JP2016013983A - Pharmaceutical composition for treating diabetes - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a novel compound that has glycogen synthase activation potency and is high in muscle transfer property.SOLUTION: The present invention provides a compound represented by the general formula or pharmaceutically acceptable salt thereof. In the formula, Aris represented by one of the following rings.

Description

  The present invention relates to a novel compound having an action of activating glycogen synthase and a pharmaceutical composition for treating diabetes containing the compound.

Diabetes is an important disease for modern people, and the incidence of diabetes has been increasing in recent years. Many antidiabetic drugs have been developed and actually used due to the mechanism of diabetes occurrence. For example, an insulin sensitivity enhancer, an α-glycosidase inhibitor, an insulin secretagogue, an insulin preparation and the like are used alone or in combination.
Under such circumstances, a technique for treating diabetes has been developed by activating glycogen synthase, which is a new mechanism different from the conventional antidiabetic drugs. Specifically, biaryloxymethylarene carboxylic acid has been proposed as a compound that can activate glycogen synthase (Patent Documents 1 to 10, Non-Patent Documents 1 and 2). On the other hand, new pharmaceutically active compounds are required to have safety such as no side effects in addition to the expected effects on disease treatment. Peroxisome proliferator-activated as a drug safety evaluation It has been proposed to examine the receptor PPAR (peroxisome proliferator-activated receptor) (Non-patent Document 3). In animal experiments such as in rats, hepatic hypertrophy, marked induction of enzymes in the liver, and long-term administration of the drug cause liver cancer. It is remarkable growth. It has been clarified that the mechanism of drug-hepatic peroxisome proliferation-hepatocarcinoma involves a receptor PPAR activated by a peroxisome proliferating drug (PP), particularly its subfamily PPAR-α. This phenomenon is attracting attention in drug safety evaluation (particularly carcinogenicity evaluation) in the drug development stage.

WO2005 / 000781 WO2006 / 058648 WO2011 / 057956 WO2011 / 057959 WO2011 / 057993 WO2011 / 058122 WO2011 / 058154 WO2011 / 067174 WO2011 / 067266 WO2013 / 065835

Bioorganic & Medicinal Chemistry Letters 23 (2013) 2936-2940. Med. Chem. Commun., 2013, 4, 833-838. History of Medicine Vol. 220, No.1 (2007) pp.75-80

An object of the present invention is to provide a novel compound having glycogen synthase activation ability and high muscle migration.
Another object of the present invention is to provide a pharmaceutical composition containing the above compound.
Another object of the present invention is to provide a pharmaceutical composition for treating diabetes containing the above compound.
Another object of the present invention is to provide a glycogen synthase activator containing the above compound.

The present invention has been intensively studied for the biaryloxymethylarene carboxylic acid compounds described in Patent Documents 1 to 10, and has a specific aryl group as the terminal aryl group of the biaryl ring located at one terminal, and another terminal. A compound in which the aryl group located at is substituted with a specific aromatic heterocycle, and the aromatic heterocycle has a specific amide and a specific amino group as an amino group, is easily transferred to a tissue (particularly muscle) and administered. The inventors have found that reduction of the amount can be expected, and have been made based on the knowledge that the use of these compounds can solve the above problems efficiently. In addition, the compound of the present invention is a novel compound with high safety because the receptor PPAR is hardly activated.
That is, the present invention provides the following [1] to [10].

（式中、Ａｒ₁は、以下の式（II−１）〜（II−４）のいずれかの環で表され、

（式中、これらの環は、同一又は異なってもよい、１又は複数の置換基を有していてもよく、該置換基は、ハロゲン原子、ヒドロキシル基、アルキル基、アセトアミド基、アミノカルボニル基、アルコキシ基、シアノ基、アミノ基、モノアルキルアミノ基、ジアルキルアミノ基及びハロゲノアルコキシ基よりなる群から選択され；
Ｒ₁は、水素原子、ハロゲン原子、ヒドロキシル基、アルキル基、重水素で置換されていてもよいアルコキシ基、ハロゲノアルコキシ基又は重水素で置換されていてもよいアルキルチオ基を表し、
Ｒ₂、Ｒ₃、Ｒ₄、Ｒ₅、Ｒ₆及びＲ₇は、それぞれ独立して、水素原子、ハロゲン原子、シアノ基、重水素で置換されてもよいアルキル基、ハロゲノアルキル基、ヒドロキシアルキル基、アルコキシアルキル基又はアルキニル基を表す。）
Ａｒ₂は、芳香族複素環を表し、
Ｌは、結合、アルキレン基又はシクロアルキレン基を表し、
Ｘは、水素原子、ハロゲン原子、ヒドロキシル基、ハロゲノアルキル基、アルコキシ基、シアノ基、シアノアルコキシ基、アミノ基、モノアルキルアミノ基、ジアルキルアミノ基、アミノカルボニル基、モノアルキルアミノカルボニル基、ジアルキルアミノカルボニル基、アミノスルホニル基、モノアルキルアミノスルホニル基、ジアルキルアミノスルホニル基、アルキルスルホニル基、アルキルスルホニルアミノ基、アルキルカルボニルアミノ基、フェニル基、もしくは、１又は複数の置換基を有していてもよい、窒素原子、酸素原子及び硫黄原子から選ばれるヘテロ原子を少なくとも１つ有する５員乃至７員の複素環基を表し、
これらの置換基は、ハロゲン原子、ヒドロキシル基、アルキル基、アセトアミド基、アミノカルボニル基、アルコキシ基、シアノ基、アミノ基、モノアルキルアミノ基、ジアルキルアミノ基及びハロゲノアルコキシ基よりなる群から選択され；
Ｚは、シアノ基又は−Ｏ−Ｒ₈を表す。
（式中、Ｒ₈は、重水素で置換されていてもよいアルキル基、ヒドロキシアルキル基、ハロゲノアルキル基、アルコキシアルキル基、シアノアルキル基又はカルボキシアルキル基を表す。））
〔２〕一般式（Ｉ）中、Ｘにおける複素環基が、フラン環、チオフェン環、オキサゾール環、イソオキサゾール環、イミダゾール環、ピラゾール環、チアゾール環、オキサジアゾール環、トリアゾール環、ピリジン環、ピリミジン環、ピリダジン環、ピラジン環、もしくは、以下の式（III−１）〜（III−４）のいずれかの式で表される前記〔１〕記載の化合物又はその医薬上許容される塩。

（式中、Ｒ₉及びＲ₁₀は、それぞれ独立して、水素原子、アルキル基又はアルキルカルボニル基で表され、
ｎ₁、ｎ₂及びｎ₃は、０〜２の整数で表される。）
〔３〕一般式（Ｉ）中、Ａｒ₂が、フラン環、チオフェン環又はチアゾール環である前記〔１〕又は〔２〕記載の化合物又はその医薬上許容される塩。
〔４〕一般式（Ｉ）中、Ａｒ₁が１又は２の置換基を有し、それらがハロゲン原子である前記〔１〕〜〔３〕のいずれか１項記載の化合物又はその医薬上許容される塩。
〔５〕一般式（Ｉ）の式（II−１）〜（II−４）中、
Ｒ₁が、水素原子、ハロゲン原子、重水素で置換されてもよい炭素数１〜３のアルコキシ基又は重水素で置換されてもよい炭素数１〜３のアルキルチオ基で表され、
Ｒ₂及びＲ₄が、水素原子、ハロゲン原子又は炭素数１〜３のアルキル基で表され、
Ｒ₃及びＲ₅が、水素原子、炭素数１〜３のアルキル基、シアノ基又はメトキシメチル基で表され、
Ｒ₆及びＲ₇が、水素原子又は炭素数１〜３のアルキル基で表される前記〔１〕〜〔４〕のいずれか１項記載の化合物又はその医薬上許容される塩。
〔６〕一般式（Ｉ）中、Ｌが、炭素数１〜３のアルキレン基で表される前記〔１〕〜〔５〕のいずれか１項記載の化合物又はその医薬上許容される塩。
〔７〕 一般式（Ｉ）中、Ｘが、アルコキシ基、モノアルキルアミノ基、ジアルキルアミノ基、フラン環、オキサゾール環、オキサジアゾール環、ピリジン環、ピリミジン環、もしくは、以下の式（IV−１）、（IV−２）又は（IV−３）のいずれかで表される

前記〔１〕〜〔６〕のいずれか１項記載の化合物又はその医薬上許容される塩。
〔８〕一般式（Ｉ）で表される化合物が、
2-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]-N-[2-(メトキシアミノ)-2-オキソ-エチル]-N-(4-ピペリジルメチル)チアゾール-4-カルボキサミド、
2-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]-N-[2-(メトキシアミノ)-2-オキソ-エチル]-N-[2-(メチルアミノ)エチル]チアゾール-4-カルボキサミド、
2-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]-N-[2-(メトキシアミノ)-2-オキソ-エチル]-N-(2-ピロリジン-1-イルエチル)チアゾール-4-カルボキサミド、
5-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]-N-(2-フリルメチル)-N-[2-(メトキシアミノ)-2-オキソ-エチル]フラン-2-カルボキサミド、
2-[[4-[4,5-ジフルオロ-2-(トリデュウテリオメトキシ)フェニル]フェノキシ]メチル]-N-(2-ジメチルアミノエチル)-N-[2-(メトキシアミノ)-2-オキソ-エチル]チアゾール-4-カルボキサミド、
2-[[4-(4,5-ジフルオロ-3-メチル-ベンゾフラン-7-イル)フェノキシ]メチル]-N-(2-ジメチルアミノエチル)-N-[2-(メトキシアミノ)-2-オキソ-エチル]チアゾール-4-カルボキサミド、又は
N-[2-(シアノアミノ)-2-オキソ-エチル]-5-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]-N-(2-メトキシエチル)フラン-2-カルボキサミドである、
請求項１〜７のいずれか１項に記載の化合物又はその医薬上許容される塩。
〔９〕前記〔１〕〜〔８〕のいずれか１項記載の化合物又はその医薬上許容される塩を含有する医薬組成物。
〔１０〕前記〔１〕〜〔８〕のいずれか１項記載の化合物又はその医薬上許容される塩を含有する糖尿病治療用医薬組成物。
〔１１〕前記〔１〕〜〔８〕のいずれか１項記載の化合物又はその医薬上許容される塩を含有するグリコーゲンシンターゼ活性化剤。 [1] A compound represented by the following general formula (I) or a pharmaceutically acceptable salt thereof.
Formula (I):

(In the formula, Ar ₁ is represented by any ring of the following formulas (II-1) to (II-4);

(In the formula, these rings may be the same or different and each may have one or more substituents, and the substituents are halogen atoms, hydroxyl groups, alkyl groups, acetamido groups, aminocarbonyl groups. Selected from the group consisting of an alkoxy group, a cyano group, an amino group, a monoalkylamino group, a dialkylamino group and a halogenoalkoxy group;
R ₁ represents a hydrogen atom, a halogen atom, a hydroxyl group, an alkyl group, an alkoxy group optionally substituted with deuterium, a halogenoalkoxy group or an alkylthio group optionally substituted with deuterium;
R ₂ , R ₃ , R ₄ , R ₅ , R ₆ and R ₇ are each independently a hydrogen atom, a halogen atom, a cyano group, an alkyl group which may be substituted with deuterium, a halogenoalkyl group or a hydroxyalkyl. Represents a group, an alkoxyalkyl group or an alkynyl group. )
Ar ₂ represents an aromatic heterocycle,
L represents a bond, an alkylene group or a cycloalkylene group,
X represents a hydrogen atom, a halogen atom, a hydroxyl group, a halogenoalkyl group, an alkoxy group, a cyano group, a cyanoalkoxy group, an amino group, a monoalkylamino group, a dialkylamino group, an aminocarbonyl group, a monoalkylaminocarbonyl group, a dialkylamino. A carbonyl group, an aminosulfonyl group, a monoalkylaminosulfonyl group, a dialkylaminosulfonyl group, an alkylsulfonyl group, an alkylsulfonylamino group, an alkylcarbonylamino group, a phenyl group, or one or more substituents. Represents a 5- to 7-membered heterocyclic group having at least one heteroatom selected from a nitrogen atom, an oxygen atom and a sulfur atom,
These substituents are selected from the group consisting of halogen atoms, hydroxyl groups, alkyl groups, acetamide groups, aminocarbonyl groups, alkoxy groups, cyano groups, amino groups, monoalkylamino groups, dialkylamino groups and halogenoalkoxy groups;
Z represents a cyano group or —O—R ₈ .
(In the formula, R ₈ represents an alkyl group, a hydroxyalkyl group, a halogenoalkyl group, an alkoxyalkyl group, a cyanoalkyl group or a carboxyalkyl group which may be substituted with deuterium.)
[2] In general formula (I), the heterocyclic group in X is a furan ring, thiophene ring, oxazole ring, isoxazole ring, imidazole ring, pyrazole ring, thiazole ring, oxadiazole ring, triazole ring, pyridine ring, The compound of the above-mentioned [1] or a pharmaceutically acceptable salt thereof represented by a pyrimidine ring, a pyridazine ring, a pyrazine ring, or any one of the following formulas (III-1) to (III-4):

(Wherein R ₉ and R ₁₀ are each independently represented by a hydrogen atom, an alkyl group or an alkylcarbonyl group,
n _1, n ₂ and n ₃ are represented by an integer from 0 to 2. )
[3] The compound of the above-mentioned [1] or [2] or a pharmaceutically acceptable salt thereof, wherein, in general formula (I), Ar ₂ is a furan ring, a thiophene ring or a thiazole ring.
[4] The compound according to any one of [1] to [3] or a pharmaceutically acceptable salt thereof, wherein Ar ₁ has 1 or 2 substituents in general formula (I), and these are halogen atoms. Salt.
[5] In the formulas (II-1) to (II-4) of the general formula (I),
R ₁ is represented by a hydrogen atom, a halogen atom, an alkoxy group having 1 to 3 carbon atoms which may be substituted with deuterium, or an alkylthio group having 1 to 3 carbon atoms which may be substituted with deuterium;
R ₂ and R ₄ are represented by a hydrogen atom, a halogen atom or an alkyl group having 1 to 3 carbon atoms,
R ₃ and R ₅ are each represented by a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, a cyano group, or a methoxymethyl group,
The compound or a pharmaceutically acceptable salt thereof according to any one of [1] to [4], wherein R ₆ and R ₇ are each represented by a hydrogen atom or an alkyl group having 1 to 3 carbon atoms.
[6] The compound according to any one of [1] to [5] or a pharmaceutically acceptable salt thereof, wherein, in the general formula (I), L is an alkylene group having 1 to 3 carbon atoms.
[7] In general formula (I), X represents an alkoxy group, a monoalkylamino group, a dialkylamino group, a furan ring, an oxazole ring, an oxadiazole ring, a pyridine ring, a pyrimidine ring, or the following formula (IV- 1) represented by either (IV-2) or (IV-3)

The compound according to any one of [1] to [6] or a pharmaceutically acceptable salt thereof.
[8] The compound represented by the general formula (I) is:
2-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] -N- [2- (methoxyamino) -2-oxo-ethyl] -N- (4-piperidylmethyl) Thiazole-4-carboxamide,
2-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] -N- [2- (methoxyamino) -2-oxo-ethyl] -N- [2- (methylamino ) Ethyl] thiazole-4-carboxamide,
2-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] -N- [2- (methoxyamino) -2-oxo-ethyl] -N- (2-pyrrolidine-1 -Ylethyl) thiazole-4-carboxamide,
5-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] -N- (2-furylmethyl) -N- [2- (methoxyamino) -2-oxo-ethyl] Furan-2-carboxamide,
2-[[4- [4,5-Difluoro-2- (trideuteriomethoxy) phenyl] phenoxy] methyl] -N- (2-dimethylaminoethyl) -N- [2- (methoxyamino) -2- Oxo-ethyl] thiazole-4-carboxamide,
2-[[4- (4,5-Difluoro-3-methyl-benzofuran-7-yl) phenoxy] methyl] -N- (2-dimethylaminoethyl) -N- [2- (methoxyamino) -2- Oxo-ethyl] thiazole-4-carboxamide, or
N- [2- (Cyanoamino) -2-oxo-ethyl] -5-[[4- (4,5-difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] -N- (2-methoxyethyl) furan -2-carboxamide,
The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof.
[9] A pharmaceutical composition comprising the compound according to any one of [1] to [8] or a pharmaceutically acceptable salt thereof.
[10] A pharmaceutical composition for treating diabetes comprising the compound according to any one of [1] to [8] above or a pharmaceutically acceptable salt thereof.
[11] A glycogen synthase activator comprising the compound according to any one of [1] to [8] or a pharmaceutically acceptable salt thereof.

Hereinafter, the definition of the compound of the formula (I) will be described.
In the present specification, the “alkyl group” may be substituted with deuterium, and may be a linear or branched aliphatic hydrocarbon having 1 to 12 carbon atoms, preferably 1 to 6 carbon atoms. It is a monovalent group derived by removing one arbitrary hydrogen atom. Specific examples include groups such as methyl, ethyl, isopropyl, butyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, 2,3-dimethylpropyl, hexyl and the like. More preferably, it is a C1-C4 alkyl group.
The “alkylene group” is a divalent group that may be substituted with deuterium and is derived by removing two arbitrary hydrogen atoms from linear and branched aliphatic hydrocarbons having 1 to 6 carbon atoms. It is the basis of. Examples include groups such as methylene, ethylene, propylene, butylene. Preferably, it is a C1-C3 alkylene group, More preferably, they are a methylene and ethylene.
The “cycloalkylene group” is a divalent group derived by removing any two hydrogen halves from a cyclic aliphatic hydrocarbon having 3 to 8 carbon atoms. Specific examples include groups such as cyclopropylene, cyclopentylene and cyclohexylene. Preferred are cyclopentylene and cyclohexylene.
The “alkynyl group” is a monovalent having at least one triple bond (two adjacent SP carbon atoms) among a linear or branched aliphatic hydrocarbon group having 2 to 6 carbon atoms. It is the basis of. Specific examples include groups such as ethynyl, 1-propynyl, propargyl, and 3-butynyl. Preferably it is C2-C3 alkynyl, More preferably, it is a propargyl.
“Aromatic heterocycle” means a 5- to 7-membered monocyclic system composed of one or more atoms selected from the oxygen atom, nitrogen atom and sulfur atom, or the same or different, and 1 to 6 carbon atoms. An aromatic heterocyclic ring or a condensed polycyclic ring composed of 9 to 14 atoms consisting of one or more atoms selected from the same or different from oxygen, nitrogen and nitrogen atoms and 1 to 13 carbon atoms Means aromatic ring. Specifically, furan ring, thiophene ring, oxazole ring, isoxazole ring, imidazole ring, pyrazole ring, thiazole ring, isothiazole ring, oxadiazole ring, oxathiazole ring, triazole ring, tetrazole ring, pyridine ring, pyridimine Ring, pyrazine ring, benzofuran ring, benzothiophene ring, indole ring, quinoline ring, quinoline ring, isoquinoline ring, benzofuran ring, benzothiophene ring and the like. A furan ring, a thiophene ring, a thiazole ring or a pyridine ring is preferred, and a furan ring, a thiophene ring or a thiazole ring is more preferred.

“Halogen atom” means a fluorine, chlorine, bromine, iodine atom or the like.
“Alkoxy group” means an alkyl-O— having 1 to 6 carbon atoms. Specifically, methoxy, ethoxy, 1-propoxy, 2-propoxy, n-butoxy, i-butoxy, sec-butoxy, t-butoxy, 1-pentyloxy, 2-pentyloxy, 3-pentyloxy, 2- Methyl-1-butyloxy, 3-methyl-1-butyloxy, 2-methyl-2-butyloxy, 3-methyl-2-butyloxy, 2,2-dimethyl-1-propyloxy, 1-hexyloxy, 2-hexyloxy , 3-hexyloxy and the like. Preferably it is C1-C3 alkoxy.
The “halogenoalkyl group” means the alkyl group substituted with the halogen atom. Specific examples include groups such as monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, and trifluoroethyl. Preferred is an alkyl group having 1 to 4 carbon atoms with 1 to 3 halogen atoms, and more preferred is trifluoromethyl.
The “alkoxyalkyl group” means the alkyl group substituted with the alkoxy group. Specific examples include groups such as methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, and ethoxyethyl. Preferably, it is an alkyl group having 1 to 3 carbon atoms with one alkoxy group having 1 or 2 carbon atoms, and more preferably memethoxymethyl or methoxyethyl.
The “halogenoalkoxy group” means the alkoxy group substituted with one or more halogen atoms. Preferred is an alkoxy group having 1 to 3 carbon atoms substituted with 1 to 3 halogen atoms, and more preferred is trifluoromethoxy or trifluoroethoxy.
The “alkylthio group” is a thio group substituted by the alkyl group, and means alkyl-S—. Alkyl is as described above. Preferably, it is a C1-C3 alkylthio group.
“Cyanoalkyl group” means the alkyl group substituted with a cyano group, and means NC-alkyl-. The alkyl group is as described above. Preferably, it is a C2-C5 cyanoalkyl group.
The “cyanoalkoxy group” is the alkoxy group substituted with a cyano group, and means NC-alkylene-O—. The alkylene group is as described above. Preferably, it is a cyanoalkoxy group having 1 to 3 carbon atoms of alkylene.

The “monoalkylamino group” is an amino group in which one hydrogen atom on a nitrogen atom is substituted with the alkyl group, and means alkyl-NH—. The alkyl group is as described above. Preferably, each alkyl group is a monoalkylaminoalkyl group having 1 to 3 carbon atoms.
The “dialkylamino group” is an amino group in which two hydrogen atoms on a nitrogen atom are each substituted with the alkyl, and means (alkyl) ₂ N—. The alkyl groups may be the same or different. Specific examples include groups such as dimethylamino and diethylamino. Preferably, each alkyl group is a dialkylamino having 1 to 4 carbon atoms.

The “monoalkylaminocarbonyl group” is a carbonyl group having an amino group in which one hydrogen atom on a nitrogen atom is substituted with the alkyl, and means alkyl-NH—C (O) —. Specific examples include groups such as methylaminocarbonyl and ethylaminocarbonyl. Preferably, it is a monoalkylaminocarbonyl group having 1 to 3 carbon atoms in the alkyl group.
The “dialkylaminocarbonyl group” is a carbonyl group having an amino group in which two hydrogen atoms on a nitrogen atom are each substituted by the alkyl, and means (alkyl) ₂ NC (O) —. The alkyl groups may be the same or different. Specific examples include carbonyl groups with groups such as dimethylamino and diethylamino. Moreover, alkyls may share the same carbon atom and form a C3-C6 ring, and specifically, groups, such as pyrrolidinyl carbonyl and piperidinyl carbonyl, are mentioned.

The “monoalkylaminosulfonyl group” is a sulfonyl group having an amino group in which one hydrogen atom on a nitrogen atom is substituted with the alkyl, and means alkyl-NH—SO ₂ —. Specific examples include groups such as methylaminosulfonyl and ethylaminosulfonyl. Preferably, it is a monoalkylaminosulfonyl group having 1 to 3 carbon atoms in the alkyl group.
The “dialkylaminosulfonyl group” is a sulfonyl group having an amino group in which two hydrogen atoms on a nitrogen atom are each substituted with the alkyl, and means (alkyl) ₂ -N—SO ₂ —. . The alkyl groups may be the same or different. Specific examples include sulfonyl groups with groups such as dimethylamino and diethylamino. In addition, alkyls may share the same carbon atom to form a ring having 3 to 6 carbon atoms, and specific examples include groups such as pyrrolidinylsulfonyl and piperidinylsulfonyl.

The “alkylsulfonyl group” is a sulfonyl group substituted by the alkyl and means alkyl-SO ₂ —. Alkyl is as described above. Preferably, it is C1-C3 alkylsulfonyl.
The “alkylsulfonylamino group” is a sulfonylamino group substituted with the alkyl, and means alkyl-SO ₂ —NH—. Alkyl is as described above. Preferably, it is C1-C3 alkylsulfonylamino.
The “alkylcarbonylamino group” is a carbonylamino group substituted by the alkyl, and means alkyl-C (O) —NH—. Alkyl is as described above. Preferably, it is C1-C3 alkylcarbonylamino.

  The “alkoxyalkyleneoxy group” is a group in which the alkoxy group is attached to one of the alkylene groups and the oxygen atom is attached to the other, and means alkyl-O-alkylene-O—. The alkyl group and the alkylene group are as described above. Preferably, it is an alkoxyalkyleneoxy group having 1 to 3 carbon atoms in each of the alkyl group and the alkylene group, and more preferably methoxyethyleneoxy.

  The “heterocyclic group” is a 5- to 7-membered non-aromatic heterocyclic ring containing 1 to 3 heteroatoms selected from the same or different from an oxygen atom, a nitrogen atom and a sulfur atom, or the aromatic heterocyclic ring Means a group obtained by removing one hydrogen atom from Specific examples of the non-aromatic heterocyclic group include groups in which one hydrogen atom has been removed from piperidine, piperazine, pyrrolidine, tetrahydrofuran, tetrahydropyran and the like. The aromatic heterocyclic group means the aromatic heterocyclic ring. Specifically, a group in which one hydrogen atom is removed from thiophene, furan, oxazole, isoxazole, thiazole, isothiazole, imidazole, pyrazole, oxadiazole, oxathiazole, triazole, pyridine, pyrimidine, pyrazine, pyridazine, etc. Is mentioned.

  Hereinafter, the compound represented by the general formula (I) of the present invention or a pharmaceutically acceptable salt thereof will be described.

式（II−２）及び（II−２−１）において、Ｒ₂及びＲ₃は、水素原子、アルキル基、シアノ基又はヒドロキシアルキル基であることが好ましく、水素原子、炭素数１〜３のアルキル基、シアノ基又はヒドロキシアルキル基であることがより好ましい。Ｒ₂及びＲ₃としては、水素原子又はメチル基が特に好適に用いられる。
式（II−３）及び（II−３−１）において、Ｒ₄及びＲ₅は、水素原子、アルキル基、シアノ基又はアルコキシアルキル基であることが好ましく、水素原子、炭素数１〜３のアルキル基又はシアノ基又は炭素数１〜３のアルコキシアルキル基であることがより好ましい。Ｒ₄及びＲ₅としては、水素原子、メチル基又はメトキシメチル基が特に好適に用いられる。
式（II−４）及び（II−４−１）において、Ｒ₆及びＲ₇は、水素原子又はアルキル基であることが好ましく、水素原子又は炭素数１〜３のアルキル基であることがより好ましい。Ｒ₆およびＲ₇としては、水素原子又はメチル基が特に好適に用いられる。 In the general formula (I), when Ar ₁ is the formula (II-1), R ₁ is a hydrogen atom, a halogen atom, a hydroxyl group, an alkoxy group optionally substituted with deuterium, a halogenoalkoxy group or a heavy atom. An alkylthio group which may be substituted with hydrogen is preferable, and a hydrogen atom, a halogen atom, an alkoxy group which may be substituted with deuterium having 1 to 3 carbon atoms or a deuterium having 1 to 3 carbon atoms is substituted. A better alkylthio group is more preferred. That is, as R ₁ , a fluorine atom, a methoxy group, a —OCD ₃ group (where D represents a deuterium atom) or a methylthio group is particularly preferably used.
In the general formula (I), when Ar ₁ is a formula (II-2) to (II-4), the following formulas (II-2-1) to (II-4-1) are more preferable.

In the formulas (II-2) and (II-2-1), R ₂ and R ₃ are preferably a hydrogen atom, an alkyl group, a cyano group, or a hydroxyalkyl group. More preferably, it is an alkyl group, a cyano group or a hydroxyalkyl group. As R ₂ and R ₃ , a hydrogen atom or a methyl group is particularly preferably used.
In the formulas (II-3) and (II-3-1), R ₄ and R ₅ are preferably a hydrogen atom, an alkyl group, a cyano group, or an alkoxyalkyl group. It is more preferably an alkyl group, a cyano group, or an alkoxyalkyl group having 1 to 3 carbon atoms. As R ₄ and R ₅ , a hydrogen atom, a methyl group or a methoxymethyl group is particularly preferably used.
In formulas (II-4) and (II-4-1), R ₆ and R ₇ are preferably a hydrogen atom or an alkyl group, more preferably a hydrogen atom or an alkyl group having 1 to 3 carbon atoms. preferable. As R ₆ and R ₇ , a hydrogen atom or a methyl group is particularly preferably used.

In the general formula (I), Ar ₂ is preferably a furan ring, a thiophene ring or a thiazole ring, and more preferably a furan ring or a thiazole ring.
In general formula (I), L is preferably an alkylene group or a cycloalkylene group, and more preferably an alkylene group having 1 to 3 carbon atoms or a cycloalkylene group having 3 to 6 carbon atoms. As L, a methylene group, an ethylene group or a cyclohexylene group is particularly preferably used.

In general formula (I), X is preferably an alkoxy group, an amino group, a monoalkylamino group, a dialkylamino group or a heterocyclic group which may have a substituent, and has 1 to 3 carbon atoms. It is more preferably an alkoxy group, an amino group, a monoalkylamino group having 1 to 3 carbon atoms, a dialkylamino group having 1 to 3 carbon atoms, or a heterocyclic group which may have a substituent.
Furthermore, the heterocyclic group of X is a furan ring, a thiophene ring, an oxazole ring, an oxadiazole ring, a pyridine ring, a pyrimidine ring, or a group of formula (III-1), (III-2) or (III-3) Either is preferred, and a furan ring, an oxazole ring, or any one of the formulas (III-2) or (III-3) is more preferred.
When the heterocyclic group of X has a substituent, these substituents are preferably a halogen atom, an alkyl group, a halogenoalkyl group, an alkoxy group or an alkoxyalkyl group, and an alkyl group having 1 to 3 carbon atoms. More preferably. As for the number of this substituent, 0-3 are more preferable, and 0-2 are still more preferable. As the heterocyclic group for X, those having no substituent or one substituent are particularly preferably used.
When X is formulas (III-1) to (III-3), n ₁ , n _2, and n ₃ are preferably integers of 0 to ₃ , and more preferably integers of 0 to 2.
When X is formula (III-2), R ₉ is preferably a hydrogen atom or an alkyl group, more preferably a hydrogen atom or an alkyl group having 1 to 3 carbon atoms.
When X is formula (III-4), R ₁₀ is preferably a hydrogen atom or an alkyl group, and more preferably a hydrogen atom.

In the general formula (I), Z is preferably a cyano group or —O—R ₈ , more preferably —O—R ₈ .
In —O—R ₈ , R ₈ is preferably an alkyl group, an alkoxyalkyl group or a halogenoalkyl group which may be substituted with deuterium, and an alkyl group having 1 to 3 carbon atoms which may be substituted with deuterium. Alternatively, a halogenoalkyl group having 1 to 3 carbon atoms is more preferable. As R ₈ , a methyl group is particularly preferably used.

Although the preferable specific example of a compound represented by general formula (I) below is enumerated below, the compound of this invention is not limited to these.
2-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] -N- [2- (methoxyamino) -2-oxo-ethyl] -N- (4-piperidylmethyl) Thiazole-4-carboxamide trifluoroacetate (Example 2)
2-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] -N- [2- (methoxyamino) -2-oxo-ethyl] -N- [2- (methylamino ) Ethyl] thiazole-4-carboxamide trifluoroacetate (Example 3)
2-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] -N- [2- (methoxyamino) -2-oxo-ethyl] -N- (2-pyrrolidine-1 -Ilethyl) thiazole-4-carboxamide trifluoroacetate (Example 4)
5-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] -N- (2-furylmethyl) -N- [2- (methoxyamino) -2-oxo-ethyl] Furan-2-carboxamide (Example 7)
2-[[4- [4,5-Difluoro-2- (trideuteriomethoxy) phenyl] phenoxy] methyl] -N- (2-dimethylaminoethyl) -N- [2- (methoxyamino) -2- Oxo-ethyl] thiazole-4-carboxamide trifluoroacetate salt (Example 9)
2-[[4- (4,5-Difluoro-3-methyl-benzofuran-7-yl) phenoxy] methyl] -N- (2-dimethylaminoethyl) -N- [2- (methoxyamino) -2- Oxo-ethyl] thiazole-4-carboxamide trifluoroacetate salt (Example 12)
N- [2- (Cyanoamino) -2-oxo-ethyl] -5-[[4- (4,5-difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] -N- (2-methoxyethyl) furan -2-carboxamide (Example 15)

Below, it describes about the manufacturing method of this invention compound.
The compound represented by the formula (I) of the present invention can be produced, for example, by the following method.

In the following reaction formula, Ar ₁ , Ar ₂ , L, X and Z are the same groups as defined in the formula (I). In the reaction formulas (A) to (E), M ₁ , M ₂ and M ₃ are represented by the formula (A-1), formula (A-3), formula (B-1) or formula (B-3). And R _a and R _b each independently represent a hydroxy group, an alkoxy group, or the like, which are bonded together to form a cyclic group. R _c and R _d each independently represents an alkyl group or a benzyl group.

対応するＡｒ₁を有するハロゲンアリール試薬（Ａ−１）を、例えば、Ｎ，Ｎ−ジメチルホルムアミドなどの溶媒中、金属触媒などを用いてカップリング反応が可能なボロン酸試薬（例えば、Ｒ_a及びＲ_bがヒドロキシル基）であるフェノール誘導体（Ａ−２）と［１，１’−ビス（ジフェニルホスフィノ）フェロセン］ジクロロパラジウム（II）などのパラジウム触媒と炭酸ナトリウムなどの塩基存在下、必要に応じて反応系を冷却、加熱等を行うことで、ビアリール誘導体（Ａ−３）を得ることができる。得られたビアリール誘導体（Ａ−３）を、例えば、Ｎ，Ｎ−ジメチルホルムアミドなどの溶媒中、対応するＡｒ₂を有するエステル誘導体（Ａ−４）と炭酸カリウムなどの塩基存在下、必要に応じて反応系を冷却、加熱等を行うことでエステル誘導体（Ａ−５）を得ることができる。得られたエステル誘導体（Ａ−５）を、例えば、テトラヒドロフラン及びメタノールなどの溶媒中、水酸化ナトリウムなどの塩基存在下、必要に応じて反応系を冷却、加熱等を行うことで、ビアリールカルボン酸誘導体（Ａ−６）を得ることができる。 Method for producing biarylcarboxylic acid derivative (A-6) (Reaction Formula A)

A halogen aryl reagent (A-1) having a corresponding Ar ₁ can be converted into a boronic acid reagent (for example, R _a and R _b is a hydroxyl group) and is necessary in the presence of a palladium catalyst such as [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) and a base such as sodium carbonate. Accordingly, the biaryl derivative (A-3) can be obtained by cooling and heating the reaction system. The obtained biaryl derivative (A-3) is used in a solvent such as N, N-dimethylformamide in the presence of a corresponding Ar ₂ -containing ester derivative (A-4) and a base such as potassium carbonate as necessary. Then, the ester derivative (A-5) can be obtained by cooling and heating the reaction system. The obtained ester derivative (A-5) is cooled, heated, or the like in the presence of a base such as sodium hydroxide in a solvent such as tetrahydrofuran and methanol, for example, to give a biarylcarboxylic acid. A derivative (A-6) can be obtained.

対応するアミン誘導体及びその塩（Ｂ−１）を、例えば、アセトニトリルなどの溶媒中、ブロモベンジル酢酸などの対応するエステル誘導体（Ｂ−２）と炭酸カリウムなどの塩基存在下、必要に応じて反応系を冷却、加熱等を行うことで、グリシン誘導体（Ｂ−３）を得ることができる。 Glycine ester derivative (B-3) of the production how (Scheme B)

Reaction of the corresponding amine derivative and its salt (B-1) with a corresponding ester derivative (B-2) such as bromobenzylacetic acid in the presence of a base such as potassium carbonate in a solvent such as acetonitrile, if necessary. A glycine derivative (B-3) can be obtained by cooling and heating the system.

対応するカルボン酸誘導体（Ａ−６）は、例えば２つの製造方法を用いてアミドエステル誘導体（Ｃ−２）へと誘導することができる。１つは縮合剤など用いて製造する方法である。対応するカルボン酸誘導体（Ａ−６）を、例えば、ジクロロメタンなどの溶媒中、対応するグリシンエステル誘導体（Ｂ−３）と１−エチル−３−（３−ジメチルアミノプロピル）−カルボジイミド 塩酸塩などの縮合剤とジイソプロピルエチルアミンなどの塩基存在下、必要に応じて反応系を冷却、加熱等を行うことでアミドエステル誘導体（Ｃ−２）を得ることができる。また、別の製造方法としては、酸ハロゲン化体（Ｃ−１）を経由して製造できる。対応するカルボン酸誘導体（Ａ−６）を、例えば、無溶媒又はＮ，Ｎ−ジメチルホルムアミドなどの溶媒中、塩化チオニルなどの酸ハロゲン化剤存在下、必要に応じて反応系を冷却、加熱等を行うことで酸ハロゲン化誘導体（Ｃ−１）を得ることができる。得られた酸ハロゲン誘導体（Ｃ−１）を、例えば、ジクロロメタンなどの溶媒中、対応するグリシンエステル誘導体（Ｂ−３）とジイソプロピルエチルアミンなどの塩基存在下、必要に応じて反応系を冷却、加熱等を行うことでアミドエステル誘導体（Ｃ−２）を得ることができる。 Method for producing amide ester derivative (C-2) (reaction formula C)

The corresponding carboxylic acid derivative (A-6) can be derived into the amide ester derivative (C-2) using, for example, two production methods. One is a production method using a condensing agent or the like. Corresponding carboxylic acid derivative (A-6), for example, corresponding glycine ester derivative (B-3) and 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride in a solvent such as dichloromethane In the presence of a condensing agent and a base such as diisopropylethylamine, the amide ester derivative (C-2) can be obtained by cooling and heating the reaction system as necessary. Moreover, as another manufacturing method, it can manufacture via an acid halide (C-1). The corresponding carboxylic acid derivative (A-6) is cooled, heated, or the like, if necessary, in the absence of a solvent or in the presence of an acid halogenating agent such as thionyl chloride in a solvent such as N, N-dimethylformamide. The acid halogenated derivative (C-1) can be obtained by performing. The obtained acid halogen derivative (C-1) is cooled and heated in a solvent such as dichloromethane in the presence of a corresponding glycine ester derivative (B-3) and a base such as diisopropylethylamine as necessary. Etc., an amide ester derivative (C-2) can be obtained.

対応するアミドエステル誘導体（Ｃ−２）を、例えば、テトラヒドロフラン及びメタノールなどの溶液中、水酸化ナトリウムまたは水酸化リチウム水溶液などの塩基存在下、必要に応じて反応系を冷却、加熱等を行うことで、アミドカルボン酸誘導体（Ｄ−１）を得ることができる。 Method for producing amidocarboxylic acid derivative (D-1) (reaction formula D)

The corresponding amide ester derivative (C-2) is cooled, heated, etc., if necessary, in the presence of a base such as sodium hydroxide or lithium hydroxide aqueous solution in a solution such as tetrahydrofuran and methanol. Thus, an amide carboxylic acid derivative (D-1) can be obtained.

対応するアミドカルボン酸誘導体（Ｄ−１）を、例えば、ジクロロメタンなどの溶媒中、対応するアミン誘導体（Ｅ−１）又はその塩と１−エチル−３−（３−ジメチルアミノプロピル）−カルボジイミド塩酸塩などの縮合剤とジイソプロピルエチルアミンなどの塩基存在下、必要に応じて反応系を冷却、加熱等を行うことで、アミド誘導体（Ｅ−２）を得ることができる。 Method for producing amide derivative (E-2) (Scheme E)

Corresponding amide carboxylic acid derivative (D-1), for example, corresponding amine derivative (E-1) or a salt thereof and 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride in a solvent such as dichloromethane The amide derivative (E-2) can be obtained by cooling and heating the reaction system as necessary in the presence of a condensing agent such as a salt and a base such as diisopropylethylamine.

In the present invention, when the compound represented by the general formula (I) can form a salt form, the salt may be pharmaceutically acceptable, for example, an acidic group such as a carboxyl group in the formula For acidic groups in the presence of ammonium salts, salts with alkali metals such as sodium and potassium, salts with alkaline earth metals such as calcium and magnesium, aluminum salts, zinc salts, triethylamine, ethanolamine, Examples thereof include salts with organic amines such as morpholine, piperidine and dicyclohexylamine, and salts with basic amino acids such as arginine and lysine. Among them, sodium is preferable.
When a basic group is present in the formula, for a basic group, salts with inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, hydrobromic acid, acetic acid, trifluoroacetic acid, citric acid, benzoic acid Organic carboxylic acids such as acid, maleic acid, fumaric acid, tartaric acid, succinic acid, tannic acid, butyric acid, hibenzic acid, pamoic acid, enanthic acid, decanoic acid, teocric acid, salicylic acid, lactic acid, oxalic acid, mandelic acid, malic acid And salts with organic sulfonic acids such as methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid, among which hydrochloric acid and trifluoroacetic acid are preferably used.
As a method for forming a salt, the compound represented by the general formula (I) and a necessary acid or base are mixed in an appropriate amount ratio in a solvent or a dispersing agent, or a cation is obtained from other salt forms. It can also be obtained by exchange or anion exchange.
The compounds of the present invention also include solvates of compounds represented by general formula (I), such as hydrates, alcohol adducts and the like.

The compounds of the present invention can also be converted into prodrugs. The prodrug in the present invention refers to a compound that is converted in the body to produce the compound of the present invention. For example, when the active main body contains a carboxyl group or the like, an ester or amide thereof can be mentioned. Further, when the active main body contains an amino group, its amide, carbamate and the like can be mentioned. When the active main body contains a hydroxyl group, its ester, carbonate, carbamate and the like can be mentioned. When the compound of the present invention is converted into a prodrug, it may be bound to an amino acid or a saccharide.
The present invention includes all isotopes of the compound represented by the general formula (I). In the isotope of the compound of the present invention, at least one atom is substituted with an atom having the same atomic number (number of protons) and different mass number (sum of the number of protons and neutrons). Examples of isotopes contained in the compounds of the present invention include a hydrogen atom, a carbon atom, a nitrogen atom, an oxygen atom, a phosphorus atom, a sulfur atom, a fluorine atom, a chlorine atom, etc., and 2H, 3H, 13C, 14C, 15N, 17O, 18O, 31P, 32P, 35S, 18F, 36Cl and the like are included. In particular, unstable radioisotopes that emit radioactivity and emit neutrons, such as 3H and 14C, are useful in a tissue distribution test of pharmaceuticals or compounds. Stable isotopes can be used safely because they do not decay, their abundances are almost unchanged, and there is no radioactivity. The isotope of the compound of the present invention can be converted according to a conventional method by replacing the reagent used in the synthesis with a reagent containing the corresponding isotope.
The pharmaceutical composition of the present invention can be suitably used for the treatment of diseases mediated by a decrease in glycogen synthase activity. In particular, it can be suitably used for the treatment of diabetes, especially type 2 diabetes and impaired glucose tolerance.
The pharmaceutical composition and glycogen synthase activator of the present invention vary depending on the administration subject, administration route, target disease, symptom, etc., but the administration route is preferably used by oral administration, and a single administration is effective. The amount is preferably 1 mg to 1000 mg / person, more preferably 1 mg to 100 mg / person of the active ingredient, and it is desirable to administer this amount once to three times a day.

The pharmaceutical composition and the glycogen synthase activator of the present invention contain the compound represented by the above general formula (I) and / or a pharmaceutically acceptable salt thereof as an active ingredient. Various components used, for example, pharmaceutically and physiologically acceptable solid or liquid carriers, additives and the like may be contained.
Examples of the carrier include glucose, lactose, sucrose, starch, mannitol, dextrin, fatty acid glyceride, polyethylene glycol, hydroxyethyl starch, ethylene glycol, polyoxyethylene sorbitan fatty acid ester, gelatin, albumin, amino acid, water, and physiological saline. Water etc. are mentioned. Further, if necessary, conventional additives such as a stabilizer, a wetting agent, an emulsifier, a binder, and an isotonic agent can be appropriately added.
The additive is not particularly limited as long as it is usually used for the purpose depending on the purpose. Specifically, for example, flavoring, sugar, sweetener, dietary fiber, vitamins, sodium glutamate Amino acids such as (MSG), nucleic acids such as inosine monophosphate (IMP), inorganic salts such as sodium chloride, and water.

The pharmaceutical composition and the glycogen synthase activator of the present invention can be used in a form that can be administered orally without any limitation on physical properties such as dry powder, paste, and solution.
Examples of such orally administrable forms include tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets), capsules (including soft capsules and microcapsules), granules, powders, and troches. Agents, syrups, emulsions, suspensions, films (eg, orally disintegrating films), lyophilizers and the like.
In addition, the pharmaceutical composition and the glycogen synthase activator of the present invention can be used for injections (eg, subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, infusions), and external preparations (eg, transdermal). Skin preparations, ointments), suppositories (eg, rectal suppositories, vaginal suppositories), pellets, nasal preparations, pulmonary preparations (inhalants), ophthalmic preparations, etc. .

These can be safely administered orally or parenterally (eg, topical, rectal, intravenous administration). These preparations may be controlled-release preparations (eg, sustained-release microcapsules) such as immediate-release preparations or sustained-release preparations. These preparations can be prepared by conventional means on the preparation.
In addition, the pharmaceutical composition and the glycogen synthase activator of the present invention include other diabetes therapeutic agents, diabetic complication therapeutic agents, hyperlipidemia therapeutic agents, antihypertensive agents, anti-obesity agents (hereinafter abbreviated as concomitant drugs). Can be used in combination. These concomitant drugs may be small molecules, high molecular proteins, polypeptides, antibodies, nucleic acids (including antisense nucleic acids, siRNA, shRNA), or vaccines. These concomitant drugs can be used alone or in combination of two or more.
The administration timing of the pharmaceutical composition, glycogen synthase activator, or concomitant drug of the present invention is not limited, and these may be administered simultaneously to the administration subject, or may be administered with a time difference.

Antidiabetic agents include insulin preparations (eg, animal insulin preparations extracted from bovine and porcine pancreas; human insulin preparations genetically engineered using Escherichia coli and yeast; insulin zinc; protamine insulin zinc; insulin Fragment or derivative (eg, INS-1), oral insulin preparation), insulin resistance improving agent (eg, pioglitazone or a salt thereof (preferably hydrochloride), rosiglitazone or a salt thereof (preferably maleate) , Tesaglitazar, Ragaglitazar, Muraglitazar, Edaglitazone, Metaglidasen, Naveglitazar, AMG-131, THR-0921, α-glucosidase, α-glucosidase , Acarbose, miglito , Emiglitate), biguanides (eg, metformin, buformin or their salts (eg, hydrochloride, fumarate, succinate)), insulin secretagogues [sulfonylurea (eg, tolbutamide, glibenclamide, gliclazide) , Chlorpropamide, tolazamide, acetohexamide, glyclopyramide, glimepiride, glipizide, glybsol), repaglinide, nateglinide, mitiglinide or its calcium salt hydrate], dipeptidyl peptidase IV inhibitor (eg, alogliptin) Dagliptin (Vildagliptin), sitagliptin (Saxagliptin), T-6666, TS-021), β3 agonist (eg, AJ-9677), GPR40 agonist, GPR120 agonist, GLP-1 receptor agoni G [Example, GLP-1, GLP-1MR agent, NN-2211, AC-2993 (exendin-4)), BIM-51077, Aib (8,35) hGLP-1 (7,37) NH2, CJC-1131 ], Amylin agonist (eg, pramlintide), phosphotyrosine phosphatase inhibitor (eg, sodium vanadate), gluconeogenesis inhibitor (eg, glycogen phosphorylase inhibitor, glucose-6-phosphatase inhibitor, glucagon antagonist), SGLT (sodium -glucose cotransporter) inhibitors (eg, dapagliflozin, canagliflozin, ipragliflozin, BI-10773), 11β-hydroxysteroid dehydrogenase inhibitors (eg, BVT-3498), adiponectin or agonists thereof, IKK inhibitors (eg, AS-2868), leptin resistance improver, somatostatin receptor agonist, glucokinase activator (eg, Ro-28-1675), GIP (Glucose-dependent insulinotropic peptide) It is done.
Further, it may be used in a form in which the compound represented by the above general formula (I) and / or a pharmaceutically acceptable salt thereof is stored in granules, tablets, gelatin capsules and the like used in supplements.

  EXAMPLES Hereinafter, although an Example demonstrates this invention in detail, this invention is not limited to these Examples.

中間体１ 5-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]チオフェン-3-カルボン酸
工程１ ４−（４，５−ジフルオロ−２−メチルスルファニル−フェニル）フェノールの合成
１−ブロモ−４，５−ジフルオロ−２−（メチルチオ）ベンゼン（１０．８ｇ，４５．０ｍｍｏｌ）を１，４−ジオキサン（７５ｍＬ）及び水（２５ｍＬ）の混合溶媒に溶解し、４−ヒドロキシフェニルボロン酸（７．５ｇ，５４．３ｍｍｏｌ）、炭酸ナトリウム（９．６ｇ，９０．０ｍｍｏｌ）および［１，１’-ビス（ジフェニルホスフィノ）フェロセン］ジクロロパラジウム（ＩＩ）（以下、ＰｄＣｌ₂（ｄｐｐｆ））（触媒量）を加えて、１００℃で２時間撹拌した。反応液を室温で冷却した後、不溶物を濾別した。減圧下で溶媒を除去して得られた残渣を酢酸エチルで希釈した後、１Ｎ 塩酸水溶液および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。減圧下で溶媒を除去した後、得られた残渣をシリカゲルクロマトグラフィーにて精製し、表題化合物を得た。
収量：１１．３ｇ（４５．０ｍｍｏｌ） 収率：１００％
工程２ 中間体１の合成
２−ホルミルチオフェン−４−カルボン酸メチル（２．２２ｇ，１３．１ｍｍｏｌ）をメタノール（２０ｍＬ）に溶解し、水素化ホウ素ナトリウム（６００ｍｇ，１５．７ｍｍｏｌ）を加えて、室温で一晩撹拌した。減圧下で溶媒を除去した後、得られた残渣を酢酸エチルで希釈し、水及び飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。減圧下で溶媒を除去した後、得られた残渣に塩化チオニル（１０ｍＬ）を加えて、室温で２時間撹拌した。減圧下で溶媒を除去して得られた残渣を酢酸エチルで希釈した後、水および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。減圧下で溶媒を除去した後、得られた残渣を、Ｎ，Ｎ−ジメチルホルムアミド（以下、ＤＭＦ）（７５ｍＬ）に溶解し、工程１で得られた化合物（２．８０ｇ，１１．１ｍｍｏｌ）、炭酸カリウム（３．０６ｇ，２２．２ｍｍｏｌ）及びヨウ化カリウム（触媒量）を加えて、室温で一晩撹拌した。反応液を酢酸エチルで希釈した後、１Ｎ 塩酸水溶液及び飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。減圧下で溶媒を除去して得られた残渣を、メタノール（２５ｍＬ）及びテトラヒドロフラン（以下、ＴＨＦ）（２５ｍＬ）の混合溶媒に溶解し、１Ｎ 水酸化ナトリウム水溶液（２５ｍＬ）を加えて、室温で一晩撹拌した。減圧下で溶媒を除去して得られた残渣を酢酸エチルで希釈した後、１Ｎ 塩酸水溶液および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。減圧下で溶媒を除去した後、得られた残渣をアセトニトリルで洗浄することにより、表題化合物を得た。
収量：２．２ｇ（５．６ｍｍｏｌ） 収率：４３％

Intermediate 1 5-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiophene-3-carboxylic acid Step 1 4- (4,5-Difluoro-2- Synthesis of methylsulfanyl-phenyl) phenol 1-bromo-4,5-difluoro-2- (methylthio) benzene (10.8 g, 45.0 mmol) is a mixed solvent of 1,4-dioxane (75 mL) and water (25 mL) 4-hydroxyphenylboronic acid (7.5 g, 54.3 mmol), sodium carbonate (9.6 g, 90.0 mmol) and [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II ) (Hereinafter PdCl ₂ (dppf)) (catalytic amount) was added, and the mixture was stirred at 100 ° C. for 2 hours. After cooling the reaction solution at room temperature, insolubles were filtered off. The residue obtained by removing the solvent under reduced pressure was diluted with ethyl acetate, washed with 1N aqueous hydrochloric acid solution and saturated brine, and dried over anhydrous magnesium sulfate. After removing the solvent under reduced pressure, the resulting residue was purified by silica gel chromatography to obtain the title compound.
Yield: 11.3 g (45.0 mmol) Yield: 100%
Step 2 Synthesis of Intermediate 1 Methyl 2-formylthiophene-4-carboxylate (2.22 g, 13.1 mmol) was dissolved in methanol (20 mL), sodium borohydride (600 mg, 15.7 mmol) was added, Stir overnight at room temperature. After removing the solvent under reduced pressure, the resulting residue was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After removing the solvent under reduced pressure, thionyl chloride (10 mL) was added to the resulting residue, and the mixture was stirred at room temperature for 2 hours. The residue obtained by removing the solvent under reduced pressure was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After removing the solvent under reduced pressure, the obtained residue was dissolved in N, N-dimethylformamide (hereinafter DMF) (75 mL), and the compound obtained in Step 1 (2.80 g, 11.1 mmol), Potassium carbonate (3.06 g, 22.2 mmol) and potassium iodide (catalytic amount) were added, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, washed with 1N aqueous hydrochloric acid solution and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by removing the solvent under reduced pressure was dissolved in a mixed solvent of methanol (25 mL) and tetrahydrofuran (hereinafter referred to as THF) (25 mL), 1N aqueous sodium hydroxide solution (25 mL) was added, and the mixture was stirred at room temperature. Stir overnight. The residue obtained by removing the solvent under reduced pressure was diluted with ethyl acetate, washed with 1N aqueous hydrochloric acid solution and saturated brine, and dried over anhydrous magnesium sulfate. After removing the solvent under reduced pressure, the resulting residue was washed with acetonitrile to give the title compound.
Yield: 2.2 g (5.6 mmol) Yield: 43%

中間体２−Ａ 2- [[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]チアゾール-4-カルボン酸
工程１ 2-ブロモメチルチアゾール-4-カルボン酸エチルの合成
２−メチルチアゾール−４−カルボン酸エチル（３．２６ｇ，１９．１ｍｍｏｌ）を四塩化炭素（５０ｍＬ）に溶解し、Ｎ−ブロモスクシンイミド（７．４６ｇ，４１．９ｍｍｏｌ）および触媒量の過酸化ベンゾイルを加えて、一晩加熱還流した。室温に戻した後、不溶物を濾別した。有機層を５％チオ硫酸ナトリウム水溶液、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。減圧下で溶媒を除去した後、得られた残渣をＴＨＦ（５０ｍＬ）に溶解し、氷冷下で亜リン酸ジエチル（２．４６ｍＬ，１９．１ｍｍｏｌ）およびジイソプロピルエチルアミン（以下、ＤＩＰＥＡ）（３．２７ｍＬ，１９．１ｍｍｏｌ）を加えて、室温で２時間撹拌した。減圧下で溶媒を除去して得られた残渣を酢酸エチルで希釈した後、水および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。減圧下で溶媒を除去した後、得られた残渣をシリカゲルクロマトグラフィーにて精製し、表題化合物を得た。
収量：３．８５ｇ（１５．２ｍｍｏｌ） 収率：８０％
工程２ 中間体２−Ａの合成
工程１で得られた化合物（３．８５ｇ，１５．２ｍｍｏｌ）をＤＭＦ（７５ｍＬ）に溶解し、中間体１の工程１で得られた化合物（３．８５ｇ，１５．２ｍｍｏｌ）および炭酸カリウム（４．２５ｇ，３０．８ｍｍｏｌ）を加えて、室温で一晩撹拌した。反応液を酢酸エチルで希釈した後、１Ｎ 塩酸水溶液および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。減圧下で溶媒を除去して得られた残渣をメタノール（５０ｍＬ）及びＴＨＦ（５０ｍＬ）の混合溶媒に溶解し、１Ｎ 水酸化ナトリウム水溶液（５０ｍＬ）を加えて、室温で一晩撹拌した。減圧下で溶媒を除去して得られた残渣を、酢酸エチルで希釈した後、１Ｎ 塩酸水溶液および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。減圧下で溶媒を除去して得られた残渣をアセトニトリルと水の混合溶媒（ｖ／ｖ＝１／１）で洗浄することにより、表題化合物を得た。
収量：３．９ｇ（９．９ｍｍｏｌ） 収率：６５％

Intermediate 2-A2-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiazole-4-carboxylic acid Step 1 2-Bromomethylthiazole-4 -carboxylic acid Synthesis of ethyl acid Ethyl 2-methylthiazole-4-carboxylate (3.26 g, 19.1 mmol) was dissolved in carbon tetrachloride (50 mL), N-bromosuccinimide (7.46 g, 41.9 mmol) and catalytic amount. Of benzoyl peroxide was added and heated to reflux overnight. After returning to room temperature, the insoluble material was filtered off. The organic layer was washed with 5% aqueous sodium thiosulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. After removing the solvent under reduced pressure, the resulting residue was dissolved in THF (50 mL), and diethyl phosphite (2.46 mL, 19.1 mmol) and diisopropylethylamine (hereinafter, DIPEA) (3. 27 mL, 19.1 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The residue obtained by removing the solvent under reduced pressure was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After removing the solvent under reduced pressure, the resulting residue was purified by silica gel chromatography to obtain the title compound.
Yield: 3.85 g (15.2 mmol) Yield: 80%
Step 2 Synthesis of Intermediate 2-A The compound obtained in Step 1 (3.85 g, 15.2 mmol) was dissolved in DMF (75 mL), and the compound obtained in Intermediate 1 Step 1 (3.85 g, 15.2 mmol) and potassium carbonate (4.25 g, 30.8 mmol) were added and stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with 1N aqueous hydrochloric acid solution and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by removing the solvent under reduced pressure was dissolved in a mixed solvent of methanol (50 mL) and THF (50 mL), 1N aqueous sodium hydroxide solution (50 mL) was added, and the mixture was stirred overnight at room temperature. The residue obtained by removing the solvent under reduced pressure was diluted with ethyl acetate, washed with 1N aqueous hydrochloric acid solution and saturated brine, and dried over anhydrous magnesium sulfate. The title compound was obtained by washing the residue obtained by removing the solvent under reduced pressure with a mixed solvent of acetonitrile and water (v / v = 1/1).
Yield: 3.9 g (9.9 mmol) Yield: 65%

中間体２−Ｂ 2-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]チアゾール-4-カルボン酸クロライド
中間体２−Ａ（３．９ｇ，９．９ｍｍｏｌ）に塩化チオニル（２５ｍＬ）を加えて、５０℃で２時間撹拌した。反応液を室温で冷却した後、減圧下で溶媒を除去することで、表題化合物を得た。
収量：３．５７ｇ（８．７ｍｍｏｌ） 収率：８８％

Intermediate 2-B 2-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiazole-4-carboxylic acid chloride intermediate 2-A (3.9 g, 9.9 mmol) Was added with thionyl chloride (25 mL), and the mixture was stirred at 50 ° C. for 2 hours. The reaction solution was cooled at room temperature, and then the solvent was removed under reduced pressure to obtain the title compound.
Yield: 3.57 g (8.7 mmol) Yield: 88%

中間体３−Ａ 5-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]フラン-2-カルボン酸の合成
中間体１−Ａの工程１で得られた化合物（３．２２ｇ，１２．８ｍｍｏｌ）をＤＭＦ（１００ｍＬ）に溶解し、５−クロロメチル−２−フランカルボン酸エチル（２．４２ｇ，１２．８ｍｍｏｌ）および炭酸カリウム（２．６６ｇ，１９．３ｍｍｏｌ）を加えて、室温で一晩撹拌した。反応液を酢酸エチルで希釈した後、１Ｎ 塩酸水溶液および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。減圧下で溶媒を除去した後、得られた残渣を、メタノール（７５ｍＬ）とＴＨＦ（５０ｍＬ）の混合溶媒に溶解し、１Ｎ 水酸化ナトリウム水溶液（５０ｍＬ）を加えて、室温で一晩撹拌した。減圧下で溶媒を除去して得られた残渣を、酢酸エチルで希釈した後、１Ｎ 塩酸水溶液および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。減圧下で溶媒を除去して得られた残渣をアセトニトリルで洗浄することにより、表題化合物を得た。
収量：３．６５ｇ（９．７０ｍｍｏｌ） 収率：７６％

Intermediate 3-A Synthesis of 5-[[4- (4,5-difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] furan-2-carboxylic acid Compound obtained in Step 1 of Intermediate 1-A (3.22 g, 12.8 mmol) was dissolved in DMF (100 mL) and ethyl 5-chloromethyl-2-furancarboxylate (2.42 g, 12.8 mmol) and potassium carbonate (2.66 g, 19.3 mmol). And stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with 1N aqueous hydrochloric acid solution and saturated brine, and dried over anhydrous magnesium sulfate. After removing the solvent under reduced pressure, the obtained residue was dissolved in a mixed solvent of methanol (75 mL) and THF (50 mL), 1N aqueous sodium hydroxide solution (50 mL) was added, and the mixture was stirred at room temperature overnight. The residue obtained by removing the solvent under reduced pressure was diluted with ethyl acetate, washed with 1N aqueous hydrochloric acid solution and saturated brine, and dried over anhydrous magnesium sulfate. The title compound was obtained by washing the residue obtained by removing the solvent under reduced pressure with acetonitrile.
Yield: 3.65 g (9.70 mmol) Yield: 76%

中間体３−Ｂ 5-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]フラン-2-カルボニルクロライドの合成
中間体３−Ａ（３．６５ｇ，９．７０ｍｍｏｌ）に塩化チオニル（１５ｍＬ）およびＤＭＦ（触媒量）を加えて、５０℃で２時間撹拌した。室温に冷却した後、減圧下で溶媒を除去して表題化合物を得た。
収量：３．３ｇ（８．４ｍｍｏｌ） 収率：８６％

Intermediate 3-B Synthesis of 5-[[4- (4,5-difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] furan-2-carbonyl chloride Intermediate 3-A (3.65 g, 9.70 mmol) ) Were added with thionyl chloride (15 mL) and DMF (catalytic amount), and the mixture was stirred at 50 ° C. for 2 hours. After cooling to room temperature, the solvent was removed under reduced pressure to give the title compound.
Yield: 3.3 g (8.4 mmol) Yield: 86%

中間体４−Ａ 2-[[4-[4,5-ジフルオロ-2-(トリデュウテリオメトキシ)フェニル]フェノキシ]メチル]チアゾール-4-カルボン酸
工程１ 1-ブロモ-4,5-ジフルオロ-2-(トリデュウテリオメトキシ)ベンゼンの合成
２−ブロモ−４，５−ジフルオロフェノール（９．６４ｇ，４６．１ｍｍｏｌ）をＤＭＦ（７５ｍＬ）に溶解し、炭酸カリウム（７．６４ｇ，５５．４ｍｍｏｌ）およびヨウ化メタン−ｄ₃（３．５２ｍＬ，５５．４ｍｍｏｌ）を加えて、室温で一晩撹拌した。反応液を酢酸エチルで希釈した後、１Ｎ 塩酸水溶液および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。減圧下で溶媒を除去した後、得られた残渣をシリカゲルクロマトグラフィーにて精製し、表題化合物を得た。
収量：９．７４ｇ（４３．１ｍｍｏｌ） 収率：９３％
工程２ 4-[4,5-ジフルオロ-2-(トリデュウテリオメトキシ)フェニル]フェノールの合成
工程１で得られた化合物（４．１５ｇ，１８．４ｍｍｏｌ）を１，４−ジオキサン（７５ｍＬ）および水（２５ｍＬ）の混合溶媒に溶解し、４−ヒドロキシフェニルボロン酸（３．０ｇ，２２ｍｍｏｌ）、炭酸ナトリウム（３．９０ｇ，３６．８ｍｍｏｌ）およびＰｄＣｌ₂（ｄｐｐｆ）（触媒量）を加えて、１００℃で２時間撹拌した。反応液を室温に冷却した後、不溶物を濾別した。減圧下で溶媒を除去して得られた残渣を酢酸エチルで希釈した後、１Ｎ 塩酸水溶液および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。減圧下で溶媒を除去した後、得られた残渣をシリカゲルクロマトグラフィーにて精製し、表題化合物を得た。
収量：４．４０ｇ（１８．４ｍｍｏｌ） 収率：１００％
工程３ 中間体４−Ａの合成
工程２で得られた化合物（２．００ｇ，８．３７ｍｍｏｌ）をＤＭＦ（７５ｍＬ）に溶解し、２−ブロモメチルチアゾール−４−カルボン酸エチル（２．１０ｇ，８．３７ｍｍｏｌ）および炭酸カリウム（２．３１ｇ，１６．７ｍｍｏｌ）を加えて、室温で一晩撹拌した。反応液を酢酸エチルで希釈した後、１Ｎ 塩酸水溶液および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。減圧下で溶媒を除去して得られた残渣を、メタノール（３０ｍＬ）及びＴＨＦ（３０ｍＬ）の混合溶媒に溶解し、１Ｎ 水酸化ナトリウム水溶液（３０ｍＬ）を加えて、室温で一晩撹拌した。減圧下で溶媒を除去して得られた残渣を、酢酸エチルで希釈した後、１Ｎ 塩酸水溶液および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。減圧下で溶媒を除去して得られた残渣をアセトニトリルと水の混合溶媒（ｖ／ｖ＝１／１）で洗浄することにより、表題化合物を得た。
収量：２．３ｇ（６．０ｍｍｏｌ） 収率：７２％

Intermediate 4-A 2-[[4- [4,5-Difluoro-2- (trideuteriomethoxy) phenyl] phenoxy] methyl] thiazole-4-carboxylic acid Step 1 1-Bromo-4, Synthesis of 5-difluoro-2- (trideuteriomethoxy) benzene 2-Bromo-4,5-difluorophenol (9.64 g, 46.1 mmol) was dissolved in DMF (75 mL) and potassium carbonate (7.64 g, 55.4 mmol) and iodomethane-d ₃ (3.52 mL, 55.4 mmol) were added and stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with 1N aqueous hydrochloric acid solution and saturated brine, and dried over anhydrous magnesium sulfate. After removing the solvent under reduced pressure, the resulting residue was purified by silica gel chromatography to obtain the title compound.
Yield: 9.74 g (43.1 mmol) Yield: 93%
Step 2 Synthesis of 4- [4,5-difluoro-2- (trideuteriomethoxy) phenyl] phenol The compound obtained in Step 1 (4.15 g, 18.4 mmol) was converted to 1,4-dioxane (75 mL) and Dissolve in a mixed solvent of water (25 mL), add 4-hydroxyphenylboronic acid (3.0 g, 22 mmol), sodium carbonate (3.90 g, 36.8 mmol) and PdCl ₂ (dppf) (catalytic amount), The mixture was stirred at 100 ° C. for 2 hours. After the reaction solution was cooled to room temperature, insoluble matters were filtered off. The residue obtained by removing the solvent under reduced pressure was diluted with ethyl acetate, washed with 1N aqueous hydrochloric acid solution and saturated brine, and dried over anhydrous magnesium sulfate. After removing the solvent under reduced pressure, the resulting residue was purified by silica gel chromatography to obtain the title compound.
Yield: 4.40 g (18.4 mmol) Yield: 100%
Step 3 Synthesis of Intermediate 4-A The compound obtained in Step 2 (2.00 g, 8.37 mmol) was dissolved in DMF (75 mL), and ethyl 2-bromomethylthiazole-4-carboxylate (2.10 g, 8.37 mmol) and potassium carbonate (2.31 g, 16.7 mmol) were added and stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with 1N aqueous hydrochloric acid solution and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by removing the solvent under reduced pressure was dissolved in a mixed solvent of methanol (30 mL) and THF (30 mL), 1N aqueous sodium hydroxide solution (30 mL) was added, and the mixture was stirred overnight at room temperature. The residue obtained by removing the solvent under reduced pressure was diluted with ethyl acetate, washed with 1N aqueous hydrochloric acid solution and saturated brine, and dried over anhydrous magnesium sulfate. The title compound was obtained by washing the residue obtained by removing the solvent under reduced pressure with a mixed solvent of acetonitrile and water (v / v = 1/1).
Yield: 2.3 g (6.0 mmol) Yield: 72%

中間体４−Ｂ 2-[[4-[4,5-ジフルオロ-2-(トリデュウテリオメトキシ)フェニル]フェノキシ]メチル]チアゾール-4-カルボン酸クロライド
中間体４−Ａ（２．３ｇ，６．０ｍｍｏｌ）に塩化チオニル（２５ｍＬ）を加えて、５０℃で２時間撹拌した。室温に冷却した後、減圧下で溶媒を除去して表題化合物を得た。
収量：２．２ｇ（５．５ｍｍｏｌ） 収率：９２％

Intermediate 4-B 2-[[4- [4,5-Difluoro-2- (trideuteriomethoxy) phenyl] phenoxy] methyl] thiazole-4-carboxylic acid chloride intermediate 4-A (2.3 g, 6 0.0 mmol) was added with thionyl chloride (25 mL), and the mixture was stirred at 50 ° C. for 2 hours. After cooling to room temperature, the solvent was removed under reduced pressure to give the title compound.
Yield: 2.2 g (5.5 mmol) Yield: 92%

中間体５−Ａ 2-[[4-(4,5-ジフルオロ-3-メチル-ベンゾフラン-7-イル)フェノキシ]メチル]チアゾール-4-カルボン酸
工程1 4-(4,5-ジフルオロ-3-メチル-ベンゾフラン-7-イル)フェノールの合成
７−ブロモ−４，５−ジフルオロ−３−メチル−ベンゾフラン（２．１ｇ，８．５ｍｍｏｌ）を１，４−ジオキサン（７５ｍＬ）および水（２５ｍＬ）の混合溶媒に溶解し、４−ヒドロキシフェニルボロン酸（１．４０ｇ，１０．２ｍｍｏｌ）、炭酸ナトリウム（１．８ｇ，１７ｍｍｏｌ）およびＰｄＣｌ₂（ｄｐｐｆ）（触媒量）を加えて、１００℃で２時間撹拌した。反応液を室温に冷却した後、不溶物を濾別した。減圧下で溶媒を除去して得られた残渣を酢酸エチルで希釈した後、１Ｎ 塩酸水溶液および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。減圧下で溶媒を除去した後、得られた残渣をシリカゲルクロマトグラフィーにて精製し、表題化合物を得た。
収量：２．１ｇ（８．１ｍｍｏｌ） 収率：９５％
工程２ 中間体５−Ａの合成
工程１で得られた化合物（２．１ｇ，８．１ｍｍｏｌ）及び２−ブロモメチルチアゾール−４−カルボン酸エチル（２．０ｇ，８．１ｍｍｏｌ）をＤＭＦ（７５ｍＬ）に溶解し、炭酸カリウム（２．２３ｇ，１６．２ｍｍｏｌ）を加えて、室温で一晩撹拌した。反応液を酢酸エチルで希釈した後、１Ｎ 塩酸水溶液および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。減圧下で溶媒を除去して得られた残渣をメタノール（３０ｍＬ）及びＴＨＦ（３０ｍＬ）の混合溶液に溶解し、１Ｎ 水酸化ナトリウム水溶液（３０ｍＬ）を加えて、室温で一晩撹拌した。減圧下で溶媒を除去して得られた残渣を、酢酸エチルで希釈した後、１Ｎ 塩酸水溶液および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。減圧下で溶媒を除去した後、得られた残渣をアセトニトリルと水の混合溶媒（ｖ／ｖ＝１／１）で洗浄することにより、表題化合物を得た。
収量：１．７ｇ（４．２ｍｍｏｌ） 収率：５２％

Intermediate 5-A 2-[[4- (4,5-Difluoro-3-methyl-benzofuran-7-yl) phenoxy] methyl] thiazole-4-carboxylic acid Step 1 4- (4,5 Synthesis of -Difluoro-3-methyl-benzofuran-7-yl) phenol 7-Bromo-4,5-difluoro-3-methyl-benzofuran (2.1 g, 8.5 mmol) and 1,4-dioxane (75 mL) and Dissolve in a mixed solvent of water (25 mL), add 4-hydroxyphenylboronic acid (1.40 g, 10.2 mmol), sodium carbonate (1.8 g, 17 mmol) and PdCl ₂ (dppf) (catalytic amount), The mixture was stirred at 100 ° C. for 2 hours. After the reaction solution was cooled to room temperature, insoluble matters were filtered off. The residue obtained by removing the solvent under reduced pressure was diluted with ethyl acetate, washed with 1N aqueous hydrochloric acid solution and saturated brine, and dried over anhydrous magnesium sulfate. After removing the solvent under reduced pressure, the resulting residue was purified by silica gel chromatography to obtain the title compound.
Yield: 2.1 g (8.1 mmol) Yield: 95%
Step 2 Synthesis of Intermediate 5-A Compound (2.1 g, 8.1 mmol) obtained in Step 1 and ethyl 2-bromomethylthiazole-4-carboxylate (2.0 g, 8.1 mmol) were added to DMF (75 mL). ), Potassium carbonate (2.23 g, 16.2 mmol) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, washed with 1N aqueous hydrochloric acid solution and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by removing the solvent under reduced pressure was dissolved in a mixed solution of methanol (30 mL) and THF (30 mL), 1N aqueous sodium hydroxide solution (30 mL) was added, and the mixture was stirred overnight at room temperature. The residue obtained by removing the solvent under reduced pressure was diluted with ethyl acetate, washed with 1N aqueous hydrochloric acid solution and saturated brine, and dried over anhydrous magnesium sulfate. After removing the solvent under reduced pressure, the resulting residue was washed with a mixed solvent of acetonitrile and water (v / v = 1/1) to obtain the title compound.
Yield: 1.7 g (4.2 mmol) Yield: 52%

中間体５−Ｂ 2-[[4-(4,5-ジフルオロ-3-メチル-ベンゾフラン-7-イル)フェノキシ]メチル]チアゾール-4-カルボニルクロリドの合成
中間体５−Ａ（７９０ｍｇ，１．９７ｍｍｏｌ）に塩化チオニル（４．６ｍＬ）と少量のＤＭＦを加えて、５５℃で４０分撹拌した。反応液を室温で冷却した後、減圧下で溶媒を除去し、表題化合物を得た。

Intermediate 5-B Synthesis of 2-[[4- (4,5-difluoro-3-methyl-benzofuran-7-yl) phenoxy] methyl] thiazole-4-carbonyl chloride Intermediate 5-A (790 mg, 1. 97 mmol) were added thionyl chloride (4.6 mL) and a small amount of DMF, and the mixture was stirred at 55 ° C. for 40 minutes. After cooling the reaction solution at room temperature, the solvent was removed under reduced pressure to obtain the title compound.

中間体６−Ａ 2-[[4-(4,5-ジフルオロベンゾチオフェン-7-イル)フェノキシ]メチル]チアゾール-4-カルボン酸の合成
工程１ 4-（4,5-ジフルオロ-1-ベンゾチオフェン-7-イル）フェノールの合成
７−ブロモ−４，５−ジフルオロ−１−ベンゾチオフェン（０．６５ｇ，２．６１ｍｍｏｌ）と４−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）フェノール（０．５７ｇ，２．６１ｍｍｏｌ）を１，４−ジオキサン（１２ｍＬ）および水（４ｍＬ）の混合溶媒に溶解し、炭酸ナトリウム（０．８３ｇ，７．８３ｍｍｏｌ）およびＰｄＣｌ₂（ｄｐｐｆ）（０．３８ｇ，０．５２ｍｍｏｌ）を加えて、マイクロウェーブ反応装置（Ｂｉｏｔａｇｅ社製Ｉｎｉｔｉａｔｏｒ^TMＳｉｘｔｙ）を用いて、１２５℃で３０分間攪拌した。反応液を室温で冷却した後、不溶物をろ過した。ろ液を酢酸エチルで希釈した後、水および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。減圧下で溶媒を除去した後、得られた残渣をシリカゲルクロマトグラフィーにて精製し、表題化合物を得た。
収量：１．１２ｇ（４．２７ｍｍｏｌ） 収率：６１％
¹H NMR (400 MHz, CDCl₃) δ 7.57 - 7.50 (m, 4H), 7.19 (dd, J = 8.0, 1.2 Hz, 1H), 6.96 (d, J = 8.0 Hz, 2H).
工程２ 2-[[4-(4,5-ジフルオロベンゾチオフェン-7-イル)フェノキシ]メチル]チアゾール-4-カルボン酸エチルの合成
２−ブロモメチルチアゾール−４−カルボン酸エチル（５００ｍｇ，２．００ｍｍｏｌ）と工程１で得られた化合物（５２４ｍｇ，２．００ｍｍｏｌ）をＤＭＦ（１０ｍＬ）に溶解し、炭酸カリウム（０．２９ｇ，２．１０ｍｍｏｌ）を加えて、室温で一晩撹拌した。反応液を酢酸エチルで希釈した後、水および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。減圧下で溶媒を除去した後、得られた残渣をシリカゲルクロマトグラフィーにて精製し、表題化合物を得た。
収量：７８３ｍｇ（１．８１ｍｍｏｌ） 収率：９１％
¹H NMR (400 MHz, CDCl₃) δ 8.23 (s, 1H), 7.62 (d, J = 8.0 Hz, 2H), 7.54 - 7.50 (m, 2H), 7.19 (dd, J = 8.0, 1.2 Hz, 1H), 7.12 (d, J = 8.0 Hz, 2H), 5.48 (s, 2H), 4.46 (q, J = 8.0 Hz, 2H), 1.42 (t, J = 8.0 Hz, 3H).
工程３ 中間体６−Ａの合成
工程２で得られた化合物（７８３ｍｇ，１．８１ｍｍｏｌ）をＴＨＦ（１４ｍＬ）およびメタノール（４ｍＬ）の混合溶媒に溶解し、１Ｎ 水酸化ナトリウム水溶液（３ｍＬ）を加えて、室温で５時間撹拌した。減圧下で溶媒を除去して得られた残渣を、酢酸エチルで希釈した後、１Ｎ 塩酸水溶液および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。減圧下で溶媒を除去して、表題化合物を無精製で得た。
収量：７２１ｍｇ（１．７９ｍｍｏｌ） 収率：９９％
¹H NMR (400 MHz, DMSO-d₆) δ 13.20 - 12.99 (brs, 1H), 8.51 (s, 1H), 8.00 (d, J = 4.0 Hz, 1H), 7.70 (d, J = 8.0 Hz, 2H), 7.64 (d, J = 4.0 Hz, 1H), 7.26 (d, J = 8.0 Hz, 2H), 5.56 (s, 2H).

Intermediate 6-A Synthesis of 2-[[4- (4,5-difluorobenzothiophen-7-yl) phenoxy] methyl] thiazole-4-carboxylic acid Step 1 4- (4,5-Difluoro Synthesis of 1-benzothiophen-7-yl) phenol 7-Bromo-4,5-difluoro-1-benzothiophene (0.65 g, 2.61 mmol) and 4- (4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl) phenol (0.57 g, 2.61 mmol) was dissolved in a mixed solvent of 1,4-dioxane (12 mL) and water (4 mL), and sodium carbonate (0.83 g) , 7.83 mmol) and _{PdCl 2 (dppf) (0.38g,} 0.52mmol) was added and using a microwave reaction device (Biotage Inc. Initiator ^TM Sixty), stirred for 30 minutes at 125 ° C. It was. After cooling the reaction solution at room temperature, insolubles were filtered off. The filtrate was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After removing the solvent under reduced pressure, the resulting residue was purified by silica gel chromatography to obtain the title compound.
Yield: 1.12 g (4.27 mmol) Yield: 61%
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.57-7.50 (m, 4H), 7.19 (dd, J = 8.0, 1.2 Hz, 1H), 6.96 (d, J = 8.0 Hz, 2H).
Step 2 Synthesis of ethyl 2-[[4- (4,5-difluorobenzothiophen-7-yl) phenoxy] methyl] thiazole-4-carboxylate ethyl 2-bromomethylthiazole-4-carboxylate (500 mg, 2. 00 mmol) and the compound obtained in Step 1 (524 mg, 2.00 mmol) were dissolved in DMF (10 mL), potassium carbonate (0.29 g, 2.10 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After removing the solvent under reduced pressure, the resulting residue was purified by silica gel chromatography to obtain the title compound.
Yield: 783 mg (1.81 mmol) Yield: 91%
¹ H NMR (400 MHz, CDCl ₃ ) δ 8.23 (s, 1H), 7.62 (d, J = 8.0 Hz, 2H), 7.54-7.50 (m, 2H), 7.19 (dd, J = 8.0, 1.2 Hz, 1H), 7.12 (d, J = 8.0 Hz, 2H), 5.48 (s, 2H), 4.46 (q, J = 8.0 Hz, 2H), 1.42 (t, J = 8.0 Hz, 3H).
Step 3 Synthesis of Intermediate 6-A The compound obtained in Step 2 (783 mg, 1.81 mmol) was dissolved in a mixed solvent of THF (14 mL) and methanol (4 mL), and 1N aqueous sodium hydroxide solution (3 mL) was added. And stirred at room temperature for 5 hours. The residue obtained by removing the solvent under reduced pressure was diluted with ethyl acetate, washed with 1N aqueous hydrochloric acid solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the title compound without purification.
Yield: 721 mg (1.79 mmol) Yield: 99%
¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.20-12.99 (brs, 1H), 8.51 (s, 1H), 8.00 (d, J = 4.0 Hz, 1H), 7.70 (d, J = 8.0 Hz, 2H), 7.64 (d, J = 4.0 Hz, 1H), 7.26 (d, J = 8.0 Hz, 2H), 5.56 (s, 2H).

中間体６−Ｂ 2-[[4-(4,5-ジフルオロベンゾチオフェン-7-イル)フェノキシ]メチル]チアゾール-4-カルボニルクロリドの合成
中間体６−Ａ（１５０ｍｇ，０．３９７ｍｍｏｌ）に塩化チオニル（２．００ｍＬ）及び少量のＤＭＦを加えて、５５℃で４５分撹拌した。反応液を室温で冷却した後、減圧下で溶媒を除去し、表題化合物を得た。

Intermediate 6-B Synthesis of 2-[[4- (4,5-difluorobenzothiophen-7-yl) phenoxy] methyl] thiazole-4-carbonyl chloride Intermediate 6-A (150 mg, 0.397 mmol) was salified. Thionyl (2.00 mL) and a small amount of DMF were added, and the mixture was stirred at 55 ° C. for 45 minutes. After cooling the reaction solution at room temperature, the solvent was removed under reduced pressure to obtain the title compound.

中間体７−Ａ 2-[[4-[4,5-ジフルオロ-2-(メトキシメチル)ベンゾチオフェン-7-イル]フェノキシ]メチル]チアゾール-4-カルボン酸の合成
工程１ 4-（4,5-ジフルオロ-2-メトキシメチル-1-ベンゾチオフェン-7-イル）フェノールの合成
ＷＯ２０１３／０６５８３５の実施例７４の工程１記載の方法を用いて得られた７−ブロモ−４，５−ジフルオロ−２−（メトキシメチル）−１−ベンゾチオフェン（５００ｍｇ，１．７１ｍｍｏｌ）と４−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）フェノール（３７５ｍｇ，１．７０ｍｍｏｌ）を１，４−ジオキサン（１２ｍＬ）および水（４ｍＬ）の混合溶媒に溶解し、炭酸ナトリウム（５４３ｍｇ，５．１２ｍｍｏｌ）およびＰｄＣｌ₂（ｄｐｐｆ）（２５０ｍｇ，０．３４ｍｍｏｌ）を加えてマイクロウェーブ装置にて１２５℃で３０分間攪拌した。反応液を室温で冷却した後、不溶物をろ過した。ろ液を酢酸エチルで希釈し、水および飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥した。減圧下で溶媒を除去することで、表題化合物を無精製で得た。
収量：４０１ｍｇ（２．３１ｍｍｏｌ） 収率：７７％
¹H NMR (400 MHz, CDCl₃) δ 7.53 (d, J = 8.0Hz, 2H), 7.38 (s, 1H), 7.15 (dd, J = 8.0, 1.2 Hz, 1H), 6.94 (d, J = 8.0 Hz, 2H), 4.87 (s, 1H), 4.70 (s, 2H), 3.44 (s, 3H).
工程２ 中間体７−Ａの合成
２−ブロモメチルチアゾール−４−カルボン酸エチル（５５２ｍｇ，２．２１ｍｍｏｌ）と工程１で得られた化合物（６７６ｍｇ，２．２１ｍｍｏｌ）をＤＭＦ（１０ｍＬ）に溶解し、炭酸カリウム（０．３２ｇ，２．３２ｍｍｏｌ）を加えて、室温で一晩撹拌した。反応液を酢酸エチルで希釈した後、水および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。減圧下で溶媒を除去して得られた残渣をＴＨＦ（１０ｍＬ）およびメタノール（２ｍＬ）の混合溶媒に溶解し、１Ｎ 水酸化ナトリウム水溶液（３ｍＬ）を加えて、室温で３時間撹拌した。減圧下で溶媒を除去して得られた残渣に少量の酢酸エチルと１Ｎ 塩酸水溶液（３ｍＬ）を加えて、室温で３０分撹拌した。反応液をろ過した後、得られた固体を水で洗浄することにより、表題化合物を得た。
収量：７４１ｍｇ（１．６６ｍｍｏｌ） 収率：７５％
¹H NMR (400 MHz, DMSO-d₆) δ 13.22 - 12.97 (brs, 1H), 8.51 (s, 1H), 7.69 (d, J = 12.0 Hz, 2H), 7.57 (s, 1H), 7.52 (dd, J = 8.0, 1.2 Hz, 1H), 7.25 (d, J = 12.0 Hz, 2H), 5.56 (s, 2H), 4.73 (s, 2H), 3.34 (s, 3H).

Intermediate 7-A Synthesis of 2-[[4- [4,5-difluoro-2- (methoxymethyl) benzothiophen-7-yl] phenoxy] methyl] thiazole-4-carboxylic acid Step 1 4 Synthesis of-(4,5-difluoro-2-methoxymethyl-1-benzothiophen-7-yl) phenol 7-Bromo-4, obtained using the method described in step 1 of example 74 of WO2013 / 065835 5-Difluoro-2- (methoxymethyl) -1-benzothiophene (500 mg, 1.71 mmol) and 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenol (375 mg, 1.70 mmol) was dissolved in a mixed solvent of 1,4-dioxane (12 mL) and water (4 mL), sodium carbonate (543 mg, 5.12 mmol) and PdCl ₂ (dppf) (250 mg, 0.34). mmol) was added and stirred at 125 ° C. for 30 minutes in a microwave apparatus. After cooling the reaction solution at room temperature, insolubles were filtered off. The filtrate was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The title compound was obtained without purification by removing the solvent under reduced pressure.
Yield: 401 mg (2.31 mmol) Yield: 77%
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.53 (d, J = 8.0Hz, 2H), 7.38 (s, 1H), 7.15 (dd, J = 8.0, 1.2 Hz, 1H), 6.94 (d, J = 8.0 Hz, 2H), 4.87 (s, 1H), 4.70 (s, 2H), 3.44 (s, 3H).
Step 2 Synthesis of Intermediate 7-A Ethyl 2-bromomethylthiazole-4-carboxylate (552 mg, 2.21 mmol) and the compound obtained in Step 1 (676 mg, 2.21 mmol) were dissolved in DMF (10 mL). , Potassium carbonate (0.32 g, 2.32 mmol) was added and stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by removing the solvent under reduced pressure was dissolved in a mixed solvent of THF (10 mL) and methanol (2 mL), 1N aqueous sodium hydroxide solution (3 mL) was added, and the mixture was stirred at room temperature for 3 hr. A small amount of ethyl acetate and 1N aqueous hydrochloric acid solution (3 mL) were added to the residue obtained by removing the solvent under reduced pressure, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was filtered, and the obtained solid was washed with water to give the title compound.
Yield: 741 mg (1.66 mmol) Yield: 75%
¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.22-12.97 (brs, 1H), 8.51 (s, 1H), 7.69 (d, J = 12.0 Hz, 2H), 7.57 (s, 1H), 7.52 ( dd, J = 8.0, 1.2 Hz, 1H), 7.25 (d, J = 12.0 Hz, 2H), 5.56 (s, 2H), 4.73 (s, 2H), 3.34 (s, 3H).

中間体７−Ｂ 2-[[4-[4,5-ジフルオロ-2-(メトキシメチル)ベンゾチオフェン-7-イル]フェノキシ]メチル]チアゾール-4-カルボニルクロリドの合成
中間体７−Ａ（７００ｍｇ，１．４７ｍｍｏｌ）に塩化チオニル（３．０ｍＬ）を加えて、５０℃で１時間撹拌した。室温で冷却した後、減圧下で溶媒を濃縮し、表題化合物を得た。

Intermediate 7-B Synthesis of 2-[[4- [4,5-difluoro-2- (methoxymethyl) benzothiophen-7-yl] phenoxy] methyl] thiazole-4-carbonyl chloride Intermediate 7-A (700 mg , 1.47 mmol) was added with thionyl chloride (3.0 mL), and the mixture was stirred at 50 ° C. for 1 hour. After cooling at room temperature, the solvent was concentrated under reduced pressure to give the title compound.

中間体８−Ａ 5-[[4-[4,5-ジフルオロ-2-((トリデュウテリオメトキシ)フェニル]フェノキシ]メチル]フラン-2-カルボン酸の合成
４−［４，５−ジフルオロ−２−（トリデュウテリオメトキシ）フェニル］フェノール（０．９７ｇ，４．１ｍｍｏｌ）、５−クロロメチル−２−フランカルボン酸エチル（０．６２ｍｌ，４．１ｍｍｏｌ）及び炭酸カリウム（１．１２ｇ，８．１２ｍｍｏｌ）にＤＭＦ（７５ｍＬ）を加え、室温で一晩撹拌した。酢酸エチルで希釈した後、１Ｎ 塩酸及び飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去して得られた残渣をメタノール（３０ｍＬ）及びＴＨＦ（３０ｍＬ）の混合溶媒に溶解し、１Ｎ 水酸化ナトリウム水溶液（３０ｍｌ）を加えて、室温で一晩撹拌した。減圧下溶媒を留去して得られた残渣を、酢酸エチルで希釈した後、１Ｎ 塩酸及び飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去して得られた残渣をアセトニトリルと水（ｖ／ｖ＝１／１）の混合溶媒で洗浄することにより、表題化合物を得た。
収量：０．８０ｇ（２．２ｍｍｏｌ） 収率：５４％

Intermediate 8-A Synthesis of 5-[[4- [4,5-difluoro-2-((trideuteriomethoxy) phenyl] phenoxy] methyl] furan-2-carboxylic acid 4- [4,5-difluoro- 2- (Trideuteriomethoxy) phenyl] phenol (0.97 g, 4.1 mmol), ethyl 5-chloromethyl-2-furancarboxylate (0.62 ml, 4.1 mmol) and potassium carbonate (1.12 g, 8 DMF (75 mL) was added to .12 mmol), and the mixture was stirred overnight at room temperature, diluted with ethyl acetate, washed with 1N hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. The obtained residue was dissolved in a mixed solvent of methanol (30 mL) and THF (30 mL), 1N aqueous sodium hydroxide solution (30 ml) was added, and the mixture was stirred overnight at room temperature. The resulting residue was diluted with ethyl acetate, washed with 1N hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain acetonitrile and water (v / v = The title compound was obtained by washing with a mixed solvent of 1/1).
Yield: 0.80 g (2.2 mmol) Yield: 54%

中間体８−Ｂ 5-[[4-[4,5-ジフルオロ-2-(トリデューテリオメトキシ)フェニル]フェノキシ]メチル]フラン-2-カルボニルクロリドの合成
中間体８−Ａ（７３ｍｇ，０．２０ｍｍｏｌ）に塩化チオニル（０．８０ｍＬ）を加えＤＭＦを少量滴下し、５５℃で３０分撹拌した。室温に冷却した後、減圧下溶媒を除去することにより、表題化合物を得た。

Intermediate 8-B Synthesis of 5-[[4- [4,5-difluoro-2- (triduteriomethoxy) phenyl] phenoxy] methyl] furan-2-carbonyl chloride Intermediate 8-A (73 mg, 0. 20 mmol), thionyl chloride (0.80 mL) was added, and a small amount of DMF was added dropwise, followed by stirring at 55 ° C. for 30 minutes. After cooling to room temperature, the title compound was obtained by removing the solvent under reduced pressure.

中間体９−Ａ 2-[[4-(4,5-ジフルオロベンゾフラン-7-イル)フェノキシ]メチル]チアゾール-4-カルボン酸の合成
工程１ 2-[[4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボラン-2-イル)フェノキシ]メチル]チアゾール-4-カルボン酸 エチルエステルの合成
２−ブロモメチルチアゾール−４−カルボン酸エチル（１．９６ｇ，７．８３ｍｍｏｌ）、４−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）フェノール（１．９０ｇ，８．６３ｍｍｏｌ）及び炭酸カリウム（１．１９ｇ，８．６１ｍｍｏｌ）にＤＭＦ（３０ｍＬ）を加え、室温で一晩撹拌した。酢酸エチルで希釈した後、水及び飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去して得られた残渣をシリカゲルクロマトグラフィーにて精製し、表題化合物を得た。
収量：２．７７ｇ（７．１２ｍｍｏｌ） 収率：９１％
¹H NMR (400 MHz, CDCl₃) δ 8.19 (s, 1H), 7.77 (d, J = 8.0 Hz, 2H), 6.98 (d, J = 8.0 Hz, 2H), 5.43 (s, 2H), 4.44 (q, J = 8.0 Hz, 2H), 1.42 (t, J = 8.0 Hz, 3H), 1.33 (s, 12H).
工程２ 中間体９−Ａの合成
７−ブロモ−４，５−ジフルオロ−ベンゾフラン（１００ｍｇ，０．２５７ｍｍоｌ）、工程１で得られた化合物（４８ｍg，０．２１４ｍｍｏｌ）、ＰｄＣｌ₂（ｄｐｐｆ）（８．０ｍg，０．０１１ｍｍｏｌ）及び１，４−ジオキサン（２．３ｍｌ）に１Ｍ 炭酸カリウム水溶液（０．７８ｍＬ）を加え、１００℃で１時間撹拌した。ジクロロメタンで希釈し、水及び飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をアセトニトリルで洗浄し、シリカゲルクロマトグラフィー（ヘキサン／酢酸エチル）で精製し、減圧濃縮した。ヘキサンと酢酸エチル（ｖ／ｖ＝１／１）の混合溶媒でスラリー洗浄を行った。得られた個体を１，４−ジオキサン（１ｍｌ）、少量のメタノールに懸濁させ、１Ｍ 水酸化リチウム水溶液（１８５μＬ）を加え１時間半撹拌した。１Ｍ 塩酸で弱酸性にし、減圧下溶媒を留去した。得られた残渣に水を加えスラリー洗浄を行い、真空乾燥させ表題化合物を得た。
収量：４９．０ｍｇ（０．１２６ｍｍｏｌ） 収率：４８％
MS (ESI) m/z 388 [M+H]⁺

Intermediate 9-A Synthesis of 2-[[4- (4,5-difluorobenzofuran-7-yl) phenoxy] methyl] thiazole-4-carboxylic acid Step 1 2-[[4- (4, Synthesis of 4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl) phenoxy] methyl] thiazole-4-carboxylic acid ethyl ester ethyl 2-bromomethylthiazole-4-carboxylate (1.96 g , 7.83 mmol), 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenol (1.90 g, 8.63 mmol) and potassium carbonate (1.19 g, (8.61 mmol) was added DMF (30 mL) and stirred overnight at room temperature. The mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel chromatography to obtain the title compound.
Yield: 2.77 g (7.12 mmol) Yield: 91%
¹ H NMR (400 MHz, CDCl ₃ ) δ 8.19 (s, 1H), 7.77 (d, J = 8.0 Hz, 2H), 6.98 (d, J = 8.0 Hz, 2H), 5.43 (s, 2H), 4.44 (q, J = 8.0 Hz, 2H), 1.42 (t, J = 8.0 Hz, 3H), 1.33 (s, 12H).
Step 2 Synthesis of Intermediate 9-A 7-Bromo-4,5-difluoro-benzofuran (100 mg, 0.257 mmol), compound obtained in Step 1 (48 mg, 0.214 mmol), PdCl ₂ (dppf) (8 0.0 mg, 0.011 mmol) and 1,4-dioxane (2.3 ml) were added 1M aqueous potassium carbonate solution (0.78 mL), and the mixture was stirred at 100 ° C. for 1 hour. The mixture was diluted with dichloromethane, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was washed with acetonitrile, purified by silica gel chromatography (hexane / ethyl acetate), and concentrated under reduced pressure. The slurry was washed with a mixed solvent of hexane and ethyl acetate (v / v = 1/1). The obtained solid was suspended in 1,4-dioxane (1 ml) and a small amount of methanol, 1M aqueous lithium hydroxide solution (185 μL) was added, and the mixture was stirred for 1.5 hours. The solution was made weakly acidic with 1M hydrochloric acid, and the solvent was distilled off under reduced pressure. Water was added to the resulting residue for slurry washing, followed by vacuum drying to obtain the title compound.
Yield: 49.0 mg (0.126 mmol) Yield: 48%
MS (ESI) m / z 388 [M + H] ⁺

中間体９−Ｂ 2-[[4-(4,5-ジフルオロベンゾフラン-7-イル)フェノキシ]メチル]チアゾール-4-カルボニルクロリドの合成
中間体９−Ａ（３９２ｍｇ，１．０１ｍｍｏｌ）に塩化チオニル（３．５ｍＬ）を加えＤＭＦを少量滴下し、５５℃で４０分撹拌した。室温に冷却した後、減圧下溶媒を除去することにより、表題化合物を得た。

Intermediate 9-B Synthesis of 2-[[4- (4,5-difluorobenzofuran-7-yl) phenoxy] methyl] thiazole-4-carbonyl chloride Intermediate 9-A (392 mg, 1.01 mmol) was mixed with thionyl chloride. (3.5 mL) was added, and a small amount of DMF was added dropwise, followed by stirring at 55 ° C. for 40 minutes. After cooling to room temperature, the title compound was obtained by removing the solvent under reduced pressure.

中間体１０ 5-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]チオフェン-3-カルボン酸の合成
２−ホルミルチオフェン−４−カルボン酸メチル（２．２２ｇ，１３．１ｍｍｏｌ）をメタノール（２０ｍＬ）に溶解し、水素化ホウ素ナトリウム（６００ｍｇ，１５．７ｍｍｏｌ）を加えて、室温で一晩撹拌した。減圧下で溶媒を除去することで得られた残渣を、酢酸エチルで希釈した後、水及び飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。減圧下で溶媒を除去して得られた残渣にチオニルクロライド（１０ｍＬ）加え、室温で２時間撹拌した。減圧下で溶媒を除去して得られた残渣を、酢酸エチルで希釈した後、水及び飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。減圧下で溶媒を除去して得られた残渣に４−（４，５−ジフルオロ−２−メチルスルファニル−フェニル）フェノール（２．８０ｇ，１１．１ｍｍｏｌ）、炭酸カリウム（３．０６ｇ，２２．２ｍｍｏｌ）及びヨウ化カリウム（触媒量）にＤＭＦ（７５ｍＬ）を加え、室温で一晩撹拌した。酢酸エチルで希釈した後、１Ｎ 塩酸及び飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。減圧下で溶媒を除去して得られた残渣をメタノール（２５ｍＬ）及びＴＨＦ（２５ｍＬ）の混合溶媒に溶解し、１Ｎ 水酸化ナトリウム水溶液（２５ｍＬ）を加え、室温で一晩撹拌した。減圧下で溶媒を除去して得られた残渣を、酢酸エチルで希釈した後、１Ｎ 塩酸及び飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。減圧下で溶媒を除去して得られた残渣をアセトニトリルで洗浄することにより、表題化合物を得た。
収量：２．２ｇ（５．６ｍｍｏｌ） 収率：４３％

Intermediate 10 Synthesis of 5-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiophene-3 -carboxylic acid Methyl 2-formylthiophene-4-carboxylate (2.22 g, 13.1 mmol) was dissolved in methanol (20 mL), sodium borohydride (600 mg, 15.7 mmol) was added, and the mixture was stirred overnight at room temperature. The residue obtained by removing the solvent under reduced pressure was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. Thionyl chloride (10 mL) was added to the residue obtained by removing the solvent under reduced pressure, and the mixture was stirred at room temperature for 2 hours. The residue obtained by removing the solvent under reduced pressure was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by removing the solvent under reduced pressure was subjected to 4- (4,5-difluoro-2-methylsulfanyl-phenyl) phenol (2.80 g, 11.1 mmol), potassium carbonate (3.06 g, 22.2 mmol). ) And potassium iodide (catalytic amount) were added DMF (75 mL) and stirred overnight at room temperature. The mixture was diluted with ethyl acetate, washed with 1N hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by removing the solvent under reduced pressure was dissolved in a mixed solvent of methanol (25 mL) and THF (25 mL), 1N aqueous sodium hydroxide solution (25 mL) was added, and the mixture was stirred overnight at room temperature. The residue obtained by removing the solvent under reduced pressure was diluted with ethyl acetate, washed with 1N hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. The title compound was obtained by washing the residue obtained by removing the solvent under reduced pressure with acetonitrile.
Yield: 2.2 g (5.6 mmol) Yield: 43%

中間体１１−Ａ 2-[[4-(4,5-ジフルオロ-2-メトキシ-フェニル)フェノキシ]メチル]チアゾール-4-カルボン酸の合成
工程１ 4-(4,5-ジフルオロ-2-メトキシ-フェニル)フェノールの合成
１−ブロモ−４，５−ジフルオロ−２−メトキシ−ベンゼン（１．０ｇ，４．５ｍｍоｌ）、４−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）フェノール（１．０９g，４．９３ｍｍｏｌ）、ＰｄＣｌ₂（ｄｐｐｆ）（３２８ｍg，０．４４８ｍｍｏｌ）及び炭酸ナトリウム（１．５１ｇ，１１．２ｍｍｏｌ）を１，４−ジオキサンと水の混合溶液（４０ｍＬ，ｖ／ｖ＝４／１）に加え、１００℃で１時間撹拌した。反応液を酢酸エチルで希釈し、水及び飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去した後、得られた残渣をシリカゲルクロマトグラフィー（ヘキサン／酢酸エチル）で精製し、表題化合物を得た。
収量：１．１３ｇ（３．５６ｍｍｏｌ） 収率：７９％
工程２ 2-[[4-(4,5-ジフルオロ-2-メトキシ-フェニル)フェノキシ]メチル]チアゾール-4-カルボン酸エチルの合成
工程１で得られた化合物（１．１３ｍｇ，３．５６ｍｍｏｌ）と２−ブロモメチルチアゾール−４−カルボン酸エチル（９７９ｍｇ，３．９２ｍｍｏｌ）をＤＭＦ（３５ｍＬ）に溶解し、炭酸カリウム（１．２０ｇ，８．９０ｍｍｏｌ）を加え、室温で５８時間撹拌した。反応液を酢酸エチルで希釈し、水、炭酸水素ナトリウム水溶液及び飽和食塩水にて洗浄して無水硫酸ナトリウムで乾燥した。減圧下で溶媒媒を除去した後、得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル）にて精製し、表題化合物を得た。
収量：１．０６ｇ（２．６１ｍｍｏｌ） 収率：７３％
MS (ESI) m/z 406 [M+H]⁺
工程３ 中間体１１−Ａ化合物の合成
工程２で得られた化合物（１．０６ｇ，２．６１ｍｍｏｌ）をＴＨＦ（６ｍＬ）及びメタノール（６ｍＬ）の混合溶媒に溶解し、２Ｎ 水酸化ナトリウム水溶液（２．６ｍＬ）を加え、室温で１時間半撹拌した。減圧下で溶媒を除去した後、得られた残渣に１Ｎ 塩酸水溶液（１．２ｍＬ）及び水（１０ｍＬ）を加えることで生じた沈殿物を濾過した。得られた沈殿物を水で洗浄して、乾燥することで表題化合物を得た。
収量：９２３ｍｇ（２．４５ｍｍｏｌ） 収率：９４％
MS (ESI) m/z 378 [M+H]⁺

Intermediate 11-A Synthesis of 2-[[4- (4,5-difluoro-2-methoxy-phenyl) phenoxy] methyl] thiazole-4-carboxylic acid Step 1 4- (4,5-Difluoro Synthesis of 2-methoxy-phenyl) phenol 1-Bromo-4,5-difluoro-2-methoxy-benzene (1.0 g, 4.5 mmol), 4- (4,4,5,5-tetramethyl-1 , 3,2-dioxaborolan-2-yl) phenol (1.09 g, 4.93 mmol), PdCl ₂ (dppf) (328 mg, 0.448 mmol) and sodium carbonate (1.51 g, 11.2 mmol) in 1,4 -It added to the mixed solution (40 mL, v / v = 4/1) of dioxane and water, and stirred at 100 degreeC for 1 hour. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel chromatography (hexane / ethyl acetate) to obtain the title compound.
Yield: 1.13 g (3.56 mmol) Yield: 79%
Step 2 Synthesis of ethyl 2-[[4- (4,5-difluoro-2-methoxy-phenyl) phenoxy] methyl] thiazole-4-carboxylate Compound obtained in Step 1 (1.13 mg, 3.56 mmol) And ethyl 2-bromomethylthiazole-4-carboxylate (979 mg, 3.92 mmol) were dissolved in DMF (35 mL), potassium carbonate (1.20 g, 8.90 mmol) was added, and the mixture was stirred at room temperature for 58 hours. The reaction mixture was diluted with ethyl acetate, washed with water, aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After removing the solvent medium under reduced pressure, the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound.
Yield: 1.06 g (2.61 mmol) Yield: 73%
MS (ESI) m / z 406 [M + H] ⁺
Step 3 Synthesis of Intermediate 11-A Compound The compound obtained in Step 2 (1.06 g, 2.61 mmol) was dissolved in a mixed solvent of THF (6 mL) and methanol (6 mL), and 2N aqueous sodium hydroxide solution (2 6 mL) and stirred at room temperature for 1.5 hours. After removing the solvent under reduced pressure, 1N aqueous hydrochloric acid (1.2 mL) and water (10 mL) were added to the resulting residue, and the resulting precipitate was filtered. The obtained precipitate was washed with water and dried to obtain the title compound.
Yield: 923 mg (2.45 mmol) Yield: 94%
MS (ESI) m / z 378 [M + H] ⁺

中間体１１−Ｂ 2-[[4-(4,5-ジフルオロ-2-メトキシ-フェニル)フェノキシ]メチル]チアゾール-4-カルボニルクロリドの合成
中間体１１−Ａ（１５０ｍｇ，０．３９７ｍｍｏｌ）に塩化チオニル（２．００ｍＬ）を加えＤＭＦを少量滴下し、５５℃で４５分撹拌した。室温に冷却した後、減圧下で溶媒を除去し、表題化合物を得た。

Intermediate 11-B Synthesis of 2-[[4- (4,5-difluoro-2-methoxy-phenyl) phenoxy] methyl] thiazole-4-carbonyl chloride Intermediate 11-A (150 mg, 0.397 mmol) was chlorinated. Thionyl (2.00 mL) was added, and a small amount of DMF was added dropwise, followed by stirring at 55 ° C. for 45 minutes. After cooling to room temperature, the solvent was removed under reduced pressure to give the title compound.

中間体１２ 2-[[4-(6,7-ジフルオロ-1H-インドール-4-イル)フェノキシ]メチル]チアゾール-4-カルボン酸の合成
工程１ 4-ブロモ-6,7-ジフルオロ-1H-インドールの合成
５−ブロモ−１，２−ジフルオロ−３−ニトロ−ベンゼン（３．００ｇ，１２．６ｍｍｏｌ）をＴＨＦ（６０ｍＬ）に溶解し、−４０℃に冷却した。その溶液に、１Ｍ ビニルマグネシウムブロマイドのＴＨＦ溶液（３８ｍＬ，３８ｍｍｏｌ）を１０分かけて加えて、−４０℃で２時間半撹拌した。反応液に酢酸エチルを加えて希釈し、有機層を飽和塩化アンモニア水溶液、水、飽和食塩水で順次洗浄後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去後、得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル）にて精製し、表題化合物を得た。
収量：８８５ｍｇ（３．９８ｍｍｏｌ） 収率： ３１．６％
工程２ 4-(6,7-ジフルオロ-1H-インドール-4-イル)フェノールの合成
工程１で得られた化合物（７００ｍｇ，２．４８ｍｍｏｌ）と４−ヒドロキシフェニルボロン酸 ピナコールエステル（５４６ｍｇ，２．４８ｍｍｏｌ）を１，４−ジオキサンと水（ｖ／ｖ＝４／１，２５ｍＬ）の混合溶媒に溶解した。その溶液に、ＰｄＣｌ₂（ｄｐｐｆ）（１８２ｍｇ，０．２４８ｍｍｏｌ）及び炭酸ナトリウム（８３８ｍｇ，６．２１ｍｍｏｌ）を加えて、１２５℃で２時間撹拌した。反応溶液を室温に冷却後、酢酸エチルを加えて希釈し、炭酸水素ナトリウム水溶液、水及び飽和食塩水で洗浄して無水硫酸ナトリウムで乾燥した。溶媒を減圧濃縮後、得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル）にて精製し、表題化合物を得た。
収量：３１９ｍｇ（１．３０ｍｍｏｌ） 収率：５３％
工程３ 2-[[4-(6,7-ジフルオロ-1H-インドール-4-イル)フェノキシ]メチル]チアゾール-4-カルボン酸エチルの合成
工程２で得られた化合物（３１９ｍｇ，１．３０ｍｍｏｌ）と中間体４−Ａの工程１で得られた化合物（３５８ｍｇ，１．４３ｍｍｏｌ）をＤＭＦ（１３ｍＬ）に溶解した。その溶液に炭酸カリウム（４４９ｍｇ，３．２５ｍｍｏｌ）を加えて、室温で２２時間撹拌した。反応溶液に酢酸エチルを加えて希釈した後、水、炭酸水素ナトリウム水溶液及び飽和食塩水にて洗浄して無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去後、得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル）にて精製し、表題化合物を得た。
収量：２３２ｍｇ（０．５６０ｍｍｏｌ） 収率：４３％
MS (ESI) m/z 415 [M+H]⁺
工程４ 中間体１２化合物の合成
工程３で得られた化合物（２３２ｍｇ，０．５６０ｍｍｏｌ）をＴＨＦ（３ｍＬ）及びメタノール（３ｍＬ）の混合溶媒に溶解し、２Ｎ 水酸化ナトリウム水溶液（０．５６ｍＬ）を加えて室温で２時間半撹拌した。減圧下溶媒を留去後、得られた残渣に１Ｎ 塩酸水溶液（１．２ｍＬ）及び水（１０ｍＬ）を加えることで生じた沈殿物を濾過した。得られた沈殿物を水で洗浄して、乾燥することで表題化合物を得た。
収量： ２１０ｍｇ（０．５４４ｍｍｏｌ） 収率： ９７％
MS (ESI) m/z 387 [M+H]⁺

Intermediate 12 Synthesis of 2-[[4- (6,7-difluoro-1H-indol-4-yl) phenoxy] methyl] thiazole-4-carboxylic acid Step 1 4-Bromo-6,7- Synthesis of difluoro-1H-indole 5-Bromo-1,2-difluoro-3-nitro-benzene (3.00 g, 12.6 mmol) was dissolved in THF (60 mL) and cooled to −40 ° C. To the solution was added 1M vinylmagnesium bromide in THF (38 mL, 38 mmol) over 10 minutes, and the mixture was stirred at −40 ° C. for 2.5 hours. Ethyl acetate was added to the reaction solution for dilution, and the organic layer was washed successively with saturated aqueous ammonium chloride solution, water and saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound.
Yield: 885 mg (3.98 mmol) Yield: 31.6%
Step 2 Synthesis of 4- (6,7-difluoro-1H-indol-4-yl) phenol The compound obtained in Step 1 (700 mg, 2.48 mmol) and 4-hydroxyphenylboronic acid pinacol ester (546 mg, 2. 48 mmol) was dissolved in a mixed solvent of 1,4-dioxane and water (v / v = 4/1, 25 mL). To the solution, PdCl ₂ (dppf) (182 mg, 0.248 mmol) and sodium carbonate (838 mg, 6.21 mmol) were added and stirred at 125 ° C. for 2 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate, washed with aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over anhydrous sodium sulfate. After the solvent was concentrated under reduced pressure, the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound.
Yield: 319 mg (1.30 mmol) Yield: 53%
Step 3 Synthesis of ethyl 2-[[4- (6,7-difluoro-1H-indol-4-yl) phenoxy] methyl] thiazole-4-carboxylate Compound obtained in Step 2 (319 mg, 1.30 mmol) The compound (358 mg, 1.43 mmol) obtained in Step 1 of Intermediate 4-A was dissolved in DMF (13 mL). To the solution was added potassium carbonate (449 mg, 3.25 mmol), and the mixture was stirred at room temperature for 22 hours. The reaction solution was diluted with ethyl acetate, washed with water, aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound.
Yield: 232 mg (0.560 mmol) Yield: 43%
MS (ESI) m / z 415 [M + H] ⁺
Step 4 Synthesis of Intermediate 12 Compound The compound obtained in Step 3 (232 mg, 0.560 mmol) was dissolved in a mixed solvent of THF (3 mL) and methanol (3 mL), and 2N aqueous sodium hydroxide solution (0.56 mL) was added. In addition, the mixture was stirred at room temperature for 2.5 hours. After evaporating the solvent under reduced pressure, the resulting precipitate was filtered by adding 1N aqueous hydrochloric acid (1.2 mL) and water (10 mL) to the resulting residue. The obtained precipitate was washed with water and dried to obtain the title compound.
Yield: 210 mg (0.544 mmol) Yield: 97%
MS (ESI) m / z 387 [M + H] ⁺

The structural formulas of the compounds obtained in the above examples are shown in Tables 1-1 and 1-2.
Table 1-1

Table 1-2

Example 1 5-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] -N- [2- (methoxyamino) -2-oxo-ethyl] -N- (2- Methoxyethyl) thiophene-3-carboxamide Step 1 Synthesis of benzyl 2- (2-methoxyethylamino) acetate 2-Methoxyethanamine (0.172 mL, 2.00 mmol) was diluted with acetonitrile (12 mL) and potassium carbonate (415 mg , 3.00 mmol) was added and cooled to −10 ° C., and benzyl 2-bromoacetate (0.329 mL, 2.10 mmol) diluted with acetonitrile (4 mL) was added dropwise and stirred overnight. The insoluble material was filtered off, and the solvent was concentrated under reduced pressure to give the title compound without purification.
MS (ESI) m / z 224 [M + H] ⁺
Step 2 Synthesis of 2-[[5-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiophene-3-carbonyl]-(2-methoxyethyl) amino] acetic acid Intermediate 1 (98.1 mg, 0.250 mmol) was added 1 drop of thionyl chloride (1 mL) and DMF, and the mixture was stirred at 50 ° C. for 30 minutes. After removing the solvent under reduced pressure, the obtained residue was dissolved in dichloromethane (2 mL), and the compound obtained in Step 1 (112 mg, 0.500 mmol) and DIPEA (0.044 mL, 0.250 mmol) were added. And stirred at room temperature for 2 hours. The reaction mixture was diluted with dichloromethane, washed successively with aqueous ammonium chloride solution, water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was dissolved in a mixed solvent of THF (1 mL) and methanol (1 mL), 1N aqueous lithium hydroxide solution (1 mL) was added under ice cooling, and the mixture was stirred at room temperature for 1 hour. . After neutralizing the reaction solution, the residue obtained by removing the solvent under reduced pressure was subjected to reverse phase HPLC using ODS as a filler, and water containing 0.1% (v / v) trifluoroacetic acid. The title compound was obtained by elution with a mixed solution of acetonitrile and lyophilization and lyophilization of the desired fraction.
Yield: 96.3 mg (0.190 mmol) Yield: 76%
MS (ESI) m / z 508 [M + H] ⁺
Step 3 Synthesis of Example 1 Compound The compound obtained in Step 1 (72.0 mg, 0.142 mmol), 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide (hereinafter, WSC) hydrochloride (32. 7 mg, 0.170 mmol), 1-hydroxybenzotriazole (hereinafter HOBt) monohydrate (26.0 mg, 0.170 mmol), methoxyamine hydrochloride (23.7 mg, 0.284 mmol), DIPEA (0. (079 mL, 0.454 mmol) and dichloromethane (2 mL) were added, and the mixture was stirred at room temperature for 3 hours. After removing the solvent under reduced pressure, the resulting residue was purified by reverse phase HPLC as in Step 2 to give the title compound.
Yield: 46.7 mg (0.0870 mmol) Yield: 61%
MS (ESI) m / z 537 (M + H) ^+
1 H NMR (400 MHz, DMSO-d ₆ ) δ 11.34-11.09 (m, 1H), 7.89-7.70 (m, 1H), 7.42-7.20 (m, 5H), 7.09 (d, J = 8.13 Hz, 2H ), 5.43-5.26 (m, 2H), 4.20-3.91 (m, 2H), 3.74-3.13 (m, 10H), 2.39 (s, 3H).

Example 2 2-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] -N- [2- (methoxyamino) -2-oxo-ethyl] -N- (4- Piperidylmethyl) thiazole-4-carboxamide Trifluoroacetate Step 1 4-[[(2-Benzyloxy-2-oxo-ethyl) amino] methyl] piperidine-1-carboxylic acid Synthesis of tert-butyl 4- (aminomethyl ) Tert-butyl piperidine-1-carboxylate (550 mg, 2.57 mmol) was dissolved in acetonitrile (4 mL), potassium carbonate (354 mg, 2.57 mmol) was added, and the mixture was cooled to -10 ° C to -15 ° C. Benzyl 2-bromoacetate (0.4 mL, 2.57 mmol) diluted with acetonitrile (1 mL) was added dropwise and stirred for 2.5 hours. The insoluble material was filtered off, and the solvent was removed under reduced pressure to give the title compound without purification.
Step 2 2-[(1-tert-Butoxycarbonyl-4-piperidyl) methyl- [2-[[4- (4,5-difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiazole-4-carbonyl] Synthesis of amino] acetic acid The compound of step 1 (1.42 g, 3.93 mmol) was dissolved in THF (15 mL), intermediate 2-B (810 mg, 1.97 mmol) and triethylamine (0.55 mL, 3.94 mmol). And stirred at room temperature for 2 hours. To the reaction solution were added 1N aqueous sodium hydroxide solution (25 mL) and methanol (25 mL), and the mixture was stirred overnight at room temperature. The reaction mixture was neutralized with 2N aqueous hydrochloric acid solution, and the solvent was removed under reduced pressure. The resulting residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 1.04 g (1.90 mmol) Yield: 96%
MS (ESI) m / z 548 (M + H) ⁺
Step 3 Synthesis of Example 2 Compound The compound obtained in Step 1 (1.04 g, 1.9 mmol) was dissolved in dichloromethane (15 mL), and WSC hydrochloride (730 mg, 3.8 mmol), methoxyamine hydrochloride (320 mg) , 3.8 mmol), HOBt.monohydrate (580 mg, 3.8 mmol) and triethylamine (0.530 mL, 3.8 mmol) were added and stirred at room temperature overnight. TFA (15 mL) was added to the residue obtained by removing the solvent under reduced pressure, and the mixture was stirred at room temperature for 1 hour. The residue obtained by removing the solvent under reduced pressure was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 530 mg (0.920 mol) Yield: 48%
MS (ESI) m / z 577 (M + H) ⁺

Example 3 2-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] -N- [2- (methoxyamino) -2-oxo-ethyl] -N- [2- (Methylamino) ethyl] thiazole-4-carboxamide trifluoroacetate step 1 Synthesis of benzyl 2- [2- [tert-butoxycarbonyl (methyl) amino] ethylamino] acetate N- (2-aminoethyl) -N- Dissolve tert-butyl methyl-carbamate (523 mg, 3.00 mmol) in acetonitrile (12 mL), add potassium carbonate (684 mg, 4.95 mmol), cool to 0 ° C., and then dilute with acetonitrile (2 mL) 2 -Benzyl bromoacetate (0.518 mL, 3.30 mmol) was added dropwise, and the mixture was stirred for 15 hours while gradually returning to room temperature. The insoluble material was filtered off, and the solvent was removed under reduced pressure to give the title compound without purification.
Yield: 849 mg
Step 2 2- [2- [tert-Butoxycarbonyl (methyl) amino] ethyl- [2-[[4- (4,5-difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiazole-4-carbonyl] Synthesis of amino] benzyl acetate The compound obtained in step 1 (161 mg, 0.500 mmol) was dissolved in dichloromethane (4 mL), and intermediate 2-B (80 mg, 0.19 mmol) and DIPEA (0.087 mL, 0. 500 mmol) was added and stirred at room temperature for 1 hour. The title compound was obtained without purification by removing the solvent under reduced pressure.
MS (ESI) m / z 698 [M + H] ⁺
Step 3 2- [2- [tert-Butoxycarbonyl (methyl) amino] ethyl- [2-[[4- (4,5-difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiazole-4-carbonyl] Synthesis of amino] acetic acid The compound obtained in Step 2 was dissolved in 1,4-dioxane (3 mL), 1N aqueous lithium hydroxide solution (0.6 mL) was added, and the mixture was stirred at room temperature for 2 hr. Furthermore, after adding 1N lithium hydroxide aqueous solution and stirring for 30 minutes, the reaction liquid was neutralized with 1N trifluoroacetic acid aqueous solution. After removing the solvent under reduced pressure, the obtained residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 81.7 mg (0.134 mmol) Yield: 71% (from step 1)
MS (ESI, m / z) 608 [M + H] ⁺
Step 3 Synthesis of Example 3 Compound The compound obtained in Step 2 (400 mg, 0.675 mmol) was dissolved in dichloromethane (7 mL), and methoxyamine hydrochloride (113 mg, 1.35 mmol), WSC hydrochloride (259 mg, 1 .35 mmol), HOBt.monohydrate (207 mg, 1.35 mmol) and DIPEA (0.470 mL, 2.70 mmol) were added and stirred at room temperature for 5 hours. After removing the solvent under reduced pressure, the obtained residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain an amide compound. The obtained amide was dissolved in dichloromethane (4 mL), TFA (2 mL) was added, and the mixture was stirred at room temperature for 1 hour. After removing the solvent under reduced pressure, the obtained residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 64.0 mg (0.0984 mmol) Yield: 15%
MS (ESI) m / z 537 (M + H) ^+
1 H NMR (400 MHz, DMSO-d ₆ ) δ 11.7-10.8 (m, 1H), 9.92-9.04 (m, 1H), 8.42-8.25 (m, 1H), 7.52-7.41 (m, 2H), 7.40 -7.32 (m, 1H), 7.24 (dd, J = 7.1, 13.0 Hz, 1H), 7.19-7.04 (m, 2H), 5.64-5.37 (m, 2H), 4.92-3.20 (m, 9H), 2.95 -2.76 (m, 6H).

Example 4 2-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] -N- [2- (methoxyamino) -2-oxo-ethyl] -N- (2- Pyrrolidin-1-ylethyl) thiazole-4-carboxamide trifluoroacetate step 1 2-[[2-[[4- (4,5-difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiazole-4-carbonyl ]-(2-Pyrrolidin-1-ylethyl) amino] Synthesis of benzyl acetate To a solution of 2-pyrrolidin-1-ylethanamine (63 μL, 0.50 mmol) in acetonitrile (4 mL), potassium carbonate (69 mg, 0.50 mmol) After cooling to −10 ° C. to −15 ° C., benzyl 2-bromoacetate (78 μL, 0.50 mmol) diluted with acetonitrile (1 mL) was added dropwise, and gradually from −10 ° C. to −15 ° C. to room temperature. And stirred overnight. The insoluble material was filtered off, the solvent was removed under reduced pressure, and the resulting residue was dissolved in dichloromethane (4 mL) to obtain DIPEA (87 μL, 0.50 mmol) and intermediate 2-B (81 mg, 0.20 mmol). And stirred at room temperature for 1.5 hours. After removing the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound without purification.
Yield: 115 mg (0.188 mmol)
MS (ESI) m / z 638 (M + H) ⁺
Step 2 of 2-[[2-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiazol-4-carbonyl]-(2-pyrrolidin-1-ylethyl) amino] acetic acid Synthesis The compound obtained in Step 1 was dissolved in 1,4-dioxane (1 mL), 1N aqueous lithium hydroxide solution (0.3 mL) was added, and the mixture was stirred at room temperature for 40 minutes. The reaction solution was neutralized with 1N aqueous trifluoroacetic acid solution, and then the solvent was removed under reduced pressure. The obtained residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 49.8 mg (0.0753 mmol) Yield: 38% (from step 1)
MS (ESI) m / z 548 (M + H) ⁺
Step 3 Synthesis of Example 4 Compound The compound obtained in Step 2 (20 mg, 0.037 mmol) was dissolved in dichloromethane (2 mL), and WSC hydrochloride (14 mg, 0.073 mmol), methoxyamine hydrochloride (6 mg, 0 0.073 mmol), HOBt.monohydrate (11 mg, 0.073 mmol) and triethylamine (0.01 mL, 0.073 mmol) were added and stirred overnight at room temperature. After removing the solvent under reduced pressure, the obtained residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 7 mg (0.01 mmol) Yield: 27%
MS (ESI) m / z 577 (M + H) ⁺

Example 5 2-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] -N- (2-dimethylaminoethyl) -N- [2- (methoxyamino) -2- Oxo-ethyl] thiazole-4-carboxamide trifluoroacetate step 1 2-[[2-[[4- (4,5-difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiazole-4-carbonyl]- Synthesis of (2-dimethylaminoethyl) amino] acetic acid benzyl To a solution of N, N-dimethylethane-1,2-diamine (54 μL, 0.50 mmol) in acetonitrile (4 mL) was added potassium carbonate (69 mg, 0.50 mmol). In addition, after cooling to −10 ° C. to −15 ° C., benzyl 2-bromoacetate (78 μL, 0.50 mmol) diluted with acetonitrile (1 mL) was added dropwise, and gradually from −10 ° C. to −15 ° C. to room temperature. Returned and stirred overnight. The insoluble material was filtered off, and the solvent was removed under reduced pressure. The resulting residue was dissolved in dichloromethane (4 mL), and DIPEA (87 μL, 0.50 mmol) and intermediate 2-B (81 mg, 0.20 mmol) were dissolved. And stirred at room temperature for 1.5 hours. After removing the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound.
Yield: 69.0 mg (0.0108 mmol)
MS (ESI) m / z 612 (M + H) ⁺
Step 2 Synthesis of 2-[[2-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiazole-4-carbonyl]-(2-dimethylaminoethyl) amino] acetic acid The compound obtained in 1 was dissolved in 1,4-dioxane (1 mL), 1N aqueous lithium hydroxide solution (0.173 mL) was added, and the mixture was stirred at room temperature for 40 min. The reaction solution was neutralized with 1N aqueous trifluoroacetic acid solution, and then the solvent was removed under reduced pressure. The obtained residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 42.6 mg (0.0670 mmol) Yield: 33% (from step 1)
MS (ESI) m / z 522 (M + H) ^+
1 H NMR (400 MHz, DMSO-d ₆ ) δ 13.13-12.61 (m, 1H), 9.54-9.10 (m, 1H), 8.41-8.28 (m, 1H), 7.48-7.04 (m, 6H), 5.61 -5.41 (m, 2H), 4.62-4.12 (m, 2H), 4.02-3.80 (m, 2H), 3.39-3.27 (m, 2H), 2.92-2.79 (m, 6H), 2.40 (s, 3H) .
Step 2 Synthesis of Example 5 Compound The compound obtained in Step 1 (20 mg, 0.031 mmol) was dissolved in dichloromethane (2 mL), WSC hydrochloride (12 mg, 0.062 mmol), methoxyamine hydrochloride (6 mg, 0 0.062 mmol), HOBt.monohydrate (10 mg, 0.062 mmol) and triethylamine (0.009 mL, 0.062 mmol) were added and stirred at room temperature overnight. After removing the solvent under reduced pressure, the obtained residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 5 mg (0.008 mmol) Yield: 26%
MS (ESI) m / z 551 (M + H) ⁺

Example 6 5-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] -N- [2- (methoxyamino) -2-oxo-ethyl] -N- (2- Pyrrolidin-1-ylethyl) furan-2-carboxamide trifluoroacetate step 1 2-[[5-[[4- (4,5-difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] furan-2-carbonyl ]-(2-Pyrrolidin-1-ylethyl) amino] acetic acid Synthesis of trifluoroacetate The same procedure as in Step 1 of Example 4 was carried out except that intermediate 3-B (90.1 mg, (0.228 mmol) to give the title compound.
Yield: 51.7 mg (0.075 mmol) Yield: 35%
MS (ESI) m / z 531 (M + H) ⁺
Step 2 Synthesis of Example 6 Compound The compound obtained in Step 1 (20 mg, 0.031 mmol) was dissolved in dichloromethane (2 mL), and WSC hydrochloride (12 mg, 0.062 mmol), methoxyamine hydrochloride (6 mg, 0 0.062 mmol), HOBt.monohydrate (10 mg, 0.062 mmol) and triethylamine (0.009 mL, 0.062 mmol) were added and stirred at room temperature overnight. After removing the solvent under reduced pressure, the obtained residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 6 mg (0.009 mmol) Yield: 29%
MS (ESI) m / z 560 (M + H) ⁺

Example 7 5-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] -N- (2-furylmethyl) -N- [2- (methoxyamino) -2-oxo -Ethyl] furan-2-carboxamide Step 1 2-[[5-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] furan-2-carbonyl]-(2-furylmethyl ) Synthesis of amino] ethyl acetate Potassium carbonate (207 mg, 1.50 mmol) was added to a solution of 3-furylmethanamine (0.139 mL, 1.50 mmol) in acetonitrile (12 mL) and cooled to −10 ° C. to −15 ° C. Then, ethyl 2-bromoacetate (165 μL, 1.50 mmol) diluted with acetonitrile (1.5 mL) was added dropwise, and the mixture was gradually raised to room temperature and stirred overnight. The insoluble material was filtered off, and the solvent was removed under reduced pressure. One third of the resulting residue was dissolved in dichloromethane (2 mL), and DIPEA (87 μL, 0.50 mmol) and intermediate 3-B (79 mg) were dissolved. , 0.20 mmol) and stirred at room temperature for 30 minutes. After removing the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound.
MS (ESI) m / z 542 (M + H) ⁺
Step 2 Synthesis of 2-[[5-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] furan-2-carbonyl]-(2-furylmethyl) amino] acetic acid Step 1 The compound obtained in 1 was dissolved in 1,4-dioxane (1 mL), 1N aqueous lithium hydroxide solution (0.205 mL) was added, and the mixture was stirred overnight at room temperature. The reaction solution was neutralized with 1N aqueous trifluoroacetic acid solution, and then the solvent was removed under reduced pressure. The obtained residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 55.6 mg (0.108 mmol) Yield: 54%
MS (ESI) m / z 514 (M + H) ^+
1 H NMR (400 MHz, DMSO-d ₆ ) δ 7.70-6.37 (m, 11H), 5.28-5.07 (m, 2H), 4.91-4.59 (m, 2H), 4.39-3.98 (m, 2H), 2.39 (s, 3H).
Step 3 Synthesis of Example 7 Compound The compound obtained in Step 2 (20 mg, 0.039 mmol) was dissolved in dichloromethane (2 mL), and WSC hydrochloride (15 mg, 0.078 mmol), methoxyamine hydrochloride (7 mg, 0 0.078 mmol), HOBt.monohydrate (12 mg, 0.078 mmol) and triethylamine (0.011 mL, 0.078 mmol) were added and stirred at room temperature overnight. After removing the solvent under reduced pressure, the obtained residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 9 mg (0.017 mmol) Yield: 42%
MS (ESI) m / z 543 (M + H) ⁺

Example 8 2-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] -N- (2-furylmethyl) -N- [2- (methoxyamino) -2-oxo -Ethyl] thiazole-4-carboxamide Step 1 2-[[2-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiazole-4-carbonyl]-(2-furylmethyl ) Synthesis of amino] acetic acid The title compound was obtained by carrying out the same operations as in Step 1 and Step 2 of Example 7, using Intermediate 2-B instead of Intermediate 3-B.
Yield: 48.7 mg (0.0918 mmol) Yield: 46%
MS (ESI) m / z 531 (M + H) ^+
1 H NMR (400 MHz, DMSO-d ₆ ) δ 8.37-8.20 (m, 1H), 7.60 (d, J = 10.7 Hz, 1H), 7.46-7.00 (m, 6H), 6.47-6.30 (m, 2H ), 5.61-5.42 (m, 2H), 5.05-4.66 (m, 2H), 4.50-4.02 (m, 2H), 2.39 (s, 3H).
Step 2 Synthesis of Example 8 Compound The compound obtained in Step 1 (20 mg, 0.038 mmol) was dissolved in dichloromethane (2 mL), and WSC hydrochloride (15 mg, 0.076 mmol), methoxyamine hydrochloride (7 mg, 0 0.076 mmol), HOBt.monohydrate (12 mg, 0.076 mmol) and triethylamine (0.011 mL, 0.076 mmol) were added and stirred at room temperature overnight. After removing the solvent under reduced pressure, the obtained residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 8 mg (0.014 mmol) Yield: 38%
MS (ESI) m / z 560 (M + H) ⁺

Example 9 2-[[4- [4,5-Difluoro-2- (trideuteriomethoxy) phenyl] phenoxy] methyl] -N- (2-dimethylaminoethyl) -N- [2- (methoxyamino) 2-Oxo-ethyl] thiazole-4-carboxamide trifluoroacetate step 1 2-[[2-[[4- [4,5-difluoro-2- (triduteriomethoxy) phenyl] phenoxy] methyl] thiazole -4-Carbonyl]-(2-dimethylaminoethyl) amino] acetic acid Synthesis of trifluoroacetate salt The same procedure as in Step 1 and Step 2 of Example 5 was repeated except that Intermediate 4-B was replaced with Intermediate 4-B. To give the title compound.
Yield: 66.5 mg (0.107 mmol) Yield: 53%
MS (ESI) m / z 509 (M + H) ^+
1 H NMR (400 MHz, DMSO-d ₆ ) δ 9.50-9.03 (m, 1H), 8.46-8.25 (m, 1H), 7.60-6.98 (m, 6H), 5.65-5.35 (m, 2H), 4.67 -3.64 (m, 6H), 3.03-2.74 (m, 6H).
Step 2 Synthesis of Example 9 Compound The compound obtained in Step 1 (25.0 mg, 0.0455 mmol) was dissolved in dichloromethane (1 mL), and methoxyamine hydrochloride (7.60 mg, 0.0910 mmol), WSC hydrochloride (17.4 mg, 0.091 mmol), HOBt.monohydrate (13.9 mg, 0.0910 mmol) and DIPEA (0.032 mL, 0.182 mmol) were added and stirred at room temperature for 65 hours. After removing the solvent under reduced pressure, the obtained residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 23.0 mg (0.0353 mmol) Yield: 78%
MS (ESI) m / z 538 (M + H) ^+
1 H NMR (400 MHz, DMSO-d ₆ ) δ11.56-10.91 (m, 1H), 8.54-8.22 (m, 3H), 7.45-7.06 (m, 6H), 5.64-5.41 (m, 2H), 4.86-3.12 (m, 7H), 2.65-2.56 (m, 3H), 2.40 (s, 3H).

Example 10 2-[[4- [4,5-Difluoro-2- (methoxymethyl) benzothiophen-7-yl] phenoxy] methyl] -N- (2-dimethylaminoethyl) -N- [2- ( Methoxyamino) -2-oxo-ethyl] thiazole-4-carboxamide trifluoroacetate step 1 2-[[2-[[4- [4,5-difluoro-2- (methoxymethyl) benzothiophen-7-yl Synthesis of [phenoxy] methyl] thiazole-4-carbonyl]-(2-dimethylaminoethyl) amino] benzyl acetate N, N-dimethylaminoethylamine (44.1 mg, 0.5 mmol) was dissolved in acetonitrile (1.0 mL). Potassium carbonate (104 mg, 0.55 mmol) was added and cooled to 0 ° C. To the solution, benzyl 2-bromoacetate (126 mg, 0.55 mmol) was added and stirred at room temperature for 15 hours while naturally heating. The insoluble material was filtered off, the solvent was removed under reduced pressure, and the resulting residue was diluted with dichloromethane (4 mL), and DIPEA (60 μL, 0.34 mmol) and intermediate 7-B (100 mg, 0.22 mmol) were added. And stirred at room temperature for 1.5 hours. The title compound was obtained without purification by removing the solvent under reduced pressure.
MS (ESI) m / z 666 (M + H) ⁺
Step 2 2-[[2-[[4- [4,5-Difluoro-2- (methoxymethyl) benzothiophen-7-yl] phenoxy] methyl] thiazole-4-carbonyl]-(2-dimethylaminoethyl) Amino] acetic acid Synthesis of trifluoroacetic acid salt The compound obtained in step 1 was dissolved in a mixed solvent of THF (2 mL) and methanol (0.5 mL), and 1N aqueous sodium hydroxide solution (1 mL) was added, Stir for hours. The reaction solution was neutralized with 1N aqueous hydrochloric acid solution, and the solvent was removed under reduced pressure. The obtained residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 38.0 mg (0.055 mmol) Yield: 26% (from step 1)
MS (ESI) m / z 576 (M + H) ^+
1 H NMR (400 MHz, DMSO-d ₆ ) δ 13.00-12.78 (m, 1H), 9.43-9.04 (m, 1H), 8.42-8.32 (m, 1H), 7.74-7.64 (m, 2H), 7.58 (s, 1H), 7.55-7.47 (m, 1H), 7.28-7.21 (m, 2H), 5.63-5.48 (m, 2H), 4.73 (s, 2H), 4.63-3.44 (m, 6H), 3.34 (s, 3H), 2.90-2.80 (m, 6H).
Step 3 Synthesis of Example 10 Compound The compound obtained in Step 2 (35 mg, 0.049 mmol) was dissolved in dichloromethane (1 mL), and WSC hydrochloride (28 mg, 0.15 mmol), HOBt • monohydrate (19 mg) , 0.13 mmol), methoxyamine hydrochloride (16 mg, 0.20 mmol) and DIPEA (40 μL, 0.23 mmol) were added and stirred at room temperature for 3 days. After removing the solvent under reduced pressure, the obtained residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 28 mg (0.039 mmol) Yield: 80%
MS (ESI) m / z 605 (M + H) ^+
1 H NMR (400 MHz, DMSO-d ₆ ) δ 11.49-11.24 (m, 1H), 9.39-9.08 (m, 1H), 8.41-8.28 (m, 1H), 7.73-7.66 (m, 2H), 7.58 (s, 1H), 7.54-7.46 (m, 1H), 7.30-7.20 (m, 2H), 5.63-5.47 (m, 2H), 4.72 (s, 2H), 4.43-3.36 (m, 9H), 3.34 (s, 3H), 2.91-2.81 (m, 6H).

Example 11 2-[[4- [4,5-Difluoro-2- (methoxymethyl) benzothiophen-7-yl] phenoxy] methyl] -N- [2- (methoxyamino) -2-oxo-ethyl] -N- (2-pyrrolidin-1-ylethyl) thiazole-4-carboxamide trifluoroacetate step 1 2-[[2-[[4- [4,5-difluoro-2- (methoxymethyl) benzothiophene-7 Synthesis of benzyl-yl] phenoxy] methyl] thiazol-4-carbonyl]-(2-pyrrolidin-1-ylethyl) amino] acetate 2- (2-pyrrolidin-1-ylethyl obtained in Step 1 of Example 4 Amino) benzyl acetate was diluted with dichloromethane (4 mL), DIPEA (60 μL, 0.34 mmol) and intermediate 7-B (100 mg, 0.22 mmol) were added, and the mixture was stirred at room temperature for 1.5 hours. The title compound was obtained without purification by removing the solvent under reduced pressure.
MS (ESI) m / z 692 (M + H) ⁺
Step 2 2-[[2-[[4- [4,5-Difluoro-2- (methoxymethyl) benzothiophen-7-yl] phenoxy] methyl] thiazole-4-carbonyl]-(2-dimethylaminoethyl) Amino] acetic acid Synthesis of trifluoroacetic acid salt The compound obtained in step 1 was dissolved in a mixed solvent of THF (2 mL) and methanol (0.5 mL), and 1N aqueous sodium hydroxide solution (1 mL) was added, Stir for hours. The reaction solution was neutralized with 1N aqueous hydrochloric acid solution, and the solvent was removed under reduced pressure. The obtained residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 47.0 mg (0.066 mmol) Yield: 24% (from step 1)
MS (ESI) m / z 602 (M + H) ^+
1 H NMR (400 MHz, DMSO-d ₆ ) δ 13.03-12.70 (m, 1H), 9.50-9.27 (m, 1H), 8.40-8.34 (m, 1H), 7.73-7.61 (m, 2H), 7.57 (s, 1H), 7.56-7.47 (m, 1H), 7.29-7.22 (m, 2H), 5.62-5.49 (m, 2H), 4.73 (s, 2H), 4.64-3.37 (m, 8H), 3.34 (s, 3H), 3.16-3.02 (m, 2H), 2.08-1.76 (m, 4H).
Step 3 Synthesis of Example 11 Compound The compound obtained in Step 2 (40 mg, 0.056 mmol) was dissolved in dichloromethane (1 mL), and WSC hydrochloride (28 mg, 0.15 mmol), HOBt • monohydrate (19 mg) , 0.13 mmol), methoxyamine hydrochloride (16.0 mg, 0.20 mmol) and DIPEA (40 μL, 0.23 mmol) were added, and the mixture was stirred at room temperature for 3 days. After removing the solvent under reduced pressure, the obtained residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 31 mg (0.042 mmol) Yield: 74%
MS (ESI) m / z 631 (M + H) ^+
1 H NMR (400 MHz, DMSO-d ₆ ) δ 11.47-11.27 (m, 1H), 9.60-9.32 (m, 1H), 8.40-8.28 (m, 1H), 7.74-7.64 (m, 2H), 7.58 (s, 1H), 7.54-7.46 (m, 1H), 7.30-7.20 (m, 2H), 5.63-5.46 (m, 2H), 4.73 (s, 2H), 4.45-3.36 (m, 11H), 3.34 (s, 3H), 3.15-3.01 (m, 2H), 2.09-1.78 (m, 4H).

Example 12 2-[[4- (4,5-Difluoro-3-methyl-benzofuran-7-yl) phenoxy] methyl] -N- (2-dimethylaminoethyl) -N- [2- (methoxyamino) 2-Oxo-ethyl] thiazole-4-carboxamide trifluoroacetate step 1 2-[[2-[[4- (4,5-difluoro-3-methyl-benzofuran-7-yl) phenoxy] methyl] thiazole Synthesis of -4-carbonyl]-(2-dimethylaminoethyl) amino] acetic acid benzyl 2- (2-dimethylaminoethylamino) acetic acid benzyl (84 mg, 0.36 mmol) obtained in Step 1 of Example 5 was added to dichloromethane. (2 mL), DIPEA (0.070 mL, 0.40 mmol) and intermediate 5-B (80 mg, 0.19 mmol) were added and stirred at room temperature for 30 minutes. The title compound was obtained without purification by removing the solvent under reduced pressure.
MS (ESI) m / z 620 [M + H] ⁺
Step 2 2-[[2-[[4- (4,5-Difluoro-3-methyl-benzofuran-7-yl) phenoxy] methyl] thiazole-4-carbonyl]-(2-dimethylaminoethyl) amino] acetic acid Synthesis of Trifluoroacetate The compound obtained in Step 1 was dissolved in 1,4-dioxane (3 mL), 1N aqueous lithium hydroxide solution (0.71 mL) was added, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was neutralized with 1N aqueous trifluoroacetic acid solution, and then the solvent was removed under reduced pressure. The obtained residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 44.1 mg (0.0686 mmol) Yield: 36%
MS (ESI) m / z 530 (M + H) ⁺
Step 3 Synthesis of Example 12 Compound The compound obtained in Step 2 (25.0 mg, 0.0442 mmol) was dissolved in dichloromethane (1 mL), and methoxyamine hydrochloride (7.37 mg, 0.0883 mmol), WSCI hydrochloride (16.9 mg, 0.0883 mmol), HOBt.monohydrate (13.5 mg, 0.0883 mmol) and DIPEA (0.031 mL, 0.177 mmol) were added and stirred at room temperature for 65 hours. After removing the solvent under reduced pressure, the obtained residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 26.6 mg (0.0395 mmol) Yield: 90%
MS (ESI) m / z 559 (M + H) ^+
1 H NMR (400 MHz, DMSO-d ₆ ) δ 11.51-10.90 (m, 1H), 9.48-8.92 (m, 1H), 8.42-8.24 (m, 1H), 7.95-7.76 (m, 3H), 7.65 -7.52 (m, 1H), 7.28-7.15 (m, 2H), 5.65-5.46 (m, 2H), 4.61-3.23 (m, 9H), 2.95-2.79 (m, 6H), 2.39-2.29 (m, 3H).

Example 13 2-[[4- (4,5-Difluoro-3-methyl-benzofuran-7-yl) phenoxy] methyl] -N- [2- (methoxyamino) -2-oxo-ethyl] -N- (2-Pyrrolidin-1-ylethyl) thiazole-4-carboxamide trifluoroacetate step 1 2-[[2-[[4- (4,5-Difluoro-3-methyl-benzofuran-7-yl) phenoxy] methyl ] Thiazol-4-carbonyl]-(2-pyrrolidin-1-ylethyl) amino] acetic acid Synthesis of trifluoroacetate The same procedure as in Step 1 of Example 4 was carried out except that intermediate 5-B was replaced with intermediate 5-B. By using B, the title compound was obtained.
Yield: 47.6 mg (0.0710 mmol) Yield: 30%
MS (ESI) m / z 556 (M + H) ^+
1 H NMR (400 MHz, DMSO-d ₆ ) δ 12.95-12.78 (m, 1H), 9.46-9.23 (m, 1H), 8.40-8.32 (m, 1H), 7.95-7.76 (m, 3H), 7.63 -7.54 (m, 1H), 7.28-7.15 (m, 2H), 5.62-5.46 (m, 2H), 4.67-4.12 (m, 2H), 4.04-3.80 (m, 2H), 3.71-2.76 (m, 6H), 2.35 (s, 3H), 2.08-1.77 (m, 4H).
Step 2 Synthesis of Example 13 Compound The compound obtained in Step 1 (25.0 mg, 0.0423 mmol) was dissolved in dichloromethane (1 mL), and methoxyamine hydrochloride (7.07 mg, 0.0846 mmol), WSC hydrochloride (16.2 mg, 0.0846 mmol), HOBt • monohydrate (13.0 mg, 0.0846 mmol) and DIPEA (0.029 mL, 0.169 mmol) were added and stirred at room temperature for 65 hours. After removing the solvent under reduced pressure, the obtained residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 23.5 mg (0.0336 mmol) Yield: 80%
MS (ESI) m / z 585 (M + H) ^+
1 H NMR (400 MHz, DMSO-d ₆ ) δ 11.60-10.88 (m, 1H), 9.68-9.29 (m, 1H), 8.40-8.27 (m, 1H), 7.95-7.80 (m, 3H), 7.72 -7.50 (m, 1H), 7.27-7.16 (m, 2H), 5.66-5.47 (m, 2H), 4.91-3.36 (m, 11H), 3.15-3.01 (m, 2H), 2.38-2.29 (m, 3H), 2.10-1.77 (m, 4H).

Example 14 2-[[4- (4,5-Difluorobenzothiophen-7-yl) phenoxy] methyl] -N- [2- (methoxyamino) -2-oxo-ethyl] -N- (2-pyrrolidine 1-ylethyl) thiazole-4-carboxamide trifluoroacetate step 1 2-[[2-[[4- (4,5-difluorobenzothiophen-7-yl) phenoxy] methyl] thiazole-4-carbonyl]- Synthesis of (2-pyrrolidin-1-ylethyl) amino] acetic acid trifluoroacetate salt The same procedure as in Step 4 of Example 4 was carried out using Intermediate 6-B instead of Intermediate 2-B. The title compound was obtained.
Yield: 37.4 mg (0.0556 mmol) Yield: 28%
MS (ESI) m / z 558 (M + H) ^+
1 H NMR (400 MHz, DMSO-d ₆ ) δ 9.56-9.29 (m, 1H), 8.42-8.30 (m, 1H), 8.01 (d, J = 5.6 Hz, 1H), 7.76-7.60 (m, 3H ), 7.60-7.48 (m, 1H), 7.32-7.20 (m, 2H), 5.63-5.49 (m, 2H), 4.69-4.13 (m, 2H), 4.04-3.78 (m, 2H), 3.64-3.02 (m, 6H), 2.11-1.74 (m, 4H).
Step 2 Synthesis of Example 14 Compound The compound obtained in Step 1 (25.0 mg, 0.0372 mmol) was dissolved in dichloromethane (1 mL), and methoxyamine hydrochloride (6.21 mg, 0.0744 mmol), WSC hydrochloride (14.3 mg, 0.0744 mmol), HOBt • monohydrate (11.4 mg, 0.0744 mmol) and DIPEA (0.026 mL, 0.149 mmol) were added and stirred at room temperature for 65 hours. After removing the solvent under reduced pressure, the obtained residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 18.8 mg (0.0268 mmol) Yield: 72%
MS (ESI) m / z 587 (M + H) ^+
1 H NMR (400 MHz, DMSO-d ₆ ) δ 11.29 (s, 1H), 9.43 (s, 1H), 8.41-8.28 (m, 1H), 8.01 (d, J = 5.6 Hz, 1H), 7.78- 7.70 (m, 2H), 7.65 (d, J = 5.6 Hz, 1H), 7.58-7.49 (m, 1H), 7.29-7.20 (m, 2H), 5.64-5.48 (m, 2H), 4.44-3.36 ( m, 11H), 3.14-3.04 (m, 2H), 2.10-1.80 (m, 4H).

Example 15 N- [2- (cyanoamino) -2-oxo-ethyl] -5-[[4- (4,5-difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] -N- (2-methoxy Ethyl) furan-2-carboxamide Step 1 2-[[5-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] furan-2-carbonyl]-(2-methoxyethyl) Synthesis of amino] acetic acid One drop of thionyl chloride (1 mL) and DMF was added to Intermediate 3-A (94.1 mg, 0.250 mmol), and the mixture was stirred at 50 ° C. for 30 minutes. After removing the solvent under reduced pressure, the obtained residue was dissolved in dichloromethane (2 mL) and DIPEA (0.044 mL, 0.250 mmol) and the compound obtained in Step 1 of Example 1 (112 mg, 0.500 mmol). ) In dichloromethane (2 mL) was added under ice cooling, and the mixture was stirred overnight at room temperature. Dichloromethane was added to the reaction solution for dilution, washed with 1N aqueous hydrochloric acid solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and then dried over anhydrous magnesium sulfate. The residue obtained by removing the solvent under reduced pressure was dissolved in a mixed solvent of THF (2 mL) and methanol (2 mL), 1N aqueous lithium hydroxide solution (1.0 mL) was added, and the mixture was stirred at room temperature for 30 min. After neutralizing the reaction solution, the solvent was removed under reduced pressure. The obtained residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 97.5 mg (0.198 mmol) Yield: 79%
MS (ESI) m / z 492 (M + H) ⁺
Step 2 Synthesis of Example 15 Compound The compound obtained in Step 1 (70.0 mg, 0.142 mmol) was dissolved in dichloromethane (2 mL), and WSC hydrochloride (30.0 mg, 0.156 mmol), HOBt · monohydrate The Japanese product (23.9 mg, 0.156 mmol), cyanoamine (12.0 mg, 0.284 mmol) and DIPEA (0.052 mL, 0.300 mmol) were added and stirred at room temperature overnight. After removing the solvent under reduced pressure, the obtained residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 47.5 mg (0.0921 mmol) Yield: 65%
MS (ESI) m / z 516 (M + H) ^+
1 H NMR (400 MHz, DMSO-d ₆ ) δ 7.40-7.25 (m, 4H), 7.16-6.99 (m, 3H), 6.77 (s, 1H), 5.31-5.04 (m, 2H), 4.65-4.06 (m, 2H), 3.92-3.44 (m, 4H), 3.22 (s, 3H), 2.39 (s, 3H).

Example 16 2-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] -N- [2- (methoxyamino) -2-oxo-ethyl] -N- (2- Pyridylmethyl) thiazole-4-carboxamide trifluoroacetate step 1 Synthesis of benzyl 2- (2-pyridylmethylamino) acetate 2-Pyridylmethanamine (1.61 g, 14.9 mmol) was dissolved in acetonitrile (80 mL), Potassium carbonate (5.14 g, 37.2 mmol) was added and cooled to 0 ° C. To the solution was added benzyl bromoacetate (2.56 mL, 16.4 mmol), and the mixture was gradually raised to room temperature and stirred overnight. The insoluble material was filtered off, and the solvent was removed under reduced pressure to give the title compound without purification.
Yield: 3.92g
MS (ESI) m / z 257 (M + H) ⁺
Step 2 2-[[2-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiazole-4-carbonyl]-(2-pyridylmethyl) amino] acetic acid trifluoroacetate Intermediate 2-B (400 mg, 0.971 mmol) was dissolved in dichloromethane (10 mL) and cooled to 0 ° C. To the solution were added the compound obtained in Step 1 (448 mg, 1.75 mmol) and DIPEA (0.42 mL, 2.43 mmol), and the mixture was stirred for 64 hours while gradually warming to room temperature. After removing the solvent under reduced pressure, the resulting residue was purified by silica gel chromatography (dichloromethane: methanol) to obtain a residue. The obtained residue was dissolved in a mixed solvent of THF (4 mL) and methanol (4 mL), 2N aqueous sodium hydroxide solution (1.5 mL) was added, and the mixture was stirred at room temperature for 2 hr. The reaction solution was neutralized with 1N hydrochloric acid, and then the solvent was removed under reduced pressure. The obtained residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 560 mg (0.854 mmol) Yield: 88%
MS (ESI) m / z 542 (M + H) ⁺
Step 3 Synthesis of Example 16 Compound The compound obtained in Step 2 (25 mg, 0.044 mmol) was dissolved in dichloromethane (1 mL), and methoxyamine hydrochloride (7.3 mg, 0.089 mmol) and WSC hydrochloride (17 mg) were dissolved. , 0.089 mmol), HOBt.monohydrate (14 mg, 0.089 mmol) and DIPEA (30 μL, 0.18 mmol) were added, and the mixture was stirred at room temperature for 21 hours. After removing the solvent under reduced pressure, the obtained residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 13 mg (0.018 mmol) Yield: 41%
MS (ESI) m / z 571 (M + H) ⁺

Example 17 5-[[4- [4,5-Difluoro-2- (trideuteriomethoxy) phenyl] phenoxy] methyl] -N- [2- (methoxyamino) -2-oxo-ethyl] -N— (Tetrahydropyran-4-ylmethyl) furan-2-carboxamide Step 1 2-[[5-[[4- [4,5-Difluoro-2- (triduteriomethoxy) phenyl] phenoxy] methyl] furan-2- Synthesis of carbonyl]-(tetrahydropyran-4-ylmethyl) amino] acetic acid benzyl tetrahydropyran-4-ylmethanamine (461 mg, 4.00 mmol) was diluted with acetonitrile (35 mL) and potassium carbonate (552 mg, 4.00 mmol) After cooling to −10 ° C., benzyl 2-bromoacetate (0.627 mL, 4.00 mmol) diluted with acetonitrile (3 mL) was added dropwise, gradually raised to room temperature and stirred for 4 nights. The insoluble material was filtered off and concentrated under reduced pressure to give a residue. Part of the resulting residue (105 mg) was diluted with dichloromethane (1 mL) and DIPEA (0.87 mL, 0.50 mmol) and intermediate 8-B (51 mg, 0.13 mmol) were added, followed by 30 at room temperature. Stir for minutes. The title compound was obtained without purification by concentrating the reaction solution under reduced pressure.
MS (ESI) m / z 609 [M + H] ⁺
Step 2 2-[[5-[[4- [4,5-Difluoro-2- (triduteriomethoxy) phenyl] phenoxy] methyl] furan-2-carbonyl]-(tetrahydropyran-4-ylmethyl) amino] Synthesis of Acetic Acid The compound obtained in Step 1 was dissolved in 1,4-dioxane (3 mL), 1N aqueous lithium hydroxide solution (1 mL) was added, and the mixture was stirred overnight at room temperature. The reaction solution was neutralized with 1N trifluoroacetic acid and the organic solvent was distilled off under reduced pressure. The resulting residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 52.2 mg (0.145 mmol) Yield: 73% (from step 1)
MS (ESI) m / z 519 [M + H] ^+
1 H NMR (400 MHz, DMSO-d ₆ ) δ 7.49-7.31 (m, 3H), 7.24 (dd, J = 13.0, 7.1 Hz, 1H), 7.18-6.93 (m, 3H), 6.83-6.70 (m , 1H), 5.25-5.05 (m, 2H), 4.47-4.04 (m, 2H), 3.87-3.10 (m, 6H), 1.97-1.80 (m, 1H), 1.62-1.46 (m, 2H), 1.29 -1.06 (m, 2H).
Step 3 Synthesis of Example 17 Compound The compound obtained in Step 2 (25 mg, 0.048 mmol) was dissolved in dichloromethane (1 mL), and methoxyamine hydrochloride (8.1 mg, 0.096 mmol) and WSC hydrochloride (18 mg) were dissolved. , 0.096 mmol), HOBt.monohydrate (15 mg, 0.096 mmol) and DIPEA (34 μL, 0.19 mmol) were added, and the mixture was stirred at room temperature for 21 hours. After removing the solvent under reduced pressure, the obtained residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 20 mg (0.037 mmol) Yield: 77%
MS (ESI) m / z 548 (M + H) ⁺

Example 18 2-[[4- [4,5-Difluoro-2- (trideuteriomethoxy) phenyl] phenoxy] methyl] -N- [2- (methoxyamino) -2-oxo-ethyl] -N- [[3-Methyl-1,2,4-oxadiazol-5-yl) methyl] thiazole-4-carboxamide Step 1 2-[(3-Methyl-1,2,4-oxadiazol-5-yl ) Synthesis of methylamino] ethyl acetate Glycine ethyl ester hydrochloride (68.5 mg, 0.491 mmol) was dissolved in acetonitrile (4 mL), potassium carbonate (204 mg, 1.47 mmol) was added, and the mixture was cooled to 0 ° C. 5- (Chloromethyl) -3-methyl-1,2,4-oxadiazole (65.0 mg, 0.491 mmol) diluted with acetonitrile (1 mL) and sodium iodide (74 mg, 0.49 mmol) were added. The mixture was stirred for 16 hours while gradually returning to room temperature. The insoluble material was filtered off, and the solvent was evaporated under reduced pressure to give the title compound without purification.
Yield: 122mg
MS (ESI) m / z 200 [M + H] ⁺
Step 2 2-[[2-[[4- [4,5-Difluoro-2- (trideuteriomethoxy) phenyl] phenoxy] methyl] thiazole-4-carbonyl]-[(3-methyl-1,2, Synthesis of 4-oxadiazol-5-yl) methyl] amino] acetic acid The compound obtained in Step 1 (80 mg, 0.40 mmol) was dissolved in dichloromethane (2 mL), and intermediate 4-B (80 mg, 0. 20 mmol) and DIPEA (0.087 mL, 0.50 mmol) were added and stirred at room temperature for 15 minutes. The compound of Step 1 (20 mg, 0.10 mmol) and DIPEA (0.030 mL, 0.17 mmol) were added and stirred. After removing the reaction solution under reduced pressure, the resulting residue was dissolved in 1,4-dioxane (3 mL), 1N aqueous lithium hydroxide solution (1 mL) was added, and the mixture was stirred at room temperature overnight. Further, 1N lithium hydroxide aqueous solution (0.8 mL) was added and stirred for 30 minutes. The reaction solution was neutralized with 1N trifluoroacetic acid aqueous solution, and the solvent was distilled off under reduced pressure to obtain the residue obtained in Example 1 Purification by reverse phase HPLC as in 2 gave the title compound.
Yield: 87.6 mg (0.164 mmol) Yield: 82%
MS (ESI) m / z 534 [M + H] ⁺
Step 3 Synthesis of Example 18 Compound The compound obtained in Step 2 (25 mg, 0.047 mmol) was dissolved in dichloromethane (1 mL), and methoxyamine hydrochloride (7.8 mg, 0.094 mmol), WSC hydrochloride (18 mg). , 0.094 mmol), HOBt.monohydrate (14 mg, 0.094 mmol) and DIPEA (33 μL, 0.19 mmol) were added, and the mixture was stirred at room temperature for 21 hours. After removing the solvent under reduced pressure, the obtained residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 20 mg (0.035 mmol) Yield: 75%
MS (ESI) m / z 563 (M + H) ⁺

Example 19 2-[[4- (4,5-Difluorobenzofuran-7-yl) phenoxy] methyl] -N- [2- (methoxyamino) -2-oxo-ethyl] -N-[(5-methyl -1,2,4-oxadiazol-3-yl) methyl] thiazole-4-carboxamide Step 1 2-[[(5-Methyl-1,2,4-oxadiazol-3-yl) methylamino] Synthesis of ethyl acetate Glycine ethyl ester hydrochloride (105 mg, 0.754 mmol) was dissolved in acetonitrile (10 mL), potassium carbonate (313 mg, 2.26 mmol) was added, and the mixture was cooled to 0 ° C. and diluted with acetonitrile (1 mL). 3- (chloromethyl) -5-methyl-1,2,4-oxadiazole (100 mg, 0.754 mmol) and sodium iodide (113 mg, 0.754 mmol) were added, and the mixture was gradually returned to room temperature. Stir overnight. The insoluble material was filtered off, and the solvent was evaporated under reduced pressure to give the title compound without purification.
Yield: 272 mg
MS (ESI) m / z 200 [M + H] ⁺
Step 2 2-[[2-[[4- (4,5-Difluorobenzofuran-7-yl) phenoxy] methyl] thiazole-4-carbonyl]-[(5-methyl-1,2,4-oxadiazole -3-yl) methyl] amino] ethyl acetate Synthesis The compound obtained in Step 1 (63 mg, 0.32 mmol) was dissolved in dichloromethane (1 mL), intermediate 9-B (51 mg, 0.13 mmol) and DIPEA (0.055 mL, 0.32 mmol) was added and stirred at room temperature for 30 minutes. After removing the reaction solution under reduced pressure, the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound.
Yield: 36 mg (0.063 mmol) Yield: 50%
MS (ESI) m / z 569 [M + H] ⁺
Step 3 2-[[2-[[4- (4,5-Difluorobenzofuran-7-yl) phenoxy] methyl] thiazole-4-carbonyl]-[(5-methyl-1,2,4-oxadiazole Synthesis of 3-yl) methyl] amino] acetic acid The compound obtained in Step 2 (36 mg, 0.063 mmol) was dissolved in 1,4-dioxane (1 mL), and 1N aqueous lithium hydroxide solution (0.101 mL) was added. The mixture was stirred overnight at room temperature. The reaction solution was neutralized with 1N aqueous trifluoroacetic acid, and the resulting residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 28.1 mg (0.0520 mmol) Yield: 82%
MS (ESI) m / z 541 [M + H] ⁺
Step 4 Synthesis of Example 19 Compound The compound obtained in Step 3 (25 mg, 0.046 mmol) was dissolved in dichloromethane (1 mL), and methoxyamine hydrochloride (8.0 mg, 0.093 mmol) and WSC hydrochloride (18 mg) were dissolved. , 0.093 mmol), HOBt · monohydrate (14 mg, 0.093 mmol) and DIPEA (32 μL, 0.19 mmol) were added, and the mixture was stirred at room temperature for 21 hours. After removing the solvent under reduced pressure, the obtained residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 21 mg (0.037 mmol) Yield: 80%
MS (ESI) m / z 570 (M + H) ⁺

Example 20 2-[[4- (4,5-Difluorobenzofuran-7-yl) phenoxy] methyl] -N- [2- (methoxyamino) -2-oxo-ethyl] -N- (oxazole-2- Ilmethyl) thiazole-4-carboxamide Step 1 Synthesis of ethyl 2- (oxazol-2-ylmethylamino) acetate To a solution of oxazol-2-ylmethanamine hydrochloride (69 mg, 0.50 mmol) in acetonitrile (3 mL) was added potassium carbonate. (173 mg, 1.25 mmol) was added and the mixture was cooled to −10 ° C. to −15 ° C., and 2-bromoethyl acetate (0.055 mL, 0.50 mmol) diluted with acetonitrile (1 mL) was added dropwise, and the mixture was gradually added to room temperature. And stirred overnight. The insoluble material was filtered off, and the solvent was evaporated under reduced pressure to give the title compound without purification.
Step 2 Synthesis of benzyl 2-[[2-[[4- (4,5-difluorobenzofuran-7-yl) phenoxy] methyl] thiazole-4-carbonyl]-(2-methoxyethyl) amino] acetate The obtained compound (77 mg, 0.32 mmol) was dissolved in dichloromethane (1 mL), intermediate 9-B (51 mg, 0.13 mmol) and DIPEA (0.055 mL, 0.32 mmol) were added, and 30 minutes at room temperature. Stir. After removing the reaction solution under reduced pressure, the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound.
Yield: 67 mg (0.11 mmol) Yield: 87%
MS (ESI) m / z 616 [M + H] ⁺
Step 3 Synthesis of 2-[[2-[[4- (4,5-Difluorobenzofuran-7-yl) phenoxy] methyl] thiazole-4-carbonyl]-(2-methoxyethyl) amino] acetic acid Obtained in Step 2 The obtained compound (67 mg, 0.11 mmol) was dissolved in 1,4-dioxane (1 mL), 1N aqueous lithium hydroxide solution (0.174 mL) was added, and the mixture was stirred overnight at room temperature. The reaction solution was neutralized with 1N aqueous trifluoroacetic acid, and the resulting residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 10.2 mg (0.0194 mmol) Yield: 18%
MS (ESI) m / z 526 [M + H] ⁺
Step 4 Synthesis of Example 20 Compound The compound obtained in Step 3 (9.0 mg, 0.017 mmol) was dissolved in dichloromethane (1 mL), methoxyamine hydrochloride (2.9 mg, 0.034 mmol), WSC hydrochloride (6.6 mg, 0.034 mmol), HOBt • monohydrate (5.2 mg, 0.034 mmol) and DIPEA (12 μL, 0.068 mmol) were added and stirred at room temperature for 54 hours. After removing the solvent under reduced pressure, the obtained residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 5.5 mg (0.0099 mmol) Yield: 58%
MS (ESI) m / z 555 (M + H) ⁺

Example 21 4-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] -N- [2- (methoxyamino) -2-oxo-ethyl] -N- (2- Methoxyethyl) thiophene-2-carboxamide Step 1 2-[[4-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiophene-2-carbonyl]-(2-methoxyethyl ) Synthesis of amino] acetic acid To intermediate 10 (51 mg, 0.13 mmol) was added thionyl chloride (0.5 mL), and the mixture was stirred at 55 ° C. for 45 minutes. After cooling to room temperature, the residue was obtained by removing the solvent under reduced pressure. The obtained residue was dissolved in dichloromethane (2.6 mL), the compound obtained in Step 1 of Example 1 (43.5 mg, 0.195 mmol) and DIPEA (0.09 mL, 0.52 mmol) were added, and room temperature was added. For 15 hours. After removing the solvent under reduced pressure, the obtained residue was dissolved in a mixed solvent of methanol (1.5 mL) and THF (1.5 mL), 1N aqueous sodium hydroxide solution (0.65 mL) was added, and the mixture was stirred at room temperature. Stir for 2.5 hours. After removing the solvent under reduced pressure, the obtained residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 51.5 mg (0.101 mmol) Yield: 78%
MS (ESI) m / z 508 (M + H) +
1H NMR (400 MHz, DMSO-d6) δ 7.80 (brs, 1H), 7.70-7.23 (m, 5H), 7.07 (d, J = 8.5 Hz, 2H), 5.14 (s, 2H), 4.45-4.04 ( m, 2H), 3.82-3.49 (m, 4H), 3.25 (s, 3H), 2.39 (s, 3H).
Step 2 Synthesis of Example 21 Compound The compound obtained in Step 2 (25 mg, 0.049 mmol) was dissolved in dichloromethane (1 mL), methoxyamine hydrochloride (8.2 mg, 0.099 mmol), WSC hydrochloride (19 mg). , 0.099 mmol), HOBt.monohydrate (15 mg, 0.099 mmol) and DIPEA (34 μL, 0.20 mmol) were added, and the mixture was stirred at room temperature for 48 hours. After removing the solvent under reduced pressure, the obtained residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 20 mg (0.038 mmol) Yield: 76%
MS (ESI) m / z 537 (M + H) ⁺

Example 22 5-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] -N- [2- (methoxyamino) -2-oxo-ethyl] -N- (pyrimidine- 2-Ilmethyl) furan-2-carboxamide Step 1 Synthesis of benzyl 2- (pyrimidin-2-ylmethylamino) acetate 1 ml), a small amount of pyrimidyl-2-carbaldehyde (162 mg, 1.50 mmol) and acetic acid were added, and the mixture was stirred overnight at room temperature. After removing the reaction solution under reduced pressure, the obtained residue was suspended in THF (10 mL), sodium triacetoxyborohydride (954 mg, 4.50 mmol) was added, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was diluted with ethyl acetate, and the organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The organic solvent was removed under reduced pressure to obtain the title compound without purification.
Yield: 271 mg
MS (ESI) m / z 258 [M + H] ⁺
Step 2 Synthesis of benzyl 2-[[5-[[4- (4,5-difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] furan-2-carbonyl]-(pyrimidin-2-ylmethyl) amino] acetate Compound of step 1 (90.0 mg, 0.500 mmol) was dissolved in dichloromethane (2 mL) and intermediate 3-B (94.8 mg, 0.240 mmol) and DIPEA (0.044 mL, 0.25 mmol) were added. Stir at room temperature for 2 hours. After removing the reaction solution under reduced pressure, the obtained residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 68.5 mg (0.111 mmol) Yield: 46%
MS (ESI) m / z 616 [M + H] ⁺
Step 3 Synthesis of 2-[[4-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiophene-2-carbonyl]-(2-methoxyethyl) amino] acetic acid Step 2 The compound (68.5 mg, 0.111 mmol) obtained in 1 was dissolved in a mixed solvent of THF (2 mL) and methanol (2 mL), and 1N lithium hydroxide aqueous solution (0.8 mL) was added under ice-cooling. Stir for hours. After neutralizing the reaction solution, the residue obtained by distilling off the solvent under reduced pressure was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 37.4 mg (0.0712 mmol) Yield: 64%
MS (ESI) m / z 526 [M + H] ^+
1 H NMR (400 MHz, DMSO-d ₆ ) δ 8.81-8.74 (m, 2H), 7.43-7.25 (m, 5H), 7.16-7.07 (m, 1H), 7.04-6.95 (m, 2H), 6.81 -6.64 (m, 1H), 5.20-5.05 (m, 2H), 5.05-4.80 (m, 2H), 4.59-4.17 (m, 2H), 2.40 (s, 3H).
Step 4 Synthesis of Example 22 Compound The compound obtained in Step 3 (25 mg, 0.048 mmol) was dissolved in dichloromethane (1 mL), and methoxyamine hydrochloride (8.0 mg, 0.095 mmol), WSC hydrochloride (18 mg). , 0.095 mmol), HOBt • monohydrate (15 mg, 0.095 mmol) and DIPEA (33 μL, 0.19 mmol) were added, and the mixture was stirred at room temperature for 48 hours. After removing the solvent under reduced pressure, the obtained residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 24 mg (0.042 mmol) Yield: 89%
MS (ESI) m / z 555 (M + H) ⁺

Example 23 2-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] -N- [2- (methoxyamino) -2-oxo-ethyl] -N-[(5 -Methyl-1,3,4-oxadiazol-2-yl) methyl] thiazole-4-carboxamide Step 1 2-[(5-Methyl-1,3,4-oxadiazol-2-yl) methylamino Synthesis of benzyl acetate (5-methyl-1,3,4-oxadiazol-2-yl) methanamine (170 mg, 1.50 mmol) was dissolved in acetonitrile (12 mL) and potassium carbonate (311 mg, 2.25 mmol) was dissolved. After cooling to −10 ° C., benzyl 2-bromoacetate (0.259 mL, 1.65 mmol) diluted with acetonitrile (3 mL) was added, and the mixture was stirred overnight while gradually returning to room temperature. The insoluble material was filtered off and concentrated under reduced pressure to give the title compound without purification.
Yield: 372 mg
MS (ESI) m / z 262 [M + H] ⁺
Step 2 2-[[2-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiazole-4-carbonyl]-[(5-methyl-1,3,4-oxa Synthesis of Diazol-2-yl) methyl] amino] benzyl acetate The compound obtained in Step 1 (124 mg, 0.475 mmol) was dissolved in dichloromethane (3 mL), and DIPEA (0.044 mL, 2.53 mmol) and intermediate Body 2-B (98.8 mg, 0.240 mmol) was added and stirred at room temperature overnight. After removing the solvent under reduced pressure, the obtained residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 56.7 mg (0.0892) Yield: 21%
MS (ESI) m / z 637 [M + H] ⁺
Step 3 2-[[2-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiazole-4-carbonyl]-[(5-methyl-1,3,4-oxa Synthesis of Diazol-2-yl) methyl] amino] acetic acid The compound obtained in Step 2 (56.7 mg, 0.0892 mmol) was dissolved in a mixed solvent of THF (2 mL) and methanol (2 mL), and ice-cooled. 1N aqueous lithium hydroxide solution (0.5 mL) was added, and the mixture was stirred at room temperature for 1 hr. After removing the solvent under reduced pressure, the obtained residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 42.7 mg (0.0781 mmol) Yield: 88%
MS (ESI) m / z 547 [M + H] ⁺
Step 4 Synthesis of Example 23 Compound The compound obtained in Step 3 (25 mg, 0.046 mmol) was dissolved in dichloromethane (1 mL), methoxyamine hydrochloride (7.6 mg, 0.092 mmol), WSC hydrochloride (18 mg). , 0.092 mmol), HOBt.monohydrate (14 mg, 0.092 mmol) and DIPEA (32 μL, 0.18 mmol) were added and stirred at room temperature for 48 hours. After removing the solvent under reduced pressure, the obtained residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 15 mg (0.026 mmol) Yield: 57%
MS (ESI) m / z 576 (M + H) ⁺

Example 24 2-[[4- (4,5-Difluoro-2-methoxy-phenyl) phenoxy] methyl] -N- [2- (methoxyamino) -2-oxo-ethyl] -N- (2-methoxy Ethyl) thiazole-4-carboxamide Step 1 2-[[2-[[4- (4,5-Difluoro-2-methoxy-phenyl) phenoxy] methyl] thiazole-4-carbonyl]-(2-methoxyethyl) amino Synthesis of benzyl acetate The compound obtained in Step 1 of Example 1 (59 mg, 0.26 mmol) was dissolved in dichloromethane (1 mL), and intermediate 11-B (51 mg, 0.13 mmol) and DIPEA (0.046 mL) were dissolved. 0.26 mmol) and stirred at room temperature for 2 days. After removing the reaction solution under reduced pressure, the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound.
Yield: 57 mg (0.098 mmol) Yield: 74%
MS (ESI) m / z 583 [M + H] ⁺
Step 2 Synthesis of 2-[[2-[[4- (4,5-Difluoro-2-methoxy-phenyl) phenoxy] methyl] thiazole-4-carbonyl]-(2-methoxyethyl) amino] acetic acid In Step 2 The obtained compound (57 mg, 0.098 mmol) was dissolved in 1,4-dioxane (1 mL), 1N aqueous lithium hydroxide solution (0.156 mL) was added, and the mixture was stirred at room temperature overnight. The reaction solution was neutralized with 1N aqueous trifluoroacetic acid, and the resulting residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 34.7 mg (0.0704 mmol) Yield: 72%
MS (ESI) m / z 493 [M + H] ^+
1 H NMR (400 MHz, DMSO-d ₆ ) δ 8.25-8.17 (m, 1H), 7.47-7.39 (m, 2H), 7.42-7.31 (m, 1H), 7.24 (dd, J = 13.0, 7.1 Hz , 1H), 7.14-7.04 (m, 2H), 5.56-5.42 (m, 2H), 4.35 (d, J = 164.8 Hz, 2H), 3.81-3.69 (m, 3H), 3.66-3.45 (m, 4H ), 3.29-3.14 (m, 3H).
Step 3 Synthesis of Example 24 Compound The compound obtained in Step 2 (33 mg, 0.068 mmol) was dissolved in dichloromethane (1 mL), and methoxyamine hydrochloride (11 mg, 0.14 mmol), WSC hydrochloride (26 mg, 0 .14 mmol), HOBt.monohydrate (10 mg, 0.068 mmol) and DIPEA (35 μL, 0.20 mmol) were added and stirred at room temperature overnight. After removing the solvent under reduced pressure, the obtained residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 27.9 mg (0.0536 mmol) Yield: 79%
MS (ESI) m / z 522 (M + H) ^+
1 H NMR (400 MHz, DMSO-d ₆ ) δ 11.25-11.05 (m, 1H), 8.28-8.15 (m, 1H), 7.54-7.30 (m, 3H), 7.25 (dd, J = 13.0, 7.0 Hz , 1H), 7.18-7.05 (m, 2H), 5.58-5.40 (m, 2H), 4.41-3.95 (m, 2H), 3.87-3.10 (m, 13H).

Example 25 2-[[4- (4,5-Difluoro-2-methoxy-phenyl) phenoxy] methyl] -N- (2-furylmethyl) -N- [2- (methoxyamino) -2-oxo- Ethyl] thiazole-4-carboxamide Step 1 2-[[2-[[4- (4,5-Difluoro-2-methoxy-phenyl) phenoxy] methyl] thiazole-4-carbonyl]-(2-furylmethyl) amino Synthesis of acetic acid The title compound was obtained by carrying out the same operations as in Step 1 and Step 2 of Example 7 using Intermediate 11-B (51 mg, 0.13 mmol) instead of Intermediate 3-B. It was.
Yield: 47.1 mg (0.0916 mmol) Yield: 69%
MS (ESI) m / z 515 [M + H] ^+
1 H NMR (400 MHz, DMSO-d ₆ ) δ 8.31-8.24 (m, 1H), 7.60 (d, J = 10.2 Hz, 1H), 7.45-7.30 (m, 3H), 7.23 (dd, J = 13.0 , 7.1 Hz, 1H), 7.15-7.06 (m, 2H), 6.44-6.33 (m, 2H), 5.60-5.42 (m, 2H), 5.03-4.65 (m, 2H), 4.49-4.02 (m, 2H ), 3.75 (s, 3H).
Step 2 Synthesis of Example 25 Compound The compound obtained in Step 2 (46 mg, 0.089 mmol) was dissolved in dichloromethane (1 mL), and methoxyamine hydrochloride (15 mg, 0.18 mmol), WSC hydrochloride (34 mg, 0 .18 mmol), HOBt • monohydrate (14 mg, 0.089 mmol) and DIPEA (47 μL, 0.27 mmol) were added and stirred at room temperature overnight. After removing the solvent under reduced pressure, the obtained residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 35.6 mg (0.0656 mmol) Yield: 73%
MS (ESI) m / z 544 (M + H) ^+
1 H NMR (400 MHz, DMSO-d ₆ ) δ 11.28-11.06 (m, 1H), 8.27 (s, 1H), 7.68-7.54 (m, 1H), 7.50-7.30 (m, 3H), 7.24 (dd , J = 13.0, 7.1 Hz, 1H), 7.19-7.07 (m, 2H), 6.47-6.30 (m, 2H), 5.60-5.40 (m, 2H), 5.11-4.60 (m, 2H), 4.33-3.82 (m, 2H), 3.76 (s, 3H), 3.64-3.50 (m, 3H).

Example 26 2-[[4- (6,7-Difluoro-1H-indol-4-yl) phenoxy] methyl] -N- [2- (methoxyamino) -2-oxo-ethyl] -N- (2 -Methoxyethyl) thiazole-4-carboxamide Step 1 2-[[2-[[4- (6,7-Difluoro-1H-indol-4-yl) phenoxy] methyl] thiazole-4-carbonyl]-(2- Synthesis of Methoxyethyl) amino] acetic acid Intermediate 12 (70.0 mg, 0.181 mmol) and the compound obtained in Step 1 of Example 1 (80.7 mg, 0.362 mmol) were dissolved in dichloromethane (2 mL), WSC hydrochloride (69.5 mg, 0.362 mmol), HOBt.monohydrate (55.5 mg, 0.362 mmol) and DIPEA (0.095 mL, 0.54 mmol) were added and stirred at room temperature for 64 hours. After the solvent was concentrated under reduced pressure, the resulting residue was purified by silica gel column chromatography (dichloromethane / methanol) to obtain a crude product. The obtained crude product was dissolved in THF (1 mL) and methanol (1 mL), 2N aqueous sodium hydroxide solution (0.27 mL) was added, and the mixture was stirred at room temperature for 2 hr. After neutralizing the reaction solution, the organic solvent was distilled off under reduced pressure, and the resulting residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 56.4 mg (0.112 mmol) Yield: 62%
MS (ESI) m / z 502 [M + H] ^+
1 H NMR (400 MHz, DMSO-d ₆ ) δ 11.91 (s, 1H), 8.30-8.17 (m, 1H), 7.69-7.54 (m, 2H), 7.53-7.45 (m, 1H), 7.27-7.15 (m, 2H), 7.14-7.02 (m, 1H), 6.64-6.53 (m, 1H), 5.62-5.44 (m, 2H), 4.63-4.09 (m, 2H), 3.82-3.49 (m, 4H) , 3.27-3.16 (m, 3H).
Step 2 Synthesis of Example 26 Compound The compound obtained in Step 1 (19 mg, 0.038 mmol) was dissolved in dichloromethane (1 mL), and methoxyamine hydrochloride (6.4 mg, 0.77 mmol), WSC hydrochloride (15 mg). , 0.077 mmol), HOBt • monohydrate (6.0 mg, 0.038 mmol) and DIPEA (20 μL, 0.12 mmol) were added and stirred overnight at room temperature. After removing the solvent under reduced pressure, the obtained residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 14.1 mg (0.0265 mmol) Yield: 69%
MS (ESI) m / z 531 (M + H) ^+
1 H NMR (400 MHz, DMSO-d ₆ ) δ 11.92 (s, 1H), 11.28-10.99 (m, 1H), 8.33-8.12 (m, 1H), 7.73-7.57 (m, 2H), 7.49 (t , J = 2.8 Hz, 1H), 7.30-6.99 (m, 3H), 6.69-6.50 (m, 1H), 5.63-5.42 (m, 2H), 4.45-3.93 (m, 2H), 3.84-3.36 (m , 7H), 3.30-3.17 (m, 3H).

Example 27 2-[[4- (6,7-Difluoro-1-methyl-indol-4-yl) phenoxy] methyl] -N- [2- (methoxyamino) -2-oxo-ethyl] -N- (2-Methoxyethyl) thiazole-4-carboxamide Step 1 2-[[2-[[4- (6,7-Difluoro-1-methyl-indol-4-yl) phenoxy] methyl] thiazole-4-carbonyl] -(2-Methoxyethyl) amino] acetic acid The compound of Example 26, step 1 (36.4 mg, 0.0726 mmol) was dissolved in THF (2 mL) and sodium hydride (60% assay, 29 mg, 0.73 mmol). And stirred at room temperature for 30 minutes. An excess amount of methyl iodide was added to the solution, and the mixture was stirred at room temperature for 1.5 hours. After concentrating the solvent under reduced pressure, the obtained residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 33.4 mg (0.0648 mmol) Yield: 89%
MS (ESI) m / z 516 [M + H] ^+
1 H NMR (400 MHz, DMSO-d ₆ ) δ 8.28-8.19 (m, 1H), 7.64-7.54 (m, 2H), 7.45-7.37 (m, 1H), 7.27-7.13 (m, 2H), 7.13 -7.02 (m, 1H), 6.60-6.43 (m, 1H), 5.60-5.43 (m, 2H), 4.63-4.09 (m, 2H), 4.05-3.92 (m, 3H), 3.82-3.49 (m, 4H), 3.27-3.14 (m, 3H).
Step 2 Synthesis of Compound of Example 26 The compound obtained in Step 1 (19 mg, 0.037 mmol) was dissolved in dichloromethane (1 mL), and methoxyamine hydrochloride (6.1 mg, 0.73 mmol), WSC hydrochloride (14 mg). , 0.073 mmol), HOBt.monohydrate (5.6 mg, 0.037 mmol) and DIPEA (19 μL, 0.11 mmol) were added and stirred at room temperature overnight. After removing the solvent under reduced pressure, the obtained residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 15.4 mg (0.0283 mmol) Yield: 77%
MS (ESI) m / z 545 (M + H) ^+
1 H NMR (400 MHz, DMSO-d ₆ ) δ 11.28-11.05 (m, 1H), 8.28-8.14 (m, 1H), 7.65-7.52 (m, 2H), 7.42 (d, J = 3.2 Hz, 1H ), 7.20 (t, J = 8.2 Hz, 2H), 7.09 (dd, J = 12.2, 6.8 Hz, 1H), 6.60-6.47 (m, 1H), 5.60-5.45 (m, 2H), 4.44-3.31 ( m, 12H), 3.29-3.17 (m, 3H).

The structural formulas and physical property values of the compounds obtained in the above Examples are shown in Tables 2-1 to 2-6.
Table 2-1.

表２−３

表２−４

表２−５

表２−６

Table 2-2

Table 2-3

Table 2-4

Table 2-5

Table 2-6

Test Example 1 Measurement of glycogen synthase activity A human GYS1 expression plasmid (pCDNA3.1 (+)-hGYS1) was constructed by the following method. Human GYS1 gene was amplified by PCR using human MTC Panel I (Takara Bio, 636742) as a template and a cloning primer (Forward Primer: ATGCCTTTAAACCGCAC, Reverse Primer: TTAGTTTACGCTCTCTCGC). The amplified human GYS1 sequence was used as a template, a restriction enzyme sequence was added by PCR using subcloning primers (Forward Primer: CCCTCGAGACCATGCCTTTAAACCGCACTTT, Reverse Primer: GGTCTAGATTTAGTTTACGCTCTCTCGCCCAG), and in vitro 20 The human GYS1 gene was introduced into the Xho I site and Xba I site.

Glycogen synthase was prepared by the following method. HEK293T cells derived from human kidney were seeded in a dish (Thermo Fisher Scientific, 168381) using DMEM (Nacalai Tesque, 0845874) medium containing 10% FBS, cultured overnight, and then Lipofectamine LTX (Invitrogen, 15338). -100) was used to transfect the human GYS1 expression vector according to the attached manual. After culturing at 37 ° C. under 5% CO ₂ conditions for 2 days, a lysis buffer (50 mM Tris-HCl (pH 8.0), 10 mM EDTA, 2 mM EGTA, 100 mM NaF, 1 mM PMSF, 1 mM DTT, 1 × Complete (Roche, 1873580) And then homogenized, the mixture was centrifuged at 16000 × g and 4 ° C. for 15 minutes, and the precipitate fraction was re-dissolved by adding a lysis buffer and used for evaluation as glycogen synthase.

The activity of glycogen synthase was measured by the following method. In a polystyrene 96-well plate, 30 mM glycylglycine (pH 7.3), 40 mM KCl, 20 mM MgCl ₂ , 9.2% DMSO containing various concentrations of test compound, 10 mM Glucose-6-phosphate (Sigma Aldrich) , G7879) was added at 12 μL / well.
Next, 30 mM glycylglycine (pH 7.3), 4.3 mg / mL glycogen (Sigma Aldrich, G8876), 21.6 mM UDP-glucose (Sigma Aldrich, U4625), 21.6 mM phosphoenolpyruvate A substrate solution containing (Sigma Aldrich, P0564) and 4.05 mM NADH (Sigma Aldrich, N8129) was added at 18 μL / well.
In addition, 50 mM Tris-HCl (pH 8.0), 27 mM DTT (Nacalai Tesque, 14128-04), 0.2 mg / mL bovine serum albumin, 0.17 mg / mL glycogen synthase, 1.5 μL pyruvate An enzyme solution containing a kinase / lactate dehydrogenase solution (Sigma Aldrich, P0294) was added at 18 μL / well to obtain a reaction solution. After incubating the reaction solution (Examples 1 and 15 were 37 ° C., 20 minutes, Examples 2 to 14 were 37 ° C. and 25 minutes), absorbance at 340 nm was measured using Benchmark Plus (Bio-Rad Laboratories).

The activity of the test compound was calculated by the following method. The absorbance change (ΔA340) was calculated by subtracting the absorbance at 340 nm of the reaction solution containing the compound and DMSO from the absorbance at 340 nm of the reaction solution containing only DMSO but not the compound. WO / 2011/058154 Example 1 The relative activity (%) at various concentrations of the test compound was calculated by setting ΔA340 of a reaction solution containing 10 μM of the compound at the final concentration to 100%. The compound concentration causing an increase in relative activity of 50% was defined as EC ₅₀ and calculated by XLfit (idbs). The results are shown in Table 3.
Table 3

Test Example 2 PPAR-α Activity Measurement The activity of PPAR-α was measured according to a previous report (THE JOURNAL OF BIOLOGICAL CHEMISTRY Vol.270, No.22: 12953-12956, 1995).
The plasmid used for measuring the activity of PPAR-α was constructed as follows. As the luciferase expression plasmid (UASx5-TK-Luc), a plasmid in which a sequence in which five GAL4-binding sequences of yeast were linked in tandem upstream of the thymidine kinase promoter of pTAL-Luc (Takara Bio, 6252-1) was used. . The PPAR-α receptor expression plasmid (hGR-GAL4-hPPARα) is the N-terminal region (1-76aa) of human GR at the Not I site and Sal I site of pExchange-1 Core Vector (Invitrogen, 21176), and GAL4 DNA of yeast. A binding region (1-147aa) and a PPARα ligand binding region (167-468aa) were used.

The reporter assay was performed by the following method using CV-1 cells derived from African green monkey kidney. CV-1 cells were seeded in a 96-well plate (Thermo Fisher Scientific, 4938) at a density of 2 × 10 ⁴ cells / well using DMEM (Nacalai Tesque, 0845874) medium containing 10% FBS. ° C., after 2 hours incubation under 5% CO _2, were transfected with plasmids. Transfection was performed using Lipofectamine LTX (Invitrogen, 15338-100) according to the attached manual. The plasmid solution was prepared by adding a mixed solution of luciferase expression plasmid and PPAR-α receptor expression plasmid to OPTI-MEM I (Invitrogen, 11058-021). After transfection, a test compound was added and cultured at 37 ° C. in the presence of 5% CO ₂ for 18 to 20 hours. After completion of the culture, luciferase activity was measured by Luminescence JNR (ATTO) using Bright-Glo (Promega, E2620).
The PPAR-α induction magnification of the test compound was calculated by the following method. 100 (A / B) where A is the maximum PPAR-α activity at 3 μM, 10 μM, 30 μM, and 100 μM of the test compound, and B is the PPAR-α activity at 100 μM of the compound of WO / 2011/058154. ) As PPAR-α relative induction magnification (%). The results are shown in Table 4. As shown in Table 4, the PPAR-α relative induction ratios of Examples 1 to 15 were lower than those of Example 1 compound of WO / 2011/058154, and good results were obtained.
Table 4

Test Example 3 Evaluation of L6 Glycogen Accumulation Glycogen accumulation activity in skeletal muscle cells was evaluated according to the following method (ANALYTICAL BIOCHEMISTRY, Vol.261, 159-163, 1998). Rat skeletal muscle-derived L6 myoblasts (ATCC) were grown in 96-well collagen using growth medium (α-MEM medium (Nacalai Tesque, 21444-05) containing 10% FBS) at ⁴ × 10 ⁴ cells / 100 μL / well. After seeding on a coated plate (IWAKI, 4860-010) and culturing overnight at 37 ° C. and 5% CO ₂ , the culture medium is replaced with a differentiation medium (α-MEM medium containing 2% FBS) and cultured for 3 days. Thus, differentiation into myotube cells was performed. On the day of evaluation, the medium was replaced with glucose starvation medium (DMEM medium containing 0.1% BSA (Gibco, 11966)) and cultured for 4 hours, and then the test compound having a concentration twice the final evaluation concentration and 0.6% Assay medium containing DMSO (DMEM medium containing 0.1% BSA (Nacalai Tesque, 08456-65)) Replaced with 15 μL / well, and 1.9 μL of D- [U-C14] glucose (PerkinElmer, NEC042V) The assay medium containing / well was added at 15 μL / well to a final volume of 30 μL / well, and then incubated at 37 ° C. under 5% CO ₂ for 3 hours. After the incubation, the medium was removed by suction with an aspirator, washed twice with PBS at 200 μL / well, 1N NaOH was added at 50 μL / well, and cells were lysed by incubation at 60 ° C. for 10 minutes. . After returning the lysed cells to room temperature, 5 μL / well of total lysed cells and 10 mg / mg glycogen (Sigma Aldrich, G8876) were added to Multiscreen HTS (Millipore, MSFCN6B) to which 100% ethanol was added in advance at 100 μL / well. Incubation at 20 ° C. for 20 minutes was performed. After the incubation, suction with Multiscreen HTS Vacuum Manifold (Millipore) was performed, and washing was performed twice with 66% ethanol at 200 μL / well. After the ethanol remaining on the filter was completely removed by drying, 50 μL / well of MicroScint40 (Perkin Elmer) was added, and the amount of [14C] glycogen was measured by TopCount NXT (Perkin Elmer).
The activity of the test compound was calculated by the following method. The measured value (cpm) of a well containing only DMSO without a compound is A, the measured value of a well containing a compound and DMSO is B, and WO / 2011/058154 Example 1 The measured value of a well containing 30 μM of the compound at the final concentration The relative activity (%) was calculated as 100 × (B−A) / (C−A) with C. The compound concentration causing an increase in activity of 50% was defined as EC ₅₀ and calculated by XLfit (idbs).
Table 5

Claims (11)

A compound represented by the following general formula (I) or a pharmaceutically acceptable salt thereof.
Formula (I):

(In the formula, Ar ₁ is represented by any ring of the following formulas (II-1) to (II-4);

(In the formula, these rings may be the same or different and each may have one or more substituents, and the substituents are halogen atoms, hydroxyl groups, alkyl groups, acetamido groups, aminocarbonyl groups. Selected from the group consisting of an alkoxy group, a cyano group, an amino group, a monoalkylamino group, a dialkylamino group and a halogenoalkoxy group;
R ₁ represents a hydrogen atom, a halogen atom, a hydroxyl group, an alkyl group, an alkoxy group optionally substituted with deuterium, a halogenoalkoxy group or an alkylthio group optionally substituted with deuterium;
R ₂ , R ₃ , R ₄ , R ₅ , R ₆ and R ₇ are each independently a hydrogen atom, a halogen atom, a cyano group, an alkyl group which may be substituted with deuterium, a halogenoalkyl group or a hydroxyalkyl. Represents a group, an alkoxyalkyl group or an alkynyl group. )
Ar ₂ represents an aromatic heterocycle,
L represents a bond, an alkylene group or a cycloalkylene group,
X represents a hydrogen atom, a halogen atom, a hydroxyl group, a halogenoalkyl group, an alkoxy group, a cyano group, a cyanoalkoxy group, an amino group, a monoalkylamino group, a dialkylamino group, an aminocarbonyl group, a monoalkylaminocarbonyl group, a dialkylamino. A carbonyl group, an aminosulfonyl group, a monoalkylaminosulfonyl group, a dialkylaminosulfonyl group, an alkylsulfonyl group, an alkylsulfonylamino group, an alkylcarbonylamino group, a phenyl group, or one or more substituents. Represents a 5- to 7-membered heterocyclic group having at least one heteroatom selected from a nitrogen atom, an oxygen atom and a sulfur atom,
These substituents are selected from the group consisting of halogen atoms, hydroxyl groups, alkyl groups, acetamide groups, aminocarbonyl groups, alkoxy groups, cyano groups, amino groups, monoalkylamino groups, dialkylamino groups and halogenoalkoxy groups;
Z represents a cyano group or —O—R ₈ .
(In the formula, R ₈ represents an alkyl group, a hydroxyalkyl group, a halogenoalkyl group, an alkoxyalkyl group, a cyanoalkyl group or a carboxyalkyl group which may be substituted with deuterium.) In the general formula (I), the heterocyclic group in X is a furan ring, thiophene ring, oxazole ring, isoxazole ring, imidazole ring, pyrazole ring, thiazole ring, oxadiazole ring, triazole ring, pyridine ring, pyrimidine ring, The compound according to claim 1 or a pharmaceutically acceptable salt thereof represented by a pyridazine ring, a pyrazine ring, or any one of the following formulas (III-1) to (III-4):

(Wherein R ₉ and R ₁₀ are each independently represented by a hydrogen atom, an alkyl group or an alkylcarbonyl group,
n _1, n ₂ and n ₃ are represented by an integer from 0 to 2. ) In the general formula (I), Ar ₂ is a furan ring, a thiophene ring or a thiazole ring, or a compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2. In general formula (I), Ar < ₁ > has a substituent of 1 or 2, and they are a halogen atom, The compound or its pharmaceutically acceptable salt of any one of Claims 1-3. In the formulas (II-1) to (II-4) of the general formula (I),
R ₁ is represented by a hydrogen atom, a halogen atom, an alkoxy group having 1 to 3 carbon atoms which may be substituted with deuterium, or an alkylthio group having 1 to 3 carbon atoms which may be substituted with deuterium;
R ₂ and R ₄ are represented by a hydrogen atom, a halogen atom or an alkyl group having 1 to 3 carbon atoms,
R ₃ and R ₅ are each represented by a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, a cyano group, or a methoxymethyl group,
The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein R ₆ and R ₇ are each represented by a hydrogen atom or an alkyl group having 1 to 3 carbon atoms.   The compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, wherein, in the general formula (I), L is represented by an alkylene group having 1 to 3 carbon atoms. In general formula (I), X is an alkoxy group, monoalkylamino group, dialkylamino group, furan ring, oxazole ring, oxadiazole ring, pyridine ring, pyrimidine ring, or the following formula (IV-1), Represented by either (IV-2) or (IV-3)

The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof. The compound represented by the general formula (I) is:
2-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] -N- [2- (methoxyamino) -2-oxo-ethyl] -N- (4-piperidylmethyl) Thiazole-4-carboxamide,
2-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] -N- [2- (methoxyamino) -2-oxo-ethyl] -N- [2- (methylamino ) Ethyl] thiazole-4-carboxamide,
2-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] -N- [2- (methoxyamino) -2-oxo-ethyl] -N- (2-pyrrolidine-1 -Ylethyl) thiazole-4-carboxamide,
5-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] -N- (2-furylmethyl) -N- [2- (methoxyamino) -2-oxo-ethyl] Furan-2-carboxamide,
2-[[4- [4,5-Difluoro-2- (trideuteriomethoxy) phenyl] phenoxy] methyl] -N- (2-dimethylaminoethyl) -N- [2- (methoxyamino) -2- Oxo-ethyl] thiazole-4-carboxamide,
2-[[4- (4,5-Difluoro-3-methyl-benzofuran-7-yl) phenoxy] methyl] -N- (2-dimethylaminoethyl) -N- [2- (methoxyamino) -2- Oxo-ethyl] thiazole-4-carboxamide, or
N- [2- (Cyanoamino) -2-oxo-ethyl] -5-[[4- (4,5-difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] -N- (2-methoxyethyl) furan -2-carboxamide,
The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof.   A pharmaceutical composition comprising the compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof.   A pharmaceutical composition for treating diabetes comprising the compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof.   A glycogen synthase activator comprising the compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof.