JP2010215511A - Heteroarylbenzene compound - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new compound exhibiting a diacylglycerol acyltransferase 1 (DGAT1)-inhibiting action and a medicine comprising the compound. <P>SOLUTION: The heteroarylbenzene compound is represented by formula (1) (wherein A is N or CH; R<SP>1</SP>is a hydrogen atom or a 1-8C alkyl group; and R<SP>2</SP>is a hydrogen atom, a halogen atom, a 1-6C alkyl group, or the like). The medicine comprising the compound is provided. The medicine is useful as a preventive-therapeutic agent for diseases which can be ameliorated by the DGAT1-inhibiting action, particularly, obesity, hyperlipidemia, hypertriglyceridemia, lipometabolic disorder, diabetes, arteriosclerosis and the like. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to novel heteroarylbenzene compounds having an inhibitory action on DGAT1 (diacylglycerol acyltransferase 1) and pharmaceuticals containing them as active ingredients.

DGAT1 is an enzyme that synthesizes triglyceride (neutral fat) from diacylglycerol, which is mainly expressed in the small intestine or adipose tissue. In the small intestine, glycerol and fatty acids absorbed by small intestinal epithelial cells are converted to triglyceride esters by DGAT1. Then, by the action of MTP (microsomal triglyceride transfer protein), it is incorporated as a constituent lipid of chylomicron, released into lymphatic vessels, and later transported to the liver. In fat cells, glycerol and fatty acids taken up are converted to triglyceride esters by DGAT1 and accumulated. When this process is abnormally increased, adipocytes become hypertrophic and secrete a large amount of malignant physiologically active substances (adipocytokines) such as TNFα. The secreted adipocytokine causes insulin resistance in skeletal muscle cells and hepatocytes, and the glucose uptake ability decreases and fat synthesis proceeds.
As for DGAT1, cloning of mouse and human homologues was reported one after another from 1998 (see Non-Patent Documents 1 and 2), and in 2000, DGAT1 knockout mice were analyzed as important target molecules for obesity treatment. The importance of DGAT1 was suggested (see Non-Patent Document 3). The DGAT1 knockout mice had no difference in body weight from normal mice when they were on a normal diet, and the amount of neutral fat was slightly decreased, but the amount of body fat was significantly less. In the case of a high-fat diet load, weight gain was strongly suppressed, and the fat amount in each part of the body was significantly reduced, and the neutral fat amount was also reduced.

  As described above, a substance that inhibits DGAT1 (hereinafter referred to as DGAT1 inhibitor) is effective against diseases such as obesity, hypertriglyceridemia, and impaired glucose tolerance by suppressing the production of triglyceride in the small intestine and / or adipose tissue. It is expected to be an effective therapeutic agent.

  Conventionally, certain biphenyl amino acid compounds, biphenylcarbonyl compounds, pyrimidooxazine compounds, urea compounds, and amide compounds have been reported as DGAT1 inhibitors, but there is no disclosure of the compounds of the present invention (Patent Documents 1, 2, and 5). 3, 4 and 5). In addition, structurally similar compounds have been reported, but there is no specific disclosure of the compounds of the present invention, and the uses are different from the compounds of the present invention (see Non-patent Document 4, Patent Document 6, and Patent Document 7). .

Cases S et al. Proceeding of the National Academy of Sciences of the United States of America, 95, 13018-13023, 1998 Oelkers P et al. The Journal of biologic chemistry, 273, 26765-26771, 1998 Smith SJ et al. Nature genetics, 25, 87-90, 2000 Zhili Xin et al. Journal of Medicinal Chemistry 49, 15, 4459-4469, 2006 WO07 / 016538 WO04 / 10081 WO04 / 047755 WO06 / 019020 WO06 / 082952 WO07 / 038669 WO00 / 055139

  An object of the present invention is to provide a compound having an excellent DGAT1 inhibitory action and useful as a pharmaceutical product.

  As a result of diligent research to find a compound having a DGAT1 inhibitory activity, the present inventors have achieved this object by the heteroarylbenzene compound represented by the general formula (1) or a pharmaceutically acceptable salt thereof. The present invention has been completed.

（式（１）中、
ＡはＮ又はＣＨを示し、
Ｒ^１は水素原子、又はＣ_１−８アルキル基を示し、
Ｒ^２は水素原子、ハロゲン原子、又はＣ_１−６アルキル基を示し、
Ｑはフェニル基（該フェニル基は置換されていないか、又はＣ_１−８アルキル基、Ｃ_１−６アルコキシ基（該Ｃ_１−６アルコキシ基は置換されていないか、又はＣ_１−６アルコキシ基、及びジ（Ｃ_１−６アルキル）アミノ基からなる群より選ばれる１個の基で置換されている。）、ハロゲン原子、トリフルオロメチル基、トリフルオロメトキシ基、シアノ基、ヒドロキシ基、及びＣ_１−６アルキルチオ基からなる群より同一若しくは異なって選ばれる１から３個の基で置換されている。）、ベンジル基（該ベンジル基は置換されていないか、又は１から２個のＣ_１−３アルキル基で置換されている。）、又はＣ_３−１０シクロアルキル基を示し、
ｍは０又は１を示し、
ｎは０又は１を示し、
Ｘは−Ｏ−、又は−ＮＲ^３−（式中Ｒ^３は水素原子、又はＣ_１−８アルキル基（該Ｃ_１−８アルキル基は、Ｙの炭素原子と結合して５から７員のヘテロシクリル環を形成しても良い。）を示す。）を示し、
ＹはＣ_１−８アルキレン基（該Ｃ_１−８アルキレン基は置換されていないか、又はＣ_１−６アルキル基及びヒドロキシＣ_１−６アルキル基よりなる群から同一若しくは異なって選ばれる１から２個の基で置換されており、該Ｃ_１−８アルキレン基の炭素原子のうちの１つは酸素原子によって置換されていても良く、該Ｃ_１−８アルキレン基の炭素原子のうちの１つは、その炭素原子自身を含んで形成される３から６員のシクロアルキル環、又は３から６員のヘテロシクリル環の一員となっていてもよい。）を示す。）で表されるヘテロアリールベンゼン化合物、該化合物の互変異性体、立体異性体、若しくはその薬学的に許容される塩又はそれらの溶媒和物を提供することである。
（ＩＩ）本発明の他の態様としては、式（２）

（式（２）中、
Ｑはフェニル基（該フェニル基は置換されていないか、又はＣ_１−８アルキル基、Ｃ_１−６アルコキシ基、ハロゲン原子、及びトリフルオロメチル基からなる群より同一若しくは異なって選ばれる１から３個の基で置換されている。）を示し、Ａ、Ｒ^１、Ｒ^２、Ｙは（I）で定義したとおりである。）で表される（Ｉ）に記載のヘテロアリールベンゼン化合物、該化合物の互変異性体、立体異性体、若しくはその薬学的に許容される塩又はそれらの溶媒和物を提供することである。
（ＩＩＩ）本発明の他の態様としては、式（３）

（式（３）中、Ｒ^１は水素原子、又はＣ_１−３アルキル基を表し、Ａ、Ｒ^２、Ｑは（ＩＩ）で定義したとおりである。）で表される（ＩＩ）に記載のヘテロアリールベンゼン化合物、該化合物の互変異性体、立体異性体、若しくはその薬学的に許容される塩又はそれらの溶媒和物を提供することである。
（ＩＶ）本発明の他の態様としては、
ＡがＮであり、Ｒ^２が水素原子であり、Ｒ^１が水素原子であり、Ｑは（ＩＩＩ）で定義したとおりである、（ＩＩＩ）に記載のヘテロアリールベンゼン化合物、該化合物の互変異性体、立体異性体、若しくはその薬学的に許容される塩又はそれらの溶媒和物を提供することである。
（Ｖ）本発明の他の態様としては、
ＡがＣＨであり、Ｒ^２が水素原子であり、Ｒ^１が水素原子であり、Ｑは（ＩＩＩ）で定義したとおりである、（ＩＩＩ）に記載のヘテロアリールベンゼン化合物、該化合物の互変異性体、立体異性体、若しくはその薬学的に許容される塩又はそれらの溶媒和物を提供することである。
（ＶＩ）本発明の他の態様としては、
式（４）

（式（４）中、Ｒ^１は水素原子、又はＣ_１−３アルキル基を表し、ｐは１〜４の整数を示し、Ａ、Ｒ^２、Ｑは（ＩＩ）で定義したとおりである。）で表される（ＩＩ）に記載のヘテロアリールベンゼン化合物、該化合物の互変異性体、立体異性体、若しくはその薬学的に許容される塩又はそれらの溶媒和物を提供することである。
（ＶＩＩ）本発明の他の態様としては、
ＡがＮであり、Ｒ^２が水素原子であり、Ｒ^１が水素原子であり、ｐが１、又は２であり、Ｑは（ＶＩ）で定義したとおりである、（ＶＩ）に記載のヘテロアリールベンゼン化合物、該化合物の互変異性体、立体異性体、若しくはその薬学的に許容される塩又はそれらの溶媒和物を提供することである。
（ＶＩＩＩ）本発明の他の態様としては、
ＡがＣＨであり、Ｒ^２が水素原子であり、Ｒ^１が水素原子であり、ｐが１、又は２であり、Ｑは（ＶＩ）で定義したとおりである、（ＶＩ）に記載のヘテロアリールベンゼン化合物、該化合物の互変異性体、立体異性体、若しくはその薬学的に許容される塩又はそれらの溶媒和物を提供することである。
（ＩＸ）本発明の他の態様としては、
式（５）

（式（５）中、
Ｑはフェニル基（該フェニル基は置換されていないか、又はＣ_１−８アルキル基、Ｃ_１−６アルコキシ基、ハロゲン原子、及びトリフルオロメチル基からなる群より同一若しくは異なって選ばれる１から３個の基で置換されている。）を示し、Ａ、Ｒ^１、Ｒ^２、Ｙは（Ｉ）で定義したとおりである。）で表される（Ｉ）に記載のヘテロアリールベンゼン化合物、該化合物の互変異性体、立体異性体、若しくはその薬学的に許容される塩又はそれらの溶媒和物を提供することである。
（Ｘ）本発明の他の態様としては、
式（６）

（式（６）中、Ｒ^１は水素原子、又はＣ_１−３アルキル基を表し、Ａ、Ｒ^２、Ｑは（ＩＸ）で定義したとおりである。）で表される（ＩＸ）に記載のヘテロアリールベンゼン化合物、該化合物の互変異性体、立体異性体、若しくはその薬学的に許容される塩又はそれらの溶媒和物を提供することである。
（ＸＩ）本発明の他の態様としては、
ＡがＮであり、Ｒ^２が水素原子であり、Ｒ^１が水素原子であり、Ｑは（Ｘ）で定義したとおりである、（Ｘ）に記載のヘテロアリールベンゼン化合物、該化合物の互変異性体、立体異性体、若しくはその薬学的に許容される塩又はそれらの溶媒和物を提供することである。
（ＸＩＩ）本発明の他の態様としては、
ＡがＣＨであり、Ｒ^２が水素原子であり、Ｒ^１が水素原子であり、Ｑは（Ｘ）で定義したとおりである、（Ｘ）に記載のヘテロアリールベンゼン化合物、該化合物の互変異性体、立体異性体、若しくはその薬学的に許容される塩又はそれらの溶媒和物を提供することである。
（ＸＩＩＩ）本発明の他の態様としては、
式（７）

（式（７）中、Ｒ^１は水素原子、又はＣ_１−３アルキル基を表し、ｐは１〜４の整数を表し、Ａ、Ｒ^２、Ｑは（ＩＸ）で定義したとおりである。）で表される（ＩＸ）に記載のヘテロアリールベンゼン化合物、該化合物の互変異性体、立体異性体、若しくはその薬学的に許容される塩又はそれらの溶媒和物を提供することである。
（ＸＩＶ）本発明の他の態様としては、
ＡがＮであり、Ｒ^２が水素原子であり、Ｒ^１が水素原子であり、ｐが１、又は２であり、Ｑは（ＸＩＩＩ）で定義したとおりである（ＸＩＩＩ）に記載のヘテロアリールベンゼン化合物、該化合物の互変異性体、立体異性体、若しくはその薬学的に許容される塩又はそれらの溶媒和物を提供することである。
（ＸＶ）本発明の他の態様としては、
ＡがＣＨであり、Ｒ^２が水素原子であり、Ｒ^１が水素原子であり、ｐが１、又は２であり、Ｑは（ＸＩＩＩ）で定義したとおりである（ＸＩＩＩ）に記載のヘテロアリールベンゼン化合物、該化合物の互変異性体、立体異性体、若しくはその薬学的に許容される塩又はそれらの溶媒和物を提供することである。
（ＸＶＩ）本発明の他の態様としては、
以下に記載のヘテロアリールベンゼン化合物、該化合物の互変異性体、立体異性体、若しくはその薬学的に許容される塩又はそれらの溶媒和物を提供することである。
２−（｛５−［４−（｛［２−メトキシ−５−（トリフルオロメチル）フェニル］カルバモイル｝アミノ）フェニル］ピリジン−２−イル｝オキシ）−２−メチルプロピオン酸
３−｛［５−（４−｛［（２，３−ジメトキシフェニル）カルバモイル］アミノ｝フェニル）ピリジン−２−イル］アミノ｝−２，２−ジメチルプロピオン酸
３−｛［５−（４−｛［（２，４−ジメチルフェニル）カルバモイル］アミノ｝フェニル）ピリジン−２−イル］アミノ｝−２，２−ジメチルプロピオン酸
３−｛［５−（４−｛［（２−クロロフェニル）カルバモイル］アミノ｝フェニル）ピリジン−２−イル］アミノ｝−２，２−ジメチルプロピオン酸
３−｛［５−（４−｛［（２，３−ジメトキシフェニル）カルバモイル］アミノ｝フェニル）ピリジン−２−イル］オキシ｝−２，２−ジメチルプロピオン酸
３−｛［５−（４−｛［（２−クロロフェニル）カルバモイル］アミノ｝フェニル）ピリジン−２−イル］オキシ｝−２，２−ジメチルプロピオン酸
３−｛［５−（４−｛［（３−エチルフェニル）カルバモイル］アミノ｝フェニル）ピリジン−２−イル］オキシ｝−２，２−ジメチルプロピオン酸
３−｛［５−（４−｛［（３，５−ジメチルフェニル）カルバモイル］アミノ｝フェニル）ピリジン−２−イル］オキシ｝−２，２−ジメチルプロピオン酸
３−｛［５−（４−｛［（２，４−ジメチルフェニル）カルバモイル］アミノ｝フェニル）ピリジン−２−イル］オキシ｝−２，２−ジメチルプロピオン酸
３−｛［５−（４−｛［（２−エチルフェニル）カルバモイル］アミノ｝フェニル）ピリジン−２−イル］オキシ｝−２，２−ジメチルプロピオン酸
（ＸＶＩＩ）本発明の他の態様としては、
以下に記載のヘテロアリールベンゼン化合物、該化合物の互変異性体、立体異性体、若しくはその薬学的に許容される塩又はそれらの溶媒和物を提供することである。
１−（｛［５−（４−｛［（２，４−ジメチルフェニル）カルバモイル］アミノ｝フェニル）ピリジン−２−イル］アミノ｝メチル）シクロプロパンカルボン酸
１−（｛［５−（４−｛［（２−クロロフェニル）カルバモイル］アミノ｝フェニル）ピリジン−２−イル］アミノ｝メチル）シクロプロパンカルボン酸
１−（｛［５−（４−｛［（２，４−ジメチルフェニル）カルバモイル］アミノ｝フェニル）ピリジン−２−イル］オキシ｝メチル）シクロプロパンカルボン酸
１−（｛［５−（４−｛［（２，４−ジメチルフェニル）カルバモイル］アミノ｝フェニル）ピリジン−２−イル］オキシ｝メチル）シクロブタンカルボン酸
１−（｛［５−（４−｛［（２−クロロ−４−フルオロフェニル）カルバモイル］アミノ｝フェニル）ピリジン−２−イル］オキシ｝メチル）シクロプロパンカルボン酸
１−（｛［５−（４−｛［（３，５−ジメチルフェニル）カルバモイル］アミノ｝フェニル）ピリジン−２−イル］オキシ｝メチル）シクロプロパンカルボン酸
１−［（｛５−［４−（｛［２−メトキシ−５−（トリフルオロメチル）フェニル］カルバモイル｝アミノ）フェニル］ピリジン−２−イル｝オキシ）メチル］シクロプロパンカルボン酸
１−（｛［５−（４−｛［（２，３−ジメトキシフェニル）カルバモイル］アミノ｝フェニル）ピリジン−２−イル］オキシ｝メチル）シクロプロパンカルボン酸
１−（｛［５−（４−｛［（２−クロロフェニル）カルバモイル］アミノ｝フェニル）ピリジン−２−イル］オキシ｝メチル）シクロプロパンカルボン酸
１−（｛［５−（４−｛［（２−エチルフェニル）カルバモイル］アミノ｝フェニル）ピリジン−２−イル］オキシ｝メチル）シクロプロパンカルボン酸
１−（｛［５−（４−｛［（２−メトキシ−５−メチルフェニル）カルバモイル］アミノ｝フェニル）ピリミジン−２−イル］オキシ｝メチル）シクロプロパンカルボン酸
（ＸＶＩＩＩ）本発明の他の態様としては、（Ｉ）から（ＸＶＩＩ）のいずれかに記載のヘテロアリールベンゼン化合物、該化合物の互変異性体、立体異性体、若しくはその薬学的に許容される塩又はそれらの溶媒和物を有効成分として含有する医薬を提供することである。
（ＸＩＸ）本発明の他の態様としては、ＤＧＡＴ１阻害作用により改善しうる疾患又は状態を予防若しくは治療するための（ＸＶＩＩＩ）に記載の医薬を提供することである。
（ＸＸ）本発明の他の態様としては、肥満症、高脂血症、高トリグリセライド血症、脂質代謝異常疾患、糖尿病、動脈硬化症、または、肥満に起因する高脂血症、高トリグリセライド血症、脂質代謝異常疾患、糖尿病、動脈硬化症、もしくは、高血圧症の予防・治療薬である（ＸＩＸ）に記載の医薬を提供することである。 That is, the present invention
(I) Formula (1)

(In the formula (1),
A represents N or CH;
R ¹ represents a hydrogen atom or a C _1-8 alkyl group,
R ² represents a hydrogen atom, a halogen atom, or a C _1-6 alkyl group,
Q is a phenyl group (the phenyl group is not substituted, or a C _1-8 alkyl group, a C _1-6 alkoxy group (the C _1-6 alkoxy group is not substituted, or a C _1-6 alkoxy group). And a group selected from the group consisting of a di (C _1-6 alkyl) amino group), a halogen atom, a trifluoromethyl group, a trifluoromethoxy group, a cyano group, a hydroxy group, And a 1 to 3 group selected from the group consisting of the same or different from the group consisting of C _1-6 alkylthio groups, a benzyl group (the benzyl group is unsubstituted or has 1 to 2 groups). Substituted with a C _1-3 alkyl group), or a C _3-10 cycloalkyl group,
m represents 0 or 1,
n represents 0 or 1,
X is —O—, or —NR ³ — (wherein R ³ is a hydrogen atom, or a C _1-8 alkyl group (the C _1-8 alkyl group is bonded to a carbon atom of Y to form a 5- to 7-membered group). A heterocyclyl ring may be formed.)
Y is a C _1-8 alkylene group (the C _1-8 alkylene group is unsubstituted or selected from the group consisting of a C _1-6 alkyl group and a hydroxy C _1-6 alkyl group, which are the same or different) Substituted with two groups, one of the carbon atoms of the C _1-8 alkylene group may be substituted by an oxygen atom, and one of the carbon atoms of the C _1-8 alkylene group. One may be a member of a 3- to 6-membered cycloalkyl ring formed by including the carbon atom itself, or a 3- to 6-membered heterocyclyl ring. ), A tautomer, a stereoisomer, or a pharmaceutically acceptable salt thereof, or a solvate thereof.
(II) As another aspect of the present invention, the compound represented by formula (2)

(In the formula (2),
Q is a phenyl group (the phenyl group is unsubstituted or selected from the group consisting of a C _1-8 alkyl group, a C _1-6 alkoxy group, a halogen atom, and a trifluoromethyl group, which is the same or different. And A, R ¹ , R ² and Y are as defined in (I). And a tautomer, a stereoisomer, or a pharmaceutically acceptable salt thereof, or a solvate thereof.
(III) In another embodiment of the present invention, the compound represented by formula (3)

(In formula (3), R ¹ represents a hydrogen atom or a C _1-3 alkyl group, and A, R ² , and Q are as defined in (II)). A heteroarylbenzene compound, a tautomer, stereoisomer or pharmaceutically acceptable salt of the compound or a solvate thereof.
(IV) As another aspect of the present invention,
The heteroarylbenzene compound according to (III), wherein A is N, R ² is a hydrogen atom, R ¹ is a hydrogen atom, and Q is as defined in (III), tautomerism of the compound It is to provide a sex isomer, a stereoisomer, or a pharmaceutically acceptable salt thereof, or a solvate thereof.
(V) As another aspect of the present invention,
The heteroarylbenzene compound according to (III), wherein A is CH, R ² is a hydrogen atom, R ¹ is a hydrogen atom, and Q is as defined in (III), tautomerism of the compound It is to provide a sex isomer, a stereoisomer, or a pharmaceutically acceptable salt thereof, or a solvate thereof.
(VI) As another aspect of the present invention,
Formula (4)

(In formula (4), R ¹ represents a hydrogen atom or a C _1-3 alkyl group, p represents an integer of 1 to 4, and A, R ² and Q are as defined in (II)). And a tautomer, stereoisomer, or pharmaceutically acceptable salt of the compound or a solvate thereof.
(VII) As another aspect of the present invention,
A heterocycle according to (VI), wherein A is N, R ² is a hydrogen atom, R ¹ is a hydrogen atom, p is 1 or 2, and Q is as defined in (VI). It is to provide an arylbenzene compound, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt thereof, or a solvate thereof.
(VIII) As another aspect of the present invention,
The heterocycle according to (VI), wherein A is CH, R ² is a hydrogen atom, R ¹ is a hydrogen atom, p is 1 or 2, and Q is as defined in (VI). It is to provide an arylbenzene compound, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt thereof, or a solvate thereof.
(IX) As another aspect of the present invention,
Formula (5)

(In Formula (5),
Q is a phenyl group (the phenyl group is unsubstituted or selected from the group consisting of a C _1-8 alkyl group, a C _1-6 alkoxy group, a halogen atom, and a trifluoromethyl group, which is the same or different. A, R ¹ , R ² , Y are as defined in (I). And a tautomer, a stereoisomer, or a pharmaceutically acceptable salt thereof, or a solvate thereof.
(X) As another aspect of the present invention,
Formula (6)

(In Formula (6), R ¹ represents a hydrogen atom or a C _1-3 alkyl group, and A, R ² , and Q are as defined in (IX)). A heteroarylbenzene compound, a tautomer, stereoisomer or pharmaceutically acceptable salt of the compound or a solvate thereof.
(XI) As another aspect of the present invention,
A heteroarylbenzene compound according to (X), wherein A is N, R ² is a hydrogen atom, R ¹ is a hydrogen atom, and Q is as defined in (X), tautomerism of the compound It is to provide a sex isomer, a stereoisomer, or a pharmaceutically acceptable salt thereof, or a solvate thereof.
(XII) As another aspect of the present invention,
A heteroarylbenzene compound according to (X), wherein A is CH, R ² is a hydrogen atom, R ¹ is a hydrogen atom, and Q is as defined in (X), tautomerism of the compound It is to provide a sex isomer, a stereoisomer, or a pharmaceutically acceptable salt thereof, or a solvate thereof.
(XIII) As another aspect of the present invention,
Formula (7)

(In formula (7), R ¹ represents a hydrogen atom or a C _1-3 alkyl group, p represents an integer of 1 to 4, and A, R ² and Q are as defined in (IX). (IX), a tautomer, a stereoisomer, or a pharmaceutically acceptable salt thereof, or a solvate thereof.
(XIV) As another aspect of the present invention,
A heteroaryl according to (XIII), wherein A is N, R ² is a hydrogen atom, R ¹ is a hydrogen atom, p is 1 or 2, and Q is as defined in (XIII) It is to provide a benzene compound, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt thereof, or a solvate thereof.
(XV) As another aspect of the present invention,
A heteroaryl according to (XIII), wherein A is CH, R ² is a hydrogen atom, R ¹ is a hydrogen atom, p is 1 or 2, and Q is as defined in (XIII) It is to provide a benzene compound, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt thereof, or a solvate thereof.
(XVI) As another aspect of the present invention,
It is to provide a heteroarylbenzene compound, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt thereof or a solvate thereof described below.
2-({5- [4-({[2-methoxy-5- (trifluoromethyl) phenyl] carbamoyl} amino) phenyl] pyridin-2-yl} oxy) -2-methylpropionic acid 3-{[5 -(4-{[(2,3-dimethoxyphenyl) carbamoyl] amino} phenyl) pyridin-2-yl] amino} -2,2-dimethylpropionic acid 3-{[5- (4-{[(2, 4-dimethylphenyl) carbamoyl] amino} phenyl) pyridin-2-yl] amino} -2,2-dimethylpropionic acid 3-{[5- (4-{[(2-chlorophenyl) carbamoyl] amino} phenyl) pyridine -2-yl] amino} -2,2-dimethylpropionic acid 3-{[5- (4-{[(2,3-dimethoxyphenyl) carbamoyl] amino} phenyl) pyridine 2-yl] oxy} -2,2-dimethylpropionic acid 3-{[5- (4-{[(2-chlorophenyl) carbamoyl] amino} phenyl) pyridin-2-yl] oxy} -2,2-dimethyl 3-{[5- (4-{[(3-Ethylphenyl) carbamoyl] amino} phenyl) pyridin-2-yl] oxy} -2,2-dimethylpropionic acid 3-{[5- (4- {[(3,5-dimethylphenyl) carbamoyl] amino} phenyl) pyridin-2-yl] oxy} -2,2-dimethylpropionic acid 3-{[5- (4-{[(2,4-dimethylphenyl) ) Carbamoyl] amino} phenyl) pyridin-2-yl] oxy} -2,2-dimethylpropionic acid 3-{[5- (4-{[(2-ethylphenyl) carbamoyl] amino} f Other aspects of) pyridin-2-yl] oxy} -2,2-dimethyl-propionic acid (XVII) The present invention,
It is to provide a heteroarylbenzene compound, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt thereof or a solvate thereof described below.
1-({[5- (4-{[(2,4-Dimethylphenyl) carbamoyl] amino} phenyl) pyridin-2-yl] amino} methyl) cyclopropanecarboxylic acid 1-({[5- (4- {[(2-Chlorophenyl) carbamoyl] amino} phenyl) pyridin-2-yl] amino} methyl) cyclopropanecarboxylic acid 1-({[5- (4-{[(2,4-dimethylphenyl) carbamoyl] amino } Phenyl) pyridin-2-yl] oxy} methyl) cyclopropanecarboxylic acid 1-({[5- (4-{[(2,4-dimethylphenyl) carbamoyl] amino} phenyl) pyridin-2-yl] oxy } Methyl) cyclobutanecarboxylic acid 1-({[5- (4-{[(2-chloro-4-fluorophenyl) carbamoyl] amino} phenyl) pyridy -2-yl] oxy} methyl) cyclopropanecarboxylic acid 1-({[5- (4-{[(3,5-dimethylphenyl) carbamoyl] amino} phenyl) pyridin-2-yl] oxy} methyl) cyclo 1-[({5- [4-({[2-Methoxy-5- (trifluoromethyl) phenyl] carbamoyl} amino) phenyl] pyridin-2-yl} oxy) methyl] cyclopropanecarboxylic acid 1 -({[5- (4-{[(2,3-dimethoxyphenyl) carbamoyl] amino} phenyl) pyridin-2-yl] oxy} methyl) cyclopropanecarboxylic acid 1-({[5- (4- { [(2-Chlorophenyl) carbamoyl] amino} phenyl) pyridin-2-yl] oxy} methyl) cyclopropanecarboxylic acid 1-({[5- ( 1-({[5- (4-{[(2-methoxy-5-methylphenyl)-{[(2-ethylphenyl) carbamoyl] amino} phenyl) pyridin-2-yl] oxy} methyl) cyclopropanecarboxylic acid ) Carbamoyl] amino} phenyl) pyrimidin-2-yl] oxy} methyl) cyclopropanecarboxylic acid (XVIII) In another embodiment of the present invention, the heteroarylbenzene compound according to any one of (I) to (XVII) It is intended to provide a medicament containing, as an active ingredient, a tautomer, stereoisomer or pharmaceutically acceptable salt of the compound or a solvate thereof.
(XIX) Another aspect of the present invention is to provide a medicament according to (XVIII) for preventing or treating a disease or condition that can be improved by a DGAT1 inhibitory action.
(XX) Other aspects of the present invention include obesity, hyperlipidemia, hypertriglycerideemia, dyslipidemia, diabetes, arteriosclerosis, or hyperlipidemia resulting from obesity, hypertriglyceride blood It is to provide a medicine described in (XIX), which is a prophylactic / therapeutic agent for diseases, dyslipidemia, diabetes, arteriosclerosis, or hypertension.

  According to the present invention, a compound having an excellent DGAT1 inhibitory action could be provided.

Hereinafter, the present invention will be described in detail, but the present invention is not particularly limited thereto.
In the present invention, “n” is normal, “i” is iso, “s” is secondary, “t” is tertiary, “c” is cyclo, “o” is ortho, “m” Indicates meta, and “p” indicates para.
The “C _1-3 alkyl group” refers to a linear or branched alkyl group having 1 to 3 carbon atoms, and examples thereof include a methyl group, an ethyl group, an n-propyl group, and an i-propyl group. A methyl group is more preferred.
The “C _1-6 alkyl group” refers to a linear or branched alkyl group having 1 to 6 carbon atoms, for example, methyl group, ethyl group, n-propyl group, i-propyl group, n -A pentyl group, n-hexyl group, i-butyl group, t-butyl group, s-butyl group, i-pentyl group can be mentioned, and a methyl group is more preferable.
The “C _1-8 alkyl group” refers to a linear or branched alkyl group having 1 to 8 carbon atoms, for example, methyl group, ethyl group, n-propyl group, n-butyl group, n -Pentyl group, n-hexyl group, n-heptyl group, n-octyl group, i-propyl group, i-butyl group, t-butyl group, s-butyl group, i-pentyl group, neopentyl group, t-pentyl Group, and a methyl group and an ethyl group are more preferable.
“C _3-10 cycloalkyl group” refers to a cyclic alkyl group having 3 to 10 carbon atoms, such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, Examples thereof include an adamantyl group, and a cyclohexyl group and an adamantyl group are more preferable.
The “halogen atom” is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, more preferably a fluorine atom or a chlorine atom.
The “C _1-6 alkoxy group” refers to a linear or branched alkoxy group having 1 to 6 carbon atoms, such as a methoxy group, an ethoxy group, an n-propoxy group, an i-propoxy group, n -Butoxy group, i-butoxy group, s-butoxy group, t-butoxy group, n-pentyloxy group, i-pentyloxy group, n-hexyloxy group can be mentioned, and methoxy group is more preferable.
“Di (C _1-6 alkyl) amino group” means an amino group having two identical or different “C _1-6 alkyl groups” as substituents, such as dimethylamino group, diethylamino group, di-n. -Propylamino group, di-i-propylamino group, di-i-butylamino group, di-s-butylamino group, di-t-butylamino group, ethyl (methyl) amino group, methyl (n-propyl) Mention may be made of amino groups.
The “C _1-6 alkylthio group” refers to a linear or branched alkylthio group having 1 to 6 carbon atoms. For example, a methylthio group, an ethylthio group, an n-propylthio group, an i-propylthio group, n -Butylthio group, i-butylthio group, s-butylthio group, t-butylthio group can be mentioned.
The “C _1-8 alkylene group” refers to a linear alkylene group having 1 to 8 carbon atoms, and examples thereof include a methylene group, an ethylene group, a propylene group, a butylene group, and a pentylene group. A group, an ethylene group, and a propylene group are more preferable.
“Hydroxy C _1-6 alkyl group” means a “C _1-6 alkyl group” having a hydroxy group as a substituent, such as a hydroxymethyl group, a 2-hydroxyethyl group, a 3-hydroxy-n-propyl group, A 2-hydroxy-n-propyl group, a 4-hydroxy-n-butyl group, and a 2-hydroxy-i-propyl group can be exemplified, and a hydroxymethyl group is more preferable.
“5- to 7-membered heterocyclyl ring” refers to a 5- to 7-membered monocyclic saturated heterocyclic ring consisting of one nitrogen atom and 4 to 6 carbon atoms, such as a pyrrolidine ring, piperidine ring, A homopiperidine ring can be mentioned, and a pyrrolidine ring and a piperidine ring are more preferable.
The “3- to 6-membered cycloalkyl ring” refers to a cyclic alkyl ring having 3 to 6 carbon atoms, and examples thereof include a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, and a cyclohexane ring. A ring and a cyclobutane ring are more preferable.
“3- to 6-membered heterocyclyl ring” refers to a 3- to 6-membered monocyclic saturated heterocycle consisting of one oxygen atom and 2 to 5 carbon atoms, such as an oxirane ring, oxetane ring, A tetrahydrofuran ring and a tetrahydropyran ring can be mentioned, and a tetrahydropyran ring is more preferable.

で表される基であり、式（Ｄ−２）又は式（Ｄ−３）で表される基がさらに好ましい。 Preferred forms of the compound of the present invention are as follows.
That is, preferable R ¹ is a hydrogen atom, a methyl group, or an ethyl group, and more preferable R ¹ is a hydrogen atom.
Preferred R ² is a hydrogen atom, a halogen atom or a methyl group, and more preferred R ² is a hydrogen atom.
Preferred Q is a phenyl group substituted with 1 to 3 groups selected from the group consisting of a C _1-8 alkyl group, a C _1-6 alkoxy group, a trifluoromethyl group and a halogen atom, which are the same or different.
Preferred X is —O— or —NR ³ —, and more preferred X is —O—.
Preferred R ³ is a hydrogen atom.
Preferred m is 1.
Preferred n is 1.
Preferred Y is the formula (D-1), (D-2), (D-3) or (D-4)

And a group represented by formula (D-2) or formula (D-3) is more preferable.

In the present invention, the pharmaceutically acceptable salt is, for example, a mineral salt such as hydrochloride, hydrobromide, hydroiodide, phosphate, sulfate, nitrate; methanesulfonate Sulfonates such as ethanesulfonate, benzenesulfonate, p-toluenesulfonate; oxalate, tartrate, citrate, maleate, succinate, acetate, benzoate, Carboxylates such as mandelate, ascorbate, lactate, gluconate, malate; amino acid salts such as glycine, lysine, arginine, ornithine, glutamate, aspartate; or Inorganic or ammonium salts such as lithium salt, sodium salt, potassium salt, calcium salt, magnesium salt, triethylamine salt, diisopropylamine salt, cyclohexyl A salt with an organic base such as a ruamine salt, preferably hydrochloride, hydrobromide, phosphate, sulfate, methanesulfonate, p-toluenesulfonate, oxalate, tartrate Citrate, acetate, lactate, glutamate, aspartate, sodium salt, potassium salt, ammonium salt or triethylamine salt.
The solvate in the present invention is a pharmaceutically acceptable solvate of the compound of the present invention or a salt thereof. The compound of the present invention and its salt may absorb moisture or be adsorbed water or become a hydrate by exposure to the atmosphere or recrystallization. The compound in the present invention includes such a hydrate.
The compounds of the present invention may have asymmetric centers, in which case various optical isomers exist. Therefore, the compound of the present invention may exist as a (+) isomer (single), a (-) isomer (single), a racemate, or a (±) mixture containing both optically active substances in an arbitrary ratio. In addition, in the case of a compound having two or more asymmetric centers, diastereomers by respective optical isomerism also exist. The compounds of the present invention also include those containing all these types in any proportion. For example, diastereomers can be separated by methods well known to those skilled in the art, such as fractional crystallization, and optically active forms can be obtained by organic chemistry techniques well known for this purpose. it can. Further, the compound of the present invention may have geometric isomers such as cis isomer and trans isomer. The compound of the present invention includes those isomers and those containing these isomers in an arbitrary ratio.
The heteroarylbenzene compound of the present invention may be a pharmaceutically acceptable salt thereof or a solvate thereof. Hereinafter, the heteroarylbenzene compound of the present invention, tautomers, stereoisomers, pharmaceutically acceptable salts or solvates thereof of the compound are referred to as “the present compound”.
Also, a compound that has a group that can be chemically or metabolically decomposed and forms a pharmacologically active compound of the present invention by solvolysis or in vivo under physiological conditions, usually a compound called a prodrug It is included in “the present compound”.

The compound of the present invention has a DGAT1 inhibitory action. Therefore, the compound of the present invention can correct obesity by inhibiting the production and accumulation of triglyceride in the small intestine and / or adipose tissue. Therefore, it can be used as a new drug having a different mechanism of action from existing drugs for treating obesity. Furthermore, the compound of the present invention is expected as a therapeutic agent for diabetes by suppressing the secretion of malignant physiologically active substances (adipocytokines) such as TNFα by suppressing the enlargement of fat cells. Diabetes includes type I diabetes, type II diabetes, and other diabetes due to specific causes. Furthermore, the compound of the present invention can be used for ketoacidosis, microangiopathy (retinopathy, nephropathy), arteriosclerosis (atherosclerosis, myocardial infarction, cerebral infarction, peripheral arterial occlusion, etc.), neuropathy (sensory nerve, motor Nerves, autonomic nerves, etc.), foot gangrene, infection and other diabetic complications.
The compound of the present invention is used in combination with an anti-obesity agent, a therapeutic agent for diabetes, a therapeutic agent for diabetic complications, a therapeutic agent for hyperlipidemia, a therapeutic agent for hypertension, etc. having a different mechanism of action other than the DGAT1 inhibitory effect. You can also By combining the compound of the present invention with other drugs, an additive effect can be expected when used in combination with the above diseases, rather than the effect obtained with a single agent.
Examples of anti-obesity drugs, anti-diabetic drugs, and diabetic complications that can be used in combination include β-adrenergic receptor agonists (eg, mazindol), serotonin agonists (eg, phenfuramin), β3-receptor agonists ( Examples, BRL26830A), norepinephrine, serotonin reuptake agonists (eg, sibutramine), pancreatic lipase inhibitors (eg, orlistat), cannabinoid receptor antagonists (eg, rimonabant, MK-0364, tranavant, CP-945598), melanin Aggregating hormone receptor antagonist (eg, 856464, AMG-076, NGD-4715), insulin preparation, insulin resistance improving drug (PPARγ agonist, PPARα / γ agonist, PPARδ agonist, PPARα / γ / δ agonist, etc.) (example) , Pioglitazone, rosiglitazone, GW-5 1516, GW-590735, ABT-335, AZD-6610, AVE-8133), α-glucosidase inhibitor (eg, voglibose, acarbose, miglitol), biguanide (eg, metformin, buformin, phenformin), insulin secretagogue (Eg, glibenclamide, glimepiride, repaglinide, nateglinide, mitiglinide), glucagon receptor antagonist, insulin receptor kinase promoter, dipeptidyl peptidase IV inhibitor (eg, vildagliptin, TS-021, sitagliptin, BMS-477118), SGLT inhibition Drugs (eg, sagliflozin, dapagliflozin, KGT-1681, YM543, TS-033, AVE-2268), PTP1b inhibitors (eg, sodium vanadate), Lucose 6 phosphatase inhibitor, glycogen phosphorylase inhibitor (eg, PSN-357, FR-258900), FBPase inhibitor (eg, MB-07803), PEPCK inhibitor, pyruvate dehydrogenase kinase inhibitor, D-kaileunositol, GSK3 Inhibitors, GLP-1 agonists (eg, liraglutide), amylin agonists (eg, pramlintide), glucocorticoid receptor antagonists, 11 beta HSD1 inhibitors (eg, AMG-221, INCB-13739), protein kinase C inhibitors ( E.g., ruboxistaurin), beta3 adrenergic receptor agonist (e.g., AJ-9679), phosphatidylinositol kinase inhibitor, phosphatidylinositol phosphatase inhibitor, ACC inhibitor , GPR40 receptor agonist, GPR119 receptor agonist (eg, APD-668), TGR5 receptor agonist, AMPK activator (eg, DRL-16536), aldose reductase inhibitor, AGE inhibitor, glucokinase activator Etc.
Examples of the drugs for diabetes-related diseases that can be used in combination include HMG-CoA reductase inhibitors, squalene synthetase inhibitors, bile acid adsorbents, IBAT inhibitors, CETP inhibitors, CPT inhibitors, fibrate drugs, ACAT inhibitors , MGAT inhibitor, DGAT inhibitor, cholesterol absorption inhibitor, MTP inhibitor, nicotinic acid derivative, LXR agonist, LDL receptor promoter, angiotensin converting enzyme inhibitor, angiotensin II antagonist, diuretic, calcium antagonist, endothelin conversion Enzyme inhibitors, endothelin receptor antagonists, uric acid production inhibitors, uric acid excretion promoters, and the like.
The compound of the present invention can be administered alone or in combination with a pharmaceutically or pharmaceutically acceptable carrier or diluent. When the compound of the present invention is used as a DGAT1 inhibitor, the compound of the present invention may be administered orally or parenterally as it is. Moreover, you may administer orally or parenterally as an agent which contains this invention compound as an active ingredient. Parenteral administration includes intravenous administration, nasal administration, transdermal administration, subcutaneous administration, intramuscular administration, and sublingual administration.
The dose of the compound of the present invention varies depending on the administration subject, administration route, target disease, symptom, etc., for example, when administered orally to an adult patient, The dose is preferably 0.05 to 30 mg / kg body weight, more preferably 0.1 to 10 mg / kg body weight, and this amount is desirably administered once to three times a day.

  The compound of the present invention can be synthesized by the method shown below, but the following production method is an example of a general production method and does not limit the production method.

（スキーム中Ｒ^１、Ｑ、Ｒ^２、及びＹは前記と同意義であり、Ｇはハロゲン原子を示す。）
工程（１−１）：溶媒中、化合物（１−ａ）と、炭酸セシウム、炭酸カリウム等の塩基存在下、式Ｚ−Ｙ−ＣＯＯＲ^１（式中Ｚはハロゲン原子を表す）で表される化合物を反応させることにより、化合物（１−ｂ）を製造することができる。
工程（１−２）：溶媒中、化合物（１−ｂ）と、炭酸ナトリウム等の塩基存在下、且つテトラキストリフェニルホスフィンパラジウム等のパラジウム触媒存在下、式（８）

又は式（９）

で表される化合物を反応させることにより、化合物（１−ｃ）を製造することができる。
工程（１−３）：溶媒中、化合物（１−ｃ）を、水素ガス雰囲気下、１０％パラジウムカーボン、２％プラチナカーボン等の金属触媒存在下反応させることにより、化合物（１−ｄ）を製造することができる。
工程（１−４）：溶媒中、化合物（１−ｄ）を、ピリジン等の塩基存在下、４−ニトロフェニルクロロホルメートと反応させ、さらに式Ｑ−ＮＨ_２で表される化合物を反応させることにより、本発明化合物（１−ｅ）を製造することができる。また、溶媒中、化合物（１−ｄ）を、トリエチルアミン等の塩基の存在下又は非存在下、式Ｑ−ＮＣＯで表される化合物と反応させることでも、本発明化合物（１−ｅ）を製造することができる。
工程（１−５）：溶媒中、本発明化合物（１−ｅ）を、水酸化ナトリウム水溶液などの塩基を用いて加水分解することにより、本発明化合物（１−ｆ）を製造することができる。

スキーム２：化合物（２−ａ）から本発明化合物（２−ｅ）（ただし、Ｒ^ｘがＣ_１−３アルキル基の時に該当する。）及び本発明化合物（２−ｆ）の製造方法

（スキーム中Ｑ、Ｒ^２、及びＹは前記と同意義であり、Ｇはハロゲン原子を示す。）
工程（２−１）：溶媒中、化合物（２−ａ）と、式ＨＣ（＝Ｏ）−Ｙ’−ＣＯＯＲ^ｘ、（式中Ｙ’は、上記スキーム２において、Ｙ基から−ＮＨ−に隣接する−ＣＨ_２−を除いた基（但し、−ＮＨ−に酸素原子が結合する場合を除く）を表し、Ｒ^ｘはＣ_１−３アルキル基又はベンジル基を表す。）で表されるアルデヒドをトリアセトキシヒドロホウ素ナトリウム、トリフルオロ酢酸等を用いて還元的にアミノ化させることにより、化合物（２−ｂ）を製造することができる。
工程（２−２）：溶媒中、化合物（２−ｂ）と、炭酸ナトリウム等の塩基存在下、且つテトラキストリフェニルホスフィンパラジウム等のパラジウム触媒存在下、式（８）

又は式（９）

で表される化合物を反応させることにより、化合物（２−ｃ）を製造することができる。
工程（２−３）：溶媒中、化合物（２−ｃ）を、水素ガス雰囲気下、１０％パラジウムカーボン、２％プラチナカーボン等の金属触媒存在下反応させることにより、化合物（２−ｄ）を製造することができる。また、溶媒中、化合物（２−ｃ）を、鉄粉及び塩化アンモニウム水又は塩酸存在下反応させることでも、化合物（２−ｄ）を製造することができる。
工程（２−４）：溶媒中、化合物（２−ｄ）を、ピリジン等の塩基存在下、４−ニトロフェニルクロロホルメートと反応させ、さらに式Ｑ−ＮＨ_２で表される化合物を反応させることにより、本発明化合物（２−ｅ）を製造することができる。また、溶媒中、化合物（２−ｄ）を、トリエチルアミン等の塩基の存在下又は非存在下、式Ｑ−ＮＣＯで表される化合物と反応させることでも、本発明化合物（２−ｅ）を製造することができる。
工程（２−５）：溶媒中、本発明化合物（２−ｅ）を、水酸化ナトリウム水溶液などの塩基を用いて加水分解することにより、本発明化合物（２−ｆ）を製造することができる。

スキーム３：化合物（３−ａ）から本発明化合物（３−ｇ）、本発明化合物（３−ｈ）、及び本発明化合物（３−ｉ）の製造方法

（スキーム中Ｒ^１、Ｑ、Ｒ^２、及びＹは前記と同意義であり、Ｇ、及びＪはハロゲン原子を示す。）
工程（３−１）：溶媒中、化合物（３−ａ）に、ｍ−クロロ過安息香酸などの酸化剤を反応させることにより、化合物（３−ｂ）を製造することができる。
工程（３−２）：溶媒中、化合物（３−ｂ）と、炭酸セシウム、炭酸カリウム等の塩基存在下、式ＨＯ−Ｙ−ＣＯＯＲ^１で表される化合物を反応させることにより、化合物（３−ｃ）を製造することができる。
工程（３−３）：溶媒中、化合物（３−ｃ）に、インジウム、又はモリブデンヘキサカルボニル等を反応させることにより、化合物（３−ｄ）を製造することができる。
工程（３−４）：溶媒中、化合物（３−ｄ）と、炭酸ナトリウム等の塩基存在下、且つテトラキストリフェニルホスフィンパラジウム等のパラジウム触媒存在下、式（８）

又は式（９）

で表される化合物を反応させることにより、化合物（３−ｅ）を製造することができる。
工程（３−５）：溶媒中、化合物（３−ｅ）を、水素ガス雰囲気下、１０％パラジウムカーボン、２％プラチナカーボン等の金属触媒存在下反応させることにより、化合物（３−ｆ）を製造することができる。
工程（３−６）：溶媒中、化合物（３−ｆ）を、ピリジン等の塩基存在下、４−ニトロフェニルクロロホルメートと反応させ、さらに式Ｑ−ＮＨ_２で表される化合物を反応させることにより、本発明化合物（３−ｇ）を製造することができる。また、溶媒中、化合物（３−ｆ）を、トリエチルアミン等の塩基の存在下又は非存在下、式Ｑ−ＮＣＯで表される化合物と反応させることでも、本発明化合物（３−ｇ）を製造することができる。
工程（３−７）：溶媒中、本発明化合物（３−ｇ）を、水酸化ナトリウム水溶液などの塩基を用いて加水分解することにより、本発明化合物（３−ｈ）を製造することができる。
工程（３−８）：溶媒中、本発明化合物（３−ｈ）を、水酸化ナトリウム水溶液などを用いてナトリウム塩を形成することにより、本発明化合物（３−ｉ）を製造することができる。

スキーム４：化合物（３−ａ）から本発明化合物（４−ｇ）の製造方法

（スキーム中Ｑ、Ｒ^２、及びＹは前記と同意義であり、Ｇ、及びＪはハロゲン原子を示す。）
工程（４−１）：溶媒中、化合物（３−ａ）と、
式（１０）

で表される化合物を、水素化ナトリウムなどの塩基存在下、反応させることにより化合物（４−ｂ）を製造することができる。
工程（４−２）：溶媒中、化合物（４−ｂ）と、炭酸ナトリウムなどの塩基存在下、且つテトラキストリフェニルホスフィンパラジウム等のパラジウム試薬存在下、
式（８）

で表される化合物を反応させることにより化合物（４−ｃ）を製造することができる。
工程（４−３）：溶媒中、化合物（４−ｃ）を水素ガス雰囲気下、１０％パラジウムカーボン、２％プラチナカーボンなどの金属触媒下反応させることにより化合物（４−ｄ）を製造することができる。また、溶媒中、化合物（４−ｃ）を鉄粉及び塩化アンモニウム水存在下反応させることでも化合物（４−ｄ）を製造することができる。
工程（４−４）：溶媒中、化合物（４−ｄ）に式Ｑ−ＮＣＯで表される化合物を、トリエチルアミンなどの塩基存在下又は非存在下、反応させることにより、化合物（４−ｅ）を製造することができる。また、溶媒中、化合物（４−ｄ）にピリジンなどの塩基存在下、４−ニトロフェニルクロロホルメートを反応させ、さらに式Ｑ−ＮＨ_２で表される化合物を反応させることにより化合物（４−ｅ）を製造することができる。
工程（４−５）：溶媒中、化合物（４−ｅ）を、ｐ−トルエンスルホン酸などの酸存在下、反応させることにより化合物（４−ｆ）を製造することができる。
工程（４−６）：溶媒中、化合物（４−ｆ）に、ｍ−クロロ過安息香酸などの酸化剤を反応させることにより本発明化合物（４−ｇ）を製造することができる。

スキーム５：化合物（３−ｂ）から本発明化合物（５−ｈ）の製造方法

（スキーム中Ｑ、Ｒ^２、及びＹは前記と同意義であり、Ｇ、及びＪはハロゲン原子を示す。）
工程（５−１）：溶媒中、化合物（３−ｂ）と、炭酸セシウム、炭酸カリウム等の塩基存在下、式ＨＯ−Ｙ−ＣＯＯＣＨ_２Ｐｈで表される化合物を反応させることにより、化合物（５−ｃ）を製造することができる。
工程（５−２）：溶媒中、化合物（５−ｃ）に、インジウム、又はモリブデンヘキサカルボニル等を反応させることにより、化合物（５−ｄ）を製造することができる。
工程（５−３）：溶媒中、化合物（５−ｄ）と、炭酸ナトリウム等の塩基存在下、且つテトラキストリフェニルホスフィンパラジウム等のパラジウム触媒存在下、式（８）

又は式（９）

で表される化合物を反応させることにより、化合物（５−ｅ）を製造することができる。
工程（５−４）：溶媒中、化合物（５−ｅ）を、鉄粉及び塩化アンモニウム水又は塩酸存在下反応させることで、化合物（５−ｆ）を製造することができる。
工程（５−５）：溶媒中、化合物（５−ｆ）を、ピリジン等の塩基存在下、４−ニトロフェニルクロロホルメートと反応させ、さらに式Ｑ−ＮＨ_２で表される化合物を反応させることにより、化合物（５−ｇ）を製造することができる。また、溶媒中、化合物（５−ｆ）を、トリエチルアミン等の塩基の存在下又は非存在下、式Ｑ−ＮＣＯで表される化合物と反応させることでも、化合物（５−ｇ）を製造することができる。
工程（５−６）：溶媒中、化合物（５−ｇ）を、水酸化ナトリウム水溶液などの塩基を用いて加水分解することにより、本発明化合物（５−ｈ）を製造することができる。

スキーム６：化合物（６−ａ）から本発明化合物（６−ｅ）及び本発明化合物（６−ｆ）の製造方法

（スキーム中Ｒ^１、Ｑ、Ｒ^２、及びＹは前記と同意義であり、Ｇ、及びＪはハロゲン原子を示す。）
工程（６−１）：溶媒中、化合物（６−ａ）と、炭酸セシウム、炭酸カリウム等の塩基存在下、式ＨＯ−Ｙ−ＣＯＯＲ^１で表される化合物を反応させることにより、化合物（６−ｂ）を製造することができる。
工程（６−２）：溶媒中、化合物（６−ｂ）と、炭酸ナトリウム等の塩基存在下、且つテトラキストリフェニルホスフィンパラジウム等のパラジウム触媒存在下、式（８）

又は式（９）

で表される化合物を反応させることにより、化合物（６−ｃ）を製造することができる。
工程（６−３）：溶媒中、化合物（６−ｃ）を、水素ガス雰囲気下、１０％パラジウムカーボン、２％プラチナカーボン等の金属触媒存在下反応させることにより、化合物（６−ｄ）を製造することができる。
工程（６−４）：溶媒中、化合物（６−ｄ）を、ピリジン等の塩基存在下、４−ニトロフェニルクロロホルメートと反応させ、さらに式Ｑ−ＮＨ_２で表される化合物を反応させることにより、本発明化合物（６−ｅ）を製造することができる。また、溶媒中、化合物（６−ｄ）を、トリエチルアミン等の塩基の存在下又は非存在下、式Ｑ−ＮＣＯで表される化合物と反応させることでも、本発明化合物（６−ｅ）を製造することができる。
工程（６−５）：溶媒中、本発明化合物（６−ｅ）を、水酸化ナトリウム水溶液などの塩基を用いて加水分解することにより、本発明化合物（６−ｆ）を製造することができる。

スキーム７：化合物（６−ａ）から本発明化合物（７−ｆ）の製造方法

（スキーム中Ｑ、Ｒ^２、及びＹは前記と同意義であり、Ｇ、及びＪはハロゲン原子を示す。）
工程（７−１）：溶媒中、化合物（６−ａ）と、炭酸セシウム、炭酸カリウム等の塩基存在下、式ＨＯ−Ｙ−ＣＯＯＣＨ_２Ｐｈで表される化合物を反応させることにより、化合物（７−ｂ）を製造することができる。
工程（７−２）：溶媒中、化合物（７−ｂ）と、炭酸ナトリウム等の塩基存在下、且つテトラキストリフェニルホスフィンパラジウム等のパラジウム触媒存在下、式（８）

又は式（９）

で表される化合物を反応させることにより、化合物（７−ｃ）を製造することができる。
工程（７−３）：溶媒中、化合物（７−ｃ）を、鉄粉及び塩化アンモニウム水存在下反応させることにより、化合物（７−ｄ）を製造することができる。
工程（７−４）：溶媒中、化合物（７−ｄ）を、ピリジン等の塩基存在下、４−ニトロフェニルクロロホルメートと反応させ、さらに式Ｑ−ＮＨ_２で表される化合物を反応させることにより、化合物（７−ｅ）を製造することができる。また、溶媒中、化合物（７−ｄ）を、トリエチルアミン等の塩基の存在下又は非存在下、式Ｑ−ＮＣＯで表される化合物と反応させることでも、化合物（７−ｅ）を製造することができる。
工程（７−５）：溶媒中、化合物（７−ｅ）を、水酸化ナトリウム水溶液などの塩基を用いて加水分解することにより、本発明化合物（７−ｆ）を製造することができる。
本発明化合物の一般的な製造方法の記載における塩基としては、例えば、炭酸ナトリウム、炭酸カリウム、炭酸セシウム、炭酸水素ナトリウム、炭酸水素カリウム、水酸化ナトリウム、水素化ナトリウム、水素化リチウム、ナトリウムアミド、ｔ−ブトキシカリウム、ｎ−ブチルリチウム若しくはリチウムジイソプロピルアミドなどのアルカリ金属塩類、トリエチルアミン、ジイソプロピルエチルアミン、ピロリジン若しくはピペリジンなどのアミン類、酢酸ナトリウム又は酢酸カリウムが挙げられる。
本発明化合物の一般的な製造方法の記載における酸化剤としては、例えば、ｍ−クロロ過安息香酸、マグネシウムモノパーフタレート６水和物、過酢酸若しくは過ぎ酸などの有機過酸、過酸化水素、尿素過酸化水素付加物／無水フタル酸、ｔ−ブチルハイドロパーオキサイド若しくはクメンハイドロパーオキサイドなどの無機及び有機過酸化物、過ヨウ素酸ナトリウム、オキソン（登録商標）、Ｎ−ブロモスクシンイミド、Ｎ−クロロスクシンイミド、クロラミン−Ｔ、次亜塩素酸t−ブチル、ヨードベンゼンジアセテート又は臭素−１，４−ジアザビシクロ［２，２，２］オクタン付加錯体が挙げられる。
本発明化合物の一般的な製造方法の記載における還元剤としては、例えば、水素化ホウ素ナトリウム又は水素化ホウ素リチウムが挙げられる。
本発明化合物の一般的な製造方法の記載における溶媒とは、当該反応条件下にて安定であり、かつ、不活性で反応を妨げないものであれば特に制限はなく、例えば、水、メタノール、エタノール、ｉ−プロピルアルコール、ｎ−ブタノール若しくはｔ−ブチルアルコールなどのアルコール類、ジオキサン若しくはテトラヒドロフランなどのエーテル類、ジメチルホルムアミド、ジメチルアセトアミド、ジメチルスルホキシド、ピリジン、酢酸エチル、塩化メチレン、クロロホルム、アセトン、酢酸、ベンゼン又はトルエンあるいはこれらの混合溶媒が挙げられる。
本発明化合物の一般的な製造方法における反応温度は、−７８℃から反応に用いる溶媒の沸点の範囲で適切な温度を選択することができ、本製造方法は常圧下、加圧下、マイクロウエーブ照射下等で実施することができる。 Scheme 1: Method for producing compound (1-e) of the present invention and compound (1-f) of the present invention from compound (1-a)

(In the scheme, R ¹ , Q, R ² and Y are as defined above, and G represents a halogen atom.)
Step (1-1): represented by the formula ZY-COOR ¹ (wherein Z represents a halogen atom) in the presence of a compound (1-a) and a base such as cesium carbonate or potassium carbonate in a solvent. Compound (1-b) can be produced by reacting the compound.
Step (1-2): In a solvent, in the presence of a compound (1-b) and a base such as sodium carbonate, and in the presence of a palladium catalyst such as tetrakistriphenylphosphine palladium, the formula (8)

Or formula (9)

Compound (1-c) can be produced by reacting the compound represented by the formula:
Step (1-3): Compound (1-d) is reacted in a solvent in the presence of a metal catalyst such as 10% palladium carbon and 2% platinum carbon in a hydrogen gas atmosphere. Can be manufactured.
Step (1-4): In a solvent, compound (1-d) is reacted with 4-nitrophenyl chloroformate in the presence of a base such as pyridine, and further reacted with a compound represented by formula Q-NH ₂ . Thus, the present compound (1-e) can be produced. Alternatively, the compound (1-e) of the present invention can also be produced by reacting the compound (1-d) with a compound represented by the formula Q-NCO in the presence or absence of a base such as triethylamine in a solvent. can do.
Step (1-5): The present compound (1-f) can be produced by hydrolyzing the present compound (1-e) in a solvent using a base such as an aqueous sodium hydroxide solution. .

Scheme 2: Compound (2-a) to compound (2-e) of the present invention (provided when R ^x is a C _1-3 alkyl group) and a method for producing the compound (2-f) of the present invention

(In the scheme, Q, R ² and Y are as defined above, and G represents a halogen atom.)
Step (2-1): In a solvent, the compound (2-a) and the formula HC (═O) —Y′—COOR ^x , wherein Y ′ is changed from Y group to —NH— in the above-mentioned scheme 2. An aldehyde represented by a group excluding the adjacent —CH ₂ — (excluding a case where an oxygen atom is bonded to —NH—, and R ^x represents a C _1-3 alkyl group or a benzyl group). Can be reductively aminated with sodium triacetoxyhydroboron, trifluoroacetic acid or the like to produce compound (2-b).
Step (2-2): In the solvent, in the presence of a compound (2-b) and a base such as sodium carbonate, and in the presence of a palladium catalyst such as tetrakistriphenylphosphine palladium, the formula (8)

Or formula (9)

Compound (2-c) can be produced by reacting the compound represented by the formula:
Step (2-3): Compound (2-d) is reacted in a solvent in the presence of a metal catalyst such as 10% palladium carbon and 2% platinum carbon in a hydrogen gas atmosphere. Can be manufactured. Alternatively, compound (2-d) can also be produced by reacting compound (2-c) in the presence of iron powder and ammonium chloride water or hydrochloric acid in a solvent.
Step (2-4): In a solvent, the compound (2-d) is reacted with 4-nitrophenyl chloroformate in the presence of a base such as pyridine, and further reacted with a compound represented by the formula Q-NH ₂ . Thus, the present compound (2-e) can be produced. Alternatively, the compound (2-e) of the present invention can also be produced by reacting the compound (2-d) with a compound represented by the formula Q-NCO in the presence or absence of a base such as triethylamine. can do.
Step (2-5): The present compound (2-f) can be produced by hydrolyzing the present compound (2-e) with a base such as an aqueous sodium hydroxide solution in a solvent. .

Scheme 3: A method for producing the present compound (3-g), the present compound (3-h), and the present compound (3-i) from the compound (3-a)

(In the scheme, R ¹ , Q, R ² and Y are as defined above, and G and J represent a halogen atom.)
Step (3-1): Compound (3-b) can be produced by reacting compound (3-a) with an oxidizing agent such as m-chloroperbenzoic acid in a solvent.
Step (3-2): Compound (3b) is reacted with a compound represented by the formula HO-Y-COOR ¹ in the presence of a base such as cesium carbonate or potassium carbonate in a solvent. -C) can be produced.
Step (3-3): Compound (3-d) can be produced by reacting compound (3-c) with indium, molybdenum hexacarbonyl, or the like in a solvent.
Step (3-4): Compound (3-d) in the solvent in the presence of a base such as sodium carbonate and in the presence of a palladium catalyst such as tetrakistriphenylphosphine palladium.

Or formula (9)

Compound (3-e) can be produced by reacting the compound represented by the formula:
Step (3-5): The compound (3-f) is reacted in a solvent in the presence of a metal catalyst such as 10% palladium carbon and 2% platinum carbon in a hydrogen gas atmosphere. Can be manufactured.
Step (3-6): In a solvent, compound (3-f) is reacted with 4-nitrophenyl chloroformate in the presence of a base such as pyridine, and further reacted with a compound represented by formula Q-NH ₂ . Thus, the present compound (3-g) can be produced. Alternatively, the compound (3-g) of the present invention can also be produced by reacting the compound (3-f) with a compound represented by the formula Q-NCO in the presence or absence of a base such as triethylamine. can do.
Step (3-7): The compound (3-h) of the present invention can be produced by hydrolyzing the compound (3-g) of the present invention with a base such as an aqueous sodium hydroxide solution in a solvent. .
Step (3-8): The compound (3-i) of the present invention can be produced by forming a sodium salt of the compound (3-h) of the present invention using a sodium hydroxide aqueous solution or the like in a solvent. .

Scheme 4: Method for producing compound (4-g) of the present invention from compound (3-a)

(In the scheme, Q, R ² and Y are as defined above, and G and J represent a halogen atom.)
Step (4-1): Compound (3-a) in a solvent,
Formula (10)

Is reacted in the presence of a base such as sodium hydride to produce compound (4-b).
Step (4-2): In a solvent, in the presence of a compound (4-b), a base such as sodium carbonate, and a palladium reagent such as tetrakistriphenylphosphine palladium,
Formula (8)

Compound (4-c) can be produced by reacting the compound represented by the formula:
Step (4-3): The compound (4-d) is produced by reacting the compound (4-c) in a solvent in a hydrogen gas atmosphere under a metal catalyst such as 10% palladium carbon or 2% platinum carbon. Can do. Alternatively, compound (4-d) can also be produced by reacting compound (4-c) in the presence of iron powder and aqueous ammonium chloride in a solvent.
Step (4-4): The compound (4-e) is reacted with a compound represented by the formula Q-NCO in a solvent in the presence or absence of a base such as triethylamine. Can be manufactured. Further, compound (4-d) is reacted with 4-nitrophenyl chloroformate in the presence of a base such as pyridine in a solvent, and further reacted with a compound represented by formula Q-NH ₂ to give compound (4- e) can be produced.
Step (4-5): Compound (4-f) can be produced by reacting compound (4-e) in the presence of an acid such as p-toluenesulfonic acid in a solvent.
Step (4-6): The compound (4-g) of the present invention can be produced by reacting the compound (4-f) with an oxidizing agent such as m-chloroperbenzoic acid in a solvent.

Scheme 5: Method for producing compound (5-h) of the present invention from compound (3-b)

(In the scheme, Q, R ² and Y are as defined above, and G and J represent a halogen atom.)
Step (5-1): In a solvent, the compound (3-b) is reacted with a compound represented by the formula HO—Y—COOCH ₂ Ph in the presence of a base such as cesium carbonate or potassium carbonate to give a compound ( 5-c) can be produced.
Step (5-2): Compound (5-d) can be produced by reacting compound (5-c) with indium, molybdenum hexacarbonyl, or the like in a solvent.
Step (5-3): Compound (5-d) in the solvent in the presence of a base such as sodium carbonate and in the presence of a palladium catalyst such as tetrakistriphenylphosphine palladium.

Or formula (9)

Compound (5-e) can be produced by reacting the compound represented by the formula:
Step (5-4): Compound (5-f) can be produced by reacting compound (5-e) in the presence of iron powder and aqueous ammonium chloride or hydrochloric acid in a solvent.
Step (5-5): In a solvent, compound (5-f) is reacted with 4-nitrophenyl chloroformate in the presence of a base such as pyridine, and further reacted with a compound represented by formula Q-NH ₂ . Thus, the compound (5-g) can be produced. Alternatively, compound (5-g) can also be produced by reacting compound (5-f) with a compound represented by formula Q-NCO in the presence or absence of a base such as triethylamine in a solvent. Can do.
Step (5-6): The compound (5-h) of the present invention can be produced by hydrolyzing the compound (5-g) in a solvent using a base such as an aqueous sodium hydroxide solution.

Scheme 6: Method for producing compound (6-e) and compound (6-f) of the present invention from compound (6-a)

(In the scheme, R ¹ , Q, R ² and Y are as defined above, and G and J represent a halogen atom.)
Step (6-1): In a solvent, the compound (6-a) is reacted with a compound represented by the formula HO-Y-COOR ¹ in the presence of a base such as cesium carbonate or potassium carbonate to give a compound (6 -B) can be produced.
Step (6-2): In a solvent, in the presence of a compound (6-b), a base such as sodium carbonate, and a palladium catalyst such as tetrakistriphenylphosphine palladium, the compound of the formula (8)

Or formula (9)

Compound (6-c) can be produced by reacting the compound represented by the formula:
Step (6-3): The compound (6-d) is reacted in a solvent in the presence of a metal catalyst such as 10% palladium carbon and 2% platinum carbon in a hydrogen gas atmosphere. Can be manufactured.
Step (6-4): In a solvent, the compound (6-d) is reacted with 4-nitrophenyl chloroformate in the presence of a base such as pyridine, and further reacted with a compound represented by the formula Q-NH ₂ . Thus, the present compound (6-e) can be produced. Alternatively, the compound (6-e) of the present invention can also be produced by reacting the compound (6-d) with a compound represented by the formula Q-NCO in the presence or absence of a base such as triethylamine in a solvent. can do.
Step (6-5): The compound (6-f) of the present invention can be produced by hydrolyzing the compound (6-e) of the present invention with a base such as an aqueous sodium hydroxide solution in a solvent. .

Scheme 7: Method for producing compound (7-f) of the present invention from compound (6-a)

(In the scheme, Q, R ² and Y are as defined above, and G and J represent a halogen atom.)
Step (7-1): In a solvent, the compound (6-a) is reacted with a compound represented by the formula HO—Y—COOCH ₂ Ph in the presence of a base such as cesium carbonate or potassium carbonate to give a compound ( 7-b) can be produced.
Step (7-2): In the solvent, in the presence of a compound (7-b) and a base such as sodium carbonate, and in the presence of a palladium catalyst such as tetrakistriphenylphosphine palladium, the formula (8)

Or formula (9)

Compound (7-c) can be produced by reacting the compound represented by the formula:
Step (7-3): Compound (7-d) can be produced by reacting compound (7-c) in the presence of iron powder and ammonium chloride water in a solvent.
Step (7-4): In a solvent, the compound (7-d) is reacted with 4-nitrophenyl chloroformate in the presence of a base such as pyridine, and further reacted with a compound represented by the formula Q-NH ₂ . Thus, compound (7-e) can be produced. Alternatively, compound (7-e) can also be produced by reacting compound (7-d) with a compound represented by formula Q-NCO in the presence or absence of a base such as triethylamine in a solvent. Can do.
Step (7-5): The compound (7-f) of the present invention can be produced by hydrolyzing the compound (7-e) in a solvent using a base such as an aqueous sodium hydroxide solution.
Examples of the base in the description of the general production method of the compound of the present invention include sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydroxide, sodium hydride, lithium hydride, sodium amide, Examples thereof include alkali metal salts such as t-butoxy potassium, n-butyl lithium and lithium diisopropylamide, amines such as triethylamine, diisopropylethylamine, pyrrolidine and piperidine, sodium acetate and potassium acetate.
Examples of the oxidizing agent in the description of the general production method of the compound of the present invention include m-chloroperbenzoic acid, magnesium monoperphthalate hexahydrate, organic peracid such as peracetic acid or excessive acid, hydrogen peroxide, Urea hydrogen peroxide adduct / inorganic and organic peroxides such as phthalic anhydride, t-butyl hydroperoxide or cumene hydroperoxide, sodium periodate, oxone (registered trademark), N-bromosuccinimide, N-chloro Examples include succinimide, chloramine-T, t-butyl hypochlorite, iodobenzene diacetate or a bromine-1,4-diazabicyclo [2,2,2] octane addition complex.
As a reducing agent in description of the general manufacturing method of this invention compound, sodium borohydride or lithium borohydride is mentioned, for example.
The solvent in the description of the general production method of the compound of the present invention is not particularly limited as long as it is stable under the reaction conditions and is inert and does not interfere with the reaction. For example, water, methanol, Alcohols such as ethanol, i-propyl alcohol, n-butanol or t-butyl alcohol, ethers such as dioxane or tetrahydrofuran, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, pyridine, ethyl acetate, methylene chloride, chloroform, acetone, acetic acid , Benzene or toluene, or a mixed solvent thereof.
The reaction temperature in the general production method of the compound of the present invention can be selected from an appropriate temperature in the range of −78 ° C. to the boiling point of the solvent used in the reaction. This production method is conducted under atmospheric pressure, under pressure, and microwave irradiation. It can be carried out under the following conditions.

  In order to show the compound of the present invention in more detail below, examples and test examples are shown, but the examples are not limited.

(Example 1)
Preparation of 2-{[5- (4-{[(2,3-dimethoxyphenyl) carbamoyl] amino} phenyl) pyridin-2-yl] oxy} -2-methylpropionic acid ethyl ester (Compound No. 1)
(1) To a solution of 5-bromopyridin-2 (1H) -one (3.0 g, 17.2 mmol) in dimethylformamide (60 ml), 2-bromoisobutyric acid ethyl ester (6.7 g, 34.5 mmol), cesium carbonate (11.2 g, 34.5 mmol) was added, and the mixture was stirred at 60 ° C. for 1.5 hours. After cooling to room temperature, the reaction solution was diluted with ethyl acetate, and the organic layer was washed with an aqueous ammonium chloride solution and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The resulting residue was purified by silica gel column chromatography [developing solvent; hexane: ethyl acetate = 9: 1] to give 2-[(5- Bromopyridin-2-yl) oxy] -2-methylpropionic acid ethyl ester (2.08 g) was obtained.
1H NMR (300 MHz, CDCl3) δ ppm 1.15 (t, J = 7.2 Hz, 3H) 1.65 (s, 6H) 4.14 (q, J = 7.2 Hz, 2H) 6.67 (d, J = 8.4 Hz, 1H) 7.64 (dd, J = 2.7 Hz, 8.4 Hz, 1H) 8.08 (d, J = 2.7 Hz, 1H)
(2) 2-[(5-Bromopyridin-2-yl) oxy] -2-methylpropionic acid ethyl ester (2.08 g, 7.22 mmol), 4-nitrophenylboric acid (1.22 g, 7.58 mmol) ), Palladium (II) acetate (162 mg, 0.722 mmol), triphenylphosphine (568 mg, 2.17 mmol) in dioxane (40 ml), 2M aqueous sodium carbonate solution (18 ml, 36.1 mmol) was added at room temperature, The mixture was stirred at 80 ° C. for 30 minutes in a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature, diluted with ethyl acetate, and the organic layer was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The obtained residue was purified by silica gel column chromatography [developing solvent; hexane: ethyl acetate = 9: 1] to give 2-methyl-2- {[5- (4-Nitrophenyl) pyridin-2-yl] oxy} propionic acid ethyl ester (1.64 g) was obtained.
MS (ESI): 331 (M + 1)
1H NMR (300 MHz, CDCl3) δ ppm 1.16 (t, J = 7.2 Hz, 3H) 1.70 (s, 6H) 4.18 (q, J = 7.2 Hz, 2H) 6.88 (d, J = 8.7 Hz, 1H) 7.66 (d, J = 9.0 Hz, 2H) 7.83 (dd, J = 2.7 Hz, 8.7 Hz, 1H) 8.29 (d, J = 9.0 Hz, 2H) 8.33 (d, J = 2.7 Hz, 1H)
(3) 2-Methyl-2-{[5- (4-nitrophenyl) pyridin-2-yl] oxy} propionic acid ethyl ester (1.64 g, 4.96 mmol) in methanol (40 ml) solution in 2% Platinum carbon (300 mg) was added, and the mixture was stirred in a hydrogen atmosphere at room temperature for 30 minutes and at 45 ° C. for 4 hours. Solids were removed by Celite filtration, the filtrate was concentrated, and 2-methyl-2-{[5- (4-aminophenyl) pyridin-2-yl] oxy} propionic acid ethyl ester (1.39 g) as a solid. )
MS (ESI): 301 (M + 1)
1H NMR (300 MHz, CDCl3) δ ppm 1.14 (t, J = 7.1 Hz, 3H) 1.69 (s, 6H) 3.64 3.82 (br, 2H) 4.15 (q, J = 7.1 Hz, 2H) 6.69 6.83 (m, 3H) 7.27 7.36 (m, 2H) 7.67 7.77 (m, 1H) 8.16 8.24 (m, 1H)
(4) 2-methyl-2-{[5- (4-aminophenyl) pyridin-2-yl] oxy} propionic acid ethyl ester (199 mg, 0.663 mmol) in chloroform (4 ml) under ice-cooling. Pyridine (0.081 ml, 0.995 mmol) and 4-nitrophenyl chloroformate (160 mg, 0.796 mmol) were added, and the mixture was stirred at 0 ° C. for 1 hour. Triethylamine (0.139 ml, 0.995 mmol) and 2,3-dimethoxyaniline (0.107 ml, 0.796 mmol) were added to the reaction solution, and the mixture was stirred at room temperature for 15 hours. The reaction solution was diluted with ethyl acetate, and the organic layer was washed with a saturated aqueous solution of ammonium chloride, a saturated aqueous solution of sodium bicarbonate, and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and then added with NH silica gel and allowed to stand. The solid was filtered and the filtrate was concentrated. The obtained solid was suspended in ethyl acetate / diisopropyl ether, collected by filtration, and 2-{[5- (4-{[(2,3-dimethoxyphenyl) carbamoyl] amino} phenyl) pyridine-2 as a colorless solid. -Il] oxy} -2-methylpropionic acid ethyl ester (306 mg) was obtained.
(Example 2)
In accordance with the production method of Example 1, instead of 2,3-dimethoxyaniline, 2-methoxy-5-methylaniline, 2-methoxy-5-trifluoromethylaniline, 2-chloro-4-fluoroaniline, 3 , 5-dimethylbenzylamine, cyclohexylamine, 2,4-dimethylaniline, 3,5-dimethylaniline, 2-chloro-5-methoxyaniline, 3-chloro-2-methylaniline, 1-adamantylamine The following compounds of the present invention were obtained.
2-{[5- (4-{[(2-methoxy-5-methylphenyl) carbamoyl] amino} phenyl) pyridin-2-yl] oxy} -2-methylpropionic acid ethyl ester (Compound No. 2)
2-({5- [4-({[2-methoxy-5- (trifluoromethyl) phenyl] carbamoyl} amino) phenyl] pyridin-2-yl} oxy) -2-methylpropionic acid ethyl ester (Compound No. 3)
2-{[5- (4-{[(2-Chloro-4-fluorophenyl) carbamoyl] amino} phenyl) pyridin-2-yl] oxy} -2-methylpropionic acid ethyl ester (Compound No. 4)
2-{[5- (4-{[(3,5-dimethylbenzyl) carbamoyl] amino} phenyl) pyridin-2-yl] oxy} -2-methylpropionic acid ethyl ester (Compound No. 5)
2-[(5- {4-[(cyclohexylcarbamoyl) amino] phenyl} pyridin-2-yl) oxy] -2-methylpropionic acid ethyl ester (Compound No. 6)
2-{[5- (4-{[(2,4-Dimethylphenyl) carbamoyl] amino} phenyl) pyridin-2-yl] oxy} -2-methylpropionic acid ethyl ester (Compound No. 7)
2-{[5- (4-{[(3,5-dimethylphenyl) carbamoyl] amino} phenyl) pyridin-2-yl] oxy} -2-methylpropionic acid ethyl ester (Compound No. 8)
2-{[5- (4-{[(2-Chloro-5-methoxyphenyl) carbamoyl] amino} phenyl) pyridin-2-yl] oxy} -2-methylpropionic acid ethyl ester (Compound No. 9)
2-{[5- (4-{[(3-Chloro-2-methylphenyl) carbamoyl] amino} phenyl) pyridin-2-yl] oxy} -2-methylpropionic acid ethyl ester (Compound No. 10)
2-[(5- {4-[(adamantan-1-ylcarbamoyl) amino] phenyl} pyridin-2-yl) oxy] -2-methylpropionic acid ethyl ester (Compound No. 11)
(Example 3)
Preparation of 2-{[5- (4-{[(2,3-dimethoxyphenyl) carbamoyl] amino} phenyl) pyridin-2-yl] oxy} -2-methylpropionic acid (Compound No. 12)
2-{[5- (4-{[(2,3-dimethoxyphenyl) carbamoyl] amino} phenyl) pyridin-2-yl] oxy} -2-methylpropionic acid ethyl ester (257 mg, 0.536 mmol) in tetrahydrofuran A 6M aqueous sodium hydroxide solution (1 ml) was added to a mixed solution of (4 ml) and methanol (2 ml), and the mixture was stirred at room temperature for 19 hours. The reaction mixture was neutralized with 1M hydrochloric acid and diluted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The resulting solid was suspended in ethyl acetate / diisopropyl ether, and the solid was collected by filtration to give 2-{[5- (4-{[(2,3-dimethoxyphenyl) carbamoyl] amino} phenyl) pyridine as a colorless solid. -2-yl] oxy} -2-methylpropionic acid (223 mg) was obtained.
Example 4
In accordance with the production method of Example 3, the following compounds of the present invention were obtained.
2-{[5- (4-{[(2-methoxy-5-methylphenyl) carbamoyl] amino} phenyl) pyridin-2-yl] oxy} -2-methylpropionic acid (Compound No. 13)
2-({5- [4-({[2-methoxy-5- (trifluoromethyl) phenyl] carbamoyl} amino) phenyl] pyridin-2-yl} oxy) -2-methylpropionic acid (Compound No. 14)
2-{[5- (4-{[(2-Chloro-4-fluorophenyl) carbamoyl] amino} phenyl) pyridin-2-yl] oxy} -2-methylpropionic acid (Compound No. 15)
2-{[5- (4-{[(3,5-dimethylbenzyl) carbamoyl] amino} phenyl) pyridin-2-yl] oxy} -2-methylpropionic acid (Compound No. 16)
2-[(5- {4-[(cyclohexylcarbamoyl) amino] phenyl} pyridin-2-yl) oxy] -2-methylpropionic acid (Compound No. 17)
2-{[5- (4-{[(2,4-Dimethylphenyl) carbamoyl] amino} phenyl) pyridin-2-yl] oxy} -2-methylpropionic acid (Compound No. 18)
2-{[5- (4-{[(3,5-dimethylphenyl) carbamoyl] amino} phenyl) pyridin-2-yl] oxy} -2-methylpropionic acid (Compound No. 19)
2-{[5- (4-{[(2-Chloro-5-methoxyphenyl) carbamoyl] amino} phenyl) pyridin-2-yl] oxy} -2-methylpropionic acid (Compound No. 20)
2-{[5- (4-{[(3-Chloro-2-methylphenyl) carbamoyl] amino} phenyl) pyridin-2-yl] oxy} -2-methylpropionic acid (Compound No. 21)
2-[(5- {4-[(adamantan-1-ylcarbamoyl) amino] phenyl} pyridin-2-yl) oxy] -2-methylpropionic acid (Compound No. 22)
(Example 5)
Preparation of 2-{[5- (4-{[(2-chlorophenyl) carbamoyl] amino} phenyl) pyridin-2-yl] oxy} -2-methylpropionic acid ethyl ester (Compound No. 23)
To a solution of 2-methyl-2-{[5- (4-aminophenyl) pyridin-2-yl] oxy} propionic acid ethyl ester (196 mg, 0.652 mmol) in tetrahydrofuran (2 ml) was added 2-chlorophenyl isocyanate (0 0.094 ml, 0.78 mmol) was added, and the mixture was stirred at room temperature for 15 hours. The reaction solution was diluted with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The obtained solid was suspended in ethyl acetate / diisopropyl ether, collected by filtration, and 2-{[5- (4-{[(2-chlorophenyl) carbamoyl] amino} phenyl) pyridin-2-yl] as a colorless solid. Oxy} -2-methylpropionic acid ethyl ester (266 mg) was obtained.
(Example 6)
Based on the production method of Example 5, the following compounds of the present invention were obtained by using 2-ethylphenyl isocyanate instead of 2-chlorophenyl isocyanate.
2-{[5- (4-{[(2-Ethylphenyl) carbamoyl] amino} phenyl) pyridin-2-yl] oxy} -2-methylpropionic acid ethyl ester (Compound No. 24)
(Example 7)
Preparation of 2-{[5- (4-{[(2-chlorophenyl) carbamoyl] amino} phenyl) pyridin-2-yl] oxy} -2-methylpropionic acid (Compound No. 25)
2-{[5- (4-{[(2-chlorophenyl) carbamoyl] amino} phenyl) pyridin-2-yl] oxy} -2-methylpropionic acid ethyl ester (263 mg, 0.578 mmol) in tetrahydrofuran (4 ml) A 6M aqueous sodium hydroxide solution (1 ml) was added to a mixed solution of methanol and methanol (2 ml), and the mixture was stirred at room temperature for 19 hours. The reaction mixture was neutralized with 1M hydrochloric acid and diluted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The resulting solid was suspended in ethyl acetate / diisopropyl ether, and the solid was collected by filtration to give 2-{[5- (4-{[(2-chlorophenyl) carbamoyl] amino} phenyl) pyridine-2- as a colorless solid. Yl] oxy} -2-methylpropionic acid (216 mg) was obtained.
(Example 8)
Based on the production methods of Examples 5 and 7, the following compounds of the present invention were obtained by using 2-ethylphenyl isocyanate instead of 2-chlorophenyl isocyanate.
2-{[5- (4-{[(2-Ethylphenyl) carbamoyl] amino} phenyl) pyridin-2-yl] oxy} -2-methylpropionic acid (Compound No. 26)
Example 9
Preparation of 3-{[5- (4-{[(2,3-dimethoxyphenyl) carbamoyl] amino} phenyl) pyridin-2-yl] amino} -2,2-dimethylpropionic acid (Compound No. 27)
(1) 2,2-Dimethyl-3-oxopropionic acid benzyl ester (literature: Org. Lett. 2003, 5) was added to a solution of 5-bromopyridin-2-amine (974 mg, 5.63 mmol) in dimethylformamide (20 ml). , 14, 2473-2475) (2.32 g, 11.3 mmol) and trifluoroacetic acid (7.7 g, 67.6 mmol), and sodium triacetoxyhydroboron (4.77 g) under ice cooling. 22.5 mmol) was added and stirred at room temperature for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction solution under ice cooling, the reaction solution was diluted with ethyl acetate, and the organic layer was washed with an aqueous ammonium chloride solution and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The obtained residue was purified by silica gel column chromatography [developing solvent; hexane: ethyl acetate = 8: 1] to give 3-[(5- Bromopyridin-2-yl) amino] -2,2-dimethylpropionic acid benzyl ester (1.26 g) was obtained.
1H NMR (300 MHz, CDCl3) δ ppm 1.27 (s, 6H) 3.40 3.56 (m, 2H) 4.69 4.90 (m, 1H) 5.13 (s, 2H) 6.16 6.29 (m, 1H) 7.18 7.45 (m, 6H) 8.00 8.11 (m, 1H)
(2) 3-[(5-Bromopyridin-2-yl) amino] -2,2-dimethylpropionic acid benzyl ester (1.26 g, 3.48 mmol), 4-nitrophenylboric acid (588 mg, 3.65 mmol) ), Palladium (II) acetate (78.1 mg, 0.348 mmol), triphenylphosphine (274 mg, 1.04 mmol) in dioxane (20 ml) at room temperature, 2M aqueous sodium carbonate solution (8.7 ml, 17.4 mmol). And stirred at 80 ° C. for 1 hour under a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature, diluted with ethyl acetate, and the organic layer was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The resulting residue was purified by silica gel column chromatography [developing solvent; hexane: ethyl acetate = 4: 1 to 2: 1], 2-Dimethyl-3-{[5- (4-nitrophenyl) pyridin-2-yl] amino} propionic acid benzyl ester (879 mg) was obtained.
(3) 2,2-Dimethyl-3-{[5- (4-nitrophenyl) pyridin-2-yl] amino} propionic acid benzyl ester (879 mg, 2.17 mmol) in ethanol (20 ml) was added water ( 2 ml), iron powder (1.21 g, 21.7 mmol) and concentrated hydrochloric acid (0.1 ml) were added, and the mixture was stirred at 80 ° C. for 1 hour. The reaction solution was allowed to cool to room temperature, solids were removed by Celite filtration, the filtrate was concentrated, and the resulting residue was diluted with ethyl acetate and an aqueous sodium bicarbonate solution, and the organic layer was saturated with an aqueous sodium bicarbonate solution, and Washed with saturated saline. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The resulting residue was purified by silica gel column chromatography [developing solvent; hexane: ethyl acetate = 3: 1 to 1: 1], and 3- {[5- (4-Aminophenyl) pyridin-2-yl] amino} -2,2-dimethylpropionic acid benzyl ester (660 mg) was obtained.
1H NMR (300 MHz, CDCl3) δ ppm 1.31 (s, 6H) 3.50 3.61 (m, 2H) 3.61 3.82 (br, 2H) 4.59 4.83 (m, 1H) 5.14 (s, 2H) 6.32 6.43 (m, 1H) 6.69 6.81 (m, 2H) 7.22 7.41 (m, 7H) 7.50 7.60 (m, 1H) 8.20 8.40 (m, 1H)
(4) A solution of 3-{[5- (4-aminophenyl) pyridin-2-yl] amino} -2,2-dimethylpropionic acid benzyl ester (149 mg, 0.396 mmol) in chloroform (3 ml) was cooled with ice. Below, pyridine (0.048 ml, 0.59 mmol) and 4-nitrophenyl chloroformate (95.8 mg, 0.475 mmol) were added and stirred at room temperature for 1 hour. Triethylamine (0.083 ml, 0.59 mmol) and 2,3-dimethoxyaniline (0.064 ml, 0.48 mmol) were added to the reaction solution, and the mixture was stirred overnight at room temperature. The reaction solution was diluted with ethyl acetate, and the organic layer was washed with a saturated aqueous solution of ammonium chloride, a saturated aqueous solution of sodium bicarbonate, and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated, and purified by silica gel column chromatography [NH silica gel, developing solvent; hexane: ethyl acetate = 5: 1] to give 3-{[5- (4 -{[(2,3-dimethoxyphenyl) carbamoyl] amino} phenyl) pyridin-2-yl] amino} -2,2-dimethylpropionic acid benzyl ester (157 mg) was obtained.
MS (ESI): 555 (M + 1), 553 (M-1)
(5) 3-{[5- (4-{[(2,3-Dimethoxyphenyl) carbamoyl] amino} phenyl) pyridin-2-yl] amino} -2,2-dimethylpropionic acid benzyl ester (156 mg, 0 .281 mmol) in a mixed solution of tetrahydrofuran (4 ml) and methanol (2 ml) was added 6M aqueous sodium hydroxide solution (1 ml), and the mixture was stirred at room temperature for 6 hours. The reaction mixture was neutralized with 1M hydrochloric acid, and diluted and suspended in ethyl acetate. The organic layer was washed with water and concentrated. The resulting solid was suspended in ethyl acetate, collected by filtration, and 3-{[5- (4-{[(2,3-dimethoxyphenyl) carbamoyl] amino} phenyl) pyridin-2-yl] as a pale yellow solid. Amino} -2,2-dimethylpropionic acid (101 mg) was obtained.
(Example 10)
According to the production method of Example 9, 2-methoxy-5-methylaniline and 2,4-dimethylaniline were used instead of 2,3-dimethoxyaniline, and benzyl 2,2-dimethyl-3-oxopropionate Instead of ester, 1-formylcyclopropanecarboxylic acid benzyl ester (reference: synthesized according to Org. Lett. 2003, 5, 14, 2473-2475), 4-formyltetrahydro-2H-pyran-4-carboxylic acid benzyl ester ( The following compounds of the present invention were obtained by using (Document: Org. Lett. 2003, 5, 14, 2473-2475).
3-{[5- (4-{[(2-methoxy-5-methylphenyl) carbamoyl] amino} phenyl) pyridin-2-yl] amino} -2,2-dimethylpropionic acid (Compound No. 28)
1-({[5- (4-{[(2,4-Dimethylphenyl) carbamoyl] amino} phenyl) pyridin-2-yl] amino} methyl) cyclopropanecarboxylic acid (Compound No. 29)
4-({[5- (4-{[(2,4-Dimethylphenyl) carbamoyl] amino} phenyl) pyridin-2-yl] amino} methyl) tetrahydro-2H-pyran-4-carboxylic acid (Compound No. 30 )
3-{[5- (4-{[(2,4-Dimethylphenyl) carbamoyl] amino} phenyl) pyridin-2-yl] amino} -2,2-dimethylpropionic acid (Compound No. 31)
(Example 11)
Preparation of 3-{[5- (4-{[(2-chlorophenyl) carbamoyl] amino} phenyl) pyridin-2-yl] amino} -2,2-dimethylpropionic acid (Compound No. 32)
(1) To a solution of 3-{[5- (4-aminophenyl) pyridin-2-yl] amino} -2,2-dimethylpropionic acid benzyl ester (127 mg, 0.337 mmol) in tetrahydrofuran (1.5 ml), 2-Chlorophenyl isocyanate (0.049 ml, 0.40 mmol) was added and stirred at room temperature for 3 hours. The reaction solution was diluted with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was concentrated, and the resulting residue was purified by silica gel column chromatography [developing solvent; hexane: ethyl acetate = 3: 1 to 1: 1] to give 3-{[5- (4-{[(2 -Chlorophenyl) carbamoyl] amino} phenyl) pyridin-2-yl] amino} -2,2-dimethylpropionic acid benzyl ester (173 mg) was obtained.
MS (ESI): 529 (M + 1), 527 (M-1)
(2) 3-{[5- (4-{[(2-chlorophenyl) carbamoyl] amino} phenyl) pyridin-2-yl] amino} -2,2-dimethylpropionic acid benzyl ester (167 mg, 0.316 mmol) To a mixed solution of tetrahydrofuran (2 ml) and methanol (1 ml) was added 6M aqueous sodium hydroxide solution (1 ml), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was neutralized with 1M hydrochloric acid and diluted with ethyl acetate. The organic layer was washed with saturated brine and water and concentrated. The resulting solid was suspended in ethyl acetate / isopropyl ether, and the solid was collected by filtration to give 3-{[5- (4-{[(2-chlorophenyl) carbamoyl] amino} phenyl) pyridine-2 as a pale yellow solid. -Il] amino} -2,2-dimethylpropionic acid (134 mg) was obtained.
Example 12
According to the production methods of Example 9 and Example 11, 1-formylcyclopropanecarboxylic acid benzyl ester, 4-formyltetrahydro-2H-pyran-instead of 2,2-dimethyl-3-oxopropionic acid benzyl ester The following compounds of the present invention were obtained by using 4-carboxylic acid benzyl ester.
1-({[5- (4-{[(2-Chlorophenyl) carbamoyl] amino} phenyl) pyridin-2-yl] amino} methyl) cyclopropanecarboxylic acid (Compound No. 33)
4-({[5- (4-{[(2-chlorophenyl) carbamoyl] amino} phenyl) pyridin-2-yl] amino} methyl) tetrahydro-2H-pyran-4-carboxylic acid (Compound No. 34)
(Example 13)
3-{[5- (4-{[(2-methoxy-5-methylphenyl) carbamoyl] amino} phenyl) pyridin-2-yl] oxy} -2,2-dimethylpropionic acid methyl ester (Compound No. 35) Manufacturing of
(1) To a solution of 2,5-dibromopyridine (9.0 g, 38 mmol) in chloroform (81 ml), m-chloroperbenzoic acid (30.2 g, 114 mmol) was added and stirred at room temperature for 15 hours. A 10% aqueous sodium thiosulfate solution was added to the reaction solution under ice-cooling, and the chloroform layer was extracted. Further, the residue obtained by washing with 1M aqueous sodium hydroxide and saturated brine, drying (anhydrous magnesium sulfate), filtration and concentration was subjected to silica gel column chromatography [NH silica gel, developing solvent; hexane: ethyl acetate = 2: 1]. To give 2,5-dibromopyridine 1-oxide (6.29 g) as a colorless powder.
MS (ESI / APCI Dual): 252 (M + 1)
1H NMR (200 MHz, CDCl3) δ ppm 7.19-7.28 (m, 1 H) 7.49-7.56 (m, 1 H) 8.49-8.53 (m, 1 H)
(2) To a solution of 2,5-dibromopyridine 1-oxide (900 mg, 3.56 mmol) in toluene (18 ml), 3-hydroxy-2,2-dimethylpropionic acid methyl ester (941 mg, 7.12 mmol), potassium carbonate ( 984 mg, 7.12 mmol) was added and heated to reflux for 18 hours. The residue obtained by filtering and concentrating the reaction solution through celite was purified by silica gel column chromatography [developing solvent; methanol: ethyl acetate = 0: 1 to 1:50] to give 3-[(5 -Bromo-1-oxidepyridin-2-yl) oxy] -2,2-dimethylpropionic acid methyl ester (545 mg) was obtained.
MS (ESI / APCI Dual): 304 (M + 1), 302 (M-1)
1H NMR (300 MHz, CDCl3) δ ppm 1.36 (s, 6 H) 3.70 (s, 3 H) 4.31 (s, 2 H) 6.83 (d, J = 8.9 Hz, 1 H) 7.29-7.34 (m, 1 H) 8.33-8.35 (m, 1 H)
(3) A solution of 3-[(5-bromo-1-oxidepyridin-2-yl) oxy] -2,2-dimethylpropionic acid methyl ester (200 mg, 0.658 mmol) in ethanol (1.9 ml) was saturated. Aqueous ammonium chloride solution (1.3 ml) and indium (90.7 mg, 0.79 mmol) were added, and the mixture was heated to reflux for 10 hours. Water was added to the reaction solution, extracted with ethyl acetate, dried (anhydrous magnesium sulfate), filtered, and concentrated, and the resulting residue was subjected to silica gel column chromatography [developing solvent; chloroform: methanol = 20: 1 to 10: 1]. To give 3-[(5-bromopyridin-2-yl) oxy] -2,2-dimethylpropionic acid methyl ester (115 mg) as a colorless oil.
MS (ESI / APCI Dual): 288 (M + 1)
1H NMR (300 MHz, CDCl3) δ ppm 1.30 (s, 6 H) 3.69 (s, 3 H) 4.29 (s, 2 H) 6.63-6.68 (m, 1 H) 7.60-7.66 (m, 1 H) 8.15 -8.19 (m, 1 H)
(4) 3-[(5-Bromopyridin-2-yl) oxy] -2,2-dimethylpropionic acid methyl ester (140 mg, 0.486 mmol), 4-nitrophenylboric acid (93.3 mg, 0.559 mmol) ), Triphenylphosphine (38.2 mg, 0.146 mmol) in dioxane (1.94 ml) and 2M aqueous sodium carbonate (1.21 ml) in palladium (II) acetate (10.9 mg, 0.0486 mmol). And stirred at an external temperature of 80 ° C. for 45 minutes. The reaction mixture was filtered through celite, water was added to the filtrate, the mixture was extracted with ethyl acetate, dried (anhydrous magnesium sulfate), filtered, and concentrated. The residue was obtained by silica gel column chromatography [developing solvent; hexane: ethyl acetate = 6: 1] gave 2,2-dimethyl-3-{[5- (4-nitrophenyl) pyridin-2-yl] oxy} propionic acid methyl ester (130 mg) as a yellow powder.
MS (ESI / APCI Dual): 331 (M + 1)
1H NMR (300 MHz, CDCl3) δ ppm 1.34 (s, 6 H) 3.71 (s, 3 H) 4.40 (s, 2 H) 6.83-6.91 (m, 1 H) 7.64-7.72 (m, 2 H) 7.79 -7.87 (m, 1 H) 8.27-8.35 (m, 2 H) 8.39-8.45 (m, 1 H)
(5) 2,2-dimethyl-3-{[5- (4-nitrophenyl) pyridin-2-yl] oxy} propionic acid methyl ester (120 mg, 0.362 mmol) in ethanol (1.5 ml) and tetrahydrofuran ( 1.5%) was added to 10% platinum carbon (12 mg), and the mixture was stirred for 15 hours at room temperature in a hydrogen gas atmosphere. The reaction mixture was filtered through Celite, and the residue obtained by concentrating the filtrate was purified by silica gel column chromatography [developing solvent; hexane: ethyl acetate = 1: 1] to give 3-{[ 5- (4-Aminophenyl) pyridin-2-yl] oxy} -2,2-dimethylpropionic acid methyl ester (99 mg) was obtained.
MS (ESI / APCI Dual): 301 (M + 1)
1H NMR (300 MHz, CDCl3) δ ppm 1.32 (s, 6 H) 3.67 −3.72 (br, 2 H) 3.69 (s, 3 H) 4.35 (s, 2 H) 6.72-6.79 (m, 3 H) 7.28 -7.36 (m, 2 H) 7.71 (dd, J = 8.6, 2.5 Hz, 1 H) 8.29 (dd, J = 2.5, 0.7 Hz, 1 H)
(6) 3-{[5- (4-Aminophenyl) pyridin-2-yl] oxy} -2,2-dimethylpropionic acid methyl ester (1.55 g, 5.16 mmol), 4-nitrophenyl chloroformate Pyridine (0.565 ml, 6.97 mmol) was added to a chloroform (25 ml) solution of (1.25 g, 6.19 mmol) under ice cooling, and the mixture was stirred for 30 minutes under ice cooling. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, dried (anhydrous magnesium sulfate), filtered and concentrated. The residue obtained was recrystallized (ethyl acetate-hexane) to give 2,2- Dimethyl-3-{[5- (4-{[(4-nitrophenoxy) carbonyl] amino} phenyl) pyridin-2-yl] oxy} propionic acid methyl ester (2.09 g) was obtained.
1H NMR (300 MHz, CDCl3) δ ppm 1.33 (s, 6 H) 3.71 (s, 3 H) 4.37 (s, 2 H) 6.79-6.84 (m, 1 H) 7.09 (br, 1 H) 7.38-7.45 (m, 2 H) 7.53 (s, 4 H) 7.75-7.80 (m, 1 H) 8.28-8.33 (m, 2 H) 8.33-8.36 (m, 1 H)
(7) 2,2-Dimethyl-3-{[5- (4-{[(4-nitrophenoxy) carbonyl] amino} phenyl) pyridin-2-yl] oxy} propionic acid methyl ester (200 mg, 0.430 mmol ), 2-methoxy-5-methylaniline (65 mg, 0.473 mmol) in chloroform (6 ml) was added triethylamine (0.12 ml, 0.860 mmol) at room temperature and stirred for 2.5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed successively with 1M aqueous sodium hydroxide solution and saturated brine, dried (anhydrous magnesium sulfate), filtered, and concentrated. , Developing solvent; hexane: ethyl acetate = 8: 1 to 1: 2] to give a pale brown amorphous 3-{[5- (4-{[(2-methoxy-5-methylphenyl) carbamoyl] Amino} phenyl) pyridin-2-yl] oxy} -2,2-dimethylpropionic acid methyl ester (140 mg) was obtained.
(Example 14)
According to the production method of Example 13, instead of 2-methoxy-5-methylaniline, 2,3-dimethoxyaniline, 2-chloroaniline, 3-ethylaniline, 3,5-dimethylaniline, 2,4- The following compounds of the present invention were obtained by using dimethylaniline, 2-ethylaniline, and cyclohexylamine.
3-{[5- (4-{[(2,3-dimethoxyphenyl) carbamoyl] amino} phenyl) pyridin-2-yl] oxy} -2,2-dimethylpropionic acid methyl ester (Compound No. 36)
3-{[5- (4-{[(2-chlorophenyl) carbamoyl] amino} phenyl) pyridin-2-yl] oxy} -2,2-dimethylpropionic acid methyl ester (Compound No. 37)
3-{[5- (4-{[(3-Ethylphenyl) carbamoyl] amino} phenyl) pyridin-2-yl] oxy} -2,2-dimethylpropionic acid ethyl ester (Compound No. 38)
3-{[5- (4-{[(3,5-dimethylphenyl) carbamoyl] amino} phenyl) pyridin-2-yl] oxy} -2,2-dimethylpropionic acid methyl ester (Compound No. 39)
3-{[5- (4-{[(2,4-Dimethylphenyl) carbamoyl] amino} phenyl) pyridin-2-yl] oxy} -2,2-dimethylpropionic acid methyl ester (Compound No. 40)
3-{[5- (4-{[(2-Ethylphenyl) carbamoyl] amino} phenyl) pyridin-2-yl] oxy} -2,2-dimethylpropionic acid methyl ester (Compound No. 41)
3-[(5- {4-[(cyclohexylcarbamoyl) amino] phenyl} pyridin-2-yl) oxy] -2,2-dimethylpropionic acid methyl ester (Compound No. 42)
(Example 15)
Preparation of 3-{[5- (4-{[(2-methoxy-5-methylphenyl) carbamoyl] amino} phenyl) pyridin-2-yl] oxy} -2,2-dimethylpropionic acid (Compound No. 43)
(1) 2- (1,3-dioxolan-2-yl) -2-methylpropan-1-ol (see Patent Document: WO05102977) (453 mg, 3.10 mmol) in dimethylformamide (1 ml) under ice-cooling Sodium hydride (45% liquid paraffin added) (119 mg, 3.10 mmol) was added, and the mixture was stirred for 10 minutes under ice cooling. The reaction solution was warmed to room temperature, 5-bromo-2-chloropyridine (199 mg, 1.03 mmol) was added, and the mixture was stirred at room temperature for 30 minutes and at an external temperature of 90 ° C. for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, dried (anhydrous magnesium sulfate), filtered, and concentrated. The resulting residue was subjected to silica gel column chromatography [developing solvent; hexane: ethyl acetate = 10: 1 to 2: 1. ] To give colorless solid 5-bromo-2- [2- (1,3-dioxolan-2-yl) -2-methylpropoxy] pyridine (275 mg).
MS (ESI / APCI Dual): 302 (M + 1)
1H NMR (300 MHz, CDCl3) δ ppm 1.04 (s, 6 H) 3.84-3.91 (m, 2 H) 3.91-3.99 (m, 2 H) 4.14 (s, 2 H) 4.84 (s, 1 H) 6.66 (dd, J = 8.7, 0.6 Hz, 1 H) 7.62 (dd, J = 8.7, 2.6 Hz, 1 H) 8.17 (dd, J = 2.6, 0.6 Hz, 1 H)
(2) 5-Bromo-2- [2- (1,3-dioxolan-2-yl) -2-methylpropoxy] pyridine (263 mg, 0.87 mmol), 4-nitrophenylboric acid (290 mg, 1.74 mmol) ) Sodium carbonate (738 mg, 6.96 mmol) was added to a mixture of 10% palladium carbon (132 mg) and triphenylphosphine (46 mg, 0.174 mmol) in ethanol (2.7 ml) and water (2.7 ml), The mixture was stirred at an external temperature of 85 ° C. for 11 hours. Water and ethyl acetate were added to the reaction mixture, and the mixture was filtered through celite. The ethyl acetate layer was extracted, dried (anhydrous magnesium sulfate), filtered and concentrated. The residue was obtained by silica gel column chromatography [developing solvent; hexane: acetic acid. By purifying with ethyl = 15: 1 to 6: 1], 2- [2- (1,3-dioxolan-2-yl) -2-methylpropoxy] -5- (4-nitro Phenyl) pyridine (278 mg) was obtained.
MS (ESI / APCI Dual): 345 (M + 1)
1H NMR (300 MHz, CDCl3) δ ppm 1.08 (s, 6 H) 3.86-3.93 (m, 2 H) 3.94-4.01 (m, 2 H) 4.25 (s, 2 H) 4.88 (s, 1 H) 6.85 -6.91 (m, 1 H) 7.64-7.71 (m, 2 H) 7.80-7.86 (m, 1 H) 8.27-8.34 (m, 2 H) 8.41-8.45 (m, 1 H)
(3) 2- [2- (1,3-Dioxolan-2-yl) -2-methylpropoxy] -5- (4-nitrophenyl) pyridine (266 mg, 0.772 mmol) in ethanol (1.8 ml) and To a mixed solution of tetrahydrofuran (1.8 ml) was added 10% platinum carbon (27 mg), and the mixture was stirred for 15 hours at room temperature in a hydrogen gas atmosphere. The reaction solution was filtered through Celite, and the residue obtained by concentrating the filtrate was purified by silica gel column chromatography [developing solvent; hexane: ethyl acetate = 10: 1 to 2: 3] to give a colorless powder. 4- {6- [2- (1,3-dioxolan-2-yl) -2-methylpropoxy] pyridin-3-yl} aniline (193 mg) was obtained.
MS (ESI / APCI Dual): 315 (M + 1)
1H NMR (300 MHz, CDCl3) δ ppm 1.07 (s, 6 H) 3.67-3.80 (m, 2 H) 3.84-3.92 (m, 2 H) 3.92-4.00 (m, 2 H) 4.19 (s, 2 H ) 4.89 (s, 1 H) 6.72-6.80 (m, 3 H) 7.29-7.36 (m, 2 H) 7.71 (dd, J = 8.6, 2.6 Hz, 1 H) 8.30 (dd, J = 2.6, 0.7 Hz , 1 H)
(4) Triethylamine in a solution of 4- {6- [2- (1,3-dioxolan-2-yl) -2-methylpropoxy] pyridin-3-yl} aniline (190 mg, 0.604 mmol) in tetrahydrofuran (2 ml) (0.084 ml, 0.604 mmol) and 2-methoxy-5-methylphenyl isocyanate (251 mg, 1.51 mmol) were added and stirred at room temperature for 15 hours. The residue obtained by concentrating the reaction solution is purified by silica gel column chromatography [developing solvent; hexane: ethyl acetate = 6: 1 to 2: 3] to give a light brown amorphous 1- (4- { 6- [2- (1,3-Dioxolan-2-yl) -2-methylpropoxy] pyridin-3-yl} phenyl) -3- (2-methoxy-5-methylphenyl) urea (223 mg) was obtained. .
MS (ESI / APCI Dual): 478 (M + 1), 476 (M-1)
1H NMR (300 MHz, CDCl3) δ ppm 1.08 (s, 6 H) 2.31 (s, 3 H) 3.82 (s, 3 H) 3.85-3.92 (m, 2 H) 3.92-4.00 (m, 2 H) 4.22 (s, 2 H) 4.89 (s, 1 H) 6.71 (s, 1 H) 6.74-6.85 (m, 3 H) 7.13 (s, 1 H) 7.47 (s, 4 H) 7.76 (dd, J = 8.6 , 2.6 Hz, 1 H) 7.93-7.95 (m, 1 H) 8.33-8.36 (m, 1 H)
(5) 1- (4- {6- [2- (1,3-Dioxolan-2-yl) -2-methylpropoxy] pyridin-3-yl} phenyl) -3- (2-methoxy-5-methyl) To a mixed solution of phenyl) urea (202 mg, 0.423 mmol) in chloroform (2.4 ml) and acetone (32 ml), water (1.2 ml) and p-toluenesulfonic acid monohydrate (121 mg, 0.635 mmol) And heated to reflux for 18 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, dried (anhydrous magnesium sulfate), filtered, and concentrated. The resulting residue was subjected to silica gel column chromatography [developing solvent; chloroform: ethyl acetate = 4: 1 to 2: 1. ] To give a light brown amorphous 1- {4- [6- (2,2-dimethyl-3-oxopropoxy) pyridin-3-yl] phenyl} -3- (2-methoxy-5- Methylphenyl) urea (176 mg) was obtained.
1H NMR (300 MHz, DMSO-d6) δ ppm 1.13 (s, 6 H) 2.24 (s, 3 H) 3.85 (s, 3 H) 4.38 (s, 2 H) 6.72-6.78 (m, 1 H) 6.83 -6.92 (m, 2 H) 7.51-7.62 (m, 4 H) 7.95-8.01 (m, 2 H) 8.18-8.22 (m, 1 H) 8.41-8.45 (m, 1 H) 9.41-9.44 (m, 1 H) 9.62 (s, 1 H)
(6) 1- {4- [6- (2,2-Dimethyl-3-oxopropoxy) pyridin-3-yl] phenyl} -3- (2-methoxy-5-methylphenyl) urea (30 mg, 0. 0692 mmol) in chloroform (1 ml) was added m-chloroperbenzoic acid (18 mg, 0.1038 mmol) under ice cooling, and the mixture was stirred at room temperature for 1.5 hours. Further, m-chloroperbenzoic acid (12 mg, 0.069 mmol) was added and stirred at room temperature for 1 hour. The residue obtained by concentrating the reaction solution was subjected to silica gel column chromatography [developing solvent; chloroform: ethyl acetate = 5: 1 to 1: 1], and preparative thin layer silica gel chromatography [developing solvent; chloroform: methanol. = 15: 1] to give a colorless powder of 3-{[5- (4-{[(2-methoxy-5-methylphenyl) carbamoyl] amino} phenyl) pyridin-2-yl] oxy}- 2,2-dimethylpropionic acid (8 mg) was obtained.
(Example 16)
Preparation of 3-{[5- (4-{[(2-methoxy-5-methylphenyl) carbamoyl] amino} phenyl) pyridin-2-yl] oxy} -2,2-dimethylpropionic acid (Compound No. 43)
3-{[5- (4-{[(2-methoxy-5-methylphenyl) carbamoyl] amino} phenyl) pyridin-2-yl] oxy} -2,2-dimethylpropionic acid methyl ester (137 mg,. To a mixed solution of 296 mmol) tetrahydrofuran (2 ml) and methanol (1 ml) was added 6M aqueous sodium hydroxide solution (0.49 ml), and the mixture was stirred at room temperature for 8 hours. The reaction solution was neutralized with 1M aqueous hydrochloric acid under ice-cooling, extracted with ethyl acetate, dried (anhydrous magnesium sulfate), filtered and concentrated to give 3-{[5- (4-{[(2 -Methoxy-5-methylphenyl) carbamoyl] amino} phenyl) pyridin-2-yl] oxy} -2,2-dimethylpropionic acid (125 mg) was obtained.
(Example 17)
In accordance with the production methods of Examples 13 and 16, 2,3-dimethoxyaniline, 2-chloroaniline, 3-ethylaniline, 3,5-dimethylaniline, 2,2-dimethoxyaniline instead of 2-methoxy-5-methylaniline, By using 4-dimethylaniline, 2-ethylaniline, and cyclohexylamine, the following compounds of the present invention were obtained.
3-{[5- (4-{[(2,3-Dimethoxyphenyl) carbamoyl] amino} phenyl) pyridin-2-yl] oxy} -2,2-dimethylpropionic acid (Compound No. 44)
3-{[5- (4-{[(2-chlorophenyl) carbamoyl] amino} phenyl) pyridin-2-yl] oxy} -2,2-dimethylpropionic acid (Compound No. 45)
3-{[5- (4-{[(3-Ethylphenyl) carbamoyl] amino} phenyl) pyridin-2-yl] oxy} -2,2-dimethylpropionic acid (Compound No. 46)
3-{[5- (4-{[(3,5-dimethylphenyl) carbamoyl] amino} phenyl) pyridin-2-yl] oxy} -2,2-dimethylpropionic acid (Compound No. 47)
3-{[5- (4-{[(2,4-Dimethylphenyl) carbamoyl] amino} phenyl) pyridin-2-yl] oxy} -2,2-dimethylpropionic acid (Compound No. 48)
3-{[5- (4-{[(2-Ethylphenyl) carbamoyl] amino} phenyl) pyridin-2-yl] oxy} -2,2-dimethylpropionic acid (Compound No. 49)
3-[(5- {4-[(cyclohexylcarbamoyl) amino] phenyl} pyridin-2-yl) oxy] -2,2-dimethylpropionic acid (Compound No. 50)
(Example 18)
Preparation of 3-{[5- (4-{[(2,4-dimethylphenyl) carbamoyl] amino} phenyl) pyridin-2-yl] oxy} -2,2-dimethylpropionic acid sodium salt (Compound No. 51)
3-{[5- (4-{[(2,4-Dimethylphenyl) carbamoyl] amino} phenyl) pyridin-2-yl] oxy} -2,2-dimethylpropionic acid (4.4 g, 10.2 mmol) 40% aqueous sodium hydroxide solution (0.66 ml) was added to an ethanol (21.3 ml) suspension, and the mixture was stirred at room temperature for 40 minutes at 25 ° C., 40 minutes at 11 ° C., and 60 minutes at 0 ° C. . The obtained solid was collected by filtration and washed with ice-cold ethanol (6.5 ml) to give 3-{[5- (4-{[(2,4-dimethylphenyl) carbamoyl] amino} phenyl as colorless powder. ) Pyridin-2-yl] oxy} -2,2-dimethylpropionic acid sodium salt (4.08 g) was obtained.
Preparation of 1- (hydroxymethyl) cyclopropanecarboxylic acid benzyl ester
(1) Potassium carbonate (24.3 g, 0.186 mol) and dibromoethane (4.55 ml, 52.8 mmol) were added to a solution of dibenzyl malonate (5 g, 17.6 mmol) in dimethylformamide (50 ml) under ice cooling. And stirred at room temperature for 17 hours. Water was added to the reaction mixture under ice cooling, and the mixture was diluted with ethyl acetate. The organic layer was washed with (saline solution) and saturated brine, the organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated, and the resulting residue was subjected to silica gel column chromatography [developing solvent; hexane: ethyl acetate. = 4: 1] to give cyclopropane-1,1-dicarboxylic acid dibenzyl ester (4.39 g) as an oil.
1H NMR (300 MHz, CDCl3) δ ppm 1.50 (s, 4H) 5.16 (s, 4H) 7.25 7.35 (m, 10H)
(2) To a solution of cyclopropane-1,1-dicarboxylic acid dibenzyl ester (4.09 g, 13.2 mmol) in methylene chloride (80 ml) with 1 M diisobutylaluminum hydride toluene solution (29 3 ml, 29.0 mmol) was added dropwise. The reaction solution was heated to −15 ° C. and stirred for 30 minutes. Saturated aqueous ammonium chloride solution (40 ml) was added to the reaction solution at the same temperature, followed by 1M hydrochloric acid (40 ml). The reaction solution was filtered through celite, and the solid was washed with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated, and the obtained residue was purified by silica gel column chromatography [developing solvent; hexane: ethyl acetate = 4: 1]. 1- (hydroxymethyl) cyclopropanecarboxylic acid benzyl ester (1.33 g) was obtained as an oily substance.
1H NMR (300 MHz, CDCl3) δ ppm 0.88 0.92 (m, 2H) 1.31 1.34 (m, 2H) 2.53 (t, J = 6.9 Hz, 1H) 3.65 (d, J = 6.9 Hz, 2H) 5.14 (s, 2H) 7.30 7.40 (m, 5H)
Preparation of 1- (hydroxymethyl) cyclobutanecarboxylic acid benzyl ester
Based on the production method of 1- (hydroxymethyl) cyclopropanecarboxylic acid benzyl ester, 1- (hydroxymethyl) cyclobutanecarboxylic acid benzyl ester was obtained by using diiodopropane instead of dibromoethane.
1H NMR (300 MHz, CDCl3) δ ppm 1.91 2.08 (m, 4H) 2.26 (t, J = 6.7 Hz, 1H) 2.40 2.55 (m, 2H) 3.85 (d, J = 6.7 Hz, 2H) 5.18 (s, 2H) 7.31 7.45 (m, 5H)
(Example 19)
1-({[5- (4-{[(2,4-Dimethylphenyl) carbamoyl] amino} phenyl) pyridin-2-yl] oxy} methyl) cyclopropanecarboxylic acid (Compound No. 52)
(1) To a solution of 2,5-dibromopyridine 1-oxide (815 mg, 3.23 mmol) in toluene (16 ml), 1- (hydroxymethyl) cyclopropanecarboxylic acid benzyl ester (1.33 g, 6.45 mmol) and carbonic acid Potassium (891 mg, 6.45 mmol) was added, and the mixture was heated to reflux for 24 hours. The reaction solution was cooled to room temperature, filtered through Celite, the filtrate was concentrated, and the obtained residue was subjected to silica gel column chromatography [developing solvent; hexane: ethyl acetate = 1: 1 to 0: 1, ethyl acetate: methanol = 50. : 1] to give 1-{[(5-bromo-1-oxidepyridin-2-yl) oxy] methyl} cyclopropanecarboxylic acid benzyl ester (178 mg).
MS (ESI): 378 (M + 1)
1H NMR (300 MHz, CDCl3) δ ppm 1.13-1.22 (m, 2H) 1.42-1.51 (m, 2H) 4.52 (s, 2H) 5.13 (s, 2H) 6.75 (d, J = 8.7 Hz, 1H) 7.18 (dd, J = 2.4 Hz, 8.7 Hz, 1H) 7.23 7.52 (m, 5H) 8.30 (d, J = 2.4 Hz, 1H)
(2) 1-{[(5-Bromo-1-oxidepyridin-2-yl) oxy] methyl} cyclopropanecarboxylic acid benzyl ester (178 mg, 0.471 mmol) in ethanol (6 ml) solution in molybdenum hexacarbonyl (137 mg) , 0.518 mmol) was added and heated to reflux for 1.5 hours. The reaction mixture was cooled to room temperature, filtered through celite, the filtrate was concentrated, and the resulting residue was diluted with ethyl acetate and washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated, and the resulting residue was purified by silica gel column chromatography [developing solvent; hexane: ethyl acetate = 4: 1] to give 1-{[(5 -Bromopyridin-2-yl) oxy] methyl} cyclopropanecarboxylic acid benzyl ester (111 mg) was obtained.
MS (ESI): 362 (M + 1)
1H NMR (300 MHz, CDCl3) δ ppm 1.01-1.12 (m, 2H) 1.38-1.49 (m, 2H) 4.47 (s, 2H) 5.15 (s, 2H) 6.66 (d, J = 8.7 Hz, 1H) 7.22 7.50 (m, 5H) 7.63 (dd, J = 2.4 Hz, 8.7 Hz, 1H) 8.14 (d, J = 2.4 Hz, 1H)
(3) 1-{[(5-Bromopyridin-2-yl) oxy] methyl} cyclopropanecarboxylic acid benzyl ester (110 mg, 0.304 mmol), 4-nitrophenylboric acid (52.8 mg, 0.334 mmol) , Palladium acetate (II) (6.8 mg, 0.030 mmol), triphenylphosphine (23.9 mg, 0.091 mmol) in dioxane (2 ml) at room temperature, 2M aqueous sodium carbonate solution (0.759 ml, 1.30 mmol). 52 mmol) was added, and the mixture was stirred at 80 ° C. for 1.5 hours under a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature, diluted with ethyl acetate, and the organic layer was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The obtained residue was purified by silica gel column chromatography [developing solvent; hexane: ethyl acetate = 5: 1] to give 1-({[5 -(4-Nitrophenyl) pyridin-2-yl] oxy} methyl) cyclopropanecarboxylic acid benzyl ester (75 mg) was obtained.
MS (ESI): 405 (M + 1)
1H NMR (300 MHz, CDCl3) δ ppm 1.10 (dd, J = 4.4 Hz, 7.4 Hz, 2H) 1.45 (dd, J = 4.4 Hz, 7.4 Hz, 2H) 4.57 (s, 2H) 5.17 (s, 2H) 6.87 (d, J = 8.7 Hz, 1H) 7.31 (s, 5H) 7.68 (d, J = 8.9 Hz, 2H) 7.83 (dd, J = 2.7 Hz, 8.7 Hz, 1H) 8.31 (d, J = 8.9 Hz , 2H) 8.39 (d, J = 2.7 Hz, 1H)
(4) 1-({[5- (4-Nitrophenyl) pyridin-2-yl] oxy} methyl) cyclopropanecarboxylic acid benzyl ester (75 mg, 0.186 mmol) in ethanol (1 ml) was added water (0 0.1 ml), iron powder (103 mg, 1.86 mmol) and concentrated hydrochloric acid (0.01 ml) were added and stirred at 80 ° C. for 1 hour. The reaction solution is allowed to cool to room temperature, solids are removed by Celite filtration, the filtrate is concentrated, the residue is diluted with ethyl acetate and aqueous sodium hydrogen carbonate solution, and the organic layer is saturated with aqueous sodium hydrogen carbonate solution and saturated brine. Washed with The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The obtained residue was purified by silica gel column chromatography [developing solvent; hexane: ethyl acetate = 3: 1] to give 1-({[5 -(4-Aminophenyl) pyridin-2-yl] oxy} methyl) cyclopropanecarboxylic acid benzyl ester (49 mg) was obtained.
1H NMR (300 MHz, CDCl3) δ ppm 1.09 (dd, J = 4.4 Hz, 7.4 Hz, 2H) 1.42 (dd, J = 4.4 Hz, 7.4 Hz, 2H) 3.68 3.82 (br, 2H) 4.52 (s, 2H ) 5.17 (s, 2H) 6.72 6.84 (m, 3H) 7.21 7.41 (m, 7H) 7.67 7.78 (m, 1H) 8.21 8.31 (m, 1H)
(5) A solution of 1-({[5- (4-aminophenyl) pyridin-2-yl] oxy} methyl) cyclopropanecarboxylic acid benzyl ester (49 mg, 0.131 mmol) in chloroform (1 ml) was cooled with ice. Added pyridine (0.016 ml, 0.196 mmol) and 4-nitrophenyl chloroformate (29 mg, 0.145 mmol) and stirred at that temperature for 1 hour. Triethylamine (0.027 ml, 0.196 mmol) and 2,4-dimethylaniline (0.019 ml, 0.157 mmol) were added to the reaction solution, and the mixture was stirred at room temperature for 19 hours. The reaction solution was diluted with ethyl acetate, and the organic layer was washed with a saturated aqueous solution of ammonium chloride, a saturated aqueous solution of sodium bicarbonate, and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated, and purified by silica gel column chromatography [NH silica gel, developing solvent; hexane: ethyl acetate = 1: 1] to give 1-({[5- ( 4-{[(2,4-Dimethylphenyl) carbamoyl] amino} phenyl) pyridin-2-yl] oxy} methyl) cyclopropanecarboxylic acid benzyl ester (47.5 mg) was obtained.
MS (ESI): 522 (M + 1), 520 (M-1)
1H NMR (300 MHz, DMSO-D6) δ ppm 1.09 1.34 (m, 4H) 2.23 (s, 3H) 2.25 (s, 3H) 4.47 (s, 2H) 5.14 (s, 2H) 6.83 7.05 (m, 3H) 7.22 7.42 (m, 5H) 7.55 (d, J = 9.0 Hz, 2H) 7.59 (d, J = 9.0 Hz, 2H) 7.68 (d, J = 8.4 Hz, 1H) 7.89 (s, 1H) 7.98 (dd, J = 2.4 Hz, 8.4 Hz, 1H) 8.41 (d, J = 2.4 Hz, 1H) 9.06 (s, 1H)
(6) 1-({[5- (4-{[(2,4-Dimethylphenyl) carbamoyl] amino} phenyl) pyridin-2-yl] oxy} methyl) cyclopropanecarboxylic acid benzyl ester (47.5 mg, To a mixed solution of 0.091 mmol) tetrahydrofuran (2 ml) and methanol (1 ml) was added 6M aqueous sodium hydroxide solution (0.5 ml), and the mixture was stirred at room temperature for 6 hours. The reaction mixture was neutralized with 1M hydrochloric acid and diluted with ethyl acetate. The organic layer was washed with saturated brine and water, and then the organic layer was concentrated. The resulting solid was suspended in ethyl acetate, the solid was collected by filtration, and 1-({[5- (4-{[(2,4-dimethylphenyl) carbamoyl] amino} phenyl) pyridine-2 as a colorless solid. -Il] oxy} methyl) cyclopropanecarboxylic acid (30.6 mg) was obtained.
(Example 20)
In accordance with the production method of Example 19, 1- (hydroxymethyl) cyclopropanecarboxylic acid benzyl ester was used instead of 1- (hydroxymethyl) cyclopropanecarboxylic acid benzyl ester, and 2,4-dimethylaniline was replaced with 2 The following compounds of the present invention were obtained by using -chloro-4-fluoroaniline, 3,5-dimethylaniline, 2-methoxy-5-trifluoromethylaniline, and 2,3-dimethoxyaniline.
1-({[5- (4-{[(2,4-Dimethylphenyl) carbamoyl] amino} phenyl) pyridin-2-yl] oxy} methyl) cyclobutanecarboxylic acid (Compound No. 53)
1-({[5- (4-{[(2-Chloro-4-fluorophenyl) carbamoyl] amino} phenyl) pyridin-2-yl] oxy} methyl) cyclopropanecarboxylic acid (Compound No. 54)
1-({[5- (4-{[(3,5-dimethylphenyl) carbamoyl] amino} phenyl) pyridin-2-yl] oxy} methyl) cyclopropanecarboxylic acid (Compound No. 55)
1-[({5- [4-({[2-methoxy-5- (trifluoromethyl) phenyl] carbamoyl} amino) phenyl] pyridin-2-yl} oxy) methyl] cyclopropanecarboxylic acid (Compound No. 56 )
1-({[5- (4-{[(2,3-Dimethoxyphenyl) carbamoyl] amino} phenyl) pyridin-2-yl] oxy} methyl) cyclopropanecarboxylic acid (Compound No. 57)
(Example 21)
1-({[5- (4-{[(2-Chlorophenyl) carbamoyl] amino} phenyl) pyridin-2-yl] oxy} methyl) cyclopropanecarboxylic acid (Compound No. 58)
(1) 1-({[5- (4-Aminophenyl) pyridin-2-yl] oxy} methyl) cyclopropanecarboxylic acid benzyl ester (73.6 mg, 0.196 mmol) in tetrahydrofuran (0.54 ml) solution 2-chlorophenyl isocyanate (0.028 ml, 0.235 mmol) was added and stirred at room temperature for 5 hours. The reaction solution was diluted with ethyl acetate, and the organic layer was washed with water. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated, and the resulting residue was purified by silica gel column chromatography [developing solvent; hexane: ethyl acetate = 3: 1 to 2: 1] ({[5- (4-{[(2-Chlorophenyl) carbamoyl] amino} phenyl) pyridin-2-yl] oxy} methyl) cyclopropanecarboxylic acid benzyl ester (91.7 mg) was obtained.
MS (ESI): 528 (M + 1), 526 (M-1)
1H NMR (300 MHz, CDCl3) δ ppm 1.03 1.11 (m, 2H) 1.37 1.45 (m, 2H) 4.54 (s, 2H) 5.17 (s, 2H) 6.67 (s, 1H) 6.76 6.84 (m, 1H) 6.97 7.10 (m, 2H) 7.21 7.38 (m, 7H) 7.44 7.54 (m, 4H) 7.73 7.80 (m, 1H) 8.16 8.23 (m, 1H) 8.26 8.33 (m, 1H)
(2) 1-({[5- (4-{[(2-Chlorophenyl) carbamoyl] amino} phenyl) pyridin-2-yl] oxy} methyl) cyclopropanecarboxylic acid benzyl ester (91.7 mg, 0.174 mmol ) To a mixed solution of tetrahydrofuran (1.16 ml) and methanol (0.58 ml) was added 6M aqueous sodium hydroxide solution (0.29 ml) under ice cooling, and the mixture was stirred at room temperature for 23 hours. The reaction mixture was neutralized with 1M hydrochloric acid and concentrated. Water is added to the resulting suspension, the solid is collected by filtration, washed with diisopropyl ether, and 1-({[5- (4-{[(2-chlorophenyl) carbamoyl] amino} phenyl) as a colorless solid. Pyridin-2-yl] oxy} methyl) cyclopropanecarboxylic acid (64.9 mg) was obtained.
(Example 22)
In accordance with the production method of Example 21, the following compounds of the present invention were obtained by using 2-ethylphenyl isocyanate instead of 2-chlorophenyl isocyanate.
1-({[5- (4-{[(2-Ethylphenyl) carbamoyl] amino} phenyl) pyridin-2-yl] oxy} methyl) cyclopropanecarboxylic acid (Compound No. 59)
(Example 23)
Preparation of 3-[(5- {4-[(benzylcarbamoyl) amino] phenyl} pyrimidin-2-yl) oxy] -2,2-dimethylpropionic acid methyl ester (Compound No. 60)
(1) 5-bromo-2-chloropyrimidine (25.0 g, 125 mmol), 3-hydroxy-2,2-dimethylpropionic acid methyl ester (33.1 g, 251 mmol), potassium carbonate (34.7 g, 251 mmol), A suspension of tetra n-butylammonium iodide (92.6 g, 251 mmol) in dimethylacetamide (500 ml) was stirred at an external temperature of 140 ° C. for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, dried (anhydrous magnesium sulfate), filtered, and concentrated. The resulting residue was subjected to silica gel column chromatography [developing solvent; hexane: ethyl acetate = 15: 1 to 3.5. : 1] to give 3-[(5-bromopyrimidin-2-yl) oxy] -2,2-dimethylpropionic acid methyl ester (17.48 g) as a colorless powder.
MS (ESI / APCI Dual): 289 (M + 1)
1H NMR (300 MHz, CDCl3) δ ppm 1.34 (s, 6 H) 3.70 (s, 3 H) 4.37 (s, 2 H) 8.52 (s, 2 H)
(2) 3-[(5-Bromopyrimidin-2-yl) oxy] -2,2-dimethylpropionic acid methyl ester (17.4 g, 60.14 mmol), 4-nitrophenylboric acid (11.04 g, 66 .16 mmol), palladium (II) acetate (1.35 g, 6.01 mmol) and triphenylphosphine (4.73 g, 18.04 mmol) in 2M aqueous sodium carbonate (150 ml) and dioxane (350 ml) Stir at 80 ° C. for 30 minutes. Water and ethyl acetate were added to the reaction mixture, and the mixture was filtered through celite. The ethyl acetate layer was extracted, dried (anhydrous magnesium sulfate), filtered and concentrated. The residue was obtained by silica gel column chromatography [developing solvent; hexane: acetic acid. 2,2-dimethyl-3-{[5- (4-nitrophenyl) pyrimidin-2-yl] oxy} propionic acid methyl ester in the form of a yellow powder by purifying with ethyl = 8: 1 to 1: 3] (16.87 g) was obtained.
MS (ESI / APCI Dual): 332 (M + 1)
1H NMR (300 MHz, CDCl3) δ ppm 1.38 (s, 6 H) 3.72 (s, 3 H) 4.48 (s, 2 H) 7.67-7.73 (m, 2 H) 8.33-8.39 (m, 2 H) 8.77 (s, 2 H)
(3) 2,2-dimethyl-3-{[5- (4-nitrophenyl) pyrimidin-2-yl] oxy} propionic acid methyl ester (16.87 g, 50.9 mmol) in methanol (200 ml) and tetrahydrofuran ( 200 ml) was mixed with 10% platinum carbon (1.69 g) and stirred at room temperature for 20 hours in a hydrogen gas atmosphere. The reaction solution was filtered through Celite, and the residue obtained by concentrating the filtrate was purified by silica gel column chromatography [developing solvent; hexane: ethyl acetate = 4: 1 to 1: 5] to give a pale yellow powder. 3-{[5- (4-aminophenyl) pyrimidin-2-yl] oxy} -2,2-dimethylpropionic acid methyl ester (14.2 g) was obtained.
MS (ESI / APCI Dual): 302 (M + 1), 300 (M-1)
1H NMR (300 MHz, CDCl3) δ ppm 1.36 (s, 6 H) 3.71 (s, 3 H) 3.75-3.88 (br, 2 H) 4.42 (s, 2 H) 6.74-6.81 (m, 2 H) 7.28 -7.35 (m, 2 H) 8.63 (s, 2 H)
(4) 3-{[5- (4-aminophenyl) pyrimidin-2-yl] oxy} -2,2-dimethylpropionic acid methyl ester (440 mg, 1.46 mmol) in chloroform (0.9 ml) in ice Under cooling, 4-nitrophenyl chloroformate (338 mg, 1.68 mmol) and pyridine (0.2 ml, 1.97 mmol) were added, and the mixture was stirred for 1.5 hours under ice cooling. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, dried (anhydrous magnesium sulfate), filtered and concentrated. The residue obtained was recrystallized (ethyl acetate-hexane) to give 2,2- Dimethyl-3-{[5- (4-{[(4-nitrophenoxy) carbonyl] amino} phenyl) pyrimidin-2-yl] oxy} propionic acid methyl ester (540 mg) was obtained.
1H NMR (300 MHz, CDCl3) δ ppm 1.37 (s, 6 H) 3.71 (s, 3 H) 4.45 (s, 2 H) 7.09-7.14 (br, 1 H) 7.38-7.46 (m, 2 H) 7.49 -7.62 (m, 4 H) 8.27-8.35 (m, 2 H) 8.70 (s, 2 H)
(5) 2,2-dimethyl-3-{[5- (4-{[(4-nitrophenoxy) carbonyl] amino} phenyl) pyrimidin-2-yl] oxy} propionic acid methyl ester (150 mg, 0.322 mmol ) In chloroform (3 ml) was added benzylamine (38 mg, 0.354 mmol) and triethylamine (0.09 ml, 0.648 mmol), and the mixture was stirred at room temperature for 15 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, dried (anhydrous magnesium sulfate), filtered, and concentrated. The resulting residue was subjected to silica gel column chromatography [developing solvent; hexane: ethyl acetate = 2: 1 to 1: 2. ] To give 3-[(5- {4-[(benzylcarbamoyl) amino] phenyl} pyrimidin-2-yl) oxy] -2,2-dimethylpropionic acid methyl ester (128 mg) as colorless powder. Obtained.
(Example 24)
In accordance with the production method of Example 23, the following compounds of the present invention were obtained by using cyclohexylamine instead of benzylamine.
3-[(5- {4-[(cyclohexylcarbamoyl) amino] phenyl} pyrimidin-2-yl) oxy] -2,2-dimethylpropionic acid methyl ester (Compound No. 61)
(Example 25)
Preparation of 3-[(5- {4-[(benzylcarbamoyl) amino] phenyl} pyrimidin-2-yl) oxy] -2,2-dimethylpropionic acid (Compound No. 62)
3-[(5- {4-[(benzylcarbamoyl) amino] phenyl} pyrimidin-2-yl) oxy] -2,2-dimethylpropionic acid methyl ester (128 mg, 0.295 mmol) in tetrahydrofuran (1.8 ml) A 6M aqueous sodium hydroxide solution (0.49 ml) was added to a mixed solution of methanol and methanol (1.8 ml), and the mixture was stirred at room temperature for 2 hours. To the reaction solution was added 2M aqueous hydrochloric acid under ice-cooling, and the mixture was extracted with ethyl acetate, dried (anhydrous magnesium sulfate), filtered, and concentrated to give 3-[(5- {4-[(benzylcarbamoyl) amino] as a colorless powder. Phenyl} pyrimidin-2-yl) oxy] -2,2-dimethylpropionic acid (82 mg) was obtained.
(Example 26)
Based on the production methods of Examples 23 and 25, the following compounds of the present invention were obtained by using cyclohexylamine instead of benzylamine.
3-[(5- {4-[(Cyclohexylcarbamoyl) amino] phenyl} pyrimidin-2-yl) oxy] -2,2-dimethylpropionic acid (Compound No. 63)
(Example 27)
1-({[5- (4-{[(2-Methoxy-5-methylphenyl) carbamoyl] amino} phenyl) pyrimidin-2-yl] oxy} methyl) cyclopropanecarboxylic acid (Compound No. 64)
(1) 5-Bromo-2-chloropyrimidine (727 mg, 3.758 mmol), 1- (hydroxymethyl) cyclopropanecarboxylic acid benzyl ester (1.55 g, 7.516 mmol), potassium carbonate (1.04 g, 7. 516 mmol) and tetra n-butylammonium iodide (1.42 g, 3.758 mmol) in toluene (14.5 ml) were stirred at an external temperature of 140 ° C. for 4 hours. The reaction solution was filtered through Celite, and the residue obtained by concentrating the filtrate was purified by silica gel column chromatography [developing solvent; hexane: ethyl acetate = 15: 1 to 3.5: 1] to give a pale yellow powder. Of 1-{[(5-bromopyrimidin-2-yl) oxy] methyl} cyclopropanecarboxylic acid benzyl ester (438 mg).
MS (ESI / APCI Dual): 363 (M + 1)
1H NMR (300 MHz, CDCl3) δ ppm 1.05-1.11 (m, 2 H) 1.41-1.46 (m, 2 H) 4.53 (s, 2 H) 5.11 (s, 2 H) 7.23-7.34 (m, 5 H ) 8.47 (s, 2 H)
(2) 1-{[(5-Bromopyrimidin-2-yl) oxy] methyl} cyclopropanecarboxylic acid benzyl ester (410 mg, 1.129 mmol), 4-nitrophenylboric acid (198 mg, 1.185 mmol), acetic acid A mixture of palladium (II) (25 mg, 0.1129 mmol) and triphenylphosphine (89 mg, 0.339 mmol) in 2M aqueous sodium carbonate solution (2.8 ml) and dioxane (8.2 ml) was added at an external temperature of 80 ° C. Stir for minutes. Water and ethyl acetate were added to the reaction mixture, and the mixture was filtered through celite. The ethyl acetate layer was extracted, dried (anhydrous magnesium sulfate), filtered and concentrated. The residue was obtained by silica gel column chromatography [developing solvent; hexane: acetic acid. By purifying with ethyl = 10: 1 to 1: 4], 1-({[5- (4-nitrophenyl) pyrimidin-2-yl] oxy} methyl) cyclopropanecarboxylic acid benzyl ester ( 180 mg) was obtained.
MS (ESI / APCI Dual): 406 (M + 1)
1H NMR (300 MHz, CDCl3) δ ppm 1.10-1.15 (m, 2 H) 1.45-1.50 (m, 2 H) 4.64 (s, 2 H) 5.13 (s, 2 H) 7.24-7.32 (m, 5 H ) 7.66-7.72 (m, 2 H) 8.33-8.38 (m, 2 H) 8.74 (s, 2 H)
(3) To a solution of 1-({[5- (4-nitrophenyl) pyrimidin-2-yl] oxy} methyl) cyclopropanecarboxylic acid benzyl ester (173 mg, 0.427 mmol) in ethanol (17.5 ml), 2M An aqueous hydrochloric acid solution (0.21 ml), water (1 ml), and iron powder (238 mg, 4.27 mmol) were added, and the mixture was heated to reflux for 1 hour. Water and ethyl acetate were added to the reaction mixture, and the mixture was filtered through celite. The ethyl acetate layer was extracted, washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried (anhydrous magnesium sulfate), filtered and concentrated to give a residue. Concentration gave 1-({[5- (4-aminophenyl) pyrimidin-2-yl] oxy} methyl) cyclopropanecarboxylic acid benzyl ester (123 mg) as a pale yellow powder.
MS (ESI / APCI Dual): 376 (M + 1)
1H NMR (200 MHz, CDCl3) δ ppm 1.05-1.16 (m, 2 H) 1.38-1.50 (m, 2 H) 3.76-3.85 (br, 2 H) 4.59 (s, 2 H) 5.13 (s, 2 H ) 6.72-6.83 (m, 2 H) 7.23-7.35 (m, 7 H) 8.61 (s, 2 H)
(4) To a solution of 1-({[5- (4-aminophenyl) pyrimidin-2-yl] oxy} methyl) cyclopropanecarboxylic acid benzyl ester (120 mg, 0.32 mmol) in chloroform (2.4 ml), ice Under cooling, pyridine (0.043 ml, 0.43 mmol) and 4-nitrophenyl chloroformate (74 mg, 0.37 mmol) were added, and the mixture was stirred at room temperature for 1.5 hours. Further, triethylamine (0.089 ml, 0.35 mmol) and 2-methoxy-5-methylaniline (48 mg, 0.35 mmol) were added under ice cooling, and the mixture was stirred at an external temperature of 40 ° C. for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed successively with 1M aqueous sodium hydroxide, 1M aqueous hydrochloric acid, saturated aqueous sodium carbonate, and saturated brine, dried (anhydrous magnesium sulfate), filtered, and concentrated. The residue was purified by silica gel column chromatography [NH silica gel, developing solvent; hexane: ethyl acetate = 4: 1 to 1: 4] to give 1-({[5- (4-{[( 2-Methoxy-5-methylphenyl) carbamoyl] amino} phenyl) pyrimidin-2-yl] oxy} methyl) cyclopropanecarboxylic acid benzyl ester (142 mg) was obtained.
MS (ESI / APCI Dual): 539 (M + 1), 537 (M-1)
1H NMR (300 MHz, DMSO-d6) δ ppm 1.14-1.21 (m, 2 H) 1.27-1.33 (m, 2 H) 2.24 (s, 3 H) 3.85 (s, 3 H) 4.52 (s, 2 H ) 5.12 (s, 2 H) 6.72-6.79 (m, 1 H) 6.90 (d, J = 8.2 Hz, 1 H) 7.24-7.35 (m, 5 H) 7.54-7.69 (m, 4 H) 7.98-8.01 (m, 1 H) 8.22 (s, 1 H) 8.87 (s, 2 H) 9.47 (s, 1 H)
(5) 1-({[5- (4-{[(2-Methoxy-5-methylphenyl) carbamoyl] amino} phenyl) pyrimidin-2-yl] oxy} methyl) cyclopropanecarboxylic acid benzyl ester (137 mg, To a mixed solution of 0.254 mmol) tetrahydrofuran (1 ml) and methanol (1 ml) was added 6M aqueous sodium hydroxide solution (0.42 ml), and the mixture was stirred at room temperature for 1 hour. A 1M aqueous hydrochloric acid solution was added to the reaction solution under ice-cooling, and the residue obtained by extraction with ethyl acetate, drying (anhydrous magnesium sulfate), filtration and concentration was subjected to preparative thin layer silica gel chromatography [developing solvent; chloroform: Purification with methanol = 10: 1] gave 1-({[5- (4-{[(2-methoxy-5-methylphenyl) carbamoyl] amino} phenyl) pyrimidin-2-yl] oxy as a colorless powder. } Methyl) cyclopropanecarboxylic acid (10 mg) was obtained.

  Tables 1-1 to 1-7 show the structures, NMR data, and MS data of the compounds obtained in the examples.

  The DGAT1 inhibitory action of the compound of the present invention was measured using the method described in the following test examples.

(Test Example 1.) -DGAT1 inhibitory action test-
The DGAT1 inhibition test of the test compound was carried out according to the method of Sylvain Cases et al. (PNAS. 1998 Oct; 95: 13018).
Human DGAT1 was expressed in insect cells (Sf9) using the Bac-to-Bac Baculovirus Expression System (Invitrogen). The cells were sonicated and centrifuged at 100,000 G (980,665 m / s ² ) × 1 hour to obtain a precipitate. This precipitate was used as the human DGAT1 enzyme fraction used in this assay.
Test compounds prepared in various concentrations with dimethyl sulfoxide (DMSO) prepared with buffers containing final concentration 2 mM magnesium chloride, 1 mg / ml bovine serum albumin, 90 μM diacylglycerol, 100 mM tris-HCl (pH = 7.5) Is added to a final concentration of DMSO of 1%, human DGAT1 enzyme fraction is added to a final concentration of 100 μg / ml, and ¹⁴ C-labeled oleoylcoenzyme A (Muromachi Yakuhin) is added to a final concentration of 18 μM to a total volume of 100 μl. did. This solution was reacted at 37 ° C. for 30 minutes.
After the reaction was stopped by adding an equal amount of isopropanol to the reaction solution, the substrate ( ¹⁴ C-labeled oleoyl coenzyme A) and the reaction product ( ¹⁴ C-labeled triacylglycerol) contained in the reaction solution were mixed with octadodecyl. It was adsorbed on a silane resin (Wakogel 50C18) and separated by eluting with isopropanol. The amount of the reaction product is measured with a liquid scintillation counter, and the concentration of ¹⁴ C-labeled triacylglycerol when no test compound is added is defined as 100%. The compound concentration at which 50% production is inhibited in the presence of the test compound ( IC ₅₀ value) was calculated.
The results are shown in Table 2 below.

(Test Example 2.)-Neutral fat absorption inhibitory effect-
The neutral fat absorption inhibitory action of the compound of the present invention was examined using SD rats. A male SD rat (8 weeks old, body weight 220-260 g, Nippon Charles River) suspended in 0.5% carboxymethylcellulose aqueous solution (1 mg / kg) and 20% neutral fat emulsion (Intralipos 20%: Otsuka Pharmaceutical) Co., Ltd.) was forcibly administered orally (5 ml / kg), while the control group was forcibly orally administered (5 ml / kg) with a 0.5% carboxymethylcellulose aqueous solution and a 20% neutral fat emulsion. One hour after administration, SD rats were opened under anesthesia by intraperitoneal administration of pentobarbital (Nembutal: Dainippon Sumitomo Pharma Co., Ltd.), and 20-30 μL of small intestinal lymph was collected from the small intestinal lymphatic vessels. The neutral fat concentration in the lymph was measured using a commercial kit (Triglyceride E Test Wako: Wako Pure Chemical Industries, Ltd.), and the drug administration group compared to the 20% emulsion, 0.5% carboxymethylcellulose administration group (control group). The neutral fat concentration decrease rate was calculated and defined as neutral fat absorption inhibitory activity. In the 1 mg / kg administration groups of Compound Nos. 44 and 48, the neutral fat absorption inhibitory activity was 81% and 80%, respectively.

(Test Example 3.) -Anti-obesity action-
The anti-obesity effect of the compound of the present invention was examined using C57BL / 6J mice. Tests were performed on 12 mice per group using male C57BL / 6J mice (7 weeks old, body weight 20-25 g, Nippon Charles River). Each mouse was bred for free consumption and drinking water during the test period. The body weight of 7-week-old mice was measured, and 12 mice were grouped so that there was no difference in the average body weight between the groups. After grouping, each mouse was given a high-fat diet with a fat-derived caloric ratio in the total energy of 60%, and the mice in the drug administration group were treated with a compound suspended in 0.5% carboxymethylcellulose aqueous solution. The group was orally administered with a 0.5% carboxymethylcellulose aqueous solution for 28 days (5 ml / kg, twice a day). The weight gain of each group was calculated, and the weight gain inhibition rate in the drug administration group relative to the weight gain of the 0.5% carboxymethylcellulose administration group was calculated. The suppression rate of body weight gain of the high-fat diet-fed mice by the administration of Compound No. 48 was 44.6% at the dose of 30 mg / kg.

Formulation examples of the compound of the present invention are shown below.
Formulation Example 1
A granule containing the following ingredients is produced.
Component Compound represented by formula (1) 10mg
Lactose 700mg
Corn starch 274mg
HPC-L 16mg
1000mg
The compound represented by formula (1) and lactose are passed through a 60 mesh sieve. Pass corn starch through a 120 mesh sieve. These are mixed in a V-type mixer. A low-viscosity hydroxypropylcellulose (HPC-L) aqueous solution is added to the powder mixture, kneaded and granulated (extruded granulation, pore diameter: 0.5 to 1 mm), and then dried. The obtained dried granules are sieved with a vibrating sieve (12/60 mesh) to obtain granules.
Formulation Example 2
A powder for capsule filling containing the following components is produced.
Component Compound represented by formula (1) 10mg
Lactose 79mg
Corn starch 10mg
Magnesium stearate 1mg
1000mg
The compound represented by formula (1) and lactose are passed through a 60 mesh sieve. Pass corn starch through a 120 mesh sieve. These and magnesium stearate are mixed in a V-type mixer. 100 mg of 10 times powder is filled into a No. 5 hard gelatin capsule.
Formulation Example 3
A capsule filling granule containing the following ingredients is produced.
Ingredients Compound represented by formula (1) 15mg
Lactose 90mg
Cornstarch 42mg
HPC-L 3mg
150mg
The compound represented by formula (1) and lactose are passed through a 60 mesh sieve. Pass corn starch through a 120 mesh sieve. These are mixed in a V-type mixer. A low-viscosity hydroxypropylcellulose (HPC-L) aqueous solution is added to the mixed powder, kneaded and granulated, and then dried. The obtained dried granules are sieved with a vibrating sieve (12/60 mesh) and sized, and 150 mg thereof is filled into a No. 4 hard gelatin capsule.
Formulation Example 4
A tablet containing the following ingredients is produced.
Component Compound represented by formula (1) 10mg
Lactose 90mg
Microcrystalline cellulose 30mg
Magnesium stearate 5mg
CMC-Na 15mg
150mg
The compound represented by formula (1), lactose, microcrystalline cellulose, and CMC-Na (carboxymethylcellulose sodium salt) are passed through a 60-mesh sieve and mixed. Magnesium stearate is added to the mixed powder to obtain a mixed powder for preparation. The mixed powder is directly hit to obtain a 150 mg tablet.
Formulation Example 5
The intravenous formulation is produced as follows.
100 mg of the compound represented by the formula (1)
Saturated fatty acid glyceride 1000ml
Solutions of the above components are usually administered intravenously to the patient at a rate of 1 ml per minute.

  The compound of the present invention has an excellent DGAT1 inhibitory action, and is obesity, hyperlipidemia, hypertriglycerideemia, dyslipidemia, diabetes, arteriosclerosis, or hyperlipidemia caused by obesity, high A prophylactic / therapeutic agent for triglycerideemia, dyslipidemia, diabetes, arteriosclerosis, or hypertension can be provided.

Claims (20)

Formula (1)

(In the formula (1),
A represents N or CH;
R ¹ represents a hydrogen atom or a C _1-8 alkyl group,
R ² represents a hydrogen atom, a halogen atom, or a C _1-6 alkyl group,
Q is a phenyl group (the phenyl group is not substituted, or a C _1-8 alkyl group, a C _1-6 alkoxy group (the C _1-6 alkoxy group is not substituted, or a C _1-6 alkoxy group). And a group selected from the group consisting of a di (C _1-6 alkyl) amino group), a halogen atom, a trifluoromethyl group, a trifluoromethoxy group, a cyano group, a hydroxy group, And a 1 to 3 group selected from the group consisting of the same or different from the group consisting of C _1-6 alkylthio groups, a benzyl group (the benzyl group is unsubstituted or has 1 to 2 groups). Substituted with a C _1-3 alkyl group), or a C _3-10 cycloalkyl group,
m represents 0 or 1,
n represents 0 or 1,
X is —O—, or —NR ³ — (wherein R ³ is a hydrogen atom, or a C _1-8 alkyl group (the C _1-8 alkyl group is bonded to a carbon atom of Y to form a 5- to 7-membered group). A heterocyclyl ring may be formed.)
Y represents a C _1-8 alkylene group (the C _1-8 alkylene group is unsubstituted or selected from the group consisting of a C _1-6 alkyl group and a hydroxy C _1-6 alkyl group, the same or different) Substituted with two groups, one of the carbon atoms of the C _1-8 alkylene group may be substituted with an oxygen atom, and one of the carbon atoms of the C _1-8 alkylene group. May be a member of a 3- to 6-membered cycloalkyl ring formed including the carbon atom itself, or a 3- to 6-membered heterocyclyl ring. ), A tautomer, stereoisomer, pharmaceutically acceptable salt of the compound, or a solvate thereof. Formula (2)

(In the formula (2),
Q is a phenyl group (the phenyl group is unsubstituted or selected from the group consisting of a C _1-8 alkyl group, a C _1-6 alkoxy group, a halogen atom, and a trifluoromethyl group, which is the same or different. And A, R ¹ , R ² , Y are as defined in claim 1. The heteroarylbenzene compound of Claim 1 represented by this, the tautomer of this compound, a stereoisomer, its pharmaceutically acceptable salt, or those solvates. Formula (3)

(In formula (3), R ¹ represents a hydrogen atom or a C _1-3 alkyl group, and A, R ² , and Q are as defined in claim 2). A heteroarylbenzene compound, a tautomer, stereoisomer or pharmaceutically acceptable salt of the compound or a solvate thereof. The heteroarylbenzene compound according to claim 3, wherein A is N, R ² is a hydrogen atom, R ¹ is a hydrogen atom, and Q is as defined in claim 3. A sex isomer, a stereoisomer, or a pharmaceutically acceptable salt thereof, or a solvate thereof. The heteroarylbenzene compound according to claim 3, wherein A is CH, R ² is a hydrogen atom, R ¹ is a hydrogen atom, and Q is as defined in claim 3. A sex isomer, a stereoisomer, or a pharmaceutically acceptable salt thereof, or a solvate thereof. Formula (4)

(In formula (4), R ¹ represents a hydrogen atom or a C _1-3 alkyl group, p represents an integer of 1 to 4, and A, R ² and Q are as defined in claim 2). The heteroarylbenzene compound of Claim 2 represented by this, the tautomer of this compound, a stereoisomer, its pharmaceutically acceptable salt, or those solvates. The heterogeneity according to claim 6, wherein A is N, R ² is a hydrogen atom, R ¹ is a hydrogen atom, p is 1 or 2, and Q is as defined in claim 6. An arylbenzene compound, a tautomer, stereoisomer, or pharmaceutically acceptable salt of the compound, or a solvate thereof. The heterogeneous group according to claim 6, wherein A is CH, R ² is a hydrogen atom, R ¹ is a hydrogen atom, p is 1 or 2, and Q is as defined in claim 6. An arylbenzene compound, a tautomer, stereoisomer, or pharmaceutically acceptable salt of the compound, or a solvate thereof. Formula (5)

(In Formula (5),
Q is a phenyl group (the phenyl group is unsubstituted or selected from the group consisting of a C _1-8 alkyl group, a C _1-6 alkoxy group, a halogen atom, and a trifluoromethyl group, which is the same or different. And A, R ¹ , R ² , Y are as defined in claim 1. The heteroarylbenzene compound of Claim 1 represented by this, the tautomer of this compound, a stereoisomer, its pharmaceutically acceptable salt, or those solvates. Formula (6)

(In formula (6), R ¹ represents a hydrogen atom or a C _1-3 alkyl group, and A, R ² , and Q are as defined in claim 9.)
The heteroarylbenzene compound of Claim 9 represented by these, the tautomer, stereoisomer of this compound, its pharmaceutically acceptable salt, or those solvates. The heteroarylbenzene compound according to claim 10, wherein A is N, R ² is a hydrogen atom, R ¹ is a hydrogen atom, and Q is as defined in claim 10. A sex isomer, a stereoisomer, or a pharmaceutically acceptable salt thereof, or a solvate thereof. The heteroarylbenzene compound according to claim 10, wherein A is CH, R ² is a hydrogen atom, R ¹ is a hydrogen atom, and Q is as defined in claim 10. A sex isomer, a stereoisomer, or a pharmaceutically acceptable salt thereof, or a solvate thereof. Formula (7)

(In the formula (7), R ¹ represents a hydrogen atom or a C _1-3 alkyl group, p represents an integer of 1 to 4, and A, R ² and Q are as defined in claim 9. The heteroarylbenzene compound of Claim 9 represented by this, the tautomer of this compound, a stereoisomer, its pharmaceutically acceptable salt, or those solvates. The heteroaryl according to claim 13, wherein A is N, R ² is a hydrogen atom, R ¹ is a hydrogen atom, p is 1 or 2, and Q is as defined in claim 13. A benzene compound, a tautomer, stereoisomer, pharmaceutically acceptable salt of the compound, or a solvate thereof. The heteroaryl according to claim 13, wherein A is CH, R ² is a hydrogen atom, R ¹ is a hydrogen atom, p is 1 or 2, and Q is as defined in claim 13. A benzene compound, a tautomer, stereoisomer, or pharmaceutically acceptable salt of the compound, or a solvate thereof. The following heteroarylbenzene compounds, tautomers, stereoisomers or pharmaceutically acceptable salts of the compounds or solvates thereof.
2-({5- [4-({[2-methoxy-5- (trifluoromethyl) phenyl] carbamoyl} amino) phenyl] pyridin-2-yl} oxy) -2-methylpropionic acid 3-{[5 -(4-{[(2,3-dimethoxyphenyl) carbamoyl] amino} phenyl) pyridin-2-yl] amino} -2,2-dimethylpropionic acid 3-{[5- (4-{[(2, 4-dimethylphenyl) carbamoyl] amino} phenyl) pyridin-2-yl] amino} -2,2-dimethylpropionic acid 3-{[5- (4-{[(2-chlorophenyl) carbamoyl] amino} phenyl) pyridine -2-yl] amino} -2,2-dimethylpropionic acid 3-{[5- (4-{[(2,3-dimethoxyphenyl) carbamoyl] amino} phenyl) pyridine 2-yl] oxy} -2,2-dimethylpropionic acid 3-{[5- (4-{[(2-chlorophenyl) carbamoyl] amino} phenyl) pyridin-2-yl] oxy} -2,2-dimethyl 3-{[5- (4-{[(3-Ethylphenyl) carbamoyl] amino} phenyl) pyridin-2-yl] oxy} -2,2-dimethylpropionic acid 3-{[5- (4- {[(3,5-dimethylphenyl) carbamoyl] amino} phenyl) pyridin-2-yl] oxy} -2,2-dimethylpropionic acid 3-{[5- (4-{[(2,4-dimethylphenyl) ) Carbamoyl] amino} phenyl) pyridin-2-yl] oxy} -2,2-dimethylpropionic acid 3-{[5- (4-{[(2-ethylphenyl) carbamoyl] amino} f ) Pyridin-2-yl] oxy} -2,2-dimethyl-propionic acid The following heteroarylbenzene compounds, tautomers, stereoisomers or pharmaceutically acceptable salts of the compounds or solvates thereof.
1-({[5- (4-{[(2,4-Dimethylphenyl) carbamoyl] amino} phenyl) pyridin-2-yl] amino} methyl) cyclopropanecarboxylic acid 1-({[5- (4- {[(2-Chlorophenyl) carbamoyl] amino} phenyl) pyridin-2-yl] amino} methyl) cyclopropanecarboxylic acid 1-({[5- (4-{[(2,4-dimethylphenyl) carbamoyl] amino } Phenyl) pyridin-2-yl] oxy} methyl) cyclopropanecarboxylic acid 1-({[5- (4-{[(2,4-dimethylphenyl) carbamoyl] amino} phenyl) pyridin-2-yl] oxy } Methyl) cyclobutanecarboxylic acid 1-({[5- (4-{[(2-chloro-4-fluorophenyl) carbamoyl] amino} phenyl) pyridy -2-yl] oxy} methyl) cyclopropanecarboxylic acid 1-({[5- (4-{[(3,5-dimethylphenyl) carbamoyl] amino} phenyl) pyridin-2-yl] oxy} methyl) cyclo 1-[({5- [4-({[2-Methoxy-5- (trifluoromethyl) phenyl] carbamoyl} amino) phenyl] pyridin-2-yl} oxy) methyl] cyclopropanecarboxylic acid 1 -({[5- (4-{[(2,3-dimethoxyphenyl) carbamoyl] amino} phenyl) pyridin-2-yl] oxy} methyl) cyclopropanecarboxylic acid 1-({[5- (4- { [(2-Chlorophenyl) carbamoyl] amino} phenyl) pyridin-2-yl] oxy} methyl) cyclopropanecarboxylic acid 1-({[5- ( -{[(2-Ethylphenyl) carbamoyl] amino} phenyl) pyridin-2-yl] oxy} methyl) cyclopropanecarboxylic acid 1-({[5- (4-{[(2-methoxy-5-methylphenyl) ) Carbamoyl] amino} phenyl) pyrimidin-2-yl] oxy} methyl) cyclopropanecarboxylic acid   The heteroarylbenzene compound according to any one of claims 1 to 17, a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof as an active ingredient. Medicine to do.   The medicament according to claim 18, for preventing or treating a disease or condition that can be ameliorated by a DGAT1 inhibitory action.   Obesity, hyperlipidemia, hypertriglyceridemia, dyslipidemia, diabetes, arteriosclerosis, or hyperlipidemia, hypertriglyceridemia, dyslipidemia, diabetes, arteriosclerosis caused by obesity Alternatively, the medicament according to claim 19, which is a prophylactic / therapeutic agent for hypertension.