JP2005320346A - 1,3-azole derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an excellent antithrombotic agent and thrombolytic agent. <P>SOLUTION: The 1,3-azole derivative is represented by formula (1). The derivative has excellent PA (plasminogen activator) activity-promoting activities and PAI-1 (plasminogen activator inhibitor) inhibition-activating activities, and is usable as the orally administrable antithrombotic agent and thrombolytic agent. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to a 1,3-azole derivative which has a plasminogen activator (PA) activity promoting action and a plasminogen activator inhibitor (PAI-1) inhibitory action action and is useful as a thrombolytic agent or antithrombotic agent. .

  In order to dissolve the thrombus, a therapy for administering PAs, that is, a thrombolytic therapy (fibrinolytic therapy) is currently widely performed. Activation of the fibrinolytic system is initiated by the activation of plasminogen, which is a precursor of the blood fibrinolytic regulator, by plasmin, and the resulting plasmin develops an enzymatic action to produce fibrin, a constituent of thrombus. The thrombolysis proceeds by decomposing. Currently, thrombolytic agents used in this fibrinolytic therapy include in vivo substances such as urokinase (UK), tissue plasminogen activator (t-PA), streptokinase (SK), staphylokinase (SAK) and the like. Fungus-producing substances and their gene recombinants are known. However, since all these existing thrombolytic drugs are protein preparations, their blood half-life is short, they are rapidly metabolized in the liver, and there are inhibitors in the living body, so there is a local thrombus. In order to develop a thrombolytic action, a large dose is required. In clinical practice, it has been reported that the higher the dose, the higher the reperfusion rate. However, the transient large-scale administration of such a thrombolytic agent significantly increases the thrombolytic activity systemically and causes thromboembolism. While it is expected to open the site, it has a problem that severe bleeding symptoms are observed as a side effect. Moreover, even if the embolization site is temporarily opened by administration of these thrombolytic agents, it is a big problem that re-occlusion is likely to occur.

  An object of the present invention is to provide a pharmaceutical composition having a thrombolytic action and an antithrombotic action that does not have the above-mentioned drawbacks.

［式中、
（１）Ｚは、
（ｉ）酸素
（ii）硫黄
（iii）

（ここでＺ_１は、
<1> 水素
<2> −低級アルキレン基−Ｚ_２ …（3）
（ここでＺ_２は、
１．−ＣＯＯＲ_１ …（4）
（ここでＲ_１は水素、低級アシルオキシ基で置換されて良い低級アルキル基）
２．

（ここでＲ_２，Ｒ_３は互いに独立して水素、低級アシルオキシ基で置換されて良い低級アルキル基）
３．ハロゲンで置換されて良いフェニル基
４．シクロヘキシル基））
(２)Ａは、
(ｉ)−アリーレン基−Ｏ−低級アルキレン基−ａ_１…（6）
（ここで
<1> a_１は、
１．−ＣＯＯＲ_４ …（7）
（ここでＲ_４は水素、低級アシルオキシ基で置換されて良い低級アルキル基、ベンジル基）
２．

（ここでＲ_５，Ｒ_６は互いに独立して水素、低級アシルオキシ基で置換されて良い低級アルキル基、ベンジル基）
３．

（ここでＲ_７は水素、低級アシルオキシ基で置換されて良い低級アルキル基、ベンジル基）
４．

（ここでＲ_８，Ｒ_９は互いに独立して水素、低級アシルオキシ基で置換されて良い低級アルキル基、ベンジル基）
５．ハロゲン
６．フェニル基
７．4-モルホリニル基
８．1-ピロリジニル基
９．1-ピペリジニル基
10．4-ピリジニル基
11．4-メチル-1-ピペラジニル基
12．

（ここでy_１，ｙ_２は互いに独立して
(1)水素
(2)低級アルキル基
(3)低級アルコキシカルボニル基）
<2>アリーレン基は、 1,4-及び1,2-フェニレン基、[1,1’-ビフェニル]-4,4’-ジイル基、2,6 -、2,3 -及び式（6）の酸素が６位に結合した6,1-ナフタレンジイル基）
(ii) −アリーレン基−ａ_２ …（12）
(ここで
<1>ａ_２は、
１．水酸基
２．低級アルコキシ基
３．−ＣＯＯＲ_１０ …（13）
（ここでＲ_１０は水素、低級アシルオキシ基で置換されて良い低級アルキル基、ベンジル基）
４．

（ここでＲ_１１，Ｒ_１２は互いに独立して水素、低級アシルオキシ基で置換されて良い低級アルキル基、ベンジル基、Ｒ_１３は水素、低級アルキル基）
５．

（ここでＲ_１４，Ｒ_１５は互いに独立して水素、低級アシルオキシ基で置換されて良い低級アルキル基、ベンジル基）
６．

（ここでＲ_１６は水素、低級アシルオキシ基で置換されて良い低級アルキル基、ベンジル基）
<2>アリーレン基は、1,4-フェニレン基、[1,1’-ビフェニル]-4,4’-ジイル基、2,6 -、2,3 -及び式（12）に於いてａ_２が６位に結合した6,1-ナフタレンジイル基）
（iii）−低級アルキレン基−ＣＯＯＲ_１７ …（17）
（ここでＲ_１７は水素、低級アシルオキシ基で置換されて良い低級アルキル基、ベンジル基）
（３）Ｂ_１，Ｂ_２は、
（ｉ）Ｚが酸素の時、それぞれ単独に、
１．Ｂ_１は、
(1)2-ナフチル基
(2)フェニル基
２．Ｂ_２は、
(1)水素
(2)フェニル基
(ii)それぞれに隣接する炭素と共に、一緒になってベンゼン環を形成し、全体として、前記式（1）が、下記一般式（18）

（ここで
(1)Ａ，Ｚは前記の通りである
(2)ｂ_１は、
1.水素
2.低級アルキル基
(3)ｂ_２は、
1.水素
2.低級アルキル基
3.フェニル基
4.ハロゲン
(4)ｂ_３は、
1.水素
2.ニトロ基
3.アミノ基
（ここでアミノ基は低級アルキル基、ベンジル基で置換されて良い）
4.低級アルキル基
5. −Ｏ−ｂ_３１ …（19）
（ここでｂ_３１は、
1.水素
2.低級アルキル基
3.低級アシル基
4.シクロヘキシル基
5.−低級アルキレン基−ｂ_３２ …（20）
（ここでｂ_３２は、
-1.フェニル基
-2.シクロヘキシル基
-3.−ＣＯＯＲ_１８ …（21）
（ここでＲ_１８は水素、低級アシルオキシ基で置換されて良い低級アルキル基、ベンジル基）
-4.

（ここでＲ_１９，Ｒ_２０は互いに独立して水素、低級アシルオキシ基で置換されて良い低級アルキル基、ベンジル基））））
である］
で表される化合物又は医薬的に許容し得るそれらの塩化合物若しくはそれらの溶媒和物からなる血栓症を治療するための医薬組成物。 By inhibiting plasminogen activator inhibitor (PAI-1), which is a potent inhibitor of PA, we can maintain the activity of PA and reduce the incidence of thrombosis or reocclusion. As a result of diligent research focusing on the fact that it can be made, it was found that the following 1,3-azole derivative or a pharmaceutically acceptable salt compound or solvate thereof meets the above purpose.
The present invention has been made based on such findings, and has excellent PA activity promoting action and PAI-1 inhibitory activity, and can be administered orally, and has a fibrinolysis promoting action, a thrombolytic action and an antithrombotic action A composition is provided.
That is, the present invention relates to the following inventions.
[1] General formula (1) as an active ingredient

[Where:
(1) Z is
(I) oxygen (ii) sulfur (iii)

(Where Z ₁ is
<1> Hydrogen
<2> -Lower alkylene group -Z ₂ (3)
(Where Z ₂ is
1. -COOR ₁ (4)
(Wherein R ₁ is hydrogen, a lower alkyl group which may be substituted with a lower acyloxy group)
2.

(Wherein R ₂ and R ₃ are each independently hydrogen, a lower alkyl group which may be substituted with a lower acyloxy group)
3. 3. Phenyl group which may be substituted with halogen. Cyclohexyl group))
(2) A is
(i) -arylene group-O-lower alkylene group-a ₁ (6)
(here
<1> a ₁ is
1. -COOR ₄ (7)
(Wherein R ₄ is hydrogen, a lower alkyl group which may be substituted with a lower acyloxy group, or a benzyl group)
2.

(Wherein R ₅ and R ₆ are each independently hydrogen, a lower alkyl group which may be substituted with a lower acyloxy group, or a benzyl group)
3.

(Wherein R ₇ is hydrogen, a lower alkyl group which may be substituted with a lower acyloxy group, or a benzyl group)
4).

(Where R ₈ and R ₉ are each independently hydrogen, a lower alkyl group which may be substituted with a lower acyloxy group, or a benzyl group)
5). Halogen 6. Phenyl group 7.4-morpholinyl group 8.1-pyrrolidinyl group 9.1-piperidinyl group
10. 4-pyridinyl group
11. 4-Methyl-1-piperazinyl group
12．

(Where y ₁ and y ₂ are independent of each other
(1) Hydrogen
(2) Lower alkyl group
(3) Lower alkoxycarbonyl group)
<2> Arylene groups include 1,4- and 1,2-phenylene groups, [1,1'-biphenyl] -4,4'-diyl groups, 2,6-, 2,3- and formula (6) 6,1-naphthalenediyl group with oxygen bonded to the 6-position)
(ii) -arylene group-a ₂ (12)
(here
<1> a ₂ is
1. Hydroxyl group 2. 2. Lower alkoxy group -COOR ₁₀ (13)
(Where R ₁₀ is hydrogen, a lower alkyl group which may be substituted with a lower acyloxy group, or a benzyl group)
4).

(Wherein R ₁₁ and R ₁₂ are each independently hydrogen, a lower alkyl group which may be substituted with a lower acyloxy group, a benzyl group, R ₁₃ is hydrogen or a lower alkyl group)
5).

(Wherein R ₁₄ and R ₁₅ are each independently hydrogen, a lower alkyl group which may be substituted with a lower acyloxy group, or a benzyl group)
6).

(Where R ₁₆ is hydrogen, a lower alkyl group which may be substituted with a lower acyloxy group, or a benzyl group)
<2> The arylene group is a 1,4-phenylene group, [1,1'-biphenyl] -4,4'-diyl group, 2,6-, 2,3-, and a _{2 in the} formula (12). 6,1-naphthalenediyl group bonded to the 6-position)
(Iii) -Lower alkylene group-COOR ₁₇ (17)
(Where R ₁₇ is hydrogen, a lower alkyl group which may be substituted with a lower acyloxy group, or a benzyl group)
(3) B ₁ and B ₂ are
(I) when Z is oxygen,
1. B ₁ is
(1) 2-naphthyl group
(2) Phenyl group B ₂ is,
(1) Hydrogen
(2) Phenyl group
(ii) together with carbons adjacent to each other to form a benzene ring, as a whole, the above formula (1) is represented by the following general formula (18)

(here
(1) A and Z are as described above.
(2) b ₁ is
1. Hydrogen
2.Lower alkyl group
(3) b ₂ is
1. Hydrogen
2.Lower alkyl group
3.Phenyl group
4.Halogen
(4) _{b 3} is,
1. Hydrogen
2.Nitro group
3. Amino group (Here, the amino group may be substituted with a lower alkyl group or a benzyl group)
4.Lower alkyl group
5. -Ob ₃₁ (19)
(Where b ₃₁ is
1. Hydrogen
2.Lower alkyl group
3. Lower acyl group
4.Cyclohexyl group
5.-Lower alkylene group-b ₃₂ (20)
(Where b ₃₂ is
-1.Phenyl group
-2.Cyclohexyl group
-3.-COOR ₁₈ (21)
(Where R ₁₈ is hydrogen, a lower alkyl group which may be substituted with a lower acyloxy group, or a benzyl group)
-Four.

(Where R ₁₉ and R ₂₀ are independently of each other hydrogen, a lower alkyl group or a benzyl group which may be substituted with a lower acyloxy group)))))
Is]
Or a pharmaceutically acceptable salt compound or a solvate thereof for treating thrombosis.

[2] The pharmaceutical composition according to the above [1], which is a thrombolytic agent.
[3] The pharmaceutical composition of the above [1], which is an antithrombotic agent.
[4] A compound represented by the formula (1) of the above [1] for use as a pharmaceutical composition, or a pharmaceutically acceptable salt compound thereof or a solvate thereof.
[5] A compound represented by the formula (1) of the above [1] or a pharmaceutically acceptable salt compound or a solvate thereof for producing a pharmaceutical composition for treating thrombosis use.
[6] Treating thrombosis comprising administering to a subject an effective amount of the compound represented by formula (1) of [1] above, or a pharmaceutically acceptable salt compound thereof, or a solvate thereof. Method.

［式中、
(１)Ａは、
(ｉ) −アリーレン基−Ｏ−低級アルキレン基−ａ_１ …（6）
（ここで
<1>ａ_１は、
１．−ＣＯＯＲ_４ …（7）
（ここでＲ_４は水素、低級アシルオキシ基で置換されて良い低級アルキル基、ベンジル基）
２．

（ここでＲ_５，Ｒ_６は互いに独立して水素、低級アシルオキシ基で置換されて良い低級アルキル基、ベンジル基）
３．

（ここでＲ_７は水素、低級アシルオキシ基で置換されて良い低級アルキル基、ベンジル基）
４．

（ここでＲ_８，Ｒ_９は互いに独立して水素、低級アシルオキシ基で置換されて良い低級アルキル基、ベンジル基）
５．ハロゲン
６．フェニル基
７．4-モルホリニル基
８．1-ピロリジニル基
９．1-ピペリジニル基
10．4-ピリジニル基
11．4-メチル-1-ピペラジニル基
12．

（ここでｙ_１，ｙ_２は互いに独立して
(1)水素
(2)低級アルキル基
(3)低級アルコキシカルボニル基）
<2>アリーレン基は、1,4-及び1,2-フェニレン基、[1,1’-ビフェニル]-4,4’-ジイル基、2,6 -、2,3 -及び式（6）の酸素が６位に結合した6,1-ナフタレンジイル基を意味する。
但し、
(1)同時にａ_１がカルボキシル基、低級アルコキシカルボニル基、アリーレン基が1,4-フェニレン基、下記するｂ_１，ｂ_２，ｂ_３が共に水素である場合は、低級アルキレン基としてメチレン基を除く。
(2)ａ_１が式（11）の場合は、1,4-フェニレン基を除く。）
(ii) −アリーレン基−ａ_２ …（12）
（ここで
<1>ａ_２は、
１．水酸基
２．低級アルコキシ基
３．

（ここでＲ_１１，Ｒ_１２は互いに独立して水素、低級アシルオキシ基で置換されて良い低級アルキル基、ベンジル基、Ｒ_１３は水素、低級アルキル基）
４．

（ここでＲ_１４，Ｒ_１５は互いに独立して水素、低級アシルオキシ基で置換されて良い低級アルキル基、ベンジル基）
５．

（ここでＲ_１６は水素、低級アシルオキシ基で置換されて良い低級アルキル基、ベンジル基）
<2>アリーレン基は[1,1’-ビフェニル]-4,4’-ジイル基、2,6 -、2,3-及び式（12）に於いてａ_２が６位に結合した6,1-ナフタレンジイル基）
（２）ｂ_１は、
1.水素
2.低級アルキル基
（３）ｂ_２は、
1.水素
2.低級アルキル基
3.フェニル基
4.ハロゲン
（４）ｂ_３は、
1.水素
2.ニトロ基
3.アミノ基
（ここでアミノ基は低級アルキル基、ベンジル基で置換されて良い）
4.低級アルキル基
5.−Ｏ−ｂ_３１ …（19）
（ここでｂ_３１は、
1.水素
2.低級アルキル基
3.低級アシル基
4.シクロヘキシル基
5.−低級アルキレン基−ｂ_３２ …（20）
（ここでｂ_３２は、
-1.フェニル基
-2.シクロヘキシル基
-3.−ＣＯＯＲ_１８ …（21）
（ここでＲ_１８は水素、低級アシルオキシ基で置換されて良い低級アルキル基、ベンジル基）
-4.

（ここでＲ_１９，Ｒ_２０は互いに独立して水素、低級アシルオキシ基で置換されて良い低級アルキル基、ベンジル基）））
である］ [7] A compound represented by the following formula (23), or a pharmaceutically acceptable salt compound thereof or a solvate thereof.

[Where:
(1) A is
(i) -arylene group-O-lower alkylene group-a ₁ (6)
(here
<1> a ₁ is
1. -COOR ₄ (7)
(Wherein R ₄ is hydrogen, a lower alkyl group which may be substituted with a lower acyloxy group, or a benzyl group)
2.

(Wherein R ₅ and R ₆ are each independently hydrogen, a lower alkyl group which may be substituted with a lower acyloxy group, or a benzyl group)
3.

(Wherein R ₇ is hydrogen, a lower alkyl group which may be substituted with a lower acyloxy group, or a benzyl group)
4).

(Where R ₈ and R ₉ are each independently hydrogen, a lower alkyl group which may be substituted with a lower acyloxy group, or a benzyl group)
5). halogen
6). Phenyl group
7. 4-morpholinyl group
8. 1-Pyrrolidinyl group
9. 1-Piperidinyl group
10. 4-pyridinyl group
11. 4-Methyl-1-piperazinyl group
12．

(Where y ₁ and y ₂ are independent of each other
(1) Hydrogen
(2) Lower alkyl group
(3) Lower alkoxycarbonyl group)
<2> Arylene groups include 1,4- and 1,2-phenylene groups, [1,1'-biphenyl] -4,4'-diyl groups, 2,6-, 2,3- and formula (6) This means a 6,1-naphthalenediyl group in which oxygen is bonded to the 6-position.
However,
(1) At the same time, when a ₁ is a carboxyl group, a lower alkoxycarbonyl group, an arylene group is a 1,4-phenylene group, and b ₁ , b ₂ , and b ₃ below are both hydrogen, a methylene group is selected as the lower alkylene group. except.
(2) If a ₁ is of formula (11), except 1,4-phenylene group. )
(ii) -arylene group-a ₂ (12)
(here
<1> a ₂ is
1. Hydroxyl group
2. Lower alkoxy group
3.

(Wherein R ₁₁ and R ₁₂ are each independently hydrogen, a lower alkyl group which may be substituted with a lower acyloxy group, a benzyl group, R ₁₃ is hydrogen or a lower alkyl group)
4).

(Wherein R ₁₄ and R ₁₅ are each independently hydrogen, a lower alkyl group which may be substituted with a lower acyloxy group, or a benzyl group)
5).

(Where R ₁₆ is hydrogen, a lower alkyl group which may be substituted with a lower acyloxy group, or a benzyl group)
<2> The arylene group is a [1,1′-biphenyl] -4,4′-diyl group, 2,6-, 2,3- and a _{2 in the} formula (12), 1-Naphthalenediyl group)
(2) b ₁ is
1. Hydrogen
2. Lower alkyl group (3) b ₂ is
1. Hydrogen
2.Lower alkyl group
3.Phenyl group
4. Halogen (4) _{b 3} is
1. Hydrogen
2.Nitro group
3.Amino group
(Here, the amino group may be substituted with a lower alkyl group or a benzyl group)
4.Lower alkyl group
5.-Ob ₃₁ (19)
(Where b ₃₁ is
1. Hydrogen
2.Lower alkyl group
3. Lower acyl group
4.Cyclohexyl group
5.-Lower alkylene group-b ₃₂ (20)
(Where b ₃₂ is
-1.Phenyl group
-2.Cyclohexyl group
-3.-COOR ₁₈ (21)
(Where R ₁₈ is hydrogen, a lower alkyl group which may be substituted with a lower acyloxy group, or a benzyl group)
-Four.

(Wherein R ₁₉ and R ₂₀ are independently of each other hydrogen, a lower alkyl group which may be substituted with a lower acyloxy group, or a benzyl group)))
Is]

[式中、
(１)Ａは、
(ｉ)−アリーレン基−Ｏ−低級アルキレン基−ａ_１ …（6）
（ここで
<1>ａ_１は、
１．−ＣＯＯＲ_４ …（7）
（ここでＲ_４は水素、低級アシルオキシ基で置換されて良い低級アルキル基、ベンジル基）
２．

（ここでＲ_５，Ｒ_６は互いに独立して水素、低級アシルオキシ基で置換されて良い低級アルキル基、ベンジル基）
３．フェニル基
<2>アリーレン基は、1,4-フェニレン基、2,6-ナフタレンジイル基である。（但し、同時にａ_１がカルボキシル基、低級アルコキシカルボニル基、低級アルキレン基がメチレン基、下記するＺ_１が水素である場合は1,4-フェニレン基を除く））
（ii）−アリーレン基−ａ_２ …（12）
（ここで
<1>ａ_２は水酸基
<2>アリーレン基は1,4-フェニレン基、2,6-ナフタレンジイル基（但し、同時にａ_２が水酸基、下記するＺ_１が水素の時、1,4-フェニレン基を除く））
（２）Ｚ_１は、
<1>水素
<2>−低級アルキレン基−Ｚ_２ …（3）
（ここでＺ_２は、
１．−ＣＯＯＲ１ …（4）
（ここでＲ_１は水素、低級アシルオキシ基で置換されて良い低級アルキル基）
２．

（ここでＲ_２，Ｒ_３は互いに独立して水素、低級アシルオキシ基で置換されて良い低級アルキル基）
３．ハロゲンで置換されて良いフェニル基
４．シクロヘキシル基）
（３）ｂ_２は、
１．水素
２．塩素
（４）ｂ_１，ｂ_３は水素
である］ [8] A compound represented by the following formula (24), or a pharmaceutically acceptable salt compound or a solvate thereof.

[Where
(1) A is
(i) -arylene group-O-lower alkylene group-a ₁ (6)
(here
<1> a ₁ is
1. -COOR ₄ (7)
(Wherein R ₄ is hydrogen, a lower alkyl group which may be substituted with a lower acyloxy group, or a benzyl group)
2.

(Wherein R ₅ and R ₆ are each independently hydrogen, a lower alkyl group which may be substituted with a lower acyloxy group, or a benzyl group)
3. Phenyl group
<2> The arylene group is a 1,4-phenylene group or a 2,6-naphthalenediyl group. (However, when a ₁ is a carboxyl group, a lower alkoxycarbonyl group, a lower alkylene group is a methylene group, and Z _{1 described} below is hydrogen, a 1,4-phenylene group is excluded.)
(Ii) -arylene group-a ₂ (12)
(here
<1> a ₂ is a hydroxyl group
<2> The arylene group is a 1,4-phenylene group or a 2,6-naphthalenediyl group (except for a 1,4-phenylene group when a ₂ is a hydroxyl group and Z _{1 described} below is hydrogen)
(2) Z ₁ is
<1> Hydrogen
<2> -Lower alkylene group-Z ₂ (3)
(Where Z ₂ is
1. -COOR1 (4)
(Wherein R ₁ is hydrogen, a lower alkyl group which may be substituted with a lower acyloxy group)
2.

(Wherein R ₂ and R ₃ are each independently hydrogen, a lower alkyl group which may be substituted with a lower acyloxy group)
3. Phenyl group which may be substituted with halogen
4). (Cyclohexyl group)
(3) b ₂ is
1. Hydrogen 2. Chlorine (4) b ₁ and b ₃ are hydrogen]

［ここで
（１）Ａは、
(ｉ)−アリーレン基−Ｏ−低級アルキレン基−ａ_１ …（6）
（ここで
<1>ａ_１は、
１．−ＣＯＯＲ_４ …（7）
（ここでＲ_４は水素、低級アシルオキシ基で置換されて良い低級アルキル基、ベンジル基）
２．

（ここでＲ_５，Ｒ_６は互いに独立して水素、低級アシルオキシ基で置換されて良い低級アルキル基、ベンジル基）
３．フェニル基
<2>アリーレン基は2,6-ナフタレンジイル基）
（ii）−アリーレン基−ａ_２ …（12）
（ここで
<1>ａ_２は水酸基
<2>アリーレン基は、2,6-ナフタレンジイル基）
（２）ｂ_１，ｂ_２，ｂ_３は水素
である］ [9] A compound represented by the following formula (25), or a pharmaceutically acceptable salt compound or a solvate thereof.

[Where (1) A is
(i) -arylene group-O-lower alkylene group-a ₁ (6)
(here
<1> a ₁ is
1. -COOR ₄ (7)
(Wherein R ₄ is hydrogen, a lower alkyl group which may be substituted with a lower acyloxy group, or a benzyl group)
2.

(Wherein R ₅ and R ₆ are each independently hydrogen, a lower alkyl group which may be substituted with a lower acyloxy group, or a benzyl group)
3. Phenyl group
<2> The arylene group is 2,6-naphthalenediyl group)
(Ii) -arylene group-a ₂ (12)
(here
<1> a ₂ is a hydroxyl group
<2> The arylene group is 2,6-naphthalenediyl group)
(2) b ₁ , b ₂ and b ₃ are hydrogen]

［ここで
（１）Ａは、
(ｉ)−アリーレン基−Ｏ−低級アルキレン基−ａ_１ …（6）
（ここで
<1>ａ_１は、
１．−ＣＯＯＲ_４ …（7）
（ここでＲ_４は水素、低級アシルオキシ基で置換されて良い低級アルキル基、ベンジル基）
２．フェニル基
<2>アリーレン基は2,6-ナフタレンジイル基）
（ii）−アリーレン基−ａ_２ …（12）
（ここで
<1>ａ_２は、
１．水酸基
２．−ＣＯＯＲ_１０ …（13）
（ここでＲ_１０は水素、低級アシルオキシ基で置換されて良い低級アルキル基、ベンジル基）
<2>アリーレン基は、2,6-ナフタレンジイル基）
（iii）−低級アルキレン基−ＣＯＯＲ_１７ …（17）
（ここでＲ_１７は水素、低級アシルオキシ基で置換されて良い低級アルキル基、ベンジル基）
（２）Ｂ_１は、
１．2-ナフチル基
２．フェニル基
（３）Ｂ_２は、
１．水素
２．フェニル基
である］ [10] A compound represented by the following formula (26), or a pharmaceutically acceptable salt compound thereof or a solvate thereof.

[Where (1) A is
(i) -arylene group-O-lower alkylene group-a ₁ (6)
(here
<1> a ₁ is
1. -COOR ₄ (7)
(Where R ₄ is hydrogen, a lower alkyl group which may be substituted with a lower acyloxy group, or a benzyl group)
2. Phenyl group
<2> The arylene group is 2,6-naphthalenediyl group)
(Ii) -arylene group-a ₂ (12)
(here
<1> a ₂ is
1. Hydroxyl group
2. -COOR ₁₀ (13)
(Where R ₁₀ is hydrogen, a lower alkyl group which may be substituted with a lower acyloxy group, or a benzyl group)
<2> The arylene group is 2,6-naphthalenediyl group)
(Iii) -Lower alkylene group-COOR ₁₇ (17)
(Where R ₁₇ is hydrogen, a lower alkyl group which may be substituted with a lower acyloxy group, or a benzyl group)
(2) _{B 1} is,
1. 2-naphthyl group Phenyl group (3) B ₂ is
1. Hydrogen 2. A phenyl group]

[11] A compound selected from the following group of compounds, or a pharmaceutically acceptable salt compound thereof or a solvate thereof.
4- (2-Naphthalenyl) -2-oxazolepropanoic acid methyl ester, 4- (2-naphthalenyl) -2-oxazolepropanoic acid, methyl 6- (4,5-diphenyl-2-oxazolyl) -2-naphthalenecarboxylate Ester, 6- (4,5-diphenyl-2-oxazolyl) -2-naphthalenecarboxylic acid, 4,5-diphenyl-2- [6- (phenylmethoxy) -2-naphthalenyl] oxazole, 6- (4,5 -Diphenyl-2-oxazolyl) -2-naphthalenol, [[6- (4,5-diphenyl-2-oxazolyl) -2-naphthalenyl] oxy] acetic acid methyl ester, [[6- (4,5-diphenyl-2 -Oxazolyl) -2-naphthalenyl] oxy] acetic acid, 4- [4- (2-benzoxazolyl) phenoxy] butanoic acid, 4- [4- (2-benzoxazolyl) phenoxy] butanoic acid (2, 2-dimethyl-1-oxopropoxy) methyl ester, 6- [4- (2-benzoxazolyl) phenoxy] hexanoic acid, 6- [4- (2-benzoxazolyl) ) Phenoxy] hexanoic acid (2,2-dimethyl-1-oxopropoxy) methyl ester, [5- [4- (2-benzoxazolyl) phenoxy] pentyl] propanedioic acid, [4- (6-nitro- 2-Benzoxazolyl) phenoxy] acetic acid methyl
Ester, [4- (6-nitro-2-benzoxazolyl) phenoxy] acetic acid, 6- [2- (2-benzoxazolyl) phenoxy] hexanoic acid, [5- [2- (2-benzoxoxa] Zolyl) phenoxy] pentyl] propanedioic acid, 2- [4 ′-(phenylmethoxy) [1,1′-biphenyl] -4-yl] benzoxazole, 4 ′-(2-benzoxazolyl) [1 , 1'-biphenyl] -4-ol, 4-[[4 '-(2-benzoxazolyl) [1,1'-biphenyl] -4-yl] oxy] butanoic acid ethyl ester, 4-[[ 4 '-(2-Benzoxazolyl) [1,1'-biphenyl] -4-yl] oxy] butanoic acid, 6-[[4'-(2-benzoxazolyl) [1,1'- Biphenyl] -4-yl] oxy] hexanoic acid ethyl ester, 6-[[4 '-(2-benzoxazolyl) [1,1'-biphenyl] -4-yl] oxy] hexanoic acid, [[4 '-(2-Benzoxazolyl) [1,1'-biphenyl] -4-yl] oxy] methylpropanedioic acid diethyl ester, [[4'-(2-benzoxazol Zolyl) [1,1'-biphenyl] -4-yl] oxy] methylpropanedioic acid, [3-[[4 '-(2-benzoxazolyl) [1,1'-biphenyl] -4-yl ] Oxy] propyl] propanedioic acid, [5-[[4 '-(2-benzoxazolyl) [1,1'-biphenyl] -4-yl] oxy] pentyl] propanedioic acid diethyl ester, 2- [6- (Phenylmethoxy) -2-naphthalenyl] benzoxazole, 6- (2-benzoxazolyl) -2-naphthalenol, [[6- (2-Benzoxazolyl) -2-naphthalenyl] oxy] acetic acid Methyl ester, [[6- (2-benzoxazolyl) -2-naphthalenyl] oxy] acetic acid, 4-[[6- (2-benzoxazolyl) -2-naphthalenyl] oxy] butanoic acid ethyl ester, 4-[[6- (2-Benzoxazolyl) -2-naphthalenyl] oxy] butanoic acid, N- [4-[[6- (2-benzoxazolyl) -2-naphthalenyl] oxy] -1 -Oxobutyl] glycine ethyl ester, 2-[[4-[[6- (2-ben Oxazolyl) -2-naphthalenyl] oxy] -1-oxobutyl] amino] pentanedioic acid diethyl ester, 2-[[4-[[6- (2-benzoxazolyl) -2-naphthalenyl] oxy] -1- Oxobutyl] amino] pentanedioic acid, 6-[[6- (2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid, 6-[[6- (2-benzoxazolyl) -2-naphthalenyl ] Oxy] hexanoic acid (2,2-dimethyl-1-oxopropoxy) methyl ester, 2-[[6-[[6- (2-benzoxazolyl) -2-naphthalenyl] oxy] -1-oxohexyl ] Amino] pentanedioic acid diethyl ester, 2-[[6-[[6- (2-benzoxazolyl) -2-naphthalenyl] oxy] -1-oxohexyl] amino] pentanedioic acid, [[6- (2-Benzoxazolyl) -2-naphthalenyl] oxy] propanedioic acid diethyl ester, [[6- (2-benzoxazolyl) -2-naphthalenyl] oxy] propanedioic acid, [3-[[6 -(2- Zooxazolyl) -2-naphthalenyl] oxy] propyl] propanedioic acid, 2- [6- [2- (1-pyrrolidinyl) ethoxy] -2-naphthalenyl] benzoxazole hydrochloride, 2- [6- [2- (1 -Piperidinyl) ethoxy] -2-naphthalenyl] benzoxazole hydrochloride, 2- [6-[(4-pyridinyl) methoxy] -2-naphthalenyl] benzoxazole, 2- [6-[(5-chloropentyl) oxy] 2-naphthalenyl] benzoxazole, 2- [6-[[5- (1-pyrrolidinyl) pentyl] oxy] -2-naphthalenyl] benzoxazole hydrochloride, 2- [6-[[5- (4-methyl- 1-piperazinyl) pentyl] oxy] -2-naphthalenyl] benzoxazole dihydrochloride, 6-methyl-2- [6- (phenylmethoxy) -2-naphthalenyl] benzoxazole, 6- (6-methyl-2-benzo Oxazolyl) -2-naphthalenol, [[6- (6-methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] acetic acid, 4-[[6- (6-methyl-2 -Benzoxazolyl) -2-naphthalenyl] oxy] butanoic acid, 5-[[6- (6-methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] pentanoic acid, 5-[[6- (6-Methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] pentanoic acid (2,2-dimethyl-1-oxopropoxy) methyl ester, 6-[[6- (6-methyl-2-benzo Oxazolyl) -2-naphthalenyl] oxy] hexanoic acid, 7-[[6- (6-methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] heptanoic acid, [5-[[6- ( 6-methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] pentyl] propanedioic acid, 6-methyl-2- [6- [2- (4-morpholinyl) ethoxy] -2-naphthalenyl] benzoxazole , [3-[[6- (6-Methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] propyl] carbamic acid 1,1-dimethylethyl ester, 3-[[6- (6-methyl- 2-Benzoxazolyl) -2-naphthalenyl] oxy]- 1-propanamine methanesulfonate, N, N-dimethyl-3-[[6- (6-methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] -1-propanamine hydrochloride, 6- [6- (1-methylethyl) -2-benzoxazolyl] -2-naphthalenol, 6-[[6- [6- (1-methylethyl) -2-benzoxazolyl] -2-naphthalenyl] Oxy] hexanoic acid, 2- [6- (phenylmethoxy) -2-naphthalenyl] -6-benzoxazolol, 2- [6- (phenylmethoxy) -2-naphthalenyl] -6-benzoxazolol acetate 2- (6-hydroxy-2-naphthalenyl) -6-benzoxazolol acetate, 6-[[6- (6-hydroxy-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid, 6-[[6- [6- (Phenylmethoxy) -2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid, 6-methoxy-2- [6- (phenylmethoxy) -2-naphthalenyl] benzo Oxazole, 6- ( 6-methoxy-2-benzoxazolyl) -2-naphthalenol, [[6- (6-methoxy-2-benzoxazolyl) -2-naphthalenyl] oxy] acetic acid, 4-[[6- (6- Methoxy-2-benzoxazolyl) -2-naphthalenyl] oxy] butanoic acid ethyl ester, 4-[[6- (6-methoxy-2-benzoxazolyl) -2-naphthalenyl] oxy] butanoic acid, 6 -[[6- (6-Methoxy-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid ethyl ester, 6-[[6- (6-methoxy-2-benzoxazolyl) -2- Naphthalenyl] oxy] hexanoic acid, [[6- (6-methoxy-2-benzoxazolyl) -2-naphthalenyl] oxy] methylpropanedioic acid, [5-[[6- (6-methoxy-2-benzo Oxazolyl) -2-naphthalenyl] oxy] pentyl] propanedioic acid diethyl
Ester, [5-[[6- (6-methoxy-2-benzoxazolyl) -2-naphthalenyl] oxy] pentyl] propanedioic acid, 6-ethoxy-2- [6- (phenylmethoxy) -2- Naphthalenyl] benzoxazole, 6- (6-ethoxy-2-benzoxazolyl) -2-naphthalenol, 6-[[6- (6-ethoxy-2-benzoxazolyl) -2-naphthalenyl] oxy] hexane Acid ethyl ester, 6-[[6- (6-ethoxy-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid, 6-[[2- [6- (phenylmethoxy) -2-naphthalenyl] -6-Benzoxazolyl] oxy] hexanoic acid ethyl ester, 6-[[2- (6-hydroxy-2-naphthalenyl) -6-benzoxazolyl] oxy] hexanoic acid, 6-[[2- ( 6-hydroxy-2-naphthalenyl) -6-benzoxazolyl] oxy] hexanoic acid ethyl ester, 6-[[6- [6-[(6-ethoxy-6-oxohexyl) oxy] -2-benzoxa Zolyl] -2- Naphthalenyl] oxy] hexanoic acid ethyl ester, 6-[[6- [6-[(5-carboxypentyl) oxy] -2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid, 6-[[2 -(6-Ethoxy-2-naphthalenyl) -6-benzoxazolyl] oxy] hexanoic acid ethyl ester, 6-[[2- (6-ethoxy-2-naphthalenyl) -6-benzoxazolyl] oxy] Hexanoic acid, [5-[[6- [6-[[7-ethoxy-6- (ethoxycarbonyl) -7-oxoheptyl] oxy] -2-benzoxazolyl] -2-naphthalenyl] oxy] pentyl] Propanedioic acid diethyl ester, [5-[[6- [6-[(6,6-dicarboxyhexyl) oxy] -2-benzoxazolyl] -2-naphthalenyl] oxy] pentyl] propanedioic acid, [ 5-[[6- [6- (cyclohexylmethoxy) -2-benzoxazolyl] -2-naphthalenyl] oxy] pentyl] propanedioic acid, [5-[[6- [6- (phenylmethoxy) -2 -Benzoxa Ryl] -2-naphthalenyl] oxy] pentyl] propanedioic acid, 6- (6-nitro-2-benzoxazolyl) -2-naphthalenol, 4-[[6- (6-nitro-2-benzoxazolyl) L) -2-Naphthalenyl] oxy] butanoic acid ethyl
Ester, 4-[[6- (6-amino-2-benzoxazolyl) -2-naphthalenyl] oxy] butanoic acid hydrochloride, 4-[[6- [6- (diethylamino) -2-benzoxazoli [Lu] -2-naphthalenyl] oxy] butanoic acid, 4-[[6- [6- [bis (phenylmethyl) amino] -2-benzoxazolyl] -2-naphthalenyl] oxy] butanoic acid ethyl ester, 4 -[[6- [6- [Bis (phenylmethyl) amino] -2-benzoxazolyl] -2-naphthalenyl] oxy] butanoic acid, 6-[[6- (6-nitro-2-benzoxazolyl L) -2-Naphthalenyl] oxy] hexanoic acid ethyl ester, 6-[[6- [6- (diethylamino) -2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid, 6-[[6- [6- [Bis (phenylmethyl) amino] -2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid ethyl ester, 6-[[6- [6- [bis (phenylmethyl) amino] -2 -Benzoxazolyl] -2-naphthalenyl] Xyl] hexanoic acid, [[6- (6-nitro-2-benzoxazolyl) -2-naphthalenyl] oxy] propanedioic acid diethyl ester, [[6- (6-nitro-2-benzoxazolyl) -2-Naphthalenyl] oxy] propanedioic acid, [5-[[6- (6-nitro-2-benzoxazolyl) -2-naphthalenyl] oxy] pentyl] propanedioic acid diethyl
Ester, [5-[[6- [6- (diethylamino) -2-benzoxazolyl] -2-naphthalenyl] oxy] pentyl] propanedioic acid disodium salt, 6-nitro-2- [6- [2 -(4-morpholinyl) ethoxy] -2-naphthalenyl] benzoxazole, 2- [6- [2- (4-morpholinyl) ethoxy] -2-naphthalenyl] -6-benzoxazolamine dihydrochloride, N, N- Diethyl-2- [6- [2- (4-morpholinyl) ethoxy] -2-naphthalenyl] -6-benzoxazolamine dihydrochloride, 6- [6- (cyclohexyloxy) -2-benzoxazolyl]- 2-naphthalenol, 6-[[6- [6- (cyclohexyloxy) -2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid, 6- (5-methyl-2-benzoxazolyl)- 2-Naphthalenol, 6-[[6- (5-methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid, 6- [5- (1,1-dimethylethyl) -2-benzoxa Zolyl] -2-naphthaleno 6-[[6- [5- (1,1-dimethylethyl) -2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid, [5-[[6- [5- (1, 1-dimethylethyl) -2-benzoxazolyl] -2-naphthalenyl] oxy] pentyl] propanedioic acid, 6- (5-phenyl-2-benzoxazolyl) -2-naphthalenol, 6-[[6 -(5-Phenyl-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid, [3-[[6- (5-phenyl-2-benzoxazolyl) -2-naphthalenyl] oxy] propyl ] Propanedioic acid diethyl ester, [3-[[6- (5-phenyl-2-benzoxazolyl) -2-naphthalenyl] oxy] propyl] propanedioic acid, 5-chloro-2- [6- (phenyl Methoxy) -2-naphthalenyl] benzoxazole, 6- (5-chloro-2-benzoxazolyl) -2-naphthalenol, 4-[[6- (5-chloro-2-benzoxazolyl) -2- Naphthalenyl] oxy] butanoic acid, 6-[[6- (5-chloro-2-benzoxa Zolyl) -2-naphthalenyl] oxy] hexanoic acid, [3-[[6- (5-chloro-2-benzoxazolyl) -2-naphthalenyl] oxy] propyl] propanedioic acid, [5-[[6 -(5-Chloro-2-benzoxazolyl) -2-naphthalenyl] oxy] pentyl] propanedioic acid, 5-chloro-2- [6- [2- (4-morpholinyl) ethoxy] -2-naphthalenyl] Benzoxazole hydrochloride, 6- (4-methyl-2-benzoxazolyl) -2-naphthalenol, 6-[[6- (4-methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] hexane Acid, [3-[[6- (4-methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] propyl] propanedioic acid, [5-[[6- (4-methyl-2-benzoxa Zolyl) -2-naphthalenyl] oxy] pentyl] propanedioic acid, 3- (6-methyl-2-benzoxazolyl) -2-naphthalenol, 4-[[3- (6-methyl-2-benzoxa) Zolyl) -2-naphthalenyl] oxy] butanoic acid, 6-[[3- (6-methyl-2 -Benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid, [5-[[3- (6-methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] pentyl] propanedioic acid, 6- Methyl-2- [3- [2- (4-morpholinyl) ethoxy] -2-naphthalenyl] benzoxazole hydrochloride, N, N-dimethyl-3-[[3- (6-methyl-2-benzoxazolyl ) -2-Naphthalenyl] oxy] -1-propanamine hydrochloride, 6-nitro-2- [3- (phenylmethoxy) -2-naphthalenyl] benzoxazole, 3- (6-nitro-2-benzoxazolyl) ) -2-Naphthalenol, 4-[[3- (6-Nitro-2-benzoxazolyl) -2-naphthalenyl] oxy] butanoic acid ethyl ester, 4-[[3- [6- (diethylamino) -2 -Benzoxazolyl] -2-naphthalenyl] oxy] butanoic acid, 4-[[3- [6- [bis (phenylmethyl) amino] -2-benzoxazolyl] -2-naphthalenyl] oxy] butanoic acid , 6-[[3- (6-Nitro-2-benzo Xazolyl) -2-naphthalenyl] oxy] hexanoic acid ethyl ester, 6-[[3- [6- (diethylamino) -2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid, 6-[[3- [6- [Bis (phenylmethyl) amino] -2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid, [5-[[3- (6-nitro-2-benzoxazolyl) -2 -Naphthalenyl] oxy] pentyl] propanedioic acid diethyl ester, 2- [3- [2- (4-morpholinyl) ethoxy] -2-naphthalenyl] -6-nitrobenzoxazole, 2- [3- [2- (4 -Morpholinyl) ethoxy] -2-naphthalenyl] -6-benzoxazolamine dihydrochloride, 3- [5- (1,1-dimethylethyl) -2-benzoxazolyl] -2-naphthalenol, 4- [[3- [5- (1,1-dimethylethyl) -2-benzoxazolyl] -2-naphthalenyl] oxy] butanoic acid, 6-[[3- [5- (1,1-dimethylethyl) -2-Benzoxazolyl] -2-naphthalenyl] oxy Ci] hexanoic acid, [5-[[3- [5- (1,1-dimethylethyl) -2-benzoxazolyl] -2-naphthalenyl] oxy] pentyl] propanedioic acid, 5- (1,1 -Dimethylethyl) -2- [3- [2- (4-morpholinyl) ethoxy] -2-naphthalenyl] benzoxazole hydrochloride, 3-[[3- [5- (1,1-dimethylethyl) -2- Benzoxazolyl] -2-naphthalenyl] oxy] -N, N-dimethyl-1-propanamine hydrochloride, 3- (5-phenyl-2-benzoxazolyl) -2-naphthalenol, 4-[[3 -(5-Phenyl-2-benzoxazolyl) -2-naphthalenyl] oxy] butanoic acid, 6-[[3- (5-phenyl-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid , [5-[[3- (5-Phenyl-2-benzoxazolyl) -2-naphthalenyl] oxy] pentyl] propanedioic acid, 2- [3- [2- (4-morpholinyl) ethoxy] -2 -Naphthalenyl] -5-phenylbenzoxazole hydrochloride, N, N-dimethyl-3-[[3- (5-phenyl-2-benzene Nzooxazolyl) -2-naphthalenyl] oxy] -1-propanamine hydrochloride, 5-chloro-2- [3- (phenylmethoxy) -2-naphthalenyl] benzoxazole, 3- (5-chloro-2-benzoxazolyl) L) -2-Naphthalenol, ethyl 4-[[3- (5-chloro-2-benzoxazolyl) -2-naphthalenyl] oxy] butanoate
Ester, 4-[[3- (5-chloro-2-benzoxazolyl) -2-naphthalenyl] oxy] butanoic acid, 6-[[3- (5-chloro-2-benzoxazolyl) -2 -Naphthalenyl] oxy] hexanoic acid, [3-[[3- (5-chloro-2-benzoxazolyl) -2-naphthalenyl] oxy] propyl] propanedioic acid, [5-[[3- (5- Chloro-2-benzoxazolyl) -2-naphthalenyl] oxy] pentyl] propanedioic acid, 5-chloro-2- [3- [2- (4-morpholinyl) ethoxy] -2-naphthalenyl] benzoxazole hydrochloride , 3-[[3- (5-Chloro-2-benzoxazolyl) -2-naphthalenyl] oxy] -N, N-dimethyl-1-propanamine hydrochloride, 5- (6-methyl-2-benzo Oxazolyl) -2-naphthalenol, 6-[[5- (6-methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid, [5-[[5- (6-methyl-2 -Benzoxazolyl) -2-naphthalenyl] oxy] pentyl] propanedioic acid, 6-nitro-2- [6- (phenyl) Phenylmethoxy) -1-naphthalenyl] benzoxazole, 5- (6-nitro-2-benzoxazolyl) -2-naphthalenol, 4-[[5- (6-nitro-2-benzoxazolyl) -2- Naphthalenyl] oxy] butanoic acid ethyl ester, 4-[[5- [6- (diethylamino) -2-benzoxazolyl] -2-naphthalenyl] oxy] butanoic acid ethyl ester, 4-[[5- [6- (Diethylamino) -2-benzoxazolyl] -2-naphthalenyl] oxy] butanoic acid, 4-[[5- [6- [bis (phenylmethyl) amino] -2-benzoxazolyl] -2-naphthalenyl ] Oxy] butanoic acid ethyl ester, 4-[[5- [6- [bis (phenylmethyl) amino] -2-benzoxazolyl] -2-naphthalenyl] oxy] butanoic acid, 6-[[5- ( 6-nitro-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid ethyl ester, 6-[[5- (6-amino-2-benzoxazolyl) -2-naphthalenyl] oxy] hexane Hydrochloride, 6-[[5- [6- (diethylamino) -2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid ethyl ester, 6-[[5- [6- (diethylamino) -2 -Benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid, 6-[[5- [6- [bis (phenylmethyl) amino] -2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid , [5-[[5- (6-Nitro-2-benzoxazolyl) -2-naphthalenyl] oxy] pentyl] propanedioic acid diethyl ester, [5-[[5- [6- (diethylamino) -2 -Benzoxazolyl] -2-naphthalenyl] oxy] pentyl] propanedioic acid, 2- [6- [2- (4-morpholinyl) ethoxy] -1-naphthalenyl] -6-nitrobenzoxazole, 2- [6 -[2- (4-morpholinyl) ethoxy] -1-naphthalenyl] -6-benzoxazolamine dihydrochloride, N, N-diethyl-2- [6- [2- (4-morpholinyl) ethoxy] -1- Naphthalenyl] -6-benzoxazo Ruamine dihydrochloride, 2- [6- (phenylmethoxy) -1-naphthalenyl] -6-benzoxazolol, 6- (cyclohexylmethoxy) -2- [6- (phenylmethoxy) -1-naphthalenyl] benzoxazole , 5- [6- (cyclohexylmethoxy) -2-benzoxazolyl] -2-naphthalenol, 4-[[5- [6- (cyclohexylmethoxy) -2-benzoxazolyl] -2-naphthalenyl] oxy ] Butanoic acid ethyl ester, 4-[[5- [6- (cyclohexylmethoxy) -2-benzoxazolyl] -2-naphthalenyl] oxy] butanoic acid, 6-[[5- [6- (cyclohexylmethoxy) -2-Benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid ethyl ester, 6-[[5- [6- (cyclohexylmethoxy) -2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid , [5-[[5- [6- (cyclohexylmethoxy) -2-benzoxazolyl] -2-naphthalenyl] oxy] pentyl] Lopandioic acid diethyl ester, 6- (cyclohexylmethoxy) -2- [6- [2- (4-morpholinyl) ethoxy] -1-naphthalenyl] benzoxazole hydrochloride, 3-[[5- [6- (cyclohexylmethoxy ) -2-Benzoxazolyl] -2-naphthalenyl] oxy] -N, N-dimethyl-1-propanamine hydrochloride, 5- [5- (1,1-dimethylethyl) -2-benzoxazolyl ] -2-Naphthalenol, 4-[[5- [5- (1,1-dimethylethyl) -2-benzoxazolyl] -2-naphthalenyl] oxy] butanoic acid ethyl ester, 4-[[5- [ 5- (1,1-dimethylethyl) -2-benzoxazolyl] -2-naphthalenyl] oxy] butanoic acid, 6-[[5- [5- (1,1-dimethylethyl) -2-benzoxa Zolyl] -2-naphthalenyl] oxy] hexanoic acid, [3-[[5- [5- (1,1-dimethylethyl) -2-benzoxazolyl] -2-naphthalenyl] oxy] propyl] propane Acid, [5-[[5- [5- (1,1-dimethylethyl) -2-benzoxazo [Lu] -2-Naphthalenyl] oxy] pentyl] propanedioic acid, 5- (1,1-dimethylethyl) -2- [6- [2- (4-morpholinyl) ethoxy] -1-naphthalenyl] benzoxazole hydrochloride , 3-[[5- [5- (1,1-dimethylethyl) -2-benzoxazolyl] -2-naphthalenyl] oxy] -N, N-dimethyl-1-propanamine hydrochloride, 5- ( 5-phenyl-2-benzoxazolyl) -2-naphthalenol, 4-[[5- (5-phenyl-2-benzoxazolyl) -2-naphthalenyl] oxy] butanoic acid ethyl ester, 4-[[ 5- (5-phenyl-2-benzoxazolyl) -2-naphthalenyl] oxy] butanoic acid, 6-[[5- (5-phenyl-2-benzoxazolyl) -2-naphthalenyl] oxy] hexane Acid ethyl ester, 6-[[5- (5-phenyl-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid, [5-[[5- (5-phenyl-2-benzoxazolyl) ) -2-Naphthalenyl] oxy] pentyl] propanedioic acid, 2- [6- [2- (4-morpholinyl) ethoxy] -1-naphthalenyl] -5-phenylbenzoxazole hydrochloride, N, N-dimethyl-3-[[5- (5-phenyl-2-benzoxa Zolyl) -2-naphthalenyl] oxy] -1-propanamine hydrochloride, 5-chloro-2- [6- (phenylmethoxy) -1-naphthalenyl] benzoxazole, 5- (5-chloro-2-benzoxa) Zolyl) -2-naphthalenol, 4-[[5- (5-Chloro-2-benzoxazolyl) -2-naphthalenyl] oxy] butanoic acid ethyl ester, 4-[[5- (5-chloro-2 -Benzoxazolyl) -2-naphthalenyl] oxy] butanoic acid, 6-[[5- (5-chloro-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid ethyl ester, 6-[[ 5- (5-Chloro-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid, [3-[[5- (5-Chloro-2-benzoxazolyl) -2-naphthalenyl] oxy] Propyl] propanedioic acid diethyl ester [5-[[5- (5-Chloro-2-benzoxazolyl) -2-naphthalenyl] oxy] pentyl] propanedioic acid diethyl ester, 5-chloro-2- [6- [2- (4-morpholinyl ) Ethoxy] -1-naphthalenyl] benzoxazole hydrochloride, 3-[[5- (5-chloro-2-benzoxazolyl) -2-naphthalenyl] oxy] -N, N-dimethyl-1-propanamine hydrochloride Salt, 2-[[[6- (2-benzoxazolyl) -2-naphthalenyl] carbonyl] amino] pentanedioic acid diethyl ester, 2-[[[6- (2-benzoxazolyl) -2- Naphthalenyl] carbonyl] amino] pentanedioic acid, 2-amino-6-[[[6- (2-benzoxazolyl) -2-naphthalenyl] carbonyl] amino] hexanoic acid hydrochloride, 2- [4- (phenyl) Methoxy) phenyl] -1H-benzimidazole, 2- [4- (phenylmethoxy) phenyl] -1H-benzimidazole-1-acetic acid methyl ester, 2- [4- (phenylmethoxy) phenyl] -1H-ben Zoimidazole-1-acetic acid, 2- (4-hydroxyphenyl) -1H-benzimidazole-1-acetic acid methyl ester, 2- (4-hydroxyphenyl) -1H-benzimidazole-1-acetic acid, 2- [4- (2-Methoxy-2-oxoethoxy) phenyl] -1H-benzimidazole-1-acetic acid methyl ester, 2- [4- (carboxymethoxy) phenyl] -1H-benzimidazole-1-acetic acid, 5-chloro-2 -[4- (phenylmethoxy) phenyl] -1H-benzimidazole, 5-chloro-2- [4- (phenylmethoxy) phenyl] -1H-benzimidazole-1-acetic acid methyl ester, 5-chloro-2- [ 4- (Phenylmethoxy) phenyl] -1H-benzimidazole-1-acetic acid, methyl 5-chloro-2- (4-hydroxyphenyl) -1H-benzimidazole-1-acetate
Ester, 5-chloro-2- (4-hydroxyphenyl) -1H-benzimidazole-1-acetic acid, 2- [4- (carboxymethoxy) phenyl] -5-chloro-1H-benzimidazole-1-acetic acid, 2 -[6- (Phenylmethoxy) -2-naphthalenyl] -1H-benzimidazole, 6- (1H-Benzimidazol-2-yl) -2-naphthalenol, [[6- (1H-Benzimidazol-2-yl) -2-Naphthalenyl] oxy] acetic acid methyl ester, [[6- (1H-benzoimidazol-2-yl) -2-naphthalenyl] oxy] acetic acid, 2- [6- (2-methoxy-2-oxoethoxy)- 2-Naphthalenyl] -1H-benzimidazole-1-acetic acid methyl ester, 2- [6- (carboxymethoxy) -2-naphthalenyl] -1H-benzimidazole-1-acetic acid, 2- [6- (3-carboxypropoxy) ) -2-Naphthalenyl] -1H-benzimidazol-1-butanoic acid, 2- [6-[(5-carboxypentyl) oxy] -2-naphthalenyl] -1H-benzimidazole- 1-hexanoic acid, [5-[[6- (1H-benzimidazol-2-yl) -2-naphthalenyl] oxy] pentyl] propanedioic acid diethyl ester, [5-[[6- (1H-benzimidazole- 2-yl) -2-naphthalenyl] oxy] pentyl] propanedioic acid, ethyl 4-[[6- (1H-benzoimidazol-2-yl) -2-naphthalenyl] oxy] butanoate
Ester, 4-[[6- (1H-Benzimidazol-2-yl) -2-naphthalenyl] oxy] butanoic acid, 4-[[6- [1- (phenylmethyl) -1H-benzimidazol-2-yl ] -2-Naphthalenyl] oxy] butanoic acid, 4-[[6- [1-[(2-chlorophenyl) methyl] -1H-benzoimidazol-2-yl] -2-naphthalenyl] oxy] butanoic acid, 1- (Cyclohexylmethyl) -2- [6- (phenylmethoxy) -2-naphthalenyl] -1H-benzimidazole, 6- [1- (cyclohexylmethyl) -1H-benzimidazol-2-yl] -2-naphthalenol, 4 -[[6- [1- (cyclohexylmethyl) -1H-benzimidazol-2-yl] -2-naphthalenyl] oxy] butanoic acid, 6-[[6- [1- (cyclohexylmethyl) -1H-benzimidazole -2-yl] -2-naphthalenyl] oxy] hexanoic acid, 2- [6- (phenylmethoxy) -2-naphthalenyl] -1H-benzimidazole-1-acetic acid methyl ester, 2- [6- (phenylmethoxy) -2-Naphthalenyl] -1H-benzimidazole-1-acetic acid, 2- (6-hydroxy-2-naphthalenyl) -1H-benzimidazole-1-acetic acid methyl ester, 2- (6-hydroxy-2-naphthalenyl)- 1H-benzimidazol-1-acetic acid, 2- [6- (phenylmethoxy) -2-naphthalenyl] -1H-benzimidazol-1-butanoic acid, 2- (6-hydroxy-2-naphthalenyl) -1H-benzimidazole -1-butanoic acid, [5- [2- [6- (phenylmethoxy) -2-naphthalenyl] -1H-benzoimidazol-1-yl] pentyl] propanedioic acid, 2- [6- (phenylmethoxy)- 2-Naphthalenyl] benzothiazole, 6- (2-benzothiazolyl) -2-naphthalenol, [[6- (2-benzothiazolyl) -2-naphthalenyl] oxy] acetic acid methyl ester, [[6- (2-benzothiazolyl) -2 -Naphthalenyl] oxy] acetic acid, 6-[[6- (2-benzothiazolyl) -2-naphthalenyl] oxy] hexanoic acid ethyl ester, [3- [ [6- (2-Benzothiazolyl) -2-naphthalenyl] oxy] propyl] propanedioic acid, [5-[[6- (2-benzothiazolyl) -2-naphthalenyl] oxy] pentyl] propanedioic acid diethyl ester

[12] The compound according to any one of [7] to [11], or a pharmaceutically acceptable salt compound or a solvate thereof, for use as a pharmaceutical composition.
[13] The compound according to any one of the above [7] to [11] for use as a thrombolytic agent or antithrombotic agent, or a pharmaceutically acceptable salt compound thereof or a solvate thereof.
[14] The compound according to any one of the above [7] to [11] for producing a pharmaceutical composition for treating thrombosis, or a pharmaceutically acceptable salt compound thereof or a solvate thereof Stuff.
[15] Thrombosis comprising administering to a subject an effective amount of the compound according to any of [7] to [11] above, or a pharmaceutically acceptable salt compound thereof, or a solvate thereof How to treat.
[16] The following compounds for use as thrombolytic agents or antithrombotic agents, or pharmaceutically acceptable salt compounds or solvates thereof:
[4- (2-Benzoxazolyl) phenoxy] acetic acid, [4- (5-chloro-1H-benzoimidazol-2-yl) phenoxy] acetic acid

  In the present specification, the “lower alkyl group” means a linear or branched alkyl group having 1 to 4 carbon atoms, and specifically includes a methyl group, an ethyl group, a propyl group, an isopropyl group, Examples thereof include a butyl group, an isobutyl group, a sec-butyl group, and a tert-butyl group. “Lower alkylene group” means a linear or branched alkylene group having 1 to 7 carbon atoms, such as methylene group, ethanediyl group, propanediyl group, butanediyl group, pentanediyl group, hexanediyl group, heptanediyl group, etc. It corresponds to these. The “lower alkoxy group” means a linear or branched alkoxy group having 1 to 4 carbon atoms, specifically, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, Examples include sec-butoxy group and tert-butoxy group. The “lower alkoxycarbonyl group” is an alkoxycarbonyl group having a lower alkoxy group having 1 to 4 carbon atoms as described above, and examples thereof include a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, and a butoxycarbonyl group. I can do it. The “lower acyloxy group” is a linear or branched 1-oxoalkyloxy group having 1 to 7 carbon atoms, such as an acetyloxy group, a 1-oxopropoxy group, or a 2,2-dimethyl-1-oxopropoxy group. 1-oxobutoxy group, 1-oxopentyloxy group, 1-oxohexyloxy group, 1-oxoheptyloxy group and the like. The compound represented by the above formula (1) of the present invention can be converted into a pharmacologically acceptable salt as necessary, or the formed salt can be converted into a free acid or an ester. Further, these compounds can be solvated. Examples of the salt include pharmacologically acceptable acid addition salts, metal salts, ammonium salts, organic amine salts, and amino acid addition salts. Specific examples of acid addition salts include inorganic acid salts such as hydrochloride, phosphate, and sulfate, and organic acid salts such as acetate, citrate, and methanesulfonate, and metal salts include sodium salt. Alkali metals such as potassium salts, alkaline earth metal salts such as magnesium salts and calcium salts, aluminum salts and the like. Examples of ammonium salts include salts such as ammonium. Examples of organic amine addition salts include morpholine and piperidine. And amino acid addition salts include addition salts such as glycine and lysine. Examples of solvates include hydrates. Examples of esters include lower alkyl esters.

Among the compounds of the present invention, [4- (2-benzoxazolyl) phenoxy] acetic acid and [4- (5-chloro-1H-benzoimidazol-2-yl) phenoxy] acetic acid are known compounds. Nothing is known about its thrombolytic and antithrombotic effects.
Any of the compounds represented by the formula (1) of the present invention can be produced by a known method. Below, the typical manufacturing method of these compounds is shown.
Monocyclic oxazole derivatives are obtained according to Scheme A below.

  [Wherein P, T1, and T2 represent A, B1, and B2 in the general formula (1) or groups that can be converted to this, and X represents a halogen, respectively. ]

In an aqueous alcohol containing an alkali carbonate such as sodium carbonate, the carboxylic acid represented by the formula (A1) and the α-haloketone compound represented by the formula (A2) are reacted, for example, under reflux to obtain the formula (A3) The oxazole represented by the formula (A4) is obtained by heating the ester represented by formula (A4) in acetic acid with a nitrogen source such as urea or ammonium acetate (reference: Heterocyclic Compounds, Wiley & Sons, Inc., 5 , 302-323).

The ester form represented by the formula (A3) is obtained by reacting the acid halide represented by the formula (A5) with the α-hydroxyketone form represented by the formula (A6) in the presence of pyridine or trialkylamine. It can also be obtained by reacting at 100 ° C. In the case where a hydroxyl group is present in the substituent P, the oxazole itself represented by the formula (A4) or the substituents T1, T2, etc. are separately protected according to a conventional method, for example, by pre-protecting with a benzyl group or the like. It can also be subjected to elimination of the protecting group at the oxazole form after conversion to a group.
The above method is an example, and other similar known methods can also be used.
The benzoxazole derivative is obtained according to Scheme B below.

［ここでＰ，ｔ1，ｔ2，ｔ3は一般式（23）に於けるＡ，ｂ1，ｂ2，ｂ3自体又はこれに変換しうる基を、又、Ｒ1は低級アルキル基、Ｘはハロゲンをそれぞれ意味する。］

[Wherein P, t1, t2, and t3 represent A, b1, b2, b3 itself or a group that can be converted into the general formula (23), R1 represents a lower alkyl group, and X represents a halogen, respectively. To do. ]

According to Route 1 (reference: Gunter et al., J. Org. Chem., 46 , (13), 2824-2826 (1981)), a 2-aminophenol compound represented by the formula (B1) in a toluene solution of trimethylaluminum Is reacted at 0 ° C. to reflux temperature and then the carboxylic acid ester represented by the formula (B2) is added and subjected to reflux reaction for several hours, or according to route 2, the carboxylic acid represented by the formula (B3) Halide and 2-aminophenol compound represented by formula (B1) in the presence of a base such as triethylamine in an inert solvent such as benzene, toluene, xylene, dioxane, 1,3-dimethyl-2-imidazolidinone By reacting at room temperature or under reflux with heating, an amide compound represented by the formula (B4) is obtained, and this amide compound is obtained in a solvent such as benzene, toluene, xylene, 1,3-dimethyl-2-imidazolidinone. P-toluenesulfonic acid monohydrate (PT ) With either the removal of water formed while heated to reflux, or by heating with thionyl halide, benzoxazole of formula (B5) can be obtained. In the case where a hydroxyl group is present in the substituent P, the benzoxazole itself represented by the formula (B5) or the substituents t1, t2, t3, etc. is protected in advance according to a conventional method, for example, with a benzyl group or the like. It is preferable to remove the protecting group at the position of the benzoxazole after each different group, for example, a hydroxyl group is converted to an acyloxy group or the like.
The above method is an example, and other similar known methods can also be used.
The benzimidazole derivative is obtained according to Scheme C.

［ここでＰ，ｔ1，ｔ2，ｔ3は一般式（24）に於けるＡ，ｂ1，ｂ2，ｂ3自体又はこれに変換しうる基を、又、Ｒ1は低級アルキル基をそれぞれ意味する。］

[Wherein P, t1, t2, t3 represent A, b1, b2, b3 per se or a group which can be converted to this in general formula (24), and R1 represents a lower alkyl group, respectively. ]

According to Route 1 (reference: Gunter et al., J. Org. Chem., 46 , (13), 2824-2826 (1981)), 1,2-phenylene represented by the formula (C1) in a toluene solution of trimethylaluminum After reacting the diamine compound at 0 ° C. to reflux temperature, the carboxylic acid ester compound represented by the formula (C2) is added and subjected to reflux reaction for several hours, or route 2 (reference: Yellow et al., Natural science). Edition, J. Wuhan Univ., 41 , (2), 142-148 (1995)), an aldehyde represented by formula (C3) in an alcohol solution of a 1,2-phenylenediamine compound represented by formula (C1) The alcohol solution and an excess of aqueous potassium ferricyanide solution are added dropwise at the same time and refluxed for several hours, or according to the route 3 (reference: N. Latif et al., Indian Journal of Chemistry, 21B , 872-874 (1982)). A 1-aryl-2-nitroethene compound represented by (C4) and an equivalent 1,2-phenylenediamine compound represented by formula (C1) Is subjected to a reflux reaction in alcohol for several hours to directly obtain a benzimidazole represented by the formula (C5). When a hydroxyl group is present in the substituent P, it can be protected in advance by, for example, a benzyl group according to a conventional method. The compound represented by the formula (C4) can be easily obtained by heating and refluxing an aldehyde represented by P-CHO and nitromethane together with a catalytic amount of n-butylamine in acetic acid (Reference: Organic Reactions, John Wiley & Sons,
Inc., 15 , Chapter 2).
The above method is an example, and other similar known methods can also be used.
The benzothiazole derivative is obtained according to Scheme D below.

［ここでＰ，ｔ1，ｔ2，ｔ3は一般式（25）に於けるＡ，ｂ1，ｂ2，ｂ3自体又はこれに変換しうる基を、又、Ｒ1は低級アルキル基をそれぞれ意味する。］

[Wherein P, t1, t2, t3 represent A, b1, b2, b3 in the general formula (25) or a group which can be converted to this, and R1 represents a lower alkyl group, respectively. ]

According to Gunter et al., J. Org. Chem., 46 , (13), 2824-2826 (1981), a 2-aminothiophenol compound represented by the formula (D1) is added at 0 ° C. to After reacting at the reflux temperature, the carboxylic acid ester represented by the formula (D2) is added and subjected to reflux reaction for several hours to obtain the benzothiazole represented by the formula (D3). In the case where a hydroxyl group is present in the substituent P, the benzothiazole itself represented by the formula (D3) or the substituents t1, t2, t3, etc. is protected in advance according to a conventional method, for example, with a benzyl group. It can also be subjected to elimination of the protecting group at the benzothiazole form after conversion to a different group.
The above method is an example, and other similar known methods can also be used.
In the case where the hydroxyl group in each of the functional groups P, T1, T2, t1, t2, and t3 displayed in the above-mentioned schemes A to D is converted to another functional group, and the 1-position of the benzimidazole derivative shown in the scheme C When introducing another functional group into nitrogen, it is carried out according to the following scheme E.

［ここで、Ｚは酸素，硫黄、Ａｒはアリーレン基、alkは低級アルキレン基、Ｘはハロゲンであり、ａ1，ｂ31，Ｚ2，Ｐは前記の通りである。］

[Wherein Z is oxygen, sulfur, Ar is an arylene group, alk is a lower alkylene group, X is halogen, and a1, b31, Z2, and P are as described above. ]

  The reaction is carried out by reacting with a halide represented by a1-alk-X at room temperature or under heating in an aprotic polar solvent such as DMF in the presence of a base such as alkali carbonate. In the case where another unsubstituted amino group is present, it is desirable to introduce a protective group such as t-butoxycarbonyl group in advance to this amino group. The introduction and removal of these protecting groups are described in, for example, TWGreen, Protective Groups in Organic Synthesis, 2nd Ed., John Willey & Sons, Inc., (1991). Is called. When regiospecificity is required for this conversion, the reaction mixture obtained using an equivalent amount of the halogenated product is subjected to column chromatography separation to obtain a desired target, or functional group conversion is performed according to Scheme F below. Can also be done.

［ここで、Ｚは酸素，硫黄、Ａｒはアリーレン基、alkは低級アルキレン基、ａ1，ｂ31，Ｚ2は前記の通りである、Ｐｒ1，Ｐｒ2はそれぞれ異なった種類の保護基を意味する。］

[Wherein Z is oxygen, sulfur, Ar is an arylene group, alk is a lower alkylene group, a1, b31 and Z2 are as described above, and Pr1 and Pr2 each represent a different kind of protecting group. ]

In the schemes A to D, the compounds represented by the formulas (F1) and (F9) are reacted with benzyl halide or the like in the presence of an alkali carbonate or the like, for example, in DMF or acetone before being subjected to the ring closure reaction. It is obtained by things.
The above method is an example, and other similar known methods can also be used.
Conversion to an ester group present in the compound represented by the general formula (1), that is, a carboxylic acid such as a lower alkoxycarbonyl group, is carried out according to a conventional method, for example, in an alcohol, an aqueous sodium hydroxide solution or the like at room temperature. Alternatively, it can be achieved by treating for several hours under reflux, followed by acid precipitation. The obtained free carboxylic acid can be dissolved in an equivalent amount of sodium hydroxide and freeze-dried to obtain an alkali metal salt such as a sodium salt. When a lower alkoxycarbonyl group is present in the compound represented by the general formula (1), it itself forms one form constituting the pharmaceutical composition of the present invention. It can be converted to the corresponding carboxyl group and its salt which is another form of the invention.

Acid addition salts of the compound represented by the general formula (1) with hydrochloric acid or the like are also one form constituting the pharmaceutical composition of the present invention, and these are prepared according to a conventional method, for example, the corresponding free form is water or aqueous alcohol, It is obtained by treating with an equivalent amount of hydrochloric acid in a solvent such as aqueous acetone and concentrating under reduced pressure if necessary.
The above method is an example, and the present invention is not limited to this.

  A pharmaceutical comprising the 1,3-azole derivative represented by the general formula (1) or a salt compound thereof or a solvate thereof thus produced as an active ingredient is usually applied to mammals (including human patients). On the other hand, it can be administered as oral preparations such as tablets, capsules, powders, fine granules, syrups, rectal preparations, or injections. The compound of the present invention can be administered as a single therapeutic agent or as a mixture with other therapeutic agents. They may be administered alone, but are generally administered in the form of a pharmaceutical composition. These preparations can be produced by conventional methods with pharmacologically and pharmaceutically acceptable additives added. That is, additives such as ordinary excipients, lubricants, binders, disintegrants, wetting agents, coating agents and the like can be used for oral preparations. Oral solutions may be in the form of aqueous or oily suspensions, solutions, emulsions, syrups, elixirs, etc., or may be provided as dry syrups prepared in water or other suitable solvent prior to use. . The solution may contain conventional additives such as suspending agents, fragrances, diluents or emulsifiers. When administered rectally, it can be administered as a suppository. Suppositories are based on suitable substances such as cacao butter, lauric fat, macrogol, glycerogelatin, witepsol, sodium stearate or mixtures thereof, and if necessary emulsifiers, suspending agents, preservatives Etc. can be added. Injections include aqueous or injectable distilled water, physiological saline, 5% glucose solution, propylene glycol and other solubilizers or solubilizers, pH adjusters, isotonic agents, Pharmaceutical ingredients such as stabilizers are used. Specific examples of excipients used in the above composition are listed below.

Excipients: calcium hydrogen phosphate, synthetic aluminum silicate, magnesium metasilicate aluminate, aluminum hydroxide / magnesium, magnesium silicate, calcium carbonate, magnesium carbonate, calcium hydrogen phosphate, light anhydrous silicic acid, anhydrous silicic acid, Avicel, various starches, dextrin, carboxymethyl starch (CMS), lactose, etc.
Binder: Ethylcellulose (EC), carboxymethylcellulose Na (CMC-Na), low-substituted hydroxypropylcellulose (L-HPC), hydroxypropylmethylcellulose (HPMC), methylcellulose (MC), hydroxypropylcellulose (HPC), various starches , Dextrin, sodium alginate, gelatin, polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP) and the like.

Disintegrating agents: synthetic aluminum silicate, magnesium metasilicate aluminate, CMC-Ca, CMC, Avicel, L-HPC, HPMC, MC, various starches, CMS, hydroxypropyl starch (CPS) and the like.
Anti-caking agent: light anhydrous silicic acid, synthetic aluminum silicate, etc.
Lubricant: Synthetic aluminum silicate, silicic anhydride, talc, Avicel, etc.
Flavoring agents: mannitol, citric acid, sodium citrate, sugar and the like.
Emulsifiers: gelatin, citric acid, sodium citrate, polyoxyethylene hydrogenated castor oil, macrogol (PEG), propylene glycol fatty acid ester, polyoxyethylene polyoxypropylene glycol, propylene glycol, lauryl sulfate Na, phospholipid and the like.

Stabilizer: Sodium bisulfite, polyoxyethylene hydrogenated castor oil, PEG, propylene glycol fatty acid ester, polyoxyethylene polyoxypropylene glycol, propylene glycol, sodium lauryl sulfate, various natural and synthetic cyclodextrins, phospholipids, and the like.
Absorption accelerators: polyoxyethylene hydrogenated castor oil, PEG, propylene glycol fatty acid ester, polyoxyethylene polyoxypropylene glycol, propylene glycol, sodium lauryl sulfate, various natural and synthetic cyclodextrins, medium chain fatty acid triglycerides, and the like.
Solubilizing agents: ethanol, polyoxyethylene hydrogenated castor oil, PEG, propylene glycol fatty acid ester, polyoxyethylene polyoxypropylene glycol, propylene glycol, sodium lauryl sulfate, various natural and synthetic cyclodextrins, and the like.

Suspending agent: CMC-Na, HPMC, MC, HPC, sodium alginate, gelatin, propylene glycol, sodium lauryl sulfate, etc.
Coating agent: EC, magnesium silicate, talc, titanium oxide, calcium carbonate, triacetin, carboxymethyl ethyl cellulose (CMEC), cellulose acetate phthalate (CAP), HPMC, hydroxypropyl methylcellulose phthalate (HPMCP), MC, HPC, sodium alginate , Polyvinyl acetal diethylaminoacetate, polyacrylic acid Na, copolymers of various acrylic acid methacrylic acid derivatives, polyglycolic acid Na and the like.
Colorant: Titanium oxide, tar pigment, caramel, etc.

  The dosage when the compound of the present invention is administered to humans varies depending on the age, symptoms, etc. of the patient, but in the case of an adult, it is usually about 1 mg to 1000 mg / person / day for oral or rectal administration, and 0 for injection. About 1 to 500 mg / person / day. However, these numerical values are merely examples, and the dosage is appropriately increased or decreased depending on various conditions such as patient symptoms.

  Next, although manufacture of the compound of this invention and a test example are given and this invention is demonstrated concretely, this invention is not limited by these examples.

Example 1
4- (2-Naphthalenyl) -2-oxazolepropanoic acid methyl ester (Compound 1), 4- (2-Naphthalenyl) -2-oxazolepropanoic acid (Compound 2), 4- (2-Naphthalenyl) -2-oxazolepropane Preparation of acid sodium salt (compound 3):
In ethanol (30 mL), water (10 mL) and sodium carbonate (0.53 g) were added to monomethyl succinate (1.32 g), and a solution of 2-bromoacetylnaphthalene (2.49 g) in ethanol (20 mL) was added dropwise under reflux. After reacting at the same temperature for 4 hours, the mixture was cooled and the precipitate was collected by filtration. Acetic acid (15 mL) and urea (5.40 g) were added to the obtained crystals and reacted under reflux for 5 hours. Water (300 mL) was added to the reaction solution and crystallized, followed by filtration to obtain a crude product. The crude product was applied to a silica gel column (chloroform) to obtain Compound 1 (158 mg, Y = 5.6%).

¹ H-NMR (DMSO-d6 / TMS):
δ = 2.88 (2H, t, J = 6Hz) 3.10 (2H, t, J = 6Hz) 3.64 (3H, s) 7.44-7.59 (2H, m)

7.92-8.00 (4H, m) 8.29 (1H, s) 8.61 (1H, s)
A 1N aqueous sodium hydroxide solution (1.35 mL) was added to compound 1 (127 mg) in methanol (25 mL), and the mixture was reacted under reflux for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in water (15 mL), and then activated carbon (20 mg) was added and filtered. 1N hydrochloric acid (1.35 mL) was added to the filtrate for acid precipitation. The precipitated crystals were collected by filtration and dried to obtain Compound 2 (88 mg, Y = 73%).

¹ H-NMR (DMSO-d6 / TMS):
δ = 2.79 (2H, t, J = 5Hz) 3.06 (2H, t, J = 5Hz) 7.43-7.59 (2H, m) 7.92 (4H, s) 8.03 (1H, s) 8.60 (1H, s) 11.41- 13.46 (1H, br)
Compound 2 (53.5 mg) and 0.1N aqueous sodium hydroxide solution (3 mL) were dissolved in water (25 mL), filtered, and the filtrate was lyophilized to obtain compound 3.

Example 2
6- (4,5-diphenyl-2-oxazolyl) -2-naphthalenecarboxylic acid methyl ester (compound 4), 6- (4,5-diphenyl-2-oxazolyl) -2-naphthalenecarboxylic acid (compound 5), Production of 6- (4,5-diphenyl-2-oxazolyl) -2-naphthalenecarboxylic acid sodium salt (Compound 6):
Thionyl chloride (1.55 g) and DMF (1 drop) were added to naphthalene-2,6-dicarboxylic acid monomethyl ester (2.53 g) in toluene (15 m), reacted for 2 hours under reflux, then concentrated under reduced pressure and acid chloride. Got the body. After adding pyridine (15 mL) and benzoin (2.12 g) to the acid chloride form and reacting at room temperature for 20 hours, methanol (75 mL) was added and crystallized. The precipitate was collected by filtration and dried to obtain an intermediate (3.67 g).
Acetic acid (60 mL) and ammonium acetate (5.94 g) were added to the intermediate (3.27 g) and reacted under reflux for 1 hour. Water (60 mL) was added to the reaction solution for crystallization, followed by filtration to obtain a crude product. The crude product was dissolved in toluene (15 mL) with heating, and methanol (150 mL) was added for crystallization. The precipitated crystals were collected by filtration and dried to obtain compound 4 (2.62 g, Y = 73%).

¹ H-NMR (DMSO-d6 / TMS):
δ = 3.95 (3H, s) 7.48-7.68 (10H, m) 8.13-8.30 (4H, m) 8.71 (1H, s) 8.78 (1H, s)
A 1N aqueous sodium hydroxide solution (7.5 mL) was added to compound 4 (1.01 g) in methanol (50 mL), and the mixture was reacted under reflux for 6 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in water (75 mL), and then activated carbon (0.1 g) was added and filtered. 1N hydrochloric acid (7.5 mL) was added to the filtrate for acid precipitation. The precipitated crystals were collected by filtration and dried to obtain compound 5 (0.87 g, Y = 89%).

¹ H-NMR (DMSO-d6 / TMS):
δ = 7.53-7.68 (10H, m) 7.96-8.28 (4H, m) 8.68 (1H, s) 8.77 (1H, s) 12.43-13.87 (1H, br)
Compound 5 (391 mg) and 0.1N aqueous sodium hydroxide solution (1.5 mL) were dissolved in water (100 mL) by heating and filtered, and then the filtrate was lyophilized to obtain compound 6.

Example 3
4,5-diphenyl-2- [6- (phenylmethoxy) -2-naphthalenyl] oxazole (compound 7), 6- (4,5-diphenyl-2-oxazolyl) -2-naphthalenol (compound 8), 6- (4,5-diphenyl-2-oxazolyl) -2-naphthalenol sodium salt (compound 9), [[6- (4,5-diphenyl-2-oxazolyl) -2-naphthalenyl] oxy] acetic acid methyl ester (compound 10), [[6- (4,5-diphenyl-2-oxazolyl) -2-naphthalenyl] oxy] acetic acid (compound 11), [[6- (4,5-diphenyl-2-oxazolyl) -2-naphthalenyl ] Oxy] acetic acid sodium salt (compound 12):
Thionyl chloride (1.55 g) and DMF (1 drop) were added to 6-benzyloxy-2-naphthoic acid (3.06 g) in toluene (15 m), reacted under reflux for 3 hours, and concentrated under reduced pressure to give the acid chloride. Got. After adding pyridine (15 mL) and benzoin (2.12 g) to the acid chloride form and reacting at room temperature for 20 hours, methanol (75 mL) was added. The precipitate was collected by filtration and dried to obtain an intermediate (3.98 g).
Acetic acid (60 mL) and ammonium acetate (5.94 g) were added to the intermediate (3.64 g) and reacted under reflux for 1 hour, and then the reaction solution was cooled. The precipitated crystals were collected by filtration, washed with water, and dried to obtain Compound 7 (3.1 g, Y = 75%).

¹ H-NMR (DMSO-d6 / TMS):
δ = 5.28 (2H, s) 7.30-7.88 (17H, m) 8.02-8.12 (3H, m) 8.64 (1H, s)
Compound 7 (2.95 g) was dissolved by heating in toluene (150 mL), ethanol (150 mL) and 5% palladium carbon (1.5 g) were added, and the mixture was reacted at room temperature in a hydrogen atmosphere for 4 days. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was recrystallized with toluene (30 m) to obtain Compound 8 (1.83 g, Y = 78%).

¹ H-NMR (DMSO-d6 / TMS):
δ = 7.13-7.25 (2H, m) 7.46-8.16 (13H, m) 8.58 (1H, s) 10.06 (1H, brs)
Compound 8 (363 mg), 1N aqueous sodium hydroxide solution (1 mL), and water (50 mL) were dissolved in methanol (250 mL) with heating, and then concentrated under reduced pressure to obtain compound 9.
In DMF (10 mL), potassium carbonate (829 mg) and methyl bromoacetate (527 mg) were added to compound 8 (1.09 g) and reacted at room temperature for 20 hours. Water (100 mL) was added to the reaction solution for crystallization, followed by filtration to obtain a crude product. The crude product was recrystallized from methanol (400 mL) to obtain Compound 10 (0.8 g, Y = 61%).

¹ H-NMR (DMSO-d6 / TMS):
δ = 3.76 (3H, s) 4.98 (2H, s) 7.27-7.45 (12H, m) 8.02-8.12 (3H, m) 8.65 (1H, s)

  A 1N aqueous sodium hydroxide solution (3 mL) was added to compound 10 (435 mg) in methanol (50 mL), and the mixture was reacted under reflux for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in water (100 mL) with heating, and then activated carbon (0.1 g) was added and filtered. 1N hydrochloric acid (3 mL) was added to the filtrate for acid precipitation. The precipitated crystals were collected by filtration and dried to obtain Compound 11 (338 mg, Y = 80%).

¹ H-NMR (DMSO-d6 / TMS):
δ = 4.85 (2H, s) 7.25-7.74 (12H, m) 8.02-8.10 (3H, m) 8.64 (1H, s)
Compound 11 (84.3 mg) and 0.1N sodium hydroxide aqueous solution (3 mL) were dissolved in water (50 mL) and filtered, and then the filtrate was lyophilized to obtain Compound 12.

Example 4
[4- (2-Benzoxazolyl) phenoxy] acetic acid methyl ester (Compound 13), [4- (2-Benzoxazolyl) phenoxy] acetic acid (Compound 14), [4- (2-Benzoxazolyl) ) Preparation of phenoxy] acetic acid sodium salt (compound 15):
In a nitrogen stream, add 15% trimethylaluminum / toluene solution (11 mL) and 2-aminophenol (2.2 g) to toluene (100 mL) under ice water cooling, react for 20 minutes under reflux, then 4-benzyloxybenzoic acid. Ethyl (3.0 g) was added and reacted under reflux for 4 hours. Methanol (30 mL) was added to the reaction mixture, and the mixture was stirred overnight and concentrated. Water (40 mL) and toluene (30 mL) were added to the residue, and the mixture was refluxed for 30 minutes, and the crystals were collected by filtration. The target compound was extracted from the obtained crystals with ethyl acetate, and washed successively with 5% aqueous hydrochloric acid and saturated brine. The ethyl acetate layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from toluene to obtain an intermediate amide compound (3.0 g, Y = 80%).
An amide compound (2.6 g), thionyl chloride (6 mL) and DMF (1 drop) were added to toluene (130 mL), and the mixture was reacted under reflux for 6 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified with a silica gel column (chloroform) to obtain 2- [4- (phenylmethoxy) phenyl] benzoxazole (1.7 g, Y = 69%).

Methanol (140 mL) and 5% palladium carbon (1 g) were added to 2- [4- (phenylmethoxy) phenyl] benzoxazole (1.4 g) and reacted at room temperature in a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure and dried to obtain 4- (2-benzoxazolyl) phenol (820 mg, Y = 84%).
4- (2-Benzoxazolyl) phenol (0.5 g) was dissolved in DMF (10 mL), and potassium carbonate (1.0 g) and methyl bromoacetate (0.52 g) were added and reacted at room temperature overnight. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified with a silica gel column (chloroform) to obtain Compound 13 (750 mg, Y = 93%).
¹ H-NMR (DMSO-d6 / TMS):

  Compound 13 (440 mg) was suspended in methanol (50 mL), 2% aqueous sodium hydroxide solution (5 mL) was added, and the mixture was reacted at about 50 ° C. for 30 min. The reaction solution was concentrated under reduced pressure, and water (80 mL) was added to the residue to dissolve it with heating. The precipitated crystals were collected by filtration and dried to obtain Compound 14 (410 mg, Y = 98%).

¹ H-NMR (DMSO-d6 / TMS):
δ = 4.84 (2H, s) 7.08-8.24 (8H, m)
Compound 14 (101 mg) was suspended in water (50 mL), 1% sodium hydroxide (1.6 mL) was added and dissolved by heating, and then filtered, and the filtrate was lyophilized to give compound 15 (111 mg, Y = 102% )

Example 5
4- [4- (2-Benzoxazolyl) phenoxy] butanoic acid ethyl ester (Compound 16), 4- [4- (2-Benzoxazolyl) phenoxy] butanoic acid (Compound 17), 4- [4 -(2-Benzoxazolyl) phenoxy] butanoic acid potassium salt (compound 18):
Potassium carbonate (1.31 g) and ethyl 4-bromo-n-butyrate (1.11 g) were added to 4- (2-benzoxazolyl) phenol (1.00 g) in DMF (15 mL) and reacted at room temperature for 18 hours. . The reaction solution was added to water (150 mL) for crystallization, and the precipitated crystals were collected by filtration and washed with water to obtain Compound 16 (1.46 g, Y = 95%).
A 14% aqueous potassium hydroxide solution (10 mL) was added to compound 16 (1.31 g) in methanol (40 mL), reacted at room temperature for 17 hours, activated carbon was added, and the filtrate was concentrated under reduced pressure. Water (100 mL) was added to the residue for dissolution, and acidified with 35% hydrochloric acid. The precipitated crystals were collected by filtration, washed with water, and dried to obtain Compound 17 (1.12 g, Y = 94%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.77-2.54 (4H, m) 4.12 (2H, t, J = 6Hz) 7.09-8.22 (8H, m) 12.20 (1H, brs)
A 0.1% aqueous potassium hydroxide solution (50 mL) was added to compound 17 (200 mg) and dissolved by heating, and then activated carbon was added and filtered while hot. The filtrate was lyophilized to give compound 18 (231 mg, Y = 100%).

Example 6
Preparation of 4- [4- (2-Benzoxazolyl) phenoxy] butanoic acid (2,2-dimethyl-1-oxopropoxy) methyl ester (Compound 19):
In DMF (10 mL), potassium carbonate (256 mg) and chloromethyl pivalate (142 mg) were added to compound 17 (150 mg) and reacted at 80 to 90 ° C. for 2 hours. The reaction solution was added to water (100 mL) for crystallization, and the precipitated crystals were collected by filtration and washed with water to obtain crude crystals. The crude crystals were recrystallized from 50% aqueous ethanol (6.4 mL) to give compound 19 (115 mg, Y = 55%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.20 (9H, s) 2.06-2.76 (4H, m) 4.10 (2H, t, J = 6Hz) 5.79 (2H, s) 7.00 (2H, d, J = 8Hz) 7.18-7.82 (4H, m) 8.19 (2H, d, J = 9Hz)

Example 7
6- [4- (2-Benzoxazolyl) phenoxy] hexanoic acid ethyl ester (Compound 20), 6- [4- (2-Benzoxazolyl) phenoxy] hexanoic acid (Compound 21), 6- [4 -(2-Benzoxazolyl) phenoxy] hexanoic acid potassium salt (compound 22):
In DMF (15 mL), potassium carbonate (1.31 g) and ethyl 6-bromohexanoate (1.28 g) were added to 4- (2-benzoxazolyl) phenol (1.00 g) and reacted at room temperature for 21 hours. The reaction solution was added to water (150 mL) for crystallization, and the precipitated crystals were collected by filtration and washed with water to obtain Compound 20 (Wet1.83 g).
A 14% aqueous potassium hydroxide solution (10 mL) was added to compound 20 (Wet 1.63 g) in methanol (40 mL) and reacted at 60 to 70 ° C. for 1 hour. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in water (100 mL) with heating, and acidified by adding 35% hydrochloric acid. Precipitated crystals were collected by filtration, washed with water, and dried to give compound 21 (1.22 g, Y = 79%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.56-2.54 (8H, m) 4.08 (2H, t, J = 6Hz) 7.07-8.22 (8H, m) 12.05 (1H, brs)
To compound 21 (200 mg), 0.1% aqueous potassium hydroxide solution (50 mL) was added and dissolved by heating, activated carbon was added, and the mixture was filtered while hot. The filtrate was lyophilized to give compound 22 (228 mg, Y = 100%).

Example 8
Preparation of 6- [4- (2-Benzoxazolyl) phenoxy] hexanoic acid (2,2-dimethyl-1-oxopropoxy) methyl ester (Compound 23):
Potassium carbonate (280 mg) and chloromethyl pivalate (155 mg) were added to compound 21 (200 mg) in DMF (10 mL) and reacted at 80 to 90 ° C. for 2.5 hours. The reaction solution was added to water (100 mL) for crystallization, and the precipitated crystals were collected by filtration and washed with water to obtain crude crystals. The crude crystals were recrystallized from 80% aqueous ethanol (4 mL) to give compound 23 (205 mg, Y = 76%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.21 (9H, s) 1.48-2.00 (6H, m) 2.41 (2H, t, J = 6Hz) 4.04 (2H, t, J = 6Hz) 5.77 (2H, s) 7.00 (2H, d, J = 9Hz) 7.23-7.83 (4H, m) 8.19 (2H, d, J = 9Hz)

Example 9
[5- [4- (2-Benzoxazolyl) phenoxy] pentyl] propanedioic acid diethyl ester (compound 24), [5- [4- (2-benzoxazolyl) phenoxy] pentyl] propanedioic acid ( Preparation of Compound 25), [5- [4- (2-Benzoxazolyl) phenoxy] pentyl] propanedioic acid disodium salt (Compound 26):
Potassium carbonate (1.0 g) and diethyl (5-bromopentyl) malonate (889 mg) were added to 4- (2-benzoxazolyl) phenol (500 mg) in DMF (10 mL), and reacted at room temperature for 23 hours. The reaction was added into water (150 mL) and the product was extracted with ethyl acetate (200 mL). The organic layer was washed with water, dehydrated with magnesium sulfate, and concentrated under reduced pressure to obtain a crude oil (1.69 g). The crude oil (1.69 g) was purified by silica gel column (toluene / ethyl acetate) to give compound 24 (1.09 g).
A 30% aqueous potassium hydroxide solution (5 mL) was added to compound 24 (1.09 g) in methanol (20 mL), and the mixture was reacted at room temperature overnight. Activated carbon was added to the reaction solution and filtered, and the filtrate was concentrated under reduced pressure. Water (50 mL) was added to the residue for dissolution, acidified with 35% hydrochloric acid, and the separated oil was extracted with ethyl acetate (200 mL). The organic layer was washed with water, dried over magnesium sulfate, concentrated under reduced pressure, and dried to obtain compound 25 (754 mg, Y = 83%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.18-1.99 (8H, m) 3.24 (1H, t, J = 7Hz) 4.08 (2H, t, J = 6Hz) 7.07-7.85 (6H, m) 8.14 (2H, d, J = 9Hz) 12.12- 13.30 (2H, br)
To the compound 25 (150 mg), 0.16% aqueous sodium hydroxide solution (20 mL) was added and dissolved, and then activated carbon was added and filtered. The filtrate was lyophilized to give compound 26 (159 mg, Y = 95%).

Example 10
[4- (6-Nitro-2-benzoxazolyl) phenoxy] acetic acid methyl ester (Compound 27), [4- (6-Nitro-2-benzoxazolyl) phenoxy] acetic acid (Compound 28), [4 Preparation of-(6-Nitro-2-benzoxazolyl) phenoxy] acetic acid sodium salt (Compound 29):
Toluene (50 mL), thionyl chloride (1.15 mL) and DMF (1 drop) were added to 4-benzyloxybenzoic acid (3 g) and reacted under reflux for 1.5 hours, followed by 2-amino-5-nitrophenol (4.2 g ) In 1,4-dioxane (100 mL) was added and reacted at room temperature overnight and under reflux for 1 hour. Thionyl chloride (6 mL) was added to the reaction solution and reacted for 9 hours under reflux. The reaction mixture was concentrated under reduced pressure, and water (150 mL) was added for crystallization. The precipitated crystals were collected by filtration, washed with methanol and dried to give 6-nitro-2- [4- (phenylmethoxy) phenyl] benzoxazole (4.145 g, Y = 91%).
Saturated hydrochloric acid / acetic acid solution (25 mL) was added to 6-nitro-2- [4- (phenylmethoxy) phenyl] benzoxazole (1.0 g) and reacted at about 100 ° C. overnight. The reaction mixture was concentrated under reduced pressure, chloroform (150 mL) and water (150 mL) were added to the residue, and 2% aqueous sodium hydroxide solution was added to make it strongly basic, followed by liquid separation. Dilute hydrochloric acid was added to the aqueous layer for acid precipitation, and the precipitated crystals were collected by filtration and dried to give 4- (6-nitro-2-benzoxazolyl) phenol (435 mg, Y = 59%).

4- (6-Nitro-2-benzoxazolyl) phenol (350 mg) was dissolved in DMF (20 mL), and potassium carbonate (500 mg) and methyl bromoacetate (300 mg) were added and reacted overnight. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column (chloroform) to obtain Compound 27 (375 mg, Y = 84%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 3.75 (3H, s) 4.98 (2H, s) 7.14-8.69 (7H, m)

Compound 27 (345 mg) was dissolved in a mixture of 1,4-dioxane (20 mL) and methanol (50 mL), 2% aqueous sodium hydroxide solution (5 mL) was added, and the mixture was reacted at about 60 ° C. for 1.5 hr. The reaction mixture was concentrated under reduced pressure, 1N hydrochloric acid was added to the residue, and the precipitated crystals were collected by filtration. The obtained crystals were recrystallized from a mixture of methanol and toluene to obtain Compound 28 (143 mg, Y = 43%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 4.85 (2H, s) 7.11-8.69 (7H, m)
Compound 28 (108 mg) was suspended in water (30 mL), dissolved by adding 1.6% aqueous sodium hydroxide solution (0.9 mL), and then filtered. The filtrate was lyophilized to give compound 29 (98 mg, Y = 85%).

Example 11
6- [2- (2-Benzoxazolyl) phenoxy] hexanoic acid ethyl ester (Compound 30), 6- [2- (2-Benzoxazolyl) phenoxy] hexanoic acid (Compound 31), 6- [2 -(2-Benzoxazolyl) phenoxy] hexanoic acid potassium salt (compound 32):
Potassium carbonate (791 mg) and ethyl 6-bromohexanoate (521 mg) were added to 2- (2-hydroxyphenyl) benzoxazole (400 mg) in DMF (10 mL) and reacted at room temperature for 17 hours. The reaction mixture was added to water (150 mL) and stirred, and then the product was extracted with ethyl acetate (100 mL). The organic layer was washed with water, dehydrated with magnesium sulfate, and concentrated under reduced pressure to give compound 30 (856 mg).
A 23% aqueous potassium hydroxide solution (5 mL) was added to compound 30 (856 mg) in ethanol (20 mL) and reacted at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in water (30 mL), and then acidified with 35% hydrochloric acid. The precipitated crystals were collected by filtration and washed with water to obtain crude crystals. The crude crystals were recrystallized from toluene (3 mL) to obtain Compound 31 (373 mg, Y = 61%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.61-2.24 (8H, m) 4.15 (2H, t, J = 6Hz) 7.01-8.10 (8H, m) 10.63-13.35 (1H, br)
0.06% aqueous potassium hydroxide solution (50 mL) was added to compound 31 (150 mg) and dissolved by heating, and then activated carbon was added and filtered while hot. The filtrate was lyophilized to give compound 32 (114 mg, Y = 68%).

Example 12
[5- [2- (2-Benzoxazolyl) phenoxy] pentyl] propanedioic acid diethyl ester (compound 33), [5- [2- (2-benzoxazolyl) phenoxy] pentyl] propanedioic acid ( Preparation of Compound 34), [5- [2- (2-Benzoxazolyl) phenoxy] pentyl] propanedioic acid disodium salt (Compound 35):
In DMF (12 mL), potassium carbonate (1.11 g) and diethyl (5-bromopentyl) malonate (932 mg) were added to 2- (2-hydroxyphenyl) benzoxazole (400 mg) and reacted at room temperature for 29 hours. The reaction mixture was added to water (150 mL) and stirred, and then the product was extracted with ethyl acetate (200 mL). The organic layer was washed with water, dehydrated with magnesium sulfate, and concentrated under reduced pressure to obtain a crude oil (1.09 g). Crude oil (1.09 g) was purified by silica gel column (toluene / ethyl acetate) to obtain compound 33 (0.92 g).
A 26% aqueous potassium hydroxide solution (5 mL) was added to compound 33 (0.92 g) in ethanol (20 mL) and reacted at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in water (30 mL), acidified with 35% hydrochloric acid, and the product was extracted with ethyl acetate (200 mL). The organic layer was washed with water, dehydrated with magnesium sulfate, concentrated under reduced pressure, and the residue was dried to obtain Compound 34 (588 mg, Y = 81%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.06-1.99 (8H, m) 3.23 (1H, t, J = 7Hz) 4.15 (2H, t, J = 5Hz) 7.01-8.12 (8H, m) 12.60 (2H, brs)
To the compound 34 (150 mg), 0.16% aqueous sodium hydroxide solution (20 mL) was added to dissolve substantially, and then activated carbon was added and filtered. The filtrate was lyophilized to give compound 35 (156 mg, Y = 93%).

Example 13
2- [4 '-(Phenylmethoxy) [1,1'-biphenyl] -4-yl] benzoxazole (Compound 36), 4'-(2-Benzoxazolyl) [1,1'-biphenyl]- 4-ol (compound 37), 4-[[4 '-(2-benzoxazolyl) [1,1'-biphenyl] -4-yl] oxy] butanoic acid ethyl ester (compound 38), 4- [ [4 '-(2-Benzoxazolyl) [1,1'-biphenyl] -4-yl] oxy] butanoic acid (Compound 39), 4-[[4'-(2-Benzoxazolyl) [ Preparation of 1,1′-biphenyl] -4-yl] oxy] butanoic acid sodium salt (Compound 40):
Toluene (50 mL), thionyl chloride (3.0 g) and DMF (1 drop) were added to 4′-benzyloxy-4-biphenylcarboxylic acid (7.0 g) and reacted under reflux for 3 hours, and then 2-aminophenol ( 5.1 g) of 1,4-dioxane (100 mL) was added, and the mixture was reacted under reflux for 3 hours. After cooling, the precipitated crystals were collected by filtration. The obtained crystals were washed successively with 5% aqueous hydrochloric acid and methanol, and dried to obtain an intermediate amide compound (7.57 g, Y = 83%).
Amide compound (7.5 g) is dissolved in 1,3-dimethyl-2-imidazolidinone (50 mL), p-toluenesulfonic acid monohydrate (10 g) and toluene (100 mL) are added, and it is formed under reflux. The reaction was carried out overnight while removing water. After cooling, the precipitated crystals were collected by filtration, and the obtained crystals were suspended under reflux with methanol (30 mL) and 0.3% aqueous sodium hydroxide solution (300 mL). The crystals were collected by filtration, washed with methanol and dried to give compound 36 (6.1 g, Y = 85%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 5.13 (2H, s) 7.00-8.38 (17H, m)

Methanol (300 mL), toluene (150 mL), and 5% palladium carbon (2.5 g) were added to compound 36 (6.05 g), and reacted at about 45 ° C. in a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure and dried to obtain Compound 37 (3.62 g, Y = 79%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 6.91 (2H, d, J = 8Hz) 7.34-7.91 (8H, m) 8.25 (2H, d, J = 8Hz) 9.50 (1H, br)
Compound 37 (0.63 g) was dissolved in DMF (15 mL), and potassium carbonate (1.5 g) and ethyl 4-bromo-n-butyrate (0.54 g) were added and reacted at room temperature overnight. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was washed with 20% aqueous methanol and recrystallized from ethanol to obtain Compound 38 (775 mg, Y = 88%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.27 (3H, t, J = 7Hz) 2.03-2.70 (4H, m) 3.98-4.35 (4H, m) 6.91-8.38 (12H, m)
Methanol (150 mL), 1,4-dioxane (20 mL), and 4% aqueous sodium hydroxide solution (10 mL) were added to compound 38 (695 mg), and reacted under reflux for 1 hour. The reaction solution was concentrated under reduced pressure, 50% acetone aqueous solution (400 mL) was added to the residue and dissolved by heating, and then acidified by adding dilute hydrochloric acid. The precipitated crystals were collected by filtration and dried to obtain Compound 39 (642 mg, Y = 99%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.83-2.57 (4H, m) 4.06 (2H, t, J = 6Hz) 6.99-8.33 (12H, m) 12.16 (1H, br)
To compound 39 (110 mg), water (200 mL) and 1% aqueous sodium hydroxide solution (1.3 mL) were added and dissolved by heating, followed by filtration. The filtrate was lyophilized to give compound 40 (122.8 mg, Y = 105%).

Example 14
6-[[4 '-(2-Benzoxazolyl) [1,1'-biphenyl] -4-yl] oxy] hexanoic acid ethyl ester (compound 41), 6-[[4'-(2-benzo Oxazolyl) [1,1'-biphenyl] -4-yl] oxy] hexanoic acid (Compound 42), 6-[[4 '-(2-Benzoxazolyl) [1,1'-biphenyl]- Preparation of 4-yl] oxy] hexanoic acid sodium salt (compound 43):
Compound 37 (0.6 g) was dissolved in DMF (15 mL), and potassium carbonate (1.5 g) and ethyl 6-bromohexanoate (0.61 g) were added and reacted at room temperature overnight. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was washed with a 17% aqueous methanol solution and recrystallized from ethanol to obtain Compound 41 (774 mg, Y = 86%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.26 (3H, t, J = 7H) 1.37-1.95 (6H, m) 2.35 (2H, t, J = 6Hz) 3.93-4.33 (4H, m) 6.91-8.38 (12H, m)
Compound 41 (700 mg) was dissolved by adding methanol (70 mL) and 1,4-dioxane (30 mL), and 5% aqueous sodium hydroxide solution (10 mL) was added and reacted under reflux for 3 hours. The reaction mixture was concentrated under reduced pressure, 33% acetone aqueous solution (450 mL) was added to the residue and dissolved by heating, and acidified by adding dilute hydrochloric acid. The precipitated crystals were collected by filtration and dried to obtain Compound 42 (651 mg, Y = 100%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.28-1.90 (6H, m) 2.26 (2H, t, J = 6Hz) 4.01 (2H, t, J = 6Hz) 6.97-8.32 (12H, m) 12.01 (1H, br)
To compound 42 (97 mg), water (200 mL) and 1% aqueous sodium hydroxide solution (1.1 mL) were added and dissolved by heating, followed by filtration. The filtrate was lyophilized to give compound 43 (104.4 mg, Y = 102%).

Example 15
[[4 '-(2-Benzoxazolyl) [1,1'-biphenyl] -4-yl] oxy] methylpropanedioic acid diethyl ester (compound 44), [[4'-(2-benzoxazolyl L) [1,1'-biphenyl] -4-yl] oxy] methylpropanedioic acid (compound 45), [[4 '-(2-benzoxazolyl) [1,1'-biphenyl] -4- [Il] oxy] methylpropanedioic acid disodium salt (compound 46):
Compound 37 (0.60 g) was dissolved in DMF (15 mL), and potassium carbonate (1.5 g) and diethyl 2-bromo-2-methylmalonate (0.70 g) were added and reacted at room temperature overnight. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was washed with 20% aqueous methanol and recrystallized from ethanol to obtain Compound 44 (636 mg, Y = 66%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.28 (6H, t, J = 7Hz) 1.82 (3H, s) 4.14-4.49 (4H, m) 7.01-8.39 (12H, m)

Compound 44 (560 mg) was dissolved in methanol (80 mL), a 4.5% aqueous sodium hydroxide solution (10 mL) was added, and the mixture was reacted under reflux for 1 hour. The reaction solution was concentrated under reduced pressure, 33% acetone aqueous solution (450 mL) was added to the residue and dissolved by heating, and then acidified by adding dilute hydrochloric acid. The precipitated crystals were collected by filtration and recrystallized from a mixed solution of toluene and ethyl acetate to obtain Compound 45 (263 mg, Y = 54%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.71 (3H, s) 6.97-8.35 (12H, m) 9.50 (2H, br)
To compound 45 (96.5 mg), water (40 mL) and 1% aqueous sodium hydroxide solution (2 mL) were added and dissolved by heating, followed by filtration. The filtrate was lyophilized to give compound 46 (105.8 mg, Y = 99%).

Example 16
[3-[[4 '-(2-Benzoxazolyl) [1,1'-biphenyl] -4-yl] oxy] propyl] propanedioic acid diethyl ester (compound 47), [3-[[4' -(2-Benzoxazolyl) [1,1'-biphenyl] -4-yl] oxy] propyl] propanedioic acid (Compound 48), [3-[[4 '-(2-Benzoxazolyl) Preparation of [1,1'-biphenyl] -4-yl] oxy] propyl] propanedioic acid disodium salt (Compound 49):
Compound 37 (500 mg) was dissolved in DMF (15 mL), potassium carbonate (2.0 g) and diethyl (3-chloropropyl) malonate (570 mg) were added, and the mixture was reacted at about 55 ° C. overnight. Ethyl acetate (150 mL) was added to the reaction mixture, and the mixture was washed successively with water and saturated brine. The ethyl acetate layer was dehydrated with magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column (chloroform) to obtain Compound 47 (302 mg, Y = 36%).
Methanol (80 mL), 1,4-dioxane (20 mL), and 10% aqueous sodium hydroxide (3 mL) were added to compound 47 (302 mg), and the mixture was reacted at about 50 ° C. overnight. After cooling, the precipitated crystals were collected by filtration and dried to obtain Compound 49 (85 mg, Y = 29%).
The filtrate of compound 49 was concentrated under reduced pressure, and water (50 mL) was added to the residue and dissolved by heating. The precipitated crystals were collected by filtration and dried to obtain Compound 48 (150 mg, Y = 56%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.64-2.11 (4H, m) 3.35 (1H, t, J = 7Hz) 4.06 (2H, t, J = 6Hz) 6.99-8.34 (12H, m) 12.69 (2H, br)

Example 17
[5-[[4 '-(2-Benzoxazolyl) [1,1'-biphenyl] -4-yl] oxy] pentyl] propanedioic acid diethyl ester (compound 50), [5-[[4' Preparation of-(2-Benzoxazolyl) [1,1'-biphenyl] -4-yl] oxy] pentyl] propanedioic acid disodium salt (Compound 51):
Compound 37 (300 mg) was dissolved in DMF (10 mL), and potassium carbonate (1.2 g) and diethyl (5-bromopentyl) malonate (440 mg) were added and reacted at room temperature overnight. Ethyl acetate (100 mL) was added to the reaction mixture, and the mixture was washed successively with water and saturated brine. The ethyl acetate layer was dehydrated with magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column (chloroform) to obtain Compound 50 (411 mg, Y = 76%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.14-2.15 (14H, m) 3.35 (1H, t, J = 7Hz) 3.91-4.39 (6H, m) 6.91-8.38 (12H, m)
Compound 50 (411 mg) was dissolved in methanol (100 mL), 10% aqueous sodium hydroxide solution (6 mL) was added, and the mixture was reacted at about 60 ° C. overnight and under reflux for 6 hours. After cooling, the precipitated crystals were collected by filtration and dried to obtain Compound 51 (362 mg, Y = 90%).

Example 18
2- [6- (Phenylmethoxy) -2-naphthalenyl] benzoxazole (Compound 52), 6- (2-Benzoxazolyl) -2-naphthalenol (Compound 53), [[6- (2-Benzoxazolid L) -2-Naphthalenyl] oxy] acetic acid methyl ester (compound 54), [[6- (2-benzoxazolyl) -2-naphthalenyl] oxy] acetic acid (compound 55), [[6- (2-benzo Preparation of Oxazolyl) -2-naphthalenyl] oxy] acetic acid sodium salt (Compound 56):
In a nitrogen stream, 15% trimethylaluminum / toluene solution (12.5 mL) and 2-aminophenol (2.5 g) were added to toluene (120 mL) under cooling with ice water, and reacted for 30 minutes under reflux. A solution of ethyl 2-naphthoate (4.0 g) in toluene (40 mL) was added and reacted under reflux for 6 hours. A 70% aqueous methanol solution (100 mL) was added to the reaction mixture, and the mixture was refluxed for 1 hour, and the crystals were collected by filtration. The target compound contained in the obtained crystals was extracted with ethyl acetate while hot, and then concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to obtain an intermediate amide compound (3.32 g, Y = 69%).

Toluene (160 mL), thionyl chloride (4 mL) and DMF (1 drop) were added to the amide compound (2.9 g) and reacted under reflux for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified with a silica gel column (chloroform) to obtain Compound 52 (1.05 g, Y = 38%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 5.29 (2H, s) 7.27-8.77 (15H, m)
Compound 52 (0.88 g) was suspended in toluene (40 mL), ethanol (80 mL) and 5% palladium carbon (1 g) were added, and the mixture was reacted at room temperature in a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure and dried to obtain Compound 53 (480 mg, Y = 73%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 7.12-8.27 (9H, m) 8.71 (1H, s)
Compound 53 (330 mg) was dissolved in DMF (20 mL), and potassium carbonate (0.5 g) and methyl bromoacetate (0.25 g) were added and reacted at room temperature overnight. Toluene (150 mL) was added to the reaction mixture, and the mixture was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The toluene layer was dehydrated with magnesium sulfate, concentrated under reduced pressure, and dried to obtain Compound 54 (420 mg, Y = 100%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 3.76 (3H, s) 5.00 (2H, s) 7.29-8.77 (10H, m)

Methanol (150 mL) was added to and dissolved in compound 54 (215 mg), and a 3.3% aqueous sodium hydroxide solution (3 mL) was added and reacted at about 50 ° C. for 1.5 hours. The reaction mixture was concentrated under reduced pressure, water (50 mL) and ethyl acetate (200 mL) were added to the residue, and dilute hydrochloric acid was added to make the solution strongly acidic. The ethyl acetate layer was washed with saturated brine, dried over magnesium sulfate, concentrated under reduced pressure, and dried to give compound 55 (190 mg, Y = 92%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 4.88 (2H, s) 7.24-8.77 (10H, m)
Methanol (50 mL) and 1% aqueous sodium hydroxide solution (1.3 mL) were added to compound 55 (101 mg), dissolved by heating, concentrated under reduced pressure, and dried to obtain compound 56 (109 mg, Y = 101%).

Example 19
4-[[6- (2-Benzoxazolyl) -2-naphthalenyl] oxy] butanoic acid ethyl ester (Compound 57), 4-[[6- (2-Benzoxazolyl) -2-naphthalenyl] oxy Preparation of butanoic acid (Compound 58), 4-[[6- (2-Benzoxazolyl) -2-naphthalenyl] oxy] butanoic acid sodium salt (Compound 59):
Compound 53 (3.5 g) was dissolved in DMF (40 mL), and potassium carbonate (8.0 g) and ethyl 4-bromo-n-butyrate (3.4 g) were added and reacted at room temperature overnight. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was washed with 20% aqueous methanol and recrystallized from ethanol to obtain Compound 57 (4.4 g, Y = 87%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.27 (3H, t, J = 7Hz) 2.00-2.68 (4H, m) 4.00-4.35 (4H, m) 7.14-8.69 (10H, m)
Compound 57 (4.35 g) was dissolved in methanol (150 mL), 20% aqueous sodium hydroxide solution (10 mL) was added, and the mixture was reacted under reflux for 3 hours. The reaction solution was concentrated under reduced pressure, 40% aqueous methanol solution (700 mL) was added to the residue and dissolved by heating, and then acidified by adding dilute hydrochloric acid. The precipitated crystals were collected by filtration and dried to obtain Compound 58 (3.99 g, Y = 99%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.83-2.60 (4H, m) 4.17 (2H, t, J = 6Hz) 7.18-8.73 (10H, m) 12.21 (1H, br)
To compound 58 (110 mg), water (100 mL) and 1% aqueous sodium hydroxide solution (1.5 mL) were added and dissolved by heating, followed by filtration. The filtrate was lyophilized to give Compound 59 (121 mg, Y = 103%).

Example 20
N- [4-[[6- (2-Benzoxazolyl) -2-naphthalenyl] oxy] -1-oxobutyl] glycine ethyl ester (compound 60), N- [4-[[6- (2-benzo Preparation of Oxazolyl) -2-naphthalenyl] oxy] -1-oxobutyl] glycine potassium salt (Compound 61):
Compound 58 (0.80 g) was reacted with thionyl chloride (0.4 g) in toluene (30 mL) for 2 hours under reflux. After cooling, a solution of glycine ethyl ester hydrochloride (0.42 g) and triethylamine (0.9 g) in 1,3-dimethyl-2-imidazolidinone (40 mL) was added and reacted for 16 hours under water cooling. The reaction solution was concentrated under reduced pressure, and water (500 mL) was added to the residue for crystallization. The precipitated crystals were collected by filtration and washed with water to obtain crude crystals. The crude crystals were recrystallized from acetone (250 mL) to obtain compound 60 (709 mg, Y = 71%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.19 (3H, t, J = 7Hz) 1.95-2.66 (4H, m) 3.80-4.38 (6H, m) 7.23-8.47 (10H, m) 8.76 (1H, s)
A 5% aqueous potassium hydroxide solution (10 mL) was added to compound 60 (500 mg) in methanol (40 mL), and the mixture was reacted at room temperature overnight. Precipitated crystals were collected by filtration, washed with 80% aqueous methanol, and dried to give compound 61 (365 mg, Y = 71%).

Example 21
2-[[4-[[6- (2-Benzoxazolyl) -2-naphthalenyl] oxy] -1-oxobutyl] amino] pentanedioic acid diethyl ester (compound 62), 2-[[4-[[ 6- (2-Benzoxazolyl) -2-naphthalenyl] oxy] -1-oxobutyl] amino] pentanedioic acid (Compound 63), 2-[[4-[[6- (2-Benzoxazolyl) Preparation of -2-naphthalenyl] oxy] -1-oxobutyl] amino] pentanedioic acid disodium salt (Compound 64):
Toluene (20 mL), thionyl chloride (0.17 mL) and DMF (1 drop) were added to compound 58 (650 mg) and reacted under reflux for 2.5 hours, and then L-glutamic acid diethyl hydrochloride (600 mg) 1,3-dimethyl -2-Imidazolidinone (20 mL) solution and triethylamine (0.85 mL) were added and reacted at room temperature overnight. The reaction solution was concentrated under reduced pressure, 2% aqueous hydrochloric acid solution (80 mL) was added to the remaining solution, and the precipitated crystals were collected by filtration. The obtained crystals were recrystallized from ethanol to obtain Compound 62 (534 mg, Y = 54%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.15-1.39 (6H, m) 1.88-2.66 (8H, m) 3.93-4.81 (7H, m) 7.16-8.70 (10H, m)

Compound 62 (500 mg) was dissolved in methanol (200 mL), 2% aqueous sodium hydroxide solution (15 mL) was added, and the mixture was reacted at about 45 ° C. overnight. The precipitated crystals were collected by filtration and dried to obtain Compound 64 (99 mg, Y = 20%).
The filtrate of compound 64 was concentrated under reduced pressure, and water (30 mL) was added to the residue for dissolution, and then acidified by adding dilute hydrochloric acid. The precipitated crystals were collected by filtration and dried to obtain Compound 63 (125 mg, Y = 28%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.66-2.64 (8H, m) 4.00-4.50 (3H, m) 7.23-8.75 (10H, m) 12.3 (2H, br)

Example 22
6-[[6- (2-Benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid ethyl ester (Compound 65), 6-[[6- (2-Benzoxazolyl) -2-naphthalenyl] oxy Preparation of hexanoic acid (Compound 66), 6-[[6- (2-Benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid potassium salt (Compound 67):
Potassium carbonate (0.92 g) and ethyl 6-bromohexanoate (0.91 g) were added to compound 53 (1.00 g) in DMF (15 mL) and reacted at room temperature for 18 hours and at 80 to 90 ° C. for 1.5 hours. The reaction solution was added to water (150 mL) for crystallization, and the precipitated crystals were collected by filtration and washed with water to obtain Compound 65 (1.39 g, Y = 100%).
A 10% aqueous potassium hydroxide solution (10 mL) was added to compound 65 (0.98 g) in methanol (40 mL), and the mixture was reacted at room temperature overnight under reflux for 1 hour. The reaction mixture was concentrated under reduced pressure, and water (200 mL) and 35% hydrochloric acid were added to the residue for acid precipitation. The crystals were collected by filtration, washed with water, and dried to obtain Compound 66 (0.90 g, Y = 99%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.28-2.51 (8H, m) 4.13 (2H, t, J = 4Hz) 7.17-8.26 (9H, m) 8.72 (1H, s)
0.066% aqueous potassium hydroxide solution (150 mL) was added to compound 66 (200 mg) and dissolved by heating, and then activated carbon was added and filtered while hot. The filtrate was lyophilized to give compound 67 (216 mg, Y = 98%).

Example 23
Preparation of 6-[[6- (2-Benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid (2,2-dimethyl-1-oxopropoxy) methyl ester (Compound 68):
In DMF (10 mL), potassium carbonate (320 mg) and chloromethyl pivalate (180 mg) were added to compound 66 (150 mg) and reacted at 80 to 90 ° C. for 20 hours. The reaction was added to water (150 mL) and the reaction product was extracted with ethyl acetate (100 mL). The organic layer was washed with water, dehydrated with magnesium sulfate, and concentrated under reduced pressure to obtain crude crystals. The crude crystals were recrystallized from an 80% aqueous ethanol solution (10 mL) to obtain Compound 68 (147 mg, Y = 75%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.22 (9H, s) 1.61-2.00 (6H, m) 2.43 (2H, t, J = 6Hz) 4.11 (2H, t, J = 6Hz) 5.77 (2H, s) 7.14-7.96 (8H, m) 8.22-8.36 (1H, dd, J = 1Hz, 9Hz) 8.70 (1H, s)

Example 24
2-[[6-[[6- (2-Benzoxazolyl) -2-naphthalenyl] oxy] -1-oxohexyl] amino] pentanedioic acid diethyl ester (Compound 69), 2-[[6- [ [6- (2-Benzoxazolyl) -2-naphthalenyl] oxy] -1-oxohexyl] amino] pentanedioic acid (Compound 70), 2-[[6-[[6- (2-Benzoxazolyl] Preparation of ru) -2-naphthalenyl] oxy] -1-oxohexyl] amino] pentanedioic acid disodium salt (compound 71):
Toluene (20 mL), thionyl chloride (0.16 mL) and DMF (1 drop) were added to compound 66 (700 mg), reacted for 3 hours under reflux, and 1,3-L-glutamic acid diethyl hydrochloride (0.55 g) 1,3- Dimethyl-2-imidazolidinone (20 mL) solution and triethylamine (0.8 mL) were added and reacted overnight at room temperature. The reaction solution was concentrated under reduced pressure, 2% aqueous hydrochloric acid solution (80 mL) was added to the remaining solution, and the precipitated crystals were collected by filtration. The obtained crystals were recrystallized from ethanol to obtain Compound 69 (425 mg, Y = 44%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.11-2.57 (18H, m) 3.96-4.83 (7H, m) 7.14-8.77 (10H, m)

Compound 69 (400 mg) was dissolved by adding methanol (100 mL), 1% aqueous sodium hydroxide solution (20 mL) was added, and the mixture was reacted at about 45 ° C. overnight. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in water (60 mL), and acidified by adding dilute hydrochloric acid. The precipitated crystals were collected by filtration and dried to obtain Compound 70 (114 mg, Y = 32%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.30-2.41 (12H, m) 4.05-4.28 (3H, m) 7.18-8.75 (10H, m) 12.3 (2H, br)
To compound 70 (90.5 mg), water (40 mL) and a 0.5% aqueous sodium hydroxide solution (2.9 mL) were added and dissolved, followed by filtration. The filtrate was lyophilized to give compound 71 (100.6 mg, Y = 102%).

Example 25
[[6- (2-Benzoxazolyl) -2-naphthalenyl] oxy] propanedioic acid diethyl ester (Compound 72), [[6- (2-Benzoxazolyl) -2-naphthalenyl] oxy] propane Preparation of acid (compound 73), [[6- (2-benzoxazolyl) -2-naphthalenyl] oxy] propanedioic acid disodium salt (compound 74):
Compound 53 (600 mg) was dissolved in DMF (18 mL), and potassium carbonate (0.9 g) and diethyl bromomalonate (650 mg) were added and reacted overnight at room temperature. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column (ethyl acetate / n-hexane) to obtain Compound 72 (156 mg, Y = 19%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.32 (6H, t, J = 7Hz) 4.18-4.54 (4H, m) 5.39 (1H, s) 7.15-8.69 (10H, m)

Methanol (50 mL) and 5% aqueous sodium hydroxide solution (2 mL) were added to compound 72 (100 mg) and reacted at about 50 ° C. for 3 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in water (50 mL), and diluted hydrochloric acid was added for acid precipitation. The precipitated crystals were collected by filtration and dried to obtain Compound 73 (97 mg, Y = 90%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 5.65 (1H, s) 7.33-8.78 (10H, m)
Compound 73 (60 mg) was suspended in water (40 mL), dissolved by adding 1.6% aqueous sodium hydroxide solution (0.8 mL), and then filtered. The filtrate was lyophilized to obtain Compound 74 (65 mg, Y = 97%).

Example 26
[3-[[6- (2-Benzoxazolyl) -2-naphthalenyl] oxy] propyl] propanedioic acid diethyl ester (compound 75), [3-[[6- (2-benzoxazolyl)- 2-Naphthalenyl] oxy] propyl] propanedioic acid (Compound 76), [3-[[6- (2-Benzoxazolyl) -2-naphthalenyl] oxy] propyl] propanedioic acid disodium salt (Compound 77) Manufacturing of:
Compound 53 (372 mg) was dissolved in DMF (15 mL), and potassium carbonate (1.0 g) and diethyl (3-chloropropyl) malonate (350 mg) were added and reacted at about 60 ° C. overnight. Ethyl acetate (300 mL) was added to the reaction mixture, and the mixture was washed successively with water and saturated brine. The ethyl acetate layer was dehydrated with magnesium sulfate and concentrated under reduced pressure. The residue was purified with a silica gel column (chloroform) to obtain Compound 75 (299 mg, Y = 52%).
Methanol (50 mL) and 30% aqueous sodium hydroxide solution (1 mL) were added to compound 75 (299 mg), and the mixture was reacted at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the residue was dissolved by adding water (50 mL), and acidified by adding dilute hydrochloric acid. The precipitated crystals were collected by filtration and dried to obtain Compound 76 (174 mg, Y = 66%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.66-2.09 (4H, m) 3.38 (1H, t, J = 6Hz) 4.10-4.30 (2H, m) 7.23-8.75 (10H, m) 12.82 (2H, br)
To compound 76 (133 mg), water (40 mL) and a 0.5% aqueous sodium hydroxide solution (5.2 mL) were added and dissolved, followed by filtration. The filtrate was lyophilized to give compound 77 (125 mg, Y = 85%).

Example 27
Preparation of 2- [6- [2- (1-pyrrolidinyl) ethoxy] -2-naphthalenyl] benzoxazole hydrochloride (Compound 78):
Potassium carbonate (690 mg) and 1- (2-chloroethyl) pyrrolidine hydrochloride (266 mg) were added to compound 53 (300 mg) in DMF (10 mL) and reacted at 70-80 ° C. for 17 hours. The reaction was added to water (100 mL) and the reaction product was extracted with ethyl acetate (100 mL). The organic layer was washed with water, dehydrated with magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column (chloroform / methanol), and then compound 78 (195 mg, Y = 49%) was obtained as hydrochloride with 35% hydrochloric acid.
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.87-2.09 (4H, m) 3.08-3.73 (6H, m) 4.58 (2H, t, J = 5Hz) 7.32-8.34 (9H, m) 8.78 (1H, s) 10.55-12.07 (1H, br)

Example 28
Preparation of 2- [6- [2- (1-piperidinyl) ethoxy] -2-naphthalenyl] benzoxazole hydrochloride (Compound 79):
Potassium carbonate (694 mg) and 1- (2-chloroethyl) piperidine hydrochloride (284 mg) were added to compound 53 (300 mg) in DMF (8 mL) and reacted at 70-80 ° C. for 3 hours. The reaction solution was added to water (100 mL) for crystallization, and the precipitated crystals were collected by filtration and washed with water. The obtained crystals were dissolved in acetone (20 mL), 35% hydrochloric acid was added, and the precipitated crystals were collected by filtration and dried to give compound 79 (331 mg, Y = 81%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.38-2.14 (6H, m) 2.77-3.61 (6H, m) 4.64 (2H, t, J = 5Hz) 7.30-8.36 (9H, m) 8.78 (1H, s) 10.20-11.69 (1H, br)

Example 29
2- [6-[(4-pyridinyl) methoxy] -2-naphthalenyl] benzoxazole hydrochloride (Compound 80), 2- [6-[(4-pyridinyl) methoxy] -2-naphthalenyl] benzoxazole (Compound 81 )Manufacturing of:
Potassium carbonate (696 mg) and 4-chloromethylpyridine hydrochloride (247 mg) were added to compound 53 (300 mg) in DMF (10 mL), and reacted at 70-80 ° C. for 2 hours and 120 ° C. for 3 hours. The reaction was added to water (100 mL) and the reaction product was extracted with ethyl acetate (200 mL). The organic layer was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified with a silica gel column (chloroform / methanol), and then compound 80 (112 mg, Y = 29%) was obtained as hydrochloride with 35% hydrochloric acid.
25% aqueous ammonia solution was added to and suspended in Compound 80 (50 mg) in water (3 mL), and the crystals were collected by filtration and dried to obtain Compound 81 (35 mg, Y = 77%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 5.23 (2H, s) 7.10-8.71 (14H, m)

Example 30
Preparation of 2- [6-[(5-chloropentyl) oxy] -2-naphthalenyl] benzoxazole (Compound 82):
Compound 53 (0.9 g) was dissolved in DMF (20 mL), and potassium carbonate (3.5 g) and 1-bromo-5-chloropentane (0.80 g) were added and reacted at room temperature overnight. Water (80 mL) was added to the reaction solution for crystallization, and the precipitated crystals were collected by filtration. The obtained crystals were washed with ethanol and dried to give compound 82 (1.15 g, Y = 105%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.3-2.1 (6H, m) 3.59 (2H, t, J = 6Hz) 4.11 (2H, t, J = 6Hz) 7.13-8.69 (10H, m)

Example 31
Preparation of 2- [6-[[5- (1-pyrrolidinyl) pentyl] oxy] -2-naphthalenyl] benzoxazole hydrochloride (Compound 83):
Xylene (60 mL) and pyrrolidine (3 mL) were added to compound 82 (370 mg) and reacted under reflux for 3 days. The reaction mixture was concentrated under reduced pressure, 0.5% aqueous sodium hydroxide solution (50 mL) was added to the residue, and the precipitated crystals were collected by filtration. The obtained crystals were dissolved in acetone (80 mL), 35% hydrochloric acid (0.3 mL) was added, and the precipitated crystals were collected by filtration and dried to give compound 83 (338 mg, Y = 77%).
¹ H-NMR (Methanol-d4 / TMS):
δ = 1.50-2.30 (10H, m) 3.02-3.54 (6H, m) 4.17 (2H, t, J = 4Hz) 7.16-8.64 (10H, m)

Example 32
Preparation of 2- [6-[[5- (4-Methyl-1-piperazinyl) pentyl] oxy] -2-naphthalenyl] benzoxazole dihydrochloride (Compound 84):
To compound 82 (300 mg), xylene (50 mL) and N-methylpiperazine (1.5 mL) were added and reacted under reflux overnight. The reaction mixture was concentrated under reduced pressure, 0.5% aqueous sodium hydroxide solution (50 mL) was added to the residue, and the precipitated crystals were collected by filtration. The obtained crystals were dissolved in acetone (50 mL), 35% hydrochloric acid (0.3 mL) was added, and the precipitated crystals were collected by filtration and dried to give compound 84 (370 mg, Y = 90%).
¹ H-NMR (Methanol-d4, D ₂ O / TMS):
δ = 1.60-2.10 (6H, m) 2.92-3.66 (13H, m) 4.19 (2H, t, J = 5Hz) 7.16-8.67 (10H, m)

Example 33
6-methyl-2- [6- (phenylmethoxy) -2-naphthalenyl] benzoxazole (compound 85), 6- (6-methyl-2-benzoxazolyl) -2-naphthalenol (compound 86), [[ 6- (6-Methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] acetic acid methyl ester (compound 87), [[6- (6-methyl-2-benzoxazolyl) -2-naphthalenyl] Production of [oxy] acetic acid (compound 88), [[6- (6-methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] acetic acid potassium salt (compound 89):
Thionyl chloride (2.4 g) was added to 6-benzyloxy-2-naphthoic acid (5.0 g) in toluene (50 mL) and reacted under reflux for 2 hours. The reaction mixture was concentrated under reduced pressure, and n-hexane (200 mL) was added to the residue and stirred. The crystals were collected by filtration and dried to obtain 6-benzyloxy-2-naphthoic acid chloride (4.9 g, Y = 92%).
6-Benzyloxy-2-naphthoic acid chloride (2.0 g) was added to a solution of 6-amino-m-cresol (1.0 g) and triethylamine (0.8 g) in 1,3-dimethyl-2-imidazolidinone (40 mL). Reacted overnight at room temperature. The reaction solution was added to a saturated aqueous potassium hydrogen carbonate solution (400 mL) for crystallization, and the crystals were collected by filtration and washed with water to obtain crude crystals. The crude crystals were suspended in methanol with stirring under reflux, and the crystals were collected by filtration to obtain an intermediate amide compound (0.46 g).

In a mixture of 1,3-dimethyl-2-imidazolidinone (150 mL) and toluene (450 mL), p-toluenesulfonic acid monohydrate (9.93 g) is added to the amide compound (10.0 g) and produced under reflux. The reaction was carried out for 27 hours while removing water. The reaction solution was concentrated under reduced pressure, and the residue was added to a 1% aqueous potassium hydroxide solution (1500 mL) for crystallization. The precipitated crystals were collected by filtration, washed with water, methanol (600 mL) and potassium hydroxide (6 g) were added to the resulting crude crystals, and the mixture was stirred and suspended under reflux for 5 hours. (6.91 g, Y = 72%) was obtained.
¹ H-NMR (DMSO-d6 / TMS):
δ = 2.49 (3H, s) 5.28 (2H, s) 7.17-8.28 (13H, m) 8.72 (1H, s)
Compound 85 (18.0 g) was added to 1,3-dimethyl-2-imidazolidinone (900 mL) and dissolved, 5% palladium carbon (2.0 g) was added, and the reaction was carried out in a hydrogen atmosphere for 23 hours. The reaction solution was filtered, and the filtrate was added to water (10 L) for crystallization. Precipitated crystals were collected by filtration, washed with water, and dried to obtain Compound 86 (13.2 g, Y = 97%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 2.49 (3H, s) 7.16-8.23 (8H, m) 8.67 (1H, s) 10.14 (1H, s)

Potassium carbonate (0.6 g) and methyl bromoacetate (0.4 g) were added to compound 86 (0.6 g) in DMF (12 mL), and reacted at room temperature for 8 hours. The reaction solution was added to water (120 mL) for crystallization, and the precipitated crystals were collected by filtration and washed with water to obtain Compound 87 (Wet 2.55 g).
A 4% aqueous sodium hydroxide solution (5 mL) was added to compound 87 (Wet 2.55 g) in methanol (20 mL), and reacted at room temperature for 3.5 hours and at 50 ° C. for 1 hour. The reaction mixture was concentrated under reduced pressure, water (100 mL) was added to the residue, and acidified with 35% hydrochloric acid. The precipitated crystals were collected by filtration and washed with water to obtain crude crystals. The crude crystals were stirred with methanol (20 mL) under reflux for 1 hour, and then the crystals were collected by filtration and dried to obtain Compound 88 (0.51 g, Y = 70%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 2.49 (3H, s) 4.87 (2H, s) 7.17-8.29 (8H, m) 8.72 (1H, s)
0.1% aqueous potassium hydroxide solution (20 mL) and ethanol (10 mL) were added to compound 88 (100 mg) and dissolved by heating. Activated carbon (0.1 g) was added and filtered while hot, and the filtrate was concentrated under reduced pressure to obtain Compound 89 (56 mg, Y = 50%).

Example 34
4-[[6- (6-Methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] butanoic acid ethyl ester (compound 90), 4-[[6- (6-methyl-2-benzoxazolyl ) -2-Naphthalenyl] oxy] butanoic acid (Compound 91), 4-[[6- (6-Methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] butanoic acid potassium salt (Compound 92) Manufacturing:
Potassium carbonate (1.0 g) and ethyl 4-bromo-n-butyrate (0.85 g) were added to compound 86 (1.0 g) in DMF (15 mL), and reacted at room temperature for 22 hours and at 45 ° C. for 4.5 hours. The reaction solution was added to water (150 mL) for crystallization, and the precipitated crystals were collected by filtration and washed with water to obtain Compound 90 (Wet 3.9 g).
A 10% aqueous potassium hydroxide solution (10 mL) was added to compound 90 (Wet 3.9 g) in methanol (40 mL), and reacted at room temperature for 3 days and at 60 to 70 ° C. for 4 hours. The reaction mixture was concentrated under reduced pressure, water (300 mL) was added to the residue and dissolved by heating, and activated carbon (0.5 g) was added and filtered while hot. 35% hydrochloric acid was added to the filtrate for acid precipitation, and the crystals were collected by filtration, washed with water, and dried to obtain Compound 91 (0.95 g, Y = 72%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.82-2.49 (7H, m) 4.17 (2H, t, J = 6Hz) 7.17-8.29 (8H, m) 8.70 (1H, s) 11.48-12.97 (1H, br)
0.02% aqueous potassium hydroxide solution (170 mL) was added to compound 91 (200 mg) and dissolved by heating, and then activated carbon (0.2 g) was added and filtered while hot. The filtrate was lyophilized to give compound 92 (112 mg, Y = 51%).

Example 35
5-[[6- (6-Methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] pentanoic acid ethyl ester (Compound 93), 5-[[6- (6-Methyl-2-benzoxazolyl ) -2-Naphthalenyl] oxy] pentanoic acid (compound 94), 5-[[6- (6-methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] pentanoic acid potassium salt (compound 95) Manufacturing:
Potassium carbonate (2.0 g) and ethyl 5-bromovalerate (1.68 g) were added to compound 86 (1.0 g) in DMF (15 mL) and reacted at room temperature for 22 hours and at 45 ° C. for 6 hours. The reaction solution was added to water (150 mL) for crystallization, and the precipitated crystals were collected by filtration and washed with water to obtain Compound 93 (1.59 g, Y = 100%).
A 10% aqueous potassium hydroxide solution (10 mL) was added to compound 93 (1.16 g) in methanol (40 mL) and reacted at 45 ° C. for 3 hours. Activated carbon (0.2 g) was added to the reaction solution and filtered, and the filtrate was concentrated under reduced pressure. Water (100 mL) was added to the residue for dissolution, and then acidified with 35% hydrochloric acid. The crystals were collected by filtration, washed with water, and dried to obtain Compound 94 (0.80 g, Y = 74%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.77-1.83 (4H, m) 2.25-2.66 (5H, m) 4.15 (2H, t, J = 6Hz) 7.17-8.28 (8H, m) 8.69 (1H, s) 11.06-12.76 (1H, br)
A 0.02% aqueous potassium hydroxide solution (170 ml) was added to compound 94 (200 mg), dissolved by heating, activated carbon (0.2 g) was added, and the mixture was filtered while hot. The filtrate was lyophilized to give compound 95 (142 mg, Y = 65%).

Example 36
Preparation of 5-[[6- (6-methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] pentanoic acid (2,2-dimethyl-1-oxopropoxy) methyl ester (Compound 96):
Potassium carbonate (177 mg) and chloromethyl pivalate (104 mg) were added to compound 94 (150 mg) in DMF (10 mL) and reacted at 80 to 90 ° C. for 2 hours. The reaction solution was added into water (100 mL), and the reaction product was extracted with ethyl acetate (200 mL). The organic layer was washed with water, dehydrated with magnesium sulfate, and concentrated under reduced pressure to obtain crude crystals. The crude crystals were recrystallized from 80% aqueous ethanol (10 mL) to obtain Compound 96 (154 mg, Y = 79%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.22 (9H, s) 1.60-1.90 (4H, m) 2.28-2.52 (5H, m) 4.12 (2H, t, J = 6Hz) 5.78 (2H, s) 7.13-7.94 (7H, m) 8.28 ( 1H, d, J = 9Hz) 8.67 (1H, s)

Example 37
6-[[6- (6-Methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid ethyl ester (Compound 97), 6-[[6- (6-Methyl-2-benzoxazolyl ) -2-Naphthalenyl] oxy] hexanoic acid (Compound 98), 6-[[6- (6-Methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid potassium salt (Compound 99) Manufacturing:
Potassium carbonate (2.0 g) and ethyl 6-bromohexanoate (1.79 g) were added to compound 86 (1.0 g) in DMF (15 mL) and reacted at room temperature for 21 hours and at 45 ° C. for 6 hours. The reaction solution was added to water (150 mL) for crystallization, and the crystals were collected by filtration and washed with water to obtain Compound 97 (1.54 g, Y = 100%).
A 10% aqueous potassium hydroxide solution (10 mL) was added to compound 97 (1.21 g) in methanol (40 mL), and reacted at 45 ° C. for 3 hours and under reflux for 17 hours. The reaction mixture was concentrated under reduced pressure, water (100 mL) was added to the residue, and the mixture was dissolved with heating. Activated carbon (0.2 g) was added, and the mixture was filtered while hot. 35% hydrochloric acid was added to the filtrate for acid precipitation, and the crystals were collected by filtration, washed with water and dried to obtain crude crystals. The crude crystals were recrystallized from ethyl acetate to obtain Compound 98 (0.74 g, Y = 66%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.59-2.05 (6H, m) 2.18-2.68 (5H, m) 4.13 (2H, t, J = 6Hz) 7.16-8.28 (8H, m) 8.69 (1H, s) 11.97 (1H, brs)
0.098% aqueous potassium hydroxide solution (120 mL) was added to compound 98 (200 mg) and dissolved by heating. Activated carbon (0.2 g) was added, and the mixture was filtered while hot. The filtrate was lyophilized to give Compound 99 (105 mg, Y = 48%).

Example 38
7-[[6- (6-Methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] heptanoic acid ethyl ester (Compound 100), 7-[[6- (6-Methyl-2-benzoxazolyl ) -2-Naphthalenyl] oxy] heptanoic acid (Compound 101), 7-[[6- (6-Methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] heptanoic acid potassium salt (Compound 102) Manufacturing:
Potassium carbonate (2.0 g) and ethyl 7-bromoheptanoate (1.1 g) were added to compound 86 (1.0 g) in DMF (20 mL) and reacted at room temperature for 19 hours and at 80 ° C. for 6 hours. The reaction solution was added to water (200 mL) for crystallization, and the precipitated crystals were collected by filtration and washed with water to obtain Compound 100 (1.44 g, Y = 92%).
A 10% aqueous potassium hydroxide solution (10 mL) was added to compound 100 (1.19 g) in methanol (40 mL) and reacted at 70 ° C. for 1 hour. Activated carbon (0.1 g) was added to the reaction solution and filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in water (100 mL), and 35% hydrochloric acid was added for acid precipitation. Precipitated crystals were collected by filtration, washed with water, and dried to obtain Compound 101 (1.05 g, Y = 94%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.13-2.49 (13H, m) 4.12 (2H, t, J = 6Hz) 7.17-8.24 (8H, m) 8.69 (1H, s) 12.00 (1H, brs)
0.05% aqueous potassium hydroxide solution (70 mL) was added to compound 101 (200 mg) and dissolved by heating, and then activated carbon was added and filtered while hot. The filtrate was lyophilized to give Compound 102 (210 mg, Y = 96%).

Example 39
[5-[[6- (6-Methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] pentyl] propanedioic acid diethyl ester (compound 103), [5-[[6- (6-methyl- 2-Benzoxazolyl) -2-naphthalenyl] oxy] pentyl] propanedioic acid (Compound 104), [5-[[6- (6-Methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] Preparation of pentyl] propanedioic acid disodium salt (compound 105):
Potassium carbonate (910 mg) and diethyl (5-bromopentyl) malonate (757 mg) were added to compound 86 (400 mg) in DMF (12 mL) and reacted at room temperature for 30 hours. The reaction solution was added to water (150 mL) for crystallization, and the precipitated crystals were collected by filtration and washed with water to obtain Compound 103 (569 mg, Y = 78%).
A 22% aqueous potassium hydroxide solution (5 mL) was added to compound 103 (496 mg) in methanol (20 mL) and reacted at room temperature for 17 hours. Activated carbon was added to the reaction solution and filtered, and the filtrate was concentrated under reduced pressure. Water (50 mL) was added to the residue, and acidified with 35% hydrochloric acid. The separated oil was extracted with ethyl acetate (200 mL). The organic layer was washed with water, dehydrated with magnesium sulfate, and concentrated under reduced pressure. Ethanol (5 mL) was added to the residue and suspended with stirring, and the crystals were collected by filtration and dried to obtain Compound 104 (279 mg, Y = 63%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.18-1.99 (8H, m) 2.49 (3H, s) 3.25 (1H, t, J = 7Hz) 4.12 (2H, t, J = 6Hz) 7.17-8.29 (8H, m) 8.70 (1H, s) 12.15-13.19 (2H, br)
To the compound 104 (150 mg), 0.14% aqueous sodium hydroxide solution (20 mL) was added and dissolved, and then activated carbon was added and filtered. The filtrate was lyophilized to give compound 105 (158 mg, Y = 96%).

Example 40
6-methyl-2- [6- [2- (4-morpholinyl) ethoxy] -2-naphthalenyl] benzoxazole hydrochloride (Compound 106), 6-methyl-2- [6- [2- (4-morpholinyl) Preparation of [Ethoxy] -2-naphthalenyl] benzoxazole (Compound 107):
Potassium carbonate (2.0 g) and N- (2-chloroethyl) morpholine hydrochloride (0.81 g) were added to compound 86 (1.0 g) in DMF (20 mL) and reacted at room temperature for 3 hours and at 80 to 90 ° C. for 3 hours. did. The reaction solution was added to water (200 mL) for crystallization, and the crystals were collected by filtration and washed with water to obtain crude crystals. The crude crystals were suspended in acetone (40 mL), and 35% hydrochloric acid was added to adjust the pH to 1 to 2, and the crystals were collected by filtration and dried to obtain Compound 106 (1.37 g, Y = 89%).
A 25% aqueous ammonia solution was added to and suspended in Compound 106 (103 mg) in water (5 mL), and the crystals were collected by filtration and dried to obtain Compound 107 (70 mg, Y = 74%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 2.49-2.59 (7H, m) 2.78 (2H, t, J = 6Hz) 3.61 (4H, t, J = 5Hz) 4.27 (2H, t, J = 6Hz) 7.18-8.30 (8H, m) 8.71 ( 1H, s)

Example 41
[3-[[6- (6-Methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] propyl] carbamic acid 1,1-dimethylethyl ester (compound 108), 3-[[6- (6 -Methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] -1-propanamine hydrochloride (Compound 109), 3-[[6- (6-Methyl-2-benzoxazolyl) -2- Preparation of naphthalenyl] oxy] -1-propanamine methanesulfonate (compound 110):
Triethylamine (4.10 g) and di-t-butyl dicarbonate (5.30 g) were added to 3-chloropropylamine hydrochloride (2.60 g) in chloroform (30 mL) and reacted at 30 ° C. for 2 hours. The reaction solution was washed with 1N aqueous citric acid solution (25 mL) and saturated brine (25 mL), and then the chloroform layer was dehydrated with magnesium sulfate. Concentration under reduced pressure gave N-Boc-3-chloropropylamine (4.22 g).
In DMF (20 mL), potassium carbonate (1.0 g) and N-Boc-3-chloropropylamine (1.0 g) were added to compound 86 (1.0 g) and reacted at 80 to 90 ° C. for 12 hours. The reaction solution was added to water (200 mL) for crystallization, and the precipitated crystals were collected by filtration and washed with water to obtain crude crystals. The crude crystals were recrystallized from acetone (20 mL) to give compound 108 (0.91 g, Y = 58%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.39 (9H, s) 1.82-2.15 (2H, m) 2.49 (3H, s) 3.16 (2H, q, J = 6Hz) 4.16 (2H, t, J = 6Hz) 6.90 (1H, brs) 7.17- 8.27 (8H, m) 8.70 (1H, s)
To compound 108 (0.90 g), a saturated hydrochloric acid / acetic acid solution (10 mL) was added under ice-water cooling and reacted for 2 hours. The reaction mixture was added to diethyl ether (200 mL) and stirred at room temperature for 2 hours. The crystals were collected by filtration, washed with diethyl ether and dried to give compound 109 (0.71 g, Y = 92%).
Methanesulfonic acid (about 0.8 g) was added to compound 109 (106 mg) in a 77% aqueous methanol solution (13 mL) and dissolved by heating. After cooling, the precipitated crystals were collected by filtration and dried to obtain Compound 110 (93 mg, Y = 76%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.81-2.49 (8H, m) 3.06 (2H, t, J = 7Hz) 4.26 (2H, t, J = 6Hz) 7.19-8.31 (10H, m) 8.73 (1H, s)

Example 42
Preparation of N, N-dimethyl-3-[[6- (6-methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] -1-propanamine hydrochloride (Compound 111):
In DMF (10 mL), potassium carbonate (1.50 g) and 3-dimethylaminopropyl chloride hydrochloride (0.50 g) were added to compound 86 (0.50 g) and reacted at room temperature for 4 hours and at 80 to 90 ° C. for 15 hours. The reaction solution was added to water (300 mL) for crystallization, and the precipitated crystals were collected by filtration and washed with water. The obtained crystals were dissolved in acetone (60 mL) with heating, and acidified with 35% hydrochloric acid. Precipitated crystals were collected by filtration and dried to obtain crude crystals (0.39 g). The crude crystal was recrystallized from methanol to obtain Compound 111 (0.22 g, Y = 31%).
¹ H-NMR (Methanol-d4 / TMS):
δ = 2.18-2.63 (5H, m) 2.98 (6H, s) 3.43 (2H, t, J = 7Hz) 4.26 (2H, t, J = 6Hz) 7.14-8.25 (8H, m) 8.56 (1H, s)

Example 43
6- (1-methylethyl) -2- [6- (phenylmethoxy) -2-naphthalenyl] benzoxazole (Compound 112), 6- [6- (1-methylethyl) -2-benzoxazolyl]- 2-Naphthalenol (Compound 113), 6-[[6- [6- (1-Methylethyl) -2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid ethyl ester (Compound 114), 6- [ [6- [6- (1-methylethyl) -2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid (compound 115), 6-[[6- [6- (1-methylethyl)- Preparation of 2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid potassium salt (Compound 116):
After 3-isopropylphenol (10 g) was dissolved in propionic acid (20 mL), a mixture of fuming nitric acid (6.1 mL) and propionic acid (30 mL) was added dropwise at 0-7 ° C. to react. The reaction mixture was added to ice water (150 g) with stirring, neutralized with 50% aqueous sodium hydroxide solution, and 2-nitro-5-isopropylphenol oil (3.79 g, Y = 29%) was added by steam distillation. Obtained.
2-Nitro-5-isopropylphenol (3.55 g) was dissolved in methanol (40 mL), 5% palladium carbon (0.2 g) was added, and the reaction was carried out overnight under a hydrogen atmosphere. The reaction mixture was filtered, 35% hydrochloric acid (5 g) was added to the filtrate, and the mixture was concentrated under reduced pressure. The residue was dissolved in methanol (10 mL), and diethyl ether (500 mL) was added for crystallization. The precipitated crystals were collected by filtration and dried to obtain 2-amino-5-isopropylphenol hydrochloride (2.59 g, Y = 70%).
6-Benzyloxy-2-naphthoic acid chloride (2.5 g) was converted to 2-amino-5-isopropylphenol hydrochloride (2.4 g) and triethylamine (2.4 g) in 1,3-dimethyl-2-imidazolidinone (50 mL) It was added to the solution and reacted at room temperature for 5 hours. The reaction solution was added to water (500 mL) for crystallization, and the crystals were collected by filtration, washed with water, and dried to obtain an intermediate amide compound (3.9 g, Y = 100%).

In a mixture of 1,3-dimethyl-2-imidazolidinone (57 mL) and toluene (171 mL), p-toluenesulfonic acid monohydrate (3.6 g) is added to the amide compound (3.8 g) and produced under reflux. The reaction was carried out for 22 hours while removing water. The reaction solution was concentrated under reduced pressure, and the residue was added to water (1000 mL) and stirred, and then the target product was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure to obtain crude crystals. Methanol (30 mL) and potassium hydroxide (0.6 g) were added to the crude crystals and suspended for 2 hours under reflux. The crystals were collected by filtration and dried to obtain Compound 112 (1.61 g, Y = 44%).
Compound 112 (1.50 g) was added to 1,3-dimethyl-2-imidazolidinone (20 mL) and dissolved, 5% palladium carbon (0.1 g) was added, and the reaction was carried out in a hydrogen atmosphere for 3 days. The reaction solution was filtered, and the filtrate was added to water (500 mL) for crystallization. The precipitated crystals were collected by filtration and washed with water to obtain crude crystals. The crude crystals were recrystallized from ethanol (35 mL) to give compound 113 (0.75 g, Y = 65%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.23-1.34 (6H, d, J = 7Hz) 2.84-3.30 (1H, m) 7.26-8.22 (8H, m) 8.66 (1H, s) 10.15 (1H, s)
Potassium carbonate (0.55 g) and ethyl 6-bromohexanoate (0.54 g) were added to compound 113 (0.60 g) in DMF (15 mL), and reacted at room temperature for 24 hours and at 80 to 90 ° C. for 1 hour. The reaction solution was added to water (400 mL) for crystallization, and the precipitated crystals were collected by filtration and washed with water to obtain Compound 114 (0.62 g, Y = 70%).

A 6% aqueous potassium hydroxide solution (10 mL) was added to compound 114 (0.53 g) in methanol (40 mL), and reacted under reflux for 1 hour. Activated charcoal was added to the reaction solution and filtered while hot, and the filtrate was concentrated under reduced pressure. The residue was dissolved in water (100 mL) with heating, and 35% hydrochloric acid was added for acid precipitation. The precipitated crystals were collected by filtration, washed with water, and dried to obtain Compound 115 (430 mg, Y = 87%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.24-2.65 (14H, m) 2.83-3.29 (1H, m) 4.14 (2H, t, J = 5Hz) 7.22-8.27 (8H, m) 8.70 (1H, s) 11.99 (1H, brs)
0.05% aqueous potassium hydroxide solution (50 mL) was added to compound 115 (150 mg) and dissolved by heating, and then activated carbon was added and filtered while hot. The filtrate was lyophilized to give Compound 116 (155 mg, Y = 95%).

Example 44
2- [6- (Phenylmethoxy) -2-naphthalenyl] -6-benzoxazolol (Compound 117), 2- [6- (Phenylmethoxy) -2-naphthalenyl] -6-benzoxazolol
Acetate ester (compound 118), 2- (6-hydroxy-2-naphthalenyl) -6-benzoxazolol Acetate ester (compound 119), 6-[[6- [6- (acetyloxy) -2-benzoxa Zolyl] -2-naphthalenyl] oxy] hexanoic acid ethyl ester (compound 120), 6-[[6- (6-hydroxy-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid (compound 121) , 6-[[6- (6-Hydroxy-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid potassium salt (Compound 122):
4-Aminoresorcinol hydrochloride (10.3 g) is dissolved in 1,3-dimethyl-2-imidazolidinone (200 mL), triethylamine (12.5 g) is added, and then 6-benzyloxy-2-naphthoic acid chloride (16.2 g). A solution of g) in 1,3-dimethyl-2-imidazolidinone (160 mL) was added and allowed to react overnight at room temperature. The reaction solution was added to water (4 L) for crystallization, and the precipitated crystals were collected by filtration and dried to obtain an intermediate amide compound (20.7 g, Y = 98.4%).

An amide compound (20.7 g) and p-toluenesulfonic acid monohydrate (17.0 g) were added to a mixed solvent of 1,3-dimethyl-2-imidazolidinone (150 mL) and toluene (300 mL), and produced under reflux. The reaction was carried out overnight while removing water. The reaction solution was concentrated under reduced pressure, and water was added to the residue to crystallize. The precipitated crystals were collected by filtration, washed with methanol and dried to obtain Compound 117 (14.75 g, Y = 75%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 5.28 (2H, s) 6.79-8.65 (14H, m) 9.86 (1H, br)
Acetic anhydride (23 mL) was added to Compound 117 (2.3 g), and the mixture was reacted at 105 to 110 ° C. overnight. After cooling, the precipitated crystals were collected by filtration, washed with n-hexane and dried to obtain Compound 118 (2.34 g, Y = 91%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 2.35 (3H, s) 5.22 (2H, s) 7.00-8.68 (14H, m)
Toluene (46 mL), methanol (92 mL) and 5% palladium carbon (0.5 g) were added to compound 118 (2.3 g), and reacted at about 45 ° C. in a hydrogen atmosphere. The reaction mixture was filtered, and the obtained crystals were recrystallized from 1,4-dioxane to obtain Compound 119 (1.59 g, Y = 89%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 2.33 (3H, s) 7.14-8.69 (9H, m) 10.2 (1H, br)

Compound 119 (1.55 g) was dissolved in DMF (50 mL), and potassium carbonate (3.0 g) and ethyl 6-bromohexanoate (2.1 g) were added and reacted at room temperature overnight. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was washed with water and dried to obtain Compound 120.
Compound 120 was dissolved in methanol (50 mL), 10% aqueous sodium hydroxide solution (10 mL) was added, and the mixture was reacted at about 50 ° C. overnight. The reaction solution was concentrated under reduced pressure, the residue was dissolved in water (100 mL), and diluted hydrochloric acid was added for acid precipitation. The precipitated crystals were collected by filtration and dried to obtain Compound 121 (902 mg, Y = 47%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.49-1.96 (6H, m) 2.27 (2H, t, J = 6Hz) 4.14 (2H, t, J = 6Hz) 6.79-8.64 (9H, m)
Compound 121 (145.4 mg) was suspended in water (70 mL), 2% aqueous potassium hydroxide solution (1 mL) was added and dissolved by heating, followed by filtration. The filtrate was lyophilized to give Compound 122 (171 mg, Y = 107%).

Example 45
6-[[6- [6- (Phenylmethoxy) -2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid phenylmethyl ester (Compound 123), 6-[[6- [6- (Phenylmethoxy ) -2-Benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid (Compound 124), 6-[[6- [6- (phenylmethoxy) -2-benzoxazolyl] -2-naphthalenyl] oxy Production of potassium hexanoate (compound 125):
Compound 121 (500 mg) was dissolved in DMF (10 mL), potassium carbonate (1.5 g) and benzyl bromide (760 mg) were added, and the mixture was reacted at room temperature overnight. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was washed with water and dried to obtain Compound 123.
70% aqueous methanol solution (500 mL) and 1,4-dioxane (50 mL) were added to compound 123, and then sodium hydroxide (0.5 g) was added and reacted at about 60 ° C. overnight. The reaction solution was concentrated under reduced pressure, and water (0.5 L) was added to the residue to dissolve it with heating. The precipitated crystals were collected by filtration and dried to obtain Compound 124 (474 mg, Y = 77%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.40-1.94 (6H, m) 2.27 (2H, t, J = 6Hz) 4.14 (2H, t, J = 7Hz) 5.22 (2H, s) 6.99-8.65 (14H, m) 10.1 (1H, br)
Compound 124 (140 mg) was suspended in water (300 mL), 2% potassium hydroxide (1.1 mL) was added and dissolved by heating, followed by filtration. The filtrate was lyophilized to give compound 125 (175 mg, Y = 116%).

Example 46
6-methoxy-2- [6- (phenylmethoxy) -2-naphthalenyl] benzoxazole (compound 126), 6- (6-methoxy-2-benzoxazolyl) -2-naphthalenol (compound 127), [[ 6- (6-Methoxy-2-benzoxazolyl) -2-naphthalenyl] oxy] acetic acid methyl ester (Compound 128), [[6- (6-Methoxy-2-benzoxazolyl) -2-naphthalenyl] Production of [oxy] acetic acid (compound 129), [[6- (6-methoxy-2-benzoxazolyl) -2-naphthalenyl] oxy] acetic acid sodium salt (compound 130):
5-Methoxy-2-aminophenol hydrochloride (3.1 g) was suspended in 1.4-dioxane (100 mL), triethylamine (4.6 mL) was added, and 1,6-benzyloxy-2-naphthoic acid chloride (4.5 g) 1, 4-Dioxane (50 mL) solution was added and reacted under reflux for 3.5 hours. The reaction mixture was concentrated to about 1/3 volume under reduced pressure, added to 2% hydrochloric acid (800 mL), and the precipitated crystals were collected by filtration. The obtained crystals were recrystallized from 1,4-dioxane to obtain an intermediate amide compound (4.79 g, Y = 79%).

Produced under reflux by adding amide compound (4.43 g) and p-toluenesulfonic acid monohydrate (3.3 g) to a mixture of 1,3-dimethyl-2-imidazolidinone (45 mL) and toluene (90 mL) The reaction was carried out overnight while removing water. The reaction solution was concentrated under reduced pressure, and water (200 mL) was added to the remaining solution for crystallization. Precipitated crystals were collected by filtration, methanol (100 mL) and 12% aqueous sodium hydroxide solution (5 mL) were added, and the mixture was suspended under reflux for 40 minutes. The crystals were collected by filtration and dried to obtain Compound 126 (3.03 g, Y = 72%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 3.87 (3H, s) 5.27 (2H, s) 6.92-8.66 (14H, m)
Toluene (100 mL) and methanol (150 mL) were added and dissolved in Compound 126 (3.63 g), and 5% palladium carbon (1 g) was added and reacted at about 45 ° C. in a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure and dried to obtain Compound 127 (2.5 g, Y = 90%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 3.87 (3H, s) 6.92-8.62 (9H, m) 10.15 (1H, br)

Compound 127 (200 mg) was dissolved in DMF (10 mL), and potassium carbonate (380 mg) and methyl bromoacetate (150 mg) were added and reacted at room temperature overnight. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was washed with water and dried to give compound 128.
1,4-Dioxane (70 mL) and 2% aqueous sodium hydroxide solution (10 mL) were added to Compound 128, and the mixture was reacted at about 50 ° C. for 30 minutes. The reaction mixture was concentrated under reduced pressure, ethyl acetate (300 mL) and water (100 mL) were added to the residue, and the mixture was made strongly acidic by adding dilute hydrochloric acid, and then separated. The ethyl acetate layer was washed with saturated brine, dried over magnesium sulfate, concentrated under reduced pressure, and dried to give compound 129 (214 mg, Y = 89%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 3.87 (3H, s) 4.87 (2H, s) 6.92-8.67 (9H, m) 13.1 (1H, br)
Methanol (30 mL) and 1% aqueous sodium hydroxide solution (0.9 mL) were added to compound 129 (78 mg), dissolved by heating, concentrated under reduced pressure, and dried to obtain compound 130 (82 mg, Y = 99%).

Example 47
4-[[6- (6-Methoxy-2-benzoxazolyl) -2-naphthalenyl] oxy] butanoic acid ethyl ester (Compound 131), 4-[[6- (6-Methoxy-2-benzoxazolyl) ) -2-Naphthalenyl] oxy] butanoic acid (compound 132), 4-[[6- (6-methoxy-2-benzoxazolyl) -2-naphthalenyl] oxy] butanoic acid sodium salt (compound 133) Manufacturing:
Compound 127 (650 mg) was dissolved in DMF (18 mL), and potassium carbonate (1.1 g) and ethyl 4-bromo-n-butyrate (760 mg) were added and reacted at room temperature overnight. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was washed with water and recrystallized from methanol to obtain Compound 131 (825 mg, Y = 91%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.27 (3H, t, J = 7Hz) 2.09-2.69 (4H, m) 3.89-4.36 (7H, m) 6.90-8.62 (9H, m)
To compound 131 (759 mg), 1,4-dioxane (40 mL) and 3% aqueous sodium hydroxide solution (10 mL) were added and reacted at about 50 ° C. for 2 hours. The reaction mixture was concentrated under reduced pressure, and water (200 mL) was added to the residue to dissolve it with heating. The precipitated crystals were collected by filtration and dried to obtain Compound 132 (613 mg, Y = 87%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.93-2.61 (4H, m) 3.87 (3H, s) 4.17 (2H, t, J = 6Hz) 6.92-8.66 (9H, m)
Compound 132 (191 mg) was suspended in water (100 mL), and a 2.7% aqueous sodium hydroxide solution (0.8 mL) was added and dissolved by heating, followed by filtration. The filtrate was lyophilized to give compound 133 (199 mg, Y = 98%).

Example 48
6-[[6- (6-Methoxy-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid ethyl ester (compound 134), 6-[[6- (6-methoxy-2-benzoxazolyl) ) -2-Naphthalenyl] oxy] hexanoic acid (compound 135), 6-[[6- (6-methoxy-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid potassium salt (compound 136) Manufacturing:
Compound 127 (350 mg) was dissolved in DMF (15 mL), and potassium carbonate (800 mg) and ethyl 6-bromohexanoate (520 mg) were added and reacted at room temperature overnight. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was washed successively with water and ethanol and recrystallized from ethanol to obtain Compound 134 (3.72 g, Y = 98%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.26 (3H, t, J = 7Hz) 1.49-2.02 (6H, m) 2.37 (2H, t, J = 6Hz) 3.90-4.33 (7H, m) 6.90-8.63 (9H, m)
Compound 134 (380 mg) was dissolved in methanol (80 mL), 5% aqueous sodium hydroxide solution (4 mL) was added, and the mixture was reacted under reflux for 2 hours. The reaction mixture was concentrated under reduced pressure, and water (200 mL) was added to the residue to dissolve it with heating. The precipitated crystals were collected by filtration and dried to obtain Compound 135 (353 mg, Y = 100%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.34-1.96 (6H, m) 2.28 (2H, t, J = 6Hz) 3.87 (3H, s) 4.12 (2H, t, J = 6Hz) 6.95-8.63 (9H, m) 12.01 (1H, br)
To compound 135 (115 mg), water (100 mL) and a 0.4% aqueous potassium hydroxide solution (4 mL) were added and dissolved by heating, followed by filtration. The filtrate was lyophilized to give Compound 136 (133 mg, Y = 106%).

Example 49
[[6- (6-Methoxy-2-benzoxazolyl) -2-naphthalenyl] oxy] methylpropanedioic acid diethyl ester (compound 137), [[6- (6-methoxy-2-benzoxazolyl) -2-Naphthalenyl] oxy] methylpropanedioic acid (Compound 138), [[6- (6-Methoxy-2-benzoxazolyl) -2-naphthalenyl] oxy] methylpropanedioic acid disodium salt (Compound 139) Manufacturing of:
Compound 127 (0.6 g) was dissolved in DMF (18 mL), and potassium carbonate (1.0 g) and diethyl 2-bromo-2-methylmalonate (0.67 g) were added and reacted at room temperature overnight. Chloroform (200 mL) was added to the reaction mixture, and the mixture was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and the chloroform layer was dehydrated with magnesium sulfate and concentrated under reduced pressure to give compound 137.

Compound 137 was dissolved in methanol (40 mL), 6% aqueous sodium hydroxide solution (7 mL) was added, and the mixture was reacted at about 50 ° C. overnight. The reaction solution was concentrated under reduced pressure, and water (200 mL) was added to the residue for dissolution. The precipitated crystals were collected by filtration and dried to obtain Compound 138 (730 mg, Y = 87%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.80 (3H, s) 3.87 (3H, s) 6.94-8.69 (9H, m)
Compound 138 (192 mg) was suspended in water (30 mL), dissolved by adding a 2.7% aqueous sodium hydroxide solution (1.4 mL), and then filtered. The filtrate was lyophilized to obtain Compound 139 (205 mg, Y = 96%).

Example 50
[5-[[6- (6-Methoxy-2-benzoxazolyl) -2-naphthalenyl] oxy] pentyl] propanedioic acid diethyl ester (compound 140), [5-[[6- (6-methoxy- 2-Benzoxazolyl) -2-naphthalenyl] oxy] pentyl] propanedioic acid (compound 141), [5-[[6- (6-methoxy-2-benzoxazolyl) -2-naphthalenyl] oxy] Preparation of pentyl] propanedioic acid disodium salt (compound 142):
Compound 127 (550 mg) was dissolved in DMF (18 mL), potassium carbonate (0.9 g) and diethyl (5-bromopentyl) malonate (1.0 g) were added, and the mixture was reacted overnight at room temperature. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was washed with water and recrystallized from ethanol to obtain Compound 140 (750 mg, Y = 76%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.08-2.20 (14H, m) 3.36 (1H, t, J = 7Hz) 3.74-4.55 (9H, m) 6.87-8.62 (9H, m)

Compound 140 (680 mg) was dissolved in 1,4-dioxane (40 mL), 6% aqueous sodium hydroxide solution (5 mL) was added, and the mixture was reacted at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in water (150 mL). The precipitated crystals were collected by filtration and dried to obtain Compound 141 (531 mg, Y = 90%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.20-1.94 (8H, m) 3.25 (1H, t, J = 7Hz) 3.87 (3H, s) 4.13 (2H, t, J = 6Hz) 6.95-8.64 (9H, m)
Compound 141 (192 mg) was suspended in water (30 mL), dissolved by adding a 2.7% aqueous sodium hydroxide solution (1.25 mL), and then filtered. The filtrate was lyophilized to give Compound 142 (202 mg, Y = 93%).

Example 51
6-ethoxy-2- [6- (phenylmethoxy) -2-naphthalenyl] benzoxazole (compound 143), 6- (6-ethoxy-2-benzoxazolyl) -2-naphthalenol (compound 144), 6- [[6- (6-Ethoxy-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid ethyl ester (Compound 145), 6-[[6- (6-Ethoxy-2-benzoxazolyl) -2-Naphthalenyl] oxy] hexanoic acid (compound 146), 6-[[6- (6-ethoxy-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid sodium salt (compound 147):
Compound 117 (2.0 g) and sodium methoxide (0.46 g) were added and dissolved in ethanol (100 mL), diethyl sulfate (1.38 g) was added, and the mixture was reacted at about 60 ° C. overnight. After cooling, the precipitated crystals were collected by filtration, washed with ethanol and dried to obtain Compound 143 (1.66 g, Y = 77%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.47 (3H, t, J = 7Hz) 3.94-4.30 (2H, m) 5.22 (2H, s) 6.86-8.65 (14H, m)

Toluene (32 mL), methanol (64 mL) and 5% palladium carbon (0.5 mg) were added to compound 143 (1.615 g), and reacted at about 40 ° C. in a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was washed with methanol and dried to obtain Compound 144 (1.06 g, Y = 85%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.38 (3H, t, J = 7Hz) 3.95-4.30 (2H, m) 6.90-8.61 (9H, m) 10.13 (1H, br)
Compound 144 (500 mg) was dissolved in DMF (15 mL), potassium carbonate (1.0 g) and ethyl 6-bromohexanoate (0.63 g) were added, and the mixture was reacted at room temperature overnight. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was washed with water and recrystallized from ethanol to obtain Compound 145 (651 mg, Y = 89%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.08-2.20 (12H, m) 2.36 (2H, t, J = 6Hz) 3.95-4.33 (6H, m) 6.86-8.62 (9H, m)
Compound 145 (600 mg) was dissolved in 1,4-dioxane (40 mL), methanol (10 mL) and 6% aqueous sodium hydroxide solution (5 mL) were added, and the mixture was reacted at about 50 ° C. for 3 hours. The reaction solution was concentrated under reduced pressure, and water (100 mL) was added to the residue to dissolve it with heating. The precipitated crystals were collected by filtration and dried to obtain Compound 146 (456 mg, Y = 81%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.26-2.02 (9H, m) 2.27 (2H, t, J = 6Hz) 3.95-4.29 (4H, m) 6.90-8.63 (9H, m) 12.0 (1H, m)
To compound 146 (157 mg), water (100 mL) and a 2.7% aqueous sodium hydroxide solution (1.8 mL) were added and dissolved by heating, followed by filtration. The filtrate was lyophilized to give compound 147 (150 mg, Y = 91%).

Example 52
6-[[2- [6- (Phenylmethoxy) -2-naphthalenyl] -6-benzoxazolyl] oxy] hexanoic acid ethyl ester (Compound 148), 6-[[2- [6- (Phenylmethoxy) -2-Naphthalenyl] -6-benzoxazolyl] oxy] hexanoic acid (Compound 149), 6-[[2- (6-Hydroxy-2-naphthalenyl) -6-benzoxazolyl] oxy] hexanoic acid ( Compound 150), 6-[[2- (6-Hydroxy-2-naphthalenyl) -6-benzoxazolyl] oxy] hexanoic acid potassium salt (Compound 151):
Compound 117 (3.0 g) was dissolved in DMF (40 mL), and potassium carbonate (5.0 g) and ethyl 6-bromohexanoate (2.8 g) were added and reacted at room temperature overnight. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was washed with water and recrystallized from ethanol to obtain Compound 148 (3.72 g, Y = 89%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.26 (3H, t, J = 7Hz) 1.48-1.97 (6H, m) 2.36 (2H, t, J = 6Hz) 3.97-4.33 (4H, m) 5.21 (2H, s) 6.89-8.64 (14H, m)
Compound 148 (1.25 g) was dissolved in 1,4-dioxane (30 mL), methanol (30 mL) and 10% aqueous sodium hydroxide solution (5 mL) were added, and the mixture was reacted under reflux for 3 hours. The reaction mixture was concentrated under reduced pressure, the residue was suspended in water (100 mL), and acidified by adding dilute hydrochloric acid. The crystals were collected by filtration to give compound 149.

Methanol (300 mL) and 5% palladium carbon (0.6 g) were added to compound 149, and reacted at about 40 ° C. in a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was recrystallized from acetone to obtain Compound 150 (604 mg, Y = 63%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.35-1.90 (6H, m) 2.27 (2H, t, J = 6Hz) 4.06 (2H, t, J = 6Hz) 6.89-8.61 (9H, m) 10.3 (1H, br) 11.7 (1H, br)
To compound 150 (116 mg), water (80 mL) and a 0.4% aqueous potassium hydroxide solution (4.2 mL) were added and dissolved by heating, followed by filtration. The filtrate was lyophilized to give compound 151 (129 mg, Y = 101%).

Example 53
6-[[2- (6-Hydroxy-2-naphthalenyl) -6-benzoxazolyl] oxy] hexanoic acid ethyl ester (Compound 152), 6-[[6- [6-[(6-Ethoxy-6 -Oxohexyl) oxy] -2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid ethyl ester (compound 153), 6-[[6- [6-[(5-carboxypentyl) oxy] -2 -Benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid (compound 154), 6-[[6- [6-[(5-carboxypentyl) oxy] -2-benzoxazolyl] -2-naphthalenyl Production of dipotassium oxy] hexanoate (compound 155):
Toluene (40 mL), ethanol (80 mL), and 5% palladium carbon (0.5 g) were added to compound 148 (2.3 g), and reacted at room temperature in a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure and dried to obtain Compound 152 (1.9 g, Y = 100%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.27 (3H, t, J = 7Hz) 1.48-2.07 (6H, m) 2.37 (2H, t, J = 6Hz) 3.90-4.37 (4H, m) 6.82-8.59 (9H, m)
Compound 152 (500 mg) was dissolved in DMF (15 mL), and potassium carbonate (800 mg) and ethyl 6-bromohexanoate (400 mg) were added and reacted at room temperature overnight. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was washed with water and recrystallized from ethanol to obtain Compound 153 (540 mg, Y = 81%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.08-2.43 (22H, m) 3.97-4.33 (8H, m) 6.88-8.61 (9H, m)

Compound 153 (510 mg) was dissolved in methanol (50 mL), 8% aqueous sodium hydroxide solution (5 mL) was added, and the mixture was reacted at about 50 ° C. overnight. The reaction mixture was concentrated under reduced pressure, water (80 mL) was added to the residue and dissolved by heating. The precipitated crystals were collected by filtration and dried to obtain Compound 154 (460 mg, Y = 100%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.23-2.45 (16H, m) 3.95-4.30 (4H, m) 6.90-8.64 (9H, m) 12.01 (2H, br)
To compound 154 (119 mg), water (50 mL) and 0.4% aqueous potassium hydroxide solution (6.6 mL) were added and dissolved by heating, followed by filtration. The filtrate was lyophilized to give compound 155 (138 mg, Y = 101%).

Example 54
6-[[2- (6-Ethoxy-2-naphthalenyl) -6-benzoxazolyl] oxy] hexanoic acid ethyl ester (Compound 156), 6-[[2- (6-Ethoxy-2-naphthalenyl)- 6-benzoxazolyl] oxy] hexanoic acid (compound 157), 6-[[2- (6-ethoxy-2-naphthalenyl) -6-benzoxazolyl] oxy] hexanoic acid sodium salt (compound 158) Manufacturing:
Compound 152 (0.50 g) was dissolved in DMF (10 mL), and potassium carbonate (0.80 g) and ethyl iodide (0.30 g) were added and reacted at room temperature overnight. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was washed with water, washed with ethanol and dried to give compound 156 (466 mg, Y = 87%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.13-1.97 (12H, m) 2.36 (2H, t, J = 6Hz) 3.93-4.33 (6H, m) 6.88-8.61 (9H, m)
Compound 156 (403 mg) was dissolved in methanol (100 mL), 10% aqueous sodium hydroxide solution (3 mL) was added, and the mixture was reacted at about 60 ° C. The reaction mixture was concentrated under reduced pressure, water (200 mL) and ethyl acetate (300 mL) were added to the residue, and the mixture was made strongly acidic by adding dilute hydrochloric acid, followed by liquid separation. The ethyl acetate layer was washed with saturated brine, dried over magnesium sulfate, concentrated under reduced pressure, and dried to give compound 157 (350 mg, Y = 93%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.18-2.09 (9H, m) 2.26 (2H, t, J = 6Hz) 3.95-4.37 (4H, m) 6.90-8.63 (9H, m) 12.0 (1H, br)
Compound 157 (78.3 mg) was suspended in water (60 mL), 0.7% aqueous sodium hydroxide solution (1.1 mL) was added and dissolved by heating, followed by filtration. The filtrate was lyophilized to give compound 158 (83 mg, Y = 101%).

Example 55
2- (6-hydroxy-2-naphthalenyl) -6-benzoxazolol (compound 159), [5-[[6- [6-[[7-ethoxy-6- (ethoxycarbonyl) -7-oxoheptyl ] Oxy] -2-benzoxazolyl] -2-naphthalenyl] oxy] pentyl] propanedioic acid diethyl ester (compound 160), [5-[[6- (6-hydroxy-2-benzoxazolyl)- Preparation of 2-naphthalenyl] oxy] pentyl] propanedioic acid diethyl ester (Compound 161):
Compound 117 (2.1 g) was suspended in methanol (40 mL), 5% palladium carbon (0.5 g) was added, and the mixture was reacted at about 45 ° C. in a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was recrystallized from a mixed solution of toluene and methanol to obtain Compound 159 (1.41 g, Y = 89%).

Compound 159 (1.35 g) was dissolved in DMF (45 mL), and potassium carbonate (5.0 g) and diethyl (5-bromopentyl) malonate (1.8 g) were added and reacted at room temperature overnight. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was fractionated on a silica gel column (chloroform) to obtain Compound 160 (0.61 g, Y = 17%) and Compound 161 (0.67 g, Y = 27%).
<Compound 160> ¹ H-NMR (CDCl ₃ / TMS):
δ = 1.14-2.22 (28H, m) 3.23-3.50 (2H, m) 3.96-6.89 (12H, m) 7.01-8.62 (9H, m)

Example 56
[5-[[6- [6-[(6,6-dicarboxyhexyl) oxy] -2-benzoxazolyl] -2-naphthalenyl] oxy] pentyl] propanedioic acid (Compound 162), [5 [ Preparation of [6- [6 [(6,6-dicarboxyhexyl) oxy] -2-benzoxazolyl] -2-naphthalenyl] oxy] pentyl] propanedioic acid tetrasodium salt (Compound 163):
Compound 160 (600 mg) was dissolved in methanol (100 mL), 1% aqueous sodium hydroxide solution (30 mL) was added, and the mixture was reacted at about 50 ° C. overnight. The reaction solution was concentrated under reduced pressure, and the residue was dissolved by adding water (50 mL), and acidified by adding dilute hydrochloric acid. The precipitated crystals were collected by filtration and dried to obtain Compound 162 (434.5 mg, Y = 85%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.23-2.02 (16H, m) 3.12-3.41 (2H, m) 3.95-4.26 (4H, m) 6.94-8.65 (9H, m) 12.64 (4H, br)
To Compound 162 (104.5 mg), water (40 mL) and 0.5% aqueous sodium hydroxide solution (5.4 mL) were added to dissolve and filtered. The filtrate was lyophilized to give Compound 163 (116 mg, Y = 97%).

Example 57
[5-[[6- [6- (cyclohexylmethoxy) -2-benzoxazolyl] -2-naphthalenyl] oxy] pentyl] propanedioic acid diethyl ester (compound 164), [5-[[6- [6 -(Cyclohexylmethoxy) -2-benzoxazolyl] -2-naphthalenyl] oxy] pentyl] propanedioic acid disodium salt (compound 165), [5-[[6- [6- (cyclohexylmethoxy) -2- Preparation of Benzoxazolyl] -2-naphthalenyl] oxy] pentyl] propanedioic acid (Compound 166):
Compound 161 (335 mg) was dissolved in DMF (6 mL), and potassium carbonate (450 mg) and bromomethylcyclohexane (153 mg) were added and reacted at room temperature overnight. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain Compound 164.
Methanol (100 mL) and 6% aqueous sodium hydroxide solution (5 mL) were added to compound 164 and reacted overnight under reflux. After cooling, the precipitated crystals were collected by filtration and dried to obtain Compound 165 (242.8 mg, Y = 62%).
Compound 165 (26 mg) was dissolved in water (5 mL), and acidified by adding dilute hydrochloric acid. The precipitated crystals were collected by filtration and dried to obtain Compound 166 (10 mg, Y = 41%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.00-2.02 (19H, m) 3.05-4.30 (5H, m) 6.90-8.64 (9H, m) 12.6 (2H, br)

Example 58
[5-[[6- [6- (Phenylmethoxy) -2-benzoxazolyl] -2-naphthalenyl] oxy] pentyl] propanedioic acid diethyl ester (Compound 167), [5-[[6- [6 -(Phenylmethoxy) -2-benzoxazolyl] -2-naphthalenyl] oxy] pentyl] propanedioic acid disodium salt (compound 168), [5-[[6- [6- (phenylmethoxy) -2- Preparation of Benzoxazolyl] -2-naphthalenyl] oxy] pentyl] propanedioic acid (Compound 169):
Compound 161 (335 mg) was dissolved in DMF (6 mL), and potassium carbonate (450 mg) and benzyl bromide (150 mg) were added and reacted at room temperature overnight. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain Compound 167.
Methanol (100 mL) and 6% aqueous sodium hydroxide solution (5 mL) were added to compound 167 and reacted overnight under reflux. After cooling, the precipitated crystals were collected by filtration and dried to obtain Compound 168 (316.5 mg, Y = 82%).
Compound 168 (26 mg) was dissolved in water (5 mL), and acidified by adding dilute hydrochloric acid. The precipitated crystals were collected by filtration and dried to obtain Compound 169 (23 mg, Y = 96%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.25-2.0 (8H, m) 4.18 (2H, t, J = 7Hz) 5.22 (2H, s) 7.18-8.65 (14H, m)

Example 59
6-nitro-2- [6- (phenylmethoxy) -2-naphthalenyl] benzoxazole (compound 170), 6- (6-nitro-2-benzoxazolyl) -2-naphthalenol (compound 171), 4- [[6- (6-Nitro-2-benzoxazolyl) -2-naphthalenyl] oxy] butanoic acid ethyl ester (Compound 172), 4-[[6- (6-Amino-2-benzoxazolyl) -2-Naphthalenyl] oxy] butanoic acid ethyl ester (Compound 173), 4-[[6- (6-Amino-2-benzoxazolyl) -2-naphthalenyl] oxy] butanoic acid hydrochloride (Compound 174) Manufacturing:
6-Benzyloxy-2-naphthoic acid (6.2 g) was suspended in toluene (100 mL), thionyl chloride (1.9 mL) and DMF (1 drop) were added and reacted under reflux for 2 hours. A solution of 5-nitrophenol (7.0 g) in 1,4-dioxane (200 mL) was added and reacted under reflux for 3 hours. After cooling, the precipitated crystals were collected by filtration, washed successively with water and methanol and dried to obtain an intermediate amide compound (8.7 g, Y = 94%).
The amide compound (8.69 g) is dissolved in 1,3-dimethyl-2-imidazolidinone (87 mL), and p-toluenesulfonic acid monohydrate (6.5 g) and toluene (174 mL) are added to produce it under reflux. The reaction was carried out overnight while removing water. After cooling, the precipitated crystals were collected by filtration, washed with methanol and dried to obtain Compound 170 (7.46 g, Y = 90%).
30% hydrogen bromide / acetic acid solution (100 mL) was added to compound 170 (6.0 g), and the mixture was reacted at about 100 ° C. for 6 hours. The reaction solution was added to water for crystallization, and the precipitated crystals were collected by filtration. The obtained crystals were recrystallized from a mixed solution of toluene and methanol to obtain Compound 171 (4.05 g, Y = 87%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 7.14-8.68 (9H, m) 10.25 (1H, s)

To compound 171 (1.96 g), DMF (30 mL), potassium carbonate (3.0 g), and ethyl 4-bromo-n-butyrate (910 mg) were added and reacted at room temperature overnight. Water (300 mL) was added to the reaction solution for crystallization, and the precipitated crystals were collected by filtration. The obtained crystals were washed with methanol and dried to obtain Compound 172 (1.4 g, Y = 94%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.27 (3H, t, J = 7Hz) 2.10-2.73 (4H, m) 4.01-4.36 (4H, m) 7.14-8.68 (9H, m)
Ethanol (100 mL) and 5% palladium carbon (0.5 g) were added to compound 172 (1.1 g) and reacted at room temperature in a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure and dried to obtain Compound 173 (915 mg, Y = 90%).
Compound 173 (242 mg) was dissolved in methanol (100 mL), 6% aqueous sodium hydroxide solution (5 mL) was added, and the mixture was reacted at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in water (50 mL) by heating, neutralized with dilute hydrochloric acid, and the precipitated crystals were collected by filtration. The obtained crystals were suspended in acetone (50 mL), 35% hydrochloric acid (0.5 mL) was added, and the crystals were collected by filtration and dried to obtain Compound 174 (151 mg, Y = 61%).
¹ H-NMR (DMSO-d6, D ₂ O / TMS):
δ = 1.80-2.58 (4H, m) 4.19 (2H, t, J = 6Hz) 7.23-8.72 (9H, m)

Example 60
4-[[6- [6- (Diethylamino) -2-benzoxazolyl] -2-naphthalenyl] oxy] butanoic acid ethyl ester (Compound 175), 4-[[6- [6- (Diethylamino) -2 -Benzoxazolyl] -2-naphthalenyl] oxy] butanoic acid (compound 176), sodium 4-[[6- [6- (diethylamino) -2-benzoxazolyl] -2-naphthalenyl] oxy] butanoate Production of the salt (compound 177):
Compound 173 (365 mg) was dissolved in DMF (13 mL), potassium carbonate (2.5 g) and ethyl iodide (2.0 g) were added, and the mixture was reacted at about 70 ° C. overnight. Ethyl acetate (100 mL) was added to the reaction mixture, and the mixture was washed successively with water and saturated brine. The ethyl acetate layer was dehydrated with magnesium sulfate and concentrated under reduced pressure, and the residue was purified with a silica gel column (chloroform) to obtain Compound 175 (266 mg, Y = 64%).
Compound 175 (266 mg) was dissolved in methanol (40 mL), 7% aqueous sodium hydroxide solution (3 mL) was added, and the mixture was reacted at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in water (50 mL) with heating, and neutralized with dilute hydrochloric acid. The precipitated crystals were collected by filtration and dried to obtain Compound 176 (220 mg, Y = 85%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.14 (6H, t, J = 7Hz) 1.90-2.51 (4H, m) 3.15-3.60 (4H, m) 4.16 (2H, t, J = 6Hz) 6.68-8.59 (9H, m) 12.16 (1H, br)
To compound 176 (80.5 mg), water (30 mL) and a 0.4% aqueous sodium hydroxide solution (2 mL) were added and dissolved by heating, followed by filtration. The filtrate was lyophilized to give compound 177 (77 mg, Y = 91%).

Example 61
4-[[6- [6- [Bis (phenylmethyl) amino] -2-benzoxazolyl] -2-naphthalenyl] oxy] butanoic acid ethyl ester (Compound 178), 4-[[6- [6- [Bis (phenylmethyl) amino] -2-benzoxazolyl] -2-naphthalenyl] oxy] butanoic acid (Compound 179), 4-[[6- [6- [Bis (phenylmethyl) amino] -2- Preparation of benzoxazolyl] -2-naphthalenyl] oxy] butanoic acid sodium salt (compound 180):
Compound 173 (317 mg) was dissolved in DMF (13 mL), and potassium carbonate (2.5 g) and benzyl bromide (550 mg) were added and reacted at room temperature overnight. Ethyl acetate (100 mL) was added to the reaction mixture, and the mixture was washed successively with water and saturated brine. The ethyl acetate layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethanol to obtain Compound 178 (1.05 g, Y = 47%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.26 (3H, t, J = 7Hz) 2.00-2.70 (4H, m) 3.98-4.35 (4H, m) 4.74 (4H, s) 6.75-8.55 (19H, m)
Compound 178 (317 mg) was dissolved in methanol (80 mL), 7% aqueous sodium hydroxide solution (4 mL) was added, and the mixture was reacted at room temperature overnight at about 50 ° C. for 1 hr. The reaction mixture was concentrated under reduced pressure, ethyl acetate (150 mL) and water (150 mL) were added to the residue, and the mixture was made strongly acidic by adding dilute hydrochloric acid, and then separated. The ethyl acetate layer was washed with water, dried over magnesium sulfate, concentrated under reduced pressure, and dried to obtain Compound 179 (265 mg, Y = 88%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 2.04-2.75 (4H, m) 4.17 (2H, t, J = 6Hz) 4.74 (4H, s) 6.75-8.54 (19H, m)
Compound 179 (93.5 mg) was suspended in water (100 mL), 0.4% aqueous sodium hydroxide solution (1.8 mL) was added and dissolved by heating, followed by filtration. The filtrate was lyophilized to give compound 180 (95 mg, Y = 98%).

Example 62
6-[[6- (6-Nitro-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid ethyl ester (compound 181), 6-[[6- (6-amino-2-benzoxazolyl ) -2-Naphthalenyl] oxy] hexanoic acid ethyl ester (Compound 182), 6-[[6- [6- (Diethylamino) -2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid ethyl ester ( Compound 183), 6-[[6- [6- (Diethylamino) -2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid (Compound 184), 6-[[6- [6- (Diethylamino) Preparation of 2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid sodium salt (Compound 185):
Compound 171 (1.2 g) was dissolved in DMF (36 mL), potassium carbonate (3.0 g) and ethyl 6-bromohexanoate (1.15 g) were added, and the mixture was reacted at room temperature overnight. Ethyl acetate (300 mL) was added to the reaction mixture, and the mixture was washed successively with water and saturated brine. The ethyl acetate layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was washed with ethanol and dried to obtain Compound 181 (1.537 g, Y = 88%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.27 (3H, t, J = 7Hz) 1.45-2.03 (6H, m) 2.37 (2H, t, J = 6Hz) 4.01-4.34 (4H, m) 7.14-8.68 (9H, m)

Ethanol (80 mL), toluene (20 mL), and 5% palladium carbon (0.6 g) were added to compound 181 (1.3 g) and reacted at room temperature in a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure and dried to obtain Compound 182 (1.04 g, Y = 86%).
Compound 182 (0.52 g) was dissolved in DMF (20 mL), potassium carbonate (3.0 g) and ethyl iodide (3.0 g) were added, and the mixture was reacted at about 70 ° C. for 24 hours. Ethyl acetate (300 mL) was added to the reaction mixture, and the mixture was washed successively with water and saturated brine. The ethyl acetate layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified with a silica gel column (chloroform) to obtain Compound 183 (500 mg, Y = 85%).
To compound 183 (500 mg), 1,4-dioxane (5 mL) and methanol (45 mL) were added and dissolved, 15% aqueous sodium hydroxide solution (2 mL) was added, and the mixture was reacted at room temperature overnight at about 50 ° C. for 7 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in water (100 mL) and neutralized with dilute hydrochloric acid. The precipitated crystals were collected by filtration and dried to obtain Compound 184 (388 mg, Y = 83%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.14 (6H, t, J = 7Hz) 1.36-1.97 (6H, m) 2.27 (2H, t, J = 6Hz) 3.14-3.61 (4H, m) 4.12 (2H, t, J = 6Hz) 6.83- 8.58 (9H, m) 12.0 (1H, br)
To compound 184 (87 mg), water (25 mL) and a 0.5% aqueous sodium hydroxide solution (1.55 mL) were added and dissolved by heating, followed by filtration. The filtrate was lyophilized to give compound 185 (87 mg, Y = 95%).

Example 63
6-[[6- [6- [Bis (phenylmethyl) amino] -2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid ethyl ester (compound 186), 6-[[6- [6- [Bis (phenylmethyl) amino] -2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid (Compound 187), 6-[[6- [6- [Bis (phenylmethyl) amino] -2- Preparation of benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid sodium salt (Compound 188):
Compound 182 (0.52 g) was dissolved in DMF (20 mL), and potassium carbonate (2.0 g) and benzyl bromide (0.8 g) were added and reacted at room temperature overnight. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. Ethyl acetate (100 mL) was added to the residue, and the mixture was washed successively with water and saturated brine. The ethyl acetate layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was washed with ethanol and dried to give compound 186 (629.3 mg, Y = 85%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.25 (3H, t, J = 7Hz) 1.53-2.05 (6H, m) 2.36 (2H, t, J = 6Hz) 3.95-4.32 (4H, m) 4.74 (4H, s) 6.72-8.55 (19H, m)
To compound 186 (580 mg), 1,4-dioxane (10 mL) and methanol (30 mL) were added and dissolved, and 15% aqueous sodium hydroxide solution (2 mL) was added and reacted at room temperature overnight and under reflux for 2 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. Water (100 mL) was added to the residue and dissolved by heating, and diluted hydrochloric acid was added for acid precipitation. The precipitated crystals were collected by filtration and dried to obtain Compound 187 (531 mg, Y = 96%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.50-2.20 (6H, m) 2.44 (2H, t, J = 6Hz) 4.10 (2H, t, J = 6Hz) 4.74 (4H, m) 6.76-8.55 (19H, m)
To compound 187 (100 mg), water (25 mL) and 0.5% aqueous sodium hydroxide solution (1.4 mL) were added and dissolved by heating, followed by filtration. The filtrate was lyophilized to give compound 188 (98 mg, Y = 94%).

Example 64
[[6- (6-Nitro-2-benzoxazolyl) -2-naphthalenyl] oxy] propanedioic acid diethyl ester (Compound 189), [[6- (6-Nitro-2-benzoxazolyl)- Preparation of 2-Naphthalenyl] oxy] propanedioic acid (Compound 190), [[6- (6-Nitro-2-benzoxazolyl) -2-naphthalenyl] oxy] propanedioic acid disodium salt (Compound 191):
Compound 171 (2.0 g) was dissolved in DMF (80 mL), and potassium carbonate (3 g) and diethyl bromomalonate (2.1 g) were added and reacted at room temperature overnight. The reaction solution was concentrated under reduced pressure, and water (200 mL) was added to the residue for crystallization. Precipitated crystals were collected by filtration, washed with ethanol, and purified by silica gel column (chloroform) to obtain Compound 189 (1.08 g, Y = 36%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.33 (6H, t, J = 7Hz) 4.19-4.55 (4H, m) 5.40 (1H, s) 7.20-8.72 (9H, m)
To compound 189 (600 mg), 1,4-dioxane (20 mL) and methanol (80 mL) were added and dissolved, 10% aqueous sodium hydroxide solution (4 mL) was added, and the mixture was reacted at about 50 ° C. for 2 hr. The reaction solution was concentrated under reduced pressure, and water (40 mL) was added to the residue for dissolution, and then dilute hydrochloric acid was added for acid precipitation. The precipitated crystals were collected by filtration and dried to obtain Compound 190 (480 mg, Y = 91%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 4.87 (1H, s) 7.28-8.78 (9H, m)
Compound 190 (80 mg) was suspended in water (40 mL), dissolved by adding 1.6% aqueous sodium hydroxide solution (1 mL), and then filtered. The filtrate was lyophilized to give compound 191 (85 mg, Y = 96%).

Example 65
[5-[[6- (6-Nitro-2-benzoxazolyl) -2-naphthalenyl] oxy] pentyl] propanedioic acid diethyl ester (compound 192), [5-[[6- (6-amino- 2-Benzoxazolyl) -2-naphthalenyl] oxy] pentyl] propanedioic acid diethyl ester (compound 193), [5-[[6- [6- (diethylamino) -2-benzoxazolyl] -2- Naphthalenyl] oxy] pentyl] propanedioic acid diethyl ester (compound 194), [5-[[6- [6- (diethylamino) -2-benzoxazolyl] -2-naphthalenyl] oxy] pentyl] propanedioic acid diacid Preparation of sodium salt (compound 195):
Compound 171 (825 mg) was dissolved in DMF (25 mL), potassium carbonate (3.2 g) and diethyl (5-bromopentyl) malonate (1.16 g) were added, and the mixture was reacted at room temperature overnight and at about 70 ° C. overnight. The reaction solution was added to water (250 mL) for crystallization, and the precipitated crystals were collected by filtration. The obtained crystals were washed with methanol and dried to obtain Compound 192 (1.28 g, Y = 89%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.15-2.20 (14H, m) 3.36 (1H, t, J = 7Hz) 4.04-4.44 (6H, m) 7.14-8.70 (9H, m)

Ethanol (100 mL), toluene (20 mL), and 5% palladium carbon (0.3 g) were added to compound 192 (970 mg), and reacted at room temperature in a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure and dried to obtain Compound 193 (866 mg, Y = 95%).
Compound 193 (446 mg) was dissolved in DMF (8 mL), potassium carbonate (1.5 g) and ethyl iodide (1.0 g) were added, and the mixture was reacted at about 70 ° C. overnight. Ethyl acetate (100 mL) was added to the reaction mixture, and the mixture was washed successively with water and saturated brine. The ethyl acetate layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column (chloroform) to obtain Compound 194 (305 mg, Y = 62%).
Compound 194 (305 mg) was dissolved in methanol (50 mL), 6% aqueous sodium hydroxide solution (5 mL) was added, and the mixture was reacted at room temperature for 4 days. The precipitated crystals were collected by filtration and dried to obtain Compound 195 (204 mg, Y = 68%).
¹ H-NMR (Methanol-d4, D ₂ O / TMS):
δ = 1.01-1.99 (14H, m) 3.00-3.59 (5H, m) 4.11 (2H, t, J = 5Hz) 6.90-8.42 (9H, m)

Example 66
6-nitro-2- [6- [2- (4-morpholinyl) ethoxy] -2-naphthalenyl] benzoxazole (Compound 196), 2- [6- [2- (4-morpholinyl) ethoxy] -2-naphthalenyl ] -6-Benzoxazolamine dihydrochloride (compound 197), N, N-diethyl-2- [6- [2- (4-morpholinyl) ethoxy] -2-naphthalenyl] -6-benzoxazolamine dihydrochloride Production of (Compound 198):
Compound 171 (498 mg) was dissolved in DMF (10 mL), potassium carbonate (1.5 g) and N- (2-chloroethyl) morpholine hydrochloride (470 mg) were added, and the mixture was reacted at 70 ° C. overnight. Water (50 mL) was added to the reaction solution for crystallization, and the precipitated crystals were collected by filtration and dried to obtain Compound 196 (648 mg, Y = 95%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 2.55-2.99 (6H, m) 3.77 (4H, t, J = 5Hz) 4.29 (2H, t, J = 6Hz) 7.18-8.73 (9H, m)
Methanol (50 mL) and 5% palladium carbon (0.4 g) were added to compound 196 (550 mg), and reacted at room temperature in a hydrogen atmosphere. 35% Hydrochloric acid (1 mL) was added to the reaction solution and filtered, and the filtrate was concentrated under reduced pressure. Acetone (50 mL) and 35% hydrochloric acid (0.5 mL) were added to the residue for suspension, and the crystals were collected by filtration and dried to obtain Compound 197 (505 mg, Y = 83%).
¹ H-NMR (Methanol-d4, D ₂ O / TMS):
δ = 3.33-4.19 (10H, m) 4.66 (2H, t, J = 5Hz) 7.49-8.75 (9H, m)
Compound 197 (220 mg) was dissolved in DMF (10 mL), potassium carbonate (1.5 g) and ethyl iodide (1.0 g) were added, and the mixture was reacted at about 70 ° C. overnight. Water (40 mL) was added to the reaction solution for crystallization, and the precipitated crystals were collected by filtration. The obtained crystals were purified with a silica gel column (chloroform), dissolved in acetone (50 mL), 35% hydrochloric acid (0.3 mL) was added, and the precipitated crystals were collected by filtration and dried to give compound 198 (67 mg, Y = 27 %).
¹ H-NMR (Methanol-d4 / TMS):
δ = 1.23 (6H, t, J = 7Hz) 3.17-4.09 (14H, m) 4.65 (2H, t, J = 5Hz) 7.31-8.77 (9H, m)

Example 67
6- (cyclohexyloxy) -2- [6- (phenylmethoxy) -2-naphthalenyl] benzoxazole (Compound 199), 6- [6- (cyclohexyloxy) -2-benzoxazolyl] -2-naphthalenol ( Compound 200), 6-[[6- [6- (cyclohexyloxy) -2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid ethyl ester (Compound 201), 6-[[6- [6- (Cyclohexyloxy) -2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid (Compound 202), 6-[[6- [6- (cyclohexyloxy) -2-benzoxazolyl] -2- Preparation of Naphthalenyl] oxy] hexanoic acid potassium salt (Compound 203):
Compound 117 (1.5 g) was dissolved in DMF (15 mL), potassium carbonate (2.0 g) and bromocyclohexane (1.5 g) were added, and the mixture was reacted at about 65 ° C. for 4 days. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was washed with 15% aqueous methanol solution, then washed with 0.5% sodium hydroxide / methanol solution and dried to obtain Compound 199 (917 mg, Y = 50%).
Toluene (20 mL), methanol (40 mL), and 5% palladium carbon (450 mg) were added to compound 199 (910 mg), and reacted at about 45 ° C. in a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was recrystallized from a mixed solution of toluene and methanol to obtain Compound 200 (430 mg, Y = 66%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.25-2.36 (11H, m) 5.85 (1H, s) 7.05-8.65 (9H, m)

Compound 200 (430 mg) was dissolved in DMF (15 mL), and potassium carbonate (1.2 g) and ethyl 6-bromohexanoate (0.80 g) were added and reacted at room temperature overnight. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was washed with water and recrystallized from ethanol to obtain Compound 201 (197 mg, Y = 33%).
Compound 201 (197 mg) was dissolved in methanol (100 mL), 4% aqueous sodium hydroxide solution (5 mL) was added, and the mixture was reacted at about 60 ° C. for 1 hr. The reaction solution was concentrated under reduced pressure, and water (100 mL) was added to the residue to dissolve it with heating. The precipitated crystals were collected by filtration and dried to obtain Compound 202 (179 mg, Y = 96%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.16-2.42 (18H, m) 4.03-4.60 (3H, m) 6.91-8.64 (9H, m) 12.0 (1H, br)
To compound 202 (89 mg), water (200 mL) and a 0.4% aqueous potassium hydroxide solution (2.7 mL) were added and dissolved by heating, followed by filtration. The filtrate was lyophilized to give Compound 203 (110 mg, Y = 114%).

Example 68
5-methyl-2- [6- (phenylmethoxy) -2-naphthalenyl] benzoxazole (compound 204), 6- (5-methyl-2-benzoxazolyl) -2-naphthalenol (compound 205), 6- [[6- (5-Methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid ethyl ester (Compound 206), 6-[[6- (5-Methyl-2-benzoxazolyl) Preparation of 2-Naphthalenyl] oxy] hexanoic acid (Compound 207), 6-[[6- (5-Methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid potassium salt (Compound 208):
After 2-amino-p-cresol (1.5 g) and triethylamine (1.2 g) were added to and dissolved in 1,3-dimethyl-2-imidazolidinone (50 mL), 6-benzyloxy-2-naphthoic acid chloride (3.0 g) was added and reacted at room temperature for 2 hours. The reaction solution was added to water (800 mL) for crystallization, and the precipitated crystals were collected by filtration, washed with water, and dried to obtain an intermediate amide compound (3.5 g, Y = 90%).

In a mixture of 1,3-dimethyl-2-imidazolidinone (34 mL) and toluene (102 mL), p-toluenesulfonic acid monohydrate (3.4 g) is added to the amide compound (3.4 g) and produced under reflux. The reaction was carried out for 22 hours while removing water. The reaction mixture was concentrated under reduced pressure, and the residue was added to water (500 mL) for crystallization. The precipitated crystals were collected by filtration and washed with water to obtain crude crystals. Methanol (120 mL) and potassium hydroxide (2.0 g) were added to the crude crystals, and suspended under reflux for 2 hours. The crystals were collected by filtration and dried to obtain Compound 204 (2.14 g, Y = 66%).
After dissolving 1,3-dimethyl-2-imidazolidinone (50 mL) in compound 204 (1.8 g), 5% palladium on carbon (0.2 g) was added and reacted under a hydrogen atmosphere for 23 hours. The reaction solution was filtered, and the filtrate was added to water (800 mL) for crystallization. The precipitated crystals were collected by filtration, washed with water, and dried to obtain Compound 205 (1.34 g, Y = 99%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 2.46 (3H, s) 7.15-8.22 (8H, m) 8.67 (1H, s) 10.13 (1H, s)
In DMF (15 mL), potassium carbonate (510 mg) and ethyl 6-bromohexanoate (490 mg) were added to compound 205 (500 mg) and reacted at room temperature for 20 hours. The reaction solution was added to water (200 mL) for crystallization, and the precipitated crystals were collected by filtration and washed with water to obtain Compound 206 (700 mg, Y = 92%).
A 5% aqueous potassium hydroxide solution (10 mL) was added to compound 206 (646 mg) in methanol (40 mL) and reacted at room temperature for 20 hours and at 60 to 70 ° C. for 4 hours. The reaction solution was concentrated under reduced pressure, water (100 mL) was added to the residue, acidified with 35% hydrochloric acid with stirring, and filtered to obtain crude crystals. Methanol (30 mL) was added to the crude crystals and suspended at 60 to 70 ° C., and then the crystals were collected by filtration and dried to obtain Compound 207 (500 mg, Y = 83%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.58-2.67 (11H, m) 4.12 (2H, t, J = 3Hz) 7.17-8.24 (8H, m) 8.68 (1H, s) 11.96 (1H, s)
0.05% aqueous potassium hydroxide solution (50 mL) was added to compound 207 (150 mg) and dissolved by heating, and then activated carbon was added and filtered while hot. The filtrate was lyophilized to obtain Compound 208 (167 mg, Y = 100%).

Example 69
5- (1,1-dimethylethyl) -2- [6- (phenylmethoxy) -2-naphthalenyl] benzoxazole (Compound 209), 6- [5- (1,1-dimethylethyl) -2-benzoxa Zolyl] -2-naphthalenol (compound 210), 6-[[6- [5- (1,1-dimethylethyl) -2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid ethyl ester (compound 211), 6-[[6- [5- (1,1-dimethylethyl) -2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid (compound 212), 6-[[6- [5 -(1,1-Dimethylethyl) -2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid potassium salt (Compound 213):
A solution of 6-benzyloxy-2-naphthoic acid chloride (7.0 g) in 2-amino-4-tert-butylphenol (4.7 g) and triethylamine (2.9 g) in 1,3-dimethyl-2-imidazolidinone (80 mL) The mixture was reacted at room temperature for 3.5 hours. The reaction solution was added to water (1.5 L) for crystallization, and the precipitated crystals were collected by filtration, washed with water and dried to obtain an intermediate amide compound (9.3 g, Y = 93%).
In a mixture of 1,3-dimethyl-2-imidazolidinone (132 mL) and toluene (396 mL), p-toluenesulfonic acid monohydrate (7.9 g) is added to the amide compound (8.8 g) and produced under reflux. The reaction was carried out for 21 hours while removing the water. After the reaction solution was concentrated under reduced pressure, the remaining solution was added to water (1500 mL) for crystallization, and the precipitated crystals were collected by filtration and washed with water to obtain crude crystals. Methanol (88 mL) and potassium hydroxide (2.4 g) were added to the crude crystals and suspended for 2 hours under reflux. The crystals were collected by filtration and dried to obtain Compound 209 (3.52 g, Y = 42%).

Compound 209 (3.30 g) was added to 1,3-dimethyl-2-imidazolidinone (50 mL) and dissolved, 5% palladium carbon (0.4 g) was added, and the reaction was carried out in a hydrogen atmosphere for 23 hours. The reaction solution was filtered, and the filtrate was added to water (1.5 L) for crystallization. The precipitated crystals were collected by filtration and washed with water to obtain crude crystals. The crude crystals were recrystallized from ethanol (52 mL) to obtain compound 210 (1.32 g, Y = 51%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.38 (9H, s) 7.16-8.25 (8H, m) 8.69 (1H, s) 10.15 (1H, s)
Potassium carbonate (0.7 g) and ethyl 6-bromohexanoate (0.69 g) were added to compound 210 (0.80 g) in DMF (12 mL), and reacted at room temperature for 3 hours and at 80 to 90 ° C. for 8.5 hours. The reaction solution was added to water (200 mL) for crystallization, and the precipitated crystals were collected by filtration and washed with water to obtain Compound 211 (1.06 g, Y = 92%).
A 7% aqueous potassium hydroxide solution (10 mL) was added to compound 211 (0.82 g) in methanol (40 mL), and reacted under reflux for 1.5 hours. Activated carbon was added and filtered while hot, and the filtrate was concentrated under reduced pressure. Water (100 mL) was added to the residue, followed by acid precipitation with 35% hydrochloric acid, and the crystals were collected by filtration and washed with water to obtain crude crystals. The crude crystal was recrystallized from methanol (45 mL) to obtain Compound 212 (0.58 g, Y = 67%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.38-2.52 (17H, m) 4.15 (2H, t, J = 6Hz) 7.20-8.30 (8H, m) 8.72 (1H, s) 11.99 (1H, brs)
A 0.03% aqueous potassium hydroxide solution (120 mL) was added to Compound 212 (200 mg) and dissolved by heating, and then activated carbon was added and filtered while hot. The filtrate was lyophilized to obtain Compound 213 (205 mg, Y = 94%).

Example 70
[5-[[6- [5- (1,1-dimethylethyl) -2-benzoxazolyl] -2-naphthalenyl] oxy] pentyl] propanedioic acid diethyl ester (compound 214), [5-[[ 6- [5- (1,1-dimethylethyl) -2-benzoxazolyl] -2-naphthalenyl] oxy] pentyl] propanedioic acid (Compound 215), [5-[[6- [5- (1 , 1-Dimethylethyl) -2-benzoxazolyl] -2-naphthalenyl] oxy] pentyl] propanedioic acid disodium salt (Compound 216):
Potassium carbonate (610 mg) and diethyl (5-bromopentyl) malonate (623 mg) were added to compound 210 (300 mg) in DMF (12 mL) and reacted at room temperature for 26 hours. The reaction was added into water (150 mL) and the product was extracted with ethyl acetate (200 mL). The organic layer was washed with water, dehydrated with magnesium sulfate, and concentrated under reduced pressure to obtain a crude oil (1.04 g). Crude oil (1.04 g) was purified with a silica gel column (toluene / ethyl acetate) to obtain Compound 214 (0.69 g).
A 13% aqueous potassium hydroxide solution (5 mL) was added to compound 214 (0.69 g) in ethanol (20 mL) and reacted at room temperature for 17 hours. Water (10 mL) was added to the reaction solution, and the precipitated crystals were dissolved, activated carbon was added and filtered, and the filtrate was concentrated under reduced pressure. Water (50 mL) was added to the residue and dissolved, and then acidified with 35% hydrochloric acid. The separated oil was extracted with ethyl acetate (100 mL), and the organic layer was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure to give compound 215 (357 mg, Y = 77%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.38-1.98 (17H, m) 3.25 (1H, t, J = 7Hz) 4.14 (2H, t, J = 5Hz) 7.21-8.30 (8H, m) 8.72 (1H, s) 11.48-14.04 (2H, br)
To the compound 215 (150 mg), 0.13% aqueous sodium hydroxide solution (20 mL) was added and dissolved, and then activated carbon was added and filtered. The filtrate was lyophilized to obtain Compound 216 (158 mg, Y = 97%).

Example 71
5-phenyl-2- [6- (phenylmethoxy) -2-naphthalenyl] benzoxazole (compound 217), 6- (5-phenyl-2-benzoxazolyl) -2-naphthalenol (compound 218), 6- [[6- (5-Phenyl-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid ethyl ester (Compound 219), 6-[[6- (5-Phenyl-2-benzoxazolyl) -2-Naphthalenyl] oxy] hexanoic acid (compound 220):
2-Amino-4-phenylphenol (2.3 g) and triethylamine (1.2 g) are added to 1,3-dimethyl-2-imidazolidinone (50 mL) and dissolved, and then 6-benzyloxy-2-naphthoic acid chloride (3.0%) is dissolved. g) was added and reacted at room temperature for 5 hours. The reaction solution was added to water (800 mL) for crystallization, and the precipitated crystals were collected by filtration, washed with water and dried to obtain an intermediate amide compound (4.5 g, Y = 100%).
In a mixture of 1,3-dimethyl-2-imidazolidinone (44 mL) and toluene (132 mL), p-toluenesulfonic acid monohydrate (3.8 g) is added to the amide compound (4.4 g) and produced under reflux. The reaction was carried out for 23 hours while removing water. The reaction solution was concentrated under reduced pressure, and the residue was added to water (600 mL) for crystallization. The precipitated crystals were collected by filtration and washed with water to obtain crude crystals. Methanol (150 mL) and potassium hydroxide (2.2 g) were added to the crude crystals and suspended for 2 hours under reflux. The crystals were collected by filtration and dried to obtain Compound 217 (1.73 g, Y = 41%).

1,3-Dimethyl-2-imidazolidinone (50 mL) and 5% palladium carbon (0.2 g) were added to Compound 217 (1.5 g), and reacted at 50 ° C. for 23 hours in a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was added to water (800 mL) for crystallization. The precipitated crystals were collected by filtration, washed with water, and dried to obtain Compound 218 (1.09 g, Y = 92%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 7.17-8.28 (13H, m) 8.73 (1H, s) 10.17 (1H, s)
In DMF (15 mL), potassium carbonate (615 mg) and ethyl 6-bromohexanoate (606 mg) were added to compound 218 (500 mg) and reacted at room temperature for 24 hours and at 80 to 90 ° C. for 1.5 hours. The reaction solution was added to water (200 mL) for crystallization, and the precipitated crystals were collected by filtration and washed with water to obtain Compound 219 (621 mg, Y = 87%).
A 5.7% aqueous potassium hydroxide solution (10 mL) was added to compound 219 (571 mg) in methanol (40 mL), and reacted at 60 to 70 ° C. for 17 hours and at room temperature overnight. The reaction mixture was concentrated under reduced pressure, water (100 mL) was added to the residue, and the mixture was stirred and acidified with 35% hydrochloric acid. The precipitated crystals were collected by filtration and washed with water to obtain crude crystals. Methanol (30 mL) was added to the crude crystals, and after stirring and suspending at 60 to 70 ° C., the crystals were collected by filtration and dried to obtain Compound 220 (466 mg, Y = 87%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.59-2.52 (8H, m) 4.13 (2H, t, J = 5Hz) 7.13-8.32 (13H, m) 8.74 (1H, s) 12.00 (1H, s)

Example 72
[3-[[6- (5-Phenyl-2-benzoxazolyl) -2-naphthalenyl] oxy] propyl] propanedioic acid diethyl ester (compound 221), [3-[[6- (5-phenyl- 2-Benzoxazolyl) -2-naphthalenyl] oxy] propyl] propanedioic acid (compound 222), [3-[[6- (5-phenyl-2-benzoxazolyl) -2-naphthalenyl] oxy] Propyl] propanedioic acid disodium salt (compound 223):
In DMF (14 mL), potassium carbonate (674 mg) and diethyl (3-chloropropyl) malonate (552 mg) were added to compound 218 (400 mg) and reacted at 80 to 90 ° C. for 3 days. The reaction solution was added to water (100 mL) and stirred, and then the product was extracted with ethyl acetate (200 mL). The organic layer was washed with water, dehydrated with magnesium sulfate, and concentrated under reduced pressure to obtain a crude oil (0.8 g). The crude oil (0.8 g) was purified by a silica gel column (toluene / ethyl acetate) to obtain Compound 221 (211 mg, Y = 33%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.28 (6H, t, J = 7Hz) 1.72-2.34 (4H, m) 3.47 (1H, t, J = 7Hz) 3.97-4.40 (6H, m) 7.15-8.38 (13H, m) 8.71 (1H, s)

In ethanol (20 mL), 4.5% aqueous potassium hydroxide solution (20 mL) was added to compound 221 (190 mg) and reacted at room temperature for 23 hours. Activated carbon (0.1 g) was added to the reaction solution and filtered, and the filtrate was concentrated under reduced pressure. Water (50 mL) was added to the residue and dissolved, and then acidified with 35% hydrochloric acid. The product was extracted with ethyl acetate (100 mL), and the organic layer was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was dried to obtain Compound 222 (144 mg, Y = 85%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.89-1.99 (4H, m) 3.38 (1H, t, J = 4Hz) 4.19 (2H, t, J = 5Hz) 7.23-8.34 (13H, m) 8.77 (1H, s) 12.28-13.19 (2H, br)
A 0.03% aqueous sodium hydroxide solution (50 mL) was added to and dissolved in compound 222 (80 mg), and then activated carbon was added and filtered. The filtrate was lyophilized to obtain Compound 223 (87 mg, Y = 100%).

Example 73
5-chloro-2- [6- (phenylmethoxy) -2-naphthalenyl] benzoxazole (Compound 224), 6- (5-chloro-2-benzoxazolyl) -2-naphthalenol (Compound 225), 4- [[6- (5-Chloro-2-benzoxazolyl) -2-naphthalenyl] oxy] butanoic acid ethyl ester (Compound 226), 4-[[6- (5-Chloro-2-benzoxazolyl) -2-Naphthalenyl] oxy] butanoic acid (Compound 227), 4-[[6- (5-Chloro-2-benzoxazolyl) -2-naphthalenyl] oxy] butanoic acid sodium salt (Compound 228):
2-Amino-4-chlorophenol (5.1 g) was dissolved in 1,4-dioxane (70 mL), 6-benzyloxy-2-naphthoic acid chloride (3.5 g) was added, and the mixture was reacted under reflux for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was washed successively with dilute hydrochloric acid and methanol and dried to obtain an intermediate amide compound (4.19 g, Y = 88%).
1,3-dimethyl-2-imidazolidinone (25 mL), toluene (50 mL), p-toluenesulfonic acid monohydrate (3.0 g) was added to the amide compound (4.19 g), and water formed under reflux overnight. It reacted, removing. The reaction solution was concentrated under reduced pressure, and water (200 mL) was added to the residue to cause crystallization, and the precipitated crystals were collected by filtration. The obtained crystals were washed with methanol and dried to obtain Compound 224 (3.73 g, Y = 93%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 5.21 (2H, s) 7.23-8.67 (14H, m)

A 30% hydrogen bromide / acetic acid solution (28 mL) was added to compound 224 (2.8 g) and reacted at about 100 ° C. for 2 hours. Water (200 mL) was added to the reaction solution for crystallization, and the precipitated crystals were collected by filtration. The obtained crystals were washed with methanol and dried to obtain Compound 225 (1.99 g, Y = 93%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 7.16-8.25 (8H, m) 8.70 (1H, s) 10.21 (1H, s)
Compound 225 (453 mg) was dissolved in DMF (12 mL), and potassium carbonate (1.5 g) and ethyl 4-bromo-n-butyrate (410 mg) were added and reacted at room temperature overnight. Ethyl acetate (100 mL) was added to the reaction mixture, and the mixture was washed successively with water and saturated brine. The ethyl acetate layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was washed with ethanol and dried to obtain Compound 226 (602 mg, Y = 96%).
Methanol (50 mL) and 1,4-dioxane (10 mL) were added and dissolved in compound 226 (602 mg), 15% aqueous sodium hydroxide solution (3 mL) was added, and the mixture was reacted at about 50 ° C. overnight. After cooling the reaction solution, the precipitated crystals were collected by filtration and dried to obtain Compound 228 (476 mg, Y = 80%).
The filtrate of compound 228 was concentrated under reduced pressure, water (50 mL) was added to the residue and dissolved by heating, and acidified by adding dilute hydrochloric acid. The precipitated crystals were collected by filtration and dried to obtain Compound 227 (58 mg, Y = 10%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.90-2.52 (4H, m) 4.17 (2H, t, J = 6Hz) 7.21-8.72 (9H, m) 12.2 (1H, br)

Example 74
6-[[6- (5-Chloro-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid ethyl ester (Compound 229), 6-[[6- (5-Chloro-2-benzoxazolyl) ) -2-Naphthalenyl] oxy] hexanoic acid (Compound 230), 6-[[6- (5-Chloro-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid sodium salt (Compound 231) Manufacturing:
Compound 225 (453 mg) was dissolved in DMF (12 mL), and potassium carbonate (1.5 g) and ethyl 6-bromohexanoate (440 mg) were added and reacted overnight at room temperature. Ethyl acetate (100 mL) was added to the reaction mixture, and the mixture was washed successively with water and saturated brine. The ethyl acetate layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was washed with ethanol and dried to obtain Compound 229 (540 mg, Y = 81%).
Compound (229) (540 mg) was dissolved by adding methanol (50 mL) and 1,4-dioxane (10 mL), and then 15% aqueous sodium hydroxide solution (3 mL) was added and reacted at about 50 ° C. overnight. After cooling, the precipitated crystals were collected by filtration and dried to obtain Compound 231 (478 mg, Y = 90%).
The filtrate of Compound 231 was concentrated under reduced pressure, water (50 mL) was added to the residue and dissolved by heating, and acidified by adding dilute hydrochloric acid. The precipitated crystals were collected by filtration and dried to obtain Compound 230 (48 mg, Y = 10%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.20-2.00 (6H, m) 2.27 (2H, t, J = 6Hz) 4.11 (2H, t, J = 6Hz) 7.15-8.69 (9H, m)

Example 75
[3-[[6- (5-Chloro-2-benzoxazolyl) -2-naphthalenyl] oxy] propyl] propanedioic acid diethyl ester (compound 232), [3-[[6- (5-chloro- 2-Benzoxazolyl) -2-naphthalenyl] oxy] propyl] propanedioic acid disodium salt (compound 233), [3-[[6- (5-chloro-2-benzoxazolyl) -2-naphthalenyl Production of [oxy] propyl] propanedioic acid (compound 234):
Compound 225 (400 mg) was dissolved in DMF (7 mL), and potassium carbonate (1.5 g) and diethyl (3-chloropropyl) malonate (460 mg) were added and reacted at about 50 ° C. overnight. Ethyl acetate (100 mL) was added to the reaction mixture, and the mixture was washed successively with water and saturated brine. The ethyl acetate layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column (chloroform) to obtain Compound 232 (309 mg, Y = 46%).
Compound 232 (309 mg) was dissolved in methanol (40 mL) and 1,4-dioxane (10 mL), 15% aqueous sodium hydroxide solution (3 mL) was added, and the mixture was reacted overnight at room temperature. The precipitated crystals were collected by filtration and dried to obtain Compound 233 (273 mg, Y = 91%).
Compound 233 (28 mg) was dissolved in water (5 mL) by heating, and acidified by adding dilute hydrochloric acid. The precipitated crystals were collected by filtration and dried to obtain Compound 234 (19 mg, Y = 75%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.75-2.10 (4H, m) 3.37 (1H, t, J = 6Hz) 4.17 (2H, t, J = 7Hz) 7.21-8.72 (9H, m) 12.75 (2H, br)

Example 76
[5-[[6- (5-Chloro-2-benzoxazolyl) -2-naphthalenyl] oxy] pentyl] propanedioic acid diethyl ester (compound 235), [5-[[6- (5-chloro- 2-Benzoxazolyl) -2-naphthalenyl] oxy] pentyl] propanedioic acid (Compound 236), [5-[[6- (5-Chloro-2-benzoxazolyl) -2-naphthalenyl] oxy] Preparation of pentyl] propanedioic acid disodium salt (compound 237):
Compound 225 (163 mg) was dissolved in DMF (5 mL), and potassium carbonate (0.6 g) and diethyl (5-bromopentyl) malonate (260 mg) were added and reacted at room temperature overnight. Ethyl acetate (100 mL) was added to the reaction mixture, and the mixture was washed successively with water and saturated brine. The ethyl acetate layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column (chloroform) to obtain Compound 235 (206 mg, Y = 71%).
Methanol (80 mL) was added to and dissolved in compound 235 (206 mg), 6% aqueous sodium hydroxide solution (5 mL) was added, and the mixture was reacted at room temperature for 7 days. The reaction solution was concentrated under reduced pressure, and water (50 mL) was added to the residue and dissolved by heating. Then, dilute hydrochloric acid was added to cause acid precipitation. The precipitated crystals were collected by filtration and dried to obtain Compound 236 (138 mg, Y = 75%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.21-1.95 (8H, m) 3.25 (1H, t, J = 7Hz) 4.12 (2H, t, J = 6Hz) 7.20-8.71 (9H, m) 12.7 (2H, br)
Compound 236 (75.6 mg) was suspended in water (30 mL), 0.4% aqueous sodium hydroxide solution (3.3 mL) was added and dissolved by heating, followed by filtration. The filtrate was lyophilized to give compound 237 (77 mg, Y = 99%).

Example 77
Preparation of 5-chloro-2- [6- [2- (4-morpholinyl) ethoxy] -2-naphthalenyl] benzoxazole hydrochloride (Compound 238) Compound 225 (127 mg) was dissolved in DMF (2.5 mL) Potassium (0.52 g) and N- (2-chloroethyl) morpholine hydrochloride (122 mg) were added and reacted at about 70 ° C. overnight. Water (25 mL) was added to the reaction solution for crystallization, and the precipitated crystals were collected by filtration. The obtained crystals were dissolved in acetone (50 mL), 35% hydrochloric acid (0.5 mL) was added, and the precipitated crystals were collected by filtration and dried to obtain Compound 238 (177 mg, Y = 93%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 3.18-4.10 (10H, m) 4.68 (2H, t, J = 5Hz) 7.30-8.77 (9H, m) 12.0 (1H, br)

Example 78
4-methyl-2- [6- (phenylmethoxy) -2-naphthalenyl] benzoxazole (compound 239), 6- (4-methyl-2-benzoxazolyl) -2-naphthalenol (compound 240), 6- [[6- (4-Methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid ethyl ester (Compound 241), 6-[[6- (4-Methyl-2-benzoxazolyl) Preparation of -2-naphthalenyl] oxy] hexanoic acid (Compound 242), 6-[[6- (4-Methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid potassium salt (Compound 243):
2-Amino-m-cresol (1.5 g) and triethylamine (1.2 g) were added to and dissolved in 1,3-dimethyl-2-imidazolidinone (50 mL), and then 6-benzyloxy-2-naphthoic acid chloride (3.0 g) was added and reacted at room temperature for 2 hours. The reaction solution was added to water (800 mL) for crystallization, and the precipitated crystals were collected by filtration, washed with water, and dried to obtain an intermediate amide compound (3.5 g, Y = 90%).
In a mixture of 1,3-dimethyl-2-imidazolidinone (34 mL) and toluene (102 mL), p-toluenesulfonic acid monohydrate (3.4 g) is added to the amide compound (3.4 g) and produced under reflux. The reaction was carried out for 23 hours while removing water. The reaction solution was concentrated under reduced pressure, and the residue was added to water (800 mL) for crystallization. The precipitated crystals were collected by filtration and washed with water to obtain crude crystals. Methanol (100 mL) and potassium hydroxide (2.0 g) were added to the crude crystals and suspended for 2 hours under reflux. The crystals were collected by filtration and dried to obtain Compound 239 (2.64 g, Y = 81%).
1,3-Dimethyl-2-imidazolidinone (50 mL) was added to Compound 239 (2.40 g) and dissolved, then 5% palladium carbon (0.2 g) was added, and the mixture was reacted under a hydrogen atmosphere for 23 hours. The reaction solution was filtered, and the filtrate was added to water (800 mL) for crystallization. The precipitated crystals were collected by filtration, washed with water, and dried to obtain Compound 240 (1.77 g, Y = 98%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 2.62 (3H, s) 7.16-8.26 (8H, m) 8.70 (1H, s) 10.14 (1H, s)
Potassium carbonate (510 mg) and ethyl 6-bromohexanoate (500 mg) were added to compound 240 (500 mg) in DMF (15 mL), and reacted at room temperature for 21 hours. The reaction mixture was added to water (200 mL) and stirred, and the target product was extracted with ethyl acetate (600 mL). The organic layer was washed with water and concentrated under reduced pressure to obtain Compound 241 (1.0 g).

5% aqueous potassium hydroxide solution (10 mL) was added to compound 241 (1.0 g) in methanol (40 mL) and reacted at 45 ° C. for 15 hours. The reaction mixture was concentrated under reduced pressure, water (150 mL) was added to the residue to dissolve it, and acidified with 35% hydrochloric acid. The precipitated crystals were collected by filtration and washed with water to obtain crude crystals. The crude crystals were recrystallized from toluene (30 mL) to give compound 242 (596 mg, Y = 84%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.60-2.62 (11H, m) 4.14 (2H, t, J = 5Hz) 7.23-8.31 (8H, m) 8.73 (1H, s) 12.01 (1H, s)
0.05% aqueous potassium hydroxide solution (50 mL) was added to compound 242 (150 mg), dissolved by heating, activated carbon was added, and the mixture was filtered while hot. The filtrate was lyophilized to obtain Compound 243 (153 mg, Y = 93%).

Example 79
[3-[[6- (4-Methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] propyl] propanedioic acid diethyl ester (compound 244), [3-[[6- (4-methyl- 2-Benzoxazolyl) -2-naphthalenyl] oxy] propyl] propanedioic acid (Compound 245), [3-[[6- (4-Methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] Propyl] propanedioic acid disodium salt (compound 246):
Potassium carbonate (460 mg) and diethyl (3-chloropropyl) malonate (426 mg) were added to compound 240 (300 mg) in DMF (12 mL) and reacted at 80 ° C. for 24 hours.
The reaction mixture was added to water (150 mL) and stirred, and then the product was extracted with ethyl acetate (500 mL). The organic layer was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure to obtain a crude oil (0.62 g). Crude oil (0.62 g) was purified by silica gel column (toluene / ethyl acetate) to obtain compound 244 (0.41 g).
18% aqueous potassium hydroxide solution (5 mL) was added to compound 244 (0.41 g) in ethanol (20 mL) and reacted at room temperature for 2 hours and at 50 ° C. for 1 hour and 20 minutes. The reaction solution was concentrated under reduced pressure, and water (20 mL) was added to the residue for dissolution, followed by acid precipitation with 35% hydrochloric acid. The precipitated crystals were collected by filtration, washed with water, and dried to obtain crude crystals (217 mg). The crude crystals were recrystallized from 50% aqueous ethanol to obtain Compound 245 (178 mg, Y = 39%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.69-2.19 (4H, m) 2.62 (3H, s) 3.37 (1H, t, J = 7Hz) 4.18 (2H, t, J = 6Hz) 7.07-8.33 (8H, m) 8.74 (1H, s) 12.12-13.22 (2H, br)
0.08% aqueous sodium hydroxide solution (20 mL) was added to compound 245 (80 mg) to dissolve it, and then activated carbon was added and filtered. The filtrate was lyophilized to give compound 246 (87 mg, Y = 98%).

Example 80
[5-[[6- (4-Methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] pentyl] propanedioic acid diethyl ester (compound 247), [5-[[6- (4-methyl- 2-Benzoxazolyl) -2-naphthalenyl] oxy] pentyl] propanedioic acid (Compound 248), [5-[[6- (4-Methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] Pentyl] propanedioic acid disodium salt (Compound 249):
In DMF (10 mL), potassium carbonate (607 mg) and diethyl (5-bromopentyl) malonate (629 mg) were added to compound 240 (300 mg) and reacted at room temperature for 25 hours. The reaction solution was added to water (100 mL) and stirred, and then the product was extracted with ethyl acetate (200 mL). The organic layer was washed with water, dehydrated with magnesium sulfate, and concentrated under reduced pressure to obtain Compound 247 (794 mg).

A 6% aqueous potassium hydroxide solution (15 mL) was added to compound 247 (765 mg) in ethanol (20 mL) and reacted at room temperature for 6 hours. Activated carbon was added to the reaction solution and filtered, and the filtrate was concentrated under reduced pressure. Water (50 mL) was added to the residue and dissolved, and then acidified with 35% hydrochloric acid. The separated oil was extracted with ethyl acetate (200 mL), and then the organic layer was washed with water, dehydrated with magnesium sulfate, and concentrated under reduced pressure to obtain crude crystals (512 mg). Methanol (20 mL) was added to the crude crystals (512 mg) and suspended by stirring, and the crystals were collected by filtration and dried to obtain Compound 248 (362 mg, Y = 74%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.05-2.17 (8H, m) 2.62 (3H, s) 3.26 (1H, t, J = 6Hz) 4.13 (2H, t, J = 6Hz) 7.24-8.36 (8H, m) 8.73 (1H, s) 11.91-13.24 (2H, br)
0.04% aqueous sodium hydroxide solution (50 mL) was added to compound 248 (100 mg), and the mixture was almost dissolved, and then activated carbon was added and filtered. The filtrate was lyophilized to obtain Compound 249 (110 mg, Y = 100%).

Example 81
6-methyl-2- [3- (phenylmethoxy) -2-naphthalenyl] benzoxazole (compound 250), 3- (6-methyl-2-benzoxazolyl) -2-naphthalenol (compound 251), 4- [[3- (6-Methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] butanoic acid ethyl ester (Compound 252), 4-[[3- (6-Methyl-2-benzoxazolyl) -2-Naphthalenyl] oxy] butanoic acid (Compound 253), 4-[[3- (6-Methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] butanoic acid potassium salt (Compound 254):
In toluene (100 mL), 3-benzyloxy-2-naphthoic acid (7.0 g) was reacted with thionyl chloride (3.6 g) under reflux for 1 hour and 20 minutes. The reaction solution was concentrated under reduced pressure to obtain 3-benzyloxy-2-naphthoic acid chloride (7.9 g).
3-Benzyloxy-2-naphthoic acid chloride oil (7.9 g) in 6-amino-m-cresol (3.8 g) and triethylamine (3.1 g) in 1,3-dimethyl-2-imidazolidinone (100 mL) And reacted at room temperature for 2.5 hours. The reaction solution was added to water (1 L) for crystallization, and the precipitated crystals were collected by filtration, washed with water and dried to obtain an intermediate amide compound (9.2 g, Y = 95%).

In a mixture of 1,3-dimethyl-2-imidazolidinone (90 mL) and toluene (270 mL), p-toluenesulfonic acid monohydrate (9.0 g) is added to the amide compound (9.0 g) and produced under reflux. The reaction was carried out while removing water. The reaction solution was concentrated under reduced pressure, and the residue was added to water (1.5 L) for crystallization. The precipitated crystals were collected by filtration and washed with water to obtain crude crystals. Methanol (300 mL) and potassium hydroxide (10.0 g) were added to the crude crystals and suspended for 2 hours under reflux. The crystals were collected by filtration and dried to obtain Compound 250 (1.93 g, Y = 23%).
Compound 250 (2.70 g) was dissolved in 1,3-dimethyl-2-imidazolidinone (40 mL), 5% palladium carbon (0.2 g) was added, and the mixture was reacted under a hydrogen atmosphere for 3 days. The reaction solution was filtered, and the filtrate was added to water (800 mL) for crystallization. The precipitated crystals were collected by filtration, washed with water, and dried to obtain Compound 251 (1.91 g, Y = 94%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 2.50 (3H, s) 7.27-8.11 (8H, m) 8.67 (1H, s) 11.01 (1H, s)
In DMF (12 mL), potassium carbonate (452 mg) and ethyl 4-bromo-n-butyrate (271 mg) were added to compound 251 (300 mg) and reacted at room temperature for 16.5 hours. The reaction solution was added to water (150 mL) for crystallization, and the precipitated crystals were collected by filtration and washed with water to obtain Compound 252 (382 mg, Y = 90%).

A 13% aqueous potassium hydroxide solution (5 mL) was added to compound 252 (321 mg) in ethanol (20 mL) and reacted at room temperature for 1.5 hours. Activated carbon was added to the reaction solution and filtered, and the filtrate was concentrated under reduced pressure. Water (50 mL) was added to the residue for dissolution, and acidified with 35% hydrochloric acid. The precipitated crystals were collected by filtration and washed with water to obtain crude crystals. The crude crystals were recrystallized from ethyl acetate (6 mL) to obtain Compound 253 (198 mg, Y = 67%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.84-2.73 (7H, m) 4.28 (2H, t, J = 6Hz) 7.19-8.12 (8H, m) 8.64 (1H, s) 12.12 (1H, brs)
To a compound 253 (100 mg), 0.1% aqueous potassium hydroxide solution (20 mL) was added and dissolved, and then activated carbon was added and filtered while hot. The filtrate was lyophilized to give compound 254 (85 mg, Y = 77%).

Example 82
6-[[3- (6-Methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid ethyl ester (Compound 255), 6-[[3- (6-Methyl-2-benzoxazoli ) -2-Naphthalenyl] oxy] hexanoic acid (Compound 256), 6-[[3- (6-Methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid potassium salt (Compound 257) Manufacturing:
In DMF (10 mL), potassium carbonate (307 mg) and ethyl 6-bromohexanoate (314 mg) were added to compound 251 (300 mg) and reacted at room temperature for 22 hours. The reaction mixture was added to water (150 mL) and stirred, and the product was extracted with ethyl acetate (200 mL). The organic layer was washed with water, dehydrated with magnesium sulfate, and concentrated under reduced pressure to obtain Compound 255 (0.66 g).
A 13% aqueous potassium hydroxide solution (5 mL) was added to compound 255 (0.66 g) in methanol (20 mL) and reacted at room temperature for 17 hours. The reaction mixture was concentrated under reduced pressure, water (20 mL) was added to the residue, and acidified with 35% hydrochloric acid. The precipitated crystals were collected by filtration and washed with water to obtain crude crystals. Ethanol (2 mL) was added to the crude crystals and suspended with stirring. The crystals were collected by filtration and dried to obtain Compound 256 (304 mg, Y = 72%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.67-2.51 (11H, m) 4.23 (2H, t, J = 5Hz) 7.19-8.12 (8H, m) 8.63 (1H, s) 11.98 (1H, s)
0.06% aqueous potassium hydroxide solution (50 mL) was added to compound 256 (150 mg) and dissolved by heating, and then activated carbon was added and filtered. The filtrate was lyophilized to obtain Compound 257 (135 mg, Y = 82%).

Example 83
[5-[[3- (6-Methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] pentyl] propanedioic acid diethyl ester (compound 258), [5-[[3- (6-methyl- 2-Benzoxazolyl) -2-naphthalenyl] oxy] pentyl] propanedioic acid (Compound 259), [5-[[3- (6-Methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] Preparation of pentyl] propanedioic acid disodium salt (compound 260):
Potassium carbonate (611 mg) and diethyl (5-bromopentyl) malonate (826 mg) were added to compound 251 (300 mg) in DMF (14 mL) and reacted overnight at room temperature. The reaction was added into water (150 mL) and the product was extracted with ethyl acetate (200 mL). The organic layer was washed with water, dehydrated with magnesium sulfate, and concentrated under reduced pressure to obtain Compound 258 (1.07 g).
A 20% aqueous potassium hydroxide solution (5 mL) was added to compound 258 (1.07 g) in methanol (20 mL) and reacted at room temperature for 20 hours. The reaction solution was concentrated under reduced pressure, and water (30 mL) was added to the residue to dissolve it, followed by acid precipitation with 35% hydrochloric acid. The precipitated crystals were collected by filtration and stirred and suspended with ethanol (6 mL), and the crystals were collected by filtration and dried to obtain Compound 259 (309 mg, Y = 63%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.19-1.78 (8H, m) 2.51 (3H, s) 3.22 (1H, t, J = 6Hz) 4.23 (2H, t, J = 5Hz) 7.19-8.10 (8H, m) 8.63 (1H, s)
A 13% aqueous sodium hydroxide solution (20 mL) was added to compound 259 (150 mg) and almost dissolved, then activated carbon was added and filtered. The filtrate was lyophilized to obtain Compound 260 (160 mg, Y = 97%).

Example 84
Preparation of 6-methyl-2- [3- [2- (4-morpholinyl) ethoxy] -2-naphthalenyl] benzoxazole hydrochloride (Compound 261):
Potassium carbonate (511 mg) and 2-chloroethylmorpholine hydrochloride (204 mg) were added to compound 251 (200 mg) in DMF (10 mL), and reacted at 70-80 ° C. for 20 hours. The reaction mixture was added to water (100 mL) and stirred, and then the product was extracted with ethyl acetate (100 mL). The organic layer was washed with water, dehydrated with magnesium sulfate, and concentrated under reduced pressure. The obtained oil (315 mg) was dissolved in acetone (10 mL), and 35% hydrochloric acid was added to adjust the pH to 1 to 2. The precipitated crystals were collected by filtration and dried to obtain Compound 261 (228 mg, Y = 76%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 2.51 (3H, s) 3.22-4.00 (10H, m) 4.78 (2H, t, J = 4Hz) 7.20-8.15 (8H, m) 8.70 (1H, s) 11.22-12.55 (1H, br)

Example 85
Preparation of N, N-dimethyl-3-[[3- (6-methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] -1-propanamine hydrochloride (Compound 262):
Potassium carbonate (405 mg) and 3-dimethylaminopropyl chloride hydrochloride (138 mg) were added to compound 251 (200 mg) in DMF (10 mL) and reacted at 80 to 90 ° C. for 16 hours. The reaction mixture was added to water (150 mL) and stirred, and then the product was extracted with ethyl acetate (200 mL). The organic layer was washed with water, dehydrated with magnesium sulfate, and concentrated to obtain an oil (263 mg) obtained by concentration under reduced pressure. The precipitated crystals were collected by filtration and dried to obtain Compound 262 (211 mg, Y = 73%).
¹ H-NMR (Methanol-d4 / TMS):
δ = 2.30-2.53 (5H, m) 3.08 (6H, s) 3.58 (2H, t, J = 6Hz) 4.44 (2H, t, J = 6Hz) 7.23-8.01 (8H, m) 8.69 (1H, s)

Example 86
6-nitro-2- [3- (phenylmethoxy) -2-naphthalenyl] benzoxazole (compound 263), 3- (6-nitro-2-benzoxazolyl) -2-naphthalenol (compound 264), 4- [[3- (6-Nitro-2-benzoxazolyl) -2-naphthalenyl] oxy] butanoic acid ethyl ester (Compound 265), 4-[[3- (6-Amino-2-benzoxazolyl) -2-Naphthalenyl] oxy] butanoic acid ethyl ester (Compound 266), 4-[[3- [6- (Diethylamino) -2-benzoxazolyl] -2-naphthalenyl] oxy] butanoic acid ethyl ester (Compound 267 ), 4-[[3- [6- (Diethylamino) -2-benzoxazolyl] -2-naphthalenyl] oxy] butanoic acid (Compound 268), 4-[[3- [6- (Diethylamino) -2 -Benzoxazolyl] -2-naphthalenyl] oxy] butanoic acid sodium salt (Compound 269):

Toluene (100 mL), thionyl chloride (3.35 mL) and DMF (1 drop) were added to 3-benzyloxy-2-naphthoic acid (10.8 g) and reacted under reflux for 3.5 hours, and then 2-amino-5nitrophenol A solution of (12.5 g) in 1,4-dioxane (150 mL) was added and reacted under reflux for 6 hours. The reaction solution was cooled, and the precipitated crystals were collected by filtration. The obtained crystals were washed with methanol and dried to obtain an intermediate amide compound (14.9 g, Y = 93%).
Amide compound (14.9 g) is dissolved in 1,3-dimethyl-2-imidazolidinone (80 mL), p-toluenesulfonic acid monohydrate (19 g) and toluene (180 mL) are added, and it is formed under reflux. The reaction was carried out overnight while removing water. After cooling, the precipitated crystals were collected by filtration, washed with toluene, and then washed with methanol. Methanol (400 mL) and 40% aqueous sodium hydroxide solution (10 mL) were added to the obtained crystals, suspended for 30 minutes under reflux, and the crystals were collected by filtration and dried to give compound 263 (6.85 g, Y = 48%). Got.
¹ H-NMR (CDCl ₃ , Methanol-d4 / TMS):
δ = 5.42 (2H, s) 7.28-8.75 (14H, m)

A 30% hydrogen bromide / acetic acid solution (70 mL) was added to compound 263 (6.8 g) and reacted at about 100 ° C. for 2.5 hours. Water (430 mL) was added to the reaction solution for crystallization, and the precipitated crystals were collected by filtration. The obtained crystals were washed with 50% aqueous methanol and dried to give compound 264 (5.2 g, Y = 91%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 7.26-8.69 (9H, m) 10.76 (1H, s)
Compound 264 (740 mg) was dissolved in DMF (15 mL), potassium carbonate (3.5 g) and ethyl 4-bromo-n-butyrate (610 mg) were added, and the mixture was reacted overnight at room temperature. Water (90 mL) was added to the reaction solution for crystallization, and the precipitated crystals were collected by filtration. The obtained crystals were washed with ethanol and dried to give compound 265 (884 mg, Y = 87%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.27 (3H, t, J = 7Hz) 2.18-2.92 (4H, m) 4.01-4.42 (4H, m) 7.31-8.74 (9H, m)

Toluene (20 mL), ethanol (80 mL), and 5% palladium carbon (0.3 g) were added to compound 265 (850 mg), and reacted at room temperature in a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure and dried to obtain Compound 266 (780 mg, Y = 99%).
Compound 266 (390 mg) was dissolved in DMF (7 mL), potassium carbonate (2.5 g) and ethyl iodide (3.0 g) were added, and the mixture was reacted at about 65 ° C. overnight. Chloroform (100 mL) was added to the reaction mixture, and the mixture was washed successively with water and saturated brine. The chloroform layer was dehydrated with magnesium sulfate and concentrated under reduced pressure. The residue was purified with a silica gel column (chloroform) to obtain Compound 267 (150 mg, Y = 34%).
Compound 267 (150 mg) was dissolved in methanol (100 mL), 10% aqueous sodium hydroxide solution (3 mL) was added, and the mixture was reacted at about 50 ° C. overnight. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in water (50 mL) with heating, and neutralized with dilute hydrochloric acid. The precipitated crystals were collected by filtration and dried to obtain Compound 268 (80 mg, Y = 57%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.14 (6H, t, J = 6Hz) 1.80-2.85 (4H, m) 3.20-3.65 (4H, m) 4.27 (2H, t, J = 7Hz) 6.69-8.15 (8H, m) 8.57 (1H, s) 12.16 (1H, br)
Compound 268 (25 mg) was suspended in water (50 mL), 0.5% aqueous sodium hydroxide solution (0.95 mL) was added and dissolved by heating, followed by filtration. The filtrate was lyophilized to give compound 269 (28 mg, Y = 106%).

Example 87
4-[[3- [6- [Bis (phenylmethyl) amino] -2-benzoxazolyl] -2-naphthalenyl] oxy] butanoic acid ethyl ester (Compound 270), 4-[[3- [6- [Bis (phenylmethyl) amino] -2-benzoxazolyl] -2-naphthalenyl] oxy] butanoic acid (Compound 271), 4-[[3- [6- [Bis (phenylmethyl) amino] -2- Preparation of benzoxazolyl] -2-naphthalenyl] oxy] butanoic acid sodium salt (Compound 272):
Compound 266 (390 mg) was dissolved in DMF (6 mL), and potassium carbonate (2.5 g) and benzyl bromide (1.2 g) were added and reacted at room temperature overnight. Chloroform (100 mL) was added to the reaction mixture, and the mixture was washed successively with water and saturated brine. The chloroform layer was dehydrated with magnesium sulfate and concentrated under reduced pressure. The residue was purified with a silica gel column (chloroform) to obtain Compound 270 (345 mg, Y = 61%).

Compound 270 (345 mg) was dissolved in methanol (100 mL), 10% aqueous sodium hydroxide solution (5 mL) was added, and the mixture was reacted at about 50 ° C. for 3 days. The reaction solution was concentrated under reduced pressure, and the residue was suspended in water (100 mL) with heating, and diluted hydrochloric acid was added for acid precipitation. The precipitated crystals were collected by filtration and dried to obtain Compound 271 (266 mg, Y = 81%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.80-2.73 (4H, m) 4.23 (2H, t, J = 5Hz) 4.82 (4H, s) 6.76-8.10 (18H, m) 8.54 (1H, s) 12.12 (1H, br)
Compound 271 (74 mg) was suspended in water (100 mL), 0.5% aqueous sodium hydroxide solution (1.1 mL) was added and dissolved by heating, followed by filtration. The filtrate was lyophilized to give compound 272 (66 mg, Y = 86%).

Example 88
6-[[3- (6-Nitro-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid ethyl ester (Compound 273), 6-[[3- (6-Amino-2-benzoxazoli ) -2-Naphthalenyl] oxy] hexanoic acid ethyl ester (compound 274), 6-[[3- [6- (diethylamino) -2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid ethyl ester ( Compound 275), 6-[[3- [6- (Diethylamino) -2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid (Compound 276), 6-[[3- [6- (Diethylamino) Preparation of 2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid sodium salt (Compound 277):
Compound 264 (740 mg) was dissolved in DMF (14 mL), potassium carbonate (3.5 g) and ethyl 6-bromohexanoate (690 mg) were added, and the mixture was reacted at room temperature overnight. Water (100 mL) was added to the reaction solution for crystallization, and the precipitated crystals were collected by filtration. The obtained crystals were recrystallized from ethanol to obtain Compound 273 (747 mg, Y = 71%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.24 (3H, t, J = 7Hz) 1.57-2.09 (6H, m) 2.38 (2H, t, J = 6Hz) 3.95-4.35 (4H, m) 7.27-8.73 (9H, m)

Toluene (20 mL), ethanol (80 mL) and 5% palladium carbon (0.3 g) were added to compound 273 (700 mg), and reacted at room temperature in a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure and dried to obtain Compound 274 (650 mg, Y = 100%).
Compound 274 (325 mg) was dissolved in DMF (6 mL), potassium carbonate (2.5 g) and ethyl iodide (2.5 g) were added, and the mixture was reacted at about 65 ° C. overnight. Chloroform (100 mL) was added to the reaction mixture, and the mixture was washed successively with water and saturated brine. The chloroform layer was dehydrated with magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column (chloroform) to obtain Compound 275 (180 mg, Y = 49%).
Compound 275 (180 mg) was dissolved in methanol (100 mL), 10% aqueous sodium hydroxide solution (3 mL) was added, and the mixture was reacted at about 50 ° C. overnight. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in water (50 mL) with heating, and neutralized with dilute hydrochloric acid. The precipitated crystals were collected by filtration and dried to obtain Compound 276 (140 mg, Y = 83%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.14 (6H, t, J = 7Hz) 1.50-2.00 (6H, m) 2.28 (2H, t, J = 6Hz) 3.25-3.61 (4H, m) 4.22 (2H, t, J = 6Hz) 6.73- 8.08 (8H, m) 8.56 (1H, m) 12.01 (1H, br)
Compound 276 (58 mg) was suspended in water (50 mL), 0.5% aqueous sodium hydroxide solution (1.1 mL) was added and dissolved with heating, followed by filtration. The filtrate was lyophilized to give compound 277 (70 mg, Y = 115%).

Example 89
6-[[3- [6- [Bis (phenylmethyl) amino] -2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid ethyl ester (Compound 278), 6-[[3- [6- [Bis (phenylmethyl) amino] -2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid (Compound 279), 6-[[3- [6- [Bis (phenylmethyl) amino] -2- Preparation of benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid sodium salt (Compound 280):
Compound 274 (325 mg) was dissolved in DMF (6 mL), potassium carbonate (2.5 g) and benzyl bromide (1.0 g) were added, and the mixture was reacted at room temperature overnight. Chloroform (100 mL) was added to the reaction mixture, and the mixture was washed successively with water and saturated brine. The chloroform layer was dehydrated with magnesium sulfate and concentrated under reduced pressure. The residue was purified with a silica gel column (chloroform) to obtain Compound 278 (267 mg, Y = 62%).
Compound 278 (267 mg) was dissolved in methanol (100 mL), 10% aqueous sodium hydroxide solution (3 mL) was added, and the mixture was reacted at about 50 ° C. overnight. The reaction solution was concentrated under reduced pressure, the residue was dissolved in water (100 mL) with heating, and acidified by adding dilute hydrochloric acid. The precipitated crystals were collected by filtration and dried to obtain Compound 279 (90 mg, Y = 35%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.39-2.39 (8H, m) 4.17 (2H, t, J = 4Hz) 4.83 (4H, s) 6.70-8.52 (19H, m) 12.0 (1H, br)
Compound 279 (36 mg) was suspended in water (80 mL), 0.5% aqueous sodium hydroxide solution (0.51 mL) was added and dissolved by heating, followed by filtration. The filtrate was lyophilized to give compound 280 (30 mg, Y = 80%).

Example 90
Preparation of [5-[[3- (6-Nitro-2-benzoxazolyl) -2-naphthalenyl] oxy] pentyl] propanedioic acid diethyl ester (Compound 281):
Compound 264 (700 mg) was dissolved in DMF (14 mL), and potassium carbonate (3.5 g) and diethyl (5-bromopentyl) malonate (920 mg) were added and reacted at room temperature overnight. Water (100 mL) was added to the reaction solution for crystallization, and the precipitated crystals were collected by filtration. The obtained crystals were recrystallized from ethanol to obtain Compound 281 (998 mg, Y = 82%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.13-2.20 (14H, m) 3.35 (1H, t, J = 7Hz) 4.02-4.37 (6H, m) 7.42-8.72 (9H, m)

Example 91
2- [3- [2- (4-morpholinyl) ethoxy] -2-naphthalenyl] -6-nitrobenzoxazole (Compound 282), 2- [3- [2- (4-morpholinyl) ethoxy] -2-naphthalenyl Production of 6-benzoxazolamine dihydrochloride (Compound 283):
Compound 264 (740 mg) was dissolved in DMF (14 mL), and potassium carbonate (3.5 g) and N- (2-chloroethyl) morpholine hydrochloride (630 mg) were added and reacted at about 65 ° C. overnight. Water (100 mL) was added to the reaction solution for crystallization, and the precipitated crystals were collected by filtration. The obtained crystals were washed with methanol and dried to give compound 282 (647 mg, Y = 64%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 2.60-3.09 (6H, m) 3.73 (4H, t, J = 5Hz) 4.14 (2H, t, J = 6Hz) 7.26-8.72 (9H, m)
Toluene (20 mL), methanol (80 mL), and 5% palladium carbon (0.3 g) were added to compound 282 (580 mg), and reacted at room temperature in a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. Acetone (50 mL) was added to the residue for dissolution, 35% hydrochloric acid (0.3 mL) was added, and the precipitated crystals were collected by filtration and dried to obtain Compound 283 (501 mg, Y = 78%).
¹ H-NMR (Methanol-d4 / TMS):
δ = 3.28-4.04 (10H, m) 4.60-4.85 (2H, m) 7.43-8.74 (9H, m)

Example 92
5- (1,1-dimethylethyl) -2- [3- (phenylmethoxy) -2-naphthalenyl] benzoxazole (Compound 284), 3- [5- (1,1-dimethylethyl) -2-benzoxa Zolyl] -2-naphthalenol (compound 285), 4-[[3- [5- (1,1-dimethylethyl) -2-benzoxazolyl] -2-naphthalenyl] oxy] butanoic acid ethyl ester (compound 286), 4-[[3- [5- (1,1-dimethylethyl) -2-benzoxazolyl] -2-naphthalenyl] oxy] butanoic acid (Compound 287), 4-[[3- [5 Preparation of-(1,1-dimethylethyl) -2-benzoxazolyl] -2-naphthalenyl] oxy] butanoic acid potassium salt (Compound 288):
3-Benzyloxy-2-naphthoic acid (20.0 g) was reacted with thionyl chloride (10.3 g) in toluene (200 mL) for 2 hours under reflux. The reaction solution was concentrated under reduced pressure to obtain 3-benzyloxy-2-naphthoic acid chloride (24.2 g).
3-Benzyloxy-2-naphthoic acid chloride oil (24.2g) was converted to 2-amino-4-tert-butylphenol (14.3g), triethylamine (8.8g) 1,3-dimethyl-2-imidazolidinone (150mL) ) Added to the solution and reacted at room temperature for 2 hours. The reaction solution was added to water (2 L) for crystallization, and the precipitated crystals were collected by filtration and washed with water to obtain crude crystals. Methanol (200 mL) was added to the crude crystals and suspended with stirring. The crystals were collected by filtration and dried to obtain an intermediate amide compound (29.6 g, Y = 97%).

An amide compound (25.0 g) and p-toluenesulfonic acid monohydrate (22.4 g) are added to a mixed solvent of 1,3-dimethyl-2-imidazolidinone (150 mL) and toluene (450 mL) and produced under reflux. The reaction was carried out overnight while removing the water. The reaction solution was concentrated under reduced pressure, and the residue was added to water (3 L) for crystallization. The precipitated crystals were collected by filtration and washed with water to obtain crude crystals. Methanol (300 mL) and potassium hydroxide (10 g) were added to the crude crystals, and suspended for 2.5 hours under reflux. The crystals were collected by filtration and dried to obtain Compound 284 (7.67 g, Y = 32%).
Methanol (200 mL) and 5% palladium carbon (0.5 g) were added to compound 284 (7.40 g), and the mixture was reacted at 50 ° C. for 22 hours in a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain crude crystals. The crude crystals were washed with methanol and recrystallized from ethyl acetate (95 mL) to obtain Compound 285 (4.27 g, Y = 74%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.42 (9H, s) 7.25-7.94 (8H, m) 8.59 (1H, s) 11.31 (1H, s)
In DMF (10 mL), potassium carbonate (524 mg) and ethyl 4-bromo-n-butyrate (229 mg) were added to compound 285 (300 mg) and reacted at room temperature for 22 hours. The reaction solution was added to water (150 mL) for crystallization, and the precipitated crystals were collected by filtration and washed with water to obtain Compound 286 (Wet 0.66 g).
11% aqueous potassium hydroxide solution (5 mL) was added to compound 286 (Wet 0.66 g) in ethanol (20 mL), and reacted at 45 ° C. for 18 hours. The reaction mixture was concentrated under reduced pressure, water (20 mL) was added to the residue, and acidified with 35% hydrochloric acid. The crystals were collected by filtration and washed with water to obtain crude crystals. The crude crystals were recrystallized from 80% aqueous ethanol (10 mL) to obtain Compound 287 (226 mg, Y = 59%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.39 (9H, s) 1.96-2.29 (2H, m) 2.51-2.75 (2H, m) 4.28 (2H, t, J = 6Hz) 7.45-8.11 (8H, m) 8.64 (1H, s)
To compound 287 (100 mg), 0.05% aqueous potassium hydroxide solution (40 mL) was added and dissolved by heating, and then activated carbon was added and filtered while hot. The filtrate was lyophilized to give compound 288 (100 mg, Y = 91%).

Example 93
6-[[3- [5- (1,1-Dimethylethyl) -2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid ethyl ester (Compound 289), 6-[[3- [5- (1,1-dimethylethyl) -2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid (Compound 290), 6-[[3- [5- (1,1-dimethylethyl) -2- Preparation of benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid potassium salt (Compound 291):
In DMF (12 mL), potassium carbonate (653 mg) and ethyl 6-bromohexanoate (338 mg) were added to compound 285 (300 mg) and reacted at room temperature for 28 hours. The reaction was added to water (150 mL) and the reaction product was extracted with ethyl acetate (100 mL). The organic layer was washed with water, dehydrated with sodium sulfate, and concentrated under reduced pressure to obtain Compound 289 (0.65 g).
11% aqueous potassium hydroxide solution (5 mL) was added to compound 289 (0.65 g) in ethanol (20 mL), and reacted at room temperature for 19 hours. The reaction solution was concentrated under reduced pressure, and water (20 mL) was added to the residue to dissolve it with heating, followed by acid precipitation with 35% hydrochloric acid. The separated product was extracted with ethyl acetate (50 mL), and then the organic layer was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained oil was dissolved in acetone (2 mL), and water (0.5 mL) was added for crystallization. The crystals were collected by filtration and dried to obtain Compound 290 (319 mg, Y = 78%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.39-2.40 (17H, m) 4.23 (2H, t, J = 6Hz) 7.40-8.11 (8H, m) 8.62 (1H, s) 11.48-12.55 (1H, br)
0.04% aqueous potassium hydroxide solution (40 mL) was added to compound 290 (100 mg) and dissolved by heating, and then activated carbon was added and filtered while hot. The filtrate was lyophilized to give compound 291 (95 mg, Y = 87%).

Example 94
[5-[[3- [5- (1,1-dimethylethyl) -2-benzoxazolyl] -2-naphthalenyl] oxy] pentyl] propanedioic acid diethyl ester (compound 292), [5-[[ 3- [5- (1,1-dimethylethyl) -2-benzoxazolyl] -2-naphthalenyl] oxy] pentyl] propanedioic acid (compound 293), [5-[[3- [5- (1 , 1-Dimethylethyl) -2-benzoxazolyl] -2-naphthalenyl] oxy] pentyl] propanedioic acid disodium salt (Compound 294):
In DMF (12 mL), potassium carbonate (654 mg) and diethyl (5-bromopentyl) malonate (449 mg) were added to compound 285 (300 mg) and reacted at room temperature for 28 hours. The reaction solution was added into water (150 mL), and the reaction product was extracted with ethyl acetate (200 mL). The organic layer was washed with water, dehydrated with magnesium sulfate, and concentrated under reduced pressure to obtain Compound 292 (0.75 g).
A 20% aqueous potassium hydroxide solution (5 mL) was added to compound 292 (0.75 g) in ethanol (20 mL) and reacted at room temperature for 20 hours. The reaction solution was concentrated under reduced pressure, water (20 mL) was added to the residue and dissolved by heating, and then acidified with 35% hydrochloric acid. The separated product was extracted with ethyl acetate (50 mL). The organic layer was washed with water, dehydrated with magnesium sulfate, and concentrated under reduced pressure to obtain a crude oil. The crude oil was purified with a silica gel column (toluene / ethyl acetate) to obtain Compound 293 (220 mg, Y = 48%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.39-2.09 (17H, m) 3.25 (1H, t, J = 7Hz) 4.23 (2H, t, J = 5Hz) 7.40-8.11 (8H, m) 8.63 (1H, s) 12.02-13.40 (2H, br)
To the compound 293 (100 mg), 0.1% aqueous sodium hydroxide solution (20 mL) was added and dissolved, and then activated carbon was added and filtered. The filtrate was lyophilized to give compound 294 (104 mg, Y = 95%).

Example 95
Preparation of 5- (1,1-dimethylethyl) -2- [3- [2- (4-morpholinyl) ethoxy] -2-naphthalenyl] benzoxazole hydrochloride (Compound 295):
In DMF (10 mL), potassium carbonate (527 mg) and N- (2-chloroethyl) morpholine hydrochloride (211 mg) were added to compound 285 (300 mg) and reacted at 70-80 ° C. for 4.5 hours. The reaction was added to water (100 mL) and the reaction product was extracted with ethyl acetate (100 mL). The organic layer was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in acetone (20 mL), 35% hydrochloric acid was added, and the precipitated crystals were collected by filtration and dried to give compound 295 (386 mg, Y = 87%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.39 (9H, s) 3.19-4.00 (10H, m) 4.77 (2H, t, J = 4Hz) 7.45-8.14 (8H, m) 8.70 (1H, s) 11.27-12.47 (1H, br)

Example 96
3-[[3- [5- (1,1-dimethylethyl) -2-benzoxazolyl] -2-naphthalenyl] oxy] -N, N-dimethyl-1-propanamine hydrochloride (Compound 296) Manufacturing:
In DMF (10 mL), potassium carbonate (525 mg) and 3-dimethylaminopropyl chloride hydrochloride (180 mg) were added to compound 285 (300 mg) and reacted at 70-80 ° C. for 4.5 hours. The reaction was added to water (150 mL) and the reaction product was extracted with ethyl acetate (300 mL). The organic layer was washed with water, dehydrated with magnesium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in acetone (30 mL), 35% hydrochloric acid was added, and the precipitated crystals were collected by filtration and dried to obtain Compound 296 (304 mg, Y = 73%).
¹ H-NMR (Methanol-d4 / TMS):
δ = 1.46 (9H, s) 2.24-2.66 (2H, m) 3.03 (6H, s) 3.55 (2H, t, J = 7Hz) 4.55 (2H, t, J = 6Hz) 7.48-8.05 (8H, m) 8.78 (1H, s)

Example 97
5-phenyl-2- [3- (phenylmethoxy) -2-naphthalenyl] benzoxazole (compound 297), 3- (5-phenyl-2-benzoxazolyl) -2-naphthalenol (compound 298), 4- [[3- (5-Phenyl-2-benzoxazolyl) -2-naphthalenyl] oxy] butanoic acid ethyl ester (Compound 299), 4-[[3- (5-Phenyl-2-benzoxazolyl) -2-Naphthalenyl] oxy] butanoic acid (compound 300):
In toluene (120 mL), 3-benzyloxy-2-naphthoic acid (12.0 g) was reacted with thionyl chloride (6.2 g) under reflux for 3 hours. The reaction solution was concentrated under reduced pressure to obtain 3-benzyloxy-2-naphthoic acid chloride (13.2 g).
3-Benzyloxy-2-naphthoic acid chloride oil (13.2g) is 2-amino-4-phenylphenol (9.6g), triethylamine (5.3g) 1,3-dimethyl-2-imidazolidinone (100mL) It was added to the solution and reacted at room temperature for 3.5 hours. The reaction solution is added to water (2 L) for crystallization, and the precipitated crystals are collected by filtration, washed with water, stirred and suspended with methanol (150 mL) at 50-60 ° C., then the crystals are collected by filtration and dried to obtain an intermediate amide compound. (18.7 g, Y = 97%) was obtained.

An amide compound (15.0 g) and p-toluenesulfonic acid monohydrate (12.8 g) are added to a mixed solvent of 1,3-dimethyl-2-imidazolidinone (150 mL) and toluene (450 mL) and produced under reflux. The reaction was carried out overnight while removing the water. The reaction solution was concentrated under reduced pressure, and the residue was added to water (2 L) for crystallization. The precipitated crystals were collected by filtration and washed with water to obtain crude crystals. Methanol (300 mL) and potassium hydroxide (6.0 g) were added to the crude crystals and suspended for 1.5 hours under reflux. The crystals were collected by filtration and recrystallized from ethyl acetate to give compound 297 (3.46 g, Y = 24%). Got.
Methanol (100 mL) and 5% palladium carbon (0.2 g) were added to compound 297 (3.30 g), and the mixture was reacted at 45 ° C. for 23 hours in a hydrogen atmosphere. The reaction solution was concentrated under reduced pressure, and 1,3-dimethyl-2-imidazolidinone (80 mL) was added to the residue and dissolved by heating. The insoluble material was removed by filtration, and the filtrate was added to water (2 L) for crystallization. The precipitated crystals were collected by filtration and washed with water to obtain crude crystals. The crude crystals were refluxed with acetone (80 mL) for 2 hours, then filtered and dried to obtain Compound 298 (2.28 g, Y = 88%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 7.25-7.93 (13H, m) 8.60 (1H, s) 11.23 (1H, s)
In DMF (12 mL), potassium carbonate (634 mg) and ethyl 4-bromo-n-butyrate (284 mg) were added to compound 298 (300 mg) and reacted at room temperature for 26 hours. The reaction solution was added into water (100 mL), and the reaction product was extracted with ethyl acetate (200 mL). The organic layer was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure to give compound 299 (545 mg).
A 13% aqueous potassium hydroxide solution (5 mL) was added to compound 299 (545 mg) in ethanol (20 mL) and reacted at 45 ° C. for 15 hours. The reaction mixture was concentrated under reduced pressure, water (50 mL) was added to the residue, and acidified with 35% hydrochloric acid. The precipitated crystals were collected by filtration and washed with water to obtain crude crystals. Acetone (4 mL) was added to the crude crystals and dissolved by heating, and then water (1 mL) was added for crystallization. Precipitated crystals were collected by filtration and dried to obtain Compound 300 (236 mg, Y = 63%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 2.00-2.31 (2H, m) 2.49-2.78 (2H, m) 4.31 (2H, t, J = 6Hz) 7.35-8.09 (13H, m) 8.71 (1H, s) 11.27-13.24 (1H, br)

Example 98
6-[[3- (5-Phenyl-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid ethyl ester (Compound 301), 6-[[3- (5-Phenyl-2-benzoxazolyl Preparation of (l) -2-naphthalenyl] oxy] hexanoic acid (Compound 302):
In DMF (12 mL), potassium carbonate (629 mg) and ethyl 6-bromohexanoate (326 mg) were added to compound 298 (300 mg) and reacted at room temperature for 26 hours. The reaction was added to water (100 mL) and the reaction product was extracted with ethyl acetate (100 mL). The organic layer was washed with water, dehydrated with magnesium sulfate, and concentrated under reduced pressure to obtain Compound 301 (676 mg).
A 15% aqueous potassium hydroxide solution (5 mL) was added to compound 301 (676 mg) in ethanol (20 mL) and reacted for 15 hours. The reaction mixture was concentrated under reduced pressure, water (50 mL) was added to the residue, acidified with 35% hydrochloric acid, and the separated product was extracted with ethyl acetate (100 mL). The organic layer was washed with water, dehydrated with magnesium sulfate, and concentrated under reduced pressure. The obtained residue was recrystallized from toluene (4 mL) to obtain Compound 302 (226 mg, Y = 56%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.67-2.38 (8H, m) 4.25 (2H, t, J = 6Hz) 7.21-8.35 (13H, m) 8.69 (1H, s) 11.98 (1H, brs)

Example 99
[5-[[3- (5-Phenyl-2-benzoxazolyl) -2-naphthalenyl] oxy] pentyl] propanedioic acid diethyl ester (compound 303), [5-[[3- (5-phenyl- 2-Benzoxazolyl) -2-naphthalenyl] oxy] pentyl] propanedioic acid (compound 304), [5-[[3- (5-phenyl-2-benzoxazolyl) -2-naphthalenyl] oxy] Preparation of pentyl] propanedioic acid disodium salt (compound 305):
Potassium carbonate (630 mg) and diethyl (5-bromopentyl) malonate (497 mg) were added to compound 298 (300 mg) in DMF (12 mL) and reacted at room temperature for 37 hours. The reaction was added to water (100 mL) and the reaction product was extracted with ethyl acetate (100 mL). The organic layer was washed with water, dehydrated with magnesium sulfate, and concentrated under reduced pressure to obtain Compound 303 (789 mg).
A 32% aqueous potassium hydroxide solution (5 mL) was added to compound 303 (789 mg) in ethanol (20 mL) and reacted at 45 ° C. for 1 hour. The reaction mixture was concentrated under reduced pressure, water (30 mL) was added to the residue, and the mixture was dissolved by heating, and then acidified with 35% hydrochloric acid. The separated product was extracted with ethyl acetate (100 mL). The organic layer was washed with water, dehydrated with magnesium sulfate, and concentrated under reduced pressure. The obtained residue was suspended with stirring at 60 to 70 ° C. with ethyl acetate (10 mL), and then filtered to obtain crude crystals. The crude crystals were purified with a silica gel column (chloroform / methanol) to obtain Compound 304 (114 mg, Y = 25%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.18-2.08 (8H, m) 3.16 (1H, t, J = 6Hz) 4.25 (2H, t, J = 5Hz) 7.42-8.10 (13H, m) 8.70 (1H, s)
0.06% aqueous sodium hydroxide solution (20 mL) was added to compound 304 (70 mg) and dissolved by heating, then activated carbon was added and filtered. The filtrate was lyophilized to give compound 305 (72 mg, Y = 95%).

Example 100
Preparation of 2- [3- [2- (4-morpholinyl) ethoxy] -2-naphthalenyl] -5-phenylbenzoxazole hydrochloride (Compound 306):
Potassium carbonate (495 mg) and (2-chloroethyl) morpholine hydrochloride (204 mg) were added to compound 298 (300 mg) in DMF (10 mL) and reacted at 70-80 ° C. for 5 hours. The reaction solution was added to water (100 mL) for crystallization, and the precipitated crystals were collected by filtration. The obtained crystals were dissolved in acetone (20 mL), acidified with 35% hydrochloric acid, and the precipitated crystals were collected by filtration and dried to obtain Compound 306 (383 mg, Y = 88%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 3.17-4.01 (10H, m) 4.76 (2H, t, J = 4Hz) 7.42-8.16 (13H, m) 8.76 (1H, s) 11.22-12.76 (1H, br)

Example 101
Preparation of N, N-dimethyl-3-[[3- (5-phenyl-2-benzoxazolyl) -2-naphthalenyl] oxy] -1-propanamine hydrochloride (Compound 307):
Potassium carbonate (494 mg) and 3-dimethylaminopropyl chloride hydrochloride (165 mg) were added to compound 298 (300 mg) in DMF (10 mL), and reacted at 70-80 ° C. for 5 hours. The reaction mixture was added to water (100 mL) and extracted with ethyl acetate (300 mL). The organic layer was washed with water, dehydrated with magnesium sulfate, and concentrated under reduced pressure. The residue obtained was dissolved in acetone (20 mL), acidified with 35% hydrochloric acid, and the precipitated crystals were collected by filtration and dried. (218 mg, Y = 53%) was obtained.
¹ H-NMR (Methanol-d4 / TMS):
δ = 2.23-2.61 (2H, m) 3.04 (6H, s) 3.56 (2H, t, J = 6Hz) 4.45 (2H, t, J = 5Hz) 7.41-7.93 (13H, m) 8.68 (1H, s)

Example 102
5-chloro-2- [3- (phenylmethoxy) -2-naphthalenyl] benzoxazole (compound 308), 3- (5-chloro-2-benzoxazolyl) -2-naphthalenol (compound 309), 4- [[3- (5-Chloro-2-benzoxazolyl) -2-naphthalenyl] oxy] butanoic acid ethyl ester (Compound 310), 4-[[3- (5-Chloro-2-benzoxazolyl) -2-Naphthalenyl] oxy] butanoic acid (compound 311):
Toluene (75 mL), thionyl chloride (2.36 mL) and DMF (1 drop) were added to 3-benzyloxy-2-naphthoic acid (7.5 g) and reacted for 2 hours under reflux, followed by 2-amino-4-chloro A solution of phenol (8 g) in 1,4-dioxane (150 mL) was added and reacted under reflux for 2.5 hours. The reaction solution was concentrated under reduced pressure, and 5% aqueous hydrochloric acid solution (500 mL) was added to the residue for suspension.The crystals were collected by filtration, washed with methanol and dried to obtain an intermediate amide compound (9.64 g, Y = 89%) Got.
Dissolve the amide compound (9.6 g) in 1,3-dimethyl-2-imidazolidinone (50 mL) and add p-toluenesulfonic acid monohydrate (7.0 g) and toluene (100 mL) to form under reflux The reaction was carried out overnight while removing water. The reaction mixture was concentrated under reduced pressure, and water (200 mL) was added to the residue to cause crystallization, and the precipitated crystals were collected by filtration. Methanol (400 mL) and 50% aqueous sodium hydroxide solution (10 mL) were added to the obtained crystals and suspended under reflux for 1 hour, and the crystals were collected by filtration and dried to give compound 308 (3.85 g, Y = 42%). Got.
¹ H-NMR (CDCl ₃ / TMS):
δ = 5.39 (2H, s) 7.26-7.98 (13H, m) 8.70 (1H, s)

A 30% hydrogen bromide / acetic acid solution (40 mL) was added to compound 308 (3.8 g) and reacted at about 100 ° C. for 2 hours. Water (260 mL) was added to the reaction solution for crystallization, and the precipitated crystals were collected by filtration. The obtained crystals were washed with methanol and dried to obtain Compound 309 (2.8 g, Y = 96%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 7.27-7.97 (8H, m) 8.56 (1H, s) 10.96 (1H, br)
Compound 309 (315 mg) was dissolved in DMF (7 mL), potassium carbonate (1.8 g) and ethyl 4-bromo-n-butyrate (260 mg) were added, and the mixture was reacted overnight at room temperature. Water (30 mL) was added to the reaction solution for crystallization, and the precipitated crystals were collected by filtration. The obtained crystals were recrystallized from ethanol to obtain Compound 310 (245 mg, Y = 56%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.25 (3H, t, J = 7Hz) 2.10-2.85 (4H, m) 3.97-4.40 (4H, m) 7.29-7.97 (8H, m) 8.65 (1H, s)
Compound 310 (225 mg) was dissolved in methanol (50 mL), 4% aqueous sodium hydroxide solution (5 mL) was added, and the mixture was reacted at about 50 ° C. overnight. The reaction solution was concentrated under reduced pressure, and water (50 mL) was added to the residue to dissolve it by heating. The precipitated crystals were collected by filtration and dried to obtain Compound 311 (180 mg, Y = 86%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.80-2.30 (2H, m) 2.61 (2H, t, J = 7Hz) 4.28 (2H, t, J = 6Hz) 7.40-8.20 (8H, m) 8.69 (1H, s) 12.10 (1H, br)

Example 103
6-[[3- (5-Chloro-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid ethyl ester (Compound 312), 6-[[3- (5-Chloro-2-benzoxazoli Preparation of (l) -2-naphthalenyl] oxy] hexanoic acid (Compound 313):
Compound 309 (304 mg) was dissolved in DMF (5 mL), and potassium carbonate (1.8 g) and ethyl 6-bromohexanoate (285 mg) were added and reacted overnight at room temperature. Ethyl acetate (50 mL) was added to the reaction mixture, and the mixture was washed successively with water and saturated brine. The ethyl acetate layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column (chloroform) to give compound 312.
The obtained compound 312 was dissolved in methanol (50 mL), 7% aqueous sodium hydroxide solution (3 mL) was added, and the mixture was reacted at about 50 ° C. overnight. The reaction mixture was concentrated under reduced pressure, and water (50 mL) was added to the residue to dissolve it with heating. The precipitated crystals were collected by filtration and dried to obtain Compound 313 (222 mg, Y = 53%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.40-2.00 (6H, m) 2.26 (2H, t, J = 6Hz) 4.23 (2H, t, J = 5Hz) 7.39-8.11 (8H, m) 8.67 (1H, s) 12.0 (1H, br)

Example 104
[3-[[3- (5-Chloro-2-benzoxazolyl) -2-naphthalenyl] oxy] propyl] propanedioic acid diethyl ester (compound 314), [3-[[3- (5-chloro- 2-Benzoxazolyl) -2-naphthalenyl] oxy] propyl] propanedioic acid (Compound 315), [3-[[3- (5-Chloro-2-benzoxazolyl) -2-naphthalenyl] oxy] Propyl] propanedioic acid disodium salt (compound 316):
Compound 309 (250 mg) was dissolved in DMF (5 mL), potassium carbonate (1.2 g) and diethyl (3-chloropropyl) malonate (260 mg) were added, and the mixture was reacted at about 65 ° C. overnight. Ethyl acetate (50 mL) was added to the reaction mixture, and the mixture was washed successively with water and saturated brine. The ethyl acetate layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column (chloroform) to obtain Compound 314 (170 mg, Y = 41%).
Compound 314 (170 mg) was dissolved in methanol (50 mL), 7% aqueous sodium hydroxide solution (3 mL) was added, and the mixture was reacted at about 50 ° C. overnight. The precipitated crystals were collected by filtration and dried to obtain Compound 316 (63 mg, Y = 38%).
The filtrate of Compound 316 was concentrated under reduced pressure, dissolved in water (30 mL), and acidified by adding dilute hydrochloric acid. The precipitated crystals were collected by filtration and dried to obtain Compound 315 (52 mg, Y = 35%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.73-2.29 (4H, m) 3.45 (1H, t, J = 7Hz) 4.28 (2H, t, J = 6Hz) 7.42-8.14 (8H, m) 8.73 (1H, s) 12.68 (2H, br)

Example 105
[5-[[3- (5-Chloro-2-benzoxazolyl) -2-naphthalenyl] oxy] pentyl] propanedioic acid diethyl ester (compound 317), [5-[[3- (5-chloro- 2-Benzoxazolyl) -2-naphthalenyl] oxy] pentyl] propanedioic acid disodium salt (compound 318), [5-[[3- (5-chloro-2-benzoxazolyl) -2-naphthalenyl Production of] oxy] pentyl] propanedioic acid (compound 319):
Compound 309 (290 mg) was dissolved in DMF (5 mL), and potassium carbonate (1.8 g) and diethyl (5-bromopentyl) malonate (375 mg) were added and reacted at room temperature overnight. Ethyl acetate (50 mL) was added to the reaction mixture, and the mixture was washed successively with water and saturated brine. The ethyl acetate layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified with a silica gel column (chloroform) to obtain Compound 317.
Compound 317 was dissolved in methanol (80 mL), 8% aqueous sodium hydroxide solution (5 mL) was added, and the mixture was reacted overnight at room temperature. The precipitated crystals were collected by filtration and dried to obtain Compound 318 (294 mg, Y = 59%).
Compound 318 (48.6 mg) was dissolved in water (5 mL), and acidified by adding dilute hydrochloric acid. The precipitated crystals were collected by filtration and dried to obtain Compound 319 (31 mg, Y = 70%).
¹ H-NMR (DMSO-D6 / TMS):
δ = 1.29-2.10 (8H, m) 3.19 (1H, t, J = 3Hz) 4.23 (2H, t, J = 5Hz) 7.38-8.11 (8H, m) 8.68 (1H, s)

Example 106
Preparation of 5-chloro-2- [3- [2- (4-morpholinyl) ethoxy] -2-naphthalenyl] benzoxazole hydrochloride (Compound 320):
To compound 309 (215 mg), DMF (4 mL), potassium carbonate (1.3 g), and N- (2-chloroethyl) morpholine hydrochloride (200 mg) were added and reacted at about 65 ° C. overnight. Water (25 mL) was added to the reaction solution for crystallization, and the precipitated crystals were collected by filtration and washed with a 50% aqueous methanol solution (30 mL). The obtained crystals were dissolved in acetone (40 mL), 35% hydrochloric acid (0.3 mL) was added, and the precipitated crystals were collected by filtration and dried to give compound 320 (246 mg, Y = 76%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 3.10-4.10 (10H, m) 4.80 (2H, t, J = 4Hz) 7.45-8.17 (8H, m) 8.75 (1H, s) 12.0 (1H, br)

Example 107
Preparation of 3-[[3- (5-Chloro-2-benzoxazolyl) -2-naphthalenyl] oxy] -N, N-dimethyl-1-propanamine hydrochloride (Compound 321):
Compound 309 (303 mg) was dissolved in DMF (5 mL), potassium carbonate (2.5 g) and 3-dimethylaminopropyl chloride hydrochloride (320 mg) were added, and the mixture was reacted at 65 ° C. overnight. Ethyl acetate (50 mL) was added to the reaction mixture, and the mixture was washed successively with water and saturated brine. The ethyl acetate layer was dried over magnesium sulfate and concentrated under reduced pressure. Crystals obtained by purifying the residue with a silica gel column (chloroform / methanol) were dissolved in acetone (30 mL), 35% hydrochloric acid (0.3 mL) was added, and the precipitated crystals were collected by filtration and dried to give compound 321 (133 mg, 133 mg, Y = 31%).
¹ H-NMR (DMSO-d6, D ₂ O / TMS):
δ = 2.20-2.52 (2H, m) 2.86 (6H, s) 3.45 (2H, t, J = 7Hz) 4.38 (2H, t, J = 6Hz) 7.45-8.15 (8H, m) 8.73 (1H, s)

Example 108
6-methyl-2- [6- (phenylmethoxy) -1-naphthalenyl] benzoxazole (compound 322), 5- (6-methyl-2-benzoxazolyl) -2-naphthalenol (compound 323), 6- [[5- (6-Methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid ethyl ester (Compound 324), 6-[[5- (6-Methyl-2-benzoxazolyl) Preparation of 2-Naphthalenyl] oxy] hexanoic acid (Compound 325), 6-[[5- (6-Methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid potassium salt (Compound 326):
6-Benzyloxy-1-naphthoic acid (7.0 g) was reacted with thionyl chloride (3.6 g) in toluene (100 mL) for 2 hours under reflux. The reaction solution was concentrated under reduced pressure to obtain 6-benzyloxy-1-naphthoic acid chloride oil.
6-Benzyloxy-1-naphthoic acid chloride was added to a solution of 6-amino-m-cresol (3.8 g) and triethylamine (3.1 g) in 1,3-dimethyl-2-imidazolidinone (100 mL) at room temperature. Reacted for hours. The reaction solution was added to water (1.5 L) for crystallization, and the precipitated crystals were collected by filtration, washed with water, and dried to obtain an intermediate amide compound (9.0 g, Y = 93%).
In a mixed solution of 1,3-dimethyl-2-imidazolidinone (90 mL) and toluene (270 mL), p-toluenesulfonic acid monohydrate (8.5 g) is added to the amide compound (8.5 g) and produced under reflux. The reaction was carried out for 20 hours while removing water. The reaction solution was concentrated under reduced pressure, and the residue was added to water (1.5 L) for crystallization. The precipitated crystals were collected by filtration and washed with water to obtain crude crystals. Methanol (150 mL) and potassium hydroxide (6.0 g) were added to the crude crystals and suspended for 14 hours under reflux. The crystals were collected by filtration and dried to obtain Compound 322 (3.27 g, Y = 40%).
Compound 322 (3.00 g) was added to and dissolved in 1,3-dimethyl-2-imidazolidinone (40 mL), 5% palladium carbon (0.2 g) was added, and the reaction was carried out in a hydrogen atmosphere for 47 hours. The reaction solution was filtered, and the filtrate was added to water (800 mL) for crystallization. The precipitated crystals were collected by filtration, washed with water, and dried to obtain Compound 323 (2.10 g, Y = 93%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 2.50 (3H, s) 7.11-8.23 (8H, m) 9.31 (1H, d, J = 10Hz) 9.97 (1H, s)

In DMF (10 mL), potassium carbonate (410 mg) and ethyl 6-bromohexanoate (445 mg) were added to compound 323 (300 mg) and reacted at room temperature for 25 hours. The reaction solution was added to water (150 mL) and stirred, and then the product was extracted with ethyl acetate (200 mL). The organic layer was washed with water, dehydrated with magnesium sulfate, and concentrated under reduced pressure to obtain Compound 324 (Wet 0.75 g).
A 12% aqueous potassium hydroxide solution (10 mL) was added to compound 324 (Wet 0.75 g) in methanol (40 mL), and the mixture was reacted overnight at room temperature. Activated carbon was added to the reaction solution and filtered, and the filtrate was concentrated under reduced pressure. Water (50 mL) was added to the residue, and after acidifying with 35% hydrochloric acid, the crystals were collected by filtration and washed with water to obtain crude crystals. Methanol (10 mL) was added to the crude crystals and suspended with stirring, and the crystals were collected by filtration and dried to obtain Compound 325 (326 mg, Y = 77%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.31-2.69 (11H, m) 4.14 (2H, t, J = 6Hz) 7.21-8.30 (8H, m) 9.36 (1H, d, J = 9Hz) 11.97 (1H, s)
0.05% aqueous potassium hydroxide solution (50 mL) was added to compound 325 (150 mg) and dissolved by heating, and then activated carbon was added and filtered while hot. The filtrate was lyophilized to give compound 326 (142 mg, Y = 86%).

Example 109
[5-[[5- (6-Methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] pentyl] propanedioic acid diethyl ester (compound 327), [5-[[5- (6-methyl- 2-Benzoxazolyl) -2-naphthalenyl] oxy] pentyl] propanedioic acid (Compound 328), [5-[[5- (6-Methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] Preparation of pentyl] propanedioic acid disodium salt (compound 329):
In DMF (10 mL), potassium carbonate (670 mg) and diethyl (5-bromopentyl) malonate (642 mg) were added to compound 323 (300 mg) and reacted at room temperature for 27 hours. The reaction was added into water (150 mL) and the product was extracted with ethyl acetate (200 mL). The organic layer was washed with water, dehydrated with magnesium sulfate, and concentrated under reduced pressure to obtain Compound 327 (0.95 g).
11% aqueous potassium hydroxide solution (10 mL) was added to compound 327 (0.95 g) in methanol (40 mL), and the mixture was reacted at room temperature overnight. Activated carbon was added to the reaction solution and filtered, and the filtrate was concentrated under reduced pressure. Water (50 mL) was added to the residue, acidified with 35% hydrochloric acid, and the separated product was extracted with ethyl acetate (100 mL). The organic layer was washed with water, dehydrated with magnesium sulfate, and concentrated under reduced pressure to obtain a crude oil (0.72 g). Crude oil (0.72 g) was purified by silica gel column (chloroform / methanol) to obtain Compound 328 (320 mg, Y = 66%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.15-1.80 (8H, m) 2.51 (3H, s) 3.25 (1H, t, J = 6Hz) 4.13 (2H, t, J = 5Hz) 7.21-8.30 (8H, m) 9.36 (1H, d, J = 9Hz) 11.48-13.83 (2H, br)
After almost dissolving 0.25% aqueous sodium hydroxide solution (20 mL) in compound 328 (268 mg), activated carbon was added and filtered. The filtrate was lyophilized to obtain Compound 329 (268 mg, Y = 91%).

Example 110
6-nitro-2- [6- (phenylmethoxy) -1-naphthalenyl] benzoxazole (compound 330), 5- (6-nitro-2-benzoxazolyl) -2-naphthalenol (compound 331), 4- [[5- (6-Nitro-2-benzoxazolyl) -2-naphthalenyl] oxy] butanoic acid ethyl ester (compound 332), 4-[[5- (6-amino-2-benzoxazolyl) -2-Naphthalenyl] oxy] butanoic acid ethyl ester (Compound 333), 4-[[5- [6- (Diethylamino) -2-benzoxazolyl] -2-naphthalenyl] oxy] butanoic acid ethyl ester (Compound 334) ), 4-[[5- [6- (Diethylamino) -2-benzoxazolyl] -2-naphthalenyl] oxy] butanoic acid (Compound 335):
Toluene (100 mL), thionyl chloride (3.35 mL) and DMF (1 drop) were added to 6-benzyloxy-1-naphthoic acid (10.8 g) and reacted under reflux for 2 hours, and then 2-amino-5-nitro A solution of phenol (12.5 g) in 1,4-dioxane (150 mL) was added and reacted under reflux for 3 hours. After cooling, the precipitated crystals were collected by filtration. The obtained crystals were washed with dilute hydrochloric acid, washed with methanol and dried to obtain an intermediate amide compound (13.4 g, Y = 89%).
Dissolve the amide compound (13.4 g) in 1,3-dimethyl-2-imidazolidinone (70 mL) and add p-toluenesulfonic acid monohydrate (10 g) and toluene (140 mL) to form under reflux The reaction was carried out overnight while removing water. The reaction solution was concentrated under reduced pressure, and water (250 mL) was added to the residue to cause crystallization, and the precipitated crystals were collected by filtration. Methanol (250 mL) and 2% aqueous sodium hydroxide solution (5 mL) were added to the obtained crystals and suspended under reflux for 1 hour, and the crystals were collected by filtration, washed with methanol and dried to give compound 330 (10.96 g, Y = 86%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 5.29 (2H, s) 7.34-8.75 (13H, m) 9.33 (1H, d, J = 9Hz)

A 30% hydrogen bromide / acetic acid solution (100 mL) was added to compound 330 (10.9 g) and reacted at about 100 ° C. for 2 hours. Water (800 mL) was added to the reaction solution for crystallization, and the precipitated crystals were collected by filtration. The obtained crystals were washed with a 60% aqueous methanol solution, washed with toluene and dried to obtain Compound 331 (7.7 g, Y = 91%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 7.21-8.74 (8H, m) 9.26 (1H, d, J = 10Hz) 10.05 (1H, s)
Compound 331 (1.1 g) was dissolved in DMF (20 mL), and potassium carbonate (5.5 g) and ethyl 4-bromo-n-butyrate (920 mg) were added and reacted at room temperature overnight. Water (100 mL) was added to the reaction solution for crystallization, and the precipitated crystals were collected by filtration. The obtained crystals were washed with ethanol and dried to give compound 332 (1.4 g, Y = 93%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.27 (3H, t, J = 7Hz) 2.09-2.70 (4H, m) 4.01-4.36 (4H, m) 7.26-8.51 (8H, m) 9.39 (1H, d, J = 9Hz)

Ethanol (80 mL), toluene (20 mL), and 5% palladium carbon (0.6 g) were added to compound 332 (1.3 g), and reacted at room temperature in a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure and dried to obtain Compound 333 (1.09 g, Y = 90%).
Compound 333 (550 mg) was dissolved in DMF (15 mL), potassium carbonate (2.5 g) and ethyl iodide (2.5 g) were added, and the mixture was reacted at about 65 ° C. overnight. Ethyl acetate (100 mL) was added to the reaction mixture, and the mixture was washed successively with water and saturated brine. The ethyl acetate layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethanol to obtain Compound 334 (450 mg, Y = 72%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.10-1.38 (9H, m) 2.04-2.73 (4H, m) 3.27-3.62 (4H, m) 3.99-4.35 (4H, m) 6.68-8.28 (8H, m) 9.40 (1H, d, J = 9Hz)
Compound 334 (380 mg) was dissolved in methanol (50 mL), 7% aqueous sodium hydroxide solution (3 mL) was added, and the mixture was reacted at about 60 ° C. for 4 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in water (50 mL) with heating, and neutralized with dilute hydrochloric acid. The precipitated crystals were collected by filtration and dried to obtain Compound 335 (312 mg, Y = 88%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.15 (6H, t, J = 7Hz) 1.85-2.51 (4H, m) 3.25-3.61 (4H, m) 4.17 (2H, t, J = 7Hz) 6.74-8.24 (8H, m) 9.41 (1H, d, J = 9Hz) 12.17 (1H, br)

Example 111
4-[[5- [6- [Bis (phenylmethyl) amino] -2-benzoxazolyl] -2-naphthalenyl] oxy] butanoic acid ethyl ester (Compound 336), 4-[[5- [6- Preparation of [bis (phenylmethyl) amino] -2-benzoxazolyl] -2-naphthalenyl] oxy] butanoic acid (Compound 337):
Compound 333 (540 mg) was dissolved in DMF (15 mL), potassium carbonate (2.5 g) and benzyl bromide (800 mg) were added, and the mixture was reacted at room temperature overnight. Water (100 mL) was added to the reaction solution for crystallization, and the precipitated crystals were collected by filtration. The obtained crystals were recrystallized from ethanol to obtain Compound 336 (679 mg, Y = 86%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.26 (3H, t, J = 7Hz) 2.00-2.80 (4H, m) 3.98-4.35 (4H, m) 4.86 (4H, s) 6.64-8.22 (18H, m) 9.36 (1H, d, J = 9Hz)
Compound 336 (550 mg) was dissolved in methanol (60 mL), 4% aqueous sodium hydroxide solution (5 mL) was added, and the mixture was reacted at about 50 ° C. for 6 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in water (80 mL) with heating, and acidified by adding dilute hydrochloric acid. The precipitated crystals were collected by filtration and dried to obtain Compound 337 (483 mg, Y = 92%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.80-2.53 (4H, m) 4.15 (2H, t, J = 6Hz) 4.83 (4H, s) 6.77-8.18 (18H, m) 9.35 (1H, d, J = 10Hz)

Example 112
6-[[5- (6-Nitro-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid ethyl ester (Compound 338), 6-[[5- (6-Amino-2-benzoxazoli L) -2-Naphthalenyl] oxy] hexanoic acid ethyl ester (Compound 339), 6-[[5- (6-Amino-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid hydrochloride (Compound 340) )Manufacturing of:
Compound 331 (1.0 g) was dissolved in DMF (20 mL), and potassium carbonate (5.0 g) and ethyl 6-bromohexanoate (930 mg) were added and reacted at room temperature overnight. Water (80 mL) was added to the reaction solution for crystallization, and the precipitated crystals were collected by filtration. The obtained crystals were washed with ethanol and dried to give compound 338 (1.4 g, Y = 95%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.27 (3H, t, J = 7Hz) 1.54-2.10 (6H, m) 2.37 (2H, t, J = 6Hz) 3.98-4.33 (4H, m) 7.19-8.51 (8H, m) 9.38 (1H, d, J = 9Hz)
Toluene (30 mL), ethanol (150 mL), and 5% palladium carbon (0.4 g) were added to compound 338 (1.2 g), and reacted at room temperature in a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure and dried to obtain Compound 339 (1.03 g, Y = 92%).

Compound 339 (220 mg) was dissolved in methanol (100 mL), 7% aqueous sodium hydroxide solution (6 mL) was added, and the mixture was reacted at about 50 ° C. for 8 hr. The reaction mixture was concentrated under reduced pressure, water (50 mL) was added to the residue and dissolved by heating, neutralized with dilute hydrochloric acid, and the precipitated crystals were collected by filtration. The obtained crystals were dissolved in acetone (50 mL), 35% hydrochloric acid (0.3 mL) was added, and the precipitated crystals were collected by filtration and dried to give compound 340 (112 mg, Y = 50%).
¹ H-NMR (DMSO-d6, D ₂ O / TMS):
δ = 1.40-2.00 (6H, m) 2.30 (2H, t, J = 6Hz) 4.15 (2H, t, J = 5Hz) 7.33-8.35 (8H, m) 9.31 (1H, d, J = 9Hz)

Example 113
6-[[5- [6- (Diethylamino) -2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid ethyl ester (Compound 341), 6-[[5- [6- (Diethylamino) -2 -Benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid (compound 342), 6-[[5- [6- (diethylamino) -2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid sodium salt Production of salt (compound 343):
Compound 339 (450 mg) was dissolved in DMF (10 mL), potassium carbonate (4.0 g) and ethyl iodide (2.5 g) were added, and the mixture was reacted at about 70 ° C. overnight. Ethyl acetate (100 mL) was added to the reaction mixture, and the mixture was washed successively with water and saturated brine. The ethyl acetate layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified with a silica gel column (chloroform) to obtain Compound 341 (385 mg, Y = 75%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.11-2.46 (17H, m) 3.27-3.62 (4H, m) 3.97-4.33 (4H, m) 6.68-8.25 (8H, m) 9.39 (1H, d, J = 9Hz)

Compound 341 (350 mg) was dissolved in methanol (50 mL), 7% aqueous sodium hydroxide solution (3 mL) was added, and the mixture was reacted at about 60 ° C. for 4 hours. The reaction solution was concentrated under reduced pressure, and water (40 mL) was added to the residue to dissolve it with heating, followed by neutralization with dilute hydrochloric acid. The precipitated crystals were collected by filtration and dried to obtain Compound 342 (250 mg, Y = 76%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.15 (6H, t, J = 7Hz) 1.39-2.00 (6H, m) 2.28 (2H, t, J = 6Hz) 3.19-3.65 (4H, m) 4.13 (2H, t, J = 5Hz) 6.75- 8.24 (8H, m) 9.42 (1H, d, J = 9Hz) 12.01 (1H, br)
Compound 342 (68 mg) was suspended in water (50 mL), 0.5% aqueous sodium hydroxide solution (1.3 mL) was added and dissolved by heating, followed by filtration. The filtrate was lyophilized to give compound 343 (63 mg, Y = 88%).

Example 114
6-[[5- [6- [Bis (phenylmethyl) amino] -2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid ethyl ester (Compound 344), 6-[[5- [6- [Bis (phenylmethyl) amino] -2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid (Compound 345), 6-[[5- [6- [Bis (phenylmethyl) amino] -2- Preparation of benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid sodium salt (Compound 346):
Compound 339 (360 mg) was dissolved in DMF (8 mL), and potassium carbonate (2.5 g) and benzyl bromide (0.5 g) were added and reacted at room temperature overnight. Ethyl acetate (50 mL) was added to the reaction mixture, and the mixture was washed successively with water and saturated brine. The ethyl acetate layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified with a silica gel column (chloroform) to obtain Compound 344 (475 mg, Y = 92%).

Compound 344 (475 mg) was dissolved in methanol (100 mL), 7% aqueous sodium hydroxide solution (3 mL) was added, and the mixture was reacted at about 60 ° C. overnight. The reaction solution was concentrated under reduced pressure, the residue was dissolved in water (100 mL) with heating, and acidified by adding dilute hydrochloric acid. The precipitated crystals were collected by filtration and dried to obtain Compound 345 (332 mg, Y = 73%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.40-1.90 (6H, m) 2.18 (2H, t, J = 4Hz) 4.12 (2H, t, J = 6Hz) 4.83 (4H, s) 6.75-8.19 (18H, m) 9.35 (1H, d, (J = 9Hz)
Compound 345 (71 mg) was suspended in water (100 mL), 0.5% aqueous sodium hydroxide solution (1 mL) was added and dissolved by heating, followed by filtration. The filtrate was lyophilized to give compound 346 (42 mg, Y = 57%).

Example 115
[5-[[5- (6-Nitro-2-benzoxazolyl) -2-naphthalenyl] oxy] pentyl] propanedioic acid diethyl ester (compound 347), [5-[[5- (6-amino- 2-Benzoxazolyl) -2-naphthalenyl] oxy] pentyl] propanedioic acid diethyl ester (compound 348), [5-[[5- [6- (diethylamino) -2-benzoxazolyl] -2- Naphthalenyl] oxy] pentyl] propanedioic acid diethyl ester (compound 349), [5-[[5- [6- (diethylamino) -2-benzoxazolyl] -2-naphthalenyl] oxy] pentyl] propanedioic acid ( Compound 350), Preparation of [5-[[5- [6- (Diethylamino) -2-benzoxazolyl] -2-naphthalenyl] oxy] pentyl] propanedioic acid disodium salt (Compound 351):
Compound 331 (900 mg) was dissolved in DMF (18 mL), and potassium carbonate (4.5 g) and diethyl (5-bromopentyl) malonate (1.2 mg) were added and reacted at room temperature overnight. Water (100 mL) was added to the reaction solution for crystallization, and the precipitated crystals were collected by filtration. The obtained crystals were washed with ethanol and dried to obtain Compound 347 (1.4 g, Y = 89%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.15-2.18 (14H, m) 3.36 (1H, t, J = 6Hz) 4.03-4.40 (6H, m) 7.23-8.52 (8H, m) 9.39 (1H, d, J = 9Hz)

Toluene (30 mL), ethanol (120 mL), and 5% palladium carbon (0.3 g) were added to compound 347 (1.2 g), and reacted at room temperature in a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure and dried to obtain Compound 348 (1.09 g, Y = 97%).
Compound 348 (550 mg) was dissolved in DMF (10 mL), potassium carbonate (2.5 g) and ethyl iodide (2.5 g) were added, and the mixture was reacted at about 70 ° C. overnight. Ethyl acetate (100 mL) was added to the reaction mixture, and the mixture was washed successively with water and saturated brine. The ethyl acetate layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified with a silica gel column (chloroform) to obtain Compound 349 (440 mg, Y = 72%).
Compound 349 (440 mg) was dissolved in methanol (100 mL), 15% aqueous sodium hydroxide solution (3 mL) was added, and the mixture was reacted at about 50 ° C. for 4 days. After cooling, the precipitated crystals were collected by filtration and dried to obtain Compound 351 (261 mg, Y = 61%).
The filtrate of Compound 351 was concentrated under reduced pressure, and the residue was dissolved in water (40 mL), and neutralized with dilute hydrochloric acid. The precipitated crystals were collected by filtration and dried to obtain Compound 350 (72 mg, Y = 18%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.03-2.41 (14H, m) 3.14-3.65 (5H, m) 4.14 (2H, t, J = 5Hz) 6.79-8.25 (8H, m) 9.40 (1H, d, J = 9Hz) 12.5 (2H, br)

Example 116
2- [6- [2- (4-morpholinyl) ethoxy] -1-naphthalenyl] -6-nitrobenzoxazole (Compound 352), 2- [6- [2- (4-morpholinyl) ethoxy] -1-naphthalenyl ] -6-Benzoxazolamine dihydrochloride (Compound 353), N, N-diethyl-2- [6- [2- (4-morpholinyl) ethoxy] -1-naphthalenyl] -6-benzoxazolamine dihydrochloride Production of (Compound 354):
Compound 331 (1.0 g) was dissolved in DMF (16 mL), and potassium carbonate (6.0 g) and N- (2-chloroethyl) morpholine hydrochloride (850 mg) were added and reacted at about 65 ° C. overnight. Water (90 mL) was added to the reaction solution for crystallization, and the precipitated crystals were collected by filtration. The obtained crystals were washed with methanol and dried to obtain Compound 352 (1.2 g, Y = 89%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 2.55-3.00 (6H, m) 3.77 (4H, t, J = 5Hz) 4.29 (2H, t, J = 6Hz) 7.22-8.51 (8H, m) 9.40 (1H, d, J = 9Hz)

Toluene (30 mL), methanol (80 mL) and 5% palladium carbon (0.3 g) were added to compound 352 (1.05 g), and reacted at room temperature in a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. Acetone (100 mL) was added to the residue for dissolution, 35% hydrochloric acid (0.3 mL) was added, and the precipitated crystals were collected by filtration and dried to obtain Compound 353 (1.01 g, Y = 86%).
¹ H-NMR (Methanol-d4, D ₂ O / TMS):
δ = 3.36-4.12 (10H, m) 4.63 (2H, t, J = 5Hz) 7.14-8.33 (8H, m) 9.23 (1H, d, J = 10Hz)
Compound 353 (450 mg) was dissolved in DMF (10 mL), potassium carbonate (2.4 g) and ethyl iodide (1.5 g) were added, and the mixture was reacted at 65 ° C. overnight. Ethyl acetate (100 mL) was added to the reaction mixture, and the mixture was washed successively with water and saturated brine. The ethyl acetate layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in acetone (50 mL), 35% hydrochloric acid (0.2 mL) was added, and the precipitated crystals were collected by filtration and dried to obtain Compound 354 (120 mg, Y = 24%).
¹ H-NMR (Methanol-d4 / TMS):
δ = 1.24 (6H, t, J = 7Hz) 3.32-4.09 (14H, m) 4.65 (2H, t, J = 5Hz) 7.43-8.44 (8H, m) 9.42 (1H, d, J = 10Hz)

Example 117
2- [6- (phenylmethoxy) -1-naphthalenyl] -6-benzoxazolol (Compound 355), 6- (cyclohexylmethoxy) -2- [6- (phenylmethoxy) -1-naphthalenyl] benzoxazole ( Compound 356), 5- [6- (cyclohexylmethoxy) -2-benzoxazolyl] -2-naphthalenol (compound 357), 4-[[5- [6- (cyclohexylmethoxy) -2-benzoxazolyl ] -2-Naphthalenyl] oxy] butanoic acid ethyl
Preparation of ester (compound 358), 4-[[5- [6- (cyclohexylmethoxy) -2-benzoxazolyl] -2-naphthalenyl] oxy] butanoic acid (compound 359):
Toluene (80 mL), thionyl chloride (4 mL), and DMF (1 drop) were added to 6-benzyloxy-1-naphthoic acid (12.8 g), reacted for 2.5 hours under reflux, and then concentrated under reduced pressure. After the residue was dissolved in 1,3-dimethyl-2-imidazolidinone (50 mL), 4-aminoresorcinol hydrochloride (7.5 g) and triethylamine (9.4 g) in 1,3-dimethyl-2-imidazolidinone (250 mL) ) Added to the solution and reacted overnight at room temperature. Ethyl acetate (1.2 L) was added to the reaction mixture, and the mixture was washed successively with water, dilute hydrochloric acid aqueous solution and saturated brine. The ethyl acetate layer was dehydrated with magnesium sulfate, concentrated under reduced pressure, and dried to obtain an intermediate amide compound (17.68 g, Y = 100%).

The amide compound (17.65 g) is dissolved in 1,3-dimethyl-2-imidazolidinone (80 mL), and p-toluenesulfonic acid monohydrate (13.1 g) and toluene (160 mL) are added to produce it under reflux. The reaction was carried out overnight while removing water. The reaction solution was concentrated under reduced pressure, and water (200 mL) was added to the residue to suspend it, and then the supernatant was decanted. The residue was washed with 20% aqueous methanol (250 mL) and dried. The obtained product was purified by silica gel column (chloroform) to obtain Compound 355 (6.5 g, Y = 39%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 5.28 (2H, s) 6.82-8.28 (13H, m) 9.40 (1H, d, J = 9Hz) 9.92 (1H, s)
Compound 355 (3.5 g) was dissolved in DMF (35 mL), potassium carbonate (15 g) and bromomethylcyclohexane (3.0 g) were added, and the mixture was reacted at about 65 ° C. for 4 days. Water (250 mL) was added to the reaction solution for crystallization, and the precipitated crystals were collected by filtration. The obtained crystals were washed with methanol and dried to obtain Compound 356 (4.11 g, Y = 93%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.00-2.10 (11H, m) 3.85 (2H, d, J = 6Hz) 5.23 (2H, s) 6.89-8.31 (13H, m) 9.42 (1H, d, J = 9Hz)
Methanol (300 mL), toluene (100 mL), and 5% palladium carbon (1 g) were added to compound 356 (4.11 g), and reacted at about 40 ° C. in a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was washed with toluene and dried to obtain Compound 357 (2.52 g, Y = 76%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 0.94-2.10 (11H, m) 3.85 (2H, d, J = 6Hz) 5.56 (1H, s) 6.89-8.25 (8H, m) 9.35 (1H, d, J = 10Hz)

Compound 357 (350 mg) was dissolved in DMF (4 mL), and potassium carbonate (1.5 g) and ethyl 4-bromo-n-butyrate (240 mg) were added and reacted at room temperature overnight. Water (36 mL) was added to the reaction solution for crystallization, and the precipitated crystals were collected by filtration. The obtained crystals were washed with methanol and dried to obtain Compound 358 (320 mg, Y = 70%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 0.97-2.70 (18H, m) 3.74-4.36 (6H, m) 6.89-8.30 (8H, m) 9.39 (1H, d, J = 9Hz)
Compound 358 (300 mg) was dissolved in methanol (60 mL), 7% aqueous sodium hydroxide solution (3 mL) was added, and the mixture was reacted at about 50 ° C. overnight. The reaction solution was concentrated under reduced pressure, and water (30 mL) was added to the residue to dissolve it with heating. The precipitated crystals were collected by filtration and dried to obtain Compound 359 (267 mg, Y = 94%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 0.95-2.57 (15H, m) 3.88 (2H, t, J = 6Hz) 4.17 (2H, t, J = 6Hz) 6.97-8.27 (8H, m) 9.36 (1H, d, J = 10Hz)

Example 118
6-[[5- [6- (cyclohexylmethoxy) -2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid ethyl ester (Compound 360), 6-[[5- [6- (cyclohexylmethoxy) Preparation of -2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid (Compound 361):
Compound 357 (340 mg) was dissolved in DMF (4 mL), potassium carbonate (1.5 g) and ethyl 6-bromohexanoate (270 mg) were added, and the mixture was reacted overnight at room temperature. Water (26 mL) was added to the reaction solution for crystallization, and the precipitated crystals were collected by filtration. The obtained crystals were washed with methanol and dried to obtain Compound 360 (443 mg, Y = 94%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.02-2.50 (22H, m) 3.79-4.33 (6H, m) 6.92-8.30 (8H, m) 9.38 (1H, d, J = 9Hz)
Compound 360 (413 mg) was dissolved in methanol (50 mL), 4% aqueous sodium hydroxide solution (5 mL) was added, and the mixture was reacted at about 60 ° C. for 3 hr. The reaction mixture was concentrated under reduced pressure, and water (50 mL) was added to the residue to dissolve it with heating. The precipitated crystals were collected by filtration and dried to obtain Compound 361 (338 mg, Y = 87%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 0.81-2.00 (17H, m) 2.27 (2H, t, J = 6Hz) 3.74-4.21 (4H, m) 6.92-8.27 (8H, m) 9.35 (1H, d, J = 9Hz)

Example 119
[5-[[5- [6- (cyclohexylmethoxy) -2-benzoxazolyl] -2-naphthalenyl] oxy] pentyl] propanedioic acid diethyl ester (compound 362), [5-[[5- [6 Preparation of-(Cyclohexylmethoxy) -2-benzoxazolyl] -2-naphthalenyl] oxy] pentyl] propanedioic acid disodium salt (Compound 363):
Compound 357 (320 mg) was dissolved in DMF (4 mL), potassium carbonate (1.5 g) and diethyl (5-bromopentyl) malonate (350 mg) were added, and the mixture was reacted overnight at room temperature. Water (25 mL) was added to the reaction solution for crystallization, and the precipitated crystals were collected by filtration. The obtained crystals were recrystallized from ethanol to obtain Compound 362 (462 mg, Y = 90%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.14-2.15 (25H, m) 3.35 (1H, t, J = 7Hz) 3.79-4.39 (8H, m) 6.88-8.29 (8H, m) 9.37 (1H, d, J = 9Hz)
Compound 362 (434 mg) was dissolved in methanol (100 mL), 8% aqueous sodium hydroxide solution (5 mL) was added, and the mixture was reacted at about 50 ° C. for 3 days. After cooling, the precipitated crystals were collected by filtration to obtain Compound 363 (384 mg, Y = 90%).

Example 120
Preparation of 6- (cyclohexylmethoxy) -2- [6- [2- (4-morpholinyl) ethoxy] -1-naphthalenyl] benzoxazole hydrochloride (Compound 364):
Compound 357 (203 mg) was dissolved in DMF (4 mL), and potassium carbonate (1.5 g) and N- (2-chloroethyl) morpholine hydrochloride (155 mg) were added and reacted at about 65 ° C. overnight. Water (25 mL) was added to the reaction solution for crystallization, and the precipitated crystals were collected by filtration. The obtained crystal was recrystallized from methanol. The obtained crystals were dissolved in acetone (30 mL), 35% hydrochloric acid (0.3 mL) was added, and the precipitated crystals were collected by filtration and dried to obtain Compound 364 (180 mg, Y = 63%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 0.98-1.92 (11H, m) 3.10-4.02 (12H, m) 4.68 (2H, t, J = 5Hz) 6.94-8.31 (8H, m) 9.40 (1H, d, J = 9Hz) 12.0 (1H, br)

Example 121
Preparation of 3-[[5- [6- (cyclohexylmethoxy) -2-benzoxazolyl] -2-naphthalenyl] oxy] -N, N-dimethyl-1-propanamine hydrochloride (Compound 365):
Compound 357 (298 mg) was dissolved in DMF (5 mL), potassium carbonate (2.2 g) and 3-dimethylaminopropyl chloride hydrochloride (250 mg) were added, and the mixture was reacted at about 65 ° C. overnight. Ethyl acetate (50 mL) was added to the reaction mixture, and the mixture was washed successively with water and saturated brine. The ethyl acetate layer was dried over magnesium sulfate and concentrated under reduced pressure. Acetone (25 mL) was added to the residue for dissolution, 35% hydrochloric acid (0.3 mL) was added, and the precipitated crystals were collected by filtration and dried to obtain Compound 365 (172 mg, Y = 44%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 0.88-2.52 (13H, m) 2.81 (6H, s) 3.32 (2H, t, J = 6Hz) 3.89 (2H, d, J = 6Hz) 4.27 (2H, t, J = 6Hz) 6.94-8.29 ( 8H, m) 9.39 (1H, d, J = 9Hz) 11.0 (1H, br)

Example 122
5- (1,1-dimethylethyl) -2- [6- (phenylmethoxy) -1-naphthalenyl] benzoxazole (Compound 366), 5- [5- (1,1-dimethylethyl) -2-benzoxa Zolyl] -2-naphthalenol (compound 367), 4-[[5- [5- (1,1-dimethylethyl) -2-benzoxazolyl] -2-naphthalenyl] oxy] butanoic acid ethyl ester (compound 368), 4-[[5- [5- (1,1-dimethylethyl) -2-benzoxazolyl] -2-naphthalenyl] oxy] butanoic acid (Compound 369), 4-[[5- [5 Preparation of-(1,1-dimethylethyl) -2-benzoxazolyl] -2-naphthalenyl] oxy] butanoic acid potassium salt (Compound 370):
6-Benzyloxy-1-naphthoic acid (10.0 g) was reacted with thionyl chloride (5.2 g) in toluene (100 mL) for 1.5 hours under reflux. The reaction solution was concentrated under reduced pressure to obtain 6-benzyloxy-1-naphthoic acid chloride (11.0 g).
A solution of 6-benzyloxy-1-naphthoic acid chloride (11.0 g) in 2-amino-4-tert-butylphenol (7.2 g) and triethylamine (4.4 g) in 1,3-dimethyl-2-imidazolidinone (120 mL) And reacted at room temperature for 2.5 hours. The reaction solution was added to water (2 L) for crystallization, and the precipitated crystals were collected by filtration, washed with water, and dried to obtain an intermediate amide compound (15.3 g, Y = 100%).

An amide compound (15.0 g) and p-toluenesulfonic acid monohydrate (13.4 g) are added to a mixed solvent of 1,3-dimethyl-2-imidazolidinone (150 mL) and toluene (450 mL) and produced under reflux. The reaction was carried out for 21 hours while removing water. The reaction solution was concentrated under reduced pressure, the residue was added to water (1.5 L) and stirred, and then the product was extracted with chloroform (1.5 L). Methanol (200 mL) and potassium hydroxide (6.0 g) were added to the residue obtained by concentrating the chloroform layer after washing with water, and suspended under reflux for 3.5 hours. The crystals were collected by filtration and dried to give compound 366 (6.55 g, Y = 46%).
Compound 366 (6.30 g) was added to 1,3-dimethyl-2-imidazolidinone (100 mL), dissolved by heating, 5% palladium carbon (0.3 g) was added, and the reaction was carried out in a hydrogen atmosphere for 24 hours. The reaction solution was filtered, the filtrate was added to water (2 L) and stirred, and then the reaction product was extracted with ethyl acetate (1 L). The organic layer was washed with water, dehydrated with magnesium sulfate, and concentrated under reduced pressure to obtain a crude oil (4.7 g). The crude oil was purified on a silica gel column (toluene / ethyl acetate) to give compound 367 (2.68 g, Y = 55%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.40 (9H, s) 7.28-8.25 (8H, m) 9.32 (1H, d, J = 10Hz) 9.98 (1H, s)
Potassium carbonate (600 mg) and ethyl 4-bromo-n-butyrate (343 mg) were added to compound 367 (300 mg) in DMF (12 mL), and reacted at room temperature for 28 hours. The reaction solution was added to water (150 mL) for crystallization, and the precipitated crystals were collected by filtration and washed with water to obtain crude crystals. The crude crystals were recrystallized from 80% aqueous ethanol (4 mL) to give compound 368 (334 mg, Y = 82%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.27 (3H, t, J = 7Hz) 1.43 (9H, s) 2.10-2.69 (4H, m) 4.00-4.35 (4H, m) 7.24-7.91 (7H, m) 8.21-8.33 (1H, dd, J = 1Hz, 7Hz) 9.40 (1H, d, J = 9Hz)
An 8% aqueous potassium hydroxide solution (5 mL) was added to compound 368 (270 mg) in ethanol (20 mL) and reacted at 45 ° C. for 3 hours. Water (20 mL) was added to the oil obtained by concentrating the reaction solution under reduced pressure, and acidified with 35% hydrochloric acid with stirring. The precipitated crystals were collected by filtration, washed with water, and dried to obtain Compound 369 (214 mg, Y = 85%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.40 (9H, s) 1.90-2.54 (4H, m) 4.19 (2H, t, J = 6Hz) 7.31-8.34 (8H, m) 9.38 (1H, d, J = 9Hz) 11.48-12.76 (1H, br)
0.04% aqueous potassium hydroxide solution (40 mL) was added to compound 369 (100 mg), dissolved by heating, activated carbon was added, and the mixture was filtered while hot. The filtrate was lyophilized to give compound 370 (97 mg, Y = 89%).

Example 123
6-[[5- [5- (1,1-Dimethylethyl) -2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid ethyl ester (Compound 371), 6-[[5- [5- (1,1-dimethylethyl) -2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid (Compound 372), 6-[[5- [5- (1,1-dimethylethyl) -2- Preparation of benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid potassium salt (Compound 373):
Potassium carbonate (810 mg) and ethyl 6-bromohexanoate (539 mg) were added to compound 367 (300 mg) in DMF (12 mL), and reacted at room temperature for 42 hours. The reaction was added to water (150 mL) and the reaction product was extracted with ethyl acetate (100 mL). The organic layer was washed with water, dehydrated with magnesium sulfate, and concentrated under reduced pressure to obtain Compound 371 (780 mg).
An 8% aqueous potassium hydroxide solution (5 mL) was added to compound 371 (780 mg) in ethanol (20 mL) and reacted at 45 ° C. for 17 hours. The reaction mixture was concentrated under reduced pressure, water (20 mL) was added to the residue and dissolved, and then acidified with 35% hydrochloric acid. The separated product was extracted with ethyl acetate (100 mL). The organic layer was washed with water, dehydrated with magnesium sulfate, and concentrated under reduced pressure to about a quarter volume. The precipitated crystals were collected by filtration and dried to obtain Compound 372 (305 mg, Y = 75%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.18-2.41 (17H, m) 4.15 (2H, t, J = 6Hz) 7.30-8.33 (8H, m) 9.37 (1H, d, J = 9Hz) 11.03-12.97 (1H, br)
0.035% aqueous potassium hydroxide solution (70 mL) was added to compound 372 (150 mg) and dissolved by heating, and then activated carbon was added and filtered while hot. The filtrate was lyophilized to give compound 373 (142 mg, Y = 87%).

Example 124
[3-[[5- [5- (1,1-dimethylethyl) -2-benzoxazolyl] -2-naphthalenyl] oxy] propyl] propanedioic acid diethyl ester (compound 374), [3-[[ 5- [5- (1,1-dimethylethyl) -2-benzoxazolyl] -2-naphthalenyl] oxy] propyl] propanedioic acid (Compound 375), [3-[[5- [5- (1 , 1-Dimethylethyl) -2-benzoxazolyl] -2-naphthalenyl] oxy] propyl] propanedioic acid disodium salt (Compound 376):
In DMF (10 mL), potassium carbonate (656 mg) and diethyl (3-chloropropyl) malonate (400 mg) were added to compound 367 (300 mg), and reacted at 70-80 ° C. for 22 hours. The reaction mixture was added to water (150 mL), and the reaction product was extracted with ethyl acetate (400 mL). The organic layer was washed with water, dehydrated with magnesium sulfate, and concentrated under reduced pressure to obtain a crude oil. The crude oil was purified with a silica gel column (toluene / ethyl acetate) to obtain Compound 374 (0.81 g).

18% aqueous potassium hydroxide solution (5 mL) was added to compound 374 (0.81 g) in ethanol (20 mL), and reacted at room temperature for 19 hours. The reaction solution was concentrated under reduced pressure, and water (50 mL) was added to the obtained oil for dissolution, followed by acid precipitation with 35% hydrochloric acid. The precipitated crystals were collected by filtration, washed with water, and dried to obtain Compound 375 (109 mg, Y = 25%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.40 (9H, s) 1.74-2.14 (4H, m) 3.37 (1H, t, J = 6Hz) 4.19 (2H, t, J = 5Hz) 7.31-8.34 (8H, m) 9.37 (1H, d, (J = 9Hz)
0.08% aqueous sodium hydroxide solution (15 mL) was added to compound 375 (70 mg) and dissolved substantially, and then activated carbon was added and filtered. The filtrate was lyophilized to obtain Compound 376 (72 mg, Y = 94%).

Example 125
[5-[[5- [5- (1,1-dimethylethyl) -2-benzoxazolyl] -2-naphthalenyl] oxy] pentyl] propanedioic acid diethyl ester (compound 377), [5-[[ 5- [5- (1,1-dimethylethyl) -2-benzoxazolyl] -2-naphthalenyl] oxy] pentyl] propanedioic acid (Compound 378), [5-[[5- [5- (1 , 1-Dimethylethyl) -2-benzoxazolyl] -2-naphthalenyl] oxy] pentyl] propanedioic acid disodium salt (Compound 379):
Potassium carbonate (600 mg) and diethyl (5-bromopentyl) malonate (520 mg) were added to compound 367 (300 mg) in DMF (12 mL) and reacted at room temperature for 28 hours. The reaction solution was added into water (150 mL), and the reaction product was extracted with ethyl acetate (200 mL). The organic layer was washed with water, dehydrated with magnesium sulfate, and concentrated under reduced pressure to obtain Compound 377 (700 mg).

An 8% aqueous potassium hydroxide solution (5 mL) was added to compound 377 (700 mg) in ethanol (20 mL) and reacted at room temperature for 3 hours and at 45 ° C. for 18 hours. The reaction solution was concentrated under reduced pressure, and water (20 mL) was added to the residue to dissolve it. Acidified with 35% hydrochloric acid, and the separated product was extracted with ethyl acetate (100 mL). The organic layer was washed with water, dehydrated with magnesium sulfate, and concentrated under reduced pressure to obtain a crude oil. The crude oil was purified with a silica gel column (toluene / ethyl acetate) to give compound 378 (263 mg, Y = 57%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.40-2.08 (17H, m) 3.24 (1H, t, J = 7Hz) 4.15 (2H, t, J = 5Hz) 7.21-8.32 (8H, m) 9.37 (1H, d, J = 9Hz)
0.08% aqueous sodium hydroxide solution (20 mL) was added to and dissolved in compound 378 (100 mg), and then activated carbon was added and filtered. The filtrate was lyophilized to give compound 379 (92 mg, Y = 84%).

Example 126
Preparation of 5- (1,1-dimethylethyl) -2- [6- [2- (4-morpholinyl) ethoxy] -1-naphthalenyl] benzoxazole hydrochloride (Compound 380):
In DMF (10 mL), potassium carbonate (350 mg) and N- (2-chloroethyl) morpholine hydrochloride (141 mg) were added to compound 367 (200 mg) and reacted at 70-80 ° C. for 16 hours. The reaction was added to water (150 mL) and the reaction product was extracted with ethyl acetate (100 mL). The organic layer was washed with water, dehydrated with magnesium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in acetone (20 mL), 35% hydrochloric acid was added, and the precipitated crystals were collected by filtration and dried to obtain Compound 380 (212 mg, Y = 72%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.40 (9H, s) 3.15-4.02 (10H, m) 4.69 (2H, t, J = 4Hz) 7.38-8.35 (8H, m) 9.41 (1H, d, J = 9Hz) 11.06-12.76 (1H, br)

Example 127
3-[[5- [5- (1,1-dimethylethyl) -2-benzoxazolyl] -2-naphthalenyl] oxy] -N, N-dimethyl-1-propanamine hydrochloride (Compound 381) Manufacturing:
Potassium carbonate (350 mg) and 3-dimethylaminopropyl chloride hydrochloride (120 mg) were added to compound 367 (200 mg) in DMF (10 mL), and reacted at 70-80 ° C. for 16 hours. The reaction was added to water (150 mL) and the reaction product was extracted with ethyl acetate (100 mL). The organic layer was washed with water, dehydrated with magnesium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in acetone (20 mL), acidified with 35% hydrochloric acid, concentrated under reduced pressure and dried to give compound 381 (171 mg, Y = 62%).
¹ H-NMR (Methanol-d4 / TMS):
δ = 1.42 (9H, s) 2.01-2.54 (2H, m) 2.98 (6H, s) 3.56 (2H, t, J = 4Hz) 4.28 (2H, t, J = 6Hz) 7.29-8.27 (8H, m) 9.25 (1H, d, J = 10Hz)

Example 128
5-phenyl-2- [6- (phenylmethoxy) -1-naphthalenyl] benzoxazole (compound 382), 5- (5-phenyl-2-benzoxazolyl) -2-naphthalenol (compound 383), 4- [[5- (5-Phenyl-2-benzoxazolyl) -2-naphthalenyl] oxy] butanoic acid ethyl ester (Compound 384), 4-[[5- (5-Phenyl-2-benzoxazolyl) -2-Naphthalenyl] oxy] butanoic acid (Compound 385), 4-[[5- (5-Phenyl-2-benzoxazolyl) -2-naphthalenyl] oxy] butanoic acid potassium salt (Compound 386):
6-Benzyloxy-1-naphthoic acid (12.0 g) was reacted with thionyl chloride (6.2 g) for 2.5 hours under reflux in toluene (120 mL). The reaction solution was concentrated under reduced pressure to obtain 6-benzyloxy-1-naphthoic acid chloride (13.2 g).
6-Benzyloxy-1-naphthoic acid chloride (13.2 g) was added to a solution of 2-amino-4-phenylphenol (9.6 g) and triethylamine (5.3 g) in 1,3-dimethyl-2-imidazolidinone (100 mL). In addition, the mixture was reacted at room temperature for 3 hours. The reaction solution was added to water (1.5 L) for crystallization, and the precipitated crystals were collected by filtration and washed with water. The obtained crystals were suspended in methanol (200 mL) with stirring at 50 to 60 ° C., and the crystals were collected by filtration and dried to obtain an intermediate amide compound (16.6 g, Y = 86%).
An amide compound (15.0 g) and p-toluenesulfonic acid monohydrate (12.8 g) are added to a mixed solvent of 1,3-dimethyl-2-imidazolidinone (150 mL) and toluene (450 mL) and produced under reflux. The reaction was carried out for 17 hours while removing water. The reaction solution was concentrated under reduced pressure, and the remaining solution was washed with water to obtain a tar-like product.

Methanol (300 mL) and potassium hydroxide (10.0 g) were added to the obtained tar-like material, and the mixture was stirred overnight at room temperature. The crystals were collected by filtration and dried to obtain Compound 382 (4.26 g, Y = 30%).
Methanol (300 mL) and 5% palladium carbon (1.0 g) were added to compound 382 (4.00 g), and reacted at 45 ° C. for 3 days in a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. Methanol (50 mL) was added to the residue for suspension, and the crystals were collected by filtration. Acetone (20 mL) was added to the obtained crystals, and the mixture was suspended under reflux. The crystals were collected by filtration and dried to obtain Compound 383 (2.57 g, Y = 81%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 7.31-8.40 (13H, m) 9.35 (1H, d, J = 10Hz) 10.02 (1H, s)
Potassium carbonate (627 mg) and ethyl 4-bromo-n-butyrate (735 mg) were added to compound 383 (300 mg) in DMF (12 mL) and reacted at room temperature for 26 hours. The reaction was added to water (100 mL) and the reaction product was extracted with ethyl acetate (100 mL). The organic layer was washed with water, dehydrated with magnesium sulfate, and concentrated under reduced pressure. Ethanol (20 mL) was added to the residue and suspended by stirring, and the crystals were collected by filtration and dried to obtain Compound 384 (277 mg, Y = 69%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.27 (3H, t, J = 7Hz) 2.06-2.73 (4H, m) 4.00-4.35 (4H, m) 7.25-8.35 (13H, m) 9.43 (1H, d, J = 9Hz)
A 10% aqueous potassium hydroxide solution (2 mL) was added to compound 384 (250 mg) in ethanol (10 mL) and reacted at 45 ° C. for 4 hours. The reaction mixture was concentrated under reduced pressure, water (20 mL) was added to the residue, and the mixture was dissolved by heating, and then acidified with 35% hydrochloric acid. The precipitated crystals were collected by filtration, washed with water, and dried to obtain Compound 385 (186 mg, Y = 79%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.95-2.64 (4H, m) 4.19 (2H, t, J = 6Hz) 7.38-8.36 (13H, m) 9.40 (1H, d, J = 9Hz) 11.48-12.76 (1H, br)
0.04% aqueous potassium hydroxide solution (40 mL) was added to compound 385 (100 mg) and dissolved by heating, and then activated carbon was added and filtered while hot. The filtrate was lyophilized to give compound 386 (105 mg, Y = 96%).

Example 129
6-[[5- (5-Phenyl-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid ethyl ester (compound 387), 6-[[5- (5-phenyl-2-benzoxazolyl) ) -2-Naphthalenyl] oxy] hexanoic acid (Compound 388), 6-[[5- (5-Phenyl-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid potassium salt (Compound 389) Manufacturing:
Potassium carbonate (630 mg) and ethyl 6-bromohexanoate (325 mg) were added to compound 383 (300 mg) in DMF (12 mL) and reacted at room temperature for 48 hours. The reaction was added to water (100 mL) and the reaction product was extracted with ethyl acetate (100 mL). The organic layer was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was suspended in a suspension with ethanol (10 mL), and the crystals were collected by filtration and dried to obtain Compound 387 (343 mg, Y = 80%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.26 (3H, t, J = 7Hz) 1.45-2.47 (8H, m) 3.97-4.33 (4H, m) 7.23-8.35 (13H, m) 9.42 (1H, d, J = 9Hz)
A 12% aqueous potassium hydroxide solution (2 mL) was added to compound 387 (320 mg) in ethanol (10 mL) and reacted at 45 ° C. for 4 hours. The reaction mixture was concentrated under reduced pressure, water (20 mL) was added to the residue, and the mixture was dissolved by heating, and then acidified with 35% hydrochloric acid. The precipitated crystals were collected by filtration, washed with water, and dried to obtain Compound 388 (228 mg, Y = 76%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.60-2.28 (8H, m) 4.14 (2H, t, J = 5Hz) 7.36-8.35 (13H, m) 9.40 (1H, d, J = 10Hz) 11.06-13.61 (1H, br)
0.04% aqueous potassium hydroxide solution (50 mL) was added to Compound 388 (100 mg) and dissolved by heating, and then activated carbon was added and filtered while hot. The filtrate was lyophilized to obtain Compound 389 (100 mg, Y = 92%).

Example 130
[5-[[5- (5-Phenyl-2-benzoxazolyl) -2-naphthalenyl] oxy] pentyl] propanedioic acid diethyl ester (compound 390), [5-[[5- (5-phenyl- 2-Benzoxazolyl) -2-naphthalenyl] oxy] pentyl] propanedioic acid (Compound 391), [5-[[5- (5-Phenyl-2-benzoxazolyl) -2-naphthalenyl] oxy] Pentyl] propanedioic acid disodium salt (compound 392):
In DMF (12 mL), potassium carbonate (623 mg) and diethyl (5-bromopentyl) malonate (451 mg) were added to compound 383 (300 mg) and reacted at room temperature for 27 hours. The reaction solution was added to water (100 mL), and the separated reaction product was extracted with ethyl acetate (100 mL). The organic layer was washed with water, dehydrated with magnesium sulfate, and concentrated under reduced pressure to obtain Compound 390 (0.76 g).

A 23% aqueous potassium hydroxide solution (5 mL) was added to compound 390 (0.76 g) in ethanol (20 mL) and reacted at 45 ° C. for 5 hours. The reaction mixture was concentrated under reduced pressure, water (20 mL) was added to the residue, and the mixture was heated to dissolve, then acidified with 35% hydrochloric acid, and the separated reaction product was extracted with ethyl acetate (50 mL). The organic layer was washed with water, dehydrated with magnesium sulfate, and concentrated under reduced pressure. The oil obtained was purified with a silica gel column (toluene / ethyl acetate) to obtain Compound 391 (155 mg, Y = 34%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.43-1.83 (8H, m) 3.25 (1H, t, J = 6Hz) 4.14 (2H, t, J = 4Hz) 7.21-8.36 (13H, m) 9.40 (1H, d, J = 10Hz) 12.65 ( 2H, brs)
To a compound 391 (70 mg), 0.06% aqueous sodium hydroxide solution (20 mL) was added and dissolved, and then activated carbon was added and filtered. The filtrate was lyophilized to give compound 392 (58 mg, Y = 76%).

Example 131
Preparation of 2- [6- [2- (4-morpholinyl) ethoxy] -1-naphthalenyl] -5-phenylbenzoxazole hydrochloride (Compound 393):
Potassium carbonate (496 mg) and (2-chloroethyl) morpholine hydrochloride (207 mg) were added to compound 383 (300 mg) in DMF (10 mL), and the mixture was stirred at 70-80 ° C. for 19 hours. The reaction solution was crystallized in water (100 mL), and the precipitated crystals were collected by filtration and washed with water. The obtained crystals were dissolved in acetone (20 mL) and acidified with 35% hydrochloric acid. The precipitated crystals were collected by filtration and dried to obtain Compound 393 (339 mg, Y = 78.3%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 3.09-4.16 (10H, m) 4.67 (2H, t, J = 4Hz) 7.43-8.40 (13H, m) 9.44 (1H, d, J = 9Hz) 11.06-12.55 (1H, br)

Example 132
Preparation of N, N-dimethyl-3-[[5- (5-phenyl-2-benzoxazolyl) -2-naphthalenyl] oxy] -1-propanamine hydrochloride (Compound 394):
In DMF (10 mL), potassium carbonate (493 mg) and 3-dimethylaminopropyl chloride hydrochloride (171 mg) were added to compound 383 (300 mg), and reacted at 70-80 ° C. for 19 hours. The reaction was added to water (100 mL) and the reaction product was extracted with ethyl acetate (300 mL). The organic layer was washed with water, dehydrated with magnesium sulfate, and concentrated under reduced pressure. The resulting residue was dissolved in acetone (20 mL) and acidified with 35% hydrochloric acid. The precipitated crystals were collected by filtration and dried to obtain Compound 394 (225 mg, Y = 55%).
¹ H-NMR (Methanol-d4 / TMS):
δ = 2.15-2.48 (2H, m) 2.95 (6H, s) 3.41 (2H, t, J = 7Hz) 4.22 (2H, t, J = 6Hz) 7.25-8.30 (13H, m) 9.27 (1H, d, (J = 10Hz)

Example 133
5-chloro-2- [6- (phenylmethoxy) -1-naphthalenyl] benzoxazole (Compound 395), 5- (5-chloro-2-benzoxazolyl) -2-naphthalenol (Compound 396), 4- [[5- (5-Chloro-2-benzoxazolyl) -2-naphthalenyl] oxy] butanoic acid ethyl ester (Compound 397), 4-[[5- (5-Chloro-2-benzoxazolyl) -2-Naphthalenyl] oxy] butanoic acid (Compound 398), 4-[[5- (5-chloro-2-benzoxazolyl) -2-naphthalenyl] oxy] butanoic acid sodium salt (Compound 399):
Toluene (75 mL), thionyl chloride (2.36 mL), and DMF (1 drop) were added to 6-benzyloxy-1-naphthoic acid (7.5 g), reacted for 2 hours under reflux, and then 2-amino-4-chloro A solution of phenol (9.8 g) in 1,4-dioxane (150 mL) was added and reacted under reflux for 3 hours. The reaction mixture was concentrated under reduced pressure, 2% aqueous hydrochloric acid (500 mL) was added to the residue to suspend it, and the crystals were collected by filtration. The obtained crystals were washed with methanol and dried to obtain an intermediate amide compound (9.7 g, Y = 89%).

Dissolve the amide compound (9.7 g) in 1,3-dimethyl-2-imidazolidinone (50 mL) and add p-toluenesulfonic acid monohydrate (7.0 g) and toluene (100 mL) to form under reflux The reaction was carried out overnight while removing water. The reaction solution was concentrated under reduced pressure, and water (250 mL) was added to the residue to cause crystallization, and the precipitated crystals were collected by filtration. The obtained crystals were washed with methanol and dried to give compound 395 (6.46 g, Y = 70%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 5.23 (2H, s) 7.25-8.35 (13H, m) 9.38 (1H, d, J = 9Hz)
A 30% hydrogen bromide / acetic acid solution (70 mL) was added to compound 395 (6.4 g), and the mixture was reacted at about 100 ° C. for 2 hours. Water (430 mL) was added to the reaction solution for crystallization, and the precipitated crystals were collected by filtration. The obtained crystals were washed with methanol and recrystallized from toluene to obtain Compound 396 (3.57 g, Y = 73%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 7.29-8.27 (8H, m) 9.26 (1H, d, J = 10Hz) 10.02 (1H, s)

Compound 396 (370 mg) was dissolved in DMF (5 mL), potassium carbonate (1.8 g) and ethyl 4-bromo-n-butyrate (315 mg) were added, and the mixture was reacted overnight at room temperature. Water (45 mL) was added to the reaction solution for crystallization, and the precipitated crystals were collected by filtration and dried to obtain Compound 397 (486 mg, Y = 95%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.27 (3H, t, J = 7Hz) 2.05-2.69 (4H, m) 4.00-4.35 (4H, m) 7.24-8.32 (8H, m) 9.35 (1H, d, J = 9Hz)
Methanol (50 mL) and 0.4% aqueous sodium hydroxide solution (2.2 mL) were added to compound 397 (450 mg) and reacted at about 50 ° C. for 4 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in water (50 mL) with heating, and acidified by adding diluted hydrochloric acid. The precipitated crystals were collected by filtration and dried to obtain Compound 398 (383 mg, Y = 87%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.91-2.63 (4H, m) 4.18 (2H, t, J = 6Hz) 7.32-8.33 (8H, m) 9.31 (1H, d, J = 9Hz) 12.2 (1H, br)
Compound 398 (78.8 mg) was suspended in water (40 mL), 0.4% aqueous sodium hydroxide solution (2.2 mL) was added and dissolved by heating, followed by filtration. The filtrate was lyophilized to give compound 399 (75 mg, Y = 90%).

Example 134
6-[[5- (5-Chloro-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid ethyl ester (Compound 400), 6-[[5- (5-Chloro-2-benzoxazolyl) ) -2-Naphthalenyl] oxy] hexanoic acid (compound 401), 6-[[5- (5-chloro-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid sodium salt (compound 402) Manufacturing:
Compound 396 (360 mg) was dissolved in DMF (5 mL), potassium carbonate (1.8 g) and ethyl 6-bromohexanoate (340 mg) were added, and the mixture was reacted at room temperature overnight. Water (45 mL) was added to the reaction solution for crystallization, and the precipitated crystals were collected by filtration and dried to obtain Compound 400 (460 mg, Y = 86%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.26 (3H, t, J = 7Hz) 1.55-2.01 (6H, m) 2.37 (2H, t, J = 6Hz) 3.97-4.33 (4H, m) 7.18-8.34 (8H, m) 9.35 (1H, d, J = 9Hz)
Methanol (50 mL) and 4% aqueous sodium hydroxide solution (5 mL) were added to compound 400 (420 mg) and reacted at about 50 ° C. for 4 hours. The reaction mixture was concentrated under reduced pressure, and water (50 mL) was added to the residue to dissolve it with heating. The precipitated crystals were collected by filtration and dried to obtain Compound 401 (352 mg, Y = 71%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.40-2.00 (6H, m) 2.28 (2H, t, J = 6Hz) 4.13 (2H, t, J = 6Hz) 7.29-8.32 (8H, m) 9.29 (1H, t, J = 9Hz) 12.04 ( 1H, br)
Compound 401 (87 mg) was suspended in water (40 mL), 0.4% aqueous sodium hydroxide solution (2.2 mL) was added and dissolved by heating, followed by filtration. The filtrate was lyophilized to give compound 402 (80 mg, Y = 87%).

Example 135
[3-[[5- (5-Chloro-2-benzoxazolyl) -2-naphthalenyl] oxy] propyl] propanedioic acid diethyl ester (compound 403), [3-[[5- (5-chloro- Preparation of 2-benzoxazolyl) -2-naphthalenyl] oxy] propyl] propanedioic acid disodium salt (Compound 404):
Compound 396 (250 mg) was dissolved in DMF (5 mL), and potassium carbonate (1.2 g) and diethyl (3-chloropropyl) malonate (260 mg) were added and reacted at about 65 ° C. overnight. Water (45 mL) was added to the reaction solution for crystallization, and the precipitated crystals were collected by filtration. The obtained crystals were purified by silica gel column (chloroform) to obtain Compound 403 (210 mg, Y = 50%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.27 (6H, t, J = 7Hz) 1.79-2.28 (4H, m) 3.47 (1H, t, J = 7Hz) 4.05-4.40 (6H, m) 7.18-8.35 (8H, m) 9.36 (1H, d, J = 9Hz)
Compound 403 (194 mg) was dissolved in methanol (60 mL), 7% aqueous sodium hydroxide solution (3 mL) was added, and the mixture was reacted at about 60 ° C. overnight. The precipitated crystals were collected by filtration and dried to obtain Compound 404 (163 mg, Y = 86.1%).

Example 136
[5-[[5- (5-Chloro-2-benzoxazolyl) -2-naphthalenyl] oxy] pentyl] propanedioic acid diethyl ester (Compound 405), [5-[[5- (5-Chloro- Preparation of 2-benzoxazolyl) -2-naphthalenyl] oxy] pentyl] propanedioic acid disodium salt (compound 406):
Compound 396 (340 mg) was dissolved in DMF (4 mL), potassium carbonate (1.8 g) and diethyl (5-bromopentyl) malonate (450 mg) were added, and the mixture was reacted overnight at room temperature. Ethyl acetate (100 mL) was added to the reaction mixture, and the mixture was washed successively with water and saturated brine. The ethyl acetate layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified with a silica gel column (chloroform) to obtain Compound 405 (500 mg, Y = 83%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.15-2.20 (14H, m) 3.36 (1H, t, J = 7Hz) 4.03-4.43 (6H, m) 7.18-8.34 (8H, m) 8.85 (1H, d, J = 9Hz)
Methanol (50 mL) and 5% aqueous sodium hydroxide solution (4 mL) were added to compound 405 (470 mg) and reacted at about 50 ° C. overnight. After cooling, the precipitated crystals were collected by filtration and dried to obtain Compound 406 (352 mg, Y = 91%).

Example 137
Preparation of 5-chloro-2- [6- [2- (4-morpholinyl) ethoxy] -1-naphthalenyl] benzoxazole hydrochloride (Compound 407):
DMF (4 mL), potassium carbonate (1.2 g), and N- (2-chloroethyl) morpholine hydrochloride (200 mg) were added to compound 396 (203 mg), and reacted at about 65 ° C. overnight. Water (25 mL) was added to the reaction solution for crystallization, and the precipitated crystals were collected by filtration. Acetone (40 mL) was added to the obtained crystals for dissolution, 35% hydrochloric acid (0.3 mL) was added, and the precipitated crystals were collected by filtration and dried to obtain Compound 407 (233 mg, Y = 76%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 3.17-4.00 (10H, m) 4.67 (2H, t, J = 4Hz) 7.39-8.74 (8H, m) 9.34 (1H, d, J = 9Hz) 11.90 (1H, br)

Example 138
Preparation of 3-[[5- (5-Chloro-2-benzoxazolyl) -2-naphthalenyl] oxy] -N, N-dimethyl-1-propanamine hydrochloride (Compound 408):
DMF (4 mL), potassium carbonate (1.2 g), and 3-dimethylaminopropyl chloride hydrochloride (185 mg) were added to compound 396 (218 mg) and reacted at about 65 ° C. overnight. Water (25 mL) was added to the reaction solution for crystallization, and the precipitated crystals were collected by filtration. Acetone (50 mL) was added and dissolved in the obtained crystals, 35% hydrochloric acid (0.3 mL) was added, and the precipitated crystals were collected by filtration and dried to obtain Compound 408 (143 mg, Y = 47%).
¹ H-NMR (Methanol-d4, D ₂ O / TMS):
δ = 2.19-2.57 (2H, m) 3.02 (6H, s) 3.50 (2H, t, J = 6Hz) 4.28 (2H, t, J = 6Hz) 7.21-8.28 (8H, m) 9.19 (1H, d, (J = 10Hz)

Example 139
2-[[[6- (2-Benzoxazolyl) -2-naphthalenyl] carbonyl] amino] pentanedioic acid diethyl ester (Compound 409), 2-[[[6- (2-Benzoxazolyl)- 2-Naphthalenyl] carbonyl] amino] pentanedioic acid (Compound 410), 2-[[[6- (2-Benzoxazolyl) -2-naphthalenyl] carbonyl] amino] pentanedioic acid disodium salt (Compound 411) Manufacturing of:
Toluene (60 mL), thionyl chloride (6.2 g) and DMF (1 drop) were added to 2,6-naphthalenedicarboxylic acid monomethyl ester (10 g) and reacted under reflux for 4 hours, followed by 2-aminophenol (9.6 g). Of 1,4-dioxane (100 mL) was added and reacted at room temperature overnight and under reflux for 1 hour. After cooling, the precipitated crystals were collected by filtration. A suspension of methanol and 1N hydrochloric acid (1: 1) (400 mL) was added to the obtained crystals, and the crystals were collected by filtration and dried to obtain an intermediate amide compound (11.2 g, Y = 80%). .
Add 1,3-dimethyl-2-imidazolidinone (70 mL), toluene (140 mL), p-toluenesulfonic acid monohydrate (10 g) to the amide compound (11.1 g), and remove the water generated under reflux While reacting overnight. The reaction solution was concentrated under reduced pressure, and water was added to the residue to cause crystallization, and the precipitated crystals were collected by filtration. The obtained crystals were washed with methanol and recrystallized from toluene to obtain 6- (2-benzoxazolyl) -2-naphthalenecarboxylic acid methyl ester (9.7 g, Y = 93%).

Toluene (300 mL) is added to 6- (2-benzoxazolyl) -2-naphthalenecarboxylic acid methyl ester (9.6 g) and heated to dissolve, then 9% potassium hydroxide / methanol solution (20 mL) is added and refluxed. For 3 hours. After cooling, the precipitated crystals were collected by filtration. The obtained crystals were dissolved in 30% acetone aqueous solution (1 L) by heating, and acidified by adding dilute hydrochloric acid. The precipitated crystals were collected by filtration and dried to obtain 6- (2-benzoxazolyl) -2-naphthalenecarboxylic acid (8.78 g, Y = 96%).
Toluene (20 mL), thionyl chloride (0.26 mL) and DMF (1 drop) were added to 6- (2-benzoxazolyl) -2-naphthalenecarboxylic acid (0.81 g) and reacted under reflux for 3.5 hours. A solution of diethyl L-glutamate hydrochloride (0.9 g) in 1,3-dimethyl-2-imidazolidinone (30 mL) and triethylamine (1.3 mL) was added, and the mixture was reacted at room temperature overnight. The reaction solution was concentrated under reduced pressure, 2% aqueous hydrochloric acid solution (100 mL) was added to the remaining solution, and the precipitated crystals were collected by filtration. The obtained crystals were washed with methanol and dried to obtain Compound 409 (959 mg, Y = 68%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.11-1.45 (6H, m) 2.14-2.63 (4H, m) 3.96-4.47 (4H, m) 4.70-5.05 (1H, m) 7.16-8.79 (10H, m)
Compound 409 (845 mg) was dissolved in methanol (200 mL), 3% aqueous sodium hydroxide solution (10 mL) was added, and the mixture was reacted at about 45 ° C. overnight. The reaction solution was concentrated under reduced pressure, and water (100 mL) was added to the residue to dissolve it. The precipitated crystals were collected by filtration and dried to obtain Compound 410 (702 mg, Y = 94%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 2.00-2.49 (4H, m) 4.35-4.75 (1H, m) 7.39-8.91 (11H, m) 12.45 (2H, br)
Water (40 mL) and 0.5% aqueous sodium hydroxide solution (4 mL) were added to compound 410 (111.4 mg) for dissolution, followed by filtration. The filtrate was lyophilized to obtain Compound 411 (125.8 mg, Y = 103%).

Example 140
Preparation of 2-amino-6-[[[6- (2-benzoxazolyl) -2-naphthalenyl] carbonyl] amino] hexanoic acid hydrochloride (Compound 412):
6- (2-Benzoxazolyl) -2-naphthalenecarboxylic acid (1.0 g) was reacted with thionyl chloride (0.7 g) in toluene (40 mL) under reflux for 3.5 hours. After cooling, a solution of N ^α (tert-butoxycarbonyl) -L-lysine (1.1 g) and triethylamine (1.0 g) in 1,3-dimethyl-2-imidazolidinone (20 mL) was added to the reaction mixture, and water-cooled for 19 hours. Reacted. The reaction solution was concentrated under reduced pressure, and the concentrated solution was added to water (400 mL) for crystallization. The precipitated crystals were collected by filtration, washed with water, suspended with stirring with acetone (20 mL), and filtered to obtain crude crystals (1.33 g). The crude crystals (1.33 g) were purified on a silica gel column (toluene / ethyl acetate) to give 6-[[[6- (2-benzoxazolyl) -2-naphthalenyl] carbonyl] amino] -2-[(tert- Butoxycarbonyl) amino] hexanoic acid (384 mg, Y = 21%) was obtained.
6-[[[6- (2-Benzoxazolyl) -2-naphthalenyl] carbonyl] amino] -2-[(tert-butoxycarbonyl) amino] hexanoic acid (200 mg) in saturated hydrochloric acid / acetic acid solution (5 mL) And reacted for 2 hours under ice-water cooling. The reaction solution was added to diethyl ether (50 mL) for crystallization. Precipitated crystals were collected by filtration and dried to obtain Compound 412 (147 mg, Y = 84%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.37-2.06 (6H, m) 3.16-3.63 (2H, m) 3.92 (1H, t, J = 5Hz) 7.39-8.89 (12H, m)

Example 141
2- [4- (phenylmethoxy) phenyl] -1H-benzimidazole (compound 413), 2- [4- (phenylmethoxy) phenyl] -1H-benzimidazole-1-acetic acid methyl ester (compound 414), 2- Of [4- (phenylmethoxy) phenyl] -1H-benzimidazole-1-acetic acid (compound 415), 2- [4- (phenylmethoxy) phenyl] -1H-benzimidazole-1-acetic acid sodium salt (compound 416) Manufacturing:
In a nitrogen stream, 15% trimethylaluminum / toluene solution (11 mL) and o-phenylenediamine (2.2 g) were added to toluene (120 mL) under ice water cooling, reacted for 30 minutes under reflux, and then o-benzyloxybenzoic acid. A solution of ethyl (3.0 g) in toluene (20 mL) was added and reacted under reflux for 6 hours. A 73% aqueous methanol solution (55 mL) was added to the reaction mixture, and the mixture was refluxed for 30 minutes. Methanol (300 mL) was added, followed by hot filtration. The filtrate was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate to obtain Compound 413 (2.2 g, Y = 63%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 5.21 (2H, s) 7.09-8.20 (13H, m) 12.75 (1H, br)
Compound 413 (760 mg) was dissolved in DMF (30 mL), and potassium carbonate (1.0 g) and methyl bromoacetate (0.50 g) were added and reacted at room temperature overnight. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in toluene (150 mL) and washed successively with saturated sodium bicarbonate, water and saturated brine. The toluene layer was dehydrated with magnesium sulfate, concentrated under reduced pressure, and dried to obtain Compound 414 (890 mg, Y = 94%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 3.67 (3H, s) 5.21 (4H, s) 7.11-7.73 (13H, m)
Compound 414 (190 mg) was dissolved in methanol (25 mL), 4% aqueous sodium hydroxide solution (2 mL) was added, and the mixture was reacted at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and water (25 mL) was added to the residue to dissolve it with heating. The precipitated crystals were collected by filtration and dried to obtain Compound 415 (165 mg, Y = 90%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 5.07 (2H, s) 5.21 (2H, s) 7.12-7.76 (13H, m)
Compound 415 (82 mg) was suspended in methanol (50 mL), dissolved by adding 0.81% aqueous sodium hydroxide solution (1.2 mL), concentrated under reduced pressure and dried to obtain compound 416 (74 mg, Y = 85%).

Example 142
Production of 2- (4-hydroxyphenyl) -1H-benzimidazole-1-acetic acid methyl ester (compound 417) and 2- (4-hydroxyphenyl) -1H-benzimidazole-1-acetic acid (compound 418):
Compound 414 (520 mg) was dissolved in methanol (100 mL), 5% palladium carbon (0.5 g) was added, and the mixture was reacted at room temperature in a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure and dried to obtain Compound 417 (215 mg, Y = 55%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 3.68 (3H, s) 5.17 (2H, s) 6.85-7.61 (8H, m)
Compound 417 (105 mg) was dissolved in methanol (100 mL), 5% aqueous sodium hydroxide solution (3 mL) was added, and the mixture was reacted at about 40 ° C. for 1.5 hr. The reaction solution was concentrated under reduced pressure, and water (30 mL) was added to the residue for dissolution. The precipitated crystals were collected by filtration and dried to obtain Compound 418 (85 mg, Y = 85%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 5.04 (2H, s) 6.86-7.75 (8H, m)

Example 143
2- [4- (2-methoxy-2-oxoethoxy) phenyl] -1H-benzimidazole-1-acetic acid methyl ester (compound 419), 2- [4- (carboxymethoxy) phenyl] -1H-benzimidazole- 1-acetic acid (compound 420), 2- [4- (carboxymethoxy) phenyl] -1H-benzimidazole-1-acetic acid disodium salt (compound 421)
In glacial acetic acid (100 mL), p-hydroxybenzaldehyde (6.1 g) and nitromethane (7.6 g) were reacted under reflux in the presence of n-butylamine (5 mL) for 4.5 hours. The reaction solution was dropped into ice water (1 L), and the precipitated crystals were collected by filtration. The obtained crystals were recrystallized from toluene to obtain an intermediate 4-hydroxy-β-nitrostyrene (4.4 g, Y = 53%).
The intermediate (2.0 g) and o-phenylenediamine (1.31 g) were reacted in ethanol (24 mL) for 4.5 hours under reflux. The reaction mixture was concentrated under reduced pressure, toluene (150 mL) was added to the residue and suspended under reflux, followed by filtration to obtain crude crystals (1.5 g). The crude crystal (1.5 g) was recrystallized from a mixture of toluene and ethanol to give 4- (1H-benzoimidazol-2-yl) phenol (880 mg, Y = 35%).
4- (1H-benzoimidazol-2-yl) phenol (200 mg) was dissolved in DMF (50 mL), and potassium carbonate (1.5 g) and methyl bromoacetate (550 mg) were added and reacted at room temperature for 2 days. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. Compound 419 (680 mg, Y = 58%) was fractionated from the residue with a silica gel column (chloroform).
¹ H-NMR (DMSO-d6 / TMS):
δ = 3.68 (3H, s) 3.73 (3H, s) 4.91 (2H, s) 5.20 (2H, s) 7.03-7.73 (8H, m)
Compound 419 (400 mg) was dissolved in methanol (30 mL), 3% aqueous sodium hydroxide solution (6 mL) was added, and the mixture was reacted at room temperature for 20 minutes. The reaction mixture was concentrated under reduced pressure, and water (40 mL) was added to the residue to dissolve it. Then, dilute hydrochloric acid was added to cause acid precipitation. The precipitated crystals were collected by filtration and dried to obtain Compound 420 (370 mg, Y = 101%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 4.79 (2H, s) 5.07 (2H, s) 7.02-7.75 (8H, m)
Compound 420 (124 mg) was suspended in water (40 mL), dissolved by adding a 1% aqueous sodium hydroxide solution (3 mL), and then filtered. The filtrate was lyophilized to obtain Compound 421 (148 mg, Y = 105%).

Example 144
5-chloro-2- [4- (phenylmethoxy) phenyl] -1H-benzimidazole (compound 422), methyl 5-chloro-2- [4- (phenylmethoxy) phenyl] -1H-benzimidazole-1-acetate Preparation of ester (compound 423), 5-chloro-2- [4- (phenylmethoxy) phenyl] -1H-benzimidazole-1-acetic acid (compound 424):
In glacial acetic acid (200 mL), 4-benzyloxybenzaldehyde (24 g) and nitromethane (14.5 g) were reacted under reflux in the presence of n-butylamine (11.5 mL) for 10 hours. The reaction solution was dropped into ice water (2 L), and the precipitated crystals were collected by filtration. The obtained crystals were recrystallized from methanol to obtain intermediate 4-benzyloxy-β-nitrostyrene (16.6 g, Y = 58%).
4-Chloro-1,2-phenylenediamine (2.8 g) and ethanol (75 mL) were added to the intermediate (5 g) and reacted under reflux for 2 days. The reaction solution was concentrated under reduced pressure, and the residue was purified with a silica gel column (chloroform) to obtain Compound 422 (2.67 g, Y = 41%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 5.22 (2H, s) 7.13-8.20 (12H, m) 12.95 (1H, br)
Compound 422 (1.2 g) was dissolved in DMF (30 mL), and potassium carbonate (1 g) and methyl bromoacetate (0.7 g) were added and reacted at room temperature overnight. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (150 mL) and washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The ethyl acetate layer was dehydrated with magnesium sulfate and concentrated under reduced pressure. The residue was purified with a silica gel column (chloroform) to obtain Compound 423 (620 mg, Y = 43%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 3.67 (3H, s) 5.21 (4H, s) 7.11-7.77 (12H, m)
Compound 423 (100 mg) was dissolved in methanol (30 mL), 2% aqueous sodium hydroxide solution (1 mL) was added, and the mixture was reacted at about 50 ° C. for 30 min. The reaction mixture was concentrated under reduced pressure, and water (20 mL) was added to the residue to dissolve it with heating. The precipitated crystals were collected by filtration and dried to obtain Compound 424 (90 mg, Y = 43%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 5.10 (2H, s) 5.20 (2H, s) 7.12-7.75 (12H, m)

Example 145
5-chloro-2- (4-hydroxyphenyl) -1H-benzimidazole-1-acetic acid methyl ester (Compound 425), 5-chloro-2- (4-hydroxyphenyl) -1H-benzimidazole-1-acetic acid ( Preparation of compound 426):
Saturated hydrochloric acid / acetic acid solution (10 mL) was added to compound 423 (440 mg) and reacted at about 100 ° C. for 8 hours. The reaction mixture was concentrated under reduced pressure, and water (50 mL) was added for crystallization, and the precipitated crystals were collected by filtration. The obtained crystals were purified with a silica gel column (chloroform / methanol) to obtain Compound 425 (175 mg, Y = 51%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 3.68 (3H, s) 5.19 (2H, s) 6.85-7.74 (7H, m)
Compound 425 (100 mg) was dissolved in methanol (40 mL), 5.2% aqueous sodium hydroxide solution (2 mL) was added, and the mixture was reacted at about 50 ° C. for 1.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved by adding water (30 mL), and then acidified by adding dilute hydrochloric acid. The precipitated crystals were collected by filtration and dried to obtain Compound 426 (84 mg, Y = 88%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 5.07 (2H, s) 6.86-7.73 (7H, m) 10.0 (1H, br)

Example 146
[4- (5-Chloro-1H-benzoimidazol-2-yl) phenoxy] acetic acid methyl ester (Compound 427), [4- (5-Chloro-1H-benzimidazol-2-yl) phenoxy] acetic acid (Compound 428) ), [4- (5-chloro-1H-benzoimidazol-2-yl) phenoxy] acetic acid sodium salt (compound 429), 5-chloro-2- [4- (2-methoxy-2-oxoethoxy) phenyl] -1H-benzimidazole-1-acetic acid methyl ester (Compound 430), 2- [4- (carboxymethoxy) phenyl] -5-chloro-1H-benzimidazole-1-acetic acid (Compound 431), 2- [4- Preparation of (carboxymethoxy) phenyl] -5-chloro-1H-benzimidazole-1-acetic acid disodium salt (compound 432):
Saturated hydrochloric acid / acetic acid solution (10 mL) was added to compound 422 (600 mg) and reacted at about 100 ° C. for 8 hours. After cooling, the precipitated crystals were collected by filtration. The obtained crystals were recrystallized from a mixed solution of toluene and methanol to obtain 4- (5-chloro-1H-benzoimidazol-2-yl) phenol (346 mg, Y = 79%).
4- (5-Chloro-1H-benzoimidazol-2-yl) phenol (290 mg) was dissolved in DMF (9 mL), potassium carbonate (500 mg) and methyl bromoacetate (280 mg) were added, and the mixture was reacted at room temperature overnight. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. From the residue, silica gel column (chloroform / methanol) was used to compound 427 (50 mg, Y = 13%), compound 430 (260 mg, Y =
56%).

Compound 427 (50 mg) was dissolved in methanol (40 mL), 3% aqueous sodium hydroxide solution (1 mL) was added, and the mixture was reacted at about 50 ° C. for 1 hour. The reaction mixture was concentrated under reduced pressure, and water (20 mL) was added to the residue to dissolve it. Then, dilute hydrochloric acid was added to cause acid precipitation. The precipitated crystals were collected by filtration and dried to obtain Compound 428 (47.8 mg, Y = 100%).
Compound 428 (48 mg) was dissolved in methanol (40 mL), 0.63% aqueous sodium hydroxide solution (1 mL) was added, and the mixture was concentrated under reduced pressure and dried to obtain compound 429 (46 mg, Y = 90%).
¹ H-NMR (Methanol-d4 / TMS):
δ = 4.48 (2H, s) 7.02-8.09 (7H, m)
Compound 430 (195 mg) was dissolved in methanol (50 mL), 5% aqueous sodium hydroxide solution (2 mL) was added, and the mixture was reacted at about 50 ° C. for 1.5 hr. The reaction solution was concentrated under reduced pressure, and the residue was dissolved by adding water (50 mL), and acidified by adding dilute hydrochloric acid. The precipitated crystals were collected by filtration and dried to obtain Compound 431 (179 mg, Y = 99%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 4.80 (2H, s) 5.11 (2H, s) 7.03-7.76 (7H, m)
Compound 431 (66 mg) was suspended in water (40 mL), dissolved by adding a 1% aqueous sodium hydroxide solution (1.5 mL), and then filtered. The filtrate was lyophilized to give compound 432 (78 mg, Y = 106%).

Example 147
2- [6- (phenylmethoxy) -2-naphthalenyl] -1H-benzimidazole (compound 433), 6- (1H-benzoimidazol-2-yl) -2-naphthalenol (compound 434), [[6- ( 1H-Benzimidazol-2-yl) -2-naphthalenyl] oxy] acetic acid methyl ester (Compound 435), [[6- (1H-Benzimidazol-2-yl) -2-naphthalenyl] oxy] acetic acid (Compound 436) , [[6- (1H-Benzimidazol-2-yl) -2-naphthalenyl] oxy] acetic acid sodium salt (Compound 437), 2- [6- (2-methoxy-2-oxoethoxy) -2-naphthalenyl] -1H-benzimidazole-1-acetic acid methyl ester (compound 438), 2- [6- (carboxymethoxy) -2-naphthalenyl] -1H-benzimidazole-1-acetic acid (compound 439), 2- [6- ( Preparation of carboxymethoxy) -2-naphthalenyl] -1H-benzimidazole-1-acetic acid disodium salt (Compound 440):
In a nitrogen stream, 15% trimethylaluminum / toluene solution (12 mL) and o-phenylenediamine (2.4 g) were added to toluene (80 mL) under cooling with ice water and reacted for 40 minutes under reflux, then 6-benzyloxy-2 -A solution of ethyl naphthoate (4.0 g) in toluene (35 mL) was added and reacted under reflux for 6 hours. 86% aqueous methanol solution (140 mL) was added to the reaction mixture, and the mixture was refluxed for 1 hour, filtered while hot, and the filtrate was concentrated under reduced pressure. The crude product was separated from the residue by a silica gel column (ethyl acetate / n-hexane). The obtained crude product (2.1 g) was recrystallized from toluene to obtain Compound 433 (1.31 g, Y = 29%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 5.28 (2H, s) 7.13-8.68 (15H, m) 13.0 (1H, br)
Toluene (100 mL) and methanol (200 mL) were added and dissolved in compound 433 (0.9 g), and 5% palladium carbon (0.6 g) was added and reacted at about 45 ° C. in a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure and dried to obtain Compound 434 (690 mg, Y = 103%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 7.24-8.95 (10H, m) 10.50 (1H, br)

Compound 434 (660 mg) was dissolved in DMF (40 mL), and potassium carbonate (1.1 g) and methyl bromoacetate (440 mg) were added and reacted at room temperature for 6 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. From the residue, a crude product of Compound 438 (270 mg) and a crude product of Compound 435 (325 mg) were fractionated by silica gel column (chloroform). The resulting crude product was purified with a silica gel column (ethyl acetate / n-hexane) to obtain Compound 435 (278 mg, Y = 33%) and Compound 438 (196 mg, Y = 19%).
<Compound 435> ¹ H-NMR (DMSO-d6 / TMS):
δ = 3.76 (3H, s) 4.98 (2H, s) 7.13-8.67 (10H, m) 12.98 (1H, br)
<Compound 438> ¹ H-NMR (DMSO-d6 / TMS):
δ = 3.66 (3H, s) 3.75 (3H, s) 4.98 (2H, s) 5.31 (2H, s) 7.21-8.21 (10H, m)
Compound 435 (210 mg) was dissolved by adding 1,4-dioxane (30 mL) and methanol (10 mL), and 2% aqueous sodium hydroxide solution (7 mL) was added and reacted at about 50 ° C. for 20 minutes. The reaction mixture was concentrated under reduced pressure, and water (40 mL) was added to the residue to dissolve it. The precipitated crystals were collected by filtration and dried to obtain Compound 436 (197 mg, Y = 98%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 4.86 (2H, s) 7.14-8.68 (10H, m)
Compound 436 (31 mg) was suspended in water (40 mL), 1% aqueous sodium hydroxide solution (0.78 mL) was added and dissolved by heating, followed by filtration. The filtrate was lyophilized to obtain Compound 437 (34.7 mg, Y = 105%).
Methanol (50 mL) was added to Compound 438 (144 mg) for dissolution, 4% aqueous sodium hydroxide solution (4 mL) was added, and the mixture was reacted at about 50 ° C. for 40 minutes. The reaction solution was concentrated under reduced pressure, and the residue was dissolved by adding water (30 mL), and then acidified by adding dilute hydrochloric acid. The precipitated crystals were collected by filtration and dried to obtain Compound 439 (127 mg, Y = 95%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 4.89 (2H, s) 5.35 (2H, s) 7.30-8.36 (10H, s)
Compound 439 (74.7 mg) was suspended in water (30 mL), 1% aqueous sodium hydroxide solution (1.6 mL) was added and dissolved by heating, followed by filtration. The filtrate was lyophilized to give compound 440 (79.1 mg, Y = 95%).

Example 148
2- [6- (4-Ethoxy-4-oxobutoxy) -2-naphthalenyl] -1H-benzimidazole-1-butanoic acid ethyl ester (Compound 441), 2- [6- (3-carboxypropoxy) -2 -Naphthalenyl] -1H-benzimidazol-1-butanoic acid (Compound 442), 2- [6- (3-Carboxypropoxy) -2-naphthalenyl] -1H-Benzimidazol-1-butanoic acid disodium salt (Compound 443) )Manufacturing of:
Compound 434 (350 mg) was dissolved in DMF (15 mL), and potassium carbonate (2.5 g) and ethyl 4-bromo-n-butyrate (680 mg) were added and reacted at room temperature overnight. Ethyl acetate (100 mL) was added to the reaction mixture, and the mixture was washed successively with water and saturated brine. The ethyl acetate layer was dehydrated with magnesium sulfate and concentrated under reduced pressure to obtain Compound 441.
Compound 441 was dissolved in methanol (50 mL), 16% aqueous sodium hydroxide solution (3 mL) was added, and the mixture was reacted overnight at room temperature. The reaction solution was concentrated under reduced pressure, and water (30 mL) was added to the residue for dissolution. The precipitated crystals were collected by filtration and dried to obtain Compound 442 (220 mg, Y = 38%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.84-2.50 (8H, m) 4.21 (2H, t, J = 6Hz) 4.57 (2H, t, J = 5Hz) 7.3-8.52 (10H, m)
To compound 442 (99.2 mg), water (30 mL) and 0.5% aqueous sodium hydroxide solution (3.8 mL) were added to dissolve and filtered. The filtrate was lyophilized to obtain Compound 443 (114 mg, Y = 104%).

Example 149
2- [6-[(6-Ethoxy-6-oxohexyl) oxy] -2-naphthalenyl] -1H-benzimidazole-1-hexanoic acid ethyl ester (compound 444), 2- [6-[(5-carboxyl Pentyl) oxy] -2-naphthalenyl] -1H-benzimidazol-1-hexanoic acid (compound 445), 2- [6-[(5-carboxypentyl) oxy] -2-naphthalenyl] -1H-benzimidazole-1 -Production of disodium hexanoate (Compound 446):
Compound 434 (350 mg) was dissolved in DMF (15 mL), and potassium carbonate (2.5 g) and ethyl 6-bromohexanoate (800 mg) were added and reacted at room temperature overnight. Ethyl acetate (100 mL) was added to the reaction mixture, and the mixture was washed successively with water and saturated brine. The ethyl acetate layer was dehydrated with magnesium sulfate and concentrated under reduced pressure to obtain Compound 444.
Compound 444 was dissolved in methanol (50 mL), 16% aqueous sodium hydroxide solution (3 mL) was added, and the mixture was reacted overnight at room temperature. The reaction solution was concentrated under reduced pressure, and the residue was dissolved by adding water (30 mL), and then acidified by adding dilute hydrochloric acid. The precipitated crystals were collected by filtration and dried to obtain compound 445 (177
mg, Y = 27%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.09-2.39 (16H, m) 4.06-4.59 (4H, m) 7.23-8.38 (10H, m)
To compound 445 (95.3 mg), water (30 mL) and 0.5% aqueous sodium hydroxide solution (3.3 mL) were added and dissolved, followed by filtration. The filtrate was lyophilized to obtain Compound 446 (110 mg, Y = 106%).

Example 150
[5-[[6- (1H-Benzimidazol-2-yl) -2-naphthalenyl] oxy] pentyl] propanedioic acid diethyl ester (compound 447), [5-[[6- (1H-benzimidazole-2 -Yl) -2-naphthalenyl] oxy] pentyl] propanedioic acid (compound 448), [5-[[6- (1H-benzoimidazol-2-yl) -2-naphthalenyl] oxy] pentyl] propanedioic acid diacid Production of sodium salt (compound 449):
Compound 434 (1.2 g) was suspended in DMF (50 mL), and potassium carbonate (6 g) and diethyl (5-bromopentyl) malonate (1.5 g) were added and reacted at room temperature overnight. Ethyl acetate (400 mL) was added to the reaction mixture, and the mixture was washed successively with water and saturated brine. The ethyl acetate layer was dried over magnesium sulfate and concentrated under reduced pressure. The crude product was separated from the residue with a silica gel column (chloroform). The crude product was recrystallized from a mixed solution of toluene and n-hexane to obtain Compound 447 (1.05 g, Y = 47%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.13-2.15 (14H, m) 3.35 (1H, t, J = 7Hz) 3.94-4.38 (6H, m) 7.06-8.45 (10H, m)
Compound 447 (160 mg) was dissolved in methanol (50 mL), 8% aqueous sodium hydroxide solution (3 mL) was added, and the mixture was reacted at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in water (30 mL), and then acidified by adding dilute hydrochloric acid. The precipitated crystals were collected by filtration and dried to obtain Compound 448 (138 mg, Y = 98%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.19-2.0 (8H, m) 3.24 (1H, t, J = 7Hz) 4.12 (2H, t, J = 5Hz) 7.14-8.66 (10H, m)
To compound 448 (99.5 mg), water (40 mL) and 0.45% aqueous sodium hydroxide solution (4.2 mL) were added and dissolved, followed by filtration. The filtrate was lyophilized to obtain Compound 449 (111 mg, Y = 101%).

Example 151
4-[[6- (1H-Benzimidazol-2-yl) -2-naphthalenyl] oxy] butanoic acid ethyl ester (Compound 450), 4-[[6- (1H-Benzimidazol-2-yl) -2 Preparation of -Naphthalenyl] oxy] butanoic acid (Compound 451), 4-[[6- (1H-Benzimidazol-2-yl) -2-naphthalenyl] oxy] butanoic acid sodium salt (Compound 452):
Compound 434 (1.2 g) was suspended in DMF (60 mL), and potassium carbonate (5.0 g) and ethyl 4-bromo-n-butyrate (0.9 g) were added and reacted at room temperature overnight. Ethyl acetate (600 mL) was added to the reaction mixture, and the mixture was washed successively with water and saturated brine. The ethyl acetate layer was dried over magnesium sulfate and concentrated under reduced pressure. The crude product was separated from the residue by a silica gel column (chloroform). The obtained crude product was recrystallized from a mixture of chloroform and toluene to obtain Compound 450 (1.06 g, Y = 61%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.25 (3H, t, J = 7Hz) 1.90-2.70 (4H, m) 3.98-4.34 (4H, m) 7.01-8.47 (10H, m)
Compound 450 (225 mg) was dissolved in methanol (50 mL), 9% aqueous sodium hydroxide solution (3 mL) was added, and the mixture was reacted at room temperature overnight. The reaction mixture was concentrated under reduced pressure, water (50 mL) was added to the residue, and the mixture was dissolved by heating, and acidified by adding dilute hydrochloric acid. The precipitated crystals were collected by filtration and dried to obtain Compound 451 (210 mg, Y = 101%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.90-2.48 (4H, m) 4.18 (2H, t, J = 7Hz) 7.21-8.23 (10H, m)
To compound 451 (125 mg), water (30 mL) and a 0.5% aqueous sodium hydroxide solution (5.9 mL) were added and dissolved by heating, followed by filtration. The filtrate was lyophilized to give compound 452 (139 mg, Y = 99%).

Example 152
4-[[6- [1- (Phenylmethyl) -1H-benzimidazol-2-yl] -2-naphthalenyl] oxy] butanoic acid ethyl ester (compound 453), 4-[[6- [1- (phenyl Methyl) -1H-benzimidazol-2-yl] -2-naphthalenyl] oxy] butanoic acid (compound 454), 4-[[6- [1- (phenylmethyl) -1H-benzimidazol-2-yl]- Preparation of 2-naphthalenyl] oxy] butanoic acid sodium salt (Compound 455):
Compound 450 (250 mg) was dissolved in DMF (5 mL), and potassium carbonate (0.6 g) and benzyl bromide (150 mg) were added and reacted at room temperature overnight. Ethyl acetate (100 mL) was added to the reaction mixture, and the mixture was washed successively with water and saturated brine. The ethyl acetate layer was dehydrated with magnesium sulfate, concentrated under reduced pressure, and dried to obtain Compound 453 (303 mg, Y = 98%).
Compound 453 (303 mg) was dissolved in methanol (50 mL), 8% aqueous sodium hydroxide solution (3 mL) was added, and the mixture was reacted at about 50 ° C. for 2.5 hours. The reaction mixture was concentrated under reduced pressure, and water (50 mL) was added to the residue to dissolve it with heating. The precipitated crystals were collected by filtration and dried to obtain Compound 454 (192 mg, Y = 67%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.80-2.50 (4H, m) 4.15 (2H, t, J = 6Hz) 5.68 (2H, s) 6.98-8.22 (15H, m)
To compound 454 (102 mg), water (50 mL) and 0.45% aqueous sodium hydroxide solution (2.1 mL) were added and dissolved by heating, followed by filtration. The filtrate was lyophilized to give compound 455 (106 mg, Y = 99%).

Example 153
4-[[6- [1-[(2-Chlorophenyl) methyl] -1H-benzimidazol-2-yl] -2-naphthalenyl] oxy] butanoic acid ethyl ester (Compound 456), 4-[[6- [ 1-[(2-Chlorophenyl) methyl] -1H-benzimidazol-2-yl] -2-naphthalenyl] oxy] butanoic acid (Compound 457), 4-[[6- [1-[(2-Chlorophenyl) methyl] ] -1H-Benzimidazol-2-yl] -2-naphthalenyl] oxy] butanoic acid sodium salt (Compound 458):
Compound 450 (250 mg) was dissolved in DMF (5 mL), potassium carbonate (0.6 g) and 2-chlorobenzyl bromide (180 mg) were added, and the mixture was reacted overnight at room temperature. Ethyl acetate (100 mL) was added to the reaction mixture, and the mixture was washed successively with water and saturated brine. The ethyl acetate layer was dehydrated with magnesium sulfate, concentrated under reduced pressure, and dried to obtain Compound 456 (325 mg, Y = 98%).
After dissolving methanol (50 mL) in compound 456 (325 mg), 8% aqueous sodium hydroxide solution (3 mL) was added and reacted at about 50 ° C. for 3 hours. The reaction solution was concentrated under reduced pressure, and water (50 mL) was added to the residue and dissolved by heating. The precipitated crystals were collected by filtration and dried to obtain Compound 457 (185 mg, Y = 60%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.80-2.50 (4H, m) 4.14 (2H, t, J = 6Hz) 5.70 (2H, s) 6.61-8.13 (14H, m) 12.17 (1H, br)
To compound 457 (100 mg), water (50 mL) and 0.45% aqueous sodium hydroxide solution (1.9 mL) were added and dissolved by heating, followed by filtration. The filtrate was lyophilized to give compound 458.

Example 154
1- (cyclohexylmethyl) -2- [6- (phenylmethoxy) -2-naphthalenyl] -1H-benzimidazole (compound 459), 6- [1- (cyclohexylmethyl) -1H-benzimidazol-2-yl] -2-Naphthalenol (Compound 460), 4-[[6- [1- (Cyclohexylmethyl) -1H-benzoimidazol-2-yl] -2-naphthalenyl] oxy] butanoic acid ethyl ester (Compound 461), 4- [[6- [1- (cyclohexylmethyl) -1H-benzimidazol-2-yl] -2-naphthalenyl] oxy] butanoic acid (Compound 462), 4-[[6- [1- (cyclohexylmethyl) -1H -Benzoimidazol-2-yl] -2-naphthalenyl] oxy] butanoic acid sodium salt (Compound 463):
Compound 433 (1.5 g) was dissolved in DMF (40 mL), potassium carbonate (7.0 g) and bromomethylcyclohexane (1.5 g) were added, and the mixture was reacted at room temperature overnight at about 70 ° C. for 17 hours. Water (400 mL) was added to the reaction solution for crystallization, and the precipitated crystals were collected by filtration and dried to obtain Compound 459 (1.0 g, Y = 52%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 0.50-1.80 (11H, m) 4.19 (2H, d, J = 7Hz) 5.23 (2H, s) 7.21-8.15 (15H, m)
Compound 459 (1.0 g) was dissolved in toluene (40 mL), methanol (80 mL) and 5% palladium carbon (0.6 g) were added, and the mixture was reacted at room temperature in a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure and dried to obtain Compound 460 (695 mg, Y = 87%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 0.69-2.00 (11H, m) 4.53 (2H, d, J = 6Hz) 7.27-8.50 (10H, m)

Compound 460 (170 mg) was dissolved in DMF (10 mL), and potassium carbonate (0.5 g) and ethyl 4-bromo-n-butyrate (140 mg) were added and reacted at room temperature overnight. Ethyl acetate (100 mL) was added to the reaction mixture, and the mixture was washed successively with water and saturated brine. The ethyl acetate layer was dehydrated with magnesium sulfate, concentrated under reduced pressure, and dried to obtain Compound 461 (200 mg, Y = 89%).
Methanol (80 mL) was added to and dissolved in Compound 461 (200 mg), 14% aqueous sodium hydroxide solution (2 mL) was added, and the mixture was reacted at 50 ° C. overnight, and then reacted under reflux for 3 hours. The reaction mixture was concentrated under reduced pressure, and water (40 mL) was added to the residue to dissolve it with heating. The precipitated crystals were collected by filtration and dried to obtain Compound 462 (163 mg, Y = 87%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 0.69-2.50 (15H, m) 4.08-4.42 (4H, m) 7.2-8.34 (10H, m) 12.3 (1H, br)
To compound 462 (79 mg), water (25 mL) and 0.5% aqueous sodium hydroxide solution (1.4 mL) were added and dissolved by heating, followed by filtration. The filtrate was lyophilized to give compound 463 (80 mg, Y = 97%).

Example 155
6-[[6- [1- (Cyclohexylmethyl) -1H-benzimidazol-2-yl] -2-naphthalenyl] oxy] hexanoic acid ethyl ester (Compound 464), 6-[[6- [1- (Cyclohexyl) Methyl) -1H-benzimidazol-2-yl] -2-naphthalenyl] oxy] hexanoic acid (compound 465), 6-[[6- [1- (cyclohexylmethyl) -1H-benzimidazol-2-yl]- Preparation of 2-naphthalenyl] oxy] hexanoic acid sodium salt (Compound 466):
Compound 460 (160 mg) was dissolved in DMF (15 mL), and potassium carbonate (0.5 g) and ethyl 6-bromohexanoate (150 mg) were added and reacted at room temperature overnight. Ethyl acetate (100 mL) was added to the reaction mixture, and the mixture was washed successively with water and saturated brine. The ethyl acetate layer was dehydrated with magnesium sulfate, concentrated under reduced pressure, and dried to obtain Compound 464 (194 mg, Y = 87%).
After dissolving methanol (80 mL) in compound 464 (194 mg), 15% aqueous sodium hydroxide solution (2 mL) was added and reacted at about 50 ° C. overnight and under reflux for 3 hours. The reaction mixture was concentrated under reduced pressure, and water (60 mL) was added to the residue to dissolve it with heating. The precipitated crystals were collected by filtration and dried to obtain Compound 465 (132 mg, Y = 72%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 0.70-2.51 (19H, m) 4.04-4.37 (4H, m) 7.19-8.29 (10H, m)
To compound 465 (75.5 mg), water (25 mL) and 0.5% aqueous sodium hydroxide solution (1.3 mL) were added, dissolved under heating and filtered. The filtrate was lyophilized to give compound 466 (76 mg, Y = 96%).

Example 156
2- [6- (Phenylmethoxy) -2-naphthalenyl] -1H-benzimidazole-1-acetic acid methyl ester (Compound 467), 2- [6- (Phenylmethoxy) -2-naphthalenyl] -1H-benzimidazole- Production of 1-acetic acid (compound 468), 2- [6- (phenylmethoxy) -2-naphthalenyl] -1H-benzimidazole-1-acetic acid sodium salt (compound 469):
Compound 433 (458 mg) was dissolved in DMF (10 mL), and potassium carbonate (400 mg) and methyl bromoacetate (240 mg) were added and reacted at room temperature overnight. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. Ethyl acetate (200 mL) was added to the residue, and the mixture was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The ethyl acetate layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column (ethyl acetate / n-hexane) to obtain Compound 467 (448 mg, Y = 81%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 3.80 (3H, s) 4.97 (2H, s) 5.22 (2H, s) 7.26-8.14 (15H, m)
To compound 467 (120 mg), 1,4-dioxane (40 mL) and methanol (20 mL) were added and dissolved, and 4.5% aqueous sodium hydroxide solution (4 mL) was added and reacted at about 50 ° C. for 2 hours. The reaction mixture was concentrated under reduced pressure, water (50 mL) was added to the residue, and the mixture was dissolved by heating, and acidified by adding dilute hydrochloric acid. The precipitated crystals were collected by filtration and dried to obtain Compound 468 (103.7 mg, Y = 89%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 5.21 (2H, s) 5.29 (2H, s) 7.20-8.25 (15H, m)
Methanol (30 mL) and 0.7% aqueous sodium hydroxide solution (1 mL) were added to compound 468 (70 mg), dissolved by heating, then concentrated under reduced pressure and dried to obtain compound 469 (66.4 mg, Y = 90%).

Example 157
2- (6-hydroxy-2-naphthalenyl) -1H-benzimidazole-1-acetic acid methyl ester (compound 470), 2- (6-hydroxy-2-naphthalenyl) -1H-benzimidazole-1-acetic acid (compound 471) ), 2- (6-hydroxy-2-naphthalenyl) -1H-benzimidazole-1-acetic acid disodium salt (compound 472):
Toluene (50 mL) and methanol (100 mL) were added to and dissolved in compound 467 (300 mg), and 5% palladium carbon (0.3 g) was added and reacted at about 45 ° C. in a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure and dried to obtain Compound 470 (229 mg, Y = 96%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 3.67 (3H, s) 5.29 (2H, s) 7.10-8.13 (10H, m) 10.02 (1H, s)
To compound 470 (194 mg), 1,4-dioxane (30 mL) and methanol (30 mL) were added and dissolved, and 4% aqueous sodium hydroxide solution (4 mL) was added and reacted at about 50 ° C. for 1 hour. The reaction solution was concentrated under reduced pressure, water (50 mL) was added to the residue and dissolved by heating, and then dilute hydrochloric acid was added for acid precipitation. The precipitated crystals were collected by filtration and dried to obtain Compound 471 (167 mg, Y = 85%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 5.17 (2H, s) 7.13-8.17 (10H, m)
Methanol (40 mL) and 2.27% aqueous sodium hydroxide solution (1 mL) were added to compound 471 (96.7 mg), dissolved by heating, and concentrated under reduced pressure to obtain compound 472 (100 mg, Y = 91%).

Example 158
2- [6- (Phenylmethoxy) -2-naphthalenyl] -1H-benzimidazole-1-butanoic acid ethyl ester (Compound 473), 2- [6- (Phenylmethoxy) -2-naphthalenyl] -1H-benzimidazole Preparation of 1-butanoic acid (compound 474), 2- [6- (phenylmethoxy) -2-naphthalenyl] -1H-benzimidazole-1-butanoic acid sodium salt (compound 475):
Compound 433 (290 mg) was dissolved in DMF (6 mL), potassium carbonate (0.8 g) and ethyl 4-bromo-n-butyrate (210 mg) were added, and the mixture was reacted overnight at room temperature and overnight at about 45 ° C. Ethyl acetate (100 mL) was added to the reaction mixture, and the mixture was washed successively with water and saturated brine. The ethyl acetate layer was dehydrated with magnesium sulfate and concentrated under reduced pressure to obtain Compound 473.
Compound 473 was dissolved in methanol (50 mL), 12% aqueous sodium hydroxide solution (4 mL) was added, and the mixture was reacted at about 60 ° C. for 3 hr. The reaction mixture was concentrated under reduced pressure, and water (50 mL) was added to the residue to dissolve it with heating. The precipitated crystals were collected by filtration and dried to obtain Compound 474 (261 mg, Y = 72%).
¹ H-NMR (DMSO-d6, D ₂ O / TMS):
δ = 1.80-2.40 (4H, m) 4.48 (2H, t, J = 5Hz) 5.31 (2H, s) 7.33-8.40 (15H, m)
To compound 474 (62 mg), water (50 mL) and 0.45% aqueous sodium hydroxide solution (1.3 mL) were added and dissolved by heating, followed by filtration. The filtrate was lyophilized to give compound 475 (67 mg, Y = 103%).

Example 159
2- (6-hydroxy-2-naphthalenyl) -1H-benzimidazol-1-butanoic acid (compound 476), 2- (6-hydroxy-2-naphthalenyl) -1H-benzimidazol-1-butanoic acid sodium salt ( Preparation of compound 477):
Methanol (80 mL) and 5% palladium carbon (0.2 g) were added to compound 474 (170 mg) and reacted at room temperature in a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure and dried to obtain Compound 476 (100 mg, Y = 74%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.80-2.27 (4H, m) 4.41 (2H, t, J = 6Hz) 7.10-8.28 (10H, m) 10.04 (1H, br) 12.2 (1H, br)
To compound 476 (80 mg), water (40 mL) and 0.45% aqueous sodium hydroxide solution (2.1 mL) were added and dissolved by heating, followed by filtration. The filtrate was lyophilized to obtain Compound 477 (86 mg, Y = 101%).

Example 160
[5- [2- [6- (phenylmethoxy) -2-naphthalenyl] -1H-benzimidazol-1-yl] pentyl] propanedioic acid diethyl ester (compound 478), [5- [2- [6- ( Preparation of phenylmethoxy) -2-naphthalenyl] -1H-benzimidazol-1-yl] pentyl] propanedioic acid (Compound 479):
Compound 433 (285 mg) was dissolved in DMF (12 mL), potassium carbonate (12 g) and diethyl (5-bromopentyl) malonate (660 mg) were added, and the mixture was reacted at room temperature overnight and at about 70 ° C. overnight. Ethyl acetate (100 mL) was added to the reaction mixture, and the mixture was washed successively with water and saturated brine. The ethyl acetate layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified with a silica gel column (chloroform) to obtain Compound 478 (80 mg, Y = 18%).
Methanol (50 mL) and 12% aqueous sodium hydroxide solution (2 mL) were added to compound 478 (80 mg) and reacted at room temperature overnight. The reaction solution was concentrated under reduced pressure, the residue was dissolved in water (20 ml), washed with ethyl acetate, and acidified by adding dilute hydrochloric acid to the aqueous layer. The precipitated crystals were collected by filtration and dried to obtain Compound 479 (31 mg, Y = 43%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.00-1.92 (8H, m) 3.08 (1H, t, J = 7Hz) 4.44 (2H, t, J = 7Hz) 5.31 (2H, s) 7.26-8.37 (15H, m)

Example 161
2- [6- (phenylmethoxy) -2-naphthalenyl] benzothiazole (compound 480), 6- (2-benzothiazolyl) -2-naphthalenol (compound 481), [[6- (2-benzothiazolyl) -2-naphthalenyl ] Oxy] acetic acid methyl ester (compound 482), [[6- (2-benzothiazolyl) -2-naphthalenyl] oxy] acetic acid (compound 483), [[6- (2-benzothiazolyl) -2-naphthalenyl] oxy] acetic acid Preparation of sodium salt (compound 484):
In a nitrogen stream, 15% trimethylaluminum / toluene solution (5 mL) and 2-aminobenzenethiol (1.2 g) were added to toluene (50 mL) under ice water cooling, and reacted for 1 hour under reflux. Toluene (50 mL) solution of methyl 2-naphthoate (1.8 g) was added and reacted overnight under reflux. A 95% aqueous methanol solution (84 mL) was added to the reaction mixture, and the mixture was refluxed for 1 hour, and then filtered while hot. The filtrate was concentrated under reduced pressure, and the residue was purified with a silica gel column (chloroform) to obtain Compound 480 (928 mg, Y = 39%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 5.21 (2H, s) 7.25-8.49 (15H, m)
A saturated hydrochloric acid / acetic acid solution (40 mL) was added to compound 480 (600 mg), and the mixture was reacted at about 95 ° C. for 3 days. The reaction solution was concentrated under reduced pressure, and the residue was purified with a silica gel column (chloroform / methanol) to obtain Compound 481 (214 mg, Y = 33%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 7.14-8.22 (9H, m) 8.56 (1H, s) 10.10 (1H, s),
Compound 481 (190 mg) was dissolved in DMF (10 mL), and potassium carbonate (300 mg) and methyl bromoacetate (130 mg) were added and reacted at room temperature overnight. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified with a silica gel column (chloroform) to give compound 482 (155
mg, Y = 65%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 3.85 (3H, s) 4.79 (2H, s) 7.13-8.50 (10H, m)

Methanol (20 mL) and 1,4-dioxane (50 mL) were added to compound 482 (120 mg), 8% aqueous sodium hydroxide solution (1 mL) was added, and the mixture was reacted at about 50 ° C. for 30 min. The reaction mixture was concentrated under reduced pressure, water (10 mL) and ethyl acetate (60 mL) were added to the residue, and the mixture was made strongly acidic by adding dilute hydrochloric acid, and then separated. The ethyl acetate layer was washed successively with water and saturated brine, dried over magnesium sulfate, concentrated under reduced pressure, and dried to give compound 483 (114 mg, Y = 93%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 4.87 (2H, s) 7.23-8.64 (10H, m) 13.0 (1H, br)
Compound 483 (70.3 mg) was dissolved in methanol (30 mL) with heating, 1.6% aqueous sodium hydroxide solution (0.5 mL) was added and stirred, and the precipitated solid was filtered and dried to give compound 484 (54
mg, Y = 76%).

Example 162
6-[[6- (2-Benzothiazolyl) -2-naphthalenyl] oxy] hexanoic acid ethyl ester (Compound 485), 6-[[6- (2-Benzothiazolyl) -2-naphthalenyl] oxy] hexanoic acid sodium salt ( Preparation of compound 486):
Compound 481 (250 mg) was dissolved in DMF (5 mL), and potassium carbonate (5.0 g) and ethyl 6-bromohexanoate (250 mg) were added and reacted at room temperature overnight. Water (20 mg) was added to the reaction solution for crystallization, and the precipitated crystals were collected by filtration. The obtained crystals were washed with ethanol and dried to obtain Compound 485 (303 mg, Y = 80%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.26 (3H, t, J = 7Hz) 1.47-2.10 (6H, m) 2.37 (2H, t, J = 6Hz) 3.97-4.33 (4H, m) 7.13-8.49 (10H, m)
Methanol (50 mL) was added to compound 485 (290 mg) and dissolved by heating, and then 30% aqueous sodium hydroxide solution (1 mL) was added and reacted under reflux for 18 hours. After cooling, the precipitated crystals were collected by filtration and dried to obtain Compound 486 (240 mg, Y = 84%).

Example 163
[3-[[6- (2-Benzothiazolyl) -2-naphthalenyl] oxy] propyl] propanedioic acid diethyl ester (compound 487), [3-[[6- (2-benzothiazolyl) -2-naphthalenyl] oxy] Propyl] propanedioic acid (Compound 488), [3-[[6- (2-Benzothiazolyl) -2-naphthalenyl] oxy] propyl] propanedioic acid disodium salt (Compound 489):
Compound 481 (250 mg) was dissolved in DMF (10 mL), potassium carbonate (1.2 g) and diethyl (3-chloropropyl) malonate (260 mg) were added, and the mixture was reacted at about 55 ° C. overnight. Ethyl acetate (150 mL) was added to the reaction mixture and washed with water. The ethyl acetate layer was dehydrated with magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column (chloroform) to obtain Compound 487 (194 mg, Y = 45%).
Compound 487 (194 mg) was dissolved in methanol (50 mL), 30% aqueous sodium hydroxide solution (1 mL) was added, and the mixture was reacted at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved by adding water (50 mL), and acidified by adding dilute hydrochloric acid. The precipitated crystals were collected by filtration and dried to obtain Compound 488 (128 mg, Y = 75%).
¹ H-NMR (DMSO-d6 / TMS):
δ = 1.70-2.00 (4H, m) 3.38 (1H, t, J = 6Hz) 4.18 (2H, t, J = 5Hz) 7.18-8.61 (10H, m) 12.7 (2H, br)
Compound 488 (109.7 mg) was dissolved by adding 0.05% aqueous sodium hydroxide solution (40 mL). After filtration, the filtrate was lyophilized to obtain Compound 489 (108 mg, Y = 89%).

Example 164
[5-[[6- (2-Benzothiazolyl) -2-naphthalenyl] oxy] pentyl] propanedioic acid diethyl ester (compound 490), [5-[[6- (2-benzothiazolyl) -2-naphthalenyl] oxy] Preparation of pentyl] propanedioic acid disodium salt (compound 491):
Compound 481 (252 mg) was dissolved in DMF (10 mL), potassium carbonate (1.2 g) and diethyl (5-bromopentyl) malonate (340 mg) were added, and the mixture was stirred overnight at room temperature. Ethyl acetate (80 mL) was added to the reaction mixture, and the mixture was washed successively with water and saturated brine. The ethyl acetate layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified with a silica gel column (chloroform) to obtain Compound 490 (360 mg, Y = 78%).
¹ H-NMR (CDCl ₃ / TMS):
δ = 1.14-2.15 (14H, m) 3.35 (1H, t, J = 7Hz) 4.02-4.39 (6H, m) 7.13-8.48 (10H, m)
Compound 490 (340 mg) was dissolved in methanol (100 mL), 9% aqueous sodium hydroxide solution (6 mL) was added, and the mixture was reacted at about 50 ° C. for 18 hours and under reflux for 8 hours. After cooling, the precipitated crystals were collected by filtration and dried to obtain Compound 491 (290 mg, Y = 87%).
The compounds obtained in the above examples are shown in Table 1. The compound number corresponds to the number assigned to the compound in each example.

Formulation example 1 (tablet):
Present compound 10.0 g
Lactose 9.0g
Hydroxypropylcellulose 2.0g
7.7 g of crystalline cellulose
Magnesium stearate 0.3g
Talc 1.0g
The above is made into a tablet containing 100 mg of the compound of the present invention by a conventional method.

Formulation example 2 (injection):
1 mg of the present compound
5% glucose injection solution 2mL
The above is made into an injection by a conventional method.
Formulation example 3 (suppository):
10 mg of the present compound
Cocoa butter
The above is made into a suppository by a conventional method.

Next, a plasmin formation promotion test, a t-PA activation activity test, and a PAI-1 inhibitory activity test of the compound of the present invention are shown.
Plasmin formation promotion test:
The compound of the present invention was prepared to 1 × 10 ⁻³ M with water for injection and DMSO to obtain a compound solution of the present invention. Place a 96-well microplate on ice, 25 μL of the compound solution of the present invention (final concentration 1.25 × 10 ⁻⁴ M), 50 μL of rt-PA diluted with 20 mM phosphate buffer (pH 7.4) containing 150 mM sodium chloride. (Final concentration 4000 IU / mL), glutamic acid type-human plasminogen 25 μL (final concentration 8.75 μg / mL), and synthetic substrate S-2251 100 μL (final concentration 0.5 mM) were added and mixed. As a control, 25 μL of DMSO solution (final concentration 1.25%) was added instead of the compound solution of the present invention. While incubating at 37 ° C., the absorbance at 405 nm was measured with a microplate reader for 2 hours. The time required to reach an absorbance of 1.4 was calculated, and the plasmin formation promoting activity was determined from the ratio to the control. As a result, it was revealed that the compound of the present invention has an excellent plasmin formation promoting action. The results are shown in Table 2.

t-PA activation activity test and PAI-1 inhibitory activity test:
The following tests were carried out on the compounds of the present invention, PAI-1, and rt-PA using the four combinations A to D shown in Table 3 below.

The compound of the present invention was prepared to 1.875 × 10 ⁻³ M with water for injection and DMSO, and this was serially diluted with water for injection to obtain a compound solution of the present invention. After incubating PAI-1 prepared with the compound solution of the present invention and water for injection on a 96-well microplate at room temperature for 10 minutes, rt-PA prepared with Tris-HCl buffer was added to each well and mixed. The mixture was further incubated at room temperature for 10 minutes. Next, 50 μL of synthetic substrate S-2288 (final concentration 0.5 mM) prepared in Tris-HCl buffer was added to and mixed with each well, and incubated at room temperature for 10 minutes. Thereafter, the absorbance at 405 nm was measured with a microplate reader while incubating at 37 ° C., and the activities of A, B, C and D were determined as a, b, c and d, and the respective activities were determined as follows.

t-PA activation activity:
a / b was defined as the t-PA activation activity value of the compound of the present invention.

PAI-1 inhibitory activity:
First, the PAI-1 inhibition rate of the compound of the present invention was determined from a linear relationship with 100% when a = c and 0% when c / d = a / b, and the obtained PAI-1 inhibition rate (%) Is the vertical axis, and the logarithmic value of the final concentration (1.25 × 10 ⁻⁴ M, 1.25 × 10 ⁻⁵ M) of the compound of the present invention is taken on the horizontal axis to obtain IC50. As a result, it was revealed that the compound of the present invention has excellent t-PA activation activity and PAI-1 inhibitory activity. The results are shown in Tables 4 and 5.

The compound of the present invention has an excellent PA activity promoting action and PAI-1 inhibitory activity action, and expresses an excellent thrombolytic action, and is therefore effective for diseases caused by thrombus. In other words, venous thrombosis, myocardial infarction, pulmonary embolism, cerebral infarction, slowly progressing cerebral thrombosis, treatment of thrombosis / embolism associated with vascular surgery and extracorporeal blood circulation, improvement of blood flow disorder, chronic arterial occlusion Improvement of various symptoms, treatment of thrombus / embolism associated with ischemic cerebrovascular disorder, etc. It can be used in combination with a symptom treatment agent.

Claims (5)

The compound shown by following formula (23), those pharmaceutically acceptable salt compounds, or those solvates.

[Where:
(1) A is
(i) -arylene group-O-lower alkylene group-a ₁ (6)
(here
<1> a ₁ is
1. -COOR ₄ (7)
(Where R ₄ is hydrogen, a lower alkyl group which may be substituted with a lower acyloxy group, or a benzyl group)
2.

(Wherein R ₅ and R ₆ are each independently hydrogen, a lower alkyl group which may be substituted with a lower acyloxy group, or a benzyl group)
3.

(Where R ₇ is hydrogen, a lower alkyl group which may be substituted with a lower acyloxy group, or a benzyl group)
4).

(Wherein R ₈ and R ₉ are each independently hydrogen, a lower alkyl group which may be substituted with a lower acyloxy group, or a benzyl group)
The <2> arylene group means a 6,1-naphthalenediyl group in which 2,6-, 2,3- and oxygen in the formula (6) are bonded to the 6-position. )
However, only when b ₃ described later is -O-b ₃₁ and b ₃₁ is -lower alkylene group -b ₃₂ and b ₃₂ is -COOR ₁₈ , A is
(ii) -arylene group-a ₂ (12)
(here
<1> a ₂ is
1. Hydroxyl group
2. Lower alkoxy group
<2> The arylene group is 2,6-, 2,3- and a 6,1-naphthalenediyl group in which a ₂ is bonded to the 6-position in the formula (12)
(2) b ₁ is
1. Hydrogen
2. Lower alkyl group (3) b ₂ is
1. Hydrogen
2.Lower alkyl group
3.Phenyl group
4. Halogen (4) _{b 3} is
1. Hydrogen
2.Nitro group
3.Amino group
(Here, the amino group may be substituted with a lower alkyl group or a benzyl group)
4.Lower alkyl group
5.-Ob ₃₁ (19)
(Where b ₃₁ is
1. Hydrogen
2.Lower alkyl group
3. Lower acyl group
4.Cyclohexyl group
5.-Lower alkylene group-b ₃₂ (20)
(Where b ₃₂ is
-1.Phenyl group
-2.Cyclohexyl group
-3.-COOR ₁₈ (21)
(Where R ₁₈ is hydrogen, a lower alkyl group which may be substituted with a lower acyloxy group, or a benzyl group)
-Four.

(Where R ₁₉ and R ₂₀ are independently of each other hydrogen, a lower alkyl group which may be substituted with a lower acyloxy group, or a benzyl group)))
Is] A compound selected from the following compound group, or a pharmaceutically acceptable salt compound thereof or a solvate thereof
[[6- (2-Benzoxazolyl) -2-naphthalenyl] oxy] acetic acid methyl ester, [[6- (2-benzoxazolyl) -2-naphthalenyl] oxy] acetic acid, 4-[[6- (2-Benzoxazolyl) -2-naphthalenyl] oxy] butanoic acid ethyl ester, 4-[[6- (2-benzoxazolyl) -2-naphthalenyl] oxy] butanoic acid, N- [4- [ [6- (2-Benzoxazolyl) -2-naphthalenyl] oxy] -1-oxobutyl] glycine ethyl ester, 2-[[4-[[6- (2-benzoxazolyl) -2-naphthalenyl] Oxy] -1-oxobutyl] amino] pentanedioic acid diethyl ester, 2-[[4-[[6- (2-benzoxazolyl) -2-naphthalenyl] oxy] -1-oxobutyl] amino] pentanedioic acid , 6-[[6- (2-Benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid, 6-[[6- (2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid (2 , 2-Dimethyl-1-oxopropoxy) methyl Ester, 2-[[6-[[6- (2-Benzoxazolyl) -2-naphthalenyl] oxy] -1-oxohexyl] amino] pentanedioic acid diethyl ester, 2-[[6-[[6 -(2-Benzoxazolyl) -2-naphthalenyl] oxy] -1-oxohexyl] amino] pentanedioic acid, [3-[[6- (2-benzoxazolyl) -2-naphthalenyl] oxy] Propyl] propanedioic acid, [[6- (6-methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] acetic acid, 4-[[6- (6-methyl-2-benzoxazolyl)- 2-Naphthalenyl] oxy] butanoic acid, 5-[[6- (6-methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] pentanoic acid, 5-[[6- (6-methyl-2- Benzoxazolyl) -2-naphthalenyl] oxy] pentanoic acid (2,2-dimethyl-1-oxopropoxy) methyl ester, 6-[[6- (6-methyl-2-benzoxazolyl) -2- Naphthalenyl] oxy] hexanoic acid, 7-[[6- (6-methyl-2-benzoxazo L) -2-Naphthalenyl] oxy] heptanoic acid, [5-[[6- (6-methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] pentyl] propanedioic acid, 6-[[6- [6- (1-Methylethyl) -2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid, 6-[[6- (6-hydroxy-2-benzoxazolyl) -2-naphthalenyl] Oxy] hexanoic acid, 6-[[6- [6- (phenylmethoxy) -2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid, [[6- (6-methoxy-2-benzoxazoli) L) -2-Naphthalenyl] oxy] acetic acid, 4-[[6- (6-methoxy-2-benzoxazolyl) -2-naphthalenyl] oxy] butanoic acid ethyl ester, 4-[[6- (6- Methoxy-2-benzoxazolyl) -2-naphthalenyl] oxy] butanoic acid, 6-[[6- (6-methoxy-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid ethyl ester, 6 -[[6- (6-Methoxy-2-benzoxazolyl) -2- Phthalenyl] oxy] hexanoic acid, [5-[[6- (6-methoxy-2-benzoxazolyl) -2-naphthalenyl] oxy] pentyl] propanedioic acid diethyl ester, [5-[[6- (6 -Methoxy-2-benzoxazolyl) -2-naphthalenyl] oxy] pentyl] propanedioic acid, 6-[[6- (6-ethoxy-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid Ethyl ester, 6-[[6- (6-ethoxy-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid, 6-[[2- (6-hydroxy-2-naphthalenyl) -6-benzo Oxazolyl] oxy] hexanoic acid, 6-[[2- (6-hydroxy-2-naphthalenyl) -6-benzoxazolyl] oxy] hexanoic acid ethyl ester, 6-[[6- [6-[( 6-ethoxy-6-oxohexyl) oxy] -2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid ethyl ester, 6-[[6- [6-[(5-carboxypentyl) oxy]- 2-benzoo Xazolyl] -2-naphthalenyl] oxy] hexanoic acid, 6-[[2- (6-ethoxy-2-naphthalenyl) -6-benzoxazolyl] oxy] hexanoic acid ethyl ester, 6-[[2- (6 -Ethoxy-2-naphthalenyl) -6-benzoxazolyl] oxy] hexanoic acid, [5-[[6- [6-[[7-ethoxy-6- (ethoxycarbonyl) -7-oxoheptyl] oxy] -2-Benzoxazolyl] -2-naphthalenyl] oxy] pentyl] propanedioic acid diethyl ester, [5-[[6- [6-[(6,6-dicarboxyhexyl) oxy] -2-benzooxa Zolyl] -2-naphthalenyl] oxy] pentyl] propanedioic acid, [5-[[6- [6- (cyclohexylmethoxy) -2-benzoxazolyl] -2-naphthalenyl] oxy] pentyl] propanedioic acid , [5-[[6- [6- (Phenylmethoxy) -2-benzoxazolyl] -2-naphthalenyl] oxy] pentyl] propanedioic acid, 4-[[6- (6-nitro-2-benzo Oxazolyl) -2-naphtha Nyl] oxy] butanoic acid ethyl ester, 4-[[6- (6-amino-2-benzoxazolyl) -2-naphthalenyl] oxy] butanoic acid hydrochloride, 4-[[6- [6- (diethylamino) ) -2-Benzoxazolyl] -2-naphthalenyl] oxy] butanoic acid, 4-[[6- [6- [bis (phenylmethyl) amino] -2-benzoxazolyl] -2-naphthalenyl] oxy ] Butanoic acid ethyl ester, 4-[[6- [6- [bis (phenylmethyl) amino] -2-benzoxazolyl] -2-naphthalenyl] oxy] butanoic acid, 6-[[6- (6- Nitro-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid ethyl ester, 6-[[6- [6- (diethylamino) -2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid , 6-[[6- [6- [Bis (phenylmethyl) amino] -2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid ethyl ester, 6-[[6- [6- [bis ( Phenylmethyl) amino] -2-benzo Xazolyl] -2-naphthalenyl] oxy] hexanoic acid, [5-[[6- (6-nitro-2-benzoxazolyl) -2-naphthalenyl] oxy] pentyl] propanedioic acid diethyl ester, [5- [ [6- [6- (Diethylamino) -2-benzoxazolyl] -2-naphthalenyl] oxy] pentyl] propanedioic acid disodium salt, 6-[[6- [6- (cyclohexyloxy) -2-benzo Oxazolyl] -2-naphthalenyl] oxy] hexanoic acid, 6-[[6- (5-methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid, 6-[[6- [5 -(1,1-Dimethylethyl) -2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid, [5-[[6- [5- (1,1-dimethylethyl) -2-benzoxa Zolyl] -2-naphthalenyl] oxy] pentyl] propanedioic acid, 6-[[6- (5-phenyl-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid, [3-[[6 -(5-Phenyl-2-benzoxazolyl) -2-naphtha [Renyl] oxy] propyl] propanedioic acid diethyl ester, [3-[[6- (5-phenyl-2-benzoxazolyl) -2-naphthalenyl] oxy] propyl] propanedioic acid, 4-[[6- (5-chloro-2-benzoxazolyl) -2-naphthalenyl] oxy] butanoic acid, 6-[[6- (5-chloro-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid, [3-[[6- (5-Chloro-2-benzoxazolyl) -2-naphthalenyl] oxy] propyl] propanedioic acid, [5-[[6- (5-Chloro-2-benzoxazolyl ) -2-Naphthalenyl] oxy] pentyl] propanedioic acid, 6-[[6- (4-methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid, [3-[[6- ( 4-methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] propyl] propanedioic acid, [5-[[6- (4-methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] Pentyl] propanedioic acid, 4-[[3- (6-methyl-2-benzoxazo Ryl) -2-naphthalenyl] oxy] butanoic acid, 6-[[3- (6-methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid, [5-[[3- (6- Methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] pentyl] propanedioic acid, 4-[[3- (6-nitro-2-benzoxazolyl) -2-naphthalenyl] oxy] butanoic acid ethyl Ester, 4-[[3- [6- (diethylamino) -2-benzoxazolyl] -2-naphthalenyl] oxy] butanoic acid, 4-[[3- [6- [bis (phenylmethyl) amino]- 2-Benzoxazolyl] -2-naphthalenyl] oxy] butanoic acid, 6-[[3- (6-nitro-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid ethyl ester, 6- [ [3- [6- (Diethylamino) -2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid, 6-[[3- [6- [bis (phenylmethyl) amino] -2-benzoxazoly [Lu] -2-naphthalenyl] oxy] hexanoic acid, [5-[[3- (6- Nitro-2-benzoxazolyl) -2-naphthalenyl] oxy] pentyl] propanedioic acid diethyl ester, 4-[[3- [5- (1,1-dimethylethyl) -2-benzoxazolyl]- 2-Naphthalenyl] oxy] butanoic acid, 6-[[3- [5- (1,1-dimethylethyl) -2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid, [5-[[3 -[5- (1,1-dimethylethyl) -2-benzoxazolyl] -2-naphthalenyl] oxy] pentyl] propanedioic acid, 4-[[3- (5-phenyl-2-benzoxazolyl) ) -2-Naphthalenyl] oxy] butanoic acid, 6-[[3- (5-phenyl-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid, [5-[[3- (5-phenyl) -2-Benzoxazolyl) -2-naphthalenyl] oxy] pentyl] propanedioic acid, 4-[[3- (5-chloro-2-benzoxazolyl) -2-naphthalenyl] oxy] butanoic acid ethyl ester , 4-[[3- (5-Chloro-2-benzoxazolyl) -2-naphthalene Nyl] oxy] butanoic acid, 6-[[3- (5-chloro-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid, [3-[[3- (5-chloro-2-benzo Oxazolyl) -2-naphthalenyl] oxy] propyl] propanedioic acid, [5-[[3- (5-chloro-2-benzoxazolyl) -2-naphthalenyl] oxy] pentyl] propanedioic acid, 6 -[[5- (6-Methyl-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid, [5-[[5- (6-methyl-2-benzoxazolyl) -2-naphthalenyl ] Oxy] pentyl] propanedioic acid, 4-[[5- (6-nitro-2-benzoxazolyl) -2-naphthalenyl] oxy] butanoic acid ethyl ester, 4-[[5- [6- (diethylamino) ) -2-Benzoxazolyl] -2-naphthalenyl] oxy] butanoic acid ethyl ester, 4-[[5- [6- (diethylamino) -2-benzoxazolyl] -2-naphthalenyl] oxy] butanoic acid , 4-[[5- [6- [Bis (phenylmethyl) amino] -2-ben Oxazolyl] -2-naphthalenyl] oxy] butanoic acid ethyl ester, 4-[[5- [6- [bis (phenylmethyl) amino] -2-benzoxazolyl] -2-naphthalenyl] oxy] butanoic acid, 6 -[[5- (6-Nitro-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid ethyl ester, 6-[[5- (6-amino-2-benzoxazolyl) -2- Naphthalenyl] oxy] hexanoic acid hydrochloride, 6-[[5- [6- (diethylamino) -2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid ethyl ester, 6-[[5- [6- (Diethylamino) -2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid, 6-[[5- [6- [bis (phenylmethyl) amino] -2-benzoxazolyl] -2-naphthalenyl ] Oxy] hexanoic acid, [5-[[5- (6-nitro-2-benzoxazolyl) -2-naphthalenyl] oxy] pentyl] propanedioic acid diethyl ester, [5-[[5- [6- (Diethylamino ) -2-Benzoxazolyl] -2-naphthalenyl] oxy] pentyl] propanedioic acid, 4-[[5- [6- (cyclohexylmethoxy) -2-benzoxazolyl] -2-naphthalenyl] oxy] Butanoic acid ethyl ester, 4-[[5- [6- (cyclohexylmethoxy) -2-benzoxazolyl] -2-naphthalenyl] oxy] butanoic acid, 6-[[5- [6- (cyclohexylmethoxy)- 2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid ethyl ester, 6-[[5- [6- (cyclohexylmethoxy) -2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid, [5-[[5- [6- (cyclohexylmethoxy) -2-benzoxazolyl] -2-naphthalenyl] oxy] pentyl] propanedioic acid diethyl ester, 4-[[5- [5- (1,1 -Dimethylethyl) -2-benzoxazolyl] -2-naphthalenyl] oxy] butanoic acid ethyl ester, 4-[[5- [5- (1,1-dimethylethyl) -2-benzoxa Zolyl] -2-naphthalenyl] oxy] butanoic acid, 6-[[5- [5- (1,1-dimethylethyl) -2-benzoxazolyl] -2-naphthalenyl] oxy] hexanoic acid, [3- [[5- [5- (1,1-dimethylethyl) -2-benzoxazolyl] -2-naphthalenyl] oxy] propyl] propanedioic acid, [5-[[5- [5- (1,1 -Dimethylethyl) -2-benzoxazolyl] -2-naphthalenyl] oxy] pentyl] propanedioic acid, 4-[[5- (5-phenyl-2-benzoxazolyl) -2-naphthalenyl] oxy] Butanoic acid ethyl ester, 4-[[5- (5-phenyl-2-benzoxazolyl) -2-naphthalenyl] oxy] butanoic acid, 6-[[5- (5-phenyl-2-benzoxazolyl) ) -2-Naphthalenyl] oxy] hexanoic acid ethyl ester, 6-[[5- (5-phenyl-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid, [5-[[5- (5 -Phenyl-2-benzoxazolyl) -2-naphthalenyl] oxy] pentyl] propane Diacid, 4-[[5- (5-chloro-2-benzene

Nzooxazolyl) -2-naphthalenyl] oxy] butanoic acid ethyl ester, 4-[[5- (5-chloro-2-benzoxazolyl) -2-naphthalenyl] oxy] butanoic acid, 6-[[5- (5 -Chloro-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid ethyl ester, 6-[[5- (5-chloro-2-benzoxazolyl) -2-naphthalenyl] oxy] hexanoic acid, [3-[[5- (5-Chloro-2-benzoxazolyl) -2-naphthalenyl] oxy] propyl] propanedioic acid diethyl ester, [5-[[5- (5-chloro-2-benzoxa Zolyl) -2-naphthalenyl] oxy] pentyl] propanedioic acid diethyl ester   The compound according to claim 1 or 2 for use as a pharmaceutical composition, or a pharmaceutically acceptable salt compound thereof or a solvate thereof.   The compound according to claim 1 or 2, or a pharmaceutically acceptable salt compound or a solvate thereof, for use as a thrombolytic agent or an antithrombotic agent. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt compound or a solvate thereof, for producing a pharmaceutical composition for treating thrombosis.