濾過し、濃縮した。減圧下、残渣を乾燥させ、表題化合物264 mg(理論値の71%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：8.19 (d、2H)、7.59 (d、2H)、7.29-7.26 (m、2H)、7.16 (s、1H)、7.03-6.98 (m、1H)、6.81 (s、1H)、5.44 (s、2H)、4.09 (quart、2H)、2.26 (s、3H)、1.52 (s、6H)、1.42-1.39 (m、2H)、1.12 (t、3H)、1.01-1.08 (m、2H)。
LC/MS (方法6、ESIpos)：R_t＝1.49分、m/z＝539 [M+H]⁺。 Example 85A
Ethyl 2-methyl-2- (3-{[5-methyl-3- (3- {4- [1- (trifluoromethyl) cyclopropyl] phenyl} -1,2,4-oxadiazole-5- Yl) -1H-pyrazol-1-yl] methyl} phenyl) propanoate

At 0 ° C., 99 mg (0.88 mmol) of potassium tert-butoxide, 5 ml of a THF solution of the compound 227 mg (0.68 mmol) from Example 30A and the compound 300 mg (0.75 mmol, purity 71%) from Example 49A Added to. The mixture was allowed to warm to room temperature followed by stirring overnight at room temperature. After adding ethyl acetate and water, the aqueous phase was extracted once with ethyl acetate. The combined organic phases were washed once with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (Method 15). The clean product fractions were combined and concentrated to the remaining volume of the aqueous phase. After adding saturated aqueous sodium bicarbonate, the mixture was extracted twice with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was dried under reduced pressure to give 264 mg (71% of theory) of the title compound.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 8.19 (d, 2H), 7.59 (d, 2H), 7.29-7.26 (m, 2H), 7.16 (s, 1H), 7.03-6.98 (m , 1H), 6.81 (s, 1H), 5.44 (s, 2H), 4.09 (quart, 2H), 2.26 (s, 3H), 1.52 (s, 6H), 1.42-1.39 (m, 2H), 1.12 ( t, 3H), 1.01-1.08 (m, 2H).
LC / MS (Method _{6, ESIpos): R t =} 1.49 min, m / z = 539 [M + H] +.

固体カリウムtert-ブトキシド58 mg(0.513 mmol)を、0℃で実施例28Aからの化合物145 mg(0.467 mmol)および実施例49Aからの化合物173 mg(0.607 mmol)の無水THF溶液5 mlに加えた。氷/水浴を取り除いた後、反応混合物を室温で16時間撹拌した。続いてメタノール1 mlを加え、反応混合物は分取用HPLC(方法11)により、直接その成分に分離した。こうして、表題化合物198 mg(理論値の77%、93%純度)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：8.15 (d、2H)、7.35 (d、2H)、7.29-7.24 (m、2H)、7.15 (s、1H)、7.00 (d、1H)、6.80 (s、1H)、5.44 (s、2H)、4.12-4.06 (m、2H)、4.09 (quart、2H)、3.55 (dt、2H)、2.87-2.80 (m、1H)、2.27 (s、3H)、1.91-1.78 (m、4H)、1.53 (s、6H)、1.14 (t、3H)。
LC/MS (方法4、ESIpos)：R_t＝1.52分、m/z＝515 [M+H]⁺。 Example 86A
Ethyl 2-methyl-2- {3-[(5-methyl-3- {3- [4- (tetrahydro-2H-pyran-4-yl) phenyl] -1,2,4-oxadiazole-5- Yl} -1H-pyrazol-1-yl) methyl] phenyl} propanoate

Solid potassium tert-butoxide 58 mg (0.513 mmol) was added at 0 ° C. to 5 ml of anhydrous THF solution of compound 145 mg (0.467 mmol) from Example 28A and compound 173 mg (0.607 mmol) from Example 49A. . After removing the ice / water bath, the reaction mixture was stirred at room temperature for 16 hours. Subsequently, 1 ml of methanol was added and the reaction mixture was separated directly into its components by preparative HPLC (Method 11). This gave 198 mg (77% of theory, 93% purity) of the title compound.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 8.15 (d, 2H), 7.35 (d, 2H), 7.29-7.24 (m, 2H), 7.15 (s, 1H), 7.00 (d, 1H ), 6.80 (s, 1H), 5.44 (s, 2H), 4.12-4.06 (m, 2H), 4.09 (quart, 2H), 3.55 (dt, 2H), 2.87-2.80 (m, 1H), 2.27 ( s, 3H), 1.91-1.78 (m, 4H), 1.53 (s, 6H), 1.14 (t, 3H).
LC / MS (Method 4, ESIpos): R _t = 1.52 min, m / z = 515 [M + H] ⁺ .

実施例85Aに記載した方法に準じて、実施例23Aからの化合物0.50 g(1.49 mmol)および実施例49Aからの化合物0.55 g(1.93 mmol)を反応させ、表題化合物0.49 g(理論値の59%)を得た。生成物の精製は、方法17に従い分取用HPLCを用いて行った。
¹H NMR (400 MHz、DMSO-d₆、δ/ppm)：8.09 (d、2H)、7.77 (d、2H)、7.34 (t、1H)、7.27 (d、1H)、7.14 (s、1H)、7.06 (d、1H)、6.93 (s、1H)、5.51 (s、2H)、4.00 (quart、2H)、2.32 (s、3H)、1.61 (s、6H)、1.47 (s、6H)、1.03 (t、3H)。
LC/MS (方法6、ESIpos)：R_t＝1.50分、m/z＝541 [M+H]⁺。 Example 87A
Ethyl 2-methyl-2- {3-[(5-methyl-3- {3- [4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenyl] -1,2, 4-oxa-diazol-5-yl} -1H-pyrazol-1-yl) methyl] phenyl} propanoate

According to the method described in Example 85A, 0.50 g (1.49 mmol) of the compound from Example 23A and 0.55 g (1.93 mmol) of the compound from Example 49A were reacted to give 0.49 g (59% of theory) of the title compound. ) The product was purified using preparative HPLC according to Method 17.
¹ H NMR (400 MHz, DMSO-d ₆ , δ / ppm): 8.09 (d, 2H), 7.77 (d, 2H), 7.34 (t, 1H), 7.27 (d, 1H), 7.14 (s, 1H ), 7.06 (d, 1H), 6.93 (s, 1H), 5.51 (s, 2H), 4.00 (quart, 2H), 2.32 (s, 3H), 1.61 (s, 6H), 1.47 (s, 6H) 1.03 (t, 3H).
LC / MS (Method _{6, ESIpos): R t =} 1.50 min, m / z = 541 [M + H] +.

実施例85Aに記載した方法に準じて、実施例22Aからの化合物0.14 g(0.44 mmol)および実施例49Aからの化合物0.15 g(0.53 mmol)を反応させ、表題化合物0.14 g(理論値の60%)を得た。生成物の精製は、方法17に従い分取用HPLCを用いて行った。
¹H NMR (400 MHz、DMSO-d₆、δ/ppm)：8.20 (d、2H)、7.60 (d、2H)、7.34 (t、1H)、7.27 (d、1H)、7.14 (s、1H)、7.06 (d、1H)、6.93 (s、1H)、5.51 (s、2H)、4.00 (quart、2H)、2.32 (s、3H)、1.46 (s、6H)、1.04 (t、3H)。
LC/MS (方法6、ESIpos)：R_t＝1.44分、m/z＝515 [M+H]⁺。 Example 88A
Ethyl 2-methyl-2- {3-[(5-methyl-3- {3- [4- (trifluoromethoxy) phenyl] -1,2,4-oxadiazol-5-yl} -1H-pyrazole -1-yl) methyl] phenyl} propanoate

In a manner similar to that described in Example 85A, 0.14 g (0.44 mmol) of the compound from Example 22A and 0.15 g (0.53 mmol) of the compound from Example 49A were reacted to give 0.14 g (60% of theory) of the title compound. ) The product was purified using preparative HPLC according to Method 17.
¹ H NMR (400 MHz, DMSO-d ₆ , δ / ppm): 8.20 (d, 2H), 7.60 (d, 2H), 7.34 (t, 1H), 7.27 (d, 1H), 7.14 (s, 1H ), 7.06 (d, 1H), 6.93 (s, 1H), 5.51 (s, 2H), 4.00 (quart, 2H), 2.32 (s, 3H), 1.46 (s, 6H), 1.04 (t, 3H) .
LC / MS (Method _{6, ESIpos): R t =} 1.44 min, m / z = 515 [M + H] +.

室温で、実施例53Aからの化合物814 mg(2.11 mmol、純度76%)を、実施例22Aからの化合物546 mg(1.76 mmol)のTHF溶液20 mlに加えた。続いて0℃で、カリウムtert-ブトキシド257 mg(2.29 mmol)を加え、混合物を室温で20時間攪拌した。さらに続いてカリウムtert-ブトキシド150 mg(1.34 mmol)を加え、混合物を室温でさらに6時間攪拌した。酢酸エチルで希釈した後、混合物を水で1回抽出し、水性の洗浄相を酢酸エチルで1回再抽出した。合わせた有機相を飽和塩化ナトリウム溶液で1回洗浄し、硫酸マグネシウムで乾燥させ、濾過し、濃縮した。残渣をメタノールに取り込み、カラムクロマトグラフィー(シリカゲル、移動相：シクロヘキサン/酢酸エチル 7:3)により精製した。溶媒を除去し、減圧下乾燥させて生成物125 mgを得て、ここでこれは¹H NMRによると表題化合物および約60%の対応するメチル エステルを含有し、そのまま続く反応に用いた。
LC/MS (方法6、ESIpos)：R_t＝1.43分、m/z＝523 [M+H]⁺。 Example 89A
Ethyl difluoro {3-[(5-methyl-3- {3- [4- (trifluoromethoxy) phenyl] -1,2,4-oxadiazol-5-yl} -1H-pyrazol-1-yl) Methyl] phenyl} acetate

At room temperature, 814 mg (2.11 mmol, purity 76%) of the compound from Example 53A was added to 20 ml of a THF solution of 546 mg (1.76 mmol) of the compound from Example 22A. Subsequently, at 0 ° C., 257 mg (2.29 mmol) of potassium tert-butoxide was added, and the mixture was stirred at room temperature for 20 hours. Subsequently, 150 mg (1.34 mmol) of potassium tert-butoxide was added, and the mixture was further stirred at room temperature for 6 hours. After dilution with ethyl acetate, the mixture was extracted once with water and the aqueous wash phase was re-extracted once with ethyl acetate. The combined organic phases were washed once with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The residue was taken up in methanol and purified by column chromatography (silica gel, mobile phase: cyclohexane / ethyl acetate 7: 3). The solvent was removed and dried under reduced pressure to give 125 mg of product, which, according to ¹ H NMR, contained the title compound and about 60% of the corresponding methyl ester and was used as such in the subsequent reaction.
LC / MS (Method 6, ESIpos): R _t = 1.43 min, m / z = 523 [M + H] ⁺ .

水素化ナトリウム0.23 g(1.23 mmol)(60%鉱油分散体)およびジエチルカーボネート0.20 ml(1.64 mmol)を、まず無水THF5.6 mlに加えた。氷浴による冷却下、実施例83Aからの化合物0.40 g(0.82 mmol)の無水THF溶液1.6 mlを滴下し、続いて混合物を還流下2時間加熱した。続いて混合物を氷水50 mlに注ぎ、酢酸エチル50 mlで2回抽出した。合わせた有機相を水および飽和塩化ナトリウム溶液により洗浄し、無水硫酸マグネシウムで乾燥させ、濾過した。ロータリーエバポレーターにより濾液から溶媒を除去し、残渣を分取用HPLC(方法17)により精製した。これにより表題化合物0.29 g(理論値の63%)を得た。
¹H NMR (400 MHz、DMSO-d₆、δ/ppm)：8.20 (d、2H)、7.59 (d、2H)、7.38 (t、1H)、7.32 (d、1H)、7.19 (d、2H)、6.93 (s、1H)、5.52 (s、2H)、4.97 (s、1H)、4.11 (m、4H)、2.33 (s、3H)、1.13 (t、6H)。
LC/MS (方法6、ESIpos)：R_t＝1.38分、m/z＝559 [M+H]⁺。 Example 90A
Diethyl {3-[(5-methyl-3- {3- [4- (trifluoromethoxy) phenyl] -1,2,4-oxadiazol-5-yl} -1H-pyrazol-1-yl) methyl ] Phenyl} malonate

Sodium hydride 0.23 g (1.23 mmol) (60% mineral oil dispersion) and diethyl carbonate 0.20 ml (1.64 mmol) were first added to anhydrous THF 5.6 ml. Under cooling in an ice bath, 1.6 ml of a solution of 0.40 g (0.82 mmol) of the compound from Example 83A in anhydrous THF was added dropwise, and then the mixture was heated under reflux for 2 hours. Subsequently, the mixture was poured into 50 ml of ice water and extracted twice with 50 ml of ethyl acetate. The combined organic phases were washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. The solvent was removed from the filtrate by rotary evaporator and the residue was purified by preparative HPLC (Method 17). This gave 0.29 g (63% of theory) of the title compound.
¹ H NMR (400 MHz, DMSO-d ₆ , δ / ppm): 8.20 (d, 2H), 7.59 (d, 2H), 7.38 (t, 1H), 7.32 (d, 1H), 7.19 (d, 2H ), 6.93 (s, 1H), 5.52 (s, 2H), 4.97 (s, 1H), 4.11 (m, 4H), 2.33 (s, 3H), 1.13 (t, 6H).
LC / MS (Method _{6, ESIpos): R t =} 1.38 min, m / z = 559 [M + H] +.

氷浴による冷却下、水素化ナトリウム(60%鉱油分散体)22 mg(0.55 mmol)を、実施例90Aからの化合物0.28 g(0.50 mmol)の無水DMF5.0 mlに加え、混合物を5分攪拌し、続いてヨウ化メチル34 μl(0.55 mmol)を加えた。混合物を室温で3時間攪拌し、少量の1 N 塩酸を加え、生成物を、直接分取用HPLCにより精製した(方法17)。これにより表題化合物0.25 g(理論値の86%)を得た。
¹H NMR (400 MHz、DMSO-d₆、δ/ppm)：8.20 (d、2H)、7.59 (d、2H)、7.38 (t、1H)、7.29 (d、1H)、7.17 (d、1H)、7.12 (s、1H)、6.93 (s、1H)、5.52 (s、2H)、4.11 (m、4H)、2.32 (s、3H)、1.73 (s、3H)、1.11 (t、6H)。
LC/MS (方法6、ESIpos)：R_t＝1.45分、m/z＝573 [M+H]⁺。 Example 91A
Diethyl methyl {3-[(5-methyl-3- {3- [4- (trifluoromethoxy) phenyl] -1,2,4-oxadiazol-5-yl} -1H-pyrazol-1-yl) Methyl] phenyl} malonate

Under cooling in an ice bath, 22 mg (0.55 mmol) of sodium hydride (60% mineral oil dispersion) was added to 5.0 ml of anhydrous DMF of compound 0.28 g (0.50 mmol) from Example 90A and the mixture was stirred for 5 minutes. Subsequently, 34 μl (0.55 mmol) of methyl iodide was added. The mixture was stirred at room temperature for 3 hours, a small amount of 1 N hydrochloric acid was added and the product was purified directly by preparative HPLC (Method 17). This gave 0.25 g (86% of theory) of the title compound.
¹ H NMR (400 MHz, DMSO-d ₆ , δ / ppm): 8.20 (d, 2H), 7.59 (d, 2H), 7.38 (t, 1H), 7.29 (d, 1H), 7.17 (d, 1H ), 7.12 (s, 1H), 6.93 (s, 1H), 5.52 (s, 2H), 4.11 (m, 4H), 2.32 (s, 3H), 1.73 (s, 3H), 1.11 (t, 6H) .
LC / MS (Method _{6, ESIpos): R t =} 1.45 min, m / z = 573 [M + H] +.

室温で、3-ジエチルアミノ-1,5-ジヒドロ-2,4,3-ベンゾジオキサホスフェピン684 mg(2.86 mmol)およびテトラゾール311 mg(4.45 mmol)を、実施例43からの化合物300 mg(0.635 mmol)のジクロロメタン溶液10 mlに加えた。混合物を室温で10分攪拌した後、まず水40 μl、続いて、-40℃で、70%メタ-クロロ過安息香酸(mCPBA)1.1 g(4.45 mmol)を加えた。混合物をまず-40℃でさらに10分攪拌し、続いて冷却浴を外し、室温で16時間撹拌を続けた。続いて水50 mlを加え、混合物を約25 mlの酢酸エチルで3回抽出した。合わせた有機層抽出物を水、続いて飽和塩化ナトリウム溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、濾過し、最後にロータリーエバポレーターにより溶媒を除去した。残渣をMPLCで精製した(シリカゲル、移動相：シクロヘキサン/酢酸エチル 5:1 → 1:1)。適切な分画を蒸発させ、生成物を酢酸エチルに再度溶解させ、飽和重炭酸ナトリウム溶液で洗浄して、最後の少量のメタ-クロロ過安息香酸を除去した。溶液をもう一度無水硫酸マグネシウムで乾燥させ、濾過し、蒸発させ、表題化合物255 mg(理論値の59%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：8.25 (d、2H)、7.37-7.31 (m、4H)、7.29-7.23 (m、3H)、7.19 (d、1H)、7.08 (s、1H)、7.05 (d、1H)、6.77 (s、1H)、5.41 (s、2H)、5.18-4.98 (m、4H)、3.04 (s、2H)、2.23 (s、3H)、1.53 (s、6H)。
LC/MS (方法4、ESIpos)：R_t＝1.55分、m/z＝455 [M-C₈H₉O₄P+H]⁺、655 [M+H]⁺。 Example 92A
5- [5-Methyl-1- (3- {2-methyl-2-[(3-oxide-1,5-dihydro-2,4,3-benzodioxaphosphin-3-yl) oxy] Propyl} benzyl) -1H-pyrazol-3-yl] -3- [4- (trifluoromethoxy) phenyl] -1,2,4-oxadiazole

At room temperature, 684 mg (2.86 mmol) of 3-diethylamino-1,5-dihydro-2,4,3-benzodioxaphosphepine and 311 mg (4.45 mmol) of tetrazole were added to 300 mg of the compound from Example 43 ( 0.635 mmol) in 10 ml dichloromethane. After the mixture was stirred at room temperature for 10 minutes, first 40 μl of water was added followed by 1.1 g (4.45 mmol) of 70% meta-chloroperbenzoic acid (mCPBA) at −40 ° C. The mixture was first stirred at −40 ° C. for a further 10 minutes, then the cooling bath was removed and stirring was continued at room temperature for 16 hours. Subsequently, 50 ml of water was added and the mixture was extracted three times with about 25 ml of ethyl acetate. The combined organic layer extracts were washed with water followed by saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and finally the solvent removed by rotary evaporator. The residue was purified by MPLC (silica gel, mobile phase: cyclohexane / ethyl acetate 5: 1 → 1: 1). The appropriate fractions were evaporated and the product was redissolved in ethyl acetate and washed with saturated sodium bicarbonate solution to remove the last small amount of meta-chloroperbenzoic acid. The solution was once again dried over anhydrous magnesium sulfate, filtered and evaporated to give 255 mg (59% of theory) of the title compound.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 8.25 (d, 2H), 7.37-7.31 (m, 4H), 7.29-7.23 (m, 3H), 7.19 (d, 1H), 7.08 (s , 1H), 7.05 (d, 1H), 6.77 (s, 1H), 5.41 (s, 2H), 5.18-4.98 (m, 4H), 3.04 (s, 2H), 2.23 (s, 3H), 1.53 ( s, 6H).
LC / MS (Method 4, ESIpos): R _t = 1.55 min, m / z = 455 [MC ₈ H ₉ O ₄ P + H] ⁺ , 655 [M + H] ⁺ .

氷浴による冷却下、水素化ナトリウム(60% 鉱油分散体)18 mg(0.44 mmol)を、実施例60からの化合物0.20 g(0.40 mmol)無水THF8 mlに加え、混合物をその温度で5分攪拌した。続いてテトラベンジルピロホスフェート0.24 g(0.44 mmol)を加え、混合物を更なる冷却なしに次の4時間攪拌した。続いて混合物を酢酸エチルで希釈し、水および飽和塩化ナトリウム溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、濾過した。ロータリーエバポレーターにより濾液から溶媒を除去し、残渣を分取用HPLC(方法17)により精製した。これにより表題化合物0.15 g(理論値の49%)を得た。
¹H NMR (400 MHz、DMSO-d₆、δ/ppm)：8.08 (d、2H)、7.76 (d、2H)、7.37-7.26 (m、13H)、6.97 (d、1H)、6.88 (s、1H)、5.46 (s、2H)、4.85 (d、4H)、3.97 (d、2H)、2.29 (s、3H)、1.61 (s、6H)、1.24 (s、6H)。
LC/MS (方法6、ESIpos)：R_t＝1.56分、m/z＝759 [M+H]⁺。 Example 93A
Dibenzyl 2-methyl-2- {3-[(5-methyl-3- {3- [4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenyl] -1,2, 4-oxadiazol-5-yl} -1H-pyrazol-1-yl) methyl] phenyl} propyl phosphate

Under cooling in an ice bath, 18 mg (0.44 mmol) of sodium hydride (60% mineral oil dispersion) was added to 0.20 g (0.40 mmol) anhydrous THF 8 ml of the compound from Example 60 and the mixture was stirred at that temperature for 5 minutes. did. Subsequently, 0.24 g (0.44 mmol) of tetrabenzylpyrophosphate was added and the mixture was stirred for the next 4 hours without further cooling. The mixture was subsequently diluted with ethyl acetate, washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. The solvent was removed from the filtrate by rotary evaporator and the residue was purified by preparative HPLC (Method 17). This gave 0.15 g (49% of theory) of the title compound.
¹ H NMR (400 MHz, DMSO-d ₆ , δ / ppm): 8.08 (d, 2H), 7.76 (d, 2H), 7.37-7.26 (m, 13H), 6.97 (d, 1H), 6.88 (s , 1H), 5.46 (s, 2H), 4.85 (d, 4H), 3.97 (d, 2H), 2.29 (s, 3H), 1.61 (s, 6H), 1.24 (s, 6H).
LC / MS (Method 6, ESIpos): R _t = 1.56 min, m / z = 759 [M + H] ⁺ .

実施例93Aに記載した方法に準じて、実施例61からの化合物0.10 g(0.21 mmol)から表題化合物92 mg(理論値の59%)を得た。
¹H NMR (400 MHz、DMSO-d₆、δ/ppm)：8.18 (d、2H)、7.58 (d、2H)、7.35-7.25 (m、13H)、6.98 (d、1H)、6.88 (s、1H)、5.46 (s、2H)、4.85 (d、4H)、3.96 (d、2H)、2.30 (s、3H)、1.24 (s、6H)。
LC/MS (方法6、ESIpos)：R_t＝1.54分、m/z＝733 [M+H]⁺。 Example 94A
Dibenzyl 2-methyl-2- {3-[(5-methyl-3- {3- [4- (trifluoromethoxy) phenyl] -1,2,4-oxadiazol-5-yl} -1H-pyrazole -1-yl) methyl] phenyl} propyl phosphate

In a manner similar to that described in Example 93A, 92 mg (59% of theory) of the title compound were obtained from 0.10 g (0.21 mmol) of the compound from Example 61.
¹ H NMR (400 MHz, DMSO-d ₆ , δ / ppm): 8.18 (d, 2H), 7.58 (d, 2H), 7.35-7.25 (m, 13H), 6.98 (d, 1H), 6.88 (s , 1H), 5.46 (s, 2H), 4.85 (d, 4H), 3.96 (d, 2H), 2.30 (s, 3H), 1.24 (s, 6H).
LC / MS (Method 6, ESIpos): R _t = 1.54 min, m / z = 733 [M + H] ⁺ .

実施例66Aに記載した方法に準じて、実施例29Aからの化合物250 mg(0.762 mmol)および実施例47Aからの化合物249 mg(0.838 mmol、純度96%)から、表題化合物411 mg(72%純度、理論値の75%)を得た。この場合、反応時間は室温で16時間であった。
LC/MS (方法6、ESIpos)：R_t＝1.39分、m/z＝517 [M+H]⁺。 Example 95A
1- {3-[(3- {3- [3-Fluoro-4- (trifluoromethoxy) phenyl] -1,2,4-oxadiazol-5-yl} -5-methyl-1H-pyrazole- 1-yl) methyl] phenyl} cyclopropyl acetate

According to the method described in Example 66A, from the compound 250 mg (0.762 mmol) from Example 29A and 249 mg (0.838 mmol, 96% purity) from Example 47A, the title compound 411 mg (72% purity). 75% of the theoretical value). In this case, the reaction time was 16 hours at room temperature.
LC / MS (Method _{6, ESIpos): R t =} 1.39 min, m / z = 517 [M + H] +.

室温で、3-ジエチルアミノ-1,5-ジヒドロ-2,4,3-ベンゾジオキサホスフェピン1.10 g(4.61 mmol)およびテトラゾール502 mg(7.16 mmol)を、実施例53からの化合物500 mg(1.02 mmol)のジクロロメタン溶液16 mlに添加した。混合物を室温で10分攪拌した後、最初に水65 μl続いて、-40℃で、70%メタ-クロロ過安息香酸(mCPBA)1.77 g(7.16 mmol)を加えた。混合物を最初に-40℃でさらに10分攪拌し、続いて冷却浴を除去し、室温で16時間撹拌を続けた。続いて水100 mlを加え、混合物を各回約50 mlの酢酸エチルで3回抽出した。合わせた有機層抽出物を、飽和重炭酸ナトリウム溶液、水および飽和塩化ナトリウム溶液で連続して洗浄し、無水硫酸マグネシウムで乾燥させ、濾過し、最後にロータリーエバポレーターにより溶媒を除去した。残渣をMPLCで精製した(シリカゲル、移動相：シクロヘキサン/酢酸エチル 5:1 → 1:1)。適切な分画を蒸発し、残渣を高真空下乾燥させ、表題化合物618 mg(理論値の85%、94%純度)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：8.27 (d、2H)、7.79 (d、2H)、7.35-7.31 (m、3H)、7.29-7.23 (m、2H、部分的にCHCl₃ シグナルに覆われている)、7.20 (d、1H)、7.08 (s、1H)、7.05 (d、1H)、6.78 (s、1H)、5.41 (s、2H)、5.17-4.99 (m、4H)、3.03 (s、2H)、2.23 (s、3H)、1.53 (s、6H)。
LC/MS (方法6、ESIpos)：R_t＝1.42分、m/z＝471 [M-C₈H₉O₄P+H]⁺、671 [M+H]⁺。 Example 96A
5- [5-Methyl-1- (3- {2-methyl-2-[(3-oxide-1,5-dihydro-2,4,3-benzodioxaphosphin-3-yl) oxy] Propyl} benzyl) -1H-pyrazol-3-yl] -3- [4- (trifluoromethyl) sulfanyl] phenyl} -1,2,4-oxadiazole

At room temperature, 1.10 g (4.61 mmol) of 3-diethylamino-1,5-dihydro-2,4,3-benzodioxaphosphepine and 502 mg (7.16 mmol) of tetrazole were added to 500 mg of the compound from Example 53 ( 1.02 mmol) in dichloromethane. After the mixture was stirred at room temperature for 10 minutes, 65 μl of water was first added followed by 1.77 g (7.16 mmol) of 70% meta-chloroperbenzoic acid (mCPBA) at −40 ° C. The mixture was first stirred at −40 ° C. for a further 10 minutes, then the cooling bath was removed and stirring was continued at room temperature for 16 hours. Subsequently, 100 ml of water was added and the mixture was extracted three times with about 50 ml of ethyl acetate each time. The combined organic layer extracts were washed successively with saturated sodium bicarbonate solution, water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and finally the solvent was removed by rotary evaporator. The residue was purified by MPLC (silica gel, mobile phase: cyclohexane / ethyl acetate 5: 1 → 1: 1). The appropriate fractions were evaporated and the residue was dried under high vacuum to give 618 mg (85% of theory, 94% purity) of the title compound.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 8.27 (d, 2H), 7.79 (d, 2H), 7.35-7.31 (m, 3H), 7.29-7.23 (m, 2H, partially CHCl ₃ ), 7.20 (d, 1H), 7.08 (s, 1H), 7.05 (d, 1H), 6.78 (s, 1H), 5.41 (s, 2H), 5.17-4.99 (m, 4H), 3.03 (s, 2H), 2.23 (s, 3H), 1.53 (s, 6H).
LC / MS (Method 6, ESIpos): R _t = 1.42 min, m / z = 471 [MC ₈ H ₉ O ₄ P + H] ⁺ , 671 [M + H] ⁺ .

0℃で、リチウムアルミニウムハイドライド7.83 mg(0.21 mmol)を、実施例54Aからの化合物100 mg(0.21 mmol)の無水THF溶液2 mlに加え、混合物を氷浴による冷却下、さらに15分攪拌した。飽和塩化ナトリウム水溶液、無水硫酸マグネシウムおよび酢酸エチルを続いて加えた。続いて混合物を濾過し、濾液をロータリーエバポレーターにより蒸発させた。残渣を分取用HPLCにより精製した。これにより表題化合物60 mg(理論値の64%)を得た。
¹H NMR (400 MHz、DMSO-d₆、δ/ppm)：8.09 (d、2H)、7.77 (d、2H)、7.32 (t、1H)、7.24 (d、1H)、7.18 (s、1H)、7.06 (d、1H)、6.93 (s、1H)、5.50 (s、2H)、5.20 (t、1H)、4.47 (d、2H)、2.34 (s、3H)、1.61 (s、6H)。
LC/MS (方法6、ESIpos)：R_t＝1.25分、m/z＝457 [M+H]⁺。 Working example:
Example 1
{3-[(5-Methyl-3- {3- [4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenyl] -1,2,4-oxadiazole-5 -Yl} -1H-pyrazol-1-yl) methyl] phenyl} methanol

At 0 ° C., 7.83 mg (0.21 mmol) of lithium aluminum hydride was added to 2 ml of an anhydrous THF solution of 100 mg (0.21 mmol) of the compound from Example 54A, and the mixture was further stirred for 15 minutes under cooling with an ice bath. Saturated aqueous sodium chloride solution, anhydrous magnesium sulfate and ethyl acetate were subsequently added. The mixture was subsequently filtered and the filtrate was evaporated on a rotary evaporator. The residue was purified by preparative HPLC. This gave 60 mg (64% of theory) of the title compound.
¹ H NMR (400 MHz, DMSO-d ₆ , δ / ppm): 8.09 (d, 2H), 7.77 (d, 2H), 7.32 (t, 1H), 7.24 (d, 1H), 7.18 (s, 1H ), 7.06 (d, 1H), 6.93 (s, 1H), 5.50 (s, 2H), 5.20 (t, 1H), 4.47 (d, 2H), 2.34 (s, 3H), 1.61 (s, 6H) .
LC / MS (Method 6, ESIpos): R _t = 1.25 min, m / z = 457 [M + H] ⁺ .

固体水素化ホウ素ナトリウム9.5 mg(0.249 mmol)を、実施例55Aからの化合物200 mg(0.383 mmol)の1,4-ジオキサン10 mlおよび水1 mlの混合物中の溶液に加えた。反応混合物を室温で1時間攪拌した後、最初に1 M 塩酸2 mlおよび続いて水約60 mlを加えた。混合物を各回約60 mlの酢酸エチルで3回抽出した。合わせた有機層抽出物を飽和塩化ナトリウム溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、濾過し、最後にロータリーエバポレーターにより溶媒を除去した。このように得られた粗成生物をペンタン25 mlおよびジクロロメタン1 mlの混合物で摩砕した。残渣を吸引濾過し、高真空下乾燥させ、表題化合物185 mg(理論値の94%、97%純度)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：8.24 (d、2H)、7.43 (d、1H)、7.39 (t、1H)、7.34 (s、1H)、7.32 (d、2H)、7.19 (d、1H)、6.82 (s、1H)、5.48 (s、2H)、5.02 (s、1H)、2.99 (s、broad、1H)、2.27 (s、3H)。
LC/MS (方法6、ESIpos)：R_t＝1.29分、m/z＝499 [M+H]⁺。 Example 2
2,2,2-trifluoro-1- {3-[(5-methyl-3- {3- [4- (trifluoromethoxy) phenyl] -1,2,4-oxadiazol-5-yl} -1H-pyrazol-1-yl) methyl] phenyl} ethanol (racemic)

9.5 mg (0.249 mmol) of solid sodium borohydride was added to a solution of 200 mg (0.383 mmol) of the compound from Example 55A in a mixture of 10 ml 1,4-dioxane and 1 ml water. After the reaction mixture was stirred at room temperature for 1 hour, first 2 ml of 1 M hydrochloric acid and then about 60 ml of water were added. The mixture was extracted three times with about 60 ml of ethyl acetate each time. The combined organic layer extracts were washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and finally the solvent was removed by rotary evaporator. The crude product thus obtained was triturated with a mixture of 25 ml pentane and 1 ml dichloromethane. The residue was filtered with suction and dried under high vacuum to give 185 mg (94% of theory, 97% purity) of the title compound.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 8.24 (d, 2H), 7.43 (d, 1H), 7.39 (t, 1H), 7.34 (s, 1H), 7.32 (d, 2H), 7.19 (d, 1H), 6.82 (s, 1H), 5.48 (s, 2H), 5.02 (s, 1H), 2.99 (s, broad, 1H), 2.27 (s, 3H).
LC / MS (Method _{6, ESIpos): R t =} 1.29 min, m / z = 499 [M + H] +.

-30℃で、1.3 Mイソプロピルマグネシウムクロライド/リチウムクロライド複合体のTHF溶液731 μl(0.950 mmol)を急速に、実施例81Aからの化合物250 mg(0.475 mmol)の無水THF溶液10 mlに加えた。-30℃で30分攪拌した後、1,1,1-トリフルオロアセトン266 mg(2.37 mmol)を加え、冷却浴を外した。反応混合物を室温に温めた後、メタノール約1 ml を加えた。続いて反応混合物を無水硫酸マグネシウムで乾燥させ、濾過し、最後にロータリーエバポレーターにより溶媒を除去した。得られた残渣から、まず非極性不純物をMPLC(シリカゲル約50 g、移動相：シクロヘキサン/酢酸エチル 4:1)により除去した。続いて更なる精製を分取用HPLC(方法13)により行った。これにより表題化合物49 mg(理論値の11%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：8.25 (d、2H)、7.51 (d、1H)、7.47 (s、1H)、7.37 (t、1H)、7.33 (d、2H)、7.14 (d、1H)、6.83 (s、1H)、5.49 (s、2H)、2.70 (s、broad、1H)、2.28 (s、3H)、1.77 (s、3H)。
LC/MS (方法6、ESIpos)：R_t＝1.31分、m/z＝513 [M+H]⁺。 Example 3
1,1,1-trifluoro-2- {3-[(5-methyl-3- {3- [4- (trifluoromethoxy) phenyl] -1,2,4-oxadiazol-5-yl} -1H-pyrazol-1-yl) methyl] phenyl} propan-2-ol (racemic)

At −30 ° C., 731 μl (0.950 mmol) of a 1.3 M isopropylmagnesium chloride / lithium chloride complex in THF was rapidly added to 10 ml of an anhydrous THF solution of 250 mg (0.475 mmol) of the compound from Example 81A. After stirring at −30 ° C. for 30 minutes, 1,1,1-trifluoroacetone 266 mg (2.37 mmol) was added, and the cooling bath was removed. After the reaction mixture was warmed to room temperature, about 1 ml of methanol was added. Subsequently, the reaction mixture was dried over anhydrous magnesium sulfate, filtered, and finally the solvent was removed by a rotary evaporator. First, nonpolar impurities were removed from the obtained residue by MPLC (silica gel about 50 g, mobile phase: cyclohexane / ethyl acetate 4: 1). Further purification was then performed by preparative HPLC (Method 13). This gave 49 mg (11% of theory) of the title compound.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 8.25 (d, 2H), 7.51 (d, 1H), 7.47 (s, 1H), 7.37 (t, 1H), 7.33 (d, 2H), 7.14 (d, 1H), 6.83 (s, 1H), 5.49 (s, 2H), 2.70 (s, broad, 1H), 2.28 (s, 3H), 1.77 (s, 3H).
LC / MS (Method 6, ESIpos): R _t = 1.31 min, m / z = 513 [M + H] ⁺ .

0℃で、メチルマグネシウムクロライド溶液(3 M THF溶液)153 μl(0.459 mmol)を、実施例56Aからの化合物100 mg(0.218 mmol)の無水THF溶液2.2 mlに加えた。氷/水浴を外し、室温で撹拌を続けた。3時間後、約5滴の飽和塩化ナトリウム水溶液を加えた。混合物を約10 mlの酢酸エチルで希釈し、水相が完全に取り込まれる量の無水硫酸マグネシウムを加えた。続いて混合物を濾過し、ロータリーエバポレーターにより濾液から溶媒を除去した。残渣から、分取用HPLC(方法11)により、表題化合物(理論値の66%、変換に基づき)36 mgを得て、出発物質45 mgが回収された。
¹H NMR (400 MHz、DMSO-d₆、δ/ppm)：8.01 (d、2H)、7.48 (d、2H)、7.41 (s、1H)、7.38 (d、1H)、7.28 (t、1H)、6.97 (d、1H)、6.91 (s、1H)、5.49 (s、2H)、5.01 (s、1H)、3.99-3.94 (m、2H)、3.46 (dt、2H)、2.91-2.83 (m、1H)、2.34 (s、3H)、1.78-1.65 (m、4H)、1.40 (s、6H)。
LC/MS (方法6、ESIpos)：R_t＝1.19分、m/z＝459 [M+H]⁺。 Example 4
2- {3-[(5-Methyl-3- {3- [4- (tetrahydro-2H-pyran-4-yl) phenyl] -1,2,4-oxadiazol-5-yl} -1H- Pyrazol-1-yl) methyl] phenyl} propan-2-ol

At 0 ° C., 153 μl (0.459 mmol) of methylmagnesium chloride solution (3 M THF solution) was added to 2.2 ml of anhydrous THF solution of 100 mg (0.218 mmol) of the compound from Example 56A. The ice / water bath was removed and stirring was continued at room temperature. After 3 hours, about 5 drops of saturated aqueous sodium chloride solution was added. The mixture was diluted with about 10 ml of ethyl acetate and an amount of anhydrous magnesium sulfate was added so that the aqueous phase was completely taken up. Subsequently, the mixture was filtered, and the solvent was removed from the filtrate by a rotary evaporator. From the residue, preparative HPLC (Method 11) gave 36 mg of the title compound (66% of theory, based on conversion) and 45 mg of starting material was recovered.
¹ H NMR (400 MHz, DMSO-d ₆ , δ / ppm): 8.01 (d, 2H), 7.48 (d, 2H), 7.41 (s, 1H), 7.38 (d, 1H), 7.28 (t, 1H ), 6.97 (d, 1H), 6.91 (s, 1H), 5.49 (s, 2H), 5.01 (s, 1H), 3.99-3.94 (m, 2H), 3.46 (dt, 2H), 2.91-2.83 ( m, 1H), 2.34 (s, 3H), 1.78-1.65 (m, 4H), 1.40 (s, 6H).
LC / MS (Method _{6, ESIpos): R t =} 1.19 min, m / z = 459 [M + H] +.

実施例4に記載した方法に準じて、実施例57Aからの化合物100 mg(0.232 mmol)およびメチルマグネシウムクロライドから表題化合物66 mg(理論値の66%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：8.13 (d、2H)、7.51 (d、2H)、7.41 (d、1H)、7.37 (s、1H)、7.30 (t、1H)、7.01 (d、1H)、6.81 (s、1H)、5.47 (s、2H)、2.29 (s、3H)、1.73 (s、1H)、1.55 (s、6H)、1.37 (s、9H)。
LC/MS (方法4、ESIpos)：R_t＝1.54分、m/z＝413 [M-H₂O+H]⁺。 Example 5
2- [3-({3- [3- (4-tert-butylphenyl) -1,2,4-oxadiazol-5-yl] -5-methyl-1H-pyrazol-1-yl} methyl) Phenyl] propan-2-ol

According to the method described in Example 4, 100 mg (0.232 mmol) of the compound from Example 57A and 66 mg (66% of theory) of the title compound were obtained from methylmagnesium chloride.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 8.13 (d, 2H), 7.51 (d, 2H), 7.41 (d, 1H), 7.37 (s, 1H), 7.30 (t, 1H), 7.01 (d, 1H), 6.81 (s, 1H), 5.47 (s, 2H), 2.29 (s, 3H), 1.73 (s, 1H), 1.55 (s, 6H), 1.37 (s, 9H).
LC / MS (Method 4, ESIpos): R _t = 1.54 min, m / z = 413 [MH ₂ O + H] ⁺ .

実施例4に記載した方法に準じて、実施例58Aからの化合物150 mg(0.317 mmol)およびメチルマグネシウムクロライドから表題化合物114 mg(理論値の75%)を得た。ここでは、反応は3時間後、室温で酢酸100 μlを加えて終了させた。続いて反応混合物を乾燥するまでロータリーエバポレーターで蒸発させた。表題化合物は、残渣からMPLC(シリカゲル、移動相：シクロヘキサン/酢酸エチル 5:1 → 3:1)により単離した。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：8.13 (d、2H)、7.40 (d、1H)、7.36 (s、1H)、7.30 (t、1H)、7.29 (d、2H)、7.01 (d、1H)、6.80 (s、1H)、5.47 (s、2H)、3.56 (s、2H)、3.28 (s、3H)、2.43-2.28 (m、4H)、2.29 (s、3H)、2.15-2.03 (m、1H)、1.93-1.83 (m、1H)、1.74 (s、1H)、1.56 (s、6H)。
LC/MS (方法4、ESIpos)：R_t＝1.49分、m/z＝455 [M-H₂O+H]⁺。 Example 6
2- (3-{[3- (3- {4- [1- (methoxymethyl) cyclobutyl] phenyl} -1,2,4-oxadiazol-5-yl) -5-methyl-1H-pyrazole- 1-yl] methyl} phenyl) propan-2-ol

According to the method described in Example 4, 150 mg (0.317 mmol) of the compound from Example 58A and 114 mg (75% of theory) of the title compound were obtained from methylmagnesium chloride. Here, after 3 hours, the reaction was terminated by adding 100 μl of acetic acid at room temperature. The reaction mixture was subsequently evaporated on a rotary evaporator until dry. The title compound was isolated from the residue by MPLC (silica gel, mobile phase: cyclohexane / ethyl acetate 5: 1 → 3: 1).
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 8.13 (d, 2H), 7.40 (d, 1H), 7.36 (s, 1H), 7.30 (t, 1H), 7.29 (d, 2H), 7.01 (d, 1H), 6.80 (s, 1H), 5.47 (s, 2H), 3.56 (s, 2H), 3.28 (s, 3H), 2.43-2.28 (m, 4H), 2.29 (s, 3H) 2.15-2.03 (m, 1H), 1.93-1.83 (m, 1H), 1.74 (s, 1H), 1.56 (s, 6H).
LC / MS (Method 4, ESIpos): R _t = 1.49 min, m / z = 455 [MH ₂ O + H] ⁺ .

実施例4に記載した方法に準じて、実施例59Aからの化合物150 mg(0.306 mmol)およびメチルマグネシウムクロライドから、表題化合物120 mg(理論値の80%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：7.93 (dd、1H)、7.82 (dd、1H)、7.40 (d、1H)、7.37 (s、1H)、7.30 (t、1H)、7.22 (d、1H)、7.00 (d、1H)、6.81 (s、1H)、5.47 (s、2H)、3.66 (s、2H)、3.28 (s、3H)、2.48-2.40 (m、2H)、2.37-2.30 (m、2H)、2.29 (s、3H)、2.19-2.07 (m、1H)、1.94-1.85 (m、1H)、1.73 (s、1H)、1.55 (s、6H)。
LC/MS (方法6、ESIpos)：R_t＝1.36分、m/z＝473 [M-H₂O+H]⁺、491 [M+H]⁺。 Example 7
2- (3-{[3- (3- {3-Fluoro-4- [1- (methoxymethyl) cyclobutyl] phenyl} -1,2,4-oxadiazol-5-yl) -5-methyl- 1H-pyrazol-1-yl] methyl} phenyl) propan-2-ol

According to the method described in Example 4, 150 mg (0.306 mmol) of the compound from Example 59A and 120 mg (80% of theory) of the title compound were obtained from methylmagnesium chloride.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 7.93 (dd, 1H), 7.82 (dd, 1H), 7.40 (d, 1H), 7.37 (s, 1H), 7.30 (t, 1H), 7.22 (d, 1H), 7.00 (d, 1H), 6.81 (s, 1H), 5.47 (s, 2H), 3.66 (s, 2H), 3.28 (s, 3H), 2.48-2.40 (m, 2H) 2.37-2.30 (m, 2H), 2.29 (s, 3H), 2.19-2.07 (m, 1H), 1.94-1.85 (m, 1H), 1.73 (s, 1H), 1.55 (s, 6H).
LC / MS (Method 6, ESIpos): R _t = 1.36 min, m / z = 473 [MH ₂ O + H] ⁺ , 491 [M + H] ⁺ .

実施例4に記載した方法に準じて、実施例60Aからの化合物145 mg(0.298 mmol)およびメチルマグネシウムクロライドから、表題化合物119 mg(理論値の82%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：8.12 (d、2H)、7.96 (d、2H)、7.40 (d、1H)、7.37 (s、1H)、7.30 (t、1H)、7.01 (d、1H)、6.81 (s、1H)、5.47 (s、2H)、3.41 (s、2H)、3.22 (s、3H)、2.29 (s、3H)、2.07-2.00 (m、2H)、1.96-1.88 (m、2H)、1.82 (s、1H)、1.78-1.70 (m、4H)、1.55 (s、6H)。
LC/MS (方法6、ESIpos)：R_t＝1.37分、m/z＝469 [M-H₂O+H]⁺、487 [M+H]⁺。 Example 8
2- (3-{[3- (3- {4- [1- (methoxymethyl) cyclopentyl] phenyl} -1,2,4-oxadiazol-5-yl) -5-methyl-1H-pyrazole- 1-yl] methyl} phenyl) propan-2-ol

According to the method described in Example 4, 145 mg (0.298 mmol) of the compound from Example 60A and 119 mg (82% of theory) of the title compound were obtained from methylmagnesium chloride.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 8.12 (d, 2H), 7.96 (d, 2H), 7.40 (d, 1H), 7.37 (s, 1H), 7.30 (t, 1H), 7.01 (d, 1H), 6.81 (s, 1H), 5.47 (s, 2H), 3.41 (s, 2H), 3.22 (s, 3H), 2.29 (s, 3H), 2.07-2.00 (m, 2H) 1.96-1.88 (m, 2H), 1.82 (s, 1H), 1.78-1.70 (m, 4H), 1.55 (s, 6H).
LC / MS (Method _{6, ESIpos): R t =} 1.37 min, m / z = 469 [MH 2 O + H] +, 487 [M + H] +.

実施例4に記載した方法に準じて、実施例61Aからの化合物36.5 mg(0.075 mmol)およびメチルマグネシウムクロライドから、表題化合物30.8 mg(理論値の84%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：8.13 (d、2H)、7.41 (d、1H)、7.36 (s、1H)、7.30 (t、1H)、7.29 (d、2H)、7.01 (d、1H)、6.81 (s、1H)、5.47 (s、2H)、3.57 (s、2H)、3.38 (quart、2H)、2.41-2.30 (m、4H)、2.28 (s、3H)、2.15-2.03 (m、1H)、1.92-1.82 (m、1H)、1.76 (s、1H)、1.55 (s、6H)、1.10 (t、3H)。
LC/MS (方法2、ESIpos)：R_t＝2.83分、m/z＝469 [M-H₂O+H]⁺、487 [M+H]⁺。 Example 9
2- (3-{[3- (3- {4- [1- (ethoxymethyl) cyclobutyl] phenyl} -1,2,4-oxadiazol-5-yl) -5-methyl-1H-pyrazole- 1-yl] methyl} phenyl) propan-2-ol

The title compound 30.8 mg (84% of theory) was obtained from 36.5 mg (0.075 mmol) of the compound from Example 61A and methylmagnesium chloride according to the method described in Example 4.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 8.13 (d, 2H), 7.41 (d, 1H), 7.36 (s, 1H), 7.30 (t, 1H), 7.29 (d, 2H), 7.01 (d, 1H), 6.81 (s, 1H), 5.47 (s, 2H), 3.57 (s, 2H), 3.38 (quart, 2H), 2.41-2.30 (m, 4H), 2.28 (s, 3H) 2.15-2.03 (m, 1H), 1.92-1.82 (m, 1H), 1.76 (s, 1H), 1.55 (s, 6H), 1.10 (t, 3H).
LC / MS (Method 2, ESIpos): R _t = 2.83 min, m / z = 469 [MH ₂ O + H] ⁺ , 487 [M + H] ⁺ .

実施例4に記載した方法に準じて、実施例62Aからの化合物100 mg(0.211 mmol)およびメチルマグネシウムクロライドから、表題化合物76 mg(理論値の77%)を得た。この場合、室温での反応時間は1.5時間であった。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：8.27 (d、2H)、7.78 (d、2H)、7.41 (d、1H)、7.37 (s、1H)、7.30 (t、1H)、7.01 (d、1H)、6.82 (s、1H)、5.47 (s、2H)、2.29 (s、3H)、1.74 (s、1H)、1.55 (s、6H)。
LC/MS (方法4、ESIpos)：R_t＝1.53分、m/z＝457 [M-H₂O+H]⁺。 Example 10
2- (3-{[5-methyl-3- (3- {4-[(trifluoromethyl) sulfanyl] phenyl} -1,2,4-oxadiazol-5-yl) -1H-pyrazole-1 -Il] methyl} phenyl) propan-2-ol

According to the method described in Example 4, 100 mg (0.211 mmol) of the compound from Example 62A and 76 mg (77% of theory) of the title compound were obtained from methylmagnesium chloride. In this case, the reaction time at room temperature was 1.5 hours.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 8.27 (d, 2H), 7.78 (d, 2H), 7.41 (d, 1H), 7.37 (s, 1H), 7.30 (t, 1H), 7.01 (d, 1H), 6.82 (s, 1H), 5.47 (s, 2H), 2.29 (s, 3H), 1.74 (s, 1H), 1.55 (s, 6H).
LC / MS (Method 4, ESIpos): R _t = 1.53 min, m / z = 457 [MH ₂ O + H] ⁺ .

実施例4実施例63に記載した方法に準じてAからの化合物100 mg(0.210 mmol)およびメチルマグネシウムクロライドから、表題化合物83 mg(理論値の83%)を得た。この場合、反応時間は室温で1.5時間であった。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：8.23 (d、2H)、7.52 (d、2H)、7.41 (d、1H)、7.37 (s、1H)、7.30 (t、1H)、7.01 (d、1H)、6.82 (s、1H)、5.47 (s、2H)、4.00-3.87 (m、4H)、2.29 (s、3H)、2.29-2.21 (m、2H)、1.98-1.91 (m、2H)、1.76 (s、1H)、1.55 (s、6H)。
LC/MS (方法6、ESIpos)：R_t＝1.16分、m/z＝459 [M-H₂O+H]⁺、477 [M+H]⁺。 Example 11
2- {3-[(3- {3- [4- (4-Fluorotetrahydro-2H-pyran-4-yl) phenyl] -1,2,4-oxadiazol-5-yl} -5-methyl -1H-pyrazol-1-yl) methyl] phenyl} propan-2-ol

Example 4 According to the method described in Example 63, 100 mg (0.210 mmol) of the compound from A and 83 mg (83% of the theoretical value) of the title compound were obtained from methylmagnesium chloride. In this case, the reaction time was 1.5 hours at room temperature.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 8.23 (d, 2H), 7.52 (d, 2H), 7.41 (d, 1H), 7.37 (s, 1H), 7.30 (t, 1H), 7.01 (d, 1H), 6.82 (s, 1H), 5.47 (s, 2H), 4.00-3.87 (m, 4H), 2.29 (s, 3H), 2.29-2.21 (m, 2H), 1.98-1.91 ( m, 2H), 1.76 (s, 1H), 1.55 (s, 6H).
LC / MS (Method _{6, ESIpos): R t =} 1.16 min, m / z = 459 [MH 2 O + H] +, 477 [M + H] +.

室温で、カリウムtert-ブトキシド58 mg(0.52 mmol)、続いて実施例46Aからの化合物147 mg(0.60 mmol)のTHF溶液1.5 mlを、実施例29Aからの化合物131 mg(0.40 mmol)のTHF溶液2 mlに加えた。混合物を室温で1時間攪拌した。続いて水30 mlを加え、混合物を各回30 mlの酢酸エチルで3回抽出した。合わせた有機相を硫酸ナトリウムで乾燥させ、濾過し、濃縮した。残渣を分取用HPLC(方法14)により精製した。透明な生成物分画を合わせ、水相の残容量まで濃縮した。飽和重炭酸ナトリウム水溶液を加えてpHを7とし、続いて水相を各回30 mlの酢酸エチルで2回抽出した。続いて合わせた有機相を硫酸ナトリウムで乾燥させ、濾過し、濃縮した。これにより表題化合物191 mg(理論値の53%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：8.08 (dd、1H)、8.06-8.01 (m、1H)、7.46-7.39 (m、2H)、7.37 (s、1H)、7.30 (t、1H)、7.01 (d、1H)、6.82 (s、1H)、5.47 (s、2H)、2.29 (s、3H)、1.56 (s、6H)。
LC/MS (方法6、ESIpos)：R_t＝1.33分、m/z＝477 [M+H]⁺。 Example 12
2- {3-[(3- {3- [3-Fluoro-4- (trifluoromethoxy) phenyl] -1,2,4-oxadiazol-5-yl} -5-methyl-1H-pyrazole- 1-yl) methyl] phenyl} propan-2-ol

At room temperature, potassium tert-butoxide 58 mg (0.52 mmol), followed by 1.5 ml of THF solution of compound 147 mg (0.60 mmol) from Example 46A, 131 mg compound (0.40 mmol) from Example 29A in THF Added to 2 ml. The mixture was stirred at room temperature for 1 hour. Subsequently, 30 ml of water were added and the mixture was extracted three times with 30 ml of ethyl acetate each time. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (Method 14). The clear product fractions were combined and concentrated to the remaining volume of the aqueous phase. Saturated aqueous sodium bicarbonate was added to bring the pH to 7, and the aqueous phase was then extracted twice with 30 ml of ethyl acetate each time. The combined organic phases were subsequently dried over sodium sulfate, filtered and concentrated. This gave 191 mg (53% of theory) of the title compound.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 8.08 (dd, 1H), 8.06-8.01 (m, 1H), 7.46-7.39 (m, 2H), 7.37 (s, 1H), 7.30 (t , 1H), 7.01 (d, 1H), 6.82 (s, 1H), 5.47 (s, 2H), 2.29 (s, 3H), 1.56 (s, 6H).
LC / MS (Method 6, ESIpos): R _t = 1.33 min, m / z = 477 [M + H] ⁺ .

実施例12に記載した方法に準じて、実施例24Aからの化合物114 mg(0.40 mmol)および実施例46Aからの化合物147 mg(0.60 mmol)を用いて表題化合物81 mg(理論値の43%)を得た。ここでは、方法15に従い分取用HPLCによる精製を行った。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：8.20 (d、2H)、7.50 (d、2H)、7.43-7.38 (d、1H)、7.36 (s、1H)、7.30 (t、1H)、7.03-6.98 (d、1H)、6.82 (s、1H)、5.47 (s、2H)、2.29 (s、3H)、1.75 (s、3H)、1.70 (s、3H)、1.55 (s、6H)。
LC/MS (方法2、ESIpos)：R_t＝2.59分、m/z＝417 [M-H₂O+H]⁺。 Example 13
2- {3-[(3- {3- [4- (2-fluoropropan-2-yl) phenyl] -1,2,4-oxadiazol-5-yl} -5-methyl-1H-pyrazole -1-yl) methyl] phenyl} propan-2-ol

In accordance with the method described in Example 12, using 114 mg (0.40 mmol) of the compound from Example 24A and 147 mg (0.60 mmol) of the compound from Example 46A, 81 mg (43% of theory) of the title compound Got. Here, purification by preparative HPLC was performed according to Method 15.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 8.20 (d, 2H), 7.50 (d, 2H), 7.43-7.38 (d, 1H), 7.36 (s, 1H), 7.30 (t, 1H ), 7.03-6.98 (d, 1H), 6.82 (s, 1H), 5.47 (s, 2H), 2.29 (s, 3H), 1.75 (s, 3H), 1.70 (s, 3H), 1.55 (s, 6H).
LC / MS (method _{2, ESIpos): R t =} 2.59 min, m / z = 417 [MH 2 O + H] +.

実施例12に記載した方法に準じて、実施例25Aからの化合物143 mg(0.40 mmol)および実施例46Aからの化合物147 mg(0.60 mmol)を用いて表題化合物78 mg(理論値の37%、純度95%)を得た。ここでは、方法15に従い分取用HPLCによる精製を行った。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：8.52 (d、2H)、8.18 (d、2H)、7.43-7.36 (m、2H)、7.31 (t、1H)、7.01 (d、1H)、6.84 (s、1H)、5.48 (s、2H)、2.31 (s、3H)、1.56 (s、6H)。
LC/MS (方法2、ESIpos)：R_t＝2.63分、m/z＝489 [M-H₂O+H]⁺。 Example 14
2- (3-{[5-Methyl-3- (3- {4-[(trifluoromethyl) sulfonyl] phenyl} -1,2,4-oxadiazol-5-yl) -1H-pyrazole-1 -Il] methyl} phenyl) propan-2-ol

In accordance with the method described in Example 12, 143 mg (0.40 mmol) of the compound from Example 25A and 147 mg (0.60 mmol) of the compound from Example 46A were used to give 78 mg of the title compound (37% of theory, Purity 95%) was obtained. Here, purification by preparative HPLC was performed according to Method 15.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 8.52 (d, 2H), 8.18 (d, 2H), 7.43-7.36 (m, 2H), 7.31 (t, 1H), 7.01 (d, 1H ), 6.84 (s, 1H), 5.48 (s, 2H), 2.31 (s, 3H), 1.56 (s, 6H).
LC / MS (Method 2, ESIpos): R _t = 2.63 min, m / z = 489 [MH ₂ O + H] ⁺ .

実施例12に記載した方法に準じて、実施例30Aからの化合物134 mg(0.40 mmol)および実施例46Aからの化合物147 mg(0.60 mmol)を用いて表題化合物103 mg(理論値の50%、純度95%)を得た。ここでは、方法15に従い分取用HPLCによる精製を行った。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：8.18 (d、2H)、7.58 (d、2H)、7.39 (d、1H)、7.36 (s、1H)、7.30 (t、1H)、7.01 (d、1H)、6.81 (s、1H)、5.46 (s、2H)、2.29 (s、3H)、1.55 (s、6H)、1.43-1.37 (m、2H)、1.12-1.05 (m、2H)。
LC/MS (方法2、ESIpos)：R_t＝2.74分、m/z＝463 [M-H₂O+H]⁺。 Example 15
2- (3-{[5-methyl-3- (3- {4- [1- (trifluoromethyl) cyclopropyl] phenyl} -1,2,4-oxadiazol-5-yl) -1H- Pyrazol-1-yl] methyl} phenyl) propan-2-ol

According to the method described in Example 12, 134 mg (0.40 mmol) of the compound from Example 30A and 147 mg (0.60 mmol) of the compound from Example 46A were used to give 103 mg of the title compound (50% of theory, Purity 95%) was obtained. Here, purification by preparative HPLC was performed according to Method 15.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 8.18 (d, 2H), 7.58 (d, 2H), 7.39 (d, 1H), 7.36 (s, 1H), 7.30 (t, 1H), 7.01 (d, 1H), 6.81 (s, 1H), 5.46 (s, 2H), 2.29 (s, 3H), 1.55 (s, 6H), 1.43-1.37 (m, 2H), 1.12-1.05 (m, 2H).
LC / MS (Method 2, ESIpos): R _t = 2.74 min, m / z = 463 [MH ₂ O + H] ⁺ .

実施例12に記載した方法に準じて、実施例26Aからの化合物120 mg(0.40 mmol)および実施例46Aからの化合物147 mg(0.60 mmol)を用いて表題化合物89 mg(理論値の46%、純度92%)を得た。ここでは、方法15に従い分取用HPLCによる精製を行った。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：8.17 (d、2H)、7.64 (d、2H)、7.40 (d、1H)、7.36 (s、1H)、7.30 (t、1H)、7.00 (d、1H)、6.82 (s、1H)、5.47 (s、2H)、2.28 (s、3H)、1.55 (s、6H)、0.31 (s、9H)。
LC/MS (方法2、ESIpos)：R_t＝2.94分、m/z＝447 [M+H]⁺。 Example 16
2- {3-[(5-Methyl-3- {3- [4- (trimethylsilyl) phenyl] -1,2,4-oxadiazol-5-yl} -1H-pyrazol-1-yl) methyl] Phenyl} propan-2-ol

According to the method described in Example 12, using 120 mg (0.40 mmol) of the compound from Example 26A and 147 mg (0.60 mmol) of the compound from Example 46A, 89 mg (46% of theory, 46% of theory) 92% purity) was obtained. Here, purification by preparative HPLC was performed according to Method 15.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 8.17 (d, 2H), 7.64 (d, 2H), 7.40 (d, 1H), 7.36 (s, 1H), 7.30 (t, 1H), 7.00 (d, 1H), 6.82 (s, 1H), 5.47 (s, 2H), 2.28 (s, 3H), 1.55 (s, 6H), 0.31 (s, 9H).
LC / MS (Method 2, ESIpos): R _t = 2.94 min, m / z = 447 [M + H] ⁺ .

実施例4に記載した方法に準じて、実施例64Aからの化合物150 mg(0.33 mmol)およびメチルマグネシウムブロマイド溶液(1.4 M THF/トルエン溶液)から、表題化合物51 mg(理論値の34%)を得た。この場合、反応時間は室温で1時間であり、粗成生物の精製は方法17に従い分取用HPLCで行った。
¹H NMR (400 MHz、DMSO-d₆、δ/ppm)：8.20 (d、2H)、7.59 (d、2H)、7.41 (s、1H)、7.38 (d、1H)、7.28 (t、1H)、6.97 (d、1H)、6.93 (s、1H)、5.49 (s、2H)、5.01 (s、1H)、2.34 (s、3H)、1.40 (s、6H)。
LC/MS (方法6、ESIpos)：R_t＝1.31分、m/z＝459 [M+H]⁺。 Example 17
2- {3-[(5-methyl-3- {3- [4- (trifluoromethoxy) phenyl] -1,2,4-oxadiazol-5-yl} -1H-pyrazol-1-yl) Methyl] phenyl} propan-2-ol

According to the method described in Example 4, from the compound from Example 64A 150 mg (0.33 mmol) and methylmagnesium bromide solution (1.4 M THF / toluene solution), the title compound 51 mg (34% of theory) was obtained. Obtained. In this case, the reaction time was 1 hour at room temperature, and the crude product was purified by preparative HPLC according to Method 17.
¹ H NMR (400 MHz, DMSO-d ₆ , δ / ppm): 8.20 (d, 2H), 7.59 (d, 2H), 7.41 (s, 1H), 7.38 (d, 1H), 7.28 (t, 1H ), 6.97 (d, 1H), 6.93 (s, 1H), 5.49 (s, 2H), 5.01 (s, 1H), 2.34 (s, 3H), 1.40 (s, 6H).
LC / MS (Method 6, ESIpos): R _t = 1.31 min, m / z = 459 [M + H] ⁺ .

0℃で、メチルマグネシウムクロライド溶液(3 M THF溶液)15.9 ml(47.7 mmol)を、実施例54Aからの化合物11.0 g(22.7 mmol)の無水THF溶液220 mlに加えた。続いて氷/水浴を外し、室温で攪拌を続けた。1時間後、飽和塩化ナトリウム水溶液約100 mlおよび水1.5リットルを加えた。混合物を各回約500 ml酢酸エチルで3回抽出した。合わせた有機層抽出物を飽和塩化ナトリウム溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、濾過し、最後にロータリーエバポレーターにより溶媒を除去した。得られた粗成生物を、シクロヘキサン/酢酸エチル 4:1 → 1:1移動相を用いてシリカゲル約330 gで、吸引濾過により精製した。合わせた生成物分画から溶媒を除去し、生成物をエタノール/水(2:1)120 ml(沸点→室温)から結晶化した。これにより、濾過した後、高真空下乾燥させ、表題化合物5.79 g(理論値の53%)を得た。
融点：167℃
¹H NMR (400 MHz、CDCl₃、δ/ppm)：8.20 (d、2H)、7.62 (d、2H)、7.41 (d、1H)、7.37 (s、1H)、7.31 (t、1H)、7.01 (d、1H)、6.83 (s、1H)、5.47 (s、2H)、2.29 (s、3H)、1.75 (s、1H)、1.62 (s、6H)、1.55 (s、6H)。
LC/MS (方法6、ESIpos)：R_t＝1.32分、m/z＝467 [M-H₂O+H]⁺、485 [M+H]⁺。 Example 18
2- {3-[(5-methyl-3- {3- [4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenyl] -1,2,4-oxadiazole -5-yl} -1H-pyrazol-1-yl) methyl] phenyl} propan-2-ol

At 0 ° C., 15.9 ml (47.7 mmol) of methylmagnesium chloride solution (3 M THF solution) was added to 220 ml of anhydrous THF solution of 11.0 g (22.7 mmol) of the compound from Example 54A. The ice / water bath was then removed and stirring was continued at room temperature. After 1 hour, about 100 ml of saturated aqueous sodium chloride solution and 1.5 liters of water were added. The mixture was extracted three times with about 500 ml ethyl acetate each time. The combined organic layer extracts were washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and finally the solvent was removed by rotary evaporator. The resulting crude product was purified by suction filtration over about 330 g of silica gel using a cyclohexane / ethyl acetate 4: 1 → 1: 1 mobile phase. The solvent was removed from the combined product fractions and the product was crystallized from 120 ml (boiling point → room temperature) of ethanol / water (2: 1). This was filtered and then dried under high vacuum to give 5.79 g (53% of theory) of the title compound.
Melting point: 167 ° C
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 8.20 (d, 2H), 7.62 (d, 2H), 7.41 (d, 1H), 7.37 (s, 1H), 7.31 (t, 1H), 7.01 (d, 1H), 6.83 (s, 1H), 5.47 (s, 2H), 2.29 (s, 3H), 1.75 (s, 1H), 1.62 (s, 6H), 1.55 (s, 6H).
LC / MS (Method _{6, ESIpos): R t =} 1.32 min, m / z = 467 [MH 2 O + H] +, 485 [M + H] +.

実施例4に記載した方法に準じて、実施例65Aからの化合物180 mg(0.40 mmol)およびメチルマグネシウムクロライドから表題化合物70 mg(理論値の40%)を得た。この場合、反応時間は室温で1時間であり、粗成生物の精製は方法17に従い分取用HPLCにより行った。
¹H NMR (400 MHz、DMSO-d₆、δ/ppm)：8.12 (d、2H)、7.70 (d、2H)、7.41 (s、1H)、7.38 (d、1H)、7.28 (t、1H)、6.96 (d、1H)、6.94 (s、1H)、5.49 (s、2H)、5.03 (s、1H)、2.64 (t、2H)、2.59 (t、2H)、2.35 (s、3H)、2.07 (m、1H)、1.77 (m、1H)、1.40 (s、6H)。
LC/MS (方法6、ESIpos)：R_t＝1.29分、m/z＝447 [M+H]⁺。 Example 19
2- {3-[(3- {3- [4- (1-Fluorocyclobutyl) phenyl] -1,2,4-oxadiazol-5-yl} -5-methyl-1H-pyrazole-1- Yl) methyl] phenyl} propan-2-ol

According to the method described in Example 4, 180 mg (0.40 mmol) of the compound from Example 65A and 70 mg (40% of theory) of the title compound were obtained from methylmagnesium chloride. In this case, the reaction time was 1 hour at room temperature, and the crude product was purified by preparative HPLC according to Method 17.
¹ H NMR (400 MHz, DMSO-d ₆ , δ / ppm): 8.12 (d, 2H), 7.70 (d, 2H), 7.41 (s, 1H), 7.38 (d, 1H), 7.28 (t, 1H ), 6.96 (d, 1H), 6.94 (s, 1H), 5.49 (s, 2H), 5.03 (s, 1H), 2.64 (t, 2H), 2.59 (t, 2H), 2.35 (s, 3H) , 2.07 (m, 1H), 1.77 (m, 1H), 1.40 (s, 6H).
LC / MS (Method _{6, ESIpos): R t =} 1.29 min, m / z = 447 [M + H] +.

実施例66Aからの化合物250 mg(0.532 mmol)の無水THF5 ml、合わせてエチルマグネシウムクロライド溶液(2 M THF溶液)2.2 ml室温で滴下した。反応の進行を分析的HPLCによりモニターし、完全な変換に必要な量のグリニャール試薬のみを添加した。続いて水2 mlを加えた。ほとんどの溶媒および水をロータリーエバポレーターで除去し、残渣を分取用HPLC(方法15)で精製した。透明な生成物分画を合わせ、水相の残容量まで濃縮した。飽和重炭酸ナトリウム水溶液を加えた後、水相を各回30 mlの酢酸エチルで2回抽出した。続いて合わせた有機相を硫酸マグネシウムで乾燥させ、濾過し、濃縮した。これにより表題化合物97 mg(理論値の32%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：8.13 (d、2H)、7.50 (d、2H)、7.29 (d、1H)、7.21-7.14 (m、2H)、6.98 (d、1H)、6.80 (s、1H)、5.44 (s、2H)、2.27 (s、3H)、1.36 (s、9H)、1.29-1.23 (m、3H)、1.01 (dd、2H)。
LC/MS (方法4、ESIpos)：R_t＝1.53分、m/z＝429 [M+H]⁺。 Example 20
1- [3-({3- [3- (4-tert-butylphenyl) -1,2,4-oxadiazol-5-yl] -5-methyl-1H-pyrazol-1-yl} methyl) Phenyl] cyclopropanol

250 ml (0.532 mmol) of the compound from Example 66A in 5 ml of anhydrous THF, combined with ethylmagnesium chloride solution (2 M THF solution) 2.2 ml was added dropwise at room temperature. The progress of the reaction was monitored by analytical HPLC and only the amount of Grignard reagent required for complete conversion was added. Subsequently, 2 ml of water was added. Most of the solvent and water were removed on a rotary evaporator and the residue was purified by preparative HPLC (Method 15). The clear product fractions were combined and concentrated to the remaining volume of the aqueous phase. After adding saturated aqueous sodium bicarbonate solution, the aqueous phase was extracted twice with 30 ml of ethyl acetate each time. The combined organic phases were subsequently dried over magnesium sulfate, filtered and concentrated. This gave 97 mg (32% of theory) of the title compound.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 8.13 (d, 2H), 7.50 (d, 2H), 7.29 (d, 1H), 7.21-7.14 (m, 2H), 6.98 (d, 1H ), 6.80 (s, 1H), 5.44 (s, 2H), 2.27 (s, 3H), 1.36 (s, 9H), 1.29-1.23 (m, 3H), 1.01 (dd, 2H).
LC / MS (Method 4, ESIpos): R _t = 1.53 min, m / z = 429 [M + H] ⁺ .

0℃で、エチルマグネシウムクロライド溶液(2 M THF溶液)1.6 ml(3.21 mmol)を実施例67Aからの化合物160 mg(0.25 mmol、79%純度)のTHF溶液5 mlに加えた。混合物を室温に戻し、室温で30分攪拌した。溶媒を除去した後、残渣をカラムクロマトグラフィー(シリカゲル、移動相：シクロヘキサン/酢酸エチル 6:4)により精製した。合わせた生成物分画を濃縮し、残渣を分取用薄層クロマトグラフィー(シリカゲル、移動相：シクロヘキサン/酢酸エチル 1:1)により再精製した。生成物分画をジクロロメタン/メタノール(95:5)で抽出した。溶媒を除去し、表題化合物15 mg(理論値の12%、純度94%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：8.15 (d、2H)、7.35 (d、2H)、7.31-7.26 (m、1H)、7.21-7.14 (m、2H)、6.99 (d、1H)、6.81 (s、1H)、5.45 (s、2H)、4.13-4.06 (m、2H)、3.55 (td、2H)、2.89-2.78 (m、1H)、2.28 (s、3H)、1.92-1.77 (m、4H)、1.29-1.24 (m、2H)、1.04-0.99 (m、2H)。
LC/MS (方法6、ESIpos)：R_t＝1.15分、m/z＝457 [M+H]⁺。 Example 21
1- {3-[(5-Methyl-3- {3- [4- (tetrahydro-2H-pyran-4-yl) phenyl] -1,2,4-oxadiazol-5-yl} -1H- Pyrazol-1-yl) methyl] phenyl} cyclopropanol

At 0 ° C., 1.6 ml (3.21 mmol) of ethylmagnesium chloride solution (2 M THF solution) was added to 5 ml of a THF solution of the compound from Example 67A 160 mg (0.25 mmol, 79% purity). The mixture was returned to room temperature and stirred at room temperature for 30 minutes. After removing the solvent, the residue was purified by column chromatography (silica gel, mobile phase: cyclohexane / ethyl acetate 6: 4). The combined product fractions were concentrated and the residue was repurified by preparative thin layer chromatography (silica gel, mobile phase: cyclohexane / ethyl acetate 1: 1). The product fraction was extracted with dichloromethane / methanol (95: 5). The solvent was removed to give 15 mg (12% of theory, purity 94%) of the title compound.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 8.15 (d, 2H), 7.35 (d, 2H), 7.31-7.26 (m, 1H), 7.21-7.14 (m, 2H), 6.99 (d , 1H), 6.81 (s, 1H), 5.45 (s, 2H), 4.13-4.06 (m, 2H), 3.55 (td, 2H), 2.89-2.78 (m, 1H), 2.28 (s, 3H), 1.92-1.77 (m, 4H), 1.29-1.24 (m, 2H), 1.04-0.99 (m, 2H).
LC / MS (Method _{6, ESIpos): R t =} 1.15 min, m / z = 457 [M + H] +.

0℃で、エチルマグネシウムクロライド溶液(2 M THF溶液)2.4 ml(4.73 mmol)を、ゆっくりと実施例68Aからの化合物230 mg(0.43 mmol、90%純度)のTHF溶液7.5 mlに加えた。混合物を室温に戻し、室温で30分攪拌した。続いて反応液をもう一度0℃に冷却し、水5 ml、続いて1 M 塩酸5 mlを滴下した。混合物は、さらに水で希釈し、酢酸エチルで2回抽出した。合わせた酢酸エチル相を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、濾過し、濃縮した。残渣を分取用HPLC(方法15)により精製した。透明な生成物分画を合わせ、水相の残容量まで濃縮した。飽和重炭酸ナトリウム水溶液を加えた後、混合物を酢酸エチルで2回抽出し、合わせた有機相を硫酸マグネシウムで乾燥させ、濾過し、濃縮した。減圧下、残渣を乾燥させ、表題化合物121 mg(理論値の58%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：8.17 (d、2H)、7.64 (d、2H)、7.30-7.26 (m、1H)、7.20 (s、1H)、7.16 (d、1H)、6.98 (d、1H)、6.81 (s、1H)、5.45 (s、2H)、2.28 (s、3H)、1.29-1.24 (m、2H)、1.03-0.99 (m、2H)、0.31 (s、9H)。
LC/MS (方法4、ESIpos)：R_t＝1.59分、m/z＝445 [M+H]⁺。 Example 22
1- {3-[(5-Methyl-3- {3- [4- (trimethylsilyl) phenyl] -1,2,4-oxadiazol-5-yl} -1H-pyrazol-1-yl) methyl] Phenyl} cyclopropanol

At 0 ° C., 2.4 ml (4.73 mmol) of ethylmagnesium chloride solution (2 M THF solution) was slowly added to 7.5 ml of a THF solution of 230 mg (0.43 mmol, 90% purity) of the compound from Example 68A. The mixture was returned to room temperature and stirred at room temperature for 30 minutes. Subsequently, the reaction solution was once again cooled to 0 ° C., and 5 ml of water and then 5 ml of 1 M hydrochloric acid were added dropwise. The mixture was further diluted with water and extracted twice with ethyl acetate. The combined ethyl acetate phases were washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (Method 15). The clear product fractions were combined and concentrated to the remaining volume of the aqueous phase. After adding saturated aqueous sodium bicarbonate solution, the mixture was extracted twice with ethyl acetate and the combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was dried under reduced pressure to give 121 mg (58% of theory) of the title compound.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 8.17 (d, 2H), 7.64 (d, 2H), 7.30-7.26 (m, 1H), 7.20 (s, 1H), 7.16 (d, 1H ), 6.98 (d, 1H), 6.81 (s, 1H), 5.45 (s, 2H), 2.28 (s, 3H), 1.29-1.24 (m, 2H), 1.03-0.99 (m, 2H), 0.31 ( s, 9H).
LC / MS (method _{4, ESIpos): R t =} 1.59 min, m / z = 445 [M + H] +.

実施例22に記載した方法に準じて、実施例69Aからの化合物285 mg(0.48 mmol、88%純度)およびエチルマグネシウムクロライド溶液から、表題化合物120 mg(理論値の52%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：8.19 (d、2H)、7.62 (d、2H)、7.28 (t、1H)、7.20 (s、1H)、7.16 (d、1H)、6.99 (d、1H)、6.81 (s、1H)、5.45 (s、2H)、2.28 (s、3H)、1.62 (s、6H)、1.27 (dd、2H)、1.01 (dd、2H)。
LC/MS (方法4、ESIpos)：R_t＝1.49分、m/z＝483 [M+H]⁺。 Example 23
1- {3-[(5-Methyl-3- {3- [4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenyl] -1,2,4-oxadiazole -5-yl} -1H-pyrazol-1-yl) methyl] phenyl} cyclopropanol

In a manner similar to that described in Example 22, the title compound 120 mg (52% of theory) was obtained from the compound 285 mg (0.48 mmol, 88% purity) from Example 69A and ethylmagnesium chloride solution.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 8.19 (d, 2H), 7.62 (d, 2H), 7.28 (t, 1H), 7.20 (s, 1H), 7.16 (d, 1H), 6.99 (d, 1H), 6.81 (s, 1H), 5.45 (s, 2H), 2.28 (s, 3H), 1.62 (s, 6H), 1.27 (dd, 2H), 1.01 (dd, 2H).
LC / MS (Method 4, ESIpos): R _t = 1.49 min, m / z = 483 [M + H] ⁺ .

実施例22に記載した方法に準じて、実施例70Aからの化合物359 mg(0.55 mmol、69%純度)およびエチルマグネシウムクロライド溶液から、表題化合物126 mg(理論値の55%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：8.12 (d、2H)、7.34 (d、2H)、7.29 (d、1H)、7.21-7.13 (m、2H)、6.99 (d、1H)、6.80 (s、1H)、5.44 (s、2H)、2.97 (sept、1H)、2.49 (s、1H)、2.27 (s、3H)、1.31-1.24 (m、8H)、1.01 (dd、2H)。
LC/MS (方法6、ESIpos)：R_t＝1.30分、m/z＝415 [M+H]⁺。 Example 24
1- [3-({3- [3- (4-Isopropylphenyl) -1,2,4-oxadiazol-5-yl] -5-methyl-1H-pyrazol-1-yl} methyl) phenyl] Cyclopropanol

According to the method described in Example 22, 359 mg (0.55 mmol, 69% purity) of the compound from Example 70A and 126 mg (55% of theory) of the title compound were obtained from an ethylmagnesium chloride solution.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 8.12 (d, 2H), 7.34 (d, 2H), 7.29 (d, 1H), 7.21-7.13 (m, 2H), 6.99 (d, 1H ), 6.80 (s, 1H), 5.44 (s, 2H), 2.97 (sept, 1H), 2.49 (s, 1H), 2.27 (s, 3H), 1.31-1.24 (m, 8H), 1.01 (dd, 2H).
LC / MS (Method 6, ESIpos): R _t = 1.30 min, m / z = 415 [M + H] ⁺ .

実施例22に記載した方法に準じて、実施例71Aからの化合物380 mg(0.57 mmol、72%純度)およびエチルマグネシウムクロライド溶液から、表題化合物132 mg(理論値の54%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：8.10 (d、2H)、7.31-7.24 (m、3H)、7.20 (s、1H)、7.16 (d、1H)、6.99 (d、1H)、6.80 (s、1H)、5.44 (s、2H)、2.54 (d、2H)、2.51 (s、1H)、2.27 (s、3H)、1.98-1.85 (m、1H)、1.26 (dd、2H)、1.01 (dd、2H)、0.93 (d、6H)。
LC/MS (方法6、ESIpos)：R_t＝1.37分、m/z＝429 [M+H]⁺。 Example 25
1- [3-({3- [3- (4-Isobutylphenyl) -1,2,4-oxadiazol-5-yl] -5-methyl-1H-pyrazol-1-yl} methyl) phenyl] Cyclopropanol

According to the method described in Example 22, 380 mg (0.57 mmol, 72% purity) of the compound from Example 71A and 132 mg (54% of theory) of the title compound were obtained from an ethylmagnesium chloride solution.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 8.10 (d, 2H), 7.31-7.24 (m, 3H), 7.20 (s, 1H), 7.16 (d, 1H), 6.99 (d, 1H ), 6.80 (s, 1H), 5.44 (s, 2H), 2.54 (d, 2H), 2.51 (s, 1H), 2.27 (s, 3H), 1.98-1.85 (m, 1H), 1.26 (dd, 2H), 1.01 (dd, 2H), 0.93 (d, 6H).
LC / MS (Method _{6, ESIpos): R t =} 1.37 min, m / z = 429 [M + H] +.

実施例22に記載した方法に準じて、実施例72Aからの化合物400 mg(0.54 mmol、70%純度)およびエチルマグネシウムクロライド溶液から、表題化合物118 mg(理論値の46%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：8.18 (d、2H)、7.58 (d、2H)、7.31-7.27 (m、1H)、7.20 (s、1H)、7.16 (d、1H)、6.99 (d、1H)、6.81 (s、1H)、5.45 (s、2H)、2.42 (s、1H)、2.28 (s、3H)、1.40 (dd、2H)、1.27 (dd、2H)、1.12-1.05 (m、2H)、1.01 (dd、2H)。
LC/MS (方法6、ESIpos)：R_t＝1.29分、m/z＝481 [M+H]⁺。 Example 26
1- (3-{[5-methyl-3- (3- {4- [1- (trifluoromethyl) cyclopropyl] phenyl} -1,2,4-oxadiazol-5-yl) -1H- Pyrazol-1-yl] methyl} phenyl) cyclopropanol

According to the method described in Example 22, from the compound from Example 72A 400 mg (0.54 mmol, 70% purity) and ethylmagnesium chloride solution 118 mg (46% of theory) of the title compound were obtained.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 8.18 (d, 2H), 7.58 (d, 2H), 7.31-7.27 (m, 1H), 7.20 (s, 1H), 7.16 (d, 1H ), 6.99 (d, 1H), 6.81 (s, 1H), 5.45 (s, 2H), 2.42 (s, 1H), 2.28 (s, 3H), 1.40 (dd, 2H), 1.27 (dd, 2H) 1.12-1.05 (m, 2H), 1.01 (dd, 2H).
LC / MS (Method _{6, ESIpos): R t =} 1.29 min, m / z = 481 [M + H] +.

実施例22に記載した方法に準じて、実施例73Aからの化合物422 mg(0.59 mmol、75%純度)およびエチルマグネシウムクロライド溶液から、表題化合物107 mg(理論値の35%、純度94%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：8.31 (d、2H)、7.89 (d、2H)、7.32-7.27 (m、1H)、7.20 (s、1H)、7.16 (d、1H)、6.99 (d、1H)、6.82 (s、1H)、5.46 (s、2H)、2.39 (s、broad、1H)、2.29 (s、3H)、1.27 (dd、2H)、1.02 (dd、2H)。
LC/MS (方法6、ESIpos)：R_t＝1.27分、m/z＝499 [M+H]⁺。 Example 27
1- {3-[(5-Methyl-3- {3- [4- (pentafluoro-λ ⁶ -sulfanyl) phenyl] -1,2,4-oxadiazol-5-yl} -1H-pyrazole- 1-yl) methyl] phenyl} cyclopropanol

According to the method described in Example 22, from the compound 422 mg (0.59 mmol, 75% purity) from Example 73A and ethylmagnesium chloride solution, 107 mg (35% of theory, purity 94%) of the title compound was obtained. Obtained.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 8.31 (d, 2H), 7.89 (d, 2H), 7.32-7.27 (m, 1H), 7.20 (s, 1H), 7.16 (d, 1H ), 6.99 (d, 1H), 6.82 (s, 1H), 5.46 (s, 2H), 2.39 (s, broad, 1H), 2.29 (s, 3H), 1.27 (dd, 2H), 1.02 (dd, 2H).
LC / MS (Method _{6, ESIpos): R t =} 1.27 min, m / z = 499 [M + H] +.

実施例22に記載した方法に準じて、実施例74Aからの化合物405 mg(0.64 mmol、75%純度)およびエチルマグネシウムクロライド溶液から表題化合物145 mg(理論値の52%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：8.19 (d、2H)、7.50 (d、2H)、7.29 (d、1H)、7.20 (s、1H)、7.16 (d、1H)、6.99 (d、1H)、6.81 (s、1H)、5.45 (s、2H)、2.42 (s、1H)、2.28 (s、3H)、1.75 (s、3H)、1.69 (s、3H)、1.26 (dd、2H)、1.01 (dd、2H)。
LC/MS (方法6、ESIpos)：R_t＝1.20分、m/z＝433 [M+H]⁺。 Example 28
1- {3-[(3- {3- [4- (2-Fluoropropan-2-yl) phenyl] -1,2,4-oxadiazol-5-yl} -5-methyl-1H-pyrazole -1-yl) methyl] phenyl} cyclopropanol

According to the method described in Example 22, 405 mg (0.64 mmol, 75% purity) of the compound from Example 74A and 145 mg (52% of theory) of the title compound were obtained from an ethylmagnesium chloride solution.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 8.19 (d, 2H), 7.50 (d, 2H), 7.29 (d, 1H), 7.20 (s, 1H), 7.16 (d, 1H), 6.99 (d, 1H), 6.81 (s, 1H), 5.45 (s, 2H), 2.42 (s, 1H), 2.28 (s, 3H), 1.75 (s, 3H), 1.69 (s, 3H), 1.26 (dd, 2H), 1.01 (dd, 2H).
LC / MS (Method _{6, ESIpos): R t =} 1.20 min, m / z = 433 [M + H] +.

実施例22実施例75に記載した方法に準じてAからの化合物375 mg(0.58 mmol、75%純度)およびエチルマグネシウムクロライド溶液から、表題化合物148 mg(理論値の58%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：8.34 (d、2H)、7.76 (d、2H)、7.31-7.27 (m、1H)、7.21 (s、1H)、7.16 (d、1H)、6.99 (d、1H)、6.82 (s、1H)、5.45 (s、2H)、2.39 (s、1H)、2.29 (s、3H)、1.27 (dd、2H)、1.02 (dd、2H)。
LC/MS (方法6、ESIpos)：R_t＝1.25分、m/z＝441 [M+H]⁺。 Example 29
1- {3-[(5-methyl-3- {3- [4- (trifluoromethyl) phenyl] -1,2,4-oxadiazol-5-yl} -1H-pyrazol-1-yl) Methyl] phenyl} cyclopropanol

Example 22 According to the method described in Example 75, 375 mg (0.58 mmol, 75% purity) of the compound from A and 148 mg (58% of theory) of the title compound were obtained from an ethylmagnesium chloride solution.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 8.34 (d, 2H), 7.76 (d, 2H), 7.31-7.27 (m, 1H), 7.21 (s, 1H), 7.16 (d, 1H ), 6.99 (d, 1H), 6.82 (s, 1H), 5.45 (s, 2H), 2.39 (s, 1H), 2.29 (s, 3H), 1.27 (dd, 2H), 1.02 (dd, 2H) .
LC / MS (Method 6, ESIpos): R _t = 1.25 min, m / z = 441 [M + H] ⁺ .

実施例22に記載した方法に準じて、実施例76Aからの化合物415 mg(0.60 mmol、75%純度)およびエチルマグネシウムクロライド溶液から、表題化合物141 mg(理論値の49%)を得た。ここでは、方法14に従い分取用HPLCを行った。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：8.22 (d、2H)、7.52 (d、2H)、7.31-7.27 (m、1H)、7.20 (s、1H)、7.16 (d、1H)、6.99 (d、1H)、6.81 (s、1H)、5.45 (s、2H)、4.00-3.94 (m、2H)、3.94-3.85 (m、2H)、2.47 (s、1H)、2.28 (s、3H)、2.28-2.10 (m、2H)、1.99-1.89 (m、2H)、1.27 (dd、2H)、1.01 (dd、2H)。
LC/MS (方法6、ESIpos)：R_t＝1.15分、m/z＝475 [M+H]⁺。 Example 30
1- {3-[(3- {3- [4- (4-Fluorotetrahydro-2H-pyran-4-yl) phenyl] -1,2,4-oxadiazol-5-yl} -5-methyl -1H-pyrazol-1-yl) methyl] phenyl} cyclopropanol

In a manner similar to that described in Example 22, 415 mg (0.60 mmol, 75% purity) of the compound from Example 76A and 141 mg (49% of theory) of the title compound were obtained from an ethylmagnesium chloride solution. Here, preparative HPLC was performed according to Method 14.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 8.22 (d, 2H), 7.52 (d, 2H), 7.31-7.27 (m, 1H), 7.20 (s, 1H), 7.16 (d, 1H ), 6.99 (d, 1H), 6.81 (s, 1H), 5.45 (s, 2H), 4.00-3.94 (m, 2H), 3.94-3.85 (m, 2H), 2.47 (s, 1H), 2.28 ( s, 3H), 2.28-2.10 (m, 2H), 1.9-1.89 (m, 2H), 1.27 (dd, 2H), 1.01 (dd, 2H).
LC / MS (Method _{6, ESIpos): R t =} 1.15 min, m / z = 475 [M + H] +.

実施例22に記載した方法に準じて、実施例77Aからの化合物318 mg(0.24 mmol、42%純度)およびエチルマグネシウムクロライド溶液から、表題化合物50 mg(理論値の37%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：8.11 (d、2H)、7.33 (d、2H)、7.30-7.26 (m、1H)、7.19 (s、1H)、7.16 (d、1H)、6.99 (d、1H)、6.80 (s、1H)、5.44 (s、2H)、2.60-2.51 (m、1H)、2.43 (s、1H)、2.27 (s、3H)、1.95-1.82 (m、4H)、1.77 (d、1H)、1.52-1.34 (m、4H)、1.32-1.22 (m、3H)、1.01 (dd、2H)。
LC/MS (方法6、ESIpos)：R_t＝1.45分、m/z＝455 [M+H]⁺。 Example 31
1- [3-({3- [3- (4-cyclohexylphenyl) -1,2,4-oxadiazol-5-yl] -5-methyl-1H-pyrazol-1-yl} methyl) phenyl] Cyclopropanol

According to the method described in Example 22, 318 mg (0.24 mmol, 42% purity) of the compound from Example 77A and 50 mg (37% of theory) of the title compound were obtained from an ethylmagnesium chloride solution.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 8.11 (d, 2H), 7.33 (d, 2H), 7.30-7.26 (m, 1H), 7.19 (s, 1H), 7.16 (d, 1H ), 6.99 (d, 1H), 6.80 (s, 1H), 5.44 (s, 2H), 2.60-2.51 (m, 1H), 2.43 (s, 1H), 2.27 (s, 3H), 1.95-1.82 ( m, 4H), 1.77 (d, 1H), 1.52-1.34 (m, 4H), 1.32-1.22 (m, 3H), 1.01 (dd, 2H).
LC / MS (Method _{6, ESIpos): R t =} 1.45 min, m / z = 455 [M + H] +.

実施例22に記載した方法に準じて、実施例78Aからの化合物395 mg(0.55 mmol、72%純度)およびエチルマグネシウムクロライド溶液から、表題化合物125 mg(理論値の46%)を得た。ここでは、方法14に従い分取用HPLCを行った。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：8.26 (d、2H)、7.78 (d、2H)、7.29 (t、1H)、7.20 (s、1H)、7.17 (d、1H)、6.99 (d、1H)、6.81 (s、1H)、5.45 (s、2H)、2.31 (s、1H)、2.28 (s、3H)、1.27 (dd、2H)、1.02 (dd、2H)。
LC/MS (方法6、ESIpos)：R_t＝1.32分、m/z＝473 [M+H]⁺。 Example 32
1- (3-{[5-Methyl-3- (3- {4-[(trifluoromethyl) sulfanyl] phenyl} -1,2,4-oxadiazol-5-yl) -1H-pyrazole-1 -Yl] methyl} phenyl) cyclopropanol

According to the method described in Example 22, 395 mg (0.55 mmol, 72% purity) of the compound from Example 78A and ethylmagnesium chloride solution gave 125 mg (46% of theory) of the title compound. Here, preparative HPLC was performed according to Method 14.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 8.26 (d, 2H), 7.78 (d, 2H), 7.29 (t, 1H), 7.20 (s, 1H), 7.17 (d, 1H), 6.99 (d, 1H), 6.81 (s, 1H), 5.45 (s, 2H), 2.31 (s, 1H), 2.28 (s, 3H), 1.27 (dd, 2H), 1.02 (dd, 2H).
LC / MS (Method _{6, ESIpos): R t =} 1.32 min, m / z = 473 [M + H] +.

実施例22に記載した方法に準じて、実施例79Aからの化合物185 mg(0.24 mmol、62%純度)およびエチルマグネシウムクロライド溶液から、表題化合物86 mg(理論値の76%)を得た。ここでは、方法14に従い分取用HPLCを行った。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：8.23 (d、2H)、7.59 (d、2H)、7.31-7.27 (m、1H)、7.20 (s、1H)、7.16 (d、1H)、6.99 (d、1H)、6.82 (s、1H)、5.45 (s、2H)、2.78-2.54 (m、4H)、2.49 (s、1H)、2.28 (s、3H)、2.19-2.07 (m、1H)、1.87-1.74 (m、1H)、1.27 (dd、2H)、1.01 (dd、2H)。
LC/MS (方法6、ESIpos)：R_t＝1.25分、m/z＝445 [M+H]⁺。 Example 33
1- {3-[(3- {3- [4- (1-Fluorocyclobutyl) phenyl] -1,2,4-oxadiazol-5-yl} -5-methyl-1H-pyrazole-1- Yl) methyl] phenyl} cyclopropanol

According to the method described in Example 22, 185 mg (0.24 mmol, 62% purity) of the compound from Example 79A and ethylmagnesium chloride solution gave 86 mg (76% of theory) of the title compound. Here, preparative HPLC was performed according to Method 14.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 8.23 (d, 2H), 7.59 (d, 2H), 7.31-7.27 (m, 1H), 7.20 (s, 1H), 7.16 (d, 1H ), 6.99 (d, 1H), 6.82 (s, 1H), 5.45 (s, 2H), 2.78-2.54 (m, 4H), 2.49 (s, 1H), 2.28 (s, 3H), 2.19-2.07 ( m, 1H), 1.87-1.74 (m, 1H), 1.27 (dd, 2H), 1.01 (dd, 2H).
LC / MS (Method 6, ESIpos): R _t = 1.25 min, m / z = 445 [M + H] ⁺ .

実施例66Aおよび実施例22に記載の方法と類似の方法により、実施例22Aからの化合物70 mg(0.23 mmol)、実施例47Aからの化合物102 mg(0.345 mmol)およびエチルマグネシウムクロライド溶液から、二工程で、表題化合物12 mg(理論値の12%)を得た。ここでは、方法18に従い分取用HPLCを行った。
¹H NMR (400 MHz、DMSO-d₆、δ/ppm)：8.20 (d、2H)、7.60 (d、2H)、7.27 (t、1H)、7.22 (s、1H)、7.08 (d、1H)、6.96 (d、1H)、6.93 (s、1H)、5.93 (s、1H)、5.48 (s、2H)、2.34 (s、3H)、1.09 (dd、2H)、0.92 (dd、2H)。
LC/MS (方法7、ESIpos)：R_t＝2.68分、m/z＝457 [M+H]⁺。 Example 34
1- {3-[(5-methyl-3- {3- [4- (trifluoromethoxy) phenyl] -1,2,4-oxadiazol-5-yl} -1H-pyrazol-1-yl) Methyl] phenyl} cyclopropanol

In a manner similar to that described in Example 66A and Example 22, from a solution of 70 mg (0.23 mmol) of the compound from Example 22A, 102 mg (0.345 mmol) of the compound from Example 47A and ethylmagnesium chloride solution, The process yielded 12 mg (12% of theory) of the title compound. Here, preparative HPLC was performed according to Method 18.
¹ H NMR (400 MHz, DMSO-d ₆ , δ / ppm): 8.20 (d, 2H), 7.60 (d, 2H), 7.27 (t, 1H), 7.22 (s, 1H), 7.08 (d, 1H ), 6.96 (d, 1H), 6.93 (s, 1H), 5.93 (s, 1H), 5.48 (s, 2H), 2.34 (s, 3H), 1.09 (dd, 2H), 0.92 (dd, 2H) .
LC / MS (Method _{7, ESIpos): R t =} 2.68 min, m / z = 457 [M + H] +.

実施例22に記載した方法に準じて、実施例80Aからの化合物192 mg(0.25 mmol、純度69%)およびエチルマグネシウムクロライド溶液から、表題化合物70 mg(理論値の57%)を得た。ここでは、粗成生物の精製のために、まず分取用薄層クロマトグラフィー(シリカゲル、移動相：シクロヘキサン/酢酸エチル 1:1)を行った。生成物分画をジクロロメタン/メタノール 95:5で抽出した。更なる精製を分取用HPLC(方法15)により行った。生成物分画に、飽和重炭酸ナトリウム水溶液を加えて濃縮すると、表題化合物が固体として沈殿し、これを濾過し、水で2回洗浄し、減圧下乾燥させた。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：7.96 (dd、1H)、7.91 (dd、1H)、7.55 (t、1H)、7.32-7.26 (m、2H)、7.20 (s、1H)、7.16 (d、1H)、6.99 (d、1H)、6.81 (s、1H)、5.45 (s、2H)、2.47 (s、1H)、2.28 (s、3H)、1.69 (s、6H)、1.27 (dd、2H)、1.02 (dd、2H)。
LC/MS (方法4、ESIpos)：R_t＝1.58分、m/z＝501 [M+H]⁺。 Example 35
1- {3-[(3- {3- [3-Fluoro-4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenyl] -1,2,4-oxadiazole -5-yl} -5-methyl-1H-pyrazol-1-yl) methyl] phenyl} cyclopropanol

According to the method described in Example 22, 192 mg (0.25 mmol, purity 69%) of the compound from Example 80A and ethylmagnesium chloride solution gave 70 mg (57% of theory) of the title compound. Here, in order to purify the crude product, first, preparative thin-layer chromatography (silica gel, mobile phase: cyclohexane / ethyl acetate 1: 1) was performed. The product fraction was extracted with dichloromethane / methanol 95: 5. Further purification was performed by preparative HPLC (Method 15). Saturated aqueous sodium bicarbonate solution was added to the product fraction and concentrated, the title compound precipitated as a solid, which was filtered, washed twice with water and dried under reduced pressure.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 7.96 (dd, 1H), 7.91 (dd, 1H), 7.55 (t, 1H), 7.32-7.26 (m, 2H), 7.20 (s, 1H ), 7.16 (d, 1H), 6.99 (d, 1H), 6.81 (s, 1H), 5.45 (s, 2H), 2.47 (s, 1H), 2.28 (s, 3H), 1.69 (s, 6H) 1.27 (dd, 2H), 1.02 (dd, 2H).
LC / MS (Method 4, ESIpos): R _t = 1.58 min, m / z = 501 [M + H] ⁺ .

実施例81Aからの化合物0.10 g(0.19 mmol)を無水THF3.8 mlに溶解し、イソプロピルマグネシウムクロライド/リチウムクロライド(14% THF溶液、0.21 mmol)0.22 gを-40℃で滴下した。続いて混合物を-40℃から-30℃で1時間撹拌した。続いてシクロブタノン16 μl(0.21 mmol)を加え、混合物を更なる冷却なしに1時間撹拌した。続いて混合物をロータリーエバポレーターで濃縮し、残渣を酢酸エチルに懸濁させ、無水硫酸マグネシウムを加えた。混合物を濾過し、濾液をロータリーエバポレーターで濃縮した。残渣を分取用HPLC(方法17)により精製した。これにより表題化合物18 mg(理論値の20%)を得た。
¹H NMR (400 MHz、DMSO-d₆、δ/ppm)：8.20 (d、2H)、7.59 (d、2H)、7.42 (d、1H)、7.39 (s、1H)、7.33 (t、1H)、7.02 (d、1H)、6.93 (s、1H)、5.51 (s、2H)、5.50 (s、1H)、2.35 (s、3H)、2.35 (m、2H)、2.25 (m、2H)、1.90 (m、1H)、1.62 (m、1H)。
LC/MS (方法6、ESIpos)：R_t＝1.31分、m/z＝471 [M+H]⁺。 Example 36
1- {3-[(5-methyl-3- {3- [4- (trifluoromethoxy) phenyl] -1,2,4-oxadiazol-5-yl} -1H-pyrazol-1-yl) Methyl] phenyl} cyclobutanol

0.10 g (0.19 mmol) of the compound from Example 81A was dissolved in 3.8 ml of anhydrous THF, and 0.22 g of isopropylmagnesium chloride / lithium chloride (14% THF solution, 0.21 mmol) was added dropwise at −40 ° C. Subsequently, the mixture was stirred at −40 ° C. to −30 ° C. for 1 hour. Subsequently, 16 μl (0.21 mmol) of cyclobutanone was added and the mixture was stirred for 1 hour without further cooling. Subsequently, the mixture was concentrated on a rotary evaporator, the residue was suspended in ethyl acetate, and anhydrous magnesium sulfate was added. The mixture was filtered and the filtrate was concentrated on a rotary evaporator. The residue was purified by preparative HPLC (Method 17). This gave 18 mg (20% of theory) of the title compound.
¹ H NMR (400 MHz, DMSO-d ₆ , δ / ppm): 8.20 (d, 2H), 7.59 (d, 2H), 7.42 (d, 1H), 7.39 (s, 1H), 7.33 (t, 1H ), 7.02 (d, 1H), 6.93 (s, 1H), 5.51 (s, 2H), 5.50 (s, 1H), 2.35 (s, 3H), 2.35 (m, 2H), 2.25 (m, 2H) 1.90 (m, 1H), 1.62 (m, 1H).
LC / MS (Method 6, ESIpos): R _t = 1.31 min, m / z = 471 [M + H] ⁺ .

実施例81Aからの化合物100 mg(0.19 mmol)を無水THF3.8 mlに溶解し、イソプロピルマグネシウムクロライド/リチウムクロライド(14% THF溶液、0.21 mmol)220 mgを-40℃で加えた。続いて混合物を約-40℃から-30℃で0.5時間撹拌した。続いてテトラヒドロ-2H-ピラン-4-オン21 μl(0.21 mmol)の無水THF0.2 mlを滴下し、混合物を更なる冷却なしに0.5時間撹拌した。続いて飽和塩化ナトリウム水溶液および酢酸エチルを加え、有機層を水および飽和塩化ナトリウム溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、濾過した。濾液をロータリーエバポレーターで除去し、残渣を分取用HPLC(方法17)により精製した。これにより表題化合物66 mg(理論値の66%)を得た。
¹H NMR (400 MHz、DMSO-d₆、δ/ppm)：8.20 (d、2H)、7.59 (d、2H)、7.42 (d、2H)、7.33 (t、1H)、7.02 (d、1H)、6.93 (s、1H)、5.51 (s、2H)、5.05 (s、1H)、3.76 (t、2H)、3.70 (dd、2H)、2.35 (s、3H)、1.93 (td、2H)、1.50 (d、2H)。
LC/MS (方法4、ESIpos)：R_t＝1.38分、m/z＝501 [M+H]⁺。 Example 37
4- {3-[(5-methyl-3- {3- [4- (trifluoromethoxy) phenyl] -1,2,4-oxadiazol-5-yl} -1H-pyrazol-1-yl) Methyl] phenyl} tetrahydro-2H-pyran-4-ol

100 mg (0.19 mmol) of the compound from Example 81A was dissolved in 3.8 ml of anhydrous THF, and 220 mg of isopropylmagnesium chloride / lithium chloride (14% THF solution, 0.21 mmol) was added at −40 ° C. The mixture was subsequently stirred at about -40 ° C to -30 ° C for 0.5 hour. Subsequently, 0.2 ml of anhydrous THF in 21 μl (0.21 mmol) of tetrahydro-2H-pyran-4-one was added dropwise and the mixture was stirred for 0.5 hours without further cooling. Subsequently, a saturated aqueous sodium chloride solution and ethyl acetate were added, and the organic layer was washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered. The filtrate was removed on a rotary evaporator and the residue was purified by preparative HPLC (Method 17). This gave 66 mg (66% of theory) of the title compound.
¹ H NMR (400 MHz, DMSO-d ₆ , δ / ppm): 8.20 (d, 2H), 7.59 (d, 2H), 7.42 (d, 2H), 7.33 (t, 1H), 7.02 (d, 1H ), 6.93 (s, 1H), 5.51 (s, 2H), 5.05 (s, 1H), 3.76 (t, 2H), 3.70 (dd, 2H), 2.35 (s, 3H), 1.93 (td, 2H) 1.50 (d, 2H).
LC / MS (method _{4, ESIpos): R t =} 1.38 min, m / z = 501 [M + H] +.

実施例82Aからの化合物0.10 g(0.20 mmol)を無水THF2.0 mlに溶解し、1 M リチウムアルミニウムハイドライドのTHF溶液0.20 ml(0.20 mmol)を0℃で加えた。混合物を氷浴による冷却下、さらに5分撹拌した。続いて、順に飽和塩化ナトリウム水溶液、無水硫酸マグネシウムおよび酢酸エチルを加えた。固体を濾過し、濾液をロータリーエバポレーターで除去した。これにより表題化合物72 mg(理論値の77%)を得た。
¹H NMR (400 MHz、DMSO-d₆、δ/ppm)：8.09 (d、2H)、7.77 (d、2H)、7.27 (t、1H)、7.16 (d、1H)、7.09 (s、1H)、6.99 (d、1H)、6.93 (s、1H)、5.47 (s、2H)、4.62 (t、1H)、3.58 (quart、2H)、2.70 (t、2H)、2.34 (s、3H)、1.61 (s、6H)。
LC/MS (方法6、ESIpos)：R_t＝1.27分、m/z＝471 [M+H]⁺。 Example 38
2- {3-[(5-methyl-3- {3- [4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenyl] -1,2,4-oxadiazole -5-yl} -1H-pyrazol-1-yl) methyl] phenyl} ethanol

0.10 g (0.20 mmol) of the compound from Example 82A was dissolved in 2.0 ml of anhydrous THF, and 0.20 ml (0.20 mmol) of 1 M lithium aluminum hydride in THF was added at 0 ° C. The mixture was further stirred for 5 minutes under cooling in an ice bath. Subsequently, a saturated aqueous sodium chloride solution, anhydrous magnesium sulfate, and ethyl acetate were sequentially added. The solid was filtered and the filtrate was removed on a rotary evaporator. This gave 72 mg (77% of theory) of the title compound.
¹ H NMR (400 MHz, DMSO-d ₆ , δ / ppm): 8.09 (d, 2H), 7.77 (d, 2H), 7.27 (t, 1H), 7.16 (d, 1H), 7.09 (s, 1H ), 6.99 (d, 1H), 6.93 (s, 1H), 5.47 (s, 2H), 4.62 (t, 1H), 3.58 (quart, 2H), 2.70 (t, 2H), 2.34 (s, 3H) 1.61 (s, 6H).
LC / MS (Method _{6, ESIpos): R t =} 1.27 min, m / z = 471 [M + H] +.

-20℃で、1.3 M イソプロピルマグネシウムクロライド/リチウムクロライド複合体のTHF溶液1.1 ml(1.43 mmol)を、実施例81Aからの化合物250 mg(0.475 mmol)の無水THF溶液10 mlに加えた。2 分後、ヨウ化銅(I)1.8 mg(0.01 mmol)を加え、次の1分でトリフルオロメチルオキシラン205 μl(2.37 mmol)を加えた。続いて反応混合物を室温に温めた。室温で20分後、25%アンモニア水溶液100 mlを加え、混合物を各回約100 mlの酢酸エチル3回抽出した。合わせた有機層抽出物を飽和塩化ナトリウム溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、濾過し、最後にロータリーエバポレーターにより溶媒を除去した。得られた残渣から、最初にMPLC(シリカゲル約50 g、移動相：シクロヘキサン/酢酸エチル 4:1)により非極性不純物を除去した。続いて生成物の更なる精製を、分取用HPLC(方法13)により行った。これにより表題化合物17 mg(理論値の7%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：8.24 (d、2H)、7.33 (d、2H)、7.32 (t、1H)、7.22 (d、1H)、7.12 (s、1H)、7.08 (d、1H)、6.82 (s、1H)、5.43 (s、2H)、4.13 (m、1H)、3.02 (dd、1H)、2.84 (dd、1H)、2.31 (d、1H)、2.29 (s、3H)。
LC/MS (方法6、ESIpos)：R_t＝1.33分、m/z＝513 [M+H]⁺。 Example 39
1,1,1-trifluoro-3- {3-[(5-methyl-3- {3- [4- (trifluoromethoxy) phenyl] -1,2,4-oxadiazol-5-yl} -1H-pyrazol-1-yl) methyl] phenyl} propan-2-ol (racemic)

At −20 ° C., 1.1 ml (1.43 mmol) of a THF solution of 1.3 M isopropylmagnesium chloride / lithium chloride complex was added to 10 ml of an anhydrous THF solution of 250 mg (0.475 mmol) of the compound from Example 81A. Two minutes later, 1.8 mg (0.01 mmol) of copper (I) iodide was added, and 205 μl (2.37 mmol) of trifluoromethyloxirane was added in the next 1 minute. The reaction mixture was subsequently warmed to room temperature. After 20 minutes at room temperature, 100 ml of 25% aqueous ammonia was added and the mixture was extracted three times with about 100 ml of ethyl acetate each time. The combined organic layer extracts were washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and finally the solvent was removed by rotary evaporator. Nonpolar impurities were first removed from the resulting residue by MPLC (silica gel about 50 g, mobile phase: cyclohexane / ethyl acetate 4: 1). Subsequent further purification of the product was performed by preparative HPLC (Method 13). This gave 17 mg (7% of theory) of the title compound.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 8.24 (d, 2H), 7.33 (d, 2H), 7.32 (t, 1H), 7.22 (d, 1H), 7.12 (s, 1H), 7.08 (d, 1H), 6.82 (s, 1H), 5.43 (s, 2H), 4.13 (m, 1H), 3.02 (dd, 1H), 2.84 (dd, 1H), 2.31 (d, 1H), 2.29 (s, 3H).
LC / MS (Method 6, ESIpos): R _t = 1.33 min, m / z = 513 [M + H] ⁺ .

0℃で、リチウムアルミニウムハイドライド溶液(1 M THF溶液)164 μlを、実施例84Aからの化合物150 mg(0.329 mmol)の無水THF溶液7.5 mlに加えた。反応混合物を0℃で1時間撹拌し、続いて反応は氷 酢酸20 μlを加えて終了させた。溶媒をロータリーエバポレーターで除去し、粗成生物をMPLCにより精製した(シリカゲル、移動相：シクロヘキサン/酢酸エチル 2:1 → 1:2)。これにより表題化合物122 mg(理論値の81%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：8.26 (d、2H)、7.33 (d、2H)、7.29 (t、1H)、7.16 (d、1H)、7.03 (d und s、zus. 2H)、6.81 (s、1H)、5.44 (s、2H)、4.03-3.97 (m、1H)、2.77 (dd、1H)、2.67 (dd、1H)、2.29 (s、3H)、1.48 (d、1H)、1.22 (d、3H)。
LC/MS (方法2、ESIpos)：R_t＝2.68分、m/z＝459 [M+H]⁺。 Example 40
1- {3-[(5-methyl-3- {3- [4- (trifluoromethoxy) phenyl] -1,2,4-oxadiazol-5-yl} -1H-pyrazol-1-yl) Methyl] phenyl} propan-2-ol (racemate)

At 0 ° C., 164 μl of lithium aluminum hydride solution (1 M in THF) was added to 7.5 ml of anhydrous THF solution of 150 mg (0.329 mmol) of the compound from Example 84A. The reaction mixture was stirred at 0 ° C. for 1 hour, and the reaction was subsequently terminated by adding 20 μl of glacial acetic acid. The solvent was removed on a rotary evaporator and the crude product was purified by MPLC (silica gel, mobile phase: cyclohexane / ethyl acetate 2: 1 → 1: 2). This gave 122 mg (81% of theory) of the title compound.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 8.26 (d, 2H), 7.33 (d, 2H), 7.29 (t, 1H), 7.16 (d, 1H), 7.03 (d und s, zus 2H), 6.81 (s, 1H), 5.44 (s, 2H), 4.03-3.97 (m, 1H), 2.77 (dd, 1H), 2.67 (dd, 1H), 2.29 (s, 3H), 1.48 ( d, 1H), 1.22 (d, 3H).
LC / MS (method _{2, ESIpos): R t =} 2.68 min, m / z = 459 [M + H] +.

実施例40からのラセミ化合物100 mgをイソプロパノール6 mlに溶解し、15個に分割し、分取用キラル相HPLCによりエナンチオマーに分離した[カラム：Daicel Chiralpak AD-H、5 μm、250 mm x 20 mm；移動相：イソヘキサン/イソプロパノール 1:1(0-10分)；流速：15 ml/分；温度：30℃；UV検出：220 nm]:
実施例41(エナンチオマー 1):
収量：33 mg
R_t＝6.63分、99% ee [分析的キラル HPLC：カラム：Daicel Chiralpak AD-H、5 μm、250 mm x 4.6 mm；移動相：イソヘキサン/イソプロパノール/ジエチルアミン 50:49.8:0.2(0-10分)；流速：1.0 ml/分；温度：30℃；UV検出：220 nm]。 Example 41 and Example 42
1- {3-[(5-methyl-3- {3- [4- (trifluoromethoxy) phenyl] -1,2,4-oxadiazol-5-yl} -1H-pyrazol-1-yl) Methyl] phenyl} propan-2-ol (enantiomers 1 and 2)

100 mg of the racemate from Example 40 was dissolved in 6 ml of isopropanol, divided into 15 portions and separated into enantiomers by preparative chiral phase HPLC [column: Daicel Chiralpak AD-H, 5 μm, 250 mm × 20 mm; mobile phase: isohexane / isopropanol 1: 1 (0-10 min); flow rate: 15 ml / min; temperature: 30 ° C .; UV detection: 220 nm]:
Example 41 (Enantiomer 1):
Yield: 33 mg
R _t = 6.63 min, 99% ee [Analytical chiral HPLC: column: Daicel Chiralpak AD-H, 5 μm, 250 mm x 4.6 mm; mobile phase: isohexane / isopropanol / diethylamine 50: 49.8: 0.2 (0-10 min ); Flow rate: 1.0 ml / min; temperature: 30 ° C .; UV detection: 220 nm].

Example 42 (Enantiomer 2):
Yield: 30 mg
R _t = 7.75 min, 98% ee [Analytical chiral HPLC: column: Daicel Chiralpak AD-H, 5 μm, 250 mm x 4.6 mm; mobile phase: isohexane / isopropanol / diethylamine 50: 49.8: 0.2 (0-10 min ); Flow rate: 1.0 ml / min; temperature: 30 ° C .; UV detection: 220 nm].
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 8.25 (d, 2H), 7.33 (d, 2H), 7.29 (t, 1H), 7.16 (d, 1H), 7.03 (d und s, zus 2H), 6.82 (s, 1H), 5.44 (s, 2H), 4.03-3.96 (m, 1H), 2.77 (dd, 1H), 2.68 (dd, 1H), 2.29 (s, 3H), 1.57 ( d, 1H), 1.22 (d, 3H).
LC / MS (Method 6, ESIpos): R _t = 1.28 min, m / z = 459 [M + H] ⁺ .

0℃で、メチルマグネシウムブロマイド溶液(3 M ジエチルエーテル溶液)を、実施例83Aからの化合物33.5 g(68.9 mmol)の無水THF700 mlに加えた。添加が終わると、氷/水浴を外し、室温で攪拌を続けた。2時間後、飽和塩化ナトリウム水溶液50 mlを注意深く加えて反応を終了させた。続いて反応液を酢酸エチル700 mlで希釈し、無水硫酸マグネシウム100 gを加えた。簡単に撹拌した後、混合物を濾過し、ロータリーエバポレーターにより濾液から溶媒を除去した。得られた粗成生物を、移動相としてシクロヘキサン/酢酸エチル勾配 [8:2(8リットル)→ 7:3(8リットル)→ 6:4(8リットル)→ 1:1(4リットル)]を用いてシリカゲル(粒子サイズ 0.06-0.2 mm)770 gで、吸引濾過により精製した。溶媒を蒸発させ粗生成物22.5 gを得て、ここでこれは主として表題化合物を含み、加えて化合物 1-{3-[(5-メチル-3-{3-[4-(トリフルオロメトキシ)フェニル]-1,2,4-オキサジアゾール-5-イル}-1H-ピラゾール-1-イル)メチル]フェニル}アセトン(実施例84A参照)を含んだ。この粗生成物7.6 gを沸騰ジイソプロピルエーテル61 mlから再結晶した。得られた結晶を室温で吸引濾過し、各回5 mlの冷ジイソプロピルエーテルで2回洗浄し、高真空下乾燥させた。これにより純粋な表題化合物5.19 g(理論値の73%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：8.25 (d、2H)、7.33 (d、2H)、7.29 (t、1H)、7.17 (d、1H)、7.05 (d、1H)、7.03 (s、1H)、6.81 (s、1H)、5.45 (s、2H)、2.73 (s、2H)、2.29 (s、3H)、1.31 (s、1H)、1.20 (s、6H)。
LC/MS (方法6、ESIpos)：R_t＝1.33分、m/z＝473 [M+H]⁺。 Example 43
2-Methyl-1- {3-[(5-methyl-3- {3- [4- (trifluoromethoxy) phenyl] -1,2,4-oxadiazol-5-yl} -1H-pyrazole- 1-yl) methyl] phenyl} propan-2-ol

At 0 ° C., methylmagnesium bromide solution (3 M diethyl ether solution) was added to 700 ml of anhydrous THF in 33.5 g (68.9 mmol) of the compound from Example 83A. When the addition was complete, the ice / water bath was removed and stirring was continued at room temperature. After 2 hours, 50 ml of a saturated aqueous sodium chloride solution was carefully added to terminate the reaction. Subsequently, the reaction solution was diluted with 700 ml of ethyl acetate, and 100 g of anhydrous magnesium sulfate was added. After briefly stirring, the mixture was filtered and the solvent was removed from the filtrate by rotary evaporator. The resulting crude product was subjected to cyclohexane / ethyl acetate gradient [8: 2 (8 liters) → 7: 3 (8 liters) → 6: 4 (8 liters) → 1: 1 (4 liters)] as the mobile phase. Used on silica gel (particle size 0.06-0.2 mm) 770 g and purified by suction filtration. Evaporation of the solvent gave 22.5 g of crude product, which mainly contained the title compound, in addition to the compound 1- {3-[(5-methyl-3- {3- [4- (trifluoromethoxy) Phenyl] -1,2,4-oxadiazol-5-yl} -1H-pyrazol-1-yl) methyl] phenyl} acetone (see Example 84A). 7.6 g of this crude product was recrystallized from 61 ml of boiling diisopropyl ether. The obtained crystals were suction filtered at room temperature, washed twice with 5 ml of cold diisopropyl ether each time and dried under high vacuum. This gave 5.19 g (73% of theory) of the pure title compound.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 8.25 (d, 2H), 7.33 (d, 2H), 7.29 (t, 1H), 7.17 (d, 1H), 7.05 (d, 1H), 7.03 (s, 1H), 6.81 (s, 1H), 5.45 (s, 2H), 2.73 (s, 2H), 2.29 (s, 3H), 1.31 (s, 1H), 1.20 (s, 6H).
LC / MS (Method 6, ESIpos): R _t = 1.33 min, m / z = 473 [M + H] ⁺ .

固体カリウムtert-ブトキシド119 mg(1.06 mmol)を、実施例42Aからの化合物200 mg(0.708 mmol)および実施例48Aからの化合物366 mg(1.42 mmol)の無水THF溶液8 mlに0℃で加えた。続いて反応混合物を室温で30分撹拌した。メタノール約1 mlを加えた後、反応混合物を分取用HPLC(方法13)により直接構成成分に分離した。これにより表題化合物242 mg(理論値の77%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：8.13 (d、2H)、7.50 (d、2H)、7.28 (t、1H)、7.16 (d、1H)、7.05 (d、1H)、7.02 (s、1H)、6.80 (s、1H)、5.45 (s、2H)、2.73 (s、2H)、2.28 (s、3H)、1.36 (s、9H)、1.29 (s、1H)、1.19 (s、6H)。
LC/MS (方法6、ESIpos)：R_t＝1.41分、m/z＝445 [M+H]⁺。 Example 44
1- [3-({3- [3- (4-tert-butylphenyl) -1,2,4-oxadiazol-5-yl] -5-methyl-1H-pyrazol-1-yl} methyl) Phenyl] -2-methylpropan-2-ol

119 mg (1.06 mmol) of solid potassium tert-butoxide was added at 0 ° C. to 8 ml of anhydrous THF solution of compound 200 mg (0.708 mmol) from Example 42A and compound 366 mg (1.42 mmol) from Example 48A. . The reaction mixture was subsequently stirred at room temperature for 30 minutes. After adding about 1 ml of methanol, the reaction mixture was separated directly into components by preparative HPLC (Method 13). This gave 242 mg (77% of theory) of the title compound.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 8.13 (d, 2H), 7.50 (d, 2H), 7.28 (t, 1H), 7.16 (d, 1H), 7.05 (d, 1H), 7.02 (s, 1H), 6.80 (s, 1H), 5.45 (s, 2H), 2.73 (s, 2H), 2.28 (s, 3H), 1.36 (s, 9H), 1.29 (s, 1H), 1.19 (s, 6H).
LC / MS (Method 6, ESIpos): R _t = 1.41 min, m / z = 445 [M + H] ⁺ .

実施例44に記載した方法に準じて、実施例40Aからの化合物105 mg(0.324 mmol)および実施例48Aからの化合物167 mg(0.647 mmol)から、表題化合物130 mg(理論値の83%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：8.13 (d、2H)、7.29 (d、2H)、7.28 (t、1H)、7.16 (d、1H)、7.04 (d、1H)、7.02 (s、1H)、6.81 (s、1H)、5.45 (s、2H)、3.55 (s、2H)、3.28 (s、3H)、2.73 (s、2H)、2.41-2.29 (m、4H)、2.27 (s、3H)、2.15-2.03 (m、1H)、1.93-1.83 (m、1H)、1.29 (s、broad、1H)、1.19 (s、6H)。
LC/MS (方法6、ESIpos)：R_t＝1.37分、m/z＝487 [M+H]⁺。 Example 45
1- (3-{[3- (3- {4- [1- (methoxymethyl) cyclobutyl] phenyl} -1,2,4-oxadiazol-5-yl) -5-methyl-1H-pyrazole- 1-yl] methyl} phenyl) -2-methylpropan-2-ol

According to the method described in Example 44, from 105 mg (0.324 mmol) of the compound from Example 40A and 167 mg (0.647 mmol) of the compound from Example 48A, 130 mg (83% of theory) of the title compound was obtained. Obtained.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 8.13 (d, 2H), 7.29 (d, 2H), 7.28 (t, 1H), 7.16 (d, 1H), 7.04 (d, 1H), 7.02 (s, 1H), 6.81 (s, 1H), 5.45 (s, 2H), 3.55 (s, 2H), 3.28 (s, 3H), 2.73 (s, 2H), 2.41-2.29 (m, 4H) 2.27 (s, 3H), 2.15-2.03 (m, 1H), 1.93-1.83 (m, 1H), 1.29 (s, broad, 1H), 1.19 (s, 6H).
LC / MS (Method _{6, ESIpos): R t =} 1.37 min, m / z = 487 [M + H] +.

実施例44に記載した方法に準じて、実施例26Aからの化合物100 mg(0.335 mmol)および実施例48Aからの化合物173 mg(0.670 mmol)から、表題化合物112 mg(理論値の73%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：8.17 (d、2H)、7.64 (d、2H)、7.28 (t、1H)、7.17 (d、1H)、7.05 (d、1H)、7.03 (s、1H)、6.81 (s、1H)、5.46 (s、2H)、2.73 (s、2H)、2.28 (s、3H)、1.30 (s、1H)、1.19 (s、6H)、0.31 (s、9H)。
LC/MS (方法6、ESIpos)：R_t＝1.46分、m/z＝461 [M+H]⁺。 Example 46
2-Methyl-1- {3-[(5-methyl-3- {3- [4- (trimethylsilyl) phenyl] -1,2,4-oxadiazol-5-yl} -1H-pyrazole-1- Yl) methyl] phenyl} propan-2-ol

According to the method described in Example 44, from 100 mg (0.335 mmol) of the compound from Example 26A and 173 mg (0.670 mmol) of the compound from Example 48A, 112 mg (73% of theory) of the title compound was obtained. Obtained.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 8.17 (d, 2H), 7.64 (d, 2H), 7.28 (t, 1H), 7.17 (d, 1H), 7.05 (d, 1H), 7.03 (s, 1H), 6.81 (s, 1H), 5.46 (s, 2H), 2.73 (s, 2H), 2.28 (s, 3H), 1.30 (s, 1H), 1.19 (s, 6H), 0.31 (s, 9H).
LC / MS (Method _{6, ESIpos): R t =} 1.46 min, m / z = 461 [M + H] +.

実施例44に記載した方法に準じて、実施例30Aからの化合物100 mg(0.285 mmol)および実施例48Aからの化合物147 mg(0.571 mmol)から、表題化合物116 mg(理論値の82%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：8.18 (d、2H)、7.58 (d、2H)、7.28 (t、1H)、7.17 (d、1H)、7.04 (d、1H)、7.03 (s、1H)、6.80 (s、1H)、5.45 (s、2H)、2.74 (s、2H)、2.28 (s、3H)、1.42-1.39 (m、2H)、1.31 (s、1H)、1.19 (s、6H)、1.11-1.07 (m、2H)。
LC/MS (方法6、ESIpos)：R_t＝1.35分、m/z＝497 [M+H]⁺。 Example 47
2-Methyl-1- (3-{[5-methyl-3- (3- {4- [1- (trifluoromethyl) cyclopropyl] phenyl} -1,2,4-oxadiazol-5-yl ) -1H-pyrazol-1-yl] methyl} phenyl) propan-2-ol

According to the method described in Example 44, from 100 mg (0.285 mmol) of the compound from Example 30A and 147 mg (0.571 mmol) of the compound from Example 48A, 116 mg (82% of theory) of the title compound was obtained. Obtained.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 8.18 (d, 2H), 7.58 (d, 2H), 7.28 (t, 1H), 7.17 (d, 1H), 7.04 (d, 1H), 7.03 (s, 1H), 6.80 (s, 1H), 5.45 (s, 2H), 2.74 (s, 2H), 2.28 (s, 3H), 1.42-1.39 (m, 2H), 1.31 (s, 1H) 1.19 (s, 6H), 1.11-1.07 (m, 2H).
LC / MS (Method _{6, ESIpos): R t =} 1.35 min, m / z = 497 [M + H] +.

実施例44に記載した方法に準じて、実施例29Aからの化合物100 mg(0.305 mmol)および実施例48Aからの化合物157 mg(0.609 mmol)から、表題化合物110 mg(理論値の74%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：8.08 (dd、1H)、8.03 (ddd、1H)、7.43 (dd、1H)、7.29 (t、1H)、7.17 (d、1H)、7.04 (d、1H)、7.03 (s、1H)、6.81 (s、1H)、5.45 (s、2H)、2.73 (s、2H)、2.29 (s、3H)、1.31 (s、1H)、1.20 (s、6H)。
LC/MS (方法6、ESIpos)：R_t＝1.35分、m/z＝491 [M+H]⁺。 Example 48
1- {3-[(3- {3- [3-Fluoro-4- (trifluoromethoxy) phenyl] -1,2,4-oxadiazol-5-yl} -5-methyl-1H-pyrazole- 1-yl) methyl] phenyl} -2-methylpropan-2-ol

According to the method described in Example 44, from 100 mg (0.305 mmol) of the compound from Example 29A and 157 mg (0.609 mmol) of the compound from Example 48A, 110 mg (74% of theory) of the title compound was obtained. Obtained.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 8.08 (dd, 1H), 8.03 (ddd, 1H), 7.43 (dd, 1H), 7.29 (t, 1H), 7.17 (d, 1H), 7.04 (d, 1H), 7.03 (s, 1H), 6.81 (s, 1H), 5.45 (s, 2H), 2.73 (s, 2H), 2.29 (s, 3H), 1.31 (s, 1H), 1.20 (s, 6H).
LC / MS (Method _{6, ESIpos): R t =} 1.35 min, m / z = 491 [M + H] +.

実施例44に記載した方法に準じて、実施例27Aからの化合物100 mg(0.340 mmol)および実施例48Aからの化合物175 mg(0.680 mmol)から、表題化合物126 mg(理論値の81%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：8.33 (d、2H)、7.76 (d、2H)、7.29 (t、1H)、7.17 (d、1H)、7.05 (d、1H)、7.03 (s、1H)、6.82 (s、1H)、5.45 (s、2H)、2.73 (s、2H)、2.29 (s、3H)、1.31 (s、1H)、1.20 (s、6H)。
LC/MS (方法6、ESIpos)：R_t＝1.31分、m/z＝457 [M+H]⁺。 Example 49
2-Methyl-1- {3-[(5-methyl-3- {3- [4- (trifluoromethyl) phenyl] -1,2,4-oxadiazol-5-yl} -1H-pyrazole- 1-yl) methyl] phenyl} propan-2-ol

According to the method described in Example 44, from 100 mg (0.340 mmol) of the compound from Example 27A and 175 mg (0.680 mmol) of the compound from Example 48A, 126 mg (81% of theory) of the title compound were obtained. Obtained.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 8.33 (d, 2H), 7.76 (d, 2H), 7.29 (t, 1H), 7.17 (d, 1H), 7.05 (d, 1H), 7.03 (s, 1H), 6.82 (s, 1H), 5.45 (s, 2H), 2.73 (s, 2H), 2.29 (s, 3H), 1.31 (s, 1H), 1.20 (s, 6H).
LC / MS (Method 6, ESIpos): R _t = 1.31 min, m / z = 457 [M + H] ⁺ .

実施例44に記載した方法に準じて、実施例43Aからの化合物58 mg(0.177 mmol)および実施例48Aからの化合物91 mg(0.353 mmol)から、表題化合物64 mg(理論値の74%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：8.22 (d、2H)、7.52 (d、2H)、7.29 (t、1H)、7.17 (d、1H)、7.05 (d、1H)、7.03 (s、1H)、6.82 (s、1H)、5.45 (s、2H)、4.00-3.88 (m、4H)、2.73 (s、2H)、2.28 (s、3H)、2.30-2.11 (m、2H)、1.98-1.91 (m、2H)、1.32 (s、broad、1H)、1.20 (s、6H)。
LC/MS (方法6、ESIpos)：R_t＝1.22分、m/z＝491 [M+H]⁺。 Example 50
1- {3-[(3- {3- [4- (4-Fluorotetrahydro-2H-pyran-4-yl) phenyl] -1,2,4-oxadiazol-5-yl} -5-methyl -1H-pyrazol-1-yl) methyl] phenyl} -2-methylpropan-2-ol

According to the method described in Example 44, 58 mg (0.177 mmol) of the compound from Example 43A and 91 mg (0.353 mmol) of the compound from Example 48A, 64 mg (74% of theory) of the title compound were obtained. Obtained.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 8.22 (d, 2H), 7.52 (d, 2H), 7.29 (t, 1H), 7.17 (d, 1H), 7.05 (d, 1H), 7.03 (s, 1H), 6.82 (s, 1H), 5.45 (s, 2H), 4.00-3.88 (m, 4H), 2.73 (s, 2H), 2.28 (s, 3H), 2.30-2.11 (m, 2H), 1.98-1.91 (m, 2H), 1.32 (s, broad, 1H), 1.20 (s, 6H).
LC / MS (Method 6, ESIpos): R _t = 1.22 min, m / z = 491 [M + H] ⁺ .

実施例44に記載した方法に準じて、実施例28Aからの化合物75 mg(0.242 mmol)および実施例48Aからの化合物94 mg(0.362 mmol)から、表題化合物98 mg(理論値の86%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：8.15 (d、2H)、7.35 (d、2H)、7.29 (t、1H)、7.16 (d、1H)、7.05 (d、1H)、7.03 (s、1H)、6.81 (s、1H)、5.45 (s、2H)、4.13-4.08 (m、2H)、3.55 (dt、2H)、2.88-2.80 (m、1H)、2.73 (s、2H)、2.28 (s、3H)、1.92-1.78 (m、4H)、1.22 (s、1H)、1.20 (s、6H)。
LC/MS (方法6、ESIpos)：R_t＝1.22分、m/z＝473 [M+H]⁺。 Example 51
2-Methyl-1- {3-[(5-methyl-3- {3- [4- (tetrahydro-2H-pyran-4-yl) phenyl] -1,2,4-oxadiazol-5-yl } -1H-pyrazol-1-yl) methyl] phenyl} propan-2-ol

According to the method described in Example 44, from 75 mg (0.242 mmol) of the compound from Example 28A and 94 mg (0.362 mmol) of the compound from Example 48A, 98 mg (86% of theory) of the title compound were obtained. Obtained.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 8.15 (d, 2H), 7.35 (d, 2H), 7.29 (t, 1H), 7.16 (d, 1H), 7.05 (d, 1H), 7.03 (s, 1H), 6.81 (s, 1H), 5.45 (s, 2H), 4.13-4.08 (m, 2H), 3.55 (dt, 2H), 2.88-2.80 (m, 1H), 2.73 (s, 2H), 2.28 (s, 3H), 1.92-1.78 (m, 4H), 1.22 (s, 1H), 1.20 (s, 6H).
LC / MS (Method 6, ESIpos): R _t = 1.22 min, m / z = 473 [M + H] ⁺ .

実施例44に記載した方法に準じて、実施例35Aからの化合物70 mg(0.233 mmol)および実施例48Aからの化合物90 mg(0.350 mmol)から、表題化合物76 mg(理論値の70%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：8.29 (d、2H)、7.71 (d、2H)、7.29 (t、1H)、7.17 (d、1H)、7.05 (d、1H)、7.03 (s、1H)、6.82 (s、1H)、5.46 (s、2H)、5.06 (dd、2H)、5.00 (dd、2H)、2.73 (s、2H)、2.29 (s、3H)、1.31 (s、broad、1H)、1.20 (s、6H)。
LC/MS (方法6、ESIpos)：R_t＝1.17分、m/z＝463 [M+H]⁺。 Example 52
1- {3-[(3- {3- [4- (3-Fluoroxetane-3-yl) phenyl] -1,2,4-oxadiazol-5-yl} -5-methyl-1H-pyrazole -1-yl) methyl] phenyl} -2-methylpropan-2-ol

According to the method described in Example 44, from 70 mg (0.233 mmol) of the compound from Example 35A and 90 mg (0.350 mmol) of the compound from Example 48A, 76 mg (70% of theory) of the title compound was obtained. Obtained.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 8.29 (d, 2H), 7.71 (d, 2H), 7.29 (t, 1H), 7.17 (d, 1H), 7.05 (d, 1H), 7.03 (s, 1H), 6.82 (s, 1H), 5.46 (s, 2H), 5.06 (dd, 2H), 5.00 (dd, 2H), 2.73 (s, 2H), 2.29 (s, 3H), 1.31 (s, broad, 1H), 1.20 (s, 6H).
LC / MS (Method _{6, ESIpos): R t =} 1.17 min, m / z = 463 [M + H] +.

実施例44に記載した方法に準じて、実施例36Aからの化合物80 mg(0.245 mmol)および実施例48Aからの化合物95 mg(0.368 mmol)から、表題化合物87 mg(理論値の73%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：8.27 (d、2H)、7.78 (d、2H)、7.29 (t、1H)、7.17 (d、1H)、7.05 (d、1H)、7.03 (s、1H)、6.82 (s、1H)、5.45 (s、2H)、2.73 (s、2H)、2.29 (s、3H)、1.29 (s、broad、1H)、1.20 (s、6H)。
LC/MS (方法6、ESIpos)：R_t＝1.38分、m/z＝489 [M+H]⁺。 Example 53
2-Methyl-1- (3-{[5-methyl-3- (3- {4-[(trifluoromethyl) sulfanyl] phenyl} -1,2,4-oxadiazol-5-yl) -1H -Pyrazol-1-yl] methyl} phenyl) propan-2-ol

According to the method described in Example 44, from 80 mg (0.245 mmol) of the compound from Example 36A and 95 mg (0.368 mmol) of the compound from Example 48A, 87 mg (73% of theory) of the title compound were obtained. Obtained.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 8.27 (d, 2H), 7.78 (d, 2H), 7.29 (t, 1H), 7.17 (d, 1H), 7.05 (d, 1H), 7.03 (s, 1H), 6.82 (s, 1H), 5.45 (s, 2H), 2.73 (s, 2H), 2.29 (s, 3H), 1.29 (s, broad, 1H), 1.20 (s, 6H) .
LC / MS (Method _{6, ESIpos): R t =} 1.38 min, m / z = 489 [M + H] +.

実施例44に記載した方法に準じて、実施例31Aからの化合物100 mg(0.292 mmol)および実施例48Aからの化合物151 mg(0.584 mmol)から、表題化合物58 mg(理論値の39%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：7.93 (dd、1H)、7.82 (dd、1H)、7.29 (t、1H)、7.24 (t、1H)、7.16 (d、1H)、7.05 (d、1H)、7.02 (s、1H)、6.81 (s、1H)、5.45 (s、2H)、3.67 (s、2H)、3.28 (s、3H)、2.73 (s、2H)、2.48-2.40 (m、2H)、2.37-2.30 (m、2H)、2.27 (s、3H)、2.19-2.06 (m、1H)、1.94-1.84 (m、1H)、1.29 (s、1H)、1.19 (s、6H)。
LC/MS (方法6、ESIpos)：R_t＝1.39分、m/z＝505 [M+H]⁺。 Example 54
1- (3-{[3- (3- {3-Fluoro-4- [1- (methoxymethyl) cyclobutyl] phenyl} -1,2,4-oxadiazol-5-yl) -5-methyl- 1H-pyrazol-1-yl] methyl} phenyl) -2-methylpropan-2-ol

According to the method described in Example 44, from 100 mg (0.292 mmol) of the compound from Example 31A and 151 mg (0.584 mmol) of the compound from Example 48A, 58 mg (39% of theory) of the title compound were obtained. Obtained.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 7.93 (dd, 1H), 7.82 (dd, 1H), 7.29 (t, 1H), 7.24 (t, 1H), 7.16 (d, 1H), 7.05 (d, 1H), 7.02 (s, 1H), 6.81 (s, 1H), 5.45 (s, 2H), 3.67 (s, 2H), 3.28 (s, 3H), 2.73 (s, 2H), 2.48 -2.40 (m, 2H), 2.37-2.30 (m, 2H), 2.27 (s, 3H), 2.19-2.06 (m, 1H), 1.94-1.84 (m, 1H), 1.29 (s, 1H), 1.19 (s, 6H).
LC / MS (Method 6, ESIpos): R _t = 1.39 min, m / z = 505 [M + H] ⁺ .

実施例44に記載した方法に準じて、実施例33Aからの化合物100 mg(0.295 mmol)および実施例48Aからの化合物153 mg(0.591 mmol)を用いて表題化合物66 mg(理論値の45%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：8.12 (d、2H)、7.45 (d、2H)、7.29 (t、1H)、7.17 (d、1H)、7.04 (d、1H)、7.03 (s、1H)、6.81 (s、1H)、5.45 (s、2H)、3.41 (s、2H)、3.23 (s、3H)、2.73 (s、2H)、2.28 (s、3H)、2.07-2.00 (m、2H)、1.96-1.88 (m、2H)、1.79-1.71 (m、4H)、1.30 (s、1H)、1.19 (s、6H)。
LC/MS (方法2、ESIpos)：R_t＝2.82分、m/z＝501 [M+H]⁺。 Example 55
1- (3-{[3- (3- {4- [1- (methoxymethyl) cyclopentyl] phenyl} -1,2,4-oxadiazol-5-yl) -5-methyl-1H-pyrazole- 1-yl] methyl} phenyl) -2-methylpropan-2-ol

According to the method described in Example 44, using 100 mg (0.295 mmol) of the compound from Example 33A and 153 mg (0.591 mmol) of the compound from Example 48A, the title compound 66 mg (45% of theory) Got.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 8.12 (d, 2H), 7.45 (d, 2H), 7.29 (t, 1H), 7.17 (d, 1H), 7.04 (d, 1H), 7.03 (s, 1H), 6.81 (s, 1H), 5.45 (s, 2H), 3.41 (s, 2H), 3.23 (s, 3H), 2.73 (s, 2H), 2.28 (s, 3H), 2.07 -2.00 (m, 2H), 1.96-1.88 (m, 2H), 1.79-1.71 (m, 4H), 1.30 (s, 1H), 1.19 (s, 6H).
LC / MS (Method 2, ESIpos): R _t = 2.82 min, m / z = 501 [M + H] ⁺ .

実施例44に記載した方法に準じて、実施例34Aからの化合物125 mg(0.385 mmol)および実施例48Aからの化合物149 mg(0.577 mmol)を用いて表題化合物60 mg(理論値の32%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：8.14 (d、1H)、8.06 (dd、1H)、7.32 (d、1H)、7.29 (t、1H)、7.17 (d、1H)、7.05 (d、1H)、7.03 (s、1H)、6.81 (s、1H)、5.46 (s、2H)、2.73 (s、2H)、2.39 (s、3H)、2.28 (s、3H)、1.30 (s、1H)、1.19 (s、6H)。
LC/MS (方法6、ESIpos)：R_t＝1.37分、m/z＝487 [M+H]⁺。 Example 56
2-Methyl-1- {3-[(5-methyl-3- {3- [3-methyl-4- (trifluoromethoxy) phenyl] -1,2,4-oxadiazol-5-yl}- 1H-pyrazol-1-yl) methyl] phenyl} propan-2-ol

According to the method described in Example 44, using 125 mg (0.385 mmol) of the compound from Example 34A and 149 mg (0.577 mmol) of the compound from Example 48A, the title compound 60 mg (32% of theory) Got.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 8.14 (d, 1H), 8.06 (dd, 1H), 7.32 (d, 1H), 7.29 (t, 1H), 7.17 (d, 1H), 7.05 (d, 1H), 7.03 (s, 1H), 6.81 (s, 1H), 5.46 (s, 2H), 2.73 (s, 2H), 2.39 (s, 3H), 2.28 (s, 3H), 1.30 (s, 1H), 1.19 (s, 6H).
LC / MS (Method _{6, ESIpos): R t =} 1.37 min, m / z = 487 [M + H] +.

0℃で、メチルマグネシウムクロライド溶液(3 M ジエチルエーテル溶液)212 μlを、実施例82Aからの化合物155 mg(0.302 mmol)の無水THF溶液3 mlに加えた。続いて氷/水浴を外し、室温で攪拌を続けた。1.5時間後、飽和塩化ナトリウム水溶液0.5 mlを加えて反応を終了させた。続いて反応液を酢酸エチル約9 mlで希釈し、無水硫酸マグネシウムを加えた。簡単に撹拌した後、混合物を濾過し、ロータリーエバポレーターにより濾液から溶媒を除去した。得られた残渣をペンタン5 mlで摩砕した。固体を濾過し、高真空下乾燥させた。これにより表題化合物125 mg(理論値の83%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：8.20 (d、2H)、7.63 (d、2H)、7.29 (t、1H)、7.16 (d、1H)、7.05 (d、1H)、7.03 (s、1H)、6.81 (s、1H)、5.46 (s、2H)、2.73 (s、2H)、2.27 (s、3H)、1.63 (s、6H)、1.30 (s、1H)、1.19 (s、6H)。
LC/MS (方法6、ESIpos)：R_t＝1.34分、m/z＝499 [M+H]⁺。 Example 57
2-Methyl-1- {3-[(5-methyl-3- {3- [4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenyl] -1,2,4 -Oxadiazol-5-yl} -1H-pyrazol-1-yl) methyl] phenyl} propan-2-ol

At 0 ° C., 212 μl of methylmagnesium chloride solution (3 M diethyl ether solution) was added to 3 ml of an anhydrous THF solution of compound 155 mg (0.302 mmol) from Example 82A. The ice / water bath was then removed and stirring was continued at room temperature. After 1.5 hours, 0.5 ml of a saturated aqueous sodium chloride solution was added to terminate the reaction. Subsequently, the reaction solution was diluted with about 9 ml of ethyl acetate, and anhydrous magnesium sulfate was added. After briefly stirring, the mixture was filtered and the solvent was removed from the filtrate by rotary evaporator. The resulting residue was triturated with 5 ml of pentane. The solid was filtered and dried under high vacuum. This gave 125 mg (83% of theory) of the title compound.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 8.20 (d, 2H), 7.63 (d, 2H), 7.29 (t, 1H), 7.16 (d, 1H), 7.05 (d, 1H), 7.03 (s, 1H), 6.81 (s, 1H), 5.46 (s, 2H), 2.73 (s, 2H), 2.27 (s, 3H), 1.63 (s, 6H), 1.30 (s, 1H), 1.19 (s, 6H).
LC / MS (Method _{6, ESIpos): R t =} 1.34 min, m / z = 499 [M + H] +.

アルゴン下、0℃で、リチウムアルミニウムハイドライド溶液(1 M THF溶液)0.37 ml(0.37 mmol)を、実施例85Aからの化合物200 mg(0.37 mmol)のTHF溶液3.5 mlに滴下した。混合物を0℃でさらに1時間攪拌し、続いて水1 mlを滴下した。室温に戻し、混合物を酢酸エチルで希釈し、存在する固体を濾過した。固体を2回酢酸エチルで洗浄し、合わせた有機相を硫酸マグネシウムで乾燥させ、濾過し、濃縮した。残渣を分取用HPLC(方法14)により精製した。溶媒を除去し、残渣を減圧下乾燥させ、表題化合物17 mg(理論値の9%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：8.18 (d、2H)、7.58 (d、2H)、7.35-7.27 (m、3H)、7.22 (s、1H)、6.99 (d、1H)、6.81 (s、1H)、5.45 (s、2H)、3.59 (s、2H)、2.29 (s、3H)、1.40 (dd、2H)、1.30 (s、6H)、1.25 (s、1H)、1.11-1.05 (m、2H)。
LC/MS (方法6、ESIpos)：R_t＝1.37分、m/z＝497 [M+H]⁺。 Example 58
2-Methyl-2- (3-{[5-methyl-3- (3- {4- [1- (trifluoromethyl) cyclopropyl] phenyl} -1,2,4-oxadiazol-5-yl ) -1H-pyrazol-1-yl] methyl} phenyl) propan-1-ol

At 0 ° C. under argon, 0.37 ml (0.37 mmol) of lithium aluminum hydride solution (1 M THF solution) was added dropwise to 3.5 ml of THF solution of 200 mg (0.37 mmol) of the compound from Example 85A. The mixture was stirred at 0 ° C. for an additional hour, followed by the dropwise addition of 1 ml of water. Returned to room temperature, the mixture was diluted with ethyl acetate and the solid present was filtered. The solid was washed twice with ethyl acetate and the combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (Method 14). The solvent was removed and the residue was dried under reduced pressure to give 17 mg (9% of theory) of the title compound.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 8.18 (d, 2H), 7.58 (d, 2H), 7.35-7.27 (m, 3H), 7.22 (s, 1H), 6.99 (d, 1H ), 6.81 (s, 1H), 5.45 (s, 2H), 3.59 (s, 2H), 2.29 (s, 3H), 1.40 (dd, 2H), 1.30 (s, 6H), 1.25 (s, 1H) 1.11-1.05 (m, 2H).
LC / MS (Method 6, ESIpos): R _t = 1.37 min, m / z = 497 [M + H] ⁺ .

-78℃で、リチウムアルミニウムハイドライド溶液(1 M THF溶液)130 μl(0.130 mmol)を、実施例86Aからの化合物74 mg(0.129 mmol)の無水THF溶液3 mlに加えた。続いて反応混合物を、最初に、-78℃で1時間攪拌し、次に0℃でさらに30分攪拌した。続いて1 M 水酸化ナトリウム水溶液約9 mlを加え、混合物を各回10 ml の酢酸エチルで3回抽出した。合わせた有機層抽出物を、水、続いて飽和塩化ナトリウム溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、濾過し、最後にロータリーエバポレーターにより溶媒を除去した。得られた残渣を分取用HPLC(方法11)により精製し、表題化合物42 mg(理論値の69%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：8.14 (d、2H)、7.36-7.28 (m、4H)、7.22 (s、1H)、6.99 (d、1H)、6.81 (s、1H)、5.45 (s、2H)、4.10 (dd、2H)、3.59 (d、2H)、3.54 (dt、2H)、2.88-2.78 (m、1H)、2.29 (s、3H)、1.91-1.78 (m、4H)、1.30 (s、6H)、1.24 (t、1H)。
LC/MS (方法6、ESIpos)：R_t＝1.21分、m/z＝473 [M+H]⁺。 Example 59
2-Methyl-2- {3-[(5-methyl-3- {3- [4- (tetrahydro-2H-pyran-4-yl) phenyl] -1,2,4-oxadiazol-5-yl } -1H-pyrazol-1-yl) methyl] phenyl} propan-1-ol

At −78 ° C., 130 μl (0.130 mmol) of lithium aluminum hydride solution (1 M THF solution) was added to 3 ml of anhydrous THF solution of 74 mg (0.129 mmol) of the compound from Example 86A. Subsequently, the reaction mixture was first stirred at −78 ° C. for 1 hour and then at 0 ° C. for a further 30 minutes. Subsequently, about 9 ml of 1 M aqueous sodium hydroxide solution was added and the mixture was extracted three times with 10 ml of ethyl acetate each time. The combined organic layer extracts were washed with water followed by saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and finally the solvent removed by rotary evaporator. The resulting residue was purified by preparative HPLC (Method 11) to give 42 mg (69% of theory) of the title compound.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 8.14 (d, 2H), 7.36-7.28 (m, 4H), 7.22 (s, 1H), 6.99 (d, 1H), 6.81 (s, 1H ), 5.45 (s, 2H), 4.10 (dd, 2H), 3.59 (d, 2H), 3.54 (dt, 2H), 2.88-2.78 (m, 1H), 2.29 (s, 3H), 1.91-1.78 ( m, 4H), 1.30 (s, 6H), 1.24 (t, 1H).
LC / MS (Method 6, ESIpos): R _t = 1.21 min, m / z = 473 [M + H] ⁺ .

実施例59に記載した方法に準じて、実施例87Aからの化合物80 mg(0.15 mmol)を反応させ、表題化合物50 mg(理論値の68%)を得た。ここでは、方法17に従い分取用HPLCによる精製を行った。
¹H NMR (400 MHz、DMSO-d₆、δ/ppm)：8.09 (d、2H)、7.77 (d、2H)、7.32-7.25 (m、3H)、6.92 (d、2H)、5.49 (s、2H)、4.67 (s、broad、1H)、3.39 (d、2H)、2.34 (s、3H)、1.61 (s、6H)、1.20 (s、6H)。
LC/MS (方法6、ESIpos)：R_t＝1.36分、m/z＝499 [M+H]⁺。 Example 60
2-Methyl-2- {3-[(5-methyl-3- {3- [4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenyl] -1,2,4 -Oxadiazol-5-yl} -1H-pyrazol-1-yl) methyl] phenyl} propan-1-ol

In a manner similar to that described in Example 59, 80 mg (0.15 mmol) of the compound from Example 87A was reacted to give 50 mg (68% of theory) of the title compound. Here, purification by preparative HPLC was performed according to Method 17.
¹ H NMR (400 MHz, DMSO-d ₆ , δ / ppm): 8.09 (d, 2H), 7.77 (d, 2H), 7.32-7.25 (m, 3H), 6.92 (d, 2H), 5.49 (s , 2H), 4.67 (s, broad, 1H), 3.39 (d, 2H), 2.34 (s, 3H), 1.61 (s, 6H), 1.20 (s, 6H).
LC / MS (Method _{6, ESIpos): R t =} 1.36 min, m / z = 499 [M + H] +.

実施例59に記載した方法に準じて、実施例88Aからの化合物80 mg(0.16 mmol)を反応させ表題化合物40 mg(理論値の54%)を得た。ここでは、方法17に従い分取用HPLCによる精製を行った。
¹H NMR (400 MHz、DMSO-d₆、δ/ppm)：8.20 (d、2H)、7.59 (d、2H)、7.32-7.25 (m、3H)、6.92 (d、2H)、5.49 (s、2H)、4.67 (t、1H)、3.39 (d、2H)、2.34 (s、3H)、1.20 (s、6H)。
LC/MS (方法4、ESIpos)：R_t＝1.48分、m/z＝473 [M+H]⁺。 Example 61
2-Methyl-2- {3-[(5-methyl-3- {3- [4- (trifluoromethoxy) phenyl] -1,2,4-oxadiazol-5-yl} -1H-pyrazole- 1-yl) methyl] phenyl} propan-1-ol

In a manner similar to that described in Example 59, 80 mg (0.16 mmol) of the compound from Example 88A was reacted to give 40 mg (54% of theory) of the title compound. Here, purification by preparative HPLC was performed according to Method 17.
¹ H NMR (400 MHz, DMSO-d ₆ , δ / ppm): 8.20 (d, 2H), 7.59 (d, 2H), 7.32-7.25 (m, 3H), 6.92 (d, 2H), 5.49 (s , 2H), 4.67 (t, 1H), 3.39 (d, 2H), 2.34 (s, 3H), 1.20 (s, 6H).
LC / MS (method _{4, ESIpos): R t =} 1.48 min, m / z = 473 [M + H] +.

実施例59に記載した方法に準じて、実施例87Aからの化合物300 mg(0.555 mmol)およびリチウムアルミニウムデューテライド溶液(1 M THF溶液)555 μl(0.555 mmol)を反応させ、表題化合物166 mg(理論値の60%)を得た。ここでは、方法13に従い分取用HPLCによる精製を行った。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：8.20 (d、2H)、7.62 (d、2H)、7.32 (d、1H)、7.31 (t、1H)、7.22 (s、1H)、7.00 (d、1H)、6.82 (s、1H)、5.45 (s、2H)、2.29 (s、3H)、1.61 (s、6H)、1.30 (s、6H)、1.24 (s、broad、1H)。
LC/MS (方法6、ESIpos)：R_t＝1.35分、m/z＝501 [M+H]⁺。 Example 62
1,1-dideutero-2-methyl-2- {3-[(5-methyl-3- {3- [4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenyl]- 1,2,4-oxadiazol-5-yl} -1H-pyrazol-1-yl) methyl] phenyl} propan-1-ol

According to the method described in Example 59, 300 mg (0.555 mmol) of the compound from Example 87A and 555 μl (0.555 mmol) of lithium aluminum deuteride solution (1 M THF solution) were reacted to give 166 mg of the title compound ( 60% of theory) was obtained. Here, purification by preparative HPLC was performed according to Method 13.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 8.20 (d, 2H), 7.62 (d, 2H), 7.32 (d, 1H), 7.31 (t, 1H), 7.22 (s, 1H), 7.00 (d, 1H), 6.82 (s, 1H), 5.45 (s, 2H), 2.29 (s, 3H), 1.61 (s, 6H), 1.30 (s, 6H), 1.24 (s, broad, 1H) .
LC / MS (Method _{6, ESIpos): R t =} 1.35 min, m / z = 501 [M + H] +.

固体カリウムtert-ブトキシド68 mg(0.604 mmol)を、実施例22Aからの化合物125 mg(0.403 mmol)および実施例50Aからの化合物249 mg(0.604 mmol)の無水THF溶液5 mlに0℃で加えた。反応混合物を室温で6 日間および続いて40℃で次の2時間攪拌した。続いて水約50 mlを加え、混合物を各回約50 mlの酢酸エチルで3回抽出した。合わせた有機層抽出物を水、続いて飽和塩化ナトリウム溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、濾過し、最後にロータリーエバポレーターにより溶媒を除去した。得られた残渣を再度THF5 mlに溶解し、テトラ-n-ブチルアンモニウムフルオライド溶液(1 M THF溶液)483 μl(0.483 mmol)を加えた。室温で1時間攪拌した後、反応混合物をメタノール2 mlで希釈し、続いて分取用HPLC(方法13)により直接構成成分に分離した。こうして、表題化合物85 mg(理論値の45%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：8.26 (d、2H)、7.33 (d、2H)、7.32-7.25 (m、2H)、7.22 (s、1H)、7.00 (d、1H)、6.81 (s、1H)、5.44 (s、2H)、3.66 (s、2H)、2.30 (s、3H)、1.39 (broad、1H)、0.85 (s、4H)。
LC/MS (方法6、ESIpos)：R_t＝1.29分、m/z＝471 [M+H]⁺。 Example 63
(1- {3-[(5-Methyl-3- {3- [4- (trifluoromethoxy) phenyl] -1,2,4-oxadiazol-5-yl} -1H-pyrazol-1-yl ) Methyl] phenyl} cyclopropyl) methanol

Solid potassium tert-butoxide 68 mg (0.604 mmol) was added at 0 ° C. to 5 ml anhydrous THF solution of compound 125 mg (0.403 mmol) from Example 22A and compound 249 mg (0.604 mmol) from Example 50A. . The reaction mixture was stirred at room temperature for 6 days and subsequently at 40 ° C. for the next 2 hours. Subsequently, about 50 ml of water was added and the mixture was extracted three times with about 50 ml of ethyl acetate each time. The combined organic layer extracts were washed with water followed by saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and finally the solvent removed by rotary evaporator. The obtained residue was dissolved again in 5 ml of THF, and 483 μl (0.483 mmol) of tetra-n-butylammonium fluoride solution (1 M THF solution) was added. After stirring for 1 hour at room temperature, the reaction mixture was diluted with 2 ml of methanol and subsequently separated directly into components by preparative HPLC (Method 13). This gave 85 mg (45% of theory) of the title compound.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 8.26 (d, 2H), 7.33 (d, 2H), 7.32-7.25 (m, 2H), 7.22 (s, 1H), 7.00 (d, 1H ), 6.81 (s, 1H), 5.44 (s, 2H), 3.66 (s, 2H), 2.30 (s, 3H), 1.39 (broad, 1H), 0.85 (s, 4H).
LC / MS (Method _{6, ESIpos): R t =} 1.29 min, m / z = 471 [M + H] +.

実施例63に記載した方法に準じて、実施例23Aからの化合物109 mg(0.323 mmol)および実施例50Aからの化合物200 mg(0.485 mmol)を用いて、2つの部分工程によって、表題化合物124 mg(理論値の77%)を得た。ここでは、第1部分工程において、反応混合物を室温で16時間撹拌した；続く40℃への加熱は省いた。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：8.20 (d、2H)、7.62 (d、2H)、7.32-7.25 (m、2H)、7.22 (s、1H)、7.00 (d、1H)、6.82 (s、1H)、5.43 (s、2H)、3.66 (d、2H)、2.29 (s、3H)、1.62 (s、6H)、1.43 (t、broad、1H)、0.86 (s、4H)。
LC/MS (方法4、ESIpos)：R_t＝1.51分、m/z＝497 [M+H]⁺。 Example 64
(1- {3-[(5-Methyl-3- {3- [4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenyl] -1,2,4-oxadi Azol-5-yl} -1H-pyrazol-1-yl) methyl] phenyl} cyclopropyl) methanol

According to the method described in Example 63, the title compound 124 mg was prepared in two partial steps using 109 mg (0.323 mmol) of the compound from Example 23A and 200 mg (0.485 mmol) of the compound from Example 50A. (77% of theory) was obtained. Here, in the first partial step, the reaction mixture was stirred at room temperature for 16 hours; subsequent heating to 40 ° C. was omitted.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 8.20 (d, 2H), 7.62 (d, 2H), 7.32-7.25 (m, 2H), 7.22 (s, 1H), 7.00 (d, 1H ), 6.82 (s, 1H), 5.43 (s, 2H), 3.66 (d, 2H), 2.29 (s, 3H), 1.62 (s, 6H), 1.43 (t, broad, 1H), 0.86 (s, 4H).
LC / MS (Method 4, ESIpos): R _t = 1.51 min, m / z = 497 [M + H] ⁺ .

実施例63に記載した方法に準じて、実施例30Aからの化合物108 mg(0.323 mmol)および実施例50Aからの化合物200 mg(0.485 mmol)を用いて、2つの部分工程によって、表題化合物141 mg(理論値の89%)を得た。ここでは、第1部分工程において、反応混合物を室温で16時間撹拌した；続く40℃への加熱は省いた。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：8.19 (d、2H)、7.59 (d、2H)、7.31-7.25 (m、2H)、7.22 (s、1H)、7.00 (d、1H)、6.82 (s、1H)、5.43 (s、2H)、3.66 (s、2H)、2.29 (s、3H)、1.46-1.39 (m、3H)、1.10-1.07 (m、2H)、0.85 (s、4H)。
LC/MS (方法4、ESIpos)：R_t＝1.50分、m/z＝495 [M+H]⁺。 Example 65
[1- (3-{[5-Methyl-3- (3- {4- [1- (trifluoromethyl) cyclopropyl] phenyl} -1,2,4-oxadiazol-5-yl) -1H -Pyrazol-1-yl] methyl} phenyl) cyclopropyl] methanol

According to the method described in Example 63, using 108 mg (0.323 mmol) of the compound from Example 30A and 200 mg (0.485 mmol) of the compound from Example 50A, the title compound was 141 mg in two partial steps. (89% of theory) was obtained. Here, in the first partial step, the reaction mixture was stirred at room temperature for 16 hours; subsequent heating to 40 ° C. was omitted.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 8.19 (d, 2H), 7.59 (d, 2H), 7.31-7.25 (m, 2H), 7.22 (s, 1H), 7.00 (d, 1H ), 6.82 (s, 1H), 5.43 (s, 2H), 3.66 (s, 2H), 2.29 (s, 3H), 1.46-1.39 (m, 3H), 1.10-1.07 (m, 2H), 0.85 ( s, 4H).
LC / MS (method _{4, ESIpos): R t =} 1.50 min, m / z = 495 [M + H] +.

実施例63に記載した方法に準じて、実施例36Aからの化合物105 mg(0.323 mmol)および実施例50Aからの化合物200 mg(0.485 mmol)を用いて、2つの部分工程によって、表題化合物130 mg(理論値の83%)を得た。ここでは、第1部分工程において、反応混合物を室温で16時間撹拌した；続く40℃への加熱は省いた。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：8.27 (d、2H)、7.78 (d、2H)、7.31-7.26 (m、2H)、7.22 (s、1H)、7.00 (d、1H)、6.82 (s、1H)、5.46 (s、2H)、3.66 (s、2H)、2.30 (s、3H)、1.43 (broad、1H)、0.86 (s、4H)。
LC/MS (方法4、ESIpos)：R_t＝1.53分、m/z＝487 [M+H]⁺。 Example 66
[1- (3-{[5-Methyl-3- (3- {4-[(trifluoromethyl) sulfanyl] phenyl} -1,2,4-oxadiazol-5-yl) -1H-pyrazole- 1-yl] methyl} phenyl) cyclopropyl] methanol

According to the method described in Example 63, using 105 mg (0.323 mmol) of the compound from Example 36A and 200 mg (0.485 mmol) of the compound from Example 50A, the title compound 130 mg by two partial steps. (83% of theory) was obtained. Here, in the first partial step, the reaction mixture was stirred at room temperature for 16 hours; subsequent heating to 40 ° C. was omitted.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 8.27 (d, 2H), 7.78 (d, 2H), 7.31-7.26 (m, 2H), 7.22 (s, 1H), 7.00 (d, 1H ), 6.82 (s, 1H), 5.46 (s, 2H), 3.66 (s, 2H), 2.30 (s, 3H), 1.43 (broad, 1H), 0.86 (s, 4H).
LC / MS (Method 4, ESIpos): R _t = 1.53 min, m / z = 487 [M + H] ⁺ .

実施例63に記載した方法に準じて、実施例25Aからの化合物116 mg(0.323 mmol)および実施例50Aからの化合物200 mg(0.485 mmol)を用いて、2つの部分工程によって、表題化合物74 mg(理論値の44%)を得た。ここでは、第1部分工程において、反応混合物を室温で16時間撹拌した；続く40℃への加熱は省いた。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：8.52 (d、2H)、8.18 (d、2H)、7.32-7.27 (m、2H)、7.23 (s、1H)、7.00 (d、1H)、6.84 (s、1H)、5.45 (s、2H)、3.66 (d、2H)、2.31 (s、3H)、1.41 (t、1H)、0.86 (s、4H)。
LC/MS (方法MHZ-QP-GO-1、ESIpos)：R_t＝1.43分、m/z＝519 [M+H]⁺。 Example 67
[1- (3-{[5-Methyl-3- (3- {4-[(trifluoromethyl) sulfonyl] phenyl} -1,2,4-oxadiazol-5-yl) -1H-pyrazole- 1-yl] methyl} phenyl) cyclopropyl] methanol

According to the method described in Example 63, the title compound 74 mg was prepared in two partial steps using 116 mg (0.323 mmol) of the compound from Example 25A and 200 mg (0.485 mmol) of the compound from Example 50A. (44% of theory) was obtained. Here, in the first partial step, the reaction mixture was stirred at room temperature for 16 hours; subsequent heating to 40 ° C. was omitted.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 8.52 (d, 2H), 8.18 (d, 2H), 7.32-7.27 (m, 2H), 7.23 (s, 1H), 7.00 (d, 1H ), 6.84 (s, 1H), 5.45 (s, 2H), 3.66 (d, 2H), 2.31 (s, 3H), 1.41 (t, 1H), 0.86 (s, 4H).
LC / MS (Method MHZ-QP-GO-1, ESIpos): R _t = 1.43 min, m / z = 519 [M + H] ⁺ .

固体カリウムtert-ブトキシド62 mg(0.556 mmol)を、実施例22Aからの化合物115 mg(0.371 mmol)および実施例51A からの化合物231 mg(0.556 mmol)の無水THF溶液5 mlに0℃で加えた。氷/水浴をはずした後、反応混合物を室温で16時間攪拌した。続いて水約50 mlを加え、混合物を各回約50 mlの酢酸エチルで3回抽出した。合わせた有機層抽出物を水、続いて飽和塩化ナトリウム溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、濾過し、最後にロータリーエバポレーターにより溶媒を除去した。得られた残渣を再度THF5 mlに溶解し、テトラ-n-ブチルアンモニウムフルオライド溶液(1 M THF溶液)445 μl(0.445 mmol)を加えた。室温で1時間攪拌した後、反応混合物をメタノール2 mlで希釈し、続いて分取用HPLC(方法13)により直接構成成分に分離した。こうして、表題化合物105 mg(理論値の60%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：8.25 (d、2H)、7.33 (d、2H)、7.30-7.24 (m、2H)、7.21 (s、1H)、7.00 (d、1H)、6.82 (s、1H)、5.43 (s、2H)、2.30 (s、3H)、1.39 (broad、1H)、0.85 (s、4H)。
LC/MS (方法6、ESIpos)：R_t＝1.28分、m/z＝473 [M+H]⁺。 Example 68
Dideutero (1- {3-[(5-methyl-3- {3- [4- (trifluoromethoxy) phenyl] -1,2,4-oxadiazol-5-yl} -1H-pyrazole-1- Yl) methyl] phenyl} cyclopropyl) methanol

Solid potassium tert-butoxide 62 mg (0.556 mmol) was added at 0 ° C. to 5 ml anhydrous THF solution of compound 115 mg (0.371 mmol) from Example 22A and compound 231 mg (0.556 mmol) from Example 51A. . After removing the ice / water bath, the reaction mixture was stirred at room temperature for 16 hours. Subsequently, about 50 ml of water was added and the mixture was extracted three times with about 50 ml of ethyl acetate each time. The combined organic layer extracts were washed with water followed by saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and finally the solvent removed by rotary evaporator. The obtained residue was dissolved again in 5 ml of THF, and 445 μl (0.445 mmol) of tetra-n-butylammonium fluoride solution (1 M THF solution) was added. After stirring for 1 hour at room temperature, the reaction mixture was diluted with 2 ml of methanol and subsequently separated directly into components by preparative HPLC (Method 13). This gave 105 mg (60% of theory) of the title compound.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 8.25 (d, 2H), 7.33 (d, 2H), 7.30-7.24 (m, 2H), 7.21 (s, 1H), 7.00 (d, 1H ), 6.82 (s, 1H), 5.43 (s, 2H), 2.30 (s, 3H), 1.39 (broad, 1H), 0.85 (s, 4H).
LC / MS (Method _{6, ESIpos): R t =} 1.28 min, m / z = 473 [M + H] +.

実施例68に記載した方法に準じて、実施例23Aからの化合物108 mg(0.322 mmol)および実施例51Aからの化合物200 mg(0.482 mmol)を用いて、2つの部分工程によって、表題化合物57 mg(理論値の35%)を得た。ここでは、第二工程において、反応混合物は室温で2時間攪拌した。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：8.20 (d、2H)、7.62 (d、2H)、7.31-7.27 (m、2H)、7.22 (s、1H)、7.00 (d、1H)、6.82 (s、1H)、5.43 (s、2H)、2.29 (s、3H)、1.63 (s、6H)、1.43 (broad、1H)、0.83 (s、4H)。
LC/MS (方法4、ESIpos)：R_t＝1.51分、m/z＝499 [M+H]⁺。 Example 69
Dideutero (1- {3-[(5-methyl-3- {3- [4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenyl] -1,2,4-oxa Diazol-5-yl} -1H-pyrazol-1-yl) methyl] phenyl} cyclopropyl) methanol

According to the method described in Example 68, using 108 mg (0.322 mmol) of the compound from Example 23A and 200 mg (0.482 mmol) of the compound from Example 51A, the title compound 57 mg (35% of theory) was obtained. Here, in the second step, the reaction mixture was stirred at room temperature for 2 hours.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 8.20 (d, 2H), 7.62 (d, 2H), 7.31-7.27 (m, 2H), 7.22 (s, 1H), 7.00 (d, 1H ), 6.82 (s, 1H), 5.43 (s, 2H), 2.29 (s, 3H), 1.63 (s, 6H), 1.43 (broad, 1H), 0.83 (s, 4H).
LC / MS (Method 4, ESIpos): R _t = 1.51 min, m / z = 499 [M + H] ⁺ .

実施例68に記載した方法に準じて、実施例30Aからの化合物107 mg(0.322 mmol)および実施例51Aからの化合物200 mg(0.482 mmol)を用いて、2つの部分工程によって、表題化合物73 mg(理論値の45%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：8.19 (d、2H)、7.59 (d、2H)、7.31-7.25 (m、2H)、7.22 (s、1H)、7.00 (d、1H)、6.82 (s、1H)、5.43 (s、2H)、2.29 (s、3H)、1.43-1.39 (m、3H)、1.11-1.07 (m、2H)、0.85 (s、4H)。
LC/MS (方法6、ESIpos)：R_t＝1.31分、m/z＝497 [M+H]⁺。 Example 70
Dideutero [1- (3-{[5-methyl-3- (3- {4- [1- (trifluoromethyl) cyclopropyl] phenyl} -1,2,4-oxadiazol-5-yl)- 1H-pyrazol-1-yl] methyl} phenyl) cyclopropyl] methanol

According to the method described in Example 68, the title compound 73 mg was prepared in two partial steps using 107 mg (0.322 mmol) of the compound from Example 30A and 200 mg (0.482 mmol) of the compound from Example 51A. (45% of theory) was obtained.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 8.19 (d, 2H), 7.59 (d, 2H), 7.31-7.25 (m, 2H), 7.22 (s, 1H), 7.00 (d, 1H ), 6.82 (s, 1H), 5.43 (s, 2H), 2.29 (s, 3H), 1.43-1.39 (m, 3H), 1.11-1.07 (m, 2H), 0.85 (s, 4H).
LC / MS (Method 6, ESIpos): R _t = 1.31 min, m / z = 497 [M + H] ⁺ .

実施例68に記載した方法に準じて、実施例36Aからの化合物105 mg(0.322 mmol)および実施例51Aからの化合物200 mg(0.482 mmol)を用いて、2つの部分工程によって、表題化合物81 mg(理論値の52%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：8.28 (d、2H)、7.79 (d、2H)、7.31-7.27 (m、2H)、7.22 (s、1H)、7.00 (d、1H)、6.83 (s、1H)、5.44 (s、2H)、2.29 (s、3H)、1.45 (broad、1H)、0.84 (s、4H)。
LC/MS (方法6、ESIpos)：R_t＝1.34分、m/z＝489 [M+H]⁺。 Example 71
Dideutero [1- (3-{[5-methyl-3- (3- {4-[(trifluoromethyl) sulfanyl] phenyl} -1,2,4-oxadiazol-5-yl) -1H-pyrazole -1-yl] methyl} phenyl) cyclopropyl] methanol

Following the method described in Example 68, using 105 mg (0.322 mmol) of the compound from Example 36A and 200 mg (0.482 mmol) of the compound from Example 51A, in two partial steps, the title compound 81 mg (52% of theory) was obtained.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 8.28 (d, 2H), 7.79 (d, 2H), 7.31-7.27 (m, 2H), 7.22 (s, 1H), 7.00 (d, 1H ), 6.83 (s, 1H), 5.44 (s, 2H), 2.29 (s, 3H), 1.45 (broad, 1H), 0.84 (s, 4H).
LC / MS (Method _{6, ESIpos): R t =} 1.34 min, m / z = 489 [M + H] +.

実施例68に記載した方法に準じて、実施例25Aからの化合物115 mg(0.322 mmol)および実施例51Aからの化合物200 mg(0.482 mmol)を用いて、2つの部分工程によって、表題化合物41 mg(理論値の25%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：8.52 (d、2H)、8.18 (d、2H)、7.32-7.27 (m、2H)、7.23 (s、1H)、7.00 (d、1H)、6.83 (s、1H)、5.45 (s、2H)、2.31 (s、3H)、1.41 (t、1H)、0.84 (s、4H)。
LC/MS (方法6、ESIpos)：R_t＝1.25分、m/z＝521 [M+H]⁺。 Example 72
Dideutero [1- (3-{[5-methyl-3- (3- {4-[(trifluoromethyl) sulfanyl] phenyl} -1,2,4-oxadiazol-5-yl) -1H-pyrazole -1-yl] methyl} phenyl) cyclopropyl] methanol

According to the method described in Example 68, 115 mg (0.322 mmol) of the compound from Example 25A and 200 mg (0.482 mmol) of the compound from Example 51A were used in two partial steps to give 41 mg of the title compound. (25% of theory) was obtained.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 8.52 (d, 2H), 8.18 (d, 2H), 7.32-7.27 (m, 2H), 7.23 (s, 1H), 7.00 (d, 1H ), 6.83 (s, 1H), 5.45 (s, 2H), 2.31 (s, 3H), 1.41 (t, 1H), 0.84 (s, 4H).
LC / MS (Method 6, ESIpos): R _t = 1.25 min, m / z = 521 [M + H] ⁺ .

実施例68に記載した方法に準じて、実施例43Aからの化合物65 mg(0.198 mmol)および実施例51Aからの化合物123 mg(0.297 mmol)を用いて、2つの部分工程によって、表題化合物60 mg(理論値の61%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：8.23 (d、2H)、7.52 (d、2H)、7.31-7.26 (m、2H)、7.21 (s、1H)、7.00 (d、1H)、6.82 (s、1H)、5.43 (s、2H)、4.00-3.87 (m、4H)、2.29 (s、3H)、2.30-2.11 (m、2H)、1.98-1.91 (m、2H)、1.41 (s、broad、1H)、0.84 (s、4H)。
LC/MS (方法6、ESIpos)：R_t＝1.18分、m/z＝491 [M+H]⁺。 Example 73
Dideutero (1- {3-[(3- {3- [4- (4-fluorotetrahydro-2H-pyran-4-yl) phenyl] -1,2,4-oxadiazol-5-yl} -5 -Methyl-1H-pyrazol-1-yl) methyl] phenyl} cyclopropyl) methanol

According to the method described in Example 68, using 65 mg (0.198 mmol) of the compound from Example 43A and 123 mg (0.297 mmol) of the compound from Example 51A, the title compound 60 mg in two partial steps. (61% of theory) was obtained.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 8.23 (d, 2H), 7.52 (d, 2H), 7.31-7.26 (m, 2H), 7.21 (s, 1H), 7.00 (d, 1H ), 6.82 (s, 1H), 5.43 (s, 2H), 4.00-3.87 (m, 4H), 2.29 (s, 3H), 2.30-2.11 (m, 2H), 1.98-1.91 (m, 2H), 1.41 (s, broad, 1H), 0.84 (s, 4H).
LC / MS (Method _{6, ESIpos): R t =} 1.18 min, m / z = 491 [M + H] +.

アルゴン下0℃で、カリウムtert-ブトキシド85 mg(0.75 mmol)を、実施例26Aからの化合物155 mg(0.52 mmol)のTHF溶液4 mlに加えた。0℃で30分攪拌した後、実施例52Aからの化合物392 mg(1.56 mmol)のTHF2 ml溶液を加え、混合物を室温で16時間攪拌した。さらに続いてカリウムtert-ブトキシド58 mg(0.52 mmol)を加え、混合物を室温で次の2時間攪拌した。続いて水30 mlおよび酢酸エチル30 mlを混合物に加えた。相分離後、水相を30 mlの酢酸エチルで1回抽出した。合わせた有機相を硫酸ナトリウムで乾燥させ、濾過し、濃縮した。残渣をカラムクロマトグラフィー(シリカゲル、移動相：シクロヘキサン/酢酸エチル 7:3)により精製した。溶媒を除去した後、生成物分画をもう一度分取用薄層クロマトグラフィー(シリカゲル、移動相：ジクロロメタン/メタノール 97:3)で精製した。溶媒を除去し、残渣を減圧下乾燥させ、表題化合物47 mg(理論値の19%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：8.17 (d、2H)、7.64 (d、2H)、7.47 (d、1H)、7.42 (t、1H)、7.36 (s、1H)、7.23 (d、1H)、6.84 (s、1H)、5.49 (s、2H)、3.95 (t、2H)、2.29 (s、3H)、0.31 (s、9H)。
LC/MS (方法6、ESIpos)：R_t＝1.37分、m/z＝469 [M+H]⁺。 Example 74
2,2-difluoro-2- {3-[(5-methyl-3- {3- [4- (trimethylsilyl) phenyl] -1,2,4-oxadiazol-5-yl} -1H-pyrazole- 1-yl) methyl] phenyl} ethanol

At 0 ° C. under argon, 85 mg (0.75 mmol) of potassium tert-butoxide was added to 4 ml of a THF solution of the compound 155 mg (0.52 mmol) from Example 26A. After stirring at 0 ° C. for 30 minutes, a solution of compound 392 mg (1.56 mmol) from Example 52A in 2 ml of THF was added and the mixture was stirred at room temperature for 16 hours. Subsequently, 58 mg (0.52 mmol) of potassium tert-butoxide was added and the mixture was stirred at room temperature for the next 2 hours. Subsequently, 30 ml of water and 30 ml of ethyl acetate were added to the mixture. After phase separation, the aqueous phase was extracted once with 30 ml of ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel, mobile phase: cyclohexane / ethyl acetate 7: 3). After removal of the solvent, the product fraction was purified once more by preparative thin layer chromatography (silica gel, mobile phase: dichloromethane / methanol 97: 3). The solvent was removed and the residue was dried under reduced pressure to give 47 mg (19% of theory) of the title compound.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 8.17 (d, 2H), 7.64 (d, 2H), 7.47 (d, 1H), 7.42 (t, 1H), 7.36 (s, 1H), 7.23 (d, 1H), 6.84 (s, 1H), 5.49 (s, 2H), 3.95 (t, 2H), 2.29 (s, 3H), 0.31 (s, 9H).
LC / MS (Method _{6, ESIpos): R t =} 1.37 min, m / z = 469 [M + H] +.

アルゴン下、0℃で、カリウムtert-ブトキシド89 mg(0.80 mmol)を、実施例42Aからの化合物155 mg(0.55 mmol)のTHF溶液3 mlに加えた。0℃で30分撹拌した後、実施例52Aからの化合物414 mg(1.65 mmol)を加えた。続いて混合物を室温に戻し、室温で16時間攪拌した。続いて水30 mlおよび酢酸エチル30 mlを加え、相を分離した。水相をもう一度30 mlの酢酸エチルで抽出した。合わせた有機相を硫酸ナトリウムで乾燥させ、濾過し、濃縮した。残渣をカラムクロマトグラフィー(シリカゲル、移動相：シクロヘキサン/酢酸エチル 4:1)により精製した。溶媒を除去し、残渣を減圧下乾燥させ、表題化合物93 mg(理論値の36%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：8.13 (d、2H)、7.51 (d、2H)、7.47 (d、1H)、7.42 (t、1H)、7.36 (s、1H)、7.23 (d、1H)、6.83 (s、1H)、5.49 (s、2H)、3.95 (dt、2H)、2.29 (s、3H)、2.10 (t、1H)、1.36 (s、9H)。
LC/MS (方法4、ESIpos)：R_t＝1.53分、m/z＝453 [M+H]⁺。 Example 75
2- [3-({3- [3- (4-tert-butylphenyl) -1,2,4-oxadiazol-5-yl] -5-methyl-1H-pyrazol-1-yl} methyl) Phenyl] -2,2-difluoroethanol

Under argon at 0 ° C., 89 mg (0.80 mmol) of potassium tert-butoxide was added to 3 ml of a THF solution of the compound 155 mg (0.55 mmol) from Example 42A. After stirring at 0 ° C. for 30 minutes, 414 mg (1.65 mmol) of the compound from Example 52A was added. Subsequently, the mixture was returned to room temperature and stirred at room temperature for 16 hours. Subsequently, 30 ml of water and 30 ml of ethyl acetate were added and the phases were separated. The aqueous phase was extracted once more with 30 ml of ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel, mobile phase: cyclohexane / ethyl acetate 4: 1). The solvent was removed and the residue was dried under reduced pressure to give 93 mg (36% of theory) of the title compound.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 8.13 (d, 2H), 7.51 (d, 2H), 7.47 (d, 1H), 7.42 (t, 1H), 7.36 (s, 1H), 7.23 (d, 1H), 6.83 (s, 1H), 5.49 (s, 2H), 3.95 (dt, 2H), 2.29 (s, 3H), 2.10 (t, 1H), 1.36 (s, 9H).
LC / MS (Method 4, ESIpos): R _t = 1.53 min, m / z = 453 [M + H] ⁺ .

実施例75に記載した方法に準じて、実施例23Aからの化合物168 mg(0.50 mmol)および実施例52Aからの化合物377 mg(1.50 mmol)を用いて表題化合物66 mg(理論値の26%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：8.19 (d、2H)、7.62 (d、2H)、7.47 (d、1H)、7.43 (t、1H)、7.36 (s、1H)、7.24 (d、1H)、6.83 (s、1H)、5.49 (s、2H)、3.95 (dt、2H)、2.29 (s、3H)、2.10 (t、1H)、1.62 (s、6H)。
LC/MS (方法6、ESIpos)：R_t＝1.30分、m/z＝507 [M+H]⁺。 Example 76
2,2-difluoro-2- {3-[(5-methyl-3- {3- [4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenyl] -1,2 , 4-Oxadiazol-5-yl} -1H-pyrazol-1-yl) methyl] phenyl} ethanol

According to the method described in Example 75, using 168 mg (0.50 mmol) of the compound from Example 23A and 377 mg (1.50 mmol) of the compound from Example 52A, the title compound 66 mg (26% of theory) Got.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 8.19 (d, 2H), 7.62 (d, 2H), 7.47 (d, 1H), 7.43 (t, 1H), 7.36 (s, 1H), 7.24 (d, 1H), 6.83 (s, 1H), 5.49 (s, 2H), 3.95 (dt, 2H), 2.29 (s, 3H), 2.10 (t, 1H), 1.62 (s, 6H).
LC / MS (Method 6, ESIpos): R _t = 1.30 min, m / z = 507 [M + H] ⁺ .

実施例75に記載した方法に準じて、実施例35Aからの化合物126 mg(0.42 mmol)および実施例52Aからの化合物317 mg(1.26 mmol)を用いて表題化合物38 mg(理論値の19%)を得た。ここでは、シリカゲルクロマトグラフィーを行った後、生成物を分取用HPLC(方法16)で再精製した。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：8.28 (d、2H)、7.71 (d、2H)、7.46 (d、1H)、7.44 (t、1H)、7.36 (s、1H)、7.24 (d、1H)、6.84 (s、1H)、5.50 (s、2H)、5.15 (dd、2H)、4.90 (d、2H)、3.95 (t、2H)、2.30 (s、3H)。
LC/MS (方法4、ESIpos)：R_t＝1.25分、m/z＝471 [M+H]⁺。 Example 77
2,2-difluoro-2- {3-[(3- {3- [4- (3-fluorooxetane-3-yl) phenyl] -1,2,4-oxadiazol-5-yl} -5 -Methyl-1H-pyrazol-1-yl) methyl] phenyl} ethanol

According to the method described in Example 75, using the compound 126 mg (0.42 mmol) from Example 35A and the compound 317 mg (1.26 mmol) from Example 52A, the title compound 38 mg (19% of theory) Got. Here, after silica gel chromatography, the product was re-purified by preparative HPLC (Method 16).
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 8.28 (d, 2H), 7.71 (d, 2H), 7.46 (d, 1H), 7.44 (t, 1H), 7.36 (s, 1H), 7.24 (d, 1H), 6.84 (s, 1H), 5.50 (s, 2H), 5.15 (dd, 2H), 4.90 (d, 2H), 3.95 (t, 2H), 2.30 (s, 3H).
LC / MS (Method 4, ESIpos): R _t = 1.25 min, m / z = 471 [M + H] ⁺ .

実施例75に記載した方法に準じて、実施例30Aからの化合物167 mg(0.50 mmol)および実施例52Aからの化合物377 mg(1.50 mmol)から表題化合物93 mg(理論値の36%)を得た。ここでは、シリカゲルクロマトグラフィーは、シクロヘキサン/酢酸エチル 3:1移動相を用いて行った。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：8.18 (d、2H)、7.59 (d、2H)、7.46 (d、1H)、7.44 (t、1H)、7.36 (s、1H)、7.24 (d、1H)、6.83 (s、1H)、5.49 (s、2H)、3.95 (td、2H)、2.29 (s、3H)、2.07 (t、1H)、1.42-1.38 (m、2H)、1.11-1.06 (m、2H)。
LC/MS (方法6、ESIpos)：R_t＝1.32分、m/z＝505 [M+H]⁺。 Example 78
2,2-difluoro-2- (3-{[5-methyl-3- (3- {4- [1- (trifluoromethyl) cyclopropyl] phenyl} -1,2,4-oxadiazole-5 -Yl) -1H-pyrazol-1-yl] methyl} phenyl) ethanol

According to the method described in Example 75, 167 mg (0.50 mmol) of the compound from Example 30A and 377 mg (1.50 mmol) of the compound from Example 52A gave 93 mg (36% of theory) of the title compound. It was. Here, silica gel chromatography was performed using a 3: 1 mobile phase of cyclohexane / ethyl acetate.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 8.18 (d, 2H), 7.59 (d, 2H), 7.46 (d, 1H), 7.44 (t, 1H), 7.36 (s, 1H), 7.24 (d, 1H), 6.83 (s, 1H), 5.49 (s, 2H), 3.95 (td, 2H), 2.29 (s, 3H), 2.07 (t, 1H), 1.42-1.38 (m, 2H) 1.11-1.06 (m, 2H).
LC / MS (Method _{6, ESIpos): R t =} 1.32 min, m / z = 505 [M + H] +.

室温で、水素化ホウ素ナトリウム38 mg(1.02 mmol)を、実施例89Aからの化合物1.33 g(1.02 mmol、純度40%)のエタノール溶液20 mlに加えた。室温で1時間撹拌した後、さらに水素化ホウ素ナトリウム38 mg(1.02 mmol)およびメタノール5 mlを加え、溶媒を除去した。残渣を酢酸エチルで砕き、固体成分をろ過し、濾液を濃縮した。LC/MSからでは、得られた残渣は実施例89Aに対応するカルボン酸を主として構成するため、この残渣をメタノール20 mlに取り込み、塩化チオニル2 ml(27 mmol)を0℃で滴下した。続いて混合物を0℃で1時間攪拌した。続いて混合物を濃縮し、残渣を減圧下乾燥させた。この残渣をエタノール20 mlに溶解し、さらに水素化ホウ素ナトリウム38 mg(1.02 mmol)を加えた。室温で30分撹拌攪拌し、混合物を濃縮した。残渣を酢酸エチルおよび水に取り込み、10%クエン酸で酸性化した。相分離後、水相を酢酸エチルで1回再抽出した。合わせた有機相を硫酸マグネシウムで乾燥させ、濾過し、濃縮した。残渣を 分取用HPLC(方法15)。続いて、カラムシリカゲルクロマトグラフィー(移動相：ジクロロメタン/メタノール 98.5:1.5)により精製し、溶媒を除去した後、残渣を減圧下乾燥させ、表題化合物248 mg(理論値の51%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：8.25 (d、2H)、7.47 (d、1H)、7.43 (t、1H)、7.36 (s、1H)、7.33 (d、2H)、7.24 (d、1H)、6.83 (s、1H)、5.49 (s、2H)、3.95 (td、2H)、2.30 (s、3H)、2.19 (t、1H)。
LC/MS (方法6、ESIpos)：R_t＝1.25分、m/z＝481 [M+H]⁺。 Example 79
2,2-difluoro-2- {3-[(5-methyl-3- {3- [4- (trifluoromethoxy) phenyl] -1,2,4-oxadiazol-5-yl} -1H- Pyrazol-1-yl) methyl] phenyl} ethanol

At room temperature, 38 mg (1.02 mmol) of sodium borohydride was added to 20 ml of ethanol solution of the compound from Example 89A 1.33 g (1.02 mmol, 40% purity). After stirring at room temperature for 1 hour, 38 mg (1.02 mmol) of sodium borohydride and 5 ml of methanol were further added, and the solvent was removed. The residue was triturated with ethyl acetate, the solid component was filtered and the filtrate was concentrated. From LC / MS, the resulting residue mainly comprised the carboxylic acid corresponding to Example 89A, so this residue was taken up in 20 ml of methanol and 2 ml (27 mmol) of thionyl chloride was added dropwise at 0 ° C. The mixture was subsequently stirred at 0 ° C. for 1 hour. Subsequently, the mixture was concentrated and the residue was dried under reduced pressure. This residue was dissolved in 20 ml of ethanol, and 38 mg (1.02 mmol) of sodium borohydride was further added. The mixture was stirred and stirred at room temperature for 30 minutes, and the mixture was concentrated. The residue was taken up in ethyl acetate and water and acidified with 10% citric acid. After phase separation, the aqueous phase was re-extracted once with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was preparative HPLC (Method 15). Subsequently, the residue was purified by column silica gel chromatography (mobile phase: dichloromethane / methanol 98.5: 1.5), the solvent was removed, and the residue was dried under reduced pressure to obtain 248 mg (51% of theory) of the title compound.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 8.25 (d, 2H), 7.47 (d, 1H), 7.43 (t, 1H), 7.36 (s, 1H), 7.33 (d, 2H), 7.24 (d, 1H), 6.83 (s, 1H), 5.49 (s, 2H), 3.95 (td, 2H), 2.30 (s, 3H), 2.19 (t, 1H).
LC / MS (Method 6, ESIpos): R _t = 1.25 min, m / z = 481 [M + H] ⁺ .

氷浴による冷却下、水素化ホウ素ナトリウム79 mg(2.10 mmol)を、実施例91Aからの化合物0.12 g(0.21 mmol)の無水THF4 mlおよびメタノール4 ml溶液に加え、混合物を40℃で一夜攪拌した。続いてさらに水素化ホウ素ナトリウム79 mgを加え、混合物を40℃で次の1時間攪拌した。続いてさらに水素化ホウ素ナトリウム79 mgを2回加え、ここで各回反応混合物は40℃で1時間攪拌した。続いて飽和塩化ナトリウム水溶液および水を加え、反応液を酢酸エチルで抽出した。有機層を水および飽和塩化ナトリウム溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、濾過した。ロータリーエバポレーターにより濾液から溶媒を除去し、残渣を分取用HPLC(方法17)により精製した。これにより表題化合物60 mg(理論値の59%)を得た。
¹H NMR (400 MHz、DMSO-d₆、δ/ppm)：8.20 (d、2H)、7.59 (d、2H)、7.32 (d、2H)、7.26 (t、1H)、6.93 (d、2H)、5.48 (s、2H)、3.54 (s、4H)、2.35 (s、3H)、1.17 (s、3H)。
LC/MS (方法2、ESIpos)：R_t＝2.46分、m/z＝489 [M+H]⁺。 Example 80
2-Methyl-2- {3-[(5-methyl-3- {3- [4- (trifluoromethoxy) phenyl] -1,2,4-oxadiazol-5-yl} -1H-pyrazole- 1-yl) methyl] phenyl} propane-1,3-diol

Under cooling in an ice bath, 79 mg (2.10 mmol) of sodium borohydride was added to a solution of compound 0.12 g (0.21 mmol) from Example 91A in 4 ml anhydrous THF and 4 ml methanol and the mixture was stirred at 40 ° C. overnight. . Subsequently, 79 mg of sodium borohydride was further added, and the mixture was stirred at 40 ° C. for the next 1 hour. Subsequently, 79 mg of sodium borohydride was further added twice, and each time the reaction mixture was stirred at 40 ° C. for 1 hour. Subsequently, a saturated aqueous sodium chloride solution and water were added, and the reaction solution was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. The solvent was removed from the filtrate by rotary evaporator and the residue was purified by preparative HPLC (Method 17). This gave 60 mg (59% of theory) of the title compound.
¹ H NMR (400 MHz, DMSO-d ₆ , δ / ppm): 8.20 (d, 2H), 7.59 (d, 2H), 7.32 (d, 2H), 7.26 (t, 1H), 6.93 (d, 2H ), 5.48 (s, 2H), 3.54 (s, 4H), 2.35 (s, 3H), 1.17 (s, 3H).
LC / MS (Method 2, ESIpos): R _t = 2.46 min, m / z = 489 [M + H] ⁺ .

実施例92Aからの化合物197 mg(0.301 mmol)のメタノール/水 10:1溶液6 mlをフロースルー水素化装置(「H-Cube」ThalesNano、Budapest、Hungary)(条件：10% Pd/C 触媒、1 bar、1 ml/分、22℃)において水素化した。溶媒をロータリーエバポレーターで除去した後、粗成生物を分取用HPLC(方法11)により精製した。これにより表題化合物91 mg(理論値の54%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：8.19 (d、2H)、7.30 (d、2H)、7.20 (t、1H)、7.19 (s、1H)、7.09 (d、1H)、6.96 (d、1H)、6.78 (s、1H)、5.43 (s、2H)、2.89 (s、2H)、2.26 (s、3H)、1.41 (s、6H)。
LC/MS (方法4、ESIpos)：R_t＝1.29分、m/z＝455 [M-H₃PO₄+H]⁺、553 [M+H]⁺。 Example 81
2-Methyl-1- {3-[(5-methyl-3- {3- [4- (trifluoromethoxy) phenyl] -1,2,4-oxadiazol-5-yl} -1H-pyrazole- 1-yl) methyl] phenyl} propan-2-yl dihydrogen phosphate

6 ml of a methanol / water 10: 1 solution of the compound 197 mg (0.301 mmol) from Example 92A was added to a flow-through hydrogenator (“H-Cube” Thales Nano, Budapest, Hungary) (conditions: 10% Pd / C catalyst, Hydrogenation at 1 bar, 1 ml / min, 22 ° C). After removing the solvent on a rotary evaporator, the crude product was purified by preparative HPLC (Method 11). This gave 91 mg (54% of theory) of the title compound.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 8.19 (d, 2H), 7.30 (d, 2H), 7.20 (t, 1H), 7.19 (s, 1H), 7.09 (d, 1H), 6.96 (d, 1H), 6.78 (s, 1H), 5.43 (s, 2H), 2.89 (s, 2H), 2.26 (s, 3H), 1.41 (s, 6H).
LC / MS (method _{4, ESIpos): R t =} 1.29 min, m / z = 455 [MH 3 PO 4 + H] +, 553 [M + H] +.

氷浴による冷却下、ブロモトリメチルシラン52 μl(0.39 mmol)を、実施例93Aからの化合物136 mg(0.18 mmol)のジクロロメタン溶液3.6 mlに加え、混合物を室温で一夜攪拌した。続いて1 N 塩酸を加え、混合物をより多くのジクロロメタンで希釈した。有機層を水および飽和塩化ナトリウム溶液で洗浄し、無水硫酸ナトリウムで乾燥させ濾過した。最後に濾液をロータリーエバポレーターにより溶媒を除去した。これにより表題化合物104 mg(理論値の95%)を得た。
¹H NMR (400 MHz、DMSO-d₆、δ/ppm)：8.08 (d、2H)、7.76 (d、2H)、7.35-7.24 (m、3H)、6.92 (d、2H)、5.49 (s、2H)、3.83 (d、2H)、2.33 (s、3H)、1.60 (s、6H)、1.25 (s、6H)。
LC/MS (方法6、ESIpos)：R_t＝1.13分、m/z＝579 [M+H]⁺。 Example 82
2-Methyl-2- {3-[(5-methyl-3- {3- [4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenyl] -1,2,4 -Oxadiazol-5-yl} -1H-pyrazol-1-yl) methyl] phenyl} propyl dihydrogen phosphate

Under cooling in an ice bath, 52 μl (0.39 mmol) of bromotrimethylsilane was added to 3.6 ml of a solution of 136 mg (0.18 mmol) of the compound from Example 93A in dichloromethane and the mixture was stirred at room temperature overnight. Subsequently 1 N hydrochloric acid was added and the mixture was diluted with more dichloromethane. The organic layer was washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate and filtered. Finally, the solvent was removed from the filtrate by a rotary evaporator. This gave 104 mg (95% of theory) of the title compound.
¹ H NMR (400 MHz, DMSO-d ₆ , δ / ppm): 8.08 (d, 2H), 7.76 (d, 2H), 7.35-7.24 (m, 3H), 6.92 (d, 2H), 5.49 (s , 2H), 3.83 (d, 2H), 2.33 (s, 3H), 1.60 (s, 6H), 1.25 (s, 6H).
LC / MS (Method _{6, ESIpos): R t =} 1.13 min, m / z = 579 [M + H] +.

実施例82に記載した方法に準じて、実施例94Aからの化合物90 mg(0.12 mmol)から表題化合物58 mg(理論値の81%)を得た。
¹H NMR (400 MHz、DMSO-d₆、δ/ppm)：8.20 (d、2H)、7.59 (d、2H)、7.35-7.28 (m、3H)、6.94 (d、1H)、6.93 (s、1H)、5.50 (s、2H)、3.84 (d、2H)、2.35 (s、3H)、1.26 (s、6H)。
LC/MS (方法6、ESIpos)：R_t＝1.09分、m/z＝553 [M+H]⁺。 Example 83
2-Methyl-2- {3-[(5-methyl-3- {3- [4- (trifluoromethoxy) phenyl] -1,2,4-oxadiazol-5-yl} -1H-pyrazole- 1-yl) methyl] phenyl} propyl dihydrogen phosphate

According to the method described in Example 82, the title compound 58 mg (81% of theory) was obtained from 90 mg (0.12 mmol) of the compound from Example 94A.
¹ H NMR (400 MHz, DMSO-d ₆ , δ / ppm): 8.20 (d, 2H), 7.59 (d, 2H), 7.35-7.28 (m, 3H), 6.94 (d, 1H), 6.93 (s , 1H), 5.50 (s, 2H), 3.84 (d, 2H), 2.35 (s, 3H), 1.26 (s, 6H).
LC / MS (Method 6, ESIpos): R _t = 1.09 min, m / z = 553 [M + H] ⁺ .

実施例60からの化合物60 mg(0.12 mmol)およびN,N-ジメチルグリシルクロライドヒドロクロライド21 mg(0.13 mmol)を最初にジクロロメタン2.4 mlに入れ、トリエチルアミン18 μl(0.13 mmol)を加え、混合物を室温で一夜攪拌した。さらにN,N-ジメチルグリシルクロライドヒドロクロライド21 mg(0.13 mmol)およびトリエチルアミン18 μlの添加後、混合物は室温で、さらに1時間攪拌した。続いて混合物を酢酸エチルで希釈し、水、飽和重炭酸ナトリウム溶液および飽和塩化ナトリウム溶液で順に洗浄した。有機相を無水硫酸マグネシウムで乾燥させ、濾過した。最後に濾液をロータリーエバポレーターにより、溶媒を除去した。これにより表題化合物65 mg(理論値の86%)を得た。
¹H NMR (400 MHz、DMSO-d₆、δ/ppm)：8.09 (d、2H)、7.77 (d、2H)、7.36-7.29 (m、3H)、6.98 (d、1H)、6.93 (s、1H)、5.50 (s、2H)、4.11 (s、2H)、3.05 (s、2H)、2.34 (s、3H)、2.10 (s、6H)、1.61 (s、6H)、1.29 (s、6H)。
LC/MS (方法6、ESIpos)：R_t＝1.12分、m/z＝584 [M+H]⁺。 Example 84
2-Methyl-2- {3-[(5-methyl-3- {3- [4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenyl] -1,2,4 -Oxadiazol-5-yl} -1H-pyrazol-1-yl) methyl] phenyl} propyl N, N-dimethylglycinate

60 mg (0.12 mmol) of the compound from Example 60 and 21 mg (0.13 mmol) of N, N-dimethylglycyl chloride hydrochloride are initially placed in 2.4 ml of dichloromethane, 18 μl (0.13 mmol) of triethylamine are added and the mixture is Stir overnight at room temperature. After addition of 21 mg (0.13 mmol) of N, N-dimethylglycyl chloride hydrochloride and 18 μl of triethylamine, the mixture was further stirred at room temperature for 1 hour. The mixture was subsequently diluted with ethyl acetate and washed sequentially with water, saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase was dried over anhydrous magnesium sulfate and filtered. Finally, the solvent was removed from the filtrate by a rotary evaporator. This gave 65 mg (86% of theory) of the title compound.
¹ H NMR (400 MHz, DMSO-d ₆ , δ / ppm): 8.09 (d, 2H), 7.77 (d, 2H), 7.36-7.29 (m, 3H), 6.98 (d, 1H), 6.93 (s , 1H), 5.50 (s, 2H), 4.11 (s, 2H), 3.05 (s, 2H), 2.34 (s, 3H), 2.10 (s, 6H), 1.61 (s, 6H), 1.29 (s, 6H).
LC / MS (Method _{6, ESIpos): R t =} 1.12 min, m / z = 584 [M + H] +.

実施例60からの化合物100 mg(0.20 mmol)を、最初にジクロロメタン4 mlに入れ、tert-ブチル(4S)-4-イソプロピル-2,5-ジオキソ-1,3-オキサゾリジン-3-カルボキシレート73 mg(0.30 mmol)および4-N,N-ジメチルアミノピリジン25 mg(0.20 mmol)を加え、混合物を室温で一夜攪拌した。続いて混合物を酢酸エチルで希釈し、飽和塩化アンモニウム溶液、水、準-濃縮重炭酸ナトリウム溶液および飽和塩化ナトリウム溶液で順に洗浄した。有機相を無水硫酸マグネシウムで乾燥させ、濾過し、ロータリーエバポレーターにより濾液から溶媒を除去した。室温で、残渣を4 M塩化水素ガスのジオキサン溶液2 ml中30分攪拌した。続いて混合物をロータリーエバポレーターにより溶媒を除去した。残渣を分取用HPLC(方法17)により精製し、表題化合物48 mg(理論値の40%)を得た。
¹H NMR (400 MHz、DMSO-d₆、δ/ppm)：8.09 (d、2H)、7.77 (d、2H)、7.37-7.28 (m、3H)、6.97 (d、1H)、6.93 (s、1H)、5.49 (s、2H)、4.16 (d、1H)、4.01 (d、1H)、2.98 (d、1H)、2.33 (s、3H)、1.64 (m、1H)、1.61 (s、6H)、1.30 (d、6H)、0.70 (d、3H)、0.63 (d、3H)。
LC/MS (方法6、ESIpos)：R_t＝1.16分、m/z＝598 [M+H]⁺。 Example 85
(S) -2-Methyl-2- {3-[(5-methyl-3- {3- [4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenyl] -1 , 2,4-oxadiazol-5-yl} -1H-pyrazol-1-yl) methyl] phenyl} propyl L-valinate

100 mg (0.20 mmol) of the compound from Example 60 was initially placed in 4 ml of dichloromethane and tert-butyl (4S) -4-isopropyl-2,5-dioxo-1,3-oxazolidine-3-carboxylate 73 mg (0.30 mmol) and 25 mg (0.20 mmol) of 4-N, N-dimethylaminopyridine were added and the mixture was stirred at room temperature overnight. The mixture was subsequently diluted with ethyl acetate and washed sequentially with saturated ammonium chloride solution, water, semi-concentrated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase was dried over anhydrous magnesium sulfate, filtered, and the solvent was removed from the filtrate by rotary evaporator. At room temperature, the residue was stirred in 2 ml of 4 M hydrogen chloride gas in dioxane for 30 minutes. Subsequently, the solvent was removed from the mixture by a rotary evaporator. The residue was purified by preparative HPLC (Method 17) to give 48 mg (40% of theory) of the title compound.
¹ H NMR (400 MHz, DMSO-d ₆ , δ / ppm): 8.09 (d, 2H), 7.77 (d, 2H), 7.37-7.28 (m, 3H), 6.97 (d, 1H), 6.93 (s , 1H), 5.49 (s, 2H), 4.16 (d, 1H), 4.01 (d, 1H), 2.98 (d, 1H), 2.33 (s, 3H), 1.64 (m, 1H), 1.61 (s, 6H), 1.30 (d, 6H), 0.70 (d, 3H), 0.63 (d, 3H).
LC / MS (Method _{6, ESIpos): R t =} 1.16 min, m / z = 598 [M + H] +.

実施例2からのラセミ体をクロマトグラフィーによりその光学異性体に分離した。この目的を達成するため、実施例2からのラセミ体157 mg(0.316 mmol)を各回イソプロパノールおよびイソヘキサンの混合物20 mlに溶解した。各回0.5 mlずつ、この溶液をキラル固定相 [カラム材：Daicel Chiralpak AS-H、5 μm、250 mm x 20 mm；移動相：イソヘキサン/イソプロパノール 90:10；流速：20 ml/分；温度：25℃；UV検出：230 nm]のHPLCで分離した。各回の分離したエナンチオマーの標的分画からロータリーエバポレーターにより溶媒を除去し、ペンタン5 mlおよびジエチルエーテル1 mlの混合物で室温で摩砕した。吸引濾過し、高真空下において固体を乾燥させ、エナンチオマーを純粋な形態で得た。
実施例86(エナンチオマー 1):
収量：48 mg(理論値の61%)
R_t＝4.32分、＞99% ee [分析的キラル HPLC：カラム：Daicel AS-H、5 μm、250 mm x 4 mm；移動相：イソヘキサン/イソプロパノール 60:40；流速：1 ml/分；温度：25℃；UV検出：230 nm]。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：8.24 (d、2H)、7.43 (d、1H)、7.39 (t、1H)、7.34 (s、1H)、7.32 (d、2H)、7.19 (d、1H)、6.82 (s、1H)、5.48 (s、2H)、5.02 (m、1H)、2.74 (s、broad、1H)、2.27 (s、3H)。
LC/MS (方法6、ESIpos)：R_t＝1.27分、m/z＝499 [M+H]⁺。 Example 86 and Example 87
2,2,2-trifluoro-1- {3-[(5-methyl-3- {3- [4- (trifluoromethoxy) phenyl] -1,2,4-oxadiazol-5-yl} -1H-pyrazol-1-yl) methyl] phenyl} ethanol (enantiomers 1 and 2)

The racemate from Example 2 was separated into its optical isomers by chromatography. To achieve this goal, 157 mg (0.316 mmol) of the racemate from Example 2 was dissolved each time in 20 ml of a mixture of isopropanol and isohexane. 0.5 ml each time, this solution was added to the chiral stationary phase [column material: Daicel Chiralpak AS-H, 5 μm, 250 mm x 20 mm; mobile phase: isohexane / isopropanol 90:10; flow rate: 20 ml / min; temperature: 25 Separation by HPLC at ° C; UV detection: 230 nm]. The solvent was removed from the target fraction of each separated enantiomer by rotary evaporator and triturated with a mixture of 5 ml pentane and 1 ml diethyl ether at room temperature. Filtration with suction and drying of the solid under high vacuum gave the enantiomer in pure form.
Example 86 (enantiomer 1):
Yield: 48 mg (61% of theory)
R _t = 4.32 min,> 99% ee [Analytical chiral HPLC: column: Daicel AS-H, 5 μm, 250 mm x 4 mm; mobile phase: isohexane / isopropanol 60:40; flow rate: 1 ml / min; temperature : 25 ° C; UV detection: 230 nm].
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 8.24 (d, 2H), 7.43 (d, 1H), 7.39 (t, 1H), 7.34 (s, 1H), 7.32 (d, 2H), 7.19 (d, 1H), 6.82 (s, 1H), 5.48 (s, 2H), 5.02 (m, 1H), 2.74 (s, broad, 1H), 2.27 (s, 3H).
LC / MS (Method _{6, ESIpos): R t =} 1.27 min, m / z = 499 [M + H] +.

Example 87 (Enantiomer 2):
Yield: 41 mg (52% of theory)
R _t = 4.62 min, 99% ee [Analytical chiral HPLC: column: Daicel AS-H, 5 μm, 250 mm × 4 mm; mobile phase: isohexane / isopropanol 60:40; flow rate: 1 ml / min; temperature: 25 ° C .; UV detection: 230 nm].
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 8.24 (d, 2H), 7.43 (d, 1H), 7.39 (t, 1H), 7.35 (s, 1H), 7.32 (d, 2H), 7.19 (d, 1H), 6.82 (s, 1H), 5.48 (s, 2H), 5.02 (m, 1H), 2.77 (s, broad, 1H), 2.27 (s, 3H).
LC / MS (Method _{6, ESIpos): R t =} 1.27 min, m / z = 499 [M + H] +.

実施例3からのラセミ体をクロマトグラフィーによりその光学異性体に分離した。この目的を達成するため、実施例3からのラセミ体191 mg(0.373 mmol)を各回イソプロパノールおよびイソヘキサンの混合物20 mlに溶解した。各回1.0 mlずつ、この溶液をキラル固定相[カラム材：Daicel Chiralpak AS-H、5 μm、250 mm x 20 mm；移動相：イソヘキサン/イソプロパノール 85:15；流速：20 ml/分；温度：25℃；UV検出：230 nm] のHPLCで分離した。分離したエナンチオマーの標的分画からロータリーエバポレーターにより溶媒を除去し、ペンタン5 mlおよびジエチルエーテル1 mlの混合物で室温で摩砕した。吸引濾過し、高真空下において固体を乾燥させ、エナンチオマーを純粋な形態で得た。
実施例88(エナンチオマー 1):
収量：54 mg(理論値の56%)
R_t＝5.65分、＞99% ee [分析的キラル HPLC：カラム：Daicel AS-H、5 μm、250 mm x 4 mm；移動相：イソヘキサン/イソプロパノール 60:40；流速：1 ml/分；温度：25℃；UV検出：230 nm]。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：8.25 (d、2H)、7.51 (d、1H)、7.47 (s、1H)、7.38 (t、1H)、7.33 (d、2H)、7.14 (d、1H)、6.83 (s、1H)、5.49 (s、2H)、2.58 (s、broad、1H)、2.28 (s、3H)、1.77 (s、3H)。
LC/MS (方法6、ESIpos)：R_t＝1.32分、m/z＝513 [M+H]⁺。
実施例89(エナンチオマー 2):
収量：73 mg(理論値の76%)
R_t＝6.44分、＞99% ee [分析的キラル HPLC：カラム：Daicel AS-H、5 μm、250 mm x 4 mm；移動相：イソヘキサン/イソプロパノール 60:40；流速：1 ml/分；温度：25℃；UV検出：230 nm]。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：8.25 (d、2H)、7.51 (d、1H)、7.47 (s、1H)、7.38 (t、1H)、7.33 (d、2H)、7.14 (d、1H)、6.83 (s、1H)、5.49 (s、2H)、2.58 (s、broad、1H)、2.28 (s、3H)、1.77 (s、3H)。
LC/MS (方法6、ESIpos)：R_t＝1.32分、m/z＝513 [M+H]⁺。 Example 88 and Example 89
1,1,1-trifluoro-2- {3-[(5-methyl-3- {3- [4- (trifluoromethoxy) phenyl] -1,2,4-oxadiazol-5-yl} -1H-pyrazol-1-yl) methyl] phenyl} propan-2-ol (enantiomers 1 and 2)

The racemate from Example 3 was separated into its optical isomers by chromatography. To achieve this goal, 191 mg (0.373 mmol) of the racemate from Example 3 was dissolved each time in 20 ml of a mixture of isopropanol and isohexane. Add 1.0 ml of this solution each time to the chiral stationary phase [column material: Daicel Chiralpak AS-H, 5 μm, 250 mm x 20 mm; mobile phase: isohexane / isopropanol 85:15; flow rate: 20 ml / min; temperature: 25 Separation by HPLC at ° C; UV detection: 230 nm]. The solvent was removed from the separated enantiomer target fraction by rotary evaporator and triturated with a mixture of 5 ml pentane and 1 ml diethyl ether at room temperature. Filtration with suction and drying of the solid under high vacuum gave the enantiomer in pure form.
Example 88 (Enantiomer 1):
Yield: 54 mg (56% of theory)
R _t = 5.65 min,> 99% ee [Analytical chiral HPLC: column: Daicel AS-H, 5 μm, 250 mm x 4 mm; mobile phase: isohexane / isopropanol 60:40; flow rate: 1 ml / min; temperature : 25 ° C; UV detection: 230 nm].
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 8.25 (d, 2H), 7.51 (d, 1H), 7.47 (s, 1H), 7.38 (t, 1H), 7.33 (d, 2H), 7.14 (d, 1H), 6.83 (s, 1H), 5.49 (s, 2H), 2.58 (s, broad, 1H), 2.28 (s, 3H), 1.77 (s, 3H).
LC / MS (Method _{6, ESIpos): R t =} 1.32 min, m / z = 513 [M + H] +.
Example 89 (enantiomer 2):
Yield: 73 mg (76% of theory)
R _t = 6.44 min,> 99% ee [Analytical chiral HPLC: column: Daicel AS-H, 5 μm, 250 mm x 4 mm; mobile phase: isohexane / isopropanol 60:40; flow rate: 1 ml / min; temperature : 25 ° C; UV detection: 230 nm].
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 8.25 (d, 2H), 7.51 (d, 1H), 7.47 (s, 1H), 7.38 (t, 1H), 7.33 (d, 2H), 7.14 (d, 1H), 6.83 (s, 1H), 5.49 (s, 2H), 2.58 (s, broad, 1H), 2.28 (s, 3H), 1.77 (s, 3H).
LC / MS (Method _{6, ESIpos): R t =} 1.32 min, m / z = 513 [M + H] +.

実施例22に記載した方法に準じて、実施例95Aからの化合物410 mg(0.571 mmol、純度72%)およびエチルマグネシウムクロライド溶液から、表題化合物100 mg(理論値の37%)を得た。ここでは、室温での反応時間は2時間であり、方法14に従い分取用HPLCによる精製を行った。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：7.96 (dd、1H)、7.91 (dd、1H)、7.55 (t、1H)、7.32-7.26 (m、2H)、7.20 (s、1H)、7.16 (d、1H)、6.99 (d、1H)、6.81 (s、1H)、5.45 (s、2H)、2.47 (s、1H)、2.28 (s、3H)、1.69 (s、6H)、1.27 (dd、2H)、1.02 (dd、2H)。
LC/MS (方法6、ESIpos)：R_t＝1.29分、m/z＝475 [M+H]⁺。 Example 90
1- {3-[(5-methyl-3- {3- [3-fluoro-4- (trifluoromethoxy) phenyl] -1,2,4-oxadiazol-5-yl} -1H-pyrazole- 1-yl) methyl] phenyl} cyclopropanol

According to the method described in Example 22, from 410 mg (0.571 mmol, purity 72%) of the compound from Example 95A and ethylmagnesium chloride solution, 100 mg (37% of theory) of the title compound was obtained. Here, the reaction time at room temperature was 2 hours, and purification by preparative HPLC was performed according to Method 14.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 7.96 (dd, 1H), 7.91 (dd, 1H), 7.55 (t, 1H), 7.32-7.26 (m, 2H), 7.20 (s, 1H ), 7.16 (d, 1H), 6.99 (d, 1H), 6.81 (s, 1H), 5.45 (s, 2H), 2.47 (s, 1H), 2.28 (s, 3H), 1.69 (s, 6H) 1.27 (dd, 2H), 1.02 (dd, 2H).
LC / MS (Method _{6, ESIpos): R t =} 1.29 min, m / z = 475 [M + H] +.

固体カリウムtert-ブトキシド77 mg(0.687 mmol)を、0℃で実施例45Aからの化合物197 mg(0.529 mmol)および実施例50Aからの化合物240 mg(0.582 mmol)の無水THF溶液4 mlに加えた。反応混合物を室温で16時間撹拌した。続いてテトラ-n-ブチルアンモニウムフルオライド溶液(1 M THF溶液)793 μl(0.793 mmol)を加えた。さらに30分後、室温で、混合物を水で希釈し、酢酸エチルで抽出した。有機相を無水硫酸マグネシウムで乾燥させ、濾過し、溶媒をロータリーエバポレーターで除去した。得られた粗成生物を分取用HPLC(方法14)により精製した。生成物含有分画を集め、飽和重炭酸ナトリウム溶液で塩基性にした。続いて少量の残水以外のすべての揮発性をロータリーエバポレーターで除去した。混合物を酢酸エチルで抽出した。抽出液を無水硫酸マグネシウムで乾燥させ、濾過し、蒸発させて、表題化合物76 mg(理論値の28%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：7.97 (d、1H)、7.92 (d、1H)、7.32-7.25 (m、3H、部分的にCHCl₃ シグナルに覆われていた)、7.22 (s、1H)、7.00 (d、1H)、6.81 (s、1H)、5.44 (s、2H)、3.66 (s、2H)、2.29 (s、3H)、1.69 (s、6H)、1.57 (broad、1H)、0.85 (s、4H)。
LC/MS (方法6、ESIpos)：R_t＝1.36分、m/z＝515 [M+H]⁺。 Example 91
(1- {3-[(3- {3- [3-Fluoro-4- (1,1,1-trifluoro-2-methylpropan-2-yl) phenyl] -1,2,4-oxadi Azol-5-yl} -5-methyl-1H-pyrazol-1-yl) methyl] phenyl} cyclopropyl) methanol

Solid potassium tert-butoxide 77 mg (0.687 mmol) was added to 4 ml of anhydrous THF solution of compound 197 mg (0.529 mmol) from Example 45A and compound 240 mg (0.582 mmol) from Example 50A at 0 ° C. . The reaction mixture was stirred at room temperature for 16 hours. Subsequently, 793 μl (0.793 mmol) of tetra-n-butylammonium fluoride solution (1 M THF solution) was added. After another 30 minutes, at room temperature, the mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate, filtered and the solvent was removed on a rotary evaporator. The resulting crude product was purified by preparative HPLC (Method 14). Product containing fractions were collected and made basic with saturated sodium bicarbonate solution. Subsequently, all volatiles except a small amount of residual water were removed on a rotary evaporator. The mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, filtered and evaporated to give 76 mg (28% of theory) of the title compound.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 7.97 (d, 1H), 7.92 (d, 1H), 7.32-7.25 (m, 3H, partially covered by CHCl ₃ signal), 7.22 (s, 1H), 7.00 (d, 1H), 6.81 (s, 1H), 5.44 (s, 2H), 3.66 (s, 2H), 2.29 (s, 3H), 1.69 (s, 6H), 1.57 (broad, 1H), 0.85 (s, 4H).
LC / MS (Method _{6, ESIpos): R t =} 1.36 min, m / z = 515 [M + H] +.

実施例63に記載した方法に準じて、2つの部分工程によって、実施例43Aからの化合物65 mg(0.198 mmol)および実施例50Aからの化合物122 mg(0.297 mmol)を用いて、表題化合物64 mg(理論値の66%)を得た。ここでは、第1部分工程反応において、混合物を室温で16時間撹拌した；続く40℃への加熱は省いた。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：8.23 (d、2H)、7.52 (d、2H)、7.32-7.25 (m、2H、部分的にCHCl₃ シグナルに覆われていた)、7.22 (s、1H)、7.00 (d、1H)、6.82 (s、1H)、5.43 (s、2H)、4.00-3.87 (m、4H)、3.65 (s、2H)、2.29 (s、3H)、2.27-2.12 (m、2H)、1.98-1.91 (m、2H)、1.43 (s、broad、1H)、0.85 (s、4H)。
LC/MS (方法6、ESIpos)：R_t＝1.18分、m/z＝489 [M+H]⁺。 Example 92
(1- {3-[(3- {3- [4- (4-Fluorotetrahydro-2H-pyran-4-yl) phenyl] -1,2,4-oxadiazol-5-yl} -5- Methyl-1H-pyrazol-1-yl) methyl] phenyl} cyclopropyl) methanol

According to the method described in Example 63, the title compound 64 mg was obtained in two partial steps using 65 mg (0.198 mmol) of the compound from Example 43A and 122 mg (0.297 mmol) of the compound from Example 50A. (66% of theory) was obtained. Here, in the first partial step reaction, the mixture was stirred at room temperature for 16 hours; subsequent heating to 40 ° C. was omitted.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 8.23 (d, 2H), 7.52 (d, 2H), 7.32-7.25 (m, 2H, partially covered by CHCl ₃ signal), 7.22 (s, 1H), 7.00 (d, 1H), 6.82 (s, 1H), 5.43 (s, 2H), 4.00-3.87 (m, 4H), 3.65 (s, 2H), 2.29 (s, 3H) 2.27-2.12 (m, 2H), 1.98-1.91 (m, 2H), 1.43 (s, broad, 1H), 0.85 (s, 4H).
LC / MS (Method _{6, ESIpos): R t =} 1.18 min, m / z = 489 [M + H] +.

実施例75に記載した方法に準じて、実施例41Aからの化合物134 mg(0.50 mmol)および実施例52Aからの化合物377 mg(1.50 mmol)を用いて表題化合物95 mg(理論値の42%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：8.12 (d、2H)、7.47 (d、1H)、7.42 (t、1H)、7.36 (s、1H)、7.35 (d、2H)、7.23 (d、1H)、6.83 (s、1H)、5.48 (s、2H)、3.95 (dt、2H)、2.98 (sept、1H)、2.29 (s、3H)、2.18 (t、1H)、1.29 (d、6H)。
LC/MS (方法6、ESIpos)：R_t＝1.29分、m/z＝439 [M+H]⁺。 Example 93
2,2-difluoro-2- [3-({3- [3- (4-isopropylphenyl) -1,2,4-oxadiazol-5-yl] -5-methyl-1H-pyrazole-1- Il} methyl) phenyl] ethanol

In accordance with the method described in Example 75, the title compound 95 mg (42% of theory) was obtained using 134 mg (0.50 mmol) of the compound from Example 41A and 377 mg (1.50 mmol) of the compound from Example 52A. Got.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 8.12 (d, 2H), 7.47 (d, 1H), 7.42 (t, 1H), 7.36 (s, 1H), 7.35 (d, 2H), 7.23 (d, 1H), 6.83 (s, 1H), 5.48 (s, 2H), 3.95 (dt, 2H), 2.98 (sept, 1H), 2.29 (s, 3H), 2.18 (t, 1H), 1.29 (d, 6H).
LC / MS (Method 6, ESIpos): R _t = 1.29 min, m / z = 439 [M + H] ⁺ .

実施例75に記載した方法に準じて、実施例29Aからの化合物164 mg(0.50 mmol)および実施例52Aからの化合物377 mg(1.50 mmol)を用いて、表題化合物101 mg(理論値の41%)を得た。ここでは、シクロヘキサン/酢酸エチル3:1移動相を用いたシリカゲルによるクロマトグラフィー精製を行った。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：8.08 (dd、1H)、8.03 (d、1H)、7.49-7.41 (m、3H)、7.36 (s、1H)、7.24 (d、1H)、6.83 (s、1H)、5.50 (s、2H)、3.95 (dt、2H)、2.30 (s、3H)、2.10 (t、1H)。
LC/MS (方法6、ESIpos)：R_t＝1.27分、m/z＝499 [M+H]⁺。 Example 94
2,2-difluoro-2- {3-[(3- {3- [3-fluoro-4- (trifluoromethoxy) phenyl] -1,2,4-oxadiazol-5-yl} -5- Methyl-1H-pyrazol-1-yl) methyl] phenyl} ethanol

According to the method described in Example 75, using 164 mg (0.50 mmol) of the compound from Example 29A and 377 mg (1.50 mmol) of the compound from Example 52A, 101 mg (41% of theory) ) Here, chromatographic purification on silica gel using a cyclohexane / ethyl acetate 3: 1 mobile phase was performed.
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 8.08 (dd, 1H), 8.03 (d, 1H), 7.49-7.41 (m, 3H), 7.36 (s, 1H), 7.24 (d, 1H ), 6.83 (s, 1H), 5.50 (s, 2H), 3.95 (dt, 2H), 2.30 (s, 3H), 2.10 (t, 1H).
LC / MS (Method _{6, ESIpos): R t =} 1.27 min, m / z = 499 [M + H] +.

実施例75に記載した方法に準じて、実施例25Aからの化合物179 mg(0.50 mmol)および実施例52Aからの化合物377 mg(1.50 mmol)を用いて、表題化合物29 mg(理論値の10%)を得た。
¹H NMR (400 MHz、CDCl₃、δ/ppm)：8.52 (d、2H)、8.18 (d、2H)、7.48 (d、1H)、7.44 (t、1H)、7.36 (s、1H)、7.25 (d、1H、部分的にCHCl₃ シグナルにより覆われていた)、6.83 (s、1H)、5.50 (s、2H)、3.96 (t、2H)、2.31 (s、3H)。
LC/MS (方法6、ESIpos)：R_t＝1.27分、m/z＝529 [M+H]⁺。 Example 95
2,2-difluoro-2- (3-{[5-methyl-3- (3- {4-[(trifluoromethyl) sulfonyl] phenyl} -1,2,4-oxadiazol-5-yl) -1H-pyrazol-1-yl] methyl} phenyl) ethanol

According to the method described in Example 75, using 179 mg (0.50 mmol) of the compound from Example 25A and 377 mg (1.50 mmol) of the compound from Example 52A, 29 mg (10% of theory) )
¹ H NMR (400 MHz, CDCl ₃ , δ / ppm): 8.52 (d, 2H), 8.18 (d, 2H), 7.48 (d, 1H), 7.44 (t, 1H), 7.36 (s, 1H), 7.25 (d, 1H, partially covered by CHCl ₃ signal), 6.83 (s, 1H), 5.50 (s, 2H), 3.96 (t, 2H), 2.31 (s, 3H).
LC / MS (Method _{6, ESIpos): R t =} 1.27 min, m / z = 529 [M + H] +.

パラジウム28 mg(10%活性炭中)(0.026 mmol)を実施例96A溶液からの化合物348 mg(0.519 mmol)に加え、室温で混合物をParr装置において水素圧1 barで水素化した。反応時間は合計6 日間であった。この期間中、28mgずつのパラジウム触媒を3回加えた。反応終了後、触媒を小kieselguhrにより濾過し、濾液を乾燥するまで蒸発させた。得られた粗成生物を分取用HPLC [カラム：X-Bridge Shield、5 μm、100 mm x 19 mm；移動相：アセトニトリル/水/1%トリフルオロ酢酸水溶液 60:35:5(0-6分)；流速：25 ml/分；温度：25℃；UV検出：210 nm]で精製した。これにより表題化合物131 mg(理論値の44%)を得た。
¹H NMR (400 MHz、DMSO-d₆、δ/ppm)：8.22 (d、2H)、7.93 (d、2H)、7.28 (t、1H)、7.22 (d、1H)、7.13 (s、1H)、7.03 (d、1H)、6.93 (s、1H)、5.48 (s、2H)、2.92 (s、2H)、2.33 (s、3H)、1.31 (s、6H)。
LC/MS (方法6、ESIpos)：R_t＝1.17分、m/z＝471 [M-H₃PO₄+H]⁺、569 [M+H]⁺。 Example 96
2-Methyl-1- (3-{[5-methyl-3- (3- {4-[(trifluoromethyl) sulfanyl] phenyl} -1,2,4-oxadiazol-5-yl) -1H -Pyrazol-1-yl] methyl} phenyl) propan-2-yldihydrogen phosphate

Palladium 28 mg (in 10% activated charcoal) (0.026 mmol) was added to compound 348 mg (0.519 mmol) from the Example 96A solution and the mixture was hydrogenated at room temperature in a Parr apparatus at 1 bar hydrogen pressure. The reaction time was 6 days in total. During this period, 28 mg of palladium catalyst was added three times. After completion of the reaction, the catalyst was filtered through a small kieselguhr and the filtrate was evaporated to dryness. The resulting crude product was subjected to preparative HPLC [Column: X-Bridge Shield, 5 μm, 100 mm x 19 mm; mobile phase: acetonitrile / water / 1% aqueous trifluoroacetic acid solution 60: 35: 5 (0-6 Min); flow rate: 25 ml / min; temperature: 25 ° C .; UV detection: 210 nm]. This gave 131 mg (44% of theory) of the title compound.
¹ H NMR (400 MHz, DMSO-d ₆ , δ / ppm): 8.22 (d, 2H), 7.93 (d, 2H), 7.28 (t, 1H), 7.22 (d, 1H), 7.13 (s, 1H ), 7.03 (d, 1H), 6.93 (s, 1H), 5.48 (s, 2H), 2.92 (s, 2H), 2.33 (s, 3H), 1.31 (s, 6H).
LC / MS (Method _{6, ESIpos): R t =} 1.17 min, m / z = 471 [MH 3 PO 4 + H] +, 569 [M + H] +.

B. Evaluation of Pharmacological Activity The pharmacological activity of the compounds of the present invention can be demonstrated by in vitro and in vivo studies known to those skilled in the art. The usefulness of the substances of the invention can be illustrated by the examples given in the following in vitro (tumor) cell tests and in vivo tumor models. The relationship between HIF transcriptional activity and tumor growth inhibition has been shown by numerous studies described in the literature (see, for example, Warburg, 1956; Semenza, 2007).
B-1. HIF-luciferase assay
HCT 116 cells were transfected in a stable manner with a plasmid containing a luciferase reporter under the control of an HIF-responsive element. These cells were seeded in microtiter plates [20 000 cells / well in RPMI 1640 medium with 10% fetal calf serum (FCS) and 100 μg / ml hygromycin]. Incubations were performed overnight under standard conditions (5% CO ₂ , 21% O ₂ , 37 ° C., wet). The next morning, cells were incubated with various concentrations of test substances (0-10 μmol / l) in a hypoxic chamber (1% O ₂ ). After 24 hours, Bright Glo reagent (Promega, Wisconsin, USA) was added according to the manufacturer's instructions and fluorescence was measured after 5 minutes. Cells cultured under normoxia were used as background control.

Representative example IC ₅₀ values from this assay are listed in the following table:

Unlike the compounds of the present invention, the compound 5- [5-methyl-1- (4-methylbenzyl) described in Example 1 of WO 2008 / 141731-A2 which does not have a hydroxyalkyl substituent in the benzyl head group ) -1H-pyrazol-3-yl] -3- [4- (trifluoromethoxy) phenyl] -1,2,4-oxadiazole exhibited an IC ₅₀ value of 30 nmol / l in this assay.

B-2. Suppression of HIF target genes in vitro:
Human bronchial carcinoma cells (H460 and A549) were incubated for 16 hours with various concentrations of test substances under steady-state oxygen tension and 1% oxygen partial pressure (see HIF-luciferase assay). Total RNA was isolated from the cells, transcribed into cDNA, and mRNA expression of the HIF target gene was analyzed by real-time PCR. The active test substance already reduced the mRNA expression of the HIF target gene compared to untreated cells in the steady oxygen state, but above all under hypoxic conditions.

B-3. Human xenograft tumor model:
A human tumor xenograft model in immunodeficient mice was used to evaluate this material. For this purpose, tumor cells were cultured in vitro and implanted subcutaneously, or tumor xenografts were further implanted subcutaneously. Animals were treated by oral, subcutaneous or intraperitoneal therapy after the tumor was established. The activity of the test substance was analyzed in monotherapy and in combination therapy with other pharmacologically active substances. In addition, the tumor inhibition ability of the test substance was characterized by the size of the advanced tumor (about 100 mm ² ). Animals were observed daily for health and treatment was performed according to animal welfare regulations. The tumor area was measured with a slide gauge (length L, width B = short surface). Tumor volume was calculated by the formula (L x B ² ) / 2. Tumor growth inhibition was calculated at the end of the study by T / C ratio and TGI value of tumor area and tumor weight (tumor growth inhibition, formula [1- (T / C)] × 100)) (T = treatment group Tumor size in C; tumor tumor size in the untreated control group).
In treated and untreated tumor-bearing mice, the effects of test substances on tumor angiogenesis and tumor blood flow were identified with the aid of computer microtomography and ultrasound microstudy.

C. Determination of Solubility and Stability The solubility of the prodrug compounds of the invention in aqueous systems and their non-specific hydrolysis and stability in plasma can be determined by the following tests:
C-1. Determination of solubility in aqueous buffer solution pH 6.5:
The test substance was dissolved in DMSO and aqueous PBS buffer (pH 6.5) was subsequently added so that the final DMSO concentration was 1 volume percent. The resulting suspension was shaken at RT for 24 hours. After ultracentrifugation at 224 000 g for 30 minutes, the supernatant was diluted with DMSO and analyzed by HPLC. Quantification was performed via a two-point calibration curve of DMSO solution of the test compound.
Some working examples determined by this method and the solubility of their prodrug forms are shown below:

C-2. Determination of pH-dependent hydrolysis stability:
0.3 mg of test substance (prodrug) was weighed into a 2 ml HPLC vial and 0.6 ml of acetonitrile or acetonitrile / DMSO mixture (up to 20 volume percent DMSO) was added. The sample container was immersed in an ultrasonic bath for about 10 seconds to dissolve the material. Subsequently, 1.0 ml of a specific aqueous buffer solution (commercial buffer solutions with pH 2.0, 7.0 and 10.0) was added and the sample was again treated with an ultrasonic bath. Over 24 hours at 25 ° C., 5 μl of the sample solution was analyzed by HPLC for the content of the active ingredient released by unchanged prodrug or hydrolysis every hour. Quantification was performed by area percent of the corresponding HPLC peak.
The stability values of representative prodrug compounds at pH 7.0 (Examples 82 and 84) and pH 6.5 (Example 96) are listed below:

Depending on the pH, the following values were obtained for these examples after 24 hours:

C-3. Determination of plasma stability in vitro:
1 mg of the test substance (prodrug) was weighed into a 2 ml HPLC vial, and 1.5 ml of DMSO and 1 ml of water were added. The sample container was immersed in an ultrasonic bath for about 10 seconds to dissolve the material. To 0.5 ml of this solution, 0.5 ml of rat plasma or human plasma was added at 37 ° C. The sample was agitated and approximately 10 μl was taken for the first analysis (time t ₀ ). Within 2 hours from the start of incubation, a further aliquot was taken for quantification 4-6 times. Samples were maintained at 37 ° C. throughout the test period. Characterization and quantification were performed by HPLC.

これらの実施例においてヒト血漿では、以下の値を得た:

The rat plasma stability values in representative prodrug examples are described below:

In these examples, the following values were obtained for human plasma:

D. Determination of pharmacokinetic parameters The pharmacokinetic parameters of the compounds of the present invention after intravenous or oral administration can be determined as follows:
The substance to be tested is administered intravenously as an animal (e.g. mouse or rat), as a solution (e.g. a small amount of DMSO in the corresponding plasma or in a PEG / ethanol / water mixture), and oral administration is a solution (e.g. / Ethanol / water or PEG / ethanol / water mixtures) or suspensions (eg in Tylose), in each case by feeding tubes. Blood was collected from the animals at certain times after administration of the substance. The blood was heparinized and subsequently plasma was obtained therefrom by centrifugation. Substances were quantified analytically in plasma by LC-MS / MS. Using internal standards and using a valid computer program, the plasma concentration / time plot thus determined from the pharmacokinetic parameters, e.g. AUC (area under time curve / time curve), C _max (maximum plasma Concentration), t _1/2 (half-life), V _SS (volume of distribution) and CL (clearance), and absolute and relative bioavailability F and F _rel (with iv / po comparison or after oral administration) Solution comparison) was calculated.
To determine the active ingredient released from the prodrug compound, the prodrug was administered intravenously or orally as described above, and both the concentration of the prodrug and the released active ingredient were quantified in the treated plasma.

国際公開第号2008/141731-A2の実施例1に記載されている化合物 5-[5-メチル-1-(4-メチルベンジル)-1H-ピラゾール-3-イル]-3-[4-(トリフルオロメトキシ)フェニル]-1,2,4-オキサジアゾールは、本発明化合物と異なり、ベンジル頭基にヒドロキシアルキル置換基を有さず、ラットへの静脈内投与後、以下のデータを示した：t_1/2＝30時間、CL_血漿＝0.4 l/h/kg、V_SS＝6.9 l/kg。 D-1. Pharmacokinetic parameters after intravenous administration in rats:
Rats were administered the test substance intravenously as a 0.3 to 1.0 mg / kg plasma solution each containing up to 2% DMSO. In the following, the kinetic parameters thus determined are shown for several exemplary working examples [CL _plasma = plasma clearance]:

The compound described in Example 1 of WO 2008 / 141731-A2- 5- [5-Methyl-1- (4-methylbenzyl) -1H-pyrazol-3-yl] -3- [4- ( (Trifluoromethoxy) phenyl] -1,2,4-oxadiazole does not have a hydroxyalkyl substituent at the benzyl head group, unlike the compounds of the present invention, and shows the following data after intravenous administration to rats. : T _1/2 = 30 hours, CL _plasma = 0.4 l / h / kg, V _SS = 6.9 l / kg.

国際公開第号2008/141731-A2の実施例1に記載されている化合物 5-[5-メチル-1-(4-メチルベンジル)-1H-ピラゾール-3-イル]-3-[4-(トリフルオロメトキシ)フェニル]-1,2,4-オキサジアゾールは、本発明化合物と異なり、ベンジル頭基にヒドロキシアルキル置換基を有さず、ラットへの経口投与後、以下のデータを示した：t_1/2＝29時間、AUC_norm＝1.9 kg・h/l、F＝74%。 D-2. Pharmacokinetic parameters after oral administration in rats:
Test substances were orally administered to rats as Solutol / ethanol / water (40:10:50 or 40:20:40) solutions at 1 to 3 mg / kg, respectively. The kinetic parameters thus determined are shown below for several exemplary working examples [AUC _norm = dose-standardized exposure (area under time curve / time curve)]:

The compound described in Example 1 of WO 2008 / 141731-A2- 5- [5-Methyl-1- (4-methylbenzyl) -1H-pyrazol-3-yl] -3- [4- ( (Trifluoromethoxy) phenyl] -1,2,4-oxadiazole, unlike the compound of the present invention, does not have a hydroxyalkyl substituent at the benzyl head group, and the following data was shown after oral administration to rats. : T _1/2 = 29 hours, AUC _norm = 1.9 kg · h / l, F = 74%.

D-3. In vivo release of active compound in rats after intravenous prodrug administration:
When rats were intravenously administered the prodrug from Example 81 (0.35 mg / kg, dissolved in plasma supplemented with 1% DMSO), there was a rapid and complete release of the corresponding active compound (Example 43): The release half-life is about 2 minutes and the dose of free active compound after prodrug administration-the standardized exposure (AUC _norm value) is 3.1 _kgh / l, hence-within the limits of measurement accuracy- The value is the same as that when the active compound (3.0 kg · h / l) was directly administered.

E. Working Examples for Pharmaceutical Compositions The compounds of the present invention may be processed into pharmaceutical formulations in the following manner:
tablet:
composition:
100 mg of the compound of the present invention, lactose (monohydrate) 50 mg, corn starch (natural) 50 mg, polyvinylpyrrolidone (PVP 25) (obtained from BASF, Ludwigshafen, Germany) and magnesium stearate 2 mg.
Tablet weight 212mg, diameter 8mm, radius of curvature 12mm.
Manufacturing:
A mixture of the compound of the invention, lactose and starch is granulated with 5% aqueous PVP solution (m / m). The granules are dried and then mixed with magnesium stearate for 5 minutes. This mixture is tableted with a conventional tableting machine (see above for tablet form). The compression force that serves as a guideline for compression is 15 kN.

Suspensions that can be administered orally:
composition:
1000 mg of the compound of 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 of the invention.
Manufacturing:
Rozigel is suspended in ethanol and the compound of the invention is added to the suspension. Add water with stirring. Stir for about 6 hours until the swelling of the logigel is complete.

Solutions that can be administered orally:
composition:
500 mg of the compound of the invention, 2.5 g of polysorbate and 400 97 g of polyethylene glycol 400. 20 g of oral solution corresponds to a single dose of 100 mg of the compound of the invention.
Manufacturing:
The compound of the invention is added to the mixture of polyethylene glycol and polysorbate with stirring. Stir until the compound of the invention is completely dissolved.
IV solution:
The compounds of the invention are dissolved at a subsaturated concentration in a physiologically acceptable solvent (eg, isotonic saline, 5% glucose solution and / or 30% PEG400 solution). The solution is filtered, sterilized and used to fill sterile, pyrogen-free injection containers.

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Claims (17)

Formula (I)

(In the formula
A is the formula

{In formula
* Represents the point of attachment to the hydroxyl group,
** represents the point of attachment to the phenyl ring,
R ^1A and R ^1B each independently represent hydrogen, deuterium, methyl, hydroxymethyl or trifluoromethyl;
Or together, together with the carbon atom to which they are attached, cyclopropane-1,1-diyl, cyclobutane-1,1-diyl, oxetane-3,3-diyl or tetrahydro-2H-pyran-4,4 -Form a diyl ring,
R ^2A and R ^2B each independently represent hydrogen, deuterium, methyl or trifluoromethyl,
R ^3A and R ^3B each independently represent hydrogen, fluorine, methyl, hydroxymethyl or trifluoromethyl, together with the carbon atom to which they are attached, together with cyclopropane-1,1-diyl , Cyclobutane-1,1-diyl, oxetane-3,3-diyl or those forming a tetrahydro-2H-pyran-4,4-diyl ring. }
The basis of
R ⁴ is trifluoromethoxy, trifluoromethylsulfanyl, trifluoromethylsulfonyl, pentafluorosulfanyl, trimethylsilyl or the formula

{Wherein # represents the point of attachment to the phenyl ring
R ^5A and R ^5B each independently represent hydrogen, fluorine, methyl, ethyl, n-propyl or isopropyl,
Or together, together with the carbon atom to which they are attached, cyclopropane-1,1-diyl, cyclobutane-1,1-diyl, cyclopentane-1,1-diyl, cyclohexane-1,1-diyl, Forming an oxetane-3,3-diyl or tetrahydro-2H-pyran-4,4-diyl ring;
R ⁶ represents hydrogen, fluorine, methyl, trifluoromethyl, methoxymethyl or ethoxymethyl. }
Represents the group of
R ⁷ represents hydrogen, fluorine or methyl. )
And their salts, solvates and solvates of salts. A is the formula

{In formula
* Represents the point of attachment to the hydroxyl group,
** represents the point of attachment to the phenyl ring
R ^2A and R ^2B both represent hydrogen or deuterium. }
Represents the group of
R ⁴ is trifluoromethyl, trifluoromethoxy, trifluoromethylsulfanyl, pentafluorosulfanyl, trimethylsilyl or the formula

{Wherein # represents the point of attachment to the phenyl ring
R ^5A and R ^5B both represent methyl, or together, together with the carbon atom to which they are attached, cyclopropane-1,1-diyl or tetrahydro-2H-pyran-4,4-diyl Forming a ring,
R ⁶ represents fluorine, methyl or trifluoromethyl. }
Represents the group of
R ⁷ represents hydrogen or fluorine,
2. A compound of formula (I) according to claim 1 and salts, solvates and solvates of salts thereof. A is the formula

{In formula
* Represents the point of attachment to the hydroxyl group,
** represents the point of attachment to the phenyl ring. }
The basis of
R ⁴ is trifluoromethoxy, trifluoromethylsulfanyl or the formula

{Wherein # represents the point of attachment to the phenyl ring}
Represents the group of
R ⁷ represents hydrogen,
3. A compound of general formula (I) according to claim 1 or 2 and salts, solvates and solvates of salts thereof. Formula (I-PD)

(Where
A, R ⁴ and R ⁷ represent the meanings described in any of claims 1, 2 and 3,
R ^PD is the formula

{Where,
# Represents the point of attachment to the oxygen atom,
R ⁸ represents hydrogen or (C ₁ -C ₄ ) -alkyl,
R ^9A and R ^9B each independently represent hydrogen or methyl. }
Represents a group of )
And their salts, solvates and solvates of salts.
R ^PD is the expression

{Where,
## represents the point of attachment to the oxygen atom,
R ⁸ represents methyl, isopropyl, isobutyl or sec-butyl. }
Which is the basis of
5. A compound of formula (I-PD) according to claim 4, their salts, solvates and solvates of salts. First, the formula (II)

(Wherein R ⁴ and R ⁷ have the meanings described in any one of claims 1 to 3).
N'-hydroxyamidines of the formula (III)

With a pyrazole carboxylic acid of formula (IV)

(Wherein R ⁴ and R ⁷ have the meanings indicated above.)
Of 1,2,4-oxadiazole, followed by compound (IV) in the presence of a base in the formula (V)

(In the formula, A has the meaning described in any one of claims 1 to 3,
X represents a leaving group such as chlorine, bromine, iodine, mesylate, triflate or tosiflate,
R ¹⁰ represents hydrogen or a conventional hydroxyl protecting group such as acetyl, tetrahydropyranyl, trimethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl or tert-butyl (diphenyl) silyl. )
Is reacted with a compound of formula (VI)

(In the formula, A, R ⁴ , R ⁷ and R ¹⁰ each have the meaning shown above.)
To obtain a compound of
The hydroxyl protecting group R ¹⁰ is subsequently removed—if present—by conventional methods and the resulting formula (I)

(Wherein A, R ⁴ and R ⁷ have the meanings indicated above.)
The compound is finally, if desired, the formula (VII)

Or an activated form of the compound (wherein R ^PD has the meaning described in claim 4 or 5) to formula (I-PD)

(In the formula, A, R ^PD , R ⁴ and R ⁷ each have the meaning shown above.)
Into a prodrug compound of
The resulting compound of formula (I) or (I-PD) is then optionally separated into enantiomers and / or diastereomers and / or using appropriate (i) solvents and / or (ii) bases or acids. Of the compounds of formulas (I) and (I-PD) as defined in any of claims 1 to 5, characterized by conversion to their solvates, salts and / or solvates of salts Production method.   6. A compound according to any one of claims 1 to 5 for the treatment and / or prevention of a disease.   6. The compound according to claim 1, which is used in a method for treatment and / or prevention of cancer or tumor.   Treatment of ischemic cardiovascular disease, heart failure, myocardial infarction, arrhythmia, stroke, pulmonary hypertension, renal and pulmonary fibrosis, psoriasis, diabetic retinopathy, macular degeneration, rheumatoid arthritis and chubash erythrocytosis and 6. The compound according to any one of claims 1 to 5, which is used in a method for prevention.   Use of a compound according to any of claims 1 to 5 in the manufacture of a medicament for the treatment and / or prevention of cancer or tumor.   Treatment of ischemic cardiovascular disease, heart failure, myocardial infarction, arrhythmia, stroke, pulmonary hypertension, renal and pulmonary fibrosis, psoriasis, diabetic retinopathy, macular degeneration, rheumatoid arthritis and chubash erythrocytosis and 6. Use of a compound according to any of claims 1 to 5 in the manufacture of a medicament for prevention.   A medicament comprising a compound according to any of claims 1 to 5 in combination with one or more inert, non-toxic, pharmaceutically suitable additives.   A medicament comprising a compound according to any of claims 1 to 5 in combination with one or more further active ingredients.   14. The medicament according to claim 12 or 13, for the treatment and / or prevention of cancer or tumor.   Treatment of ischemic cardiovascular disease, heart failure, myocardial infarction, arrhythmia, stroke, pulmonary hypertension, renal and pulmonary fibrosis, psoriasis, diabetic retinopathy, macular degeneration, rheumatoid arthritis and chubash erythrocytosis and 14. A medicament according to claim 12 or 13 for prevention.   A method for the treatment and / or prevention of cancer or tumor in humans and animals using at least one of the compounds according to any one of claims 1 to 5 or an effective amount of the medicament according to any one of claims 12 to 14.   Ischemic cardiovascular disease, heart failure, myocardium in humans and animals using at least one compound according to any one of claims 1 to 5, or an effective amount of a medicament according to any one of claims 12, 13 and 15. Methods for treating and / or preventing infarction, arrhythmia, stroke, pulmonary hypertension, renal fibrosis and lung, psoriasis, diabetic retinopathy, macular degeneration, rheumatoid arthritis and Chubash erythrocytosis.