JP2005179281A - Biphenyl compound - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a compound having agonist activity to peroxisome proliferator-activated receptor δ (PPARδ) and useful as an agent for raising the blood concentration of high density lipoprotein (HDL), therapeutic agent for low HDL lipoproteinemia and/or treating agent for arteriosclerosis. <P>SOLUTION: There is provided a compound represented by formula (1) (wherein R<SP>1</SP>to R<SP>8</SP>are each H, hydroxy, a 1-6C alkyl which may have a substituent, or the like; R<SP>9</SP>and R<SP>10</SP>are each H, a 1-6C alkyl which may have a substituent; R<SP>11</SP>and R<SP>12</SP>are each H, F, a 1-6C alkyl which may have a substituent, or the like; W<SP>1</SP>and W<SP>2</SP>are each O, S, or the like; and R<SP>13</SP>is carboxy, a 2-7C alkoxycarbonyl which may have a substituent, or the like, provided that at least one of R<SP>9</SP>and R<SP>10</SP>is not H, or they are not H at the same time) or its salt. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  TECHNICAL FIELD The present invention relates to a novel biphenyl compound and an activator of peroxisome proliferator-responsive receptor δ (PPARδ) containing them as an active ingredient, and as a specific application, blood high-density lipoprotein (HDL) concentration And / or a therapeutic agent for arteriosclerosis.

Peroxisome proliferator-responsive receptor (PPAR), identified as a transcriptional regulator responsible for controlling the expression of genes that maintain lipid metabolism, is a ligand-dependent transcriptional regulator belonging to the nuclear receptor family. PPAR was initially identified as an endogenous ligand-unknown orphan receptor with a peroxisome proliferator such as a fibrate as a ligand. This is PPARα. Later, cDNA homologues were identified in many biological species including humans, and PPARs currently known in mammals include three subtypes of α, γ, and δ located on different chromosomes. Exists.
Among them, PPARδ was cloned in 1992, but the physiological ligand is unknown, and specific agonists have not existed so far, so analysis of physiological roles is delayed compared to PPARα and PPARγ. It was.
However, recently, literature on PPARδ-specific agonists has been reported (for example, Non-Patent Document 1), and important findings on the physiological functions of PPARδ have been published. Accordingly, the activation of PPARδ promotes the expression of ABCA1 gene having a function of pumping out cholesterol in the macrophages, and as a result, increases the withdrawal of cholesterol from the cells. Also in vivo, PPARδ activation has been shown to lead to an increase in blood HDL-cholesterol, and activation of the reverse cholesterol transport system has been considered as a physiological role of PPARδ. From these facts, the PPARδ agonist compound is expected to have an effect of increasing blood HDL level and a regression of arteriosclerotic lesions by activating the cholesterol reverse transfer system.
As a compound having a PPARδ agonistic action, for example, a compound of development number GW-501516 and its analogs are known (see, for example, Patent Document 1 and Non-Patent Document 1). Until now, this development number GW-501516 compound and its analogs were the only potent and highly selective agonists for PPARδ.
International Publication No. 01/00603 Pamphlet Oliver et al., Proceedings of the National Academy of Sciences, (USA), 2001, Vol. 98, p. 5306-5311)

  An object of the present invention is to provide a compound having a PPARδ activating action and useful as an agent for increasing a high density lipoprotein concentration in blood, a therapeutic agent for hypoHDL disease, and / or a therapeutic agent for arteriosclerosis. .

The present inventors have found that a compound represented by the following formula (1) or a salt thereof has PPARδ agonist activity, and has completed the present invention.
That is, the present invention relates to the following.
[1] Formula (1):

［式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６、Ｒ^７、およびＲ^８はそれぞれ独立して、水素原子、水酸基、置換基を有してもよいＣ_１−Ｃ_６アルキル基、置換基を有してもよいＣ_２−Ｃ_６アルケニル基、置換基を有してもよいＣ_１−Ｃ_６アルコキシ基、置換基を有してもよいＣ_１−Ｃ_１１アシルオキシ基、カルボキシル基、置換基を有してもよいＣ_２−Ｃ_７アルコキシカルボニル基、カルバモイル基、置換基を有してもよい（Ｃ_１−Ｃ_６アルキル）カルバモイル基、置換基を有してもよいジ（Ｃ_１−Ｃ_６アルキル）カルバモイル基、置換基を有してもよいＣ_１−Ｃ_６アルキルスルホニルオキシ基、置換基を有してもよいＣ_６−Ｃ_１０アリールスルホニルオキシ基、炭素原子の一つが式：−Ｏ−、−Ｓ（Ｏ）_ｎ−（ｎは０、１または２を表す。）、または−Ｎ（Ｒ^１５）−（Ｒ^１５は水素原子、置換基を有してもよいＣ_１−Ｃ_６アルキル基、または置換基を有してもよいＣ_１−Ｃ_１１アシル基を表す。）で表される基で置き換えられていてもよいＣ_５−Ｃ_７環状アミノカルボニル基（当該Ｃ_５−Ｃ_７環状アミノカルボニル基は置換基を有してもよい）、シアノ基、およびハロゲン原子より選ばれる基を表す。但し、Ｒ^１とＲ^２、Ｒ^３とＲ^４、Ｒ^５とＲ^７、またはＲ^６とＲ^８がベンゼン環上に互いに隣り合って存在する場合には、一緒になってベンゼン環、飽和または不飽和の５員または６員炭素環、または１または２個のヘテロ原子を含む飽和または不飽和の５員または６員複素環を形成してもよく、これらの環は置換基を有してもよい。
Ｒ⁹およびＲ¹⁰はそれぞれ独立して、水素原子、フッ素原子、置換基を有してもよいＣ_１−Ｃ_６アルキル基、置換基を有してもよいＣ_２−Ｃ_６アルケニル基、置換基を有してもよいＣ₆−Ｃ₁₀アリール基、置換基を有してもよいＣ₁−Ｃ₁₁アシル基、カルボキシル基、置換基を有してもよいＣ_２−Ｃ_７アルコキシカルボニル基、カルバモイル基、置換基を有してもよい（Ｃ_１−Ｃ_６アルキル）カルバモイル基、置換基を有してもよいジ（Ｃ_１−Ｃ_６アルキル）カルバモイル基、およびシアノ基より選ばれる基を表すか、または一緒になってそれらが結合する炭素原子と共に炭素数３から７のシクロアルカン環を形成してもよく、当該シクロアルカン環は置換基を有してもよい。
但し、Ｒ⁹およびＲ¹⁰は同時に水素原子を表さない。
Ｒ^１１およびＲ^１２はそれぞれ独立して、水素原子、フッ素原子、または置換基を有してもよいＣ_１−Ｃ_６アルキル基を表すか、または一緒になってそれらが結合する炭素原子と共に炭素数３から７のシクロアルカン環を形成してもよく、当該シクロアルカン環は置換基を有してもよい。
Ｗ^１およびＷ^２はそれぞれ独立して、酸素原子、硫黄原子、または式：−Ｎ（Ｒ^１６）−（Ｒ^１６は、複数ある場合にはそれぞれ独立して、水素原子または置換基を有してもよいＣ_１−Ｃ_６アルキル基を表す。）で表される基を表す。
Ｒ^１３はカルボキシル基、置換基を有してもよいＣ_２−Ｃ_７アルコキシカルボニル基、置換基を有してもよいＣ_３−Ｃ_７アルケニルオキシカルボニル基、または置換基を有してもよいＣ_７−Ｃ_１６アリールアルコキシカルボニル基、カルバモイル基、置換基を有してもよい（Ｃ_１−Ｃ_６アルキル）カルバモイル基、置換基を有してもよいジ（Ｃ_１−Ｃ_６アルキル）カルバモイル基、置換基を有してもよい（Ｃ_３−Ｃ_６シクロアルキル）カルバモイル基、炭素原子の一つが式：−Ｏ−、−Ｓ（Ｏ）_ｍ−（ｍは０、１または２を表す。）、または−Ｎ（Ｒ^１７）−（Ｒ^１７は水素原子、置換基を有してもよいＣ_１−Ｃ_６アルキル基、または置換基を有してもよいＣ_１−Ｃ_１１アシル基を表す。）で表される基で置き換えられていてもよいＣ_５−Ｃ_７環状アミノカルボニル基（当該Ｃ_５−Ｃ_７環状アミノカルボニル基は置換基を有してもよい）、またはテトラゾリル基を表す。］で表される化合物またはその塩。
〔２〕 式（２）：

[Wherein, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ are each independently a C ₁ − which may have a hydrogen atom, a hydroxyl group, or a substituent. C ₆ alkyl group, C ₂ -C ₆ alkenyl group which may have a substituent, C ₁ -C ₆ alkoxy group which may have a substituent, C ₁ -C ₁₁ which may have a substituent acyloxy group, a carboxyl group, an optionally substituted C ₂ -C ₇ alkoxycarbonyl group, a carbamoyl group, an optionally substituted (C ₁ -C ₆ alkyl) carbamoyl group, substituted Di (C ₁ -C ₆ alkyl) carbamoyl group which may be substituted, C ₁ -C ₆ alkylsulfonyloxy group which may be substituted, C ₆ -C ₁₀ arylsulfonyloxy group which may be substituted , One of the carbon atoms has the formula: —O—, —S (O) _n - (n represents 0, 1 or 2.), Or ^{-N (R 15) - (R} 15 represents a hydrogen atom, have a an optionally substituted _C 1 -C ₆ alkyl group or a substituted group, C ₅ -C ₇ cyclic aminocarbonyl group which may be substituted with a group represented by C ₁ -C ₁₁ acyl group which may be substituted (the C ₅ -C ₇ cyclic aminocarbonyl group is a substituent). A group selected from a cyano group and a halogen atom. However, when R ¹ and R ² , R ³ and R ⁴ , R ⁵ and R ⁷ , or R ⁶ and R ⁸ are adjacent to each other on the benzene ring, together, the benzene ring, saturated or Unsaturated 5- or 6-membered carbocycles, or saturated or unsaturated 5- or 6-membered heterocycles containing 1 or 2 heteroatoms may be formed, these rings having substituents Also good.
R ⁹ and R ¹⁰ are each independently a hydrogen atom, a fluorine atom, an optionally substituted C ₁ -C ₆ alkyl group, an optionally substituted C ₂ -C ₆ alkenyl group, or a substituted group. C ₆ -C ₁₀ aryl group which may have a group, C ₁ -C ₁₁ acyl group which may have a substituent, a carboxyl group, a C ₂ -C ₇ alkoxycarbonyl group which may have a substituent , A carbamoyl group, an optionally substituted (C ₁ -C ₆ alkyl) carbamoyl group, an optionally substituted di (C ₁ -C ₆ alkyl) carbamoyl group, and a group selected from a cyano group Or together with the carbon atom to which they are bonded, a C3-C7 cycloalkane ring may be formed, and the cycloalkane ring may have a substituent.
However, R ⁹ and R ¹⁰ do not represent a hydrogen atom at the same time.
R ¹¹ and R ¹² each independently represent a hydrogen atom, a fluorine atom, or an optionally substituted C ₁ -C ₆ alkyl group, or together with the carbon atom to which they are attached, carbon A cycloalkane ring of formula 3 to 7 may be formed, and the cycloalkane ring may have a substituent.
W ¹ and W ² are each independently an oxygen atom, a sulfur atom, or a formula: —N (R ¹⁶ ) — (R ¹⁶ is independently a hydrogen atom or a substituent when there are a plurality thereof. Represents a C ₁ -C ₆ alkyl group which may be substituted).
R ¹³ may have a carboxyl group, a C ₂ -C ₇ alkoxycarbonyl group which may have a substituent, a C ₃ -C ₇ alkenyloxycarbonyl group which may have a substituent, or a substituent. C ₇ -C ₁₆ arylalkoxycarbonyl group, carbamoyl group, optionally substituted (C ₁ -C ₆ alkyl) carbamoyl group, optionally substituted di (C ₁ -C ₆ alkyl) carbamoyl Group, an optionally substituted (C ₃ -C ₆ cycloalkyl) carbamoyl group, one of the carbon atoms is represented by the formula: —O—, —S (O) _m — (m represents 0, 1 or 2). ), Or —N (R ¹⁷ ) — (R ¹⁷ is a hydrogen atom, an optionally substituted C ₁ -C ₆ alkyl group, or an optionally substituted C ₁ -C ₁₁ acyl group. Is replaced by a group represented by Optionally have C ₅ -C ₇ cyclic aminocarbonyl group (said C ₅ -C ₇ cyclic amino carbonyl group may have a substituent), or represents tetrazolyl group. Or a salt thereof.
[2] Formula (2):

［式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６、Ｒ^７、Ｒ^８、Ｒ^９、Ｒ^１０、Ｒ^１１、Ｒ^１２、Ｒ^１３、Ｗ^１、およびＷ^２はそれぞれ〔１〕と同意義を表す。］で表される、〔１〕記載の化合物またはその塩。
〔３〕 式（３）：

[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , W ¹ , and W ² are Each represents the same meaning as [1]. Or a salt thereof according to [1].
[3] Formula (3):

［式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６、Ｒ^７、Ｒ^８、Ｒ^９、Ｒ^１０、Ｒ^１１、Ｒ^１２、Ｒ^１３、Ｗ^１、およびＷ^２はそれぞれ〔１〕と同意義を表す。］で表される、〔１〕または〔２〕記載の化合物またはその塩。
〔４〕 Ｗ^２が酸素原子である、〔１〕〜〔３〕のいずれかに記載の化合物またはその塩。
〔５〕 Ｗ^２が硫黄原子である、〔１〕〜〔３〕のいずれかに記載の化合物またはその塩。
〔６〕 Ｗ^２が式：−Ｎ（Ｒ^１６）−で表される基である、〔１〕〜〔３〕のいずれかに記載の化合物またはその塩。
〔７〕 Ｗ^１が酸素原子である、〔１〕〜〔６〕のいずれかに記載の化合物またはその塩。
〔８〕 Ｗ^１およびＷ^２が共に酸素原子である、〔１〕〜〔３〕のいずれかに記載の化合物またはその塩。
〔９〕 Ｗ^１が酸素原子であり、Ｗ^２が硫黄原子である、〔１〕〜〔３〕のいずれかに記載の化合物またはその塩。
〔１０〕 Ｗ^１が硫黄原子である、〔１〕〜〔６〕のいずれかに記載の化合物またはその塩。
〔１１〕 Ｗ^１が硫黄原子であり、Ｗ^２が酸素原子である、〔１〕〜〔３〕のいずれかに記載の化合物またはその塩。
〔１２〕 Ｗ^１が式：−Ｎ（Ｒ^１６）−で表される基である、〔１〕〜〔５〕のいずれかに記載の化合物またはその塩。
〔１３〕 Ｒ^１３がカルボキシル基である、〔１〕〜〔１２〕のいずれかに記載の化合物またはその塩。
〔１４〕 Ｒ^５およびＲ^６の少なくとも一方が水素原子以外の基である、〔１〕〜〔１３〕のいずれかに記載の化合物またはその塩。
〔１５〕 Ｒ^５およびＲ^６のいずれか一方が水素原子であり、他方が水素原子以外の基である、〔１〕〜〔１４〕のいずれかに記載の化合物またはその塩。
〔１６〕 式（４）：

[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , W ¹ , and W ² are Each represents the same meaning as [1]. Or a salt thereof according to [1] or [2].
[4] The compound or salt thereof according to any one of [1] to [3], wherein W ² is an oxygen atom.
[5] The compound or salt thereof according to any one of [1] to [3], wherein W ² is a sulfur atom.
[6] The compound or salt thereof according to any one of [1] to [3], wherein W ² is a group represented by the formula: —N (R ¹⁶ ) —.
[7] The compound or salt thereof according to any one of [1] to [6], wherein W ¹ is an oxygen atom.
[8] The compound or salt thereof according to any one of [1] to [3], wherein both W ¹ and W ² are oxygen atoms.
[9] The compound or salt thereof according to any one of [1] to [3], wherein W ¹ is an oxygen atom and W ² is a sulfur atom.
[10] The compound or salt thereof according to any one of [1] to [6], wherein W ¹ is a sulfur atom.
[11] The compound or salt thereof according to any one of [1] to [3], wherein W ¹ is a sulfur atom and W ² is an oxygen atom.
[12] The compound or salt thereof according to any one of [1] to [5], wherein W ¹ is a group represented by the formula: -N (R ¹⁶ )-.
[13] The compound or salt thereof according to any one of [1] to [12], wherein R ¹³ is a carboxyl group.
[14] The compound or salt thereof according to any one of [1] to [13], wherein at least one of R ⁵ and R ⁶ is a group other than a hydrogen atom.
[15] The compound or salt thereof according to any one of [1] to [14], wherein either one of R ⁵ and R ⁶ is a hydrogen atom, and the other is a group other than a hydrogen atom.
[16] Formula (4):

［式中、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６、Ｒ^７、Ｒ^８、Ｒ^９、Ｒ^１０、Ｒ^１１、Ｒ^１２、Ｒ^１３、Ｗ^１、およびＷ^２はそれぞれ〔１〕と同意義を表し、Ｒ^１’はトリフルオロメチル基またはトリフルオロメトキシ基を表す。］で表される、〔１〕〜〔１５〕のいずれかに記載の化合物またはその塩。
〔１７〕 式（５）：

[Wherein R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , W ¹ , and W ² are each represented by [1 And R ^{1 ′} represents a trifluoromethyl group or a trifluoromethoxy group. Or a salt thereof according to any one of [1] to [15].
[17] Formula (5):

［式中、Ｒ^２、Ｒ^４、Ｒ^５、Ｒ^６、Ｒ^７、Ｒ^８、Ｒ^９、Ｒ^１０、Ｒ^１１、Ｒ^１２、Ｒ^１３、Ｗ^１、およびＷ^２はそれぞれ〔１〕と同意義を表し、Ｒ^１’はトリフルオロメチル基またはトリフルオロメトキシ基を表し、Ｒ^３’はフッ素原子を表す。］で表される、〔１〕〜〔１６〕のいずれかに記載の化合物またはその塩。
〔１８〕 〔１〕〜〔１７〕のいずれかに記載の化合物またはその塩を有効成分として含有する医薬。
〔１９〕 〔１〕〜〔１７〕のいずれかに記載の化合物またはその塩を有効成分として含有する、ペルオキシソーム増殖剤応答性受容体δの活性化剤。
〔２０〕 〔１〕〜〔１７〕のいずれかに記載の化合物またはその塩を有効成分として含有する、血中高密度リポ蛋白質濃度の上昇剤。
〔２１〕 〔１〕〜〔１７〕のいずれかに記載の化合物またはその塩を有効成分として含有する、低ＨＤＬ血症の治療剤。
〔２２〕 〔１〕〜〔１７〕のいずれかに記載の化合物またはその塩を有効成分として含有する、動脈硬化の治療剤。
本明細書に於いては上記式（１）で表される化合物またはその塩を、必要に応じ本発明化合物と略称する。

[Wherein R ² , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , W ¹ and W ² are the same as [1]. R ^{1 ′} represents a trifluoromethyl group or a trifluoromethoxy group, and R ^{3 ′} represents a fluorine atom. ] The compound or its salt in any one of [1]-[16] represented by these.
[18] A medicament comprising the compound or salt thereof according to any one of [1] to [17] as an active ingredient.
[19] An activator of peroxisome proliferator-responsive receptor δ, comprising as an active ingredient the compound or salt thereof according to any one of [1] to [17].
[20] An agent for increasing blood high-density lipoprotein concentration, comprising the compound or salt thereof according to any one of [1] to [17] as an active ingredient.
[21] A therapeutic agent for hypoHDLemia comprising the compound or salt thereof according to any one of [1] to [17] as an active ingredient.
[22] A therapeutic agent for arteriosclerosis comprising the compound or salt thereof according to any one of [1] to [17] as an active ingredient.
In the present specification, the compound represented by the above formula (1) or a salt thereof is abbreviated as the present compound as necessary.

  The substituents in the compound of the present invention will be described below. Unless otherwise specified, the following description also applies when the substituent is a part of another substituent.

As a halogen atom, a fluorine atom, a chlorine atom, or a bromine atom is mentioned, Preferably a fluorine atom is mentioned.
The C ₁ -C ₆ alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms, specifically a methyl group, an ethyl group, a propyl group, a 2-propyl group (isopropyl group), A butyl group, 2-methylpropyl group, 3-methylpropyl group (isobutyl group), t-butyl group, pentyl group, neopentyl group, hexyl group and the like can be exemplified.
The C ₂ -C ₆ alkenyl group means a straight chain or branched alkenyl group having 2 to 6 carbon atoms, specifically vinyl group, allyl group, 1-propenyl group, 2-methyl-1-propenyl group. Group, 2-butenyl group and 1,3-butadienyl group.
The C ₃ -C ₇ alkenyloxycarbonyl group means a carbonyl group substituted with a linear or branched alkenyl group having 2 to 6 carbon atoms, specifically, a vinyloxycarbonyl group, an allyloxycarbonyl group, Examples thereof include 1-propenyloxycarbonyl group, 2-methyl-1-propenyloxycarbonyl group, 2-butenyloxycarbonyl group, and 1,3-butadienyloxycarbonyl group. The C ₃ -C ₇ alkenyloxycarbonyl group for R ¹³ is preferably an allyloxycarbonyl group.
The C ₆ -C ₁₀ aryl group means an aryl group having 6 to 10 carbon atoms, and specifically includes a phenyl group and a (1- or 2-) naphthyl group.
And C ₃ -C ₆ cycloalkyl group means a cycloalkyl group having 3 to 6 carbon atoms, and specifically include cyclopentyl, cyclohexyl and the like.

The C ₁ -C ₆ alkoxy group means a group in which a C ₁ -C ₆ alkyl group is bonded to one of oxygen atom bonds, specifically, a methoxy group, an ethoxy group, a propoxy group, or an isopropoxy group. , Butoxy group, t-butoxy group, pentoxy group, hexyloxy group and the like.
The C ₁ -C ₆ alkylamino group means an amino group substituted by a linear or branched alkyl group having 1 to 6 carbon atoms, specifically a methylamino group, an ethylamino group, a propylamino group, Examples thereof include an isopropylamino group, a butylamino group, a t-butylamino group, a pentylamino group, and a hexylamino group.
The di (C ₁ -C ₆ alkyl) amino group means an amino group in which a linear or branched alkyl group having 1 to 6 carbon atoms is the same or different and is substituted, specifically, a dimethylamino group , Diethylamino group, ethylmethylamino group, dipropylamino group, methylpropylamino group, and the like.
The C ₂ -C ₇ alkoxycarbonyl group means a carbonyl group substituted with the above C ₁ -C ₆ alkoxy group, specifically, a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group. , Butoxycarbonyl group, t-butoxycarbonyl group, pentoxycarbonyl group, hexyloxycarbonyl group and the like.

A carbamoyl group means an unsubstituted aminocarbonyl group.
The (C ₁ -C ₆ alkyl) carbamoyl group means an alkylcarbamoyl group in which a linear or branched alkyl group having 1 to 6 carbon atoms is substituted on a nitrogen atom, specifically a methylcarbamoyl group, ethyl Examples thereof include a carbamoyl group, a propylcarbamoyl group, an isopropylcarbamoyl group, a butylcarbamoyl group, a t-butylcarbamoyl group, a pentylcarbamoyl group, and a hexylcarbamoyl group.
The di (C ₁ -C ₆ alkyl) carbamoyl group means an alkylcarbamoyl group in which a linear or branched alkyl group having 1 to 6 carbon atoms is the same or different and is substituted on a nitrogen atom by two. Specific examples include a dimethylcarbamoyl group and a diethylcarbamoyl group.
The (C ₃ -C ₆ cycloalkyl) carbamoyl group means a carbamoyl group substituted with a cycloalkyl group having 3 to 6 carbon atoms, and specific examples thereof include a cyclopentylcarbamoyl group and a cyclohexylcarbamoyl group.

The C ₁ -C ₆ alkylsulfonyloxy group means a sulfonyloxy group substituted by a linear or branched alkyl group having 1 to 6 carbon atoms, specifically, a methanesulfonyloxy group, an ethanesulfonyloxy group, or the like. Can be mentioned.
The C ₆ -C ₁₀ arylsulfonyloxy group means a sulfonyloxy group to which an aryl group having 6 to 10 carbon atoms is bonded, specifically, a benzenesulfonyloxy group and a (1- or 2-) naphthylsulfonyloxy group. Is mentioned.
The substituents of the substituted C ₆ -C ₁₀ aryl group and the substituted C ₆ -C ₁₀ arylsulfonyloxy group may be present in one or more, the same or different. Such substituents include C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, methylenedioxy groups, and halogen atoms.
More specific examples of the substituted C ₇ -C ₁₆ arylsulfonyloxy group include a p-toluenesulfonyloxy group.
Specific examples of the cycloalkane ring having 3 to 7 carbon atoms include cyclopropane, cyclobutane, cyclopentane, cyclohexane and cycloheptane.

Examples of the C ₁ -C ₁₁ acyl group include a formyl group, a C ₂ -C ₇ alkanoyl group, a C ₄ -C ₇ cycloalkanecarbonyl group, and a C ₇ -C ₁₁ aroyl group.
The C ₁ -C ₁₁ acyloxy group means a group in which a C ₁ -C ₁₁ acyl group is bonded to one of oxygen bond bonds.
The C ₁ -C ₁₁ acylamino group means an amino group substituted with a C ₁ -C ₁₁ acyl group.
The C ₂ -C ₇ alkanoyl group means a carbonyl group substituted by a linear or branched alkyl group having 1 to 6 carbon atoms, specifically, an acetyl group, a propionyl group, a butyryl group, an isobutyryl group. , Valeryl group, isovaleryl group, pivaloyl group and the like.
The C ₄ -C ₇ cycloalkanecarbonyl group means a carbonyl group substituted by a cycloalkyl group having 3 to 6 carbon atoms, and specific examples include a cyclopentylcarbonyl group and a cyclohexylcarbonyl group.
The C ₇ -C ₁₁ aroyl group means a carbonyl group substituted with a phenyl group or a (1- or 2-) naphthyl group, and specifically includes a benzoyl group, a 1-naphthoyl group, and a 2-naphthoyl group. It is done.
Examples of the substituent of the substituted C ₇ -C ₁₁ aroyl group include a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group, a methylenedioxy group, and a halogen atom. Can do. Specific examples of such a substituted C ₇ -C ₁₁ aroyl group include a 4-methoxybenzoyl group, a 4-chlorobenzoyl group, a 2-toluoyl group, a 3-toluoyl group, and a 4-toluoyl group.

The substituents in the substituted C ₁ -C ₆ alkyl group can be present one or more, the same or different. Examples of such substituents include phenyl groups, aryl groups such as (1- or 2-) naphthyl groups, (2-, 3-, or 4-) pyridyl groups, 2-furyl groups, 2-thienyl groups, 2-one or two 5- or 6-membered heterocyclic group, saturated or unsaturated heteroatom containing imidazolyl, _etc., C 3 -C ₆ cycloalkyl group, a vinyl group, hydroxyl _group, C 1 -C ₆ alkoxy group , Amino group, C ₁ -C ₆ alkylamino group, di (C ₁ -C ₆ alkyl) amino group, C ₁ -C ₁₁ acylamino group, carboxyl group, C ₁ -C ₆ alkoxycarbonyl group, halogen atom, etc. be able to.
Specific examples of the substituted C ₁ -C ₆ alkyl group include a benzyl group, 2-pyridylmethyl group, 3-pyridylmethyl group, 4-pyridylmethyl group, 2-furfuryl group, 2-thienylmethyl group, 2- Imidazolylmethyl group, allyl group, methoxymethyl group, 2-hydroxyethyl group, 2-methoxyethyl group, 2-ethoxyethyl group, 2-aminoethyl group, 2- (methylamino) ethyl group, 2- (dimethylamino) Examples thereof include an ethyl group, 2- (acetamido) ethyl group, and trifluoromethyl group.
Preferred examples of the substituted C ₁ -C ₆ alkyl group include a trifluoromethyl group.

Substituted _C 3 -C ₇ alkenyloxycarbonyl group, a substituted _C 1 -C ₆ alkoxy group, a substituted _C 2 -C ₇ alkoxycarbonyl group, substituted _(C 1 -C ₆ alkyl) carbamoyl group, a substituted di _(C 1 -C ₆ Alkyl) carbamoyl group, (C ₃ -C ₆ cycloalkyl) carbamoyl group, substituted C ₁ -C ₆ alkylsulfonyloxy group, substituted C ₂ -C ₇ alkanoyl group, substituted C ₂ -C ₇ alkanoyloxy group and the like The groups can be present one or more, the same or different. Examples of such a substituent include the same groups as those of the above substituted C ₁ -C ₆ alkyl group.

Preferred examples of the substituted C ₁ -C ₆ alkoxy group include a trifluoromethoxy group.
Preferable substituents in the substituted C ₂ -C ₇ alkoxycarbonyl group include a phenyl group and a vinyl group. Specific examples of the substituted C ₂ -C ₇ alkoxycarbonyl group include a benzyloxycarbonyl group and an allyloxycarbonyl group.
A preferable substituent in the substituted (C ₁ -C ₆ alkyl) carbamoyl group includes a phenyl group. Specific examples of the substituted (C ₁ -C ₆ alkyl) carbamoyl group include a benzylcarbamoyl group, a 2-hydroxyethylcarbamoyl group, and a 2-methoxyethylcarbamoyl group.
A preferable substituent in the substituted di (C ₁ -C ₆ alkyl) carbamoyl group includes a phenyl group. Specific examples of the substituted di (C ₁ -C ₆ alkyl) carbamoyl group include an N-benzyl-N-methylcarbamoyl group and an N-benzyl-N-ethylcarbamoyl group.

Substituted cycloalkane ring having 3 to 7 carbon atoms, a substituted C ₄ -C ₇ cycloalkane carbonyl group and a substituted C ₄ -C ₇ substituents cycloalkane carbonyl group, is 1 or more, there same or different obtain. Examples of such a substituent include a group similar to the substituent of the substituted C ₁ -C ₆ alkyl group and a C ₁ -C ₆ alkyl group.
One of the carbon atoms is represented by the formula: —O—, —S (O) _n — (n represents 0, 1 or 2), —S (O) _m — (m represents 0, 1 or 2). ^{, -N (R 15) - (} R 15 represents a hydrogen atom, an optionally substituted _C 1 -C ₆ alkyl group or an optionally substituted _C 1 _{-C 11} acyl group. ), Or —N (R ¹⁷ ) — (R ¹⁷ is a hydrogen atom, an optionally substituted C ₁ -C ₆ alkyl group, or an optionally substituted C ₁ -C ₁₁ acyl group. As the C ₅ -C ₇ cyclic aminocarbonyl group optionally substituted with a group represented by the above formula (the C ₅ -C ₇ cyclic aminocarbonyl group may have a substituent), 1-pyrrolidinylcarbonyl group, piperidinocarbonyl group, morpholinocarbonyl group, thiomorpholinocarboni And 1-piperazinylcarbonyl group.
Substituents that substitute on such C ₄ -C ₆ cyclic aminocarbonyl groups can be present one or more, the same or different. Such substituents, the substituted C ₁ -C ₆ alkyl same groups as the substituents of groups, optionally C ₁ may have a substituent as a substituent on the nitrogen atom as a substituent on a carbon atom -C ₆ alkyl group, and a substituent is exemplified by an _C 1 _{-C 11} acyl group, in particular such as 4-methyl-1-piperazinyl group, 4-acetyl-1-piperazinyl Razinylcarbonyl group etc. are mentioned.
The C ₇ -C ₁₆ arylalkoxycarbonyl group means an alkoxycarbonyl group to which an aryl group is bonded and has a total of 7 to 16 carbon atoms. As the alkyl moiety, a C ₁ -C ₆ alkyl group is an aryl moiety. Examples thereof include a phenyl group and a (1- or 2-) naphthyl group.
The substituents of the substituted C ₇ -C ₁₆ arylalkoxycarbonyl group may be present as one or more, the same or different. As such substituents, the same groups as the substituents of the substituted C ₁ -C ₆ alkyl group as a substituent on the alkyl group, C ₁ -C ₆ alkyl group as a substituent on the aryl group, C ₁ -C ₆ alkoxy group, a methylenedioxy group, and a halogen atom.
The C ₇ -C ₁₆ arylalkoxycarbonyl group for R ¹³ is preferably a benzyloxycarbonyl group.

Specific examples of the saturated or unsaturated 5-membered or 6-membered carbocycle include cyclopentene, cyclohexene, and benzene ring.
Substituted saturated or C ₁ -C ₆ alkyl group as a 5-membered or 6-membered substituents carbocyclic unsaturated, C ₁ -C ₆ alkoxy group, a methylenedioxy group, and a halogen atom.
Saturated or unsaturated 5- or 6-membered heteroatoms containing 1 or 2 heteroatoms include oxygen, sulfur, and nitrogen.
Examples of such a saturated or unsaturated 5- or 6-membered heterocyclic ring include a 5- or 6-membered ring containing 1 to 2 nitrogen atoms such as pyrrole, pyrroline, imidazole and pyridine, one nitrogen atom such as oxazole and the like. 5- or 6-membered ring containing one oxygen atom, 5- or 6-membered ring containing one nitrogen atom such as thiazole and one sulfur atom, 1,3-dioxole, 2,3-dihydro-1,4-dioxin, etc. 5- or 6-membered rings containing 1 to 2 oxygen atoms, or 5- or 6-membered rings containing 1 to 2 sulfur atoms such as thiophene and 2,3-dihydro-1,4-dithiin.
Substituted, saturated, 3-membered, 4-membered, 5-membered or 6-membered heterocyclic substituents containing 1 or 2 heteroatoms may be present in one or more, identical or different. Such substituents, C ₁ -C ₆ alkyl as a substituent on a carbon atom, C ₁ -C ₆ alkoxy groups, and halogen atoms, which may have a substituent group as a substituent on the nitrogen atom Examples thereof include a good C ₁ -C ₆ alkyl group and an optionally substituted C ₁ -C ₁₁ acyl group.

The compound represented by formula (1) can be synthesized, for example, by the following production method.
That is, Formula (6):

［式中、Ｒ^２１、Ｒ^２２、Ｒ^２３、およびＲ^２４はそれぞれ独立して、水素原子、適宜保護された水酸基、置換基を有してもよいＣ_１−Ｃ_６アルキル基、置換基を有してもよいＣ_１−Ｃ_６アルコキシ基、置換基を有してもよいＣ_１−Ｃ_１１アシルオキシ基、置換基を有してもよいＣ_２−Ｃ_７アルコキシカルボニル基、カルバモイル基、置換基を有してもよい（Ｃ_１−Ｃ_６アルキル）カルバモイル基、置換基を有してもよいジ（Ｃ_１−Ｃ_６アルキル）カルバモイル基、置換基を有してもよいＣ_１−Ｃ_６アルキルスルホニルオキシ基、置換基を有してもよいＣ_６−Ｃ_１０アリールスルホニルオキシ基、炭素原子の一つが式：−Ｏ−、−Ｓ（Ｏ）_ｎ−（ｎは前記と同意義を表す。）、または−Ｎ（Ｒ^３５）−（Ｒ^３５は保護基、置換基を有してもよいＣ_１−Ｃ_６アルキル基または置換基を有してもよいＣ_１−Ｃ_１１アシル基を表す。）で表される基で置き換えられていてもよいＣ_５−Ｃ_７環状アミノカルボニル基（当該Ｃ_５−Ｃ_７環状アミノカルボニル基は置換基を有してもよい）、シアノ基、およびハロゲン原子より選ばれる基を表す。Ｒ^２１とＲ^２２、またはＲ^２３とＲ^２４がベンゼン環上に互いに隣り合って存在する場合には、一緒になってベンゼン環、飽和または不飽和の５員または６員炭素環、または１または２個のヘテロ原子を含む飽和または不飽和の５員または６員複素環を形成してもよく、これらの環は置換されていてもよい。Ｒ^９およびＲ^１０は前記と同意義を表す。Ｘは脱離基を表す。］で表されるビフェニル化合物と、式（７）：

[Wherein R ²¹ , R ²² , R ²³ , and R ²⁴ each independently represent a hydrogen atom, a suitably protected hydroxyl group, a C ₁ -C ₆ alkyl group that may have a substituent, or a substituent. C ₁ -C ₆ alkoxy group which may have, C ₁ -C ₁₁ acyloxy group which may have a substituent, C ₂ -C ₇ alkoxycarbonyl group which may have a substituent, carbamoyl group, substituted (C ₁ -C ₆ alkyl) carbamoyl group which may have a group, di (C ₁ -C ₆ alkyl) carbamoyl group which may have a substituent, C ₁ -C which may have a substituent ₆ alkylsulfonyloxy group, C ₆ -C ₁₀ arylsulfonyloxy group which may have a substituent, and one of the carbon atoms has the formula: —O—, —S (O) _n — (n is as defined above. . represented), or ^{-N (R 35) - (R} 35 is the coercive Group, may be replaced with a group represented by represents.) Good C ₁ -C ₁₁ acyl group that may have an optionally substituted C ₁ -C ₆ alkyl group or a substituted group C ₅ -C ₇ cyclic aminocarbonyl group (said C ₅ -C ₇ cyclic amino carbonyl group may have a substituent), a cyano group, and a group selected from a halogen atom. When R ²¹ and R ²² , or R ²³ and R ²⁴ are present next to each other on a benzene ring, together they are a benzene ring, a saturated or unsaturated 5- or 6-membered carbocyclic ring, or 1 or A saturated or unsaturated 5- or 6-membered heterocyclic ring containing 2 heteroatoms may be formed, and these rings may be substituted. R ⁹ and R ¹⁰ are as defined above. X represents a leaving group. A biphenyl compound represented by formula (7):

［式中、Ｒ^２５、Ｒ^２６、Ｒ^２７、およびＲ^２８はそれぞれ独立して、水素原子、適宜保護された水酸基、置換基を有してもよいＣ_１−Ｃ_６アルキル基、置換基を有してもよいＣ_１−Ｃ_６アルコキシ基、置換基を有してもよいＣ_１−Ｃ_１１アシルオキシ基、置換基を有してもよいＣ_２−Ｃ_７アルコキシカルボニル基、カルバモイル基、置換基を有してもよい（Ｃ_１−Ｃ_６アルキル）カルバモイル基、置換基を有してもよいジ（Ｃ_１−Ｃ_６アルキル）カルバモイル基、置換基を有してもよいＣ_１−Ｃ_６アルキルスルホニルオキシ基、置換基を有してもよいＣ_６−Ｃ_１０アリールスルホニルオキシ基、炭素原子の一つが式：−Ｏ−、−Ｓ（Ｏ）_ｎ−（ｎは前記と同意義を表す。）、または−Ｎ（Ｒ^３５）−（Ｒ^３５は前記と同じ意味を表す。）で表される基で置き換えられていてもよいＣ_５−Ｃ_７環状アミノカルボニル基（当該Ｃ_５−Ｃ_７環状アミノカルボニル基は置換基を有してもよい）、シアノ基、およびハロゲン原子より選ばれる基を表す。但し、Ｒ^２５とＲ^２７、またはＲ^２６とＲ^２８がベンゼン環上に互いに隣り合って存在する場合には、一緒になってベンゼン環、飽和または不飽和の５員または６員炭素環、または１または２個のヘテロ原子を含む飽和または不飽和の５員または６員複素環を形成してもよく、これらの環は置換されていてもよい。Ｒ^１１、Ｒ^１２およびＷ^１は前記と同意義を表す。Ｗ^３は酸素原子、硫黄原子または式：−Ｎ（Ｒ^３６）−（Ｒ^３６は置換基を有してもよいＣ_１−Ｃ_６アルキル基、または保護基を表す。）で表される基を表す。Ｒ^３３は置換基を有してもよいＣ_１−Ｃ_６アルコキシカルボニル基、置換基を有してもよいＣ_３−Ｃ_７アルケニルオキシカルボニル基、または置換基を有してもよいＣ_７−Ｃ_１６アリールアルコキシカルボニル基を表す。］で表される化合物とを塩基の存在下反応させた後に、必要に応じ各種保護基を脱保護することによって、式（１）で表される化合物を得ることができる。

[Wherein R ²⁵ , R ²⁶ , R ²⁷ , and R ²⁸ each independently represent a hydrogen atom, a suitably protected hydroxyl group, a C ₁ -C ₆ alkyl group optionally having substituent (s), or a substituent group. C ₁ -C ₆ alkoxy group which may have, C ₁ -C ₁₁ acyloxy group which may have a substituent, C ₂ -C ₇ alkoxycarbonyl group which may have a substituent, carbamoyl group, substituted (C ₁ -C ₆ alkyl) carbamoyl group which may have a group, di (C ₁ -C ₆ alkyl) carbamoyl group which may have a substituent, C ₁ -C which may have a substituent ₆ alkylsulfonyloxy group, C ₆ -C ₁₀ arylsulfonyloxy group which may have a substituent, and one of the carbon atoms has the formula: —O—, —S (O) _n — (n is as defined above. . expressed) or ^{-N (R 35,) - (} R 35 before The same meaning as.) -C C ₅ optionally replaced with a group represented by ₇ cyclic aminocarbonyl group (said C ₅ -C ₇ cyclic amino carbonyl group may have a substituent), Represents a group selected from a cyano group and a halogen atom. Provided that when R ²⁵ and R ²⁷ , or R ²⁶ and R ²⁸ are present adjacent to each other on the benzene ring, together, a benzene ring, a saturated or unsaturated 5- or 6-membered carbocyclic ring, or A saturated or unsaturated 5- or 6-membered heterocyclic ring containing 1 or 2 heteroatoms may be formed, and these rings may be substituted. R ¹¹ , R ¹² and W ¹ are as defined above. W ³ is an oxygen atom, a sulfur atom or a group represented by the formula: —N (R ³⁶ ) — (R ³⁶ represents a C ₁ -C ₆ alkyl group which may have a substituent, or a protecting group). Represents. R ³³ is a C ₁ -C ₆ alkoxycarbonyl group which may have a substituent, a C ₃ -C ₇ alkenyloxycarbonyl group which may have a substituent, or a C _7- which may have a substituent. It represents a C ₁₆ aryl alkoxycarbonyl group. The compound represented by the formula (1) can be obtained by reacting the compound represented by formula (I) in the presence of a base and then deprotecting various protecting groups as necessary.

Examples of the reaction solvent include highly polar aprotic solvents such as dimethylformamide (DMF), dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), and N-methylpiperidinone (NMP), such as tetrahydrofuran (THF), 1 And ether solvents such as 2-dimethoxyethane, halogen solvents such as dichloromethane and 1,2-dichloroethane, ketone solvents such as acetone and methyl ethyl ketone, and the like.
Bases used include cesium carbonate, potassium carbonate, sodium carbonate, lithium carbonate, potassium phosphate, sodium phosphate, dipotassium hydrogen phosphate, disodium hydrogen phosphate, potassium hydroxide, sodium hydroxide, lithium hydroxide, hydrogen Inorganic bases such as sodium hydride and lithium hydride, and organic bases such as pyridine, lutidine, collidine, dimethylaminopyridine (DMAP), triethylamine, diisopropylethylamine, imidazole, butyllithium, lithium diisopropylamide (LDA), lithium hexamethyl Disilazide (lithium bistrimethylsilylamide, LiHMDS), sodium hexamethyldisilazide (sodium bistrimethylsilylamide, NaHMDS), potassium hexamethyldisilazide (potassium) Bistrimethylsilylamide, KHMDS), sodium methoxide, sodium ethoxide, and organic metal bases, such as t- butoxy potassium.

When selecting a combination of a reaction solvent and a base, it is necessary to be stable with respect to the base used by the reaction solvent itself, and care must be taken particularly when an organometallic base is used. For example, butyl lithium, lithium diisopropylamide (LDA), lithium hexamethyldisilazide (lithium bistrimethylsilylamide, LiHMDS), sodium hexamethyldisilazide (sodium bistrimethylsilylamide, NaHMDS), potassium hexamethyldisilazide (potassium) When an organic metal base such as bistrimethylsilylamide or KHMDS) is used, an ether solvent such as tetrahydrofuran (THF) or 1,2-dimethoxyethane is preferable, and sodium methoxide, sodium ethoxide, t- When using an organic metal base such as butoxy potassium, sodium hydride, lithium hydride, etc., an ether solvent such as tetrahydrofuran (THF) or 1,2-dimethoxyethane may be used. For example dimethylformamide (DMF), dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), highly polar aprotic solvents such as N- methyl-piperidinium Non (NMP) are preferred.
The reaction temperature in each of the above reactions varies depending on the type of base used, but can be appropriately selected within the range of -78 ° C to the boiling point of the solvent. The reaction time for each reaction varies greatly depending on the reaction temperature and the combination of the reaction solvent and the base used, but is generally between 30 minutes and 2-3 days. Further, for the purpose of accelerating the reaction, an iodine salt such as sodium iodide or potassium iodide or a phase transfer catalyst such as tetrabutylammonium bromide or tetrabutylammonium iodide is added as an additive as necessary. be able to.

The leaving group X in the biphenyl compound represented by the formula (6) includes halogen atoms such as iodine atom, bromine atom and chlorine atom, methanesulfonyloxy group (mesyloxy group), trifluoromethanesulfonyloxy group, paratoluene. A sulfonyloxy group (tosyloxy group) etc. can be mentioned.
The biphenyl compound represented by the formula (6) and the functional groups such as hydroxyl group, amino group, and carboxyl group present on the compound represented by (7) may be protected in advance before carrying out this reaction. preferable. It is desirable to select those protecting groups that are stable under the reaction conditions and that can be appropriately deprotected after the completion of the reaction, if necessary. The selection of such protecting groups largely depends on the type of other substituents. Examples of protecting groups for amino groups include benzyloxycarbonyl group (Z group, Cbz group), t-butoxycarbonyl group (Boc group), allyloxy. Carbamate protecting groups such as a carbonyl group (Alloc group) and 9-fluorenylmethoxycarbonyl group (Fmoc group), and as a protecting group for a hydroxyl group, for example, an ester protecting group such as an acetyl group or a benzoyl group, benzyl Examples of the protecting group for the carboxyl group include ester-type protecting groups such as methyl, ethyl, t-butyl, benzyl and allyl. The method for introducing, deprotecting and selecting such a protecting group is described in, for example, Greene et al., Protecting Groups in Organic Synthesis (Second Edition, John Wiley & Sons, Inc., New York, 1991). The contents of can be referred to.

When it is desired to obtain a compound in which R ¹³ in formula (1) is a carboxyl group, the ester group may be hydrolyzed. Examples of the ester group hydrolysis method include an alcohol solvent such as methanol, ethanol and isopropyl alcohol, an ether solvent such as tetrahydrofuran (THF) and dioxane, or a mixed solvent thereof. Examples thereof include a method in which a base such as cesium hydroxide, potassium hydroxide, sodium hydroxide, lithium hydroxide, cesium carbonate, potassium carbonate and sodium carbonate is allowed to act in the presence.
Further, when R ¹³ is a benzyloxycarbonyl group, hydrolysis can also be performed by catalytic hydrogenation using palladium-activated carbon (Pd—C) as a catalyst.
When R ¹³ is an allyloxycarbonyl group, a palladium catalyst such as tetrakis (triphenylphosphine) palladium is used in the presence of an allyl scavenger such as pyrrolidine, piperidine, morpholine, dimedone, or polymethylhydrosiloxane. Hydrolysis can also be performed by the method.
When R ¹³ is a t-butoxycarbonyl group, a method using an acid such as formic acid, trifluoroacetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, paratoluenesulfonic acid, camphorsulfonic acid, etc. Also, hydrolysis can be performed.
In any reaction, the reaction temperature varies depending on the type of reagent and solvent used, but can be appropriately selected within the range of ice cooling to the boiling point of the solvent. The reaction time for each reaction varies greatly depending on the reaction temperature and the combination of the reaction solvent and the reagent used, but is generally between 10 minutes and 2-3 days.

The compound represented by the formula (7) can be synthesized by a known method, and specific examples thereof are described in, for example, WO01 / 00603. In WO01 / 00603, compounds in which W ¹ is a sulfur atom among the compounds represented by the formula (7) are obtained by reducing the corresponding chlorosulfonyl compound by using tin powder. Even if zinc powder is used instead of the powder, the reaction proceeds in the same manner, and the same target product can be obtained. This compound can also be obtained by reacting the corresponding chlorosulfonyl compound with an equivalent or 10 equivalents of triphenylphosphine in a solvent such as hydrous dioxane.
Alternatively, the compound represented by the formula (7) is represented by the formula (8):

（式中、Ｒ^２５、Ｒ^２６、Ｒ^２７、Ｒ^２８、Ｗ^１、およびＷ^２は前記と同意義を表す。Ｒ^１７は水素原子または保護基を表す。）で表される化合物と式（９）：

(Wherein R ²⁵ , R ²⁶ , R ²⁷ , R ²⁸ , W ¹ , and W ² are as defined above. R ¹⁷ represents a hydrogen atom or a protecting group) and the formula ( 9):

（式中、Ｒ^１１、Ｒ^１２、Ｒ^３３、およびＸは前記と同意義を表す。）で表される化合物とを、溶媒中、塩基の存在下反応させた後に、必要に応じ保護基Ｒ^１７を脱保護することによって得ることができる。

(Wherein R ¹¹ , R ¹² , R ³³ , and X are as defined above) and a compound in the presence of a base in a solvent, and then, if necessary, a protecting group R ¹⁷ can be obtained by deprotection.

Examples of the reaction solvent include highly polar aprotic solvents such as dimethylformamide (DMF), dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), and N-methylpiperidinone (NMP), such as tetrahydrofuran (THF), 1 And ether solvents such as 2-dimethoxyethane, halogen solvents such as dichloromethane and 1,2-dichloroethane, ketone solvents such as acetone and methyl ethyl ketone, and the like.
Bases used include cesium carbonate, potassium carbonate, sodium carbonate, lithium carbonate, potassium phosphate, sodium phosphate, dipotassium hydrogen phosphate, disodium hydrogen phosphate, potassium hydroxide, sodium hydroxide, lithium hydroxide, hydrogen Inorganic bases such as sodium hydride and lithium hydride, and organic bases such as pyridine, lutidine, collidine, dimethylaminopyridine (DMAP), triethylamine, diisopropylethylamine, imidazole, butyllithium, lithium diisopropylamide (LDA), lithium hexamethyl Disilazide (lithium bistrimethylsilylamide, LiHMDS), sodium hexamethyldisilazide (sodium bistrimethylsilylamide, NaHMDS), potassium hexamethyldisilazide (potassium) Bistrimethylsilylamide, KHMDS), sodium methoxide, sodium ethoxide, and organic metal bases, such as t- butoxy potassium.

When selecting a combination of a reaction solvent and a base, it is necessary to be stable with respect to the base used by the reaction solvent itself, and care must be taken particularly when an organometallic base is used. For example, butyl lithium, lithium diisopropylamide (LDA), lithium hexamethyldisilazide (lithium bistrimethylsilylamide, LiHMDS), sodium hexamethyldisilazide (sodium bistrimethylsilylamide, NaHMDS), potassium hexamethyldisilazide (potassium) When an organic metal base such as bistrimethylsilylamide or KHMDS) is used, an ether solvent such as tetrahydrofuran (THF) or 1,2-dimethoxyethane is preferable, and sodium methoxide, sodium ethoxide, t- When using an organic metal base such as butoxy potassium, sodium hydride, lithium hydride, etc., an ether solvent such as tetrahydrofuran (THF) or 1,2-dimethoxyethane may be used. For example dimethylformamide (DMF), dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), highly polar aprotic solvents such as N- methyl-piperidinium Non (NMP) are preferred.
The reaction temperature in each of the above reactions varies depending on the type of base used, but can be appropriately selected within the range of -78 ° C to the boiling point of the solvent. The reaction time for each reaction varies greatly depending on the reaction temperature and the combination of the reaction solvent and the base used, but is generally between 30 minutes and 2-3 days. Further, for the purpose of accelerating the reaction, an iodine salt such as sodium iodide or potassium iodide or a phase transfer catalyst such as tetrabutylammonium bromide or tetrabutylammonium iodide is added as an additive as necessary. be able to.

As the protecting group R ¹⁷ in the compound represented by the formula (8), when W ¹ is an oxygen atom or a sulfur atom, for example, an ester protecting group such as an acetyl group or a benzoyl group, a benzyl group, In the case where W ¹ is a group represented by the formula: —N (R ¹⁶ ) — (wherein R ¹⁶ is as defined above), an ether-based protecting group such as a paramethoxybenzyl group, For example, carbamates such as benzyloxycarbonyl group (Z group, Cbz group), t-butoxycarbonyl group (Boc group), allyloxycarbonyl group (Alloc group), 9-fluorenylmethoxycarbonyl group (Fmoc group) Mention may be made of protecting groups. These compounds can also be obtained by appropriately selectively protecting ^one functional group -W ¹ H of a known compound. Regarding the introduction method, deprotection method and selection method of the protecting group R ¹⁷ , for example, the contents described in Protecting Groups in Organic Synthesis (Second Edition, John Wiley & Sons, Inc., New York, 1991) by Greene et al. Can be helpful.
In this reaction, by setting the amount of the base used to 1 equivalent, even when R ¹⁷ in the compound represented by the formula (8) is a hydrogen atom, the target compound represented by the formula (7) Can be obtained. In this method, for example, when W ¹ is an oxygen atom and W ² is a sulfur atom, W ¹ is represented by the formula: —N (R ¹⁶ ) — (wherein R ¹⁶ is as defined above). It is particularly effective when it is a group represented and W ² is a sulfur atom. Specifically, ether solvents such as tetrahydrofuran (THF) and 1,2-dimethoxyethane or solvents such as dimethylformamide (DMF), dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), N-methylpiperidi Using a highly polar aprotic solvent such as NON (NMP), using only one equivalent of sodium methoxide, sodium ethoxide, t-butoxypotassium, sodium hydride, lithium hydride, etc. as the base, only the thiol group After selective anionization, the compound represented by the formula (9) may be added.

  Further, the biphenyl compound represented by the above formula (6) has the formula (10):

［式中、Ｒ^２１およびＲ^２２は前記と同意義を表し、Ｙはヨウ素原子、臭素原子、またはトリフルオロメタンスルホニルオキシ基を表す。］で表される化合物と、式（１１）：

[Wherein, R ²¹ and R ²² represent the same meaning as described above, and Y represents an iodine atom, a bromine atom, or a trifluoromethanesulfonyloxy group. And a compound represented by formula (11):

［式中、Ｒ^２３およびＲ^２４は前記と同意義を表す。Ｒ^３７は式：−ＭｇＸ^２（式中、Ｘ^２は塩素原子、臭素原子またはヨウ素原子を表す。）、式：−ＺｎＸ^３（式中、Ｘ^３は塩素原子、臭素原子またはヨウ素原子を表す。）、式：−ＭｎＸ^４（式中、Ｘ^４は塩素原子、臭素原子またはヨウ素原子を表す。）、式：−Ｓｎ（Ｒ^３９）_３（式中、Ｒ^３９はＣ_１−Ｃ_６アルキル基を表す。）、または式：―Ｂ（ＯＲ^４０）_２（式中、Ｒ^４０は水素原子またはＣ_１−Ｃ_６アルキル基を表すか、または２つのＲ^４０が一緒になってオルトフェニレン基、エチレン基、１，１，２，２−テトラメチルエチレン基または１，３−プロピレン基を形成する。）で表される基を表す。Ｒ^３８は水素原子、置換基を有してもよいＣ_１−Ｃ_６アルキル基、カルボキシル基、Ｃ_２−Ｃ_７アルコキシカルボニル基、ジ（Ｃ_１−Ｃ_６アルキル）カルバモイル基、（Ｃ_３−Ｃ_６シクロアルキル）カルバモイル基、モルホリルカルバモイル基、Ｎ，Ｏ−ジメチルカルバモイル基、式：−ＣＲ^９Ｒ^１０ＯＲ^４１（式中、Ｒ^９およびＲ^１０は前記と同意義を表す。Ｒ^４１は水素原子または水酸基の保護基を表す。）、置換基を有してもよいＣ_１−Ｃ₁₁アシル基、またはニトリル基で表される基を表す。］で表される有機金属化合物とのカップリング反応、あるいは、式（１２）：

[Wherein, R ²³ and R ²⁴ represent the same meaning as described above. R ³⁷ has the formula: -MgX ² (wherein, ^{X 2} represents a chlorine atom, a bromine atom or an iodine atom.), Wherein: -ZnX ³ (wherein, ^{X 3} represents a chlorine atom, a bromine atom or an iodine atom .), the formula: -MnX ⁴ (wherein, ^{X 4} represents a chlorine atom, a bromine atom or an iodine atom), the _{^{formula:. -Sn (R 39) 3}} ( ^{wherein, R 39} is _C 1 -C ₆ alkyl Or a formula: —B (OR ⁴⁰ ) ₂ (wherein R ⁴⁰ represents a hydrogen atom or a C ₁ -C ₆ alkyl group, or two R ⁴⁰ together represent an orthophenylene group). , An ethylene group, a 1,1,2,2-tetramethylethylene group or a 1,3-propylene group.). R ³⁸ represents a hydrogen atom, an optionally substituted _C 1 -C ₆ alkyl group, a carboxyl _group, C 2 -C ₇ alkoxycarbonyl group, a di _(C 1 -C ₆ alkyl) carbamoyl group, _{(C 3} - C ₆ cycloalkyl) carbamoyl group, morpholylcarbamoyl group, N, O-dimethylcarbamoyl group, formula: —CR ⁹ R ¹⁰ OR ⁴¹ (wherein R ⁹ and R ¹⁰ are as defined above. R ⁴¹ represents Represents a protecting group for a hydrogen atom or a hydroxyl group), a C ₁ -C ₁₁ acyl group which may have a substituent, or a group represented by a nitrile group. Or a coupling reaction with an organometallic compound represented by formula (12):

［式中、Ｒ^２１、Ｒ^２２、およびＲ^３７は前記と同意義を表す。］で表される有機金属化合物と、式（１３）：

[Wherein, R ²¹ , R ²² , and R ³⁷ represent the same meaning as described above. An organic metal compound represented by formula (13):

［式中、Ｒ^２３、Ｒ^２４、Ｒ^３８、およびＹは前記と同意義を表す。］で表される化合物とのカップリング反応によりビフェニル構造を構築し、引き続き、Ｒ^３８を適宜変換することにより合成することができる。

[Wherein, R ²³ , R ²⁴ , R ³⁸ , and Y are as defined above. Constructs a biphenyl structure by a coupling reaction with the compound represented by, subsequently, it can be synthesized by converting a R ³⁸ as appropriate.

Such an aryl-aryl cross-coupling reaction can be carried out by using a palladium, rhodium or nickel catalyst in a solvent in the presence or absence of a base and adding an additive as necessary. .
Examples of the reaction solvent include highly polar aprotic compounds such as dimethylformamide (DMF), dimethylacetamide (DMA), dimethylsulfoxide (DMSO), N-methylpiperidinone (NMP), and hexamethylphosphoramide (HMPA). Solvents such as ethereal solvents such as tetrahydrofuran (THF), 1,2-dimethoxyethane, dioxane, diethyl ether, diisopropyl ether, t-butyl methyl ether, such as aromatic solvents such as toluene, benzene, chlorobenzene, etc. Examples thereof include alcohol solvents such as methanol, ethanol and isopropyl alcohol, water, and mixed solvents thereof. When R ³⁷ is a group represented by the formula: —B (OR ⁴⁰ ) ₂ (wherein R ⁴⁰ is as defined above), any of the above-described solvents can be used. However, when other organometallic reagents are used, the reaction is preferably performed in a non-aqueous solvent. For example, R ³⁷ is represented by the formula: -MgX ² (wherein X ² is as defined above), the formula: -ZnX ³ (wherein X ³ is as defined above) or the formula:- In the case of a group represented by MnX ⁴ (wherein X ⁴ is as defined above), an ether solvent, R ³⁷ is represented by the formula: —Sn (R ³⁹ ) ₃ (where R ³⁹ Represents the same meaning as described above.) In the case of the group represented by the above formula, an ether solvent or a highly polar aprotic solvent is preferable.
Examples of the catalyst used include tetrakis (triphenylphosphine) palladium, bis (triphenylphosphine) dichloropalladium, [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium, and [1,2-bis (diphenylphosphino). )] Ethane] dichloropalladium, [1,3-bis (diphenylphosphino) propane] dichloropalladium, tris (dibenzylideneacetone) dipalladium, palladium acetate, palladium black, palladium-activated carbon and other palladium-based catalysts, bis (1 , 5-cyclooctadiene) dichlorodichloro, rhodium-based catalyst, [1,1′-bis (diphenylphosphino) ferrocene] dichloronickel, [1,2-bis (diphenylphosphino) ethane] dichloronickel, [1,3-bi (Diphenylphosphino) propane] dichloro nickel, nickel chloride, and nickel-based catalysts such as nickel-triethylamine complex chloride. These catalysts are used in an amount of 0.01 mol% to 2 to 3 equivalents based on the substrate.

Additives used as necessary include, for example, organic phosphorus reagents such as triphenylphosphine, trimethoxyline, tri (2-furyl) phosphorus, sodium iodide, potassium iodide, such as tetrabutylammonium bromide, tetraiodide Examples thereof include phase transfer catalysts such as butylammonium.
Bases used in the reaction in the presence of a base include cesium carbonate, potassium carbonate, sodium carbonate, lithium carbonate, potassium bicarbonate, sodium bicarbonate, potassium phosphate, sodium phosphate, dipotassium hydrogen phosphate, phosphorus Inorganic bases such as disodium hydrogen oxyhydrogen, barium hydroxide, potassium hydroxide, sodium hydroxide, lithium hydroxide, cesium fluoride, and pyridine, lutidine, collidine, dimethylaminopyridine (DMAP), triethylamine, diisopropylethylamine, imidazole And organic bases such as
The reaction temperature in each of the above reactions varies depending on the type of base used, but can be appropriately selected within the range of -78 ° C to the boiling point of the solvent. The reaction time for each reaction varies greatly depending on the reaction temperature and the combination of the reaction solvent and the base used, but is generally between 30 minutes and 2-3 days.
In the above aryl-aryl cross-coupling reaction, R ³⁷ is represented by the formula: -MgX ² (wherein X ² is as defined above), and the formula: -ZnX ³ (wherein X ³ is the same as defined above). Or a group represented by the formula: —MnX ⁴ (wherein X ⁴ represents the same meaning as described above), these are the groups within the system from the corresponding aryl halide. It is desirable to prepare and use for cross-coupling reaction.
In the above aryl-aryl cross-coupling reaction, R ³⁷ is particularly preferably represented by the formula: —B (OR ⁴⁰ ) ₂ (wherein R ⁴⁰ represents the same meaning as described above) from the viewpoint of operability and versatility. And the cross-coupling reaction is referred to as “Suzuki-Miyaura coupling reaction”. The “Suzuki-Miyaura coupling reaction” can also be performed under the above reaction conditions.

  Formula (14) obtained by the above reaction:

［式中、Ｒ^２１、Ｒ^２２、Ｒ^２３、Ｒ^２４、およびＲ^３８は前記と同意義を表す。］で表されるビフェニル化合物を用いて、式（１５）：

[Wherein R ²¹ , R ²² , R ²³ , R ²⁴ , and R ³⁸ represent the same meaning as described above. And a biphenyl compound represented by the formula (15):

［式中、Ｒ^９、Ｒ^１０、Ｒ^２１、Ｒ^２２、Ｒ^２３、およびＲ^２４は前記と同意義を表す。］で表されるビフェニル化合物を合成するには、以下に示す方法を用いることができる。

[Wherein, R ⁹ , R ¹⁰ , R ²¹ , R ²² , R ²³ , and R ²⁴ represent the same meaning as described above. In order to synthesize a biphenyl compound represented by the following formula, the following method can be used.

Hydroxyl when R ³⁸ is a hydrogen atom, at least one of ^{R 23} or ^{R 24} is present next to one another on the ^{R 38} and the benzene ring, and ^{that R 23} or ^{R 24} is a fluorine atom, suitably protected, an optionally substituted _C 1 -C ₆ alkoxy group, an optionally substituted _C 1 -C ₁₁ acyloxy group, a carboxyl group, an optionally substituted _C 2 -C ₇ alkoxycarbonyl group, an optionally substituted _(C 1 -C ₆ alkyl) carbamoyl group, an optionally substituted di _(C 1 -C ₆ alkyl) carbamoyl group or (one of the carbon atoms has the formula: —O—, —S (O) _n — (n represents 0, 1 or 2), or —N (R ¹⁵ ) — (R ¹⁵ is a hydrogen atom, C ₁ may have a substituent). C ₆ alkyl group or C _1- which may have a substituent C ₅ -C ₇ cyclic aminocarbonyl group which may be substituted with a group represented by C ₁₁ acyl group) (The C ₅ -C ₇ cyclic aminocarbonyl group may have a substituent) In the case of any one of the following formula (16):

［式中、Ｒ^９およびＲ^１０は前記と同意義を表す。］で表される化合物を添加することで、式（１５）で表される化合物を得ることができる。かかる有機金属塩基としては、ブチルリチウム、リチウムジイソプロピルアミド（ＬＤＡ）、リチウムヘキサメチルジシラジド（リチウムビストリメチルシリルアミド、ＬｉＨＭＤＳ）、ナトリウムヘキサメチルジシラジド（ナトリウムビストリメチルシリルアミド、ＮａＨＭＤＳ）、カリウムヘキサメチルジシラジド（カリウムビストリメチルシリルアミド、ＫＨＭＤＳ）、ｔ−ブトキシカリウム等が挙げられ、必要に応じてＮ，Ｎ，Ｎ'，Ｎ’−テトラメチルエチレンジアミン（ＴＭＥＤＡ）、２，２，６，６−テトラメチルピペリジン等の有機塩基を共存させて用いることができる。

[Wherein, R ⁹ and R ¹⁰ are as defined above. The compound represented by Formula (15) can be obtained by adding the compound represented by]. Such organometallic bases include butyl lithium, lithium diisopropylamide (LDA), lithium hexamethyldisilazide (lithium bistrimethylsilylamide, LiHMDS), sodium hexamethyldisilazide (sodium bistrimethylsilylamide, NaHMDS), potassium hexamethyl. Disilazide (potassium bistrimethylsilylamide, KHMDS), t-butoxypotassium, etc. may be mentioned. N, N, N ′, N′-tetramethylethylenediamine (TMEDA), 2,2,6,6- An organic base such as tetramethylpiperidine can be used together.

When R ³⁸ is an optionally substituted C ₁ -C ₁₁ acyl group, these are reduced using a reducing agent or represented by formula (17):

［式中、Ｒ^９は前記と同意義を表す。Ｒ^４２はハロゲン原子、リチウム原子、式：−ＭｇＸ^２（式中、Ｘ^２は塩素原子、臭素原子またはヨウ素原子を表す。）、式：−ＺｎＸ^３（式中、Ｘ^３は塩素原子、臭素原子またはヨウ素原子を表す。）、または式：−ＣｅＸ^５ _２（式中、Ｘ^５は塩素原子、臭素原子またはヨウ素原子を表す。）で表される基を表す。］で表される化合物を作用させることにより、式（１５）で表される化合物を得ることができる。かかる還元剤としては、ジボラン、水素化ホウ素ナトリウム、水素化ホウ素リチウム、水素化アルミニウムリチウム、水素化ジイソブチルアルミニウム等を挙げることができる。式（１７）で表される化合物を用いる場合、必要に応じて金属リチウム、金属マグネシウム、ヨウ化銅、二塩化亜鉛、四塩化チタン、三塩化セリウム、二ヨウ化サマリウム等の金属試薬を添加剤として用いることができる。

[Wherein R ⁹ represents the same meaning as described above. R ⁴² represents a halogen atom, a lithium atom, the formula: -MgX ² (wherein, ^{X 2} represents a chlorine atom, a bromine atom or an iodine atom.), Wherein: -ZnX ³ (wherein, ^{X 3} is a chlorine atom, a bromine An atom or an iodine atom), or a group represented by the formula: -CeX ⁵ ₂ (wherein X ⁵ represents a chlorine atom, a bromine atom or an iodine atom); The compound represented by Formula (15) can be obtained by allowing the compound represented by formula (I) to act. Examples of the reducing agent include diborane, sodium borohydride, lithium borohydride, lithium aluminum hydride, diisobutylaluminum hydride, and the like. When using the compound represented by the formula (17), if necessary, a metal reagent such as metallic lithium, metallic magnesium, copper iodide, zinc dichloride, titanium tetrachloride, cerium trichloride, samarium diiodide is used as an additive Can be used as

When R ³⁸ is a C ₁ -C ₁₁ acyl group which may have a substituent, a compound represented by the formula (15) wherein R ⁹ is a nitrile group is obtained by the action of a cyanating reagent. Can do. Examples of the cyanide reagent include hydrogen cyanide, sodium cyanide, potassium cyanide, zinc cyanide, trimethylsilyl cyanide and the like, and zinc chloride, zinc bromide, zinc iodide, trimethylsilyl chloride, paratoluenesulfonyl chloride, Alternatively, tetraisopropoxy titanium or the like can be used as an additive.

In the case where R ³⁸ is an optionally substituted C ₁ -C ₁₁ acyl group, R ⁹ is a carboxyl group by the action of haloform such as chloroform, bromoform, iodoform and the like in the presence of a base (15 ) Can be obtained. Examples of such bases include lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide and the like, and if necessary, phase transfer catalysts such as tetrabutylammonium bromide and tetrabutylammonium iodide as additives. Can be used as

When R ³⁸ is a carboxyl group or a C ₂ -C ₇ alkoxycarbonyl group, the compound represented by the formula (15) is obtained by allowing 2 equivalents or more of the compound represented by the formula (17) to act. Can do.

When R ³⁸ is a carboxyl group, a di (C ₁ -C ₆ alkyl) carbamoyl group, a (C ₃ -C ₆ cycloalkyl) carbamoyl group, a morpholylcarbamoyl group, an N, O-dimethylcarbamoyl group, or a nitrile group, By allowing the compound represented by the formula (17) to act, R ³⁸ can be converted to an optionally substituted C ₁ -C ₁₁ acyl group, and further represented by the formula (15) by the method described above. A compound can be obtained.

R ³⁸ is a group represented by the formula: —CR ⁹ R ¹⁰ OR ⁴¹ (wherein R ⁹ and R ¹⁰ are as defined above. R ⁴¹ represents a hydrogen atom or a hydroxyl-protecting group). In some cases, the compound represented by the formula (15) can be obtained by appropriate deprotection.

Further, by appropriately converting the hydroxyl group of the compound represented by the formula (15) into the leaving group X, the compound can be converted into the biphenyl compound represented by the above formula (6). For example, as a method for obtaining a compound in which X is a bromine atom, a method of allowing phosphorus tribromide to act in a solvent, a method of causing carbon tetrabromide to act in the presence of triphenylphosphine, and the like can be mentioned. Examples of a method for obtaining a compound that is an atom include a method in which thionyl chloride is allowed to act in a solvent and a method in which carbon tetrachloride is allowed to act in the presence of triphenylphosphine. Regarding the method for converting a hydroxyl group to a leaving group as appropriate, for example, Harrison, Wade, Smith et al., Compendium of Organic Synthetic Methods (Vol. 1-9, John Wiley & Sons, Inc., New York, 1971- 2001). In the compound represented by formula (14), when R ³⁸ is an optionally substituted C ₁ -C ₆ alkyl group, the leaving group is directly present on the benzylic carbon atom in the alkyl group. By introducing X, it can be converted into the biphenyl compound represented by the above formula (6). For example, in a solvent such as carbon tetrachloride, cyclohexane, benzene or chlorobenzene, in the presence of a catalytic amount of a radical initiator such as α, α′-azobis (isobutyronitrile) or dibenzoyl peroxide, a halogen such as N-bromosuccinimide Examples thereof include a method of allowing a activating reagent to act.

The compound represented by the formula (1) can also be synthesized, for example, by the following production method.
That is, Formula (18):

［式中、Ｒ^９、Ｒ^１０、Ｒ^２１、Ｒ^２２、Ｒ^２３、Ｒ^２４、Ｒ^２５、Ｒ^２６、Ｒ^２７、Ｒ^２８、およびＷ^２は前記と同意義を表す。Ｗ^４は酸素原子、硫黄原子または式：−Ｎ（Ｒ^３６）−（Ｒ^３６は前記と同意義を表す。）で表される基を表す。］で表される化合物と、前記の式（９）で表される化合物とを、溶媒中、塩基の存在下反応させた後に、必要に応じ各種保護基を脱保護することによって、式（１）で表される化合物を得ることができる。
式（１８）で表される化合物と式（９）で表される化合物との反応における反応条件は、前記の式（８）で表される化合物と式（９）で表される化合物との反応における反応条件を適用することが可能である。

[Wherein R ⁹ , R ¹⁰ , R ²¹ , R ²² , R ²³ , R ²⁴ , R ²⁵ , R ²⁶ , R ²⁷ , R ²⁸ , and W ² have the same meanings as described above. W ⁴ represents an oxygen atom, a sulfur atom, or a group represented by the formula: —N (R ³⁶ ) — (R ³⁶ is as defined above). The compound represented by formula (9) and the compound represented by formula (9) are reacted in a solvent in the presence of a base, and then various protecting groups are removed as necessary to obtain a compound represented by formula (1). ) Can be obtained.
The reaction conditions in the reaction between the compound represented by the formula (18) and the compound represented by the formula (9) are the same as the compound represented by the above formula (8) and the compound represented by the formula (9). It is possible to apply reaction conditions in the reaction.

  In addition, the compound represented by the formula (18) is represented by the formula (19):

［式中、Ｒ^２５、Ｒ^２６、Ｒ^２７、Ｒ^２８、Ｗ^１、およびＷ^２は前記と同意義を表す。Ｒ^１８は水素原子または保護基を表す。］で表される化合物と、前記の式（６）で表されるビフェニル化合物とを反応させた後に、必要に応じ保護基Ｒ^１８を脱保護することによって得ることができる。
ここで、Ｒ^１８における保護基は、前出のＲ^１７における保護基と同様のものが挙げられる。
式（１９）で表される化合物と式（６）で表される化合物との反応における反応条件は、前記の式（６）で表される化合物と式（７）で表される化合物との反応における反応条件を適用することが可能である。
また本反応においても、使用する塩基の量を１当量とすることにより、式（１９）で表される化合物におけるＲ^１８が水素原子の場合でも、目的とする式（１８）で表される化合物を入手することが可能である。この方法は、例えば、Ｗ^１が硫黄原子でありＷ^２が酸素原子である場合、Ｗ^１が硫黄原子でありＷ^２が式：−Ｎ（Ｒ^１６）−（式中、Ｒ^１６は前記と同意義を表す。）で表される基である場合等に、特に有効である。具体的には、溶媒として例えばテトラヒドロフラン（ＴＨＦ）、１，２−ジメトキシエタンのようなエーテル系溶媒もしくは例えばジメチルホルムアミド（ＤＭＦ）、ジメチルアセトアミド（ＤＭＡ）、ジメチルスルホキシド（ＤＭＳＯ）、Ｎ−メチルピペリジノン（ＮＭＰ）のような高極性非プロトン性溶媒を用い、塩基として１当量のナトリウムメトキシド、ナトリウムエトキシド、ｔ−ブトキシカリウム、水素化ナトリウム、水素化リチウム等を用いて、チオール基のみを選択的にアニオン化させた後に、式（６）で表される化合物を加えれば良い。

[Wherein, R ²⁵ , R ²⁶ , R ²⁷ , R ²⁸ , W ¹ and W ² are as defined above. R ¹⁸ represents a hydrogen atom or a protecting group. ] And the biphenyl compound represented by the above formula (6) are reacted, and then the protective group R ¹⁸ is removed as necessary.
Here, examples of the protecting group for R ¹⁸ include the same protecting groups as those described above for R ¹⁷ .
The reaction conditions in the reaction of the compound represented by formula (19) and the compound represented by formula (6) are the same as those of the compound represented by formula (6) and the compound represented by formula (7). It is possible to apply reaction conditions in the reaction.
Also in this reaction, by setting the amount of the base used to 1 equivalent, even when R ¹⁸ in the compound represented by the formula (19) is a hydrogen atom, the target compound represented by the formula (18) Can be obtained. In this method, for example, when W ¹ is a sulfur atom and W ² is an oxygen atom, W ¹ is a sulfur atom and W ² is represented by the formula: —N (R ¹⁶ ) — (wherein R ¹⁶ is as defined above. It is particularly effective when it is a group represented by the same meaning. Specifically, ether solvents such as tetrahydrofuran (THF) and 1,2-dimethoxyethane or solvents such as dimethylformamide (DMF), dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), N-methylpiperidi Using a highly polar aprotic solvent such as NON (NMP), using only one equivalent of sodium methoxide, sodium ethoxide, t-butoxypotassium, sodium hydride, lithium hydride, etc. as the base, only the thiol group After selective anionization, the compound represented by formula (6) may be added.

Among the compounds represented by the formula (1), R ¹³ may have a substituent (C ₁ -C ₆ alkyl) carbamoyl group, and may have a substituent (C ₁ -C ₆ alkyl). ) A carbamoyl group, or one of the carbon atoms is represented by the formula: —O—, —S (O) _n — (n represents 0, 1 or 2), or —N (R ¹⁷ ) — (R ¹⁷ is a hydrogen atom) And a C ₁ -C ₆ alkyl group that may have a substituent, or a C ₁ -C ₁₁ acyl group that may have a substituent. _The compound which is a _5- C ₇ cyclic aminocarbonyl group (the C ₅ -C ₇ cyclic aminocarbonyl group may have a substituent) is a compound represented by the formula (1) synthesized by the method described above. Of these, R ¹³ can be derived from a carboxyl group. That is, it can be synthesized by reacting the carboxyl group of the carboxylic acid represented by the formula (1) with various amines or salts thereof for amidation.
Specific examples of the amidation of the carboxyl group include, for example, dimethylaminopyridine (DMAP) in a highly polar aprotic solvent such as dimethylformamide (DMF) and N-methylpiperidinone (NMP) as necessary. ), Triethylamine, diisopropylethylamine and the like, and in the presence of an additive such as 1-hydroxybenzotriazole (HOBt) and 1-hydroxy-7-azabenzotriazole (HOAt) as necessary, for example, 1 -Condensation with various amines or their salts using condensing agents such as-(3-dimethylaminopropyl) -3-ethylcarbodiimide-hydrochloride (EDC, EDCI or WSC.HCl), 1,3-dicyclohexylcarbodiimide (DCC) The method of making it etc. can be illustrated.

  Alternatively, the target product can also be synthesized by converting the carboxylic acid represented by the formula (1) into an acid chloride and then amidating it by reacting with various amines or salts thereof. That is, by reacting such carboxylic acid with thionyl chloride or oxalyl chloride in a solvent such as dichloromethane or 1,2-dichloroethane, if necessary, in the presence of a catalytic amount of dimethylformamide (DMF). It can be converted into a thing. The acid chloride thus obtained can be obtained in the presence of a base such as dimethylaminopyridine (DMAP), triethylamine or diisopropylethylamine in a solvent such as dichloromethane, 1,2-dichloroethane or tetrahydrofuran (THF), if necessary. The desired product can be obtained by reacting with various amines or salts thereof.

Among the compounds represented by the formula (1), a compound in which R ¹³ is a carbamoyl group is obtained by reacting the above acid chloride with ammonia gas in a solvent such as dichloromethane, 1,2-dichloroethane, tetrahydrofuran (THF). Or it can synthesize | combine by making it react with aqueous ammonia.
Further, the carbamoyl group of the compound thus obtained is chlorinated in a solvent such as dimethylformamide (DMF) or N-methylpiperidinone (NMP) in the presence of a base such as pyridine or 2,6-lutidine. Conversion to a nitrile group by reaction with methanesulfonyl, followed by reaction with trimethylsilyl azide in the presence of dibutyltin (IV) oxide in a solvent such as toluene, for example, is represented by formula (1). Among compounds, R ¹³ can be converted to a compound having a tetrazolyl group.

  When the compound represented by the formula (1) or a salt thereof includes an asymmetric carbon atom depending on the substituent and an optically active substance may exist, the compound represented by the formula (1) is a racemate. Can be represented by the following formula (1a) by optical resolution or fractionation by high performance liquid chromatography using an optically active substance separation column:

［式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６、Ｒ^７、Ｒ^８、Ｒ^９、Ｒ^１０、Ｒ^１１、Ｒ^１２、Ｒ^１３、Ｗ^１、およびＷ^２はそれぞれ前記と同意義を表す。］で表される（＋）−体である化合物と式（１ｂ）：

[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , W ¹ , and W ² are Each represents the same meaning as described above. And a compound represented by the formula (1b):

［式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６、Ｒ^７、Ｒ^８、Ｒ^９、Ｒ^１０、Ｒ^１１、Ｒ^１２、Ｒ^１３、Ｗ^１、およびＷ^２はそれぞれ前記と同意義を表す。］で表される（−）−体である化合物の２つの光学活性体にそれぞれ単離することができる。光学分割は光学活性な塩基を分割剤として用いて通常行われている方法にて行い得るが、優先晶析法にても行い得ることがある。

[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , W ¹ , and W ² are Each represents the same meaning as described above. The compound can be isolated into two optically active forms of the compound represented by the formula (−)-. The optical resolution can be performed by a conventional method using an optically active base as a resolving agent, but may also be performed by a preferential crystallization method.

  Further, the compound represented by the formula (1a) and the compound represented by the formula (1b) are the optically active compounds of the compound represented by the above formula (15):

［式中、Ｒ^９、Ｒ^１０、Ｒ^２１、Ｒ^２２、Ｒ^２３、およびＲ^２４は前記と同意義を表す。］で表される（＋）−体であるビフェニル化合物、と式（１５ｂ）：

[Wherein, R ⁹ , R ¹⁰ , R ²¹ , R ²² , R ²³ , and R ²⁴ represent the same meaning as described above. A biphenyl compound represented by the formula (15b):

［式中、Ｒ^９、Ｒ^１０、Ｒ^２１、Ｒ^２２、Ｒ^２３、およびＲ^２４は前記と同意義を表す。］で表される（−）−体であるビフェニル化合物を用いて合成することもできる。
すなわち、式（１５ａ）で表される化合物と式（１５ｂ）で表される化合物をそれぞれ別個に水酸基を脱離基Ｘに変換し、得られた化合物を式（７）で表される化合物と反応させるか、または式（１９）で表される化合物との反応に引き続き式（９）で表される化合物と反応させるかした後に、必要に応じ各種保護基を脱保護することによって、式（１ａ）で表される化合物と式（１ｂ）で表される化合物を得ることができる。

[Wherein, R ⁹ , R ¹⁰ , R ²¹ , R ²² , R ²³ , and R ²⁴ represent the same meaning as described above. It can also synthesize | combine using the biphenyl compound which is a (-)-body represented by this.
That is, the compound represented by the formula (15a) and the compound represented by the formula (15b) are each independently converted into a leaving group X, and the resulting compound is converted to a compound represented by the formula (7): After reacting with or reacting with the compound represented by the formula (9) following the reaction with the compound represented by the formula (19), by removing various protecting groups as necessary, the formula (9) A compound represented by 1a) and a compound represented by formula (1b) can be obtained.

When the compound represented by the formula (15a) and the compound represented by the formula (15b) are racemic, an optical resolution or an optically active substance separation column was used. Each can be isolated by high-performance liquid chromatography. The optical resolution can be performed by a conventional method using an optically active base as a resolving agent, but may also be performed by a preferential crystallization method.
Alternatively, by subjecting the compound represented by the formula (14) to an asymmetric reduction or an asymmetric carbon-carbon bond formation reaction, a compound in which one of the stereos has priority can be selectively obtained. As the asymmetric reduction, for example, when R ³⁸ in the compound represented by the formula (14) is a C ₁ -C ₁₁ acyl group which may have a substituent, diborane, sodium borohydride, borohydride Application of asymmetric modifiers to metal hydrides such as lithium, lithium aluminum hydride, diisobutylaluminum hydride, and asymmetric hydrogenation reactions performed in the presence of optically active metal catalysts modified with asymmetric ligands can do. Examples of such asymmetric modifiers include (R)-(+)-1,1′-bi-2-naphthol ((R)-(+)-BINOL), (S)-(−)-1,1 ′. -Alcoholic modifier represented by bi-2-naphthol ((S)-(-)-BINOL), (2S, 3R)-(+)-4-dimethylamino-3-methyl-1,2- An aminoalcoholic modifier represented by diphenyl-2-butanol, (2R, 3S)-(−)-4-dimethylamino-3-methyl-1,2-diphenyl-2-butanol, (S)-( +)-2- (2,6-xylidinomethyl) pyrrolidine, (R)-(−)-2- (2,6-xylidinomethyl) pyrrolidine and other diamine-based additives. it can. Examples of the optically active metal catalyst modified with such an asymmetric ligand include dichloro [(R)-(+)-2,2′-bis (diphenylphosphino) -1,1′-binaphthyl] ruthenium (II), Dichloro [(S)-(−)-2,2′-bis (diphenylphosphino) -1,1′-binaphthyl] ruthenium (II), dichloro [(R)-(+)-2,2′-bis (Diphenylphosphino) -1,1′-binaphthyl] [(1R, 2R)-(+)-1,2-diphenylethylenediamine] ruthenium (II), dichloro [(S)-(−)-2,2 ′ And a ruthenium metal complex compound such as -bis (diphenylphosphino) -1,1'-binaphthyl] [(1S, 2S)-(-)-1,2-diphenylethylenediamine] ruthenium (II). As an asymmetric carbon-carbon bond formation reaction, for example, when R ³⁸ in the compound represented by the formula (14) is a C ₁ -C ₁₁ acyl group which may have a substituent, the formula (17) An asymmetric 1,2-addition reaction to a carbonyl group, which is performed by adding an asymmetric modifier to a reaction reagent such as a compound represented by the formula, a cyanating reagent, or haloform, can be applied. Examples of the asymmetric modifier include compounds similar to the compounds exemplified in the asymmetric reduction using the above-described metal hydride.

  In order to isolate and purify the compound of the present invention synthesized by the above-mentioned method from the reaction solution, means usually used in the isolation and purification of reaction products can be used. That is, when isolating and purifying the target product from the reaction mixture, usual isolation and purification methods from the reaction mixture, such as solvent extraction, ion exchange resin, column chromatography using silica gel, alumina, etc. as a carrier, high speed Liquid chromatography (HPLC) fractionation, recrystallization and the like can be used, and these isolation / purification methods can be performed alone or in combination.

The compound represented by the formula (1) or a salt thereof includes a solvate with a pharmaceutically acceptable solvent such as water or ethanol.
In addition, the compound represented by the formula (1) or a salt thereof may contain an asymmetric carbon atom and an optically active substance may exist depending on the substituent. Including things.
In the compounds of the present invention, salts thereof, preferably pharmaceutically or veterinary acceptable salts are also included in the scope of the present invention. Here, as the salt, inorganic base salts such as sodium salt, potassium salt, calcium salt, magnesium salt, aluminum salt and ammonium salt; organic base salts such as triethylammonium salt, triethanolammonium salt, pyridinium salt and diisopropylammonium salt Basic amino acid salts such as arginine and lysine; and
Salts with mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid; organic carboxylic acids such as formic acid, acetic acid, fumaric acid, maleic acid, oxalic acid, citric acid, malic acid, tartaric acid, aspartic acid, glutamic acid And salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydroxybenzenesulfonic acid, dihydroxybenzenesulfonic acid, and the like.
These salts can be prepared by reacting the corresponding base or acid in a suitable solvent such as water, methanol, ethanol, isopropyl alcohol, acetone, ethyl acetate, chloroform, ether or the like.

When administering the compound of the present invention or a salt thereof, a usual pharmaceutically acceptable carrier, binder, stabilizer, excipient, diluent, pH buffer, disintegrant, solubilizer, dissolution Various preparation compounding ingredients such as adjuvants and isotonic agents can be added. The compound of the present invention or a salt thereof can be administered orally or parenterally. That is, it can be administered orally in dosage forms such as powders, granules, capsules, tablets, syrups, suspensions or the like that are usually used, or agents such as solutions, emulsions, suspensions, etc. The mold can be administered parenterally in the form of an injection or can be administered intranasally in the form of a spray.
The dose and the number of administrations vary depending on the administration method and the age, weight, medical condition, etc. of the patient, but the method of oral or intravenous administration is usually preferred 1 to 3 times a day. The dose can be 100 μg to 2 g, preferably 1 mg to 200 mg per dose, and a sustained release preparation can be used to reduce the number of administrations.
The therapeutic agent containing the compound of the present invention or a salt thereof as an active ingredient includes those administered prophylactically to patients who are likely to suffer from the target disease.

Specific examples of the compound of the present invention are illustrated below. However, the compound of the present invention is not limited to these exemplified compounds.
In the following table, Me represents a methyl group, Et represents an ethyl group, Pr represents an n-propyl group, iPr represents an isopropyl group, Bu represents an n-butyl group, and Ph represents a phenyl group.
In the following examples, these compounds are referred to by compound number as necessary.

  Hereinafter, the present invention will be described in more detail with reference to production examples and examples, but the technical scope of the present invention is not limited to these examples.

Synthesis of (4- {1- [4-fluoro-4 ′-(trifluoromethyl) -1,1′-biphenyl-3-yl] ethoxy} -2-methylphenoxy) acetic acid (Compound 1) (Example 1 -1) Synthesis of 4-fluoro-4 '-(trifluoromethyl) -1,1'-biphenyl-3-carbaldehyde 5-bromo-2-fluorobenzaldehyde (700.0 mg, 3.448 mmol), 4- (trifluoro Methyl) phenylboronic acid (683.5 mg, 3.616 mmol) and tetrakis (triphenylphosphine) palladium (100.0 mg, 0.087 mmol) in 1,4-dioxane solution (15 ml) of potassium carbonate (1000.0 mg, 7.235 mmol) An aqueous solution (3 ml) was added, and the mixture was stirred for 2 hours under reflux and then cooled to room temperature. Saturated aqueous sodium hydrogen carbonate was added to the reaction solution, and the organic matter was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified using silica gel column chromatography to obtain 784.9 mg of the desired product as a white solid (yield 85%).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 10.43 (1H, s), 8.10 (1H, dd, J = 2.6, 6.4 Hz), 7.84 (1H, ddd, J = 2.6, 5.0, 8.6 Hz), 7.72 (2H, d, J = 8.6 Hz), 7.68 (2H, d, J = 8.6 Hz), 7.30 (2H, dd, J = 8.6, 9.7 Hz).
Example 1-2 Synthesis of 1- [4-fluoro-4 ′-(trifluoromethyl) -1,1′-biphenyl-3-yl] ethanol Obtained in Example 1-1 at 0 ° C. 4-fluoro-4 ′-(trifluoromethyl) -1,1′-biphenyl-3-carbaldehyde (205.6 mg, 0.767 mmol) in tetrahydrofuran (5 ml) was added to a solution of methylmagnesium bromide in tetrahydrofuran (0.93 mol / l). , 1.00 ml, 0.930 mmol) and stirred at 0 ° C. for 30 minutes, and then stirred at room temperature for 30 minutes. A 10% aqueous potassium hydrogen sulfate solution was added to the reaction solution, and the organic matter was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel thin layer chromatography to obtain 176.7 mg of the desired product as a white solid (yield 81%).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.74 (1H, dd, J = 2.4, 7.0 Hz), 7.68 (2H, d, J = 9.2 Hz), 7.65 (2H, d, J = 9.2 Hz) , 7.46 (1H, ddd, J = 2.4, 4.7, 8.4 Hz), 7.11 (1H, dd, J = 8.4, 10.1 Hz), 5.26 (1H, q, J = 6.4 Hz), 2.09 (1H, bs), 1.56 (3H, d, J = 6.4 Hz).

(Example 1-3) Synthesis of 3- (1-bromoethyl) -4-fluoro-4 '-(trifluoromethyl) -1,1'-biphenyl 1- [4- obtained in Example 1-2 Fluoro-4 ′-(trifluoromethyl) -1,1′-biphenyl-3-yl] ethanol (176.7 mg, 0.626 mmol) was dissolved in dichloromethane (5 ml), and triphenylphosphine (262.0 mg, 1.000) was dissolved therein. mmol) Carbon tetrabromide (500.0 mg, 1.511 mmol) was then added, and the mixture was stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, and the residue was purified using silica gel column chromatography to obtain 188.0 mg of the desired product as a colorless oily substance (yield 87%).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.72 (1H, dd, J = 2.4, 7.0 Hz), 7.70 (2H, d, J = 8.8 Hz), 7.64 (2H, d, J = 8.8 Hz) , 7.49 (1H, ddd, J = 2.4, 4.7, 8.4 Hz), 7.14 (1H, dd, J = 8.6, 9.7 Hz), 5.52 (1H, q, J = 7.0 Hz), 2.10 (3H, d, J = 7.0 Hz).
Example 1-4 Synthesis of (4- {1- [4-fluoro-4 ′-(trifluoromethyl) -1,1′-biphenyl-3-yl] ethoxy} -2-methylphenoxy) ethyl acetate In 3- (1-bromoethyl) -4-fluoro-4 ′-(trifluoromethyl) -1,1′-biphenyl (188.0 mg, 0.542 mmol) obtained in Example 1-3 and Reference Example 1-2 Potassium carbonate (500.0 mg, 1.538 mmol) and tetrabutyl iodide were added to a solution of the obtained ethyl (4-hydroxy-2-methylphenoxy) acetate (111.0 mg, 0.542 mmol) in N, N′-dimethylformamide (5 ml). Ammonium (19.2 mg, 0.052 mmol) was added and stirred at room temperature for 24 hours. A 10% aqueous potassium hydrogen sulfate solution was added to the reaction solution, and the organic matter was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel thin layer chromatography to obtain 227.2 mg of the desired product as a colorless oil (yield 88%).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.68 (1H, dd, J = 2.5, 6.4 Hz), 7.66 (2H, d, J = 8.4 Hz), 7.58 (2H, d, J = 8.4 Hz) , 7.44 (1H, ddd, J = 2.5, 5.0, 8.6 Hz), 7.13 (1H, dd, J = 8.6, 9.7 Hz), 6.77 (1H, d, J = 2.0 Hz), 6.65-6.55 (2H, m ), 5.58 (1H, q, J = 6.4 Hz), 4.53 (2H, s), 4.22 (2H, q, J = 7.0 Hz), 2.23 (3H, s), 1.65 (3H, d, J = 6.4 Hz) ), 1.26 (3H, t, J = 7.0 Hz).
Example 1-5 Synthesis of (4- {1- [4-Fluoro-4 ′-(trifluoromethyl) -1,1′-biphenyl-3-yl] ethoxy} -2-methylphenoxy) acetic acid (4- {1- [4-Fluoro-4 ′-(trifluoromethyl) -1,1′-biphenyl-3-yl] ethoxy} -2-methylphenoxy) ethyl acetate obtained in Example 1-4 ( 227.2 mg, 0.477 mmol) was dissolved in tetrahydrofuran (6 ml) and methanol (3 ml), 2N aqueous sodium hydroxide solution (3 ml) was added, and the mixture was stirred at room temperature for 1 hour. A 10% aqueous potassium hydrogen sulfate solution was added to the reaction solution to make the solution weakly acidic, and the organic matter was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give 207.7 mg of the desired product as a white solid (97% yield).
Melting point 140-141 [deg.] C.

The following compounds were obtained in the same manner as in Example 1.
(4- {1- [4-fluoro-4 ′-(trifluoromethyl) -1,1′-biphenyl-3-yl] propoxy} -2-methylphenoxy) acetic acid (compound 2); white solid (sodium salt ); Melting point (sodium salt) 227-232 ° C. (decomposition).
(4- {1- [4-fluoro-4 ′-(trifluoromethyl) -1,1′-biphenyl-3-yl] butoxy} -2-methylphenoxy) acetic acid (compound 3); colorless oil; FT-IR (film) ν: 1735, 1618, 1492, 1323, 1203, 1163, 1122, 1111, 1070, 1029, 1014, 846, 817, 704 cm ^-1 .
(4- {1- [4-Fluoro-4 ′-(trifluoromethyl) -1,1′-biphenyl-3-yl] -2-methylpropoxy} -2-methylphenoxy) acetic acid (Compound 4); colorless FT-IR (film) ν: 1735, 1618, 1493, 1323, 1257, 1203, 1163, 1122, 1111, 1070, 1030, 1014, 847, 818, 802, 703 cm ⁻¹ .
[4-({1- [4-Fluoro-4 ′-(trifluoromethyl) -1,1′-biphenyl-3-yl] pentyl} oxy) -2-methylphenoxy] acetic acid (Compound 5); FT-IR (film) ν: 1735, 1618, 1492, 1323, 1203, 1163, 1122, 1111, 1070, 1034, 1014, 847, 818, 704 cm ⁻¹ .
{4-[[4-Fluoro-4 ′-(trifluoromethyl) -1,1′-biphenyl-3-yl] (phenyl) methoxy] -2-methylphenoxy} acetic acid (Compound 6); white solid; 174-176 ° C.

Synthesis of [4- (carboxymethoxy) -3-methylphenoxy] [4-fluoro-4 ′-(trifluoromethyl) -1,1′-biphenyl-3-yl] acetic acid (Compound 7) (Example 3- 1) Synthesis of [4-fluoro-4 ′-(trifluoromethyl) -1,1′-biphenyl-3-yl] (hydroxy) acetic acid Lithium chloride (32.0 mg, 0.746 mmol) and potassium hydroxide (84.0 mg, 1.49 mmol) was dissolved in a mixed solvent of water (1.3 ml) and 1,4-dioxane (1.3 ml), and 4-fluoro-4 ′-(trifluoromethyl)-obtained in Example 1-1 at 0 ° C. 1,1′-biphenyl-3-carbaldehyde (100.0 mg, 0.373 mmol) and bromoform (0.039 ml, 0.447 mmol) were added, and the mixture was stirred at room temperature for 23 hours. 1N hydrochloric acid was added to the reaction solution, and the organic matter was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified using silica gel column chromatography to obtain 69.0 mg of the desired product as white crystals (yield 59%).
¹ H-NMR (300 MHz, (CD ₃ ) ₂ SO) δ: 7.91 (1H, dd, J = 7.1, 2.6 Hz), 7.84 (4H, s), 7.84-7.77 (1H, m), 7.40 (1H , dd, J = 10.1, 8.6 Hz), 6.07 (1H, s).
Example 3-2 [4- (2-Ethoxy-2-oxoethoxy) -3-methylphenoxy] [4-fluoro-4 ′-(trifluoromethyl) -1,1′-biphenyl-3-yl Synthesis of ethyl acetate [4-Fluoro-4 ′-(trifluoromethyl) -1,1′-biphenyl-3-yl] (hydroxy) acetic acid (600.0 mg, 1.91 mmol) obtained in Example 3-1. To an ethanol solution (4 ml), thionyl chloride (0.28 ml, 3.81 mmol) was added dropwise at 0 ° C., and the mixture was stirred at room temperature for 3 hours 30 minutes. The reaction solution was poured into saturated sodium bicarbonate water, and the organic matter was extracted with ethyl acetate. The organic layer was washed with water and then saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified using silica gel column chromatography to obtain 0.562 g of [4-fluoro-4 ′-(trifluoromethyl) -1,1′-biphenyl-3-yl] (hydroxy) ethyl acetate as colorless. Obtained as an oil (yield 86%).
[4-Fluoro-4 ′-(trifluoromethyl) -1,1′-biphenyl-3-yl] (hydroxy) ethyl acetate (100.0 mg, 0.292 mmol) obtained in the above method in dichloromethane (1 ml) ) Were added with thionyl chloride (0.062 ml, 0.702 mmol) and 1,2,3-benzotriazole (10.0 mg, 0.08 mmol) at 0 ° C., and the mixture was stirred at room temperature for 3 hours. The reaction solution was poured into a saturated aqueous ammonium chloride solution, and the organic matter was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in N, N′-dimethylformamide (2 ml), ethyl (4-hydroxy-2-methylphenoxy) acetate (61.0 mg, 0.292 mmol) obtained in Reference Example 1-2, carbonic acid Potassium (200.0 mg, 1.46 mmol) and tetrabutylammonium iodide (11.0 mg, 0.029 mmol) were added, and the mixture was stirred at room temperature for 14 hours. The reaction solution was diluted with ethyl acetate, and the organic layer was washed with water and then saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified using silica gel column chromatography to obtain 109.0 mg of the desired product as a colorless oil (2 step yield: 70%). .
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.84 (1H, dd, J = 6.6, 2.4 Hz), 7.69 (2H, d, J = 8.4 Hz), 7.64 (2H, d, J = 8.4 Hz) , 7.56 (1H, ddd, J = 9.2, 4.4, 2.4 Hz), 7.21 (1H, dd, J = 9.2, 8.8 Hz), 6.85 (1H, d, J = 2.9 Hz), 6.73 (1H, dd, J = 8.8, 2.9 Hz), 6.62 (1H, d, J = 8.8 Hz), 5.93 (1H, s), 4.56 (2H, s), 4.34-4.14 (2H, m), 2.26 (3H, s), 1.28 (3H, t, J = 7.1 Hz), 1.24 (3H, t, J = 7.1 Hz).
Example 3-3 Synthesis of [4- (carboxymethoxy) -3-methylphenoxy] [4-fluoro-4 ′-(trifluoromethyl) -1,1′-biphenyl-3-yl] acetic acid [4- (2-Ethoxy-2-oxoethoxy) -3-methylphenoxy] [4-fluoro-4 ′-(trifluoromethyl) -1,1′-biphenyl-3-yl obtained in 3-2 Ethyl acetate (88.0 mg, 0.165 mmol) was hydrolyzed in the same manner as in Example 1-5 to obtain 71.0 mg of the desired product as white crystals (yield 90%).
Melting point 101-106 ° C.

Synthesis of (4- {1- [4-fluoro-4 ′-(trifluoromethyl) -1,1′-biphenyl-3-yl] -2-hydroxyethoxy} -2-methylphenoxy) acetic acid (Compound 8) Example 4-1 Synthesis of [4- (acetyloxy) -3-methylphenoxy] [4-fluoro-4 ′-(trifluoromethyl) -1,1′-biphenyl-3-yl] ethyl acetate
Using 4-acetoxy-3-methylphenol (0.265 g, 1.26 mmol) obtained in Reference Example 1-1 instead of (4-hydroxy-2-methylphenoxy) ethyl acetate, Example 3-2 and By performing the reaction in the same manner, 0.255 g of the target product was obtained as a colorless oil (2 step yield: 50%).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.84 (1H, dd, J = 6.6, 2.4 Hz), 7.69 (2H, J = 8.6 Hz), 7.64 (2H, d, J = 8.6 Hz), 7.57 (1H, ddd, J = 8.6, 5.0, 2.4 Hz), 7.22 (1H, dd, 9.2, 8.6 Hz), 7.03-6.86 (2H, m), 6.80 (1H, dd, J = 8.6, 2.9 Hz), 5.97 (1H, s), 4.35-4.17 (2H, m), 2.29 (3H, s), 2.13 (3H, s), 1.24 (3H, t, J = 7.1 Hz).
Example 4-2 Synthesis of 4- {1- [4-fluoro-4 ′-(trifluoromethyl) -1,1′-biphenyl-3-yl] -2-hydroxyethoxy} -2-methylphenol [4- (Acetyloxy) -3-methylphenoxy] [4-fluoro-4 ′-(trifluoromethyl) -1,1′-biphenyl-3-yl] ethyl acetate obtained in Example 4-1 ( A tetrahydrofuran solution (1.1 mmol / l, 6.8 ml, 7.480 mmol) of borane-tetrahydrofuran complex at 0 ° C. was added dropwise to a tetrahydrofuran solution (10 ml) of 720.0 mg, 1.468 mmol), and the mixture was stirred at room temperature for 5 hours and then refluxed. Stir for 4 hours. A 10% aqueous potassium hydrogen sulfate solution was added to the reaction solution, and the organic matter was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 583.2 mg of the desired product as white crystals (yield 98%).
¹ H-NMR (300 MHz, (CD ₃ ) ₂ SO) δ: 8.79 (1H, s), 7.90-7.65 (6H, m), 7.33 (1H, t, J = 9.1 Hz), 6.69 (1H, s ), 6.62-6.50 (2H, m), 5.39 (1H, t, J = 5.0 Hz), 5.17 (1H, t, J = 6.0 Hz), 3.94-3.78 (1H, m), 3.78-3.62 (1H, m), 2.01 (3H, s).

Example 4-3 (4- {1- [4-Fluoro-4 ′-(trifluoromethyl) -1,1′-biphenyl-3-yl] -2-hydroxyethoxy} -2-methylphenoxy) Synthesis of ethyl acetate 4- {1- [4-Fluoro-4 ′-(trifluoromethyl) -1,1′-biphenyl-3-yl] -2-hydroxyethoxy}-obtained in Example 4-2 2-methylphenol (580.0 mg, 1.427 mmol) is dissolved in N, N′-dimethylformamide (10 ml), potassium carbonate (600.0 mg, 4.341 mmol) and ethyl bromoacetate (500.0 mg, 2.994 mmol) are added, Stir at room temperature for 6 hours. A 10% aqueous potassium hydrogen sulfate solution was added to the reaction solution, and the organic matter was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 528.1 mg of the desired product as a colorless oil (yield 75%).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.66 (2H, d, J = 8.6 Hz), 7.62 (1H, d, J = 6.8, 2.4 Hz), 7.56 (2H, d, J = 8.6 Hz) , 7.49 (1H, ddd, J = 8.6, 4.9, 2.4 Hz), 7.17 (1H, dd, J = 9.5, 8.6 Hz), 6.79 (1H, d, J = 2.9 Hz), 6.63 (1H, dd, J = 8.8, 2.9 Hz), 6.56 (1H, d, J = 8.8 Hz), 5.57 (1H, dd, J = 5.7, 5.3 Hz), 4.53 (2H, s), 4.22 (2H, q, J = 7.1 Hz ), 3.95 (1H, d, J = 5.3 Hz), 3.92 (1H, d, J = 5.7 Hz), 2.23 (3H, s), 1.26 (3H, t, J = 7.4 Hz).
Example 4-4 (4- {1- [4-Fluoro-4 ′-(trifluoromethyl) -1,1′-biphenyl-3-yl] -2-hydroxyethoxy} -2-methylphenoxy) Synthesis of acetic acid (4- {1- [4-fluoro-4 ′-(trifluoromethyl) -1,1′-biphenyl-3-yl] -2-hydroxyethoxy}-obtained in Example 4-3 2-Methylphenoxy) ethyl acetate (8.0 mg, 0.0162 mmol) was hydrolyzed in the same manner as in Example 1-5 to obtain 8.0 mg of the desired product as a colorless oil (yield 100%). .
FT-IR (film) ν: 1734, 1616, 1496, 1323, 1202, 1163, 1120, 1111, 1070, 1039, 1014, 847, 822, 704 cm ^-1 .

Synthesis of (4- {1- [4-fluoro-4 ′-(trifluoromethyl) -1,1′-biphenyl-3-yl] -2-methoxyethoxy} -2-methylphenoxy) acetic acid (Compound 9) Example 5-1 (4- {1- [4-Fluoro-4 ′-(trifluoromethyl) -1,1′-biphenyl-3-yl] -2-methoxyethoxy} -2-methylphenoxy) Synthesis of ethyl acetate (4- {1- [4-fluoro-4 ′-(trifluoromethyl) -1,1′-biphenyl-3-yl] -2-hydroxyethoxy} obtained in Example 4-3 2-methylphenoxy) ethyl acetate (117.7 mg, 0.239 mmol) was dissolved in N, N′-dimethylformamide (10 ml), and 60% sodium hydride (14.3 mg, 0.357 mmol) and methyl iodide (67.8 mg) were dissolved. , 0.478 mmol) and stirred at room temperature for 1 hour. A 10% aqueous potassium hydrogen sulfate solution was added to the reaction solution, and the organic matter was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel thin layer chromatography to obtain 91.0 mg of the desired product as a colorless oil. (Yield 75%)
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.70-7.62 (3H, m), 7.57 (2H, d, J = 8.4 Hz), 7.48 (1H, ddd, J = 2.4, 5.0, 6.3 Hz), 7.16 (1H, t, J = 9.1 Hz), 6.80 (1H, d, J = 2.8 Hz), 6.63 (1H, dd, J = 2.8, 8.8 Hz), 6.55 (1H, d, J = 8.8 Hz), 5.64 (1H, q, J = 3.5 Hz), 4.52 (2H, s), 4.21 (2H, q, J = 7.0 Hz), 3.82 (1H, dd, J = 7.1, 10.8 Hz), 3.72 (1H, dd , J = 3.5, 10.8 Hz), 3.43 (3H, s), 2.22 (3H, s), 1.25 (3H, t, J = 7.0 Hz).
Example 5-2 (4- {1- [4-Fluoro-4 ′-(trifluoromethyl) -1,1′-biphenyl-3-yl] -2-methoxyethoxy} -2-methylphenoxy) Synthesis of acetic acid (4- {1- [4-fluoro-4 ′-(trifluoromethyl) -1,1′-biphenyl-3-yl] -2-methoxyethoxy}-obtained in Example 5-1 2-Methylphenoxy) ethyl acetate (91.0 mg, 0.180 mmol) was hydrolyzed in the same manner as in Example 1-5 to obtain 86.0 mg of the desired product as a colorless oil (yield 100%). .
FT-IR (film) ν: 1735, 1492, 1323, 1201, 1163, 1121, 1111, 1070, 1014, 847, 820, 704 cm ^-1 .

(4- {2-Amino-1- [4-fluoro-4 ′-(trifluoromethyl) -1,1′-biphenyl-3-yl] -2-oxoethoxy} -2-methylphenoxy) acetic acid (compound Synthesis of 10) (Example 6-1) Synthesis of [4-fluoro-4 ′-(trifluoromethyl) -1,1′-biphenyl-3-yl] (4-hydroxy-3-methylphenoxy) acetic acid [4-Acetyloxy-3-methylphenoxy] [4-fluoro-4 ′-(trifluoromethyl) -1,1′-biphenyl-3-yl] ethyl acetate obtained in Example 4-1 (250.0 mg, 0.51 mmol) was hydrolyzed in the same manner as in Example 1-5 to obtain 196.0 mg of the desired product as a white solid (91% yield).
¹ H-NMR (300 MHz, (CD ₃ ) ₂ SO) δ: 8.90 (1H, bs), 7.86 (1H, dd, J = 6.6, 2.4 Hz), 7.82 (4H, s), 7.82-7.75 (1H m), 5.88 (1H, s), 2.06 (3H, s).
Example 6-2 Synthesis of 2- [4-fluoro-4 ′-(trifluoromethyl) -1,1′-biphenyl-3-yl] -2- (4-hydroxy-3-methylphenoxy) acetamide [4-Fluoro-4 ′-(trifluoromethyl) -1,1′-biphenyl-3-yl] (4-hydroxy-3-methylphenoxy) acetic acid (169.0 mg, 0.40) obtained in Example 6-1 mmol) in N, N'-dimethylformamide solution (3 ml), ammonium chloride (65.0 mg, 1.21 mmol), 1-ethyl-3- (3'-dimethylaminopropyl) carbodiimide hydrochloride (92.0 mg, 0.48 mmol) , N-hydroxybenzotriazole (54.0 mg, 0.40 mmol) and triethylamine (0.169 ml, 1.21 mmol) were added, and the mixture was stirred at room temperature for 15 hours. The reaction solution was poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with water and then saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified using silica gel column chromatography to obtain 127.0 mg of the desired product as a white solid (yield 76%).
¹ H-NMR (300 MHz, (CD ₃ ) ₂ SO) δ: 8.90 (1H, s), 7.90 (1H, dd, J = 6.6, 2.4 Hz), 7.83 (4H, s), 7.75 (1H, ddd , J = 8.3, 5.0, 2.4 Hz), 7.54 (1H, br.s), 7.36 (1H, dd, J = 9.5, 8.3 Hz), 6.68-6.60 (2H, m), 5.68 (1H, s), 2.04 (3H, s).

Example 6-3 (4- {2-amino-1- [4-fluoro-4 ′-(trifluoromethyl) -1,1′-biphenyl-3-yl] -2-oxoethoxy} -2 -Methylphenoxy) Synthesis of ethyl acetate 4- {1- [4-Fluoro-4 '-(trifluoromethyl) -1,1'-biphenyl-3-yl] -2-hydroxyethoxy} -2-methylphenol Instead, 2- [4-fluoro-4 ′-(trifluoromethyl) -1,1′-biphenyl-3-yl] -2- (4-hydroxy-3-methyl) obtained in Example 6-2. The reaction was carried out in the same manner as in Example 4-3 using phenoxy) acetamide (60.0 mg, 0.143 mmol) to obtain 63.0 mg of the target product as a white solid (yield 87%).
¹ H-NMR (300 MHz, (CD ₃ ) ₂ SO) δ: 7.98 (1H, dd, J = 6.8, 2.4 Hz), 7.95 (1H, br. S), 7.88 (4H, s), 7.81 (1H , ddd, J = 9.0, 4.9, 2.4 Hz), 7.64 (1H, br.s), 7.42 (1H, dd, J = 9.5, 9.0 Hz), 6.97 (1H, d, J = 2.0 Hz), 6.87- 6.77 (2H, m), 5.84 (1H, s), 4.75 (2H, s), 4.18 (2H, q, J = 7.1 Hz), 3.40 (2H, s), 2.20 (3H, s), 1.22 (3H , t, J = 7.1 Hz).
Example 6-4 (4- {2-Amino-1- [4-fluoro-4 ′-(trifluoromethyl) -1,1′-biphenyl-3-yl] -2-oxoethoxy} -2 -Methylphenoxy) acetic acid synthesis (4- {2-amino-1- [4-fluoro-4 '-(trifluoromethyl) -1,1'-biphenyl-3-yl) obtained in Example 6-3 ] -2-oxoethoxy} -2-methylphenoxy) ethyl acetate (43.0 mg, 0.0851 mmol) was hydrolyzed in the same manner as in Example 1-5 to obtain 41.0 mg of the desired product as a white solid. (Yield 100%).
Melting point 214-215 [deg.] C.

Synthesis of (4- {1- [4-fluoro-4 ′-(trifluoromethyl) -1,1′-biphenyl-3-yl] -2-oxopropoxy} -2-methylphenoxy) acetic acid (Compound 11) Example 7-1 2- [4-Fluoro-4 ′-(trifluoromethyl) -1,1′-biphenyl-3-yl] -2- (4-hydroxy-3-methylphenoxy) -N— Synthesis of Methoxy-N-methylacetamide [4-Fluoro-4 ′-(trifluoromethyl) -1,1′-biphenyl-3-yl] (4-hydroxy-3-methyl) obtained in Example 6-1 Phenoxy) acetic acid (393.0 mg, 0.935 mmol) in N, N′-dimethylformamide solution (18 ml) was added N, O-dimethylhydroxylamine hydrochloride (273.0 mg, 2.80 mmol), 1-ethyl-3- (3′- Dimethylaminopropyl) carbodiimide Salt (215.0 mg, 1.12 mmol), N- hydroxybenzotriazole (126.0 mg, 0.935 mmol) and triethylamine (0.390 ml, 2.80 mmol) and the mixture was stirred at room temperature for 15 hours. The reaction solution was poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with water and then saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified using silica gel column chromatography to obtain 318.0 mg of the desired product as a colorless amorphous substance (yield 73%).
¹ H-NMR (300 MHz, (CD ₃ ) ₂ SO) δ: 7.88 (1H, dd, J = 2.6, 6.8 Hz), 7.68-7.62 (4H, m), 7.56 (1H, ddd, J = 2.4, 5.0, 9.0 Hz), 7.19 (1H, t, J = 9.1 Hz), 6.82 (1H, d, J = 2.9 Hz), 6.71 (1H, dd, J = 2.8, 8.6 Hz), 6.65 (1H, d, J = 8.6 Hz), 6.36 (1H, s), 4.73 (1H, s), 3.61 (3H, s), 3.21 (3H, s), 2.19 (3H, s).
Example 7-2 Synthesis of 1- [4-fluoro-4 ′-(trifluoromethyl) -1,1′-biphenyl-3-yl] -1- (4-hydroxy-3-methylphenoxy) acetone 2- [4-Fluoro-4 ′-(trifluoromethyl) -1,1′-biphenyl-3-yl] -2- (4-hydroxy-3-methylphenoxy)-obtained in Example 7-1 To a diethyl ether solution (2 ml) of N-methoxy-N-methylacetamide (100.0 mg, 0.216 mmol) was added a tetrahydrofuran solution (0.93 mol / l, 0.511 ml, 0.475 mmol) of methylmagnesium bromide, and the mixture was kept at 0 ° C. for 1 hour. Stir. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the organic matter was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified using silica gel column chromatography to obtain 97.0 mg of the desired product as a colorless oil (yield 100%).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.70 (1H, dd, J = 2.4, 6.6 Hz), 7.68 (2H, d, J = 8.8 Hz), 7.61 (2H, d, J = 8.8 Hz) , 7.55 (1H, ddd, J = 2.4, 5.0, 9.0 Hz), 7.23 (1H, t, J = 9.1 Hz), 6.79-6.77 (1H, m), 6.68-6.62 (2H, m), 5.83 (1H , s), 4.54 (1H, s), 2.32 (3H, s), 2.20 (3H, s).

Example 7-3 (4- {1- [4-Fluoro-4 ′-(trifluoromethyl) -1,1′-biphenyl-3-yl] -2-oxopropoxy} -2-methylphenoxy) Synthesis of ethyl acetate Performed instead of 4- {1- [4-fluoro-4 ′-(trifluoromethyl) -1,1′-biphenyl-3-yl] -2-hydroxyethoxy} -2-methylphenol 1- [4-Fluoro-4 ′-(trifluoromethyl) -1,1′-biphenyl-3-yl] -1- (4-hydroxy-3-methylphenoxy) acetone obtained in Example 7-2 ( 97.0 mg, 0.216 mmol) was used in the same manner as in Example 4-3 to obtain 84.0 mg of the target product as a white solid (77% yield).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.68 (1H, dd, J = 2.4, 8.8 Hz), 7.67 (2H, d, J = 8.6 Hz), 7.61 (2H, d, J = 8.6 Hz) , 7.55 (1H, ddd, J = 2.4, 4.7, 8.8 Hz), 7.22 (1H, t, J = 9.0 Hz), 6.83 (1H, d, J = 2.8 Hz), 6.67 (1H, dd, J = 2.8 , 8.8 Hz), 6.61 (1H, d, J = 8.8 Hz), 5.84 (1H, s), 4.55 (2H, s), 4.24 (2H, q, J = 7.1 Hz), 2.32 (3H, s), 2.25 (3H, s), 1.27 (3H, t, J = 7.1 Hz).
Example 7-4 (4- {1- [4-Fluoro-4 ′-(trifluoromethyl) -1,1′-biphenyl-3-yl] -2-oxopropoxy} -2-methylphenoxy) Synthesis of acetic acid (4- {1- [4-fluoro-4 ′-(trifluoromethyl) -1,1′-biphenyl-3-yl] -2-oxopropoxy}-obtained in Example 7-3 2-Methylphenoxy) ethyl acetate (84.0 mg, 0.168 mmol) was hydrolyzed in the same manner as in Example 1-5 to obtain 27.0 mg of the desired product as a colorless amorphous substance (yield 34%).
FT-IR (film) ν: 1732, 1618, 1497, 1323, 1201, 1163, 1120, 1111, 1070, 1014, 848, 822, 802, 704 cm ⁻¹ .

Synthesis of (4- {cyano [4-fluoro-4 ′-(trifluoromethyl) -1,1′-biphenyl-3-yl] methoxy} -2-methylphenoxy) acetic acid (compound 12) (Example 8- 1) Synthesis of ethyl (4- {cyano [4-fluoro-4 ′-(trifluoromethyl) -1,1′-biphenyl-3-yl] methoxy} -2-methylphenoxy) acetate In Example 6-3 Obtained (4- {2-amino-1- [4-fluoro-4 ′-(trifluoromethyl) -1,1′-biphenyl-3-yl] -2-oxoethoxy} -2-methylphenoxy) Methanesulfonyl chloride (0.250 ml, 2.718 mmol) and pyridine (0.512 ml, 6.340 mmol) are added to a solution of ethyl acetate (229.0 mg, 0.453 mmol) in N, N'-dimethylformamide (3 ml) and stirred at room temperature for 2 hours. did. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, water and saturated brine in that order, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 182.0 mg of the desired product as a colorless oil (yield 82%).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.94 (1H, dd, J = 2.4, 6.8 Hz), 7.73 (2H, d, J = 8.8 Hz), 7.70-7.65 (1H, m), 7.61 ( 2H, d, J = 8.8 Hz), 7.28 (1H, t, J = 9.0 Hz), 6.98 (1H, d, J = 2.9 Hz), 6.91 (1H, dd, J = 2.9, 8.8 Hz), 6.70 ( 1H, d, J = 8.8 Hz), 6.04 (1H, s), 4.62 (2H, s), 4.26 (2H, q, J = 7.1 Hz), 2.30 (3H, s), 1.30 (3H, t, J = 7.1 Hz).
Example 8-2 Synthesis of (4- {cyano [4-fluoro-4 ′-(trifluoromethyl) -1,1′-biphenyl-3-yl] methoxy} -2-methylphenoxy) acetic acid (4- {Cyano [4-fluoro-4 ′-(trifluoromethyl) -1,1′-biphenyl-3-yl] methoxy} -2-methylphenoxy) ethyl acetate (182.0 mg) obtained in 8-1. , 0.373 mmol) was hydrolyzed in the same manner as in Example 1-5 to obtain 65.0 mg of the desired product as a colorless amorphous (yield 35%).
FT-IR (film) ν: 2390, 1727, 1616, 1497, 1323, 1202, 1163, 1120, 1111, 1070, 1014, 847, 822, 808, 700 cm ^-1 .

Synthesis of [4-({1- [4-fluoro-4 ′-(trifluoromethyl) -1,1′-biphenyl-3-yl] ethyl} thio) -2-methylphenoxy] acetic acid (Compound 13) Example 9-1) [4-({1- [4-Fluoro-4 ′-(trifluoromethyl) -1,1′-biphenyl-3-yl] ethyl} thio) -2-methylphenoxy] ethyl acetate Synthesis of 3- (1-bromoethyl) -4-fluoro-4 ′-(trifluoromethyl) -1,1′-biphenyl (104.2 mg, 0.300 mmol) obtained in Example 1-3 and Reference Example 2 Potassium carbonate (200.0 mg, 1.447 mmol) was added to a solution of the obtained ethyl (4-mercapto-2-methylphenoxy) acetate (67.9 mg, 0.300 mmol) in N, N′-dimethylformamide (3 ml) at room temperature. Stir for 1 hour. A 10% aqueous potassium hydrogen sulfate solution was added to the reaction solution, and the organic matter was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel thin layer chromatography to obtain 132.0 mg of the desired product as a colorless oil (yield 89%).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.68 (2H, d, J = 8.4 Hz), 7.54 (2H, d, J = 8.4 Hz), 7.43-7.30 (2H, m), 7.15-7.03 ( 3H, m), 6.56 (1H, d, J = 9.0 Hz), 4.59 (2H, s), 4.58 (1H, q, J = 7.0 Hz), 4.24 (2H, q, J = 7.0 Hz), 2.18 ( 3H, s), 1.62 (3H, d, J = 7.0 Hz), 1.28 (3H, t, J = 7.0 Hz).
Example 9-2 [4-({1- [4-Fluoro-4 ′-(trifluoromethyl) -1,1′-biphenyl-3-yl] ethyl} thio) -2-methylphenoxy] acetic acid Synthesis of [4-({1- [4-fluoro-4 ′-(trifluoromethyl) -1,1′-biphenyl-3-yl] ethyl} thio) -2- obtained in Example 9-1 Methylphenoxy] ethyl acetate (132.0 mg, 0.268 mmol) was hydrolyzed in the same manner as in Example 1-5 to obtain 124.5 mg of the desired product as a colorless oil (yield 100%).
FT-IR (film) ν: 1735, 1489, 1323, 1224, 1190, 1163, 1108, 1070, 1014, 893, 846, 818 cm ^-1 .

(+)-(4- {1- [4-Fluoro-4 ′-(trifluoromethyl) -1,1′-biphenyl-3-yl] ethoxy} -2-methylphenoxy) acetic acid (compound 14) and ( Synthesis of −)-(4- {1- [4-fluoro-4 ′-(trifluoromethyl) -1,1′-biphenyl-3-yl] ethoxy} -2-methylphenoxy) acetic acid (compound 15) (4- {1- [4-Fluoro-4 ′-(trifluoromethyl) -1,1′-biphenyl-3-yl] ethoxy} -2-methylphenoxy) acetic acid (Compound 1) obtained in Example 1 540 mg was fractionated by high performance liquid chromatography using an optically active column under the following conditions, separated and purified into components that flowed out first and components that flowed out later, and the solutions that flowed out were concentrated under reduced pressure. Each residue was dissolved in tetrahydrofuran (6 ml) and methanol (3 ml), 1N aqueous sodium hydroxide solution (3 ml) was added, and the mixture was stirred at room temperature for 1 hour. A 10% aqueous potassium hydrogen sulfate solution was added to the reaction solution to make the solution weakly acidic, and the organic matter was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then evaporated under reduced pressure to remove 209 mg of (+)-(4- {1- [4-fluoro-4 ′-(tri Fluoromethyl) -1,1′-biphenyl-3-yl] ethoxy} -2-methylphenoxy) acetic acid as colorless amorphous, 229 mg of (−)-(4- {1- [4-fluoro-4′- (Trifluoromethyl) -1,1′-biphenyl-3-yl] ethoxy} -2-methylphenoxy) acetic acid was obtained as a colorless amorphous, respectively.
Column: A column (trade name CHIRALCEL (registered trademark) OJ-H (Daicel Chemical) Industrial Corporation)).
Moving bed: hexane / ethanol / trifluoroacetic acid = 89.95 / 9.95 / 0.1
Flow rate: 9.9 ml / min
Detection wavelength: 254 nm
Specific rotation (+)-body: [α] _D ²⁷ + 166.8 ° (c = 0.552, methanol)
Specific rotation (-)-body: [α] _D ²⁷ -163.2 ° (c = 1.029, methanol)

The sodium salt of each optically active substance was synthesized by the following method.
(+)-(4- {1- [4-Fluoro-4 ′-(trifluoromethyl) -1,1′-biphenyl-3-yl] ethoxy} -2-methylphenoxy) acetic acid (192.0 mg, 0.428 mmol ) In methanol (10 ml) was added 28% sodium methoxide methanol solution (0.414 ml, 0.423 mmol) at room temperature and stirred at room temperature for 1 hour. After distilling off the solvent under reduced pressure, the residue was diluted with toluene, and the solid precipitated by distilling off the solvent again under reduced pressure was washed with diethyl ether, whereby 200.0 mg of (+)-(4- {1- [ 4-Fluoro-4 '-(trifluoromethyl) -1,1'-biphenyl-3-yl] ethoxy} -2-methylphenoxy) acetic acid sodium salt was obtained as a colorless solid. In the same manner, (−)-(4- {1- [4-fluoro-4 ′-(trifluoromethyl) -1,1′-biphenyl-3-yl] ethoxy} -2-methylphenoxy) From acetic acid (199.0 mg, 0.449 mmol), 205.0 mg of (−)-(4- {1- [4-fluoro-4 ′-(trifluoromethyl) -1,1′-biphenyl-3-yl] ethoxy} 2-Methylphenoxy) acetic acid sodium salt was obtained as a colorless solid.
Melting point of (+)-sodium salt: 195-200 ° C. (decomposition)
(−)-Melting point of sodium salt: 227-232 ° C. (decomposition)
Specific rotation of (+)-sodium salt: [α] _D ²⁶ + 152.1 ° (c = 0.958, methanol)
Specific rotation of (−)-sodium salt: [α] _D ²⁷ −163.8 ° (c = 1.016, methanol)

Reference example 1
Synthesis of ethyl (4-hydroxy-2-methylphenoxy) acetate (synthesis intermediate of compound 1) (Reference Example 1-1) Synthesis of 4-acetoxy-2-methylphenol and 4-acetoxy-3-methylphenol 2- Methyl-1,4-hydroquinone (9.39 g, 75.6 mmol) was dissolved in DMF (30 ml), potassium carbonate (20.7 g, 150 mmol) was added, and the mixture was stirred under ice-cooling. Acetic anhydride (4.7 ml, 50 mmol) was added dropwise thereto, and the mixture was stirred at the same temperature for 3 hours and then at room temperature overnight. The reaction mixture was diluted with toluene and filtered. The filtered product was washed with toluene, and the filtrate washings were combined and washed successively with saturated aqueous ammonium chloride solution, water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified using silica gel column chromatography to obtain 1.86 g of 4-acetoxy-2-methylphenol (yield 15%) and 1.50. g of 4-acetoxy-3-methylphenol (12% yield) was obtained.
¹ H-NMR (300 MHz, CDCl ₃ ) 2-methyl isomer δ: 6.83 (1H, d, J = 2.6 Hz), 6.77 (1H, dd, J = 8.6 and 2.6 Hz), 6.71 (1H, d, J = 8.6 Hz), 4.81 (1H, s), 2.27 (3H, s), 2.22 (3H, s).
¹ H-NMR (300 MHz, CDCl ₃ ) 3-methyl isomer δ: 6.83 (1H, d, J = 8.4 Hz), 6.64 (1H, d, J = 2.8 Hz), 6.60 (1H, dd, J = 8.4 and 2.8 Hz), 5.00 (1H, s), 2.30 (3H, s), 2.11 (3H, s).
(Reference Example 1-2) Synthesis of ethyl (4-hydroxy-2-methylphenoxy) acetate 4-Acetoxy-2-methylphenol (200 mg, 1.20 mmol) obtained in Reference Example 15-1 was added to DMF (3 ml). ), Potassium carbonate (333 mg, 2.41 mmol) was added, and the mixture was stirred under ice-cooling. A solution of ethyl bromoacetate (221 mg, 1.32 mmol) in DMF (1 ml) was added dropwise thereto, and the mixture was stirred at room temperature for 3.5 hours. The reaction mixture was diluted with toluene and washed with water and then saturated brine. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified using silica gel column chromatography to obtain 275 mg of (4-acetoxy-2-methylphenoxy) ethyl acetate as a colorless oil. Obtained as material. (Yield 91%)
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 6.89 (1H, d, J = 2.6 Hz), 6.84 (1H, dd, J = 8.6 and 2.6 Hz), 6.69 (1H, d, J = 8.6 Hz) , 4.61 (2H, s), 4.26 (2H, q, J = 7.2 Hz), 2.28 (3H, s), 2.27 (3H, s), 1.30 (3H, t, J = 7.2 Hz).
(4-Acetoxy-2-methylphenoxy) ethyl acetate (2.293 g, 9.09 mmol) obtained by the above method was dissolved in ethanol (12 ml), and potassium carbonate (2.51 g, 18.2 mmol) was added under ice cooling. In addition, the mixture was stirred at the same temperature for 1 hour and further at room temperature for 1 hour. The reaction mixture was diluted with ethanol and filtered. The filtered product was washed with ethanol, and the filtrate was combined and concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified using silica gel column chromatography to obtain 1.576 g of the desired product as a white solid. (Yield 83%)
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 6.65 (1H, d, J = 2.8 Hz), 6.61 (1H, d, J = 8.6 Hz), 6.56 (1H, dd, J = 2.8 and 8.6 Hz) , 4.80 (1H, s), 4.56 (2H, s), 4.26 (2H, q, J = 7.2 Hz), 2.24 (3H, s), 1.29 (3H, t, J = 7.2 Hz).

Reference example 2
Synthesis of (4-mercapto-2-methylphenoxy) ethyl acetate
[4- (Chlorosulfonyl) -2-methylphenoxy] ethyl acetate (1.00 g, 3.42 mmol) and zinc powder (0.522 g, 34.2 mmol) in ethanol suspension (100 ml) and 4N hydrochloric acid dioxane solution (4.28 ml) , 17.1 mmol) was added at room temperature, and the mixture was warmed to 30 ° C. and stirred for 2 hours. Furthermore, zinc powder (1.04 g, 68.4 mmol) and 4N hydrochloric acid dioxane solution (9.56 ml, 34.2 mmol) were added at room temperature, and the mixture was warmed to 70 ° C. and stirred for 2 hours. After the reaction was completed by adding water, extraction was performed with ether, and the organic layer was washed once with water. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. Purification using silica gel column chromatography gave 718 mg of the desired product as an oil (yield 93%).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.14 (1H, d, J = 2.3 Hz), 7.09 (1H, dd, J = 8.3, 2.3 Hz), 6.59 (1H, d, J = 8.3 Hz) , 4.60 (2H, s), 4.26 (2H, q, J = 7.2 Hz), 3.33 (1H, s), 2.24 (3H, s), 1.29 (3H, t, J = 7.2 Hz).

Experimental Example 1 PPARδ Agonist Activity Test Cultured COS-1 cells were seeded into a 24-well culture dish at 1.0 × 10 ⁵ cells / ml and 0.5 ml / well (Day 1). On the second day, the following three plasmid DNAs (1) to (3) were transiently introduced into the cells. (1) A plasmid that forcibly expresses a protein in which PPARδ-LBD (ligand binding domain) and the DNA binding domain of Gal-4, a transcription factor of yeast, are fused. (2) A firefly-derived luciferase reporter plasmid having a DNA sequence to which Gal-4 binds in the promoter region. (3) Renilla luciferase expression plasmid.
Four hours after DNA introduction, the medium was replaced with a medium supplemented with a test compound (0.1 to 1000 nM). 16 hours after compound addition, the cells were lysed and the luciferase activity in the cell lysate was measured.
The DNA introduction efficiency was corrected by the Renilla luciferase activity.
The agonist activity of each compound is defined as the EC ₅₀ value giving 50% of the activity at the maximum concentration tested (ie 1000 nM), and EC ₅₀ values from dose response curves obtained in the range of 0.1 to 1000 nM. Was calculated.
PPARδ agonist activity EC ₅₀ values for each of the compounds of Examples are shown below.
In the table, “NA” means that the luciferase activity at 1000 nM was not more than 5 times the luciferase activity in the condition where the test compound was not added.

Experimental Example 2 Test for Elevating Action of PPARδ Agonist in Blood High Density Lipoprotein (HDL) Mice (C57BL / 6J, 7 weeks old, male; Claire Japan) were used for the test. The test compound was orally administered by gavage once a day to the mice under free feeding conditions of a normal diet (CE2; Nippon Claire), and this was continued for 6 days. As a dose of the test compound, a 1.5 mg / kg / day group was set. The test compound was suspended or dissolved in a 0.5% methylcellulose solution and used as the administration solution. In the control group (drug non-administration group), only 0.5% methylcellulose solution was administered. On the day after the last administration day of the test compound, blood was collected from the abdominal aorta of the mouse to prepare serum. The HDL cholesterol level in the prepared serum was measured using a commercially available kit (HDL-cholesterol E-Test Wako; Wako Pure Chemical Industries). From the ratio of the HDL cholesterol value of the test compound administration group to the HDL cholesterol value of the drug non-administration group, the increase rate of the HDL cholesterol value was determined.
As an experimental result, for example, in the case of Compound 14 of Example 10, an increase in HDL cholesterol level of 28% was observed compared to the control group, and in the case of Compound 15 of Example 10, 29% compared to the control group. An increase in the HDL cholesterol level was observed.

The compound of the present invention has agonistic activity on peroxisome proliferator-responsive receptor δ (PPARδ), and increases the blood high density lipoprotein (HDL) concentration in normolipidemic mice. Therefore, it can be advantageously used as an agent for increasing blood high density lipoprotein (HDL) concentration, a therapeutic agent for hypoHDLemia, and / or a therapeutic agent for arteriosclerosis.
In particular, the compound of the present invention is such that at least one of R ⁹ and R ¹⁰ is not a hydrogen atom, that is, a peroxisome proliferator-responsive receptor δ as compared with an unsubstituted compound by having a substituent on the carbon atom to which they are bonded. Agonist activity to (PPARδ) is improved.

Claims (22)

Formula (1):

[Wherein, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ are each independently a C ₁ − which may have a hydrogen atom, a hydroxyl group, or a substituent. C ₆ alkyl group, C ₂ -C ₆ alkenyl group which may have a substituent, C ₁ -C ₆ alkoxy group which may have a substituent, C ₁ -C ₁₁ which may have a substituent acyloxy group, a carboxyl group, an optionally substituted C ₂ -C ₇ alkoxycarbonyl group, a carbamoyl group, an optionally substituted (C ₁ -C ₆ alkyl) carbamoyl group, substituted Di (C ₁ -C ₆ alkyl) carbamoyl group which may be substituted, C ₁ -C ₆ alkylsulfonyloxy group which may be substituted, C ₆ -C ₁₀ arylsulfonyloxy group which may be substituted , One of the carbon atoms has the formula: —O—, —S (O) _n - (n represents 0, 1 or 2.), Or ^{-N (R 15) - (R} 15 represents a hydrogen atom, have a an optionally substituted _C 1 -C ₆ alkyl group or a substituted group, C ₅ -C ₇ cyclic aminocarbonyl group which may be substituted with a group represented by C ₁ -C ₁₁ acyl group which may be substituted (the C ₅ -C ₇ cyclic aminocarbonyl group is a substituent). A group selected from a cyano group and a halogen atom. However, when R ¹ and R ² , R ³ and R ⁴ , R ⁵ and R ⁷ , or R ⁶ and R ⁸ are adjacent to each other on the benzene ring, together, the benzene ring, saturated or Unsaturated 5- or 6-membered carbocycles, or saturated or unsaturated 5- or 6-membered heterocycles containing 1 or 2 heteroatoms may be formed, these rings having substituents Also good.
R ⁹ and R ¹⁰ are each independently a hydrogen atom, a fluorine atom, an optionally substituted C ₁ -C ₆ alkyl group, an optionally substituted C ₂ -C ₆ alkenyl group, or a substituted group. C ₆ -C ₁₀ aryl group which may have a group, C ₁ -C ₁₁ acyl group which may have a substituent, a carboxyl group, a C ₂ -C ₇ alkoxycarbonyl group which may have a substituent , A carbamoyl group, an optionally substituted (C ₁ -C ₆ alkyl) carbamoyl group, an optionally substituted di (C ₁ -C ₆ alkyl) carbamoyl group, and a group selected from a cyano group Or together with the carbon atom to which they are bonded, a C3-C7 cycloalkane ring may be formed, and the cycloalkane ring may have a substituent.
However, R ⁹ and R ¹⁰ do not represent a hydrogen atom at the same time.
R ¹¹ and R ¹² each independently represent a hydrogen atom, a fluorine atom, or an optionally substituted C ₁ -C ₆ alkyl group, or together with the carbon atom to which they are attached, carbon A cycloalkane ring of formula 3 to 7 may be formed, and the cycloalkane ring may have a substituent.
W ¹ and W ² are each independently an oxygen atom, a sulfur atom, or a formula: —N (R ¹⁶ ) — (R ¹⁶ is independently a hydrogen atom or a substituent when there are a plurality thereof. Represents a C ₁ -C ₆ alkyl group which may be substituted).
R ¹³ may have a carboxyl group, a C ₂ -C ₇ alkoxycarbonyl group which may have a substituent, a C ₃ -C ₇ alkenyloxycarbonyl group which may have a substituent, or a substituent. C ₇ -C ₁₆ arylalkoxycarbonyl group, carbamoyl group, optionally substituted (C ₁ -C ₆ alkyl) carbamoyl group, optionally substituted di (C ₁ -C ₆ alkyl) carbamoyl Group, an optionally substituted (C ₃ -C ₆ cycloalkyl) carbamoyl group, one of the carbon atoms is represented by the formula: —O—, —S (O) _m — (m represents 0, 1 or 2). ), Or —N (R ¹⁷ ) — (R ¹⁷ is a hydrogen atom, an optionally substituted C ₁ -C ₆ alkyl group, or an optionally substituted C ₁ -C ₁₁ acyl group. Is replaced by a group represented by Optionally have C ₅ -C ₇ cyclic aminocarbonyl group (said C ₅ -C ₇ cyclic amino carbonyl group may have a substituent), or represents tetrazolyl group. Or a salt thereof. Formula (2):

[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , W ¹ , and W ² are Each has the same meaning as in claim 1. The compound or its salt of Claim 1 represented by these. Formula (3):

[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , W ¹ , and W ² are Each has the same meaning as in claim 1. The compound or its salt of Claim 1 or 2 represented by these. W ² is an oxygen atom, or a salt thereof according to any one of claims 1 to 3. W ² is a sulfur atom, or a salt thereof according to any one of claims 1 to 3. W ² has the formula: -N ^{(R 16)} - is a group represented by The compound or a salt thereof according to any one of claims 1-3. W ¹ is an oxygen atom, or a salt thereof according to any one of claims 1 to 6. The compound or a salt thereof according to any one of claims 1 to 3, wherein W ¹ and W ² are both oxygen atoms. W ¹ is an oxygen atom, W ² is a sulfur atom, or a salt thereof according to any one of claims 1 to 3. W ¹ is a sulfur atom, or a salt thereof according to any one of claims 1 to 6. W ¹ is a sulfur atom, W ² is an oxygen atom, or a salt thereof according to any one of claims 1 to 3. The compound or a salt thereof according to any one of claims 1 to 5, wherein W ¹ is a group represented by the formula: -N (R ¹⁶ )-. The compound or its salt of any one of Claims 1-12 whose R < ¹³ > is a carboxyl group. The compound or a salt thereof according to any one of claims 1 to 13, wherein at least one of R ⁵ and R ⁶ is a group other than a hydrogen atom. The compound or a salt thereof according to any one of claims 1 to 14, wherein any one of R ⁵ and R ⁶ is a hydrogen atom, and the other is a group other than a hydrogen atom. Formula (4):

[Wherein R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , W ¹ , and W ² are claimed respectively. 1 and R ^{1 ′} represents a trifluoromethyl group or a trifluoromethoxy group. The compound or its salt of any one of Claims 1-15 represented by these. Formula (5):

[Wherein R ² , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , W ¹ and W ² are the same as in claim 1 R ^{1 ′} represents a trifluoromethyl group or a trifluoromethoxy group, and R ^{3 ′} represents a fluorine atom. The compound or its salt of any one of Claims 1-16 represented by these.   The pharmaceutical which contains the compound or its salt of any one of Claims 1-17 as an active ingredient.   An activator of peroxisome proliferator-responsive receptor δ, comprising the compound according to any one of claims 1 to 17 or a salt thereof as an active ingredient.   An agent for increasing blood high density lipoprotein concentration, comprising the compound or salt thereof according to any one of claims 1 to 17 as an active ingredient.   A therapeutic agent for hypoHDLemia comprising the compound according to any one of claims 1 to 17 or a salt thereof as an active ingredient.   The therapeutic agent of arteriosclerosis containing the compound or its salt of any one of Claims 1-17 as an active ingredient.