JP2004256525A - N-[1-substituted-2-(arylamino)ethyl] amide derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a preventing or treating agent of osteoporosis and osteoarthritis. <P>SOLUTION: This compound having a structure of formula (I) (wherein, R<SP>1</SP>, R<SP>2</SP>are each H, an alkyl or the like; R<SP>3</SP>is H, a substituted alkyl, a substituted alkoxy, a substitutable aryl or the like; R<SP>4</SP>is a substitutable alkyl or a substitutable aryl; Ar is a substitutable aryl or the like; X is a single bond, NH, O or the like; and Z is a substituted alkyl, a substitutable aryl or the like), or its pharmacologically acceptable salt is provided. <P>COPYRIGHT: (C)2004,JPO&NCIPI

Description

Translated fromJapanese

本発明はカテプシンＫを阻害する化合物に関する。  The present invention relates to compounds that inhibit cathepsin K.

近年、骨粗鬆症及び変形性関節症等の治療薬として、カテプシンＫを阻害する化合物についての研究がおこなわれているが、未だ実際に医薬として用いられている化合物はない。  In recent years, research on compounds that inhibit cathepsin K as therapeutic agents for osteoporosis and osteoarthritis has been conducted, but none of the compounds has actually been used as a medicine.

カテプシンＫを阻害する低分子化合物としては、例えば、下記一般式（Ａ）を有する化合物が知られている（特許文献１参照。）。  As a low-molecular compound that inhibits cathepsin K, for example, a compound having the following general formula (A) is known (see Patent Document 1).

（式中、Ｒ、Ｒ_２及びＲ_３は、それぞれ、アルキル基等であり、Ａｒは置換されていてもよいアリール基であり、Ｘ_１はカルボニル等であり、Ｌは酸素原子等であり、ｎは０又は１であり、ｍは１乃至５であり、ｘは０又は１である）
国際公開第００／４８９９３号パンフレット(Wherein, R, R₂ and R₃ are each an alkyl group or the like, Ar is an optionally substituted aryl group, X₁ is a carbonyl or the like, L is an oxygen atom or the like, n is 0 or 1, m is 1 to 5, and x is 0 or 1.
International Publication No. 00/48993 pamphlet

本発明者らは、カテプシンＫを阻害する化合物について鋭意研究を行った結果、上記一般式（Ａ）で表される化合物のアミド部分の窒素原子に隣接する炭素原子に置換基（本発明の一般式（Ｉ）のＲ^４に相当する）を導入することにより、カテプシンＫ阻害活性がより強くなることを見出し、本発明を完成した。
The present inventors have conducted intensive studies on compounds that inhibit cathepsin K, and as a result, have found that the compound represented by the general formula (A) has a substituent (carbon atom of the present invention) by introducing corresponding to R⁴⁾ of formula (I), found that cathepsin K inhibitory activity is stronger, and have completed the present invention.

本発明は、
（１） 下記一般式（Ｉ）The present invention
(1) The following general formula (I)

｛式中、
Ｒ^１及びＲ^２は、同一若しくは異なって、それぞれ、水素原子又はＣ_１−Ｃ_８アルキル基を示すか、或いは、Ｒ^１及びＲ^２は、それらが結合している炭素原子と一緒になって、置換基群αから選択される基で置換されていてもよいＣ_３−Ｃ_８シクロアルキル基を形成し、
Ｒ^３は、水素原子；置換基群βから選択される少なくとも１個の基で置換されたＣ_１−Ｃ_６アルキル基；置換基群βから選択される少なくとも１個の基で置換されたＣ_１−Ｃ_６アルコキシ基；置換基群αから選択される基で置換されていてもよいＣ_６−Ｃ_１０アリール基；置換基群αから選択される基で置換されていてもよい、硫黄原子、酸素原子及び／又は窒素原子を１乃至３個含む５乃至７員ヘテロアリール基；置換基群αから選択される基で置換されていてもよいＣ_３−Ｃ_８シクロアルキル基；置換基群αから選択される基で置換されていてもよい、硫黄原子、酸素原子及び／又は窒素原子を１乃至３個含む５乃至７員ヘテロシクリル基；置換基群αから選択される基で置換されていてもよいＣ_６−Ｃ_１０アリールオキシ基；置換基群αから選択される基で置換されていてもよい、硫黄原子、酸素原子及び／又は窒素原子を１乃至３個含む５乃至７員ヘテロアリールオキシ基；置換基群αから選択される基で置換されていてもよいＣ_３−Ｃ_８シクロアルキルオキシ基；或いは、置換基群αから選択される基で置換されていてもよい、硫黄原子、酸素原子及び／又は窒素原子を１乃至３個含む５乃至７員ヘテロシクリルオキシ基を示し、
Ｒ^４は、Ｃ_１−Ｃ_８アルキル基、置換基群αから選択される基で置換されていてもよいＣ_６−Ｃ_１０アリール基、又は下記一般式（ＩＩ）
Ｒ^５−（ＣＨ_２）_ｍ− （ＩＩ）
［式中、
ｍは１乃至８の整数を示し、
Ｒ^５は、置換基群αから選択される基で置換されていてもよいＣ_６−Ｃ_１０アリール基；置換基群αから選択される基で置換されていてもよい、硫黄原子、酸素原子及び／又は窒素原子を１乃至３個含む５乃至７員ヘテロアリール基；置換基群αから選択される基で置換されていてもよいＣ_３−Ｃ_８シクロアルキル基；カルバモイル基；アミノ基；Ｃ_１−Ｃ_６アルキルアミノ基；ジ（Ｃ_１−Ｃ_６アルキル）アミノ基；グアニジル基；或いは、式Ｒ^６−Ｏ−、Ｒ^６−Ｓ−又はＲ^６−Ｏ−ＣＯ−（式中、Ｒ^６は、水素原子、置換基群βから選択される基で置換されていてもよいＣ_１−Ｃ_６アルキル基、又は置換基群αから選択される基で置換されていてもよいＣ_６−Ｃ_１０アリール基を示す。）で表される基を示す。］
で表される基を示し、
Ａｒは、置換基群α、置換基群β及び置換基群γから選択される基で置換されていてもよいＣ_６−Ｃ_１０アリール基；或いは、置換基群α、置換基群β及び置換基群γから選択される基で置換されていてもよい、硫黄原子、酸素原子及び／又は窒素原子を１乃至３個含む５乃至７員ヘテロアリール基を示し、
Ｘは、単結合、−ＮＨ−、−Ｏ−、−Ｓ−、−ＣＯＮＨ−、−ＳＯ_２ＮＨ−、−ＳＯＮＨ−、又は−Ｏ−ＣＯＮＨ−を示し、
Ｚは、置換基群βから選択される少なくとも１個の基で置換されたＣ_１−Ｃ_６アルキル基；置換基群αから選択される基で置換されていてもよいＣ_６−Ｃ_１０アリール基；置換基群αから選択される基で置換されていてもよい、硫黄原子、酸素原子及び／又は窒素原子を１乃至３個含む５乃至７員ヘテロアリール基；置換基群αから選択される基で置換されていてもよいＣ_３−Ｃ_８シクロアルキル基；或いは、置換基群αから選択される基で置換されていてもよい、硫黄原子、酸素原子及び／又は窒素原子を１乃至３個含む５乃至７員ヘテロシクリル基を示し、
置換基群αは、ハロゲン原子、Ｃ_１−Ｃ_６アルキル基、Ｃ_１−Ｃ_６ハロゲン化アルキル基、ホルミル基、（Ｃ_１−Ｃ_６アルキル）カルボニル基、（Ｃ_１−Ｃ_６ハロゲン化アルキル）カルボニル基、ニトロ基、シアノ基、アミノ基、Ｃ_１−Ｃ_６アルキルアミノ基、ジ（Ｃ_１−Ｃ_６アルキル）アミノ基、Ｃ_１−Ｃ_６アルコキシ基、Ｃ_１−Ｃ_６ハロゲン化アルコキシ基、Ｃ_１−Ｃ_６アルキルチオ基、Ｃ_１−Ｃ_６アルキルスルホニル基、Ｃ_１−Ｃ_６ヒドロキシアルキル基、Ｃ_１−Ｃ_６アルコキシＣ_１−Ｃ_６アルキル基、Ｃ_１−Ｃ_６アルキレンジオキシ基、Ｃ_１−Ｃ_６アミノアルキル基、Ｃ_２−Ｃ_６アミノアルコキシ基、式−ＣＯ−Ｒ^７（式中、Ｒ^７は、水酸基、Ｃ_１−Ｃ_６アルコキシ基、Ｃ_６−Ｃ_１０アリールオキシ基、Ｃ_６−Ｃ_１０アリールＣ_１−Ｃ_６アルコキシ基、アミノ基、Ｃ_１−Ｃ_６アルキルアミノ基、ジ（Ｃ_１−Ｃ_６アルキル）アミノ基を示す）で表される基、及びテトラゾリル基からなる群を示し、
置換基群βは、置換基群αから選択される基で置換されていてもよいＣ_６−Ｃ_１０アリール基；置換基群αから選択される基で置換されていてもよい、硫黄原子、酸素原子及び／又は窒素原子を１乃至３個含む５乃至７員ヘテロアリール基；置換基群αから選択される基で置換されていてもよいＣ_３−Ｃ_８シクロアルキル基；置換基群αから選択される基で置換されていてもよい、硫黄原子、酸素原子及び／又は窒素原子を１乃至３個含む５乃至７員ヘテロシクリル基；置換基群αから選択される基で置換されていてもよいＣ_６−Ｃ_１０アリールオキシ基；置換基群αから選択される基で置換されていてもよい、硫黄原子、酸素原子及び／又は窒素原子を１乃至３個含む５乃至７員ヘテロアリールオキシ基；置換基群αから選択される基で置換されていてもよいＣ_３−Ｃ_８シクロアルキルオキシ基；並びに、置換基群αから選択される基で置換されていてもよい、硫黄原子、酸素原子及び／又は窒素原子を１乃至３個含む５乃至７員ヘテロシクリルオキシ基からなる群を示し、
置換基群γは、置換基群α及び置換基群βから選択される基で置換されていてもよいＣ_１−Ｃ_６アルキル基、置換基群α及び置換基群βから選択される基で置換されていてもよいＣ_１−Ｃ_６アルコキシ基、置換基群α及び置換基群βから選択される基で置換されていてもよいＣ_２−Ｃ_６アルケニル基、並びに、置換基群α及び置換基群βから選択される基で置換されていてもよいＣ_２−Ｃ_６アルケニルオキシ基からなる群を示す。｝
を有する化合物又はその薬理上許容される塩に関する。

上記のうち、好適な化合物は、
（２） 一般式（Ｉ）が、下記一般式（Ｉ’）であり、Ｒ^１が水素原子であり、Ｒ^２がＣ_１−Ｃ_８アルキル基であるか、或いは、Ｒ^１及びＲ^２が、それらが結合している炭素原子と一緒になって、置換基群αから選択される基で置換されていてもよいＣ_３−Ｃ_８シクロアルキル基を形成している化合物、中
R¹ and R² are the same or different and each represent a hydrogen atom or a C₁ -C₈ alkyl group, or R¹ and R² together with the carbon atom to which they are attached Forming a C₃ -C₈ cycloalkyl group which may be substituted with a group selected from substituent group α,
R³ represents a hydrogen atom; a C₁ -C₆ alkyl group substituted with at least one group selected from substituent group β; a C₁ -C₆ alkyl group substituted with at least one group selected from substituent group β.₁ -C₆ alkoxy groups; optionally substituted with a group selected from substituent group α C₆ -C₁₀ aryl group; optionally substituted with a group selected from substituent group alpha, a sulfur atom A 5- to 7-membered heteroaryl group containing 1 to 3 oxygen atoms and / or nitrogen atoms; a C₃ -C₈ cycloalkyl group optionally substituted with a group selected from the substituent group α; a 5- to 7-membered heterocyclyl group containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms, which may be substituted with a group selected from α; substituted with a group selected from substituent group α which may be_C 6_{-C 10} aryloxy group; location A 5- to 7-membered heteroaryloxy group containing 1 to 3 sulfur, oxygen and / or nitrogen atoms, which may be substituted with a group selected from group α; a group selected from substituent group α in an optionally substituted C₃ -C₈ cycloalkyloxy group; or optionally substituted with a group selected from substituent group alpha, a sulfur atom, an oxygen atom and / or nitrogen atoms from 1 to 3 Represents a 5- to 7-membered heterocyclyloxy group,
R⁴ is a C₁ -C₈ alkyl group, a C₆ -C₁₀ aryl group which may be substituted with a group selected from substituent group α, or the following general formula (II)
R^5- (CH₂ )_m- (II)
[Where,
m represents an integer of 1 to 8,
R⁵ is a C₆ -C₁₀ aryl group which may be substituted with a group selected from substituent group α; a sulfur atom, an oxygen atom which may be substituted with a group selected from substituent group α. And / or a 5- to 7-membered heteroaryl group containing 1 to 3 nitrogen atoms; a C₃ -C₈ cycloalkyl group optionally substituted with a group selected from substituent group α; a carbamoyl group; an amino group; A C₁ -C₆ alkylamino group; a di (C₁ -C₆ alkyl) amino group; a guanidyl group; or a compound represented by the formula R⁶ —O—, R⁶ —S— or R⁶ —O—CO— R⁶ is a hydrogen atom, it may be substituted with a group selected from the substituent group beta C₁ -C₆ alkyl group, or optionally substituted with a group selected from substituent group alpha C₆ -C shows a₁₀ aryl group.) a group represented by. ]
Represents a group represented by
Ar is a C₆ -C₁₀ aryl group which may be substituted with a group selected from substituent group α, substituent group β and substituent group γ; or, substituent group α, substituent group β and substituent A 5- to 7-membered heteroaryl group containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms, which may be substituted with a group selected from group γ,
X is a single bond, -NH -, - O -, - S -, - CONH -, - SO 2 NH -, - SONH-, or indicates -O-CONH-,
Z is a C₁ -C₆ alkyl group substituted with at least one group selected from substituent group β; C₆ -C₁₀ aryl optionally substituted with a group selected from substituent group α. A 5- to 7-membered heteroaryl group containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms, which may be substituted with a group selected from substituent group α; selected from substituent group α A C₃ -C₈ cycloalkyl group which may be substituted with a group selected from the group consisting of a sulfur atom, an oxygen atom and / or a nitrogen atom which may be substituted with a group selected from the substituent group α. A 5- to 7-membered heterocyclyl group containing 3
Substituent group α is a halogen atom, a C₁ -C₆ alkyl group, a C₁ -C₆ halogenated alkyl group, a formyl group, a (C₁ -C₆ alkyl) carbonyl group, a (C₁ -C₆ halogenated alkyl) ) Carbonyl, nitro, cyano, amino, C₁ -C₆ alkylamino, di (C₁ -C₆ alkyl) amino, C₁ -C₆ alkoxy, C₁ -C₆ halogenated alkoxy Group, C₁ -C₆ alkylthio group, C₁ -C₆ alkylsulfonyl group, C₁ -C₆ hydroxyalkyl group, C₁ -C₆ alkoxy C₁ -C₆ alkyl group, C₁ -C₆ alkylenedioxy_group, C 1 -C₆ aminoalkyl_group, C 2 -C₆ aminoalkoxy groups, wherein^{-CO-R 7} (wherein,^{R 7} is_hydroxyl, C 1 -C₆ alkoxy_group, C 6_{-C 10} arylene Oxy_group, C 6_{-C 10} aryl_C 1 -C₆ alkoxy group, amino_group, C 1 -C₆ alkylamino group, a group represented by di showing a_(C 1 -C₆ alkyl) amino group) and, A group consisting of a tetrazolyl group,
Substituent group β is a C₆ -C₁₀ aryl group which may be substituted with a group selected from substituent group α; a sulfur atom which may be substituted with a group selected from substituent group α, oxygen atom and / or nitrogen atoms from 1 to 3 5 to 7-membered containing heteroaryl group; which may be substituted with a group selected from the substituent group alpha C₃ -C₈ cycloalkyl group; substituent group alpha A 5- to 7-membered heterocyclyl group containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms, which may be substituted with a group selected from the group consisting of: A C₆ -C₁₀ aryloxy group; a 5- to 7-membered heteroaryl containing 1 to 3 sulfur, oxygen and / or nitrogen atoms which may be substituted with a group selected from the substituent group α. An oxy group; a group selected from the substituent group α Optionally substituted C₃ -C₈ cycloalkyloxy group; and 1 to 3 sulfur, oxygen and / or nitrogen atoms which may be substituted with a group selected from substituent group α. A group consisting of a 5- to 7-membered heterocyclyloxy group,
Substituent group γ is a C₁ -C₆ alkyl group which may be substituted with a group selected from substituent group α and substituent group β, and a group selected from substituent group α and substituent group β. A C₁ -C₆ alkoxy group which may be substituted, a C₂ -C₆ alkenyl group which may be substituted with a group selected from substituent group α and substituent group β, and substituent group α and shows a group consisting of optionally substituted C₂ -C₆ alkenyloxy group with a group selected from the substituent group beta. ｝
Or a pharmacologically acceptable salt thereof.

Among the above, preferred compounds are
(2) General formula (I) is the following general formula (I ′), R¹ is a hydrogen atom, R² is a C₁ -C₈ alkyl group, or R¹ and R² are Compounds which together with the carbon atom to which they are attached form a C₃ -C₈ cycloalkyl group which may be substituted by a group selected from substituent group α,

（３） Ｒ^１が水素原子であり、Ｒ^２がＣ_１−Ｃ_４アルキル基であるか、或いは、Ｒ^１及びＲ^２が、それらが結合している炭素原子と一緒になって、置換基群αから選択される基で置換されていてもよいＣ_５−Ｃ_６シクロアルキル基を形成している化合物、
（４） Ｒ^１が水素原子であり、Ｒ^２がイソブチルであるか、或いは、Ｒ^１及びＲ^２が、それらが結合している炭素原子と一緒になって、シクロヘキシルを形成している化合物、
（５） Ｒ^３が、置換基群αから選択される基で置換されていてもよいＣ_６−Ｃ_１０アリール基；置換基群αから選択される基で置換されていてもよい、硫黄原子、酸素原子及び／又は窒素原子を１乃至３個含む５乃至７員ヘテロアリール基；置換基群αから選択される基で置換されていてもよいＣ_３−Ｃ_８シクロアルキル基；置換基群αから選択される基で置換されていてもよい、硫黄原子、酸素原子及び／又は窒素原子を１乃至３個含む５乃至７員ヘテロシクリル基；置換基群αから選択される基で置換されていてもよいＣ_６−Ｃ_１０アリールオキシ基；置換基群αから選択される基で置換されていてもよい、硫黄原子、酸素原子及び／又は窒素原子を１乃至３個含む５乃至７員ヘテロアリールオキシ基；置換基群αから選択される基で置換されていてもよいＣ_３−Ｃ_８シクロアルキルオキシ基；或いは、置換基群αから選択される基で置換されていてもよい、硫黄原子、酸素原子及び／又は窒素原子を１乃至３個含む５乃至７員ヘテロシクリルオキシ基である化合物、
（６） Ｒ^３が、置換基群αから選択される基で置換されていてもよいＣ_６−Ｃ_１０アリール基；置換基群αから選択される基で置換されていてもよい、硫黄原子、酸素原子及び／又は窒素原子を１乃至３個含む５乃至７員ヘテロアリール基；置換基群αから選択される基で置換されていてもよいＣ_３−Ｃ_８シクロアルキル基；或いは、置換基群αから選択される基で置換されていてもよい、硫黄原子、酸素原子及び／又は窒素原子を１乃至３個含む５乃至７員ヘテロシクリル基；置換基群αから選択される基で置換されていてもよいＣ_６−Ｃ_１０アリールオキシ基である化合物、
（７） Ｒ^３が、置換基群αから選択される基で置換されていてもよいＣ_６−Ｃ_１０アリール基；或いは、置換基群αから選択される基で置換されていてもよい、硫黄原子、酸素原子及び／又は窒素原子を１乃至３個含む５乃至７員ヘテロアリール基である化合物、
（８） Ｒ^３が、フェニル；メチル、メトキシ、フッ素原子、塩素原子、トリフロロメチル、トリフロロメトキシ、水酸基、ヒドロキシメチル及びアミノ基からなる群から選択される１個の基で置換されたフェニル；チエニル又はフリルである化合物、
（９） Ｒ^３が、フェニル、２−メチルフェニル、３−メチルフェニル、４−メチルフェニル、２−メトキシフェニル、３−メトキシフェニル、４−メトキシフェニル、２−フロロフェニル、３−フロロフェニル、４−フロロフェニル、２−クロロフェニル、３−クロロフェニル、４−クロロフェニル、３−トリフロロメチルフェニル、４−トリフロロメチルフェニル、３−トリフロロメトキシフェニル、４−トリフロロメトキシフェニル、３−ヒドロキシフェニル、４−ヒドロキシフェニル、３−ヒドロキシメチルフェニル、４−ヒドロキシメチルフェニル、３−アミノフェニル又は４−アミノフェニルである化合物、
（１０） Ｒ^４が、Ｃ_１−Ｃ_８アルキル基、４−アミノブチル、３−グアニジルプロピル、又は下記一般式（ＩＩ）
Ｒ^５−（ＣＨ_２）_ｍ− （ＩＩ）
（式中、ｍは１又は２を示す。）で表される基である化合物、
（１１） Ｒ^４が、Ｃ_１−Ｃ_４アルキル基、ベンジル、フェネチル、シクロヘキシルメチル、シクロヘキシルエチル、ヒドロキシメチル、ベンジルオキシメチル、メルカプトメチル、メチルチオエチル、ベンジルチオメチル、カルボキシメチル、カルボキシエチル、カルバモイルメチル、カルバモイルエチル、アミノブチル、グアニジルプロピル、イミダゾール−４−イルメチル又はインドール−３−イルメチルである化合物、
（１２） Ｒ^４が、Ｃ_１−Ｃ_４アルキル基である化合物、
（１３） Ａｒが、置換基群α、置換基群β及び置換基群γから選択される基で置換されていてもよいＣ_６−Ｃ_１０アリール基である化合物、
（１４） Ａｒが、置換基群α及び置換基群βから選択される基で置換されていてもよいＣ_１−Ｃ_６アルコキシ基で置換されたＣ_６−Ｃ_１０アリール基である化合物、
（１５） Ａｒが、パラ位に、置換基群α及び置換基群βから選択される基で置換されていてもよいＣ_１−Ｃ_６アルコキシ基を有するフェニルである化合物、
（１６） Ａｒが、ｐ−メトキシフェニル、ｐ−ベンジルオキシフェニル、ｐ−カルボキシメチルオキシフェニル又はｐ−（ｔ−ブトキシカルボニルメチル）フェニルである化合物、
（１７） Ｘが、単結合、−ＮＨ−、−Ｏ−、−ＣＯＮＨ−、−ＳＯ_２ＮＨ−、又は−Ｏ−ＣＯＮＨ−である化合物、
（１８） Ｘが、−ＮＨ−、−ＣＯＮＨ−、又は−ＳＯ_２ＮＨ−である化合物、
（１９） Ｘが、−ＮＨ−である化合物、
（２０） Ｚが、置換基群βから選択される少なくとも１個の基で置換されたＣ_１−Ｃ_６アルキル基；置換基群αから選択される基で置換されていてもよいＣ_６−Ｃ_１０アリール基；或いは、置換基群αから選択される基で置換されていてもよい、硫黄原子、酸素原子及び／又は窒素原子を１乃至３個含む５乃至７員ヘテロアリール基である化合物、
（２１） Ｚが、置換基群αから選択される基で置換されていてもよいＣ_６−Ｃ_１０アリール基；或いは、置換基群αから選択される基で置換されていてもよい、硫黄原子、酸素原子及び／又は窒素原子を１乃至３個含む５乃至７員ヘテロアリール基である化合物、
（２２） Ｚが、置換基群αから選択される基で置換されていてもよいＣ_６−Ｃ_１０アリール基である化合物、及び
（２３） Ｚが、置換基群αから選択される基で置換されていてもよい１，３−フェニレンである化合物
並びにその薬理上許容される塩であり、
特に好適な化合物は、
（２４） 下記から選択される1つの化合物又はその薬理上許容される塩である：
・Ｎ^２−１，１’−ビフェニル−３−イル−Ｎ^１−（（１Ｓ）−１−｛［（４−メトキシフェニル）アミノ］メチル｝プロピル）−Ｌ−ロイシンアミド、
・Ｎ^２−１，１’−ビフェニル−３−イル−Ｎ^１−（（１Ｓ）−１−｛［（４−メトキシフェニル）アミノ］メチル｝ブチル）−Ｌ−ロイシンアミド
・Ｎ^２−１，１’−ビフェニル−３−イル−Ｎ^１−（（１Ｓ）−１−｛［（４−メトキシフェニル）アミノ］メチル｝ペンチル）−Ｌ−ロイシンアミド
・Ｎ^１−（（１Ｓ）−１−｛［（４−ベンジルオキシフェニル）アミノ］メチル｝プロピル）−Ｎ^２−（１，１‘−ビフェニル−３−イル）−L−ロイシナミド、
・１−（１，１’−ビフェニル−３−イルアミノ）−Ｎ−（（１Ｓ）−１−｛［（４−メトキシフェニル）アミノ］メチル｝プロピル）シクロヘキサンカルボキサミド、
・１−（１，１’−ビフェニル−３−イルアミノ）−Ｎ−（（１Ｓ）−１−｛［（４−メトキシフェニル）アミノ］メチル｝ブチル）シクロヘキサンカルボキサミド、
・１−（１，１’−ビフェニル−３−イルアミノ）−Ｎ−（（１Ｓ）−１−｛［（４−メトキシフェニル）アミノ］メチル｝ペンチル）シクロヘキサンカルボキサミド、
・１−（１，１‘−ビフェニル−３−イルアミノ）−Ｎ−（（１Ｓ）−１−｛［（４−ベンジルオキシフェニル）アミノ］メチル｝プロピル）シクロヘキサンカルボキサミド、
・ｔｅｒｔ−ブチル （４−｛[（２Ｓ）−２−（｛[１−（１，１‘−ビフェニル−３−イルアミノ）シクロヘキシル]カルボニル｝アミノ）ブチル]アミノ｝フェノキシ）アセテート、
・（４−｛[（２Ｓ）−２−（｛[１−（１，１‘−ビフェニル−３−イルアミノ）シクロヘキシル]カルボニル｝アミノ）ブチル]アミノ｝フェノキシ）酢酸、
・［４−（｛（２Ｓ）−２−［（Ｎ−１，１‘−ビフェニル−３−イル−Ｌ−ロイシル）アミノ］ブチル｝アミノ）フェノキシ］酢酸 ｔｅｒｔ−ブチル、及び
・［４−（｛（２Ｓ）−２−［（Ｎ−１，１‘−ビフェニル−３−イル−Ｌ−ロイシル）アミノ］ブチル｝アミノ）フェノキシ］酢酸。

本発明は、更に、
（２５） 上記（１）乃至（２４）から選択されるいずれか１項に記載された化合物又はその薬理上許容される塩を有効成分として含有する医薬（特に、カテプシンＫ阻害剤、或いは、骨粗鬆症又は変形性関節症の予防若しくは治療剤）、
（２６） 医薬（特に、カテプシンＫ阻害剤、或いは、骨粗鬆症又は変形性関節症の予防若しくは治療剤）を製造するための、有効成分としての上記（１）乃至（２４）から選択されるいずれか１項に記載された化合物又はその薬理上許容される塩の使用、及び、
（２７） 上記（１）乃至（２４）から選択されるいずれか１項に記載された化合物又はその薬理上許容される塩を有効量哺乳動物（特に、ヒト）に投与することからなる、カテプシンＫを阻害する方法（特に、骨粗鬆症又は変形性関節症の予防若しくは治療方法）
に関する。

上記一般式（Ｉ）において、
Ｒ^１、Ｒ^２及びＲ^４の定義における「Ｃ_１−Ｃ_８アルキル基」とは、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、ｓ−ブチル、tert−ブチル、ペンチル、イソペンチル、２−メチルブチル、ネオペンチル、１−エチルプロピル、ヘキシル、イソヘキシル、４−メチルペンチル、３−メチルペンチル、２−メチルペンチル、１−メチルペンチル、３，３−ジメチルブチル、２，２−ジメチルブチル、１，１−ジメチルブチル、１，２−ジメチルブチル、１，３−ジメチルブチル、２，３−ジメチルブチル、２−エチルブチル、ヘプチル、５−メチルヘキシル、オクチル又は６−メチルオクチル基のような直鎖若しくは分枝鎖アルキル基であり得、好適には、Ｃ_１−Ｃ_６直鎖若しくは分枝鎖アルキル基であり、更に好適には、Ｃ_１−Ｃ_４直鎖若しくは分枝鎖アルキル基である。Ｒ^１及びＲ^２は、より更に好適には、エチル、プロピル、イソプロピル、ブチル又はイソブチル基であり、特に好適には、イソプロピル又はイソブチル基であり、最適には、イソブチル基である。Ｒ^４は、より更に好適には、メチル、エチル、プロピル、イソプロピル又はブチル基である。

Ｒ^１及びＲ^２が、それらが結合している炭素原子と一緒になって形成する「置換基群αから選択される基で置換されていてもよいＣ_３−Ｃ_８シクロアルキル基」並びに、Ｒ^３、Ｒ^５、Ｚ及び置換基群βの定義における「置換基群αから選択される基で置換されていてもよいＣ_３−Ｃ_８シクロアルキル基」のＣ_３−Ｃ_８シクロアルキル基は、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、シクロヘプチル又はシクロオクチル基であり得、好適には、Ｃ_３−Ｃ_６シクロアルキル基であり、更に好適には、シクロペンチル又はシクロヘキシル基であり、特に好適には、シクロヘキシル基である。

置換基群αの定義における「Ｃ_１−Ｃ_６アルキル基」；Ｒ^３及びZの定義における「置換基群βから選択される少なくとも１個の基で置換されたＣ_１−Ｃ_６アルキル基」のＣ_１−Ｃ_６アルキル基；Ｒ^６の定義における「置換基群βから選択される基で置換されていてもよいＣ_１−Ｃ_６アルキル基」のＣ_１−Ｃ_６アルキル基；並びに、置換基群γの定義における「置換基群α及び置換基群βから選択される基で置換されていてもよいＣ_１−Ｃ_６アルキル基」のＣ_１−Ｃ_６アルキル基は、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、ｓ−ブチル、tert−ブチル、ペンチル、イソペンチル、２−メチルブチル、ネオペンチル、１−エチルプロピル、ヘキシル、イソヘキシル、４−メチルペンチル、３−メチルペンチル、２−メチルペンチル、１−メチルペンチル、３，３−ジメチルブチル、２，２−ジメチルブチル、１，１−ジメチルブチル、１，２−ジメチルブチル、１，３−ジメチルブチル、２，３−ジメチルブチル又は２−エチルブチル基のような直鎖若しくは分枝鎖アルキル基であり得、好適には、Ｃ_１−Ｃ_４直鎖若しくは分枝鎖アルキル基であり、更に好適には、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル又はtert−ブチル基であり、より更に好適には、メチル、エチル、プロピル、イソプロピル又はブチルであり、特に好適には、メチル又はエチルである。

Ｒ^７及び置換基群αの定義における「Ｃ_１−Ｃ_６アルコキシ基」；Ｒ^３の定義における「置換基群βから選択される少なくとも１個の基で置換されたＣ_１−Ｃ_６アルコキシ基」のＣ_１−Ｃ_６アルコキシ基；置換基群γの定義における「置換基群α及び置換基群βから選択される基で置換されていてもよいＣ_１−Ｃ_６アルコキシ基」のＣ_１−Ｃ_６アルコキシ基；並びに、Ｒ^７の定義における「Ｃ_６−Ｃ_１０アリールＣ_１−Ｃ_６アルコキシ基」のＣ_１−Ｃ_６アルコキシ基は、「Ｃ_１−Ｃ_６アルコキシ基」は、上記「Ｃ_１−Ｃ_６アルキル基」に酸素原子が結合した基であり、好適には、Ｃ_１−Ｃ_４直鎖若しくは分枝鎖アルコキシ基であり、更に好適には、メトキシ、エトキシ、プロポキシ、イソプロポキシ、ブトキシ、イソブトキシ又はtert-ブトキシであり、より更に好適には、メトキシ、エトキシ、プロポキシ、イソプロポキシ又はブトキシであり、特に好適には、メトキシ又はエトキシである。

Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６、Ｚ及び置換基群βの定義における「置換基群αから選択される基で置換されていてもよいＣ_６−Ｃ_１０アリール基」のＣ_６−Ｃ_１０アリール基；Ａｒの定義における「置換基群α、置換基群β及び置換基群γから選択される基で置換されていてもよいＣ_６−Ｃ_１０アリール基」のＣ_６−Ｃ_１０アリール基；並びに、Ｒ^７の定義における「Ｃ_６−Ｃ_１０アリールＣ_１−Ｃ_６アルコキシ基」のＣ_６−Ｃ_１０アリール基は、例えば、フェニル又はナフチルであり得、好適には、フェニルである。(3) R¹ is a hydrogen atom and R² is a C₁ -C₄ alkyl group, or R¹ and R² together with the carbon atom to which they are attached form a substituent A compound forming a C₅ -C₆ cycloalkyl group which may be substituted with a group selected from the group α,
(4) compounds wherein R¹ is a hydrogen atom and R² is isobutyl, or R¹ and R² together with the carbon atom to which they are attached form cyclohexyl;
(5) R³ is, which may C₆ -C even though₁₀ aryl group substituted with a group selected from substituent group alpha; may be substituted with a group selected from alpha substituent group, a sulfur atom A 5- to 7-membered heteroaryl group containing 1 to 3 oxygen atoms and / or nitrogen atoms; a C₃ -C₈ cycloalkyl group optionally substituted with a group selected from the substituent group α; a 5- to 7-membered heterocyclyl group containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms, which may be substituted with a group selected from α; substituted with a group selected from substituent group α A C₆ -C₁₀ aryloxy group; a 5- to 7-membered heteroatom containing 1 to 3 sulfur, oxygen and / or nitrogen atoms which may be substituted with a group selected from the substituent group α. Aryloxy group; a group selected from substituent group α Optionally substituted C₃ -C₈ cycloalkyl group; or optionally substituted with a group selected from Substituent group alpha, a sulfur atom, 1 to 3 oxygen atoms and / or nitrogen atom A compound which is a 5- to 7-membered heterocyclyloxy group,
(6) R³ is, which may C₆ -C even though₁₀ aryl group substituted with a group selected from substituent group alpha; may be substituted with a group selected from alpha substituent group, a sulfur atom A 5- to 7-membered heteroaryl group containing 1 to 3 oxygen atoms and / or nitrogen atoms; a C₃ -C₈ cycloalkyl group optionally substituted with a group selected from substituent group α; A 5- to 7-membered heterocyclyl group containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms, which may be substituted with a group selected from group α; substituted with a group selected from group α A compound which is an optionally substituted C₆ -C₁₀ aryloxy group,
(7) R³ is a C₆ -C₁₀ aryl group optionally substituted with a group selected from substituent group α; or, R³ may be substituted with a group selected from substituent group α. A compound which is a 5- to 7-membered heteroaryl group containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms,
(8) R³ is phenyl; phenyl substituted with one group selected from the group consisting of methyl, methoxy, fluorine atom, chlorine atom, trifluoromethyl, trifluoromethoxy, hydroxyl group, hydroxymethyl and amino group A compound that is thienyl or furyl,
(9) R³ is phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-fluorophenyl, 3-fluorophenyl, -Fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3-trifluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 3-hydroxyphenyl, A compound which is -hydroxyphenyl, 3-hydroxymethylphenyl, 4-hydroxymethylphenyl, 3-aminophenyl or 4-aminophenyl,
(10) R⁴ is a C₁ -C₈ alkyl group, 4-aminobutyl, 3-guanidylpropyl, or the following general formula (II)
R^5- (CH₂ )_m- (II)
(Wherein m represents 1 or 2), a compound represented by the formula:
(11) R⁴ is a C₁ -C₄ alkyl group, benzyl, phenethyl, cyclohexylmethyl, cyclohexylethyl, hydroxymethyl, benzyloxymethyl, mercaptomethyl, methylthioethyl, benzylthiomethyl, carboxymethyl, carboxyethyl, carbamoylmethyl A compound which is carbamoylethyl, aminobutyl, guanidylpropyl, imidazol-4-ylmethyl or indol-3-ylmethyl;
(12) the compound, wherein R⁴ is a C₁ -C₄ alkyl group,
(13) A compound wherein Ar is a C₆ -C₁₀ aryl group optionally substituted with a group selected from substituent group α, substituent group β and substituent group γ.
(14) a compound wherein Ar is a C₆ -C₁₀ aryl group substituted with a C₁ -C₆ alkoxy group which may be substituted with a group selected from substituent group α and substituent group β;
(15) a compound wherein Ar is phenyl having a C₁ -C₆ alkoxy group which may be substituted at the para position with a group selected from substituent group α and substituent group β;
(16) The compound wherein Ar is p-methoxyphenyl, p-benzyloxyphenyl, p-carboxymethyloxyphenyl or p- (t-butoxycarbonylmethyl) phenyl,
(17) X is a single bond, -NH -, - O -, - CONH -, - SO 2 NH-, or -O-CONH-, compound,
(18) X is, -NH -, - CONH-, or_-SO 2 NH-, compound,
(19) a compound wherein X is -NH-
(20) Z is at least one C₁ -C₆ alkyl group substituted by a group selected from Substituent group beta; may be substituted with a group selected from α substituent group C₆ - A C₁₀ aryl group; or a 5- to 7-membered heteroaryl group containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms, which may be substituted with a group selected from the substituent group α. ,
(21) Z is a C₆ -C₁₀ aryl group optionally substituted with a group selected from the substituent group α; or sulfur, which may be substituted with a group selected from the substituent group α. A compound which is a 5- to 7-membered heteroaryl group containing 1 to 3 atoms, oxygen atoms and / or nitrogen atoms,
(22) a compound wherein Z is a C₆ -C₁₀ aryl group optionally substituted with a group selected from substituent group α, and (23) Z is a group selected from substituent group α. A compound which is an optionally substituted 1,3-phenylene and a pharmacologically acceptable salt thereof,
Particularly preferred compounds are
(24) One compound selected from the following or a pharmacologically acceptable salt thereof:
·^N 2-1,1'-biphenyl-3-yl^{-N 1 - ((1S) -1} - {[(4- methoxyphenyl) amino] methyl} propyl) -L- leucinamide,
·^N 2-1,1'-biphenyl-3-yl^{-N 1 - ((1S) -1} - {[(4- methoxyphenyl) amino] methyl} butyl) -L- leucinamide^· N 2 -1, 1′-biphenyl-3-yl-N¹ -((1S) -1-{[(4-methoxyphenyl) amino] methyl} pentyl) -L-leucinamide / N¹ -((1S) -1-} [(4-benzyloxyphenyl) amino] methyl} propyl) -N^2- (1,1′-biphenyl-3-yl) -L-leucinamide,
1- (1,1′-biphenyl-3-ylamino) -N-((1S) -1-{[(4-methoxyphenyl) amino] methyl} propyl) cyclohexanecarboxamide;
1- (1,1'-biphenyl-3-ylamino) -N-((1S) -1-{[(4-methoxyphenyl) amino] methyl} butyl) cyclohexanecarboxamide;
1- (1,1′-biphenyl-3-ylamino) -N-((1S) -1-{[(4-methoxyphenyl) amino] methyl} pentyl) cyclohexanecarboxamide;
1- (1,1′-biphenyl-3-ylamino) -N-((1S) -1-{[(4-benzyloxyphenyl) amino] methyl} propyl) cyclohexanecarboxamide;
-Tert-butyl (4-{[(2S) -2-({[1- (1,1'-biphenyl-3-ylamino) cyclohexyl] carbonyl} amino) butyl] amino} phenoxy) acetate,
-(4-{[(2S) -2-({[1- (1,1'-biphenyl-3-ylamino) cyclohexyl] carbonyl} amino) butyl] amino} phenoxy) acetic acid,
Tert-butyl [4-({(2S) -2-[(N-1,1′-biphenyl-3-yl-L-leucyl) amino] butyl} amino) phenoxy] acetate; {(2S) -2-[(N-1,1′-biphenyl-3-yl-L-leucyl) amino] butyl} amino) phenoxy] acetic acid.

The present invention further provides:
(25) A medicine (particularly a cathepsin K inhibitor or osteoporosis) containing, as an active ingredient, the compound described in any one of the above (1) to (24) or a pharmacologically acceptable salt thereof. Or a preventive or therapeutic agent for osteoarthritis),
(26) Any one selected from the above (1) to (24) as an active ingredient for producing a medicament (in particular, a cathepsin K inhibitor or a prophylactic or therapeutic agent for osteoporosis or osteoarthritis) Use of the compound or a pharmacologically acceptable salt thereof described in item 1, and
(27) Cathepsin comprising administering to a mammal (particularly a human) an effective amount of the compound or the pharmaceutically acceptable salt thereof described in any one of the above (1) to (24). Method for inhibiting K (particularly, method for preventing or treating osteoporosis or osteoarthritis)
About.

In the above general formula (I),
“C₁ -C₈ alkyl group” in the definition of R¹ , R² and R⁴ means methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, tert-butyl, pentyl, isopentyl, 2-methylbutyl , Neopentyl, 1-ethylpropyl, hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1- Linear or branched such as dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, heptyl, 5-methylhexyl, octyl or 6-methyloctyl group It is a chain alkyl group, preferably a C₁ -C₆ straight or branched chain alkyl group, more favorable In_is a C 1 -C₄ straight or branched chain alkyl group. R¹ and R² are more preferably an ethyl, propyl, isopropyl, butyl or isobutyl group, particularly preferably an isopropyl or isobutyl group, and most preferably an isobutyl group. R⁴ is even more preferably a methyl, ethyl, propyl, isopropyl or butyl group.

A “C₃ -C₈ cycloalkyl group optionally substituted with a group selected from the substituent group α” formed by R¹ and R² together with the carbon atom to which they are bonded; C₃ -C₈ cycloalkyl group of “C₃ -C₈ cycloalkyl group optionally substituted with a group selected from substituent group α” in the definition of R³ , R⁵ , Z and substituent group β. It is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, be a cycloheptyl or cyclooctyl group, preferably a C₃ -C₆ cycloalkyl group, more preferably a cyclopentyl or cyclohexyl, particularly preferably Is a cyclohexyl group.

R³ and Z "C₁ -C₆ alkyl group substituted with at least one group selected from substituent group β" in the definition of; "C₁ -C₆ alkyl group" in the definition of Substituent group α_C 1 -C₆ alkyl group "may be substituted with a group selected from the substituent group beta_C 1 -C₆ alkyl group" in the definition of^{R 6;;}_C 1 -C₆ alkyl group and, In the definition of the substituent group γ, the C₁ -C₆ alkyl group of the “C₁ -C₆ alkyl group optionally substituted with a group selected from the substituent group α and the substituent group β” is methyl, ethyl , Propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl , 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3- It is straight-chain or branched-chain alkyl groups such as dimethylbutyl or 2-ethylbutyl group, preferably a C₁ -C₄ straight or branched chain alkyl group, more preferably a methyl, ethyl , Propyl, isopropyl, butyl, isobutyl or tert-butyl group, even more preferably methyl, ethyl, propyl, isopropyl or butyl, particularly preferably methyl or ethyl.

C₁ -C₆ alkoxy group "is substituted with at least one group selected from substituent group β in the definition of R^3;" C₁ -C₆ alkoxy group "in the definition of R⁷ and Substituent group α C₁ -C₆ alkoxy group "; C₁ of the" optionally substituted with a group selected from substituent group α and substituent group beta C₁ -C₆ alkoxy group "in the definition of substituent group γ -C₆ alkoxy group; and,_C 1 -C₆ alkoxy group_"C 6_{-C 10} aryl_C 1 -C₆ alkoxy group" in the definition of^{R 7} are,_"C 1 -C₆ alkoxy group", the A group in which an oxygen atom is bonded to a “C₁ -C₆ alkyl group”, preferably a C₁ -C₄ linear or branched alkoxy group, more preferably methoxy, ethoxy, propoxy, Isopropoxy, butoxy, isobu Toxic or tert-butoxy, even more preferably methoxy, ethoxy, propoxy, isopropoxy or butoxy, particularly preferably methoxy or ethoxy.

C_6-of “C₆ -C₁₀ aryl group optionally substituted with a group selected from substituent group α” in the definition of R³ , R⁴ , R⁵ , R⁶ , Z and substituent group β. C₆ -C₁₀ of "substituent group alpha, which may be substituted with a group selected from γ substituent group β and substituent group C₆ -C₁₀ aryl group" in the definition of Ar; C₁₀ aryl group An aryl group; and the C₆ -C₁₀ aryl group of the “C₆ -C₁₀ aryl C₁ -C₆ alkoxy group” in the definition of R⁷ can be, for example, phenyl or naphthyl, preferably phenyl. is there.

尚、上記「Ｃ_６−Ｃ_１０アリール基」は、Ｃ_３−Ｃ_１０シクロアルキル基（好適には、Ｃ_５−Ｃ_６シクロアルキル基）と縮環していてもよく、そのような基としては、例えば、５−インダニルなどを挙げることができる。The “C₆ -C₁₀ aryl group” may be condensed with a C₃ -C₁₀ cycloalkyl group (preferably, a C₅ -C₆ cycloalkyl group). Is, for example, 5-indanyl.

Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６、Ｚ又は置換基群βが、置換基群αで置換されたＣ_６−Ｃ_１０アリール基である場合、好適には、置換基群αから選択される１乃至３個の基で置換されたＣ_６−Ｃ_１０アリール基であり、更に好適には、置換基群αから選択される１又は２個の基で置換されたＣ_６−Ｃ_１０アリール基であり、最適には、置換基群αから選択される１個の基で置換されたＣ_６−Ｃ_１０アリール基である。特に、Ｒ^３が、置換基群αで置換されたＣ_６−Ｃ_１０アリール基である場合、置換基群αは、好適には、メチル、メトキシ、フッ素原子、塩素原子、トリフロロメチル、トリフロロメトキシ、水酸基、ヒドロキシメチル及びアミノ基からなる群である。When R³ , R⁴ , R⁵ , R⁶ , Z or the substituent group β is a C₆ -C₁₀ aryl group substituted with the substituent group α, it is preferably selected from the substituent group α. that 1 to a 3 C₆ -C₁₀ aryl group substituted with a group, even more preferably, C₆ -C₁₀ aryl substituted with one or two groups selected from substituent group α a group, and optimally, a C₆ -C₁₀ aryl group substituted with one group selected from substituent group alpha. In particular, when R³ is a C₆ -C₁₀ aryl group substituted with the substituent group α, the substituent group α is preferably methyl, methoxy, a fluorine atom, a chlorine atom, trifluoromethyl, A group consisting of fluoromethoxy, hydroxyl, hydroxymethyl and amino groups.

Ａｒが、置換基群α、置換基群β及び置換基群γから選択される基で置換されたＣ_６−Ｃ_１０アリール基である場合、好適には、置換基群α、置換基群β及び置換基群γから選択される１乃至３個の基で置換されたＣ_６−Ｃ_１０アリール基であり、更に好適には、置換基群α、置換基群β及び置換基群γから選択される１又は２個の基で置換されたＣ_６−Ｃ_１０アリール基であり、より更に好適には、置換基群α、置換基群β及び置換基群γから選択される１個の基で置換されたＣ_６−Ｃ_１０アリール基であり、特に好適には、メトキシ又はベンジルオキシで置換されたフェニルであり、最も好適には、４−メトキシフェニルである。

Ｒ^３、Ｒ^５、Ｚ及び置換基群βの定義における「置換基群αから選択される基で置換されていてもよい、硫黄原子、酸素原子及び／又は窒素原子を１乃至３個含む５乃至７員ヘテロアリール基」の硫黄原子、酸素原子及び／又は窒素原子を１乃至３個含む５乃至７員ヘテロアリール基；並びに、Ａｒの定義における「置換基群α、置換基群β及び置換基群γから選択される基で置換されていてもよい、硫黄原子、酸素原子及び／又は窒素原子を１乃至３個含む５乃至７員ヘテロアリール基」の硫黄原子、酸素原子及び／又は窒素原子を１乃至３個含む５乃至７員ヘテロアリール基は、例えば、フリル、チエニル、ピロリル、ピラゾリル、イミダゾリル、オキサゾリル、イソキサゾリル、チアゾリル、イソチアゾリル、トリアゾリル、チアジアゾリル、ピリジル、ピリダジニル、ピリミジニル、ピラジニル又はアゼピニルであり得、好適には、フリル、チエニル、ピロリル、ピラゾリル、イミダゾリル、オキサゾリル、イソキサゾリル、チアゾリル、イソチアゾリル、ピリジル、ピリダジニル、ピリミジニル又はピラジニルのような、硫黄原子、酸素原子及び／又は窒素原子を１若しくは２個含む５乃至６員ヘテロアリール基である。Ｒ^３及びＺとしては、更に好適には、フリル、チエニル、ピロリル又はピリジルである。When Ar is a C₆ -C₁₀ aryl group substituted with a group selected from substituent group α, substituent group β and substituent group γ, preferably, substituent group α and substituent group β And a C₆ -C₁₀ aryl group substituted with 1 to 3 groups selected from a substituent group γ, and more preferably selected from a substituent group α, a substituent group β, and a substituent group γ. A C₆ -C₁₀ aryl group substituted with one or two groups, more preferably one group selected from substituent group α, substituent group β and substituent group γ in a substituted C₆ -C₁₀ aryl group, particularly preferably a phenyl substituted with methoxy or benzyloxy, and most preferably a 4-methoxyphenyl.

In the definition of R³ , R⁵ , Z and the substituent group β, “a group containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms which may be substituted with a group selected from the substituent group α” A 5- to 7-membered heteroaryl group containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms of a "to 7-membered heteroaryl group"; and "substituent group α, substituent group β and A 5- to 7-membered heteroaryl group containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms, which may be substituted with a group selected from group γ, sulfur atoms, oxygen atoms and / or nitrogen 5- to 7-membered heteroaryl groups containing 1 to 3 atoms include, for example, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, thiadia Sulfur atom, such as ryl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or azepinyl, preferably furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl. , A 5- or 6-membered heteroaryl group containing one or two oxygen atoms and / or nitrogen atoms. R³ and Z are more preferably furyl, thienyl, pyrrolyl or pyridyl.

尚、上記「硫黄原子、酸素原子及び／又は窒素原子を１乃至３個含む５乃至７員ヘテロアリール基」は、他の環式基［例えば、Ｃ_６−Ｃ_１０アリール基又はＣ_３−Ｃ_８シクロアルキル基（好適には、Ｃ_５−Ｃ_６シクロアルキル基）］と縮環していてもよく、そのような基は、例えば、インドリル、ベンゾフラニル、ベンゾチエニル、キノリル、イソキノリル、キナゾリニル、テトラヒドロキノリル、又はテトラヒドロイソキノリルであり得る。The “5- to 7-membered heteroaryl group containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms” may be another cyclic group [for example, a C₆ -C₁₀ aryl group or a C₃ -C₈ cycloalkyl group (preferably C₅ -C₆ cycloalkyl group)], and such a group may be, for example, indolyl, benzofuranyl, benzothienyl, quinolyl, isoquinolyl, quinazolinyl, tetrahydro It can be quinolyl, or tetrahydroisoquinolyl.

Ｒ^３、Ｒ^５、Ｚ又は置換基群βが、置換基群αから選択される基で置換された、硫黄原子、酸素原子及び／又は窒素原子を１乃至３個含む５乃至７員ヘテロアリール基である場合、好適には、置換基群αから選択される１又は２個の基で置換された、硫黄原子、酸素原子及び／又は窒素原子を１乃至３個含む５乃至７員ヘテロアリール基であり、更に好適には、置換基群αから選択される１個の基で置換された、硫黄原子、酸素原子及び／又は窒素原子を１乃至３個含む５乃至７員ヘテロアリール基である。A 5- to 7-membered heteroaryl containing 1 to 3 sulfur, oxygen and / or nitrogen atoms, wherein R³ , R⁵ , Z or the substituent group β is substituted by a group selected from the substituent group α. When it is a group, it is preferably a 5- to 7-membered heteroaryl containing 1 to 3 sulfur, oxygen and / or nitrogen atoms, which is substituted with one or two groups selected from the substituent group α. And more preferably a 5- to 7-membered heteroaryl group containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms substituted with one group selected from the substituent group α. is there.

Ａｒが、置換基群α、置換基群β及び置換基群γから選択される基で置換された、硫黄原子、酸素原子及び／又は窒素原子を１乃至３個含む５乃至７員ヘテロアリール基である場合、好適には、置換基群α、置換基群β及び置換基群γから選択される１又は２個の基で置換された、硫黄原子、酸素原子及び／又は窒素原子を１乃至３個含む５乃至７員ヘテロアリール基であり、更に好適には、置換基群α、置換基群β及び置換基群γから選択される１個の基で置換された、硫黄原子、酸素原子及び／又は窒素原子を１乃至３個含む５乃至７員ヘテロアリール基である。

Ｒ^３、Ｚ及び置換基群βの定義における「置換基群αから選択される基で置換されていてもよい、硫黄原子、酸素原子及び／又は窒素原子を１乃至３個含む５乃至７員ヘテロシクリル基」の硫黄原子、酸素原子及び／又は窒素原子を１乃至３個含む５乃至７員ヘテロシクリル基は、例えば、アゼチジニル、ピロリジニル、ピロリニル、イミダゾリジニル、イミダゾリニル、ピラゾリジニル、ピラゾリニル、オキサゾリジニル、チアゾリジニル、オキサジアゾリジニル、ピペリジル、テトラヒドロピリジル、ジヒドロピリジル、２Ｈ−ピラニル、２−オキソ−２Ｈ−ピラニル、ピペラジニル、モルホリニル、チオモルホリニル又はホモピペリジルであり得、好適には、硫黄原子、酸素原子及び／又は窒素原子を１又は２個含む５又は６員ヘテロシクリル基である。Ｒ^３及びＺとしては、特に好適には、ピペリジル、２−オキソ−２Ｈ−ピラニル、ピペラジニル又はモルホリニルである。Ar is a 5- to 7-membered heteroaryl group containing 1 to 3 sulfur, oxygen and / or nitrogen atoms, substituted with a group selected from substituent group α, substituent group β and substituent group γ In the case where is preferably a sulfur atom, an oxygen atom and / or a nitrogen atom, which is substituted with one or two groups selected from the substituent group α, the substituent group β and the substituent group γ, from 1 to 2 A 5- to 7-membered heteroaryl group containing three, more preferably, a sulfur atom or an oxygen atom substituted with one group selected from substituent group α, substituent group β and substituent group γ And / or a 5- to 7-membered heteroaryl group containing 1 to 3 nitrogen atoms.

In the definition of R³ , Z and the substituent group β, “a 5- to 7-membered member containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms, which may be substituted by a group selected from the substituent group α. The 5- to 7-membered heterocyclyl group containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms of the "heterocyclyl group" is, for example, azetidinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, oxazolidinyl, thiazolidinyl, oxadiazoline It can be ridinyl, piperidyl, tetrahydropyridyl, dihydropyridyl, 2H-pyranyl, 2-oxo-2H-pyranyl, piperazinyl, morpholinyl, thiomorpholinyl or homopiperidyl, preferably with sulfur, oxygen and / or nitrogen atoms. 5- or 6-membered hetero containing 1 or 2 It is an acrylic group. R³ and Z are particularly preferably piperidyl, 2-oxo-2H-pyranyl, piperazinyl or morpholinyl.

尚、上記「硫黄原子、酸素原子及び／又は窒素原子を１乃至３個含む５乃至７員ヘテロシクリル基」は、他の環式基（例えば、フェニル基）と縮環していてもよく、そのような基は、例えば、テトラヒドロキノリニル、テトラヒドロイソキノリニル、クロマニル、インドリニル又はイソインドリニルであり得る。  The “5- to 7-membered heterocyclyl group containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms” may be condensed with another cyclic group (for example, a phenyl group). Such a group can be, for example, tetrahydroquinolinyl, tetrahydroisoquinolinyl, chromanyl, indolinyl or isoindolinyl.

Ｒ^３、Ｚ又は置換基群βが、置換基群αから選択される基で置換された、硫黄原子、酸素原子及び／又は窒素原子を１乃至３個含む５乃至７員ヘテロシクリル基である場合、好適には、置換基群αから選択される１又は２個の基で置換された、硫黄原子、酸素原子及び／又は窒素原子を１乃至３個含む５乃至７員ヘテロシクリル基であり、更に好適には、置換基群αから選択される１個の基で置換された、硫黄原子、酸素原子及び／又は窒素原子を１乃至３個含む５乃至７員ヘテロシクリル基である。

Ｒ^７の定義における「Ｃ_６−Ｃ_１０アリールオキシ基」；並びに、Ｒ^３及び置換基群βの定義における「置換基群αから選択される基で置換されていてもよいＣ_６−Ｃ_１０アリールオキシ基」のＣ_６−Ｃ_１０アリールオキシ基は、上記「Ｃ_６−Ｃ_１０アリール基」に酸素原子が結合した基であり、好適には、フェノキシである。

Ｒ^３及び置換基群βの定義における「置換基群αから選択される基で置換されていてもよい、硫黄原子、酸素原子及び／又は窒素原子を１乃至３個含む５乃至７員ヘテロアリールオキシ基」の硫黄原子、酸素原子及び／又は窒素原子を１乃至３個含む５乃至７員ヘテロアリールオキシ基は、上記「硫黄原子、酸素原子及び／又は窒素原子を１乃至３個含む５乃至７員ヘテロアリール基」に酸素原子が結合した基であり、好適には、硫黄原子、酸素原子及び／又は窒素原子を１若しくは２個含む５乃至６員ヘテロアリールオキシ基であり、更に好適には、ピリジルオキシ又はキノリルオキシである。

Ｒ^３及び置換基群βの定義における「置換基群αから選択される基で置換されていてもよいＣ_３−Ｃ_８シクロアルキルオキシ基」のＣ_３−Ｃ_８シクロアルキルオキシ基は、上記「Ｃ_３−Ｃ_８シクロアルキルオキシ基」に酸素原子が結合した基であり、好適には、シクロペンチルオキシ又はシクロヘキシルオキシである。

Ｒ^３及び置換基群βの定義における「置換基群αから選択される基で置換されていてもよい、硫黄原子、酸素原子及び／又は窒素原子を１乃至３個含む５乃至７員ヘテロシクリルオキシ基」の硫黄原子、酸素原子及び／又は窒素原子を１乃至３個含む５乃至７員ヘテロシクリルオキシ基は、上記「硫黄原子、酸素原子及び／又は窒素原子を１乃至３個含む５乃至７員ヘテロシクリルオキシ基」に酸素原子が結合した基であり、好適には、硫黄原子、酸素原子及び／又は窒素原子を１又は２個含む５又は６員ヘテロシクリルオキシ基であり、更に好適には、ピペリジルオキシ、ピロリジルオキシ又はテトラヒドロフラニルオキシである。

Ｒ^５、Ｒ^７及び置換基群αの定義における「Ｃ_１−Ｃ_６アルキルアミノ基」は、１個の上記「Ｃ_１−Ｃ_６アルキル基」で置換されたアミノ基であり、好適には、Ｃ_１−Ｃ_４アルキルアミノ基であり、更に好適には、メチルアミノ、エチルアミノ、プロピルアミノ、イソプロピルアミノ又はイソブチルアミノであり、特に好適には、メチルアミノ又はエチルアミノである。

Ｒ^５、Ｒ^７及び置換基群αの定義における「ジ（Ｃ_１−Ｃ_６アルキル）アミノ基」は、２個の上記「Ｃ_１−Ｃ_６アルキル基」で置換されたアミノ基であり、好適には、ジ（Ｃ_１−Ｃ_４アルキル）アミノ基であり、更に好適には、ジメチルアミノ、ジエチルアミノ、ジプロピルアミノ、ジイソプロピルアミノ又はジイソブチルアミノであり、特に好適には、ジメチルアミノ又はジエチルアミノである。

Ｒ^７の定義における「Ｃ_６−Ｃ_１０アリールＣ_１−Ｃ_６アルコキシ基」は、上記「Ｃ_１−Ｃ_６アルコキシ基」が上記「Ｃ_６−Ｃ_１０アリール基」で置換された基であり、好適には、ベンジル又はフェネチルであり、更に好適には、ベンジルである。

置換基群αの定義における「ハロゲン原子」は、フッ素原子、塩素原子、臭素原子又はヨウ素原子であり、好適には、フッ素原子又は塩素原子である。

置換基群αの定義における「Ｃ_１−Ｃ_６ハロゲン化アルキル基」は、前記「Ｃ_１−Ｃ_６アルキル基」の１個若しくは２個以上の水素原子が前記「ハロゲン原子」で置換された基であり、好適には、Ｃ_１−Ｃ_４ハロゲン化アルキル基であり、更に好適にはトリフルオロメチル、トリクロロメチル、ジフルオロメチル、ジクロロメチル、ジブロモメチル、フルオロメチル、２，２，２−トリクロロエチル、２，２，２−トリフルオロエチル、２−ブロモエチル、２−クロロエチル、２−フルオロエチル又は２，２−ジブロモエチルであり、より更に好適には、トリフルオロメチル、トリクロロメチル、ジフルオロメチル又はフルオロメチルであり、最も好適には、トリフルオロメチルである。

置換基群αの定義における「（Ｃ_１−Ｃ_６アルキル）カルボニル基」は、上記「Ｃ_１−Ｃ_６アルキル基にカルボニル基が結合した基であり、好適には、（Ｃ_１−Ｃ_４アルキル）カルボニル基であり、更に好適には、アセチル、プロピオニル又はブチリルであり、特に好適には、アセチルである。

置換基群αの定義における「（Ｃ_１−Ｃ_６ハロゲン化アルキル）カルボニル基」は、上記「Ｃ_１−Ｃ_６ハロゲン化アルキル基」にカルボニル基が結合した基であり、好適には、（Ｃ_１−Ｃ_４ハロゲン化アルキル）カルボニル基であり、更に好適には、トリフルオロアセチル、トリクロロアセチル、ジフルオロアセチル又はフルオロアセチルであり、最も好適には、トリフルオロアセチルである。

置換基群αの定義における「Ｃ_１−Ｃ_６ハロゲン化アルコキシ基」は、上記「Ｃ_１−Ｃ_６ハロゲン化アルキル基」に酸素原子が結合した基であり、好適には、（Ｃ_１−Ｃ_４ハロゲン化アルコキシ基であり、更に好適には、トリフルオロメトキシ、トリクロロメトキシ、ジフルオロメトキシ又はフルオロメトキシであり、最も好適には、トリフルオロメトキシである。

置換基群αの定義における「Ｃ_１−Ｃ_６アルキルチオ基」は、上記「Ｃ_１−Ｃ_６アルキル基」に硫黄原子が結合した基であり、好適には、Ｃ_１−Ｃ_４アルキルチオ基であり、更に好適には、メチルチオ、エチルチオ、プロピルチオ、イソプロピルチオ又はブチルチオであり、より更に好適には、メチルチオ、エチルチオ又はプロピルチオであり、特に好適には、メチルチオである。

置換基群αの定義における「Ｃ_１−Ｃ_６アルキルスルホニル基」は、上記「Ｃ_１−Ｃ_６アルキル基」にスルホニル（ＳＯ_２）が結合した基であり、好適には、Ｃ_１−Ｃ_４アルキルスルホニル基であり、更に好適には、メチルスルホニル、エチルスルホニル、プロピルスルホニル、イソプロピルスルホニル又はブチルスルホニルであり、より更に好適には、メチルスルホニル、エチルスルホニル又はプロピルスルホニルであり、特に好適には、メチルスルホニルである。

置換基群αの定義における「Ｃ_１−Ｃ_６ヒドロキシアルキル基」は、上記「Ｃ_１−Ｃ_６アルキル基」が１個の水酸基で置換された基であり、好適には、Ｃ_１−Ｃ_４ヒドロキシアルキル基であり、更に好適には、ヒドロキシメチル、ヒドロキシエチル又はヒドロキシプロピルであり、特に好適には、ヒドロキシメチルである。

置換基群αの定義における「Ｃ_１−Ｃ_６アルコキシＣ_１−Ｃ_６アルキル基」は、上記「Ｃ_１−Ｃ_６アルキル基」が１個のＣ_１−Ｃ_６アルコキシ基で置換された基であり、好適には、Ｃ_１−Ｃ_４アルコキシＣ_１−Ｃ_４アルキル基であり、更に好適には、メトキシメチル、メトキシエチル、メトキシプロピル、エトキシメチル又はエトキシエチルであり、特に好適には、メトキシエチルである。

置換基群αの定義における「Ｃ_１−Ｃ_６アルキレンジオキシ基」は、メチレンジオキシ、メチルメチレンジオキシ、ジメチルメチレンジオキシ、エチレンジオキシ、トリメチレンジオキシ、テトラメチレンジオキシ、２−メチルテトラメチレンジオキシ又は２，２−ジメチルテトラメチレンジオキシであり得、好適には、Ｃ_１−Ｃ_４アルキレンジオキシ基であり、更に好適には、メチレンジオキシ又はエチレンジオキシであり、特に好適には、メチレンジオキシである。

置換基群αの定義における「Ｃ_１−Ｃ_６アミノアルキル基」は、上記「Ｃ_１−Ｃ_６アルキル基」が１個のアミノ基で置換された基であり、好適には、Ｃ_１−Ｃ_４アミノアルキル基であり、更に好適には、アミノメチル、アミノエチル又はアミノプロピルであり、特に好適には、アミノメチルである。

置換基群αの定義における「Ｃ_２−Ｃ_６アミノアルコキシ基」は、例えば、アミノエトキシ、アミノプロポキシ、アミノブトキシ、アミノペンチルオキシ又はアミノヘキシルオキシであり得、好適には、Ｃ_２−Ｃ_４アミノアルコキシ基であり、更に好適には、アミノエトキシ又はアミノプロポキシであり、特に好適には、アミノエトキシである。

置換基群γの定義における「置換基群α及び置換基群βから選択される基で置換されていてもよいＣ_２−Ｃ_６アルケニル基」のＣ_２−Ｃ_６アルケニル基は、ビニル、２−プロペニル、１−メチル−２−プロペニル、２−メチル−２−プロペニル、２−エチル−２−プロペニル、２−ブテニル、１−メチル−２−ブテニル、２−メチル−２−ブテニル、１−エチル−２−ブテニル、３−ブテニル、１−メチル−３−ブテニル、２−メチル−３−ブテニル、１−エチル−３−ブテニル、２−ペンテニル、１−メチル−２−ペンテニル、２−メチル−２−ペンテニル、３−ペンテニル、１−メチル−３−ペンテニル、２−メチル−３−ペンテニル、４−ペンテニル、１−メチル−４−ペンテニル、２−メチル−４−ペンテニル、２−ヘキセニル、３−ヘキセニル、４−ヘキセニル又は５−ヘキセニル基のような直鎖若しくは分枝鎖アルケニル基であり得、好適には、Ｃ_２−Ｃ_４直鎖若しくは分枝鎖アルキル基であり、更に好適には、ビニル又は２−プロペニルであり、特に好適には、ビニルである。R³ , Z or the substituent group β is a 5- to 7-membered heterocyclyl group containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms substituted with a group selected from the substituent group α. A 5- to 7-membered heterocyclyl group containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms, which is substituted with one or two groups selected from the substituent group α. Preferably, it is a 5- to 7-membered heterocyclyl group containing 1 to 3 sulfur, oxygen and / or nitrogen atoms substituted with one group selected from the substituent group α.

“C₆ -C₁₀ aryloxy group” in the definition of R⁷ ; and “C₆ -C₁₀ which may be substituted with a group selected from substituent group α in the definition of R³ and substituent group β. The C₆ -C₁₀ aryloxy group of the “aryloxy group” is a group in which an oxygen atom is bonded to the above “C₆ -C₁₀ aryl group”, and is preferably phenoxy.

5 to 7-membered heteroaryl containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms, which may be substituted with a group selected from substituent group α in the definition of R³ and substituent group β. The 5- to 7-membered heteroaryloxy group containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms of the "oxy group" is the above-mentioned 5 to 7-membered heteroaryloxy group containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms. A group in which an oxygen atom is bonded to a "7-membered heteroaryl group", preferably a 5- or 6-membered heteroaryloxy group containing one or two sulfur atoms, oxygen atoms and / or nitrogen atoms, more preferably Is pyridyloxy or quinolyloxy.

In the definition of R³ and the substituent group β, the C₃ -C₈ cycloalkyloxy group of the “C₃ -C₈ cycloalkyloxy group optionally substituted with a group selected from the substituent group α” is as defined above. a "C₃ -C₈ cycloalkyl group" in the group having an oxygen atom attached thereto, preferably a cyclopentyloxy or cyclohexyloxy.

In the definition of R³ and the substituent group β, “5- to 7-membered heterocyclyloxy containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms, which may be substituted with a group selected from the substituent group α. The 5- to 7-membered heterocyclyloxy group containing 1 to 3 sulfur, oxygen and / or nitrogen atoms of the “group” is the 5- to 7-membered heterocyclyloxy group containing 1 to 3 sulfur, oxygen and / or nitrogen atoms. A heterocyclyloxy group "to which an oxygen atom is bonded, preferably a 5- or 6-membered heterocyclyloxy group containing one or two sulfur atoms, oxygen atoms and / or nitrogen atoms, more preferably piperidyl Oxy, pyrrolidyloxy or tetrahydrofuranyloxy.

“C₁ -C₆ alkylamino group” in the definition of R⁵ , R⁷ and the substituent group α is an amino group substituted with one of the above “C₁ -C₆ alkyl group”, and is preferably , C₁ -C₄ alkylamino group, more preferably methylamino, ethylamino, propylamino, isopropylamino or isobutylamino, particularly preferably methylamino or ethylamino.

The “di (C₁ -C₆ alkyl) amino group” in the definition of R⁵ , R⁷ and the substituent group α is an amino group substituted with two of the above “C₁ -C₆ alkyl groups”, It is preferably a di (C₁ -C₄ alkyl) amino group, more preferably dimethylamino, diethylamino, dipropylamino, diisopropylamino or diisobutylamino, particularly preferably dimethylamino or diethylamino. is there.

The “C₆ -C₁₀ aryl C₁ -C₆ alkoxy group” in the definition of R⁷ is a group in which the above “C₁ -C₆ alkoxy group” is substituted by the above “C₆ -C₁₀ aryl group”. Preferably, it is benzyl or phenethyl, more preferably benzyl.

The “halogen atom” in the definition of the substituent group α is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, and is preferably a fluorine atom or a chlorine atom.

The “C₁ -C₆ alkyl group” in the definition of the substituent group α is such that one or more hydrogen atoms of the “C₁ -C₆ alkyl group” are substituted with the “halogen atom”. a group,_preferably a C 1 -C₄ halogenated alkyl group, more preferably a trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, dibromomethyl, fluoromethyl, 2,2,2-trichloroethyl Ethyl, 2,2,2-trifluoroethyl, 2-bromoethyl, 2-chloroethyl, 2-fluoroethyl or 2,2-dibromoethyl, even more preferably trifluoromethyl, trichloromethyl, difluoromethyl or Fluoromethyl, most preferably trifluoromethyl.

The “(C₁ -C₆ alkyl) carbonyl group” in the definition of the substituent group α is a group in which a carbonyl group is bonded to the above “C₁ -C₆ alkyl group”, and is preferably (C₁ -C₄ alkyl). Alkyl) carbonyl group, more preferably acetyl, propionyl or butyryl, and particularly preferably acetyl.

The “(C₁ -C₆ halogenated alkyl) carbonyl group” in the definition of the substituent group α is a group in which a carbonyl group is bonded to the above “C₁ -C₆ halogenated alkyl group”. C₁ -C₄ halogenated alkyl) carbonyl group, more preferably trifluoroacetyl, trichloroacetyl, difluoroacetyl or fluoroacetyl, most preferably trifluoroacetyl.

"C₁ -C₆ halogenated alkoxy group" in the definition of Substituent group α is a group in the "C₁ -C₆ halogenated alkyl group" is an oxygen atom is bonded, preferably, (C₁ - a C₄ halogenated alkoxy group, more preferably a trifluoromethoxy, a trichloromethoxy, difluoromethoxy or trifluoromethoxy, most preferably a trifluoromethoxy.

The “C₁ -C₆ alkylthio group” in the definition of the substituent group α is a group in which a sulfur atom is bonded to the above “C₁ -C₆ alkyl group”, and is preferably a C₁ -C₄ alkylthio group. Yes, more preferably, methylthio, ethylthio, propylthio, isopropylthio or butylthio, even more preferably methylthio, ethylthio or propylthio, and particularly preferably methylthio.

_"C 1 -C₆ alkylsulfonyl group" in the definition of Substituent group α is a group sulfonyl above_"C 1 -C₆ alkyl group" (SO₂₎ is bonded,_preferably, C 1 -C₄ alkylsulfonyl group, more preferably methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl or butylsulfonyl, even more preferably methylsulfonyl, ethylsulfonyl or propylsulfonyl, particularly preferably , Methylsulfonyl.

"C₁ -C₆ hydroxyalkyl group" in the definition of Substituent group α is a group in which the above "C₁ -C₆ alkyl group" is substituted with one hydroxy group, preferably, C₁ -C_{It is a 4} -hydroxyalkyl group, more preferably hydroxymethyl, hydroxyethyl or hydroxypropyl, and particularly preferably hydroxymethyl.

The “C₁ -C₆ alkoxy C₁ -C₆ alkyl group” in the definition of the substituent group α is a group in which the above “C₁ -C₆ alkyl group” is substituted with one C₁ -C₆ alkoxy group. And is preferably a C₁ -C₄ alkoxy C₁ -C₄ alkyl group, more preferably methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl or ethoxyethyl, particularly preferably Methoxyethyl.

The “C₁ -C₆ alkylenedioxy group” in the definition of the substituent group α is methylenedioxy, methylmethylenedioxy, dimethylmethylenedioxy, ethylenedioxy, trimethylenedioxy, tetramethylenedioxy, 2-methylenedioxy, It can be methyltetramethylenedioxy or 2,2-dimethyltetramethylenedioxy, preferably a C₁ -C₄ alkylenedioxy group, more preferably methylenedioxy or ethylenedioxy, Particularly preferred is methylenedioxy.

"C₁ -C₆ aminoalkyl group" in the definition of Substituent group α is a group in which the above "C₁ -C₆ alkyl group" is substituted with one amino group, preferably, C₁ - a C₄ aminoalkyl group, more preferably a aminomethyl, aminoethyl or aminopropyl, particularly preferably aminomethyl.

The “C₂ -C₆ aminoalkoxy group” in the definition of the substituent group α may be, for example, aminoethoxy, aminopropoxy, aminobutoxy, aminopentyloxy or aminohexyloxy, preferably C₂ -C₄ It is an aminoalkoxy group, more preferably aminoethoxy or aminopropoxy, particularly preferably aminoethoxy.

C₂ -C₆ alkenyl group "may be substituted with a group selected from Substituent group α and Substituent group beta C₂ -C₆ alkenyl group" in the definition of Substituent group γ is vinyl, 2 -Propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 2-ethyl-2-propenyl, 2-butenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 1-ethyl -2-butenyl, 3-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 1-ethyl-3-butenyl, 2-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2 -Pentenyl, 3-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 4-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 2-hexenyl, - hexenyl, be straight-chain or branched alkenyl groups such as 4-hexenyl or 5-hexenyl group, preferably a C₂ -C₄ straight or branched chain alkyl group, more preferably the , Vinyl or 2-propenyl, particularly preferably vinyl.

置換基群γの定義における「置換基群α及び置換基群βから選択される基で置換されていてもよいＣ_２−Ｃ_６アルケニルオキシ基」のＣ_２−Ｃ_６アルケニルオキシ基は、上記「Ｃ_２−Ｃ_６アルケニル基」に酸素原子が結合した基であり、好適には、Ｃ_２−Ｃ_４直鎖若しくは分枝鎖アルケニルオキシ基であり、更に好適には、ビニルオキシ又は２−プロペニルオキシであり、特に好適には、ビニルオキシである。

一般式（Ｉ）は、好適には下記一般式（Ｉ’）The C₂ -C₆ alkenyloxy group of the “C₂ -C₆ alkenyloxy group optionally substituted with a group selected from the substituent group α and the substituent group β” in the definition of the substituent group γ is as described above. A group in which an oxygen atom is bonded to a “C₂ -C₆ alkenyl group”, preferably a C₂ -C₄ straight-chain or branched-chain alkenyloxy group, more preferably vinyloxy or 2-propenyl Oxy, particularly preferably vinyloxy.

The general formula (I) preferably has the following general formula (I ′)

であり、更に好適には、下記一般式（Ｉ’’）And more preferably the following general formula (I ''):

である。

「その薬理上許容される塩」とは、本発明の化合物（Ｉ）は、アミノ基のような塩基性の官能基を有する場合には酸と反応させることにより、又、カルボキシル基のような酸性の官能基を有する場合には塩基と反応させることにより、塩にすることができるので、その塩を示す。It is.

“Pharmacologically acceptable salt” means that the compound (I) of the present invention is reacted with an acid when it has a basic functional group such as an amino group, When the compound has an acidic functional group, it can be converted into a salt by reacting with a base.

塩基性の官能基に基づく塩は、例えば、塩酸塩、臭化水素酸塩若しくは沃化水素酸塩のようなハロゲン化水素酸塩、硝酸塩、過塩素酸塩、硫酸塩又は燐酸塩等の無機酸塩；メタンスルホン酸塩、トリフルオロメタンスルホン酸塩若しくはエタンスルホン酸塩のような低級アルカンスルホン酸塩、ベンゼンスルホン酸塩若しくはｐ−トルエンスルホン酸塩のようなアリ−ルスルホン酸塩又は酢酸塩、りんご酸塩、フマ−ル酸塩、コハク酸塩、クエン酸塩、アスコルビン酸塩、酒石酸塩、蓚酸塩若しくはマレイン酸塩のようなカルボン酸塩等の有機酸塩；或いは、グリシン塩、リジン塩、アルギニン塩、オルニチン塩、グルタミン酸塩又はアスパラギン酸塩のようなアミノ酸塩であり得る。  Salts based on basic functional groups include, for example, inorganic salts such as hydrochlorides, hydrobromides or hydroiodides, nitrates, perchlorates, sulfates or phosphates. Acid salts; lower alkane sulfonates such as methanesulfonate, trifluoromethanesulfonate or ethanesulfonate, arylsulfonates or acetates such as benzenesulfonate or p-toluenesulfonate; Organic acid salts such as malate, fumarate, succinate, citrate, ascorbate, tartrate, oxalate or maleate; or glycine salts, lysine salts , Arginine, ornithine, glutamate or aspartate.

酸性の官能基に基づく塩は、例えば、ナトリウム塩、カリウム塩若しくはリチウム塩のようなアルカリ金属塩、カルシウム塩若しくはマグネシウム塩のようなアルカリ土類金属塩、アルミニウム塩、又は鉄塩等の金属塩；アンモニウム塩；ｔ−オクチルアミン塩、ジベンジルアミン塩、モルホリン塩、グルコサミン塩、フェニルグリシンアルキルエステル塩、エチレンジアミン塩、Ｎ−メチルグルカミン塩、グアニジン塩、ジエチルアミン塩、トリエチルアミン塩、ジシクロヘキシルアミン塩、Ｎ，Ｎ’−ジベンジルエチレンジアミン塩、クロロプロカイン塩、プロカイン塩、ジエタノールアミン塩、Ｎ−ベンジルフェネチルアミン塩、ピペラジン塩、テトラメチルアンモニウム塩又はトリス（ヒドロキシメチル）アミノメタン塩のような有機アミン塩；或いは、グリシン塩、リジン塩、アルギニン塩、オルニチン塩、グルタミン酸塩又はアスパラギン酸塩のようなアミノ酸塩であり得る。  Salts based on acidic functional groups include, for example, alkali metal salts such as sodium salt, potassium salt or lithium salt, alkaline earth metal salts such as calcium salt or magnesium salt, aluminum salts, and metal salts such as iron salts. Ammonium salts; t-octylamine salts, dibenzylamine salts, morpholine salts, glucosamine salts, phenylglycine alkyl ester salts, ethylenediamine salts, N-methylglucamine salts, guanidine salts, diethylamine salts, triethylamine salts, dicyclohexylamine salts, Such as N, N'-dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzylphenethylamine salt, piperazine salt, tetramethylammonium salt or tris (hydroxymethyl) aminomethane salt; Amine salts; or glycine salts, lysine salts, arginine salts, ornithine salts, amino acid salts such as glutamate or aspartate.

本発明の一般式（Ｉ）を有する化合物又はその薬理上許容される塩は、大気中に放置したり、又は、再結晶をすることにより、水分を吸収し、吸着水が付いたり、水和物となる場合があり、そのような水和物も本発明に包含される。  The compound of the present invention having the general formula (I) or a pharmacologically acceptable salt thereof is allowed to stand in the air or recrystallize to absorb moisture, adhere to adsorbed water, or hydrate. In some cases, such hydrates are included in the present invention.

本発明の一般式（Ｉ）を有する化合物には、分子内の不斉中心に基づく光学異性体が存在する場合がある。本発明の化合物においては、これらの異性体およびこれらの異性体の混合物がすべて単一の式、即ち一般式（Ｉ）で示されている。従って、本発明はこれらの異性体およびこれらの異性体の任意の割合の混合物をもすべて含む。  The compound having the general formula (I) of the present invention may have an optical isomer based on an asymmetric center in the molecule. In the compounds of the present invention, these isomers and mixtures of these isomers are all represented by a single formula, that is, the general formula (I). Accordingly, the present invention also includes all these isomers and mixtures of these isomers in any proportion.

本発明の一般式（Ｉ）を有する化合物の具体例としては、例えば、下記例示化合物表１乃至例示化合物表５に記載の化合物を挙げることができる。  Specific examples of the compound having the general formula (I) of the present invention include, for example, the compounds described in Table 1 to Table 5 below.

例示化合物表１
---------------------------------------------------------
化合物
番 号 R¹ R² R R⁴ Ar X
---------------------------------------------------------
1-1 H iBu Br Me 4-MeO-Ph NH
1-2 H iBu Ph Me 4-MeO-Ph NH
1-3 H iBu 2-Me-Ph Me 4-MeO-Ph NH
1-4 H iBu 3-Me-Ph Me 4-MeO-Ph NH
1-5 H iBu 4-Me-Ph Me 4-MeO-Ph NH
1-6 H iBu 2-MeO-Ph Me 4-MeO-Ph NH
1-7 H iBu 3-MeO-Ph Me 4-MeO-Ph NH
1-8 H iBu 4-MeO-Ph Me 4-MeO-Ph NH
1-9 H iBu 2-Cl-Ph Me 4-MeO-Ph NH
1-10 H iBu 3-Cl-Ph Me 4-MeO-Ph NH
1-11 H iBu 4-Cl-Ph Me 4-MeO-Ph NH
1-12 H iBu 2-F-Ph Me 4-MeO-Ph NH
1-13 H iBu 3-F-Ph Me 4-MeO-Ph NH
1-14 H iBu 4-F-Ph Me 4-MeO-Ph NH
1-15 H iBu 3-CF₃-Ph Me 4-MeO-Ph NH
1-16 H iBu 4-CF₃-Ph Me 4-MeO-Ph NH
1-17 H iBu 3-CF₃O-Ph Me 4-MeO-Ph NH
1-18 H iBu 4-CF₃O-Ph Me 4-MeO-Ph NH
1-19 H iBu 3-HO-Ph Me 4-MeO-Ph NH
1-20 H iBu 4-HO-Ph Me 4-MeO-Ph NH
1-21 H iBu 3-HOCH₂-Ph Me 4-MeO-Ph NH
1-22 H iBu 4-HOCH₂-Ph Me 4-MeO-Ph NH
1-23 H iBu 3-H₂N-Ph Me 4-MeO-Ph NH
1-24 H iBu 4-H₂N-Ph Me 4-MeO-Ph NH
1-25 H iBu 2-Thi Me 4-MeO-Ph NH
1-26 H iBu 3-Thi Me 4-MeO-Ph NH
1-27 H iBu 2-Fur Me 4-MeO-Ph NH
1-28 H iBu Br Et 4-MeO-Ph NH
1-29 H iBu Ph Et 4-MeO-Ph NH
1-30 H iBu 2-Me-Ph Et 4-MeO-Ph NH
1-31 H iBu 3-Me-Ph Et 4-MeO-Ph NH
1-32 H iBu 4-Me-Ph Et 4-MeO-Ph NH
1-33 H iBu 2-MeO-Ph Et 4-MeO-Ph NH
1-34 H iBu 3-MeO-Ph Et 4-MeO-Ph NH
1-35 H iBu 4-MeO-Ph Et 4-MeO-Ph NH
1-36 H iBu 2-Cl-Ph Et 4-MeO-Ph NH
1-37 H iBu 3-Cl-Ph Et 4-MeO-Ph NH
1-38 H iBu 4-Cl-Ph Et 4-MeO-Ph NH
1-39 H iBu 2-F-Ph Et 4-MeO-Ph NH
1-40 H iBu 3-F-Ph Et 4-MeO-Ph NH
1-41 H iBu 4-F-Ph Et 4-MeO-Ph NH
1-42 H iBu 3-CF₃-Ph Et 4-MeO-Ph NH
1-43 H iBu 4-CF₃-Ph Et 4-MeO-Ph NH
1-44 H iBu 3-CF₃O-Ph Et 4-MeO-Ph NH
1-45 H iBu 4-CF₃O-Ph Et 4-MeO-Ph NH
1-46 H iBu 3-HO-Ph Et 4-MeO-Ph NH
1-47 H iBu 4-HO-Ph Et 4-MeO-Ph NH
1-48 H iBu 3-HOCH₂-Ph Et 4-MeO-Ph NH
1-49 H iBu 4-HOCH₂-Ph Et 4-MeO-Ph NH
1-50 H iBu 3-H₂N-Ph Et 4-MeO-Ph NH
1-51 H iBu 4-H₂N-Ph Et 4-MeO-Ph NH
1-52 H iBu 2-Thi Et 4-MeO-Ph NH
1-53 H iBu 3-Thi Et 4-MeO-Ph NH
1-54 H iBu 2-Fur Et 4-MeO-Ph NH
1-55 H iBu Br Pr 4-MeO-Ph NH
1-56 H iBu Ph Pr 4-MeO-Ph NH
1-57 H iBu 2-Me-Ph Pr 4-MeO-Ph NH
1-58 H iBu 3-Me-Ph Pr 4-MeO-Ph NH
1-59 H iBu 4-Me-Ph Pr 4-MeO-Ph NH
1-60 H iBu 2-MeO-Ph Pr 4-MeO-Ph NH
1-61 H iBu 3-MeO-Ph Pr 4-MeO-Ph NH
1-62 H iBu 4-MeO-Ph Pr 4-MeO-Ph NH
1-63 H iBu 2-Cl-Ph Pr 4-MeO-Ph NH
1-64 H iBu 3-Cl-Ph Pr 4-MeO-Ph NH
1-65 H iBu 4-Cl-Ph Pr 4-MeO-Ph NH
1-66 H iBu 2-F-Ph Pr 4-MeO-Ph NH
1-67 H iBu 3-F-Ph Pr 4-MeO-Ph NH
1-68 H iBu 4-F-Ph Pr 4-MeO-Ph NH
1-69 H iBu 3-CF₃-Ph Pr 4-MeO-Ph NH
1-70 H iBu 4-CF₃-Ph Pr 4-MeO-Ph NH
1-71 H iBu 3-CF₃O-Ph Pr 4-MeO-Ph NH
1-72 H iBu 4-CF₃O-Ph Pr 4-MeO-Ph NH
1-73 H iBu 3-HO-Ph Pr 4-MeO-Ph NH
1-74 H iBu 4-HO-Ph Pr 4-MeO-Ph NH
1-75 H iBu 3-HOCH₂-Ph Pr 4-MeO-Ph NH
1-76 H iBu 4-HOCH₂-Ph Pr 4-MeO-Ph NH
1-77 H iBu 3-H₂N-Ph Pr 4-MeO-Ph NH
1-78 H iBu 4-H₂N-Ph Pr 4-MeO-Ph NH
1-79 H iBu 2-Thi Pr 4-MeO-Ph NH
1-80 H iBu 3-Thi Pr 4-MeO-Ph NH
1-81 H iBu 2-Fur Pr 4-MeO-Ph NH
1-82 H iBu Br Bu 4-MeO-Ph NH
1-83 H iBu Ph Bu 4-MeO-Ph NH
1-84 H iBu 2-Me-Ph Bu 4-MeO-Ph NH
1-85 H iBu 3-Me-Ph Bu 4-MeO-Ph NH
1-86 H iBu 4-Me-Ph Bu 4-MeO-Ph NH
1-87 H iBu 2-MeO-Ph Bu 4-MeO-Ph NH
1-88 H iBu 3-MeO-Ph Bu 4-MeO-Ph NH
1-89 H iBu 4-MeO-Ph Bu 4-MeO-Ph NH
1-90 H iBu 2-Cl-Ph Bu 4-MeO-Ph NH
1-91 H iBu 3-Cl-Ph Bu 4-MeO-Ph NH
1-92 H iBu 4-Cl-Ph Bu 4-MeO-Ph NH
1-93 H iBu 2-F-Ph Bu 4-MeO-Ph NH
1-94 H iBu 3-F-Ph Bu 4-MeO-Ph NH
1-95 H iBu 4-F-Ph Bu 4-MeO-Ph NH
1-96 H iBu 3-CF₃-Ph Bu 4-MeO-Ph NH
1-97 H iBu 4-CF₃-Ph Bu 4-MeO-Ph NH
1-98 H iBu 3-CF₃O-Ph Bu 4-MeO-Ph NH
1-99 H iBu 4-CF₃O-Ph Bu 4-MeO-Ph NH
1-100 H iBu 3-HO-Ph Bu 4-MeO-Ph NH
1-101 H iBu 4-HO-Ph Bu 4-MeO-Ph NH
1-102 H iBu 3-HOCH₂-Ph Bu 4-MeO-Ph NH
1-103 H iBu 4-HOCH₂-Ph Bu 4-MeO-Ph NH
1-104 H iBu 3-H₂N-Ph Bu 4-MeO-Ph NH
1-105 H iBu 4-H₂N-Ph Bu 4-MeO-Ph NH
1-106 H iBu 2-Thi Bu 4-MeO-Ph NH
1-107 H iBu 3-Thi Bu 4-MeO-Ph NH
1-108 H iBu 2-Fur Bu 4-MeO-Ph NH
1-109 H iBu Br iPr 4-MeO-Ph NH
1-110 H iBu Ph iPr 4-MeO-Ph NH
1-111 H iBu 2-Me-Ph iPr 4-MeO-Ph NH
1-112 H iBu 3-Me-Ph iPr 4-MeO-Ph NH
1-113 H iBu 4-Me-Ph iPr 4-MeO-Ph NH
1-114 H iBu 2-MeO-Ph iPr 4-MeO-Ph NH
1-115 H iBu 3-MeO-Ph iPr 4-MeO-Ph NH
1-116 H iBu 4-MeO-Ph iPr 4-MeO-Ph NH
1-117 H iBu 2-Cl-Ph iPr 4-MeO-Ph NH
1-118 H iBu 3-Cl-Ph iPr 4-MeO-Ph NH
1-119 H iBu 4-Cl-Ph iPr 4-MeO-Ph NH
1-120 H iBu 2-F-Ph iPr 4-MeO-Ph NH
1-121 H iBu 3-F-Ph iPr 4-MeO-Ph NH
1-122 H iBu 4-F-Ph iPr 4-MeO-Ph NH
1-123 H iBu 3-CF₃-Ph iPr 4-MeO-Ph NH
1-124 H iBu 4-CF₃-Ph iPr 4-MeO-Ph NH
1-125 H iBu 3-CF₃O-Ph iPr 4-MeO-Ph NH
1-126 H iBu 4-CF₃O-Ph iPr 4-MeO-Ph NH
1-127 H iBu 3-HO-Ph iPr 4-MeO-Ph NH
1-128 H iBu 4-HO-Ph iPr 4-MeO-Ph NH
1-129 H iBu 3-HOCH₂-Ph iPr 4-MeO-Ph NH
1-130 H iBu 4-HOCH₂-Ph iPr 4-MeO-Ph NH
1-131 H iBu 3-H₂N-Ph iPr 4-MeO-Ph NH
1-132 H iBu 4-H₂N-Ph iPr 4-MeO-Ph NH
1-133 H iBu 2-Thi iPr 4-MeO-Ph NH
1-134 H iBu 3-Thi iPr 4-MeO-Ph NH
1-135 H iBu 2-Fur iPr 4-MeO-Ph NH
1-136 H iBu Br iBu 4-MeO-Ph NH
1-137 H iBu Ph iBu 4-MeO-Ph NH
1-138 H iBu 2-Me-Ph iBu 4-MeO-Ph NH
1-139 H iBu 3-Me-Ph iBu 4-MeO-Ph NH
1-140 H iBu 4-Me-Ph iBu 4-MeO-Ph NH
1-141 H iBu 2-MeO-Ph iBu 4-MeO-Ph NH
1-142 H iBu 3-MeO-Ph iBu 4-MeO-Ph NH
1-143 H iBu 4-MeO-Ph iBu 4-MeO-Ph NH
1-144 H iBu 2-Cl-Ph iBu 4-MeO-Ph NH
1-145 H iBu 3-Cl-Ph iBu 4-MeO-Ph NH
1-146 H iBu 4-Cl-Ph iBu 4-MeO-Ph NH
1-147 H iBu 2-F-Ph iBu 4-MeO-Ph NH
1-148 H iBu 3-F-Ph iBu 4-MeO-Ph NH
1-149 H iBu 4-F-Ph iBu 4-MeO-Ph NH
1-150 H iBu 3-CF₃-Ph iBu 4-MeO-Ph NH
1-151 H iBu 4-CF₃-Ph iBu 4-MeO-Ph NH
1-152 H iBu 3-CF₃O-Ph iBu 4-MeO-Ph NH
1-153 H iBu 4-CF₃O-Ph iBu 4-MeO-Ph NH
1-154 H iBu 3-HO-Ph iBu 4-MeO-Ph NH
1-155 H iBu 4-HO-Ph iBu 4-MeO-Ph NH
1-156 H iBu 3-HOCH₂-Ph iBu 4-MeO-Ph NH
1-157 H iBu 4-HOCH₂-Ph iBu 4-MeO-Ph NH
1-158 H iBu 3-H₂N-Ph iBu 4-MeO-Ph NH
1-159 H iBu 4-H₂N-Ph iBu 4-MeO-Ph NH
1-160 H iBu 2-Thi iBu 4-MeO-Ph NH
1-161 H iBu 3-Thi iBu 4-MeO-Ph NH
1-162 H iBu 2-Fur iBu 4-MeO-Ph NH
1-163 H iBu Br Ph 4-MeO-Ph NH
1-164 H iBu Ph Ph 4-MeO-Ph NH
1-165 H iBu 2-Me-Ph Ph 4-MeO-Ph NH
1-166 H iBu 3-Me-Ph Ph 4-MeO-Ph NH
1-167 H iBu 4-Me-Ph Ph 4-MeO-Ph NH
1-168 H iBu 2-MeO-Ph Ph 4-MeO-Ph NH
1-169 H iBu 3-MeO-Ph Ph 4-MeO-Ph NH
1-170 H iBu 4-MeO-Ph Ph 4-MeO-Ph NH
1-171 H iBu 2-Cl-Ph Ph 4-MeO-Ph NH
1-172 H iBu 3-Cl-Ph Ph 4-MeO-Ph NH
1-173 H iBu 4-Cl-Ph Ph 4-MeO-Ph NH
1-174 H iBu 2-F-Ph Ph 4-MeO-Ph NH
1-175 H iBu 3-F-Ph Ph 4-MeO-Ph NH
1-176 H iBu 4-F-Ph Ph 4-MeO-Ph NH
1-177 H iBu 3-CF₃-Ph Ph 4-MeO-Ph NH
1-178 H iBu 4-CF₃-Ph Ph 4-MeO-Ph NH
1-179 H iBu 3-CF₃O-Ph Ph 4-MeO-Ph NH
1-180 H iBu 4-CF₃O-Ph Ph 4-MeO-Ph NH
1-181 H iBu 3-HO-Ph Ph 4-MeO-Ph NH
1-182 H iBu 4-HO-Ph Ph 4-MeO-Ph NH
1-183 H iBu 3-HOCH₂-Ph Ph 4-MeO-Ph NH
1-184 H iBu 4-HOCH₂-Ph Ph 4-MeO-Ph NH
1-185 H iBu 3-H₂N-Ph Ph 4-MeO-Ph NH
1-186 H iBu 4-H₂N-Ph Ph 4-MeO-Ph NH
1-187 H iBu 2-Thi Ph 4-MeO-Ph NH
1-188 H iBu 3-Thi Ph 4-MeO-Ph NH
1-189 H iBu 2-Fur Ph 4-MeO-Ph NH
1-190 H iBu Br Bn 4-MeO-Ph NH
1-191 H iBu Ph Bn 4-MeO-Ph NH
1-192 H iBu 2-Me-Ph Bn 4-MeO-Ph NH
1-193 H iBu 3-Me-Ph Bn 4-MeO-Ph NH
1-194 H iBu 4-Me-Ph Bn 4-MeO-Ph NH
1-195 H iBu 2-MeO-Ph Bn 4-MeO-Ph NH
1-196 H iBu 3-MeO-Ph Bn 4-MeO-Ph NH
1-197 H iBu 4-MeO-Ph Bn 4-MeO-Ph NH
1-198 H iBu 2-Cl-Ph Bn 4-MeO-Ph NH
1-199 H iBu 3-Cl-Ph Bn 4-MeO-Ph NH
1-200 H iBu 4-Cl-Ph Bn 4-MeO-Ph NH
1-201 H iBu 2-F-Ph Bn 4-MeO-Ph NH
1-202 H iBu 3-F-Ph Bn 4-MeO-Ph NH
1-203 H iBu 4-F-Ph Bn 4-MeO-Ph NH
1-204 H iBu 3-CF₃-Ph Bn 4-MeO-Ph NH
1-205 H iBu 4-CF₃-Ph Bn 4-MeO-Ph NH
1-206 H iBu 3-CF₃O-Ph Bn 4-MeO-Ph NH
1-207 H iBu 4-CF₃O-Ph Bn 4-MeO-Ph NH
1-208 H iBu 3-HO-Ph Bn 4-MeO-Ph NH
1-209 H iBu 4-HO-Ph Bn 4-MeO-Ph NH
1-210 H iBu 3-HOCH₂-Ph Bn 4-MeO-Ph NH
1-211 H iBu 4-HOCH₂-Ph Bn 4-MeO-Ph NH
1-212 H iBu 3-H₂N-Ph Bn 4-MeO-Ph NH
1-213 H iBu 4-H₂N-Ph Bn 4-MeO-Ph NH
1-214 H iBu 2-Thi Bn 4-MeO-Ph NH
1-215 H iBu 3-Thi Bn 4-MeO-Ph NH
1-216 H iBu 2-Fur Bn 4-MeO-Ph NH
1-217 H iBu Br Phet 4-MeO-Ph NH
1-218 H iBu Ph Phet 4-MeO-Ph NH
1-219 H iBu 2-Me-Ph Phet 4-MeO-Ph NH
1-220 H iBu 3-Me-Ph Phet 4-MeO-Ph NH
1-221 H iBu 4-Me-Ph Phet 4-MeO-Ph NH
1-222 H iBu 2-MeO-Ph Phet 4-MeO-Ph NH
1-223 H iBu 3-MeO-Ph Phet 4-MeO-Ph NH
1-224 H iBu 4-MeO-Ph Phet 4-MeO-Ph NH
1-225 H iBu 2-Cl-Ph Phet 4-MeO-Ph NH
1-226 H iBu 3-Cl-Ph Phet 4-MeO-Ph NH
1-227 H iBu 4-Cl-Ph Phet 4-MeO-Ph NH
1-228 H iBu 2-F-Ph Phet 4-MeO-Ph NH
1-229 H iBu 3-F-Ph Phet 4-MeO-Ph NH
1-230 H iBu 4-F-Ph Phet 4-MeO-Ph NH
1-231 H iBu 3-CF₃-Ph Phet 4-MeO-Ph NH
1-232 H iBu 4-CF₃-Ph Phet 4-MeO-Ph NH
1-233 H iBu 3-CF₃O-Ph Phet 4-MeO-Ph NH
1-234 H iBu 4-CF₃O-Ph Phet 4-MeO-Ph NH
1-235 H iBu 3-HO-Ph Phet 4-MeO-Ph NH
1-236 H iBu 4-HO-Ph Phet 4-MeO-Ph NH
1-237 H iBu 3-HOCH₂-Ph Phet 4-MeO-Ph NH
1-238 H iBu 4-HOCH₂-Ph Phet 4-MeO-Ph NH
1-239 H iBu 3-H₂N-Ph Phet 4-MeO-Ph NH
1-240 H iBu 4-H₂N-Ph Phet 4-MeO-Ph NH
1-241 H iBu 2-Thi Phet 4-MeO-Ph NH
1-242 H iBu 3-Thi Phet 4-MeO-Ph NH
1-243 H iBu 2-Fur Phet 4-MeO-Ph NH
1-244 H iBu Br Me 4-BnO-Ph NH
1-245 H iBu Ph Me 4-BnO-Ph NH
1-246 H iBu 2-Me-Ph Me 4-BnO-Ph NH
1-247 H iBu 3-Me-Ph Me 4-BnO-Ph NH
1-248 H iBu 4-Me-Ph Me 4-BnO-Ph NH
1-249 H iBu 2-MeO-Ph Me 4-BnO-Ph NH
1-250 H iBu 3-MeO-Ph Me 4-BnO-Ph NH
1-251 H iBu 4-MeO-Ph Me 4-BnO-Ph NH
1-252 H iBu 2-Cl-Ph Me 4-BnO-Ph NH
1-253 H iBu 3-Cl-Ph Me 4-BnO-Ph NH
1-254 H iBu 4-Cl-Ph Me 4-BnO-Ph NH
1-255 H iBu 2-F-Ph Me 4-BnO-Ph NH
1-256 H iBu 3-F-Ph Me 4-BnO-Ph NH
1-257 H iBu 4-F-Ph Me 4-BnO-Ph NH
1-258 H iBu 3-CF₃-Ph Me 4-BnO-Ph NH
1-259 H iBu 4-CF₃-Ph Me 4-BnO-Ph NH
1-260 H iBu 3-CF₃O-Ph Me 4-BnO-Ph NH
1-261 H iBu 4-CF₃O-Ph Me 4-BnO-Ph NH
1-262 H iBu 3-HO-Ph Me 4-BnO-Ph NH
1-263 H iBu 4-HO-Ph Me 4-BnO-Ph NH
1-264 H iBu 3-HOCH₂-Ph Me 4-BnO-Ph NH
1-265 H iBu 4-HOCH₂-Ph Me 4-BnO-Ph NH
1-266 H iBu 3-H₂N-Ph Me 4-BnO-Ph NH
1-267 H iBu 4-H₂N-Ph Me 4-BnO-Ph NH
1-268 H iBu 2-Thi Me 4-BnO-Ph NH
1-269 H iBu 3-Thi Me 4-BnO-Ph NH
1-270 H iBu 2-Fur Me 4-BnO-Ph NH
1-271 H iBu Br Et 4-BnO-Ph NH
1-272 H iBu Ph Et 4-BnO-Ph NH
1-273 H iBu 2-Me-Ph Et 4-BnO-Ph NH
1-274 H iBu 3-Me-Ph Et 4-BnO-Ph NH
1-275 H iBu 4-Me-Ph Et 4-BnO-Ph NH
1-276 H iBu 2-MeO-Ph Et 4-BnO-Ph NH
1-277 H iBu 3-MeO-Ph Et 4-BnO-Ph NH
1-278 H iBu 4-MeO-Ph Et 4-BnO-Ph NH
1-279 H iBu 2-Cl-Ph Et 4-BnO-Ph NH
1-280 H iBu 3-Cl-Ph Et 4-BnO-Ph NH
1-281 H iBu 4-Cl-Ph Et 4-BnO-Ph NH
1-282 H iBu 2-F-Ph Et 4-BnO-Ph NH
1-283 H iBu 3-F-Ph Et 4-BnO-Ph NH
1-284 H iBu 4-F-Ph Et 4-BnO-Ph NH
1-285 H iBu 3-CF₃-Ph Et 4-BnO-Ph NH
1-286 H iBu 4-CF₃-Ph Et 4-BnO-Ph NH
1-287 H iBu 3-CF₃O-Ph Et 4-BnO-Ph NH
1-288 H iBu 4-CF₃O-Ph Et 4-BnO-Ph NH
1-289 H iBu 3-HO-Ph Et 4-BnO-Ph NH
1-290 H iBu 4-HO-Ph Et 4-BnO-Ph NH
1-291 H iBu 3-HOCH₂-Ph Et 4-BnO-Ph NH
1-292 H iBu 4-HOCH₂-Ph Et 4-BnO-Ph NH
1-293 H iBu 3-H₂N-Ph Et 4-BnO-Ph NH
1-294 H iBu 4-H₂N-Ph Et 4-BnO-Ph NH
1-295 H iBu 2-Thi Et 4-BnO-Ph NH
1-296 H iBu 3-Thi Et 4-BnO-Ph NH
1-297 H iBu 2-Fur Et 4-BnO-Ph NH
1-298 H iBu Br Pr 4-BnO-Ph NH
1-299 H iBu Ph Pr 4-BnO-Ph NH
1-300 H iBu 2-Me-Ph Pr 4-BnO-Ph NH
1-301 H iBu 3-Me-Ph Pr 4-BnO-Ph NH
1-302 H iBu 4-Me-Ph Pr 4-BnO-Ph NH
1-303 H iBu 2-MeO-Ph Pr 4-BnO-Ph NH
1-304 H iBu 3-MeO-Ph Pr 4-BnO-Ph NH
1-305 H iBu 4-MeO-Ph Pr 4-BnO-Ph NH
1-306 H iBu 2-Cl-Ph Pr 4-BnO-Ph NH
1-307 H iBu 3-Cl-Ph Pr 4-BnO-Ph NH
1-308 H iBu 4-Cl-Ph Pr 4-BnO-Ph NH
1-309 H iBu 2-F-Ph Pr 4-BnO-Ph NH
1-310 H iBu 3-F-Ph Pr 4-BnO-Ph NH
1-311 H iBu 4-F-Ph Pr 4-BnO-Ph NH
1-312 H iBu 3-CF₃-Ph Pr 4-BnO-Ph NH
1-313 H iBu 4-CF₃-Ph Pr 4-BnO-Ph NH
1-314 H iBu 3-CF₃O-Ph Pr 4-BnO-Ph NH
1-315 H iBu 4-CF₃O-Ph Pr 4-BnO-Ph NH
1-316 H iBu 3-HO-Ph Pr 4-BnO-Ph NH
1-317 H iBu 4-HO-Ph Pr 4-BnO-Ph NH
1-318 H iBu 3-HOCH₂-Ph Pr 4-BnO-Ph NH
1-319 H iBu 4-HOCH₂-Ph Pr 4-BnO-Ph NH
1-320 H iBu 3-H₂N-Ph Pr 4-BnO-Ph NH
1-321 H iBu 4-H₂N-Ph Pr 4-BnO-Ph NH
1-322 H iBu 2-Thi Pr 4-BnO-Ph NH
1-323 H iBu 3-Thi Pr 4-BnO-Ph NH
1-324 H iBu 2-Fur Pr 4-BnO-Ph NH
1-325 H iBu Br Bu 4-BnO-Ph NH
1-326 H iBu Ph Bu 4-BnO-Ph NH
1-327 H iBu 2-Me-Ph Bu 4-BnO-Ph NH
1-328 H iBu 3-Me-Ph Bu 4-BnO-Ph NH
1-329 H iBu 4-Me-Ph Bu 4-BnO-Ph NH
1-330 H iBu 2-MeO-Ph Bu 4-BnO-Ph NH
1-331 H iBu 3-MeO-Ph Bu 4-BnO-Ph NH
1-332 H iBu 4-MeO-Ph Bu 4-BnO-Ph NH
1-333 H iBu 2-Cl-Ph Bu 4-BnO-Ph NH
1-334 H iBu 3-Cl-Ph Bu 4-BnO-Ph NH
1-335 H iBu 4-Cl-Ph Bu 4-BnO-Ph NH
1-336 H iBu 2-F-Ph Bu 4-BnO-Ph NH
1-337 H iBu 3-F-Ph Bu 4-BnO-Ph NH
1-338 H iBu 4-F-Ph Bu 4-BnO-Ph NH
1-339 H iBu 3-CF₃-Ph Bu 4-BnO-Ph NH
1-340 H iBu 4-CF₃-Ph Bu 4-BnO-Ph NH
1-341 H iBu 3-CF₃O-Ph Bu 4-BnO-Ph NH
1-342 H iBu 4-CF₃O-Ph Bu 4-BnO-Ph NH
1-343 H iBu 3-HO-Ph Bu 4-BnO-Ph NH
1-344 H iBu 4-HO-Ph Bu 4-BnO-Ph NH
1-345 H iBu 3-HOCH₂-Ph Bu 4-BnO-Ph NH
1-346 H iBu 4-HOCH₂-Ph Bu 4-BnO-Ph NH
1-347 H iBu 3-H₂N-Ph Bu 4-BnO-Ph NH
1-348 H iBu 4-H₂N-Ph Bu 4-BnO-Ph NH
1-349 H iBu 2-Thi Bu 4-BnO-Ph NH
1-350 H iBu 3-Thi Bu 4-BnO-Ph NH
1-351 H iBu 2-Fur Bu 4-BnO-Ph NH
1-352 H iBu HO Me 4-MeO-Ph NH
1-353 H iBu MeO Me 4-MeO-Ph NH
1-354 H iBu EtO Me 4-MeO-Ph NH
1-355 H iBu PrO Me 4-MeO-Ph NH
1-356 H iBu BuO Me 4-MeO-Ph NH
1-357 H iBu BnO Me 4-MeO-Ph NH
1-358 H iBu iPrO Me 4-MeO-Ph NH
1-359 H iBu iBuO Me 4-MeO-Ph NH
1-360 H iBu tBuO Me 4-MeO-Ph NH
1-361 H iBu HOC(O) Me 4-MeO-Ph NH
1-362 H iBu MeOC(O) Me 4-MeO-Ph NH
1-363 H iBu Me₂N-CO Me 4-MeO-Ph NH
1-364 H iBu 2,3-diMe-Ph Me 4-MeO-Ph NH
1-365 H iBu 2,5-diMe-Ph Me 4-MeO-Ph NH
1-366 H iBu 2,6-diMe-Ph Me 4-MeO-Ph NH
1-367 H iBu 3,5-diMe-Ph Me 4-MeO-Ph NH
1-368 H iBu 2,4-di(MeO)-Ph Me 4-MeO-Ph NH
1-369 H iBu 2,5-di(MeO)-Ph Me 4-MeO-Ph NH
1-370 H iBu 2,6-di(MeO)-Ph Me 4-MeO-Ph NH
1-371 H iBu 3,4-di(MeO)-Ph Me 4-MeO-Ph NH
1-372 H iBu 2,5-diCl-Ph Me 4-MeO-Ph NH
1-373 H iBu 3,4-diCl-Ph Me 4-MeO-Ph NH
1-374 H iBu 2-MeO-5-Cl-Ph Me 4-MeO-Ph NH
1-375 H iBu 2,4-diF-Ph Me 4-MeO-Ph NH
1-376 H iBu 2,5-diF-Ph Me 4-MeO-Ph NH
1-377 H iBu 2,6-diF-Ph Me 4-MeO-Ph NH
1-378 H iBu 3,4-diF-Ph Me 4-MeO-Ph NH
1-379 H iBu 3,5-diF-Ph Me 4-MeO-Ph NH
1-380 H iBu 2,3,4,5,6-pentaF-Ph Me 4-MeO-Ph NH
1-381 H iBu 3-Cl-4-F-Ph Me 4-MeO-Ph NH
1-382 H iBu 3-Me-4-F-Ph Me 4-MeO-Ph NH
1-383 H iBu 2-MeO-5-F-Ph Me 4-MeO-Ph NH
1-384 H iBu 2-CF₃-Ph Me 4-MeO-Ph NH
1-385 H iBu 3,5-di(CF₃)-Ph Me 4-MeO-Ph NH
1-386 H iBu 2-HO-Ph Me 4-MeO-Ph NH
1-387 H iBu 2-HOCH₂-Ph Me 4-MeO-Ph NH
1-388 H iBu 2-H₂N-Ph Me 4-MeO-Ph NH
1-389 H iBu 3-NO₂-Ph Me 4-MeO-Ph NH
1-390 H iBu 3-CN-Ph Me 4-MeO-Ph NH
1-391 H iBu 2-HCO-Ph Me 4-MeO-Ph NH
1-392 H iBu 3-HCO-Ph Me 4-MeO-Ph NH
1-393 H iBu 4-HCO-Ph Me 4-MeO-Ph NH
1-394 H iBu 3-HOOC-Ph Me 4-MeO-Ph NH
1-395 H iBu 4-HOOC-Ph Me 4-MeO-Ph NH
1-396 H iBu 3,4-(-OCH₂O-)-Ph Me 4-MeO-Ph NH
1-397 H iBu 4-MeS-Ph Me 4-MeO-Ph NH
1-398 H iBu 3-Ac-Ph Me 4-MeO-Ph NH
1-399 H iBu 4-Ac-Ph Me 4-MeO-Ph NH
1-400 H iBu 1-Nph Me 4-MeO-Ph NH
1-401 H iBu 2-Nph Me 4-MeO-Ph NH
1-402 H iBu 4-tBu-Ph Me 4-MeO-Ph NH
1-403 H iBu 5-Cl-2-Thi Me 4-MeO-Ph NH
1-404 H iBu 5-Me-2-Thi Me 4-MeO-Ph NH
1-405 H iBu 1-Boc-2-Pyro Me 4-MeO-Ph NH
1-406 H iBu 2-Bzfur Me 4-MeO-Ph NH
1-407 H iBu 2-Py Me 4-MeO-Ph NH
1-408 H iBu 3-Py Me 4-MeO-Ph NH
1-409 H iBu 4-Py Me 4-MeO-Ph NH
1-410 H iBu HO Et 4-MeO-Ph NH
1-411 H iBu MeO Et 4-MeO-Ph NH
1-412 H iBu EtO Et 4-MeO-Ph NH
1-413 H iBu PrO Et 4-MeO-Ph NH
1-414 H iBu BuO Et 4-MeO-Ph NH
1-415 H iBu BnO Et 4-MeO-Ph NH
1-416 H iBu iPrO Et 4-MeO-Ph NH
1-417 H iBu iBuO Et 4-MeO-Ph NH
1-418 H iBu tBuO Et 4-MeO-Ph NH
1-419 H iBu HOC(O) Et 4-MeO-Ph NH
1-420 H iBu MeOC(O) Et 4-MeO-Ph NH
1-421 H iBu Me₂N-CO Et 4-MeO-Ph NH
1-422 H iBu 2,3-diMe-Ph Et 4-MeO-Ph NH
1-423 H iBu 2,5-diMe-Ph Et 4-MeO-Ph NH
1-424 H iBu 2,6-diMe-Ph Et 4-MeO-Ph NH
1-425 H iBu 3,5-diMe-Ph Et 4-MeO-Ph NH
1-426 H iBu 2,4-di(MeO)-Ph Et 4-MeO-Ph NH
1-427 H iBu 2,5-di(MeO)-Ph Et 4-MeO-Ph NH
1-428 H iBu 2,6-di(MeO)-Ph Et 4-MeO-Ph NH
1-429 H iBu 3,4-di(MeO)-Ph Et 4-MeO-Ph NH
1-430 H iBu 2,5-diCl-Ph Et 4-MeO-Ph NH
1-431 H iBu 3,4-diCl-Ph Et 4-MeO-Ph NH
1-432 H iBu 2-MeO-5-Cl-Ph Et 4-MeO-Ph NH
1-433 H iBu 2,4-diF-Ph Et 4-MeO-Ph NH
1-434 H iBu 2,5-diF-Ph Et 4-MeO-Ph NH
1-435 H iBu 2,6-diF-Ph Et 4-MeO-Ph NH
1-436 H iBu 3,4-diF-Ph Et 4-MeO-Ph NH
1-437 H iBu 3,5-diF-Ph Et 4-MeO-Ph NH
1-438 H iBu 2,3,4,5,6-pentaF-Ph Et 4-MeO-Ph NH
1-439 H iBu 3-Cl-4-F-Ph Et 4-MeO-Ph NH
1-440 H iBu 3-Me-4-F-Ph Et 4-MeO-Ph NH
1-441 H iBu 2-MeO-5-F-Ph Et 4-MeO-Ph NH
1-442 H iBu 2-CF₃-Ph Et 4-MeO-Ph NH
1-443 H iBu 3,5-di(CF₃)-Ph Et 4-MeO-Ph NH
1-444 H iBu 2-HO-Ph Et 4-MeO-Ph NH
1-445 H iBu 2-HOCH₂-Ph Et 4-MeO-Ph NH
1-446 H iBu 2-H₂N-Ph Et 4-MeO-Ph NH
1-447 H iBu 3-NO₂-Ph Et 4-MeO-Ph NH
1-448 H iBu 3-CN-Ph Et 4-MeO-Ph NH
1-449 H iBu 2-HCO-Ph Et 4-MeO-Ph NH
1-450 H iBu 3-HCO-Ph Et 4-MeO-Ph NH
1-451 H iBu 4-HCO-Ph Et 4-MeO-Ph NH
1-452 H iBu 3-HOOC-Ph Et 4-MeO-Ph NH
1-453 H iBu 4-HOOC-Ph Et 4-MeO-Ph NH
1-454 H iBu 3,4-(-OCH₂O-)-Ph Et 4-MeO-Ph NH
1-455 H iBu 4-MeS-Ph Et 4-MeO-Ph NH
1-456 H iBu 3-Ac-Ph Et 4-MeO-Ph NH
1-457 H iBu 4-Ac-Ph Et 4-MeO-Ph NH
1-458 H iBu 1-Nph Et 4-MeO-Ph NH
1-459 H iBu 2-Nph Et 4-MeO-Ph NH
1-460 H iBu 4-tBu-Ph Et 4-MeO-Ph NH
1-461 H iBu 5-Cl-2-Thi Et 4-MeO-Ph NH
1-462 H iBu 5-Me-2-Thi Et 4-MeO-Ph NH
1-463 H iBu 1-Boc-2-Pyro Et 4-MeO-Ph NH
1-464 H iBu 2-Bzfur Et 4-MeO-Ph NH
1-465 H iBu 2-Py Et 4-MeO-Ph NH
1-466 H iBu 3-Py Et 4-MeO-Ph NH
1-467 H iBu 4-Py Et 4-MeO-Ph NH
1-468 H iBu HO Pr 4-MeO-Ph NH
1-469 H iBu MeO Pr 4-MeO-Ph NH
1-470 H iBu EtO Pr 4-MeO-Ph NH
1-471 H iBu PrO Pr 4-MeO-Ph NH
1-472 H iBu BuO Pr 4-MeO-Ph NH
1-473 H iBu BnO Pr 4-MeO-Ph NH
1-474 H iBu iPrO Pr 4-MeO-Ph NH
1-475 H iBu iBuO Pr 4-MeO-Ph NH
1-476 H iBu tBuO Pr 4-MeO-Ph NH
1-477 H iBu HOC(O) Pr 4-MeO-Ph NH
1-478 H iBu MeOC(O) Pr 4-MeO-Ph NH
1-479 H iBu Me₂N-CO Pr 4-MeO-Ph NH
1-480 H iBu 2,3-diMe-Ph Pr 4-MeO-Ph NH
1-481 H iBu 2,5-diMe-Ph Pr 4-MeO-Ph NH
1-482 H iBu 2,6-diMe-Ph Pr 4-MeO-Ph NH
1-483 H iBu 3,5-diMe-Ph Pr 4-MeO-Ph NH
1-484 H iBu 2,4-di(MeO)-Ph Pr 4-MeO-Ph NH
1-485 H iBu 2,5-di(MeO)-Ph Pr 4-MeO-Ph NH
1-486 H iBu 2,6-di(MeO)-Ph Pr 4-MeO-Ph NH
1-487 H iBu 3,4-di(MeO)-Ph Pr 4-MeO-Ph NH
1-488 H iBu 2,5-diCl-Ph Pr 4-MeO-Ph NH
1-489 H iBu 3,4-diCl-Ph Pr 4-MeO-Ph NH
1-490 H iBu 2-MeO-5-Cl-Ph Pr 4-MeO-Ph NH
1-491 H iBu 2,4-diF-Ph Pr 4-MeO-Ph NH
1-492 H iBu 2,5-diF-Ph Pr 4-MeO-Ph NH
1-493 H iBu 2,6-diF-Ph Pr 4-MeO-Ph NH
1-494 H iBu 3,4-diF-Ph Pr 4-MeO-Ph NH
1-495 H iBu 3,5-diF-Ph Pr 4-MeO-Ph NH
1-496 H iBu 2,3,4,5,6-pentaF-Ph Pr 4-MeO-Ph NH
1-497 H iBu 3-Cl-4-F-Ph Pr 4-MeO-Ph NH
1-498 H iBu 3-Me-4-F-Ph Pr 4-MeO-Ph NH
1-499 H iBu 2-MeO-5-F-Ph Pr 4-MeO-Ph NH
1-500 H iBu 2-CF₃-Ph Pr 4-MeO-Ph NH
1-501 H iBu 3,5-di(CF₃)-Ph Pr 4-MeO-Ph NH
1-502 H iBu 2-HO-Ph Pr 4-MeO-Ph NH
1-503 H iBu 2-HOCH₂-Ph Pr 4-MeO-Ph NH
1-504 H iBu 2-H₂N-Ph Pr 4-MeO-Ph NH
1-505 H iBu 3-NO₂-Ph Pr 4-MeO-Ph NH
1-506 H iBu 3-CN-Ph Pr 4-MeO-Ph NH
1-507 H iBu 2-HCO-Ph Pr 4-MeO-Ph NH
1-508 H iBu 3-HCO-Ph Pr 4-MeO-Ph NH
1-509 H iBu 4-HCO-Ph Pr 4-MeO-Ph NH
1-510 H iBu 3-HOOC-Ph Pr 4-MeO-Ph NH
1-511 H iBu 4-HOOC-Ph Pr 4-MeO-Ph NH
1-512 H iBu 3,4-(-OCH₂O-)-Ph Pr 4-MeO-Ph NH
1-513 H iBu 4-MeS-Ph Pr 4-MeO-Ph NH
1-514 H iBu 3-Ac-Ph Pr 4-MeO-Ph NH
1-515 H iBu 4-Ac-Ph Pr 4-MeO-Ph NH
1-516 H iBu 1-Nph Pr 4-MeO-Ph NH
1-517 H iBu 2-Nph Pr 4-MeO-Ph NH
1-518 H iBu 4-tBu-Ph Pr 4-MeO-Ph NH
1-519 H iBu 5-Cl-2-Thi Pr 4-MeO-Ph NH
1-520 H iBu 5-Me-2-Thi Pr 4-MeO-Ph NH
1-521 H iBu 1-Boc-2-Pyro Pr 4-MeO-Ph NH
1-522 H iBu 2-Bzfur Pr 4-MeO-Ph NH
1-523 H iBu 2-Py Pr 4-MeO-Ph NH
1-524 H iBu 3-Py Pr 4-MeO-Ph NH
1-525 H iBu 4-Py Pr 4-MeO-Ph NH
1-526 H iBu HO Bu 4-MeO-Ph NH
1-527 H iBu MeO Bu 4-MeO-Ph NH
1-528 H iBu EtO Bu 4-MeO-Ph NH
1-529 H iBu PrO Bu 4-MeO-Ph NH
1-530 H iBu BuO Bu 4-MeO-Ph NH
1-531 H iBu BnO Bu 4-MeO-Ph NH
1-532 H iBu iPrO Bu 4-MeO-Ph NH
1-533 H iBu iBuO Bu 4-MeO-Ph NH
1-534 H iBu tBuO Bu 4-MeO-Ph NH
1-535 H iBu HOC(O) Bu 4-MeO-Ph NH
1-536 H iBu MeOC(O) Bu 4-MeO-Ph NH
1-537 H iBu Me₂N-CO Bu 4-MeO-Ph NH
1-538 H iBu 2,3-diMe-Ph Bu 4-MeO-Ph NH
1-539 H iBu 2,5-diMe-Ph Bu 4-MeO-Ph NH
1-540 H iBu 2,6-diMe-Ph Bu 4-MeO-Ph NH
1-541 H iBu 3,5-diMe-Ph Bu 4-MeO-Ph NH
1-542 H iBu 2,4-di(MeO)-Ph Bu 4-MeO-Ph NH
1-543 H iBu 2,5-di(MeO)-Ph Bu 4-MeO-Ph NH
1-544 H iBu 2,6-di(MeO)-Ph Bu 4-MeO-Ph NH
1-545 H iBu 3,4-di(MeO)-Ph Bu 4-MeO-Ph NH
1-546 H iBu 2,5-diCl-Ph Bu 4-MeO-Ph NH
1-547 H iBu 3,4-diCl-Ph Bu 4-MeO-Ph NH
1-548 H iBu 2-MeO-5-Cl-Ph Bu 4-MeO-Ph NH
1-549 H iBu 2,4-diF-Ph Bu 4-MeO-Ph NH
1-550 H iBu 2,5-diF-Ph Bu 4-MeO-Ph NH
1-551 H iBu 2,6-diF-Ph Bu 4-MeO-Ph NH
1-552 H iBu 3,4-diF-Ph Bu 4-MeO-Ph NH
1-553 H iBu 3,5-diF-Ph Bu 4-MeO-Ph NH
1-554 H iBu 2,3,4,5,6-pentaF-Ph Bu 4-MeO-Ph NH
1-555 H iBu 3-Cl-4-F-Ph Bu 4-MeO-Ph NH
1-556 H iBu 3-Me-4-F-Ph Bu 4-MeO-Ph NH
1-557 H iBu 2-MeO-5-F-Ph Bu 4-MeO-Ph NH
1-558 H iBu 2-CF₃-Ph Bu 4-MeO-Ph NH
1-559 H iBu 3,5-di(CF₃)-Ph Bu 4-MeO-Ph NH
1-560 H iBu 2-HO-Ph Bu 4-MeO-Ph NH
1-561 H iBu 2-HOCH₂-Ph Bu 4-MeO-Ph NH
1-562 H iBu 2-H₂N-Ph Bu 4-MeO-Ph NH
1-563 H iBu 3-NO₂-Ph Bu 4-MeO-Ph NH
1-564 H iBu 3-CN-Ph Bu 4-MeO-Ph NH
1-565 H iBu 2-HCO-Ph Bu 4-MeO-Ph NH
1-566 H iBu 3-HCO-Ph Bu 4-MeO-Ph NH
1-567 H iBu 4-HCO-Ph Bu 4-MeO-Ph NH
1-568 H iBu 3-HOOC-Ph Bu 4-MeO-Ph NH
1-569 H iBu 4-HOOC-Ph Bu 4-MeO-Ph NH
1-570 H iBu 3,4-(-OCH₂O-)-Ph Bu 4-MeO-Ph NH
1-571 H iBu 4-MeS-Ph Bu 4-MeO-Ph NH
1-572 H iBu 3-Ac-Ph Bu 4-MeO-Ph NH
1-573 H iBu 4-Ac-Ph Bu 4-MeO-Ph NH
1-574 H iBu 1-Nph Bu 4-MeO-Ph NH
1-575 H iBu 2-Nph Bu 4-MeO-Ph NH
1-576 H iBu 4-tBu-Ph Bu 4-MeO-Ph NH
1-577 H iBu 5-Cl-2-Thi Bu 4-MeO-Ph NH
1-578 H iBu 5-Me-2-Thi Bu 4-MeO-Ph NH
1-579 H iBu 1-Boc-2-Pyro Bu 4-MeO-Ph NH
1-580 H iBu 2-Bzfur Bu 4-MeO-Ph NH
1-581 H iBu 2-Py Bu 4-MeO-Ph NH
1-582 H iBu 3-Py Bu 4-MeO-Ph NH
1-583 H iBu 4-Py Bu 4-MeO-Ph NH
---------------------------------------------------------
Exemplary Compound Table 1
-------------------------------------------------- -------
Compound number R¹ R² RR⁴ Ar X
-------------------------------------------------- -------
1-1 H iBu Br Me 4-MeO-Ph NH
1-2 H iBu Ph Me 4-MeO-Ph NH
1-3 H iBu 2-Me-Ph Me 4-MeO-Ph NH
1-4 H iBu 3-Me-Ph Me 4-MeO-Ph NH
1-5 H iBu 4-Me-Ph Me 4-MeO-Ph NH
1-6 H iBu 2-MeO-Ph Me 4-MeO-Ph NH
1-7 H iBu 3-MeO-Ph Me 4-MeO-Ph NH
1-8 H iBu 4-MeO-Ph Me 4-MeO-Ph NH
1-9 H iBu 2-Cl-Ph Me 4-MeO-Ph NH
1-10 H iBu 3-Cl-Ph Me 4-MeO-Ph NH
1-11 H iBu 4-Cl-Ph Me 4-MeO-Ph NH
1-12 H iBu 2-F-Ph Me 4-MeO-Ph NH
1-13 H iBu 3-F-Ph Me 4-MeO-Ph NH
1-14 H iBu 4-F-Ph Me 4-MeO-Ph NH
1-15 H iBu 3-CF₃ -Ph Me 4-MeO-Ph NH
1-16 H iBu 4-CF₃ -Ph Me 4-MeO-Ph NH
1-17 H iBu 3-CF₃ O-Ph Me 4-MeO-Ph NH
1-18 H iBu 4-CF₃ O-Ph Me 4-MeO-Ph NH
1-19 H iBu 3-HO-Ph Me 4-MeO-Ph NH
1-20 H iBu 4-HO-Ph Me 4-MeO-Ph NH
1-21 H iBu 3-HOCH₂ -Ph Me 4-MeO-Ph NH
1-22 H iBu 4-HOCH₂ -Ph Me 4-MeO-Ph NH
1-23 H iBu 3-H₂ N-Ph Me 4-MeO-Ph NH
1-24 H iBu 4-H₂ N-Ph Me 4-MeO-Ph NH
1-25 H iBu 2-Thi Me 4-MeO-Ph NH
1-26 H iBu 3-Thi Me 4-MeO-Ph NH
1-27 H iBu 2-Fur Me 4-MeO-Ph NH
1-28 H iBu Br Et 4-MeO-Ph NH
1-29 H iBu Ph Et 4-MeO-Ph NH
1-30 H iBu 2-Me-Ph Et 4-MeO-Ph NH
1-31 H iBu 3-Me-Ph Et 4-MeO-Ph NH
1-32 H iBu 4-Me-Ph Et 4-MeO-Ph NH
1-33 H iBu 2-MeO-Ph Et 4-MeO-Ph NH
1-34 H iBu 3-MeO-Ph Et 4-MeO-Ph NH
1-35 H iBu 4-MeO-Ph Et 4-MeO-Ph NH
1-36 H iBu 2-Cl-Ph Et 4-MeO-Ph NH
1-37 H iBu 3-Cl-Ph Et 4-MeO-Ph NH
1-38 H iBu 4-Cl-Ph Et 4-MeO-Ph NH
1-39 H iBu 2-F-Ph Et 4-MeO-Ph NH
1-40 H iBu 3-F-Ph Et 4-MeO-Ph NH
1-41 H iBu 4-F-Ph Et 4-MeO-Ph NH
1-42 H iBu 3-CF₃ -Ph Et 4-MeO-Ph NH
1-43 H iBu 4-CF₃ -Ph Et 4-MeO-Ph NH
1-44 HiBu 3-CF₃ O-Ph Et 4-MeO-Ph NH
1-45 H iBu 4-CF₃ O-Ph Et 4-MeO-Ph NH
1-46 H iBu 3-HO-Ph Et 4-MeO-Ph NH
1-47 H iBu 4-HO-Ph Et 4-MeO-Ph NH
1-48 H iBu 3-HOCH₂ -Ph Et 4-MeO-Ph NH
1-49 H iBu 4-HOCH₂ -Ph Et 4-MeO-Ph NH
1-50 H iBu 3-H₂ N-Ph Et 4-MeO-Ph NH
1-51 H iBu 4-H₂ N-Ph Et 4-MeO-Ph NH
1-52 H iBu 2-Thi Et 4-MeO-Ph NH
1-53 H iBu 3-Thi Et 4-MeO-Ph NH
1-54 H iBu 2-Fur Et 4-MeO-Ph NH
1-55 H iBu Br Pr 4-MeO-Ph NH
1-56 H iBu Ph Pr 4-MeO-Ph NH
1-57 H iBu 2-Me-Ph Pr 4-MeO-Ph NH
1-58 H iBu 3-Me-Ph Pr 4-MeO-Ph NH
1-59 H iBu 4-Me-Ph Pr 4-MeO-Ph NH
1-60 H iBu 2-MeO-Ph Pr 4-MeO-Ph NH
1-61 H iBu 3-MeO-Ph Pr 4-MeO-Ph NH
1-62 H iBu 4-MeO-Ph Pr 4-MeO-Ph NH
1-63 H iBu 2-Cl-Ph Pr 4-MeO-Ph NH
1-64 H iBu 3-Cl-Ph Pr 4-MeO-Ph NH
1-65 H iBu 4-Cl-Ph Pr 4-MeO-Ph NH
1-66 H iBu 2-F-Ph Pr 4-MeO-Ph NH
1-67 H iBu 3-F-Ph Pr 4-MeO-Ph NH
1-68 H iBu 4-F-Ph Pr 4-MeO-Ph NH
1-69 H iBu 3-CF₃ -Ph Pr 4-MeO-Ph NH
1-70 H iBu 4-CF₃ -Ph Pr 4-MeO-Ph NH
1-71 H iBu 3-CF₃ O-Ph Pr 4-MeO-Ph NH
1-72 H iBu 4-CF₃ O-Ph Pr 4-MeO-Ph NH
1-73 H iBu 3-HO-Ph Pr 4-MeO-Ph NH
1-74 H iBu 4-HO-Ph Pr 4-MeO-Ph NH
1-75 H iBu 3-HOCH₂ -Ph Pr 4-MeO-Ph NH
1-76 H iBu 4-HOCH₂ -Ph Pr 4-MeO-Ph NH
1-77 H iBu 3-H₂ N-Ph Pr 4-MeO-Ph NH
1-78 H iBu 4-H₂ N-Ph Pr 4-MeO-Ph NH
1-79 H iBu 2-Thi Pr 4-MeO-Ph NH
1-80 H iBu 3-Thi Pr 4-MeO-Ph NH
1-81 H iBu 2-Fur Pr 4-MeO-Ph NH
1-82 H iBu Br Bu 4-MeO-Ph NH
1-83 H iBu Ph Bu 4-MeO-Ph NH
1-84 H iBu 2-Me-Ph Bu 4-MeO-Ph NH
1-85 H iBu 3-Me-Ph Bu 4-MeO-Ph NH
1-86 H iBu 4-Me-Ph Bu 4-MeO-Ph NH
1-87 H iBu 2-MeO-Ph Bu 4-MeO-Ph NH
1-88 H iBu 3-MeO-Ph Bu 4-MeO-Ph NH
1-89 H iBu 4-MeO-Ph Bu 4-MeO-Ph NH
1-90 H iBu 2-Cl-Ph Bu 4-MeO-Ph NH
1-91 H iBu 3-Cl-Ph Bu 4-MeO-Ph NH
1-92 H iBu 4-Cl-Ph Bu 4-MeO-Ph NH
1-93 H iBu 2-F-Ph Bu 4-MeO-Ph NH
1-94 H iBu 3-F-Ph Bu 4-MeO-Ph NH
1-95 H iBu 4-F-Ph Bu 4-MeO-Ph NH
1-96 H iBu 3-CF₃ -Ph Bu 4-MeO-Ph NH
1-97 H iBu 4-CF₃ -Ph Bu 4-MeO-Ph NH
1-98 H iBu 3-CF₃ O-Ph Bu 4-MeO-Ph NH
1-99 H iBu 4-CF₃ O-Ph Bu 4-MeO-Ph NH
1-100 H iBu 3-HO-Ph Bu 4-MeO-Ph NH
1-101 H iBu 4-HO-Ph Bu 4-MeO-Ph NH
1-102 H iBu 3-HOCH₂ -Ph Bu 4-MeO-Ph NH
1-103 H iBu 4-HOCH₂ -Ph Bu 4-MeO-Ph NH
1-104 H iBu 3-H₂ N-Ph Bu 4-MeO-Ph NH
1-105 H iBu 4-H₂ N-Ph Bu 4-MeO-Ph NH
1-106 H iBu 2-Thi Bu 4-MeO-Ph NH
1-107 H iBu 3-Thi Bu 4-MeO-Ph NH
1-108 H iBu 2-Fur Bu 4-MeO-Ph NH
1-109 H iBu Br iPr 4-MeO-Ph NH
1-110 H iBu Ph iPr 4-MeO-Ph NH
1-111 H iBu 2-Me-Ph iPr 4-MeO-Ph NH
1-112 H iBu 3-Me-Ph iPr 4-MeO-Ph NH
1-113 H iBu 4-Me-Ph iPr 4-MeO-Ph NH
1-114 H iBu 2-MeO-Ph iPr 4-MeO-Ph NH
1-115 H iBu 3-MeO-Ph iPr 4-MeO-Ph NH
1-116 H iBu 4-MeO-Ph iPr 4-MeO-Ph NH
1-117 H iBu 2-Cl-Ph iPr 4-MeO-Ph NH
1-118 H iBu 3-Cl-Ph iPr 4-MeO-Ph NH
1-119 H iBu 4-Cl-Ph iPr 4-MeO-Ph NH
1-120 H iBu 2-F-Ph iPr 4-MeO-Ph NH
1-121 H iBu 3-F-Ph iPr 4-MeO-Ph NH
1-122 H iBu 4-F-Ph iPr 4-MeO-Ph NH
1-123 H iBu 3-CF₃ -Ph iPr 4-MeO-Ph NH
1-124 H iBu 4-CF₃ -Ph iPr 4-MeO-Ph NH
1-125 H iBu 3-CF₃ O-Ph iPr 4-MeO-Ph NH
1-126 H iBu 4-CF₃ O-Ph iPr 4-MeO-Ph NH
1-127 H iBu 3-HO-Ph iPr 4-MeO-Ph NH
1-128 H iBu 4-HO-Ph iPr 4-MeO-Ph NH
1-129 H iBu 3-HOCH₂ -Ph iPr 4-MeO-Ph NH
1-130 H iBu 4-HOCH₂ -Ph iPr 4-MeO-Ph NH
1-131 H iBu 3-H₂ N-Ph iPr 4-MeO-Ph NH
1-132 H iBu 4-H₂ N-Ph iPr 4-MeO-Ph NH
1-133 H iBu 2-Thi iPr 4-MeO-Ph NH
1-134 H iBu 3-Thi iPr 4-MeO-Ph NH
1-135 H iBu 2-Fur iPr 4-MeO-Ph NH
1-136 H iBu Br iBu 4-MeO-Ph NH
1-137 H iBu Ph iBu 4-MeO-Ph NH
1-138 H iBu 2-Me-Ph iBu 4-MeO-Ph NH
1-139 H iBu 3-Me-Ph iBu 4-MeO-Ph NH
1-140 H iBu 4-Me-Ph iBu 4-MeO-Ph NH
1-141 H iBu 2-MeO-Ph iBu 4-MeO-Ph NH
1-142 H iBu 3-MeO-Ph iBu 4-MeO-Ph NH
1-143 H iBu 4-MeO-Ph iBu 4-MeO-Ph NH
1-144 H iBu 2-Cl-Ph iBu 4-MeO-Ph NH
1-145 H iBu 3-Cl-Ph iBu 4-MeO-Ph NH
1-146 H iBu 4-Cl-Ph iBu 4-MeO-Ph NH
1-147 H iBu 2-F-Ph iBu 4-MeO-Ph NH
1-148 H iBu 3-F-Ph iBu 4-MeO-Ph NH
1-149 H iBu 4-F-Ph iBu 4-MeO-Ph NH
1-150 H iBu 3-CF₃ -Ph iBu 4-MeO-Ph NH
1-151 H iBu 4-CF₃ -Ph iBu 4-MeO-Ph NH
1-152 H iBu 3-CF₃ O-Ph iBu 4-MeO-Ph NH
1-153 H iBu 4-CF₃ O-Ph iBu 4-MeO-Ph NH
1-154 H iBu 3-HO-Ph iBu 4-MeO-Ph NH
1-155 H iBu 4-HO-Ph iBu 4-MeO-Ph NH
1-156 H iBu 3-HOCH₂ -Ph iBu 4-MeO-Ph NH
1-157 H iBu 4-HOCH₂ -Ph iBu 4-MeO-Ph NH
1-158 H iBu 3-H₂ N-Ph iBu 4-MeO-Ph NH
1-159 H iBu 4-H₂ N-Ph iBu 4-MeO-Ph NH
1-160 H iBu 2-Thi iBu 4-MeO-Ph NH
1-161 H iBu 3-Thi iBu 4-MeO-Ph NH
1-162 H iBu 2-Fur iBu 4-MeO-Ph NH
1-163 H iBu Br Ph 4-MeO-Ph NH
1-164 H iBu Ph Ph 4-MeO-Ph NH
1-165 H iBu 2-Me-Ph Ph 4-MeO-Ph NH
1-166 H iBu 3-Me-Ph Ph 4-MeO-Ph NH
1-167 H iBu 4-Me-Ph Ph 4-MeO-Ph NH
1-168 H iBu 2-MeO-Ph Ph 4-MeO-Ph NH
1-169 H iBu 3-MeO-Ph Ph 4-MeO-Ph NH
1-170 H iBu 4-MeO-Ph Ph 4-MeO-Ph NH
1-171 H iBu 2-Cl-Ph Ph 4-MeO-Ph NH
1-172 H iBu 3-Cl-Ph Ph 4-MeO-Ph NH
1-173 H iBu 4-Cl-Ph Ph 4-MeO-Ph NH
1-174 H iBu 2-F-Ph Ph 4-MeO-Ph NH
1-175 H iBu 3-F-Ph Ph 4-MeO-Ph NH
1-176 H iBu 4-F-Ph Ph 4-MeO-Ph NH
1-177 H iBu 3-CF₃ -Ph Ph 4-MeO-Ph NH
1-178 H iBu 4-CF₃ -Ph Ph 4-MeO-Ph NH
1-179 H iBu 3-CF₃ O-Ph Ph 4-MeO-Ph NH
1-180 H iBu 4-CF₃ O-Ph Ph 4-MeO-Ph NH
1-181 H iBu 3-HO-Ph Ph 4-MeO-Ph NH
1-182 H iBu 4-HO-Ph Ph 4-MeO-Ph NH
1-183 H iBu 3-HOCH₂ -Ph Ph 4-MeO-Ph NH
1-184 H iBu 4-HOCH₂ -Ph Ph 4-MeO-Ph NH
1-185 H iBu 3-H₂ N-Ph Ph 4-MeO-Ph NH
1-186 H iBu 4-H₂ N-Ph Ph 4-MeO-Ph NH
1-187 H iBu 2-Thi Ph 4-MeO-Ph NH
1-188 H iBu 3-Thi Ph 4-MeO-Ph NH
1-189 H iBu 2-Fur Ph 4-MeO-Ph NH
1-190 H iBu Br Bn 4-MeO-Ph NH
1-191 H iBu Ph Bn 4-MeO-Ph NH
1-192 H iBu 2-Me-Ph Bn 4-MeO-Ph NH
1-193 H iBu 3-Me-Ph Bn 4-MeO-Ph NH
1-194 H iBu 4-Me-Ph Bn 4-MeO-Ph NH
1-195 H iBu 2-MeO-Ph Bn 4-MeO-Ph NH
1-196 H iBu 3-MeO-Ph Bn 4-MeO-Ph NH
1-197 H iBu 4-MeO-Ph Bn 4-MeO-Ph NH
1-198 H iBu 2-Cl-Ph Bn 4-MeO-Ph NH
1-199 H iBu 3-Cl-Ph Bn 4-MeO-Ph NH
1-200 H iBu 4-Cl-Ph Bn 4-MeO-Ph NH
1-201 H iBu 2-F-Ph Bn 4-MeO-Ph NH
1-202 H iBu 3-F-Ph Bn 4-MeO-Ph NH
1-203 H iBu 4-F-Ph Bn 4-MeO-Ph NH
1-204 H iBu 3-CF₃ -Ph Bn 4-MeO-Ph NH
1-205 H iBu 4-CF₃ -Ph Bn 4-MeO-Ph NH
1-206 H iBu 3-CF₃ O-Ph Bn 4-MeO-Ph NH
1-207 H iBu 4-CF₃ O-Ph Bn 4-MeO-Ph NH
1-208 H iBu 3-HO-Ph Bn 4-MeO-Ph NH
1-209 H iBu 4-HO-Ph Bn 4-MeO-Ph NH
1-210 H iBu 3-HOCH₂ -Ph Bn 4-MeO-Ph NH
1-211 H iBu 4-HOCH₂ -Ph Bn 4-MeO-Ph NH
1-212 H iBu 3-H₂ N-Ph Bn 4-MeO-Ph NH
1-213 H iBu 4-H₂ N-Ph Bn 4-MeO-Ph NH
1-214 H iBu 2-Thi Bn 4-MeO-Ph NH
1-215 H iBu 3-Thi Bn 4-MeO-Ph NH
1-216 H iBu 2-Fur Bn 4-MeO-Ph NH
1-217 H iBu Br Phet 4-MeO-Ph NH
1-218 H iBu Ph Phet 4-MeO-Ph NH
1-219 H iBu 2-Me-Ph Phet 4-MeO-Ph NH
1-220 H iBu 3-Me-Ph Phet 4-MeO-Ph NH
1-221 H iBu 4-Me-Ph Phet 4-MeO-Ph NH
1-222 H iBu 2-MeO-Ph Phet 4-MeO-Ph NH
1-223 H iBu 3-MeO-Ph Phet 4-MeO-Ph NH
1-224 H iBu 4-MeO-Ph Phet 4-MeO-Ph NH
1-225 H iBu 2-Cl-Ph Phet 4-MeO-Ph NH
1-226 H iBu 3-Cl-Ph Phet 4-MeO-Ph NH
1-227 H iBu 4-Cl-Ph Phet 4-MeO-Ph NH
1-228 H iBu 2-F-Ph Phet 4-MeO-Ph NH
1-229 H iBu 3-F-Ph Phet 4-MeO-Ph NH
1-230 H iBu 4-F-Ph Phet 4-MeO-Ph NH
1-231 H iBu 3-CF₃ -Ph Phet 4-MeO-Ph NH
1-232 H iBu 4-CF₃ -Ph Phet 4-MeO-Ph NH
1-233 H iBu 3-CF₃ O-Ph Phet 4-MeO-Ph NH
1-234 H iBu 4-CF₃ O-Ph Phet 4-MeO-Ph NH
1-235 H iBu 3-HO-Ph Phet 4-MeO-Ph NH
1-236 H iBu 4-HO-Ph Phet 4-MeO-Ph NH
1-237 H iBu 3-HOCH₂ -Ph Phet 4-MeO-Ph NH
1-238 H iBu 4-HOCH₂ -Ph Phet 4-MeO-Ph NH
1-239 H iBu 3-H₂ N-Ph Phet 4-MeO-Ph NH
1-240 H iBu 4-H₂ N-Ph Phet 4-MeO-Ph NH
1-241 H iBu 2-Thi Phet 4-MeO-Ph NH
1-242 H iBu 3-Thi Phet 4-MeO-Ph NH
1-243 H iBu 2-Fur Phet 4-MeO-Ph NH
1-244 H iBu Br Me 4-BnO-Ph NH
1-245 H iBu Ph Me 4-BnO-Ph NH
1-246 H iBu 2-Me-Ph Me 4-BnO-Ph NH
1-247 H iBu 3-Me-Ph Me 4-BnO-Ph NH
1-248 H iBu 4-Me-Ph Me 4-BnO-Ph NH
1-249 H iBu 2-MeO-Ph Me 4-BnO-Ph NH
1-250 H iBu 3-MeO-Ph Me 4-BnO-Ph NH
1-251 H iBu 4-MeO-Ph Me 4-BnO-Ph NH
1-252 H iBu 2-Cl-Ph Me 4-BnO-Ph NH
1-253 H iBu 3-Cl-Ph Me 4-BnO-Ph NH
1-254 H iBu 4-Cl-Ph Me 4-BnO-Ph NH
1-255 H iBu 2-F-Ph Me 4-BnO-Ph NH
1-256 H iBu 3-F-Ph Me 4-BnO-Ph NH
1-257 H iBu 4-F-Ph Me 4-BnO-Ph NH
1-258 H iBu 3-CF₃ -Ph Me 4-BnO-Ph NH
1-259 H iBu 4-CF₃ -Ph Me 4-BnO-Ph NH
1-260 H iBu 3-CF₃ O-Ph Me 4-BnO-Ph NH
1-261 H iBu 4-CF₃ O-Ph Me 4-BnO-Ph NH
1-262 H iBu 3-HO-Ph Me 4-BnO-Ph NH
1-263 H iBu 4-HO-Ph Me 4-BnO-Ph NH
1-264 H iBu 3-HOCH₂ -Ph Me 4-BnO-Ph NH
1-265 H iBu 4-HOCH₂ -Ph Me 4-BnO-Ph NH
1-266 H iBu 3-H₂ N-Ph Me 4-BnO-Ph NH
1-267 H iBu 4-H₂ N-Ph Me 4-BnO-Ph NH
1-268 H iBu 2-Thi Me 4-BnO-Ph NH
1-269 H iBu 3-Thi Me 4-BnO-Ph NH
1-270 H iBu 2-Fur Me 4-BnO-Ph NH
1-271 H iBu Br Et 4-BnO-Ph NH
1-272 H iBu Ph Et 4-BnO-Ph NH
1-273 H iBu 2-Me-Ph Et 4-BnO-Ph NH
1-274 H iBu 3-Me-Ph Et 4-BnO-Ph NH
1-275 H iBu 4-Me-Ph Et 4-BnO-Ph NH
1-276 H iBu 2-MeO-Ph Et 4-BnO-Ph NH
1-277 H iBu 3-MeO-Ph Et 4-BnO-Ph NH
1-278 H iBu 4-MeO-Ph Et 4-BnO-Ph NH
1-279 H iBu 2-Cl-Ph Et 4-BnO-Ph NH
1-280 H iBu 3-Cl-Ph Et 4-BnO-Ph NH
1-281 H iBu 4-Cl-Ph Et 4-BnO-Ph NH
1-282 H iBu 2-F-Ph Et 4-BnO-Ph NH
1-283 H iBu 3-F-Ph Et 4-BnO-Ph NH
1-284 H iBu 4-F-Ph Et 4-BnO-Ph NH
1-285 H iBu 3-CF₃ -Ph Et 4-BnO-Ph NH
1-286 H iBu 4-CF₃ -Ph Et 4-BnO-Ph NH
1-287 H iBu 3-CF₃ O-Ph Et 4-BnO-Ph NH
1-288 H iBu 4-CF₃ O-Ph Et 4-BnO-Ph NH
1-289 H iBu 3-HO-Ph Et 4-BnO-Ph NH
1-290 H iBu 4-HO-Ph Et 4-BnO-Ph NH
1-291 H iBu 3-HOCH₂ -Ph Et 4-BnO-Ph NH
1-292 H iBu 4-HOCH₂ -Ph Et 4-BnO-Ph NH
1-293 H iBu 3-H₂ N-Ph Et 4-BnO-Ph NH
1-294 H iBu 4-H₂ N-Ph Et 4-BnO-Ph NH
1-295 H iBu 2-Thi Et 4-BnO-Ph NH
1-296 H iBu 3-Thi Et 4-BnO-Ph NH
1-297 H iBu 2-Fur Et 4-BnO-Ph NH
1-298 H iBu Br Pr 4-BnO-Ph NH
1-299 H iBu Ph Pr 4-BnO-Ph NH
1-300 H iBu 2-Me-Ph Pr 4-BnO-Ph NH
1-301 H iBu 3-Me-Ph Pr 4-BnO-Ph NH
1-302 H iBu 4-Me-Ph Pr 4-BnO-Ph NH
1-303 H iBu 2-MeO-Ph Pr 4-BnO-Ph NH
1-304 H iBu 3-MeO-Ph Pr 4-BnO-Ph NH
1-305 H iBu 4-MeO-Ph Pr 4-BnO-Ph NH
1-306 H iBu 2-Cl-Ph Pr 4-BnO-Ph NH
1-307 H iBu 3-Cl-Ph Pr 4-BnO-Ph NH
1-308 H iBu 4-Cl-Ph Pr 4-BnO-Ph NH
1-309 H iBu 2-F-Ph Pr 4-BnO-Ph NH
1-310 H iBu 3-F-Ph Pr 4-BnO-Ph NH
1-311 H iBu 4-F-Ph Pr 4-BnO-Ph NH
1-312 H iBu 3-CF₃ -Ph Pr 4-BnO-Ph NH
1-313 H iBu 4-CF₃ -Ph Pr 4-BnO-Ph NH
1-314 H iBu 3-CF₃ O-Ph Pr 4-BnO-Ph NH
1-315 H iBu 4-CF₃ O-Ph Pr 4-BnO-Ph NH
1-316 H iBu 3-HO-Ph Pr 4-BnO-Ph NH
1-317 H iBu 4-HO-Ph Pr 4-BnO-Ph NH
1-318 H iBu 3-HOCH₂ -Ph Pr 4-BnO-Ph NH
1-319 H iBu 4-HOCH₂ -Ph Pr 4-BnO-Ph NH
1-320 H iBu 3-H₂ N-Ph Pr 4-BnO-Ph NH
1-321 H iBu 4-H₂ N-Ph Pr 4-BnO-Ph NH
1-322 H iBu 2-Thi Pr 4-BnO-Ph NH
1-323 H iBu 3-Thi Pr 4-BnO-Ph NH
1-324 H iBu 2-Fur Pr 4-BnO-Ph NH
1-325 H iBu Br Bu 4-BnO-Ph NH
1-326 H iBu Ph Bu 4-BnO-Ph NH
1-327 H iBu 2-Me-Ph Bu 4-BnO-Ph NH
1-328 H iBu 3-Me-Ph Bu 4-BnO-Ph NH
1-329 H iBu 4-Me-Ph Bu 4-BnO-Ph NH
1-330 H iBu 2-MeO-Ph Bu 4-BnO-Ph NH
1-331 H iBu 3-MeO-Ph Bu 4-BnO-Ph NH
1-332 H iBu 4-MeO-Ph Bu 4-BnO-Ph NH
1-333 H iBu 2-Cl-Ph Bu 4-BnO-Ph NH
1-334 H iBu 3-Cl-Ph Bu 4-BnO-Ph NH
1-335 H iBu 4-Cl-Ph Bu 4-BnO-Ph NH
1-336 H iBu 2-F-Ph Bu 4-BnO-Ph NH
1-337 H iBu 3-F-Ph Bu 4-BnO-Ph NH
1-338 H iBu 4-F-Ph Bu 4-BnO-Ph NH
1-339 H iBu 3-CF₃ -Ph Bu 4-BnO-Ph NH
1-340 H iBu 4-CF₃ -Ph Bu 4-BnO-Ph NH
1-341 H iBu 3-CF₃ O-Ph Bu 4-BnO-Ph NH
1-342 H iBu 4-CF₃ O-Ph Bu 4-BnO-Ph NH
1-343 H iBu 3-HO-Ph Bu 4-BnO-Ph NH
1-344 H iBu 4-HO-Ph Bu 4-BnO-Ph NH
1-345 H iBu 3-HOCH₂ -Ph Bu 4-BnO-Ph NH
1-346 H iBu 4-HOCH₂ -Ph Bu 4-BnO-Ph NH
1-347 H iBu 3-H₂ N-Ph Bu 4-BnO-Ph NH
1-348 H iBu 4-H₂ N-Ph Bu 4-BnO-Ph NH
1-349 H iBu 2-Thi Bu 4-BnO-Ph NH
1-350 H iBu 3-Thi Bu 4-BnO-Ph NH
1-351 H iBu 2-Fur Bu 4-BnO-Ph NH
1-352 H iBu HO Me 4-MeO-Ph NH
1-353 H iBu MeO Me 4-MeO-Ph NH
1-354 H iBu EtO Me 4-MeO-Ph NH
1-355 H iBu PrO Me 4-MeO-Ph NH
1-356 H iBu BuO Me 4-MeO-Ph NH
1-357 H iBu BnO Me 4-MeO-Ph NH
1-358 H iBu iPrO Me 4-MeO-Ph NH
1-359 H iBu iBuO Me 4-MeO-Ph NH
1-360 H iBu tBuO Me 4-MeO-Ph NH
1-361 H iBu HOC (O) Me 4-MeO-Ph NH
1-362 H iBu MeOC (O) Me 4-MeO-Ph NH
1-363 H iBu Me₂ N-CO Me 4-MeO-Ph NH
1-364 H iBu 2,3-diMe-Ph Me 4-MeO-Ph NH
1-365 H iBu 2,5-diMe-Ph Me 4-MeO-Ph NH
1-366 H iBu 2,6-diMe-Ph Me 4-MeO-Ph NH
1-367 H iBu 3,5-diMe-Ph Me 4-MeO-Ph NH
1-368 H iBu 2,4-di (MeO) -Ph Me 4-MeO-Ph NH
1-369 H iBu 2,5-di (MeO) -Ph Me 4-MeO-Ph NH
1-370 H iBu 2,6-di (MeO) -Ph Me 4-MeO-Ph NH
1-371 H iBu 3,4-di (MeO) -Ph Me 4-MeO-Ph NH
1-372 H iBu 2,5-diCl-Ph Me 4-MeO-Ph NH
1-373 H iBu 3,4-diCl-Ph Me 4-MeO-Ph NH
1-374 H iBu 2-MeO-5-Cl-Ph Me 4-MeO-Ph NH
1-375 H iBu 2,4-diF-Ph Me 4-MeO-Ph NH
1-376 H iBu 2,5-diF-Ph Me 4-MeO-Ph NH
1-377 H iBu 2,6-diF-Ph Me 4-MeO-Ph NH
1-378 H iBu 3,4-diF-Ph Me 4-MeO-Ph NH
1-379 H iBu 3,5-diF-Ph Me 4-MeO-Ph NH
1-380 H iBu 2,3,4,5,6-pentaF-Ph Me 4-MeO-Ph NH
1-381 H iBu 3-Cl-4-F-Ph Me 4-MeO-Ph NH
1-382 H iBu 3-Me-4-F-Ph Me 4-MeO-Ph NH
1-383 H iBu 2-MeO-5-F-Ph Me 4-MeO-Ph NH
1-384 H iBu 2-CF₃ -Ph Me 4-MeO-Ph NH
1-385 H iBu 3,5-di (CF₃ ) -Ph Me 4-MeO-Ph NH
1-386 H iBu 2-HO-Ph Me 4-MeO-Ph NH
1-387 H iBu 2-HOCH₂ -Ph Me 4-MeO-Ph NH
1-388 H iBu 2-H₂ N-Ph Me 4-MeO-Ph NH
1-389 H iBu 3-NO₂ -Ph Me 4-MeO-Ph NH
1-390 H iBu 3-CN-Ph Me 4-MeO-Ph NH
1-391 H iBu 2-HCO-Ph Me 4-MeO-Ph NH
1-392 H iBu 3-HCO-Ph Me 4-MeO-Ph NH
1-393 H iBu 4-HCO-Ph Me 4-MeO-Ph NH
1-394 H iBu 3-HOOC-Ph Me 4-MeO-Ph NH
1-395 H iBu 4-HOOC-Ph Me 4-MeO-Ph NH
1-396 H iBu 3,4-(-OCH₂ O-)-Ph Me 4-MeO-Ph NH
1-397 H iBu 4-MeS-Ph Me 4-MeO-Ph NH
1-398 H iBu 3-Ac-Ph Me 4-MeO-Ph NH
1-399 H iBu 4-Ac-Ph Me 4-MeO-Ph NH
1-400 H iBu 1-Nph Me 4-MeO-Ph NH
1-401 H iBu 2-Nph Me 4-MeO-Ph NH
1-402 H iBu 4-tBu-Ph Me 4-MeO-Ph NH
1-403 H iBu 5-Cl-2-Thi Me 4-MeO-Ph NH
1-404 H iBu 5-Me-2-Thi Me 4-MeO-Ph NH
1-405 H iBu 1-Boc-2-Pyro Me 4-MeO-Ph NH
1-406 H iBu 2-Bzfur Me 4-MeO-Ph NH
1-407 H iBu 2-Py Me 4-MeO-Ph NH
1-408 H iBu 3-Py Me 4-MeO-Ph NH
1-409 H iBu 4-Py Me 4-MeO-Ph NH
1-410 H iBu HO Et 4-MeO-Ph NH
1-411 H iBu MeO Et 4-MeO-Ph NH
1-412 H iBu EtO Et 4-MeO-Ph NH
1-413 H iBu PrO Et 4-MeO-Ph NH
1-414 H iBu BuO Et 4-MeO-Ph NH
1-415 H iBu BnO Et 4-MeO-Ph NH
1-416 H iBu iPrO Et 4-MeO-Ph NH
1-417 H iBu iBuO Et 4-MeO-Ph NH
1-418 H iBu tBuO Et 4-MeO-Ph NH
1-419 H iBu HOC (O) Et 4-MeO-Ph NH
1-420 H iBu MeOC (O) Et 4-MeO-Ph NH
1-421 H iBu Me₂ N-CO Et 4-MeO-Ph NH
1-422 H iBu 2,3-diMe-Ph Et 4-MeO-Ph NH
1-423 H iBu 2,5-diMe-Ph Et 4-MeO-Ph NH
1-424 H iBu 2,6-diMe-Ph Et 4-MeO-Ph NH
1-425 H iBu 3,5-diMe-Ph Et 4-MeO-Ph NH
1-426 H iBu 2,4-di (MeO) -Ph Et 4-MeO-Ph NH
1-427 H iBu 2,5-di (MeO) -Ph Et 4-MeO-Ph NH
1-428 H iBu 2,6-di (MeO) -Ph Et 4-MeO-Ph NH
1-429 H iBu 3,4-di (MeO) -Ph Et 4-MeO-Ph NH
1-430 H iBu 2,5-diCl-Ph Et 4-MeO-Ph NH
1-431 H iBu 3,4-diCl-Ph Et 4-MeO-Ph NH
1-432 HiBu 2-MeO-5-Cl-Ph Et 4-MeO-Ph NH
1-433 H iBu 2,4-diF-Ph Et 4-MeO-Ph NH
1-434 H iBu 2,5-diF-Ph Et 4-MeO-Ph NH
1-435 H iBu 2,6-diF-Ph Et 4-MeO-Ph NH
1-436 H iBu 3,4-diF-Ph Et 4-MeO-Ph NH
1-437 H iBu 3,5-diF-Ph Et 4-MeO-Ph NH
1-438 H iBu 2,3,4,5,6-pentaF-Ph Et 4-MeO-Ph NH
1-439 H iBu 3-Cl-4-F-Ph Et 4-MeO-Ph NH
1-440 H iBu 3-Me-4-F-Ph Et 4-MeO-Ph NH
1-441 H iBu 2-MeO-5-F-Ph Et 4-MeO-Ph NH
1-442 H iBu 2-CF₃ -Ph Et 4-MeO-Ph NH
1-443 H iBu 3,5-di (CF₃ ) -Ph Et 4-MeO-Ph NH
1-444 H iBu 2-HO-Ph Et 4-MeO-Ph NH
1-445 H iBu 2-HOCH₂ -Ph Et 4-MeO-Ph NH
1-446 H iBu 2-H₂ N-Ph Et 4-MeO-Ph NH
1-447 H iBu 3-NO₂ -Ph Et 4-MeO-Ph NH
1-448 H iBu 3-CN-Ph Et 4-MeO-Ph NH
1-449 H iBu 2-HCO-Ph Et 4-MeO-Ph NH
1-450 H iBu 3-HCO-Ph Et 4-MeO-Ph NH
1-451 HiBu 4-HCO-Ph Et 4-MeO-Ph NH
1-452 H iBu 3-HOOC-Ph Et 4-MeO-Ph NH
1-453 HiBu 4-HOOC-Ph Et 4-MeO-Ph NH
1-454 H iBu 3,4-(-OCH₂ O-)-Ph Et 4-MeO-Ph NH
1-455 H iBu 4-MeS-Ph Et 4-MeO-Ph NH
1-456 H iBu 3-Ac-Ph Et 4-MeO-Ph NH
1-457 H iBu 4-Ac-Ph Et 4-MeO-Ph NH
1-458 H iBu 1-Nph Et 4-MeO-Ph NH
1-459 H iBu 2-Nph Et 4-MeO-Ph NH
1-460 H iBu 4-tBu-Ph Et 4-MeO-Ph NH
1-461 H iBu 5-Cl-2-Thi Et 4-MeO-Ph NH
1-462 H iBu 5-Me-2-Thi Et 4-MeO-Ph NH
1-463 H iBu 1-Boc-2-Pyro Et 4-MeO-Ph NH
1-464 H iBu 2-Bzfur Et 4-MeO-Ph NH
1-465 H iBu 2-Py Et 4-MeO-Ph NH
1-466 H iBu 3-Py Et 4-MeO-Ph NH
1-467 H iBu 4-Py Et 4-MeO-Ph NH
1-468 H iBu HO Pr 4-MeO-Ph NH
1-469 H iBu MeO Pr 4-MeO-Ph NH
1-470 H iBu EtO Pr 4-MeO-Ph NH
1-471 H iBu PrO Pr 4-MeO-Ph NH
1-472 H iBu BuO Pr 4-MeO-Ph NH
1-473 H iBu BnO Pr 4-MeO-Ph NH
1-474 H iBu iPrO Pr 4-MeO-Ph NH
1-475 H iBu iBuO Pr 4-MeO-Ph NH
1-476 H iBu tBuO Pr 4-MeO-Ph NH
1-477 H iBu HOC (O) Pr 4-MeO-Ph NH
1-478 H iBu MeOC (O) Pr 4-MeO-Ph NH
1-479 H iBu Me₂ N-CO Pr 4-MeO-Ph NH
1-480 H iBu 2,3-diMe-Ph Pr 4-MeO-Ph NH
1-481 H iBu 2,5-diMe-Ph Pr 4-MeO-Ph NH
1-482 H iBu 2,6-diMe-Ph Pr 4-MeO-Ph NH
1-483 H iBu 3,5-diMe-Ph Pr 4-MeO-Ph NH
1-484 H iBu 2,4-di (MeO) -Ph Pr 4-MeO-Ph NH
1-485 H iBu 2,5-di (MeO) -Ph Pr 4-MeO-Ph NH
1-486 H iBu 2,6-di (MeO) -Ph Pr 4-MeO-Ph NH
1-487 H iBu 3,4-di (MeO) -Ph Pr 4-MeO-Ph NH
1-488 H iBu 2,5-diCl-Ph Pr 4-MeO-Ph NH
1-489 H iBu 3,4-diCl-Ph Pr 4-MeO-Ph NH
1-490 H iBu 2-MeO-5-Cl-Ph Pr 4-MeO-Ph NH
1-491 H iBu 2,4-diF-Ph Pr 4-MeO-Ph NH
1-492 H iBu 2,5-diF-Ph Pr 4-MeO-Ph NH
1-493 H iBu 2,6-diF-Ph Pr 4-MeO-Ph NH
1-494 H iBu 3,4-diF-Ph Pr 4-MeO-Ph NH
1-495 H iBu 3,5-diF-Ph Pr 4-MeO-Ph NH
1-496 H iBu 2,3,4,5,6-pentaF-Ph Pr 4-MeO-Ph NH
1-497 H iBu 3-Cl-4-F-Ph Pr 4-MeO-Ph NH
1-498 H iBu 3-Me-4-F-Ph Pr 4-MeO-Ph NH
1-499 H iBu 2-MeO-5-F-Ph Pr 4-MeO-Ph NH
1-500 H iBu 2-CF₃ -Ph Pr 4-MeO-Ph NH
1-501 H iBu 3,5-di (CF₃ ) -Ph Pr 4-MeO-Ph NH
1-502 H iBu 2-HO-Ph Pr 4-MeO-Ph NH
1-503 H iBu 2-HOCH₂ -Ph Pr 4-MeO-Ph NH
1-504 H iBu 2-H₂ N-Ph Pr 4-MeO-Ph NH
1-505 H iBu 3-NO₂ -Ph Pr 4-MeO-Ph NH
1-506 H iBu 3-CN-Ph Pr 4-MeO-Ph NH
1-507 H iBu 2-HCO-Ph Pr 4-MeO-Ph NH
1-508 H iBu 3-HCO-Ph Pr 4-MeO-Ph NH
1-509 HiBu 4-HCO-Ph Pr 4-MeO-Ph NH
1-510 H iBu 3-HOOC-Ph Pr 4-MeO-Ph NH
1-511 H iBu 4-HOOC-Ph Pr 4-MeO-Ph NH
1-512 H iBu 3,4-(-OCH₂ O-)-Ph Pr 4-MeO-Ph NH
1-513 H iBu 4-MeS-Ph Pr 4-MeO-Ph NH
1-514 H iBu 3-Ac-Ph Pr 4-MeO-Ph NH
1-515 H iBu 4-Ac-Ph Pr 4-MeO-Ph NH
1-516 H iBu 1-Nph Pr 4-MeO-Ph NH
1-517 H iBu 2-Nph Pr 4-MeO-Ph NH
1-518 H iBu 4-tBu-Ph Pr 4-MeO-Ph NH
1-519 H iBu 5-Cl-2-Thi Pr 4-MeO-Ph NH
1-520 H iBu 5-Me-2-Thi Pr 4-MeO-Ph NH
1-521 H iBu 1-Boc-2-Pyro Pr 4-MeO-Ph NH
1-522 H iBu 2-Bzfur Pr 4-MeO-Ph NH
1-523 H iBu 2-Py Pr 4-MeO-Ph NH
1-524 H iBu 3-Py Pr 4-MeO-Ph NH
1-525 H iBu 4-Py Pr 4-MeO-Ph NH
1-526 H iBu HO Bu 4-MeO-Ph NH
1-527 H iBu MeO Bu 4-MeO-Ph NH
1-528 H iBu EtO Bu 4-MeO-Ph NH
1-529 H iBu PrO Bu 4-MeO-Ph NH
1-530 H iBu BuO Bu 4-MeO-Ph NH
1-531 H iBu BnO Bu 4-MeO-Ph NH
1-532 H iBu iPrO Bu 4-MeO-Ph NH
1-533 H iBu iBuO Bu 4-MeO-Ph NH
1-534 H iBu tBuO Bu 4-MeO-Ph NH
1-535 H iBu HOC (O) Bu 4-MeO-Ph NH
1-536 H iBu MeOC (O) Bu 4-MeO-Ph NH
1-537 H iBu Me₂ N-CO Bu 4-MeO-Ph NH
1-538 H iBu 2,3-diMe-Ph Bu 4-MeO-Ph NH
1-539 H iBu 2,5-diMe-Ph Bu 4-MeO-Ph NH
1-540 H iBu 2,6-diMe-Ph Bu 4-MeO-Ph NH
1-541 H iBu 3,5-diMe-Ph Bu 4-MeO-Ph NH
1-542 H iBu 2,4-di (MeO) -Ph Bu 4-MeO-Ph NH
1-543 H iBu 2,5-di (MeO) -Ph Bu 4-MeO-Ph NH
1-544 H iBu 2,6-di (MeO) -Ph Bu 4-MeO-Ph NH
1-545 H iBu 3,4-di (MeO) -Ph Bu 4-MeO-Ph NH
1-546 H iBu 2,5-diCl-Ph Bu 4-MeO-Ph NH
1-547 H iBu 3,4-diCl-Ph Bu 4-MeO-Ph NH
1-548 H iBu 2-MeO-5-Cl-Ph Bu 4-MeO-Ph NH
1-549 H iBu 2,4-diF-Ph Bu 4-MeO-Ph NH
1-550 H iBu 2,5-diF-Ph Bu 4-MeO-Ph NH
1-551 H iBu 2,6-diF-Ph Bu 4-MeO-Ph NH
1-552 H iBu 3,4-diF-Ph Bu 4-MeO-Ph NH
1-553 H iBu 3,5-diF-Ph Bu 4-MeO-Ph NH
1-554 H iBu 2,3,4,5,6-pentaF-Ph Bu 4-MeO-Ph NH
1-555 H iBu 3-Cl-4-F-Ph Bu 4-MeO-Ph NH
1-556 H iBu 3-Me-4-F-Ph Bu 4-MeO-Ph NH
1-557 H iBu 2-MeO-5-F-Ph Bu 4-MeO-Ph NH
1-558 H iBu 2-CF₃ -Ph Bu 4-MeO-Ph NH
1-559 H iBu 3,5-di (CF₃ ) -Ph Bu 4-MeO-Ph NH
1-560 H iBu 2-HO-Ph Bu 4-MeO-Ph NH
1-561 H iBu 2-HOCH₂ -Ph Bu 4-MeO-Ph NH
1-562 H iBu 2-H₂ N-Ph Bu 4-MeO-Ph NH
1-563 H iBu 3-NO₂ -Ph Bu 4-MeO-Ph NH
1-564 H iBu 3-CN-Ph Bu 4-MeO-Ph NH
1-565 H iBu 2-HCO-Ph Bu 4-MeO-Ph NH
1-566 H iBu 3-HCO-Ph Bu 4-MeO-Ph NH
1-567 H iBu 4-HCO-Ph Bu 4-MeO-Ph NH
1-568 H iBu 3-HOOC-Ph Bu 4-MeO-Ph NH
1-569 H iBu 4-HOOC-Ph Bu 4-MeO-Ph NH
1-570 H iBu 3,4-(-OCH₂ O-)-Ph Bu 4-MeO-Ph NH
1-571 H iBu 4-MeS-Ph Bu 4-MeO-Ph NH
1-572 H iBu 3-Ac-Ph Bu 4-MeO-Ph NH
1-573 H iBu 4-Ac-Ph Bu 4-MeO-Ph NH
1-574 H iBu 1-Nph Bu 4-MeO-Ph NH
1-575 H iBu 2-Nph Bu 4-MeO-Ph NH
1-576 H iBu 4-tBu-Ph Bu 4-MeO-Ph NH
1-577 H iBu 5-Cl-2-Thi Bu 4-MeO-Ph NH
1-578 H iBu 5-Me-2-Thi Bu 4-MeO-Ph NH
1-579 H iBu 1-Boc-2-Pyro Bu 4-MeO-Ph NH
1-580 H iBu 2-Bzfur Bu 4-MeO-Ph NH
1-581 H iBu 2-Py Bu 4-MeO-Ph NH
1-582 H iBu 3-Py Bu 4-MeO-Ph NH
1-583 H iBu 4-Py Bu 4-MeO-Ph NH
-------------------------------------------------- -------

例示化合物表２
------------------------------------------------
化合物
番 号 R R⁴ Ar X
------------------------------------------------
2-1 Br Me 4-MeO-Ph NH
2-2 Ph Me 4-MeO-Ph NH
2-3 2-Me-Ph Me 4-MeO-Ph NH
2-4 3-Me-Ph Me 4-MeO-Ph NH
2-5 4-Me-Ph Me 4-MeO-Ph NH
2-6 2-MeO-Ph Me 4-MeO-Ph NH
2-7 3-MeO-Ph Me 4-MeO-Ph NH
2-8 4-MeO-Ph Me 4-MeO-Ph NH
2-9 2-Cl-Ph Me 4-MeO-Ph NH
2-10 3-Cl-Ph Me 4-MeO-Ph NH
2-11 4-Cl-Ph Me 4-MeO-Ph NH
2-12 2-F-Ph Me 4-MeO-Ph NH
2-13 3-F-Ph Me 4-MeO-Ph NH
2-14 4-F-Ph Me 4-MeO-Ph NH
2-15 3-CF₃-Ph Me 4-MeO-Ph NH
2-16 4-CF₃-Ph Me 4-MeO-Ph NH
2-17 3-CF₃O-Ph Me 4-MeO-Ph NH
2-18 4-CF₃O-Ph Me 4-MeO-Ph NH
2-19 3-HO-Ph Me 4-MeO-Ph NH
2-20 4-HO-Ph Me 4-MeO-Ph NH
2-21 3-HOCH₂-Ph Me 4-MeO-Ph NH
2-22 4-HOCH₂-Ph Me 4-MeO-Ph NH
2-23 3-H₂N-Ph Me 4-MeO-Ph NH
2-24 4-H₂N-Ph Me 4-MeO-Ph NH
2-25 2-Thi Me 4-MeO-Ph NH
2-26 3-Thi Me 4-MeO-Ph NH
2-27 2-Fur Me 4-MeO-Ph NH
2-28 Br Et 4-MeO-Ph NH
2-29 Ph Et 4-MeO-Ph NH
2-30 2-Me-Ph Et 4-MeO-Ph NH
2-31 3-Me-Ph Et 4-MeO-Ph NH
2-32 4-Me-Ph Et 4-MeO-Ph NH
2-33 2-MeO-Ph Et 4-MeO-Ph NH
2-34 3-MeO-Ph Et 4-MeO-Ph NH
2-35 4-MeO-Ph Et 4-MeO-Ph NH
2-36 2-Cl-Ph Et 4-MeO-Ph NH
2-37 3-Cl-Ph Et 4-MeO-Ph NH
2-38 4-Cl-Ph Et 4-MeO-Ph NH
2-39 2-F-Ph Et 4-MeO-Ph NH
2-40 3-F-Ph Et 4-MeO-Ph NH
2-41 4-F-Ph Et 4-MeO-Ph NH
2-42 3-CF₃-Ph Et 4-MeO-Ph NH
2-43 4-CF₃-Ph Et 4-MeO-Ph NH
2-44 3-CF₃O-Ph Et 4-MeO-Ph NH
2-45 4-CF₃O-Ph Et 4-MeO-Ph NH
2-46 3-HO-Ph Et 4-MeO-Ph NH
2-47 4-HO-Ph Et 4-MeO-Ph NH
2-48 3-HOCH₂-Ph Et 4-MeO-Ph NH
2-49 4-HOCH₂-Ph Et 4-MeO-Ph NH
2-50 3-H₂N-Ph Et 4-MeO-Ph NH
2-51 4-H₂N-Ph Et 4-MeO-Ph NH
2-52 2-Thi Et 4-MeO-Ph NH
2-53 3-Thi Et 4-MeO-Ph NH
2-54 2-Fur Et 4-MeO-Ph NH
2-55 Br Pr 4-MeO-Ph NH
2-56 Ph Pr 4-MeO-Ph NH
2-57 2-Me-Ph Pr 4-MeO-Ph NH
2-58 3-Me-Ph Pr 4-MeO-Ph NH
2-59 4-Me-Ph Pr 4-MeO-Ph NH
2-60 2-MeO-Ph Pr 4-MeO-Ph NH
2-61 3-MeO-Ph Pr 4-MeO-Ph NH
2-62 4-MeO-Ph Pr 4-MeO-Ph NH
2-63 2-Cl-Ph Pr 4-MeO-Ph NH
2-64 3-Cl-Ph Pr 4-MeO-Ph NH
2-65 4-Cl-Ph Pr 4-MeO-Ph NH
2-66 2-F-Ph Pr 4-MeO-Ph NH
2-67 3-F-Ph Pr 4-MeO-Ph NH
2-68 4-F-Ph Pr 4-MeO-Ph NH
2-69 3-CF₃-Ph Pr 4-MeO-Ph NH
2-70 4-CF₃-Ph Pr 4-MeO-Ph NH
2-71 3-CF₃O-Ph Pr 4-MeO-Ph NH
2-72 4-CF₃O-Ph Pr 4-MeO-Ph NH
2-73 3-HO-Ph Pr 4-MeO-Ph NH
2-74 4-HO-Ph Pr 4-MeO-Ph NH
2-75 3-HOCH₂-Ph Pr 4-MeO-Ph NH
2-76 4-HOCH₂-Ph Pr 4-MeO-Ph NH
2-77 3-H₂N-Ph Pr 4-MeO-Ph NH
2-78 4-H₂N-Ph Pr 4-MeO-Ph NH
2-79 2-Thi Pr 4-MeO-Ph NH
2-80 3-Thi Pr 4-MeO-Ph NH
2-81 2-Fur Pr 4-MeO-Ph NH
2-82 Br Bu 4-MeO-Ph NH
2-83 Ph Bu 4-MeO-Ph NH
2-84 2-Me-Ph Bu 4-MeO-Ph NH
2-85 3-Me-Ph Bu 4-MeO-Ph NH
2-86 4-Me-Ph Bu 4-MeO-Ph NH
2-87 2-MeO-Ph Bu 4-MeO-Ph NH
2-88 3-MeO-Ph Bu 4-MeO-Ph NH
2-89 4-MeO-Ph Bu 4-MeO-Ph NH
2-90 2-Cl-Ph Bu 4-MeO-Ph NH
2-91 3-Cl-Ph Bu 4-MeO-Ph NH
2-92 4-Cl-Ph Bu 4-MeO-Ph NH
2-93 2-F-Ph Bu 4-MeO-Ph NH
2-94 3-F-Ph Bu 4-MeO-Ph NH
2-95 4-F-Ph Bu 4-MeO-Ph NH
2-96 3-CF₃-Ph Bu 4-MeO-Ph NH
2-97 4-CF₃-Ph Bu 4-MeO-Ph NH
2-98 3-CF₃O-Ph Bu 4-MeO-Ph NH
2-99 4-CF₃O-Ph Bu 4-MeO-Ph NH
2-100 3-HO-Ph Bu 4-MeO-Ph NH
2-101 4-HO-Ph Bu 4-MeO-Ph NH
2-102 3-HOCH₂-Ph Bu 4-MeO-Ph NH
2-103 4-HOCH₂-Ph Bu 4-MeO-Ph NH
2-104 3-H₂N-Ph Bu 4-MeO-Ph NH
2-105 4-H₂N-Ph Bu 4-MeO-Ph NH
2-106 2-Thi Bu 4-MeO-Ph NH
2-107 3-Thi Bu 4-MeO-Ph NH
2-108 2-Fur Bu 4-MeO-Ph NH
2-109 Br iPr 4-MeO-Ph NH
2-110 Ph iPr 4-MeO-Ph NH
2-111 2-Me-Ph iPr 4-MeO-Ph NH
2-112 3-Me-Ph iPr 4-MeO-Ph NH
2-113 4-Me-Ph iPr 4-MeO-Ph NH
2-114 2-MeO-Ph iPr 4-MeO-Ph NH
2-115 3-MeO-Ph iPr 4-MeO-Ph NH
2-116 4-MeO-Ph iPr 4-MeO-Ph NH
2-117 2-Cl-Ph iPr 4-MeO-Ph NH
2-118 3-Cl-Ph iPr 4-MeO-Ph NH
2-119 4-Cl-Ph iPr 4-MeO-Ph NH
2-120 2-F-Ph iPr 4-MeO-Ph NH
2-121 3-F-Ph iPr 4-MeO-Ph NH
2-122 4-F-Ph iPr 4-MeO-Ph NH
2-123 3-CF₃-Ph iPr 4-MeO-Ph NH
2-124 4-CF₃-Ph iPr 4-MeO-Ph NH
2-125 3-CF₃O-Ph iPr 4-MeO-Ph NH
2-126 4-CF₃O-Ph iPr 4-MeO-Ph NH
2-127 3-HO-Ph iPr 4-MeO-Ph NH
2-128 4-HO-Ph iPr 4-MeO-Ph NH
2-129 3-HOCH₂-Ph iPr 4-MeO-Ph NH
2-130 4-HOCH₂-Ph iPr 4-MeO-Ph NH
2-131 3-H₂N-Ph iPr 4-MeO-Ph NH
2-132 4-H₂N-Ph iPr 4-MeO-Ph NH
2-133 2-Thi iPr 4-MeO-Ph NH
2-134 3-Thi iPr 4-MeO-Ph NH
2-135 2-Fur iPr 4-MeO-Ph NH
2-136 Br iBu 4-MeO-Ph NH
2-137 Ph iBu 4-MeO-Ph NH
2-138 2-Me-Ph iBu 4-MeO-Ph NH
2-139 3-Me-Ph iBu 4-MeO-Ph NH
2-140 4-Me-Ph iBu 4-MeO-Ph NH
2-141 2-MeO-Ph iBu 4-MeO-Ph NH
2-142 3-MeO-Ph iBu 4-MeO-Ph NH
2-143 4-MeO-Ph iBu 4-MeO-Ph NH
2-144 2-Cl-Ph iBu 4-MeO-Ph NH
2-145 3-Cl-Ph iBu 4-MeO-Ph NH
2-146 4-Cl-Ph iBu 4-MeO-Ph NH
2-147 2-F-Ph iBu 4-MeO-Ph NH
2-148 3-F-Ph iBu 4-MeO-Ph NH
2-149 4-F-Ph iBu 4-MeO-Ph NH
2-150 3-CF₃-Ph iBu 4-MeO-Ph NH
2-151 4-CF₃-Ph iBu 4-MeO-Ph NH
2-152 3-CF₃O-Ph iBu 4-MeO-Ph NH
2-153 4-CF₃O-Ph iBu 4-MeO-Ph NH
2-154 3-HO-Ph iBu 4-MeO-Ph NH
2-155 4-HO-Ph iBu 4-MeO-Ph NH
2-156 3-HOCH₂-Ph iBu 4-MeO-Ph NH
2-157 4-HOCH₂-Ph iBu 4-MeO-Ph NH
2-158 3-H₂N-Ph iBu 4-MeO-Ph NH
2-159 4-H₂N-Ph iBu 4-MeO-Ph NH
2-160 2-Thi iBu 4-MeO-Ph NH
2-161 3-Thi iBu 4-MeO-Ph NH
2-162 2-Fur iBu 4-MeO-Ph NH
2-163 Br Ph 4-MeO-Ph NH
2-164 Ph Ph 4-MeO-Ph NH
2-165 2-Me-Ph Ph 4-MeO-Ph NH
2-166 3-Me-Ph Ph 4-MeO-Ph NH
2-167 4-Me-Ph Ph 4-MeO-Ph NH
2-168 2-MeO-Ph Ph 4-MeO-Ph NH
2-169 3-MeO-Ph Ph 4-MeO-Ph NH
2-170 4-MeO-Ph Ph 4-MeO-Ph NH
2-171 2-Cl-Ph Ph 4-MeO-Ph NH
2-172 3-Cl-Ph Ph 4-MeO-Ph NH
2-173 4-Cl-Ph Ph 4-MeO-Ph NH
2-174 2-F-Ph Ph 4-MeO-Ph NH
2-175 3-F-Ph Ph 4-MeO-Ph NH
2-176 4-F-Ph Ph 4-MeO-Ph NH
2-177 3-CF₃-Ph Ph 4-MeO-Ph NH
2-178 4-CF₃-Ph Ph 4-MeO-Ph NH
2-179 3-CF₃O-Ph Ph 4-MeO-Ph NH
2-180 4-CF₃O-Ph Ph 4-MeO-Ph NH
2-181 3-HO-Ph Ph 4-MeO-Ph NH
2-182 4-HO-Ph Ph 4-MeO-Ph NH
2-183 3-HOCH₂-Ph Ph 4-MeO-Ph NH
2-184 4-HOCH₂-Ph Ph 4-MeO-Ph NH
2-185 3-H₂N-Ph Ph 4-MeO-Ph NH
2-186 4-H₂N-Ph Ph 4-MeO-Ph NH
2-187 2-Thi Ph 4-MeO-Ph NH
2-188 3-Thi Ph 4-MeO-Ph NH
2-189 2-Fur Ph 4-MeO-Ph NH
2-190 Br Bn 4-MeO-Ph NH
2-191 Ph Bn 4-MeO-Ph NH
2-192 2-Me-Ph Bn 4-MeO-Ph NH
2-193 3-Me-Ph Bn 4-MeO-Ph NH
2-194 4-Me-Ph Bn 4-MeO-Ph NH
2-195 2-MeO-Ph Bn 4-MeO-Ph NH
2-196 3-MeO-Ph Bn 4-MeO-Ph NH
2-197 4-MeO-Ph Bn 4-MeO-Ph NH
2-198 2-Cl-Ph Bn 4-MeO-Ph NH
2-199 3-Cl-Ph Bn 4-MeO-Ph NH
2-200 4-Cl-Ph Bn 4-MeO-Ph NH
2-201 2-F-Ph Bn 4-MeO-Ph NH
2-202 3-F-Ph Bn 4-MeO-Ph NH
2-203 4-F-Ph Bn 4-MeO-Ph NH
2-204 3-CF₃-Ph Bn 4-MeO-Ph NH
2-205 4-CF₃-Ph Bn 4-MeO-Ph NH
2-206 3-CF₃O-Ph Bn 4-MeO-Ph NH
2-207 4-CF₃O-Ph Bn 4-MeO-Ph NH
2-208 3-HO-Ph Bn 4-MeO-Ph NH
2-209 4-HO-Ph Bn 4-MeO-Ph NH
2-210 3-HOCH₂-Ph Bn 4-MeO-Ph NH
2-211 4-HOCH₂-Ph Bn 4-MeO-Ph NH
2-212 3-H₂N-Ph Bn 4-MeO-Ph NH
2-213 4-H₂N-Ph Bn 4-MeO-Ph NH
2-214 2-Thi Bn 4-MeO-Ph NH
2-215 3-Thi Bn 4-MeO-Ph NH
2-216 2-Fur Bn 4-MeO-Ph NH
2-217 Br Phet 4-MeO-Ph NH
2-218 Ph Phet 4-MeO-Ph NH
2-219 2-Me-Ph Phet 4-MeO-Ph NH
2-220 3-Me-Ph Phet 4-MeO-Ph NH
2-221 4-Me-Ph Phet 4-MeO-Ph NH
2-222 2-MeO-Ph Phet 4-MeO-Ph NH
2-223 3-MeO-Ph Phet 4-MeO-Ph NH
2-224 4-MeO-Ph Phet 4-MeO-Ph NH
2-225 2-Cl-Ph Phet 4-MeO-Ph NH
2-226 3-Cl-Ph Phet 4-MeO-Ph NH
2-227 4-Cl-Ph Phet 4-MeO-Ph NH
2-228 2-F-Ph Phet 4-MeO-Ph NH
2-229 3-F-Ph Phet 4-MeO-Ph NH
2-230 4-F-Ph Phet 4-MeO-Ph NH
2-231 3-CF₃-Ph Phet 4-MeO-Ph NH
2-232 4-CF₃-Ph Phet 4-MeO-Ph NH
2-233 3-CF₃O-Ph Phet 4-MeO-Ph NH
2-234 4-CF₃O-Ph Phet 4-MeO-Ph NH
2-235 3-HO-Ph Phet 4-MeO-Ph NH
2-236 4-HO-Ph Phet 4-MeO-Ph NH
2-237 3-HOCH₂-Ph Phet 4-MeO-Ph NH
2-238 4-HOCH₂-Ph Phet 4-MeO-Ph NH
2-239 3-H₂N-Ph Phet 4-MeO-Ph NH
2-240 4-H₂N-Ph Phet 4-MeO-Ph NH
2-241 2-Thi Phet 4-MeO-Ph NH
2-242 3-Thi Phet 4-MeO-Ph NH
2-243 2-Fur Phet 4-MeO-Ph NH
2-244 Br Me 4-BnO-Ph NH
2-245 Ph Me 4-BnO-Ph NH
2-246 2-Me-Ph Me 4-BnO-Ph NH
2-247 3-Me-Ph Me 4-BnO-Ph NH
2-248 4-Me-Ph Me 4-BnO-Ph NH
2-249 2-MeO-Ph Me 4-BnO-Ph NH
2-250 3-MeO-Ph Me 4-BnO-Ph NH
2-251 4-MeO-Ph Me 4-BnO-Ph NH
2-252 2-Cl-Ph Me 4-BnO-Ph NH
2-253 3-Cl-Ph Me 4-BnO-Ph NH
2-254 4-Cl-Ph Me 4-BnO-Ph NH
2-255 2-F-Ph Me 4-BnO-Ph NH
2-256 3-F-Ph Me 4-BnO-Ph NH
2-257 4-F-Ph Me 4-BnO-Ph NH
2-258 3-CF₃-Ph Me 4-BnO-Ph NH
2-259 4-CF₃-Ph Me 4-BnO-Ph NH
2-260 3-CF₃O-Ph Me 4-BnO-Ph NH
2-261 4-CF₃O-Ph Me 4-BnO-Ph NH
2-262 3-HO-Ph Me 4-BnO-Ph NH
2-263 4-HO-Ph Me 4-BnO-Ph NH
2-264 3-HOCH₂-Ph Me 4-BnO-Ph NH
2-265 4-HOCH₂-Ph Me 4-BnO-Ph NH
2-266 3-H₂N-Ph Me 4-BnO-Ph NH
2-267 4-H₂N-Ph Me 4-BnO-Ph NH
2-268 2-Thi Me 4-BnO-Ph NH
2-269 3-Thi Me 4-BnO-Ph NH
2-270 2-Fur Me 4-BnO-Ph NH
2-271 Br Et 4-BnO-Ph NH
2-272 Ph Et 4-BnO-Ph NH
2-273 2-Me-Ph Et 4-BnO-Ph NH
2-274 3-Me-Ph Et 4-BnO-Ph NH
2-275 4-Me-Ph Et 4-BnO-Ph NH
2-276 2-MeO-Ph Et 4-BnO-Ph NH
2-277 3-MeO-Ph Et 4-BnO-Ph NH
2-278 4-MeO-Ph Et 4-BnO-Ph NH
2-279 2-Cl-Ph Et 4-BnO-Ph NH
2-280 3-Cl-Ph Et 4-BnO-Ph NH
2-281 4-Cl-Ph Et 4-BnO-Ph NH
2-282 2-F-Ph Et 4-BnO-Ph NH
2-283 3-F-Ph Et 4-BnO-Ph NH
2-284 4-F-Ph Et 4-BnO-Ph NH
2-285 3-CF₃-Ph Et 4-BnO-Ph NH
2-286 4-CF₃-Ph Et 4-BnO-Ph NH
2-287 3-CF₃O-Ph Et 4-BnO-Ph NH
2-288 4-CF₃O-Ph Et 4-BnO-Ph NH
2-289 3-HO-Ph Et 4-BnO-Ph NH
2-290 4-HO-Ph Et 4-BnO-Ph NH
2-291 3-HOCH₂-Ph Et 4-BnO-Ph NH
2-292 4-HOCH₂-Ph Et 4-BnO-Ph NH
2-293 3-H₂N-Ph Et 4-BnO-Ph NH
2-294 4-H₂N-Ph Et 4-BnO-Ph NH
2-295 2-Thi Et 4-BnO-Ph NH
2-296 3-Thi Et 4-BnO-Ph NH
2-297 2-Fur Et 4-BnO-Ph NH
2-298 Br Pr 4-BnO-Ph NH
2-299 Ph Pr 4-BnO-Ph NH
2-300 2-Me-Ph Pr 4-BnO-Ph NH
2-301 3-Me-Ph Pr 4-BnO-Ph NH
2-302 4-Me-Ph Pr 4-BnO-Ph NH
2-303 2-MeO-Ph Pr 4-BnO-Ph NH
2-304 3-MeO-Ph Pr 4-BnO-Ph NH
2-305 4-MeO-Ph Pr 4-BnO-Ph NH
2-306 2-Cl-Ph Pr 4-BnO-Ph NH
2-307 3-Cl-Ph Pr 4-BnO-Ph NH
2-308 4-Cl-Ph Pr 4-BnO-Ph NH
2-309 2-F-Ph Pr 4-BnO-Ph NH
2-310 3-F-Ph Pr 4-BnO-Ph NH
2-311 4-F-Ph Pr 4-BnO-Ph NH
2-312 3-CF₃-Ph Pr 4-BnO-Ph NH
2-313 4-CF₃-Ph Pr 4-BnO-Ph NH
2-314 3-CF₃O-Ph Pr 4-BnO-Ph NH
2-315 4-CF₃O-Ph Pr 4-BnO-Ph NH
2-316 3-HO-Ph Pr 4-BnO-Ph NH
2-317 4-HO-Ph Pr 4-BnO-Ph NH
2-318 3-HOCH₂-Ph Pr 4-BnO-Ph NH
2-319 4-HOCH₂-Ph Pr 4-BnO-Ph NH
2-320 3-H₂N-Ph Pr 4-BnO-Ph NH
2-321 4-H₂N-Ph Pr 4-BnO-Ph NH
2-322 2-Thi Pr 4-BnO-Ph NH
2-323 3-Thi Pr 4-BnO-Ph NH
2-324 2-Fur Pr 4-BnO-Ph NH
2-325 Br Bu 4-BnO-Ph NH
2-326 Ph Bu 4-BnO-Ph NH
2-327 2-Me-Ph Bu 4-BnO-Ph NH
2-328 3-Me-Ph Bu 4-BnO-Ph NH
2-329 4-Me-Ph Bu 4-BnO-Ph NH
2-330 2-MeO-Ph Bu 4-BnO-Ph NH
2-331 3-MeO-Ph Bu 4-BnO-Ph NH
2-332 4-MeO-Ph Bu 4-BnO-Ph NH
2-333 2-Cl-Ph Bu 4-BnO-Ph NH
2-334 3-Cl-Ph Bu 4-BnO-Ph NH
2-335 4-Cl-Ph Bu 4-BnO-Ph NH
2-336 2-F-Ph Bu 4-BnO-Ph NH
2-337 3-F-Ph Bu 4-BnO-Ph NH
2-338 4-F-Ph Bu 4-BnO-Ph NH
2-339 3-CF₃-Ph Bu 4-BnO-Ph NH
2-340 4-CF₃-Ph Bu 4-BnO-Ph NH
2-341 3-CF₃O-Ph Bu 4-BnO-Ph NH
2-342 4-CF₃O-Ph Bu 4-BnO-Ph NH
2-343 3-HO-Ph Bu 4-BnO-Ph NH
2-344 4-HO-Ph Bu 4-BnO-Ph NH
2-345 3-HOCH₂-Ph Bu 4-BnO-Ph NH
2-346 4-HOCH₂-Ph Bu 4-BnO-Ph NH
2-347 3-H₂N-Ph Bu 4-BnO-Ph NH
2-348 4-H₂N-Ph Bu 4-BnO-Ph NH
2-349 2-Thi Bu 4-BnO-Ph NH
2-350 3-Thi Bu 4-BnO-Ph NH
2-351 2-Fur Bu 4-BnO-Ph NH
2-352 HO Me 4-MeO-Ph NH
2-353 MeO Me 4-MeO-Ph NH
2-354 EtO Me 4-MeO-Ph NH
2-355 PrO Me 4-MeO-Ph NH
2-356 BuO Me 4-MeO-Ph NH
2-357 BnO Me 4-MeO-Ph NH
2-358 iPrO Me 4-MeO-Ph NH
2-359 iBuO Me 4-MeO-Ph NH
2-360 tBuO Me 4-MeO-Ph NH
2-361 HOC(O) Me 4-MeO-Ph NH
2-362 MeOC(O) Me 4-MeO-Ph NH
2-363 Me₂N-CO Me 4-MeO-Ph NH
2-364 2,3-diMe-Ph Me 4-MeO-Ph NH
2-365 2,5-diMe-Ph Me 4-MeO-Ph NH
2-366 2,6-diMe-Ph Me 4-MeO-Ph NH
2-367 3,5-diMe-Ph Me 4-MeO-Ph NH
2-368 2,4-di(MeO)-Ph Me 4-MeO-Ph NH
2-369 2,5-di(MeO)-Ph Me 4-MeO-Ph NH
2-370 2,6-di(MeO)-Ph Me 4-MeO-Ph NH
2-371 3,4-di(MeO)-Ph Me 4-MeO-Ph NH
2-372 2,5-diCl-Ph Me 4-MeO-Ph NH
2-373 3,4-diCl-Ph Me 4-MeO-Ph NH
2-374 2-MeO-5-Cl-Ph Me 4-MeO-Ph NH
2-375 2,4-diF-Ph Me 4-MeO-Ph NH
2-376 2,5-diF-Ph Me 4-MeO-Ph NH
2-377 2,6-diF-Ph Me 4-MeO-Ph NH
2-378 3,4-diF-Ph Me 4-MeO-Ph NH
2-379 3,5-diF-Ph Me 4-MeO-Ph NH
2-380 2,3,4,5,6-pentaF-Ph Me 4-MeO-Ph NH
2-381 3-Cl-4-F-Ph Me 4-MeO-Ph NH
2-382 3-Me-4-F-Ph Me 4-MeO-Ph NH
2-383 2-MeO-5-F-Ph Me 4-MeO-Ph NH
2-384 2-CF₃-Ph Me 4-MeO-Ph NH
2-385 3,5-di(CF₃)-Ph Me 4-MeO-Ph NH
2-386 2-HO-Ph Me 4-MeO-Ph NH
2-387 2-HOCH₂-Ph Me 4-MeO-Ph NH
2-388 2-H₂N-Ph Me 4-MeO-Ph NH
2-389 3-NO₂-Ph Me 4-MeO-Ph NH
2-390 3-CN-Ph Me 4-MeO-Ph NH
2-391 2-HCO-Ph Me 4-MeO-Ph NH
2-392 3-HCO-Ph Me 4-MeO-Ph NH
2-393 4-HCO-Ph Me 4-MeO-Ph NH
2-394 3-HOOC-Ph Me 4-MeO-Ph NH
2-395 4-HOOC-Ph Me 4-MeO-Ph NH
2-396 3,4-(-OCH₂O-)-Ph Me 4-MeO-Ph NH
2-397 4-MeS-Ph Me 4-MeO-Ph NH
2-398 3-Ac-Ph Me 4-MeO-Ph NH
2-399 4-Ac-Ph Me 4-MeO-Ph NH
2-400 1-Nph Me 4-MeO-Ph NH
2-401 2-Nph Me 4-MeO-Ph NH
2-402 4-tBu-Ph Me 4-MeO-Ph NH
2-403 5-Cl-2-Thi Me 4-MeO-Ph NH
2-404 5-Me-2-Thi Me 4-MeO-Ph NH
2-405 1-Boc-2-Pyro Me 4-MeO-Ph NH
2-406 2-Bzfur Me 4-MeO-Ph NH
2-407 2-Py Me 4-MeO-Ph NH
2-408 3-Py Me 4-MeO-Ph NH
2-409 4-Py Me 4-MeO-Ph NH
2-410 HO Et 4-MeO-Ph NH
2-411 MeO Et 4-MeO-Ph NH
2-412 EtO Et 4-MeO-Ph NH
2-413 PrO Et 4-MeO-Ph NH
2-414 BuO Et 4-MeO-Ph NH
2-415 BnO Et 4-MeO-Ph NH
2-416 iPrO Et 4-MeO-Ph NH
2-417 iBuO Et 4-MeO-Ph NH
2-418 tBuO Et 4-MeO-Ph NH
2-419 HOC(O) Et 4-MeO-Ph NH
2-420 MeOC(O) Et 4-MeO-Ph NH
2-421 Me₂N-CO Et 4-MeO-Ph NH
2-422 2,3-diMe-Ph Et 4-MeO-Ph NH
2-423 2,5-diMe-Ph Et 4-MeO-Ph NH
2-424 2,6-diMe-Ph Et 4-MeO-Ph NH
2-425 3,5-diMe-Ph Et 4-MeO-Ph NH
2-426 2,4-di(MeO)-Ph Et 4-MeO-Ph NH
2-427 2,5-di(MeO)-Ph Et 4-MeO-Ph NH
2-428 2,6-di(MeO)-Ph Et 4-MeO-Ph NH
2-429 3,4-di(MeO)-Ph Et 4-MeO-Ph NH
2-430 2,5-diCl-Ph Et 4-MeO-Ph NH
2-431 3,4-diCl-Ph Et 4-MeO-Ph NH
2-432 2-MeO-5-Cl-Ph Et 4-MeO-Ph NH
2-433 2,4-diF-Ph Et 4-MeO-Ph NH
2-434 2,5-diF-Ph Et 4-MeO-Ph NH
2-435 2,6-diF-Ph Et 4-MeO-Ph NH
2-436 3,4-diF-Ph Et 4-MeO-Ph NH
2-437 3,5-diF-Ph Et 4-MeO-Ph NH
2-438 2,3,4,5,6-pentaF-Ph Et 4-MeO-Ph NH
2-439 3-Cl-4-F-Ph Et 4-MeO-Ph NH
2-440 3-Me-4-F-Ph Et 4-MeO-Ph NH
2-441 2-MeO-5-F-Ph Et 4-MeO-Ph NH
2-442 2-CF₃-Ph Et 4-MeO-Ph NH
2-443 3,5-di(CF₃)-Ph Et 4-MeO-Ph NH
2-444 2-HO-Ph Et 4-MeO-Ph NH
2-445 2-HOCH₂-Ph Et 4-MeO-Ph NH
2-446 2-H₂N-Ph Et 4-MeO-Ph NH
2-447 3-NO₂-Ph Et 4-MeO-Ph NH
2-448 3-CN-Ph Et 4-MeO-Ph NH
2-449 2-HCO-Ph Et 4-MeO-Ph NH
2-450 3-HCO-Ph Et 4-MeO-Ph NH
2-451 4-HCO-Ph Et 4-MeO-Ph NH
2-452 3-HOOC-Ph Et 4-MeO-Ph NH
2-453 4-HOOC-Ph Et 4-MeO-Ph NH
2-454 3,4-(-OCH₂O-)-Ph Et 4-MeO-Ph NH
2-455 4-MeS-Ph Et 4-MeO-Ph NH
2-456 3-Ac-Ph Et 4-MeO-Ph NH
2-457 4-Ac-Ph Et 4-MeO-Ph NH
2-458 1-Nph Et 4-MeO-Ph NH
2-459 2-Nph Et 4-MeO-Ph NH
2-460 4-tBu-Ph Et 4-MeO-Ph NH
2-461 5-Cl-2-Thi Et 4-MeO-Ph NH
2-462 5-Me-2-Thi Et 4-MeO-Ph NH
2-463 1-Boc-2-Pyro Et 4-MeO-Ph NH
2-464 2-Bzfur Et 4-MeO-Ph NH
2-465 2-Py Et 4-MeO-Ph NH
2-466 3-Py Et 4-MeO-Ph NH
2-467 4-Py Et 4-MeO-Ph NH
2-468 HO Pr 4-MeO-Ph NH
2-469 MeO Pr 4-MeO-Ph NH
2-470 EtO Pr 4-MeO-Ph NH
2-471 PrO Pr 4-MeO-Ph NH
2-472 BuO Pr 4-MeO-Ph NH
2-473 BnO Pr 4-MeO-Ph NH
2-474 iPrO Pr 4-MeO-Ph NH
2-475 iBuO Pr 4-MeO-Ph NH
2-476 tBuO Pr 4-MeO-Ph NH
2-477 HOC(O) Pr 4-MeO-Ph NH
2-478 MeOC(O) Pr 4-MeO-Ph NH
2-479 Me₂N-CO Pr 4-MeO-Ph NH
2-480 2,3-diMe-Ph Pr 4-MeO-Ph NH
2-481 2,5-diMe-Ph Pr 4-MeO-Ph NH
2-482 2,6-diMe-Ph Pr 4-MeO-Ph NH
2-483 3,5-diMe-Ph Pr 4-MeO-Ph NH
2-484 2,4-di(MeO)-Ph Pr 4-MeO-Ph NH
2-485 2,5-di(MeO)-Ph Pr 4-MeO-Ph NH
2-486 2,6-di(MeO)-Ph Pr 4-MeO-Ph NH
2-487 3,4-di(MeO)-Ph Pr 4-MeO-Ph NH
2-488 2,5-diCl-Ph Pr 4-MeO-Ph NH
2-489 3,4-diCl-Ph Pr 4-MeO-Ph NH
2-490 2-MeO-5-Cl-Ph Pr 4-MeO-Ph NH
2-491 2,4-diF-Ph Pr 4-MeO-Ph NH
2-492 2,5-diF-Ph Pr 4-MeO-Ph NH
2-493 2,6-diF-Ph Pr 4-MeO-Ph NH
2-494 3,4-diF-Ph Pr 4-MeO-Ph NH
2-495 3,5-diF-Ph Pr 4-MeO-Ph NH
2-496 2,3,4,5,6-pentaF-Ph Pr 4-MeO-Ph NH
2-497 3-Cl-4-F-Ph Pr 4-MeO-Ph NH
2-498 3-Me-4-F-Ph Pr 4-MeO-Ph NH
2-499 2-MeO-5-F-Ph Pr 4-MeO-Ph NH
2-500 2-CF₃-Ph Pr 4-MeO-Ph NH
2-501 3,5-di(CF₃)-Ph Pr 4-MeO-Ph NH
2-502 2-HO-Ph Pr 4-MeO-Ph NH
2-503 2-HOCH₂-Ph Pr 4-MeO-Ph NH
2-504 2-H₂N-Ph Pr 4-MeO-Ph NH
2-505 3-NO₂-Ph Pr 4-MeO-Ph NH
2-506 3-CN-Ph Pr 4-MeO-Ph NH
2-507 2-HCO-Ph Pr 4-MeO-Ph NH
2-508 3-HCO-Ph Pr 4-MeO-Ph NH
2-509 4-HCO-Ph Pr 4-MeO-Ph NH
2-510 3-HOOC-Ph Pr 4-MeO-Ph NH
2-511 4-HOOC-Ph Pr 4-MeO-Ph NH
2-512 3,4-(-OCH₂O-)-Ph Pr 4-MeO-Ph NH
2-513 4-MeS-Ph Pr 4-MeO-Ph NH
2-514 3-Ac-Ph Pr 4-MeO-Ph NH
2-515 4-Ac-Ph Pr 4-MeO-Ph NH
2-516 1-Nph Pr 4-MeO-Ph NH
2-517 2-Nph Pr 4-MeO-Ph NH
2-518 4-tBu-Ph Pr 4-MeO-Ph NH
2-519 5-Cl-2-Thi Pr 4-MeO-Ph NH
2-520 5-Me-2-Thi Pr 4-MeO-Ph NH
2-521 1-Boc-2-Pyro Pr 4-MeO-Ph NH
2-522 2-Bzfur Pr 4-MeO-Ph NH
2-523 2-Py Pr 4-MeO-Ph NH
2-524 3-Py Pr 4-MeO-Ph NH
2-525 4-Py Pr 4-MeO-Ph NH
2-526 HO Bu 4-MeO-Ph NH
2-527 MeO Bu 4-MeO-Ph NH
2-528 EtO Bu 4-MeO-Ph NH
2-529 PrO Bu 4-MeO-Ph NH
2-530 BuO Bu 4-MeO-Ph NH
2-531 BnO Bu 4-MeO-Ph NH
2-532 iPrO Bu 4-MeO-Ph NH
2-533 iBuO Bu 4-MeO-Ph NH
2-534 tBuO Bu 4-MeO-Ph NH
2-535 HOC(O) Bu 4-MeO-Ph NH
2-536 MeOC(O) Bu 4-MeO-Ph NH
2-537 Me₂N-CO Bu 4-MeO-Ph NH
2-538 2,3-diMe-Ph Bu 4-MeO-Ph NH
2-539 2,5-diMe-Ph Bu 4-MeO-Ph NH
2-540 2,6-diMe-Ph Bu 4-MeO-Ph NH
2-541 3,5-diMe-Ph Bu 4-MeO-Ph NH
2-542 2,4-di(MeO)-Ph Bu 4-MeO-Ph NH
2-543 2,5-di(MeO)-Ph Bu 4-MeO-Ph NH
2-544 2,6-di(MeO)-Ph Bu 4-MeO-Ph NH
2-545 3,4-di(MeO)-Ph Bu 4-MeO-Ph NH
2-546 2,5-diCl-Ph Bu 4-MeO-Ph NH
2-547 3,4-diCl-Ph Bu 4-MeO-Ph NH
2-548 2-MeO-5-Cl-Ph Bu 4-MeO-Ph NH
2-549 2,4-diF-Ph Bu 4-MeO-Ph NH
2-550 2,5-diF-Ph Bu 4-MeO-Ph NH
2-551 2,6-diF-Ph Bu 4-MeO-Ph NH
2-552 3,4-diF-Ph Bu 4-MeO-Ph NH
2-553 3,5-diF-Ph Bu 4-MeO-Ph NH
2-554 2,3,4,5,6-pentaF-Ph Bu 4-MeO-Ph NH
2-555 3-Cl-4-F-Ph Bu 4-MeO-Ph NH
2-556 3-Me-4-F-Ph Bu 4-MeO-Ph NH
2-557 2-MeO-5-F-Ph Bu 4-MeO-Ph NH
2-558 2-CF₃-Ph Bu 4-MeO-Ph NH
2-559 3,5-di(CF₃)-Ph Bu 4-MeO-Ph NH
2-560 2-HO-Ph Bu 4-MeO-Ph NH
2-561 2-HOCH₂-Ph Bu 4-MeO-Ph NH
2-562 2-H₂N-Ph Bu 4-MeO-Ph NH
2-563 3-NO₂-Ph Bu 4-MeO-Ph NH
2-564 3-CN-Ph Bu 4-MeO-Ph NH
2-565 2-HCO-Ph Bu 4-MeO-Ph NH
2-566 3-HCO-Ph Bu 4-MeO-Ph NH
2-567 4-HCO-Ph Bu 4-MeO-Ph NH
2-568 3-HOOC-Ph Bu 4-MeO-Ph NH
2-569 4-HOOC-Ph Bu 4-MeO-Ph NH
2-570 3,4-(-OCH₂O-)-Ph Bu 4-MeO-Ph NH
2-571 4-MeS-Ph Bu 4-MeO-Ph NH
2-572 3-Ac-Ph Bu 4-MeO-Ph NH
2-573 4-Ac-Ph Bu 4-MeO-Ph NH
2-574 1-Nph Bu 4-MeO-Ph NH
2-575 2-Nph Bu 4-MeO-Ph NH
2-576 4-tBu-Ph Bu 4-MeO-Ph NH
2-577 5-Cl-2-Thi Bu 4-MeO-Ph NH
2-578 5-Me-2-Thi Bu 4-MeO-Ph NH
2-579 1-Boc-2-Pyro Bu 4-MeO-Ph NH
2-580 2-Bzfur Bu 4-MeO-Ph NH
2-581 2-Py Bu 4-MeO-Ph NH
2-582 3-Py Bu 4-MeO-Ph NH
2-583 4-Py Bu 4-MeO-Ph NH
------------------------------------------------Exemplary Compound Table 2
------------------------------------------------
Compound number RR⁴ Ar X
------------------------------------------------
2-1 Br Me 4-MeO-Ph NH
2-2 Ph Me 4-MeO-Ph NH
2-3 2-Me-Ph Me 4-MeO-Ph NH
2-4 3-Me-Ph Me 4-MeO-Ph NH
2-5 4-Me-Ph Me 4-MeO-Ph NH
2-6 2-MeO-Ph Me 4-MeO-Ph NH
2-7 3-MeO-Ph Me 4-MeO-Ph NH
2-8 4-MeO-Ph Me 4-MeO-Ph NH
2-9 2-Cl-Ph Me 4-MeO-Ph NH
2-10 3-Cl-Ph Me 4-MeO-Ph NH
2-11 4-Cl-Ph Me 4-MeO-Ph NH
2-12 2-F-Ph Me 4-MeO-Ph NH
2-13 3-F-Ph Me 4-MeO-Ph NH
2-14 4-F-Ph Me 4-MeO-Ph NH
2-15 3-CF₃ -Ph Me 4-MeO-Ph NH
2-16 4-CF₃ -Ph Me 4-MeO-Ph NH
2-17 3-CF₃ O-Ph Me 4-MeO-Ph NH
2-18 4-CF₃ O-Ph Me 4-MeO-Ph NH
2-19 3-HO-Ph Me 4-MeO-Ph NH
2-20 4-HO-Ph Me 4-MeO-Ph NH
2-21 3-HOCH₂ -Ph Me 4-MeO-Ph NH
2-22 4-HOCH₂ -Ph Me 4-MeO-Ph NH
2-23 3-H₂ N-Ph Me 4-MeO-Ph NH
2-24 4-H₂ N-Ph Me 4-MeO-Ph NH
2-25 2-Thi Me 4-MeO-Ph NH
2-26 3-Thi Me 4-MeO-Ph NH
2-27 2-Fur Me 4-MeO-Ph NH
2-28 Br Et 4-MeO-Ph NH
2-29 Ph Et 4-MeO-Ph NH
2-30 2-Me-Ph Et 4-MeO-Ph NH
2-31 3-Me-Ph Et 4-MeO-Ph NH
2-32 4-Me-Ph Et 4-MeO-Ph NH
2-33 2-MeO-Ph Et 4-MeO-Ph NH
2-34 3-MeO-Ph Et 4-MeO-Ph NH
2-35 4-MeO-Ph Et 4-MeO-Ph NH
2-36 2-Cl-Ph Et 4-MeO-Ph NH
2-37 3-Cl-Ph Et 4-MeO-Ph NH
2-38 4-Cl-Ph Et 4-MeO-Ph NH
2-39 2-F-Ph Et 4-MeO-Ph NH
2-40 3-F-Ph Et 4-MeO-Ph NH
2-41 4-F-Ph Et 4-MeO-Ph NH
2-42 3-CF₃ -Ph Et 4-MeO-Ph NH
2-43 4-CF₃ -Ph Et 4-MeO-Ph NH
2-44 3-CF₃ O-Ph Et 4-MeO-Ph NH
2-45 4-CF₃ O-Ph Et 4-MeO-Ph NH
2-46 3-HO-Ph Et 4-MeO-Ph NH
2-47 4-HO-Ph Et 4-MeO-Ph NH
2-48 3-HOCH₂ -Ph Et 4-MeO-Ph NH
2-49 4-HOCH₂ -Ph Et 4-MeO-Ph NH
2-50 3-H₂ N-Ph Et 4-MeO-Ph NH
2-51 4-H₂ N-Ph Et 4-MeO-Ph NH
2-52 2-Thi Et 4-MeO-Ph NH
2-53 3-Thi Et 4-MeO-Ph NH
2-54 2-Fur Et 4-MeO-Ph NH
2-55 Br Pr 4-MeO-Ph NH
2-56 Ph Pr 4-MeO-Ph NH
2-57 2-Me-Ph Pr 4-MeO-Ph NH
2-58 3-Me-Ph Pr 4-MeO-Ph NH
2-59 4-Me-Ph Pr 4-MeO-Ph NH
2-60 2-MeO-Ph Pr 4-MeO-Ph NH
2-61 3-MeO-Ph Pr 4-MeO-Ph NH
2-62 4-MeO-Ph Pr 4-MeO-Ph NH
2-63 2-Cl-Ph Pr 4-MeO-Ph NH
2-64 3-Cl-Ph Pr 4-MeO-Ph NH
2-65 4-Cl-Ph Pr 4-MeO-Ph NH
2-66 2-F-Ph Pr 4-MeO-Ph NH
2-67 3-F-Ph Pr 4-MeO-Ph NH
2-68 4-F-Ph Pr 4-MeO-Ph NH
2-69 3-CF₃ -Ph Pr 4-MeO-Ph NH
2-70 4-CF₃ -Ph Pr 4-MeO-Ph NH
2-71 3-CF₃ O-Ph Pr 4-MeO-Ph NH
2-72 4-CF₃ O-Ph Pr 4-MeO-Ph NH
2-73 3-HO-Ph Pr 4-MeO-Ph NH
2-74 4-HO-Ph Pr 4-MeO-Ph NH
2-75 3-HOCH₂ -Ph Pr 4-MeO-Ph NH
2-76 4-HOCH₂ -Ph Pr 4-MeO-Ph NH
2-77 3-H₂ N-Ph Pr 4-MeO-Ph NH
2-78 4-H₂ N-Ph Pr 4-MeO-Ph NH
2-79 2-Thi Pr 4-MeO-Ph NH
2-80 3-Thi Pr 4-MeO-Ph NH
2-81 2-Fur Pr 4-MeO-Ph NH
2-82 Br Bu 4-MeO-Ph NH
2-83 Ph Bu 4-MeO-Ph NH
2-84 2-Me-Ph Bu 4-MeO-Ph NH
2-85 3-Me-Ph Bu 4-MeO-Ph NH
2-86 4-Me-Ph Bu 4-MeO-Ph NH
2-87 2-MeO-Ph Bu 4-MeO-Ph NH
2-88 3-MeO-Ph Bu 4-MeO-Ph NH
2-89 4-MeO-Ph Bu 4-MeO-Ph NH
2-90 2-Cl-Ph Bu 4-MeO-Ph NH
2-91 3-Cl-Ph Bu 4-MeO-Ph NH
2-92 4-Cl-Ph Bu 4-MeO-Ph NH
2-93 2-F-Ph Bu 4-MeO-Ph NH
2-94 3-F-Ph Bu 4-MeO-Ph NH
2-95 4-F-Ph Bu 4-MeO-Ph NH
2-96 3-CF₃ -Ph Bu 4-MeO-Ph NH
2-97 4-CF₃ -Ph Bu 4-MeO-Ph NH
2-98 3-CF₃ O-Ph Bu 4-MeO-Ph NH
2-99 4-CF₃ O-Ph Bu 4-MeO-Ph NH
2-100 3-HO-Ph Bu 4-MeO-Ph NH
2-101 4-HO-Ph Bu 4-MeO-Ph NH
2-102 3-HOCH₂ -Ph Bu 4-MeO-Ph NH
2-103 4-HOCH₂ -Ph Bu 4-MeO-Ph NH
2-104 3-H₂ N-Ph Bu 4-MeO-Ph NH
2-105 4-H₂ N-Ph Bu 4-MeO-Ph NH
2-106 2-Thi Bu 4-MeO-Ph NH
2-107 3-Thi Bu 4-MeO-Ph NH
2-108 2-Fur Bu 4-MeO-Ph NH
2-109 Br iPr 4-MeO-Ph NH
2-110 Ph iPr 4-MeO-Ph NH
2-111 2-Me-Ph iPr 4-MeO-Ph NH
2-112 3-Me-Ph iPr 4-MeO-Ph NH
2-113 4-Me-Ph iPr 4-MeO-Ph NH
2-114 2-MeO-Ph iPr 4-MeO-Ph NH
2-115 3-MeO-Ph iPr 4-MeO-Ph NH
2-116 4-MeO-Ph iPr 4-MeO-Ph NH
2-117 2-Cl-Ph iPr 4-MeO-Ph NH
2-118 3-Cl-Ph iPr 4-MeO-Ph NH
2-119 4-Cl-Ph iPr 4-MeO-Ph NH
2-120 2-F-Ph iPr 4-MeO-Ph NH
2-121 3-F-Ph iPr 4-MeO-Ph NH
2-122 4-F-Ph iPr 4-MeO-Ph NH
2-123 3-CF₃ -Ph iPr 4-MeO-Ph NH
2-124 4-CF₃ -Ph iPr 4-MeO-Ph NH
2-125 3-CF₃ O-Ph iPr 4-MeO-Ph NH
2-126 4-CF₃ O-Ph iPr 4-MeO-Ph NH
2-127 3-HO-Ph iPr 4-MeO-Ph NH
2-128 4-HO-Ph iPr 4-MeO-Ph NH
2-129 3-HOCH₂ -Ph iPr 4-MeO-Ph NH
2-130 4-HOCH₂ -Ph iPr 4-MeO-Ph NH
2-131 3-H₂ N-Ph iPr 4-MeO-Ph NH
2-132 4-H₂ N-Ph iPr 4-MeO-Ph NH
2-133 2-Thi iPr 4-MeO-Ph NH
2-134 3-Thi iPr 4-MeO-Ph NH
2-135 2-Fur iPr 4-MeO-Ph NH
2-136 Br iBu 4-MeO-Ph NH
2-137 Ph iBu 4-MeO-Ph NH
2-138 2-Me-Ph iBu 4-MeO-Ph NH
2-139 3-Me-Ph iBu 4-MeO-Ph NH
2-140 4-Me-Ph iBu 4-MeO-Ph NH
2-141 2-MeO-Ph iBu 4-MeO-Ph NH
2-142 3-MeO-Ph iBu 4-MeO-Ph NH
2-143 4-MeO-Ph iBu 4-MeO-Ph NH
2-144 2-Cl-Ph iBu 4-MeO-Ph NH
2-145 3-Cl-Ph iBu 4-MeO-Ph NH
2-146 4-Cl-Ph iBu 4-MeO-Ph NH
2-147 2-F-Ph iBu 4-MeO-Ph NH
2-148 3-F-Ph iBu 4-MeO-Ph NH
2-149 4-F-Ph iBu 4-MeO-Ph NH
2-150 3-CF₃ -Ph iBu 4-MeO-Ph NH
2-151 4-CF₃ -Ph iBu 4-MeO-Ph NH
2-152 3-CF₃ O-Ph iBu 4-MeO-Ph NH
2-153 4-CF₃ O-Ph iBu 4-MeO-Ph NH
2-154 3-HO-Ph iBu 4-MeO-Ph NH
2-155 4-HO-Ph iBu 4-MeO-Ph NH
2-156 3-HOCH₂ -Ph iBu 4-MeO-Ph NH
2-157 4-HOCH₂ -Ph iBu 4-MeO-Ph NH
2-158 3-H₂ N-Ph iBu 4-MeO-Ph NH
2-159 4-H₂ N-Ph iBu 4-MeO-Ph NH
2-160 2-Thi iBu 4-MeO-Ph NH
2-161 3-Thi iBu 4-MeO-Ph NH
2-162 2-Fur iBu 4-MeO-Ph NH
2-163 Br Ph 4-MeO-Ph NH
2-164 Ph Ph 4-MeO-Ph NH
2-165 2-Me-Ph Ph 4-MeO-Ph NH
2-166 3-Me-Ph Ph 4-MeO-Ph NH
2-167 4-Me-Ph Ph 4-MeO-Ph NH
2-168 2-MeO-Ph Ph 4-MeO-Ph NH
2-169 3-MeO-Ph Ph 4-MeO-Ph NH
2-170 4-MeO-Ph Ph 4-MeO-Ph NH
2-171 2-Cl-Ph Ph 4-MeO-Ph NH
2-172 3-Cl-Ph Ph 4-MeO-Ph NH
2-173 4-Cl-Ph Ph 4-MeO-Ph NH
2-174 2-F-Ph Ph 4-MeO-Ph NH
2-175 3-F-Ph Ph 4-MeO-Ph NH
2-176 4-F-Ph Ph 4-MeO-Ph NH
2-177 3-CF₃ -Ph Ph 4-MeO-Ph NH
2-178 4-CF₃ -Ph Ph 4-MeO-Ph NH
2-179 3-CF₃ O-Ph Ph 4-MeO-Ph NH
2-180 4-CF₃ O-Ph Ph 4-MeO-Ph NH
2-181 3-HO-Ph Ph 4-MeO-Ph NH
2-182 4-HO-Ph Ph 4-MeO-Ph NH
2-183 3-HOCH₂ -Ph Ph 4-MeO-Ph NH
2-184 4-HOCH₂ -Ph Ph 4-MeO-Ph NH
2-185 3-H₂ N-Ph Ph 4-MeO-Ph NH
2-186 4-H₂ N-Ph Ph 4-MeO-Ph NH
2-187 2-Thi Ph 4-MeO-Ph NH
2-188 3-Thi Ph 4-MeO-Ph NH
2-189 2-Fur Ph 4-MeO-Ph NH
2-190 Br Bn 4-MeO-Ph NH
2-191 Ph Bn 4-MeO-Ph NH
2-192 2-Me-Ph Bn 4-MeO-Ph NH
2-193 3-Me-Ph Bn 4-MeO-Ph NH
2-194 4-Me-Ph Bn 4-MeO-Ph NH
2-195 2-MeO-Ph Bn 4-MeO-Ph NH
2-196 3-MeO-Ph Bn 4-MeO-Ph NH
2-197 4-MeO-Ph Bn 4-MeO-Ph NH
2-198 2-Cl-Ph Bn 4-MeO-Ph NH
2-199 3-Cl-Ph Bn 4-MeO-Ph NH
2-200 4-Cl-Ph Bn 4-MeO-Ph NH
2-201 2-F-Ph Bn 4-MeO-Ph NH
2-202 3-F-Ph Bn 4-MeO-Ph NH
2-203 4-F-Ph Bn 4-MeO-Ph NH
2-204 3-CF₃ -Ph Bn 4-MeO-Ph NH
2-205 4-CF₃ -Ph Bn 4-MeO-Ph NH
2-206 3-CF₃ O-Ph Bn 4-MeO-Ph NH
2-207 4-CF₃ O-Ph Bn 4-MeO-Ph NH
2-208 3-HO-Ph Bn 4-MeO-Ph NH
2-209 4-HO-Ph Bn 4-MeO-Ph NH
2-210 3-HOCH₂ -Ph Bn 4-MeO-Ph NH
2-211 4-HOCH₂ -Ph Bn 4-MeO-Ph NH
2-212 3-H₂ N-Ph Bn 4-MeO-Ph NH
2-213 4-H₂ N-Ph Bn 4-MeO-Ph NH
2-214 2-Thi Bn 4-MeO-Ph NH
2-215 3-Thi Bn 4-MeO-Ph NH
2-216 2-Fur Bn 4-MeO-Ph NH
2-217 Br Phet 4-MeO-Ph NH
2-218 Ph Phet 4-MeO-Ph NH
2-219 2-Me-Ph Phet 4-MeO-Ph NH
2-220 3-Me-Ph Phet 4-MeO-Ph NH
2-221 4-Me-Ph Phet 4-MeO-Ph NH
2-222 2-MeO-Ph Phet 4-MeO-Ph NH
2-223 3-MeO-Ph Phet 4-MeO-Ph NH
2-224 4-MeO-Ph Phet 4-MeO-Ph NH
2-225 2-Cl-Ph Phet 4-MeO-Ph NH
2-226 3-Cl-Ph Phet 4-MeO-Ph NH
2-227 4-Cl-Ph Phet 4-MeO-Ph NH
2-228 2-F-Ph Phet 4-MeO-Ph NH
2-229 3-F-Ph Phet 4-MeO-Ph NH
2-230 4-F-Ph Phet 4-MeO-Ph NH
2-231 3-CF₃ -Ph Phet 4-MeO-Ph NH
2-232 4-CF₃ -Ph Phet 4-MeO-Ph NH
2-233 3-CF₃ O-Ph Phet 4-MeO-Ph NH
2-234 4-CF₃ O-Ph Phet 4-MeO-Ph NH
2-235 3-HO-Ph Phet 4-MeO-Ph NH
2-236 4-HO-Ph Phet 4-MeO-Ph NH
2-237 3-HOCH₂ -Ph Phet 4-MeO-Ph NH
2-238 4-HOCH₂ -Ph Phet 4-MeO-Ph NH
2-239 3-H₂ N-Ph Phet 4-MeO-Ph NH
2-240 4-H₂ N-Ph Phet 4-MeO-Ph NH
2-241 2-Thi Phet 4-MeO-Ph NH
2-242 3-Thi Phet 4-MeO-Ph NH
2-243 2-Fur Phet 4-MeO-Ph NH
2-244 Br Me 4-BnO-Ph NH
2-245 Ph Me 4-BnO-Ph NH
2-246 2-Me-Ph Me 4-BnO-Ph NH
2-247 3-Me-Ph Me 4-BnO-Ph NH
2-248 4-Me-Ph Me 4-BnO-Ph NH
2-249 2-MeO-Ph Me 4-BnO-Ph NH
2-250 3-MeO-Ph Me 4-BnO-Ph NH
2-251 4-MeO-Ph Me 4-BnO-Ph NH
2-252 2-Cl-Ph Me 4-BnO-Ph NH
2-253 3-Cl-Ph Me 4-BnO-Ph NH
2-254 4-Cl-Ph Me 4-BnO-Ph NH
2-255 2-F-Ph Me 4-BnO-Ph NH
2-256 3-F-Ph Me 4-BnO-Ph NH
2-257 4-F-Ph Me 4-BnO-Ph NH
2-258 3-CF₃ -Ph Me 4-BnO-Ph NH
2-259 4-CF₃ -Ph Me 4-BnO-Ph NH
2-260 3-CF₃ O-Ph Me 4-BnO-Ph NH
2-261 4-CF₃ O-Ph Me 4-BnO-Ph NH
2-262 3-HO-Ph Me 4-BnO-Ph NH
2-263 4-HO-Ph Me 4-BnO-Ph NH
2-264 3-HOCH₂ -Ph Me 4-BnO-Ph NH
2-265 4-HOCH₂ -Ph Me 4-BnO-Ph NH
2-266 3-H₂ N-Ph Me 4-BnO-Ph NH
2-267 4-H₂ N-Ph Me 4-BnO-Ph NH
2-268 2-Thi Me 4-BnO-Ph NH
2-269 3-Thi Me 4-BnO-Ph NH
2-270 2-Fur Me 4-BnO-Ph NH
2-271 Br Et 4-BnO-Ph NH
2-272 Ph Et 4-BnO-Ph NH
2-273 2-Me-Ph Et 4-BnO-Ph NH
2-274 3-Me-Ph Et 4-BnO-Ph NH
2-275 4-Me-Ph Et 4-BnO-Ph NH
2-276 2-MeO-Ph Et 4-BnO-Ph NH
2-277 3-MeO-Ph Et 4-BnO-Ph NH
2-278 4-MeO-Ph Et 4-BnO-Ph NH
2-279 2-Cl-Ph Et 4-BnO-Ph NH
2-280 3-Cl-Ph Et 4-BnO-Ph NH
2-281 4-Cl-Ph Et 4-BnO-Ph NH
2-282 2-F-Ph Et 4-BnO-Ph NH
2-283 3-F-Ph Et 4-BnO-Ph NH
2-284 4-F-Ph Et 4-BnO-Ph NH
2-285 3-CF₃ -Ph Et 4-BnO-Ph NH
2-286 4-CF₃ -Ph Et 4-BnO-Ph NH
2-287 3-CF₃ O-Ph Et 4-BnO-Ph NH
2-288 4-CF₃ O-Ph Et 4-BnO-Ph NH
2-289 3-HO-Ph Et 4-BnO-Ph NH
2-290 4-HO-Ph Et 4-BnO-Ph NH
2-291 3-HOCH₂ -Ph Et 4-BnO-Ph NH
2-292 4-HOCH₂ -Ph Et 4-BnO-Ph NH
2-293 3-H₂ N-Ph Et 4-BnO-Ph NH
2-294 4-H₂ N-Ph Et 4-BnO-Ph NH
2-295 2-Thi Et 4-BnO-Ph NH
2-296 3-Thi Et 4-BnO-Ph NH
2-297 2-Fur Et 4-BnO-Ph NH
2-298 Br Pr 4-BnO-Ph NH
2-299 Ph Pr 4-BnO-Ph NH
2-300 2-Me-Ph Pr 4-BnO-Ph NH
2-301 3-Me-Ph Pr 4-BnO-Ph NH
2-302 4-Me-Ph Pr 4-BnO-Ph NH
2-303 2-MeO-Ph Pr 4-BnO-Ph NH
2-304 3-MeO-Ph Pr 4-BnO-Ph NH
2-305 4-MeO-Ph Pr 4-BnO-Ph NH
2-306 2-Cl-Ph Pr 4-BnO-Ph NH
2-307 3-Cl-Ph Pr 4-BnO-Ph NH
2-308 4-Cl-Ph Pr 4-BnO-Ph NH
2-309 2-F-Ph Pr 4-BnO-Ph NH
2-310 3-F-Ph Pr 4-BnO-Ph NH
2-311 4-F-Ph Pr 4-BnO-Ph NH
2-312 3-CF₃ -Ph Pr 4-BnO-Ph NH
2-313 4-CF₃ -Ph Pr 4-BnO-Ph NH
2-314 3-CF₃ O-Ph Pr 4-BnO-Ph NH
2-315 4-CF₃ O-Ph Pr 4-BnO-Ph NH
2-316 3-HO-Ph Pr 4-BnO-Ph NH
2-317 4-HO-Ph Pr 4-BnO-Ph NH
2-318 3-HOCH₂ -Ph Pr 4-BnO-Ph NH
2-319 4-HOCH₂ -Ph Pr 4-BnO-Ph NH
2-320 3-H₂ N-Ph Pr 4-BnO-Ph NH
2-321 4-H₂ N-Ph Pr 4-BnO-Ph NH
2-322 2-Thi Pr 4-BnO-Ph NH
2-323 3-Thi Pr 4-BnO-Ph NH
2-324 2-Fur Pr 4-BnO-Ph NH
2-325 Br Bu 4-BnO-Ph NH
2-326 Ph Bu 4-BnO-Ph NH
2-327 2-Me-Ph Bu 4-BnO-Ph NH
2-328 3-Me-Ph Bu 4-BnO-Ph NH
2-329 4-Me-Ph Bu 4-BnO-Ph NH
2-330 2-MeO-Ph Bu 4-BnO-Ph NH
2-331 3-MeO-Ph Bu 4-BnO-Ph NH
2-332 4-MeO-Ph Bu 4-BnO-Ph NH
2-333 2-Cl-Ph Bu 4-BnO-Ph NH
2-334 3-Cl-Ph Bu 4-BnO-Ph NH
2-335 4-Cl-Ph Bu 4-BnO-Ph NH
2-336 2-F-Ph Bu 4-BnO-Ph NH
2-337 3-F-Ph Bu 4-BnO-Ph NH
2-338 4-F-Ph Bu 4-BnO-Ph NH
2-339 3-CF₃ -Ph Bu 4-BnO-Ph NH
2-340 4-CF₃ -Ph Bu 4-BnO-Ph NH
2-341 3-CF₃ O-Ph Bu 4-BnO-Ph NH
2-342 4-CF₃ O-Ph Bu 4-BnO-Ph NH
2-343 3-HO-Ph Bu 4-BnO-Ph NH
2-344 4-HO-Ph Bu 4-BnO-Ph NH
2-345 3-HOCH₂ -Ph Bu 4-BnO-Ph NH
2-346 4-HOCH₂ -Ph Bu 4-BnO-Ph NH
2-347 3-H₂ N-Ph Bu 4-BnO-Ph NH
2-348 4-H₂ N-Ph Bu 4-BnO-Ph NH
2-349 2-Thi Bu 4-BnO-Ph NH
2-350 3-Thi Bu 4-BnO-Ph NH
2-351 2-Fur Bu 4-BnO-Ph NH
2-352 HO Me 4-MeO-Ph NH
2-353 MeO Me 4-MeO-Ph NH
2-354 EtO Me 4-MeO-Ph NH
2-355 PrO Me 4-MeO-Ph NH
2-356 BuO Me 4-MeO-Ph NH
2-357 BnO Me 4-MeO-Ph NH
2-358 iPrO Me 4-MeO-Ph NH
2-359 iBuO Me 4-MeO-Ph NH
2-360 tBuO Me 4-MeO-Ph NH
2-361 HOC (O) Me 4-MeO-Ph NH
2-362 MeOC (O) Me 4-MeO-Ph NH
2-363 Me₂ N-CO Me 4-MeO-Ph NH
2-364 2,3-diMe-Ph Me 4-MeO-Ph NH
2-365 2,5-diMe-Ph Me 4-MeO-Ph NH
2-366 2,6-diMe-Ph Me 4-MeO-Ph NH
2-367 3,5-diMe-Ph Me 4-MeO-Ph NH
2-368 2,4-di (MeO) -Ph Me 4-MeO-Ph NH
2-369 2,5-di (MeO) -Ph Me 4-MeO-Ph NH
2-370 2,6-di (MeO) -Ph Me 4-MeO-Ph NH
2-371 3,4-di (MeO) -Ph Me 4-MeO-Ph NH
2-372 2,5-diCl-Ph Me 4-MeO-Ph NH
2-373 3,4-diCl-Ph Me 4-MeO-Ph NH
2-374 2-MeO-5-Cl-Ph Me 4-MeO-Ph NH
2-375 2,4-diF-Ph Me 4-MeO-Ph NH
2-376 2,5-diF-Ph Me 4-MeO-Ph NH
2-377 2,6-diF-Ph Me 4-MeO-Ph NH
2-378 3,4-diF-Ph Me 4-MeO-Ph NH
2-379 3,5-diF-Ph Me 4-MeO-Ph NH
2-380 2,3,4,5,6-pentaF-Ph Me 4-MeO-Ph NH
2-381 3-Cl-4-F-Ph Me 4-MeO-Ph NH
2-382 3-Me-4-F-Ph Me 4-MeO-Ph NH
2-383 2-MeO-5-F-Ph Me 4-MeO-Ph NH
2-384 2-CF₃ -Ph Me 4-MeO-Ph NH
2-385 3,5-di (CF₃ ) -Ph Me 4-MeO-Ph NH
2-386 2-HO-Ph Me 4-MeO-Ph NH
2-387 2-HOCH₂ -Ph Me 4-MeO-Ph NH
2-388 2-H₂ N-Ph Me 4-MeO-Ph NH
2-389 3-NO₂ -Ph Me 4-MeO-Ph NH
2-390 3-CN-Ph Me 4-MeO-Ph NH
2-391 2-HCO-Ph Me 4-MeO-Ph NH
2-392 3-HCO-Ph Me 4-MeO-Ph NH
2-393 4-HCO-Ph Me 4-MeO-Ph NH
2-394 3-HOOC-Ph Me 4-MeO-Ph NH
2-395 4-HOOC-Ph Me 4-MeO-Ph NH
2-396 3,4-(-OCH₂ O-)-Ph Me 4-MeO-Ph NH
2-397 4-MeS-Ph Me 4-MeO-Ph NH
2-398 3-Ac-Ph Me 4-MeO-Ph NH
2-399 4-Ac-Ph Me 4-MeO-Ph NH
2-400 1-Nph Me 4-MeO-Ph NH
2-401 2-Nph Me 4-MeO-Ph NH
2-402 4-tBu-Ph Me 4-MeO-Ph NH
2-403 5-Cl-2-Thi Me 4-MeO-Ph NH
2-404 5-Me-2-Thi Me 4-MeO-Ph NH
2-405 1-Boc-2-Pyro Me 4-MeO-Ph NH
2-406 2-Bzfur Me 4-MeO-Ph NH
2-407 2-Py Me 4-MeO-Ph NH
2-408 3-Py Me 4-MeO-Ph NH
2-409 4-Py Me 4-MeO-Ph NH
2-410 HO Et 4-MeO-Ph NH
2-411 MeO Et 4-MeO-Ph NH
2-412 EtO Et 4-MeO-Ph NH
2-413 PrO Et 4-MeO-Ph NH
2-414 BuO Et 4-MeO-Ph NH
2-415 BnO Et 4-MeO-Ph NH
2-416 iPrO Et 4-MeO-Ph NH
2-417 iBuO Et 4-MeO-Ph NH
2-418 tBuO Et 4-MeO-Ph NH
2-419 HOC (O) Et 4-MeO-Ph NH
2-420 MeOC (O) Et 4-MeO-Ph NH
2-421 Me₂ N-CO Et 4-MeO-Ph NH
2-422 2,3-diMe-Ph Et 4-MeO-Ph NH
2-423 2,5-diMe-Ph Et 4-MeO-Ph NH
2-424 2,6-diMe-Ph Et 4-MeO-Ph NH
2-425 3,5-diMe-Ph Et 4-MeO-Ph NH
2-426 2,4-di (MeO) -Ph Et 4-MeO-Ph NH
2-427 2,5-di (MeO) -Ph Et 4-MeO-Ph NH
2-428 2,6-di (MeO) -Ph Et 4-MeO-Ph NH
2-429 3,4-di (MeO) -Ph Et 4-MeO-Ph NH
2-430 2,5-diCl-Ph Et 4-MeO-Ph NH
2-431 3,4-diCl-Ph Et 4-MeO-Ph NH
2-432 2-MeO-5-Cl-Ph Et 4-MeO-Ph NH
2-433 2,4-diF-Ph Et 4-MeO-Ph NH
2-434 2,5-diF-Ph Et 4-MeO-Ph NH
2-435 2,6-diF-Ph Et 4-MeO-Ph NH
2-436 3,4-diF-Ph Et 4-MeO-Ph NH
2-437 3,5-diF-Ph Et 4-MeO-Ph NH
2-438 2,3,4,5,6-pentaF-Ph Et 4-MeO-Ph NH
2-439 3-Cl-4-F-Ph Et 4-MeO-Ph NH
2-440 3-Me-4-F-Ph Et 4-MeO-Ph NH
2-441 2-MeO-5-F-Ph Et 4-MeO-Ph NH
2-442 2-CF₃ -Ph Et 4-MeO-Ph NH
2-443 3,5-di (CF₃ ) -Ph Et 4-MeO-Ph NH
2-444 2-HO-Ph Et 4-MeO-Ph NH
2-445 2-HOCH₂ -Ph Et 4-MeO-Ph NH
2-446 2-H₂ N-Ph Et 4-MeO-Ph NH
2-447 3-NO₂ -Ph Et 4-MeO-Ph NH
2-448 3-CN-Ph Et 4-MeO-Ph NH
2-449 2-HCO-Ph Et 4-MeO-Ph NH
2-450 3-HCO-Ph Et 4-MeO-Ph NH
2-451 4-HCO-Ph Et 4-MeO-Ph NH
2-452 3-HOOC-Ph Et 4-MeO-Ph NH
2-453 4-HOOC-Ph Et 4-MeO-Ph NH
2-454 3,4-(-OCH₂ O-)-Ph Et 4-MeO-Ph NH
2-455 4-MeS-Ph Et 4-MeO-Ph NH
2-456 3-Ac-Ph Et 4-MeO-Ph NH
2-457 4-Ac-Ph Et 4-MeO-Ph NH
2-458 1-Nph Et 4-MeO-Ph NH
2-459 2-Nph Et 4-MeO-Ph NH
2-460 4-tBu-Ph Et 4-MeO-Ph NH
2-461 5-Cl-2-Thi Et 4-MeO-Ph NH
2-462 5-Me-2-Thi Et 4-MeO-Ph NH
2-463 1-Boc-2-Pyro Et 4-MeO-Ph NH
2-464 2-Bzfur Et 4-MeO-Ph NH
2-465 2-Py Et 4-MeO-Ph NH
2-466 3-Py Et 4-MeO-Ph NH
2-467 4-Py Et 4-MeO-Ph NH
2-468 HO Pr 4-MeO-Ph NH
2-469 MeO Pr 4-MeO-Ph NH
2-470 EtO Pr 4-MeO-Ph NH
2-471 PrO Pr 4-MeO-Ph NH
2-472 BuO Pr 4-MeO-Ph NH
2-473 BnO Pr 4-MeO-Ph NH
2-474 iPrO Pr 4-MeO-Ph NH
2-475 iBuO Pr 4-MeO-Ph NH
2-476 tBuO Pr 4-MeO-Ph NH
2-477 HOC (O) Pr 4-MeO-Ph NH
2-478 MeOC (O) Pr 4-MeO-Ph NH
2-479 Me₂ N-CO Pr 4-MeO-Ph NH
2-480 2,3-diMe-Ph Pr 4-MeO-Ph NH
2-481 2,5-diMe-Ph Pr 4-MeO-Ph NH
2-482 2,6-diMe-Ph Pr 4-MeO-Ph NH
2-483 3,5-diMe-Ph Pr 4-MeO-Ph NH
2-484 2,4-di (MeO) -Ph Pr 4-MeO-Ph NH
2-485 2,5-di (MeO) -Ph Pr 4-MeO-Ph NH
2-486 2,6-di (MeO) -Ph Pr 4-MeO-Ph NH
2-487 3,4-di (MeO) -Ph Pr 4-MeO-Ph NH
2-488 2,5-diCl-Ph Pr 4-MeO-Ph NH
2-489 3,4-diCl-Ph Pr 4-MeO-Ph NH
2-490 2-MeO-5-Cl-Ph Pr 4-MeO-Ph NH
2-491 2,4-diF-Ph Pr 4-MeO-Ph NH
2-492 2,5-diF-Ph Pr 4-MeO-Ph NH
2-493 2,6-diF-Ph Pr 4-MeO-Ph NH
2-494 3,4-diF-Ph Pr 4-MeO-Ph NH
2-495 3,5-diF-Ph Pr 4-MeO-Ph NH
2-496 2,3,4,5,6-pentaF-Ph Pr 4-MeO-Ph NH
2-497 3-Cl-4-F-Ph Pr 4-MeO-Ph NH
2-498 3-Me-4-F-Ph Pr 4-MeO-Ph NH
2-499 2-MeO-5-F-Ph Pr 4-MeO-Ph NH
2-500 2-CF₃ -Ph Pr 4-MeO-Ph NH
2-501 3,5-di (CF₃ ) -Ph Pr 4-MeO-Ph NH
2-502 2-HO-Ph Pr 4-MeO-Ph NH
2-503 2-HOCH₂ -Ph Pr 4-MeO-Ph NH
2-504 2-H₂ N-Ph Pr 4-MeO-Ph NH
2-505 3-NO₂ -Ph Pr 4-MeO-Ph NH
2-506 3-CN-Ph Pr 4-MeO-Ph NH
2-507 2-HCO-Ph Pr 4-MeO-Ph NH
2-508 3-HCO-Ph Pr 4-MeO-Ph NH
2-509 4-HCO-Ph Pr 4-MeO-Ph NH
2-510 3-HOOC-Ph Pr 4-MeO-Ph NH
2-511 4-HOOC-Ph Pr 4-MeO-Ph NH
2-512 3,4-(-OCH₂ O-)-Ph Pr 4-MeO-Ph NH
2-513 4-MeS-Ph Pr 4-MeO-Ph NH
2-514 3-Ac-Ph Pr 4-MeO-Ph NH
2-515 4-Ac-Ph Pr 4-MeO-Ph NH
2-516 1-Nph Pr 4-MeO-Ph NH
2-517 2-Nph Pr 4-MeO-Ph NH
2-518 4-tBu-Ph Pr 4-MeO-Ph NH
2-519 5-Cl-2-Thi Pr 4-MeO-Ph NH
2-520 5-Me-2-Thi Pr 4-MeO-Ph NH
2-521 1-Boc-2-Pyro Pr 4-MeO-Ph NH
2-522 2-Bzfur Pr 4-MeO-Ph NH
2-523 2-Py Pr 4-MeO-Ph NH
2-524 3-Py Pr 4-MeO-Ph NH
2-525 4-Py Pr 4-MeO-Ph NH
2-526 HO Bu 4-MeO-Ph NH
2-527 MeO Bu 4-MeO-Ph NH
2-528 EtO Bu 4-MeO-Ph NH
2-529 PrO Bu 4-MeO-Ph NH
2-530 BuO Bu 4-MeO-Ph NH
2-531 BnO Bu 4-MeO-Ph NH
2-532 iPrO Bu 4-MeO-Ph NH
2-533 iBuO Bu 4-MeO-Ph NH
2-534 tBuO Bu 4-MeO-Ph NH
2-535 HOC (O) Bu 4-MeO-Ph NH
2-536 MeOC (O) Bu 4-MeO-Ph NH
2-537 Me₂ N-CO Bu 4-MeO-Ph NH
2-538 2,3-diMe-Ph Bu 4-MeO-Ph NH
2-539 2,5-diMe-Ph Bu 4-MeO-Ph NH
2-540 2,6-diMe-Ph Bu 4-MeO-Ph NH
2-541 3,5-diMe-Ph Bu 4-MeO-Ph NH
2-542 2,4-di (MeO) -Ph Bu 4-MeO-Ph NH
2-543 2,5-di (MeO) -Ph Bu 4-MeO-Ph NH
2-544 2,6-di (MeO) -Ph Bu 4-MeO-Ph NH
2-545 3,4-di (MeO) -Ph Bu 4-MeO-Ph NH
2-546 2,5-diCl-Ph Bu 4-MeO-Ph NH
2-547 3,4-diCl-Ph Bu 4-MeO-Ph NH
2-548 2-MeO-5-Cl-Ph Bu 4-MeO-Ph NH
2-549 2,4-diF-Ph Bu 4-MeO-Ph NH
2-550 2,5-diF-Ph Bu 4-MeO-Ph NH
2-551 2,6-diF-Ph Bu 4-MeO-Ph NH
2-552 3,4-diF-Ph Bu 4-MeO-Ph NH
2-553 3,5-diF-Ph Bu 4-MeO-Ph NH
2-554 2,3,4,5,6-pentaF-Ph Bu 4-MeO-Ph NH
2-555 3-Cl-4-F-Ph Bu 4-MeO-Ph NH
2-556 3-Me-4-F-Ph Bu 4-MeO-Ph NH
2-557 2-MeO-5-F-Ph Bu 4-MeO-Ph NH
2-558 2-CF₃ -Ph Bu 4-MeO-Ph NH
2-559 3,5-di (CF₃ ) -Ph Bu 4-MeO-Ph NH
2-560 2-HO-Ph Bu 4-MeO-Ph NH
2-561 2-HOCH₂ -Ph Bu 4-MeO-Ph NH
2-562 2-H₂ N-Ph Bu 4-MeO-Ph NH
2-563 3-NO₂ -Ph Bu 4-MeO-Ph NH
2-564 3-CN-Ph Bu 4-MeO-Ph NH
2-565 2-HCO-Ph Bu 4-MeO-Ph NH
2-566 3-HCO-Ph Bu 4-MeO-Ph NH
2-567 4-HCO-Ph Bu 4-MeO-Ph NH
2-568 3-HOOC-Ph Bu 4-MeO-Ph NH
2-569 4-HOOC-Ph Bu 4-MeO-Ph NH
2-570 3,4-(-OCH₂ O-)-Ph Bu 4-MeO-Ph NH
2-571 4-MeS-Ph Bu 4-MeO-Ph NH
2-572 3-Ac-Ph Bu 4-MeO-Ph NH
2-573 4-Ac-Ph Bu 4-MeO-Ph NH
2-574 1-Nph Bu 4-MeO-Ph NH
2-575 2-Nph Bu 4-MeO-Ph NH
2-576 4-tBu-Ph Bu 4-MeO-Ph NH
2-577 5-Cl-2-Thi Bu 4-MeO-Ph NH
2-578 5-Me-2-Thi Bu 4-MeO-Ph NH
2-579 1-Boc-2-Pyro Bu 4-MeO-Ph NH
2-580 2-Bzfur Bu 4-MeO-Ph NH
2-581 2-Py Bu 4-MeO-Ph NH
2-582 3-Py Bu 4-MeO-Ph NH
2-583 4-Py Bu 4-MeO-Ph NH
------------------------------------------------

例示化合物表３
---------------------------------------------------------------
化合物
番 号 R¹ R² R³-Z- R⁴ X
---------------------------------------------------------------
3-1 H iBu 6-Ph-2-O-Pyra Me NH
3-2 H iBu 6-Ph-2-O-Pyra Et NH
3-3 H iBu 6-Ph-2-O-Pyra Pr NH
3-4 H iBu 6-Ph-2-O-Pyra Bu NH
3-5 H iBu Bn Me O-CONH
3-6 H iBu Bn Et O-CONH
3-7 H iBu Bn Pr O-CONH
3-8 H iBu Bn Bu O-CONH
3-9 H iBu 2-Bzfur Me CONH
3-10 H iBu 2-Bzfur Et CONH
3-11 H iBu 2-Bzfur Pr CONH
3-12 H iBu 2-Bzfur Bu CONH
3-13 H iBu 3-Me-2-Bzfur Me CONH
3-14 H iBu 3-Me-2-Bzfur Et CONH
3-15 H iBu 3-Me-2-Bzfur Pr CONH
3-16 H iBu 3-Me-2-Bzfur Bu CONH
3-17 H iBu 5-Cl-2-Bzfur Me CONH
3-18 H iBu 5-Cl-2-Bzfur Et CONH
3-19 H iBu 5-Cl-2-Bzfur Pr CONH
3-20 H iBu 5-Cl-2-Bzfur Bu CONH
3-21 H iBu 5-MeO-2-Bzfur Me CONH
3-22 H iBu 5-MeO-2-Bzfur Et CONH
3-23 H iBu 5-MeO-2-Bzfur Pr CONH
3-24 H iBu 5-MeO-2-Bzfur Bu CONH
3-25 H iBu 7-MeO-2-Bzfur Me CONH
3-26 H iBu 7-MeO-2-Bzfur Et CONH
3-27 H iBu 7-MeO-2-Bzfur Pr CONH
3-28 H iBu 7-MeO-2-Bzfur Bu CONH
3-29 H iBu 5-Cl-2-Ind Me CONH
3-30 H iBu 5-Cl-2-Ind Et CONH
3-31 H iBu 5-Cl-2-Ind Pr CONH
3-32 H iBu 5-Cl-2-Ind Bu CONH
3-33 H iBu 5-F-2-Ind Me CONH
3-34 H iBu 5-F-2-Ind Et CONH
3-35 H iBu 5-F-2-Ind Pr CONH
3-36 H iBu 5-F-2-Ind Bu CONH
3-37 H iBu 5-Me-2-Ind Me CONH
3-38 H iBu 5-Me-2-Ind Et CONH
3-39 H iBu 5-Me-2-Ind Pr CONH
3-40 H iBu 5-Me-2-Ind Bu CONH
3-41 H iBu 5-MeO-2-Ind Me CONH
3-42 H iBu 5-MeO-2-Ind Et CONH
3-43 H iBu 5-MeO-2-Ind Pr CONH
3-44 H iBu 5-MeO-2-Ind Bu CONH
3-45 H iBu 5-Ind Me CONH
3-46 H iBu 5-Ind Et CONH
3-47 H iBu 5-Ind Pr CONH
3-48 H iBu 5-Ind Bu CONH
3-49 H iBu 3-Cl-2-Bzthi Me CONH
3-50 H iBu 3-Cl-2-Bzthi Et CONH
3-51 H iBu 3-Cl-2-Bzthi Pr CONH
3-52 H iBu 3-Cl-2-Bzthi Bu CONH
3-53 H iBu 3-Me-2-Bzthi Me CONH
3-54 H iBu 3-Me-2-Bzthi Et CONH
3-55 H iBu 3-Me-2-Bzthi Pr CONH
3-56 H iBu 3-Me-2-Bzthi Bu CONH
3-57 H iBu 3-CF₃-2-Bzthi Me CONH
3-58 H iBu 3-CF₃-2-Bzthi Et CONH
3-59 H iBu 3-CF₃-2-Bzthi Pr CONH
3-60 H iBu 3-CF₃-2-Bzthi Bu CONH
3-61 H iBu 1-Nph Me CONH
3-62 H iBu 1-Nph Et CONH
3-63 H iBu 1-Nph Pr CONH
3-64 H iBu 1-Nph Bu CONH
3-65 H iBu 2-Nph Me CONH
3-66 H iBu 2-Nph Et CONH
3-67 H iBu 2-Nph Pr CONH
3-68 H iBu 2-Nph Bu CONH
3-69 H iBu 2-Qui Me CONH
3-70 H iBu 2-Qui Et CONH
3-71 H iBu 2-Qui Pr CONH
3-72 H iBu 2-Qui Bu CONH
3-73 H iBu 3-Qui Me CONH
3-74 H iBu 3-Qui Et CONH
3-75 H iBu 3-Qui Pr CONH
3-76 H iBu 3-Qui Bu CONH
3-77 H iBu 4-Qui Me CONH
3-78 H iBu 4-Qui Et CONH
3-79 H iBu 4-Qui Pr CONH
3-80 H iBu 4-Qui Bu CONH
3-81 H iBu 8-Qui Me CONH
3-82 H iBu 8-Qui Et CONH
3-83 H iBu 8-Qui Pr CONH
3-84 H iBu 8-Qui Bu CONH
3-85 H iBu 1-Iqui Me CONH
3-86 H iBu 1-Iqui Et CONH
3-87 H iBu 1-Iqui Pr CONH
3-88 H iBu 1-Iqui Bu CONH
3-89 H iBu 3-Iqui Me CONH
3-90 H iBu 3-Iqui Et CONH
3-91 H iBu 3-Iqui Pr CONH
3-92 H iBu 3-Iqui Bu CONH
3-93 H iBu 4-Br-Ph Me CONH
3-94 H iBu 4-Br-Ph Et CONH
3-95 H iBu 4-Br-Ph Pr CONH
3-96 H iBu 4-Br-Ph Bu CONH
3-97 H iBu 3-Br-Ph Me CONH
3-98 H iBu 3-Br-Ph Et CONH
3-99 H iBu 3-Br-Ph Pr CONH
3-100 H iBu 3-Br-Ph Bu CONH
3-101 H iBu 4-Ph-Ph Me CONH
3-102 H iBu 4-Ph-Ph Et CONH
3-103 H iBu 4-Ph-Ph Pr CONH
3-104 H iBu 4-Ph-Ph Bu CONH
3-105 H iBu 3-Ph-Ph Me CONH
3-106 H iBu 3-Ph-Ph Et CONH
3-107 H iBu 3-Ph-Ph Pr CONH
3-108 H iBu 3-Ph-Ph Bu CONH
3-109 H iBu 4-(2-Me-Ph)-Ph Me CONH
3-110 H iBu 4-(2-Me-Ph)-Ph Et CONH
3-111 H iBu 4-(2-Me-Ph)-Ph Pr CONH
3-112 H iBu 4-(2-Me-Ph)-Ph Bu CONH
3-113 H iBu 4-(3-Me-Ph)-Ph Me CONH
3-114 H iBu 4-(3-Me-Ph)-Ph Et CONH
3-115 H iBu 4-(3-Me-Ph)-Ph Pr CONH
3-116 H iBu 4-(3-Me-Ph)-Ph Bu CONH
3-117 H iBu 4-(4-Me-Ph)-Ph Me CONH
3-118 H iBu 4-(4-Me-Ph)-Ph Et CONH
3-119 H iBu 4-(4-Me-Ph)-Ph Pr CONH
3-120 H iBu 4-(4-Me-Ph)-Ph Bu CONH
3-121 H iBu 4-(2-F-Ph)-Ph Me CONH
3-122 H iBu 4-(2-F-Ph)-Ph Et CONH
3-123 H iBu 4-(2-F-Ph)-Ph Pr CONH
3-124 H iBu 4-(2-F-Ph)-Ph Bu CONH
3-125 H iBu 4-(3-F-Ph)-Ph Me CONH
3-126 H iBu 4-(3-F-Ph)-Ph Et CONH
3-127 H iBu 4-(3-F-Ph)-Ph Pr CONH
3-128 H iBu 4-(3-F-Ph)-Ph Bu CONH
3-129 H iBu 4-(4-F-Ph)-Ph Me CONH
3-130 H iBu 4-(4-F-Ph)-Ph Et CONH
3-131 H iBu 4-(4-F-Ph)-Ph Pr CONH
3-132 H iBu 4-(4-F-Ph)-Ph Bu CONH
3-133 H iBu 4-(2-Cl-Ph)-Ph Me CONH
3-134 H iBu 4-(2-Cl-Ph)-Ph Et CONH
3-135 H iBu 4-(2-Cl-Ph)-Ph Pr CONH
3-136 H iBu 4-(2-Cl-Ph)-Ph Bu CONH
3-137 H iBu 4-(3-Cl-Ph)-Ph Me CONH
3-138 H iBu 4-(3-Cl-Ph)-Ph Et CONH
3-139 H iBu 4-(3-Cl-Ph)-Ph Pr CONH
3-140 H iBu 4-(3-Cl-Ph)-Ph Bu CONH
3-141 H iBu 4-(4-Cl-Ph)-Ph Me CONH
3-142 H iBu 4-(4-Cl-Ph)-Ph Et CONH
3-143 H iBu 4-(4-Cl-Ph)-Ph Pr CONH
3-144 H iBu 4-(4-Cl-Ph)-Ph Bu CONH
3-145 H iBu 4-(2-MeO-Ph)-Ph Me CONH
3-146 H iBu 4-(2-MeO-Ph)-Ph Et CONH
3-147 H iBu 4-(2-MeO-Ph)-Ph Pr CONH
3-148 H iBu 4-(2-MeO-Ph)-Ph Bu CONH
3-149 H iBu 4-(3-MeO-Ph)-Ph Me CONH
3-150 H iBu 4-(3-MeO-Ph)-Ph Et CONH
3-151 H iBu 4-(3-MeO-Ph)-Ph Pr CONH
3-152 H iBu 4-(3-MeO-Ph)-Ph Bu CONH
3-153 H iBu 4-(4-MeO-Ph)-Ph Me CONH
3-154 H iBu 4-(4-MeO-Ph)-Ph Et CONH
3-155 H iBu 4-(4-MeO-Ph)-Ph Pr CONH
3-156 H iBu 4-(4-MeO-Ph)-Ph Bu CONH
3-157 H iBu 4-(2-CF₃-Ph)-Ph Me CONH
3-158 H iBu 4-(2-CF₃-Ph)-Ph Et CONH
3-159 H iBu 4-(2-CF₃-Ph)-Ph Pr CONH
3-160 H iBu 4-(2-CF₃-Ph)-Ph Bu CONH
3-161 H iBu 4-(3-CF₃-Ph)-Ph Me CONH
3-162 H iBu 4-(3-CF₃-Ph)-Ph Et CONH
3-163 H iBu 4-(3-CF₃-Ph)-Ph Pr CONH
3-164 H iBu 4-(3-CF₃-Ph)-Ph Bu CONH
3-165 H iBu 4-(4-CF₃-Ph)-Ph Me CONH
3-166 H iBu 4-(4-CF₃-Ph)-Ph Et CONH
3-167 H iBu 4-(4-CF₃-Ph)-Ph Pr CONH
3-168 H iBu 4-(4-CF₃-Ph)-Ph Bu CONH
3-169 H iBu 4-(3-CF₃O-Ph)-Ph Me CONH
3-170 H iBu 4-(3-CF₃O-Ph)-Ph Et CONH
3-171 H iBu 4-(3-CF₃O-Ph)-Ph Pr CONH
3-172 H iBu 4-(3-CF₃O-Ph)-Ph Bu CONH
3-173 H iBu 4-(4-CF₃O-Ph)-Ph Me CONH
3-174 H iBu 4-(4-CF₃O-Ph)-Ph Et CONH
3-175 H iBu 4-(4-CF₃O-Ph)-Ph Pr CONH
3-176 H iBu 4-(4-CF₃O-Ph)-Ph Bu CONH
3-177 H iBu 4-PhO-Ph Me CONH
3-178 H iBu 4-PhO-Ph Et CONH
3-179 H iBu 4-PhO-Ph Pr CONH
3-180 H iBu 4-PhO-Ph Bu CONH
3-181 H iBu 3-PhO-Ph Me CONH
3-182 H iBu 3-PhO-Ph Et CONH
3-183 H iBu 3-PhO-Ph Pr CONH
3-184 H iBu 3-PhO-Ph Bu CONH
3-185 H iBu 4-BnO-Ph Me CONH
3-186 H iBu 4-BnO-Ph Et CONH
3-187 H iBu 4-BnO-Ph Pr CONH
3-188 H iBu 4-BnO-Ph Bu CONH
3-189 H iBu 3-BnO-Ph Me CONH
3-190 H iBu 3-BnO-Ph Et CONH
3-191 H iBu 3-BnO-Ph Pr CONH
3-192 H iBu 3-BnO-Ph Bu CONH
3-193 H iBu 4-MeO-Ph Me CONH
3-194 H iBu 4-MeO-Ph Et CONH
3-195 H iBu 4-MeO-Ph Pr CONH
3-196 H iBu 4-MeO-Ph Bu CONH
3-197 H iBu 3-MeO-Ph Me CONH
3-198 H iBu 3-MeO-Ph Et CONH
3-199 H iBu 3-MeO-Ph Pr CONH
3-200 H iBu 3-MeO-Ph Bu CONH
3-201 H iBu 4-EtO-Ph Me CONH
3-202 H iBu 4-EtO-Ph Et CONH
3-203 H iBu 4-EtO-Ph Pr CONH
3-204 H iBu 4-EtO-Ph Bu CONH
3-205 H iBu 3-EtO-Ph Me CONH
3-206 H iBu 3-EtO-Ph Et CONH
3-207 H iBu 3-EtO-Ph Pr CONH
3-208 H iBu 3-EtO-Ph Bu CONH
3-209 H iBu 4-PrO-Ph Me CONH
3-210 H iBu 4-PrO-Ph Et CONH
3-211 H iBu 4-PrO-Ph Pr CONH
3-212 H iBu 4-PrO-Ph Bu CONH
3-213 H iBu 3-PrO-Ph Me CONH
3-214 H iBu 3-PrO-Ph Et CONH
3-215 H iBu 3-PrO-Ph Pr CONH
3-216 H iBu 3-PrO-Ph Bu CONH
3-217 H iBu 4-BuO-Ph Me CONH
3-218 H iBu 4-BuO-Ph Et CONH
3-219 H iBu 4-BuO-Ph Pr CONH
3-220 H iBu 4-BuO-Ph Bu CONH
3-221 H iBu 3-BuO-Ph Me CONH
3-222 H iBu 3-BuO-Ph Et CONH
3-223 H iBu 3-BuO-Ph Pr CONH
3-224 H iBu 3-BuO-Ph Bu CONH
3-225 H iBu 4-iPrO-Ph Me CONH
3-226 H iBu 4-iPrO-Ph Et CONH
3-227 H iBu 4-iPrO-Ph Pr CONH
3-228 H iBu 4-iPrO-Ph Bu CONH
3-229 H iBu 3-iPrO-Ph Me CONH
3-230 H iBu 3-iPrO-Ph Et CONH
3-231 H iBu 3-iPrO-Ph Pr CONH
3-232 H iBu 3-iPrO-Ph Bu CONH
3-233 H iBu 4-Me-Ph Me CONH
3-234 H iBu 4-Me-Ph Et CONH
3-235 H iBu 4-Me-Ph Pr CONH
3-236 H iBu 4-Me-Ph Bu CONH
3-237 H iBu 4-Et-Ph Me CONH
3-238 H iBu 4-Et-Ph Et CONH
3-239 H iBu 4-Et-Ph Pr CONH
3-240 H iBu 4-Et-Ph Bu CONH
3-241 H iBu 4-Pr-Ph Me CONH
3-242 H iBu 4-Pr-Ph Et CONH
3-243 H iBu 4-Pr-Ph Pr CONH
3-244 H iBu 4-Pr-Ph Bu CONH
3-245 H iBu 4-Bu-Ph Me CONH
3-246 H iBu 4-Bu-Ph Et CONH
3-247 H iBu 4-Bu-Ph Pr CONH
3-248 H iBu 4-Bu-Ph Bu CONH
3-249 H iBu 4-iPr-Ph Me CONH
3-250 H iBu 4-iPr-Ph Et CONH
3-251 H iBu 4-iPr-Ph Pr CONH
3-252 H iBu 4-iPr-Ph Bu CONH
3-253 H iBu 4-cHx-Ph Me CONH
3-254 H iBu 4-cHx-Ph Et CONH
3-255 H iBu 4-cHx-Ph Pr CONH
3-256 H iBu 4-cHx-Ph Bu CONH
3-257 H iBu 4-(Me₂N)-Ph Me CONH
3-258 H iBu 4-(Me₂N)-Ph Et CONH
3-259 H iBu 4-(Me₂N)-Ph Pr CONH
3-260 H iBu 4-(Me₂N)-Ph Bu CONH
3-261 H iBu 4-(Et₂N)-Ph Me CONH
3-262 H iBu 4-(Et₂N)-Ph Et CONH
3-263 H iBu 4-(Et₂N)-Ph Pr CONH
3-264 H iBu 4-(Et₂N)-Ph Bu CONH
3-265 H iBu 4-(1-Pip)-Ph Me CONH
3-266 H iBu 4-(1-Pip)-Ph Et CONH
3-267 H iBu 4-(1-Pip)-Ph Pr CONH
3-268 H iBu 4-(1-Pip)-Ph Bu CONH
3-269 H iBu 4-(1-Mor)-Ph Me CONH
3-270 H iBu 4-(1-Mor)-Ph Et CONH
3-271 H iBu 4-(1-Mor)-Ph Pr CONH
3-272 H iBu 4-(1-Mor)-Ph Bu CONH
3-273 H iBu 4-(4-Me-1-Pipra)-Ph Me CONH
3-274 H iBu 4-(4-Me-1-Pipra)-Ph Et CONH
3-275 H iBu 4-(4-Me-1-Pipra)-Ph Pr CONH
3-276 H iBu 4-(4-Me-1-Pipra)-Ph Bu CONH
3-277 H iBu 4-(1-Me-4-Pip)-Ph Me CONH
3-278 H iBu 4-(1-Me-4-Pip)-Ph Et CONH
3-279 H iBu 4-(1-Me-4-Pip)-Ph Pr CONH
3-280 H iBu 4-(1-Me-4-Pip)-Ph Bu CONH
3-281 H iBu 4-[1-(2-MeO-Et)-4-Pip]-Ph Me CONH
3-282 H iBu 4-[1-(2-MeO-Et)-4-Pip]-Ph Et CONH
3-283 H iBu 4-[1-(2-MeO-Et)-4-Pip]-Ph Pr CONH
3-284 H iBu 4-[1-(2-MeO-Et)-4-Pip]-Ph Bu CONH
3-285 H iBu 4-Br-Ph Me O
3-286 H iBu 4-Br-Ph Et O
3-287 H iBu 4-Br-Ph Pr O
3-288 H iBu 4-Br-Ph Bu O
3-289 H iBu 3-Br-Ph Me O
3-290 H iBu 3-Br-Ph Et O
3-291 H iBu 3-Br-Ph Pr O
3-292 H iBu 3-Br-Ph Bu O
3-293 H iBu 4-Ph-Ph Me O
3-294 H iBu 4-Ph-Ph Et O
3-295 H iBu 4-Ph-Ph Pr O
3-296 H iBu 4-Ph-Ph Bu O
3-297 H iBu 3-Ph-Ph Me O
3-298 H iBu 3-Ph-Ph Et O
3-299 H iBu 3-Ph-Ph Pr O
3-300 H iBu 3-Ph-Ph Bu O
3-301 H iBu 4-PhO-Ph Me O
3-302 H iBu 4-PhO-Ph Et O
3-303 H iBu 4-PhO-Ph Pr O
3-304 H iBu 4-PhO-Ph Bu O
3-305 H iBu 3-PhO-Ph Me O
3-306 H iBu 3-PhO-Ph Et O
3-307 H iBu 3-PhO-Ph Pr O
3-308 H iBu 3-PhO-Ph Bu O
3-309 H iBu 4-BnO-Ph Me O
3-310 H iBu 4-BnO-Ph Et O
3-311 H iBu 4-BnO-Ph Pr O
3-312 H iBu 4-BnO-Ph Bu O
3-313 H iBu 3-BnO-Ph Me O
3-314 H iBu 3-BnO-Ph Et O
3-315 H iBu 3-BnO-Ph Pr O
3-316 H iBu 3-BnO-Ph Bu O
3-317 H iBu 4-cHx-Ph Me O
3-318 H iBu 4-cHx-Ph Et O
3-319 H iBu 4-cHx-Ph Pr O
3-320 H iBu 4-cHx-Ph Bu O
3-321 H iBu 3-cHx-Ph Me O
3-322 H iBu 3-cHx-Ph Et O
3-323 H iBu 3-cHx-Ph Pr O
3-324 H iBu 3-cHx-Ph Bu O
3-325 H iBu 4-(2-Fur)-Ph Me O
3-326 H iBu 4-(2-Fur)-Ph Et O
3-327 H iBu 4-(2-Fur)-Ph Pr O
3-328 H iBu 4-(2-Fur)-Ph Bu O
3-329 H iBu 3-(2-Fur)-Ph Me O
3-330 H iBu 3-(2-Fur)-Ph Et O
3-331 H iBu 3-(2-Fur)-Ph Pr O
3-332 H iBu 3-(2-Fur)-Ph Bu O
3-333 H iBu 4-(3-Fur)-Ph Me O
3-334 H iBu 4-(3-Fur)-Ph Et O
3-335 H iBu 4-(3-Fur)-Ph Pr O
3-336 H iBu 4-(3-Fur)-Ph Bu O
3-337 H iBu 3-(3-Fur)-Ph Me O
3-338 H iBu 3-(3-Fur)-Ph Et O
3-339 H iBu 3-(3-Fur)-Ph Pr O
3-340 H iBu 3-(3-Fur)-Ph Bu O
3-341 H iBu 4-(2-Thi)-Ph Me O
3-342 H iBu 4-(2-Thi)-Ph Et O
3-343 H iBu 4-(2-Thi)-Ph Pr O
3-344 H iBu 4-(2-Thi)-Ph Bu O
3-345 H iBu 3-(2-Thi)-Ph Me O
3-346 H iBu 3-(2-Thi)-Ph Et O
3-347 H iBu 3-(2-Thi)-Ph Pr O
3-348 H iBu 3-(2-Thi)-Ph Bu O
3-349 H iBu 4-(3-Thi)-Ph Me O
3-350 H iBu 4-(3-Thi)-Ph Et O
3-351 H iBu 4-(3-Thi)-Ph Pr O
3-352 H iBu 4-(3-Thi)-Ph Bu O
3-353 H iBu 3-(3-Thi)-Ph Me O
3-354 H iBu 3-(3-Thi)-Ph Et O
3-355 H iBu 3-(3-Thi)-Ph Pr O
3-356 H iBu 3-(3-Thi)-Ph Bu O
3-357 H iBu 4-(1-Boc-2-Pyro)-Ph Me O
3-358 H iBu 4-(1-Boc-2-Pyro)-Ph Et O
3-359 H iBu 4-(1-Boc-2-Pyro)-Ph Pr O
3-360 H iBu 4-(1-Boc-2-Pyro)-Ph Bu O
3-361 H iBu 3-(1-Boc-2-Pyro)-Ph Me O
3-362 H iBu 3-(1-Boc-2-Pyro)-Ph Et O
3-363 H iBu 3-(1-Boc-2-Pyro)-Ph Pr O
3-364 H iBu 3-(1-Boc-2-Pyro)-Ph Bu O
3-365 H iBu 4-(2-F-Ph)-Ph Me O
3-366 H iBu 4-(2-F-Ph)-Ph Et O
3-367 H iBu 4-(2-F-Ph)-Ph Pr O
3-368 H iBu 4-(2-F-Ph)-Ph Bu O
3-369 H iBu 4-(3-F-Ph)-Ph Me O
3-370 H iBu 4-(3-F-Ph)-Ph Et O
3-371 H iBu 4-(3-F-Ph)-Ph Pr O
3-372 H iBu 4-(3-F-Ph)-Ph Bu O
3-373 H iBu 4-(4-F-Ph)-Ph Me O
3-374 H iBu 4-(4-F-Ph)-Ph Et O
3-375 H iBu 4-(4-F-Ph)-Ph Pr O
3-376 H iBu 4-(4-F-Ph)-Ph Bu O
3-377 H iBu 3-(2-Cl-Ph)-Ph Me O
3-378 H iBu 3-(2-Cl-Ph)-Ph Et O
3-379 H iBu 3-(2-Cl-Ph)-Ph Pr O
3-380 H iBu 3-(2-Cl-Ph)-Ph Bu O
3-381 H iBu 3-(3-Cl-Ph)-Ph Me O
3-382 H iBu 3-(3-Cl-Ph)-Ph Et O
3-383 H iBu 3-(3-Cl-Ph)-Ph Pr O
3-384 H iBu 3-(3-Cl-Ph)-Ph Bu O
3-385 H iBu 3-(4-Cl-Ph)-Ph Me O
3-386 H iBu 3-(4-Cl-Ph)-Ph Et O
3-387 H iBu 3-(4-Cl-Ph)-Ph Pr O
3-388 H iBu 3-(4-Cl-Ph)-Ph Bu O
3-389 H iBu 3-(2-Me-Ph)-Ph Me O
3-390 H iBu 3-(2-Me-Ph)-Ph Et O
3-391 H iBu 3-(2-Me-Ph)-Ph Pr O
3-392 H iBu 3-(2-Me-Ph)-Ph Bu O
3-393 H iBu 3-(3-Me-Ph)-Ph Me O
3-394 H iBu 3-(3-Me-Ph)-Ph Et O
3-395 H iBu 3-(3-Me-Ph)-Ph Pr O
3-396 H iBu 3-(3-Me-Ph)-Ph Bu O
3-397 H iBu 3-(4-Me-Ph)-Ph Me O
3-398 H iBu 3-(4-Me-Ph)-Ph Et O
3-399 H iBu 3-(4-Me-Ph)-Ph Pr O
3-400 H iBu 3-(4-Me-Ph)-Ph Bu O
3-401 H iBu 3-(2-MeO-Ph)-Ph Me O
3-402 H iBu 3-(2-MeO-Ph)-Ph Et O
3-403 H iBu 3-(2-MeO-Ph)-Ph Pr O
3-404 H iBu 3-(2-MeO-Ph)-Ph Bu O
3-405 H iBu 3-(3-MeO-Ph)-Ph Me O
3-406 H iBu 3-(3-MeO-Ph)-Ph Et O
3-407 H iBu 3-(3-MeO-Ph)-Ph Pr O
3-408 H iBu 3-(3-MeO-Ph)-Ph Bu O
3-409 H iBu 3-(4-MeO-Ph)-Ph Me O
3-410 H iBu 3-(4-MeO-Ph)-Ph Et O
3-411 H iBu 3-(4-MeO-Ph)-Ph Pr O
3-412 H iBu 3-(4-MeO-Ph)-Ph Bu O
3-413 H iBu 3-(2-CF₃-Ph)-Ph Me O
3-414 H iBu 3-(2-CF₃-Ph)-Ph Et O
3-415 H iBu 3-(2-CF₃-Ph)-Ph Pr O
3-416 H iBu 3-(2-CF₃-Ph)-Ph Bu O
3-417 H iBu 3-(3-CF₃-Ph)-Ph Me O
3-418 H iBu 3-(3-CF₃-Ph)-Ph Et O
3-419 H iBu 3-(3-CF₃-Ph)-Ph Pr O
3-420 H iBu 3-(3-CF₃-Ph)-Ph Bu O
3-421 H iBu 3-(4-CF₃-Ph)-Ph Me O
3-422 H iBu 3-(4-CF₃-Ph)-Ph Et O
3-423 H iBu 3-(4-CF₃-Ph)-Ph Pr O
3-424 H iBu 3-(4-CF₃-Ph)-Ph Bu O
3-425 H iBu 3-(3-CF₃O-Ph)-Ph Me O
3-426 H iBu 3-(3-CF₃O-Ph)-Ph Et O
3-427 H iBu 3-(3-CF₃O-Ph)-Ph Pr O
3-428 H iBu 3-(3-CF₃O-Ph)-Ph Bu O
3-429 H iBu 3-(4-CF₃O-Ph)-Ph Me O
3-430 H iBu 3-(4-CF₃O-Ph)-Ph Et O
3-431 H iBu 3-(4-CF₃O-Ph)-Ph Pr O
3-432 H iBu 3-(4-CF₃O-Ph)-Ph Bu O
3-433 H iBu 3-(2-HO-Ph)-Ph Me O
3-434 H iBu 3-(2-HO-Ph)-Ph Et O
3-435 H iBu 3-(2-HO-Ph)-Ph Pr O
3-436 H iBu 3-(2-HO-Ph)-Ph Bu O
3-437 H iBu 3-(3-HO-Ph)-Ph Me O
3-438 H iBu 3-(3-HO-Ph)-Ph Et O
3-439 H iBu 3-(3-HO-Ph)-Ph Pr O
3-440 H iBu 3-(3-HO-Ph)-Ph Bu O
3-441 H iBu 3-(4-HO-Ph)-Ph Me O
3-442 H iBu 3-(4-HO-Ph)-Ph Et O
3-443 H iBu 3-(4-HO-Ph)-Ph Pr O
3-444 H iBu 3-(4-HO-Ph)-Ph Bu O
3-445 H iBu 3-(2-HOCH₂-Ph)-Ph Me O
3-446 H iBu 3-(2-HOCH₂-Ph)-Ph Et O
3-447 H iBu 3-(2-HOCH₂-Ph)-Ph Pr O
3-448 H iBu 3-(2-HOCH₂-Ph)-Ph Bu O
3-449 H iBu 3-(3-HOCH₂-Ph)-Ph Me O
3-450 H iBu 3-(3-HOCH₂-Ph)-Ph Et O
3-451 H iBu 3-(3-HOCH₂-Ph)-Ph Pr O
3-452 H iBu 3-(3-HOCH₂-Ph)-Ph Bu O
3-453 H iBu 3-(4-HOCH₂-Ph)-Ph Me O
3-454 H iBu 3-(4-HOCH₂-Ph)-Ph Et O
3-455 H iBu 3-(4-HOCH₂-Ph)-Ph Pr O
3-456 H iBu 3-(4-HOCH₂-Ph)-Ph Bu O
3-457 H iBu 3-(2-H₂N-Ph)-Ph Me O
3-458 H iBu 3-(2-H₂N-Ph)-Ph Et O
3-459 H iBu 3-(2-H₂N-Ph)-Ph Pr O
3-460 H iBu 3-(2-H₂N-Ph)-Ph Bu O
3-461 H iBu 3-(3-H₂N-Ph)-Ph Me O
3-462 H iBu 3-(3-H₂N-Ph)-Ph Et O
3-463 H iBu 3-(3-H₂N-Ph)-Ph Pr O
3-464 H iBu 3-(3-H₂N-Ph)-Ph Bu O
3-465 H iBu 3-(4-H₂N-Ph)-Ph Me O
3-466 H iBu 3-(4-H₂N-Ph)-Ph Et O
3-467 H iBu 3-(4-H₂N-Ph)-Ph Pr O
3-468 H iBu 3-(4-H₂N-Ph)-Ph Bu O
3-469 H iBu Ph Me SO₂NH
3-470 H iBu Ph Et SO₂NH
3-471 H iBu Ph Pr SO₂NH
3-472 H iBu Ph Bu SO₂NH
3-473 H iBu 4-Br-Ph Me SO₂NH
3-474 H iBu 4-Br-Ph Et SO₂NH
3-475 H iBu 4-Br-Ph Pr SO₂NH
3-476 H iBu 4-Br-Ph Bu SO₂NH
3-477 H iBu 3-Br-Ph Me SO₂NH
3-478 H iBu 3-Br-Ph Et SO₂NH
3-479 H iBu 3-Br-Ph Pr SO₂NH
3-480 H iBu 3-Br-Ph Bu SO₂NH
3-481 H iBu 4-Ph-Ph Me SO₂NH
3-482 H iBu 4-Ph-Ph Et SO₂NH
3-483 H iBu 4-Ph-Ph Pr SO₂NH
3-484 H iBu 4-Ph-Ph Bu SO₂NH
3-485 H iBu 3-Ph-Ph Me SO₂NH
3-486 H iBu 3-Ph-Ph Et SO₂NH
3-487 H iBu 3-Ph-Ph Pr SO₂NH
3-488 H iBu 3-Ph-Ph Bu SO₂NH
3-489 H iBu 1-Nph Me SO₂NH
3-490 H iBu 1-Nph Et SO₂NH
3-491 H iBu 1-Nph Pr SO₂NH
3-492 H iBu 1-Nph Bu SO₂NH
3-493 H iBu 2-Nph Me SO₂NH
3-494 H iBu 2-Nph Et SO₂NH
3-495 H iBu 2-Nph Pr SO₂NH
3-496 H iBu 2-Nph Bu SO₂NH
3-497 H iBu 4-(2-Py)-Ph Me SO₂NH
3-498 H iBu 4-(2-Py)-Ph Et SO₂NH
3-499 H iBu 4-(2-Py)-Ph Pr SO₂NH
3-500 H iBu 4-(2-Py)-Ph Bu SO₂NH
3-501 H iBu 4-(3-Py)-Ph Me SO₂NH
3-502 H iBu 4-(3-Py)-Ph Et SO₂NH
3-503 H iBu 4-(3-Py)-Ph Pr SO₂NH
3-504 H iBu 4-(3-Py)-Ph Bu SO₂NH
3-505 H iBu 4-(4-Py)-Ph Me SO₂NH
3-506 H iBu 4-(4-Py)-Ph Et SO₂NH
3-507 H iBu 4-(4-Py)-Ph Pr SO₂NH
3-508 H iBu 4-(4-Py)-Ph Bu SO₂NH
3-509 H iBu 3-(2-Py)-Ph Me SO₂NH
3-510 H iBu 3-(2-Py)-Ph Et SO₂NH
3-511 H iBu 3-(2-Py)-Ph Pr SO₂NH
3-512 H iBu 3-(2-Py)-Ph Bu SO₂NH
3-513 H iBu 3-(3-Py)-Ph Me SO₂NH
3-514 H iBu 3-(3-Py)-Ph Et SO₂NH
3-515 H iBu 3-(3-Py)-Ph Pr SO₂NH
3-516 H iBu 3-(3-Py)-Ph Bu SO₂NH
3-517 H iBu 3-(4-Py)-Ph Me SO₂NH
3-518 H iBu 3-(4-Py)-Ph Et SO₂NH
3-519 H iBu 3-(4-Py)-Ph Pr SO₂NH
3-520 H iBu 3-(4-Py)-Ph Bu SO₂NH
---------------------------------------------------------------

Exemplary Compound Table 3
-------------------------------------------------- -------------
Compound number R¹ R² R³ -Z- R⁴ X
-------------------------------------------------- -------------
3-1 H iBu 6-Ph-2-O-Pyra Me NH
3-2 H iBu 6-Ph-2-O-Pyra Et NH
3-3 H iBu 6-Ph-2-O-Pyra Pr NH
3-4 H iBu 6-Ph-2-O-Pyra Bu NH
3-5 H iBu Bn Me O-CONH
3-6 H iBu Bn Et O-CONH
3-7 H iBu Bn Pr O-CONH
3-8 H iBu Bn Bu O-CONH
3-9 H iBu 2-Bzfur Me CONH
3-10 H iBu 2-Bzfur Et CONH
3-11 H iBu 2-Bzfur Pr CONH
3-12 H iBu 2-Bzfur Bu CONH
3-13 H iBu 3-Me-2-Bzfur Me CONH
3-14 H iBu 3-Me-2-Bzfur Et CONH
3-15 H iBu 3-Me-2-Bzfur Pr CONH
3-16 H iBu 3-Me-2-Bzfur Bu CONH
3-17 H iBu 5-Cl-2-Bzfur Me CONH
3-18 H iBu 5-Cl-2-Bzfur Et CONH
3-19 H iBu 5-Cl-2-Bzfur Pr CONH
3-20 H iBu 5-Cl-2-Bzfur Bu CONH
3-21 H iBu 5-MeO-2-Bzfur Me CONH
3-22 H iBu 5-MeO-2-Bzfur Et CONH
3-23 H iBu 5-MeO-2-Bzfur Pr CONH
3-24 H iBu 5-MeO-2-Bzfur Bu CONH
3-25 H iBu 7-MeO-2-Bzfur Me CONH
3-26 H iBu 7-MeO-2-Bzfur Et CONH
3-27 H iBu 7-MeO-2-Bzfur Pr CONH
3-28 H iBu 7-MeO-2-Bzfur Bu CONH
3-29 H iBu 5-Cl-2-Ind Me CONH
3-30 H iBu 5-Cl-2-Ind Et CONH
3-31 H iBu 5-Cl-2-Ind Pr CONH
3-32 H iBu 5-Cl-2-Ind Bu CONH
3-33 H iBu 5-F-2-Ind Me CONH
3-34 H iBu 5-F-2-Ind Et CONH
3-35 H iBu 5-F-2-Ind Pr CONH
3-36 H iBu 5-F-2-Ind Bu CONH
3-37 H iBu 5-Me-2-Ind Me CONH
3-38 H iBu 5-Me-2-Ind Et CONH
3-39 H iBu 5-Me-2-Ind Pr CONH
3-40 H iBu 5-Me-2-Ind Bu CONH
3-41 H iBu 5-MeO-2-Ind Me CONH
3-42 H iBu 5-MeO-2-Ind Et CONH
3-43 H iBu 5-MeO-2-Ind Pr CONH
3-44 H iBu 5-MeO-2-Ind Bu CONH
3-45 H iBu 5-Ind Me CONH
3-46 H iBu 5-Ind Et CONH
3-47 H iBu 5-Ind Pr CONH
3-48 H iBu 5-Ind Bu CONH
3-49 H iBu 3-Cl-2-Bzthi Me CONH
3-50 H iBu 3-Cl-2-Bzthi Et CONH
3-51 H iBu 3-Cl-2-Bzthi Pr CONH
3-52 H iBu 3-Cl-2-Bzthi Bu CONH
3-53 H iBu 3-Me-2-Bzthi Me CONH
3-54 H iBu 3-Me-2-Bzthi Et CONH
3-55 H iBu 3-Me-2-Bzthi Pr CONH
3-56 H iBu 3-Me-2-Bzthi Bu CONH
3-57 H iBu 3-CF₃ -2-Bzthi Me CONH
3-58 H iBu 3-CF₃ -2-Bzthi Et CONH
3-59 H iBu 3-CF₃ -2-Bzthi Pr CONH
3-60 H iBu 3-CF₃ -2-Bzthi Bu CONH
3-61 H iBu 1-Nph Me CONH
3-62 H iBu 1-Nph Et CONH
3-63 H iBu 1-Nph Pr CONH
3-64 H iBu 1-Nph Bu CONH
3-65 H iBu 2-Nph Me CONH
3-66 H iBu 2-Nph Et CONH
3-67 H iBu 2-Nph Pr CONH
3-68 H iBu 2-Nph Bu CONH
3-69 H iBu 2-Qui Me CONH
3-70 H iBu 2-Qui Et CONH
3-71 H iBu 2-Qui Pr CONH
3-72 H iBu 2-Qui Bu CONH
3-73 H iBu 3-Qui Me CONH
3-74 H iBu 3-Qui Et CONH
3-75 H iBu 3-Qui Pr CONH
3-76 H iBu 3-Qui Bu CONH
3-77 H iBu 4-Qui Me CONH
3-78 H iBu 4-Qui Et CONH
3-79 H iBu 4-Qui Pr CONH
3-80 H iBu 4-Qui Bu CONH
3-81 H iBu 8-Qui Me CONH
3-82 H iBu 8-Qui Et CONH
3-83 H iBu 8-Qui Pr CONH
3-84 H iBu 8-Qui Bu CONH
3-85 H iBu 1-Iqui Me CONH
3-86 H iBu 1-Iqui Et CONH
3-87 H iBu 1-Iqui Pr CONH
3-88 H iBu 1-Iqui Bu CONH
3-89 H iBu 3-Iqui Me CONH
3-90 H iBu 3-Iqui Et CONH
3-91 H iBu 3-Iqui Pr CONH
3-92 H iBu 3-Iqui Bu CONH
3-93 H iBu 4-Br-Ph Me CONH
3-94 H iBu 4-Br-Ph Et CONH
3-95 H iBu 4-Br-Ph Pr CONH
3-96 H iBu 4-Br-Ph Bu CONH
3-97 H iBu 3-Br-Ph Me CONH
3-98 H iBu 3-Br-Ph Et CONH
3-99 H iBu 3-Br-Ph Pr CONH
3-100 H iBu 3-Br-Ph Bu CONH
3-101 H iBu 4-Ph-Ph Me CONH
3-102 H iBu 4-Ph-Ph Et CONH
3-103 H iBu 4-Ph-Ph Pr CONH
3-104 H iBu 4-Ph-Ph Bu CONH
3-105 H iBu 3-Ph-Ph Me CONH
3-106 H iBu 3-Ph-Ph Et CONH
3-107 H iBu 3-Ph-Ph Pr CONH
3-108 H iBu 3-Ph-Ph Bu CONH
3-109 H iBu 4- (2-Me-Ph) -Ph Me CONH
3-110 H iBu 4- (2-Me-Ph) -Ph Et CONH
3-111 H iBu 4- (2-Me-Ph) -Ph Pr CONH
3-112 H iBu 4- (2-Me-Ph) -Ph Bu CONH
3-113 H iBu 4- (3-Me-Ph) -Ph Me CONH
3-114 H iBu 4- (3-Me-Ph) -Ph Et CONH
3-115 H iBu 4- (3-Me-Ph) -Ph Pr CONH
3-116 H iBu 4- (3-Me-Ph) -Ph Bu CONH
3-117 H iBu 4- (4-Me-Ph) -Ph Me CONH
3-118 H iBu 4- (4-Me-Ph) -Ph Et CONH
3-119 H iBu 4- (4-Me-Ph) -Ph Pr CONH
3-120 H iBu 4- (4-Me-Ph) -Ph Bu CONH
3-121 HiBu 4- (2-F-Ph) -Ph Me CONH
3-122 H iBu 4- (2-F-Ph) -Ph Et CONH
3-123 H iBu 4- (2-F-Ph) -Ph Pr CONH
3-124 H iBu 4- (2-F-Ph) -Ph Bu CONH
3-125 H iBu 4- (3-F-Ph) -Ph Me CONH
3-126 H iBu 4- (3-F-Ph) -Ph Et CONH
3-127 H iBu 4- (3-F-Ph) -Ph Pr CONH
3-128 H iBu 4- (3-F-Ph) -Ph Bu CONH
3-129 H iBu 4- (4-F-Ph) -Ph Me CONH
3-130 H iBu 4- (4-F-Ph) -Ph Et CONH
3-131 HiBu 4- (4-F-Ph) -Ph Pr CONH
3-132 H iBu 4- (4-F-Ph) -Ph Bu CONH
3-133 H iBu 4- (2-Cl-Ph) -Ph Me CONH
3-134 H iBu 4- (2-Cl-Ph) -Ph Et CONH
3-135 H iBu 4- (2-Cl-Ph) -Ph Pr CONH
3-136 H iBu 4- (2-Cl-Ph) -Ph Bu CONH
3-137 H iBu 4- (3-Cl-Ph) -Ph Me CONH
3-138 H iBu 4- (3-Cl-Ph) -Ph Et CONH
3-139 H iBu 4- (3-Cl-Ph) -Ph Pr CONH
3-140 H iBu 4- (3-Cl-Ph) -Ph Bu CONH
3-141 H iBu 4- (4-Cl-Ph) -Ph Me CONH
3-142 H iBu 4- (4-Cl-Ph) -Ph Et CONH
3-143 H iBu 4- (4-Cl-Ph) -Ph Pr CONH
3-144 H iBu 4- (4-Cl-Ph) -Ph Bu CONH
3-145 H iBu 4- (2-MeO-Ph) -Ph Me CONH
3-146 H iBu 4- (2-MeO-Ph) -Ph Et CONH
3-147 H iBu 4- (2-MeO-Ph) -Ph Pr CONH
3-148 H iBu 4- (2-MeO-Ph) -Ph Bu CONH
3-149 H iBu 4- (3-MeO-Ph) -Ph Me CONH
3-150 H iBu 4- (3-MeO-Ph) -Ph Et CONH
3-151 H iBu 4- (3-MeO-Ph) -Ph Pr CONH
3-152 H iBu 4- (3-MeO-Ph) -Ph Bu CONH
3-153 H iBu 4- (4-MeO-Ph) -Ph Me CONH
3-154 H iBu 4- (4-MeO-Ph) -Ph Et CONH
3-155 H iBu 4- (4-MeO-Ph) -Ph Pr CONH
3-156 H iBu 4- (4-MeO-Ph) -Ph Bu CONH
3-157 H iBu 4- (2-CF₃ -Ph) -Ph Me CONH
3-158 H iBu 4- (2-CF₃ -Ph) -Ph Et CONH
3-159 H iBu 4- (2-CF₃ -Ph) -Ph Pr CONH
3-160 H iBu 4- (2-CF₃ -Ph) -Ph Bu CONH
3-161 H iBu 4- (3-CF₃ -Ph) -Ph Me CONH
3-162 H iBu 4- (3-CF₃ -Ph) -Ph Et CONH
3-163 H iBu 4- (3-CF₃ -Ph) -Ph Pr CONH
3-164 H iBu 4- (3-CF₃ -Ph) -Ph Bu CONH
3-165 H iBu 4- (4-CF₃ -Ph) -Ph Me CONH
3-166 H iBu 4- (4-CF₃ -Ph) -Ph Et CONH
3-167 H iBu 4- (4-CF₃ -Ph) -Ph Pr CONH
3-168 H iBu 4- (4-CF₃ -Ph) -Ph Bu CONH
3-169 H iBu 4- (3-CF₃ O-Ph) -Ph Me CONH
3-170 H iBu 4- (3-CF₃ O-Ph) -Ph Et CONH
3-171 H iBu 4- (3-CF₃ O-Ph) -Ph Pr CONH
3-172 H iBu 4- (3-CF₃ O-Ph) -Ph Bu CONH
3-173 H iBu 4- (4-CF₃ O-Ph) -Ph Me CONH
3-174 H iBu 4- (4-CF₃ O-Ph) -Ph Et CONH
3-175 H iBu 4- (4-CF₃ O-Ph) -Ph Pr CONH
3-176 H iBu 4- (4-CF₃ O-Ph) -Ph Bu CONH
3-177 H iBu 4-PhO-Ph Me CONH
3-178 H iBu 4-PhO-Ph Et CONH
3-179 H iBu 4-PhO-Ph Pr CONH
3-180 H iBu 4-PhO-Ph Bu CONH
3-181 H iBu 3-PhO-Ph Me CONH
3-182 H iBu 3-PhO-Ph Et CONH
3-183 H iBu 3-PhO-Ph Pr CONH
3-184 H iBu 3-PhO-Ph Bu CONH
3-185 H iBu 4-BnO-Ph Me CONH
3-186 H iBu 4-BnO-Ph Et CONH
3-187 H iBu 4-BnO-Ph Pr CONH
3-188 H iBu 4-BnO-Ph Bu CONH
3-189 H iBu 3-BnO-Ph Me CONH
3-190 H iBu 3-BnO-Ph Et CONH
3-191 H iBu 3-BnO-Ph Pr CONH
3-192 H iBu 3-BnO-Ph Bu CONH
3-193 H iBu 4-MeO-Ph Me CONH
3-194 H iBu 4-MeO-Ph Et CONH
3-195 H iBu 4-MeO-Ph Pr CONH
3-196 H iBu 4-MeO-Ph Bu CONH
3-197 H iBu 3-MeO-Ph Me CONH
3-198 H iBu 3-MeO-Ph Et CONH
3-199 H iBu 3-MeO-Ph Pr CONH
3-200 H iBu 3-MeO-Ph Bu CONH
3-201 H iBu 4-EtO-Ph Me CONH
3-202 H iBu 4-EtO-Ph Et CONH
3-203 H iBu 4-EtO-Ph Pr CONH
3-204 H iBu 4-EtO-Ph Bu CONH
3-205 H iBu 3-EtO-Ph Me CONH
3-206 H iBu 3-EtO-Ph Et CONH
3-207 H iBu 3-EtO-Ph Pr CONH
3-208 H iBu 3-EtO-Ph Bu CONH
3-209 H iBu 4-PrO-Ph Me CONH
3-210 H iBu 4-PrO-Ph Et CONH
3-211 H iBu 4-PrO-Ph Pr CONH
3-212 H iBu 4-PrO-Ph Bu CONH
3-213 H iBu 3-PrO-Ph Me CONH
3-214 H iBu 3-PrO-Ph Et CONH
3-215 H iBu 3-PrO-Ph Pr CONH
3-216 H iBu 3-PrO-Ph Bu CONH
3-217 H iBu 4-BuO-Ph Me CONH
3-218 H iBu 4-BuO-Ph Et CONH
3-219 H iBu 4-BuO-Ph Pr CONH
3-220 H iBu 4-BuO-Ph Bu CONH
3-221 H iBu 3-BuO-Ph Me CONH
3-222 H iBu 3-BuO-Ph Et CONH
3-223 H iBu 3-BuO-Ph Pr CONH
3-224 H iBu 3-BuO-Ph Bu CONH
3-225 H iBu 4-iPrO-Ph Me CONH
3-226 H iBu 4-iPrO-Ph Et CONH
3-227 H iBu 4-iPrO-Ph Pr CONH
3-228 H iBu 4-iPrO-Ph Bu CONH
3-229 H iBu 3-iPrO-Ph Me CONH
3-230 H iBu 3-iPrO-Ph Et CONH
3-231 H iBu 3-iPrO-Ph Pr CONH
3-232 H iBu 3-iPrO-Ph Bu CONH
3-233 H iBu 4-Me-Ph Me CONH
3-234 H iBu 4-Me-Ph Et CONH
3-235 H iBu 4-Me-Ph Pr CONH
3-236 H iBu 4-Me-Ph Bu CONH
3-237 H iBu 4-Et-Ph Me CONH
3-238 H iBu 4-Et-Ph Et CONH
3-239 H iBu 4-Et-Ph Pr CONH
3-240 H iBu 4-Et-Ph Bu CONH
3-241 H iBu 4-Pr-Ph Me CONH
3-242 H iBu 4-Pr-Ph Et CONH
3-243 H iBu 4-Pr-Ph Pr CONH
3-244 H iBu 4-Pr-Ph Bu CONH
3-245 H iBu 4-Bu-Ph Me CONH
3-246 H iBu 4-Bu-Ph Et CONH
3-247 H iBu 4-Bu-Ph Pr CONH
3-248 H iBu 4-Bu-Ph Bu CONH
3-249 H iBu 4-iPr-Ph Me CONH
3-250 H iBu 4-iPr-Ph Et CONH
3-251 H iBu 4-iPr-Ph Pr CONH
3-252 H iBu 4-iPr-Ph Bu CONH
3-253 H iBu 4-cHx-Ph Me CONH
3-254 H iBu 4-cHx-Ph Et CONH
3-255 H iBu 4-cHx-Ph Pr CONH
3-256 H iBu 4-cHx-Ph Bu CONH
3-257 H iBu 4- (Me₂ N) -Ph Me CONH
3-258 H iBu 4- (Me₂ N) -Ph Et CONH
3-259 H iBu 4- (Me₂ N) -Ph Pr CONH
3-260 H iBu 4- (Me₂ N) -Ph Bu CONH
3-261 H iBu 4- (Et₂ N) -Ph Me CONH
3-262 H iBu 4- (Et₂ N) -Ph Et CONH
3-263 H iBu 4- (Et₂ N) -Ph Pr CONH
3-264 H iBu 4- (Et₂ N) -Ph Bu CONH
3-265 H iBu 4- (1-Pip) -Ph Me CONH
3-266 H iBu 4- (1-Pip) -Ph Et CONH
3-267 H iBu 4- (1-Pip) -Ph Pr CONH
3-268 H iBu 4- (1-Pip) -Ph Bu CONH
3-269 H iBu 4- (1-Mor) -Ph Me CONH
3-270 H iBu 4- (1-Mor) -Ph Et CONH
3-271 H iBu 4- (1-Mor) -Ph Pr CONH
3-272 H iBu 4- (1-Mor) -Ph Bu CONH
3-273 H iBu 4- (4-Me-1-Pipra) -Ph Me CONH
3-274 H iBu 4- (4-Me-1-Pipra) -Ph Et CONH
3-275 H iBu 4- (4-Me-1-Pipra) -Ph Pr CONH
3-276 H iBu 4- (4-Me-1-Pipra) -Ph Bu CONH
3-277 H iBu 4- (1-Me-4-Pip) -Ph Me CONH
3-278 H iBu 4- (1-Me-4-Pip) -Ph Et CONH
3-279 H iBu 4- (1-Me-4-Pip) -Ph Pr CONH
3-280 H iBu 4- (1-Me-4-Pip) -Ph Bu CONH
3-281 H iBu 4- [1- (2-MeO-Et) -4-Pip] -Ph Me CONH
3-282 H iBu 4- [1- (2-MeO-Et) -4-Pip] -Ph Et CONH
3-283 H iBu 4- [1- (2-MeO-Et) -4-Pip] -Ph Pr CONH
3-284 H iBu 4- [1- (2-MeO-Et) -4-Pip] -Ph Bu CONH
3-285 H iBu 4-Br-Ph Me O
3-286 H iBu 4-Br-Ph Et O
3-287 H iBu 4-Br-Ph Pr O
3-288 H iBu 4-Br-Ph Bu O
3-289 H iBu 3-Br-Ph Me O
3-290 H iBu 3-Br-Ph Et O
3-291 H iBu 3-Br-Ph Pr O
3-292 H iBu 3-Br-Ph Bu O
3-293 H iBu 4-Ph-Ph Me O
3-294 H iBu 4-Ph-Ph Et O
3-295 H iBu 4-Ph-Ph Pr O
3-296 H iBu 4-Ph-Ph Bu O
3-297 H iBu 3-Ph-Ph Me O
3-298 H iBu 3-Ph-Ph Et O
3-299 H iBu 3-Ph-Ph Pr O
3-300 H iBu 3-Ph-Ph Bu O
3-301 H iBu 4-PhO-Ph Me O
3-302 H iBu 4-PhO-Ph Et O
3-303 H iBu 4-PhO-Ph Pr O
3-304 H iBu 4-PhO-Ph Bu O
3-305 H iBu 3-PhO-Ph Me O
3-306 H iBu 3-PhO-Ph Et O
3-307 H iBu 3-PhO-Ph Pr O
3-308 H iBu 3-PhO-Ph Bu O
3-309 H iBu 4-BnO-Ph Me O
3-310 H iBu 4-BnO-Ph Et O
3-311 H iBu 4-BnO-Ph Pr O
3-312 H iBu 4-BnO-Ph Bu O
3-313 H iBu 3-BnO-Ph Me O
3-314 H iBu 3-BnO-Ph Et O
3-315 H iBu 3-BnO-Ph Pr O
3-316 H iBu 3-BnO-Ph Bu O
3-317 H iBu 4-cHx-Ph Me O
3-318 H iBu 4-cHx-Ph Et O
3-319 H iBu 4-cHx-Ph Pr O
3-320 H iBu 4-cHx-Ph Bu O
3-321 H iBu 3-cHx-Ph Me O
3-322 H iBu 3-cHx-Ph Et O
3-323 H iBu 3-cHx-Ph Pr O
3-324 H iBu 3-cHx-Ph Bu O
3-325 H iBu 4- (2-Fur) -Ph Me O
3-326 H iBu 4- (2-Fur) -Ph Et O
3-327 H iBu 4- (2-Fur) -Ph Pr O
3-328 H iBu 4- (2-Fur) -Ph Bu O
3-329 H iBu 3- (2-Fur) -Ph Me O
3-330 H iBu 3- (2-Fur) -Ph Et O
3-331 H iBu 3- (2-Fur) -Ph Pr O
3-332 H iBu 3- (2-Fur) -Ph Bu O
3-333 H iBu 4- (3-Fur) -Ph Me O
3-334 H iBu 4- (3-Fur) -Ph Et O
3-335 H iBu 4- (3-Fur) -Ph Pr O
3-336 H iBu 4- (3-Fur) -Ph Bu O
3-337 H iBu 3- (3-Fur) -Ph Me O
3-338 H iBu 3- (3-Fur) -Ph Et O
3-339 H iBu 3- (3-Fur) -Ph Pr O
3-340 H iBu 3- (3-Fur) -Ph Bu O
3-341 H iBu 4- (2-Thi) -Ph Me O
3-342 H iBu 4- (2-Thi) -Ph Et O
3-343 H iBu 4- (2-Thi) -Ph Pr O
3-344 H iBu 4- (2-Thi) -Ph Bu O
3-345 H iBu 3- (2-Thi) -Ph Me O
3-346 H iBu 3- (2-Thi) -Ph Et O
3-347 H iBu 3- (2-Thi) -Ph Pr O
3-348 H iBu 3- (2-Thi) -Ph Bu O
3-349 H iBu 4- (3-Thi) -Ph Me O
3-350 H iBu 4- (3-Thi) -Ph Et O
3-351 H iBu 4- (3-Thi) -Ph Pr O
3-352 H iBu 4- (3-Thi) -Ph Bu O
3-353 H iBu 3- (3-Thi) -Ph Me O
3-354 H iBu 3- (3-Thi) -Ph Et O
3-355 H iBu 3- (3-Thi) -Ph Pr O
3-356 H iBu 3- (3-Thi) -Ph Bu O
3-357 H iBu 4- (1-Boc-2-Pyro) -Ph Me O
3-358 H iBu 4- (1-Boc-2-Pyro) -Ph Et O
3-359 H iBu 4- (1-Boc-2-Pyro) -Ph Pr O
3-360 H iBu 4- (1-Boc-2-Pyro) -Ph Bu O
3-361 H iBu 3- (1-Boc-2-Pyro) -Ph Me O
3-362 H iBu 3- (1-Boc-2-Pyro) -Ph Et O
3-363 H iBu 3- (1-Boc-2-Pyro) -Ph Pr O
3-364 H iBu 3- (1-Boc-2-Pyro) -Ph Bu O
3-365 H iBu 4- (2-F-Ph) -Ph Me O
3-366 H iBu 4- (2-F-Ph) -Ph Et O
3-367 HiBu 4- (2-F-Ph) -Ph Pr O
3-368 H iBu 4- (2-F-Ph) -Ph Bu O
3-369 H iBu 4- (3-F-Ph) -Ph Me O
3-370 H iBu 4- (3-F-Ph) -Ph Et O
3-371 H iBu 4- (3-F-Ph) -Ph Pr O
3-372 H iBu 4- (3-F-Ph) -Ph Bu O
3-373 H iBu 4- (4-F-Ph) -Ph Me O
3-374 H iBu 4- (4-F-Ph) -Ph Et O
3-375 H iBu 4- (4-F-Ph) -Ph Pr O
3-376 H iBu 4- (4-F-Ph) -Ph Bu O
3-377 H iBu 3- (2-Cl-Ph) -Ph Me O
3-378 H iBu 3- (2-Cl-Ph) -Ph Et O
3-379 H iBu 3- (2-Cl-Ph) -Ph Pr O
3-380 H iBu 3- (2-Cl-Ph) -Ph Bu O
3-381 H iBu 3- (3-Cl-Ph) -Ph Me O
3-382 H iBu 3- (3-Cl-Ph) -Ph Et O
3-383 H iBu 3- (3-Cl-Ph) -Ph Pr O
3-384 H iBu 3- (3-Cl-Ph) -Ph Bu O
3-385 H iBu 3- (4-Cl-Ph) -Ph Me O
3-386 H iBu 3- (4-Cl-Ph) -Ph Et O
3-387 HiBu 3- (4-Cl-Ph) -Ph Pr O
3-388 H iBu 3- (4-Cl-Ph) -Ph Bu O
3-389 H iBu 3- (2-Me-Ph) -Ph Me O
3-390 H iBu 3- (2-Me-Ph) -Ph Et O
3-391 H iBu 3- (2-Me-Ph) -Ph Pr O
3-392 H iBu 3- (2-Me-Ph) -Ph Bu O
3-393 H iBu 3- (3-Me-Ph) -Ph Me O
3-394 H iBu 3- (3-Me-Ph) -Ph Et O
3-395 H iBu 3- (3-Me-Ph) -Ph Pr O
3-396 H iBu 3- (3-Me-Ph) -Ph Bu O
3-397 H iBu 3- (4-Me-Ph) -Ph Me O
3-398 H iBu 3- (4-Me-Ph) -Ph Et O
3-399 H iBu 3- (4-Me-Ph) -Ph Pr O
3-400 H iBu 3- (4-Me-Ph) -Ph Bu O
3-401 H iBu 3- (2-MeO-Ph) -Ph Me O
3-402 H iBu 3- (2-MeO-Ph) -Ph Et O
3-403 H iBu 3- (2-MeO-Ph) -Ph Pr O
3-404 H iBu 3- (2-MeO-Ph) -Ph Bu O
3-405 H iBu 3- (3-MeO-Ph) -Ph Me O
3-406 H iBu 3- (3-MeO-Ph) -Ph Et O
3-407 H iBu 3- (3-MeO-Ph) -Ph Pr O
3-408 H iBu 3- (3-MeO-Ph) -Ph Bu O
3-409 H iBu 3- (4-MeO-Ph) -Ph Me O
3-410 H iBu 3- (4-MeO-Ph) -Ph Et O
3-411 H iBu 3- (4-MeO-Ph) -Ph Pr O
3-412 H iBu 3- (4-MeO-Ph) -Ph Bu O
3-413 H iBu 3- (2-CF₃ -Ph) -Ph Me O
3-414 H iBu 3- (2-CF₃ -Ph) -Ph Et O
3-415 H iBu 3- (2-CF₃ -Ph) -Ph Pr O
3-416 H iBu 3- (2-CF₃ -Ph) -Ph Bu O
3-417 H iBu 3- (3-CF₃ -Ph) -Ph Me O
3-418 H iBu 3- (3-CF₃ -Ph) -Ph Et O
3-419 H iBu 3- (3-CF₃ -Ph) -Ph Pr O
3-420 H iBu 3- (3-CF₃ -Ph) -Ph Bu O
3-421 H iBu 3- (4-CF₃ -Ph) -Ph Me O
3-422 H iBu 3- (4-CF₃ -Ph) -Ph Et O
3-423 H iBu 3- (4-CF₃ -Ph) -Ph Pr O
3-424 H iBu 3- (4-CF₃ -Ph) -Ph Bu O
3-425 H iBu 3- (3-CF₃ O-Ph) -Ph Me O
3-426 H iBu 3- (3-CF₃ O-Ph) -Ph Et O
3-427 H iBu 3- (3-CF₃ O-Ph) -Ph Pr O
3-428 H iBu 3- (3-CF₃ O-Ph) -Ph Bu O
3-429 H iBu 3- (4-CF₃ O-Ph) -Ph Me O
3-430 H iBu 3- (4-CF₃ O-Ph) -Ph Et O
3-431 H iBu 3- (4-CF₃ O-Ph) -Ph Pr O
3-432 H iBu 3- (4-CF₃ O-Ph) -Ph Bu O
3-433 H iBu 3- (2-HO-Ph) -Ph Me O
3-434 H iBu 3- (2-HO-Ph) -Ph Et O
3-435 H iBu 3- (2-HO-Ph) -Ph Pr O
3-436 H iBu 3- (2-HO-Ph) -Ph Bu O
3-437 H iBu 3- (3-HO-Ph) -Ph Me O
3-438 H iBu 3- (3-HO-Ph) -Ph Et O
3-439 H iBu 3- (3-HO-Ph) -Ph Pr O
3-440 H iBu 3- (3-HO-Ph) -Ph Bu O
3-441 H iBu 3- (4-HO-Ph) -Ph Me O
3-442 H iBu 3- (4-HO-Ph) -Ph Et O
3-443 H iBu 3- (4-HO-Ph) -Ph Pr O
3-444 H iBu 3- (4-HO-Ph) -Ph Bu O
3-445 H iBu 3- (2-HOCH₂ -Ph) -Ph Me O
3-446 H iBu 3- (2-HOCH₂ -Ph) -Ph Et O
3-447 HiBu 3- (2-HOCH₂ -Ph) -Ph Pr O
3-448 H iBu 3- (2-HOCH₂ -Ph) -Ph Bu O
3-449 H iBu 3- (3-HOCH₂ -Ph) -Ph Me O
3-450 H iBu 3- (3-HOCH₂ -Ph) -Ph Et O
3-451 H iBu 3- (3-HOCH₂ -Ph) -Ph Pr O
3-452 H iBu 3- (3-HOCH₂ -Ph) -Ph Bu O
3-453 H iBu 3- (4-HOCH₂ -Ph) -Ph Me O
3-454 H iBu 3- (4-HOCH₂ -Ph) -Ph Et O
3-455 H iBu 3- (4-HOCH₂ -Ph) -Ph Pr O
3-456 H iBu 3- (4-HOCH₂ -Ph) -Ph Bu O
3-457 H iBu 3- (2-H₂ N-Ph) -Ph Me O
3-458 H iBu 3- (2-H₂ N-Ph) -Ph Et O
3-459 H iBu 3- (2-H 2 N-Ph) -Ph Pr O
3-460 H iBu 3- (2-H₂ N-Ph) -Ph Bu O
3-461 H iBu 3- (3-H₂ N-Ph) -Ph Me O
3-462 H iBu 3- (3-H₂ N-Ph) -Ph Et O
3-463 H iBu 3- (3-H₂ N-Ph) -Ph Pr O
3-464 H iBu 3- (3-H₂ N-Ph) -Ph Bu O
3-465 H iBu 3- (4-H₂ N-Ph) -Ph Me O
3-466 H iBu 3- (4-H₂ N-Ph) -Ph Et O
3-467 H iBu 3- (4-H₂ N-Ph) -Ph Pr O
3-468 H iBu 3- (4-H₂ N-Ph) -Ph Bu O
3-469 H iBu Ph Me SO₂ NH
3-470 H iBu Ph Et SO₂ NH
3-471 H iBu Ph Pr SO₂ NH
3-472 H iBu Ph Bu SO₂ NH
3-473 H iBu 4-Br-Ph Me SO₂ NH
3-474 H iBu 4-Br-Ph Et SO₂ NH
3-475 H iBu 4-Br-Ph Pr SO₂ NH
3-476 H iBu 4-Br-Ph Bu SO₂ NH
3-477 H iBu 3-Br-Ph Me SO₂ NH
3-478 H iBu 3-Br-Ph Et SO₂ NH
3-479 H iBu 3-Br-Ph Pr SO₂ NH
3-480 H iBu 3-Br-Ph Bu SO₂ NH
3-481 H iBu 4-Ph-Ph Me SO₂ NH
3-482 H iBu 4-Ph-Ph Et SO₂ NH
3-483 H iBu 4-Ph-Ph Pr SO₂ NH
3-484 H iBu 4-Ph-Ph Bu SO₂ NH
3-485 H iBu 3-Ph-Ph Me SO₂ NH
3-486 H iBu 3-Ph-Ph Et SO₂ NH
3-487 H iBu 3-Ph-Ph Pr SO₂ NH
3-488 H iBu 3-Ph-Ph Bu SO₂ NH
3-489 H iBu 1-Nph Me SO₂ NH
3-490 H iBu 1-Nph Et SO₂ NH
3-491 H iBu 1-Nph Pr SO₂ NH
3-492 H iBu 1-Nph Bu SO₂ NH
3-493 H iBu 2-Nph Me SO₂ NH
3-494 H iBu 2-Nph Et SO₂ NH
3-495 H iBu 2-Nph Pr SO₂ NH
3-496 H iBu 2-Nph Bu SO₂ NH
3-497 H iBu 4- (2-Py) -Ph Me SO₂ NH
3-498 H iBu 4- (2-Py) -Ph Et SO₂ NH
3-499 H iBu 4- (2-Py) -Ph Pr SO₂ NH
3-500 H iBu 4- (2-Py) -Ph Bu SO₂ NH
3-501 H iBu 4- (3-Py) -Ph Me SO₂ NH
3-502 H iBu 4- (3-Py) -Ph Et SO₂ NH
3-503 H iBu 4- (3-Py) -Ph Pr SO₂ NH
3-504 H iBu 4- (3-Py) -Ph Bu SO₂ NH
3-505 H iBu 4- (4-Py) -Ph Me SO₂ NH
3-506 H iBu 4- (4-Py) -Ph Et SO₂ NH
3-507 H iBu 4- (4-Py) -Ph Pr SO₂ NH
3-508 H iBu 4- (4-Py) -Ph Bu SO₂ NH
3-509 H iBu 3- (2-Py) -Ph Me SO₂ NH
3-510 H iBu 3- (2-Py) -Ph Et SO₂ NH
3-511 H iBu 3- (2-Py) -Ph Pr SO₂ NH
3-512 H iBu 3- (2-Py) -Ph Bu SO₂ NH
3-513 H iBu 3- (3-Py) -Ph Me SO₂ NH
3-514 H iBu 3- (3-Py) -Ph Et SO₂ NH
3-515 H iBu 3- (3-Py) -Ph Pr SO₂ NH
3-516 H iBu 3- (3-Py) -Ph Bu SO₂ NH
3-517 H iBu 3- (4-Py) -Ph Me SO₂ NH
3-518 H iBu 3- (4-Py) -Ph Et SO₂ NH
3-519 H iBu 3- (4-Py) -Ph Pr SO₂ NH
3-520 H iBu 3- (4-Py) -Ph Bu SO₂ NH
-------------------------------------------------- -------------

例示化合物表４
-----------------------------------------------------
化合物
番 号 R³-Z- R⁴ X
-----------------------------------------------------
4-1 6-Ph-2-O-Pyra Me NH
4-2 6-Ph-2-O-Pyra Et NH
4-3 6-Ph-2-O-Pyra Pr NH
4-4 6-Ph-2-O-Pyra Bu NH
4-5 Bn Me O-CONH
4-6 Bn Et O-CONH
4-7 Bn Pr O-CONH
4-8 Bn Bu O-CONH
4-9 2-Bzfur Me CONH
4-10 2-Bzfur Et CONH
4-11 2-Bzfur Pr CONH
4-12 2-Bzfur Bu CONH
4-13 3-Me-2-Bzfur Me CONH
4-14 3-Me-2-Bzfur Et CONH
4-15 3-Me-2-Bzfur Pr CONH
4-16 3-Me-2-Bzfur Bu CONH
4-17 5-Cl-2-Bzfur Me CONH
4-18 5-Cl-2-Bzfur Et CONH
4-19 5-Cl-2-Bzfur Pr CONH
4-20 5-Cl-2-Bzfur Bu CONH
4-21 5-MeO-2-Bzfur Me CONH
4-22 5-MeO-2-Bzfur Et CONH
4-23 5-MeO-2-Bzfur Pr CONH
4-24 5-MeO-2-Bzfur Bu CONH
4-25 7-MeO-2-Bzfur Me CONH
4-26 7-MeO-2-Bzfur Et CONH
4-27 7-MeO-2-Bzfur Pr CONH
4-28 7-MeO-2-Bzfur Bu CONH
4-29 5-Cl-2-Ind Me CONH
4-30 5-Cl-2-Ind Et CONH
4-31 5-Cl-2-Ind Pr CONH
4-32 5-Cl-2-Ind Bu CONH
4-33 5-F-2-Ind Me CONH
4-34 5-F-2-Ind Et CONH
4-35 5-F-2-Ind Pr CONH
4-36 5-F-2-Ind Bu CONH
4-37 5-Me-2-Ind Me CONH
4-38 5-Me-2-Ind Et CONH
4-39 5-Me-2-Ind Pr CONH
4-40 5-Me-2-Ind Bu CONH
4-41 5-MeO-2-Ind Me CONH
4-42 5-MeO-2-Ind Et CONH
4-43 5-MeO-2-Ind Pr CONH
4-44 5-MeO-2-Ind Bu CONH
4-45 5-Ind Me CONH
4-46 5-Ind Et CONH
4-47 5-Ind Pr CONH
4-48 5-Ind Bu CONH
4-49 3-Cl-2-Bzthi Me CONH
4-50 3-Cl-2-Bzthi Et CONH
4-51 3-Cl-2-Bzthi Pr CONH
4-52 3-Cl-2-Bzthi Bu CONH
4-53 3-Me-2-Bzthi Me CONH
4-54 3-Me-2-Bzthi Et CONH
4-55 3-Me-2-Bzthi Pr CONH
4-56 3-Me-2-Bzthi Bu CONH
4-57 3-CF₃-2-Bzthi Me CONH
4-58 3-CF₃-2-Bzthi Et CONH
4-59 3-CF₃-2-Bzthi Pr CONH
4-60 3-CF₃-2-Bzthi Bu CONH
4-61 1-Nph Me CONH
4-62 1-Nph Et CONH
4-63 1-Nph Pr CONH
4-64 1-Nph Bu CONH
4-65 2-Nph Me CONH
4-66 2-Nph Et CONH
4-67 2-Nph Pr CONH
4-68 2-Nph Bu CONH
4-69 2-Qui Me CONH
4-70 2-Qui Et CONH
4-71 2-Qui Pr CONH
4-72 2-Qui Bu CONH
4-73 3-Qui Me CONH
4-74 3-Qui Et CONH
4-75 3-Qui Pr CONH
4-76 3-Qui Bu CONH
4-77 4-Qui Me CONH
4-78 4-Qui Et CONH
4-79 4-Qui Pr CONH
4-80 4-Qui Bu CONH
4-81 8-Qui Me CONH
4-82 8-Qui Et CONH
4-83 8-Qui Pr CONH
4-84 8-Qui Bu CONH
4-85 1-Iqui Me CONH
4-86 1-Iqui Et CONH
4-87 1-Iqui Pr CONH
4-88 1-Iqui Bu CONH
4-89 3-Iqui Me CONH
4-90 3-Iqui Et CONH
4-91 3-Iqui Pr CONH
4-92 3-Iqui Bu CONH
4-93 4-Br-Ph Me CONH
4-94 4-Br-Ph Et CONH
4-95 4-Br-Ph Pr CONH
4-96 4-Br-Ph Bu CONH
4-97 3-Br-Ph Me CONH
4-98 3-Br-Ph Et CONH
4-99 3-Br-Ph Pr CONH
4-100 3-Br-Ph Bu CONH
4-101 4-Ph-Ph Me CONH
4-102 4-Ph-Ph Et CONH
4-103 4-Ph-Ph Pr CONH
4-104 4-Ph-Ph Bu CONH
4-105 3-Ph-Ph Me CONH
4-106 3-Ph-Ph Et CONH
4-107 3-Ph-Ph Pr CONH
4-108 3-Ph-Ph Bu CONH
4-109 4-(2-Me-Ph)-Ph Me CONH
4-110 4-(2-Me-Ph)-Ph Et CONH
4-111 4-(2-Me-Ph)-Ph Pr CONH
4-112 4-(2-Me-Ph)-Ph Bu CONH
4-113 4-(3-Me-Ph)-Ph Me CONH
4-114 4-(3-Me-Ph)-Ph Et CONH
4-115 4-(3-Me-Ph)-Ph Pr CONH
4-116 4-(3-Me-Ph)-Ph Bu CONH
4-117 4-(4-Me-Ph)-Ph Me CONH
4-118 4-(4-Me-Ph)-Ph Et CONH
4-119 4-(4-Me-Ph)-Ph Pr CONH
4-120 4-(4-Me-Ph)-Ph Bu CONH
4-121 4-(2-F-Ph)-Ph Me CONH
4-122 4-(2-F-Ph)-Ph Et CONH
4-123 4-(2-F-Ph)-Ph Pr CONH
4-124 4-(2-F-Ph)-Ph Bu CONH
4-125 4-(3-F-Ph)-Ph Me CONH
4-126 4-(3-F-Ph)-Ph Et CONH
4-127 4-(3-F-Ph)-Ph Pr CONH
4-128 4-(3-F-Ph)-Ph Bu CONH
4-129 4-(4-F-Ph)-Ph Me CONH
4-130 4-(4-F-Ph)-Ph Et CONH
4-131 4-(4-F-Ph)-Ph Pr CONH
4-132 4-(4-F-Ph)-Ph Bu CONH
4-133 4-(2-Cl-Ph)-Ph Me CONH
4-134 4-(2-Cl-Ph)-Ph Et CONH
4-135 4-(2-Cl-Ph)-Ph Pr CONH
4-136 4-(2-Cl-Ph)-Ph Bu CONH
4-137 4-(3-Cl-Ph)-Ph Me CONH
4-138 4-(3-Cl-Ph)-Ph Et CONH
4-139 4-(3-Cl-Ph)-Ph Pr CONH
4-140 4-(3-Cl-Ph)-Ph Bu CONH
4-141 4-(4-Cl-Ph)-Ph Me CONH
4-142 4-(4-Cl-Ph)-Ph Et CONH
4-143 4-(4-Cl-Ph)-Ph Pr CONH
4-144 4-(4-Cl-Ph)-Ph Bu CONH
4-145 4-(2-MeO-Ph)-Ph Me CONH
4-146 4-(2-MeO-Ph)-Ph Et CONH
4-147 4-(2-MeO-Ph)-Ph Pr CONH
4-148 4-(2-MeO-Ph)-Ph Bu CONH
4-149 4-(3-MeO-Ph)-Ph Me CONH
4-150 4-(3-MeO-Ph)-Ph Et CONH
4-151 4-(3-MeO-Ph)-Ph Pr CONH
4-152 4-(3-MeO-Ph)-Ph Bu CONH
4-153 4-(4-MeO-Ph)-Ph Me CONH
4-154 4-(4-MeO-Ph)-Ph Et CONH
4-155 4-(4-MeO-Ph)-Ph Pr CONH
4-156 4-(4-MeO-Ph)-Ph Bu CONH
4-157 4-(2-CF₃-Ph)-Ph Me CONH
4-158 4-(2-CF₃-Ph)-Ph Et CONH
4-159 4-(2-CF₃-Ph)-Ph Pr CONH
4-160 4-(2-CF₃-Ph)-Ph Bu CONH
4-161 4-(3-CF₃-Ph)-Ph Me CONH
4-162 4-(3-CF₃-Ph)-Ph Et CONH
4-163 4-(3-CF₃-Ph)-Ph Pr CONH
4-164 4-(3-CF₃-Ph)-Ph Bu CONH
4-165 4-(4-CF₃-Ph)-Ph Me CONH
4-166 4-(4-CF₃-Ph)-Ph Et CONH
4-167 4-(4-CF₃-Ph)-Ph Pr CONH
4-168 4-(4-CF₃-Ph)-Ph Bu CONH
4-169 4-(3-CF₃O-Ph)-Ph Me CONH
4-170 4-(3-CF₃O-Ph)-Ph Et CONH
4-171 4-(3-CF₃O-Ph)-Ph Pr CONH
4-172 4-(3-CF₃O-Ph)-Ph Bu CONH
4-173 4-(4-CF₃O-Ph)-Ph Me CONH
4-174 4-(4-CF₃O-Ph)-Ph Et CONH
4-175 4-(4-CF₃O-Ph)-Ph Pr CONH
4-176 4-(4-CF₃O-Ph)-Ph Bu CONH
4-177 4-PhO-Ph Me CONH
4-178 4-PhO-Ph Et CONH
4-179 4-PhO-Ph Pr CONH
4-180 4-PhO-Ph Bu CONH
4-181 3-PhO-Ph Me CONH
4-182 3-PhO-Ph Et CONH
4-183 3-PhO-Ph Pr CONH
4-184 3-PhO-Ph Bu CONH
4-185 4-BnO-Ph Me CONH
4-186 4-BnO-Ph Et CONH
4-187 4-BnO-Ph Pr CONH
4-188 4-BnO-Ph Bu CONH
4-189 3-BnO-Ph Me CONH
4-190 3-BnO-Ph Et CONH
4-191 3-BnO-Ph Pr CONH
4-192 3-BnO-Ph Bu CONH
4-193 4-MeO-Ph Me CONH
4-194 4-MeO-Ph Et CONH
4-195 4-MeO-Ph Pr CONH
4-196 4-MeO-Ph Bu CONH
4-197 3-MeO-Ph Me CONH
4-198 3-MeO-Ph Et CONH
4-199 3-MeO-Ph Pr CONH
4-200 3-MeO-Ph Bu CONH
4-201 4-EtO-Ph Me CONH
4-202 4-EtO-Ph Et CONH
4-203 4-EtO-Ph Pr CONH
4-204 4-EtO-Ph Bu CONH
4-205 3-EtO-Ph Me CONH
4-206 3-EtO-Ph Et CONH
4-207 3-EtO-Ph Pr CONH
4-208 3-EtO-Ph Bu CONH
4-209 4-PrO-Ph Me CONH
4-210 4-PrO-Ph Et CONH
4-211 4-PrO-Ph Pr CONH
4-212 4-PrO-Ph Bu CONH
4-213 3-PrO-Ph Me CONH
4-214 3-PrO-Ph Et CONH
4-215 3-PrO-Ph Pr CONH
4-216 3-PrO-Ph Bu CONH
4-217 4-BuO-Ph Me CONH
4-218 4-BuO-Ph Et CONH
4-219 4-BuO-Ph Pr CONH
4-220 4-BuO-Ph Bu CONH
4-221 3-BuO-Ph Me CONH
4-222 3-BuO-Ph Et CONH
4-223 3-BuO-Ph Pr CONH
4-224 3-BuO-Ph Bu CONH
4-225 4-iPrO-Ph Me CONH
4-226 4-iPrO-Ph Et CONH
4-227 4-iPrO-Ph Pr CONH
4-228 4-iPrO-Ph Bu CONH
4-229 3-iPrO-Ph Me CONH
4-230 3-iPrO-Ph Et CONH
4-231 3-iPrO-Ph Pr CONH
4-232 3-iPrO-Ph Bu CONH
4-233 4-Me-Ph Me CONH
4-234 4-Me-Ph Et CONH
4-235 4-Me-Ph Pr CONH
4-236 4-Me-Ph Bu CONH
4-237 4-Et-Ph Me CONH
4-238 4-Et-Ph Et CONH
4-239 4-Et-Ph Pr CONH
4-240 4-Et-Ph Bu CONH
4-241 4-Pr-Ph Me CONH
4-242 4-Pr-Ph Et CONH
4-243 4-Pr-Ph Pr CONH
4-244 4-Pr-Ph Bu CONH
4-245 4-Bu-Ph Me CONH
4-246 4-Bu-Ph Et CONH
4-247 4-Bu-Ph Pr CONH
4-248 4-Bu-Ph Bu CONH
4-249 4-iPr-Ph Me CONH
4-250 4-iPr-Ph Et CONH
4-251 4-iPr-Ph Pr CONH
4-252 4-iPr-Ph Bu CONH
4-253 4-cHx-Ph Me CONH
4-254 4-cHx-Ph Et CONH
4-255 4-cHx-Ph Pr CONH
4-256 4-cHx-Ph Bu CONH
4-257 4-(Me₂N)-Ph Me CONH
4-258 4-(Me₂N)-Ph Et CONH
4-259 4-(Me₂N)-Ph Pr CONH
4-260 4-(Me₂N)-Ph Bu CONH
4-261 4-(Et₂N)-Ph Me CONH
4-262 4-(Et₂N)-Ph Et CONH
4-263 4-(Et₂N)-Ph Pr CONH
4-264 4-(Et₂N)-Ph Bu CONH
4-265 4-(1-Pip)-Ph Me CONH
4-266 4-(1-Pip)-Ph Et CONH
4-267 4-(1-Pip)-Ph Pr CONH
4-268 4-(1-Pip)-Ph Bu CONH
4-269 4-(1-Mor)-Ph Me CONH
4-270 4-(1-Mor)-Ph Et CONH
4-271 4-(1-Mor)-Ph Pr CONH
4-272 4-(1-Mor)-Ph Bu CONH
4-273 4-(4-Me-1-Pipra)-Ph Me CONH
4-274 4-(4-Me-1-Pipra)-Ph Et CONH
4-275 4-(4-Me-1-Pipra)-Ph Pr CONH
4-276 4-(4-Me-1-Pipra)-Ph Bu CONH
4-277 4-(1-Me-4-Pip)-Ph Me CONH
4-278 4-(1-Me-4-Pip)-Ph Et CONH
4-279 4-(1-Me-4-Pip)-Ph Pr CONH
4-280 4-(1-Me-4-Pip)-Ph Bu CONH
4-281 4-[1-(2-MeO-Et)-4-Pip]-Ph Me CONH
4-282 4-[1-(2-MeO-Et)-4-Pip]-Ph Et CONH
4-283 4-[1-(2-MeO-Et)-4-Pip]-Ph Pr CONH
4-284 4-[1-(2-MeO-Et)-4-Pip]-Ph Bu CONH
4-285 4-Br-Ph Me O
4-286 4-Br-Ph Et O
4-287 4-Br-Ph Pr O
4-288 4-Br-Ph Bu O
4-289 3-Br-Ph Me O
4-290 3-Br-Ph Et O
4-291 3-Br-Ph Pr O
4-292 3-Br-Ph Bu O
4-293 4-Ph-Ph Me O
4-294 4-Ph-Ph Et O
4-295 4-Ph-Ph Pr O
4-296 4-Ph-Ph Bu O
4-297 3-Ph-Ph Me O
4-298 3-Ph-Ph Et O
4-299 3-Ph-Ph Pr O
4-300 3-Ph-Ph Bu O
4-301 4-PhO-Ph Me O
4-302 4-PhO-Ph Et O
4-303 4-PhO-Ph Pr O
4-304 4-PhO-Ph Bu O
4-305 3-PhO-Ph Me O
4-306 3-PhO-Ph Et O
4-307 3-PhO-Ph Pr O
4-308 3-PhO-Ph Bu O
4-309 4-BnO-Ph Me O
4-310 4-BnO-Ph Et O
4-311 4-BnO-Ph Pr O
4-312 4-BnO-Ph Bu O
4-313 3-BnO-Ph Me O
4-314 3-BnO-Ph Et O
4-315 3-BnO-Ph Pr O
4-316 3-BnO-Ph Bu O
4-317 4-cHx-Ph Me O
4-318 4-cHx-Ph Et O
4-319 4-cHx-Ph Pr O
4-320 4-cHx-Ph Bu O
4-321 3-cHx-Ph Me O
4-322 3-cHx-Ph Et O
4-323 3-cHx-Ph Pr O
4-324 3-cHx-Ph Bu O
4-325 4-(2-Fur)-Ph Me O
4-326 4-(2-Fur)-Ph Et O
4-327 4-(2-Fur)-Ph Pr O
4-328 4-(2-Fur)-Ph Bu O
4-329 3-(2-Fur)-Ph Me O
4-330 3-(2-Fur)-Ph Et O
4-331 3-(2-Fur)-Ph Pr O
4-332 3-(2-Fur)-Ph Bu O
4-333 4-(3-Fur)-Ph Me O
4-334 4-(3-Fur)-Ph Et O
4-335 4-(3-Fur)-Ph Pr O
4-336 4-(3-Fur)-Ph Bu O
4-337 3-(3-Fur)-Ph Me O
4-338 3-(3-Fur)-Ph Et O
4-339 3-(3-Fur)-Ph Pr O
4-340 3-(3-Fur)-Ph Bu O
4-341 4-(2-Thi)-Ph Me O
4-342 4-(2-Thi)-Ph Et O
4-343 4-(2-Thi)-Ph Pr O
4-344 4-(2-Thi)-Ph Bu O
4-345 3-(2-Thi)-Ph Me O
4-346 3-(2-Thi)-Ph Et O
4-347 3-(2-Thi)-Ph Pr O
4-348 3-(2-Thi)-Ph Bu O
4-349 4-(3-Thi)-Ph Me O
4-350 4-(3-Thi)-Ph Et O
4-351 4-(3-Thi)-Ph Pr O
4-352 4-(3-Thi)-Ph Bu O
4-353 3-(3-Thi)-Ph Me O
4-354 3-(3-Thi)-Ph Et O
4-355 3-(3-Thi)-Ph Pr O
4-356 3-(3-Thi)-Ph Bu O
4-357 4-(1-Boc-2-Pyro)-Ph Me O
4-358 4-(1-Boc-2-Pyro)-Ph Et O
4-359 4-(1-Boc-2-Pyro)-Ph Pr O
4-360 4-(1-Boc-2-Pyro)-Ph Bu O
4-361 3-(1-Boc-2-Pyro)-Ph Me O
4-362 3-(1-Boc-2-Pyro)-Ph Et O
4-363 3-(1-Boc-2-Pyro)-Ph Pr O
4-364 3-(1-Boc-2-Pyro)-Ph Bu O
4-365 4-(2-F-Ph)-Ph Me O
4-366 4-(2-F-Ph)-Ph Et O
4-367 4-(2-F-Ph)-Ph Pr O
4-368 4-(2-F-Ph)-Ph Bu O
4-369 4-(3-F-Ph)-Ph Me O
4-370 4-(3-F-Ph)-Ph Et O
4-371 4-(3-F-Ph)-Ph Pr O
4-372 4-(3-F-Ph)-Ph Bu O
4-373 4-(4-F-Ph)-Ph Me O
4-374 4-(4-F-Ph)-Ph Et O
4-375 4-(4-F-Ph)-Ph Pr O
4-376 4-(4-F-Ph)-Ph Bu O
4-377 3-(2-Cl-Ph)-Ph Me O
4-378 3-(2-Cl-Ph)-Ph Et O
4-379 3-(2-Cl-Ph)-Ph Pr O
4-380 3-(2-Cl-Ph)-Ph Bu O
4-381 3-(3-Cl-Ph)-Ph Me O
4-382 3-(3-Cl-Ph)-Ph Et O
4-383 3-(3-Cl-Ph)-Ph Pr O
4-384 3-(3-Cl-Ph)-Ph Bu O
4-385 3-(4-Cl-Ph)-Ph Me O
4-386 3-(4-Cl-Ph)-Ph Et O
4-387 3-(4-Cl-Ph)-Ph Pr O
4-388 3-(4-Cl-Ph)-Ph Bu O
4-389 3-(2-Me-Ph)-Ph Me O
4-390 3-(2-Me-Ph)-Ph Et O
4-391 3-(2-Me-Ph)-Ph Pr O
4-392 3-(2-Me-Ph)-Ph Bu O
4-393 3-(3-Me-Ph)-Ph Me O
4-394 3-(3-Me-Ph)-Ph Et O
4-395 3-(3-Me-Ph)-Ph Pr O
4-396 3-(3-Me-Ph)-Ph Bu O
4-397 3-(4-Me-Ph)-Ph Me O
4-398 3-(4-Me-Ph)-Ph Et O
4-399 3-(4-Me-Ph)-Ph Pr O
4-400 3-(4-Me-Ph)-Ph Bu O
4-401 3-(2-MeO-Ph)-Ph Me O
4-402 3-(2-MeO-Ph)-Ph Et O
4-403 3-(2-MeO-Ph)-Ph Pr O
4-404 3-(2-MeO-Ph)-Ph Bu O
4-405 3-(3-MeO-Ph)-Ph Me O
4-406 3-(3-MeO-Ph)-Ph Et O
4-407 3-(3-MeO-Ph)-Ph Pr O
4-408 3-(3-MeO-Ph)-Ph Bu O
4-409 3-(4-MeO-Ph)-Ph Me O
4-410 3-(4-MeO-Ph)-Ph Et O
4-411 3-(4-MeO-Ph)-Ph Pr O
4-412 3-(4-MeO-Ph)-Ph Bu O
4-413 3-(2-CF₃-Ph)-Ph Me O
4-414 3-(2-CF₃-Ph)-Ph Et O
4-415 3-(2-CF₃-Ph)-Ph Pr O
4-416 3-(2-CF₃-Ph)-Ph Bu O
4-417 3-(3-CF₃-Ph)-Ph Me O
4-418 3-(3-CF₃-Ph)-Ph Et O
4-419 3-(3-CF₃-Ph)-Ph Pr O
4-420 3-(3-CF₃-Ph)-Ph Bu O
4-421 3-(4-CF₃-Ph)-Ph Me O
4-422 3-(4-CF₃-Ph)-Ph Et O
4-423 3-(4-CF₃-Ph)-Ph Pr O
4-424 3-(4-CF₃-Ph)-Ph Bu O
4-425 3-(3-CF₃O-Ph)-Ph Me O
4-426 3-(3-CF₃O-Ph)-Ph Et O
4-427 3-(3-CF₃O-Ph)-Ph Pr O
4-428 3-(3-CF₃O-Ph)-Ph Bu O
4-429 3-(4-CF₃O-Ph)-Ph Me O
4-430 3-(4-CF₃O-Ph)-Ph Et O
4-431 3-(4-CF₃O-Ph)-Ph Pr O
4-432 3-(4-CF₃O-Ph)-Ph Bu O
4-433 3-(2-HO-Ph)-Ph Me O
4-434 3-(2-HO-Ph)-Ph Et O
4-435 3-(2-HO-Ph)-Ph Pr O
4-436 3-(2-HO-Ph)-Ph Bu O
4-437 3-(3-HO-Ph)-Ph Me O
4-438 3-(3-HO-Ph)-Ph Et O
4-439 3-(3-HO-Ph)-Ph Pr O
4-440 3-(3-HO-Ph)-Ph Bu O
4-441 3-(4-HO-Ph)-Ph Me O
4-442 3-(4-HO-Ph)-Ph Et O
4-443 3-(4-HO-Ph)-Ph Pr O
4-444 3-(4-HO-Ph)-Ph Bu O
4-445 3-(2-HOCH₂-Ph)-Ph Me O
4-446 3-(2-HOCH₂-Ph)-Ph Et O
4-447 3-(2-HOCH₂-Ph)-Ph Pr O
4-448 3-(2-HOCH₂-Ph)-Ph Bu O
4-449 3-(3-HOCH₂-Ph)-Ph Me O
4-450 3-(3-HOCH₂-Ph)-Ph Et O
4-451 3-(3-HOCH₂-Ph)-Ph Pr O
4-452 3-(3-HOCH₂-Ph)-Ph Bu O
4-453 3-(4-HOCH₂-Ph)-Ph Me O
4-454 3-(4-HOCH₂-Ph)-Ph Et O
4-455 3-(4-HOCH₂-Ph)-Ph Pr O
4-456 3-(4-HOCH₂-Ph)-Ph Bu O
4-457 3-(2-H₂N-Ph)-Ph Me O
4-458 3-(2-H₂N-Ph)-Ph Et O
4-459 3-(2-H₂N-Ph)-Ph Pr O
4-460 3-(2-H₂N-Ph)-Ph Bu O
4-461 3-(3-H₂N-Ph)-Ph Me O
4-462 3-(3-H₂N-Ph)-Ph Et O
4-463 3-(3-H₂N-Ph)-Ph Pr O
4-464 3-(3-H₂N-Ph)-Ph Bu O
4-465 3-(4-H₂N-Ph)-Ph Me O
4-466 3-(4-H₂N-Ph)-Ph Et O
4-467 3-(4-H₂N-Ph)-Ph Pr O
4-468 3-(4-H₂N-Ph)-Ph Bu O
4-469 Ph Me SO₂NH
4-470 Ph Et SO₂NH
4-471 Ph Pr SO₂NH
4-472 Ph Bu SO₂NH
4-473 4-Br-Ph Me SO₂NH
4-474 4-Br-Ph Et SO₂NH
4-475 4-Br-Ph Pr SO₂NH
4-476 4-Br-Ph Bu SO₂NH
4-477 3-Br-Ph Me SO₂NH
4-478 3-Br-Ph Et SO₂NH
4-479 3-Br-Ph Pr SO₂NH
4-480 3-Br-Ph Bu SO₂NH
4-481 4-Ph-Ph Me SO₂NH
4-482 4-Ph-Ph Et SO₂NH
4-483 4-Ph-Ph Pr SO₂NH
4-484 4-Ph-Ph Bu SO₂NH
4-485 3-Ph-Ph Me SO₂NH
4-486 3-Ph-Ph Et SO₂NH
4-487 3-Ph-Ph Pr SO₂NH
4-488 3-Ph-Ph Bu SO₂NH
4-489 1-Nph Me SO₂NH
4-490 1-Nph Et SO₂NH
4-491 1-Nph Pr SO₂NH
4-492 1-Nph Bu SO₂NH
4-493 2-Nph Me SO₂NH
4-494 2-Nph Et SO₂NH
4-495 2-Nph Pr SO₂NH
4-496 2-Nph Bu SO₂NH
4-497 4-(2-Py)-Ph Me SO₂NH
4-498 4-(2-Py)-Ph Et SO₂NH
4-499 4-(2-Py)-Ph Pr SO₂NH
4-500 4-(2-Py)-Ph Bu SO₂NH
4-501 4-(3-Py)-Ph Me SO₂NH
4-502 4-(3-Py)-Ph Et SO₂NH
4-503 4-(3-Py)-Ph Pr SO₂NH
4-504 4-(3-Py)-Ph Bu SO₂NH
4-505 4-(4-Py)-Ph Me SO₂NH
4-506 4-(4-Py)-Ph Et SO₂NH
4-507 4-(4-Py)-Ph Pr SO₂NH
4-508 4-(4-Py)-Ph Bu SO₂NH
4-509 3-(2-Py)-Ph Me SO₂NH
4-510 3-(2-Py)-Ph Et SO₂NH
4-511 3-(2-Py)-Ph Pr SO₂NH
4-512 3-(2-Py)-Ph Bu SO₂NH
4-513 3-(3-Py)-Ph Me SO₂NH
4-514 3-(3-Py)-Ph Et SO₂NH
4-515 3-(3-Py)-Ph Pr SO₂NH
4-516 3-(3-Py)-Ph Bu SO₂NH
4-517 3-(4-Py)-Ph Me SO₂NH
4-518 3-(4-Py)-Ph Et SO₂NH
4-519 3-(4-Py)-Ph Pr SO₂NH
4-520 3-(4-Py)-Ph Bu SO₂NH
-----------------------------------------------------Exemplary Compound Table 4
-------------------------------------------------- ---
Compound number R³ -Z- R⁴ X
-------------------------------------------------- ---
4-1 6-Ph-2-O-Pyra Me NH
4-2 6-Ph-2-O-Pyra Et NH
4-3 6-Ph-2-O-Pyra Pr NH
4-4 6-Ph-2-O-Pyra Bu NH
4-5 Bn Me O-CONH
4-6 Bn Et O-CONH
4-7 Bn Pr O-CONH
4-8 Bn Bu O-CONH
4-9 2-Bzfur Me CONH
4-10 2-Bzfur Et CONH
4-11 2-Bzfur Pr CONH
4-12 2-Bzfur Bu CONH
4-13 3-Me-2-Bzfur Me CONH
4-14 3-Me-2-Bzfur Et CONH
4-15 3-Me-2-Bzfur Pr CONH
4-16 3-Me-2-Bzfur Bu CONH
4-17 5-Cl-2-Bzfur Me CONH
4-18 5-Cl-2-Bzfur Et CONH
4-19 5-Cl-2-Bzfur Pr CONH
4-20 5-Cl-2-Bzfur Bu CONH
4-21 5-MeO-2-Bzfur Me CONH
4-22 5-MeO-2-Bzfur Et CONH
4-23 5-MeO-2-Bzfur Pr CONH
4-24 5-MeO-2-Bzfur Bu CONH
4-25 7-MeO-2-Bzfur Me CONH
4-26 7-MeO-2-Bzfur Et CONH
4-27 7-MeO-2-Bzfur Pr CONH
4-28 7-MeO-2-Bzfur Bu CONH
4-29 5-Cl-2-Ind Me CONH
4-30 5-Cl-2-Ind Et CONH
4-31 5-Cl-2-Ind Pr CONH
4-32 5-Cl-2-Ind Bu CONH
4-33 5-F-2-Ind Me CONH
4-34 5-F-2-Ind Et CONH
4-35 5-F-2-Ind Pr CONH
4-36 5-F-2-Ind Bu CONH
4-37 5-Me-2-Ind Me CONH
4-38 5-Me-2-Ind Et CONH
4-39 5-Me-2-Ind Pr CONH
4-40 5-Me-2-Ind Bu CONH
4-41 5-MeO-2-Ind Me CONH
4-42 5-MeO-2-Ind Et CONH
4-43 5-MeO-2-Ind Pr CONH
4-44 5-MeO-2-Ind Bu CONH
4-45 5-Ind Me CONH
4-46 5-Ind Et CONH
4-47 5-Ind Pr CONH
4-48 5-Ind Bu CONH
4-49 3-Cl-2-Bzthi Me CONH
4-50 3-Cl-2-Bzthi Et CONH
4-51 3-Cl-2-Bzthi Pr CONH
4-52 3-Cl-2-Bzthi Bu CONH
4-53 3-Me-2-Bzthi Me CONH
4-54 3-Me-2-Bzthi Et CONH
4-55 3-Me-2-Bzthi Pr CONH
4-56 3-Me-2-Bzthi Bu CONH
4-57 3-CF₃ -2-Bzthi Me CONH
4-58 3-CF₃ -2-Bzthi Et CONH
4-59 3-CF₃ -2-Bzthi Pr CONH
4-60 3-CF₃ -2-Bzthi Bu CONH
4-61 1-Nph Me CONH
4-62 1-Nph Et CONH
4-63 1-Nph Pr CONH
4-64 1-Nph Bu CONH
4-65 2-Nph Me CONH
4-66 2-Nph Et CONH
4-67 2-Nph Pr CONH
4-68 2-Nph Bu CONH
4-69 2-Qui Me CONH
4-70 2-Qui Et CONH
4-71 2-Qui Pr CONH
4-72 2-Qui Bu CONH
4-73 3-Qui Me CONH
4-74 3-Qui Et CONH
4-75 3-Qui Pr CONH
4-76 3-Qui Bu CONH
4-77 4-Qui Me CONH
4-78 4-Qui Et CONH
4-79 4-Qui Pr CONH
4-80 4-Qui Bu CONH
4-81 8-Qui Me CONH
4-82 8-Qui Et CONH
4-83 8-Qui Pr CONH
4-84 8-Qui Bu CONH
4-85 1-Iqui Me CONH
4-86 1-Iqui Et CONH
4-87 1-Iqui Pr CONH
4-88 1-Iqui Bu CONH
4-89 3-Iqui Me CONH
4-90 3-Iqui Et CONH
4-91 3-Iqui Pr CONH
4-92 3-Iqui Bu CONH
4-93 4-Br-Ph Me CONH
4-94 4-Br-Ph Et CONH
4-95 4-Br-Ph Pr CONH
4-96 4-Br-Ph Bu CONH
4-97 3-Br-Ph Me CONH
4-98 3-Br-Ph Et CONH
4-99 3-Br-Ph Pr CONH
4-100 3-Br-Ph Bu CONH
4-101 4-Ph-Ph Me CONH
4-102 4-Ph-Ph Et CONH
4-103 4-Ph-Ph Pr CONH
4-104 4-Ph-Ph Bu CONH
4-105 3-Ph-Ph Me CONH
4-106 3-Ph-Ph Et CONH
4-107 3-Ph-Ph Pr CONH
4-108 3-Ph-Ph Bu CONH
4-109 4- (2-Me-Ph) -Ph Me CONH
4-110 4- (2-Me-Ph) -Ph Et CONH
4-111 4- (2-Me-Ph) -Ph Pr CONH
4-112 4- (2-Me-Ph) -Ph Bu CONH
4-113 4- (3-Me-Ph) -Ph Me CONH
4-114 4- (3-Me-Ph) -Ph Et CONH
4-115 4- (3-Me-Ph) -Ph Pr CONH
4-116 4- (3-Me-Ph) -Ph Bu CONH
4-117 4- (4-Me-Ph) -Ph Me CONH
4-118 4- (4-Me-Ph) -Ph Et CONH
4-119 4- (4-Me-Ph) -Ph Pr CONH
4-120 4- (4-Me-Ph) -Ph Bu CONH
4-121 4- (2-F-Ph) -Ph Me CONH
4-122 4- (2-F-Ph) -Ph Et CONH
4-123 4- (2-F-Ph) -Ph Pr CONH
4-124 4- (2-F-Ph) -Ph Bu CONH
4-125 4- (3-F-Ph) -Ph Me CONH
4-126 4- (3-F-Ph) -Ph Et CONH
4-127 4- (3-F-Ph) -Ph Pr CONH
4-128 4- (3-F-Ph) -Ph Bu CONH
4-129 4- (4-F-Ph) -Ph Me CONH
4-130 4- (4-F-Ph) -Ph Et CONH
4-131 4- (4-F-Ph) -Ph Pr CONH
4-132 4- (4-F-Ph) -Ph Bu CONH
4-133 4- (2-Cl-Ph) -Ph Me CONH
4-134 4- (2-Cl-Ph) -Ph Et CONH
4-135 4- (2-Cl-Ph) -Ph Pr CONH
4-136 4- (2-Cl-Ph) -Ph Bu CONH
4-137 4- (3-Cl-Ph) -Ph Me CONH
4-138 4- (3-Cl-Ph) -Ph Et CONH
4-139 4- (3-Cl-Ph) -Ph Pr CONH
4-140 4- (3-Cl-Ph) -Ph Bu CONH
4-141 4- (4-Cl-Ph) -Ph Me CONH
4-142 4- (4-Cl-Ph) -Ph Et CONH
4-143 4- (4-Cl-Ph) -Ph Pr CONH
4-144 4- (4-Cl-Ph) -Ph Bu CONH
4-145 4- (2-MeO-Ph) -Ph Me CONH
4-146 4- (2-MeO-Ph) -Ph Et CONH
4-147 4- (2-MeO-Ph) -Ph Pr CONH
4-148 4- (2-MeO-Ph) -Ph Bu CONH
4-149 4- (3-MeO-Ph) -Ph Me CONH
4-150 4- (3-MeO-Ph) -Ph Et CONH
4-151 4- (3-MeO-Ph) -Ph Pr CONH
4-152 4- (3-MeO-Ph) -Ph Bu CONH
4-153 4- (4-MeO-Ph) -Ph Me CONH
4-154 4- (4-MeO-Ph) -Ph Et CONH
4-155 4- (4-MeO-Ph) -Ph Pr CONH
4-156 4- (4-MeO-Ph) -Ph Bu CONH
4-157 4- (2-CF₃ -Ph) -Ph Me CONH
4-158 4- (2-CF₃ -Ph) -Ph Et CONH
4-159 4- (2-CF₃ -Ph) -Ph Pr CONH
4-160 4- (2-CF₃ -Ph) -Ph Bu CONH
4-161 4- (3-CF₃ -Ph) -Ph Me CONH
4-162 4- (3-CF₃ -Ph) -Ph Et CONH
4-163 4- (3-CF₃ -Ph) -Ph Pr CONH
4-164 4- (3-CF₃ -Ph) -Ph Bu CONH
4-165 4- (4-CF₃ -Ph) -Ph Me CONH
4-166 4- (4-CF₃ -Ph) -Ph Et CONH
4-167 4- (4-CF₃ -Ph) -Ph Pr CONH
4-168 4- (4-CF₃ -Ph) -Ph Bu CONH
4-169 4- (3-CF₃ O-Ph) -Ph Me CONH
4-170 4- (3-CF₃ O-Ph) -Ph Et CONH
4-171 4- (3-CF₃ O-Ph) -Ph Pr CONH
4-172 4- (3-CF₃ O-Ph) -Ph Bu CONH
4-173 4- (4-CF₃ O-Ph) -Ph Me CONH
4-174 4- (4-CF₃ O-Ph) -Ph Et CONH
4-175 4- (4-CF₃ O-Ph) -Ph Pr CONH
4-176 4- (4-CF₃ O-Ph) -Ph Bu CONH
4-177 4-PhO-Ph Me CONH
4-178 4-PhO-Ph Et CONH
4-179 4-PhO-Ph Pr CONH
4-180 4-PhO-Ph Bu CONH
4-181 3-PhO-Ph Me CONH
4-182 3-PhO-Ph Et CONH
4-183 3-PhO-Ph Pr CONH
4-184 3-PhO-Ph Bu CONH
4-185 4-BnO-Ph Me CONH
4-186 4-BnO-Ph Et CONH
4-187 4-BnO-Ph Pr CONH
4-188 4-BnO-Ph Bu CONH
4-189 3-BnO-Ph Me CONH
4-190 3-BnO-Ph Et CONH
4-191 3-BnO-Ph Pr CONH
4-192 3-BnO-Ph Bu CONH
4-193 4-MeO-Ph Me CONH
4-194 4-MeO-Ph Et CONH
4-195 4-MeO-Ph Pr CONH
4-196 4-MeO-Ph Bu CONH
4-197 3-MeO-Ph Me CONH
4-198 3-MeO-Ph Et CONH
4-199 3-MeO-Ph Pr CONH
4-200 3-MeO-Ph Bu CONH
4-201 4-EtO-Ph Me CONH
4-202 4-EtO-Ph Et CONH
4-203 4-EtO-Ph Pr CONH
4-204 4-EtO-Ph Bu CONH
4-205 3-EtO-Ph Me CONH
4-206 3-EtO-Ph Et CONH
4-207 3-EtO-Ph Pr CONH
4-208 3-EtO-Ph Bu CONH
4-209 4-PrO-Ph Me CONH
4-210 4-PrO-Ph Et CONH
4-211 4-PrO-Ph Pr CONH
4-212 4-PrO-Ph Bu CONH
4-213 3-PrO-Ph Me CONH
4-214 3-PrO-Ph Et CONH
4-215 3-PrO-Ph Pr CONH
4-216 3-PrO-Ph Bu CONH
4-217 4-BuO-Ph Me CONH
4-218 4-BuO-Ph Et CONH
4-219 4-BuO-Ph Pr CONH
4-220 4-BuO-Ph Bu CONH
4-221 3-BuO-Ph Me CONH
4-222 3-BuO-Ph Et CONH
4-223 3-BuO-Ph Pr CONH
4-224 3-BuO-Ph Bu CONH
4-225 4-iPrO-Ph Me CONH
4-226 4-iPrO-Ph Et CONH
4-227 4-iPrO-Ph Pr CONH
4-228 4-iPrO-Ph Bu CONH
4-229 3-iPrO-Ph Me CONH
4-230 3-iPrO-Ph Et CONH
4-231 3-iPrO-Ph Pr CONH
4-232 3-iPrO-Ph Bu CONH
4-233 4-Me-Ph Me CONH
4-234 4-Me-Ph Et CONH
4-235 4-Me-Ph Pr CONH
4-236 4-Me-Ph Bu CONH
4-237 4-Et-Ph Me CONH
4-238 4-Et-Ph Et CONH
4-239 4-Et-Ph Pr CONH
4-240 4-Et-Ph Bu CONH
4-241 4-Pr-Ph Me CONH
4-242 4-Pr-Ph Et CONH
4-243 4-Pr-Ph Pr CONH
4-244 4-Pr-Ph Bu CONH
4-245 4-Bu-Ph Me CONH
4-246 4-Bu-Ph Et CONH
4-247 4-Bu-Ph Pr CONH
4-248 4-Bu-Ph Bu CONH
4-249 4-iPr-Ph Me CONH
4-250 4-iPr-Ph Et CONH
4-251 4-iPr-Ph Pr CONH
4-252 4-iPr-Ph Bu CONH
4-253 4-cHx-Ph Me CONH
4-254 4-cHx-Ph Et CONH
4-255 4-cHx-Ph Pr CONH
4-256 4-cHx-Ph Bu CONH
4-257 4- (Me₂ N) -Ph Me CONH
4-258 4- (Me₂ N) -Ph Et CONH
4-259 4- (Me₂ N) -Ph Pr CONH
4-260 4- (Me₂ N) -Ph Bu CONH
4-261 4- (Et₂ N) -Ph Me CONH
4-262 4- (Et₂ N) -Ph Et CONH
4-263 4- (Et₂ N) -Ph Pr CONH
4-264 4- (Et₂ N) -Ph Bu CONH
4-265 4- (1-Pip) -Ph Me CONH
4-266 4- (1-Pip) -Ph Et CONH
4-267 4- (1-Pip) -Ph Pr CONH
4-268 4- (1-Pip) -Ph Bu CONH
4-269 4- (1-Mor) -Ph Me CONH
4-270 4- (1-Mor) -Ph Et CONH
4-271 4- (1-Mor) -Ph Pr CONH
4-272 4- (1-Mor) -Ph Bu CONH
4-273 4- (4-Me-1-Pipra) -Ph Me CONH
4-274 4- (4-Me-1-Pipra) -Ph Et CONH
4-275 4- (4-Me-1-Pipra) -Ph Pr CONH
4-276 4- (4-Me-1-Pipra) -Ph Bu CONH
4-277 4- (1-Me-4-Pip) -Ph Me CONH
4-278 4- (1-Me-4-Pip) -Ph Et CONH
4-279 4- (1-Me-4-Pip) -Ph Pr CONH
4-280 4- (1-Me-4-Pip) -Ph Bu CONH
4-281 4- [1- (2-MeO-Et) -4-Pip] -Ph Me CONH
4-282 4- [1- (2-MeO-Et) -4-Pip] -Ph Et CONH
4-283 4- [1- (2-MeO-Et) -4-Pip] -Ph Pr CONH
4-284 4- [1- (2-MeO-Et) -4-Pip] -Ph Bu CONH
4-285 4-Br-Ph Me O
4-286 4-Br-Ph Et O
4-287 4-Br-Ph Pr O
4-288 4-Br-Ph Bu O
4-289 3-Br-Ph Me O
4-290 3-Br-Ph Et O
4-291 3-Br-Ph Pr O
4-292 3-Br-Ph Bu O
4-293 4-Ph-Ph Me O
4-294 4-Ph-Ph Et O
4-295 4-Ph-Ph Pr O
4-296 4-Ph-Ph Bu O
4-297 3-Ph-Ph Me O
4-298 3-Ph-Ph Et O
4-299 3-Ph-Ph Pr O
4-300 3-Ph-Ph Bu O
4-301 4-PhO-Ph Me O
4-302 4-PhO-Ph Et O
4-303 4-PhO-Ph Pr O
4-304 4-PhO-Ph Bu O
4-305 3-PhO-Ph Me O
4-306 3-PhO-Ph Et O
4-307 3-PhO-Ph Pr O
4-308 3-PhO-Ph Bu O
4-309 4-BnO-Ph Me O
4-310 4-BnO-Ph Et O
4-311 4-BnO-Ph Pr O
4-312 4-BnO-Ph Bu O
4-313 3-BnO-Ph Me O
4-314 3-BnO-Ph Et O
4-315 3-BnO-Ph Pr O
4-316 3-BnO-Ph Bu O
4-317 4-cHx-Ph Me O
4-318 4-cHx-Ph Et O
4-319 4-cHx-Ph Pr O
4-320 4-cHx-Ph Bu O
4-321 3-cHx-Ph Me O
4-322 3-cHx-Ph Et O
4-323 3-cHx-Ph Pr O
4-324 3-cHx-Ph Bu O
4-325 4- (2-Fur) -Ph Me O
4-326 4- (2-Fur) -Ph Et O
4-327 4- (2-Fur) -Ph Pr O
4-328 4- (2-Fur) -Ph Bu O
4-329 3- (2-Fur) -Ph Me O
4-330 3- (2-Fur) -Ph Et O
4-331 3- (2-Fur) -Ph Pr O
4-332 3- (2-Fur) -Ph Bu O
4-333 4- (3-Fur) -Ph Me O
4-334 4- (3-Fur) -Ph Et O
4-335 4- (3-Fur) -Ph Pr O
4-336 4- (3-Fur) -Ph Bu O
4-337 3- (3-Fur) -Ph Me O
4-338 3- (3-Fur) -Ph Et O
4-339 3- (3-Fur) -Ph Pr O
4-340 3- (3-Fur) -Ph Bu O
4-341 4- (2-Thi) -Ph Me O
4-342 4- (2-Thi) -Ph Et O
4-343 4- (2-Thi) -Ph Pr O
4-344 4- (2-Thi) -Ph Bu O
4-345 3- (2-Thi) -Ph Me O
4-346 3- (2-Thi) -Ph Et O
4-347 3- (2-Thi) -Ph Pr O
4-348 3- (2-Thi) -Ph Bu O
4-349 4- (3-Thi) -Ph Me O
4-350 4- (3-Thi) -Ph Et O
4-351 4- (3-Thi) -Ph Pr O
4-352 4- (3-Thi) -Ph Bu O
4-353 3- (3-Thi) -Ph Me O
4-354 3- (3-Thi) -Ph Et O
4-355 3- (3-Thi) -Ph Pr O
4-356 3- (3-Thi) -Ph Bu O
4-357 4- (1-Boc-2-Pyro) -Ph Me O
4-358 4- (1-Boc-2-Pyro) -Ph Et O
4-359 4- (1-Boc-2-Pyro) -Ph Pr O
4-360 4- (1-Boc-2-Pyro) -Ph Bu O
4-361 3- (1-Boc-2-Pyro) -Ph Me O
4-362 3- (1-Boc-2-Pyro) -Ph Et O
4-363 3- (1-Boc-2-Pyro) -Ph Pr O
4-364 3- (1-Boc-2-Pyro) -Ph Bu O
4-365 4- (2-F-Ph) -Ph Me O
4-366 4- (2-F-Ph) -Ph Et O
4-367 4- (2-F-Ph) -Ph Pr O
4-368 4- (2-F-Ph) -Ph Bu O
4-369 4- (3-F-Ph) -Ph Me O
4-370 4- (3-F-Ph) -Ph Et O
4-371 4- (3-F-Ph) -Ph Pr O
4-372 4- (3-F-Ph) -Ph Bu O
4-373 4- (4-F-Ph) -Ph Me O
4-374 4- (4-F-Ph) -Ph Et O
4-375 4- (4-F-Ph) -Ph Pr O
4-376 4- (4-F-Ph) -Ph Bu O
4-377 3- (2-Cl-Ph) -Ph Me O
4-378 3- (2-Cl-Ph) -Ph Et O
4-379 3- (2-Cl-Ph) -Ph Pr O
4-380 3- (2-Cl-Ph) -Ph Bu O
4-381 3- (3-Cl-Ph) -Ph Me O
4-382 3- (3-Cl-Ph) -Ph Et O
4-383 3- (3-Cl-Ph) -Ph Pr O
4-384 3- (3-Cl-Ph) -Ph Bu O
4-385 3- (4-Cl-Ph) -Ph Me O
4-386 3- (4-Cl-Ph) -Ph Et O
4-387 3- (4-Cl-Ph) -Ph Pr O
4-388 3- (4-Cl-Ph) -Ph Bu O
4-389 3- (2-Me-Ph) -Ph Me O
4-390 3- (2-Me-Ph) -Ph Et O
4-391 3- (2-Me-Ph) -Ph Pr O
4-392 3- (2-Me-Ph) -Ph Bu O
4-393 3- (3-Me-Ph) -Ph Me O
4-394 3- (3-Me-Ph) -Ph Et O
4-395 3- (3-Me-Ph) -Ph Pr O
4-396 3- (3-Me-Ph) -Ph Bu O
4-397 3- (4-Me-Ph) -Ph Me O
4-398 3- (4-Me-Ph) -Ph Et O
4-399 3- (4-Me-Ph) -Ph Pr O
4-400 3- (4-Me-Ph) -Ph Bu O
4-401 3- (2-MeO-Ph) -Ph Me O
4-402 3- (2-MeO-Ph) -Ph Et O
4-403 3- (2-MeO-Ph) -Ph Pr O
4-404 3- (2-MeO-Ph) -Ph Bu O
4-405 3- (3-MeO-Ph) -Ph Me O
4-406 3- (3-MeO-Ph) -Ph Et O
4-407 3- (3-MeO-Ph) -Ph Pr O
4-408 3- (3-MeO-Ph) -Ph Bu O
4-409 3- (4-MeO-Ph) -Ph Me O
4-410 3- (4-MeO-Ph) -Ph Et O
4-411 3- (4-MeO-Ph) -Ph Pr O
4-412 3- (4-MeO-Ph) -Ph Bu O
4-413 3- (2-CF₃ -Ph) -Ph Me O
4-414 3- (2-CF₃ -Ph) -Ph Et O
4-415 3- (2-CF₃ -Ph) -Ph Pr O
4-416 3- (2-CF₃ -Ph) -Ph Bu O
4-417 3- (3-CF₃ -Ph) -Ph Me O
4-418 3- (3-CF₃ -Ph) -Ph Et O
4-419 3- (3-CF₃ -Ph) -Ph Pr O
4-420 3- (3-CF₃ -Ph) -Ph Bu O
4-421 3- (4-CF₃ -Ph) -Ph Me O
4-422 3- (4-CF₃ -Ph) -Ph Et O
4-423 3- (4-CF₃ -Ph) -Ph Pr O
4-424 3- (4-CF₃ -Ph) -Ph Bu O
4-425 3- (3-CF₃ O-Ph) -Ph Me O
4-426 3- (3-CF₃ O-Ph) -Ph Et O
4-427 3- (3-CF₃ O-Ph) -Ph Pr O
4-428 3- (3-CF₃ O-Ph) -Ph Bu O
4-429 3- (4-CF₃ O-Ph) -Ph Me O
4-430 3- (4-CF₃ O-Ph) -Ph Et O
4-431 3- (4-CF₃ O-Ph) -Ph Pr O
4-432 3- (4-CF₃ O-Ph) -Ph Bu O
4-433 3- (2-HO-Ph) -Ph Me O
4-434 3- (2-HO-Ph) -Ph Et O
4-435 3- (2-HO-Ph) -Ph Pr O
4-436 3- (2-HO-Ph) -Ph Bu O
4-437 3- (3-HO-Ph) -Ph Me O
4-438 3- (3-HO-Ph) -Ph Et O
4-439 3- (3-HO-Ph) -Ph Pr O
4-440 3- (3-HO-Ph) -Ph Bu O
4-441 3- (4-HO-Ph) -Ph Me O
4-442 3- (4-HO-Ph) -Ph Et O
4-443 3- (4-HO-Ph) -Ph Pr O
4-444 3- (4-HO-Ph) -Ph Bu O
4-445 3- (2-HOCH₂ -Ph) -Ph Me O
4-446 3- (2-HOCH₂ -Ph) -Ph Et O
4-447 3- (2-HOCH₂ -Ph) -Ph Pr O
4-448 3- (2-HOCH₂ -Ph) -Ph Bu O
4-449 3- (3-HOCH₂ -Ph) -Ph Me O
4-450 3- (3-HOCH₂ -Ph) -Ph Et O
4-451 3- (3-HOCH₂ -Ph) -Ph Pr O
4-452 3- (3-HOCH₂ -Ph) -Ph Bu O
4-453 3- (4-HOCH₂ -Ph) -Ph Me O
4-454 3- (4-HOCH₂ -Ph) -Ph Et O
4-455 3- (4-HOCH₂ -Ph) -Ph Pr O
4-456 3- (4-HOCH₂ -Ph) -Ph Bu O
4-457 3- (2-H₂ N-Ph) -Ph Me O
4-458 3- (2-H₂ N-Ph) -Ph Et O
4-459 3- (2-H₂ N-Ph) -Ph Pr O
4-460 3- (2-H₂ N-Ph) -Ph Bu O
4-461 3- (3-H₂ N-Ph) -Ph Me O
4-462 3- (3-H₂ N-Ph) -Ph Et O
4-463 3- (3-H₂ N-Ph) -Ph Pr O
4-464 3- (3-H₂ N-Ph) -Ph Bu O
4-465 3- (4-H₂ N-Ph) -Ph Me O
4-466 3- (4-H₂ N-Ph) -Ph Et O
4-467 3- (4-H₂ N-Ph) -Ph Pr O
4-468 3- (4-H₂ N-Ph) -Ph Bu O
4-469 Ph Me SO₂ NH
4-470 Ph Et SO₂ NH
4-471 Ph Pr SO₂ NH
4-472 Ph Bu SO₂ NH
4-473 4-Br-Ph Me SO₂ NH
4-474 4-Br-Ph Et SO₂ NH
4-475 4-Br-Ph Pr SO₂ NH
4-476 4-Br-Ph Bu SO₂ NH
4-477 3-Br-Ph Me SO₂ NH
4-478 3-Br-Ph Et SO₂ NH
4-479 3-Br-Ph Pr SO₂ NH
4-480 3-Br-Ph Bu SO₂ NH
4-481 4-Ph-Ph Me SO₂ NH
4-482 4-Ph-Ph Et SO₂ NH
4-483 4-Ph-Ph Pr SO₂ NH
4-484 4-Ph-Ph Bu SO₂ NH
4-485 3-Ph-Ph Me SO₂ NH
4-486 3-Ph-Ph Et SO₂ NH
4-487 3-Ph-Ph Pr SO₂ NH
4-488 3-Ph-Ph Bu SO₂ NH
4-489 1-Nph Me SO₂ NH
4-490 1-Nph Et SO₂ NH
4-491 1-Nph Pr SO₂ NH
4-492 1-Nph Bu SO₂ NH
4-493 2-Nph Me SO₂ NH
4-494 2-Nph Et SO₂ NH
4-495 2-Nph Pr SO₂ NH
4-496 2-Nph Bu SO₂ NH
4-497 4- (2-Py) -Ph Me SO₂ NH
4-498 4- (2-Py) -Ph Et SO₂ NH
4-499 4- (2-Py) -Ph Pr SO₂ NH
4-500 4- (2-Py) -Ph Bu SO₂ NH
4-501 4- (3-Py) -Ph Me SO₂ NH
4-502 4- (3-Py) -Ph Et SO₂ NH
4-503 4- (3-Py) -Ph Pr SO₂ NH
4-504 4- (3-Py) -Ph Bu SO₂ NH
4-505 4- (4-Py) -Ph Me SO₂ NH
4-506 4- (4-Py) -Ph Et SO₂ NH
4-507 4- (4-Py) -Ph Pr SO₂ NH
4-508 4- (4-Py) -Ph Bu SO₂ NH
4-509 3- (2-Py) -Ph Me SO₂ NH
4-510 3- (2-Py) -Ph Et SO₂ NH
4-511 3- (2-Py) -Ph Pr SO₂ NH
4-512 3- (2-Py) -Ph Bu SO₂ NH
4-513 3- (3-Py) -Ph Me SO₂ NH
4-514 3- (3-Py) -Ph Et SO₂ NH
4-515 3- (3-Py) -Ph Pr SO₂ NH
4-516 3- (3-Py) -Ph Bu SO₂ NH
4-517 3- (4-Py) -Ph Me SO₂ NH
4-518 3- (4-Py) -Ph Et SO₂ NH
4-519 3- (4-Py) -Ph Pr SO₂ NH
4-520 3- (4-Py) -Ph Bu SO₂ NH
-------------------------------------------------- ---

上記表１乃至表４において、「Ac」はアセチルを示し、「Bn」はベンジルを示し、「Boc」はtert-ブトキシカルボニルを示し、「Bu」はブチルを示し、「iBu」はイソブチルを示し、「tBu」はtert-ブチルを示し、「Bzfur」はベンゾフラニルを示し、「Bzthi」はベンゾチオフェニルを示し、「Et」はエチルを示し、「Fur」はフリルを示し、「cHx」はシクロヘキシルを示し、「Ind」はインドリルを示し、「Iqui」はイソキノリルを示し、「Me」はメチルを示し、「Mor」はモルホリニルを示し、「Nph」はナフチルを示し、「Ph」はフェニルを示し、「Phet」はフェネチルを示し、「Pip」はピペリジニルを示し、「Pipra」はピペラジニルを示し、「Pr」はプロピルを示し、「iPr」はイソプロピル、「Py」はピリジルを示し、「2-O-Pyra」は２−オキソ−２Ｈ−ピラン−４−イルを示し、「Pyro」はピロリルを示し、「Qui」はキノリルを示し、「Thi」はチエニルを示す。  In Tables 1 to 4, “Ac” represents acetyl, “Bn” represents benzyl, “Boc” represents tert-butoxycarbonyl, “Bu” represents butyl, and “iBu” represents isobutyl. , `` TBu '' indicates tert-butyl, `` Bzfur '' indicates benzofuranyl, `` Bzthi '' indicates benzothiophenyl, `` Et '' indicates ethyl, `` Fur '' indicates furyl, `` cHx '' indicates cyclohexyl `` Ind '' indicates indolyl, `` Iqui '' indicates isoquinolyl, `` Me '' indicates methyl, `` Mor '' indicates morpholinyl, `` Nph '' indicates naphthyl, and `` Ph '' indicates phenyl , `` Phet '' indicates phenethyl, `` Pip '' indicates piperidinyl, `` Pipra '' indicates piperazinyl, `` Pr '' indicates propyl, `` iPr '' indicates isopropyl, `` Py '' indicates pyridyl, `` 2- “O-Pyra” is 2-oxo-2H-pyran-4 Indicates yl, "Pyro" indicates pyrrolyl, "Qui" indicates quinolyl, "Thi" indicates thienyl.

上記表１乃至表４において好適な化合物は、例示化合物番号１−２乃至１−２７、１−２９乃至１−５４、１−５６乃至１−８１、１−８３乃至１−１０８、１−１１０乃至１−１３５、１−１３７乃至１−１６２、１−１６４乃至１−１８９、１−１９１乃至１−２１６、１−２１８乃至１−２４３、１−２４５乃至１−２７０、１−２７２乃至１−２９７、１−２９９乃至１−３２４、１−３２６乃至１−３５１、１−３６４乃至１−３９９、１−４０２乃至１−４０９、１−４２２乃至１−４５７、１−４６０乃至１−４６７、１−４８０乃至１−５１５、１−５１８乃至１−５２５、１−５３８乃至１−５７３、及び１−５７６乃至１−５８３、
２−２乃至２−２７、２−２９乃至２−５４、２−５６乃至２−８１、２−８３乃至２−１０８、２−１１０乃至２−１３５、２−１３７乃至２−１６２、２−１６４乃至２−１８９、２−１９１乃至２−２１６、２−２１８乃至２−２４３、２−２４５乃至２−２７０、２−２７２乃至２−２９７、２−２９９乃至２−３２４、２−３２６乃至２−３５１、２−３６４乃至２−３９９、２−４０２乃至２−４０９、２−４２２乃至２−４５７、２−４６０乃至２−４６７、２−４８０乃至２−５１５、２−５１８乃至２−５２５、２−５３８乃至２−５７３、及び２−５７６乃至２−５８３、
３−１乃至３−６０、３−１０１乃至３−２８４、３−２９３乃至３−４６８、及び３−４８１乃至３−５２０、
４−１乃至４−６０、４−１０１乃至４−２８４、４−２９３乃至４−４６８、及び４−４８１乃至４−５２０、並びに
５−１、５−２、５−７、及び５−９の化合物であり、
更に好適な化合物は、例示化合物番号１−２乃至１−５、１−９乃至１−１４、１−２９乃至１−３２、１−３６乃至１−４１、１−５６乃至１−５９、１−６３乃至１−６８、１−８３乃至１−８６、１−９０乃至１−９５、１−１１０乃至１−１１３、１−１３７乃至１−１４０、１−１６４乃至１−１６７、１−１９１乃至１−１９４、１−２１８乃至１−２２１、１−２４５乃至１−２４８、１−２５２乃至１−２５７、１−２７２乃至１−２７５、１−２７９乃至１−２８４、１−２９９乃至１−３０２、１−３０６乃至１−３１１、１−３２６乃至１−３２９、及び１−３３３乃至１−３３８、
２−２乃至２−５、２−９乃至２−１４、２−２９乃至２−３２、２−３６乃至２−４１、２−５６乃至２−５９、２−６３乃至２−６８、２−８３乃至２−８６、２−９０乃至２−９５、２−１１０乃至２−１１３、２−１３７乃至２−１４０、２−１６４乃至２−１６７、２−１９１乃至２−１９４、２−２１８乃至２−２２１、２−２４５乃至２−２４８、２−２７２乃至２−２７５、２−２９９乃至２−３０２、及び２−３２６乃至２−３２９、
３−１乃至３−４、及び３−９乃至３−１２、
４−１乃至４−４、及び４−９乃至４−１２、並びに
５−１、５−２、５−７、及び５−９の化合物であり、
より更に好適な化合物は、例示化合物番号１−２乃至１−５、１−９乃至１−１４、１−２９乃至１−３２、１−３６乃至１−４１、１−５６乃至１−５９、１−６３乃至１−６８、１−８３乃至１−８６、１−９０乃至１−９５、１−２４５乃至１−２４８、１−２５２乃至１−２５７、１−２７２乃至１−２７５、１−２７９乃至１−２８４、１−２９９乃至１−３０２、１−３０６乃至１−３１１、１−３２６乃至１−３２９、及び１−３３３乃至１−３３８、
２−２乃至２−５、２−９乃至２−１４、２−２９乃至２−３２、２−３６乃至２−４１、２−５６乃至２−５９、２−６３乃至２−６８、２−８３乃至２−８６、及び２−９０乃至２−９５、
３−１乃至３−４、
４−１乃至４−４、並びに
５−１、５−２、５−７、及び５−９の化合物である。Preferred compounds in Tables 1 to 4 are exemplified compound numbers 1-2 to 1-27, 1-29 to 1-54, 1-56 to 1-81, 1-83 to 1-108, 1-110. To 1-135, 1-137 to 1-162, 1-164 to 1-189, 1-191 to 1-216, 1-218 to 1-243, 1-245 to 1-270, and 1-272 to 1 -297, 1-299 through 1-324, 1-326 through 1-351, 1-364 through 1-399, 1-402 through 1-409, 1-422 through 1-457, 1-460 through 1-467 1-480 to 1-515, 1-518 to 1-525, 1-538 to 1-573, and 1-576 to 1-583;
2-2 to 2-27, 2-29 to 2-54, 2-56 to 2-81, 2-83 to 2-108, 2-110 to 2-135, 2-137 to 2-162, 2- 164 through 2-189, 2-191 through 2-216, 2-218 through 2-243, 2-245 through 2-270, 2-272 through 2-297, 2-299 through 2-324, 2-326 through 2-351, 2-364 to 2-399, 2-402 to 2-409, 2-422 to 2-457, 2-460 to 2-467, 2-480 to 2-515, 2-518 to 2- 525, 2-538 to 2-573, and 2-576 to 2-583,
3-1 to 3-60, 3-101 to 3-284, 3-293 to 3-468, and 3-481 to 3-520,
4-1 to 4-60, 4-101 to 4-284, 4-293 to 4-468, and 4-481 to 4-520, and 5-1 to 5-2, 5 to 7, and 5 to 9 Is a compound of
Further preferred compounds are exemplified compound numbers 1-2 to 1-5, 1-9 to 1-14, 1-29 to 1-32, 1-36 to 1-41, 1-56 to 1-59, 1 -63 to 1-68, 1-83 to 1-86, 1-90 to 1-95, 1-110 to 1-113, 1-137 to 1-140, 1-164 to 1-167, 1-191 To 1-194, 1-218 to 1-221, 1-245 to 1-248, 1-252 to 1-257, 1-272 to 1-275, 1-279 to 1-284, and 1-299 to 1 -302, 1-306 through 1-311, 1-326 through 1-329, and 1-333 through 1-338,
2-2 to 2-5, 2-9 to 2-14, 2-29 to 2-32, 2-36 to 2-41, 2-56 to 2-59, 2-63 to 2-68, 2- 83 to 2-86, 2-90 to 2-95, 2-110 to 2-113, 2-137 to 2-140, 2-164 to 2-167, 2-191 to 2-194, 2-218 to 2-221, 2-245 to 2-248, 2-272 to 2-275, 2-299 to 2-302, and 2-326 to 2-329,
3-1 to 3-4, and 3-9 to 3-12,
4-1 to 4-4, and 4-9 to 4-12, and compounds of 5-1 5-2, 5-7, and 5-9,
Even more preferred compounds are exemplified compound numbers 1-2 to 1-5, 1-9 to 1-14, 1-29 to 1-32, 1-36 to 1-41, 1-56 to 1-59, 1-63 to 1-68, 1-83 to 1-86, 1-90 to 1-95, 1-245 to 1-248, 1-252 to 1-257, 1-272 to 1-275, 1- 279 through 1-284, 1-299 through 1-302, 1-306 through 1-311, 1-326 through 1-329, and 1-333 through 1-338,
2-2 to 2-5, 2-9 to 2-14, 2-29 to 2-32, 2-36 to 2-41, 2-56 to 2-59, 2-63 to 2-68, 2- 83 to 2-86, and 2-90 to 2-95,
3-1 to 3-4,
4-1 to 4-4, and 5-1 to 5-2, 5-7, and 5-9.

これらのうち、特に好適な化合物は、
・Ｎ^２−１，１’−ビフェニル−３−イル−Ｎ^１−（（１Ｓ）−１−｛［（４−メトキシフェニル）アミノ］メチル｝プロピル）−Ｌ−ロイシンアミド（例示化合物番号１−２９）、
・Ｎ^２−１，１’−ビフェニル−３−イル−Ｎ^１−（（１Ｓ）−１−｛［（４−メトキシフェニル）アミノ］メチル｝ブチル）−Ｌ−ロイシンアミド（例示化合物番号１−５６）、
・Ｎ^２−１，１’−ビフェニル−３−イル−Ｎ^１−（（１Ｓ）−１−｛［（４−メトキシフェニル）アミノ］メチル｝ペンチル）−Ｌ−ロイシンアミド（例示化合物番号１−８３）、
・Ｎ^１−（（１Ｓ）−１−｛［（４−ベンジルオキシフェニル）アミノ］メチル｝プロピル）−Ｎ^２−（１，１‘−ビフェニル−３−イル）−L−ロイシナミド（例示化合物番号１−２７２）、
・１−（１，１’−ビフェニル−３−イルアミノ）−Ｎ−（（１Ｓ）−１−｛［（４−メトキシフェニル）アミノ］メチル｝プロピル）シクロヘキサンカルボキサミド（例示化合物番号２−２９）、
・１−（１，１’−ビフェニル−３−イルアミノ）−Ｎ−（（１Ｓ）−１−｛［（４−メトキシフェニル）アミノ］メチル｝ブチル）シクロヘキサンカルボキサミド（例示化合物番号２−５６）、
・１−（１，１’−ビフェニル−３−イルアミノ）−Ｎ−（（１Ｓ）−１−｛［（４−メトキシフェニル）アミノ］メチル｝ペンチル）シクロヘキサンカルボキサミド（例示化合物番号２−８３）、
・１−（１，１‘−ビフェニル−３−イルアミノ）−Ｎ−（（１Ｓ）−１−｛［（４−ベンジルオキシフェニル）アミノ］メチル｝プロピル）シクロヘキサンカルボキサミド（例示化合物番号２−２７２）、
・ｔｅｒｔ−ブチル （４−｛[（２Ｓ）−２−（｛[１−（１，１‘−ビフェニル−３−イルアミノ）シクロヘキシル]カルボニル｝アミノ）ブチル]アミノ｝フェノキシ）アセテート（例示化合物番号５−１）、
・（４−｛[（２Ｓ）−２−（｛[１−（１，１‘−ビフェニル−３−イルアミノ）シクロヘキシル]カルボニル｝アミノ）ブチル]アミノ｝フェノキシ）酢酸（例示化合物番号５−２）、
・［４−（｛（２Ｓ）−２−［（Ｎ−１，１‘−ビフェニル−３−イル−Ｌ−ロイシル）アミノ］ブチル｝アミノ）フェノキシ］酢酸 ｔｅｒｔ−ブチル（例示化合物番号５−７）、及び
・［４−（｛（２Ｓ）−２−［（Ｎ−１，１‘−ビフェニル−３−イル−Ｌ−ロイシル）アミノ］ブチル｝アミノ）フェノキシ］酢酸（例示化合物番号５−９）
である。

本発明の一般式（Ｉ）を有する化合物は、以下に記載する方法によって製造することができる。
＜Ａ法＞Among these, particularly preferred compounds are
·^N 2-1,1'-biphenyl-3-yl^{-N 1 - ((1S) -1} - {[(4- methoxyphenyl) amino] methyl} propyl) -L- leucinamide (Compound No. 1- 29),
·^N 2-1,1'-biphenyl-3-yl^{-N 1 - ((1S) -1} - {[(4- methoxyphenyl) amino] methyl} butyl) -L- leucinamide (Compound No. 1- 56),
·^N 2-1,1'-biphenyl-3-yl^{-N 1 - ((1S) -1} - {[(4- methoxyphenyl) amino] methyl} pentyl) -L- leucinamide (Compound No. 1- 83),
^{· N 1 - ((1S)} -1 - {[(4- benzyloxyphenyl) amino] methyl}^propyl) -N 2 - (1,1'-biphenyl-3-yl) -L- Roishinamido (Compound No. 1-272),
1- (1,1′-biphenyl-3-ylamino) -N-((1S) -1-{[(4-methoxyphenyl) amino] methyl} propyl) cyclohexanecarboxamide (Exemplary Compound No. 2-29);
1- (1,1′-biphenyl-3-ylamino) -N-((1S) -1-{[(4-methoxyphenyl) amino] methyl} butyl) cyclohexanecarboxamide (Exemplary Compound No. 2-56);
1- (1,1′-biphenyl-3-ylamino) -N-((1S) -1-{[(4-methoxyphenyl) amino] methyl} pentyl) cyclohexanecarboxamide (Exemplified Compound No. 2-83);
-1- (1,1'-biphenyl-3-ylamino) -N-((1S) -1-{[(4-benzyloxyphenyl) amino] methyl} propyl) cyclohexanecarboxamide (Exemplary Compound No. 2-272) ,
-Tert-butyl (4-{[(2S) -2-({[1- (1,1'-biphenyl-3-ylamino) cyclohexyl] carbonyl} amino) butyl] amino} phenoxy) acetate (Exemplified Compound No. 5 -1),
-(4-{[(2S) -2-({[1- (1,1'-biphenyl-3-ylamino) cyclohexyl] carbonyl} amino) butyl] amino} phenoxy) acetic acid (Exemplary Compound No. 5-2) ,
-Tert-butyl [4-({(2S) -2-[(N-1,1'-biphenyl-3-yl-L-leucyl) amino] butyl} amino) phenoxy] acetate (Exemplified Compound No. 5-7 )), And [4-({(2S) -2-[(N-1,1′-biphenyl-3-yl-L-leucyl) amino] butyl} amino) phenoxy] acetic acid (exemplary compound number 5-9) )
It is.

The compound having the general formula (I) of the present invention can be produced by the method described below.
<Method A>

（式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ａｒ、Ｘ及びＺは前記と同意義を示す。）
第１工程は、カルボン酸化合物（１）とアミン化合物（２）とを、不活性溶媒中、塩基の存在下若しくは非存在下、縮合剤の存在下で反応させ、本発明の化合物（Ｉ）を製造する工程である。(In the formula, R¹ , R² , R³ , R⁴ , Ar, X and Z have the same meanings as described above.)
In the first step, the carboxylic acid compound (1) is reacted with the amine compound (2) in an inert solvent, in the presence or absence of a base, in the presence of a condensing agent, to give the compound (I) of the present invention. This is the step of manufacturing.

使用される不活性溶媒は、例えば、メチレンクロリド、クロロホルム、四塩化炭素又はジクロロエタンなどのハロゲン化炭化水素類；ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサン又は１，２−ジメトキシエタンのようなエーテル類；ホルムアミド、Ｎ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルアセトアミド、Ｎ−メチル−２−ピロリドン、Ｎ−メチルピロリジノン又はヘキサメチルホスホロトリアミドのようなアミド類；或いは、ベンゼン、トルエン又はキシレンのような芳香族炭化水素類であり得、好適には、ハロゲン化炭化水素類又はアミド類であり、更に好適には、メチレンクロリド又はＮ，Ｎ−ジメチルホルムアミドである。  Inert solvents used are, for example, halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride or dichloroethane; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane or 1,2-dimethoxyethane; Amides such as formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone or hexamethylphosphorotriamide; or, such as benzene, toluene or xylene It can be an aromatic hydrocarbon, preferably a halogenated hydrocarbon or an amide, more preferably methylene chloride or N, N-dimethylformamide.

使用される塩基は、例えば、トリエチルアミン、トリブチルアミン、ジイソプロピルエチルアミン、Ｎ−メチルピペリジン、Ｎ−メチルモルホリン、ピリジン、４−ピロリジノピリジン、ピコリン、４−（Ｎ，Ｎ−ジメチルアミノ）ピリジン、２，６−ジ（tert−ブチル）−４−メチルピリジン、キノリン、Ｎ，Ｎ−ジメチルアニリン又はＮ，Ｎ−ジエチルアニリンのようなのような三級アミン類であり得、好適にはトリエチルアミン又はＮ−メチルモルホリンである。  The base used is, for example, triethylamine, tributylamine, diisopropylethylamine, N-methylpiperidine, N-methylmorpholine, pyridine, 4-pyrrolidinopyridine, picoline, 4- (N, N-dimethylamino) pyridine, 2, Tertiary amines such as 6-di (tert-butyl) -4-methylpyridine, quinoline, N, N-dimethylaniline or N, N-diethylaniline, preferably triethylamine or N-methyl Morpholine.

使用される縮合剤は、例えば、ジシクロヘキシルカルボジイミド、ジイソプロピルカルボジイミド又は１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミドのようなカルボジイミド類と、Ｎ−ヒドロキシスクシイミド、１−ヒドロキシベンゾトリアゾール又はＮ−ヒドロキシ−５−ノルボルネン−２，３−ジカルボキシイミドのようなＮ−ヒドロキシ類の組み合わせ；或いは、ジエチルホスホリルシアニド又はジフェニルホスホリルアジドのような燐酸エステル類と上記塩基の組合せであり得、好適には、Ｎ−ヒドロキシルアミン類（好適には、１−ヒドロキシベンゾトリアゾール又はＮ−ヒドロキシスクシンイミド）とカルボジイミド類（好適には、ジシクロヘキシルカルボジイミド又は１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド）の組み合わせである。  The condensing agent used is, for example, carbodiimides such as dicyclohexylcarbodiimide, diisopropylcarbodiimide or 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, N-hydroxysuccinimide, 1-hydroxybenzotriazole or N-hydroxybenzotriazole. A combination of N-hydroxys such as -hydroxy-5-norbornene-2,3-dicarboximide; or a combination of a phosphoric ester such as diethylphosphoryl cyanide or diphenylphosphoryl azide with the above base, which is preferable. Include N-hydroxylamines (preferably 1-hydroxybenzotriazole or N-hydroxysuccinimide) and carbodiimides (preferably dicyclohexylcarbodiimide or 1-ethyl-3- (3-dimethylamido). A combination of propyl) carbodiimide).

反応温度は、原料化合物、使用される溶媒、塩基又は縮合剤によって変化するが、通常、−３０℃乃至溶媒の還流温度であり、好適には、０℃乃至室温である。  The reaction temperature varies depending on the starting compound, the solvent used, the base or the condensing agent, but is usually from -30 ° C to the reflux temperature of the solvent, preferably from 0 ° C to room temperature.

反応時間は、原料化合物、使用される溶媒、塩基、縮合剤又は反応温度によって異なるが、通常、１時間乃至９６時間であり、好適には、１時間乃至２４時間である。  The reaction time varies depending on the starting compound, the solvent used, the base, the condensing agent and the reaction temperature, but is usually 1 hour to 96 hours, preferably 1 hour to 24 hours.

また、化合物（Ｉ）は、化合物（１）と、上記一般式（２）において基Ａｒが結合している窒素がアリルオキシカルボニルで保護されている化合物とを用いて、上記と同様に反応を行い、得られた化合物の脱保護（アリルオキシカルボニルの除去）を行うことによって製造することもできる。アリルオキシカルボニルの除去は、例えば、パラジウム触媒（例えば、酢酸パラジウム、テトラキス（トリフェニルホスフィン）パラジウム（０）又はトリス（ジベンジリデンアセトン）ジパラジウム（０）のような０価パラジウムと１，３−ビス（ジフェニルホスフィノプロパンのような配位子の組み合わせなど）の存在下に不活性溶媒（例えば、アニソール、ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサン又は１，２−ジメトキシエタンのようなエーテル類）中で、求核剤（例えば、2−エチルヘキサン酸ナトリウムなどのカルボン酸塩、ピロリジン、ピペリジン又はブチルアミンなどのアミン類或いはギ酸アンモニウムなどのアンモニウム塩類）を作用させることで行われる。反応温度は、通常、−１０℃乃至１５０℃（好適には、０℃乃至１００℃）であり、反応時間は、通常、５分乃至４８時間（好適には、１０分乃至１５時間）である。

反応終了後、目的化合物は常法に従って、反応混合物から採取される。Compound (I) is reacted in the same manner as described above using compound (1) and a compound in which the nitrogen to which group Ar is bonded in the general formula (2) is protected by allyloxycarbonyl. The compound can also be produced by deprotecting (removing allyloxycarbonyl) the resulting compound. Allyloxycarbonyl can be removed, for example, by removing a zero-valent palladium such as a palladium catalyst (eg, palladium acetate, tetrakis (triphenylphosphine) palladium (0) or tris (dibenzylideneacetone) dipalladium (0) and 1,3- Inert solvents (eg, ethers such as anisole, diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane or 1,2-dimethoxyethane) in the presence of bis (such as a combination of ligands such as diphenylphosphinopropane) In the reaction, a nucleophilic agent (for example, a carboxylate such as sodium 2-ethylhexanoate, an amine such as pyrrolidine, piperidine or butylamine, or an ammonium salt such as ammonium formate) is used. Usually -10 C. to 150 ° C. (preferably 0 ° C. to 100 ° C.), and the reaction time is usually 5 minutes to 48 hours (preferably 10 minutes to 15 hours).

After completion of the reaction, the target compound is collected from the reaction mixture according to a conventional method.

例えば、反応混合物を適宜中和し、また、不溶物が存在する場合にはろ過により除去した後、水を加え、酢酸エチル又はトルエンのような水に混和しない有機溶剤で抽出し、水等で洗浄し、抽出液を無水硫酸マグネシウム等で乾燥した後、溶剤を留去することによって得られる。  For example, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration, water is added, and the mixture is extracted with a water-immiscible organic solvent such as ethyl acetate or toluene. It is obtained by washing, drying the extract with anhydrous magnesium sulfate or the like, and then distilling off the solvent.

得られた化合物は必要ならば、常法、例えばシリカゲルカラムクロマトグラフィーで分離、精製することができる。

一般式（Ｉ）を有する化合物のうち、Ｘが、−ＣＯＮＨ−、−ＳＯ_２ＮＨ−、−ＳＯＮＨ−又は−Ｏ−ＣＯＮＨ−である化合物は、下記＜Ｂ法＞に従って製造することもできる。
＜Ｂ法＞If necessary, the obtained compound can be separated and purified by a conventional method, for example, silica gel column chromatography.

Among the compounds having the general formula (I), X_{is, -CONH -, - SO 2 NH} -, - SONH- or -O-CONH-, compound can also be produced in accordance with the following <B Method>.
<Method B>

（式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ａｒ及びＺは前記と同意義を示し、Ｍ^１は、−ＣＯ−、−ＳＯ_２−、−ＳＯ−又は−Ｏ−ＣＯ−を示し、Ｍ^２は、−ＣＯ−、−ＳＯ_２−又は−ＳＯ−を示し、Ｒ^８は、アミノ基の保護基を示す。）
Ｒ^８の定義における「アミノ基の保護基」は、有機合成化学の分野で一般にアミノ基の保護基として使用される基であれば特に限定はなく、例えば、ホルミル、アセチル、プロピオニル、ブチリル、イソブチリル、ペンタノイル、ピバロイル、バレリル、イソバレリル又はヘキサノイル基のようなＣ₁−Ｃ₆アルカノイル基；クロロアセチル、ジクロロアセチル、トリクロロアセチル、トリフルオロアセチル、３−フルオロプロピオニル、４，４−ジクロロブチリル、メトキシアセチル、ブトキシアセチル、エトキシプロピオニル又はプロポキシブチリル基のような、ハロゲン若しくはＣ₁−Ｃ₄アルコキシで置換されたＣ₁−Ｃ₄アルカノイル基；アクリロイル、プロピオロイル、メタクリロイル、クロトノイル又はイソクロトノイル基のような不飽和Ｃ_２−Ｃ₄アルカノイル基；ベンゾイル、α−ナフトイル、β−ナフトイル、２−フルオロベンゾイル、２−ブロモベンゾイル、２，４−ジクロロベンゾイル、６−クロロ−α−ナフトイル、４−トルオイル、４−プロピルベンゾイル、４−tert−ブチルベンゾイル、２，４，６−トリメチルベンゾイル、６−エチル−α−ナフトイル、４−アニソイル、４−プロポキシベンゾイル、４−tert−ブトキシベンゾイル、６−エトキシ−α−ナフトイル、２−エトキシカルボニルベンゾイル、４−tert−ブトキシカルボニルベンゾイル、６−メトキシカルボニル−α−ナフトイル、４−フェニルベンゾイル、４−フェニル−α−ナフトイル、６−α−ナフチルベンゾイル、４−ニトロベンゾイル、２−ニトロベンゾイル又は６−ニトロ−α−ナフトイル基のような、ハロゲン、Ｃ₁−Ｃ₄アルキル、Ｃ₁−Ｃ₄アルコキシ、Ｃ₁−Ｃ₄アルコキシカルボニル、Ｃ₆−Ｃ₁₀アリ−ル又はニトロで置換されてもよいＣ₆−Ｃ₁₀アリ−ルカルボニル基；スクシノイル基又はフタロイル基のようにアミンと環状イミドを形成する基；メトキシカルボニル、エトキシカルボニル、プロポキシカルボニル、イソプロポキシカルボニル、ブトキシカルボニル、イソブトキシカルボニル、ｓ−ブトキシカルボニル、tert−ブトキシカルボニル、クロロメトキシカルボニル、２，２，２−トリクロロエトキシカルボニル、２−フルオロプロポキシカルボニル、２−ブロモ−tert−ブトキシカルボニル、２，２−ジブロモ−tert−ブトキシカルボニル、トリエチルシリルメトキシカルボニル、２−トリメチルシリルエトキシカルボニル、４−トリプロピルシリルブトキシカルボニル又はtert−ブチルジメチルシリルプロポキシカルボニル基のような、ハロゲン又はトリＣ₁−Ｃ₄アルキルシリルで置換されてもよいＣ₁−Ｃ₄アルコキシカルボニル基；ビニルオキシカルボニル、アリルオキシカルボニル、１，３−ブタジエニルオキシカルボニル又は２−ペンテニルオキシカルボニル基のようなＣ₂−Ｃ₅アルケニルオキシカルボニル基；或いは、ベンジルオキシカルボニル、（１−フェニル）ベンジルオキシカルボニル、α−ナフチルメチルオキシカルボニル、β−ナフチルメチルオキシカルボニル、９−アンスリルメチルオキシカルボニル、９−フルオレニルメチルオキシカルボニル、ｐ−メトキシベンジルオキシカルボニル又はｐ−ニトロベンジルオキシカルボニル基のような、メトキシ又はニトロで置換されてもよいＣ₇−Ｃ₁₅アラルキルオキシカルボニル基であり得、好適には、Ｃ₁−Ｃ₄アルカノイル、トリフルオロアセチル、メトキシアセチル、ベンゾイル、α−ナフトイル、β−ナフトイル、アニソイル、ニトロベンゾイル、Ｃ₁−Ｃ₄アルコキシカルボニル、２，２，２−トリクロロエトキシカルボニル、トリエチルシリルメトキシカルボニル、２−トリメチルシリルエトキシカルボニル、ビニルオキシカルボニル、アリルオキシカルボニル、９−フルオレニルメチルオキシカルボニル、ベンジルオキシカルボニル又はニトロベンジルオキシカルボニル基であり、更に好適には、ホルミル、アセチル、トリフルオロアセチル、ベンゾイル、４−アニソイル、４−ニトロベンゾイル、メトキシカルボニル、エトキシカルボニル、ブトキシカルボニル、tert−ブトキシカルボニル、アリルオキシカルボニル、９−フルオレニルメチルオキシカルボニル、ベンジルオキシカルボニル又はｐ−ニトロベンジルオキシカルボニル基であり、特に好適には、ホルミル、tert−ブトキシカルボニル、９−フルオレニルメチルオキシカルボニル、アリルオキシカルボニル又はベンジルオキシカルボニル基である。

第２工程は、カルボン酸化合物（３）とアミン化合物（４）とを、不活性溶媒中、塩基の存在下若しくは非存在下、縮合剤の存在下で反応させ、化合物（５）を製造する工程であり、第１工程に記載された方法と同様に実施される。

第３工程は、化合物（５）の保護基を除去することによって、化合物（６）を製造する工程である。(Wherein, R¹ , R² , R³ , R⁴ , Ar and Z have the same meanings as described above, and M¹ represents —CO—, —SO₂ —, —SO— or —O—CO— shown,^{M 2} is, -CO -, - SO₂ - or -SO- indicates,^{R 8} is an amino-protecting group).
The “amino-protecting group” in the definition of R⁸ is not particularly limited as long as it is a group generally used as an amino-protecting group in the field of synthetic organic chemistry. For example, formyl, acetyl, propionyl, butyryl, isobutyryl , pentanoyl, pivaloyl, valeryl, C₁ -C₆ alkanoyl group such as isovaleryl or hexanoyl group; chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, 3-fluoro-propionyl, 4,4-dichloro-butyryl, methoxyacetyl A C₁ -C₄ alkanoyl group substituted by halogen or C₁ -C₄ alkoxy, such as butoxyacetyl, ethoxypropionyl or propoxybutyryl group; Such unsaturated C₂ -C₄ alkanoyl groups; benzoyl, α-naphthoyl, β-naphthoyl, 2-fluorobenzoyl, 2-bromobenzoyl, 2,4-dichlorobenzoyl, 6-chloro-α-naphthoyl, 4-toluoyl, 4-propylbenzoyl, 4-tert-butylbenzoyl, 2,4,6-trimethylbenzoyl, 6-ethyl-α-naphthoyl, 4-anisoyl, 4-propoxybenzoyl, 4-tert-butoxybenzoyl, 6-ethoxy-α -Naphthoyl, 2-ethoxycarbonylbenzoyl, 4-tert-butoxycarbonylbenzoyl, 6-methoxycarbonyl-α-naphthoyl, 4-phenylbenzoyl, 4-phenyl-α-naphthoyl, 6-α-naphthylbenzoyl, 4-nitrobenzoyl , 2-nitrobenzoyl or 6-nitro-α-naph Such as toyl group halogen, C₁ -C₄ alkyl, C₁ -C₄ alkoxy, C₁ -C₄ alkoxycarbonyl, C₆ -C₁₀ ants - good C₆ -C be substituted Le or nitro₁₀ arylcarbonyl group; group forming a cyclic imide with an amine such as succinoyl group or phthaloyl group; methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, s-butoxycarbonyl, tert -Butoxycarbonyl, chloromethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-fluoropropoxycarbonyl, 2-bromo-tert-butoxycarbonyl, 2,2-dibromo-tert-butoxycarbonyl, triethylsilylmethoxycarbonyl, -Trimethylsilyl Butoxycarbonyl, 4-tripropylsilyl-butoxycarbonyl or tert- butyldimethylsilyl propoxycarbonyl group such as halogen or tri C₁ -C₄ alkylsilyl which may be substituted with C₁ -C₄ alkoxycarbonyl group; vinyloxy carbonyl, allyloxycarbonyl, 1,3 C₂ -C₅ alkenyloxycarbonyl group such as butadienyl oxycarbonyl or 2-pentenyl oxycarbonyl group; or benzyloxycarbonyl, (1-phenyl) benzyloxycarbonyl, α-naphthylmethyloxycarbonyl, β-naphthylmethyloxycarbonyl, 9-anthrylmethyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, p-methoxybenzyloxycarbonyl or p-nitrobenzyloxy It may be a C₇ -C₁₅ aralkyloxycarbonyl group which may be substituted by methoxy or nitro, such as a carbonyl group, and is preferably a C₁ -C₄ alkanoyl, trifluoroacetyl, methoxyacetyl, benzoyl, α- Naphthoyl, β-naphthoyl, anisoyl, nitrobenzoyl, C₁ -C₄ alkoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, triethylsilylmethoxycarbonyl, 2-trimethylsilylethoxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl, 9- A fluorenylmethyloxycarbonyl, benzyloxycarbonyl or nitrobenzyloxycarbonyl group, more preferably formyl, acetyl, trifluoroacetyl, benzoyl, 4-anisoyl, 4-nitrobenzoyl, Xycarbonyl, ethoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, benzyloxycarbonyl or p-nitrobenzyloxycarbonyl group, particularly preferably formyl, tert- Butoxycarbonyl, 9-fluorenylmethyloxycarbonyl, allyloxycarbonyl or benzyloxycarbonyl.

In the second step, the carboxylic acid compound (3) is reacted with the amine compound (4) in an inert solvent in the presence or absence of a base in the presence of a condensing agent to produce a compound (5). This is a step, and is performed in the same manner as the method described in the first step.

The third step is a step of producing a compound (6) by removing the protecting group of the compound (5).

アミノ基の保護基（Ｒ^８）の除去は、周知の方法に準じて実施され、例えば、不活性溶媒中、酸又は塩基による処理、アルカリ金属による還元処理、接触水添、或いはパラジウム触媒存在下に求核剤を作用させることによって除去することができる。The removal of the amino-protecting group (R⁸ ) is carried out according to a well-known method. For example, treatment with an acid or a base, reduction with an alkali metal, catalytic hydrogenation, or in the presence of a palladium catalyst Can be removed by the action of a nucleophile on

使用される不活性溶媒は、例えば、ヘキサン、ヘプタン、リグロイン又は石油エーテルのような脂肪族炭化水素類；ベンゼン、トルエン又はキシレンのような芳香族炭化水素類；メチレンクロリド、クロロホルム、四塩化炭素、ジクロロエタン、クロロベンゼン、ｏ−ジクロロベンゼン、ｍ−ジクロロベンゼン、フルオロベンゼン、トリクロロメチルベンゼン又はトリフルオロメチルベンゼンのようなハロゲン化炭化水素類；アニソール、ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサン又は１，２−ジメトキシエタンのようなエーテル類；酢酸メチル又は酢酸エチルのようなエステル類；メタノール、エタノール、プロパノール、２−プロパノール又はブタノールのようなアルコール類；ホルムアミド、Ｎ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルアセトアミド又はヘキサメチルリン酸トリアミドのようなアミド類；ジメチルスルホキシド又はスルホランのようなスルホキシド類；蟻酸又は酢酸のような脂肪酸類；或いは、水又は水と上記溶媒との混合溶媒であり得、好適には、ハロゲン化炭化水素類、エーテル類、アルコール類、脂肪酸類又は水と上記溶媒との混合溶媒であり、更に好適にはハロゲン化炭化水素類（特に、メチレンクロリド又はクロロホルム）、エーテル類（特にアニソール、テトラヒドロフラン又はジオキサン）、脂肪酸類（特に酢酸）、アルコール類（特にメタノール又はエタノール）、或は、水と上記溶媒との混合溶媒である。  Inert solvents used are, for example, aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; methylene chloride, chloroform, carbon tetrachloride, Halogenated hydrocarbons such as dichloroethane, chlorobenzene, o-dichlorobenzene, m-dichlorobenzene, fluorobenzene, trichloromethylbenzene or trifluoromethylbenzene; anisole, diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane or 1,2- Ethers such as dimethoxyethane; esters such as methyl acetate or ethyl acetate; alcohols such as methanol, ethanol, propanol, 2-propanol or butanol; formamide, N, Amides such as dimethylformamide, N, N-dimethylacetamide or hexamethylphosphoric triamide; sulfoxides such as dimethylsulfoxide or sulfolane; fatty acids such as formic acid or acetic acid; or water or water and the above solvent. And is preferably a mixed solvent of halogenated hydrocarbons, ethers, alcohols, fatty acids or water and the above solvent, more preferably a halogenated hydrocarbon (particularly, methylene Chloride or chloroform), ethers (particularly anisole, tetrahydrofuran or dioxane), fatty acids (particularly acetic acid), alcohols (particularly methanol or ethanol), or a mixed solvent of water and the above solvent.

使用される酸は、例えば、塩酸、硫酸、リン酸、臭化水素酸、フッ化水素酸又はトリフルオロ酢酸であり得、好適には、塩酸、臭化水素酸、フッ化水素酸又はトリフルオロ酢酸である。  The acid used can be, for example, hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, hydrofluoric acid or trifluoroacetic acid, preferably hydrochloric acid, hydrobromic acid, hydrofluoric acid or trifluoroacetic acid. Acetic acid.

使用される塩基は、例えば、炭酸ナトリウム、炭酸カリウム又は炭酸リチウムのようなアルカリ金属炭酸塩類；炭酸水素ナトリウム、炭酸水素カリウム又は炭酸水素リチウムのようなアルカリ金属重炭酸塩類；水酸化ナトリウム、水酸化カリウム又は水酸化リチウムのようなアルカリ金属水酸化物類；ナトリウムメトキシド、ナトリウムエトキシド、カリウムtert−ブトキシド又はリチウムメトキシドのようなアルカリ金属アルコキシド類；メチルメルカプタンナトリウム又はエチルメルカプタンナトリウムのようなメルカプタンアルカリ金属類；ヒドラジン、メチルアミン、ジメチルアミン、エチルアミン、トリエチルアミン、ブチルアミン、トリブチルアミン、ジイソプロピルエチルアミン、ピロリジン、ピペリジン、Ｎ−メチルモルホリン、ピリジン、４−（Ｎ，Ｎ−ジメチルアミノ）ピリジン、Ｎ，Ｎ−ジメチルアニリン、Ｎ，Ｎ−ジエチルアニリン、１，５−ジアザビシクロ［４．３．０］ノナ−５−エン、１，４−ジアザビシクロ［２．２．２］オクタン（ＤＡＢＣＯ）又は１，８−ジアザビシクロ［５．４．０］ウンデク−７−エン（ＤＢＵ）のような有機塩基類であり得、好適には、アルカリ金属炭酸塩類（特に炭酸ナトリウム又は炭酸カリウム）、アルカリ金属水酸化物類（特に水酸化ナトリウム又は水酸化カリウム）、アルカリ金属アルコキシド類（特にナトリウムメトキシド、ナトリウムエトキシド又はカリウム−tert−ブトキシド）或は有機塩基類（特にヒドラジン、ピペリジン又はメチルアミン）である。  The base used is, for example, an alkali metal carbonate such as sodium carbonate, potassium carbonate or lithium carbonate; an alkali metal bicarbonate such as sodium hydrogen carbonate, potassium hydrogen carbonate or lithium hydrogen carbonate; sodium hydroxide, hydroxide Alkali metal hydroxides such as potassium or lithium hydroxide; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide or lithium methoxide; mercaptans such as sodium methyl mercaptan or sodium ethyl mercaptan Alkali metals: hydrazine, methylamine, dimethylamine, ethylamine, triethylamine, butylamine, tributylamine, diisopropylethylamine, pyrrolidine, piperidine, N-methylmorpholy Pyridine, 4- (N, N-dimethylamino) pyridine, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] non-5-ene, 1, It can be an organic base such as 4-diazabicyclo [2.2.2] octane (DABCO) or 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), preferably alkali Metal carbonates (especially sodium or potassium carbonate), alkali metal hydroxides (especially sodium hydroxide or potassium hydroxide), alkali metal alkoxides (especially sodium methoxide, sodium ethoxide or potassium tert-butoxide) or Are organic bases, especially hydrazine, piperidine or methylamine.

アルカリ金属による還元処理は、例えば、酢酸、メタノール又はエタノール中、或いは、これらのうち一つと水との混合溶媒中で亜鉛末と処理することで行なわれる。  The reduction treatment with an alkali metal is performed, for example, by treating with zinc dust in acetic acid, methanol, or ethanol, or in a mixed solvent of one of these and water.

接触水添による脱保護は、例えば、パラジウム−炭素、水酸化パラジウム又は塩化パラジウムなどの触媒の存在下に、不活性溶媒中、加圧あるいは定圧の水素雰囲気下で行なわれる。  The deprotection by catalytic hydrogenation is performed, for example, in the presence of a catalyst such as palladium-carbon, palladium hydroxide or palladium chloride in an inert solvent under a pressurized or constant-pressure hydrogen atmosphere.

パラジウム触媒存在下に求核剤を作用させることによる脱保護は、例えば、酢酸パラジウム又はテトラキス（トリフェニルホスフィン）パラジウム（０）などの触媒の存在下に、不活性溶媒中で、2−エチルヘキサン酸ナトリウムなどのカルボン酸塩、ピロリジン、ピペリジン又はブチルアミンなどのアミン類或いはギ酸アンモニウムなどのアンモニウム塩類を作用させることで行なわれる。  Deprotection by the action of a nucleophile in the presence of a palladium catalyst can be performed, for example, by using 2-ethylhexane in an inert solvent in the presence of a catalyst such as palladium acetate or tetrakis (triphenylphosphine) palladium (0). The reaction is carried out by reacting a carboxylate such as sodium acid, an amine such as pyrrolidine, piperidine or butylamine, or an ammonium salt such as ammonium formate.

反応温度は、原料化合物、溶媒又は使用される酸若しくは塩基によって変化するが、通常、−１０℃乃至１５０℃であり、好適には０℃乃至１００℃である。  The reaction temperature varies depending on the starting compound, solvent or acid or base used, but is usually from -10 ° C to 150 ° C, preferably from 0 ° C to 100 ° C.

反応時間は、原料化合物、溶媒、使用される酸若しくは塩基、又は反応温度によって変化するが、通常５分乃至４８時間であり、好適には１０分乃至１５時間である。  The reaction time varies depending on the starting compound, the solvent, the acid or base used, or the reaction temperature, but is usually from 5 minutes to 48 hours, preferably from 10 minutes to 15 hours.

反応終了後、必要により、目的化合物は常法に従って、反応混合物から採取される。  After the completion of the reaction, the desired compound is collected from the reaction mixture according to a conventional method, if necessary.

例えば、反応混合物を適宜中和し、また、不溶物が存在する場合にはろ過により除去した後、水を加え、酢酸エチル又はトルエンのような水に混和しない有機溶剤で抽出し、水等で洗浄し、抽出液を無水硫酸マグネシウム等で乾燥した後、溶剤を留去することによって得られる。  For example, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration, water is added, and the mixture is extracted with a water-immiscible organic solvent such as ethyl acetate or toluene. It is obtained by washing, drying the extract with anhydrous magnesium sulfate or the like, and then distilling off the solvent.

得られた化合物は必要ならば、常法、例えばシリカゲルカラムクロマトグラフィーで分離、精製することができる。

第４工程は、化合物（６）とアシルクロリド、スルホニルクロリド又はスルフィニルクロリド化合物（７）とを、不活性溶媒中、塩基の存在下で反応させ、本発明の化合物（Ｉ−１）を製造する工程である。If necessary, the obtained compound can be separated and purified by a conventional method, for example, silica gel column chromatography.

In the fourth step, the compound (6) is reacted with an acyl chloride, a sulfonyl chloride or a sulfinyl chloride compound (7) in an inert solvent in the presence of a base to produce the compound (I-1) of the present invention. It is a process.

使用される不活性溶媒は、例えば、ピリジン；メチレンクロリド、クロロホルム、四塩化炭素又はジクロロエタンなどのハロゲン化炭化水素類；ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサン又は１，２−ジメトキシエタンのようなエーテル類；ホルムアミド、Ｎ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルアセトアミド、Ｎ−メチル−２−ピロリドン、Ｎ−メチルピロリジノン又はヘキサメチルホスホロトリアミドのようなアミド類；ベンゼン、トルエン又はキシレンのような芳香族炭化水素類；或いは、上記有機溶媒と水との混合物であり得、好適には、ピリジン、メチレンクロリド、ジエチルエーテル、Ｎ，Ｎ−ジメチルホルムアミド、トルエン又はこれらのうち１つと水との混合溶媒である。  Inert solvents used are, for example, pyridine; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride or dichloroethane; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane or 1,2-dimethoxyethane. Amides such as formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone or hexamethylphosphorotriamide; benzene, toluene or xylene Aromatic hydrocarbons; or a mixture of the above organic solvent and water, preferably pyridine, methylene chloride, diethyl ether, N, N-dimethylformamide, toluene or a mixture of water with one of these. Solvent.

使用される塩基は、例えば、炭酸ナトリウム、炭酸カリウム又は炭酸リチウムのようなアルカリ金属炭酸塩類、炭酸水素ナトリウム、炭酸水素カリウム又は炭酸水素リチウムのようなアルカリ金属炭酸水素塩類、水酸化ナトリウム、水酸化カリウム、水酸化バリウム又は水酸化リチウムのようなアルカリ金属水酸化物類、弗化ナトリウム又は弗化カリウムのようなアルカリ金属弗化物類等の無機塩基類；或いは、Ｎ−メチルモルホリン、トリエチルアミン、トリプロピルアミン、トリブチルアミン、ジイソプロピルエチルアミン、ジシクロヘキシルアミン、Ｎ−メチルピペリジン、ピリジン、４−ピロリジノピリジン、ピコリン、４−（Ｎ，Ｎ−ジメチルアミノ）ピリジン、２，６−ジ（tert−ブチル）−４−メチルピリジン、キノリン、Ｎ，Ｎ−ジメチルアニリン、Ｎ，Ｎ−ジエチルアニリン、１，５−ジアザビシクロ［４．３．０］ノナ−５−エン（ＤＢＮ）、１，４−ジアザビシクロ［２．２．２］オクタン（ＤＡＢＣＯ）、１，８−ジアザビシクロ［５．４．０］ウンデカ−７−エン（ＤＢＵ）のような有機塩基類であり得、好適には、アルカリ金属炭酸塩類、アルカリ金属炭酸水素塩類、アルカリ金属水酸化物類又は有機塩基類であり、更に好適には、水酸化ナトリウム、トリエチルアミン又はピリジンである。  The base used is, for example, an alkali metal carbonate such as sodium carbonate, potassium carbonate or lithium carbonate, an alkali metal bicarbonate such as sodium hydrogen carbonate, potassium hydrogen carbonate or lithium hydrogen carbonate, sodium hydroxide, hydroxide. Inorganic bases such as alkali metal hydroxides such as potassium, barium hydroxide or lithium hydroxide, alkali metal fluorides such as sodium fluoride or potassium fluoride; or N-methylmorpholine, triethylamine, triethylamine Propylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4- (N, N-dimethylamino) pyridine, 2,6-di (tert-butyl)- 4-methylpyridine, quinoline, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), 1,4-diazabicyclo [2.2.2] octane (DABCO), Organic bases such as 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), preferably alkali metal carbonates, alkali metal bicarbonates, alkali metal hydroxides Or organic bases, more preferably sodium hydroxide, triethylamine or pyridine.

反応温度は、原料化合物、使用される溶媒又は塩基によって変化するが、通常、０℃乃至溶媒の還流温度であり、好適には、０℃乃至室温である。  The reaction temperature varies depending on the starting compound, the solvent or the base used, but is usually from 0 ° C. to the reflux temperature of the solvent, and preferably from 0 ° C. to room temperature.

反応時間は、原料化合物、使用される溶媒、塩基又は反応温度によって異なるが、通常、１時間乃至９６時間であり、好適には、１時間乃至１２時間である。  The reaction time varies depending on the starting compound, the solvent used, the base and the reaction temperature, but is usually 1 hour to 96 hours, preferably 1 hour to 12 hours.

反応終了後、目的化合物は常法に従って、反応混合物から採取される。  After completion of the reaction, the target compound is collected from the reaction mixture according to a conventional method.

例えば、反応混合物を適宜中和し、また、不溶物が存在する場合にはろ過により除去した後、水を加え、酢酸エチル又はトルエンのような水に混和しない有機溶剤で抽出し、水等で洗浄し、抽出液を無水硫酸マグネシウム等で乾燥した後、溶剤を留去することによって得られる。  For example, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration, water is added, and the mixture is extracted with a water-immiscible organic solvent such as ethyl acetate or toluene. It is obtained by washing, drying the extract with anhydrous magnesium sulfate or the like, and then distilling off the solvent.

得られた化合物は必要ならば、常法、例えばシリカゲルカラムクロマトグラフィーで分離、精製することができる。

第５工程は、化合物（６）と化合物（７）とを、不活性溶媒中、塩基の存在下若しくは非存在下、縮合剤の存在下で反応させ、本発明の化合物（Ｉｂ）を製造する工程であり、第１工程に記載された方法と同様に実施される。

一般式（Ｉ）を有する化合物のうち、Ｒ^３が、置換基群αから選択される基で置換されていてもよいＣ_６−Ｃ_１０アリール基；又は、置換基群αから選択される基で置換されていてもよい、硫黄原子、酸素原子及び／又は窒素原子を１乃至３個含む５乃至７員ヘテロアリール基である化合物は、例えば、下記＜Ｃ法＞に従って製造することもできる。
＜Ｃ法＞If necessary, the obtained compound can be separated and purified by a conventional method, for example, silica gel column chromatography.

In the fifth step, compound (6) and compound (7) are reacted in an inert solvent in the presence or absence of a base in the presence of a condensing agent to produce compound (Ib) of the present invention. This is a step, and is performed in the same manner as the method described in the first step.

Among the compounds having the general formula (I), R³ is a C₆ -C₁₀ aryl group which may be substituted with a group selected from the substituent group α; or a group selected from the substituent group α. The compound which is a 5- to 7-membered heteroaryl group containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms, which may be substituted, can also be produced, for example, according to the following <Method C>.
<Method C>

［式中、Ｒ^１、Ｒ^２、Ｒ^４、Ａｒ、Ｘ及びＺは前記と同意義を示し、
Ｒ^３ａは、Ｒ^３の定義における、「置換基群αから選択される基で置換されていてもよいＣ_６−Ｃ_１０アリール基」又は「置換基群αから選択される基で置換されていてもよい、硫黄原子、酸素原子及び／又は窒素原子を１乃至３個含む５乃至７員ヘテロアリール基」を示し、
Ｒ^９は、水素原子を示すか、又は２つのＲ^９は、一緒になって、１，１，２，２−テトラメチルエチレン、１，２−フェニレン又は２，２−ジメチルトリメチレンを示し、
Ｙは、フッ素原子、塩素原子、臭素原子又はヨウ素原子（好適には、臭素又はヨウ素である）を示す。］

第６工程は、ハロゲン化化合物（９）とボロン化合物（１０）とを、不活性溶媒中、塩基及びパラジウム触媒の存在下で反応させ（鈴木カップリング）、本発明の化合物（Ｉｃ）を製造する工程である。[Wherein, R¹ , R² , R⁴ , Ar, X and Z have the same meanings as described above;
R^3a is substituted with a “C₆ -C₁₀ aryl group optionally substituted with a group selected from substituent group α” or “a group selected from substituent group α” in the definition of R^3. A 5- to 7-membered heteroaryl group containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms which may be represented by
R⁹ represents a hydrogen atom or two R^{9 taken} together represent 1,1,2,2-tetramethylethylene, 1,2-phenylene or 2,2-dimethyltrimethylene;
Y represents a fluorine atom, a chlorine atom, a bromine atom or an iodine atom (preferably bromine or iodine). ]

In the sixth step, the halogenated compound (9) is reacted with the boron compound (10) in an inert solvent in the presence of a base and a palladium catalyst (Suzuki coupling) to produce the compound (Ic) of the present invention. This is the process of doing.

使用される不活性溶媒は、例えば、ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサン又は１，２−ジメトキシエタンのようなエーテル類；ホルムアミド、Ｎ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルアセトアミド、Ｎ−メチル−２−ピロリドン、Ｎ−メチルピロリジノン又はヘキサメチルホスホロトリアミドのようなアミド類；ベンゼン、トルエン又はキシレンのような芳香族炭化水素類；アセトニトリル又はイソブチロニトリルのようなニトリル類；これらのうち１つと水との混合物；或いは水であり得、好適には、１，２−ジメトキシエタン、トルエン、アセトニトリル又はジメチルホルムアミド、これらのうち一つと水との混合物、或いは、水である。  Inert solvents used are, for example, ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane or 1,2-dimethoxyethane; formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N- Amides such as methyl-2-pyrrolidone, N-methylpyrrolidinone or hexamethylphosphorotriamide; aromatic hydrocarbons such as benzene, toluene or xylene; nitriles such as acetonitrile or isobutyronitrile; A mixture of one of them with water; or water, preferably 1,2-dimethoxyethane, toluene, acetonitrile or dimethylformamide, a mixture of one of these with water, or water.

使用される塩基は、例えば、炭酸ナトリウム、炭酸カリウム又は炭酸リチウムのようなアルカリ金属炭酸塩類、炭酸水素ナトリウム、炭酸水素カリウム又は炭酸水素リチウムのようなアルカリ金属炭酸水素塩類、水酸化ナトリウム、水酸化カリウム、水酸化バリウム又は水酸化リチウムのようなアルカリ金属水酸化物類、弗化ナトリウム又は弗化カリウムのようなアルカリ金属弗化物類等の無機塩基類；或いは、Ｎ−メチルモルホリン、トリエチルアミン、トリプロピルアミン、トリブチルアミン、ジイソプロピルエチルアミン、ジシクロヘキシルアミン、Ｎ−メチルピペリジン、ピリジン、４−ピロリジノピリジン、ピコリン、４−（Ｎ，Ｎ−ジメチルアミノ）ピリジン、２，６−ジ（tert−ブチル）−４−メチルピリジン、キノリン、Ｎ，Ｎ−ジメチルアニリン、Ｎ，Ｎ−ジエチルアニリン、１，５−ジアザビシクロ［４．３．０］ノナ−５−エン（ＤＢＮ）、１，４−ジアザビシクロ［２．２．２］オクタン（ＤＡＢＣＯ）、１，８−ジアザビシクロ［５．４．０］ウンデカ−７−エン（ＤＢＵ）のような有機塩基類であり得、好適には、アルカリ金属炭酸塩類又は有機塩基類であり、更に好適には、炭酸ナトリウム又はトリエチルアミンである。  The base used is, for example, an alkali metal carbonate such as sodium carbonate, potassium carbonate or lithium carbonate, an alkali metal bicarbonate such as sodium hydrogen carbonate, potassium hydrogen carbonate or lithium hydrogen carbonate, sodium hydroxide, hydroxide. Inorganic bases such as alkali metal hydroxides such as potassium, barium hydroxide or lithium hydroxide, alkali metal fluorides such as sodium fluoride or potassium fluoride; or N-methylmorpholine, triethylamine, triethylamine Propylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4- (N, N-dimethylamino) pyridine, 2,6-di (tert-butyl)- 4-methylpyridine, quinoline, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), 1,4-diazabicyclo [2.2.2] octane (DABCO), It can be an organic base such as 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), preferably an alkali metal carbonate or an organic base, more preferably Sodium carbonate or triethylamine.

使用されるパラジウム触媒は、例えば、テトラキス（トリフェニルホスフィン）パラジウム（０）、塩化ビス（トリフェニルホスフェン）パラジウム（ＩＩ）、ビス（アセトニトリル）パラジウム（ＩＩ） クロリド、［１，１’−ビス（ジフェニルホスフィノ）フェロセン］パラジウム（ＩＩ） クロリド、トリス（ジベンジリデンアセトン）ジパラジウム（０）、［１，２−ビス（ジフェニルホスフィノ）エタン］ジクロロパラジウム（ＩＩ）、塩化パラジウム、水酸化パラジウム、パラジウム−炭素又は酢酸パラジウムであり得、好適には、酢酸パラジウム、テトラキス（トリフェニルホスフィン）パラジウム（０）又は塩化ビス（トリフェニルホスフェン）パラジウム（ＩＩ）である。  The palladium catalyst used is, for example, tetrakis (triphenylphosphine) palladium (0), bis (triphenylphosphene) palladium (II) chloride, bis (acetonitrile) palladium (II) chloride, [1,1′-bis (Diphenylphosphino) ferrocene] palladium (II) chloride, tris (dibenzylideneacetone) dipalladium (0), [1,2-bis (diphenylphosphino) ethane] dichloropalladium (II), palladium chloride, palladium hydroxide , Palladium-carbon or palladium acetate, preferably palladium acetate, tetrakis (triphenylphosphine) palladium (0) or bis (triphenylphosphene) palladium (II) chloride.

反応温度は、原料化合物、使用される溶媒、塩基又は試薬によって変化するが、通常、室温乃至溶媒の還流温度であり、好適には、室温乃至１２０℃である。  The reaction temperature varies depending on the starting compound, the solvent used, the base or the reagent, but is usually from room temperature to the reflux temperature of the solvent, preferably from room temperature to 120 ° C.

反応時間は、原料化合物、使用される溶媒、塩基、試薬又は反応温度によって異なるが、通常、１時間乃至９６時間であり、好適には、１時間乃至１２時間である。  The reaction time varies depending on the starting compound, the solvent used, the base, the reagent and the reaction temperature, but is usually 1 hour to 96 hours, preferably 1 hour to 12 hours.

反応終了後、目的化合物は常法に従って、反応混合物から採取される。  After completion of the reaction, the target compound is collected from the reaction mixture according to a conventional method.

例えば、反応混合物を適宜中和し、また、不溶物が存在する場合にはろ過により除去した後、水を加え、酢酸エチル又はトルエンのような水に混和しない有機溶剤で抽出し、水等で洗浄し、抽出液を無水硫酸マグネシウム等で乾燥した後、溶剤を留去することによって得られる。  For example, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration, water is added, and the mixture is extracted with a water-immiscible organic solvent such as ethyl acetate or toluene. It is obtained by washing, drying the extract with anhydrous magnesium sulfate or the like, and then distilling off the solvent.

得られた化合物は必要ならば、常法、例えばシリカゲルカラムクロマトグラフィーで分離、精製することができる。

上記＜Ａ法＞における出発原料であるカルボン酸化合物（１）のうち、Ｘが−ＮＨ−である化合物は、例えば、下記＜Ｄ法＞に従って製造することができる。
＜Ｄ法＞If necessary, the obtained compound can be separated and purified by a conventional method, for example, silica gel column chromatography.

Among the carboxylic acid compounds (1), which are starting materials in the above <Method A>, the compound wherein X is -NH- can be produced, for example, according to the following <Method D>.
<Method D>

［式中、Ｒ^１、Ｒ^２、Ｒ^３及びＺは前記と同意義を示し、
Ｙ’は、フッ素原子、塩素原子、臭素原子又はヨウ素原子（好適には、臭素原子又はヨウ素原子）を示す。］
第７工程は、ハロゲン化化合物（１１）とα−アミノ酸化合物（１２）とを、不活性溶媒中、塩基及び銅触媒の存在下で反応させ、化合物（１ａ）を製造する工程である。[Wherein, R¹ , R² , R³ and Z have the same meanings as described above;
Y 'represents a fluorine atom, a chlorine atom, a bromine atom or an iodine atom (preferably a bromine atom or iodine atom). ]
The seventh step is a step of reacting the halogenated compound (11) with the α-amino acid compound (12) in an inert solvent in the presence of a base and a copper catalyst to produce a compound (1a).

使用される不活性溶媒は、例えば、ホルムアミド、Ｎ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルアセトアミド、Ｎ−メチル−２−ピロリドン、Ｎ−メチルピロリジノン又はヘキサメチルホスホロトリアミドのようなアミド類、或いは、tert−ブチルアルコールのような三級アルコール類であり得、好適には、アミド類であり、更に好適には、Ｎ，Ｎ−ジメチルアセトアミドである。  Inert solvents used are, for example, amides such as formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone or hexamethylphosphorotriamide, Alternatively, it can be a tertiary alcohol such as tert-butyl alcohol, preferably an amide, and more preferably N, N-dimethylacetamide.

使用される塩基は、例えば、炭酸ナトリウム、炭酸カリウム又は炭酸リチウムのようなアルカリ金属炭酸塩類、炭酸水素ナトリウム、炭酸水素カリウム又は炭酸水素リチウムのようなアルカリ金属炭酸水素塩類、水酸化ナトリウム、水酸化カリウム、水酸化バリウム又は水酸化リチウムのようなアルカリ金属水酸化物類、或いは、弗化ナトリウム又は弗化カリウムのようなアルカリ金属弗化物類等の無機塩基類であり得、好適には、アルカリ金属炭酸塩類であり、更に好適には、炭酸カリウムである。  The base used is, for example, an alkali metal carbonate such as sodium carbonate, potassium carbonate or lithium carbonate, an alkali metal bicarbonate such as sodium hydrogen carbonate, potassium hydrogen carbonate or lithium hydrogen carbonate, sodium hydroxide, hydroxide. It can be an alkali metal hydroxide such as potassium, barium hydroxide or lithium hydroxide, or an inorganic base such as an alkali metal fluoride such as sodium fluoride or potassium fluoride. Metal carbonates, more preferably potassium carbonate.

使用される銅触媒は、例えば、塩化第一銅、臭化第一銅、ヨウ化第一銅又は臭化第一銅ジメチルスルフィド錯体のような銅塩であり得、好適には、ヨウ化第一銅又は臭化第一銅ジメチルスルフィド錯体である。  The copper catalyst used can be a copper salt such as, for example, cuprous chloride, cuprous bromide, cuprous iodide or cuprous bromide dimethyl sulfide complex, preferably It is a cuprous or cuprous bromide dimethylsulfide complex.

反応温度は、原料化合物、使用される溶媒、塩基又は試薬によって変化するが、通常、室温乃至１６０℃であり、好適には、５０℃乃至１３０℃である。  The reaction temperature varies depending on the starting compound, the solvent used, the base or the reagent, but is usually room temperature to 160 ° C, preferably 50 ° C to 130 ° C.

反応時間は、原料化合物、使用される溶媒、塩基又は反応温度によって異なるが、通常、１時間乃至９６時間であり、好適には、１時間乃至１２時間である。  The reaction time varies depending on the starting compound, the solvent used, the base and the reaction temperature, but is usually 1 hour to 96 hours, preferably 1 hour to 12 hours.

反応終了後、目的化合物は常法に従って、反応混合物から採取される。  After completion of the reaction, the target compound is collected from the reaction mixture according to a conventional method.

例えば、反応混合物を適宜中和し、また、不溶物が存在する場合にはろ過により除去した後、水を加え、酢酸エチル又はトルエンのような水に混和しない有機溶剤で抽出し、水等で洗浄し、抽出液を無水硫酸マグネシウム等で乾燥した後、溶剤を留去することによって得られる。  For example, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration, water is added, and the mixture is extracted with a water-immiscible organic solvent such as ethyl acetate or toluene. It is obtained by washing, drying the extract with anhydrous magnesium sulfate or the like, and then distilling off the solvent.

得られた化合物は必要ならば、常法、例えばシリカゲルカラムクロマトグラフィーで分離、精製することができる。

上記＜Ａ法＞における出発原料であるカルボン酸化合物（１）のうち、Ｘが−ＮＨ−、−Ｏ−又は−Ｓ−である化合物は、例えば、下記＜Ｅ法＞に従って製造することができる。
＜Ｅ法＞If necessary, the obtained compound can be separated and purified by a conventional method, for example, silica gel column chromatography.

Among the carboxylic acid compounds (1) which are starting materials in the above <Method A>, those in which X is -NH-, -O- or -S- can be produced, for example, according to the following <Method E>. .
<Method E>

［式中、Ｒ^１、Ｒ^２、Ｒ^３及びＺは前記と同意義を示し、
Ｘ^ａは、Ｘの定義における−ＮＨ−、−Ｏ−又は−Ｓ−を示し、
Ｙ’’は、フッ素原子、塩素原子、臭素原子又はヨウ素原子（好適には、塩素原子又は臭素原子）を示す。］
第８工程は、化合物（１３）とハロゲン化化合物（１４）とを、不活性溶媒中、塩基の存在下で反応させ、化合物（１ｂ）を製造する工程である。[Wherein, R¹ , R² , R³ and Z have the same meanings as described above;
X^a is, -NH in the definition of X -, - O-or -S- shown,
Y ″ represents a fluorine atom, a chlorine atom, a bromine atom or an iodine atom (preferably, a chlorine atom or a bromine atom). ]
The eighth step is a step of reacting the compound (13) with the halogenated compound (14) in an inert solvent in the presence of a base to produce the compound (1b).

使用される不活性溶媒は、例えば、ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサン又は１，２−ジメトキシエタンのようなエーテル類；ホルムアミド、Ｎ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルアセトアミド、Ｎ−メチル−２−ピロリドン、Ｎ−メチルピロリジノン又はヘキサメチルホスホロトリアミドのようなアミド類；或いは、メタノール、エタノール、プロパノール、２−プロパノール、ブタノール又はtert−ブチルアルコールのようなアルコール類であり得、好適には、アミド類又はアルコール類であり、更に好適には、Ｎ，Ｎ−ジメチルホルムアミド又はtert−ブチルアルコールである。  Inert solvents used are, for example, ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane or 1,2-dimethoxyethane; formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N- Amides such as methyl-2-pyrrolidone, N-methylpyrrolidinone or hexamethylphosphorotriamide; or alcohols such as methanol, ethanol, propanol, 2-propanol, butanol or tert-butyl alcohol; Are amides or alcohols, more preferably N, N-dimethylformamide or tert-butyl alcohol.

使用される塩基は、例えば、炭酸ナトリウム、炭酸カリウム又は炭酸リチウムのようなアルカリ金属炭酸塩類；炭酸水素ナトリウム、炭酸水素カリウム又は炭酸水素リチウムのようなアルカリ金属炭酸水素塩類；水素化リチウム、水素化ナトリウム又は水素化カリウムのようなアルカリ金属水素化物類；水酸化ナトリウム、水酸化カリウム、水酸化バリウム又は水酸化リチウムのようなアルカリ金属水酸化物類；弗化ナトリウム又は弗化カリウムのようなアルカリ金属弗化物類；或いは、ナトリウムメトキシド、ナトリウムエトキシド、カリウムtert−ブトキシド又はリチウムメトキシドのようなアルカリ金属アルコキシド類であり得、好適には、アルカリ金属水素化物類又はアルカリ金属アルコキシド類であり、更に好適には、水素化ナトリウム、水素化カリウム又はカリウムtert−ブトキシドである。  Bases used are, for example, alkali metal carbonates such as sodium carbonate, potassium carbonate or lithium carbonate; alkali metal hydrogen carbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate or lithium hydrogen carbonate; lithium hydride, hydrogenated Alkali metal hydrides such as sodium or potassium hydride; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, barium hydroxide or lithium hydroxide; alkali such as sodium fluoride or potassium fluoride Metal fluorides; or alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide or lithium methoxide, preferably alkali metal hydrides or alkali metal alkoxides. And more preferably hydrogenated sodium , Potassium hydride or potassium tert-butoxide.

反応温度は、原料化合物、使用される溶媒又は塩基によって変化するが、通常、０℃乃至１５０℃であり、好適には、室温乃至１２０℃である。  The reaction temperature varies depending on the starting compound, the solvent or the base used, but is usually from 0 ° C to 150 ° C, preferably from room temperature to 120 ° C.

反応時間は、原料化合物、使用される溶媒、塩基又は反応温度によって異なるが、通常、１時間乃至９６時間であり、好適には、１時間乃至２４時間である。  The reaction time varies depending on the starting compound, the solvent used, the base and the reaction temperature, but is usually from 1 hour to 96 hours, preferably from 1 hour to 24 hours.

反応終了後、目的化合物は常法に従って、反応混合物から採取される。  After completion of the reaction, the target compound is collected from the reaction mixture according to a conventional method.

例えば、反応混合物を適宜中和し、また、不溶物が存在する場合にはろ過により除去した後、水を加え、酢酸エチル又はトルエンのような水に混和しない有機溶剤で抽出し、水等で洗浄し、抽出液を無水硫酸マグネシウム等で乾燥した後、溶剤を留去することによって得られる。  For example, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration, water is added, and the mixture is extracted with a water-immiscible organic solvent such as ethyl acetate or toluene. It is obtained by washing, drying the extract with anhydrous magnesium sulfate or the like, and then distilling off the solvent.

得られた化合物は必要ならば、常法、例えばシリカゲルカラムクロマトグラフィーで分離、精製することができる。

上記＜Ａ法＞における出発原料であるカルボン酸化合物（１）のうち、Ｚが、２−オキソ−２Ｈ−ピラン−４，６−ジイルであり、Ｘが−ＮＨ−である化合物は、例えば、下記＜Ｆ法＞に従って製造することができる。
＜Ｆ法＞If necessary, the obtained compound can be separated and purified by a conventional method, for example, silica gel column chromatography.

Among the carboxylic acid compounds (1) which are starting materials in the above <Method A>, compounds wherein Z is 2-oxo-2H-pyran-4,6-diyl and X is -NH- are, for example, It can be produced according to the following <Method F>.
<F method>

（式中、Ｒ^１、Ｒ^２、Ｒ^３及びＺは前記と同意義を示す。）
第９工程は、不活性溶媒中で化合物（１５）の水酸基を臭素原子に変換することにより、臭化化合物（１６）を製造する工程である。(In the formula, R¹ , R² , R³ and Z have the same meanings as described above.)
The ninth step is a step for producing a brominated compound (16) by converting a hydroxyl group of the compound (15) into a bromine atom in an inert solvent.

使用される不活性溶媒は、例えば、メチレンクロリド、クロロホルム、四塩化炭素又はジクロロエタンなどのハロゲン化炭化水素類；ベンゼン又はトルエンなどの芳香族炭化水素類；ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサン又は１，２−ジメトキシエタンのようなエーテル類；或いは、ホルムアミド、Ｎ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルアセトアミド、Ｎ−メチル−２−ピロリドン、Ｎ−メチルピロリジノン又はヘキサメチルホスホロトリアミドのようなアミド類であり得、好適には、ハロゲン化炭化水素類、芳香族炭化水素類、又は、アミド類であり、更に好適には、クロロホルム、トルエン又はＮ，Ｎ−ジメチルホルムアミドである。  Inert solvents used are, for example, halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride or dichloroethane; aromatic hydrocarbons such as benzene or toluene; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane or 1 Ethers, such as, for example, formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone or hexamethylphosphorotriamide; It may be an amide, preferably a halogenated hydrocarbon, an aromatic hydrocarbon or an amide, more preferably chloroform, toluene or N, N-dimethylformamide.

水酸基を臭素原子に変換するための試薬は、例えば、酸化リン（Ｖ）／臭化テトラブチルアンモニウム、三臭化リン、又はトリフェニルホスフィン／四臭化炭素であり得、好適には、三臭化リンである。  The reagent for converting a hydroxyl group to a bromine atom can be, for example, phosphorus (V) oxide / tetrabutylammonium bromide, phosphorus tribromide, or triphenylphosphine / carbon tetrabromide; Phosphorus chloride.

反応温度は、原料化合物、使用される溶媒又は試薬によって変化するが、通常、０℃乃至１００℃であり、好適には、室温乃至８０℃である。  The reaction temperature varies depending on the starting compound, the solvent or the reagent used, but is usually from 0 ° C to 100 ° C, preferably from room temperature to 80 ° C.

反応時間は、原料化合物、使用される溶媒、試薬又は反応温度によって異なるが、通常、１時間乃至９６時間であり、好適には、１時間乃至１２時間である。  The reaction time varies depending on the starting compound, the solvent used, the reagent and the reaction temperature, but is usually 1 hour to 96 hours, preferably 1 hour to 12 hours.

反応終了後、目的化合物は常法に従って、反応混合物から採取される。  After completion of the reaction, the target compound is collected from the reaction mixture according to a conventional method.

例えば、反応混合物を適宜中和し、また、不溶物が存在する場合にはろ過により除去した後、水を加え、酢酸エチル又はトルエンのような水に混和しない有機溶剤で抽出し、水等で洗浄し、抽出液を無水硫酸マグネシウム等で乾燥した後、溶剤を留去することによって得られる。  For example, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration, water is added, and the mixture is extracted with a water-immiscible organic solvent such as ethyl acetate or toluene. It is obtained by washing, drying the extract with anhydrous magnesium sulfate or the like, and then distilling off the solvent.

得られた化合物は必要ならば、常法、例えばシリカゲルカラムクロマトグラフィーで分離、精製することができる。  If necessary, the obtained compound can be separated and purified by a conventional method, for example, silica gel column chromatography.

尚、本工程における出発原料である化合物（１５）は、例えば、Tetrahedron Vol.55, 1999, 13683-13696に記載されている方法に準じて製造することができる。

第１０工程は、臭素化化合物（１６）とα−アミノ酸化合物（１２）とを、不活性溶媒中、塩基の存在下で反応させ、化合物（１ｃ）を製造する工程である。Compound (15) as a starting material in this step can be produced, for example, according to the method described in Tetrahedron Vol. 55, 1999, 13683-13696.

The tenth step is a step of reacting the brominated compound (16) with the α-amino acid compound (12) in an inert solvent in the presence of a base to produce a compound (1c).

使用される不活性溶媒は、例えば、ホルムアミド、Ｎ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルアセトアミド、Ｎ−メチル−２−ピロリドン、Ｎ−メチルピロリジノン又はヘキサメチルホスホロトリアミドのようなアミド類；或いは、メタノール、エタノール、プロパノール、２−プロパノール、ブタノール又はtert−ブチルアルコールのようなアルコール類であり得、好適には、Ｎ，Ｎ−ジメチルホルムアミド又はtert−ブチルアルコールであり、更に好適には、tert−ブチルアルコールである。  Inert solvents used are, for example, amides such as formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone or hexamethylphosphorotriamide; Alternatively, it may be an alcohol such as methanol, ethanol, propanol, 2-propanol, butanol or tert-butyl alcohol, preferably N, N-dimethylformamide or tert-butyl alcohol, more preferably tert-butyl alcohol.

使用される塩基は、例えば、炭酸ナトリウム、炭酸カリウム又は炭酸リチウムのようなアルカリ金属炭酸塩類、炭酸水素ナトリウム、炭酸水素カリウム又は炭酸水素リチウムのようなアルカリ金属炭酸水素塩類、水素化リチウム、水素化ナトリウム又は水素化カリウムのようなアルカリ金属水素化物類、水酸化ナトリウム、水酸化カリウム、水酸化バリウム又は水酸化リチウムのようなアルカリ金属水酸化物類、弗化ナトリウム又は弗化カリウムのようなアルカリ金属弗化物類等の無機塩基類；或いは、Ｎ−メチルモルホリン、トリエチルアミン、トリプロピルアミン、トリブチルアミン、ジイソプロピルエチルアミン、ジシクロヘキシルアミン、Ｎ−メチルピペリジン、ピリジン、４−ピロリジノピリジン、ピコリン、４−（Ｎ，Ｎ−ジメチルアミノ）ピリジン、２，６−ジ（tert−ブチル）−４−メチルピリジン、キノリン、Ｎ，Ｎ−ジメチルアニリン、Ｎ，Ｎ−ジエチルアニリン、１，５−ジアザビシクロ［４．３．０］ノナ−５−エン（ＤＢＮ）、１，４−ジアザビシクロ［２．２．２］オクタン（ＤＡＢＣＯ）又は１，８−ジアザビシクロ［５．４．０］ウンデカ−７−エン（ＤＢＵ）のような有機塩基類であり得、好適には、アルカリ金属炭酸塩類又は有機塩基類であり、更に好適には、炭酸ナトリウム、炭酸カリウム又はトリエチルアミンである。  The base used is, for example, an alkali metal carbonate such as sodium carbonate, potassium carbonate or lithium carbonate, an alkali metal bicarbonate such as sodium hydrogen carbonate, potassium hydrogen carbonate or lithium hydrogen carbonate, lithium hydride, hydride Alkali metal hydrides such as sodium or potassium hydride, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, barium hydroxide or lithium hydroxide, alkalis such as sodium or potassium fluoride Inorganic bases such as metal fluorides; or N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4- ( N, N-Jim Lamino) pyridine, 2,6-di (tert-butyl) -4-methylpyridine, quinoline, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] nona- Organic bases such as 5-ene (DBN), 1,4-diazabicyclo [2.2.2] octane (DABCO) or 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) And are preferably alkali metal carbonates or organic bases, more preferably sodium carbonate, potassium carbonate or triethylamine.

反応温度は、原料化合物、使用される溶媒又は塩基によって変化するが、通常、室温乃至溶媒の還流温度であり、好適には、５０℃乃至溶媒の還流温度である。  The reaction temperature varies depending on the starting compound, the solvent or the base used, and is usually from room temperature to the reflux temperature of the solvent, preferably from 50 ° C to the reflux temperature of the solvent.

反応時間は、原料化合物、使用される溶媒、塩基又は反応温度によって異なるが、通常、１時間乃至２４時間であり、好適には、１時間乃至６時間である。  The reaction time varies depending on the starting compound, the solvent used, the base or the reaction temperature, but is usually 1 hour to 24 hours, preferably 1 hour to 6 hours.

反応終了後、目的化合物は常法に従って、反応混合物から採取される。  After completion of the reaction, the target compound is collected from the reaction mixture according to a conventional method.

例えば、反応混合物を適宜中和し、また、不溶物が存在する場合にはろ過により除去した後、水を加え、酢酸エチル又はトルエンのような水に混和しない有機溶剤で抽出し、水等で洗浄し、抽出液を無水硫酸マグネシウム等で乾燥した後、溶剤を留去することによって得られる。  For example, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration, water is added, and the mixture is extracted with a water-immiscible organic solvent such as ethyl acetate or toluene. It is obtained by washing, drying the extract with anhydrous magnesium sulfate or the like, and then distilling off the solvent.

得られた化合物は必要ならば、常法、例えばシリカゲルカラムクロマトグラフィーで分離、精製することができる。

上記＜Ａ法＞における出発原料であるカルボン酸化合物（１）のうち、Ｘが、単結合である化合物は、例えば、下記＜Ｇ法＞に従って製造することができる。
＜Ｇ法＞If necessary, the obtained compound can be separated and purified by a conventional method, for example, silica gel column chromatography.

Among the carboxylic acid compounds (1) that are the starting materials in the above <Method A>, those in which X is a single bond can be produced, for example, according to the following <Method G>.
<G method>

（式中、Ｒ^１、Ｒ^２、Ｒ^３ａ、Ｒ^９及びＺは前記と同意義を示し、Ｒ^１０は、水素原子、メチル、エチル又はtert−ブチルのようなＣ_１−Ｃ_６アルキル基、ベンジルのようなＣ_７−Ｃ_１１アラルキル基、或いは、アリルのようなＣ_３−Ｃ_６アルケニル基を示す。）

第１１工程は、化合物（１７）とボロン化合物（１０）とを、不活性溶媒中、塩基及びパラジウム触媒の存在下で反応させ（鈴木カップリング）、化合物（１８）を製造する工程であり、第６工程に記載された方法と同様に実施される。(Wherein, R¹ , R² , R^3a , R⁹ and Z have the same meanings as described above, and R¹⁰ is a hydrogen atom, a C₁ -C₆ alkyl group such as methyl, ethyl or tert-butyl, It represents a C₇ -C₁₁ aralkyl group such as benzyl or a C₃ -C₆ alkenyl group such as allyl.)

The eleventh step is a step of reacting the compound (17) with the boron compound (10) in an inert solvent in the presence of a base and a palladium catalyst (Suzuki coupling) to produce a compound (18), It is carried out in the same manner as the method described in the sixth step.

尚、本工程においては、好適には、Ｒ^１０が水素原子である化合物（１７）が出発原料として用いられる。

第１２工程は、化合物（１８）に、Ｒ^１及びＲ^２を導入するための試薬（例えば、臭化イソプロピル、臭化イソブチル又は１，５−ジブロモペンタンなど）を、不活性溶媒中、塩基の存在下で反応させて、化合物（１９）を製造する工程である。In this step, the compound (17) in which R¹⁰ is a hydrogen atom is preferably used as a starting material.

In the twelfth step, a reagent (for example, isopropyl bromide, isobutyl bromide or 1,5-dibromopentane) for introducing R¹ and R² into compound (18) is added to an inert solvent in the presence of a base. This is a step of producing a compound (19) by reacting in the presence.

使用される不活性溶媒は、例えば、ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサン又は１，２−ジメトキシエタンのようなエーテル類；ホルムアミド、Ｎ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルアセトアミド又はヘキサメチルリン酸トリアミドのようなアミド類；或いは、ジメチルスルホキシド又はスルホランのようなスルホキシド類であり得、好適には、テトラヒドロフラン、Ｎ，Ｎ−ジメチルホルムアミド又はジメチルスルホキシドである。  Inert solvents used are, for example, ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane or 1,2-dimethoxyethane; formamide, N, N-dimethylformamide, N, N-dimethylacetamide or hexamethyl It may be an amide such as phosphoric acid triamide; or a sulfoxide such as dimethyl sulfoxide or sulfolane, preferably tetrahydrofuran, N, N-dimethylformamide or dimethyl sulfoxide.

使用される塩基は、例えば、水素化リチウム、水素化ナトリウム又は水素化カリウムのようなアルカリ金属水素化物類；或いは、リチウムジイソプロピルアミドのような金属アミド類であり得、好適には、水素化ナトリウム又はリチウムジイソプロピルアミドである。  The base used can be, for example, an alkali metal hydride such as lithium hydride, sodium hydride or potassium hydride; or a metal amide such as lithium diisopropylamide, preferably sodium hydride. Or lithium diisopropylamide.

反応温度は、原料化合物、使用される溶媒、試薬又は塩基によって変化するが、通常、−１００℃乃至溶媒の還流温度であり、好適には、０℃乃至６０℃である。  The reaction temperature varies depending on the starting compound, the solvent used, the reagent or the base, but is usually from -100 ° C to the reflux temperature of the solvent, and preferably from 0 ° C to 60 ° C.

反応時間は、原料化合物、使用される溶媒、塩基、試薬又は反応温度によって異なるが、通常、１時間乃至９６時間であり、好適には、１時間乃至２４時間である。  The reaction time varies depending on the starting compound, the solvent used, the base, the reagent and the reaction temperature, but is usually 1 hour to 96 hours, preferably 1 hour to 24 hours.

本工程は、好適には、Ｒ^１０が上記「Ｃ_１−Ｃ_６アルキル基」、「Ｃ_７−Ｃ_１１アラルキル基」又は「Ｃ_３−Ｃ_６アルケニル基」である化合物（１８）が出発原料として用いられる。In this step, the compound (18) in which R¹⁰ is the above “C₁ -C₆ alkyl group”, “C₇ -C₁₁ aralkyl group” or “C₃ -C₆ alkenyl group” is preferably used as a starting material. Used as

Ｒ１０が水素原子である化合物（１８）を出発原料として用いる場合は、本工程を行う前に、予めアルキルエステル誘導体へ変換しておくのが好ましく、そのような誘導体への変換は、例えば、有機化学実験のてびき（化学同人）第４巻、２２−２４頁、又は、Ｐｒｏｔｅｃｔｉｖｅ Ｇｒｏｕｐｓ ｉｎ Ｏｒｇａｎｉｃ Ｓｙｎｔｈｅｓｉｓ（Ｊｏｈｎ Ｗｉｌｅｙ ＆ Ｓｏｎｓ，Ｉｎｃ．，１９９９），３６９−４５３に記載の方法に準じておこなわれる。  When the compound (18) in which R10 is a hydrogen atom is used as a starting material, it is preferable to convert the compound into an alkyl ester derivative before performing this step. This is performed according to the method described in Chemistry Laboratory Handbook (Chemical Doujin), Vol. 4, pp. 22-24, or Protective Groups in Organic Synthesis (John Wiley & Sons, Inc., 1999), 369-453.

特に、メチルエステルまたはエチルエステルなどのアルキルエステルに変換する場合、Ｒ^１０が水素原子である化合物（１８）を、溶媒中（例えば、メタノール又はエタノールのようなアルコール類）、酸触媒（例えば、塩酸又は硫酸のような鉱酸、或いはメタンスルホン酸のような有機酸類）の存在下、室温乃至溶媒の還流温度で、３０分間乃至２４時間処理することにより実施できる。また、メチルエステル、エチルエステル、ベンジルエステルまたはアリルエステルへの変換は、Ｒ^１０が水素原子である化合物（１８）とハロゲン化アルキル（例えば、ヨウ化メチル、ヨウ化エチル、臭化ベンジル又は臭化アリル）を、溶媒（例えばN，N‐ジメチルスルホンアミドのようなアミド類、又はアセトニトリルのようなニトリル類）中、塩基（例えば、炭酸セシウム又は炭酸カリウムのようなアルカリ金属炭酸塩、或いは１，８−ジアザビシクロ［５．４．０］ウンデカ−７−エン（ＤＢＵ）のような有機塩基類）存在下で、室温乃至１００℃で、３０分間乃至２４時間処理することにより実施できる。tert−ブチルエステルへの変換は、例えば、Ｒ^１０が水素原子である化合物（１８）と２−メチルプロペンを、溶媒（例えば、ジエチルエーテルのようなエーテル類）中、酸触媒（例えば、硫酸のような鉱酸或いはメタンスルホン酸のような有機酸類）存在下で、０℃乃至室温で、３０分間乃至２４時間処理することにより実施できる。In particular, when converting to an alkyl ester such as a methyl ester or an ethyl ester, the compound (18) in which R¹⁰ is a hydrogen atom is reacted with a solvent (eg, an alcohol such as methanol or ethanol) in an acid catalyst (eg, hydrochloric acid). Or a mineral acid such as sulfuric acid or an organic acid such as methanesulfonic acid) at room temperature to the reflux temperature of the solvent for 30 minutes to 24 hours. In addition, conversion to a methyl ester, an ethyl ester, a benzyl ester or an allyl ester can be carried out by compound (18) wherein R¹⁰ is a hydrogen atom and an alkyl halide (eg, methyl iodide, ethyl iodide, benzyl bromide or bromide). Allyl) in a solvent (for example, amides such as N, N-dimethylsulfonamide or nitriles such as acetonitrile) in a base (for example, an alkali metal carbonate such as cesium carbonate or potassium carbonate, or 1,1). Organic bases such as 8-diazabicyclo [5.4.0] undec-7-ene (DBU)) at room temperature to 100 ° C. for 30 minutes to 24 hours. The conversion to tert-butyl ester can be performed, for example, by reacting a compound (18) in which R¹⁰ is a hydrogen atom with 2-methylpropene in a solvent (eg, ethers such as diethyl ether) in an acid catalyst (eg, sulfuric acid). In the presence of such a mineral acid or an organic acid such as methanesulfonic acid), the treatment can be performed at 0 ° C. to room temperature for 30 minutes to 24 hours.

反応終了後、目的化合物は常法に従って、反応混合物から採取される。  After completion of the reaction, the target compound is collected from the reaction mixture according to a conventional method.

例えば、反応混合物を適宜中和し、また、不溶物が存在する場合にはろ過により除去した後、水を加え、酢酸エチル又はトルエンのような水に混和しない有機溶剤で抽出し、水等で洗浄し、抽出液を無水硫酸マグネシウム等で乾燥した後、溶剤を留去することによって得られる。  For example, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration, water is added, and the mixture is extracted with a water-immiscible organic solvent such as ethyl acetate or toluene. It is obtained by washing, drying the extract with anhydrous magnesium sulfate or the like, and then distilling off the solvent.

得られた化合物は必要ならば、常法、例えばシリカゲルカラムクロマトグラフィーで分離、精製することができる。  If necessary, the obtained compound can be separated and purified by a conventional method, for example, silica gel column chromatography.

尚、本工程は、第１１工程の前に行うこともできる。

第１３工程は、化合物（１９）を、不活性溶媒中、酸又は塩基で処理して脱保護することにより、化合物（１ｄ）を製造する工程であり、Ｐｒｏｔｅｃｔｉｖｅ Ｇｒｏｕｐｓ ｉｎ Ｏｒｇａｎｉｃ Ｓｙｎｔｈｅｓｉｓ（Ｊｏｈｎ Ｗｉｌｅｙ ＆ Ｓｏｎｓ，Ｉｎｃ．，１９９９），３６９−４５３に記載の方法に準じて実施される。This step can be performed before the eleventh step.

The thirteenth step is a step of producing the compound (1d) by treating the compound (19) with an acid or a base in an inert solvent to thereby deprotect the compound (19). The protective group in Organic Synthesis (John Wiley & Sons). , Inc., 1999), 369-453.

例えば、化合物（１９）の脱保護は、塩基（例えば、水酸化ナトリウム、水酸化カリウム又はtert−ブトキシカリウムのようなアルカリ金属アルコキシド及び水から調整したアルカリ金属水酸化物）の存在下、溶媒（例えば、メタノール又はエタノールのようなアルコール類と水との混合溶媒、或いは、ジエチルエーテル又はジオキサンのようなエーテル類）中で、室温乃至溶媒の還流温度で、３０分間乃至２４時間処理することにより実施できる。化合物（１９）がベンジルエステルの場合、例えばパラジウム−炭素などの触媒存在下、溶媒（例えば、メタノール又はエタノールのようなアルコール類）中で、水素添加することにより実施できる。化合物（１９）がアリルエステルの場合、酢酸パラジウム又はテトラキス（トリフェニルホスフィン）パラジウム（０）などの触媒の存在下に、溶媒（例えば、テトラヒドロフランのようなエーテル類）中で、2−エチルヘキサン酸ナトリウムなどのカルボン酸塩、ピロリジン、ピペリジン又はブチルアミンなどのアミン類、或いはギ酸アンモニウムなどのアンモニウム塩類を作用させることにより実施できる。化合物（１９）がtert‐ブチルエステルの場合、例えば、酸（例えば、塩酸、臭化水素酸又は硫酸などの鉱酸、或いは、ギ酸、メタンスルホン酸又はトリフルオロ酢酸などの有機酸）の存在下、溶媒（例えば、メチレンクロリドのようなハロゲン化炭化水素類、又はジオキサンのようなエーテル類）中で、０℃乃至室温で、３０分間乃至２４時間処理することで実施できる。

第１４工程は、アセトニトリル誘導体（２０）と、Ｒ^１及びＲ^２を導入するための試薬（例えば、臭化イソプロピル、臭化イソブチル又は１，５−ジブロモペンタンなど）を、不活性溶媒中、塩基の存在下で反応させて、化合物（２１）を製造する工程であり、第１２工程に記載された方法と同様に実施される。

第１５工程は、化合物（２１）とボロン化合物（１０）とを、不活性溶媒中、塩基及びパラジウム触媒の存在下で反応させ（鈴木カップリング）、化合物（２２）を製造する工程であり、第６工程に記載された方法と同様に実施される。For example, the deprotection of compound (19) can be carried out in the presence of a base (for example, an alkali metal alkoxide such as sodium hydroxide, potassium hydroxide or potassium tert-butoxide and an alkali metal hydroxide prepared from water) in a solvent ( For example, in a mixed solvent of water and an alcohol such as methanol or ethanol, or an ether such as diethyl ether or dioxane), at room temperature to the reflux temperature of the solvent for 30 minutes to 24 hours. it can. When the compound (19) is a benzyl ester, the reaction can be carried out by hydrogenation in a solvent (for example, an alcohol such as methanol or ethanol) in the presence of a catalyst such as palladium-carbon. When the compound (19) is an allyl ester, 2-ethylhexanoic acid is added in a solvent (for example, ethers such as tetrahydrofuran) in the presence of a catalyst such as palladium acetate or tetrakis (triphenylphosphine) palladium (0). The reaction can be carried out by reacting with a carboxylate such as sodium, an amine such as pyrrolidine, piperidine or butylamine, or an ammonium salt such as ammonium formate. When compound (19) is a tert-butyl ester, for example, in the presence of an acid (for example, a mineral acid such as hydrochloric acid, hydrobromic acid or sulfuric acid, or an organic acid such as formic acid, methanesulfonic acid or trifluoroacetic acid) In a solvent (eg, a halogenated hydrocarbon such as methylene chloride, or an ether such as dioxane), the treatment can be performed at 0 ° C. to room temperature for 30 minutes to 24 hours.

In the fourteenth step, the acetonitrile derivative (20) and a reagent for introducing R¹ and R² (for example, isopropyl bromide, isobutyl bromide or 1,5-dibromopentane) are added to a base in an inert solvent. This is a step of producing a compound (21) by reacting in the presence of, and is carried out in the same manner as the method described in the twelfth step.

The fifteenth step is a step of reacting the compound (21) with the boron compound (10) in an inert solvent in the presence of a base and a palladium catalyst (Suzuki coupling) to produce a compound (22). It is carried out in the same manner as the method described in the sixth step.

尚、本工程は、第１４工程の前に行うこともできる。

第１６工程は、化合物（２２）を、不活性溶媒中、酸又は塩基で加水分解することにより、化合物（Ｉｄ）を製造する工程である。This step can be performed before the fourteenth step.

The sixteenth step is a step of producing compound (Id) by hydrolyzing compound (22) with an acid or a base in an inert solvent.

使用される溶媒は、例えば、メタノール、エタノール、プロパノール、２−プロパノール、ブタノール、エチレングリコール又はジエチレングリコールのようなアルコール類；水、或いは、水とアルコールの混合物であり得、好適には、メタノール、エタノール、エチレングリコール、ジエチレングリコール、水、含水メタノール又は含水エタノールである。  The solvent used can be, for example, alcohols such as methanol, ethanol, propanol, 2-propanol, butanol, ethylene glycol or diethylene glycol; water or a mixture of water and alcohol, preferably methanol, ethanol. , Ethylene glycol, diethylene glycol, water, hydrated methanol or hydrated ethanol.

使用される酸は、例えば、塩酸、硫酸、リン酸又は臭化水素酸のような無機酸類、メタンスルホン酸又はエタンスルホン酸のようなスルホン酸類、或いは、酢酸、プロピオン酸又はトリフルオロ酢酸のようなカルボン酸類であり得、好適には、塩酸又は硫酸である。  Acids used are, for example, inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid or hydrobromic acid, sulfonic acids such as methanesulfonic acid or ethanesulfonic acid, or acetic acid, propionic acid or trifluoroacetic acid. Carboxylic acids, preferably hydrochloric acid or sulfuric acid.

使用される塩基は、例えば、水酸化ナトリウム、水酸化カリウム、水酸化バリウム又は水酸化リチウムのようなアルカリ金属水酸化物類であり得、好適には、水酸化ナトリウム又は水酸化カリウムである。  The base used can be, for example, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, barium hydroxide or lithium hydroxide, preferably sodium hydroxide or potassium hydroxide.

反応温度は、原料化合物、使用される溶媒又は酸若しくは塩基によって変化するが、通常、室温乃至２００℃であり、好適には、５０℃乃至２００℃である。  The reaction temperature varies depending on the starting compound, the solvent used or the acid or base, but is usually from room temperature to 200 ° C, preferably from 50 ° C to 200 ° C.

反応時間は、原料化合物、使用される溶媒、塩基又は反応温度によって異なるが、通常、１時間乃至９６時間であり、好適には、１時間乃至２４時間である。  The reaction time varies depending on the starting compound, the solvent used, the base and the reaction temperature, but is usually from 1 hour to 96 hours, preferably from 1 hour to 24 hours.

反応終了後、目的化合物は常法に従って、反応混合物から採取される。  After completion of the reaction, the target compound is collected from the reaction mixture according to a conventional method.

例えば、反応混合物を適宜中和し、また、不溶物が存在する場合にはろ過により除去した後、水を加え、酢酸エチル又はトルエンのような水に混和しない有機溶剤で抽出し、水等で洗浄し、抽出液を無水硫酸マグネシウム等で乾燥した後、溶剤を留去することによって得られる。  For example, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration, water is added, and the mixture is extracted with a water-immiscible organic solvent such as ethyl acetate or toluene. It is obtained by washing, drying the extract with anhydrous magnesium sulfate or the like, and then distilling off the solvent.

得られた化合物は必要ならば、常法、例えばシリカゲルカラムクロマトグラフィーで分離、精製することができる。

上記＜Ａ法＞における出発原料であるアミン化合物（２）は、例えば、下記＜Ｈ法＞に従って製造することができる。
＜Ｈ法＞If necessary, the obtained compound can be separated and purified by a conventional method, for example, silica gel column chromatography.

The amine compound (2) as a starting material in the above <Method A> can be produced, for example, according to the following <Method H>.
<H method>

［式中、Ｒ^４及びＡｒは、前記と同意義を示し、
Ｒ^１１は、tert−ブトキシカルボニルを示し、
Ｒ^１２は、o−ニトロフェニル、ｐ−ニトロフェニル又は２，４−ジニトロフェニルのようなニトロ基で置換されたフェニル基（好適には、o−ニトロフェニル）を示す。］
第１７工程は、α−アミノ酸化合物（２３）とtert−ブトキシカルボニル化剤とを、不活性溶媒中、塩基の存在下で反応させてアミノ基を保護することにより、化合物（２４）を製造する工程である。Wherein R⁴ and Ar are as defined above,
R¹¹ represents tert-butoxycarbonyl,
R¹² represents a phenyl group (preferably o-nitrophenyl) substituted with a nitro group such as o-nitrophenyl, p-nitrophenyl or 2,4-dinitrophenyl. ]
In the seventeenth step, a compound (24) is produced by reacting the α-amino acid compound (23) with a tert-butoxycarbonylating agent in an inert solvent in the presence of a base to protect the amino group. It is a process.

使用される不活性溶媒は、例えば、ヘキサン又はヘプタンのような脂肪族炭化水素類、ベンゼン、トルエン又はキシレンのような芳香族炭化水素類、メチレンクロリド、クロロホルム、四塩化炭素、ジクロロエタン、クロロベンゼン又はジクロロベンゼンのようなハロゲン化炭化水素類、蟻酸エチル、酢酸エチル、酢酸プロピル、酢酸ブチル又は炭酸ジエチルのようなエステル類、ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサン又は１，２−ジメトキシエタンのようなエーテル類、アセトニトリル又はイソブチロニトリルのようなニトリル類、ホルムアミド、Ｎ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルアセトアミド、Ｎ−メチル−２−ピロリドン、Ｎ−メチルピロリジノン又はヘキサメチルホスホロトリアミドのようなアミド類等の有機溶媒；アセトンなどのケトン類；水；或いは、水と上記有機溶媒の混合物であり得、好適には、メチレンクロリド、テトラヒドロフラン、ジオキサン又はアセトン、或いは、水又は水とこれらのうち１つとの混合物、であり、更に好適には、メチレンクロリド又はテトラヒドロフランである。  Inert solvents used are, for example, aliphatic hydrocarbons such as hexane or heptane, aromatic hydrocarbons such as benzene, toluene or xylene, methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene. Halogenated hydrocarbons such as chlorobenzene, esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate or diethyl carbonate, ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane or 1,2-dimethoxyethane , Nitriles such as acetonitrile or isobutyronitrile, formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone or hexamethyl phosphoroyl Organic solvents such as amides such as lamide; ketones such as acetone; water; or a mixture of water and the above organic solvent, preferably methylene chloride, tetrahydrofuran, dioxane or acetone, or water or water. And a mixture of one of these, and more preferably, methylene chloride or tetrahydrofuran.

使用される塩基は、例えば、炭酸ナトリウム、炭酸カリウム又は炭酸リチウムのようなアルカリ金属炭酸塩類、炭酸水素ナトリウム、炭酸水素カリウム又は炭酸水素リチウムのようなアルカリ金属炭酸水素塩類、水酸化ナトリウム、水酸化カリウム、水酸化バリウム又は水酸化リチウムのようなアルカリ金属水酸化物類、Ｎ−メチルモルホリン、トリエチルアミン、トリブチルアミン、ジイソプロピルエチルアミン、ジシクロヘキシルアミン、Ｎ−メチルピペリジン、ピリジン、４−ピロリジノピリジン、ピコリン、４−（Ｎ，Ｎ−ジメチルアミノ）ピリジン、２，６−ジ（tert−ブチル）−４−メチルピリジン、キノリン、Ｎ，Ｎ−ジメチルアニリン又はＮ，Ｎ−ジエチルアニリンのような有機塩基類であり得、好適には、アルカリ金属炭酸塩類、アルカリ金属水酸化物類、又は有機塩基類であり、更に好適には、水酸化ナトリウム、ピリジン又はトリエチルアミンである。  The base used is, for example, an alkali metal carbonate such as sodium carbonate, potassium carbonate or lithium carbonate, an alkali metal bicarbonate such as sodium hydrogen carbonate, potassium hydrogen carbonate or lithium hydrogen carbonate, sodium hydroxide, hydroxide. Potassium, alkali metal hydroxides such as barium hydroxide or lithium hydroxide, N-methylmorpholine, triethylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, Organic bases such as 4- (N, N-dimethylamino) pyridine, 2,6-di (tert-butyl) -4-methylpyridine, quinoline, N, N-dimethylaniline or N, N-diethylaniline Possible and preferably alkali metal carbonate Salts, alkali metal hydroxides or organic bases, more preferably sodium hydroxide, pyridine or triethylamine.

使用されるtert−ブトキシカルボニル化剤は、例えば、ジ−tert−ブチルジカーボネート、２−（tert−ブトキシカルボニルオキシイミノ）−２−フェニルアセトニトリル、Ｓ−（４，６−ジメチルピリミジン−２−イル）チオールカルボン酸 tert−ブチルエステル又は１，２，２，２−テトラクロロエチル tert−ブチルカーボネートであり得、好適には、ジ−tert−ブチルジカーボネート、２−（tert−ブトキシカルボニルオキシイミノ）−２−フェニルアセトニトリルであり、更に好適には、ジ−tert−ブチルジカーボネートである。  The tert-butoxycarbonylating agent used is, for example, di-tert-butyldicarbonate, 2- (tert-butoxycarbonyloxyimino) -2-phenylacetonitrile, S- (4,6-dimethylpyrimidin-2-yl) ) Thiolcarboxylic acid tert-butyl ester or 1,2,2,2-tetrachloroethyl tert-butyl carbonate, preferably di-tert-butyl dicarbonate, 2- (tert-butoxycarbonyloxyimino)- 2-phenylacetonitrile, more preferably di-tert-butyl dicarbonate.

反応温度は、原料化合物、使用される溶媒、塩基又は試薬によって変化するが、通常、−２０℃乃至８０℃であり、好適には、０℃乃至室温である。  The reaction temperature varies depending on the starting compound, the solvent used, the base or the reagent, but is usually from -20 ° C to 80 ° C, preferably from 0 ° C to room temperature.

反応時間は、原料化合物、使用される溶媒、塩基、試薬又は反応温度によって異なるが、通常、１０分間乃至７２時間であり、好適には、３０分間乃至２４時間である。

第１８工程は、化合物（２４）とアミン化合物（２５）とを、不活性溶媒中、塩基の存在下若しくは非存在下、縮合剤の存在下で反応させ、化合物（２６）を製造する工程であり、第１工程に記載された方法と同様に実施される。

第１９工程は、化合物（２６）を、不活性溶媒中、還元剤を用いて還元することにより、化合物（２７）を製造する工程である。The reaction time varies depending on the starting compound, the solvent used, the base, the reagent and the reaction temperature, but is usually from 10 minutes to 72 hours, preferably from 30 minutes to 24 hours.

The eighteenth step is a step of reacting the compound (24) with the amine compound (25) in an inert solvent in the presence or absence of a base in the presence of a condensing agent to produce a compound (26). Yes, it is performed in the same manner as the method described in the first step.

The nineteenth step is a step for producing a compound (27) by reducing the compound (26) with a reducing agent in an inert solvent.

使用される不活性溶媒は、例えば、ベンゼン、トルエン又はキシレンのような芳香族炭化水素類、ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサン又は１，２−ジメトキシエタンのようなエーテル類であり得、好適には、ジエチルエーテル又はテトラヒドロフランである。  Inert solvents used can be, for example, aromatic hydrocarbons such as benzene, toluene or xylene, ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane or 1,2-dimethoxyethane, and are suitable. Is diethyl ether or tetrahydrofuran.

使用される還元剤は、例えば、ボラン、ジボラン、ボラン−ジメチルスルフィド錯体、ボラン−テトラヒドロフラン錯体；水素化シアノホウ素ナトリウム、水素化ホウ素ナトリウム、水素化ホウ素亜鉛又は水素化ホウ素リチウムのような水素化ホウ素アルカリ金属；或いは、水素化アルミニウムリチウム又は水素化リチウムトリ−tert−ブトキシドアルミニウムのような水素化アルミニウム化合物であり得、好適には、水素化アルミニウムリチウム、ボラン、ボラン−ジメチルスルフィド錯体又はボラン−テトラヒドロフラン錯体であり、更に好適には、水素化アルミニウムリチウム又はボラン−テトラヒドロフラン錯体である。  The reducing agent used is, for example, borane, diborane, borane-dimethylsulfide complex, borane-tetrahydrofuran complex; borohydride such as sodium cyanoborohydride, sodium borohydride, zinc borohydride or lithium borohydride. Alkali metal; alternatively, it may be an aluminum hydride compound such as lithium aluminum hydride or lithium tri-tert-butoxide aluminum, preferably lithium aluminum hydride, borane, borane-dimethyl sulfide complex or borane-tetrahydrofuran. And more preferably a lithium aluminum hydride or borane-tetrahydrofuran complex.

反応温度は、原料化合物、使用される溶媒又は試薬によって変化するが、通常、−５０℃乃至溶媒の還流温度であり、好適には、０℃乃至室温である。  The reaction temperature varies depending on the starting compound, the solvent or the reagent used, but is usually from -50 ° C to the reflux temperature of the solvent, and preferably from 0 ° C to room temperature.

反応時間は、原料化合物、使用される溶媒、試薬又は反応温度によって異なるが、通常、１時間乃至９６時間であり、好適には、１時間乃至１２時間である。  The reaction time varies depending on the starting compound, the solvent used, the reagent and the reaction temperature, but is usually 1 hour to 96 hours, preferably 1 hour to 12 hours.

反応終了後、目的化合物は常法に従って、反応混合物から採取される。  After completion of the reaction, the target compound is collected from the reaction mixture according to a conventional method.

例えば、反応混合物を適宜中和し、また、不溶物が存在する場合にはろ過により除去した後、水を加え、酢酸エチル又はトルエンのような水に混和しない有機溶剤で抽出し、水等で洗浄し、抽出液を無水硫酸マグネシウム等で乾燥した後、溶剤を留去することによって得られる。  For example, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration, water is added, and the mixture is extracted with a water-immiscible organic solvent such as ethyl acetate or toluene. It is obtained by washing, drying the extract with anhydrous magnesium sulfate or the like, and then distilling off the solvent.

得られた化合物は必要ならば、常法、例えばシリカゲルカラムクロマトグラフィーで分離、精製することができる。

第２０工程は、化合物（２７）を、不活性溶媒中、酸で処理して脱保護することにより、アミン化合物（２）を製造する工程である。If necessary, the obtained compound can be separated and purified by a conventional method, for example, silica gel column chromatography.

The twentieth step is a step of producing an amine compound (2) by treating the compound (27) with an acid in an inert solvent to deprotect the compound.

使用される不活性溶媒は、例えば、メチレンクロリド、クロロホルム、四塩化炭素又はジクロロエタンなどのハロゲン化炭化水素類；或いは、ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサン又は１，２−ジメトキシエタンのようなエーテル類であり得、好適には、メチレンクロリド、ジエチルエーテル又はジオキサンである。  The inert solvent used is, for example, a halogenated hydrocarbon such as methylene chloride, chloroform, carbon tetrachloride or dichloroethane; or an ether such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane or 1,2-dimethoxyethane. And preferably methylene chloride, diethyl ether or dioxane.

使用される酸は、例えば、塩酸、塩化水素−ジオキサン溶液、硫酸、リン酸又は臭化水素酸のような無機酸類、メタンスルホン酸又はエタンスルホン酸のようなスルホン酸類、或いは、酢酸、プロピオン酸又はトリフルオロ酢酸のようなカルボン酸類であり得、好適には、塩化水素−ジオキサン溶液、メタンスルホン酸又はトリフルオロ酢酸である。  Acids used are, for example, hydrochloric acid, hydrogen chloride-dioxane solution, sulfuric acid, inorganic acids such as phosphoric acid or hydrobromic acid, sulfonic acids such as methanesulfonic acid or ethanesulfonic acid, or acetic acid, propionic acid Alternatively, it may be a carboxylic acid such as trifluoroacetic acid, preferably a hydrogen chloride-dioxane solution, methanesulfonic acid or trifluoroacetic acid.

反応温度は、原料化合物、使用される溶媒又は試薬によって変化するが、通常、０℃乃至５０℃であり、好適には、０℃乃至室温である。  The reaction temperature varies depending on the starting compound, the solvent or the reagent used, but is usually 0 ° C to 50 ° C, preferably 0 ° C to room temperature.

反応時間は、原料化合物、使用される溶媒、試薬又は反応温度によって異なるが、通常、３０分間乃至２４時間であり、好適には、３０分間乃至６時間である。  The reaction time varies depending on the starting compound, the solvent used, the reagent or the reaction temperature, but is usually 30 minutes to 24 hours, preferably 30 minutes to 6 hours.

尚、本工程を行う前に化合物（２７）とアリルオキシカルボニルクロリドとを不活性溶媒（例えば、メチレンクロリド、クロロホルム、四塩化炭素又はジクロロエタンなどのハロゲン化炭化水素類）中、塩基（例えば、ピリジンのような有機塩基類）の存在下に、０℃乃至室温で１時間乃至１２時間反応させ、次いで本工程の反応を行うことにより、上記一般式（２）において基Ａｒが結合している窒素がアリルオキシカルボニルで保護されている化合物を得ることができる。  Before performing this step, compound (27) and allyloxycarbonyl chloride are mixed with an inert solvent (eg, methylene chloride, chloroform, halogenated hydrocarbons such as carbon tetrachloride or dichloroethane) in a base (eg, pyridine). In the presence of an organic base (such as an organic base) at 0 ° C. to room temperature for 1 hour to 12 hours, and then the reaction of this step is carried out. Is protected by allyloxycarbonyl.

反応終了後、目的化合物は常法に従って、反応混合物から採取される。  After completion of the reaction, the target compound is collected from the reaction mixture according to a conventional method.

例えば、反応混合物を適宜中和し、また、不溶物が存在する場合にはろ過により除去した後、水を加え、酢酸エチル又はトルエンのような水に混和しない有機溶剤で抽出し、水等で洗浄し、抽出液を無水硫酸マグネシウム等で乾燥した後、溶剤を留去することによって得られる。  For example, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration, water is added, and the mixture is extracted with a water-immiscible organic solvent such as ethyl acetate or toluene. It is obtained by washing, drying the extract with anhydrous magnesium sulfate or the like, and then distilling off the solvent.

得られた化合物は必要ならば、常法、例えばシリカゲルカラムクロマトグラフィーで分離、精製することができる。

第２１工程は、β−アミノアルコール化合物（２８）と化合物（２９）とを用いた光延反応により、化合物（３０）を製造する工程である。If necessary, the obtained compound can be separated and purified by a conventional method, for example, silica gel column chromatography.

The twenty-first step is a step of producing a compound (30) by a Mitsunobu reaction using the β-amino alcohol compound (28) and the compound (29).

反応は、通常、不活性溶媒中でおこなわれ、使用される不活性溶媒は、例えば、ベンゼン、トルエン又はキシレンのような芳香族炭化水素類；或いは、ジエチルエ−テル、ジイソプロピルエ−テル、テトラヒドロフラン、ジオキサン又は１，２−ジメトキシエタンのようなエ−テル類であり得、好適には、トルエン又はテトラヒドロフランである。  The reaction is usually carried out in an inert solvent, and the inert solvent used is, for example, aromatic hydrocarbons such as benzene, toluene or xylene; or diethyl ether, diisopropyl ether, tetrahydrofuran, It can be an ether such as dioxane or 1,2-dimethoxyethane, preferably toluene or tetrahydrofuran.

光延反応に使用される試薬は、例えば、ジエチルアゾジカルボキシレート若しくはジイソプロピルアゾジカルボキシレートのようなジ（Ｃ_１−Ｃ_６アルキル）アゾジカルボキシレート類又は１，１’−（アゾジカルボニル）ジピペリジンのようなアゾジカルボニル類等のアゾ化合物と、トリフェニルホスフィンのようなトリ（Ｃ_６−Ｃ_１０アリール）ホスフィン類又はトリｎ−ブチルホスフィンのようなトリ（Ｃ_１−Ｃ_６アルキル）ホスフィン類等のホスフィン類の組合せであり、更に好適には、ジ（Ｃ_１−Ｃ_６アルキル）アゾジカルボキシレート類とトリ（Ｃ_６−Ｃ_１０アリール）ホスフィン類の組合せであり、最も好適には、ジエチルアゾジカルボキシレートとトリフェニルホスフィンの組合せである。The reagent used for the Mitsunobu reaction is, for example, di (C₁ -C₆ alkyl) azodicarboxylates such as diethylazodicarboxylate or diisopropylazodicarboxylate or 1,1 ′-(azodicarbonyl) Azo compounds such as azodicarbonyls such as dipiperidine, and tri (C₆ -C₁₀ aryl) phosphines such as triphenylphosphine or tri (C₁ -C₆ alkyl) phosphine such as tri-n-butylphosphine And more preferably a combination of di (C₁ -C₆ alkyl) azodicarboxylates and tri (C₆ -C₁₀ aryl) phosphines, most preferably , A combination of diethyl azodicarboxylate and triphenylphosphine.

反応温度は、原料化合物、使用される溶媒又は試薬によって変化するが、通常、０℃乃至溶媒の還流温度であり、好適には、０℃乃至室温である。  The reaction temperature varies depending on the starting compound, the solvent or the reagent used, but is usually from 0 ° C. to the reflux temperature of the solvent, preferably from 0 ° C. to room temperature.

反応時間は、原料化合物、使用される溶媒、試薬又は反応温度によって異なるが、通常、１時間乃至２４時間であり、好適には、１時間乃至６時間である。  The reaction time varies depending on the starting compound, the solvent used, the reagent or the reaction temperature, but is usually 1 hour to 24 hours, preferably 1 hour to 6 hours.

反応終了後、目的化合物は常法に従って、反応混合物から採取される。  After completion of the reaction, the target compound is collected from the reaction mixture according to a conventional method.

例えば、反応混合物を適宜中和し、また、不溶物が存在する場合にはろ過により除去した後、水を加え、酢酸エチル又はトルエンのような水に混和しない有機溶剤で抽出し、水等で洗浄し、抽出液を無水硫酸マグネシウム等で乾燥した後、溶剤を留去することによって得られる。  For example, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration, water is added, and the mixture is extracted with a water-immiscible organic solvent such as ethyl acetate or toluene. It is obtained by washing, drying the extract with anhydrous magnesium sulfate or the like, and then distilling off the solvent.

得られた化合物は必要ならば、常法、例えばシリカゲルカラムクロマトグラフィーで分離、精製することができる。

第２２工程は、化合物（３０）の保護基（「Ｒ^１１」及び「Ｒ^１２」）を除去することにより、化合物（２）を製造する工程である。
［「Ｒ^１１」の除去］
「Ｒ^１１」の除去は、第２０工程に記載された方法と同様に実施される。
［「Ｒ^１２ＳＯ_２」の除去］
「Ｒ^１２ＳＯ_２」の除去は、不活性溶媒中、塩基の存在下で化合物（３０）と、チオール類又はアミン類とを反応させることにより実施される。If necessary, the obtained compound can be separated and purified by a conventional method, for example, silica gel column chromatography.

The 22nd step is a step of producing a compound (2) by removing the protecting groups (“R¹¹ ” and “R¹² ”) of the compound (30).
[Removal of “R¹¹ ”]
Removal of “R¹¹ ” is performed in the same manner as in the method described in the twentieth step.
[Removal of “R¹² SO₂ ”]
The removal of “R¹² SO₂ ” is performed by reacting compound (30) with a thiol or amine in an inert solvent in the presence of a base.

使用される溶媒は、例えば、メチレンクロリドのようなハロゲン化炭化水素類；ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサン又は１，２−ジメトキシエタンのようなエーテル類；ホルムアミド、Ｎ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルアセトアミド、Ｎ−メチル−２−ピロリドン、Ｎ−メチルピロリジノン又はヘキサメチルホスホロトリアミドのようなアミド類；或いは、アセトニトリル又はイソブチロニトリルのようなニトリル類であり得、好適には、アミド類又はニトリル類であり、更に好適には、Ｎ，Ｎ−ジメチルホルムアミド又はアセトニトリルである。  Solvents used are, for example, halogenated hydrocarbons such as methylene chloride; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane or 1,2-dimethoxyethane; formamide, N, N-dimethylformamide, Amides such as N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone or hexamethylphosphorotriamide; or nitriles such as acetonitrile or isobutyronitrile, preferably Is an amide or a nitrile, more preferably N, N-dimethylformamide or acetonitrile.

使用される塩基は、例えば、炭酸セシウム、炭酸ナトリウム、炭酸カリウム又は炭酸リチウムのようなアルカリ金属炭酸塩類、炭酸水素ナトリウム、炭酸水素カリウム又は炭酸水素リチウムのようなアルカリ金属炭酸水素塩類、水素化リチウム、水素化ナトリウム又は水素化カリウムのようなアルカリ金属水素化物類、水酸化ナトリウム、水酸化カリウム、水酸化バリウム又は水酸化リチウムのようなアルカリ金属水酸化物類等の無機塩基類、或いは、トリエチルアミン、ジイソプロピルエチルアミン又は１，８−ジアザビシクロ［５．４．０］ウンデカ−７−エン（ＤＢＵ）のような有機塩基類であり得、好適には、アルカリ金属炭酸塩類であり、更に好適には、炭酸セシウム又は炭酸カリウムである。  Bases used are, for example, alkali metal carbonates such as cesium carbonate, sodium carbonate, potassium carbonate or lithium carbonate, alkali metal bicarbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate or lithium hydrogen carbonate, lithium hydride Inorganic bases such as alkali metal hydrides such as sodium hydride or potassium hydride, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, barium hydroxide or lithium hydroxide, or triethylamine , Diisopropylethylamine or organic bases such as 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), preferably alkali metal carbonates, more preferably Cesium carbonate or potassium carbonate.

使用されるチオール類は、例えば、ベンゼンチオール、チオグリコール酸又は２−メルカプトエタノールであり得、好適には、ベンゼンチオールである。  The thiols used can be, for example, benzenethiol, thioglycolic acid or 2-mercaptoethanol, preferably benzenethiol.

使用されるアミン類は、例えば、プロピルアミン又はピロリジンであり得、好適には、ピロリジンである。  The amines used can be, for example, propylamine or pyrrolidine, preferably pyrrolidine.

反応温度は、原料化合物、使用される溶媒、塩基又は試薬によって変化するが、通常、室温乃至溶媒の還流温度であり、好適には、室温乃至５０℃である。  The reaction temperature varies depending on the starting compound, the solvent used, the base or the reagent, but is usually from room temperature to the reflux temperature of the solvent, and preferably from room temperature to 50 ° C.

反応時間は、原料化合物、使用される溶媒、塩基、試薬又は反応温度によって異なるが、通常、１時間乃至２４時間であり、好適には、１時間乃至１２時間である。  The reaction time varies depending on the starting compound, the solvent used, the base, the reagent and the reaction temperature, but is usually 1 hour to 24 hours, preferably 1 hour to 12 hours.

尚、本工程の、［「Ｒ^１１」の除去］及び［「Ｒ^１２ＳＯ_２」の除去］は、どちらを先に行ってもよい。Either [Removal of “R¹¹ ”] or [Removal of “R¹² SO₂ ”] in this step may be performed first.

反応終了後、目的化合物は常法に従って、反応混合物から採取される。  After completion of the reaction, the target compound is collected from the reaction mixture according to a conventional method.

例えば、反応混合物を適宜中和し、また、不溶物が存在する場合にはろ過により除去した後、水を加え、酢酸エチル又はトルエンのような水に混和しない有機溶剤で抽出し、水等で洗浄し、抽出液を無水硫酸マグネシウム等で乾燥した後、溶剤を留去することによって得られる。  For example, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration, water is added, and the mixture is extracted with a water-immiscible organic solvent such as ethyl acetate or toluene. It is obtained by washing, drying the extract with anhydrous magnesium sulfate or the like, and then distilling off the solvent.

得られた化合物は必要ならば、常法、例えばシリカゲルカラムクロマトグラフィーで分離、精製することができる。

化合物（Ｉ）のうち、Ａｒが置換基として「置換基群α及び置換基群βから選択される基で置換されていてもよいＣ_１−Ｃ_６アルコキシ基」を有する基である化合物は、まず、ベンジルオキシ体について通常用いられる方法（例えば、接触水添（第３工程参照））を行って脱ベンジル化し、得られた化合物とＲ^１３−Halo（式中、Ｒ^１３は、置換基群γの定義における「置換基群α及び置換基群βから選択される基で置換されていてもよいＣ_１−Ｃ_６アルキル基」と同様の基を示し、Haloは、ハロゲン原子を示し、好適には臭素原子である。）とを、第７工程で述べた不活性溶媒及び塩基を用いて反応させることにより製造することができる。If necessary, the obtained compound can be separated and purified by a conventional method, for example, silica gel column chromatography.

In the compound (I), a compound in which Ar is a group having “a C₁ -C₆ alkoxy group optionally substituted with a group selected from a substituent group α and a group of substituents β” as a substituent, First, the benzyloxy form is debenzylated by a method generally used (for example, catalytic hydrogenation (see the third step)), and the obtained compound is combined with R¹³ -Halo (where R¹³ is a group of substituents) In the definition of γ, the same group as the “C₁ -C₆ alkyl group optionally substituted with a group selected from the substituent group α and the substituent group β” is used, and Halo represents a halogen atom. Is a bromine atom.) With the inert solvent and the base described in the seventh step.

化合物（Ｉ）のうち、Ａｒが置換基として「置換基群α及び置換基群βから選択される基で置換されていてもよいＣ_２−Ｃ_６アルケニルオキシ基」を有する基である化合物は、まず、ベンジルオキシ体について通常用いられる方法（例えば、接触水添（第３工程参照））を行って脱ベンジル化し、得られた化合物と上記アルケニル部分を付与するためのアルキン類との付加反応を行うことにより製造することができる。付加反応は、例えば、不活性溶媒（例えば、テトラヒドロフランのようなエーテル類）中、窒素雰囲気下、塩基（例えば、Ｎ−メチルモルホリンのような有機塩基類）の存在下、０℃乃至５０℃で、１時間乃至４８時間行われる。Among the compound (I), compound Ar is a group having the "optionally substituted with a group selected from Substituent group α and Substituent group β C₂ -C₆ alkenyloxy group" as a substituent First, the benzyloxy form is debenzylated by a method usually used (for example, catalytic hydrogenation (see the third step)), and the addition reaction between the obtained compound and an alkyne for imparting the alkenyl moiety is performed. Can be produced. The addition reaction is carried out, for example, in an inert solvent (eg, ethers such as tetrahydrofuran) under a nitrogen atmosphere in the presence of a base (eg, an organic base such as N-methylmorpholine) at 0 ° C. to 50 ° C. For 1 to 48 hours.

更に、分子内にカルボキシル基を有する化合物は、相当する「保護されたカルボキシル基を有する化合物について、第１３工程で述べたのと同様に反応を行うことにより製造することができ、また、分子内にテトラゾリル基を有する化合物は、相当するシアノ化合物から定法に従って容易に製造することができる。


本発明の一般式（Ｉ）を有する化合物又はその薬理上許容される塩は、優れたカテプシンＫ阻害作用を有するので、カテプシンＫ阻害剤（特に、骨粗鬆症又は変形性関節症の予防剤又は治療剤）として有用である。その投与形態は、例えば、錠剤、カプセル剤、顆粒剤、散剤又はシロップ剤等による経口投与、或いは、注射剤又は座剤等による非経口投与であり得、そのための製剤は賦形剤、滑沢剤、結合剤、崩壊剤、安定剤、矯味矯臭剤、希釈剤などの添加剤を用いて周知の方法で製造される。Further, a compound having a carboxyl group in the molecule can be produced by performing a reaction in the same manner as described in the thirteenth step with respect to the corresponding compound having a protected carboxyl group. Can be easily produced from the corresponding cyano compound according to a conventional method.


Since the compound having the general formula (I) of the present invention or a pharmaceutically acceptable salt thereof has an excellent cathepsin K inhibitory activity, it is a cathepsin K inhibitor (particularly, a prophylactic or therapeutic agent for osteoporosis or osteoarthritis). ) Is useful. The dosage form may be, for example, oral administration such as tablets, capsules, granules, powders or syrups, or parenteral administration such as injections or suppositories. It is manufactured by a known method using additives such as an agent, a binder, a disintegrant, a stabilizer, a flavoring agent, and a diluent.

賦形剤は、例えば、乳糖、白糖、ぶどう糖、マンニット若しくはソルビットのような糖誘導体、トウモロコシデンプン、バレイショデンプン、α−デンプン、デキストリン若しくはカルボキシメチルデンプンのような澱粉誘導体、結晶セルロース、低置換度ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、カルボキシメチルセルロース、カルボキシメチルセルロースカルシウム若しくは内部架橋カルボキシメチルセルロースナトリウムのようなセルロース誘導体、アラビアゴム、デキストラン、又は、プルラン等の有機系賦形剤；或いは、軽質無水珪酸、合成珪酸アルミニウム若しくはメタ珪酸アルミン酸マグネシウムのような珪酸塩誘導体、燐酸カルシウムのような燐酸塩、炭酸カルシウムのような炭酸塩、又は、硫酸カルシウムのような硫酸塩等の無機系賦形剤であり得る。  Excipients include, for example, sugar derivatives such as lactose, sucrose, glucose, mannitol or sorbitol, corn starch, potato starch, α-starch, starch derivatives such as dextrin or carboxymethyl starch, crystalline cellulose, low degree of substitution. Cellulose derivatives such as hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium or internally crosslinked sodium carboxymethylcellulose; organic excipients such as gum arabic, dextran or pullulan; Silicate derivatives such as aluminum or magnesium metasilicate aluminate, phosphates such as calcium phosphate, carbonates such as calcium carbonate, or It may be inorganic excipients such as sulfuric acid salts, such as calcium.

滑沢剤は、例えば、ステアリン酸、ステアリン酸カルシウム若しくはステアリン酸マグネシウムのようなステアリン酸金属塩；タルク；コロイドシリカ；ビーガム若しくはゲイ蝋のようなワックス類；硼酸；アジピン酸；硫酸ナトリウムのような硫酸塩；グリコール；フマル酸；安息香酸ナトリウム；ＤＬ−ロイシン；脂肪酸ナトリウム塩；ラウリル硫酸ナトリウム若しくはラウリル硫酸マグネシウムのようなラウリル硫酸塩；無水珪酸若しくは珪酸水和物のような珪酸類；又は、上記澱粉誘導体であり得る。  Lubricants include, for example, stearic acid, metal stearates such as calcium stearate or magnesium stearate; talc; colloidal silica; waxes such as veegum or gay wax; boric acid; adipic acid; Salts; glycol; fumaric acid; sodium benzoate; DL-leucine; fatty acid sodium salt; lauryl sulfate such as sodium lauryl sulfate or magnesium lauryl sulfate; silicic acids such as anhydrous silicic acid or hydrated silicic acid; It may be a derivative.

結合剤は、例えば、ポリビニルピロリドン若しくはマクロゴール、或いは、前記賦形剤と同様の化合物であり得る。  The binder can be, for example, polyvinylpyrrolidone or macrogol, or a compound similar to the excipient.

崩壊剤は、例えば、前記賦形剤と同様の化合物、又は、クロスカルメロースナトリウム、カルボキシメチルスターチナトリウム若しくは架橋ポリビニルピロリドンのような化学修飾されたデンプン・セルロース類であり得る。  Disintegrants may be, for example, compounds similar to the above-mentioned excipients or chemically modified starch celluloses such as croscarmellose sodium, sodium carboxymethyl starch or cross-linked polyvinyl pyrrolidone.

安定剤は、例えば、メチルパラベン若しくはプロピルパラベンのようなパラオキシ安息香酸エステル類；クロロブタノール、ベンジルアルコール若しくはフェニルエチルアルコールのようなアルコール類；塩化ベンザルコニウム；フェノール若しくはクレゾールのようなフェエノール類；チメロサール；デヒドロ酢酸；又は、ソルビン酸であり得る。  Stabilizers include, for example, paraoxybenzoic esters such as methyl paraben or propyl paraben; alcohols such as chlorobutanol, benzyl alcohol or phenylethyl alcohol; benzalkonium chloride; phenols such as phenol or cresol; thimerosal; Dehydroacetic acid; or sorbic acid.

矯味矯臭剤は、通常使用される甘味料、酸味料若しくは香料等であり得る。

本発明の一般式（Ｉ）を有する化合物又はその薬理上許容される塩の使用量は症状、年齢、投与方法等によって異なるが、例えば経口投与の場合には、成人に対して１日あたり、下限として０．１ｍｇ（好ましくは１ｍｇ）、上限として、１０００ｍｇ（好ましくは１００ｍｇ）を１回または数回に分けて、症状に応じて投与することが望ましい。静脈内投与の場合には、成人に対して１日当たり、下限として０．０１ｍｇ（好ましくは０．１ｍｇ）、上限として、１００ｍｇ（好ましくは１０ｍｇ）を１回または数回に分けて、症状に応じて投与することが望ましい。
Flavoring agents can be commonly used sweeteners, sour agents or flavors.

The amount of the compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof varies depending on symptoms, age, administration method, and the like. It is desirable to administer the lower limit of 0.1 mg (preferably 1 mg) and the upper limit of 1000 mg (preferably 100 mg) in one or several divided doses according to the symptoms. In the case of intravenous administration, 0.01 mg (preferably 0.1 mg) as the lower limit and 100 mg (preferably 10 mg) as the upper limit are divided into one or several doses per day for adults, depending on the symptoms. Administration.

本発明の化合物は、カテプシンＫを阻害するので、カテプシンＫ阻害剤（特に、骨粗鬆症又は変形性関節症の予防剤又は治療剤）として有用である。
Since the compound of the present invention inhibits cathepsin K, it is useful as a cathepsin K inhibitor (particularly, a prophylactic or therapeutic agent for osteoporosis or osteoarthritis).

以下に、実施例、製剤例及び試験例を挙げて本発明をより具体的に説明するが、本発明はこれらに限定されるものではない。
［実施例］
［実施例１］ Ｎ^２−１，１’−ビフェニル−３−イル−Ｎ^１−｛（１Ｓ）−２−［（４−メトキシフェニル）アミノ］−１−メチルエチル｝−Ｌ−ロイシンアミド（例示化合物番号１−２）
（１ａ） Ｎ−１，１’−ビフェニル−３−イル−Ｌ−ロイシン
文献（J.Am.Chem.Soc., vol. 120, 1998, 12459-12467）の方法を参考にし，以下の方法で合成した。Hereinafter, the present invention will be described more specifically with reference to Examples, Formulation Examples, and Test Examples, but the present invention is not limited thereto.
[Example]
Example^1] N 2-1,1'-biphenyl-3-yl^{-N 1 - {(1S) -2} - [(4- methoxyphenyl) amino] -1-methylethyl}-L-leucinamide ( Exemplified compound number 1-2)
(1a) N-1,1'-biphenyl-3-yl-L-leucine Referring to the method of literature (J. Am. Chem. Soc., Vol. 120, 1998, 12459-12467), the following method is used. Synthesized.

窒素雰囲気下、３−ブロモビフェニル（１５．１５ｇ，６５．０ｍｍｏｌ）、Ｌ−ロイシン（８．５２ｇ，６５．０ｍｍｏｌ）、炭酸カリウム（１３．４７ｇ，９７．５ｍｍｏｌ）及びブロモ（ジメチルスルフィド）銅（Ｉ）（２．６７ｇ，１３．０ｍｍｏｌ）の混合物をＮ，Ｎ−ジメチルアセトアミド（２００ｍＬ）中、１２０℃で３時間撹拌した。反応液を酢酸エチル（２００ｍＬ）と水（２００ｍＬ）で分液した。水層に濃塩酸を加え酸性（ｐＨ＝３）とし、酢酸エチル（２００ｍＬ）で抽出した。抽出液を食塩水（２００ｍＬ）で洗浄し、硫酸ナトリウムで乾燥したのち、溶媒を留去して、得られた残留物をシリカゲルカラムクロマトグラフィー（１００％酢酸エチル）で精製し、標記化合物（１２．４３ｇ，収率６７％）を得た。
Mp 101-102 ℃;
IR (KBr) ν_max 2957, 1714, 1605, 1481, 1333, 1201, 795, 745, 698 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 0.92 (3H, d, J = 7.3 Hz), 0.97 (3H, d, J = 6.6 Hz), 1.62-1.89 (3H, m), 4.06-4.11 (1H, m), 6.58 (1H, d, J = 7.3 Hz), 6.82 (1H, s), 6.97 (1H, d, J = 7.3 Hz), 7.22 (1H, d, J = 7.3 Hz), 7.26-7.30 (1H, m), 7.37 (2H, t, J = 8.1 Hz), 7.51 (2H, d, J = 8.1 Hz);
HRMS m/z calcd for C₁₈H₂₁NO₂283.1572, found 283.1578.

（１ｂ） tert−ブチル （１Ｓ）−２−［（４−メトキシフェニル）アミノ］−１−メチルエチルカーバメート
（Ｓ）−２−（tert−ブトキシカルボニルアミノ）−１−プロパノール（市販品）（１７．５３ｇ，１００ｍｍｏｌ）、Ｎ−（４−メトキシフェニル）−２−ニトロベンゼンスルホンアミド（Chem.Heterocycl.Compd., (Engl.Transl), vol. 13, 1977, 1201-1204）（１５．４０ｇ，５０ｍｍｏｌ）及びトリフェニルホスフィン（２６．２０ｇ，１００ｍｍｏｌ）のテトラヒドロフラン（２５０ｍＬ）溶液に、氷冷下、アゾジカルボン酸ジエチル（１７．４０ｇ，１００ｍｍｏｌ）のテトラヒドロフラン（１００ｍＬ）溶液を２０分で滴下した。反応温度を室温に戻したのち、さらに反応液を３時間撹拌した。溶媒を減圧下留去し得られた残渣をジエチルエーテル（１００ｍＬ）に溶解し氷冷した。析出した結晶を濾別し濾液を減圧下濃縮した。得られた残渣をアセトニトリル（１００ｍＬ）に溶解し、チオフェノール（１１．０２ｇ，１００ｍｍｏｌ）及び炭酸カリウム（２０．７４ｇ，１５０ｍｍｏｌ）を加えた。反応混合物を室温で１６時間撹拌したのち、酢酸エチル（２００ｍＬ）を加えた。有機層を水（２００ｍＬ）と食塩水（１００ｍＬ）で順次洗浄し、硫酸ナトリウムで乾燥後、溶媒を減圧下留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル，４：１−３：１）で精製後、さらにヘキサン／酢酸エチル（５：１）混合溶媒（１５０ｍＬ）から再結晶し、標記化合物（１０．２５ｇ，収率７３％）を得た。
Mp 107-108 ℃;
IR (KBr) ν_max3390, 1679, 1515, 1239, 1169, 816 cm^-1;
¹H NMR(CDCl₃, 400MHz) δ 1.21 (3H, d, J = 6.7 Hz), 1.45 (9H, s), 3.04 (1H, dd, J = 7.3, 12.3 Hz), 3.12 (1H, dd, J = 4.9, 12.3 Hz), 3.73 (1H, br), 3.74 (3H, s), 3.92 (1H, br), 4.50 (1H, br), 6.58 (2H, d, J = 8.9 Hz), 6.77 (2H, d, J = 8.9 Hz);
MS (EI) m/z: 280 [M⁺], 136, 57;
Anal. Calcd for C₁₅H₂₄N₂O₃: C,64.26; H,8.63; N,9.99. Found: C,64.20; H,8.86; N,9.96.

（１ｃ） Ｎ^２−１，１’−ビフェニル−３−イル−Ｎ^１−｛（１Ｓ）−２−［（４−メトキシフェニル）アミノ］−１−メチルエチル｝−Ｌ−ロイシンアミド
実施例１（１ｂ）で製造したtert−ブチル （１Ｓ）−２−［（４−メトキシフェニル）アミノ］−１−メチルエチルカーバメート（２．８０ｇ，１０．０ｍｍｏｌ）を１，４−ジオキサン（１０ｍＬ）に溶解したのち、４規定塩酸−ジオキサン溶液（１０ｍＬ）を加え、室温にて３０分間攪拌した。反応液を減圧下濃縮して得られた残留物をＮ，Ｎ−ジメチルホルムアミド（１００ｍＬ）に溶解し，実施例１（１ａ）で製造したＮ−１，１’−ビフェニル−３−イル−Ｌ−ロイシン（２．８３ｇ，１０．０ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール 水和物（１．６２ｇ，１２．０ｍｍｏｌ）、トリエチルアミン（３．３ｍＬ，２４．０ｍｍｏｌ）及び１−エチル−３−（３−ジメチルアミノプロピル）−カルボジイミド 塩酸塩（２．３０ｇ，１２．０ｍｍｏｌ）を順次加えた。反応液を室温で９時間攪拌後、反応液に酢酸エチル（１００ｍＬ）を加えた。有機層を炭酸水素ナトリウム水溶液で洗浄後、硫酸ナトリウムで乾燥した。溶媒を減圧下留去して、得られた残留物をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル，２：１）にて精製し、標記化合物（４．３４ｇ，収率９７％）を得た。
IR (KBr) ν_max 3353, 2956, 1650, 1605, 1513, 1323, 1235, 821, 758, 700 cm^-1;
¹H NMR (CDCl₃, 400 MHz) 0.94 (3H, d, J = 6.6 Hz), 1.01 (3H, d, J = 5.9 Hz), 1.19 (3H, d, J = 6.6 Hz), 1.56-1.91 (3H, m), 3.00 (1H, dd, J = 7.3, 12.5 Hz), 3.07 (1H, dd, J = 4.4, 12.5 Hz), 3.52 (1H, br s), 3.70 (3H, s), 3.74-3.79 (1H, m), 3.93 (1H, d, J = 2.9 Hz), 4.19-4.28 (1H, m), 6.36 (2H, d, J = 8.8 Hz), 6.58 (1H, d, J = 8.1 Hz), 6.67 (2H, d, J = 8.8 Hz), 6.82-6.84 (2H, m), 7.05 (1H, d, J = 7.3 Hz), 7.20 (1H, t, J = 7.3 Hz), 7.31-7.37 (3H, m), 7.52 (2H, d, J = 6.6 Hz);
HRMS calcd for C₂₈H₃₆N₃O₂446.2807 [M + H]⁺, found =446.2813.

［実施例２］ Ｎ^２−１，１’−ビフェニル−３−イル−Ｎ^１−（（１Ｓ）−１−｛［（４−メトキシフェニル）アミノ］メチル｝プロピル）−Ｌ−ロイシンアミド（例示化合物番号１−２９）
（２ａ） tert−ブチル （１Ｓ）−１−｛［（４−メトキシフェニル）アミノ］メチル｝プロピルカーバメート
（Ｓ）−２−（tert−ブトキシカルボニルアミノ）−１−ブタノール（Tetrahedron, Vol. 51, 12337-12350, 1995）（１８．９３ｇ，１００ｍｍｏｌ）を（Ｓ）−２−（tert−ブトキシカルボニルアミノ）−1−プロパノールの代わりに用いて、実施例１（１ｂ）に記載された反応と同様の反応をおこなって、標記化合物（１２．１６ｇ，収率８３％）を得た。
Mp 97-99 ℃;
IR (KBr) ν_max3388, 1681, 1517, 1238, 1174, 1041, 816 cm^-1;
¹H NMR (CDCl₃, 400MHz) δ 0.97 (3H, t, J = 7.3 Hz), 1.45 (9H, s), 1.42-1.68 (2H, m), 2.99-3.04 (1H, m), 3.18 (1H, dd, J = 4.4, 11.7 Hz), 3.68-3.78 (2H, m), 3.74 (3H, s), 4.46 (1H, br s), 6.58 (2H, d, J = 8.8 Hz), 6.77 (2H, d, J = 8.8 Hz);
MS (FAB) m/z: 295 [M + H]⁺, 294, 239, 136, 57;
HRMS (ESI) calcd for C₁₆H₂₇N₂O₃295.2022 [M + H]⁺, found 295.2023.
Anal. Calcd for C₁₆H₂₆N₂O₃: C,65.28; H,8.90; N,9.52. Found: C,65.16; H,8.58; N,9.57.

（２ｂ） Ｎ^２−１，１’−ビフェニル−３−イル−Ｎ^１−（（１Ｓ）−１−｛［（４−メトキシフェニル）アミノ］メチル｝プロピル）−Ｌ−ロイシンアミド
実施例２（２ａ）で製造したtert−ブチル （１Ｓ）−１−｛［（４−メトキシフェニル）アミノ］メチル｝プロピルカーバメート（５８９ｍｇ，２．０ｍｍｏｌ）の１，４−ジオキサン（３ｍＬ）溶液に４規定塩酸−ジオキサン溶液（３ｍＬ）を加え室温にて３０分間攪拌した。混合物を減圧下濃縮して得られた残留物を塩化メチレン（２０ｍＬ）に溶解し、実施例１（１ａ）で製造したＮ−１，１’−ビフェニル−３−イル−Ｌ−ロイシン（５６７ｍｇ，２．０ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール 水和物（４０５ｍｇ，３．０ｍｍｏｌ）、トリエチルアミン（０．８４ｍＬ，６．０ｍｍｏｌ）及び１−エチル−３−（３−ジメチルアミノプロピル）−カルボジイミド 塩酸塩（５７５ｍｇ，３．０ｍｍｏｌ）を加えた。反応混合物を室温にて２時間攪拌したのち、酢酸エチル（２０ｍＬ）と飽和炭酸水素ナトリウム水溶液で分液した。有機層を硫酸ナトリウムで乾燥したのち減圧下に溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル，２：１）で精製し、さらにイソプロピルエーテルで結晶化し標記化合物（５６０ｍｇ，収率６１％）を得た。
Mp 99-101 ℃;
IR (KBr) ν_max 3336, 2961, 1645, 1606, 1514, 1479 , 1235, 1038, 821, 759, 699 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 0.89 (3H, d, J = 7.3 Hz), 0.90 (3H, d, J = 5.9 Hz), 0.98 (3H, d, J = 6.6 Hz), 1.37-1.88 (5H, m), 2.93 (1H, dd, J = 7.3, 12.5 Hz), 3.07 (1H, dd, J = 4.4, 12.5 Hz), 3.66 (3H, s), 3.72-3.75 (1H, m), 3.89 (1H, br s), 3.97-4.05 (1H, m), 6.31 (2H, d, J = 8.8 Hz), 6.55 (1H, d, J = 8.1 Hz), 6.62 (2H, d, J = 8.8 Hz), 6.73 (1H, d, J = 7.3 Hz), 6.80 (1H, s), 7.00 (1H, d, J = 7.3 Hz), 7.15 (1H, t, J = 7.3 Hz), 7.25-7.33 (3H, m), 7.47 (2H, d, J = 7.3 Hz).

［実施例３］ Ｎ^１−｛（１Ｓ）−２−［（４−メトキシフェニル）アミノ］−１−メチルエチル｝−Ｎ^２−（２−オキソ−６−フェニル−２Ｈ−ピラン−４−イル）−Ｌ−ロイシンアミド（例示化合物番号３−１）
（３ａ） ４−ブロモ−６−フェニル−２Ｈ−ピラン−２−オン
４−ヒドロキシ−６−フェニル−２Ｈ−ピラン−２−オン（Synth.Commun., Vol. 19, 2453-2460,1989）（１４．２３ｇ，７５．６ｍｍｏｌ）のＮ，Ｎ−ジメチルホルムアミド（３００ｍＬ）溶液に三臭化リン（２８．７ｍＬ，３０２．４ｍｍｏｌ）を加えた。反応液を６０°Ｃで１０時間撹拌したのち、水（３００ｍＬ）及び酢酸エチル（３００ｍＬ）を加えた。有機層を分離後、水（３００ｍｌｘ３）及び食塩水（３００ｍＬ）で順次洗浄し、硫酸ナトリウム上で乾燥後、濃縮した。粗生成物を再結晶（塩化メチレン／ヘキサン）により精製し標記化合物（１０．５６ｇ，収率５６％）を得た。
IR (KBr) ν_max 1724, 1608, 1532, 1494, 1323, 1149, 855, 777 cm^-1,
¹H NMR (CDCl₃, 400 MHz) δ 6.58 (1H, d, J = 1.5 Hz), 6.83 (1H, d, J = 1.5 Hz), 7.46-7.53 (3H, m), 7.80-7.84 (2H, m);
HRMS m/z calcd for C₁₁H₇O₂Br 249.9629, found 249.9628.

（３ｂ） Ｎ−（２−オキソ−６−フェニル−２Ｈ−ピラン−４−イル）−Ｌ−ロイシン
４−ブロモ−６−フェニル−２Ｈ−ピラン−２−オン（１０．３５ｇ，４１．２ｍｍｏｌ）、Ｌ−ロイシン（１０．８１ｇ，８２．４ｍｍｏｌ）、炭酸カリウム（１１．３９ｇ，８２．４ｍｍｏｌ）及びtert−ブタノール（２００ｍＬ）の混合物を３時間加熱還流した。反応液に１Ｎ塩酸（１２０ｍＬ）を加え、酢酸エチル（１２０ｍＬ）で抽出した。抽出液を水（１００ｍＬｘ３）及び食塩水（１００ｍＬｘ１）で順次洗浄し、硫酸ナトリウム上で乾燥後、濃縮した。粗結晶をエーテルで洗浄し標記化合物（９．５６ｇ，収率７７％）を得た。
Mp 255-258 ℃;
IR (KBr) ν_max 2964, 1746, 1652, 1610, 1542, 1194, 1068, 778, 692 cm^-1.
¹H NMR(DMSO-d₆, 400 MHz) δ 0.88 (3H, d, J = 6.6 Hz), 0.93 (3H, d, J = 5.9 Hz), 1.60-1.76 (3H, m), 3.94-4.01 (1H, m), 4.84 (1H, s), 6.63 (1H, s), 7.46-7.53 (3H, m), 7.69-7.71 (2H, m);
HRMS m/z calcd for C₁₇H₂₀NO₄302.1393 [M + H]⁺, found 302.1393.

（３ｃ） （２Ｓ）−Ｎ^１−（４−メトキシフェニル）プロパン−１，２−ジアミン
実施例１（１ｂ）で製造したtert−ブチル （１Ｓ）−２−［（４−メトキシフェニル）アミノ］−１−メチルエチルカーバメート（４．９５ｇ，１７．７ｍｍｏｌ）を４規定塩酸−ジオキサン（５０ｍＬ）に溶解し４５分間攪拌した。残留物を水（５０ｍＬ）及び塩化メチレン（５０ｍＬ）で分液した。分液した水層を飽和炭酸水素ナトリウム水溶液で中和した後、塩化メチレン（５０ｍＬｘ８）で抽出した。抽出液を硫酸ナトリウム上で乾燥後、減圧下にて溶媒を留去し標記化合物（３．０２ｇ，収率９５％）を得た。
IR (film) ν_max3356, 2958, 1514, 1236, 1037, 821 cm^-1;
¹H NMR (CDCl₃, 400MHz) δ 1.15 (3H, d, J = 6.6 Hz), 2.83 (1H, dd, J = 8.1, 12.5 Hz), 3.09 (1H, dd, J = 4.4, 12.5 Hz), 3.13-3.18 (1H, m), 3.75 (3H, s), 6.61 (2H, d, J = 8.8 Hz), 6.78 (2H, d, J = 8.8 Hz);
MS (EI) m/z: 180 [M⁺], 122, 136;
Anal. Calcd for C₁₀H₁₆N₂O・0.18H₂O: C, 65.46; H 8.99,; N, 15.27. Found: C, 65.27; H, 9.28; N, 15.16.

（３ｄ） Ｎ^１−｛（１Ｓ）−２−［（４−メトキシフェニル）アミノ］−１−メチルエチル｝−Ｎ^２−（２−オキソ−６−フェニル−２Ｈ−ピラン−４−イル）−Ｌ−ロイシンアミド
実施例３（３ｂ）で製造したＮ−（２−オキソ−６−フェニル−２Ｈ−ピラン−４−イル）−Ｌ−ロイシン（３１６ｍｇ，１．０５ｍｍｏｌ）のＮ，Ｎ−ジメチルホルムアミド（５ｍＬ）溶液に、実施例３（３ｃ）で製造した（２Ｓ）−Ｎ１−（４−メトキシフェニル）プロパン−１，２−ジアミン（１８０ｍｇ，１．０ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール 水和物（１６８ｍｇ，１．１ｍｍｏｌ）及び１−エチル−３−（３−ジメチルアミノプロピル）−カルボジイミド 塩酸塩（２１１ｍｇ，１．１ｍｍｏｌ）を加え室温にて２時間攪拌した。反応混合物を水（５０ｍＬ）及び酢酸エチル（５０ｍＬ）で分液し、有機層を硫酸ナトリウム上で乾燥後、減圧下で濃縮した。残留物をシリカゲルクロマトグラフィー（ヘキサン／酢酸エチル，１：５）で精製し、標記化合物（４２３ｍｇ，収率９１％）を得た。
IR (KBr) 1654, 1550, 1514, 1235 cm^-1;
¹H NMR (CDCl₃, 400 MHz) δ 0.84 (3H, d, J = 4.3 Hz), 0.92 (3H, d, J = 5.8 Hz), 1.23 (3H, d, J = 6.7 Hz), 1.66 -1.73 (3H, m), 3.10-3.20 (2H, m), 3.69 (3H, s), 3.87 (1H, br), 4.10-4.15 (1H, m), 4.19-4.24 (1H, m), 5.41 (1H, br s), 6.33 (1H, br s), 6.40 (1H, br), 6.56 (2H, d, J = 8.9 Hz), 6.72 (2H, d, J = 8.9 Hz), 7.35 -7.40 (3H, m), 7.66-7.67 (2H, m), 7.86 (1H, br);
MS (FAB) m/z: 464 [M + H]⁺.
Anal. Calcd for C₂₇H₃₃N₃O₄・0.4 H₂O: C, 68.88; H, 7.24; N, 8.93. Found: C, 68.93; H, 6.91; N, 8.94.

［実施例４］ Ｎ^１−（（１Ｓ）−１−｛［（４−メトキシフェニル）アミノ］メチル｝プロピル）Ｎ^２−（２−オキソ−６−フェニル−２Ｈ−ピラン−４−イル）−Ｌ−ロイシンアミド（例示化合物番号３−２）
Ｎ−１，１’−ビフェニル−３−イル−Ｌ−ロイシンに代えて実施例３（３ｂ）で製造したＮ−（２−オキソ−６−フェニル−２Ｈ−ピラン−４−イル）−Ｌ−ロイシン（６０３ｍｇ，２．０ｍｍｏｌ）を用いて、実施例２（２ｂ）に記載された反応と同様の反応をおこなった。得られた粗生成物をシリカゲルカラムクロマトグラフィー（１００％酢酸エチル）で精製したのち、さらにイソプロピルエーテルで結晶化し、標記化合物（８６０ｍｇ、収率９０％）を得た。
Mp 170-173 ℃;
IR (KBr) ν_max 3271, 3088, 2959, 1651, 1549, 1514, 1298, 1237, 820, 767, 693, 626 cm^-1;
¹H NMR (CDCl₃, 400 MHz) δ 0.89 (3H, d, J = 5.9 Hz), 0.95 (3H, d, J = 7.3 Hz), 0.96 (3H, d, J = 8.1 Hz), 1.62-1.74 (5H, m), 3.15 (1H, dd, J = 6.6, 12.5 Hz), 3.21 (1H, dd, J = 4.4, 12.5 Hz), 3.69 (3H, s), 3.98-4.11 (2H, m), 5.25 (1H, s), 6.34 (1H, d, J = 6.6 Hz), 6.20 (1H, s), 6.56 (2H, d, J = 8.8 Hz), 6.72 (2H, d, J = 8.8 Hz), 7.37-7.45 (3H, m), 7.71-7.74 (2H, m).

［実施例５］ １−（１，１’−ビフェニル−３−イルアミノ）−Ｎ−｛（１Ｓ）−２−［（４−メトキシフェニル）アミノ］−１−メチルエチル｝シクロヘキサンカルボキサミド（例示化合物番号２−２）
（５ａ） １−（１，１’−ビフェニル−３−イルアミノ）シクロヘキサンカルボン酸
文献（J.Am.Chem.Soc., vol. 120, 1998, 12459-12467）の方法を参考にし、以下の方法（Ａ法およびＢ法）で合成した。
＜Ａ法＞
（５ａＡ−１）
窒素雰囲気下、３−ブロモビフェニル（９．３３ｇ，４０ｍｍｏｌ）、１−アミノシクロヘキサンカルボン酸（５．７３ｇ，４０ｍｍｏｌ）、炭酸カリウム（８．２９ｇ，６０ｍｍｏｌ）及びブロモ（ジメチルスルフィド）銅（Ｉ）（１．６４ｇ，８ｍｍｏｌ）の混合物をＮ，Ｎ−ジメチルアセトアミド（５０ｍＬ）中、１２０℃で５時間撹拌した。酢酸エチル（２００ｍＬ）及び水（２００ｍＬ）を反応液に加え、不溶物をセライトを用いて除去した。分離した水層を濃塩酸にて酸性（ｐＨ＝３）とし、酢酸エチル（１５０ｍＬｘ２）で抽出した。抽出液を硫酸ナトリウム上で乾燥したのち、溶媒を留去して、得られた残留物を７０％エタノール（４０ｍＬ）で結晶化した。結晶を濾別し、さらに７０％エタノールで数回洗浄して１−（１，１’−ビフェニル−３−イルアミノ）シクロヘキサンカルボン酸（５．１０ｇ，収率４３％）を得た。
Mp 173-174 ℃;
IR (KBr) ν_max3404, 1621, 757, 699 cm^-1;
¹H NMR (CDCl₃, 400 MHz) δ 1.40-2.03 (10H, m), 6.67 (1H, ddd, J = 1.0, 2.0, 8.0 Hz), 6.89 (1H, t, J = 2.0 Hz), 7.13 (1H, br d, J = 8.0 Hz), 7.29 (1H, t, J = 8.0 Hz), 7.36-7.33 (1H, m), 7.44-7.41 (2H, m), 7.55-7.52 (2H, m);
MS (EI⁺) m/z: 295 [M⁺];
Anal. Calcd for C₁₉H₂₁NO₂・0.1 H₂O: C, 76.79; H, 7.19; N, 4.71. Found: C, 76.85; H, 7.12; N, 4.67.
＜Ｂ法＞
（５ａＢ−１）
窒素雰囲気下、１，３−ジブロモベンゼン（２４．２５ｇ，１０３ｍｍｏｌ）、１−アミノシクロヘキサンカルボン酸（１４．７２ｇ，１０３ｍｍｏｌ），炭酸カリウム（２１．３１ｇ，１５４ｍｍｏｌ）及びブロモ（ジメチルスルフィド）銅（Ｉ）（２．１１ｇ，１０ｍｍｏｌ）をＮ，Ｎ−ジメチルアセトアミド（１３０ｍＬ）に混合し、１２０℃で３時間撹拌した。酢酸エチル（２００ｍＬ）と水（２００ｍｌ）を反応液に加え、不溶物をセライトにて除去した。分離した水層を濃塩酸にて酸性（ｐＨ＝４）とし、酢酸エチル（１５０ｍＬｘ２）で抽出した。抽出液を硫酸ナトリウムで乾燥したのち，溶媒を減圧下留去して得られた粗生成物をシリカゲルカラムクロマトグラフィー（100％酢酸エチル）で精製し、得られた結晶（２３ｇ）をさらにエーテルで洗浄し，1-［（３-ブロモフェニル）アミノ］シクロヘキサンカルボン酸（１３．５５ｇ，収率４４％）を得た。
Mp 141-143 ℃;
IR (KBr) ν_max3250, 1705, 1592, 1479, 1227, 770 cm^-1;
¹H NMR (CDCl₃, 400MHz) δ 1.30-1.70 (6H, m), 1.90-2.10 (4H, m), 6.57 (1H, ddd, J = 0.8, 2.3, 8.0 Hz), 6.83 (1H, dd, J = 1.7, 2.3 Hz), 6.97 (1H, ddd, J = 0.8, 1.7, 8.0 Hz), 7.05 (1H, t, J = 8.0 Hz);
MS (EI) m/z: 297 [M⁺], 252.
（５ａＢ−２） 窒素雰囲気下、1-［（３-ブロモフェニル）アミノ］シクロヘキサンカルボン酸（１２．８５ｇ，４３．１ｍｍｏｌ）、フェニルホウ酸（７．８８ｇ，６４．６ｍｍｏｌ）、炭酸ナトリウム（１３．７１ｇ，１２９．３ｍｍｏｌ）及び酢酸パラジウム（０．４８ｇ，２．２ｍｍｏｌ）を水（１３０ｍＬ）に混合し、加熱還流下、４時間攪拌した。不溶物をセライトろ過により除去し，濾液をエーテル（１００ｍＬ）で洗浄した。有機層は、０．４Ｍ炭酸ナトリウム水溶液でさらに洗浄（２ｘ５０ｍＬ）した。すべての水層をあわせた混合物を、濃塩酸を加えて中性とした。析出した結晶を濾別したのち、濾液をさらに酢酸エチルで抽出（２ｘ１００ｍＬ）した。抽出液は硫酸ナトリウムで乾燥後、溶媒を減圧下留去した。得られた粗結晶と先に濾別した結晶とをあわせ、７０％含水エタノール（３００ｍＬ）より再結晶し、１−（１，１’−ビフェニル−３−イルアミノ）シクロヘキサンカルボン酸（７．２３ｇ，収率５７％）を得た。

（５ｂ） １−（１，１’−ビフェニル−３−イルアミノ）−Ｎ−｛（１Ｓ）−２−［（４−メトキシフェニル）アミノ］−１−メチルエチル｝シクロヘキサンカルボキサミド
実施例５（５ａ）で製造した１−（１，１’−ビフェニル−３−イルアミノ）シクロヘキサンカルボン酸（１６９ｍｇ，０．５７ｍｍｏｌ）をＮ，Ｎ−ジメチルホルムアミド（３ｍＬ）に溶解し、実施例３（３ｃ）で製造した（２Ｓ）−Ｎ^１−（４−メトキシフェニル）プロパン−１，２−ジアミン（１０３ｍｇ，０．５７ｍｍｏｌ），１−ヒドロキシベンゾトリアゾール 水和物（９２ｍｇ，０．６８ｍｍｏｌ）及び１−エチル−３−（３−ジメチルアミノプロピル）−カルボジイミド 塩酸塩（１３１ｍｇ，０．６８ｍｍｏｌ）を加え、室温で１６時間攪拌した。反応混合物に、水及び酢酸エチルを加えて分液した。有機層を水及び飽和食塩水で順次洗浄後、硫酸ナトリウム上で乾燥し、溶媒を減圧下留去した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル，３：１−２：１）で精製し、標記化合物（１９４ｍｇ，収率７４％）を得た。
IR (KBr) ν_max3368, 2933, 2856, 1652, 1601, 1513 cm^-1;
¹H NMR (CDCl₃, 400MHz) δ 1.17 (3H, d, J = 6.6 Hz), 1.32-1.34 (3H, m), 1.60-1.66 (3H, m), 1.92-2.03 (4H, m), 3.03 (1H, dd, J = 7.3, 12.5 Hz), 3.09 (1H, dd, J = 5.1, 12.5 Hz), 3.64 (1H, br s), 3.72 (3H, s), 4.04 (1H, s), 4.20-4.27 (1H, m), 6.44 (2H, d, J = 8.8 Hz), 6.58 (1H, dd, J = 2.2, 8.1 Hz), 6.71 (2H, d, J = 8.8 Hz), 6.83-6.84 (1H, m), 7.03 (1H, d, J = 8.1 Hz), 7.08 (1H, d, J = 8.8 Hz), 7.15 (1H, t, J = 8.1 Hz), 7.31 (1H, t, J = 7.3 Hz), 7.38 (2H, t, J = 7.3 Hz), 7.53 (2H, d, J = 7.3 Hz);
MS (FAB) m/z: 457 [M + H]⁺, 250.

［実施例６］ １−（１，１’−ビフェニル−３−イルアミノ）−Ｎ−｛（１Ｒ）−２−［（４−メトキシフェニル）アミノ］−１−メチルエチル｝シクロヘキサンカルボキサミド（例示化合物番号２−２）
（６ａ） （１Ｒ）−［１−（４−メトキシフェニルカルバモイル）エチル］カルバミン酸 tert−ブチル
Ｎ−（tert−ブトキシカルボニル）−Ｄ−アラニン（１．００ｇ，５．３ｍｍｏｌ），ｐ−アニシジン（０．６５ｇ，５．３ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール 水和物（０．９７ｇ，６．３ｍｍｏｌ）及び１−エチル−３−（３−ジメチルアミノプロピル）−カルボジイミド 塩酸塩（１．２２ｇ，６．３ｍｍｏｌ）をＮ，Ｎ−ジメチルホルムアミド（２０ｍＬ）に加えて、室温で１６時間攪拌した。反応混合物を水及び酢酸エチルで分液した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥後減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（塩化メチレン／酢酸エチル，２０：１〜８：１）で精製し、標記化合物（１．２２ｇ，収率７８％）を得た。
IR (KBr) ν_max3338, 1686, 1666, 1533, 1516, 1235, 1171, 822 cm^-1;
¹H NMR (CDCl₃, 400MHz) δ 1.43 (3H, d, J = 6.9 Hz), 1.46 (9H, s), 3.78 (3H, s), 4.30 (1H, br), 5.06 (1H, br), 6.84 (2H, d, J = 9.0 Hz), 7.40 (2H, d, J = 9.0 Hz);
MS (FAB) m/z: 294 [M⁺], 239, 57;
Anal. Calcd for C₁₅H₂₂N₂O₄: C,61.21; H,7.53; N,9.52. Found: C,61.03; H,7.40; N,9.43.
（６ｂ） tert−ブチル （１Ｒ）−２−［（４−メトキシフェニル）アミノ］−１−メチルエチルカーバメート
実施例６（６ａ）で製造した（１Ｒ）−［１−（４−メトキシフェニルカルバモイル）エチル］カルバミン酸 tert−ブチル（１．２１ｇ，４．１ｍｍｏｌ）をテトラヒドロフラン（２５ｍＬ）に溶解し、氷冷下に、水素化アルミニウムリチウム（０．４７ｇ，１２．３ｍｍｏｌ）を加えた。反応混合物を室温にて８時間攪拌したのち、氷冷下に、１Ｎ−水酸化ナトリウム水溶液を加えた。固形物をろ過により除いたのち、濾液を濃縮した。得られた残渣を水と酢酸エチルで分液し、有機層を飽和食塩水で洗浄した。抽出液を硫酸ナトリウム上で乾燥後、減圧下濃縮して、得られた残留物をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル，３：１）で精製し、標記化合物（０．８０ｇ，収率６９％）を得た。
IR (KBr) ν_max3390, 1680, 1515, 1239, 1169, 816 cm^-1;
¹H NMR (CDCl₃, 400MHz) δ 1.21 (3H, d, J = 6.7 Hz), 1.45 (9H, s), 3.04 (1H, dd, J = 7.3, 12.3 Hz), 3.12 (1H, dd, J = 4.9, 12.3 Hz), 3.74 (3H, s), 3.75 (1H, br), 3.92 (1H, br), 4.52 (1H, br), 6.58 (2H, d, J = 8.9 Hz), 6.77 (2H, d, J = 8.9 Hz);
MS (FAB) m/z: 280 [M⁺], 136, 57;
Anal. Calcd for C₁₅H₂₄N₂O₃: C,64.26; H,8.63; N,9.99. Found: C,64.10; H,8.74; N,9.97.
（６ｃ） （２Ｒ）−Ｎ^１−（４−メトキシフェニル）プロパン−１，２−ジアミン
tert−ブチル （１Ｓ）−２−［（４−メトキシフェニル）アミノ］−１−メチルエチルカーバメートに代えて、実施例６（６ｂ）で製造したtert−ブチル （１Ｒ）−２−［（４−メトキシフェニル）アミノ］−１−メチルエチルカーバメート（７７４ｍｇ，２．８ｍｍｏｌ）を用いて、実施例３（３ｃ）に記載された反応と同様の反応をおこなって、標記化合物（４８５ｍｇ，収率９７％）を得た。
IR (neat) ν_max3353, 3267, 3039, 2962, 2899, 2831, 1535, 1514 cm^-1;
¹H NMR (CDCl₃, 400MHz) δ 1.15 (3H, d, J = 6.6 Hz), 2.83 (1H, dd, J = 8.1, 12.5 Hz), 3.09 (1H, dd, J = 4.4, 12.5 Hz), 3.13-3.18 (1H, m), 3.75 (3H, s), 6.61 (2H, d, J = 8.8 Hz), 6.78 (2H, d, J = 8.8 Hz);
MS (EI) m/z: 180 [M⁺], 122, 136;
Anal. Calcd for C₁₀H₁₆N₂O・0.2 H₂O: C, 66.63; H 8.99,; N, 15.24. Found: C, 65.67; H, 8.62; N, 14.93.

（６ｄ） １−（１，１’−ビフェニル−３−イルアミノ）−Ｎ−｛（１Ｒ）−２−［（４−メトキシフェニル）アミノ］−１−メチルエチル｝シクロヘキサンカルボキサミド
（２Ｓ）−Ｎ^１−（４−メトキシフェニル）プロパン−１，２−ジアミンに代えて、実施例６（６ｃ）で製造した（２Ｒ）−Ｎ^１−（４−メトキシフェニル）プロパン−１，２−ジアミン（８９ｍｇ，０．４９ｍｍｏｌ）を用いて、実施例５（５ｂ）に記載された反応と同様の反応をおこなった。得られた粗生成物をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル，３：１〜２：１）で精製し、標記化合物（１９５ｍｇ，収率８６％）を得た。
IR (KBr) ν_max3368, 2933, 2856, 1652, 1601, 1513 cm^-1;
¹H NMR (CDCl₃, 400MHz) δ 1.17 (3H, d, J = 6.6 Hz), 1.32-1.34 (3H, m), 1.60-1.66 (3H, m), 1.92-2.03 (4H, m), 3.03 (1H, dd, J = 7.3, 12.5 Hz), 3.09 (1H, dd, J = 5.1, 12.5 Hz), 3.64 (1H, br s), 3.72 (3H, s), 4.04 (1H, s), 4.20-4.27 (1H, m), 6.44 (2H, d, J = 8.8 Hz), 6.58 (1H, dd, J = 2.2, 8.1 Hz), 6.71 (2H, d, J = 8.8 Hz), 6.83-6.84 (1H, m), 7.03 (1H, d, J = 8.1 Hz), 7.08 (1H, d, J = 8.8 Hz), 7.15 (1H, t, J = 8.1 Hz), 7.31 (1H, t, J = 7.3 Hz), 7.38 (2H, t, J = 7.3 Hz), 7.53 (2H, d, J = 7.3 Hz);
MS (FAB) m/z: 458 [M + H]⁺, 457, 250;
Anal. Calcd for C₂₉H₃₅N₃O₂・0.44 H₂O: C,74.89; H,7.77; N,9.03. Found: C,74.89; H,7.48; N,8.86.

［実施例７］ １−（１，１’−ビフェニル−３−イルアミノ）−Ｎ−（（１Ｓ）−１−｛［（４−メトキシフェニル）アミノ］メチル｝−２−メチルプロピル）シクロヘキサンカルボキサミド（例示化合物番号２−１１０）
（７ａ） tert−ブチル （１Ｓ）−１−｛［（４−メトキシフェニル）アミノ］メチル｝−２−メチルプロピルカーバメート
（Ｓ）−２−（tert−ブトキシカルボニルアミノ）−１−プロパノールに代えて、（Ｓ）−２−（tert−ブトキシカルボニルアミノ）−３−メチル−１−ブタノール（Tetrahedron, Vol. 51, 12337-12350, 1995）（３３０ｍｇ，１．６２ｍｍｏｌ）を用いて、実施例１（１ｂ）に記載された反応と同様の反応をおこなって、標記化合物（１６０ｍｇ，ニトロベンゼンスルホンアミドをもとに収率６４％）を合成した。
IR (KBr) ν_max3376, 2973, 2957, 2935, 1680, 1518 cm^-1;
¹H NMR (CDCl₃, 400MHz) δ 0.95 (3H, d, J = 7.3 Hz), 0.98 (3H, d, J = 6.6 Hz), 1.45 (9H, s), 1.83-1.88 (1H, m), 2.96-3.01 (1H, m), 3.19-3.23 (1H, m), 3.64-3.73 (2H, m), 3.74 (3H, s), 4.48-4.50 (1H, m), 6.57 (2H, d, J = 8.8 Hz), 6.78 (2H, d, J = 8.8 Hz);
MS (FAB) m/z: 309 [M + H]⁺, 308, 253, 136, 57;
Anal. Calcd for C₁₇H₂₈N₂O₃: C,66.20; H,9.15; N,9.08. Found: C,65.91; H,9.08; N,9.09.

（７ｂ） （２Ｓ）−Ｎ^１−（４−メトキシフェニル）−３−メチルブタン−１，２−ジアミン ２塩酸塩
実施例７（７ａ）で製造したtert−ブチル （１Ｓ）−１−｛［（４−メトキシフェニル）アミノ］メチル｝−２−メチルプロピルカーバメート（１３８ｍｇ，０．４５ｍｍｏｌ）の１，４−ジオキサン（２ｍＬ）溶液に、４規定塩酸−ジオキサン溶液（２ｍＬ）を加え、室温にて２時間攪拌した後、反応混合物を濃縮した。残留物にイソプロピルエーテルを加えて得られた粉末を濾取し、標記化合物（１２５mg，９９％）を得た。
IR (KBr) ν_max2963, 1512, 1462, 1261, 1030, 831 cm^-1;
¹H NMR (CDCl₃, 400MHz) δ 1.09 (3H, d, J = 5.9 Hz), 1.11 (3H, d, J = 6.6 Hz), 2.17-2.22 (1H, m), 3.36 (1H, d, J = 11.7 Hz), 3.79 (3H, s), 4.09-4.17 (2H, m), 6.92 (2H, d, J = 8.8 Hz), 7.59 (2H, d, J = 8.8 Hz);
MS (FAB) m/z: 209 [M + H]⁺, 43, 57, 65, 69, 120;
Anal. Calcd for C₁₂H₂₂N₂OCl₂・0.18 H₂O: C, 50.67; H, 7.92; N, 9.85. Found: C, 50.80; H, 8.02; N, 9.59.

（７ｃ） １−（１，１’−ビフェニル−３−イルアミノ）−Ｎ−（（１Ｓ）−１−｛［（４−メトキシフェニル）アミノ］メチル｝−２−メチルプロピル）シクロヘキサンカルボキサミド
実施例５（５ａ）で製造した１−（１，１’−ビフェニル−３−イルアミノ）シクロヘキサンカルボン酸（６０ｍｇ，０．２０ｍｍｏｌ）をＮ，Ｎ−ジメチルホルムアミド（２ｍＬ）に溶解し、実施例７（７ｂ）で製造した（２Ｓ）−Ｎ^１−（４−メトキシフェニル）−３−メチルブタン−１，２−ジアミン ２塩酸塩（６０ｍｇ，０．２１ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール 水和物（３３ｍｇ，０．２４ｍｍｏｌ）、１−エチル−３−（３−ジメチルアミノプロピル）−カルボジイミド 塩酸塩（４７ｍｇ，０．２４ｍｍｏｌ）及びトリエチルアミン（０．０８５ｍL，０．６１ｍｍoｌ）を加えた。反応混合物を室温で６時間攪拌し、水及び酢酸エチルで分液した。有機層を水及び飽和食塩水で順次洗浄後、硫酸ナトリウム上で乾燥し、溶媒を減圧下留去した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル，３：１）で精製し、標記化合物（９２ｍｇ，収率９３％）を得た。
IR (KBr) ν_max3368, 2932, 2857, 1654, 1601, 1513 cm^-1;
¹H NMR (CDCl₃, 400MHz) δ 0.87 (3H, d, J = 6.6 Hz), 0.91 (3H, d, J = 7.3 Hz), 1.22-1.43 (3H, m), 1.58-1.69 (3H, m), 1.83-1.91 (1H, m), 1.94-2.05 (4H, m), 2.98 (1H, dd, J = 8.8, 11.7 Hz), 3.17 (1H, dd, J = 4.4, 11.7 Hz), 3.64 (1H, br s), 3.73 (3H, s), 3.97-4.04 (1H, m), 4.06 (1H, s), 6.41 (2H, dd, J = 8.8 Hz), 6.61 (1H, dd, J = 1.5, 8.1 Hz), 6.71 (2H, d, J = 8.8 Hz), 6.85-6.86 (1H, m), 7.01 (1H, d, J = 8.1 Hz), 7.10 (1H, t, J = 8.1 Hz), 7.14 (1H, d, J = 9.5 Hz), 7.30 (1H, t, J = 7.3 Hz), 7.36 (2H, t, J = 7.3 Hz), 7.52 (2H, d, J = 7.3 Hz);
MS (FAB) m/z: 486 [M + H]⁺, 485, 250, 136;
Anal. Calcd for C₃₁H₃₉N₃O₂・0.44 H₂O: C,75.43; H,8.14; N,8.51. Found: C,75.50; H,7.79; N,8.41.

［実施例８］ １−（１，１’−ビフェニル−３−イルアミノ）−Ｎ−（（１Ｓ）−１−｛［（４−メトキシフェニル）アミノ］メチル｝−３−メチルブチル）シクロヘキサンカルボキサミド（例示化合物番号２−１３７）
（８ａ） tert−ブチル （１Ｓ）−１−｛［（４−メトキシフェニル）アミノ］メチル｝−３−メチルブチルカーバメート
（Ｓ）−２−（tert−ブトキシカルボニルアミノ）−１−プロパノールに代えて、（Ｓ）−２−（tert−ブトキシカルボニルアミノ）−４−メチル−１−ペンタノール（Tetrahedron, Vol. 51, 12337-12350, 1995）（３５２ｍｇ，１．６２ｍｍｏｌ）を用いて、実施例１（１ｂ）に記載された反応と同様の反応をおこなって、標記化合物（１９８ｍｇ，ニトロベンゼンスルホンアミドをもとに収率７６％）を得た。
IR (KBr) ν_max3405, 2978, 2953, 2911, 1678, 1516 cm^-1;
¹H NMR (CDCl₃, 400MHz) δ 0.92-0.95 (6H, m), 1.32-1.38 (2H, m), 1.44 (9H, s), 1.68-1.74 (1H, m), 2.96-3.01 (1H, m), 3.17 (1H, dd, J = 4.0, 12.1 Hz), 3.74 (3H, s), 3.76 (1H, br s), 3.86-3.89 (1H, m), 4.40 (1H, br s), 6.57 (2H, d, J = 8.8 Hz), 6.77 (2H, d, J = 8.8 Hz);
MS (FAB) m/z: 323 [M + H]⁺, 322, 267, 136, 57;
Anal. Calcd for C₁₈H₃₀N₂O₃・0.2 H₂O: C,66.31; H,9.40; N,8.59. Found: C,66.30; H,9.36; N,8.60.

（８ｂ） （２Ｓ）−Ｎ^１−（４−メトキシフェニル）−４−メチルペンタン−１，２−ジアミン ２塩酸塩
tert−ブチル （１Ｓ）−１−｛［（４−メトキシフェニル）アミノ］メチル｝−２−メチルプロピルカーバメートの代わりに、実施例７（７ａ）で製造したtert−ブチル （１Ｓ）−１−｛［（４−メトキシフェニル）アミノ］メチル｝−３−メチルブチルカーバメート（１９０ｍｇ，０．５９ｍｍｏｌ）を用いて、実施例７（７ｂ）に記載された反応と同様の反応をおこなって、標記化合物（１７２ｍｇ，９９％）を得た。
IR (KBr) ν_max2958, 1512, 1466, 1258, 1030, 834 cm^-1;
¹H NMR (CDCl₃, 400MHz) δ 0.90 (6H, d, J = 5.9 Hz), 1.61-1.89 (3H, m), 3.36 (1H, d, J = 13.9 Hz), 3.67 (3H, s), 4.21-4.27 (1H, m), 4.34-4.39 (1H, m), 7.88 (2H, d, J = 8.8 Hz), 7.73 (2H, d, J = 8.8 Hz);
MS (EI) m/z: 222 [M + H]⁺, 137, 122, 86.

（８ｃ） １−（１，１’−ビフェニル−３−イルアミノ）−Ｎ−（（１Ｓ）−１−｛［（４−メトキシフェニル）アミノ］メチル｝−３−メチルブチル）シクロヘキサンカルボキサミド
（２Ｓ）−Ｎ^１−（４−メトキシフェニル）−３−メチルブタン−１，２−ジアミン ２塩酸塩の代わりに、実施例８（８ｂ）で製造した（２Ｓ）−Ｎ^１−（４−メトキシフェニル）−４−メチルペンタン−１，２−ジアミン ２塩酸塩（８０ｍｇ，０．２７ｍｍｏｌ）を用いて、実施例７（７ｃ）に記載された反応と同様の反応をおこなって、標記化合物（１１５ｍｇ，収率８８％）を得た。
IR (neat) ν_max3368, 2934, 2858, 1650, 1601, 1513 cm^-1;
¹H NMR (CDCl₃, 400MHz) δ 0.82 (3H, d, J = 6.6 Hz), 0.83 (3H, d, J = 6.6 Hz), 1.26-1.39 (5H, m), 1.51-1.65 (4H, m), 1.94-2.02 (4H, m), 2.99 (1H, dd, J = 7.3, 11.7 Hz), 3.11 (1H, dd, J = 4.4, 11.7 Hz), 3.73 (1H, br s), 3.73 (3H, s), 4.04 (1H, s), 4.18-4.25 (1H, m), 6.45 (2H, d, J = 8.8 Hz), 6.59 (1H, dd, J = 1.5, 8.1 Hz), 6.73 (2H, d, J = 8.8 Hz), 6.83 (1H, s), 6.99-7.02 (2H, m), 7.11 (1H, t, J = 8.1 Hz), 7.30 (1H, t, J = 7.3 Hz), 7.36 (2H, t, J = 7.3 Hz), 7.52 (2H, d, J = 7.3 Hz);
MS (FAB) m/z: 500 (M + H)⁺, 499, 250;
Anal. Calcd for C₃₂H₄₁N₃O₂・0.38 H₂O: C,75.88; H,8.31; N,7.52. Found: C,75.90; H,8.03; N,8.30.

［実施例９］ １−（１，１’−ビフェニル−３−イルアミノ）−Ｎ−（（１Ｓ）−１−｛［（４−メトキシフェニル）アミノ］メチル｝プロピル）シクロヘキサンカルボキサミド（例示化合物番号２−２９）
（９ａ） （２Ｓ）−Ｎ^１−（４−メトキシフェニル）ブタン−１，２−ジアミン
tert−ブチル （１Ｓ）−２−［（４−メトキシフェニル）アミノ］−１−メチルエチルカーバメートの代わりに、実施例２（２ａ）で製造したtert−ブチル （１Ｓ）−１−｛［（４−メトキシフェニル）アミノ］メチル｝プロピルカーバメート（７５ｍｇ，０．２６ｍｍｏｌ）を用いて、実施例３（３ｃ）に記載された反応と同様の反応をおこなって、標記化合物（４１ｍｇ，収率８３％）を得た。
¹H NMR (CDCl₃, 400MHz) δ 0.98 (3H, t, J = 7.3 Hz), 1.30-1.59 (2H, m), 2.81 (1H, dd, J = 8.1, 11.7 Hz), 2.85-2.91 (1H, m), 3.16 (1H, dd, J = 3.7, 11.7 Hz), 3.75 (3H, s), 6.61 (2H, d, J = 8.8 Hz), 6.78 (2H, d, J = 8.8 Hz);
MS (EI) m/z: 194 [M + H]⁺, 137, 122, 58;
HRMS (EI) m/z calcd for C₁₁H₁₈N₂O 194.1419, found 194.1417.

（９ｂ） １−（１，１’−ビフェニル−３−イルアミノ）−Ｎ−（（１Ｓ）−１−｛［（４−メトキシフェニル）アミノ］メチル｝プロピル）シクロヘキサンカルボキサミド
（２Ｓ）−Ｎ^１−（４−メトキシフェニル）プロパン−１，２−ジアミンの代わりに、実施例９（９ａ）で製造した（２Ｓ）−Ｎ^１−（４−メトキシフェニル）ブタン−１，２−ジアミン（４１ｍｇ，０．２１ｍｍｏｌ）を用いて、実施例５（５ｂ）に記載された反応と同様の反応をおこなって、標記化合物（８４ｍｇ，収率８５％）を得た。
IR (KBr) ν_max3366, 2933, 2856, 1651, 1601, 1513 cm^-1;
¹H NMR (CDCl₃, 400MHz) δ 0.88 (3H, t, J = 7.7 Hz), 1.24-1.48 (5H, m), 1.60-1.66 (3H, m), 1.94-2.08 (4H, m), 3.02 (1H, dd, J = 8.1, 12.5 Hz), 3.13 (1H, dd, J = 4.4, 12.5 Hz), 3.66 (1H, br s), 3.72 (3H, s), 4.03-4.09 (2H, m), 6.43 (2H, d, J = 8.8 Hz), 6.60 (1H, dd, J = 1.5, 8.1 Hz), 6.72 (2H, d, J = 8.8 Hz), 6.85 (1H, m), 7.01-7.05 (2H, m), 7.13 (1H, t, J = 8.1 Hz), 7.31 (1H, t, J = 7.3 Hz), 7.37 (2H, t, J = 7.3 Hz), 7.53 (2H, d, J = 7.3 Hz);
MS (FAB) m/z: 472 [M + H]⁺, 471, 250, 136.

［実施例１０］ １−（１，１’−ビフェニル−３−イルアミノ）−Ｎ−｛（１Ｓ）−２−［（４−メトキシフェニル）アミノ］−１−フェニルエチル｝シクロヘキサンカルボキサミド（例示化合物番号２−１６４）
（１０ａ） tert−ブチル （１Ｓ）−２−［（４−メトキシフェニル）アミノ］−１−フェニルエチルカーバメート
（Ｓ）−２−（tert−ブトキシカルボニルアミノ）−１−プロパノールに代えて、（Ｓ）−２−（tert−ブトキシカルボニルアミノ）−２−フェニル−１−エタノール（Tetrahedron, Vol. 51, 12337-12350, 1995）（３８０ｍｇ，１．６ｍｍｏｌ）を用いて、実施例１（１ｂ）に記載された反応と同様の反応をおこなって、標記化合物（１５０ｍｇ，ニトロベンゼンスルホンアミドをもとに収率５５％）を得た。
IR (KBr) ν_max3387, 3362, 2976, 2936, 1685, 1517 cm^-1;
¹H NMR (CDCl₃, 400MHz) δ 1.43 (9H, s), 3.40-3.50 (3H, m), 3.74 (3H, s), 4.88-4.96 (1H, m), 5.08-5.16 (1H, m), 6.58 (2H, d, J = 8.8 Hz), 6.77 (2H, d, J = 8.8 Hz), 7.28-7.31 (3H, m), 7.35-7.39 (2H, m);
MS (FAB) m/z: 343 [M + H]⁺, 342, 287, 226, 136, 57;

（１０ｂ） （１Ｓ）−Ｎ^２−（４−メトキシフェニル）−１−フェニルエタン−１，２−ジアミン ２塩酸塩
tert−ブチル （１Ｓ）−１−｛［（４−メトキシフェニル）アミノ］メチル｝−２−メチルプロピルカーバメートの代わりに、実施例１０（１０ａ）で製造したtert−ブチル （１Ｓ）−２−［（４−メトキシフェニル）アミノ］−１−フェニルエチルカーバメート（１３０ｍｇ，０．３８ｍｍｏｌ）を用いて、実施例７（７ｂ）に記載された反応と同様の反応をおこなって、標記化合物（１１９ｍｇ，９９％）を得た。
IR (KBr) ν_max2911, 1512, 1261, 1029, 831, 764, 699 cm^-1;
¹H NMR (CDCl₃, 400MHz) δ 3.49 (1H, d, J = 11.0 Hz), 3.70 (3H, s), 4.73 (1H, t, J = 11.0 Hz), 5.61 (1H, d, J = 11.0 Hz), 6.85 (2H, d, J = 8.8 Hz), 7.25-7.28 (3H, m), 7.61-7.63 (4H, m);
MS (EI) m/z: 242 [M⁺], 77, 106, 120, 136;
HRMS (EI) m/z calcd for C₁₅H₁₈N₂O 242.1419 [M + H]⁺, found 242.1413.

（１０ｃ） １−（１，１’−ビフェニル−３−イルアミノ）−Ｎ−｛（１Ｓ）−２−［（４−メトキシフェニル）アミノ］−１−フェニルエチル｝シクロヘキサンカルボキサミド
（２Ｓ）−Ｎ^１−（４−メトキシフェニル）−３−メチルブタン−１，２−ジアミン ２塩酸塩の代わりに、実施例１０（１０ｂ）で製造した（１Ｓ）−Ｎ^２−（４−メトキシフェニル）−１−フェニルエタン−１，２−ジアミン ２塩酸塩（３１ｍｇ，０．１０ｍｍｏｌ）を用いて、実施例７（７ｃ）に記載された反応と同様の反応をおこなって、標記化合物（４４ｍｇ，収率９６％）を得た。
IR (KBr) ν_max3369, 2934, 1658, 1601, 1513 cm^-1;
¹H NMR (CDCl₃, 400MHz) δ 1.31-2.05 (10H, m), 3.31-3.41 (3H, m), 3.70 (3H, s), 4.07 (1H, s), 5.19-5.24 (1H, m), 6.39 (2H, d, J = 8.8 Hz), 6.59 (1H, dd, J = 2.2, 8.1 Hz), 6.68 (2H, d, J = 8.8 Hz), 6.82 (1H, s), 7.04 (1H, d, J = 8.1 Hz), 7.17 (1H, t, J = 7.3Hz), 7.21-7.26 (5H, m), 7.30-7.33 (1H, m), 7.37 (2H, t, J = 7.3 Hz), 7.48 (2H, d, J = 7.3 Hz), 7.64 (1H, d, J = 8.1 Hz);
MS (FAB) m/z: 520 [M + H]⁺, 519, 250;

［実施例１１］ Ｎ−｛（１Ｓ）−１−ベンジル−２−［（４−メトキシフェニル）アミノ］エチル｝−１−（１，１’−ビフェニル−３−イルアミノ）シクロヘキサンカルボキサミド（例示化合物番号２−１９１）
（１１ａ） tert−ブチル （１Ｓ）−１−ベンジル−２−［（４−メトキシフェニル）アミノ］エチルカーバメート
（Ｓ）−２−（tert−ブトキシカルボニルアミノ）−１−プロパノールに代えて、（Ｓ）−２−（tert−ブトキシカルボニルアミノ）−３−フェニル−１−プロパノール（Tetrahedron, Vol. 51, 12337-12350, 1995）（４０２ｍｇ，１．６ｍｍｏｌ）を用いて、実施例１（１ｂ）に記載された反応と同様の反応をおこなって、標記化合物（１５０ｍｇ，ニトロベンゼンスルホンアミドをもとに収率５３％）を合成した。
IR (KBr) ν_max3400, 3378, 2983, 2934, 2905, 1676, 1517 cm^-1;
¹H NMR (CDCl₃, 400MHz) δ 1.41 (9H, s), 2.82-2.90 (2H, m), 3.00-3.04 (1H, m), 3.19 (1H, dd, J = 4.4, 12.5 Hz), 3.63 (1H, br s), 3.74 (3H, s), 4.01-4.10 (1H, m), 4.50-4.59 (1H, m), 6.54 (2H, d, J = 8.8 Hz), 6.76 (2H, d, J = 8.8 Hz), 7.19-7.25 (3H, m), 7.31 (2H, t, J = 7.3 Hz);
MS (FAB) m/z: 357 [M + H]⁺, 356, 301, 136, 57;
Anal. Calcd for C₂₁H₂₈N₂O₃: C,70.76; H,7.92; N,7.86. Found: C,70.60; H,7.78; N,7.83.

（１１ｂ） （２Ｓ）−Ｎ^１−（４−メトキシフェニル）−３−フェニルプロパン−１，２−ジアミン ２塩酸塩
tert−ブチル （１Ｓ）−１−｛［（４−メトキシフェニル）アミノ］メチル｝−２−メチルプロピルカーバメートの代わりに、実施例１１（１１ａ）で製造したtert−ブチル （１Ｓ）−１−ベンジル−２−［（４−メトキシフェニル）アミノ］エチルカーバメート（１３８ｍｇ，０．３９ｍｍｏｌ）を用いて、実施例７（７ｂ）に記載された反応と同様の反応をおこなって、標記化合物（１２５ｍｇ，９９％）を得た。
¹H NMR (CDCl₃, 400MHz) δ 3.08 (1H, dd, J = 10.8, 13.8 Hz), 3.31 (1H, d, J = 13.8 Hz), 3.59-3.62 (1H, m), 3.70 (3H, s), 4.30-4.37 (1H, m), 4.47-4.55 (1H, m), 6.72 (2H, d, J = 8.7 Hz), 7.16-7.19 (5H, m), 7.41 (2H, d, J = 8.7 Hz);
MS (FAB) m/z: 257 [M + H]⁺, 43, 57, 69, 97, 229;

（１１ｃ） Ｎ−｛（１Ｓ）−１−ベンジル−２−［（４−メトキシフェニル）アミノ］エチル｝−１−（１，１’−ビフェニル−３−イルアミノ）シクロヘキサンカルボキサミド
（２Ｓ）−Ｎ^１−（４−メトキシフェニル）−３−メチルブタン−１，２−ジアミン ２塩酸塩に代えて、実施例１１（１１ｂ）で製造した（２Ｓ）−Ｎ^１−（４−メトキシフェニル）−３−フェニルプロパン−１，２−ジアミン ２塩酸塩（５４ｍｇ，０．１７ｍｍｏｌ）を用いて、実施例７（７ｃ）に記載された反応と同様の反応をおこなって、標記化合物（６９ｍｇ，収率８６％）を得た。
IR (KBr) ν_max3369, 2934, 2956, 1654, 1601, 1513 cm^-1;
¹H NMR (CDCl₃, 400MHz) δ 1.24-2.04 (10H, m), 2.86 (2H, d, J = 6.6 Hz), 3.04 (1H, dd, J = 7.3, 12.5 Hz), 3.16 (1H, dd, J = 4.4, 12.5 Hz), 3.60 (1H, s), 3.71 (3H, s), 3.99 (1H, s), 4.37-4.47 (1H, m), 6.38 (2H, d, J = 8.8 Hz), 6.52 (1H, d, J = 8.1 Hz), 6.69 (2H, d, J = 8.8 Hz), 6.82 (1H, s), 7.02 (1H, d, J = 8.1 Hz), 7.08-7.25 (7H, m), 7.29-7.32 (1H, m), 7.37 (2H, t, J = 6.6 Hz), 7.53 (2H, d, J = 7.3 Hz);
MS (FAB) m/z: 534 [M + H]⁺, 533, 250;
Anal. Calcd for C₃₅H₃₉N₃O₂・0.54 H₂O: C,77.36; H,7.43; N,7.73. Found: C,77.35; H,7.51; N,7.80.

［実施例１２］ １−（１，１’−ビフェニル−３−イルアミノ）−Ｎ−（（１Ｓ）−１−｛［（４−メトキシフェニル）アミノ］メチル｝−３−フェニルプロピル）シクロヘキサンカルボキサミド（例示化合物番号２−２１８）
（１２ａ） tert−ブチル （１Ｓ）−１−（ヒドロキシメチル）−３−フェニルプロピルカーバメート
文献（J.Org.Chem., Vol. 66, 1919-1923, 2001）に記載された方法に準じて以下のように合成した。  Under a nitrogen atmosphere, 3-bromobiphenyl (15.15 g, 65.0 mmol), L-leucine (8.52 g, 65.0 mmol), potassium carbonate (13.47 g, 97.5 mmol) and bromo (dimethylsulfide) copper ( A mixture of I) (2.67 g, 13.0 mmol) was stirred in N, N-dimethylacetamide (200 mL) at 120 ° C. for 3 hours. The reaction solution was partitioned between ethyl acetate (200 mL) and water (200 mL). The aqueous layer was made acidic (pH = 3) by adding concentrated hydrochloric acid, and extracted with ethyl acetate (200 mL). The extract was washed with brine (200 mL), dried over sodium sulfate, evaporated, and the resulting residue was purified by silica gel column chromatography (100% ethyl acetate) to give the title compound (12 .43 g, 67% yield).
Mp 101-102 ° C;
IR (KBr) ν_max 2957, 1714, 1605, 1481, 1333, 1201, 795, 745, 698 cm^-1;
¹H NMR (CDCl_Three, 400 MHz) δ 0.92 (3H, d, J = 7.3 Hz), 0.97 (3H, d, J = 6.6 Hz), 1.62-1.89 (3H, m), 4.06-4.11 (1H, m), 6.58 (1H , d, J = 7.3 Hz), 6.82 (1H, s), 6.97 (1H, d, J = 7.3 Hz), 7.22 (1H, d, J = 7.3 Hz), 7.26-7.30 (1H, m), 7.37 (2H, t, J = 8.1 Hz), 7.51 (2H, d, J = 8.1 Hz);
HRMS m / z calcd for C₁₈H_{twenty one}NO_Two283.1572, found 283.1578.

(1b) tert-butyl (1S) -2-[(4-methoxyphenyl) amino] -1-methylethylcarbamate
  (S) -2- (tert-butoxycarbonylamino) -1-propanol (commercially available) (17.53 g, 100 mmol), N- (4-methoxyphenyl) -2-nitrobenzenesulfonamide (Chem. Heterocycl. Compd. Azodicarboxylic acid was added to a solution of (Engl. Transl), vol. 13, 1977, 1201-1204) (15.40 g, 50 mmol) and triphenylphosphine (26.20 g, 100 mmol) in tetrahydrofuran (250 mL) under ice-cooling. A solution of diethyl (17.40 g, 100 mmol) in tetrahydrofuran (100 mL) was added dropwise over 20 minutes. After returning the reaction temperature to room temperature, the reaction solution was further stirred for 3 hours. The solvent was distilled off under reduced pressure, and the obtained residue was dissolved in diethyl ether (100 mL) and cooled with ice. The precipitated crystals were separated by filtration and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in acetonitrile (100 mL), and thiophenol (11.02 g, 100 mmol) and potassium carbonate (20.74 g, 150 mmol) were added. After the reaction mixture was stirred at room temperature for 16 hours, ethyl acetate (200 mL) was added. The organic layer was washed sequentially with water (200 mL) and brine (100 mL), dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate, 4: 1-3: 1), and further recrystallized from a mixed solvent of hexane / ethyl acetate (5: 1) (150 mL) to give the title compound. (10.25 g, yield 73%) was obtained.
Mp 107-108 ° C;
IR (KBr) ν_max3390, 1679, 1515, 1239, 1169, 816 cm^-1;
¹H NMR (CDCl_Three, 400MHz) δ 1.21 (3H, d, J = 6.7 Hz), 1.45 (9H, s), 3.04 (1H, dd, J = 7.3, 12.3 Hz), 3.12 (1H, dd, J = 4.9, 12.3 Hz) , 3.73 (1H, br), 3.74 (3H, s), 3.92 (1H, br), 4.50 (1H, br), 6.58 (2H, d, J = 8.9 Hz), 6.77 (2H, d, J = 8.9) Hz);
MS (EI) m / z: 280 [M⁺], 136, 57;
Anal. Calcd for C_FifteenH_{twenty four}N_TwoO_Three: C, 64.26; H, 8.63; N, 9.99. Found: C, 64.20; H, 8.86; N, 9.96.

(1c) N²-1,1'-biphenyl-3-yl-N¹-{(1S) -2-[(4-methoxyphenyl) amino] -1-methylethyl} -L-leucinamide
  The tert-butyl (1S) -2-[(4-methoxyphenyl) amino] -1-methylethylcarbamate (2.80 g, 10.0 mmol) produced in Example 1 (1b) was mixed with 1,4-dioxane (10 mL). ), A 4N hydrochloric acid-dioxane solution (10 mL) was added, and the mixture was stirred at room temperature for 30 minutes. The residue obtained by concentrating the reaction solution under reduced pressure was dissolved in N, N-dimethylformamide (100 mL), and N-1,1′-biphenyl-3-yl-L prepared in Example 1 (1a) was dissolved. -Leucine (2.83 g, 10.0 mmol), 1-hydroxybenzotriazole hydrate (1.62 g, 12.0 mmol), triethylamine (3.3 mL, 24.0 mmol) and 1-ethyl-3- (3- (Dimethylaminopropyl) -carbodiimide hydrochloride (2.30 g, 12.0 mmol) was added sequentially. After stirring the reaction solution at room temperature for 9 hours, ethyl acetate (100 mL) was added to the reaction solution. The organic layer was washed with an aqueous sodium hydrogen carbonate solution and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate, 2: 1) to obtain the title compound (4.34 g, yield 97%).
IR (KBr) ν_max 3353, 2956, 1650, 1605, 1513, 1323, 1235, 821, 758, 700 cm^-1;
¹H NMR (CDCl_Three, 400 MHz) 0.94 (3H, d, J = 6.6 Hz), 1.01 (3H, d, J = 5.9 Hz), 1.19 (3H, d, J = 6.6 Hz), 1.56-1.91 (3H, m), 3.00 (1H, dd, J = 7.3, 12.5 Hz), 3.07 (1H, dd, J = 4.4, 12.5 Hz), 3.52 (1H, br s), 3.70 (3H, s), 3.74-3.79 (1H, m) , 3.93 (1H, d, J = 2.9 Hz), 4.19-4.28 (1H, m), 6.36 (2H, d, J = 8.8 Hz), 6.58 (1H, d, J = 8.1 Hz), 6.67 (2H, d, J = 8.8 Hz), 6.82-6.84 (2H, m), 7.05 (1H, d, J = 7.3 Hz), 7.20 (1H, t, J = 7.3 Hz), 7.31-7.37 (3H, m), 7.52 (2H, d, J = 6.6 Hz);
HRMS calcd for C₂₈H₃₆N_ThreeO_Two446.2807 [M + H]⁺, found = 446.2813.

[Example 2] N²-1,1'-biphenyl-3-yl-N¹-((1S) -1-{[(4-methoxyphenyl) amino] methyl} propyl) -L-leucinamide (Exemplary Compound No. 1-29)
(2a) tert-butyl (1S) -1-{[(4-methoxyphenyl) amino] methyl} propyl carbamate
  (S) -2- (tert-Butoxycarbonylamino) -1-butanol (Tetrahedron, Vol. 51, 12337-12350, 1995) (18.93 g, 100 mmol) was converted to (S) -2- (tert-butoxycarbonylamino). ) A similar reaction to that described in Example 1 (1b) was performed in place of 1-propanol to give the title compound (12.16 g, yield 83%).
Mp 97-99 ° C;
IR (KBr) ν_max3388, 1681, 1517, 1238, 1174, 1041, 816 cm^-1;
¹H NMR (CDCl_Three, 400MHz) δ 0.97 (3H, t, J = 7.3 Hz), 1.45 (9H, s), 1.42-1.68 (2H, m), 2.99-3.04 (1H, m), 3.18 (1H, dd, J = 4.4 , 11.7 Hz), 3.68-3.78 (2H, m), 3.74 (3H, s), 4.46 (1H, br s), 6.58 (2H, d, J = 8.8 Hz), 6.77 (2H, d, J = 8.8 Hz);
MS (FAB) m / z: 295 [M + H]⁺, 294, 239, 136, 57;
HRMS (ESI) calcd for C₁₆H₂₇N_TwoO_Three295.2022 [M + H]⁺, found 295.2023.
Anal. Calcd for C₁₆H₂₆N_TwoO_Three: C, 65.28; H, 8.90; N, 9.52. Found: C, 65.16; H, 8.58; N, 9.57.

(2b) N²-1,1'-biphenyl-3-yl-N¹-((1S) -1-{[(4-methoxyphenyl) amino] methyl} propyl) -L-leucinamide
  To a solution of tert-butyl (1S) -1-{[(4-methoxyphenyl) amino] methyl} propylcarbamate (589 mg, 2.0 mmol) prepared in Example 2 (2a) in 1,4-dioxane (3 mL) A 4N hydrochloric acid-dioxane solution (3 mL) was added, and the mixture was stirred at room temperature for 30 minutes. The residue obtained by concentrating the mixture under reduced pressure was dissolved in methylene chloride (20 mL), and N-1,1′-biphenyl-3-yl-L-leucine (567 mg, prepared in Example 1 (1a)) was used. 2.0 mmol), 1-hydroxybenzotriazole hydrate (405 mg, 3.0 mmol), triethylamine (0.84 mL, 6.0 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride ( 575 mg, 3.0 mmol). After the reaction mixture was stirred at room temperature for 2 hours, it was partitioned between ethyl acetate (20 mL) and a saturated aqueous solution of sodium hydrogen carbonate. After the organic layer was dried over sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate, 2: 1), and crystallized from isopropyl ether to obtain the title compound (560 mg, yield 61%).
Mp 99-101 ° C;
IR (KBr) ν_max 3336, 2961, 1645, 1606, 1514, 1479, 1235, 1038, 821, 759, 699 cm^-1;
¹H NMR (CDCl_Three, 400 MHz) δ 0.89 (3H, d, J = 7.3 Hz), 0.90 (3H, d, J = 5.9 Hz), 0.98 (3H, d, J = 6.6 Hz), 1.37-1.88 (5H, m), 2.93 (1H, dd, J = 7.3, 12.5 Hz), 3.07 (1H, dd, J = 4.4, 12.5 Hz), 3.66 (3H, s), 3.72-3.75 (1H, m), 3.89 (1H, br s ), 3.97-4.05 (1H, m), 6.31 (2H, d, J = 8.8 Hz), 6.55 (1H, d, J = 8.1 Hz), 6.62 (2H, d, J = 8.8 Hz), 6.73 (1H , d, J = 7.3 Hz), 6.80 (1H, s), 7.00 (1H, d, J = 7.3 Hz), 7.15 (1H, t, J = 7.3 Hz), 7.25-7.33 (3H, m), 7.47 (2H, d, J = 7.3 Hz).

[Example 3] N¹-{(1S) -2-[(4-methoxyphenyl) amino] -1-methylethyl} -N²-(2-oxo-6-phenyl-2H-pyran-4-yl) -L-leucinamide (Exemplary Compound No. 3-1)
(3a) 4-bromo-6-phenyl-2H-pyran-2-one
  4-Hydroxy-6-phenyl-2H-pyran-2-one (Synth. Commun., Vol. 19, 2453-2460, 1989) (14.23 g, 75.6 mmol) in N, N-dimethylformamide (300 mL). Phosphorus tribromide (28.7 mL, 302.4 mmol) was added to the solution. After stirring the reaction solution at 60 ° C. for 10 hours, water (300 mL) and ethyl acetate (300 mL) were added. After separating the organic layer, the organic layer was washed successively with water (300 ml × 3) and brine (300 mL), dried over sodium sulfate, and concentrated. The crude product was purified by recrystallization (methylene chloride / hexane) to obtain the title compound (10.56 g, yield 56%).
IR (KBr) ν_max 1724, 1608, 1532, 1494, 1323, 1149, 855, 777 cm^-1,
¹H NMR (CDCl_Three, 400 MHz) δ 6.58 (1H, d, J = 1.5 Hz), 6.83 (1H, d, J = 1.5 Hz), 7.46-7.53 (3H, m), 7.80-7.84 (2H, m);
HRMS m / z calcd for C₁₁H₇O_TwoBr 249.9629, found 249.9628.

(3b) N- (2-oxo-6-phenyl-2H-pyran-4-yl) -L-leucine
  4-bromo-6-phenyl-2H-pyran-2-one (10.35 g, 41.2 mmol), L-leucine (10.81 g, 82.4 mmol), potassium carbonate (11.39 g, 82.4 mmol) and A mixture of tert-butanol (200 mL) was heated at reflux for 3 hours. 1N Hydrochloric acid (120 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (120 mL). The extract was washed successively with water (100 mL × 3) and brine (100 mL × 1), dried over sodium sulfate and concentrated. The crude crystals were washed with ether to give the title compound (9.56 g, yield 77%).
Mp 255-258 ° C;
IR (KBr) ν_max 2964, 1746, 1652, 1610, 1542, 1194, 1068, 778, 692 cm^-1.
¹H NMR (DMSO-d₆, 400 MHz) δ 0.88 (3H, d, J = 6.6 Hz), 0.93 (3H, d, J = 5.9 Hz), 1.60-1.76 (3H, m), 3.94-4.01 (1H, m), 4.84 (1H , s), 6.63 (1H, s), 7.46-7.53 (3H, m), 7.69-7.71 (2H, m);
HRMS m / z calcd for C₁₇H₂₀NO_Four302.1393 [M + H]⁺, found 302.1393.

(3c) (2S) -N¹-(4-methoxyphenyl) propane-1,2-diamine
  The tert-butyl (1S) -2-[(4-methoxyphenyl) amino] -1-methylethylcarbamate (4.95 g, 17.7 mmol) produced in Example 1 (1b) was added to 4N hydrochloric acid-dioxane (50 mL). ) And stirred for 45 minutes. The residue was partitioned between water (50 mL) and methylene chloride (50 mL). The separated aqueous layer was neutralized with a saturated aqueous solution of sodium hydrogen carbonate, and then extracted with methylene chloride (50 mL × 8). After the extract was dried over sodium sulfate, the solvent was distilled off under reduced pressure to obtain the title compound (3.02 g, yield: 95%).
IR (film) ν_max3356, 2958, 1514, 1236, 1037, 821 cm^-1;
¹H NMR (CDCl_Three, 400MHz) δ 1.15 (3H, d, J = 6.6 Hz), 2.83 (1H, dd, J = 8.1, 12.5 Hz), 3.09 (1H, dd, J = 4.4, 12.5 Hz), 3.13-3.18 (1H, m), 3.75 (3H, s), 6.61 (2H, d, J = 8.8 Hz), 6.78 (2H, d, J = 8.8 Hz);
MS (EI) m / z: 180 [M⁺], 122, 136;
Anal. Calcd for C_TenH₁₆N_TwoO ・ 0.18H_TwoO: C, 65.46; H 8.99 ,; N, 15.27. Found: C, 65.27; H, 9.28; N, 15.16.

(3d) N¹-{(1S) -2-[(4-methoxyphenyl) amino] -1-methylethyl} -N²-(2-oxo-6-phenyl-2H-pyran-4-yl) -L-leucinamide
  N, N-dimethylformamide (5 mL) solution of N- (2-oxo-6-phenyl-2H-pyran-4-yl) -L-leucine (316 mg, 1.05 mmol) produced in Example 3 (3b) In addition, (2S) -N1- (4-methoxyphenyl) propane-1,2-diamine (180 mg, 1.0 mmol) produced in Example 3 (3c), 1-hydroxybenzotriazole hydrate (168 mg, 1 .1 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (211 mg, 1.1 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was partitioned between water (50 mL) and ethyl acetate (50 mL), and the organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane / ethyl acetate, 1: 5) to obtain the title compound (423 mg, yield: 91%).
IR (KBr) 1654, 1550, 1514, 1235 cm^-1;
¹H NMR (CDCl_Three, 400 MHz) δ 0.84 (3H, d, J = 4.3 Hz), 0.92 (3H, d, J = 5.8 Hz), 1.23 (3H, d, J = 6.7 Hz), 1.66 -1.73 (3H, m), 3.10-3.20 (2H, m), 3.69 (3H, s), 3.87 (1H, br), 4.10-4.15 (1H, m), 4.19-4.24 (1H, m), 5.41 (1H, br s), 6.33 (1H, br s), 6.40 (1H, br), 6.56 (2H, d, J = 8.9 Hz), 6.72 (2H, d, J = 8.9 Hz), 7.35 -7.40 (3H, m), 7.66-7.67 (2H, m), 7.86 (1H, br);
MS (FAB) m / z: 464 [M + H]⁺.
Anal. Calcd for C₂₇H₃₃N_ThreeO_Four・ 0.4 H_TwoO: C, 68.88; H, 7.24; N, 8.93. Found: C, 68.93; H, 6.91; N, 8.94.

[Example 4] N¹-((1S) -1-{[(4-methoxyphenyl) amino] methyl} propyl) N²-(2-oxo-6-phenyl-2H-pyran-4-yl) -L-leucinamide (Exemplary Compound No. 3-2)
  N- (2-oxo-6-phenyl-2H-pyran-4-yl) -L- produced in Example 3 (3b) in place of N-1,1'-biphenyl-3-yl-L-leucine Using leucine (603 mg, 2.0 mmol), a reaction similar to the reaction described in Example 2 (2b) was performed. The obtained crude product was purified by silica gel column chromatography (100% ethyl acetate), and then crystallized from isopropyl ether to give the title compound (860 mg, yield 90%).
Mp 170-173 ° C;
IR (KBr) ν_max 3271, 3088, 2959, 1651, 1549, 1514, 1298, 1237, 820, 767, 693, 626 cm^-1;
¹H NMR (CDCl_Three, 400 MHz) δ 0.89 (3H, d, J = 5.9 Hz), 0.95 (3H, d, J = 7.3 Hz), 0.96 (3H, d, J = 8.1 Hz), 1.62-1.74 (5H, m), 3.15 (1H, dd, J = 6.6, 12.5 Hz), 3.21 (1H, dd, J = 4.4, 12.5 Hz), 3.69 (3H, s), 3.98-4.11 (2H, m), 5.25 (1H, s) , 6.34 (1H, d, J = 6.6 Hz), 6.20 (1H, s), 6.56 (2H, d, J = 8.8 Hz), 6.72 (2H, d, J = 8.8 Hz), 7.37-7.45 (3H, m), 7.71-7.74 (2H, m).

Example 5 1- (1,1′-biphenyl-3-ylamino) -N-{(1S) -2-[(4-methoxyphenyl) amino] -1-methylethyl} cyclohexanecarboxamide (Exemplary compound number 2-2)
(5a) 1- (1,1′-biphenyl-3-ylamino) cyclohexanecarboxylic acid
  The compound was synthesized by the following methods (Method A and Method B) with reference to the method of literature (J. Am. Chem. Soc., Vol. 120, 1998, 12459-12467).
<Method A>
(5aA-1)
  Under a nitrogen atmosphere, 3-bromobiphenyl (9.33 g, 40 mmol), 1-aminocyclohexanecarboxylic acid (5.73 g, 40 mmol), potassium carbonate (8.29 g, 60 mmol) and bromo (dimethylsulfide) copper (I) ( (1.64 g, 8 mmol) was stirred in N, N-dimethylacetamide (50 mL) at 120 ° C. for 5 hours. Ethyl acetate (200 mL) and water (200 mL) were added to the reaction solution, and insolubles were removed using Celite. The separated aqueous layer was made acidic (pH = 3) with concentrated hydrochloric acid, and extracted with ethyl acetate (150 mL × 2). After the extract was dried over sodium sulfate, the solvent was distilled off, and the obtained residue was crystallized from 70% ethanol (40 mL). The crystals were separated by filtration and washed several times with 70% ethanol to obtain 1- (1,1'-biphenyl-3-ylamino) cyclohexanecarboxylic acid (5.10 g, yield 43%).
Mp 173-174 ° C;
IR (KBr) ν_max3404, 1621, 757, 699 cm^-1;
¹H NMR (CDCl_Three, 400 MHz) δ 1.40-2.03 (10H, m), 6.67 (1H, ddd, J = 1.0, 2.0, 8.0 Hz), 6.89 (1H, t, J = 2.0 Hz), 7.13 (1H, br d, J = 8.0 Hz), 7.29 (1H, t, J = 8.0 Hz), 7.36-7.33 (1H, m), 7.44-7.41 (2H, m), 7.55-7.52 (2H, m);
MS (EI⁺) m / z: 295 [M⁺];
Anal. Calcd for C₁₉H_{twenty one}NO_Two・ 0.1 H_TwoO: C, 76.79; H, 7.19; N, 4.71. Found: C, 76.85; H, 7.12; N, 4.67.
<Method B>
(5aB-1)
  Under a nitrogen atmosphere, 1,3-dibromobenzene (24.25 g, 103 mmol), 1-aminocyclohexanecarboxylic acid (14.72 g, 103 mmol), potassium carbonate (21.31 g, 154 mmol) and bromo (dimethylsulfide) copper (I ) (2.11 g, 10 mmol) was mixed with N, N-dimethylacetamide (130 mL) and stirred at 120 ° C. for 3 hours. Ethyl acetate (200 mL) and water (200 mL) were added to the reaction solution, and insolubles were removed with Celite. The separated aqueous layer was made acidic (pH = 4) with concentrated hydrochloric acid, and extracted with ethyl acetate (150 mL × 2). After the extract was dried over sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (100% ethyl acetate), and the obtained crystal (23 g) was further diluted with ether. After washing, 1-[(3-bromophenyl) amino] cyclohexanecarboxylic acid (13.55 g, yield 44%) was obtained.
Mp 141-143 ° C;
IR (KBr) ν_max3250, 1705, 1592, 1479, 1227, 770 cm^-1;
¹H NMR (CDCl_Three, 400MHz) δ 1.30-1.70 (6H, m), 1.90-2.10 (4H, m), 6.57 (1H, ddd, J = 0.8, 2.3, 8.0 Hz), 6.83 (1H, dd, J = 1.7, 2.3 Hz ), 6.97 (1H, ddd, J = 0.8, 1.7, 8.0 Hz), 7.05 (1H, t, J = 8.0 Hz);
MS (EI) m / z: 297 [M⁺], 252.
(5aB-2) Under a nitrogen atmosphere, 1-[(3-bromophenyl) amino] cyclohexanecarboxylic acid (12.85 g, 43.1 mmol), phenylboric acid (7.88 g, 64.6 mmol), sodium carbonate (13. 71 g, 129.3 mmol) and palladium acetate (0.48 g, 2.2 mmol) were mixed in water (130 mL), and the mixture was stirred with heating under reflux for 4 hours. Insolubles were removed by Celite filtration, and the filtrate was washed with ether (100 mL). The organic layer was further washed with a 0.4 M aqueous sodium carbonate solution (2 × 50 mL). The mixture of all aqueous layers was neutralized by adding concentrated hydrochloric acid. After the precipitated crystals were separated by filtration, the filtrate was further extracted with ethyl acetate (2 × 100 mL). After the extract was dried over sodium sulfate, the solvent was distilled off under reduced pressure. The obtained crude crystals and the crystals previously filtered are combined, recrystallized from 70% aqueous ethanol (300 mL), and 1- (1,1′-biphenyl-3-ylamino) cyclohexanecarboxylic acid (7.23 g, (57% yield).

(5b) 1- (1,1'-biphenyl-3-ylamino) -N-{(1S) -2-[(4-methoxyphenyl) amino] -1-methylethyl} cyclohexanecarboxamide
  Example 5 1- (1,1′-Biphenyl-3-ylamino) cyclohexanecarboxylic acid (169 mg, 0.57 mmol) produced in (5a) was dissolved in N, N-dimethylformamide (3 mL), and Example 3 was dissolved. (2S) -N produced in (3c)¹-(4-methoxyphenyl) propane-1,2-diamine (103 mg, 0.57 mmol), 1-hydroxybenzotriazole hydrate (92 mg, 0.68 mmol) and 1-ethyl-3- (3-dimethylaminopropyl ) -Carbodiimide hydrochloride (131 mg, 0.68 mmol) was added, and the mixture was stirred at room temperature for 16 hours. Water and ethyl acetate were added to the reaction mixture for liquid separation. The organic layer was washed sequentially with water and saturated saline, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate, 3: 1-2: 1) to give the title compound (194 mg, yield 74%).
IR (KBr) ν_max3368, 2933, 2856, 1652, 1601, 1513 cm^-1;
¹H NMR (CDCl_Three, 400MHz) δ 1.17 (3H, d, J = 6.6 Hz), 1.32-1.34 (3H, m), 1.60-1.66 (3H, m), 1.92-2.03 (4H, m), 3.03 (1H, dd, J = 7.3, 12.5 Hz), 3.09 (1H, dd, J = 5.1, 12.5 Hz), 3.64 (1H, br s), 3.72 (3H, s), 4.04 (1H, s), 4.20-4.27 (1H, m ), 6.44 (2H, d, J = 8.8 Hz), 6.58 (1H, dd, J = 2.2, 8.1 Hz), 6.71 (2H, d, J = 8.8 Hz), 6.83-6.84 (1H, m), 7.03 (1H, d, J = 8.1 Hz), 7.08 (1H, d, J = 8.8 Hz), 7.15 (1H, t, J = 8.1 Hz), 7.31 (1H, t, J = 7.3 Hz), 7.38 (2H , t, J = 7.3 Hz), 7.53 (2H, d, J = 7.3 Hz);
MS (FAB) m / z: 457 [M + H]⁺, 250.

Example 6 1- (1,1′-biphenyl-3-ylamino) -N-{(1R) -2-[(4-methoxyphenyl) amino] -1-methylethyl} cyclohexanecarboxamide (Exemplary compound number 2-2)
(6a) tert-butyl (1R)-[1- (4-methoxyphenylcarbamoyl) ethyl] carbamate
  N- (tert-butoxycarbonyl) -D-alanine (1.00 g, 5.3 mmol), p-anisidine (0.65 g, 5.3 mmol), 1-hydroxybenzotriazole hydrate (0.97 g, 6. 3 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (1.22 g, 6.3 mmol) were added to N, N-dimethylformamide (20 mL), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with saturated saline, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (methylene chloride / ethyl acetate, 20: 1 to 8: 1) to give the title compound (1.22 g, yield 78%).
IR (KBr) ν_max3338, 1686, 1666, 1533, 1516, 1235, 1171, 822 cm^-1;
¹H NMR (CDCl_Three, 400MHz) δ 1.43 (3H, d, J = 6.9 Hz), 1.46 (9H, s), 3.78 (3H, s), 4.30 (1H, br), 5.06 (1H, br), 6.84 (2H, d, J = 9.0 Hz), 7.40 (2H, d, J = 9.0 Hz);
MS (FAB) m / z: 294 [M⁺], 239, 57;
Anal. Calcd for C_FifteenH_{twenty two}N_TwoO_Four: C, 61.21; H, 7.53; N, 9.52. Found: C, 61.03; H, 7.40; N, 9.43.
(6b) tert-butyl (1R) -2-[(4-methoxyphenyl) amino] -1-methylethylcarbamate
  The tert-butyl (1R)-[1- (4-methoxyphenylcarbamoyl) ethyl] carbamate (1.21 g, 4.1 mmol) prepared in Example 6 (6a) was dissolved in tetrahydrofuran (25 mL) and cooled with ice. Underneath, lithium aluminum hydride (0.47 g, 12.3 mmol) was added. After stirring the reaction mixture at room temperature for 8 hours, a 1N aqueous solution of sodium hydroxide was added thereto under ice cooling. After removing the solid by filtration, the filtrate was concentrated. The obtained residue was partitioned between water and ethyl acetate, and the organic layer was washed with saturated saline. The extract was dried over sodium sulfate, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate, 3: 1) to give the title compound (0.80 g, yield 69). %).
IR (KBr) ν_max3390, 1680, 1515, 1239, 1169, 816 cm^-1;
¹H NMR (CDCl_Three, 400MHz) δ 1.21 (3H, d, J = 6.7 Hz), 1.45 (9H, s), 3.04 (1H, dd, J = 7.3, 12.3 Hz), 3.12 (1H, dd, J = 4.9, 12.3 Hz) , 3.74 (3H, s), 3.75 (1H, br), 3.92 (1H, br), 4.52 (1H, br), 6.58 (2H, d, J = 8.9 Hz), 6.77 (2H, d, J = 8.9) Hz);
MS (FAB) m / z: 280 [M⁺], 136, 57;
Anal. Calcd for C_FifteenH_{twenty four}N_TwoO_Three: C, 64.26; H, 8.63; N, 9.99. Found: C, 64.10; H, 8.74; N, 9.97.
(6c) (2R) -N¹-(4-methoxyphenyl) propane-1,2-diamine
  tert-Butyl (1S) -2-[(4-methoxyphenyl) amino] -1-methylethyl carbamate was replaced with tert-butyl (1R) -2-[(4- [Methoxyphenyl) amino] -1-methylethylcarbamate (774 mg, 2.8 mmol) was reacted in the same manner as in Example 3 (3c) to give the title compound (485 mg, 97% yield). ) Got.
IR (neat) ν_max3353, 3267, 3039, 2962, 2899, 2831, 1535, 1514 cm^-1;
¹H NMR (CDCl_Three, 400MHz) δ 1.15 (3H, d, J = 6.6 Hz), 2.83 (1H, dd, J = 8.1, 12.5 Hz), 3.09 (1H, dd, J = 4.4, 12.5 Hz), 3.13-3.18 (1H, m), 3.75 (3H, s), 6.61 (2H, d, J = 8.8 Hz), 6.78 (2H, d, J = 8.8 Hz);
MS (EI) m / z: 180 [M⁺], 122, 136;
Anal. Calcd for C_TenH₁₆N_TwoO ・ 0.2 H_TwoO: C, 66.63; H 8.99 ,; N, 15.24. Found: C, 65.67; H, 8.62; N, 14.93.

(6d) 1- (1,1'-biphenyl-3-ylamino) -N-{(1R) -2-[(4-methoxyphenyl) amino] -1-methylethyl} cyclohexanecarboxamide
  (2S) -N¹(2R) -N prepared in Example 6 (6c) in place of-(4-methoxyphenyl) propane-1,2-diamine¹The same reaction as that described in Example 5 (5b) was carried out using-(4-methoxyphenyl) propane-1,2-diamine (89 mg, 0.49 mmol). The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate, 3: 1 to 2: 1) to give the title compound (195 mg, yield 86%).
IR (KBr) ν_max3368, 2933, 2856, 1652, 1601, 1513 cm^-1;
¹H NMR (CDCl_Three, 400MHz) δ 1.17 (3H, d, J = 6.6 Hz), 1.32-1.34 (3H, m), 1.60-1.66 (3H, m), 1.92-2.03 (4H, m), 3.03 (1H, dd, J = 7.3, 12.5 Hz), 3.09 (1H, dd, J = 5.1, 12.5 Hz), 3.64 (1H, br s), 3.72 (3H, s), 4.04 (1H, s), 4.20-4.27 (1H, m ), 6.44 (2H, d, J = 8.8 Hz), 6.58 (1H, dd, J = 2.2, 8.1 Hz), 6.71 (2H, d, J = 8.8 Hz), 6.83-6.84 (1H, m), 7.03 (1H, d, J = 8.1 Hz), 7.08 (1H, d, J = 8.8 Hz), 7.15 (1H, t, J = 8.1 Hz), 7.31 (1H, t, J = 7.3 Hz), 7.38 (2H , t, J = 7.3 Hz), 7.53 (2H, d, J = 7.3 Hz);
MS (FAB) m / z: 458 [M + H]⁺, 457, 250;
Anal. Calcd for C₂₉H₃₅N_ThreeO_Two・ 0.44 H_TwoO: C, 74.89; H, 7.77; N, 9.03. Found: C, 74.89; H, 7.48; N, 8.86.

Example 7 1- (1,1′-biphenyl-3-ylamino) -N-((1S) -1-{[(4-methoxyphenyl) amino] methyl} -2-methylpropyl) cyclohexanecarboxamide ( Exemplified Compound No. 2-110)
(7a) tert-butyl (1S) -1-{[(4-methoxyphenyl) amino] methyl} -2-methylpropylcarbamate
  Instead of (S) -2- (tert-butoxycarbonylamino) -1-propanol, (S) -2- (tert-butoxycarbonylamino) -3-methyl-1-butanol (Tetrahedron, Vol. 51, 12337) -12350, 1995) (330 mg, 1.62 mmol) and the same reaction as described in Example 1 (1b) was carried out to give the title compound (160 mg, yield 64 based on nitrobenzenesulfonamide). %) Was synthesized.
IR (KBr) ν_max3376, 2973, 2957, 2935, 1680, 1518 cm^-1;
¹H NMR (CDCl_Three, 400MHz) δ 0.95 (3H, d, J = 7.3 Hz), 0.98 (3H, d, J = 6.6 Hz), 1.45 (9H, s), 1.83-1.88 (1H, m), 2.96-3.01 (1H, m), 3.19-3.23 (1H, m), 3.64-3.73 (2H, m), 3.74 (3H, s), 4.48-4.50 (1H, m), 6.57 (2H, d, J = 8.8 Hz), 6.78 (2H, d, J = 8.8 Hz);
MS (FAB) m / z: 309 [M + H]⁺, 308, 253, 136, 57;
Anal. Calcd for C₁₇H₂₈N_TwoO_Three: C, 66.20; H, 9.15; N, 9.08. Found: C, 65.91; H, 9.08; N, 9.09.

(7b) (2S) -N¹-(4-methoxyphenyl) -3-methylbutane-1,2-diamine dihydrochloride
  Tert-Butyl (1S) -1-{[(4-methoxyphenyl) amino] methyl} -2-methylpropylcarbamate (138 mg, 0.45 mmol) prepared in Example 7 (7a) in 1,4-dioxane ( (2 mL), 4N hydrochloric acid-dioxane solution (2 mL) was added to the solution, and the mixture was stirred at room temperature for 2 hours, and then the reaction mixture was concentrated. The powder obtained by adding isopropyl ether to the residue was collected by filtration to obtain the title compound (125 mg, 99%).
IR (KBr) ν_max2963, 1512, 1462, 1261, 1030, 831 cm^-1;
¹H NMR (CDCl_Three, 400MHz) δ 1.09 (3H, d, J = 5.9 Hz), 1.11 (3H, d, J = 6.6 Hz), 2.17-2.22 (1H, m), 3.36 (1H, d, J = 11.7 Hz), 3.79 (3H, s), 4.09-4.17 (2H, m), 6.92 (2H, d, J = 8.8 Hz), 7.59 (2H, d, J = 8.8 Hz);
MS (FAB) m / z: 209 [M + H]⁺, 43, 57, 65, 69, 120;
Anal. Calcd for C₁₂H_{twenty two}N_TwoOCl_Two・ 0.18 H_TwoO: C, 50.67; H, 7.92; N, 9.85. Found: C, 50.80; H, 8.02; N, 9.59.

(7c) 1- (1,1'-biphenyl-3-ylamino) -N-((1S) -1-{[(4-methoxyphenyl) amino] methyl} -2-methylpropyl) cyclohexanecarboxamide
  Example 5 1- (1,1′-Biphenyl-3-ylamino) cyclohexanecarboxylic acid (60 mg, 0.20 mmol) prepared in (5a) was dissolved in N, N-dimethylformamide (2 mL), and Example 7 was performed. (2S) -N produced in (7b)¹-(4-methoxyphenyl) -3-methylbutane-1,2-diamine dihydrochloride (60 mg, 0.21 mmol), 1-hydroxybenzotriazole hydrate (33 mg, 0.24 mmol), 1-ethyl-3- (3-Dimethylaminopropyl) -carbodiimide hydrochloride (47 mg, 0.24 mmol) and triethylamine (0.085 mL, 0.61 mmol) were added. The reaction mixture was stirred at room temperature for 6 hours and partitioned between water and ethyl acetate. The organic layer was washed sequentially with water and saturated saline, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate, 3: 1) to give the title compound (92 mg, yield 93%).
IR (KBr) ν_max3368, 2932, 2857, 1654, 1601, 1513 cm^-1;
¹H NMR (CDCl_Three, 400MHz) δ 0.87 (3H, d, J = 6.6 Hz), 0.91 (3H, d, J = 7.3 Hz), 1.22-1.43 (3H, m), 1.58-1.69 (3H, m), 1.83-1.91 ( 1H, m), 1.94-2.05 (4H, m), 2.98 (1H, dd, J = 8.8, 11.7 Hz), 3.17 (1H, dd, J = 4.4, 11.7 Hz), 3.64 (1H, br s), 3.73 (3H, s), 3.97-4.04 (1H, m), 4.06 (1H, s), 6.41 (2H, dd, J = 8.8 Hz), 6.61 (1H, dd, J = 1.5, 8.1 Hz), 6.71 (2H, d, J = 8.8 Hz), 6.85-6.86 (1H, m), 7.01 (1H, d, J = 8.1 Hz), 7.10 (1H, t, J = 8.1 Hz), 7.14 (1H, d, J = 9.5 Hz), 7.30 (1H, t, J = 7.3 Hz), 7.36 (2H, t, J = 7.3 Hz), 7.52 (2H, d, J = 7.3 Hz);
MS (FAB) m / z: 486 [M + H]⁺, 485, 250, 136;
Anal. Calcd for C₃₁H₃₉N_ThreeO_Two・ 0.44 H_TwoO: C, 75.43; H, 8.14; N, 8.51. Found: C, 75.50; H, 7.79; N, 8.41.

Example 8 1- (1,1′-biphenyl-3-ylamino) -N-((1S) -1-{[(4-methoxyphenyl) amino] methyl} -3-methylbutyl) cyclohexanecarboxamide (example) Compound No. 2-137)
(8a) tert-butyl (1S) -1-{[(4-methoxyphenyl) amino] methyl} -3-methylbutylcarbamate
  Instead of (S) -2- (tert-butoxycarbonylamino) -1-propanol, (S) -2- (tert-butoxycarbonylamino) -4-methyl-1-pentanol (Tetrahedron, Vol. 51, 12337-12350, 1995) (352 mg, 1.62 mmol) and the same reaction as described in Example 1 (1b) was carried out to give the title compound (198 mg, yield based on nitrobenzenesulfonamide). 76%).
IR (KBr) ν_max3405, 2978, 2953, 2911, 1678, 1516 cm^-1;
¹H NMR (CDCl_Three, 400MHz) δ 0.92-0.95 (6H, m), 1.32-1.38 (2H, m), 1.44 (9H, s), 1.68-1.74 (1H, m), 2.96-3.01 (1H, m), 3.17 (1H , dd, J = 4.0, 12.1 Hz), 3.74 (3H, s), 3.76 (1H, br s), 3.86-3.89 (1H, m), 4.40 (1H, br s), 6.57 (2H, d, J = 8.8 Hz), 6.77 (2H, d, J = 8.8 Hz);
MS (FAB) m / z: 323 [M + H]⁺, 322, 267, 136, 57;
Anal. Calcd for C₁₈H₃₀N_TwoO_Three・ 0.2 H_TwoO: C, 66.31; H, 9.40; N, 8.59. Found: C, 66.30; H, 9.36; N, 8.60.

(8b) (2S) -N¹-(4-methoxyphenyl) -4-methylpentane-1,2-diamine dihydrochloride
  tert-Butyl (1S) -1-{[(4-methoxyphenyl) amino] methyl} -2-methylpropylcarbamate is replaced with tert-butyl (1S) -1-} produced in Example 7 (7a). Using [(4-methoxyphenyl) amino] methyl} -3-methylbutylcarbamate (190 mg, 0.59 mmol), a reaction similar to the reaction described in Example 7 (7b) was carried out to give the title compound ( 172 mg, 99%).
IR (KBr) ν_max2958, 1512, 1466, 1258, 1030, 834 cm^-1;
¹H NMR (CDCl_Three, 400MHz) δ 0.90 (6H, d, J = 5.9 Hz), 1.61-1.89 (3H, m), 3.36 (1H, d, J = 13.9 Hz), 3.67 (3H, s), 4.21-4.27 (1H, m), 4.34-4.39 (1H, m), 7.88 (2H, d, J = 8.8 Hz), 7.73 (2H, d, J = 8.8 Hz);
MS (EI) m / z: 222 [M + H]⁺, 137, 122, 86.

(8c) 1- (1,1'-biphenyl-3-ylamino) -N-((1S) -1-{[(4-methoxyphenyl) amino] methyl} -3-methylbutyl) cyclohexanecarboxamide
  (2S) -N¹(2S) -N prepared in Example 8 (8b) instead of-(4-methoxyphenyl) -3-methylbutane-1,2-diamine dihydrochloride¹Using-(4-methoxyphenyl) -4-methylpentane-1,2-diamine dihydrochloride (80 mg, 0.27 mmol), a reaction similar to the reaction described in Example 7 (7c) was performed. The title compound (115 mg, yield 88%) was obtained.
IR (neat) ν_max3368, 2934, 2858, 1650, 1601, 1513 cm^-1;
¹H NMR (CDCl_Three, 400MHz) δ 0.82 (3H, d, J = 6.6 Hz), 0.83 (3H, d, J = 6.6 Hz), 1.26-1.39 (5H, m), 1.51-1.65 (4H, m), 1.94-2.02 ( 4H, m), 2.99 (1H, dd, J = 7.3, 11.7 Hz), 3.11 (1H, dd, J = 4.4, 11.7 Hz), 3.73 (1H, br s), 3.73 (3H, s), 4.04 ( 1H, s), 4.18-4.25 (1H, m), 6.45 (2H, d, J = 8.8 Hz), 6.59 (1H, dd, J = 1.5, 8.1 Hz), 6.73 (2H, d, J = 8.8 Hz) ), 6.83 (1H, s), 6.99-7.02 (2H, m), 7.11 (1H, t, J = 8.1 Hz), 7.30 (1H, t, J = 7.3 Hz), 7.36 (2H, t, J = 7.3 Hz), 7.52 (2H, d, J = 7.3 Hz);
MS (FAB) m / z: 500 (M + H)⁺, 499, 250;
Anal. Calcd for C₃₂H₄₁N_ThreeO_Two・ 0.38 H_TwoO: C, 75.88; H, 8.31; N, 7.52. Found: C, 75.90; H, 8.03; N, 8.30.

Example 9 1- (1,1′-biphenyl-3-ylamino) -N-((1S) -1-{[(4-methoxyphenyl) amino] methyl} propyl) cyclohexanecarboxamide (Exemplified Compound No. 2) -29)
(9a) (2S) -N¹-(4-methoxyphenyl) butane-1,2-diamine
  tert-butyl (1S) -2-[(4-methoxyphenyl) amino] -1-methylethyl carbamate was replaced with tert-butyl (1S) -1-{[(4 The same reaction as that described in Example 3 (3c) was carried out using -methoxyphenyl) amino] methyl} propylcarbamate (75 mg, 0.26 mmol) to give the title compound (41 mg, yield 83%). Got.
¹H NMR (CDCl_Three, 400MHz) δ 0.98 (3H, t, J = 7.3 Hz), 1.30-1.59 (2H, m), 2.81 (1H, dd, J = 8.1, 11.7 Hz), 2.85-2.91 (1H, m), 3.16 ( 1H, dd, J = 3.7, 11.7 Hz), 3.75 (3H, s), 6.61 (2H, d, J = 8.8 Hz), 6.78 (2H, d, J = 8.8 Hz);
MS (EI) m / z: 194 [M + H]⁺, 137, 122, 58;
HRMS (EI) m / z calcd for C₁₁H₁₈N_TwoO 194.1419, found 194.1417.

(9b) 1- (1,1'-biphenyl-3-ylamino) -N-((1S) -1-{[(4-methoxyphenyl) amino] methyl} propyl) cyclohexanecarboxamide
  (2S) -N¹(2S) -N prepared in Example 9 (9a) instead of-(4-methoxyphenyl) propane-1,2-diamine¹Using-(4-methoxyphenyl) butane-1,2-diamine (41 mg, 0.21 mmol), a reaction similar to the reaction described in Example 5 (5b) was carried out to give the title compound (84 mg, yield 85%).
IR (KBr) ν_max3366, 2933, 2856, 1651, 1601, 1513 cm^-1;
¹H NMR (CDCl_Three, 400MHz) δ 0.88 (3H, t, J = 7.7 Hz), 1.24-1.48 (5H, m), 1.60-1.66 (3H, m), 1.94-2.08 (4H, m), 3.02 (1H, dd, J = 8.1, 12.5 Hz), 3.13 (1H, dd, J = 4.4, 12.5 Hz), 3.66 (1H, br s), 3.72 (3H, s), 4.03-4.09 (2H, m), 6.43 (2H, d , J = 8.8 Hz), 6.60 (1H, dd, J = 1.5, 8.1 Hz), 6.72 (2H, d, J = 8.8 Hz), 6.85 (1H, m), 7.01-7.05 (2H, m), 7.13 (1H, t, J = 8.1 Hz), 7.31 (1H, t, J = 7.3 Hz), 7.37 (2H, t, J = 7.3 Hz), 7.53 (2H, d, J = 7.3 Hz);
MS (FAB) m / z: 472 [M + H]⁺, 471, 250, 136.

Example 10 1- (1,1′-biphenyl-3-ylamino) -N-{(1S) -2-[(4-methoxyphenyl) amino] -1-phenylethyl} cyclohexanecarboxamide (Exemplary compound number 2-164)
(10a) tert-butyl (1S) -2-[(4-methoxyphenyl) amino] -1-phenylethylcarbamate
  Instead of (S) -2- (tert-butoxycarbonylamino) -1-propanol, (S) -2- (tert-butoxycarbonylamino) -2-phenyl-1-ethanol (Tetrahedron, Vol. 51, 12337) -12350, 1995) (380 mg, 1.6 mmol) and the same reaction as described in Example 1 (1b) was carried out to give the title compound (150 mg, yield 55 based on nitrobenzenesulfonamide). %).
IR (KBr) ν_max3387, 3362, 2976, 2936, 1685, 1517 cm^-1;
¹H NMR (CDCl_Three, 400MHz) δ 1.43 (9H, s), 3.40-3.50 (3H, m), 3.74 (3H, s), 4.88-4.96 (1H, m), 5.08-5.16 (1H, m), 6.58 (2H, d , J = 8.8 Hz), 6.77 (2H, d, J = 8.8 Hz), 7.28-7.31 (3H, m), 7.35-7.39 (2H, m);
MS (FAB) m / z: 343 [M + H]⁺, 342, 287, 226, 136, 57;

(10b) (1S) -N²-(4-methoxyphenyl) -1-phenylethane-1,2-diamine dihydrochloride
  tert-butyl (1S) -1-{[(4-methoxyphenyl) amino] methyl} -2-methylpropylcarbamate is replaced with tert-butyl (1S) -2- [produced in Example 10 (10a). (4-Methoxyphenyl) amino] -1-phenylethylcarbamate (130 mg, 0.38 mmol) was reacted in the same manner as in Example 7 (7b) to give the title compound (119 mg, 99 mg). %).
IR (KBr) ν_max2911, 1512, 1261, 1029, 831, 764, 699 cm^-1;
¹H NMR (CDCl_Three, 400MHz) δ 3.49 (1H, d, J = 11.0 Hz), 3.70 (3H, s), 4.73 (1H, t, J = 11.0 Hz), 5.61 (1H, d, J = 11.0 Hz), 6.85 (2H , d, J = 8.8 Hz), 7.25-7.28 (3H, m), 7.61-7.63 (4H, m);
MS (EI) m / z: 242 [M⁺], 77, 106, 120, 136;
HRMS (EI) m / z calcd for C_FifteenH₁₈N_TwoO 242.1419 [M + H]⁺, found 242.1413.

(10c) 1- (1,1'-biphenyl-3-ylamino) -N-{(1S) -2-[(4-methoxyphenyl) amino] -1-phenylethyl} cyclohexanecarboxamide
  (2S) -N¹(1S) -N prepared in Example 10 (10b) instead of-(4-methoxyphenyl) -3-methylbutane-1,2-diamine dihydrochloride²The same reaction as that described in Example 7 (7c) was carried out using-(4-methoxyphenyl) -1-phenylethane-1,2-diamine dihydrochloride (31 mg, 0.10 mmol). The title compound (44 mg, yield 96%) was obtained.
IR (KBr) ν_max3369, 2934, 1658, 1601, 1513 cm^-1;
¹H NMR (CDCl_Three, 400MHz) δ 1.31-2.05 (10H, m), 3.31-3.41 (3H, m), 3.70 (3H, s), 4.07 (1H, s), 5.19-5.24 (1H, m), 6.39 (2H, d , J = 8.8 Hz), 6.59 (1H, dd, J = 2.2, 8.1 Hz), 6.68 (2H, d, J = 8.8 Hz), 6.82 (1H, s), 7.04 (1H, d, J = 8.1 Hz) ), 7.17 (1H, t, J = 7.3 Hz), 7.21-7.26 (5H, m), 7.30-7.33 (1H, m), 7.37 (2H, t, J = 7.3 Hz), 7.48 (2H, d, J = 7.3 Hz), 7.64 (1H, d, J = 8.1 Hz);
MS (FAB) m / z: 520 [M + H]⁺, 519, 250;

Example 11 N-{(1S) -1-benzyl-2-[(4-methoxyphenyl) amino] ethyl} -1- (1,1′-biphenyl-3-ylamino) cyclohexanecarboxamide (exemplary compound number 2-191)
(11a) tert-butyl (1S) -1-benzyl-2-[(4-methoxyphenyl) amino] ethylcarbamate
  Instead of (S) -2- (tert-butoxycarbonylamino) -1-propanol, (S) -2- (tert-butoxycarbonylamino) -3-phenyl-1-propanol (Tetrahedron, Vol. 51, 12337) -12350, 1995) (402 mg, 1.6 mmol), and the same reaction as described in Example 1 (1b) was carried out to give the title compound (150 mg, yield 53 based on nitrobenzenesulfonamide). %) Was synthesized.
IR (KBr) ν_max3400, 3378, 2983, 2934, 2905, 1676, 1517 cm^-1;
¹H NMR (CDCl_Three, 400MHz) δ 1.41 (9H, s), 2.82-2.90 (2H, m), 3.00-3.04 (1H, m), 3.19 (1H, dd, J = 4.4, 12.5 Hz), 3.63 (1H, br s) , 3.74 (3H, s), 4.01-4.10 (1H, m), 4.50-4.59 (1H, m), 6.54 (2H, d, J = 8.8 Hz), 6.76 (2H, d, J = 8.8 Hz), 7.19-7.25 (3H, m), 7.31 (2H, t, J = 7.3 Hz);
MS (FAB) m / z: 357 [M + H]⁺, 356, 301, 136, 57;
Anal. Calcd for C_{twenty one}H₂₈N_TwoO_Three: C, 70.76; H, 7.92; N, 7.86. Found: C, 70.60; H, 7.78; N, 7.83.

(11b) (2S) -N¹-(4-methoxyphenyl) -3-phenylpropane-1,2-diamine dihydrochloride
  tert-Butyl (1S) -1-benzyl prepared in Example 11 (11a) instead of (1S) -1-{[(4-methoxyphenyl) amino] methyl} -2-methylpropylcarbamate Using the same reaction as described in Example 7 (7b) using -2-[(4-methoxyphenyl) amino] ethyl carbamate (138 mg, 0.39 mmol), the title compound (125 mg, 99 mg) was obtained. %).
¹H NMR (CDCl_Three, 400MHz) δ 3.08 (1H, dd, J = 10.8, 13.8 Hz), 3.31 (1H, d, J = 13.8 Hz), 3.59-3.62 (1H, m), 3.70 (3H, s), 4.30-4.37 ( 1H, m), 4.47-4.55 (1H, m), 6.72 (2H, d, J = 8.7 Hz), 7.16-7.19 (5H, m), 7.41 (2H, d, J = 8.7 Hz);
MS (FAB) m / z: 257 [M + H]⁺, 43, 57, 69, 97, 229;

(11c) N-{(1S) -1-benzyl-2-[(4-methoxyphenyl) amino] ethyl} -1- (1,1'-biphenyl-3-ylamino) cyclohexanecarboxamide
  (2S) -N¹(2S) -N produced in Example 11 (11b) in place of-(4-methoxyphenyl) -3-methylbutane-1,2-diamine dihydrochloride¹A reaction similar to the reaction described in Example 7 (7c) was carried out using-(4-methoxyphenyl) -3-phenylpropane-1,2-diamine dihydrochloride (54 mg, 0.17 mmol). The title compound (69 mg, yield 86%) was obtained.
IR (KBr) ν_max3369, 2934, 2956, 1654, 1601, 1513 cm^-1;
¹H NMR (CDCl_Three, 400MHz) δ 1.24-2.04 (10H, m), 2.86 (2H, d, J = 6.6 Hz), 3.04 (1H, dd, J = 7.3, 12.5 Hz), 3.16 (1H, dd, J = 4.4, 12.5 Hz), 3.60 (1H, s), 3.71 (3H, s), 3.99 (1H, s), 4.37-4.47 (1H, m), 6.38 (2H, d, J = 8.8 Hz), 6.52 (1H, d , J = 8.1 Hz), 6.69 (2H, d, J = 8.8 Hz), 6.82 (1H, s), 7.02 (1H, d, J = 8.1 Hz), 7.08-7.25 (7H, m), 7.29-7.32 (1H, m), 7.37 (2H, t, J = 6.6 Hz), 7.53 (2H, d, J = 7.3 Hz);
MS (FAB) m / z: 534 [M + H]⁺, 533, 250;
Anal. Calcd for C₃₅H₃₉N_ThreeO_Two・ 0.54 H_TwoO: C, 77.36; H, 7.43; N, 7.73. Found: C, 77.35; H, 7.51; N, 7.80.

Example 12 1- (1,1′-biphenyl-3-ylamino) -N-((1S) -1-{[(4-methoxyphenyl) amino] methyl} -3-phenylpropyl) cyclohexanecarboxamide ( Exemplified compound number 2-218)
(12a) tert-butyl (1S) -1- (hydroxymethyl) -3-phenylpropylcarbamate
  It was synthesized as follows according to the method described in the literature (J. Org. Chem., Vol. 66, 1919-1923, 2001).

Ｎ−（tert−ブトキシカルボニル）−Ｌ−ホモフェニルアラニン（４７６ｍｇ，１．７０ｍｍｏｌ）のテトラヒドロフラン（１０ｍＬ）溶液に、−１０℃で、Ｎ−メチルモルホリン（０．１９ｍＬ，１．７０ｍｍｏｌ）及びクロロ炭酸エチル（０．１６ｍＬ，１．７０ｍｍｏｌ）を加え、２０分間攪拌した。同温度で水素化ホウ素ナトリウム（１９３ｍｇ，５．１０ｍｍｏｌ）を加えたのち、反応温度を０℃に昇温し、メタノール（２０ｍＬ）を２０分間で滴下した。反応混合物を同温度でさらに２０分間攪拌したのち、１Ｍ硫酸水素カリウム水溶液を加え中和した。溶媒を減圧下留去したのち、残留物を水及び酢酸エチルで分液した。有機層を飽和食塩水で洗浄し、硫酸ナトリウム上で乾燥後、溶媒を減圧下留去した。残留物をシリカゲルカラムクロマトグラフィー（塩化メチレン／酢酸エチル，５：１）で精製し、標記化合物（４２０ｍｇ，収率９３％）を得た。
IR (KBr) ν_max3375, 1686, 1517, 1245, 1175, 744, 700 cm^-1;
¹H NMR (CDCl₃, 400MHz) δ 1.45 (9H, s), 1.74-1.86 (2H, m), 2.22 (1H, br s), 2.65-2.73 (2H, m), 3.56-3.71 (3H, m), 4.64 (1H, br s), 7.18-7.30 (5H, m);
MS (FAB) m/z: 266 [M + H]⁺, 210, 166, 57;
Anal. Calcd for C₁₅H₂₃NO₃: C,67.90; H,8.74; N,5.28. Found: C,67.79; H,8.33; N,5.29.

（１２ｂ） tert−ブチル （１Ｓ）−１−｛［（４−メトキシフェニル）アミノ］メチル｝−３−フェニルプロピルカーバメート
（Ｓ）−２−（tert−ブトキシカルボニルアミノ）−１−プロパノールに代えて、実施例１２（１２ａ）で製造したtert−ブチル （１Ｓ）−１−（ヒドロキシメチル）−３−フェニルプロピルカーバメート（４３９ｍｇ，１．６５ｍｍｏｌ）を用いて、実施例１（１ｂ）に記載された反応と同様の反応をおこなって、標記化合物（１６３ｍｇ，ニトロスルホンアミドをもとにした収率５３％）を得た。
IR (KBr) ν_max3395, 3378, 2980, 2950, 2927, 2861, 1679, 1513 cm^-1;
¹H NMR (CDCl₃, 400MHz) δ 1.46 (9H, s), 1.72-1.81 (1H, m), 1.86-1.95 (1H, m), 3.04-3.09 (2H, m), 3.17-3.21 (2H, m), 3.69 (1H, br s), 3.74 (3H, s), 3.81-3.88 (1H, m), 4.48-4.54 (1H, m), 6.56 (2H, d, J = 8.8 Hz), 6.77 (2H, d, J = 8.8 Hz), 7.17-7.21 (3H, m), 7.27-7.30 (2H, m);
MS (FAB) m/z: 371 [M + H]⁺, 370, 315, 136, 57;
Anal. Calcd for C₂₂H₃₀N₂O₃・0.32 H₂O: C,70.23; H,8.21; N,7.45. Found: C,70.26; H,7.99; N,7.53.

（１２ｃ） （２Ｓ）−Ｎ^１−（４−メトキシフェニル）−４−フェニルブタン−１，２−ジアミン ２塩酸塩
tert−ブチル （１Ｓ）−１−｛［（４−メトキシフェニル）アミノ］メチル｝−２−メチルプロピルカーバメートの代わりに、実施例１２（１２ｂ）で製造したtert−ブチル （１Ｓ）−１−｛［（４−メトキシフェニル）アミノ］メチル｝−３−フェニルプロピルカーバメート（１５２ｍｇ，０．４１ｍｍｏｌ）を用いて、実施例７（７ｂ）に記載された反応と同様の反応をおこなって、標記化合物（１２８ｍｇ，９１％）を得た。
¹H NMR (CDCl₃, 400MHz) δ 2.05-2.14 (1H, m), 2.29-2.40 (1H, m), 2.70-2.83 (2H, m), 3.35 (1H, d, J = 13.2 Hz), 3.69 (3H, s), 4.14-4.20 (1H, m), 4.26-4.35 (1H, m), 6.73 (2H, d, J = 9.5 Hz), 7.07-7.15 (5H, m), 7.52 (2H, d, J = 8.1 Hz);
MS (FAB) m/z: 271 [M + H]⁺, 29, 39, 57, 120, 254;
HRMS (ESI) m/z calcd for C₁₇H₂₃N₂O 271.1810 [M + H]⁺, found 271.1823.

（１２ｄ） １−（１，１’−ビフェニル−３−イルアミノ）−Ｎ−（（１Ｓ）−１−｛［（４−メトキシフェニル）アミノ］メチル｝−３−フェニルプロピル）シクロヘキサンカルボキサミド
（２Ｓ）−Ｎ^１−（４−メトキシフェニル）−３−メチルブタン−１，２−ジアミン ２塩酸塩の代わりに、実施例１２（１２ｃ）で製造した（２Ｓ）−Ｎ^１−（４−メトキシフェニル）−４−フェニルブタン−１，２−ジアミン ２塩酸塩（６０ｍｇ，０．１８ｍｍｏｌ）を用いて、実施例７（７ｃ）に記載された反応と同様の反応をおこなって、標記化合物（８５ｍｇ，収率９７％）を得た。
IR (KBr) ν_max3367, 2935, 2856, 1653, 1602, 1513 cm^-1;
¹H NMR (CDCl₃, 400MHz) δ 1.29-2.04 (12H, m), 2.53-2.66 (2H, m), 3.06 (1H, dd, J = 7.3, 12.5 Hz), 3.14 (1H, dd, J = 5.1, 12.5 Hz), 3.60 (1H, s), 3.71 (3H, s), 4.05 (1H, s), 4.14-4.22 (1H, m), 6.41 (2H, d, J = 8.8 Hz), 6.61 (1H, d, J = 1.5, 8.1 Hz), 6.70 (2H, d, J = 8.8 Hz), 6.86 (1H, s), 7.00-7.87 (11H, m), 7.52 (2H, d, J = 7.3 Hz);
MS (FAB) m/z: 548 [M + H]⁺, 547, 250;
Anal. Calcd for C₃₆H₄₁N₃O₂・0.84 H₂O: C,76.82; H,7.64; N,7.47. Found: C,76.68; H,7.54; N,7.61.

［実施例１３］ １−（１，１’−ビフェニル−３−イルアミノ）−Ｎ−（（１Ｓ）−１−｛［（４−メトキシフェニル）アミノ］メチル｝ブチル）シクロヘキサンカルボキサミド（例示化合物番号２−５６）
（１３ａ） tert−ブチル （１Ｓ）−１−（ヒドロキシメチル）ブチルカーバメート
Ｎ−（tert−ブトキシカルボニル）−Ｌ−ホモフェニルアラニンに代えて，Ｎ−（tert−ブトキシカルボニル）−Ｌ−ノルバリン（４３５ｍｇ，２．０ｍｍｏｌ）を使用して，実施例１２（１２ａ）に記載の方法に従い，標記化合物（３６９ｍｇ，収率９１％）を得た。
Mp 43-45 ℃;
IR (KBr) ν_max3355, 1687, 1531, 1176 cm^-1;
¹H NMR (CDCl₃, 400MHz) δ 0.94 (3H, t, J = 7.1 Hz), 1.33-1.51 (4H, m), 1.45 (9H, s), 2.38 (1H, br s), 3.51-3.70 (3H, m), 4.59 (1H, br s);
MS (FAB) m/z: 204 [M + H]⁺, 148, 57;

（１３ｂ） tert−ブチル （１Ｓ）−１−｛［（４−メトキシフェニル）アミノ］メチル｝ブチルカーバメート
（Ｓ）−２−（tert−ブトキシカルボニルアミノ）−１−プロパノールに代えて、実施例１３（１３ａ）で製造したtert−ブチル （１Ｓ）−１−（ヒドロキシメチル）ブチルカーバメート（３４０ｍｇ，１．６７ｍｍｏｌ）を用いて、実施例１（１ｂ）に記載された反応と同様の反応をおこなって、標記化合物（２５７ｍｇ，ニトロスルホンアミドをもとにした収率９９％）を得た。
IR (KBr) ν_max3392, 3381, 2980, 2953, 2872, 1676, 1516 cm^-1;
¹H NMR (CDCl₃, 400MHz) δ 0.94 (3H, t, J = 7.0 Hz), 1.45 (9H, s), 1.19-1.48 (4H, m), 2.98-3.03 (1H, m), 3.17 (1H, dd, J = 4.4, 12.5 Hz), 3.74 (3H, s), 3.76-3.84 (1H, m), 4.13-4.23 (1H, m), 4.42-4.48 (1H, m), 6.58 (2H, d, J = 8.8 Hz), 6.77 (2H, d, J = 8.8 Hz);
MS (FAB) m/z: 309 [M + H]⁺, 308, 262, 253, 136, 57;
HRMS (ESI) m/z calcd for C₁₇H₂₉N₂O₃309.2187 [M + H]⁺, found 309.2188.

（１３ｃ） （２Ｓ）−Ｎ^１−（４−メトキシフェニル）ペンタン−１，２−ジアミン
tert−ブチル （１Ｓ）−２−［（４−メトキシフェニル）アミノ］−１−メチルエチルカーバメートの代わりに、実施例１３（１３ｂ）で製造したtert−ブチル （１Ｓ）−１−｛［（４−メトキシフェニル）アミノ］メチル｝ブチルカーバメート（２４９ｍｇ，０．８１ｍｍｏｌ）を用いて、実施例３（３ｃ）に記載された反応と同様の反応をおこなって、標記化合物（１２６ｍｇ，収率７５％）を得た。
IR (film) ν_max3360, 2957, 1514, 1466, 1236, 1038, 820 cm^-1;
¹H NMR (CDCl₃, 400MHz) δ 0.95 (3H, t, J = 6.6 Hz), 1.24-1.50 (4H, m), 2.81 (1H, dd, J = 8.8, 12.5 Hz), 2.94-3.00 (1H, m), 3.15 (1H, dd, J = 3.7, 12.5 Hz), 3.75 (3H, s), 6.61 (2H, d, J = 8.8 Hz), 6.78 (2H, d, J = 8.8 Hz;
MS (EI) m/z: 208 [M⁺], 72, 122, 137;
Anal. Calcd for C₁₂H₂₀N₂O・0.28 H₂O: C, 67.56; H, 9.71; N, 13.13. Found: C, 67.51; H, 9.45; N, 13.15.

（１３ｄ） １−（１，１’−ビフェニル−３−イルアミノ）−Ｎ−（（１Ｓ）−１−｛［（４−メトキシフェニル）アミノ］メチル｝ブチル）シクロヘキサンカルボキサミド
（２Ｓ）−Ｎ^１−（４−メトキシフェニル）プロパン−１，２−ジアミンの代わりに、実施例１３（１３ｃ）で製造した（２Ｓ）−Ｎ^１−（４−メトキシフェニル）ペンタン−１，２−ジアミン（４０ｍｇ，０．１９ｍｍｏｌ）を用いて、実施例５（５ｂ）に記載された反応と同様の反応をおこなって、標記化合物（６１ｍｇ，収率７２％）を得た。
IR (KBr) ν_max3366, 2932, 2857, 1651, 1601, 1513 cm^-1;
¹H NMR (CDCl₃, 400MHz) δ 0.83 (3H, t, J = 7.3 Hz), 1.24-1.70 (10H, m), 1.92-2.07 (4H, m), 3.02 (1H, dd, J = 8.1, 12.5 Hz), 3.12 (1H, dd, J = 4.4, 12.5 Hz), 3.66 (1H, s), 3.72 (3H, s), 4.05 (1H, s), 4.09-4.18 (1H, m), 6.43 (2H, d, J = 8.8 Hz), 6.60 (1H, dd, J = 2.2, 8.1 Hz), 6.72 (2H, d, J = 8.8 Hz), 6.84 (1H, s), 7.01-7.04 (2H, m), 7.12 (1H, t, J = 8.1 Hz), 7.29-7.32 (1H, m), 7.36 (2H, t, J = 6.6 Hz), 7.53 (2H, d, J = 6.6 Hz);
MS (FAB) m/z: 486 [M + H]⁺, 485, 250;
Anal. Calcd for C₃₁H₃₉N₃O₂・0.32 H₂O: C,75.77; H,8.13; N,8.55. Found: C,75.76; H,7.79; N,8.61.

［実施例１４］ １−（１，１’−ビフェニル−３−イルアミノ）−Ｎ−（（１Ｓ）−１−｛［（４−メトキシフェニル）アミノ］メチル｝ペンチル）シクロヘキサンカルボキサミド（例示化合物番号２−８３）
（１４ａ） tert−ブチル （１Ｓ）−１−（ヒドロキシメチル）ペンチルカーバメート
Ｎ−（tert−ブトキシカルボニル）−Ｌ−ホモフェニルアラニンに代えて、Ｎ−（tert−ブトキシカルボニル）−Ｌ−ノルロイシン（６９４ｍｇ，３．０ｍｍｏｌ）を用いて、実施例１２（１２ａ）に記載された反応と同様の反応をおこなって、標記化合物（５５７ｍｇ，収率８５％）を得た。
Mp 42-44 ℃;
IR (KBr) ν_max3359, 1684, 1531, 1174 cm^-1;
¹H NMR (CDCl₃, 400MHz) δ 0.90 (3H, t, J = 7.0 Hz), 1.24-1.54 (6H, m), 1.45 (9H, s), 2.41 (1H, br s), 3.51-3.70 (3H, m), 4.60 (1H, br s);
MS (FAB) m/z: 218 [M + H]⁺, 162, 118, 57;
Anal. Calcd for C₁₁H₂₃NO₃: C,60.80; H,10.67; N,6.45. Found: C,60.58; H,10.36; N,6.41.

（１４ｂ） tert−ブチル （１Ｓ）−１−｛［（４−メトキシフェニル）アミノ］メチル｝ペンチルカーバメート
（Ｓ）−２−（tert−ブトキシカルボニルアミノ）−１−プロパノールに代えて、実施例１４（１４ａ）で製造したtert−ブチル （１Ｓ）−１−（ヒドロキシメチル）ペンチルカーバメート（５２５ｍｇ，２．４２ｍｍｏｌ）を用いて、実施例１（１ｂ）に記載された反応と同様の反応をおこなって、標記化合物（３０３ｍｇ，ニトロスルホンアミドをもとにした収率７８％）を合成した。
IR (KBr) ν_max 3389, 2982, 2956, 2934, 2872, 1676, 1516 cm^-1;
¹H NMR (CDCl₃, 400MHz) δ 0.90 (3H, t, J = 7.0 Hz), 1.30-1.48 (6H, m), 1.45 (9H, s), 2.97-3.03 (1H, m), 3.18 (1H, dd, J = 4.4, 12.5 Hz), 3.74 (3H, s), 3.75-3.81 (2H, m), 4.41-4.48 (1H, m), 6.58 (2H, d, J = 8.8 Hz), 6.77 (2H, d, J = 8.8 Hz);
MS (FAB) m/z: 323 [M + H]⁺, 322, 267, 136, 57;
Anal. Calcd for C₁₈H₃₀N₂O₃・0.22 H₂O: C,66.23; H,9.40; N,8.58. Found: C,66.26; H,9.24; N,8.73.

（１４ｃ） （２Ｓ）−Ｎ^１−（４−メトキシフェニル）ヘキサン−１，２−ジアミン
tert−ブチル （１Ｓ）−２−［（４−メトキシフェニル）アミノ］−１−メチルエチルカーバメートの代わりに、実施例１４（１４ｂ）で製造したtert−ブチル （１Ｓ）−１−｛［（４−メトキシフェニル）アミノ］メチル｝ペンチルカーバメート（２９５ｍｇ，０．９１ｍｍｏｌ）を用いて、実施例３（３ｃ）に記載された反応と同様の反応をおこなって、標記化合物（２００ｍｇ，収率９８％）を得た。
IR (film) ν_max3361, 2930, 1514, 1466, 1236, 1039, 820 cm^-1;
¹H NMR (CDCl₃, 400MHz) δ 0.91 (3H, t, J = 7.3 Hz), 1.21-1.52 (6H, m), 2.80 (1H, dd, J = 8.8, 12.5 Hz), 2.91-2.97 (1H, m), 3.14 (1H, dd, J = 3.7, 12.5 Hz), 3.74 (3H, s), 6.60 (2H, d, J = 8.8 Hz), 6.77 (2H, d, J = 8.8 Hz);
MS (EI) m/z: 222 [M⁺], 86, 122, 137;
Anal. Calcd for C₁₃H₂₂N₂O₁・0.12 H₂O: C,69.55; H,9.99; N,12.48. Found: C,69.72; H,9.68; N,12.24.

（１４ｄ） １−（１，１’−ビフェニル−３−イルアミノ）−Ｎ−（（１Ｓ）−１−｛［（４−メトキシフェニル）アミノ］メチル｝ペンチル）シクロヘキサンカルボキサミド
（２Ｓ）−Ｎ^１−（４−メトキシフェニル）プロパン−１，２−ジアミンの代わりに、実施例１４（１４ｃ）で製造した（２Ｓ）−Ｎ^１−（４−メトキシフェニル）ヘキサン−１，２−ジアミン（４２ｍｇ，０．１９ｍｍｏｌ）を用いて、実施例５（５ｂ）に記載された反応と同様の反応をおこなって、標記化合物（６１ｍｇ，収率６８％）を得た。
IR (KBr) ν_max3366, 3054, 3029, 2931, 1651, 1601, 1574, 1513 cm^-1;
¹H NMR (CDCl₃, 400MHz) δ 0.72 (3H, t, J = 6.6 Hz), 1.11-1.63 (12H, m), 1.88-2.00 (4H, m), 2.95 (1H, dd, J = 8.1, 12.5 Hz), 3.05 (1H, dd, J = 4.4, 12.5 Hz), 3.60 (1H, s), 3.65 (3H, s), 3.98 (1H, s), 4.02-4.09 (1H, m), 6.37 (2H, d, J = 8.8 Hz), 6.52 (1H, dd, J = 1.5, 8.1 Hz), 6.65 (2H, d, J = 8.8 Hz), 6.77 (1H, s), 6.96 (2H, t, J = 7.3 Hz), 7.05 (1H, t, J = 8.1 Hz), 7.21-7.25 (1H, m), 7.29 (2H, t, J = 7.3 Hz), 7.46 (2H, d, J = 7.3 Hz);
MS (FAB) m/z: 500 [M + H]⁺, 499, 250, 136;
Anal. Calcd for C₃₂H₄₁N₃O₂・0.30 H₂O: C,76.09; H,8.30; N,8.32. Found: C,76.10; H,8.43; N,8.30.

［実施例１５］ Ｎ−（（１Ｓ）−１−｛［（４−メトキシフェニル）アミノ］メチル｝プロピル）−１−［（３’−メチル−１，１’−ビフェニル−３−イル）アミノ］シクロヘキサンカルボキサミド（例示化合物番号２−３１）
（１５ａ） １−［（３−ブロモフェニル）アミノ］シクロヘキサンカルボン酸
文献（J.Am.Chem.Soc., vol. 120, 1998, 12459-12467）に記載された方法を参考にし、以下の方法で合成した。In a solution of N- (tert-butoxycarbonyl) -L-homophenylalanine (476 mg, 1.70 mmol) in tetrahydrofuran (10 mL) at −10 ° C., N-methylmorpholine (0.19 mL, 1.70 mmol) and ethyl chlorocarbonate (0.16 mL, 1.70 mmol) and stirred for 20 minutes. After sodium borohydride (193 mg, 5.10 mmol) was added at the same temperature, the reaction temperature was raised to 0 ° C., and methanol (20 mL) was added dropwise over 20 minutes. The reaction mixture was further stirred at the same temperature for 20 minutes, and then neutralized by adding a 1M aqueous solution of potassium hydrogen sulfate. After the solvent was distilled off under reduced pressure, the residue was partitioned between water and ethyl acetate. The organic layer was washed with saturated saline, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride / ethyl acetate, 5: 1) to give the title compound (420 mg, yield 93%).
IR (KBr) ν_max 3375, 1686, 1517, 1245, 1175, 744, 700 cm^-1 ;
¹ H NMR (CDCl₃ , 400 MHz) δ 1.45 (9H, s), 1.74-1.86 (2H, m), 2.22 (1H, br s), 2.65-2.73 (2H, m), 3.56-3.71 (3H, m ), 4.64 (1H, br s), 7.18-7.30 (5H, m);
MS (FAB) m / z: 266 [M + H]⁺ , 210, 166, 57;
Anal.Calcd for C₁₅ H₂₃ NO₃ : C, 67.90; H, 8.74; N, 5.28. Found: C, 67.79; H, 8.33; N, 5.29.

(12b) tert-butyl (1S) -1-{[(4-methoxyphenyl) amino] methyl} -3-phenylpropylcarbamate Instead of (S) -2- (tert-butoxycarbonylamino) -1-propanol Described in Example 1 (1b) using tert-butyl (1S) -1- (hydroxymethyl) -3-phenylpropylcarbamate (439 mg, 1.65 mmol) produced in Example 12 (12a). The same reaction as in the reaction was carried out to obtain the title compound (163 mg, yield 53% based on nitrosulfonamide).
IR (KBr) ν_max 3395, 3378, 2980, 2950, 2927, 2861, 1679, 1513 cm^-1 ;
¹ H NMR (CDCl₃ , 400 MHz) δ 1.46 (9H, s), 1.72-1.81 (1H, m), 1.86-1.95 (1H, m), 3.04-3.09 (2H, m), 3.17-3.21 (2H, m), 3.69 (1H, br s), 3.74 (3H, s), 3.81-3.88 (1H, m), 4.48-4.54 (1H, m), 6.56 (2H, d, J = 8.8 Hz), 6.77 ( 2H, d, J = 8.8 Hz), 7.17-7.21 (3H, m), 7.27-7.30 (2H, m);
MS (FAB) m / z: 371 [M + H]⁺ , 370, 315, 136, 57;
Anal.Calcd for C₂₂ H₃₀ N₂ O₃・ 0.32 H₂ O: C, 70.23; H, 8.21; N, 7.45. Found: C, 70.26; H, 7.99; N, 7.53.

(12c) (2S) -N^1- (4-methoxyphenyl) -4-phenylbutane-1,2-diamine dihydrochloride
tert-Butyl (1S) -1-{[(4-methoxyphenyl) amino] methyl} -2-methylpropylcarbamate is replaced with tert-butyl (1S) -1-} produced in Example 12 (12b). Using [(4-methoxyphenyl) amino] methyl} -3-phenylpropylcarbamate (152 mg, 0.41 mmol), a reaction similar to the reaction described in Example 7 (7b) was carried out to give the title compound ( 128 mg, 91%).
¹ H NMR (CDCl₃ , 400MHz) δ 2.05-2.14 (1H, m), 2.29-2.40 (1H, m), 2.70-2.83 (2H, m), 3.35 (1H, d, J = 13.2 Hz), 3.69 (3H, s), 4.14-4.20 (1H, m), 4.26-4.35 (1H, m), 6.73 (2H, d, J = 9.5 Hz), 7.07-7.15 (5H, m), 7.52 (2H, d , J = 8.1 Hz);
MS (FAB) m / z: 271 [M + H]⁺ , 29, 39, 57, 120, 254;
HRMS (ESI) m / z calcd for C₁₇ H₂₃ N₂ O 271.1810 [M + H]⁺ , found 271.1823.

(12d) 1- (1,1′-biphenyl-3-ylamino) -N-((1S) -1-{[(4-methoxyphenyl) amino] methyl} -3-phenylpropyl) cyclohexanecarboxamide (2S) (2S) -N^1- (4-methoxyphenyl)-produced in Example 12 (12c) instead of -N^1- (4-methoxyphenyl) -3-methylbutane-1,2-diamine dihydrochloride The same reaction as that described in Example 7 (7c) was carried out using 4-phenylbutane-1,2-diamine dihydrochloride (60 mg, 0.18 mmol) to give the title compound (85 mg, yield). 97%).
IR (KBr) ν_max 3367, 2935, 2856, 1653, 1602, 1513 cm^-1 ;
¹ H NMR (CDCl₃ , 400 MHz) δ 1.29-2.04 (12H, m), 2.53-2.66 (2H, m), 3.06 (1H, dd, J = 7.3, 12.5 Hz), 3.14 (1H, dd, J = 5.1, 12.5 Hz), 3.60 (1H, s), 3.71 (3H, s), 4.05 (1H, s), 4.14-4.22 (1H, m), 6.41 (2H, d, J = 8.8 Hz), 6.61 ( 1H, d, J = 1.5, 8.1 Hz), 6.70 (2H, d, J = 8.8 Hz), 6.86 (1H, s), 7.00-7.87 (11H, m), 7.52 (2H, d, J = 7.3 Hz );
MS (FAB) m / z: 548 [M + H]⁺ , 547, 250;
Anal.Calcd for C₃₆ H₄₁ N₃ O₂・ 0.84 H₂ O: C, 76.82; H, 7.64; N, 7.47. Found: C, 76.68; H, 7.54; N, 7.61.

Example 13 1- (1,1′-biphenyl-3-ylamino) -N-((1S) -1-{[(4-methoxyphenyl) amino] methyl} butyl) cyclohexanecarboxamide (Exemplified Compound No. 2) -56)
(13a) tert-butyl (1S) -1- (hydroxymethyl) butyl carbamate Instead of N- (tert-butoxycarbonyl) -L-homophenylalanine, N- (tert-butoxycarbonyl) -L-norvaline (435 mg, The title compound (369 mg, yield 91%) was obtained according to the method described in Example 12 (12a) using 2.0 mmol).
Mp 43-45 ° C;
IR (KBr) ν_max 3355, 1687, 1531, 1176 cm^-1 ;
¹ H NMR (CDCl₃ , 400 MHz) δ 0.94 (3H, t, J = 7.1 Hz), 1.33-1.51 (4H, m), 1.45 (9H, s), 2.38 (1H, br s), 3.51-3.70 ( 3H, m), 4.59 (1H, br s);
MS (FAB) m / z: 204 [M + H]⁺ , 148, 57;

(13b) tert-butyl (1S) -1-{[(4-methoxyphenyl) amino] methyl} butylcarbamate Example 13 in place of (S) -2- (tert-butoxycarbonylamino) -1-propanol Using tert-butyl (1S) -1- (hydroxymethyl) butyl carbamate (340 mg, 1.67 mmol) produced in (13a), a reaction similar to the reaction described in Example 1 (1b) was carried out. The title compound (257 mg, yield 99% based on nitrosulfonamide) was obtained.
IR (KBr) ν_max 3392, 3381, 2980, 2953, 2872, 1676, 1516 cm^-1 ;
¹ H NMR (CDCl₃ , 400 MHz) δ 0.94 (3H, t, J = 7.0 Hz), 1.45 (9H, s), 1.19-1.48 (4H, m), 2.98-3.03 (1H, m), 3.17 (1H , dd, J = 4.4, 12.5 Hz), 3.74 (3H, s), 3.76-3.84 (1H, m), 4.13-4.23 (1H, m), 4.42-4.48 (1H, m), 6.58 (2H, d , J = 8.8 Hz), 6.77 (2H, d, J = 8.8 Hz);
MS (FAB) m / z: 309 [M + H]⁺ , 308, 262, 253, 136, 57;
HRMS (ESI) m / z calcd for C₁₇ H₂₉ N₂ O₃ 309.2187 [M + H]⁺ , found 309.2188.

(13c) (2S) -N^1- (4-methoxyphenyl) pentane-1,2-diamine
Instead of tert-butyl (1S) -2-[(4-methoxyphenyl) amino] -1-methylethyl carbamate, tert-butyl (1S) -1-{[(4 The same reaction as that described in Example 3 (3c) was carried out using -methoxyphenyl) amino] methyldibutylcarbamate (249 mg, 0.81 mmol) to give the title compound (126 mg, yield 75%). Got.
IR (film) ν_max 3360, 2957, 1514, 1466, 1236, 1038, 820 cm^-1 ;
¹ H NMR (CDCl₃ , 400 MHz) δ 0.95 (3H, t, J = 6.6 Hz), 1.24-1.50 (4H, m), 2.81 (1H, dd, J = 8.8, 12.5 Hz), 2.94-3.00 (1H , m), 3.15 (1H, dd, J = 3.7, 12.5 Hz), 3.75 (3H, s), 6.61 (2H, d, J = 8.8 Hz), 6.78 (2H, d, J = 8.8 Hz;
MS (EI) m / z: 208 [M⁺ ], 72, 122, 137;
Anal.Calcd for C₁₂ H₂₀ N₂ O ・ 0.28 H₂ O: C, 67.56; H, 9.71; N, 13.13. Found: C, 67.51; H, 9.45; N, 13.15.

(13d) 1- (1,1′-biphenyl-3-ylamino) -N-((1S) -1-{[(4-methoxyphenyl) amino] methyl} butyl) cyclohexanecarboxamide (2S) -N¹ − Instead of (4-methoxyphenyl) propane-1,2-diamine, (2S) -N^1- (4-methoxyphenyl) pentane-1,2-diamine (40 mg, 0) prepared in Example 13 (13c). .19 mmol) to carry out a reaction similar to the reaction described in Example 5 (5b) to obtain the title compound (61 mg, yield: 72%).
IR (KBr) ν_max 3366, 2932, 2857, 1651, 1601, 1513 cm^-1 ;
¹ H NMR (CDCl₃ , 400 MHz) δ 0.83 (3H, t, J = 7.3 Hz), 1.24-1.70 (10H, m), 1.92-2.07 (4H, m), 3.02 (1H, dd, J = 8.1, 12.5 Hz), 3.12 (1H, dd, J = 4.4, 12.5 Hz), 3.66 (1H, s), 3.72 (3H, s), 4.05 (1H, s), 4.09-4.18 (1H, m), 6.43 ( 2H, d, J = 8.8 Hz), 6.60 (1H, dd, J = 2.2, 8.1 Hz), 6.72 (2H, d, J = 8.8 Hz), 6.84 (1H, s), 7.01-7.04 (2H, m ), 7.12 (1H, t, J = 8.1 Hz), 7.29-7.32 (1H, m), 7.36 (2H, t, J = 6.6 Hz), 7.53 (2H, d, J = 6.6 Hz);
MS (FAB) m / z: 486 [M + H]⁺ , 485, 250;
Anal.Calcd for C₃₁ H₃₉ N₃ O₂・ 0.32 H₂ O: C, 75.77; H, 8.13; N, 8.55. Found: C, 75.76; H, 7.79; N, 8.61.

[Example 14] 1- (1,1'-biphenyl-3-ylamino) -N-((1S) -1-{[(4-methoxyphenyl) amino] methyl} pentyl) cyclohexanecarboxamide (Exemplary Compound No. 2) -83)
(14a) tert-Butyl (1S) -1- (hydroxymethyl) pentylcarbamate Instead of N- (tert-butoxycarbonyl) -L-homophenylalanine, N- (tert-butoxycarbonyl) -L-norleucine (694 mg, 3.0 mmol) to carry out a reaction similar to the reaction described in Example 12 (12a) to obtain the title compound (557 mg, yield 85%).
Mp 42-44 ° C;
IR (KBr) ν_max 3359, 1684, 1531, 1174 cm^-1 ;
¹ H NMR (CDCl₃ , 400 MHz) δ 0.90 (3H, t, J = 7.0 Hz), 1.24-1.54 (6H, m), 1.45 (9H, s), 2.41 (1H, br s), 3.51-3.70 ( 3H, m), 4.60 (1H, br s);
MS (FAB) m / z: 218 [M + H]⁺ , 162, 118, 57;
_{. Anal Calcd for C 11 H 23} NO 3:. C, 60.80; H, 10.67; N, 6.45 Found: C, 60.58; H, 10.36; N, 6.41.

(14b) tert-butyl (1S) -1-{[(4-methoxyphenyl) amino] methyl} pentylcarbamate Example 14 in place of (S) -2- (tert-butoxycarbonylamino) -1-propanol Using tert-butyl (1S) -1- (hydroxymethyl) pentylcarbamate (525 mg, 2.42 mmol) produced in (14a), a reaction similar to the reaction described in Example 1 (1b) was carried out. And the title compound (303 mg, yield 78% based on nitrosulfonamide).
IR (KBr) ν_max 3389, 2982, 2956, 2934, 2872, 1676, 1516 cm^-1 ;
¹ H NMR (CDCl₃ , 400MHz) δ 0.90 (3H, t, J = 7.0 Hz), 1.30-1.48 (6H, m), 1.45 (9H, s), 2.97-3.03 (1H, m), 3.18 (1H , dd, J = 4.4, 12.5 Hz), 3.74 (3H, s), 3.75-3.81 (2H, m), 4.41-4.48 (1H, m), 6.58 (2H, d, J = 8.8 Hz), 6.77 ( 2H, d, J = 8.8 Hz);
MS (FAB) m / z: 323 [M + H]⁺ , 322, 267, 136, 57;
_{. Anal Calcd for C 18 H 30} N 2 O 3 · 0.22 H 2 O:. C, 66.23; H, 9.40; N, 8.58 Found: C, 66.26; H, 9.24; N, 8.73.

(14c) (2S) -N^1- (4-methoxyphenyl) hexane-1,2-diamine
tert-butyl (1S) -2-[(4-methoxyphenyl) amino] -1-methylethyl carbamate was replaced with tert-butyl (1S) -1-{[(4 The same reaction as that described in Example 3 (3c) was carried out using -methoxyphenyl) amino] methyl} pentylcarbamate (295 mg, 0.91 mmol) to give the title compound (200 mg, yield 98%). Got.
IR (film) ν_max 3361, 2930, 1514, 1466, 1236, 1039, 820 cm^-1 ;
¹ H NMR (CDCl₃ , 400 MHz) δ 0.91 (3H, t, J = 7.3 Hz), 1.21-1.52 (6H, m), 2.80 (1H, dd, J = 8.8, 12.5 Hz), 2.91-2.97 (1H , m), 3.14 (1H, dd, J = 3.7, 12.5 Hz), 3.74 (3H, s), 6.60 (2H, d, J = 8.8 Hz), 6.77 (2H, d, J = 8.8 Hz);
MS (EI) m / z: 222 [M⁺ ], 86, 122, 137;
Anal.Calcd for C₁₃ H₂₂ N₂ O₁・ 0.12 H₂ O: C, 69.55; H, 9.99; N, 12.48. Found: C, 69.72; H, 9.68; N, 12.24.

(14d) 1- (1,1′-biphenyl-3-ylamino) -N-((1S) -1-{[(4-methoxyphenyl) amino] methyl} pentyl) cyclohexanecarboxamide (2S) -N^1- Instead of (4-methoxyphenyl) propane-1,2-diamine, (2S) -N^1- (4-methoxyphenyl) hexane-1,2-diamine (42 mg, 0) prepared in Example 14 (14c). .19 mmol) to carry out a reaction similar to the reaction described in Example 5 (5b) to obtain the title compound (61 mg, yield 68%).
IR (KBr) ν_max 3366, 3054, 3029, 2931, 1651, 1601, 1574, 1513 cm^-1 ;
¹ H NMR (CDCl₃ , 400 MHz) δ 0.72 (3H, t, J = 6.6 Hz), 1.11-1.63 (12H, m), 1.88-2.00 (4H, m), 2.95 (1H, dd, J = 8.1, 12.5 Hz), 3.05 (1H, dd, J = 4.4, 12.5 Hz), 3.60 (1H, s), 3.65 (3H, s), 3.98 (1H, s), 4.02-4.09 (1H, m), 6.37 ( 2H, d, J = 8.8 Hz), 6.52 (1H, dd, J = 1.5, 8.1 Hz), 6.65 (2H, d, J = 8.8 Hz), 6.77 (1H, s), 6.96 (2H, t, J = 7.3 Hz), 7.05 (1H, t, J = 8.1 Hz), 7.21-7.25 (1H, m), 7.29 (2H, t, J = 7.3 Hz), 7.46 (2H, d, J = 7.3 Hz);
MS (FAB) m / z: 500 [M + H]⁺ , 499, 250, 136;
Anal.Calcd for C₃₂ H₄₁ N₃ O₂・ 0.30 H₂ O: C, 76.09; H, 8.30; N, 8.32. Found: C, 76.10; H, 8.43; N, 8.30.

Example 15 N-((1S) -1-{[(4-methoxyphenyl) amino] methyl} propyl) -1-[(3′-methyl-1,1′-biphenyl-3-yl) amino Cyclohexanecarboxamide (Exemplary Compound No. 2-31)
(15a) 1-[(3-Bromophenyl) amino] cyclohexanecarboxylic acid Referring to the method described in the literature (J. Am. Chem. Soc., Vol. 120, 1998, 12459-12467), the following method is used. Was synthesized.

窒素雰囲気下、１，３−ジブロモベンゼン（２４．２５ｇ，１０３ｍｍｏｌ）、１−アミノシクロヘキサンカルボン酸（１４．７２ｇ，１０３ｍｍｏｌ）、炭酸カリウム（２１．３１ｇ，１５４ｍｍｏｌ）及びブロモ（ジメチルスルフィド）銅（Ｉ）（２．１１ｇ，１０ｍｍｏｌ）をＮ，Ｎ−ジメチルアセトアミド（１３０ｍＬ）に混合し、１２０℃で３時間撹拌した。酢酸エチル（２００ｍＬ）及び水（２００ｍｌ）を反応液に加え、不溶物をセライトを用いて除去した。分離した水層を濃塩酸にて酸性（ｐＨ＝４）とし、酢酸エチル（１５０ｍＬｘ２）で抽出した。抽出液を硫酸ナトリウム上で乾燥したのち、溶媒を留去して、得られた組成生物をシリカゲルカラムクロマトグラフィー（１００％酢酸エチル）で精製した。得られた結晶（２３ｇ）をさらにエーテルで洗浄し、標記化合物（１３．５５ｇ，収率４４％）を得た。
Mp 141-143 ℃;
IR (KBr) ν_max3250, 1705, 1592, 1479, 1227, 770 cm^-1;
¹H NMR (CDCl₃, 400MHz) δ 1.30-1.70 (6H, m), 1.90-2.10 (4H, m), 6.57 (1H, ddd, J = 0.8, 2.3, 8.0 Hz), 6.83 (1H, dd, J = 1.7, 2.3 Hz), 6.97 (1H, ddd, J = 0.8, 1.7, 8.0 Hz), 7.05 (1H, t, J = 8.0 Hz);
MS (EI) m/z: 297 [M⁺], 252.

（１５ｂ） １−［（３−ブロモフェニル）アミノ］−Ｎ−（（１Ｓ）−１−｛［（４−メトキシフェニル）アミノ］メチル｝プロピル）シクロヘキサンカルボキサミド ２塩酸塩
実施例２（２ａ）で製造したtert−ブチル （１Ｓ）−１−｛［（４−メトキシフェニル）アミノ］メチル｝プロピルカーバメート（１．７７ｇ，６．０ｍｍｏｌ）及び４Ｎ塩酸−ジオキサン（６ｍＬ）を混合し、室温で１時間攪拌した。減圧下に溶媒を留去して得られた残留物に飽和炭酸水素ナトリウム水溶液（５０ｍＬ）を加えた。水層を塩化メチレン（３０ｍＬｘ３）で抽出し、抽出液を硫酸ナトリウム上で乾燥後、溶媒を減圧下留去した。得られた粗製のアミンをＮ，Ｎ−ジメチルホルムアミド（１２ｍＬ）に溶解し、実施例１５（１５ａ）で製造した１−［（３−ブロモフェニル）アミノ］シクロヘキサンカルボン酸（１．７９ｇ，６．０ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール 水和物（０．９６ｇ，６．３ｍｍｏｌ）及び１−エチル−３−（３−ジメチルアミノプロピル）−カルボジイミド 塩酸塩（１．２１ｇ，６．３ｍｍｏｌ）を加えた。反応溶液を室温で３日間撹拌したのち水（１００ｍＬ）を加え、酢酸エチル（１００ｍＬ）で抽出した。抽出液を飽和炭酸水素ナトリウム水溶液（５０ｍＬ）で洗浄し硫酸ナトリウムで乾燥した。溶媒を減圧下留去して、得られた残渣をカラムクロマトグラフィー（ヘキサン／酢酸エチル，２：１）により精製しガラス状のアミド生成物（１．９９ｇ）を得た。得られたアミドに４Ｎ塩酸−ジオキサン（５ｍＬ）を加えたのち、混合物を減圧下濃縮して得られた残渣にエーテルを加えて、塩酸塩を粉末化し、溶媒を除去した。得られた粉末をさらに数回エーテルで洗浄したのち減圧下乾燥し、標記化合物（２．２９ｇ，収率７０％）を得た。
IR (KBr) ν_max1671, 1594, 1512, 1257, 1031, 873, 835, 688 cm^-1;
¹H NMR (DMSO-d₆, 400MHz) δ 0.65 (3H, t, J = 7.3 Hz), 1.21-1.93 (12H, m), 3.08 (1H, dd, J = 5.2, 12.8 Hz), 3.32 (1H, dd, J = 6.8, 12.8 Hz), 3.77 (3H, s), 3.92-3.96 (1H, m), 6.58 (1H, dd, J = 1.8, 8.2 Hz), 6.71 (1H, dd, J = 1.2, 7.8 Hz), 6.79 (1H, br s), 6.97 (1H, dd, J = 7.8, 8.2 Hz), 7.02 (2H, d, J = 8.9 Hz), 7.34 (2H, d, J = 8.9 Hz), 8.02 (1H, d, J = 8.6 Hz);
MS (EI) m/z: 474 [M + H]⁺, 252, 174.

（１５ｃ） Ｎ−（（１Ｓ）−１−｛［（４−メトキシフェニル）アミノ］メチル｝プロピル）−１−［（３’−メチル−１，１’−ビフェニル−３−イル）アミノ］シクロヘキサンカルボキサミド
実施例１５（１５ｂ）で製造した１−［（３−ブロモフェニル）アミノ］−Ｎ−（（１Ｓ）−１−｛［（４−メトキシフェニル）アミノ］メチル｝プロピル）シクロヘキサンカルボキサミド ２塩酸塩（２７４ｍｇ，０．５０ｍｍｏｌ）、ｍ−トリルホウ酸（７５ｍｇ，０．５５ｍｍｏｌ）及びテトラキス（トリフェニルホスフィン）パラジウム（０）（２３ｍｇ，０．０２ｍｍｏｌ）を１，２−ジメトキシエタン（５ｍＬ）と２Ｍ炭酸ナトリウム水溶液（５ｍＬ）との混合液に加え、窒素雰囲気下、４時間加熱還流した。反応混合物に酢酸エチル（５０ｍＬ）を加え、有機層を食塩水（５０ｍＬ）で洗浄したのち、硫酸ナトリウム上で乾燥した。溶媒を減圧下に留去して、得られた残留物をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル，１：１）で精製し、標記化合物（２２４ｍｇ，収率９２％）を得た。
IR (KBr): ν_max 3366, 1651, 1603, 1513, 1235, 820, 775, 702 cm^-1;
¹H NMR (CDCl₃, 400 MHz) δ 1.24-1.70 (8 H, m), 1.94-2.08 (4 H, m), 3.03 (1 H, dd, J = 7.6, 12.3 Hz), 3.14 (1 H, dd, J = 4.6, 12.3 Hz), 3.63 (1 H, br s), 3.72 (3 H, s), 4.03-4.10 (2 H, m), 6.44 (2 H, d, J = 8.9 Hz), 6.58 (1 H, dd, J = 2.0, 7.8 Hz), 6.71 (2 H, d, J = 8.9 Hz), 6.84 (1 H, t, J = 2.0 Hz), 7.01 (1 H, br d, J = 7.8 Hz), 7.04 (1 H, br d, J = 8.7 Hz), 7.11 (1 H, t, J = 7.8 Hz), 7.13 (1 H, br d, J = 7.5 Hz), 7.26 (1 H, t, J = 7.5 Hz), 7.33 (1 H, br d, J = 7.5 Hz), 7.34 (1 H, br s);
MS (FAB) m/z: 486 [M + H]⁺;
Anal. Calcd for C₃₁H₃₉N₃O_2・0.5 H₂O: C, 75.27; H, 8.15; N, 8.49. Found: C, 75.30; H, 7.96; N, 8.29.

［実施例１６］ Ｎ−｛（１Ｓ）−２−［（４−メトキシフェニル）アミノ］−１−メチルエチル｝−１−（４−フェノキシフェノキシ）シクロヘキサンカルボキサミド （例示化合物番号４−３０１）
（１６ａ） １−（４−フェノキシフェノキシ）シクロヘキサンカルボン酸
１−ブロモシクロヘキサンカルボン酸 メチル エステル（１１１ｍｇ，０．５０ｍｍｏｌ）、４−フェノキシフェノール（９３ｍｇ，０．５０ｍｍｏｌ）及び水酸化カリウム（２８０ｍｇ，５．００ｍｍｏｌ）の混合物を、tert−ブタノール（５ｍＬ）中で、２３時間加熱攪拌した。反応混合液を冷却後、１規定塩酸を加えて酸性とし、メチレンクロリド（１０ｍＬ×５）で抽出した。抽出液を硫酸ナトリウム上で乾燥後、溶媒を減圧下留去して、得られた残留物を薄層クロマトグラフィー（ヘキサン／酢酸エチル，１：１）で精製し、標記化合物（６２ｍｇ，収率４０％）を得た。
IR (neat) ν_max 1709, 1502, 1489, 1216 cm^-1;
¹H NMR (CDCl₃, 400 MHz) δ 1.26-2.25 (10H, m), 6.88-6.97 (6H, m), 7.05 (1H, t, J = 7.4 Hz), 7.29 (t, 2H, J = 7.4 Hz);
MS (EI) m/z: 312 [M⁺], 186.

（１６ｂ） Ｎ−｛（１Ｓ）−２−［（４−メトキシフェニル）アミノ］−１−メチルエチル｝−１−（４−フェノキシフェノキシ）シクロヘキサンカルボキサミド
実施例１６（１６ａ）で製造した１−（４−フェノキシフェノキシ）シクロヘキサンカルボン酸（１８７ｍｇ，０．６０ｍｍｏｌ）のメチレンクロリド（１０ｍＬ）溶液に、実施例３（３ｃ）で製造した（２Ｓ）−Ｎ^１−（４−メトキシフェニル）プロパン−１，２−ジアミン（１０８ｍｇ，０．６０ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール 水和物（１２１ｍｇ，０．９０ｍｍｏｌ）、１−エチル−３−（３−ジメチルアミノプロピル）−カルボジイミド 塩酸塩（１７２ｍｇ，０．９０ｍｍｏｌ）及びトリエチルアミン（９１ｍｇ，０．９０ｍｍｏｌ）を加え、室温で１７時間攪拌した。反応混合物を水とメチレンクロリドで分液し、有機層を硫酸ナトリウム上で乾燥後、減圧下に溶媒を留去した。残留物を薄層クロマトグラフィー（ヘキサン／酢酸エチル，１：１）で精製し、標記化合物（２３３ｍｇ，収率８２％）を得た。
IR (KBr) ν_max 3382,1655 cm^-1;
¹H NMR (CDCl₃, 400 MHz) δ 1.20 (3H, d, J = 7.2 Hz), 1.24-1.38 (1H, m), 1. 1.43-1.57 (4H, m), 1.62-1.68 (1H, m), 1.90-1.96 (2H, m), 2.00-2.08 (2H, m), 3.03-3.16 (2H, m), 3.70 (3H, s), 4.27 (1H, m), 6.41 (1H, d, J = 8.0 Hz), 6.51 (2H, d, J = 8.8 Hz), 6.73 (2H, d, J = 8.0 Hz), 6.84 (4H, dd, J = 8.8, 11.6 Hz), 6.95 (2H, d, J = 8.0Hz), 7.07 (1H, t, J = 7.8 Hz), 7.31 (2H, t, J = 7.8 Hz).

［実施例１７］ Ｎ^２−［（ベンジルオキシ）カルボニル］−Ｎ^１−｛（１Ｓ）−２−［（４−メトキシフェニル）アミノ］−１−メチルエチル｝−Ｌ−ロイシンアミド（例示化合物番号３−５）
１−（１，１’−ビフェニル−３−イルアミノ）シクロヘキサンカルボン酸に代えて、Ｎ−カルボベンジロキシ−Ｌ−ロイシン（１７５ｍｇ，０．６６ｍｍｏｌ）を用いて、実施例５（５ｂ）に記載された反応と同様の反応をおこなった。得られた粗生成物をヘキサン／酢酸エチル（１：１）混合溶媒（４ｍＬ）から再結晶し、標記化合物（１４２ｍｇ，収率５５％）を得た。
Mp 122-123 ℃;
IR (KBr) ν_max 1718, 1639, 1515, 1254, 1037 cm^-1;
¹H NMR (CDCl₃, 400 MHz) δ 0.91 (6 H, d, J = 6.3 Hz), 1.21 (3 H, d, J = 6.6 Hz), 1.45-1.69 (3 H, m), 3.06-3.16 (2 H, m), 3.72 (1 H, br), 3.73 (3 H, s), 4.06-4.11 (1 H, m), 4.15-4.22 (1 H, m), 5.11 (1 H, br), 5.19 (2 H, s), 5.99 (1 H, br), 6.58 (2 H, d, J = 8.9 Hz), 6.77 (2 H, d, J = 8.9 Hz), 7.29-7.36 (5 H, m);
MS (FAB) m/z: 428 [M + H]⁺;
Anal. Calcd for C₂₄H₃₃N₃O₄: C, 67.42; H, 7.78; N, 9.83. Found: C, 67.17; H, 7.31; N, 9.62.

［実施例１８］ Ｎ^２−（ベンゾフラン−２−イルカルボニル）−Ｎ^１−｛（１Ｓ）−２−［（４−メトキシフェニル）アミノ］−１−メチルエチル｝−Ｌ−ロイシンアミド（例示化合物番号３−９）
（１８ａ） Ｎ−（ベンゾフラン−２−イルカルボニル）−Ｌ−ロイシン
２−ベンゾフランカルボン酸（１０．４３ｇ，６４．３ｍｍｏｌ）、塩化チオニル（１４ｍｌ，１９３ｍｍｏｌ）及びトルエン（５００ｍＬ）の混合物を、６時間加熱還流したのち、反応液を濃縮した。得られた粗製の酸クロリドをエーテル（２００ｍｌ）に溶解し、Ｌ−ロイシン（９．２８ｇ，７０．８ｍｍｏｌ）の１Ｎ水酸化ナトリウム水溶液（２００ｍＬ）に氷冷下滴下した。反応液を室温で１８時間撹拌後、１Ｎ塩酸（４００ｍＬ）を加えた。混合液を酢酸エチル（２００ｍＬｘ２）で抽出し、抽出液を硫酸ナトリウム上で乾燥し濃縮した。得られた粗結晶をエーテルより再結晶し、標記化合物（１２．０５ｇ，収率６８％）を得た。
Mp 150-151 ℃;
[α]_D²³=29.0 (CHCl₃, c=0.58);
IR (KBr) ν_max 3416, 2957, 1745, 1659, 1632, 1599, 1529, 1449, 1224, 1182, 1150, 1077 cm^-1;
¹H NMR (CDCl₃, 400 MHz) δ 7.67(1H, d, J = 7.3 Hz), 7.53(1H, d, J = 7.3 Hz), 7.52(1H, s), 7.43(1H, t, J = 7.3 Hz), 7.30(1H, t, J = 7.3 Hz), 6.97(1H, t, J = 8.1 Hz), 4.91-4.85(1H, m), 1.90-1.74(3H, m), 1.01(6H, d, J = 5.9 Hz);
¹³C NMR (CDCl₃, 125 MHz) δ 177.3, 159.7, 155.6, 148.5, 128.2, 127.9, 124.5, 123.6, 112.6, 112.2, 51.4, 42.1, 25.7, 23.6, 22.5;
HRMS m/z calcd for C₁₅H₁₈NO₄276.1235 [M + H]⁺, found 276.1223.

（１８ｂ） Ｎ^２−（ベンゾフラン−２−イルカルボニル）−Ｎ^１−｛（１Ｓ）−２−［（４−メトキシフェニル）アミノ］−１−メチルエチル｝−Ｌ−ロイシンアミド
実施例１９（１９ａ）で製造したＮ−（ベンゾフラン−２−イルカルボニル）−Ｌ−ロイシン（１３９ｍｇ，０．５１ｍｍｏｌ）のメチレンクロリド（５ｍＬ）溶液に、実施例３（３ｃ）で製造した（２Ｓ）−Ｎ^１−（４−メトキシフェニル）プロパン−１，２−ジアミン（１１０ｍｇ，０．６１ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール 水和物（１１６ｍｇ，０．７６ｍｍｏｌ）、１−エチル−３−（３−ジメチルアミノプロピル）−カルボジイミド 塩酸塩（１６６ｍｇ，０．７６ｍｍｏｌ）及びトリエチルアミン（０．２ｍＬ，１．４３ｍｍｏｌ）を加え、２．５時間攪拌した。反応混合物を水と塩化メチレンで分液し、有機層を硫酸ナトリウム上で乾燥後、減圧下にて溶媒を留去した。残留物をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル，１：１）で精製し、標記化合物（１５２ｍｇ，収率６７％）を得た。
IR (KBr) ν_max 3284, 3066, 2956, 2932, 2871, 2831, 1641, 1595, 1564, 1513 cm^-1;
¹H NMR (CDCl₃, 400 MHz) δ 0.94 (3H, d, J = 6.6 Hz), 0.96 (3H, d, J = 6.6 Hz), 1.21 (3H, d, J = 6.6 Hz), 1.66-1.80 (3H, m), 3.11-3.20 (2H, m), 3.73 (1H, s), 3.77 (1H, br s), 4.22 (1H, septet, J = 6.6 Hz), 4.61-4.70 (1H, m), 6.48 (1H, d, J = 8.1 Hz), 6.60 (2H, ddd, J = 2.2, 3.7, 8.8 Hz), 6.77 (2H, ddd, J = 2.2, 3.7, 8.8 Hz), 7.12 (1H, d, J = 8.8 Hz), 7.29 (1H, t, J = 8.1 Hz), 7.39-7.48 (2H, m), 7.51 (1H, d, J = 9.5 Hz), 7.64 (1H, d, J = 8.1 Hz);
MS (FAB) m/z: 438 [M + H]⁺.

［実施例１９］ １−（１，１’−ビフェニル−３−イルアミノ）−Ｎ−（（１Ｓ）−１−｛［（４−ベンジルオキシフェニル）アミノ］メチル｝プロピル）シクロヘキサンカルボキサミド（例示化合物番号２−２７２）
（１９ａ） Ｎ−［４−（ベンジルオキシ）フェニル］−２−ニトロベンゼンスルホンアミド
４−（ベンジルオキシ）アニリン 塩酸塩（１１．７９ｇ，５０．０ｍｍｏｌ）と２−ニトロベンゼンスルホニルクロリド（１１．０８ｇ，５０．０ｍｍｏｌ）を塩化メチレン（１５０ｍＬ）に懸濁し、トリエチルアミン（１０．６３ｇ，１４．６ｍＬ，１０５ｍｍｌ）を氷冷化で徐々に滴下した。滴下終了後、反応混合物を室温に戻し、さらに４時間攪拌した。反応液に水（２００ｍＬ）を加え、有機層を分離した。有機層を飽和重曹水（１００ｍＬ）と１Ｎ塩酸（１００ｍＬ）で洗浄後、硫酸ナトリウムで乾燥した。溶媒を留去して得られた粗結晶をエタノール（３５０ｍＬ）から再結晶し、標記化合物（１６．６３ｇ，収率８７％）を得た。
Mp 154-156 ℃;
IR (KBr) ν_max 3312, 1540, 1507, 1166, 1005, 595 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 5.00 (2H, s), 6.85 (1H, d, J = 8.9 Hz), 7.09 (1H, d, J = 8.9 Hz), 7.10 (1H, br), 7.30-7.40 (5H, m), 7.55 (1H, dt, J = 1.2, 7.8 Hz), 7.68 (1H, dt, J = 1.4, 7.8 Hz), 7.75 (1H, dd, J = 1.4, 7.8 Hz), 7.85 (1H, dd, J = 1.2, 7.8 Hz);
MS (FAB) m/z: 384 [M⁺];
Anal. Calcd for C₁₉H₁₆N₂O₅S: C,59.37; H,4.20; N,7.29; S,8.34. Found: C,59.21; H,4.05; N,7.27; S,8.33.

（１９ｂ） ｔｅｒｔ−ブチル （１Ｓ）-１−（｛［４−（ベンジルオキシ）フェニル］アミノ｝メチル）プロピルカーバメート
（Ｓ）−２−（ｔｅｒｔ−ブトキシカルボニルアミノ）−１−ブタノール（Ｔｅｔｒａｈｅｄｒｏｎ，Ｖｏｌ５１，１２３３７−１２３５０，１９９５）（１．８９ｇ，１０．０ｍｍｏｌ）、実施例１９（１９ａ）で製造したＮ−［４−（ベンジルオキシ）フェニル］−２−ニトロベンゼンスルホンアミド（１．９２ｇ，５．０ｍｍｏｌ）及びトリフェニルホスフィン（２．６２ｇ，１０．０ｍｍｏｌ）のテトラヒドロフラン（２５ｍＬ）溶液に、氷冷下、アゾジカルボン酸ジエチル（２．２Ｍトルエン溶液，４．５０ｍＬ，１０．０ｍｍｏｌ）のテトラヒドロフラン（５ｍＬ）溶液を２０分で滴下した。反応温度を室温に戻したのち、さらに反応液を４時間撹拌した。溶媒を減圧下留去し得られた残渣をエーテル（１００ｍＬ）に溶解し氷冷した。析出した結晶を濾別し濾液を減圧下濃縮した。得られた残留物をアセトニトリル（１５ｍＬ）に溶解し、チオフェノール（１．１０ｇ，１０．０ｍｍｏｌ）と炭酸カリウム（２．０７ｇ，１５．０ｍｍｏｌ）を加えた。反応混合物を４８時間撹拌したのち、酢酸エチル（１００ｍＬ）を加えた。有機層を水（１００ｍＬｘ１）と食塩水（５０ｍＬｘ１）で洗浄し、硫酸ナトリウムで乾燥後、溶媒を減圧下留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル，４：１）で精製し、標記化合物（１．５２ｇ，収率８２％）を得た。
Mp 108-111 ℃;
IR (KBr) ν_max 3375, 1683, 1514, 1245, 1175, 1018, 816 cm^-1;
¹H NMR (CDCl₃, 400MHz) δ 0.97 (3H, t, J = 7.5 Hz), 1.45 (9H, s), 1.40-1.66 (2H, m), 3.01 (1H, dd, J = 7.6, 12.2 Hz), 3.17 (1H, dd, J = 4.6, 12.2 Hz), 3.65-3.80 (2H, m), 4.46 (1H, br s), 4.99 (2H, s), 6.57 (2H, d, J = 8.9 Hz), 6.84 (2H, d, J = 8.9 Hz), 7.28-7.43 (5H, m);
MS (FAB) m/z: 370 [M⁺], 223, 91, 57;
Anal. Calcd for C₂₂H₃₀N₂O₃: C,71.32; H,8.16; N,7.56. Found: C,71.16; H,7.93; N,7.55.

（１９ｃ） １−（１，１’−ビフェニル−３−イルアミノ）−Ｎ−（（１Ｓ）−１−｛［（４−ベンジルオキシフェニル）アミノ］メチル｝プロピル）シクロヘキサンカルボキサミド
実施例１９（１９ｂ）で製造したｔｅｒｔ−ブチル （１Ｓ）-１−（｛［４−（ベンジルオキシ）フェニル］アミノ｝メチル）プロピルカーバメート（４１２ｍｇ，１．１１ｍｍol）をトリフルオロ酢酸（２ｍＬ）と混合し室温で１時間攪拌した。混合物を減圧下濃縮し、飽和重曹水（５０ｍＬ）と酢酸エチル（５０ｍＬ）で分液した。有機層を硫酸ナトリウムで乾燥し、溶媒を留去して得られた残留物をＮ，Ｎ−ジメチルホルムアミド（３ｍＬ）に溶解した。溶液に、実施例５で製造した１−（１，１’−ビフェニル−３−イルアミノ）シクロヘキサンカルボン酸（３４５ｍｇ，１．１７ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾ−ル １水和物（２０４ｍｇ，１．３３ｍｍｏｌ）、１−エチル−３−(３−ジメチルアミノプロピル)−カルボジイミド 塩酸塩（２５５ｍｇ，１．３３ｍｍｏｌ）とトリエチルアミン（１３５ｍｇ，０．１８５ｍＬ，１．３３ｍｍol）を順次加えた。反応混合物を室温で４８時間攪拌し、水（５０ｍＬ）と酢酸エチル（５０ｍＬ）で分液した。有機層を飽和重曹水（３０ｍＬ）で洗浄後、硫酸ナトリウムで乾燥し、溶媒を減圧下留去した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル，２：１）で精製し、標記化合物（５１０ｍｇ，収率８４％）を得た。
IR (KBr) ν_max3367, 1652, 1601, 1511, 1228, 758, 699 cm^-1;
¹H NMR (CDCl₃, 400MHz) δ 0.88 (3H, t, J = 7.4 Hz), 1.24-1.70 (8H, m), 1.93-2.04 (4H, m), 3.02 (1H, dd, J = 7.7, 12.1 Hz), 3.12 (1H, dd, J = 4.6, 12.1 Hz), 3.67 (1H, br s), 4.00-4.10 (2H, m), 4.96 (2H, s), 6.42 (2H, d, J = 8.9 Hz), 6.59 (1H, dd, J = 2.0, 7.8 Hz), 6.78 (2H, d, J = 8.9 Hz), 6.85 (1H, br s), 7.01 (1H, d, J = 7.8 Hz), 7.03 (1H, br), 7.12 (1H, t, J = 7.8 Hz), 7.27-7.55 (10H, m);
MS (FAB) m/z: 548 [M + H]⁺, 250.

［実施例２０］ ｔｅｒｔ−ブチル （４−｛[（２Ｓ）−２−（｛[１−（１，１’−ビフェニル−３−イルアミノ）シクロヘキシル]カルボニル｝アミノ）ブチル]アミノ｝フェノキシ）アセテート（例示化合物番号５−１）
（２０ａ） １−（１，１’−ビフェニル−３−イルアミノ）−Ｎ−（（１Ｓ）−１−｛［（４−ヒドロキシフェニル）アミノ］メチル｝プロピル）シクロヘキサンカルボキサミド
実施例１９（１９ｃ）で製造した１−（１，１’−ビフェニル−３−イルアミノ）−Ｎ−（（１Ｓ）−１−｛［（４−ベンジルオキシフェニル）アミノ］メチル｝プロピル）シクロヘキサンカルボキサミド（２．０４ｇ，３．７ｍｍｏｌ）を水素雰囲気下（１気圧）、１０％パラジウム−炭素触媒（０．４０ｇ，０．３７ｍｍｏｌ）存在下に、エタノール（２０ｍＬ）溶媒中、４０℃で６時間水素化分解した。触媒を除去したのち、溶媒を留去して得られた残留物をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル，１：１）で精製し、標記化合物（１．６９ｇ，収率９９％）を得た。
IR (KBr) ν_max3367, 1647, 1601, 1515, 1241, 1225, 758 cm^-1;
¹H NMR (CDCl₃, 400MHz) δ 0.85 (3H, t, J = 7.4 Hz), 1.23-1.63 (8H, m), 1.95-2.08 (4H, m), 2.98 (1H, dd, J = 7.7, 12.2 Hz), 3.08 (1H, dd, J = 4.4, 12.2 Hz), 4.00-4.14 (2H, m), 6.34 (2H, d, J = 8.6 Hz), 6.59 (1H, dd, J = 2.0, 8.0 Hz), 6.67 (2H, d, J = 8.6 Hz), 6.86 (1H, t, J = 2.0 Hz), 7.01 (1H, d, J = 8.0 Hz), 7.12 (1H, br d, J = 8.9 Hz), 7.12 (1H, t, J = 8.0 Hz), 7.28-7.38 (3H, m), 7.51-7.53 (2H, m);
MS (FAB) m/z: 458 [M + H]⁺, 250.

（２０ｂ） ｔｅｒｔ−ブチル （４−｛［（２Ｓ）−２−（｛［１−（１，１’−ビフェニル−３−イルアミノ）シクロヘキシル］カルボニル｝アミノ）ブチル］アミノ｝フェノキシ）アセテート
実施例２０（２０ａ）で製造した１−（１，１’−ビフェニル−３−イルアミノ）−Ｎ−（（１Ｓ）−１−｛［（４−ヒドロキシフェニル）アミノ］メチル｝プロピル）シクロヘキサンカルボキサミド（１．６９ｇ，３．７ｍｍｏｌ）のテトラヒドロフラン（１５ｍＬ）溶液に、氷冷下、水素化ナトリウム（５５％油性）（０．１８ｇ，４．１ｍｍｏｌ）を加え、さらに、ブロモ酢酸 ｔ−ブチルエステル（０．７９ｇ，４．１ｍｍｏｌ）のＮ，Ｎ−ジメチルホルムアミド（４ｍＬ）溶液を滴下した。反応温度を室温に戻したのち、反応液をさらに１時間攪拌した。氷冷下、水（１００ｍＬ）を反応液に加え、水層を酢酸エチル（２×５０ｍＬ）で抽出した。抽出液を硫酸ナトリウムで乾燥し、溶媒を留去して得られた残留物をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル，２：１）で精製し、標記化合物（１．６６ｇ，収率７９％）を得た。
IR (KBr) ν_max3370, 1750, 1653, 1601, 1512, 1217, 1154, 758 cm^-1;
¹H NMR (CDCl₃, 400MHz) δ 0.88 (3H, t, J = 7.4 Hz), 1.24-1.67 (8H, m), 1.97-2.04 (4H, m), 3.01 (1H, dd, J = 7.8, 12.2 Hz), 3.13 (1H, dd, J = 4.5, 12.2 Hz), 3.72 (1H, br s), 4.00-4.11 (2H, m), 4.40 (2H, s), 6.41 (2H, d, J = 8.9 Hz), 6.59 (1H, dd, J = 2.0, 8.0 Hz), 6.72 (2H, d, J = 8.9 Hz), 6.85 (1H, t, J = 2.0 Hz), 7.01 (1H, d, J = 8.0 Hz), 7.03 (1H, br d, J = 8.2 Hz), 7.11 (1H, t, J = 8.0 Hz), 7.29-7.38 (3H, m), 7.51-7.53 (2H, m);
MS (FAB) m/z: 572 [M + H]⁺, 325, 250.
Anal. Calcd for C₃₅H₄₅N₃O_4・0.2 H₂O: C, 73.06; H, 7.95; N, 7.30. Found: C, 72.96; H, 7.87; N, 7.25.

［実施例２１］ （４−｛［（２Ｓ）−２−（｛［１−（１，１’−ビフェニル−３−イルアミノ）シクロヘキシル］カルボニル｝アミノ）ブチル］アミノ｝フェノキシ）酢酸 ２塩酸塩（例示化合物番号５−２）
実施例２０（２０ｂ）で製造したｔｅｒｔ−ブチル （４−｛［（２Ｓ）−２−（｛［１−（１，１’−ビフェニル−３−イルアミノ）シクロヘキシル］カルボニル｝アミノ）ブチル］アミノ｝フェノキシ）アセテート（１．６４ｇ，２．９ｍｍｏｌ）の塩化メチレン（５ｍＬ）溶液にトリフルオロ酢酸（５ｍＬ）を氷冷下に加え、さらに、室温で２時間攪拌した。反応溶液を減圧下濃縮し、残留物に４Ｎ塩酸−ジオキサン溶液（３ｍＬ）を加えた。溶媒を減圧下留去したのち得られた残渣をエーテル（２０ｍＬ）から粉末化し、ろ過とエーテルによる洗浄を行い、標記化合物（１．６０ｇ，収率９５％）を得た。
IR (KBr) ν_max3343, 1740, 1668, 1605, 1510, 1194, 1177, 1075, 759, 700 cm^-1;
¹H NMR (DMSO-d₆, 400MHz) δ 0.64 (3H, t, J = 7.4 Hz), 1.14-1.98 (12H, m), 3.07 (1H, dd, J = 5.0, 12.5 Hz), 3.28 (1H, dd, J = 6.5, 12.5 Hz), 3.96-4.01 (1H, br), 4.68 (2H, s), 6.72-6.73 (1H, br d), 6.95 (2H, d, J = 9.0 Hz), 6.96-7.10 (2H, m), 7.19 (1H, t, J = 8.0 Hz), 7.25 (2H, br d, J = 9.0 Hz), 7.31-7.52 (5H, m), 8.07 (1H, br d, J = 8.7 Hz);
MS (FAB) m/z: 516 [M + H]⁺, 250.

［実施例２２］ Ｎ^１−（（１Ｓ）−１−｛［（４−ベンジルオキシフェニル）アミノ］メチル｝プロピル）−Ｎ^２−（１，１’−ビフェニル−３−イル）−Ｌ−ロイシナミド（例示化合物番号１−２７２）
実施例１９（１９ｃ）に記載の反応と同様に、１−（１，１’−ビフェニル−３−イルアミノ）シクロヘキサンカルボン酸に代えてＮ−（１，１’−ビフェニル−３−イル）−Ｌ−ロイシン（５．５０ｇ、１９．４ｍｍｏｌ）を用いて反応を行ない、標記化合物（１０．３０ｇ、収率９９％）を無色結晶としてえた。
Mp 117-119 ℃;
IR (KBr) ν_max 3324, 1624, 1511, 1231, 1214, 755 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 0.93 (3H, t, J = 7.3 Hz), 0.94 (3H, d, J = 6.6 Hz), 1.01(3H, d, J = 6.6 Hz ),1.39-1.92 (5H, m), 2.96 (1H, dd, J = 7.3, 12.5 Hz), 3.11 (1H, dd, J = 4.4, 12.5 Hz), 3.40-3.55 (1H, br s), 3.74-3.82 (1H, m), 3.92-3.95 (1H, m), 4.00-4.12 (1H, m), 4.93 (2H，s), 6.33 (2H, d, J = 9.5 Hz), 6.58 (1H, dd, J = 2.2, 8.1 Hz), 6.72 (2H, d, J = 9.5 Hz), 6.74-6.85 (2H, m), 7.03 (1H, d, J = 8.1 Hz), 7.18 (1H, t, J = 8.1 Hz), 7.28-7.58 ( 10H, m)
Anal. Calcd for C₃₅H₄₁N₃O₂: C,78.47; H,7.71; N,7.84. Found: C,78.47; H,7.52; N,7.78
MS (FAB) m/z: 536 [M+H⁺], 444, 238;.

［実施例２３］ Ｎ^２−（１，１’−ビフェニル−３−イル）−Ｎ^１−（（１Ｓ）−１−｛［（４−シアノメトキシフェニル）アミノ］メチル｝プロピル）−L−ロイシナミド（例示化合物番号５−５）
（２３ａ） Ｎ^１−（（１Ｓ）−１−｛［（４−ヒドロキシフェニル）アミノ］メチル｝プロピル）−Ｎ^２−（１，１’−ビフェニル−３−イル）−Ｌ−ロイシナミド
実施例２２で製造したＮ^１−（（１Ｓ）−１−｛［（４−ベンジルオキシフェニル）アミノ］メチル｝プロピル）−Ｎ^２−（１，１’−ビフェニル−３−イル）−Ｌ−ロイシナミド（１０．４ｇ、１９．４ｍｍｏｌ）をエタノール（６５０ｍｌ）に溶解し、１０％パラジウム−炭素（２．１ｇ）を加えて、水素雰気化、５０℃で４時間撹拌した。１０％パラジウム−炭素をセライトを用いて濾別し、濾液を濃縮した。残渣をシリカゲルカラムクロマトグラフィー（３０−５０％酢酸エチル−ヘキサン）で精製し、標記化合物（７．４９ｇ，収率８７％）を泡状物質として得た。
¹H NMR(CDCl₃, 400 MHz) δ 0.93 (3H, t, J = 7.3 Hz), 0.94 (3H, d, J = 6.6 Hz), 1.01(3H, d, J = 6.6 Hz ),1.53-1.93 (5H, m), 3.71 (1H, dd, J = 4.4, 9.5 Hz), 3.75-3.82 (1H, m), 3.85 (1H, dd, J = 3.7, 9.5Hz), 4.91 (1H, br s), 6.47 (2H, d, J = 8.8Hz), 6.54-6.62 (1H, m), 6.59 (2H, d, J = 8.8Hz), 6.79-6.82(1H, m), 6.96 (1H, d, J = 8.1Hz), 7.03 (1H, br d, J = 9.5Hz), 7.14 (1H, t, J = 8.1Hz), 7.28-7.55 (6H, m)
IR (KBr) ν_max 2961, 1649, 1605, 1509, 1228 cm^-1;
MS (FAB) m/z: 447 [M+H⁺], 238;.

（２３ｂ） Ｎ^２−（１，１’−ビフェニル−３−イル）−Ｎ^１−（（１Ｓ）−１−｛［（４−シアノメトキシフェニル）アミノ］メチル｝プロピル）−Ｌ−ロイシナミド
実施例２３（２３ａ）で製造したＮ^１−（（１Ｓ）−１−｛［（４−ヒドロキシフェニル）アミノ］メチル｝プロピル）−Ｎ^２−（１，１’−ビフェニル−３−イル）−Ｌ−ロイシナミド（２．８７ｇ、６．４４ｍｍｏｌ）をテトラヒドロフラン／Ｎ，Ｎ−ジメチルホルムアミド混合溶媒（６０ｍｌ、５：１）に溶解し、水素化ナトリウム（５５％油性）（２８１ｍｇ、６．４４ｍｍｏｌ）を加え、さらにブロモアセトニトリル（０．５１６ｍｌ、７．４１ｍｍｏｌ）を加え、室温下１７時間撹拌した。反応液を飽和塩化アンモニウム水溶液に注ぎ、エーテルで抽出した。水、飽和食塩水で順次洗浄し、乾燥後、濃縮した。残渣をシリカゲルカラムクロマトグラフィー（４０−５０％酢酸エチル−ヘキサン）で精製し、標記化合物（１．８３ｇ，収率５９％）を泡状物質として得た。
¹H NMR(CDCl₃, 400 MHz) 0.94 (3H, t, J = 7.3Hz), 0.95 (3H, d, J = 5.9Hz), 1.02 (3H, d, J = 5.9Hz), 1.40-1.68 (3H, m), 1.79-1.92 (2H, m), 2.97(1H, dd, J = 8.5, 12.5Hz), 3.13 (1H, dd, J = 3.7, 12.5Hz), 3.72-3.81 (2H, m), 3.91-3.95(1H, m), 4.02-4.11(1H, m), 4.60 (2H, s), 6.34(2H, J = 8.8Hz), 6.58(1H, dd, J = 1.5, 8.1Hz), 6.72-6.79(1H, m), 6.74(2H, d, J = 8.8Hz), 6.82-6.85(1H，m), 7.03-7.07(1H, m), 7.18 (1H, t, J = 8.1Hz), 7.30-7.38(3H, m), 7.48-7.55(2H, m)
IR (KBr) ν_max 2962, 1652, 1606, 1512, 1215, 758 cm^-1;
MS (FAB) m/z: 485 [M+H⁺], 446, 238;
HRMS(ESI) [M+H⁺] calcd for C₃₀H₃₇N₄O₂:485.2917;obserbed 485.2906.

［実施例２４］ Ｎ^２−（１，１’−ビフェニル−３−イル）−Ｎ^１−｛（１Ｓ）−１−（［｛４−（２Ｈ−ピラゾール−５−イル）メトキシフェニル｝アミノ］メチル）プロピル｝−L−ロイシナミド（例示化合物番号５−６）
実施例２３（２３ｂ）で製造したＮ^２−（１，１’−ビフェニル−３−イル）−Ｎ^１−（（１Ｓ）−１−｛［（４−シアノメトキシフェニル）アミノ］メチル｝プロピル）−L−ロイシナミド（１．１３ｇ、２．３３ｍｍｏｌ）、アジ化ナトリウム（４５４ｍｇ）、塩化アンモニウム（３７４ｍｇ）をＮ，Ｎ−ジメチルホルムアミド（２５ｍｌ）に溶解し、１００℃で５時間３０分撹拌した。反応液を冷却した飽和塩化アンモニウム水溶液に注ぎ、酢酸エチルで５回抽出した。飽和食塩水で２回洗浄後、乾燥、濃縮した。残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル）で精製し、標記化合物（７４５ｍｇ，収率６９％）を無色結晶として得た。
Mp 154-158℃;
¹H NMR(CDCl₃, 400 MHz) δ 0.93 (3H, t, J = 7.4Hz), 0.93 (3H, d, J = 6.3Hz), 1.01 (3H, d, J = 6.3Hz), 1.36-1.45 (1H, m), 1.56-1.68 (2H, m), 1.77-1.92(3H, m), 2.86 (1H, dd, J = 8.2, 12.9Hz), 3.10 (1H, dd, J = 4.3, 12.9Hz), 3.80-3.84 (1H, m), 4.04-4.11 (1H, m), 5.21-5.24 (2H, br s), 6.22 (2H, d, J = 8.8Hz), 6.55-6.59(1H, m), 6.58 (2H, d, J = 8.8Hz), 6.79-6.86(2H, m), 7.02 (1H, d, J = 7.8Hz), 7.16 (1H, t, J = 7.8Hz), 7.25-7.52 (6H, m)
IR (KBr) ν_max 2960, 1637, 1605, 1512, 1231, 700 cm^-1;
Anal. Calcd for C₃₀H₃₇N₇O₂: C,68.29; H,7.07; N,18.58. Found: C,68.43; H,6.88; N,18.35.
MS (FAB) m/z: 528 [M+H⁺], 444, 238;.

［実施例２５］ ［４−（｛（２Ｓ）−２−［（Ｎ−１，１’−ビフェニル−３−イル−Ｌ−ロイシル）アミノ］ブチル｝アミノ）フェノキシ］酢酸 ｔｅｒｔ−ブチル（例示化合物番号５−７）
実施例２３（２３ａ）で製造したＮ^１−（（１Ｓ）−１−｛［（４−ヒドロキシフェニル）アミノ］メチル｝プロピル）−Ｎ^２−（１，１’−ビフェニル−３−イル）−L−ロイシナミド（４．６２ｇ、１０．４ｍｍｏｌ）をテトラヒドロフラン／Ｎ，Ｎ−ジメチルホルムアミド混合溶媒（１００ｍｌ、４：１）に溶解し、氷冷下に、水素化ナトリウム（５５％油性）（４５２ｍｇ、１０．４ｍｍｏｌ）を加え、さらにα−ブロモ酢酸ｔｅｒｔ−ブチル（１．８４ｍｌ）を加えた。室温に戻し１時間３０分撹拌した後、水中に注ぎ、酢酸エチルで抽出した。水、飽和食塩水で洗浄、乾燥後、濃縮した。残渣をシリカゲルカラムクロマトグラフィー（３０−４５％酢酸エチルーヘキサン）で精製し、標記化合物（４．７ｇ，収率８１％）を泡状物質として得た。
¹H NMR(CDCl₃, 400 MHz) δ 0.93 (3H, t, J = 7.4Hz), 0.94 (3H, d, J = 6.3Hz), 1.01 (3H, d, J = 6.3Hz), 1.40-1.50(1H, m), 1.48 (9H, s), 1.55-1.66 (2H, m), 1.80-1.91 (2H, m), 2.95 (1H, dd, J = 7.4, 12.5Hz), 3.10 (1H, dd, J = 4.7, 12.5Hz), 3.74-3.78 (1H, m), 3.91-3.94 (1H, m), 4.00-4.08 (1H, m), 4.36 (2H, s), 6.30 (2H, d, J = 9.0 Hz), 6.56 (1H, dd, J = 2.2, 7.8 Hz), 6.65 (2H, d, J = 9.0Hz), 6.74 (1H, d, J = 8.6Hz), 6.82 (1H, t, J = 2.2 Hz), 7.01(1H, d, J = 7.8Hz), 7.15 (1H, t, J = 7.8Hz), 7.27-7.37 (3H, m), 7.47-7.51 (2H, m)
IR (KBr) ν_max 2961, 1751, 1652, 1605, 1513, 1217, 1155 cm^-1;
Anal. Calcd for C₃₄H₄₅N₃O₄: C,72.96; H,8.10; N,7.51. Found: C,72.95; H,8.00; N,7.49.
MS (FAB) m/z: 560 [M+H⁺], 446, 238;.

［実施例２６］ ２−［４−（｛（２Ｓ）−２−［（Ｎ−１，１’−ビフェニル−３−イル−Ｌ−ロイシル）アミノ］ブチル｝アミノ）フェノキシ］−２−プロピオン酸エチル（例示化合物番号５−８）
実施例２３（２３ａ）で製造したＮ^１−（（１Ｓ）−１−｛［（４−ヒドロキシフェニル）アミノ］メチル｝プロピル）−Ｎ^２−（１，１’−ビフェニル−３−イル）−L−ロイシナミド（１２７ｍｇ、０．２８ｍｍｏｌ）をテトラヒドロフラン／Ｎ，Ｎ−ジメチルホルムアミド混合溶媒（２ｍｌ、４：１）に溶解し、氷冷下に、水素化ナトリウム（５５％油性）（１２．４ｍｇ、０．２８ｍｍｏｌ）を加え、さらに２−ブロモ−２−メチルプロピオン酸エチル（５２μｌ、０．３６ｍｍｏｌ）を加えた。室温に戻し、１７時間撹拌した。反応液を水に注ぎ、酢酸エチルで抽出した。飽和食塩水で洗浄、乾燥後、濃縮した。残渣を薄層クロマトグラフィーにて精製し、標記化合物（９５ｍｇ，収率６１％）を油状物質として得た。
¹H NMR(CDCl₃, 400 MHz) δ 0.93 (3H, t, J = 7.4Hz), 0.94 (3H, d, J = 6.3Hz), 1.01 (3H, d, J = 6.3Hz),1.27 (3H, t, J = 7.0Hz),1.40-1.70 (3H, m),1.49 (6H, s), 1.77-1.92 (2H, m), 2.95 (1H, dd, J = 7.8, 12.1Hz), 3.10 (1H, dd, J = 4.3, 12.1Hz), 3.73-3.82 (1H, m), 3.88-4.10(3H, m), 4.21 (2H, q, J = 7.0Hz), 6.29 (2H, d, J = 8.6Hz), 6.57 (1H, dd, J = 2.3, 7.8Hz), 6.60 (2H, d, J = 8.6Hz), 6.74-6.83 (2H, m), 6.97-7.03 (1H, m), 7.13 (1H, t, J = 7.8Hz), 7.25-7.34 (3H, m), 7.46-7.54(2H, m)
IR (KBr) ν_max 2961, 1732, 1651, 1607, 1511, 1227, 1140 cm^-1;
MS (FAB) m/z: 560 [M+H⁺], 444, 238;
HRMS(ESI) [M+H⁺] calcd for C₃₄H₄₆N₃O₄:560.3488;obserbed 560.3491.

［実施例２７］ ［４−（｛（２Ｓ）−２−［（Ｎ−１，１’−ビフェニル−３−イル−Ｌ−ロイシル）アミノ］ブチル｝アミノ）フェノキシ］酢酸二塩酸塩（例示化合物番号５−９）
実施例２５で製造した［４−（｛（２Ｓ）−２−［（Ｎ−１，１’−ビフェニル−３−イル−Ｌ−ロイシル）アミノ］ブチル｝アミノ）フェノキシ］酢酸ｔｅｒｔ−ブチル（３．６９ｇ、６．５９ｍｍｏｌ）を塩化メチレン（２５ｍｌ）−トリフルオロ酢酸（２５ｍｌ）に溶解し、室温下１時間撹拌した。反応溶液を濃縮し、残渣をトルエンで３回共沸した。残渣を塩化メチレン（５ｍｌ）に溶解し、４規定塩酸−ジオキサン溶液（２０ｍｌ）を加えた。生じた結晶をジイソプロピルエーテルで洗浄し、標記化合物（２．８０ｇ、収率７４％）を無色結晶として得た。
Mp 89-91 ℃;
¹H NMR(CDCl₃, 400 MHz) δ0.74-0.90 (9H, m), 1.51-1.69 (4H, m), 2.11-2.22 (1H, m), 3.22-3.27 (1H, m), 3.65-3.72 (2H, m), 4.43-4.50(2H, m), 4.47 (2H, s), 6.77 (2H, d, J = 7.4 Hz), 7.34-7.75 (9H, m), 8.03 (1H, br s), 9.52 (1H, m)
IR (KBr) ν_max 2963, 1739, 1674, 1605, 1554, 1228, 1193 cm^-1;
MS (FAB) m/z: 560 [M+H⁺], 444, 238;.

［実施例２８］ Ｎ^１−［（１Ｓ）−１−（｛［４−（ベンジルオキシ）フェニル］アミノ｝メチル）プロピル］−Ｎ^２−（モルホリン−４−イルカルボニル）−Ｌ−ロイシナミド（例示化合物番号５−１２）
（２８ａ） ベンジル Ｎ−（モルホリン−４−イルカルボニル）−Ｌ−ロイシネート
ロイシン ベンジルエステル ｐ−トルエンスルホネート（３．９４ｇ，１０ｍｍｏｌ）及びトリエチルアミン（４．２ｍｌ，３０ｍｍｏｌ）を塩化メチレン（１００ｍｌ）に溶解し、氷冷下モルホリンカルボニルクロリド（２．３ｍｌ，２０ｍｍｏｌ）を滴下し、室温で２４時間撹拌した。溶媒を減圧下留去し得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル，１：１）を用いて精製し、標記目的化合物（３．３４ｇ，収率１００％）を得た。
IR (film) ν_max 3347, 2959, 1742, 1632, 1534, 1456, 1387, 1268, 1192, 1119, 999, 751, 698 cm^-1;
¹H NMR (CDCl₃, 400MHz) δ 0.93 (6H, t, J=4.9 Hz), 1.49-1.71 (3H, m), 3.33-3.41 (4H, m), 3.68 (4H, t, J=4.9 Hz), 4.56-4.60 (1H, m), 4.83 (1H, d, J=8.8 Hz), 5.13 (1H, d, J=12.7 Hz), 5.20 (1H, d, J=12.7 Hz), 7.32-7.38 (5H, m);
HRMS(FAB): 335.1977 [M+H]⁺ (calcd 335.1960 for C₁₈H₂₇N₂O₄)

（２８ｂ） Ｎ−（モルホリン−４−イルカルボニル）−Ｌ−ロイシン
実施例２８（２８ａ）で製造したベンジル Ｎ−（モルホリン−４−イルカルボニル）−Ｌ−ロイシネート（３．３４ｇ，１０ｍｍｏｌ）を水素雰囲気下（１気圧）、１０％パラジウム炭素触媒（０．５３ｇ，０．５０ｍｍｏｌ）存在下に、エタノール（１００ｍｌ）溶媒中、室温で３時間水素化分解した。触媒を除去したのち、溶媒を留去して得られた残留物をシリカゲルカラムクロマトグラフィー（酢酸エチル／メタノール，２０：１）を用いて精製し、標記目的化合物（２．４４ｇ，収率１００％）を得た。
IR(film) ν_max3360, 2960, 1726, 1631, 1538, 1270, 1118, 1000, 860, 593 cm^-1;
¹H NMR (CDCl₃, 400MHz) δ 0.95 (6H, t, J=6.7 Hz), 1.53-1.78 (3H, m), 3.33-3.43 (4H, m), 3.69 (4H, t, J=4.7 Hz), 4.35-4.40 (1H, m), 4.79 (1H, d, J=6.3 Hz);
HRMS(FAB): 245.1496 [M+H]⁺ (calcd 245.1518 for C₁₁H₂₁N₂O₄)

（２８ｃ） Ｎ^１−［（１Ｓ）−１−（｛［４−（ベンジルオキシ）フェニル］アミノ｝メチル）プロピル］−Ｎ^２−（モルホリン−４−イルカルボニル）−Ｌ−ロイシナミド
実施例１９（１９ｂ）で製造したｔｅｒｔ−ブチル （１Ｓ）-１−（｛［４−（ベンジルオキシ）フェニル］アミノ｝メチル）プロピルカーバメート（８１７ｍｇ，２．２１ｍｍｏｌ）を４Ｍ塩酸ジオキサン溶液（１０ｍｌ）に溶解し、室温で２時間撹拌した。溶媒を減圧下留去し得られた残渣をＮ，Ｎ−ジメチルホルムアミド（１０ｍｌ）に溶解し、実施例２８（２８ｂ）で製造したＮ−（モルホリン−４−イルカルボニル）−Ｌ−ロイシン（５４０ｍｇ，２．２１ｍｍｏｌ）、トリエチルアミン（３７０μｌ，２．６５ｍｍｏｌ），ヒドロキシベンゾトリアゾール １水和物（３５８ｍｇ，２．６５ｍｍｏｌ）及び１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩（５０８ｍｇ，２．６５ｍｍｏｌ）を加え、室温で７時間撹拌した。反応液に酢酸エチル（２０ｍｌ）及び水（２０ｍＬ）を加え、分液後、有機相を水（２０ｍｌ×５）、食塩水（２０ｍｌ）で洗浄し、硫酸ナトリウムで乾燥後、溶媒を減圧下留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（酢酸エチル）を用いて精製し、標記目的化合物（９５６ｍｇ，収率８７％）を得た。
IR(KBr) ν_max3283, 2958, 1622, 1545, 1512, 1455, 1384, 1267, 1233, 1119, 1024, 1000, 819, 738, 696 cm^-1;
¹H NMR (CDCl₃, 400MHz) δ0.90-0.95 (9H, m), 1.49-1.69 (5H, m), 3.09 (1H, dd, J=8.1, 12.5 Hz), 3.19 (1H, dd, J=5.1, 12.5 Hz), 3.32-3.35 (4H, m), 3.64-3.66 (4H, m), 3.96-4.03 (1H, m), 4.24-4.30 (1H, m), 4.95 (1H, d, J=8.1 Hz), 4.98 (2H, s), 6.32 (1H, d, J=8.1 Hz), 6.56 (2H, d, J=8.8 Hz), 6.83 (2H, d, J=8.8 Hz), 7.28-7.42 (5H, m);
HRMS(FAB): 497.3124 [M+H]^+・ (calcd 497.3132 for C₂₈H₄₁N₄O₄)

［実施例２９］ Ｎ^１−［（１Ｓ）−１−（｛［４−（ベンジルオキシ）フェニル］アミノ｝メチル）プロピル］−Ｎ^２−（２−オキソ−６−フェニル−２Ｈ−ピラン−４−イル）−Ｌ−ロイシナミド（例示化合物番号５−１３）
実施例２８（２８ｃ）に記載の反応と同様にして、Ｎ−（モルホリン−４−イルカルボニル）−Ｌ−ロイシンに代えて、実施例３（３ｂ）で製造したＮ−（２−オキソ−６−フェニル−２Ｈ−ピラン−４−イル）−Ｌ−ロイシン（８３８ｍｇ，２．７８ｍｍｏｌ）を使用して、標記目的化合物（１３１５ｍｇ，収率８５％）を得た。
M.p. 142-146 ℃
IR(KBr) ν_max3269, 3088, 2959, 1650, 1549, 1512, 1298, 1232, 818, 767, 694 cm^-1;
¹H NMR (CDCl₃, 400MHz) δ0.87 (3H, d, J=5.9 Hz), 0.93 (3H, d, J=5.9 Hz), 0.95 (3H, t, J=7.5 Hz), 1.52-1.72 (5H, m), 3.12-3.21 (2H, m), 4.03-4.09 (2H, m), 4.91 (2H, s), 5.33 (1H, d, J=1.6 Hz), 5.72 (1H ,br s), 6.22 (1H, d, J=1.6 Hz), 6.53 (2H, d, J=9.0 Hz), 6.77 (2H, d, J=9.0 Hz), 7.14 (1H, br s), 7.27-7.39 (8H, m), 7.66-7.68 (2H, m);
HRMS(FAB): 554.3012 [M+H]^+・ (calcd 554.3024 for C₃₄H₄₀N₃O₄)

［実施例３０］ ｔｅｒｔ−ブチル ｛４−［（（２Ｓ）−２−｛［Ｎ−（モルホリン−４−イルカルボニル）−Ｌ−ロイシル］アミノ｝ブチル）アミノ］フェノキシ｝アセテート（例示化合物番号５−１４）
（３０ａ） Ｎ^１−（（１Ｓ）−１−｛［（４−ヒドロキシフェニル）アミノ］メチル｝プロピル）−Ｎ^２−（モルホリン−４−イルカルボニル）−Ｌ−ロイシナミド
実施例２８（２８ｃ）で製造したＮ^１−［（１Ｓ）−１−（｛［４−（ベンジルオキシ）フェニル］アミノ｝メチル）プロピル］−Ｎ^２−（モルホリン−４−イルカルボニル）−Ｌ−ロイシナミド（１１６７ｍｇ，２．３５ｍｍｏｌ）を水素雰囲気下（１気圧）、１０％パラジウム炭素触媒（２５０ｍｇ，０．２４ｍｍｏｌ）存在下に、エタノール（２０ｍｌ）溶媒中、５０℃で１２時間水素化分解した。触媒を除去したのち、溶媒を留去して得られた残留物をシリカゲルカラムクロマトグラフィー（酢酸エチル／メタノール，２０：１）を用いて精製し、標記目的化合物（７９７ｍｇ，収率８３％）を得た。
IR(KBr) ν_max3293, 2959, 1626, 1517, 1245, 1119, 1000, 822 cm^-1;
¹H NMR (CDCl₃, 400MHz) δ0.91 (3H, d, J=6.6 Hz), 0.92 (3H, d, J=6.6 Hz), 0.94 (3H, t, J=7.3 Hz), 1.46-1.71 (5H, m), 3.10 (1H, dd, J=7.3, 12.5 Hz), 3.17 (1H, dd, J=4.4, 12.5 Hz), 3.33-3.35 (4H, m), 3.66 (4H, t, J=4.4 Hz), 3.94-4.02 (1H, m), 4.23-4.29 (1H, m), 4.87 (1H, d, J=8.1 Hz), 6.21 (1H, d, J=8.1 Hz), 6.53 (2H, d, J=8.8 Hz), 6.69 (2H, d, J=8.8 Hz);
HRMS(FAB): 407.2665 [M+H]^+・ (calcd 407.2648 for C₂₁H₃₅N₄O₄)

（３０ｂ） ｔｅｒｔ−ブチル ｛４−［（（２Ｓ）−２−｛［Ｎ−（モルホリン−４−イルカルボニル）−Ｌ−ロイシル］アミノ｝ブチル）アミノ］フェノキシ｝アセテート
実施例３０（３０ａ）で製造したＮ^１−（（１Ｓ）−１−｛［（４−ヒドロキシフェニル）アミノ］メチル｝プロピル）−Ｎ^２−（モルホリン−４−イルカルボニル）−Ｌ−ロイシナミド（７１４ｍｇ，１．７６ｍｍｏｌ）のテトラヒドロフラン（８ｍＬ）溶液に、氷冷下、水素化ナトリウム（５５％油性）（８４ｍｇ，１．９４ｍｍｏｌ）を加え、さらに、ブロモ酢酸 ｔ−ブチルエステル（２８６μｌ，１．９４ｍｍｏｌ）のＮ，Ｎ−ジメチルホルムアミド（２ｍＬ）溶液を滴下した。反応温度を室温に戻したのち、反応液をさらに１時間攪拌した。氷冷下、水（２０ｍＬ）を反応液に加え、水層を酢酸エチル（２ｘ５０ｍＬ）で抽出した。抽出液を硫酸ナトリウムで乾燥し、溶媒を留去して得られた残留物をシリカゲルカラムクロマトグラフィー（酢酸エチル／メタノール，２０：１）で精製し、標記化合物（６９８ｍｇ，収率７６％）を得た。
IR(KBr) ν_max3285, 2960, 1754, 1623, 1514, 1368, 1267, 1156, 1119, 1081, 1000, 820 cm^-1;
¹H NMR (CDCl₃, 400MHz) δ0.91 (3H, d, J=5.9 Hz), 0.92 (3H, d, J=5.9 Hz), 0.94 (3H, t, J=7.4 Hz), 1.48 (9H, s), 1.49-1.68 (5H, m), 3.08 (1H, dd, J=7.8, 12.5 Hz), 3.17 (1H, dd, J=5.1, 12.5 Hz), 3.32-3.35 (4H, m), 3.65 (4H, t, J=4.7 Hz), 3.94-4.02 (1H, m), 4.20-4.26 (1H, m), 4.40 (2H, s), 4.81 (1H, d, J=7.8 Hz), 6.17 (1H, d, J=8.7 Hz), 6.54 (2H, d, J=9.0 Hz), 6.75 (2H, d, J=9.0 Hz);
HRMS(FAB): 521.3344 [M+H]^+・ (calcd 521.3336 for C₂₇H₄₅N₄O₆)

［実施例３１］ ｔｅｒｔ−ブチル ｛４−［（（２Ｓ）−２−｛［Ｎ−（２−オキソ−６−フェニル−２Ｈ−ピラン−４−イル）−Ｌ−ロイシル］アミノ｝ブチル）アミノ］フェノキシ｝アセテート（例示化合物番号５−１８）
（３１ａ） Ｎ^１−（（１Ｓ）−１−｛［（４−ヒドロキシフェニル）アミノ］メチル｝プロピル）−Ｎ^２−（２−オキソ−６−フェニル−２Ｈ−ピラン−４−イル）−Ｌ−ロイシナミド
実施例３０（３０ａ）に記載の反応と同様にし、Ｎ^１−［（１Ｓ）−１−（｛［４−（ベンジルオキシ）フェニル］アミノ｝メチル）プロピル］−Ｎ^２−（モルホリン−４−イルカルボニル）−Ｌ−ロイシナミドに代えて、実施例２９で製造したＮ^１−［（１Ｓ）−１−（｛［４−（ベンジルオキシ）フェニル］アミノ｝メチル）プロピル］−Ｎ^２−（２−オキソ−６−フェニル−２Ｈ−ピラン−４−イル）−Ｌ−ロイシナミド（１３００ｍｇ，２．３５ｍｍｏｌ）を使用して、標記目的化合物（１０４０ｍｇ，収率９５％）を得た。
M.p. 171-175 ℃
IR(KBr) ν_max3280, 2960, 1656, 1549, 1516, 1242, 822, 767, 627 cm^-1;
¹H NMR (CD₃OD, 400MHz) δ0.84 (3H, d, J=5.9 Hz), 0.87 (3H, t, J=8.1 Hz), 0.90 (3H, d, J=6.6 Hz), 1.37-1.69 (5H, m), 2.96-3.07 (2H, m), 3.86-3.92 (2H, m), 5.04 (1H, br s), 6.44 (2H, d, J=8.8 Hz), 6.51 (2H, d, J=8.8 Hz), 6.54 (1H, d, J=2.2 Hz), 7.39-7.40 (3H, m), 7.71-7.73 (2H, m);
HRMS(FAB): 464.2546 [M+H]^+・ (calcd 464.2553 for C₂₇H₃₄N₃O₄)

（３１ｂ） ｔｅｒｔ−ブチル ｛４−［（（２Ｓ）−２−｛［Ｎ−（２−オキソ−６−フェニル−２Ｈ−ピラン−４−イル）−Ｌ−ロイシル］アミノ｝ブチル）アミノ］フェノキシ｝アセテート
実施例３０（３０ｂ）に記載の反応と同様にし、Ｎ^１−（（１Ｓ）−１−｛［（４−ヒドロキシフェニル）アミノ］メチル｝プロピル）−Ｎ^２−（モルホリン−４−イルカルボニル）−Ｌ−ロイシナミドに代えて、実施例３１（３１ａ）で製造したＮ^１−（（１Ｓ）−１−｛［（４−ヒドロキシフェニル）アミノ］メチル｝プロピル）−Ｎ^２−（２−オキソ−６−フェニル−２Ｈ−ピラン−４−イル）−Ｌ−ロイシナミド（１０４０ｍｇ，２．２４ｍｍｏｌ）を使用して、標記目的化合物（９５５ｍｇ，収率７６％）を得た。
M.p. 122-126 ℃
IR(KBr) ν_max3272, 3088, 2961, 1653, 1549, 1513, 1368, 1299, 1215, 1155, 1066, 821, 767, 693 cm^-1;
¹H NMR (CDCl₃, 400MHz) δ0.87 (3H, d, J=5.9 Hz), 0.94 (3H, d, J=5.9 Hz), 0.96 (3H, t, J=7.3 Hz), 1.48 (9H, s), 1.53-1.73 (5H, m), 3.11-3.22 (2H, m), 4.02-4.10 (2H, m), 4.38 (2H, s), 5.33 (1H, d, J=2.2 Hz), 5.71 (1H ,br s), 6.24 (1H, d, J=2.2 Hz), 6.53 (2H, d, J=8.8 Hz), 6.73 (2H, d, J=8.8 Hz), 7.14 (1H, br s), 7.38-7.43 (3H, m), 7.69-7.71 (2H, m);
HRMS(FAB): 600.3064 [M+Na]^+・ (calcd 600.3040 for C₃₃H₄₃N₃O₆Na)

［実施例３２］ ｛４−［（（２Ｓ）−２−｛［Ｎ−（モルホリン−４−イルカルボニル）−Ｌ−ロイシル］アミノ｝ブチル）アミノ］フェノキシ｝酢酸 塩酸塩（例示化合物番号５−１９）
実施例３０（３０ｂ）で製造したｔｅｒｔ−ブチル ｛４−［（（２Ｓ）−２−｛［Ｎ−（モルホリン−４−イルカルボニル）−Ｌ−ロイシル］アミノ｝ブチル）アミノ］フェノキシ｝アセテート（６４３ｍｇ，１．２３ｍｍｏｌ）の塩化メチレン（５ｍＬ）溶液にトリフルオロ酢酸（５ｍＬ）を氷冷下に加え、さらに，室温で２時間攪拌した。反応溶液を減圧下濃縮し、残留物に４Ｍ塩酸ジオキサン溶液（３ｍＬ）を加えた。溶媒を減圧下留去したのち得られた残渣をエーテル（２０ｍＬ）から粉末化し、ろ過とエーテルによる洗浄を行い、標記化合物（５７１ｍｇ，収率９３％）を得た。
IR(KBr) ν_max 3264, 2961, 1740, 1607, 1512, 1444, 1263, 1199, 1118, 1072, 833 cm^-1;
¹H NMR (CD₃OD, 400MHz) δ0.89-0.97 (9H, m), 1.55-1.74 (5H, m), 3.30-3.64 (10H, m), 3.84-3.92 (1H, m), 4.06-4.09 (1H, m), 4.70 (2H, s), 7.06 (2H, d, J=8.8 Hz), 7.40 (2H, d, J=8.8 Hz);
HRMS(FAB): 465.2700 [M+H]^+・ (calcd 465.2728 for C₂₃H₃₇N₄O₆)

［実施例３３］ Ｎ−［１−（｛［（１Ｓ）−１−（｛［４−（ベンジルオキシ）フェニル］アミノ｝メチル）プロピル］アミノ｝カルボニル）シクロヘキシル］−１−ベンゾフラン−２−カルボキサミド（例示化合物番号５−２１）
（３３ａ） ｔｅｒｔ−ブチル １−｛［（９Ｈ−フルオレン−９−イルメトキシ）カルボニル］アミノ｝シクロヘキサンカルボキシレート
Ｎ，Ｎ’−ジイソプロピルカルボジイミド（３６ｇ、２８５ｍｍｏｌ）、ｔｅｒｔ−ブチルアルコール（２３．３ｇ、３１４ｍｍｏｌ）、塩化銅（Ｉ）（３０３ｍｇ、３．０ｍｍｏｌ）を室温下、５日間撹拌する。その溶液を塩化メチレン１００ｍｌで希釈し、１−｛［（９Ｈ−フルオレン−９−イルメトキシ）カルボニル］アミノ｝シクロヘキサンカルボン酸（１５．３ｇ、４２ｍｍｏｌ）を加え、同温度で４５分撹拌した。生じた沈殿物（Ｎ，Ｎ’−ジイソプロピル尿素）を取り除き、ろ液を濃縮した。残渣をカラムクロマトグラフィーにて精製し、標記化合物（１５．６ｇ、８８％）を無色固体として得た。
¹H NMR(CDCl₃, 400 MHz) δ1.30-1.50(4H,m), 1.42(9H, s), 1.57-1.68(2H, m), 1.75-2.06(4H, m), 4.23-4.27(1H, br), 4.34-4.45(2H, br), 4.84-4.92(1H, br), 7.32(2H, t, J=7.3Hz), 7.40(2H, t, J=7.3Hz), 7.62(2H, d, J=7.3Hz), 7.77(2H, d, J=7.3Hz).

（３３ｂ） ｔｅｒｔ−ブチル １−アミノシクロヘキサンカルボキシレート
実施例３３（３３ａ）で製造したｔｅｒｔ−ブチル エステル（１５．６ｇ、３７ｍｍｏｌ）をテトラヒドロフラン１００ｍｌに溶解し、ピロリジン（３．７ｍｌ、４４．４ｍｍｏｌ）加えて、室温下、1４時間撹拌した。反応液を濃縮し、残渣をカラムクロマトグラフィーにて精製し、標記化合物（７．３７ｇ、９９％）を油状物質として得た。
¹H NMR(CDCl₃, 400 MHz) δ1.38(9H, s), 1.42-1.46(4H,m),1.52-1.58(2H, m), 1.74-1.82(4H, m).

（３３ｃ） ｔｅｒｔ−ブチル １−［（１−ベンゾフラン−２−イルカルボニル）アミノ］シクロヘキサンカルボキシレート
実施例３３（３３ｂ）で製造したｔｅｒｔ−ブチル １−アミノシクロヘキサンカルボキシレート（７．３７ｇ、３７ｍｍｏｌ）、ベンゾフラン−２−カルボン酸（７．１３ｇ、４４ｍｍｏｌ）、１−エチル−３−(３−ジメチルアミノプロピル)−カルボジイミド 塩酸塩（８．４ｇ、４４ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾ−ル １水和物（６．７４ｇ、４４ｍｍｏｌ）をＮ，Ｎ−ジメチルホルムアミド（２００ｍｌ）に溶解し、室温下、1４時間撹拌した。反応液を水に注ぎ、エーテルで抽出した。エーテル層を水、飽和食塩水で洗浄し、硫酸マグネシウムで乾燥後、濃縮した。残渣をカラムクロマトグラフィーにて精製し、標記化合物（１２．７ｇ、９９％）を油状物質として得た。
¹H NMR(CDCl₃, 400 MHz) δ1.34-1.60(4H,m), 1.45(9H, s), 1.63-1.77(2H, m), 1.87-1.97(2H, m), 2.15-2.22(2H, m), 5.68(1H, s), 7.29(1H, t, J=8.0Hz), 7.42(1H, t, J=8.0Hz), 7.45(1H, s), 7.53(1H, d, J=8.0Hz), 7.67(1H, d, J=7.3Hz).

（３３ｄ） １−［（１−ベンゾフラン−２−イルカルボニル）アミノ］シクロヘキサンカルボン酸
実施例３３（３３ｃ）で製造したｔｅｒｔ−ブチル １−［（１−ベンゾフラン−２−イルカルボニル）アミノ］シクロヘキサンカルボキシレート（１２．７ｇ、３７ｍｍｏｌ）を塩化メチレン（１５０ｍｌ）に溶解し、氷冷化に、トリフルオロ酢酸（１４ｍｌ）を滴下し、さらに室温で２４時間撹拌した。反応液を濃縮後、標記化合物（１０．４ｇ、９８％）を無色固体としてえた。
M.p. 220-224 ℃
IR(KBr) ν_max2937, 1740, 1596, 1518, 746 cm^-1;
¹H NMR (CDCl₃, 400MHz) δ1.35-2.07 (6H, m), 1.99-2.07 (2H, m), 2.24-2.31 (2H, m), 6.77 (1H, brs), 7.32 (1H, dd, J=7.0, 7.5 Hz), 7.45 (1H, dd, J=7.0, 8.2 Hz), 7.53 (1H, s), 7.54 (1H, d, J=8.2 Hz), 7.69 (1H, dd, J=7.5 Hz);
MS (EI⁺) m/z: 287 [M⁺], 243, 161, 145；
Anal. Calcd for C₁₆H₁₇NO_4・0.1 H₂O: C, 66.47; H, 6.00; N, 4.84. Found: C, 66.30; H, 5.99; N, 4.80.

（３３ｅ） Ｎ−［１−（｛［（１Ｓ）−１−（｛［４−（ベンジルオキシ）フェニル］アミノ｝メチル）プロピル］アミノ｝カルボニル）シクロヘキシル］−１−ベンゾフラン−２−カルボキサミド
実施例２８（２８ｃ）に記載した方法に従い、Ｎ−（モルホリン−４−イルカルボニル）−Ｌ−ロイシンに代えて、実施例３３（３３ｄ）で製造した１−［（１−ベンゾフラン−２−イルカルボニル）アミノ］シクロヘキサンカルボン酸（８６８ｍｇ，３．０５ｍｍｏｌ）を使用して、標記目的化合物（１３９８ｍｇ，収率８５％）を得た。
M.p. 112-114 ℃
IR(KBr) ν_max3345, 2932, 1659, 1592, 1512, 1448, 1296, 1228, 1177, 1025, 820, 749, 6966 cm^-1;
¹H NMR (CDCl₃, 400MHz) δ0.95 (3H, t, J=7.4 Hz), 1.35-1.74 (8H, m), 2.01 (2H, dq, J=3.9, 13.3 Hz), 2.24 (2H,dt, J=2.7, 13.7 Hz), 3.03 (1H, dd, J=7.8, 12.5 Hz), 3.23 (1H, dd, J=4.3, 12.5 Hz), 4.00-4.10 (1H, m), 4.90 (2H, s), 6.55 (2H, d, J=8.6 Hz), 6.61 (1H, s), 6.72-6.77 (3H, m), 7.26-7.43 (8H, m), 7.50 (1H, d, J=7.8 Hz), 7,64 (1H, d, J=7.4 Hz);
HRMS(FAB): 540.2854 [M+H]^+・ (calcd 540.2869 for C₃₃H₃₈N₃O₄)

［実施例３４］ ｔｅｒｔ−ブチル ［４−（｛（２Ｓ）−２−［（｛１−［（１−ベンゾフラン−２−イルカルボニル）アミノ］シクロヘキシル｝カルボニル）アミノ］ブチル｝アミノ）フェノキシアセテート（例示化合物番号５−２２）
（３４ａ） Ｎ−（１−｛［（（１Ｓ）−１−｛［（４−ヒドロキシフェニル）アミノ］メチル｝プロピル）アミノ］カルボニル｝シクロヘキシル）−１−ベンゾフラン−２−カルボキサミド
実施例３３（３３e）で製造したＮ−［１−（｛［（１Ｓ）−１−（｛［４−（ベンジルオキシ）フェニル］アミノ｝メチル）プロピル］アミノ｝カルボニル）シクロヘキシル］−１−ベンゾフラン−２−カルボキサミド（１３９８ｍｇ，２．５９ｍｍｏｌ）を酢酸（３０ｍｌ）に溶解し濃塩酸（１５ｍｌ）を加え、１０分間加熱還流した。反応液に酢酸エチル（５０ｍｌ）及び水（５０ｍｌ）を加え、分液後、有機相を水（２０ｍＬ×５）及び飽和食塩水（５０ｍｌ）で洗浄し、硫酸ナトリウムで乾燥後、溶媒を減圧下留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル，１：１）を用いて精製し、標記目的化合物（７８９ｍｇ，収率６８％）を得た。
M.p. 185-188 oC
IR(KBr) ν_max3315, 2934, 1657, 1593, 1515, 1296, 1244, 1178, 823, 749 cm^-1;
¹H NMR (CD₃OD, 400MHz) δ0.93 (3H, d, J=7.4 Hz), 1.41-1.75 (8H, m), 1.93 (2H, dq, J=3.9, 11.7 Hz), 2.21 (2H, t, J=14.5 Hz), 2.93 (1H, dd, J=8.6, 12.5 Hz), 3.16 (1H, dd, J=4.3, 12.5 Hz), 3.97-4.02 (1H, m), 6.60 (2H, d, J=9.0 Hz), 6.64 (2H, d, J=9.0 Hz), 7.32 (1H, t, J=8.2 Hz), 7.47 (1H, d, J=8.2 Hz), 7.51 (1H, s), 7.62 (1H, d, J=8.2 Hz), 7.71 (1H, d, J=8.2 Hz);
HRMS(FAB): 450.2385 [M+H]^+・ (calcd 450.2402 for C₂₆H₃₂N₃O₄)

（３４ｂ） ｔｅｒｔ−ブチル ［４−（｛（２Ｓ）−２−［（｛１−［（１−ベンゾフラン−２−イルカルボニル）アミノ］シクロヘキシル｝カルボニル）アミノ］ブチル｝アミノ）フェノキシアセテート
実施例３０（３０ｂ）に記載した方法に従い，Ｎ^１−（（１Ｓ）−１−｛［（４−ヒドロキシフェニル）アミノ］メチル｝プロピル）−Ｎ^２−（モルホリン−４−イルカルボニル）−Ｌ−ロイシナミドに代えて、実施例３４（３４ａ）で製造したＮ−（１−｛［（（１Ｓ）−１−｛［（４−ヒドロキシフェニル）アミノ］メチル｝プロピル）アミノ］カルボニル｝シクロヘキシル）−１−ベンゾフラン−２−カルボキサミド（６９０ｍｇ，１．５３ｍｍｏｌ）を使用して、標記目的化合物（６１４ｍｇ，収率７１％）を得た。
M.p. 145-148 oC
IR(KBr) ν_max3358, 2933, 1660, 1593, 1513, 1447, 1368, 1297, 1257, 1215, 1154, 1082, 822, 750 cm^-1;
¹H NMR (CDCl₃, 400MHz) δ0.95 (3H, d, J=7.0 Hz), 1.34-1.75 (17H, m), 1.95-2.07 (2H, m), 2.20-2.29 (2H, m), 3.02 (1H, dd, J=8.2, 12.5 Hz), 3.23 (1H, dd, J=4.3, 12.5 Hz), 4.00-4.09 (1H, m), 4.33 (2H, s), 6.53 (2H, d, J=8.6 Hz), 6.61 (1H, s), 6.68 (2H, d, J=8.6 Hz), 6.77 (1H, d, J=8.2 Hz), 7.29 (1H, t, J=7.2 Hz), 7.41 (1H, s), 7.42 (1H, t, J=8.2 Hz), 7.51 (1H, d, J=8.2 Hz), 7.66 (1H, d, J=8.2 Hz);
HRMS(FAB): 564.3064 [M+H]^+・ (calcd 564.3081 for C₃₂H₄₂N₃O₆)

［実施例３５］ ［４−（｛（２Ｓ）−２−［（｛１−［（１−ベンゾフラン−２−イルカルボニル）アミノ］シクロヘキシル｝カルボニル）アミノ］ブチル｝アミノ）フェノキシ酢酸 塩酸塩（例示化合物番号５−１５）
実施例３２に記載した方法に従い、ｔｅｒｔ−ブチル ｛４−［（（２Ｓ）−２−｛［Ｎ−（モルホリン−４−イルカルボニル）−Ｌ−ロイシル］アミノ｝ブチル）アミノ］フェノキシ｝アセテートに代えて、実施例３４（３４ｂ）で製造したｔｅｒｔ−ブチル ［４−（｛（２Ｓ）−２−［（｛１−［（１−ベンゾフラン−２−イルカルボニル）アミノ］シクロヘキシル｝カルボニル）アミノ］ブチル｝アミノ）フェノキシアセテート（６０４ｍｇ，１．０７ｍｍｏｌ）を使用して、標記目的化合物（５１５ｍｇ，収率８８％）を得た。
IR(KBr) ν_max 3273, 2935, 1640, 1953, 1511, 1447, 1182, 835, 751 cm^-1;
¹H NMR (CD₃OD, 400MHz) δ0.99 (3H, t, J=7.4 Hz), 1.50-1.84 (8H, m), 2.00-2.24 (4H, m), 3.25 (1H, t, J=12.5 Hz), 3.60 (1H, dd, J=2.7, 12.5 Hz), 4.21-4.26 (1H, m), 4.77 (2H, s), 7.14 (2H, d, J=9.0 Hz), 7.35 (1H, t, J=8.1 Hz), 7.50 (1H, t, J=8.1 Hz), 7.54 (1H, s), 7.58 (2H, d, J=9.0 Hz), 7.65 (1H, d, J=8.1 Hz), 7,75 (1H, d, J=8.1 Hz), 8.00 (1H, d, J=9.0 Hz), 8.41 (1H, s);
HRMS(FAB): 508.2460 [M+H]^+・ (calcd 508.2436 for C₂₈H₃₄N₃O₆)

［実施例３６］ ｛４−［（（２Ｓ）−２−｛［Ｎ−（２−オキソ−６−フェニル−２Ｈ−ピラン−４−イル）−Ｌ−ロイシル］アミノ｝ブチル）アミノ］フェノキシ｝酢酸（例示化合物番号５−１６）
実施例３１（３１ｂ）で製造したｔｅｒｔ−ブチル ｛４−［（（２Ｓ）−２−｛［Ｎ−（２−オキソ−６−フェニル−２Ｈ−ピラン−４−イル）−Ｌ−ロイシル］アミノ｝ブチル）アミノ］フェノキシ｝アセテート（９４３ｍｇ，１．６３ｍｍｏｌ）の塩化メチレン（５ｍＬ）溶液にトリフルオロ酢酸（５ｍＬ）を氷冷下に加え、さらに、室温で２時間攪拌した。溶媒を減圧下留去し得られた残渣を高速液体クロマトグラフィー（４０％アセトニトリル，０．０６％トリエチルアミン，酢酸）を用いて精製し、標記目的化合物（３９５ｍｇ，収率４６％）を得た。
IR(KBr) ν_max 3262, 3065, 2960, 1664, 1548, 1511, 1201, 1068, 830, 769, 692 cm^-1;
¹H NMR (CD₃OD, 400MHz) δ0.97 (3H, d, J=6.7 Hz), 1.00 (3H, t, J=6.3 Hz), 1.02 (3H, d, J=6.7 Hz), 1.59-1.84 (5H, m), 3.40 (2H, brs), 4.00-4.09 (2H, m), 4.65 (2H, s), 5.14 (1H, s), 6.66 (1H, s), 6.99 (2H, d, J=8.6 Hz), 7.18 (2H, br s),7.45-7.49 (3H, m), 7.78-7.80 (2H, m);
HRMS(FAB): 522.2594 [M+H]^+・ (calcd 522.2613 for C₂₉H₃₆N₃O₆)

［実施例３７］ ベンジル （２Ｅ）−３−（４−｛［（２Ｓ）−２−（｛［１−（１，１’−ビフェニル−３−イルアミノ）シクロヘキシル］カルボニル｝アミノ）ブチル］アミノ｝フェノキシ）アクリレート（例示化合物番号５−１７）
実施例２０（２０ａ）で製造した１−（１，１’−ビフェニル−３−イルアミノ）−Ｎ−（（１Ｓ）−１−｛［（４−ヒドロキシフェニル）アミノ］メチル｝プロピル）シクロヘキサンカルボキサミド（９０ｍｇ，０．２０ｍｍｏｌ）をテトラヒドロフラン（３ｍｌ）に溶解し、窒素雰囲気下、Ｎ−メチルモルホリン（５５μｌ，０．５０ｍｍｏｌ）及びプロピオール酸ベンジル（８０ｍｇ，０．５０ｍｍｏｌ）を加え室温で３０時間撹拌した。溶媒を減圧下留去し得られた残渣を薄層クロマトグラフィー（ヘキサン／酢酸エチル，３：１）を用いて精製し、標記目的化合物（８２ｍｇ，収率６６％）を得た。
IR(KBr) ν_max3374, 2935, 1705, 1645, 1509, 1320, 1287, 1208, 1116, 828, 757, 699 cm^-1;
¹H NMR (CDCl₃, 400MHz) :δ0.89 (3H, d, J=7.4 Hz), 1.24-1.66 (8H, m), 1.93-2.04 (4H, m), 2.99-3.04 (1H, m), 3.13-3.16 (1H, m), 4.03-4.09 (1H, m), 5.17 (2H, s), 5.44 (1H, d, J=12.1 Hz), 6.41 (2H, d, J=9.0 Hz), 6.58 (1H, d, J=7.1 Hz), 6.81 (2H, d, J=9.0 Hz), 6.85 (1H, s), 7.03 (2H, t, J=7.8 Hz), 7.10 (1H, t, J=7.1 Hz), 7.80-7.86 (8H, m), 7.51 (2H, d, J=7.1 Hz), 7.76 (1H, d, J=12.1);
HRMS(FAB): 618.3337 [M+H]^+・ (calcd 618.3329 for C₃₉H₄₄N₃O₄)

［実施例３８］ メチル （２Ｅ）−３−（４−｛［（２Ｓ）−２−（｛［１−（１，１’−ビフェニル−３−イルアミノ）シクロヘキシル］カルボニル｝アミノ）ブチル］アミノ｝フェノキシ）アクリレート（例示化合物番号５−２５）
実施例２０（２０ａ）で製造した１−（１，１’−ビフェニル−３−イルアミノ）−Ｎ−（（１Ｓ）−１−｛［（４−ヒドロキシフェニル）アミノ］メチル｝プロピル）シクロヘキサンカルボキサミド（８１ｍｇ，０．１８ｍｍｏｌ）をテトラヒドロフラン（３ｍｌ）に溶解し、窒素雰囲気下、Ｎ−メチルモルホリン（４０μｌ，０．３６ｍｍｏｌ）及びプロピオール酸メチル（３２μｌ，０．３６ｍｍｏｌ）を加え室温で３０時間撹拌した。溶媒を減圧下留去し得られた残渣を薄層クロマトグラフィー（ヘキサン／酢酸エチル，２：１）を用いて精製し、標記目的化合物（６３ｍｇ，収率６４％）を得た。
IR(KBr) ν_max3371, 2933, 1709, 1646, 1509, 1210, 1123, 828, 758, 701 cm^-1;
¹H NMR (CDCl₃, 400MHz) :δ0.89 (3H, d, J=7.4 Hz), 1.30-1.67 (8H, m), 1.92-2.04 (4H, m), 3.01 (1H, dd, J=8.2, 12.1 Hz), 3.14 (1H, dd, J=4.3, 12.1 Hz), 3.70 (3H, s), 4.02-4.08 (1H, m), 5.40 (1H, d, J=12.1 Hz), 6.40 (2H, d, J=9.0 Hz), 6.56 (1H, d, J=9.0 Hz), 6.80 (2H, d, J=8.6 Hz), 6.82 (1H, d, J=5.9 Hz), 7.01 (2H, t, J=5.9 Hz), 7.08 (1H, t, J=7.8 Hz), 7.28-7.35 (8H, m), 7.49 (2H, d, J=8.6 Hz), 7.71 (1H, d, J=12.1);
HRMS(FAB): 542.3016 [M+H]^+・ (calcd 542.3019 for C₃₃H₄₀N₃O₄)

［実施例３９］ ３−（４−｛［（２Ｓ）−２−（｛［１−（１，１’−ビフェニル−３−イルアミノ）シクロヘキシル］カルボニル｝アミノ）ブチル］アミノ｝フェノキシ）プロパン酸（例示化合物番号５−２７）
実施例３７で製造したベンジル （２Ｅ）−３−（４−｛［（２Ｓ）−２−（｛［１−（１，１’−ビフェニル−３−イルアミノ）シクロヘキシル］カルボニル｝アミノ）ブチル］アミノ｝フェノキシ）アクリレート（６８ｍｇ，０．１１ｍｍｏｌ）を水素雰囲気下（１気圧）、１０％パラジウム炭素触媒（１２ｍｇ，０．０１１ｍｍｏｌ）存在下に、エタノール（５ｍｌ）溶媒中、室温で２０時間水素化分解した。触媒を除去したのち、溶媒を留去して得られた残留物を薄層クロマトグラフィー（ヘキサン／酢酸エチル，１：１）を用いて精製し、標記目的化合物（２２ｍｇ，収率３７％）を得た。
IR(KBr) ν_max3369, 2933, 1650, 1602, 1513, 1229, 758, 701 cm^-1;
¹H NMR (CDCl₃, 400MHz) δ0.98 (3H, d, J=7.4 Hz), 1.32-1.65 (8H, m), 1.95-2.04 (4H, m), 2.78 (2H, t, J=6.3 Hz), 3.01 (1H, dd, J=10.1, 12.5 Hz), 3.13 (1H, dd, J=4.3, 12.5 Hz), 4.02-4.09 (1H, m), 4.16 (2H, t, J=6.3 Hz), 6.42 (2H, d, J=8.6 Hz), 6.59 (1H, d, J=8.2 Hz), 6.72 (2H, d, J=8.6 Hz), 6.85 (1H, s), 7.02 (1H, d, J=7.8 Hz), 7.07 (1H, d, J=7.8 Hz), 7.12 (1H, t, J=7.8 Hz), 7.31 (1H, d, J=7.0 Hz), 7.37 (2H, t, J=7.0 Hz), 7.52 (2H, d, J=7.0 Hz);
HRMS(FAB): 530.3009 [M+H]^+・ (calcd 530.3027 for C₃₂H₄₀N₃O₄)

［実施例４０］ Ｎ^１−（（１Ｓ）−１−｛［（４−メトキシフェニル）アミノ］メチル｝プロピル）−Ｎ^２−（５−フェニルイソオキサゾ−ル−３−イル）−Ｌ−ロイシンアミド（例示化合物番号５−３）
（４０ａ） Ｎ−[（１Ｚ）−１−（メチルチオ）−３−オキソ−３−フェニルプロプ−１−エニル]−Ｌ―ロイシン
（Ｌ）―ロイシン（４．８４ｇ，３６．８ｍｍｏｌ）及び水酸化ナトリウム（１．５０ｇ，３７．３ｍｍｏｌ）を９０％エタノール（１５０ｍＬ）に懸濁し、１時間加熱還流した。更に３，３−ビス（メチルチオ）−１−フェニルプロプ−２−エン−１−オン（Ｂｕｌｌ．Ｃｈｅｍ．Ｓｏｃ．Ｊｐｎ．，ｖｏｌ６４，１９９１，３７２７−３７２８）（４．１８ｇ，１８．６ｍｍｏｌ）を加え、２４時間加熱還流をした。溶媒を留去した後、残留物に酢酸エチル（１００ｍＬ）、水（１００ｍＬ）を加え、分離した水層を１Ｎ塩酸（３０ｍＬ）で酸性にした。酢酸エチル（１００ｍＬ）で抽出し、硫酸ナトリウムで乾燥した。溶媒を留去して結晶の標記化合物（４．０１ｇ，収率７０％）を得た。
IR (KBr) ν_max 2959, 1721, 1561, 1472, 1280, 756 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 0.90 (3H, d, J = 6.2 Hz), 0.91 (3H, d, J = 6.2 Hz), 1.77 (2H, dd, J = 6.1, 12.6 Hz), 1.78-1.85 (1H, m), 2.39 (3H, s), 4.33 (1H, br s), 5.60 (1H, s), 7.28-7.41 (3H, m), 7.75-7.80 (2H, m);
MS (FAB) m/z: 308.13 [M + H]⁺;

（４０ｂ） Ｎ−（５−フェニルイソオキサゾ−ル−３−イル）−Ｌ−ロイシン
実施例４０（４０ａ）で製造した（Ｎ−[（１Ｚ）−１−（メチルチオ）−３−オキソ−３−フェニルプロプ−１−エニル]−Ｌ―ロイシン（１．８６ｇ，６．０７ｍｍｏｌ）及び水酸化ナトリウム（１．５０ｇ，３７．３ｍｍｏｌ）をエタノール（５０ｍＬ）に懸濁した。ヒドロキシルアミン塩酸塩（１．６９ｇ，２４．４ｍｍｏｌ）及び水酸化カリウム（１．３７ｇ，２４．４ｍｍｏｌ）を水に溶解し、反応溶液に加え４．５時間加熱還流した。溶媒を留去した後、残留物に酢酸エチル（１００ｍＬ）、水（１００ｍＬ）を加え、分離した有機層を硫酸ナトリウムで乾燥した。溶媒を留去して結晶の標記化合物（１．２７ｇ，収率７６％）を得た。
IR (KBr) ν_max 3362, 2958, 1723, 1625, 1579, 1561, 1450, 1209, 762, 688 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 0.98 (6H, t, J = 6.4 Hz), 1.63-1.94 (3H, m), 4.26 (1H, dd, J = 5.1, 8.8 Hz), 4.53 (1H, br s), 6.06(1H, s), 7.39-7.44 (3H, m), 7.67-7.71 (2H, m);
MS (FAB) m/z: 275.13 [M + H]⁺;

（４０ｃ） Ｎ^１−（（１Ｓ）−１−｛［（４−メトキシフェニル）アミノ］メチル｝プロピル）−Ｎ^２−（５−フェニルイソオキサゾ−ル−３−イル）−Ｌ−ロイシンアミド
実施例２（２ａ）で製造したｔｅｒｔ−ブチル （１Ｓ）-１−｛［（４−メトキシフェニル）アミノ］メチル｝プロピルカーバメート（２．１４ｇ，７．２８ｍｍｏｌ）を１，４−ジオキサン（６０ｍＬ）に溶解し、４Ｎ塩酸―ジオキサン（４０ｍＬ）を加え１２時間撹拌した。溶媒を留去後、真空乾燥し白色の粗生成物を得た。得られた粗生成物に、実施例４０（４０ｂ）で製造したＮ−（５−フェニルイソオキサゾ−ル−３−イル）−Ｌ−ロイシン（２．２１ｇ，８．０６ｍｍｏｌ）、１−エチル−３−(３−ジメチルアミノプロピル)−カルボジイミド 塩酸塩（１．５３ｇ，８．０３ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾ−ル １水和物（１．０８ｇ，８．０３ｍｍｏｌ）、塩化メチレン（２００ｍＬ）を加え、トリエチルアミン（２．２４ｍＬ，１６．０６ｍｍｏｌ）を滴下し２０時間撹拌した。有機層を飽和食塩水（２ｘ８０ｍＬ）で洗浄し、硫酸ナトリウムで乾燥後、溶媒を減圧下留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（塩化メチレン／メタノール，９９：１）で精製し、標記化合物（２．２０ｇ，収率６７％）を得た。
Mp 165-167 ℃;
IR (KBr) ν_max 3278, 3065, 1649, 1556, 1512, 1235, 1039, 820, 761, 690 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 0.92 (3H, d, J = 7.4 Hz), 0.97 (3H, d, J = 7.4 Hz), 1.43-1.55 (1H, m), 1.58-1.71 (2H, m), 1.74-1.86 (2H, m), 3.01 (1H, dd, J = 8.3, 12.3 Hz), 3.19 (1H, dd, J = 4.3, 12.3 Hz), 3.70 (3H, s), 3.95-4.01 (1H, m), 4.03-4.12 (1H, m), 4.51 (1H, d, J = 6.3 Hz), 6.06 (1H, s), 6.49-6.55 (3H, m), 6.66-6.72 (2H, m), 7.34-7.41 (3H, m), 7.55-7.60 (2H, m);
MS (FAB) m/z: 451.27 [M + H]⁺;

［実施例４１］ Ｎ^１−[（１Ｓ）−１−（｛［４−（ベンジルオキシ）フェニル］アミノ｝メチル）プロピル]−Ｎ^２−（５−フェニルイソオキサゾ−ル−３−イル）−Ｌ−ロイシンアミド（例示化合物番号５−２３）
実施例１９（１９ｂ）で製造したｔｅｒｔ−ブチル （１Ｓ）-１−（｛［４−（ベンジルオキシ）フェニル］アミノ｝メチル）プロピルカーバメート（９０４ｍｇ，２．４３ｍｍｏｌ）に４Ｎ塩酸―ジオキサン（１４ｍＬ）を加え１２時間撹拌した。溶媒を留去後、残渣に酢酸エチル（４０ｍＬ）、飽和重曹水（３０ｍＬ）を加え、分離した水層を酢酸エチル（４０ｍＬ）で抽出した。合わせた有機層を硫酸ナトリウムで乾燥し、溶媒を減圧下留去した。得られた粗生成物をＮ，Ｎ−ジメチルホルムアミド（２０ｍＬ）に溶解し、実施例４０（４０ｂ）で製造したＮ−（５−フェニルイソオキサゾ−ル−３−イル）−Ｌ−ロイシン（６６６ｍｇ，２．４２ｍｍｏｌ）、１−エチル−３−(３−ジメチルアミノプロピル)−カルボジイミド 塩酸塩（５４２ｍｇ，２．８３ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾ−ル １水和物（３６７ｍｇ，２．７１ｍｍｏｌ）を加え２０時間撹拌した。有機層を飽和食塩水（２ｘ８０ｍＬ）で洗浄し、硫酸ナトリウムで乾燥後、溶媒を減圧下留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（酢酸エチル／へキサン，１：１）で精製し、標記化合物（１．０４ｇ，１．９７ｍｍｏｌ，収率８１％）を得た。
Mp 184-186 ℃;
IR (KBr) ν_max 3279, 2960, 1645, 1511, 1231, 1025, 816, 762, 692 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 0.93 (3H, t, J = 7.4 Hz), 0.95 (3H, d, J = 6.1 Hz), 0.98 (3H, d, J = 6.1 Hz), 1.42-1.70 (3H, m), 1.74-1.83 (2H, m), 3.00 (1H, dd, J = 8.5, 12.2 Hz), 3.19 (1H, dd, J = 4.2, 12.2 Hz), 3.54 (1H, br s), 3.80 (1H, br s), 3.92-3.99 (1H, m), 4.01-4.12 (1H, m), 4.31 (1H, d, J = 5.8 Hz), 4.92 (2H, s), 6.04 (1H, s), 6.41 (1H, d, J = 9.1 Hz), 6.50 (2H, d, J = 8.9 Hz), 6.75 (2H, d, J = 8.9 Hz), 7.25-7.41 (8H, m), 7.53-7.58 (2H, m);
MS (FAB) m/z: 527.30 [M + H]⁺;

［実施例４２］ ｔｅｒｔ−ブチル ｛４−[（（２Ｓ）−２−｛［Ｎ−（５−フェニルイソオキサゾ−ル−３−イル）−Ｌ−ロイシル］アミノ｝ブチル）アミノ]フェノキシ｝アセテート（例示化合物番号５−２４）
（４２ａ） Ｎ^１−（（１Ｓ）−１−｛［（４−ヒドロキシフェニル）アミノ］メチル｝プロピル）−Ｎ^２−（５−フェニルイソオキサゾ−ル−３−イル）−Ｌ−ロイシンアミド
実施例４１で製造したＮ^１−[（１Ｓ）−１−（｛［４−（ベンジルオキシ）フェニル］アミノ｝メチル）プロピル]−Ｎ^２−（５−フェニルイソオキサゾ−ル−３−イル）−Ｌ−ロイシンアミド（１．１３ｍｇ、２．１５ｍｍｏｌ）を酢酸（５ｍＬ）に溶解し、濃塩酸（２．５ｍＬ）を加え１時間１５分加熱還流した。室温まで放冷後、溶液に酢酸エチル（７０ｍＬ）、飽和重曹水（７０ｍＬ）を加え、分離した有機層を硫酸ナトリウムで乾燥後、溶媒を減圧下留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（酢酸エチル／へキサン，１：１）で精製し、標記化合物（５２２ｍｇ，１．２０ｍｍｏｌ，収率５６％）を得た。
Mp 197-198 ℃;
IR (KBr) ν_max 3297, 2961, 1649, 1626, 1515, 1240, 819, 761, 690 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 0.89 (3H, t, J = 7.4 Hz), 0.91 (3H, d, J = 6.0 Hz), 0.95 (3H, d, J = 6.0 Hz), 1.40-1.51 (1H, m), 1.56-1.66 (2H, m), 1.70-1.82 (2H, m), 2.98 (1H, dd, J = 8.2, 12.5 Hz), 3.14 (1H, dd, J = 4.3, 12.5 Hz), 3.93-4.07 (2H, m), 4.56 (1H, d, J = 6.3 Hz), 6.02 (1H, s), 6.42 (2H, d, J = 8.6 Hz), 6.57 (1H, d, J = 8.2 Hz), 6.60 (2H, d, J = 8.6 Hz), 7.32-7.37 (3H, m), 7.52-7.57 (2H, m);
MS (FAB) m/z: 436.26 [M⁺];

（４２ｂ） 実施例４２（４２ａ）で製造したＮ^１−（（１Ｓ）−１−｛［（４−ヒドロキシフェニル）アミノ］メチル｝プロピル）−Ｎ^２−（５−フェニルイソオキサゾ−ル−３−イル）−Ｌ−ロイシンアミド（５２２ｍｇ、１．２０ｍｍｏｌ）のテトラヒドロフラン（１５ｍＬ）溶液に、氷冷下、水素化ナトリウム（５５％油性）（６３ｍｇ，１．４４ｍｍｏｌ）を加え、更にブロモ酢酸 ｔ−ブチルエステル（０．２１ｍＬ，１．４４ｍｍｏｌ）のＮ，Ｎ−ジメチルホルムアミド（２ｍＬ）溶液を滴下した。反応温度を室温に戻したのち、反応液をさらに２時間攪拌した。氷冷下、水（５０ｍＬ）を反応液に加え、水層を酢酸エチル（２ｘ７０ｍＬ）で抽出した。有機層を硫酸ナトリウムで乾燥し、溶媒を留去して得られた残留物をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル，３：１）で精製し、標記化合物（３７０ｍｇ，０．６７ｍｍｏｌ，収率５６％）を得た。
IR (KBr) ν_max 3275, 2961, 1753, 1648, 1557, 1511, 1214, 1155, 820, 763, 690 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 0.90 (3H, t, J = 7.4 Hz), 0.93 (3H, d, J = 6.3 Hz), 0.96 (3H, d, J = 6.3 Hz), 1.47 (9H, s), 1.56-1.70 (2H, m), 1.74-1.84 (2H, m), 2.99 (1H, dd, J = 8.2, 12.1 Hz), 3.16 (1H, dd, J = 4.3, 12.1 Hz), 3.86 (1H, br s), 3.97-4.07 (2H, m), 4.35 (2H, s), 4.91 (1H, br s), 6.06 (1H, s), 6.47 (2H, d, J = 8.6 Hz), 6.67 (2H, d, J = 8.6 Hz), 7.32-7.38 (3H, m), 7.53-7.58 (2H, m);
MS (FAB) m/z: 551.32 [M + H]⁺;

［実施例４３］ ｛４−[（（２Ｓ）−２−｛［Ｎ−（５−フェニルイソオキサゾ−ル−３−イル）−Ｌ−ロイシル］アミノ｝ブチル）アミノ]フェノキシ｝酢酸 ２塩酸塩（例示化合物番号５−２６）
実施例４２（４２ｂ）で製造したｔｅｒｔ−ブチル ｛４−[（（２Ｓ）−２−｛［Ｎ−（５−フェニルイソオキサゾ−ル−３−イル）−Ｌ−ロイシル］アミノ｝ブチル）アミノ]フェノキシ｝アセテート（１６６ｍｇ，０．３０ｍｍｏｌ）の塩化メチレン（３ｍＬ）溶液にトリフルオロ酢酸（３ｍＬ）を氷冷下に加え、更に室温で２時間攪拌した。反応溶液を減圧下濃縮し、残留物に４Ｎ塩酸−ジオキサン溶液（４ｍＬ）を加えた。溶媒を減圧下留去したのち得られた残渣をエーテル（２０ｍＬ）から粉末化し、ろ過とエーテルによる洗浄を行い、標記化合物（１４７ｍｇ，０．２６ｍｍｏｌ，収率８６％）を得た。
IR (KBr) ν_max 3265, 2961, 1740, 1625, 1546, 1511, 1198, 1075, 832, 763, 690 cm^-1;
¹H NMR(CD₃OD, 400 MHz) δ 0.96 (3H, t, J = 6.7 Hz), 1.00 (3H, d, J = 6.3 Hz), 1.05 (3H, d, J = 6.3 Hz), 1.58-1.68 (2H, m), 1.69-1.76 (2H, m), 1.84-1.94 (1H, m), 3.31 (1H, d, J = 6.3 Hz), 3.48 (1H, d, J = 6.3 Hz), 4.00 (1H, br s), 4.65 (2H, s), 6.38 (1H, s), 7.00 (2H, d, J = 8.6 Hz), 7.33 (2H, d, J = 8.6 Hz), 7.41-7.49 (3H, m), 7.59-7.67 (2H, m));
MS (FAB) m/z: 495.26 [M + H]⁺;

［実施例４４］ Ｎ−（１−｛［（（１Ｓ）−１−｛［（４−メトキシフェニル）アミノ］メチル｝プロピル）アミノ］カルボニル｝シクロヘキシル）−１−ベンゾフラン−２−カルボキサミド（例示化合物番号４−１０）
実施例２（２ａ）で製造したｔｅｒｔ−ブチル （１Ｓ）-１−｛［（４−メトキシフェニル）アミノ］メチル｝プロピルカーバメート（１４７ｍｇ，０．５ｍｍｏｌ）に４Ｎ塩酸―ジオキサン（１ｍＬ）を加え１時間撹拌した。溶媒を留去後、得られた粗生成物をＮ，Ｎ−ジメチルホルムアミド（２ｍＬ）に溶解し、実施例３３（３３ｄ）で製造した１−［（１−ベンゾフラン−２−イルカルボニル）アミノ］シクロヘキサンカルボン酸（１５８ｍｇ，０．５５ｍｍｏｌ）、１−エチル−３−(３−ジメチルアミノプロピル)−カルボジイミド 塩酸塩（１０５ｍｇ，０．５５ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾ−ル １水和物（８４ｍｇ，０．５５ｍｍｏｌ）、トリエチルアミン（０．２１ｍＬ，１．５ｍｍｏｌ）を加え３時間撹拌した。反応液を酢酸エチル（５０ｍＬ）と水（５０ｍＬ）で分液し、有機層を飽和重曹水（３０ｍＬ）で洗浄し、硫酸ナトリウムで乾燥後、溶媒を減圧下留去した。得られた粗結晶をヘキサン／酢酸エチル混合溶媒（１：１）（４ｍＬ）から再結晶し、標記化合物（１５９ｍｇ，収率６９％）を得た。
Mp 131-134 ℃;
IR (KBr) ν_max3328, 1657, 1514, 1235, 821, 750 cm^-1;
¹H NMR (CDCl₃, 400MHz) δ 0.95 (3H, t, J = 7.4 Hz), 1.35-2.29 (12H, m), 3.02 (1H, dd, J = 7.9, 12.5 Hz), 3.23 (1H, dd, J = 4.4, 12.5 Hz), 3.66 (3H, s), 3.95 (1H, br), 4.02-4.08 (1H, m), 6.55 (2H, d, J = 8.9 Hz), 6.61 (1H, brs), 6.67 (2H, d, J = 8.9 Hz), 6.76 (1H, brd, J = 8.6 Hz), 7.29 (1H, dd, J = 7.2, 7.7 Hz), 7.41 (1H, brs), 7.42 (1H, dd, J = 7.2, 8.2 Hz), 7.50 (1H, d, J = 8.2 Hz), 7.65 (1H, d, J = 7.7 Hz);
MS (FAB) m/z: 464 [M + H]⁺, 238.
Anal. Calcd for C₃₅H₄₅N₃O_4・0.6 H₂O: C, 68.36; H, 7.27; N, 8.86. Found: C, 68.39; H, 6.99; N, 8.76.

［実施例４５］ Ｎ^２−（１−ベンゾフラン−２−カルボニル）−Ｎ^１−（（１Ｓ）−１−｛［（４−メトキシフェニル）アミノ］メチル｝プロピル）−Ｌ−ロイシンアミド（例示化合物番号３−１０）
（４５ａ） Ｎ^２−（ｔｅｒｔ−ブトキシカルボニル）−Ｎ^１−（（１Ｓ）−１−｛［（４−メトキシフェニル）アミノ］メチル｝プロピル）−Ｌ−ロイシンアミド
実施例２（２ａ）で製造したｔｅｒｔ−ブチル （１Ｓ）-１−｛［（４−メトキシフェニル）アミノ］メチル｝プロピルカーバメート（５８９ｍｇ，２．０ｍｍｏｌ）に４Ｎ塩酸―ジオキサン（４ｍＬ）を加え１時間撹拌した。溶媒を留去後、得られた粗生成物をＮ，Ｎ−ジメチルホルムアミド（５ｍＬ）に溶解し、Ｎ−（ｔｅｒｔ−ブトキシカルボニル）−Ｌ−ロイシン １水和物（５４８ｍｇ，２．２ｍｍｏｌ）、１−エチル−３−(３−ジメチルアミノプロピル)−カルボジイミド 塩酸塩（４２２ｍｇ，２．２ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾ−ル １水和物（３３７ｍｇ，２．２ｍｍｏｌ）、トリエチルアミン（０．８４ｍＬ，６．０ｍｍｏｌ）を加え１５時間撹拌した。反応液を酢酸エチル（１００ｍＬ）と水（１００ｍＬ）で分液し、有機層を飽和重曹水（５０ｍＬ）で洗浄し、硫酸ナトリウムで乾燥後、溶媒を減圧下留去した。残留物をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル、２：１）により精製し、標記化合物（３３０ｍｇ，収率４０％）を得た。
Mp 142-144 ℃;
IR (KBr) ν_max3354, 1682, 1651, 1517, 1237, 1174, 819 cm^-1;
¹H NMR (CDCl₃, 400MHz) δ 0.91 (3H, d, J = 6.2 Hz), 0.92 (3H, d, J = 6.2 Hz), 0.95 (3H, t, J = 7.4 Hz), 1.42 (9H, s), 1.44-1.69 (5H, m), 3.06 (1H, dd, J = 7.5, 12.7 Hz), 3.18 (1H, dd, J = 4.6, 12.7 Hz), 3.71 (1H, br), 3.74 (3H, s), 3.98-4.06 (1H, m), 4.81 (1H, br), 6.05 (1H, brd, J = 7.9 Hz), 6.58 (2H, d, J = 8.9 Hz), 6.76 (2H, d, J = 8.9 Hz);
MS (FAB) m/z: 464 [M + H]⁺, 408.
Anal. Calcd for C₂₂H₃₇N₃O₄: C, 64.84; H, 9.15; N, 10.31. Found: C, 64.82; H, 8.84; N, 10.17.

（４５ｂ） Ｎ^２−（１−ベンゾフラン−２−カルボニル）−Ｎ^１−（（１Ｓ）−１−｛［（４−メトキシフェニル）アミノ］メチル｝プロピル）−Ｌ−ロイシンアミド
実施例４５（４５ａ）で製造したＮ^２−（ｔｅｒｔ−ブトキシカルボニル）−Ｎ^１−（（１Ｓ）−１−｛［（４−メトキシフェニル）アミノ］メチル｝プロピル）−Ｌ−ロイシンアミド（０．３２ｇ，０．８ｍｍｏｌ）にトリフルオロ酢酸（４ｍＬ）を加え１時間撹拌した。混合物を濃縮後、得られた残留物に飽和重曹水（５０ｍＬ）を加え、酢酸エチル（５０ｍＬ）で抽出した。抽出液を硫酸ナトリウムで乾燥後、溶媒を減圧下留去して得られた残留物をＮ，Ｎ−ジメチルホルムアミド（３ｍＬ）に溶解し、ベンゾフラン−２−カルボン酸（０．１５ｇ，０．９ｍｍｏｌ）、１−エチル−３−(３−ジメチルアミノプロピル)−カルボジイミド 塩酸塩（０．１７ｇ，０．９ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾ−ル １水和物（０．１４ｇ，０．９ｍｍｏｌ）を加え５時間撹拌した。反応液を酢酸エチル（５０ｍＬ）と水（５０ｍＬ）で分液した。有機層を飽和重曹水（３０ｍＬ）で洗浄し、硫酸ナトリウムで乾燥後、溶媒を減圧下留去した。残留物をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル、１：１）により精製し、標記化合物（０．２１ｇ，収率５９％）を得た。
IR (KBr) ν_max3289, 1642, 1514, 1235, 820, 749 cm^-1;
¹H NMR (CDCl₃, 400MHz) δ0.88 (3H, t, J = 7.4 Hz), 0.94 (3H, d, J = 5.8 Hz), 0.95 (3H, d, J = 5.8 Hz), 1.43-1.79 (5H, m), 3.13 (1H, dd, J = 7.6, 12.5 Hz), 3.22 (1H, dd, J = 4.7, 12.5 Hz), 3.73 (3H, s), 3.82 (1H, br), 4.03-4.11 (1H, m), 4.76-4.78 (1H, m), 6.59 (2H, d, J = 8.9 Hz), 6.76 (2H, d, J = 8.9 Hz), 6.81-6.86 (1H, m), 7.26-7.29 (2H, m), 7.40 (1H, dd, J = 7.3, 8.3 Hz), 7.43 (1H, brs), 7.48 (1H, d, J = 8.3 Hz), 7.59 (1H, d, J = 7.3 Hz);
MS (FAB) m/z: 464 [M + H]⁺, 452.
Anal. Calcd for C₂₂H₃₇N₃O_4・0.2 H₂O: C, 68.61; H, 7.40; N, 9.23. Found: C, 68.46; H, 7.43; N, 9.41.

［実施例４６］ Ｎ^１−（（１Ｓ）−１−｛［（４−メトキシフェニル）アミノ］メチル｝プロピル）−Ｎ^２−（モルホリン−４−イルカルボニル）−Ｌ−ロイシナミド（例示化合物番号５−１０）
（４６ａ） アリル （２Ｓ）−２−［（ｔｅｒｔ−ブトキシカルボニル）アミノ］ブチル（（４−メトキシフェニル）カルバメート
実施例２（２ａ）で製造したｔｅｒｔ−ブチル （１Ｓ）−１−｛［（４−メトキシフェニル）アミノ］メチル｝プロピルカルバメート（３．０６ｇ，１０．４ｍｍｏｌ）とピリジン（１．１ｍｌ，１３．５ｍｍｏｌ）の塩化メチレン（１００ｍＬ）溶液に、氷冷下、アリルオキシカルボニルクロリド（１．１ｍｌ，１３．５ｍｍｏｌ）を滴下した。反応温度を室温に戻したのち、さらに反応液を２時間撹拌した。溶媒を減圧下留去し得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル，１：１）を用いて精製し、標記目的化合物（３．９３ｇ，収率１００％）を得た。
¹H NMR (CDCl₃, 400MHz) δ 0.89 (3H, t, J = 7.3 Hz), 1.43 (9H, s), 1.31-1.48 (2H, m), 3.29-3.32 (1H, m), 3.71-3.75(1H, m), 3.80 (3H, s), 3.84-3.85 (1H, m), 4.51-4.61 (2H, m), 4.78-4.79 (1H, m), 5.10 (2H, d, J=9.5 Hz), 5.82 (1H, br s), 6.88 (2H, d, J=8.8 Hz), 7.14 (2H, d, J=8.8 Hz);

（４６ｂ） アリル （２Ｓ）−２−［（１−［（１Ｓ）−１−［（ｔｅｒｔ−ブトキシカルボニル）アミノ］−３−メチルブチル］ビニル）アミノ］ブチル（４−メトキシフェニル）カルバメート
実施例４６（４６ａ）で製造したアリル （２Ｓ）−２−［（ｔｅｒｔ−ブトキシカルボニル）アミノ］ブチル（（４−メトキシフェニル）カルバメート（２．０６ｇ，５．４３ｍｍｏｌ）を４Ｍ塩酸−ジオキサン溶液（１０ｍｌ）に溶解し、室温で２時間撹拌した。溶媒を減圧下留去し得られた残渣をＮ，Ｎ−ジメチルホルムアミド（８０ｍｌ）に溶解し、ｔｅｒｔ−ブトキシカルボニル−Ｌ−ロイシン 水和物（１．４９ｇ，５．９７ｍｍｏｌ）、トリエチルアミン（０．９１ｍｌ，６．５２ｍｍｏｌ）、ヒドロキシベンゾトリアゾール １水和物（０．８８ｇ，６．５２ｍｍｏｌ）及び１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩（１．２５ｇ，６．５２ｍｍｏｌ）を加え、室温で９時間撹拌した。反応液に酢酸エチル（２０ｍｌ）及び水（２０ｍＬ）を加え、分液後、有機相を水（２０ｍｌ×５）、食塩水（２０ｍｌ）で洗浄し、硫酸ナトリウムで乾燥後、溶媒を減圧下留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル，２：１）を用いて精製し、標記目的化合物（２．６７ｇ，収率１００％）を得た。
¹H NMR (CDCl₃, 400MHz) δ 0.86 (3H, t, J = 7.3 Hz), 0.93 (6H, t, J=7.3 Hz), 1.44 (9H, s), 1.38-1.59 (5H, m), 3.29-3.30 (1H, m), 3.80 (3H, s), 3.98-4.03(3H, m), 4.50-4.61 (2H, m), 4.89-5.09 (3H, m), 5.79 (1H, br s), 6.28 (1H, br s), 6.88 (2H, d, J=8.8 Hz), 7.08 (2H, d, J=8.8 Hz);

（４６ｃ） アリル ４−メトキシフェニル｛（２Ｓ）−２−［（１−｛（１Ｓ）−３−メチル−１−［（モルホリン−４−イルカルボニル）アミノ］ブチル｝ビニル）アミノ］ブチル｝カルバメート
実施例４６（４６ｂ）で製造したアリル （２Ｓ）−２−［（１−［（１Ｓ）−１−［（ｔｅｒｔ−ブトキシカルボニル）アミノ］−３−メチルブチル］ビニル）アミノ］ブチル（４−メトキシフェニル）カルバメート（１４７ｍｇ，０．３０ｍｍｏｌ）を４Ｍ塩酸−ジオキサン溶液（２ｍｌ）に溶解し、室温で２時間撹拌した。溶媒を減圧下留去し得られた残渣を塩化メチレン（５ｍｌ）に溶解し、トリエチルアミン（１２５μｌ，０．９０ｍｍｏｌ）及びモルホリン−４−カルボニルクロリド（７０μｌ，０．６０ｍｍｏｌ）を加え、室温で２日撹拌した。溶媒を減圧下留去し得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／メタノール，２０：１）を用いて精製し、標記目的化合物（１４７ｍｇ，収率９８％）を得た。
¹H NMR (CDCl₃, 400MHz) δ 0.85 (3H, t, J = 7.3 Hz), 0.93 (3H, d, J=6.6 Hz), 0.96 (3H, d, J=5.9 Hz), 1.39-1.73 (5H, m), 3.34-3.38 (5H, m), 3.67 (4H, t, J=4.4 Hz), 3.80 (3H, s), 3.98-4.05 (2H, m), 4.32-4.61 (3H, m), 5.05-5.10 (3H, m), 5.79 (1H, br s), 6.35 (1H, br s), 6.88 (2H, d, J=8.8 Hz), 7.09 (2H, d, J=8.8 Hz);

（４６ｄ）Ｎ^１−（（１Ｓ）−１−｛［（４−メトキシフェニル）アミノ］メチル｝プロピル）−Ｎ^２−（モルホリン−４−イルカルボニル）−Ｌ−ロイシナミド
実施例４６（４６ｃ）で製造したアリル ４−メトキシフェニル｛（２Ｓ）−２−［（１−｛（１Ｓ）−３−メチル−１−［（モルホリン−４−イルカルボニル）アミノ］ブチル｝ビニル）アミノ］ブチル｝カルバメート（１４７ｍｇ，０．２９ｍｍｏｌ）のテトラヒドロフラン（５ｍｌ）溶液に、窒素雰囲気下、ピロリジン（２４０μｌ，２．９ｍｍｏｌ）、トリス（ジベンジリデンアセトン）ジパラジウム（０）（１３ｍｇ，０．０１５ｍｍｏｌ）及び１，３−ビス（ジフェニルホスフィノ）プロパン（１２ｍｇ，０．０２９ｍｍｏｌ）を加え、室温で１８時間撹拌した。溶媒を減圧下留去し得られた残渣を薄層クロマトグラフィー（１００％酢酸エチル）を用いて精製し、標記目的化合物（８９ｍｇ，収率７３％）を得た。
IR (KBr) ν_max 3284, 2957, 1623, 1515, 1239, 1119, 820 cm^-1;
¹H NMR (CDCl₃, 400MHz) δ 0.91-0.96 (9H, m), 1.47-1.70 (5H, m), 3.09 (1H, dd, J=7.3, 12.5 Hz), 3.19 (1H, dd, J=5.1, 12.5 Hz), 3.33-3.36 (4H, m), 3.66 (4H, t, J=4.4 Hz), 3.74 (3H, s), 3.99-4.02 (1H, m), 4.25-4.29 (1H, m), 4.84 (1H, d, J=8.1 Hz), 6.17 (1H, d, J=8.1 Hz), 6.58 (2H, d, J=8.8 Hz), 6.77 (2H, d, J=8.8 Hz);
HRMS(FAB): 421.2801 [M+H]⁺ (calcd 421.2815 for C₂₂H₃₇N₄O₄)

［実施例４７］ Ｎ^１−（（１Ｓ）−１−｛［（４−メトキシフェニル）アミノ］メチル｝プロピル）−Ｎ^２−［４−（４−メチルピペラジン−１−イル）ベンゾイル］−Ｌ−ロイシナミド（例示化合物番号３−２７４）
（４７ａ） Ｎ^１−（（１Ｓ）−１−｛［［（アリルオキシ）カルボニル］（４−メトキシフェニル）アミノ］メチル｝プロピル）−Ｎ^２−［４−（４−メチルピペラジン−１−イル）ベンゾイル］−Ｌ−ロイシナミド
実施例４６（４６ｂ）で製造したアリル （２Ｓ）−２−［（１−［（１Ｓ）−１−［（ｔｅｒｔ−ブトキシカルボニル）アミノ］−３−メチルブチル］ビニル）アミノ］ブチル（４−メトキシフェニル）カルバメート（１５７ｍｇ，０．３２ｍｍｏｌ）を４Ｍ塩酸−ジオキサン溶液（２ｍｌ）に溶解し、室温で２時間撹拌した。溶媒を減圧下留去し得られた残渣をＮ，Ｎ−ジメチルホルムアミド（５ｍｌ）に溶解し、４−（４−メチルピペラジンン−１−イル）安息香酸（７０ｍｇ，０．３２ｍｍｏｌ）、トリエチルアミン（５４μｌ，０．３８ｍｍｏｌ）、ヒドロキシベンゾトリアゾール １水和物（５３ｍｇ，０．３８ｍｍｏｌ）及び１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩（７４ｍｇ，０．３８ｍｍｏｌ）を加え、室温で２日撹拌した。溶媒を減圧下留去し得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／メタノール，２０：１）を用いて精製し、標記目的化合物（１６３ｍｇ，収率８６％）を得た。
¹H NMR (CDCl₃, 400MHz) δ 0.71 (3H, t, J = 7.3 Hz), 0.94 (3H, d, J=5.9 Hz), 0.98 (3H, d, J=5.1 Hz), 1.42-1.73 (5H, m), 2.35 (3H ,s), 2.55 (4H, t, J=4.4 Hz), 3.15-3.27 (1H, m), 3.30 (4H, t, J=4.4 Hz), 3.80 (3H, s), 4.02-4.06 (2H, m), 4.42-4.61 (3H, m), 5.03-5.07 (2H, m), 5.76 (1H, br s), 6.52 (2H, br s), 6.88 (2H, d, J=8.8 Hz), 6.89 (2H, d, J=8.8 Hz), 7.10 (2H, d, J=8.1 Hz), 7.71 (2H, d, J=8.1 Hz);

（４７ｂ） Ｎ^１−（（１Ｓ）−１−｛［（４−メトキシフェニル）アミノ］メチル｝プロピル）−Ｎ^２−［４−（４−メチルピペラジン−１−イル）ベンゾイル］−Ｌ−ロイシナミド
実施例４７（４７ａ）で製造した Ｎ^１−（（１Ｓ）−１−｛［［（アリルオキシ）カルボニル］（４−メトキシフェニル）アミノ］メチル｝プロピル）−Ｎ^２−［４−（４−メチルピペラジン−１−イル）ベンゾイル］−Ｌ−ロイシナミド（１６３ｍｇ，０．２７ｍｍｏｌ）のテトラヒドロフラン（５ｍｌ）溶液に、窒素雰囲気下、ピロリジン（２３０μｌ，２．７ｍｍｏｌ）、テトラキス（トリフェニルホスフィン）パラジウム（０）（３１ｍｇ，０．０２７ｍｍｏｌ）及びトリフェニルホスフィン（１４ｍｇ，０．０５４ｍｍｏｌ）を加え、１８時間撹拌した。溶媒を減圧下留去し得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル）を用いて精製し、標記目的化合物（１３０ｍｇ，収率９４％）を得た。
IR (KBr) ν_max 3316, 2959, 1626, 1513, 1237 cm^-1;
¹H NMR (CDCl₃, 400MHz) δ 0.89 (3H, t, J=7,3 Hz), 0.94 (6H, t, J=5.9 Hz), 1.42-1.79 (5H, m), 2.35 (3H, s), 2.56 (4H, t, J=5.1 Hz), 3.10 (1H, dd, J=8.1, 12.5 Hz), 3.19 (1H, dd, J=5.1, 12.5 Hz), 3.32 (4H, t, J=5.1 Hz), 3.74 (3H, s), 3.99-4.04 (1H, m), 4.54-4.60 (1H, m), 6.33 (2H, t, J=8.1 Hz), 6.59 (2H, d, J=8.8 Hz), 6.77 (2H, d, J=8.8 Hz), 6.88 (2H, d, J=8.8 Hz), 7.67 (2H, d, J=8.8 Hz);
HRMS(FAB): 510.3431 [M+H]⁺ (calcd 510.3444 for C₂₉H₄₄N₃O₅)

［実施例４８］ Ｎ^１−（（１Ｓ）−１−｛［（４−メトキシフェニル）アミノ］メチル｝プロピル）−Ｎ^２−［４−モルホリン−４−イルベンゾイル］−Ｌ−ロイシナミド（例示化合物番号３−２７０）
（４８ａ） Ｎ^１−（（１Ｓ）−１−｛［［（アリルオキシ）カルボニル］（４−メトキシフェニル）アミノ］メチル｝プロピル）−Ｎ^２−（４−モルホリン−４−イルベンゾイル）−Ｌ−ロイシナミド
実施例４６（４６ｂ）で製造したアリル （２Ｓ）−２−［（１−［（１Ｓ）−１−［（ｔｅｒｔ−ブトキシカルボニル）アミノ］−３−メチルブチル］ビニル）アミノ］ブチル（４−メトキシフェニル）カルバメート（１２８ｍｇ，０．２６ｍｍｏｌ）を４Ｍ塩酸−ジオキサン溶液（２ｍｌ）に溶解し、室温で２時間撹拌した。溶媒を減圧下留去し得られた残渣をＮ，Ｎ−ジメチルホルムアミド（５ｍｌ）に溶解し、４−モルホリン−４−イル安息香酸（５３ｍｇ，０．２６ｍｍｏｌ），トリエチルアミン（４３μｌ，０．３１ｍｍｏｌ）、ヒドロキシベンゾトリアゾール １水和物（４２ｍｇ，０．３１ｍｍｏｌ）及び１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩（６０ｍｇ，０．３１ｍｍｏｌ）を加え、室温で１日撹拌した。溶媒を減圧下留去し得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル）を用いて精製し，標記目的化合物（１４８ｍｇ，収率９８％）を得た。
¹H NMR (CDCl₃, 400MHz) δ 0.81 (3H, t, J = 7.4 Hz), 0.94 (3H, d, J=6.3 Hz), 0.98 (3H, d, J=5.9 Hz), 1.41-1.74 (5H, m), 3.23 (4H, t, J=4.7 Hz), 3.29-3.39 (1H, m), 3.79 (3H, s), 3.84 (4H, t, J=5.1 Hz), 3.98-4.04 (2H, m), 4.40-4.61 (3H, m), 5.01-5.04 (2H, m), 5.75 (1H, br s), 6.48-6.51 (2H, br s), 6.85 (2H, d, J=8.2 Hz), 6.86 (2H, d, J=8.6 Hz), 7.08 (2H, d, J=8.2 Hz), 7.71 (2H, d, J=8.6 Hz);

（４８ｂ） Ｎ^１−（（１Ｓ）−１−｛［（４−メトキシフェニル）アミノ］メチル｝プロピル）−Ｎ^２−［４−モルホリン−４−イルベンゾイル］−Ｌ−ロイシナミド
実施例４６（４６ｄ）に記載した方法に従い、アリル ４−メトキシフェニル｛（２Ｓ）−２−［（１−｛（１Ｓ）−３−メチル−１−［（モルホリン−４−イルカルボニル）アミノ］ブチル｝ビニル）アミノ］ブチル｝カルバメートに代えて、実施例４８（４８ａ）で製造したＮ^１−（（１Ｓ）−１−｛［［（アリルオキシ）カルボニル］（４−メトキシフェニル）アミノ］メチル｝プロピル）−Ｎ^２−（４−モルホリン−４−イルベンゾイル）−Ｌ−ロイシナミド（１４７ｍｇ，０．２５ｍｍｏｌ）を使用して、標記目的化合物（１２２ｍｇ，収率９８％）を得た。
IR (KBr) ν_max 3324, 2960, 1627, 1513, 1234, 1125, 928, 817 cm^-1;
¹H NMR (CDCl₃, 400MHz) δ 0.87 (3H, t, J=7,3 Hz), 0.94 (6H, t, J=5.1 Hz), 1.43-1.78 (5H, m), 3.09 (1H, dd, J=7.3, 12.5 Hz), 3.18 (1H, dd, J=5.1, 12.5 Hz), 3.24 (4H, t, J=5.1 Hz), 3.74 (3H, s), 3.84 (4H t, J=4.4 Hz), 3.98-4.02 (1H, m), 4.60-4.66 (1H, m), 6.54-6.59 (4H, m), 6.77 (2H, d, J=8.8 Hz), 6.85 (2H, d, J=8.8 Hz), 7.70 (2H, d, J=8.8 Hz);
HRMS(FAB): 497.3116 [M+H]⁺ (calcd 497.3128 for C₂₈H₄₁N₄O₄)

［実施例４９］ Ｎ^１−（（１Ｓ）−１−｛［（４−メトキシフェニル）アミノ］メチル｝プロピル）−Ｎ^２−（ピペリジン−１−イルカルボニル）−Ｌ−ロイシナミド（例示化合物番号５−１１）
（４９ａ） アリル ４−メトキシフェニル｛（２Ｓ）−２−［（１−｛（１Ｓ）−３−メチル−１−［（ピペリジン−１−イルカルボニル）アミノ］ブチル｝ビニル）アミノ］ブチル｝カルバメート
実施例４６（４６ｂ）で製造したアリル （２Ｓ）−２−［（１−［（１Ｓ）−１−［（ｔｅｒｔ−ブトキシカルボニル）アミノ］−３−メチルブチル］ビニル）アミノ］ブチル（４−メトキシフェニル）カルバメート（１７７ｍｇ，０．３６ｍｍｏｌ）を４Ｍ塩酸−ジオキサン溶液（２ｍｌ）に溶解し、室温で２時間撹拌した。溶媒を減圧下留去し得られた残渣を塩化メチレン（５ｍｌ）に溶解し、トリエチルアミン（１５１μｌ，１．０８ｍｍｏｌ）及びピペリジン−１−カルボニルクロリド（９０μｌ，０．７２ｍｍｏｌ）を加え、室温で１日撹拌した。溶媒を減圧下留去し得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル，１：１）を用いて精製し、標記目的化合物（１８１ｍｇ，収率１００％）を得た。
¹H NMR (CDCl₃, 400MHz) δ 0.84 (3H, t, J = 7.4 Hz), 0.92 (3H, d, J=6.6 Hz), 0.95 (3H, d, J=6.6 Hz), 1.38-1.72 (11H, m), 3.31-3.33 (5H, m), 3.79 (3H, s), 3.94-4.03 (2H, m), 4.28-4.59 (3H, m), 4.88-5.08 (3H, m), 5.77 (1H, br s), 6.37 (1H, br s), 6.86 (2H, d, J=8.8 Hz), 7.07 (2H, d, J=8.8 Hz);

（４９ｂ）Ｎ^１−（（１Ｓ）−１−｛［（４−メトキシフェニル）アミノ］メチル｝プロピル）−Ｎ^２−（ピペリジン−１−イルカルボニル）−Ｌ−ロイシナミド
実施例４６（４６ｄ）に記載した方法に従い、アリル ４−メトキシフェニル｛（２Ｓ）−２−［（１−｛（１Ｓ）−３−メチル−１−［（モルホリン−４−イルカルボニル）アミノ］ブチル｝ビニル）アミノ］ブチル｝カルバメートに代えて、実施例４９（４９ａ）で製造したアリル ４−メトキシフェニル｛（２Ｓ）−２−［（１−｛（１Ｓ）−３−メチル−１−［（ピペリジン−１−イルカルボニル）アミノ］ブチル｝ビニル）アミノ］ブチル｝カルバメート（１８１ｍｇ，０．３６ｍｍｏｌ）を使用して、標記目的化合物（１２６ｍｇ，収率８３％）を得た。
IR (KBr) ν_max 3275, 29 34, 1619, 1514, 1237, 1040, 817 cm^-1;
¹H NMR (CDCl₃, 400MHz) δ 0.90-0.95 (9H, m), 1.46-1.68 (11H, m), 3.08 (1H, dd, J=8.1, 12.5 Hz), 3.18 (1H, dd, J=4.4, 12.5 Hz), 3.31 (4H, t, J=5.1 Hz), 3.73 (3H, s), 3.80 (1H, br s), 3.96-4.01 (1H, m), 4.24-4.30 (1H, m), 4.83 (1H, d, J=8.1 Hz), 6.55 (1H, d, J=8.8 Hz), 6.58 (2H, d, J=8.8 Hz), 6.76 (2H, d, J=8.8 Hz);
HRMS(FAB): 419.3049 [M+H]⁺ (calcd 419.3022 for C₂₃H₃₉N₄O₃)

［実施例５０］ Ｎ^１−（（１Ｓ）−１−｛［（４−メトキシフェニル）アミノ］メチル｝プロピル）−Ｎ^２−（４−ピペリジン−１−イルベンゾイル）−Ｌ−ロイシナミド（例示化合物番号３−２６６）
（５０ａ） Ｎ^１−（（１Ｓ）−１−｛［［（アリルオキシ）カルボニル］（４−メトキシフェニル）アミノ］メチル｝プロピル）−Ｎ^２−（４−ピペリジン−１−イルベンゾイル）−Ｌ−ロイシナミド
実施例４６（４６ｂ）で製造したアリル （２Ｓ）−２−［（１−［（１Ｓ）−１−［（ｔｅｒｔ−ブトキシカルボニル）アミノ］−３−メチルブチル］ビニル）アミノ］ブチル（４−メトキシフェニル）カルバメート（１４７ｍｇ，０．３０ｍｍｏｌ）を４Ｍ塩酸−ジオキサン溶液（２ｍｌ）に溶解し、室温で２時間撹拌した。溶媒を減圧下留去し得られた残渣をＮ，Ｎ−ジメチルホルムアミド（５ｍｌ）に溶解し、４−ピペリジン−１−イル安息香酸（６２ｍｇ，０．３０ｍｍｏｌ）、トリエチルアミン（５０μｌ，０．３６ｍｍｏｌ）、ヒドロキシベンゾトリアゾール １水和物（４９ｍｇ，０．３６ｍｍｏｌ）及び１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩（６９ｍｇ，０．３６ｍｍｏｌ）を加え、室温で１日撹拌した。溶媒を減圧下留去し得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル，１：１）を用いて精製し、標記目的化合物（１７１ｍｇ，収率９８％）を得た。
¹H NMR (CDCl₃, 400MHz) δ 0.80 (3H, t, J = 7.3 Hz), 0.94 (3H, d, J=5.9 Hz), 0.98 (3H, d, J=5.9 Hz), 1.41-1.74 (11, m), 3.27 (4H, t, J=5.9 Hz), 3.33 (1H, br s), 3.80 (3H, s), 4.00-4.02 (2H, m), 4.43-4.61 (3H, m), 5.05-5.07 (2H, m), 5.76 (1H, br s), 6.50-6.52 (2H, br s), 6.85 (2H, d, J=8.8 Hz), 6.88 (2H, d, J=8.8 Hz), 7.11 (2H, d, J=8.1 Hz), 7.69 (2H, d, J=8.1 Hz);

（５０ｂ） Ｎ^１−（（１Ｓ）−１−｛［（４−メトキシフェニル）アミノ］メチル｝プロピル）−Ｎ^２−（４−ピペリジン−１−イルベンゾイル）−Ｌ−ロイシナミド
実施例４６（４６ｄ）に記載した方法に従い、アリル ４−メトキシフェニル｛（２Ｓ）−２−［（１−｛（１Ｓ）−３−メチル−１−［（モルホリン−４−イルカルボニル）アミノ］ブチル｝ビニル）アミノ］ブチル｝カルバメートに代えて，実施例５０（５０ａ）で製造したＮ^１−（（１Ｓ）−１−｛［［（アリルオキシ）カルボニル］（４−メトキシフェニル）アミノ］メチル｝プロピル）−Ｎ^２−（４−ピペリジン−１−イルベンゾイル）−Ｌ−ロイシナミド（１７０ｍｇ，０．２９ｍｍｏｌ）を使用して、標記目的化合物（１３４ｍｇ，収率９３％）を得た。
M.p. 152-154 oC
IR (KBr) ν_max 3324, 2936, 1625, 1512, 1236, 1125, 1041 cm^-1;
¹H NMR (CDCl₃, 400MHz) δ 0.88 (3H, t, J=7.4 Hz), 0.94 (6H, t, J=6.3 Hz), 1.45-1.78 (11H, m), 3.11 (1H, dd, J=7.8, 12.5 Hz), 3.18 (1H, dd, J=5.1, 12.5 Hz), 3.28 (4H, t, J=5.9 Hz), 3.73 (3H, s), 3.97-4.03 (1H, m), 4.53-4.59 (1H, m), 6.34 (1H, d, J=7.8 Hz), 6.45 (1H, d, J=7.8 Hz), 6.61 (2H, d, J=9.0 Hz), 6.75 (2H, d, J=9.0 Hz), 6.83 (2H, d, J=8.6 Hz), 7.63 (2H, d, J=8.6 Hz);
HRMS(FAB): 495.3327 [M+H]⁺ (calcd 495.3335 for C₂₉H₄₃N₄O₃)

［実施例５１］ Ｎ^１−（（１Ｓ）−１−｛［（４−メトキシフェニル）アミノ］メチル｝プロピル）−Ｎ^２−［（４−メチルピペラジン−１−イル）カルボニル］−Ｌ−ロイシナミド（例示化合物番号５−２０）
（５１ａ） ベンジル Ｎ−［（４−メチルピペラジン−１−イル）カルボニル］−Ｌ−ロイシネート
文献（Ｊ．Ｍｅｄ．Ｃｈｅｍ．Ｓｏｃ．，ｖｏｌ４０，１９９７，３８２０）の方法を参考にし，以下の方法で合成した。  Under a nitrogen atmosphere, 1,3-dibromobenzene (24.25 g, 103 mmol), 1-aminocyclohexanecarboxylic acid (14.72 g, 103 mmol), potassium carbonate (21.31 g, 154 mmol) and bromo (dimethylsulfide) copper (I ) (2.11 g, 10 mmol) was mixed with N, N-dimethylacetamide (130 mL) and stirred at 120 ° C. for 3 hours. Ethyl acetate (200 mL) and water (200 mL) were added to the reaction solution, and insolubles were removed using Celite. The separated aqueous layer was made acidic (pH = 4) with concentrated hydrochloric acid, and extracted with ethyl acetate (150 mL × 2). After the extract was dried over sodium sulfate, the solvent was distilled off, and the resulting product was purified by silica gel column chromatography (100% ethyl acetate). The obtained crystals (23 g) were further washed with ether to give the title compound (13.55 g, yield 44%).
Mp 141-143 ° C;
IR (KBr) ν_max3250, 1705, 1592, 1479, 1227, 770 cm^-1;
¹H NMR (CDCl_Three, 400MHz) δ 1.30-1.70 (6H, m), 1.90-2.10 (4H, m), 6.57 (1H, ddd, J = 0.8, 2.3, 8.0 Hz), 6.83 (1H, dd, J = 1.7, 2.3 Hz ), 6.97 (1H, ddd, J = 0.8, 1.7, 8.0 Hz), 7.05 (1H, t, J = 8.0 Hz);
MS (EI) m / z: 297 [M⁺], 252.

(15b) 1-[(3-bromophenyl) amino] -N-((1S) -1-{[(4-methoxyphenyl) amino] methyl} propyl) cyclohexanecarboxamide dihydrochloride
  The tert-butyl (1S) -1-{[(4-methoxyphenyl) amino] methyl} propyl carbamate (1.77 g, 6.0 mmol) and 4N hydrochloric acid-dioxane (6 mL) produced in Example 2 (2a) were added. Mix and stir at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and a saturated aqueous solution of sodium hydrogen carbonate (50 mL) was added to the resulting residue. The aqueous layer was extracted with methylene chloride (30 mL × 3), the extract was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude amine was dissolved in N, N-dimethylformamide (12 mL), and 1-[(3-bromophenyl) amino] cyclohexanecarboxylic acid (1.79 g, 6.9 g) produced in Example 15 (15a) was used. 0 mmol), 1-hydroxybenzotriazole hydrate (0.96 g, 6.3 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (1.21 g, 6.3 mmol). . After the reaction solution was stirred at room temperature for 3 days, water (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL). The extract was washed with a saturated aqueous solution of sodium hydrogen carbonate (50 mL) and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (hexane / ethyl acetate, 2: 1) to obtain a glassy amide product (1.99 g). After adding 4N hydrochloric acid-dioxane (5 mL) to the obtained amide, the mixture was concentrated under reduced pressure, ether was added to the obtained residue, the hydrochloride was powdered, and the solvent was removed. The obtained powder was further washed several times with ether and dried under reduced pressure to obtain the title compound (2.29 g, yield 70%).
IR (KBr) ν_max1671, 1594, 1512, 1257, 1031, 873, 835, 688 cm^-1;
¹H NMR (DMSO-d₆, 400MHz) δ 0.65 (3H, t, J = 7.3 Hz), 1.21-1.93 (12H, m), 3.08 (1H, dd, J = 5.2, 12.8 Hz), 3.32 (1H, dd, J = 6.8, 12.8 Hz), 3.77 (3H, s), 3.92-3.96 (1H, m), 6.58 (1H, dd, J = 1.8, 8.2 Hz), 6.71 (1H, dd, J = 1.2, 7.8 Hz), 6.79 (1H , br s), 6.97 (1H, dd, J = 7.8, 8.2 Hz), 7.02 (2H, d, J = 8.9 Hz), 7.34 (2H, d, J = 8.9 Hz), 8.02 (1H, d, J = 8.6 Hz);
MS (EI) m / z: 474 [M + H]⁺, 252, 174.

(15c) N-((1S) -1-{[(4-methoxyphenyl) amino] methyl} propyl) -1-[(3'-methyl-1,1'-biphenyl-3-yl) amino] cyclohexane Carboxamide
  1-[(3-Bromophenyl) amino] -N-((1S) -1-{[(4-methoxyphenyl) amino] methyl} propyl) cyclohexanecarboxamide dihydrochloride prepared in Example 15 (15b) 274 mg, 0.50 mmol), m-tolyl boric acid (75 mg, 0.55 mmol), and tetrakis (triphenylphosphine) palladium (0) (23 mg, 0.02 mmol) in 1,2-dimethoxyethane (5 mL) and 2M sodium carbonate The mixture was added to a mixed solution with an aqueous solution (5 mL), and the mixture was heated and refluxed for 4 hours under a nitrogen atmosphere. Ethyl acetate (50 mL) was added to the reaction mixture, and the organic layer was washed with brine (50 mL) and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate, 1: 1) to obtain the title compound (224 mg, yield 92%).
IR (KBr): ν_max 3366, 1651, 1603, 1513, 1235, 820, 775, 702 cm^-1;
¹H NMR (CDCl_Three, 400 MHz) δ 1.24-1.70 (8 H, m), 1.94-2.08 (4 H, m), 3.03 (1 H, dd, J = 7.6, 12.3 Hz), 3.14 (1 H, dd, J = 4.6 , 12.3 Hz), 3.63 (1 H, br s), 3.72 (3 H, s), 4.03-4.10 (2 H, m), 6.44 (2 H, d, J = 8.9 Hz), 6.58 (1 H, dd, J = 2.0, 7.8 Hz), 6.71 (2 H, d, J = 8.9 Hz), 6.84 (1 H, t, J = 2.0 Hz), 7.01 (1 H, br d, J = 7.8 Hz), 7.04 (1 H, br d, J = 8.7 Hz), 7.11 (1 H, t, J = 7.8 Hz), 7.13 (1 H, br d, J = 7.5 Hz), 7.26 (1 H, t, J = 7.5 Hz), 7.33 (1 H, br d, J = 7.5 Hz), 7.34 (1 H, br s);
MS (FAB) m / z: 486 [M + H]⁺;
Anal. Calcd for C₃₁H₃₉N_ThreeO_2.0.5 H_TwoO: C, 75.27; H, 8.15; N, 8.49. Found: C, 75.30; H, 7.96; N, 8.29.

Example 16 N-{(1S) -2-[(4-methoxyphenyl) amino] -1-methylethyl} -1- (4-phenoxyphenoxy) cyclohexanecarboxamide (Exemplary Compound No. 4-301)
(16a) 1- (4-phenoxyphenoxy) cyclohexanecarboxylic acid
  A mixture of 1-bromocyclohexanecarboxylic acid methyl ester (111 mg, 0.50 mmol), 4-phenoxyphenol (93 mg, 0.50 mmol) and potassium hydroxide (280 mg, 5.00 mmol) was dissolved in tert-butanol (5 mL). And stirred for 23 hours. After cooling, the reaction mixture was acidified with 1N hydrochloric acid and extracted with methylene chloride (10 mL × 5). After the extract was dried over sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by thin-layer chromatography (hexane / ethyl acetate, 1: 1) to give the title compound (62 mg, yield). 40%).
IR (neat) ν_max 1709, 1502, 1489, 1216 cm^-1;
¹H NMR (CDCl_Three, 400 MHz) δ 1.26-2.25 (10H, m), 6.88-6.97 (6H, m), 7.05 (1H, t, J = 7.4 Hz), 7.29 (t, 2H, J = 7.4 Hz);
MS (EI) m / z: 312 [M⁺], 186.

(16b) N-{(1S) -2-[(4-methoxyphenyl) amino] -1-methylethyl} -1- (4-phenoxyphenoxy) cyclohexanecarboxamide
  (2S) -N prepared in Example 3 (3c) in a solution of 1- (4-phenoxyphenoxy) cyclohexanecarboxylic acid (187 mg, 0.60 mmol) in methylene chloride (10 mL) prepared in Example 16 (16a).¹-(4-methoxyphenyl) propane-1,2-diamine (108 mg, 0.60 mmol), 1-hydroxybenzotriazole hydrate (121 mg, 0.90 mmol), 1-ethyl-3- (3-dimethylaminopropyl ) -Carbodiimide hydrochloride (172 mg, 0.90 mmol) and triethylamine (91 mg, 0.90 mmol) were added, and the mixture was stirred at room temperature for 17 hours. The reaction mixture was partitioned between water and methylene chloride, the organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by thin-layer chromatography (hexane / ethyl acetate, 1: 1) to give the title compound (233 mg, yield 82%).
IR (KBr) ν_max 3382,1655 cm^-1;
¹H NMR (CDCl_Three, 400 MHz) δ 1.20 (3H, d, J = 7.2 Hz), 1.24-1.38 (1H, m), 1.1.43-1.57 (4H, m), 1.62-1.68 (1H, m), 1.90-1.96 ( 2H, m), 2.00-2.08 (2H, m), 3.03-3.16 (2H, m), 3.70 (3H, s), 4.27 (1H, m), 6.41 (1H, d, J = 8.0 Hz), 6.51 (2H, d, J = 8.8 Hz), 6.73 (2H, d, J = 8.0 Hz), 6.84 (4H, dd, J = 8.8, 11.6 Hz), 6.95 (2H, d, J = 8.0Hz), 7.07 (1H, t, J = 7.8 Hz), 7.31 (2H, t, J = 7.8 Hz).

[Example 17] N²-[(Benzyloxy) carbonyl] -N¹-{(1S) -2-[(4-methoxyphenyl) amino] -1-methylethyl} -L-leucinamide (Exemplary Compound No. 3-5)
  Example 5 (5b) using N-carbobenzyloxy-L-leucine (175 mg, 0.66 mmol) instead of 1- (1,1′-biphenyl-3-ylamino) cyclohexanecarboxylic acid. A reaction similar to the above reaction was performed. The obtained crude product was recrystallized from a mixed solvent (4 mL) of hexane / ethyl acetate (1: 1) to give the title compound (142 mg, yield 55%).
Mp 122-123 ° C;
IR (KBr) ν_max 1718, 1639, 1515, 1254, 1037 cm^-1;
¹H NMR (CDCl_Three, 400 MHz) δ 0.91 (6 H, d, J = 6.3 Hz), 1.21 (3 H, d, J = 6.6 Hz), 1.45-1.69 (3 H, m), 3.06-3.16 (2 H, m) , 3.72 (1 H, br), 3.73 (3 H, s), 4.06-4.11 (1 H, m), 4.15-4.22 (1 H, m), 5.11 (1 H, br), 5.19 (2 H, s), 5.99 (1 H, br), 6.58 (2 H, d, J = 8.9 Hz), 6.77 (2 H, d, J = 8.9 Hz), 7.29-7.36 (5 H, m);
MS (FAB) m / z: 428 [M + H]⁺;
Anal. Calcd for C_{twenty four}H₃₃N_ThreeO_Four: C, 67.42; H, 7.78; N, 9.83. Found: C, 67.17; H, 7.31; N, 9.62.

[Example 18] N²-(Benzofuran-2-ylcarbonyl) -N¹-{(1S) -2-[(4-methoxyphenyl) amino] -1-methylethyl} -L-leucinamide (Exemplary Compound No. 3-9)
(18a) N- (benzofuran-2-ylcarbonyl) -L-leucine
  After a mixture of 2-benzofurancarboxylic acid (10.43 g, 64.3 mmol), thionyl chloride (14 ml, 193 mmol) and toluene (500 mL) was heated under reflux for 6 hours, the reaction solution was concentrated. The obtained crude acid chloride was dissolved in ether (200 ml) and added dropwise to a 1N aqueous sodium hydroxide solution (200 mL) of L-leucine (9.28 g, 70.8 mmol) under ice-cooling. After stirring the reaction solution at room temperature for 18 hours, 1N hydrochloric acid (400 mL) was added. The mixture was extracted with ethyl acetate (200 mL × 2), and the extract was dried over sodium sulfate and concentrated. The obtained crude crystals were recrystallized from ether to give the title compound (12.05 g, yield 68%).
Mp 150-151 ° C;
[α]_D^{twenty three}= 29.0 (CHCl_Three, c = 0.58);
IR (KBr) ν_max 3416, 2957, 1745, 1659, 1632, 1599, 1529, 1449, 1224, 1182, 1150, 1077 cm^-1;
¹H NMR (CDCl_Three, 400 MHz) δ 7.67 (1H, d, J = 7.3 Hz), 7.53 (1H, d, J = 7.3 Hz), 7.52 (1H, s), 7.43 (1H, t, J = 7.3 Hz), 7.30 ( 1H, t, J = 7.3 Hz), 6.97 (1H, t, J = 8.1 Hz), 4.91-4.85 (1H, m), 1.90-1.74 (3H, m), 1.01 (6H, d, J = 5.9 Hz );
¹³C NMR (CDCl_Three, 125 MHz) δ 177.3, 159.7, 155.6, 148.5, 128.2, 127.9, 124.5, 123.6, 112.6, 112.2, 51.4, 42.1, 25.7, 23.6, 22.5;
HRMS m / z calcd for C_FifteenH₁₈NO_Four276.1235 [M + H]⁺, found 276.1223.

(18b) N²-(Benzofuran-2-ylcarbonyl) -N¹-{(1S) -2-[(4-methoxyphenyl) amino] -1-methylethyl} -L-leucinamide
  In a methylene chloride (5 mL) solution of N- (benzofuran-2-ylcarbonyl) -L-leucine (139 mg, 0.51 mmol) prepared in Example 19 (19a), (2S) prepared in Example 3 (3c). ) -N¹-(4-methoxyphenyl) propane-1,2-diamine (110 mg, 0.61 mmol), 1-hydroxybenzotriazole hydrate (116 mg, 0.76 mmol), 1-ethyl-3- (3-dimethylaminopropyl ) -Carbodiimide hydrochloride (166 mg, 0.76 mmol) and triethylamine (0.2 mL, 1.43 mmol) were added, and the mixture was stirred for 2.5 hours. The reaction mixture was partitioned between water and methylene chloride, the organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate, 1: 1) to give the title compound (152 mg, yield 67%).
IR (KBr) ν_max 3284, 3066, 2956, 2932, 2871, 2831, 1641, 1595, 1564, 1513 cm^-1;
¹H NMR (CDCl_Three, 400 MHz) δ 0.94 (3H, d, J = 6.6 Hz), 0.96 (3H, d, J = 6.6 Hz), 1.21 (3H, d, J = 6.6 Hz), 1.66-1.80 (3H, m), 3.11-3.20 (2H, m), 3.73 (1H, s), 3.77 (1H, br s), 4.22 (1H, septet, J = 6.6 Hz), 4.61-4.70 (1H, m), 6.48 (1H, d , J = 8.1 Hz), 6.60 (2H, ddd, J = 2.2, 3.7, 8.8 Hz), 6.77 (2H, ddd, J = 2.2, 3.7, 8.8 Hz), 7.12 (1H, d, J = 8.8 Hz) , 7.29 (1H, t, J = 8.1 Hz), 7.39-7.48 (2H, m), 7.51 (1H, d, J = 9.5 Hz), 7.64 (1H, d, J = 8.1 Hz);
MS (FAB) m / z: 438 [M + H]⁺.

[Example 19] 1- (1,1'-biphenyl-3-ylamino) -N-((1S) -1-{[(4-benzyloxyphenyl) amino] methyl} propyl) cyclohexanecarboxamide (Exemplary compound number 2-272)
(19a) N- [4- (benzyloxy) phenyl] -2-nitrobenzenesulfonamide
  4- (Benzyloxy) aniline hydrochloride (11.79 g, 50.0 mmol) and 2-nitrobenzenesulfonyl chloride (11.08 g, 50.0 mmol) were suspended in methylene chloride (150 mL), and triethylamine (10.63 g, 14 (0.6 mL, 105 mmL) was gradually added dropwise with ice cooling. After completion of the dropwise addition, the reaction mixture was returned to room temperature, and further stirred for 4 hours. Water (200 mL) was added to the reaction solution, and the organic layer was separated. The organic layer was washed with saturated aqueous sodium hydrogen carbonate (100 mL) and 1N hydrochloric acid (100 mL), and dried over sodium sulfate. The crude crystals obtained by distilling off the solvent were recrystallized from ethanol (350 mL) to obtain the title compound (16.63 g, yield 87%).
Mp 154-156 ° C;
IR (KBr) ν_max 3312, 1540, 1507, 1166, 1005, 595 cm^-1;
¹H NMR (CDCl_Three, 400 MHz) δ 5.00 (2H, s), 6.85 (1H, d, J = 8.9 Hz), 7.09 (1H, d, J = 8.9 Hz), 7.10 (1H, br), 7.30-7.40 (5H, m ), 7.55 (1H, dt, J = 1.2, 7.8 Hz), 7.68 (1H, dt, J = 1.4, 7.8 Hz), 7.75 (1H, dd, J = 1.4, 7.8 Hz), 7.85 (1H, dd, J = 1.2, 7.8 Hz);
MS (FAB) m / z: 384 [M⁺];
Anal. Calcd for C₁₉H₁₆N_TwoO_FiveS: C, 59.37; H, 4.20; N, 7.29; S, 8.34. Found: C, 59.21; H, 4.05; N, 7.27; S, 8.33.

(19b) tert-butyl (1S) -1-({[4- (benzyloxy) phenyl] amino} methyl) propyl carbamate
  (S) -2- (tert-Butoxycarbonylamino) -1-butanol (Tetrahedron, Vol 51, 12337-12350, 1995) (1.89 g, 10.0 mmol), N- [produced in Example 19 (19a). 4- (Benzyloxy) phenyl] -2-nitrobenzenesulfonamide (1.92 g, 5.0 mmol) and triphenylphosphine (2.62 g, 10.0 mmol) in tetrahydrofuran (25 mL) under ice-cooling A solution of diethyl acid (2.2 M in toluene, 4.50 mL, 10.0 mmol) in tetrahydrofuran (5 mL) was added dropwise over 20 minutes. After returning the reaction temperature to room temperature, the reaction solution was further stirred for 4 hours. The residue obtained by evaporating the solvent under reduced pressure was dissolved in ether (100 mL) and cooled with ice. The precipitated crystals were separated by filtration and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in acetonitrile (15 mL), and thiophenol (1.10 g, 10.0 mmol) and potassium carbonate (2.07 g, 15.0 mmol) were added. After stirring the reaction mixture for 48 hours, ethyl acetate (100 mL) was added. The organic layer was washed with water (100 mL × 1) and brine (50 mL × 1), dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate, 4: 1) to give the title compound (1.52 g, yield 82%).
Mp 108-111 ° C;
IR (KBr) ν_max 3375, 1683, 1514, 1245, 1175, 1018, 816 cm^-1;
¹H NMR (CDCl_Three, 400MHz) δ 0.97 (3H, t, J = 7.5 Hz), 1.45 (9H, s), 1.40-1.66 (2H, m), 3.01 (1H, dd, J = 7.6, 12.2 Hz), 3.17 (1H, dd, J = 4.6, 12.2 Hz), 3.65-3.80 (2H, m), 4.46 (1H, br s), 4.99 (2H, s), 6.57 (2H, d, J = 8.9 Hz), 6.84 (2H, d, J = 8.9 Hz), 7.28-7.43 (5H, m);
MS (FAB) m / z: 370 [M⁺], 223, 91, 57;
Anal. Calcd for C_{twenty two}H₃₀N_TwoO_Three: C, 71.32; H, 8.16; N, 7.56. Found: C, 71.16; H, 7.93; N, 7.55.

(19c) 1- (1,1'-biphenyl-3-ylamino) -N-((1S) -1-{[(4-benzyloxyphenyl) amino] methyl} propyl) cyclohexanecarboxamide
  The tert-butyl (1S) -1-({[4- (benzyloxy) phenyl] amino} methyl) propyl carbamate (412 mg, 1.11 mmol) prepared in Example 19 (19b) was treated with trifluoroacetic acid (2 mL). Mix and stir at room temperature for 1 hour. The mixture was concentrated under reduced pressure, and separated with saturated aqueous sodium hydrogen carbonate (50 mL) and ethyl acetate (50 mL). The organic layer was dried over sodium sulfate, and the residue obtained by evaporating the solvent was dissolved in N, N-dimethylformamide (3 mL). 1- (1,1′-Biphenyl-3-ylamino) cyclohexanecarboxylic acid (345 mg, 1.17 mmol) prepared in Example 5 and 1-hydroxybenzotriazole monohydrate (204 mg, 1 .33 mmol), 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (255 mg, 1.33 mmol) and triethylamine (135 mg, 0.185 mL, 1.33 mmol) were sequentially added. The reaction mixture was stirred at room temperature for 48 hours, and partitioned between water (50 mL) and ethyl acetate (50 mL). The organic layer was washed with saturated aqueous sodium hydrogen carbonate (30 mL), dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate, 2: 1) to give the title compound (510 mg, yield 84%).
IR (KBr) ν_max3367, 1652, 1601, 1511, 1228, 758, 699 cm^-1;
¹H NMR (CDCl_Three, 400MHz) δ 0.88 (3H, t, J = 7.4 Hz), 1.24-1.70 (8H, m), 1.93-2.04 (4H, m), 3.02 (1H, dd, J = 7.7, 12.1 Hz), 3.12 ( 1H, dd, J = 4.6, 12.1 Hz), 3.67 (1H, br s), 4.00-4.10 (2H, m), 4.96 (2H, s), 6.42 (2H, d, J = 8.9 Hz), 6.59 ( 1H, dd, J = 2.0, 7.8 Hz), 6.78 (2H, d, J = 8.9 Hz), 6.85 (1H, br s), 7.01 (1H, d, J = 7.8 Hz), 7.03 (1H, br) , 7.12 (1H, t, J = 7.8 Hz), 7.27-7.55 (10H, m);
MS (FAB) m / z: 548 [M + H]⁺, 250.

Example 20 tert-butyl (4-{[(2S) -2-({[1- (1,1′-biphenyl-3-ylamino) cyclohexyl] carbonyl} amino) butyl] amino} phenoxy) acetate ( Exemplified compound number 5-1)
(20a) 1- (1,1'-biphenyl-3-ylamino) -N-((1S) -1-{[(4-hydroxyphenyl) amino] methyl} propyl) cyclohexanecarboxamide
  1- (1,1′-biphenyl-3-ylamino) -N-((1S) -1-{[(4-benzyloxyphenyl) amino] methyl} propyl) cyclohexanecarboxamide prepared in Example 19 (19c) (2.04 g, 3.7 mmol) in a hydrogen atmosphere (1 atm) in the presence of a 10% palladium-carbon catalyst (0.40 g, 0.37 mmol) in an ethanol (20 mL) solvent at 40 ° C for 6 hours. Was decomposed. After removing the catalyst, the residue obtained by evaporating the solvent was purified by silica gel column chromatography (hexane / ethyl acetate, 1: 1) to obtain the title compound (1.69 g, yield 99%). Was.
IR (KBr) ν_max3367, 1647, 1601, 1515, 1241, 1225, 758 cm^-1;
¹H NMR (CDCl_Three, 400MHz) δ 0.85 (3H, t, J = 7.4 Hz), 1.23-1.63 (8H, m), 1.95-2.08 (4H, m), 2.98 (1H, dd, J = 7.7, 12.2 Hz), 3.08 ( 1H, dd, J = 4.4, 12.2 Hz), 4.00-4.14 (2H, m), 6.34 (2H, d, J = 8.6 Hz), 6.59 (1H, dd, J = 2.0, 8.0 Hz), 6.67 (2H , d, J = 8.6 Hz), 6.86 (1H, t, J = 2.0 Hz), 7.01 (1H, d, J = 8.0 Hz), 7.12 (1H, br d, J = 8.9 Hz), 7.12 (1H, t, J = 8.0 Hz), 7.28-7.38 (3H, m), 7.51-7.53 (2H, m);
MS (FAB) m / z: 458 [M + H]⁺, 250.

(20b) tert-butyl (4-{[(2S) -2-({[1- (1,1'-biphenyl-3-ylamino) cyclohexyl] carbonyl} amino) butyl] amino} phenoxy) acetate
  1- (1,1′-biphenyl-3-ylamino) -N-((1S) -1-{[(4-hydroxyphenyl) amino] methyl} propyl) cyclohexanecarboxamide (prepared in Example 20 (20a)) To a solution of 1.69 g, 3.7 mmol) in tetrahydrofuran (15 mL) was added sodium hydride (55% oil) (0.18 g, 4.1 mmol) under ice-cooling, and further, bromoacetic acid t-butyl ester (0%). (.79 g, 4.1 mmol) in N, N-dimethylformamide (4 mL) was added dropwise. After returning the reaction temperature to room temperature, the reaction solution was further stirred for 1 hour. Under ice cooling, water (100 mL) was added to the reaction solution, and the aqueous layer was extracted with ethyl acetate (2 × 50 mL). The extract was dried over sodium sulfate, and the residue obtained by evaporating the solvent was purified by silica gel column chromatography (hexane / ethyl acetate, 2: 1) to give the title compound (1.66 g, yield 79%). ) Got.
IR (KBr) ν_max3370, 1750, 1653, 1601, 1512, 1217, 1154, 758 cm^-1;
¹H NMR (CDCl_Three, 400MHz) δ 0.88 (3H, t, J = 7.4 Hz), 1.24-1.67 (8H, m), 1.97-2.04 (4H, m), 3.01 (1H, dd, J = 7.8, 12.2 Hz), 3.13 ( 1H, dd, J = 4.5, 12.2 Hz), 3.72 (1H, br s), 4.00-4.11 (2H, m), 4.40 (2H, s), 6.41 (2H, d, J = 8.9 Hz), 6.59 ( 1H, dd, J = 2.0, 8.0 Hz), 6.72 (2H, d, J = 8.9 Hz), 6.85 (1H, t, J = 2.0 Hz), 7.01 (1H, d, J = 8.0 Hz), 7.03 ( 1H, br d, J = 8.2 Hz), 7.11 (1H, t, J = 8.0 Hz), 7.29-7.38 (3H, m), 7.51-7.53 (2H, m);
MS (FAB) m / z: 572 [M + H]⁺, 325, 250.
Anal. Calcd for C₃₅H₄₅N_ThreeO_Four·0.2 H_TwoO: C, 73.06; H, 7.95; N, 7.30. Found: C, 72.96; H, 7.87; N, 7.25.

Example 21 (4-{[(2S) -2-({[1- (1,1′-biphenyl-3-ylamino) cyclohexyl] carbonyl} amino) butyl] amino} phenoxy) acetic acid dihydrochloride ( Exemplified compound number 5-2)
  Tert-Butyl (4-{[(2S) -2-({[1- (1,1'-biphenyl-3-ylamino) cyclohexyl] carbonyl} amino) butyl] amino} prepared in Example 20 (20b). To a solution of (phenoxy) acetate (1.64 g, 2.9 mmol) in methylene chloride (5 mL) was added trifluoroacetic acid (5 mL) under ice-cooling, and the mixture was further stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and a 4N hydrochloric acid-dioxane solution (3 mL) was added to the residue. After evaporating the solvent under reduced pressure, the obtained residue was triturated from ether (20 mL), and filtered and washed with ether to obtain the title compound (1.60 g, yield 95%).
IR (KBr) ν_max3343, 1740, 1668, 1605, 1510, 1194, 1177, 1075, 759, 700 cm^-1;
¹H NMR (DMSO-d₆, 400MHz) δ 0.64 (3H, t, J = 7.4 Hz), 1.14-1.98 (12H, m), 3.07 (1H, dd, J = 5.0, 12.5 Hz), 3.28 (1H, dd, J = 6.5, 12.5 Hz), 3.96-4.01 (1H, br), 4.68 (2H, s), 6.72-6.73 (1H, br d), 6.95 (2H, d, J = 9.0 Hz), 6.96-7.10 (2H, m), 7.19 (1H, t, J = 8.0 Hz), 7.25 (2H, br d, J = 9.0 Hz), 7.31-7.52 (5H, m), 8.07 (1H, br d, J = 8.7 Hz);
MS (FAB) m / z: 516 [M + H]⁺, 250.

[Example 22] N¹-((1S) -1-{[(4-benzyloxyphenyl) amino] methyl} propyl) -N²-(1,1'-biphenyl-3-yl) -L-leucinamide (Exemplary Compound No. 1-272)
  Similarly to the reaction described in Example 19 (19c), N- (1,1′-biphenyl-3-yl) -L was used instead of 1- (1,1′-biphenyl-3-ylamino) cyclohexanecarboxylic acid. The reaction was carried out using -leucine (5.50 g, 19.4 mmol) to obtain the title compound (10.30 g, yield 99%) as colorless crystals.
Mp 117-119 ° C;
IR (KBr) ν_max 3324, 1624, 1511, 1231, 1214, 755 cm^-1;
¹H NMR (CDCl_Three, 400 MHz) δ 0.93 (3H, t, J = 7.3 Hz), 0.94 (3H, d, J = 6.6 Hz), 1.01 (3H, d, J = 6.6 Hz), 1.39-1.92 (5H, m), 2.96 (1H, dd, J = 7.3, 12.5 Hz), 3.11 (1H, dd, J = 4.4, 12.5 Hz), 3.40-3.55 (1H, br s), 3.74-3.82 (1H, m), 3.92-3.95 (1H, m), 4.00-4.12 (1H, m), 4.93 (2H, s), 6.33 (2H, d, J = 9.5 Hz), 6.58 (1H, dd, J = 2.2, 8.1 Hz), 6.72 ( 2H, d, J = 9.5 Hz), 6.74-6.85 (2H, m), 7.03 (1H, d, J = 8.1 Hz), 7.18 (1H, t, J = 8.1 Hz), 7.28-7.58 (10H, m )
Anal. Calcd for C₃₅H₄₁N_ThreeO_Two: C, 78.47; H, 7.71; N, 7.84. Found: C, 78.47; H, 7.52; N, 7.78
MS (FAB) m / z: 536 [M + H⁺], 444, 238 ;.

[Example 23] N²-(1,1'-biphenyl-3-yl) -N¹-((1S) -1-{[(4-cyanomethoxyphenyl) amino] methyl} propyl) -L-leucinamide (Exemplified Compound No. 5-5)
(23a) N¹-((1S) -1-{[(4-hydroxyphenyl) amino] methyl} propyl) -N²-(1,1'-biphenyl-3-yl) -L-leucinamide
  N produced in Example 22¹-((1S) -1-{[(4-benzyloxyphenyl) amino] methyl} propyl) -N²-(1,1′-Biphenyl-3-yl) -L-leucinamide (10.4 g, 19.4 mmol) was dissolved in ethanol (650 ml), 10% palladium-carbon (2.1 g) was added, and hydrogen was added. It was agitated and stirred at 50 ° C. for 4 hours. 10% palladium-carbon was filtered off using Celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (30-50% ethyl acetate-hexane) to give the title compound (7.49 g, yield 87%) as a foam.
¹H NMR (CDCl_Three, 400 MHz) δ 0.93 (3H, t, J = 7.3 Hz), 0.94 (3H, d, J = 6.6 Hz), 1.01 (3H, d, J = 6.6 Hz), 1.53-1.93 (5H, m), 3.71 (1H, dd, J = 4.4, 9.5 Hz), 3.75-3.82 (1H, m), 3.85 (1H, dd, J = 3.7, 9.5 Hz), 4.91 (1H, br s), 6.47 (2H, d , J = 8.8Hz), 6.54-6.62 (1H, m), 6.59 (2H, d, J = 8.8Hz), 6.79-6.82 (1H, m), 6.96 (1H, d, J = 8.1Hz), 7.03 (1H, br d, J = 9.5Hz), 7.14 (1H, t, J = 8.1Hz), 7.28-7.55 (6H, m)
IR (KBr) ν_max 2961, 1649, 1605, 1509, 1228 cm^-1;
MS (FAB) m / z: 447 [M + H⁺], 238 ;.

(23b) N²-(1,1'-biphenyl-3-yl) -N¹-((1S) -1-{[(4-cyanomethoxyphenyl) amino] methyl} propyl) -L-leucinamide
  N produced in Example 23 (23a)¹-((1S) -1-{[(4-hydroxyphenyl) amino] methyl} propyl) -N²-(1,1′-Biphenyl-3-yl) -L-leucinamide (2.87 g, 6.44 mmol) was dissolved in a mixed solvent of tetrahydrofuran / N, N-dimethylformamide (60 ml, 5: 1) and hydrogenated. Sodium (55% oily) (281 mg, 6.44 mmol) was added, and bromoacetonitrile (0.516 ml, 7.41 mmol) was further added, followed by stirring at room temperature for 17 hours. The reaction solution was poured into a saturated aqueous solution of ammonium chloride and extracted with ether. The extract was washed sequentially with water and saturated saline, dried, and concentrated. The residue was purified by silica gel column chromatography (40-50% ethyl acetate-hexane) to give the title compound (1.83 g, yield 59%) as a foam.
¹H NMR (CDCl_Three, 400 MHz) 0.94 (3H, t, J = 7.3Hz), 0.95 (3H, d, J = 5.9Hz), 1.02 (3H, d, J = 5.9Hz), 1.40-1.68 (3H, m), 1.79 -1.92 (2H, m), 2.97 (1H, dd, J = 8.5, 12.5Hz), 3.13 (1H, dd, J = 3.7, 12.5Hz), 3.72-3.81 (2H, m), 3.91-3.95 (1H , m), 4.02-4.11 (1H, m), 4.60 (2H, s), 6.34 (2H, J = 8.8Hz), 6.58 (1H, dd, J = 1.5, 8.1Hz), 6.72-6.79 (1H, m), 6.74 (2H, d, J = 8.8Hz), 6.82-6.85 (1H, m), 7.03-7.07 (1H, m), 7.18 (1H, t, J = 8.1Hz), 7.30-7.38 (3H , m), 7.48-7.55 (2H, m)
IR (KBr) ν_max 2962, 1652, 1606, 1512, 1215, 758 cm^-1;
MS (FAB) m / z: 485 [M + H⁺], 446, 238;
HRMS (ESI) [M + H⁺] calcd for C₃₀H₃₇N_FourO_Two: 485.2917; obserbed 485.2906.

[Example 24] N²-(1,1'-biphenyl-3-yl) -N¹-{(1S) -1-([{4- (2H-pyrazol-5-yl) methoxyphenyl} amino] methyl) propyl} -L-leucinamide (Exemplified Compound No. 5-6)
  N produced in Example 23 (23b)²-(1,1'-biphenyl-3-yl) -N¹-((1S) -1-{[(4-cyanomethoxyphenyl) amino] methyl} propyl) -L-leucinamide (1.13 g, 2.33 mmol), sodium azide (454 mg), ammonium chloride (374 mg) It was dissolved in N, N-dimethylformamide (25 ml) and stirred at 100 ° C. for 5 hours and 30 minutes. The reaction solution was poured into a cooled saturated aqueous ammonium chloride solution and extracted five times with ethyl acetate. After washing twice with a saturated saline solution, it was dried and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate) to give the title compound (745 mg, yield 69%) as colorless crystals.
Mp 154-158 ° C;
¹H NMR (CDCl_Three, 400 MHz) δ 0.93 (3H, t, J = 7.4Hz), 0.93 (3H, d, J = 6.3Hz), 1.01 (3H, d, J = 6.3Hz), 1.36-1.45 (1H, m), 1.56-1.68 (2H, m), 1.77-1.92 (3H, m), 2.86 (1H, dd, J = 8.2, 12.9Hz), 3.10 (1H, dd, J = 4.3, 12.9Hz), 3.80-3.84 ( 1H, m), 4.04-4.11 (1H, m), 5.21-5.24 (2H, br s), 6.22 (2H, d, J = 8.8Hz), 6.55-6.59 (1H, m), 6.58 (2H, d , J = 8.8Hz), 6.79-6.86 (2H, m), 7.02 (1H, d, J = 7.8Hz), 7.16 (1H, t, J = 7.8Hz), 7.25-7.52 (6H, m)
IR (KBr) ν_max 2960, 1637, 1605, 1512, 1231, 700 cm^-1;
Anal. Calcd for C₃₀H₃₇N₇O_Two: C, 68.29; H, 7.07; N, 18.58.Found: C, 68.43; H, 6.88; N, 18.35.
MS (FAB) m / z: 528 [M + H⁺], 444, 238 ;.

Example 25 Tert-butyl [4-({(2S) -2-[(N-1,1′-biphenyl-3-yl-L-leucyl) amino] butyl} amino) phenoxy] acetate (exemplified compound) No. 5-7)
  N produced in Example 23 (23a)¹-((1S) -1-{[(4-hydroxyphenyl) amino] methyl} propyl) -N²-(1,1'-Biphenyl-3-yl) -L-leucinamide (4.62 g, 10.4 mmol) is dissolved in a mixed solvent of tetrahydrofuran / N, N-dimethylformamide (100 ml, 4: 1) and cooled with ice. Underneath, sodium hydride (55% oily) (452 mg, 10.4 mmol) was added, and tert-butyl α-bromoacetate (1.84 ml) was further added. After returning to room temperature and stirring for 1 hour and 30 minutes, the mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and saturated saline, dried, and concentrated. The residue was purified by silica gel column chromatography (30-45% ethyl acetate-hexane) to give the title compound (4.7 g, yield 81%) as a foam.
¹H NMR (CDCl_Three, 400 MHz) δ 0.93 (3H, t, J = 7.4Hz), 0.94 (3H, d, J = 6.3Hz), 1.01 (3H, d, J = 6.3Hz), 1.40-1.50 (1H, m), 1.48 (9H, s), 1.55-1.66 (2H, m), 1.80-1.91 (2H, m), 2.95 (1H, dd, J = 7.4, 12.5Hz), 3.10 (1H, dd, J = 4.7, 12.5 Hz), 3.74-3.78 (1H, m), 3.91-3.94 (1H, m), 4.00-4.08 (1H, m), 4.36 (2H, s), 6.30 (2H, d, J = 9.0 Hz), 6.56 (1H, dd, J = 2.2, 7.8 Hz), 6.65 (2H, d, J = 9.0Hz), 6.74 (1H, d, J = 8.6Hz), 6.82 (1H, t, J = 2.2 Hz), 7.01 (1H, d, J = 7.8Hz), 7.15 (1H, t, J = 7.8Hz), 7.27-7.37 (3H, m), 7.47-7.51 (2H, m)
IR (KBr) ν_max 2961, 1751, 1652, 1605, 1513, 1217, 1155 cm^-1;
Anal. Calcd for C₃₄H₄₅N_ThreeO_Four: C, 72.96; H, 8.10; N, 7.51. Found: C, 72.95; H, 8.00; N, 7.49.
MS (FAB) m / z: 560 [M + H⁺], 446, 238 ;.

Example 26 2- [4-({(2S) -2-[(N-1,1′-biphenyl-3-yl-L-leucyl) amino] butyl} amino) phenoxy] -2-propionic acid Ethyl (Exemplified Compound No. 5-8)
  N produced in Example 23 (23a)¹-((1S) -1-{[(4-hydroxyphenyl) amino] methyl} propyl) -N²-(1,1′-Biphenyl-3-yl) -L-leucinamide (127 mg, 0.28 mmol) was dissolved in a mixed solvent of tetrahydrofuran / N, N-dimethylformamide (2 ml, 4: 1), and the solution was cooled with ice. , Sodium hydride (55% oil) (12.4 mg, 0.28 mmol) was added, and ethyl 2-bromo-2-methylpropionate (52 μl, 0.36 mmol) was further added. It returned to room temperature and stirred for 17 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with saturated saline, dried, and concentrated. The residue was purified by thin layer chromatography to give the title compound (95 mg, yield 61%) as an oil.
¹H NMR (CDCl_Three, 400 MHz) δ 0.93 (3H, t, J = 7.4Hz), 0.94 (3H, d, J = 6.3Hz), 1.01 (3H, d, J = 6.3Hz), 1.27 (3H, t, J = 7.0 Hz), 1.40-1.70 (3H, m), 1.49 (6H, s), 1.77-1.92 (2H, m), 2.95 (1H, dd, J = 7.8, 12.1Hz), 3.10 (1H, dd, J = 4.3, 12.1Hz), 3.73-3.82 (1H, m), 3.88-4.10 (3H, m), 4.21 (2H, q, J = 7.0Hz), 6.29 (2H, d, J = 8.6Hz), 6.57 ( 1H, dd, J = 2.3, 7.8Hz), 6.60 (2H, d, J = 8.6Hz), 6.74-6.83 (2H, m), 6.97-7.03 (1H, m), 7.13 (1H, t, J = (7.8Hz), 7.25-7.34 (3H, m), 7.46-7.54 (2H, m)
IR (KBr) ν_max 2961, 1732, 1651, 1607, 1511, 1227, 1140 cm^-1;
MS (FAB) m / z: 560 [M + H⁺], 444, 238;
HRMS (ESI) [M + H⁺] calcd for C₃₄H₄₆N_ThreeO_Four: 560.3488; obserbed 560.3491.

Example 27 [4-({(2S) -2-[(N-1,1′-biphenyl-3-yl-L-leucyl) amino] butyl} amino) phenoxy] acetic acid dihydrochloride (exemplified compound No. 5-9)
  Tert-butyl [4-({(2S) -2-[(N-1,1′-biphenyl-3-yl-L-leucyl) amino] butyl} amino) phenoxy] acetate (3 (0.69 g, 6.59 mmol) in methylene chloride (25 ml) -trifluoroacetic acid (25 ml) and stirred at room temperature for 1 hour. The reaction solution was concentrated, and the residue was azeotroped with toluene three times. The residue was dissolved in methylene chloride (5 ml), and 4N hydrochloric acid-dioxane solution (20 ml) was added. The resulting crystals were washed with diisopropyl ether to give the title compound (2.80 g, yield 74%) as colorless crystals.
Mp 89-91 ° C;
¹H NMR (CDCl_Three, 400 MHz) δ0.74-0.90 (9H, m), 1.51-1.69 (4H, m), 2.11-2.22 (1H, m), 3.22-3.27 (1H, m), 3.65-3.72 (2H, m) , 4.43-4.50 (2H, m), 4.47 (2H, s), 6.77 (2H, d, J = 7.4 Hz), 7.34-7.75 (9H, m), 8.03 (1H, br s), 9.52 (1H, m)
IR (KBr) ν_max 2963, 1739, 1674, 1605, 1554, 1228, 1193 cm^-1;
MS (FAB) m / z: 560 [M + H⁺], 444, 238 ;.

[Example 28] N¹-[(1S) -1-({[4- (benzyloxy) phenyl] amino} methyl) propyl] -N²-(Morpholin-4-ylcarbonyl) -L-leucinamide (Exemplary Compound No. 5-12)
(28a) benzyl N- (morpholin-4-ylcarbonyl) -L-leucinate
  Leucine benzyl ester p-toluenesulfonate (3.94 g, 10 mmol) and triethylamine (4.2 ml, 30 mmol) were dissolved in methylene chloride (100 ml), and morpholine carbonyl chloride (2.3 ml, 20 mmol) was added dropwise under ice-cooling. Stirred at room temperature for 24 hours. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate, 1: 1) to obtain the title compound (3.34 g, yield 100%).
IR (film) ν_max 3347, 2959, 1742, 1632, 1534, 1456, 1387, 1268, 1192, 1119, 999, 751, 698 cm^-1;
¹H NMR (CDCl_Three, 400MHz) δ 0.93 (6H, t, J = 4.9 Hz), 1.49-1.71 (3H, m), 3.33-3.41 (4H, m), 3.68 (4H, t, J = 4.9 Hz), 4.56-4.60 ( 1H, m), 4.83 (1H, d, J = 8.8 Hz), 5.13 (1H, d, J = 12.7 Hz), 5.20 (1H, d, J = 12.7 Hz), 7.32-7.38 (5H, m);
HRMS (FAB): 335.1977 [M + H]⁺ (calcd 335.1960 for C₁₈H₂₇N_TwoO_Four)

(28b) N- (morpholin-4-ylcarbonyl) -L-leucine
  Benzyl N- (morpholin-4-ylcarbonyl) -L-leucinate (3.34 g, 10 mmol) produced in Example 28 (28a) was placed under a hydrogen atmosphere (1 atm), 10% palladium on carbon catalyst (0.53 g, (0.50 mmol) in an ethanol (100 ml) solvent at room temperature for 3 hours. After removing the catalyst, the residue obtained by evaporating the solvent was purified by silica gel column chromatography (ethyl acetate / methanol, 20: 1) to give the title compound (2.44 g, yield 100%). ) Got.
IR (film) ν_max3360, 2960, 1726, 1631, 1538, 1270, 1118, 1000, 860, 593 cm^-1;
¹H NMR (CDCl_Three, 400MHz) δ 0.95 (6H, t, J = 6.7 Hz), 1.53-1.78 (3H, m), 3.33-3.43 (4H, m), 3.69 (4H, t, J = 4.7 Hz), 4.35-4.40 ( 1H, m), 4.79 (1H, d, J = 6.3 Hz);
HRMS (FAB): 245.1496 [M + H]⁺ (calcd 245.1518 for C₁₁H_{twenty one}N_TwoO_Four)

(28c) N¹-[(1S) -1-({[4- (benzyloxy) phenyl] amino} methyl) propyl] -N²-(Morpholin-4-ylcarbonyl) -L-leucinamide
  Tert-Butyl (1S) -1-({[4- (benzyloxy) phenyl] amino} methyl) propylcarbamate (817 mg, 2.21 mmol) produced in Example 19 (19b) was dissolved in 4 M hydrochloric acid in dioxane (10 ml). And stirred at room temperature for 2 hours. The residue obtained by evaporating the solvent under reduced pressure was dissolved in N, N-dimethylformamide (10 ml), and N- (morpholin-4-ylcarbonyl) -L-leucine (540 mg) produced in Example 28 (28b) was used. , 2.21 mmol), triethylamine (370 μl, 2.65 mmol), hydroxybenzotriazole monohydrate (358 mg, 2.65 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (508 mg, 2 .65 mmol) and stirred at room temperature for 7 hours. Ethyl acetate (20 ml) and water (20 mL) were added to the reaction solution, and after separation, the organic phase was washed with water (20 ml × 5) and brine (20 ml), dried over sodium sulfate, and the solvent was distilled off under reduced pressure. I left. The obtained residue was purified using silica gel column chromatography (ethyl acetate) to obtain the title compound (956 mg, yield 87%).
IR (KBr) ν_max3283, 2958, 1622, 1545, 1512, 1455, 1384, 1267, 1233, 1119, 1024, 1000, 819, 738, 696 cm^-1;
¹H NMR (CDCl_Three, 400MHz) δ0.90-0.95 (9H, m), 1.49-1.69 (5H, m), 3.09 (1H, dd, J = 8.1, 12.5 Hz), 3.19 (1H, dd, J = 5.1, 12.5 Hz) , 3.32-3.35 (4H, m), 3.64-3.66 (4H, m), 3.96-4.03 (1H, m), 4.24-4.30 (1H, m), 4.95 (1H, d, J = 8.1 Hz), 4.98 (2H, s), 6.32 (1H, d, J = 8.1 Hz), 6.56 (2H, d, J = 8.8 Hz), 6.83 (2H, d, J = 8.8 Hz), 7.28-7.42 (5H, m) ;
HRMS (FAB): 497.3124 [M + H]^{+ ・} (calcd 497.3132 for C₂₈H₄₁N_FourO_Four)

[Example 29] N¹-[(1S) -1-({[4- (benzyloxy) phenyl] amino} methyl) propyl] -N²-(2-oxo-6-phenyl-2H-pyran-4-yl) -L-leucinamide (Exemplified Compound No. 5-13)
  In the same manner as in the reaction described in Example 28 (28c), N- (2-oxo-6) produced in Example 3 (3b) was used instead of N- (morpholin-4-ylcarbonyl) -L-leucine. -Phenyl-2H-pyran-4-yl) -L-leucine (838 mg, 2.78 mmol) was used to give the title compound (1315 mg, yield 85%).
M.p. 142-146 ℃
IR (KBr) ν_max3269, 3088, 2959, 1650, 1549, 1512, 1298, 1232, 818, 767, 694 cm^-1;
¹H NMR (CDCl_Three, 400MHz) δ0.87 (3H, d, J = 5.9 Hz), 0.93 (3H, d, J = 5.9 Hz), 0.95 (3H, t, J = 7.5 Hz), 1.52-1.72 (5H, m), 3.12-3.21 (2H, m), 4.03-4.09 (2H, m), 4.91 (2H, s), 5.33 (1H, d, J = 1.6 Hz), 5.72 (1H, br s), 6.22 (1H, d , J = 1.6 Hz), 6.53 (2H, d, J = 9.0 Hz), 6.77 (2H, d, J = 9.0 Hz), 7.14 (1H, br s), 7.27-7.39 (8H, m), 7.66- 7.68 (2H, m);
HRMS (FAB): 554.3012 [M + H]^{+ ・} (calcd 554.3024 for C₃₄H₄₀N_ThreeO_Four)

Example 30 tert-butyl {4-[((2S) -2-{[N- (morpholin-4-ylcarbonyl) -L-leucyl] amino} butyl) amino] phenoxy} acetate (Exemplified Compound No. 5) -14)
(30a) N¹-((1S) -1-{[(4-hydroxyphenyl) amino] methyl} propyl) -N²-(Morpholin-4-ylcarbonyl) -L-leucinamide
  N produced in Example 28 (28c)¹-[(1S) -1-({[4- (benzyloxy) phenyl] amino} methyl) propyl] -N²-(Morpholin-4-ylcarbonyl) -L-leucinamide (1167 mg, 2.35 mmol) was dissolved in an ethanol (20 ml) solvent in a hydrogen atmosphere (1 atm), in the presence of a 10% palladium carbon catalyst (250 mg, 0.24 mmol). Hydrocracking at 50 ° C. for 12 hours. After removing the catalyst, the solvent was distilled off, and the obtained residue was purified by silica gel column chromatography (ethyl acetate / methanol, 20: 1) to give the title compound (797 mg, yield 83%). Obtained.
IR (KBr) ν_max3293, 2959, 1626, 1517, 1245, 1119, 1000, 822 cm^-1;
¹H NMR (CDCl_Three, 400MHz) δ0.91 (3H, d, J = 6.6 Hz), 0.92 (3H, d, J = 6.6 Hz), 0.94 (3H, t, J = 7.3 Hz), 1.46-1.71 (5H, m), 3.10 (1H, dd, J = 7.3, 12.5 Hz), 3.17 (1H, dd, J = 4.4, 12.5 Hz), 3.33-3.35 (4H, m), 3.66 (4H, t, J = 4.4 Hz), 3.94 -4.02 (1H, m), 4.23-4.29 (1H, m), 4.87 (1H, d, J = 8.1 Hz), 6.21 (1H, d, J = 8.1 Hz), 6.53 (2H, d, J = 8.8 Hz), 6.69 (2H, d, J = 8.8 Hz);
HRMS (FAB): 407.2665 [M + H]^{+ ・} (calcd 407.2648 for C_{twenty one}H₃₅N_FourO_Four)

(30b) tert-butyl {4-[((2S) -2-{[N- (morpholin-4-ylcarbonyl) -L-leucyl] amino} butyl) amino] phenoxy} acetate
  N produced in Example 30 (30a)¹-((1S) -1-{[(4-hydroxyphenyl) amino] methyl} propyl) -N²To a solution of-(morpholin-4-ylcarbonyl) -L-leucinamide (714 mg, 1.76 mmol) in tetrahydrofuran (8 mL) was added sodium hydride (55% oily) (84 mg, 1.94 mmol) under ice-cooling. Further, a solution of bromoacetic acid t-butyl ester (286 μl, 1.94 mmol) in N, N-dimethylformamide (2 mL) was added dropwise. After returning the reaction temperature to room temperature, the reaction solution was further stirred for 1 hour. Under ice cooling, water (20 mL) was added to the reaction solution, and the aqueous layer was extracted with ethyl acetate (2 × 50 mL). The extract was dried over sodium sulfate, and the residue obtained by evaporating the solvent was purified by silica gel column chromatography (ethyl acetate / methanol, 20: 1) to give the title compound (698 mg, yield 76%). Obtained.
IR (KBr) ν_max3285, 2960, 1754, 1623, 1514, 1368, 1267, 1156, 1119, 1081, 1000, 820 cm^-1;
¹H NMR (CDCl_Three, 400MHz) δ0.91 (3H, d, J = 5.9 Hz), 0.92 (3H, d, J = 5.9 Hz), 0.94 (3H, t, J = 7.4 Hz), 1.48 (9H, s), 1.49- 1.68 (5H, m), 3.08 (1H, dd, J = 7.8, 12.5 Hz), 3.17 (1H, dd, J = 5.1, 12.5 Hz), 3.32-3.35 (4H, m), 3.65 (4H, t, J = 4.7 Hz), 3.94-4.02 (1H, m), 4.20-4.26 (1H, m), 4.40 (2H, s), 4.81 (1H, d, J = 7.8 Hz), 6.17 (1H, d, J = 8.7 Hz), 6.54 (2H, d, J = 9.0 Hz), 6.75 (2H, d, J = 9.0 Hz);
HRMS (FAB): 521.3344 [M + H]^{+ ・} (calcd 521.3336 for C₂₇H₄₅N_FourO₆)

Example 31 tert-butyl {4-[((2S) -2-{[N- (2-oxo-6-phenyl-2H-pyran-4-yl) -L-leucyl] amino} butyl) amino ] Phenoxy diacetate (Exemplary Compound No. 5-18)
(31a) N¹-((1S) -1-{[(4-hydroxyphenyl) amino] methyl} propyl) -N²-(2-oxo-6-phenyl-2H-pyran-4-yl) -L-leucinamide
    In the same manner as in the reaction described in Example 30 (30a),¹-[(1S) -1-({[4- (benzyloxy) phenyl] amino} methyl) propyl] -N²Instead of-(morpholin-4-ylcarbonyl) -L-leucinamide, the N prepared in Example 29¹-[(1S) -1-({[4- (benzyloxy) phenyl] amino} methyl) propyl] -N²Using-(2-oxo-6-phenyl-2H-pyran-4-yl) -L-leucinamide (1300 mg, 2.35 mmol), the title compound (1040 mg, yield 95%) was obtained.
M.p. 171-175 ° C
IR (KBr) ν_max3280, 2960, 1656, 1549, 1516, 1242, 822, 767, 627 cm^-1;
¹H NMR (CD_ThreeOD, 400MHz) δ0.84 (3H, d, J = 5.9 Hz), 0.87 (3H, t, J = 8.1 Hz), 0.90 (3H, d, J = 6.6 Hz), 1.37-1.69 (5H, m) , 2.96-3.07 (2H, m), 3.86-3.92 (2H, m), 5.04 (1H, br s), 6.44 (2H, d, J = 8.8 Hz), 6.51 (2H, d, J = 8.8 Hz) , 6.54 (1H, d, J = 2.2 Hz), 7.39-7.40 (3H, m), 7.71-7.73 (2H, m);
HRMS (FAB): 464.2546 [M + H]^{+ ・} (calcd 464.2553 for C₂₇H₃₄N_ThreeO_Four)

(31b) tert-butyl {4-[((2S) -2-{[N- (2-oxo-6-phenyl-2H-pyran-4-yl) -L-leucyl] amino} butyl) amino] phenoxy }acetate
  In the same manner as in the reaction described in Example 30 (30b),¹-((1S) -1-{[(4-hydroxyphenyl) amino] methyl} propyl) -N²Instead of-(morpholin-4-ylcarbonyl) -L-leucinamide, N prepared in Example 31 (31a) was used.¹-((1S) -1-{[(4-hydroxyphenyl) amino] methyl} propyl) -N²The title compound (955 mg, yield 76%) was obtained using-(2-oxo-6-phenyl-2H-pyran-4-yl) -L-leucinamide (1040 mg, 2.24 mmol).
M.p. 122-126 ° C
IR (KBr) ν_max3272, 3088, 2961, 1653, 1549, 1513, 1368, 1299, 1215, 1155, 1066, 821, 767, 693 cm^-1;
¹H NMR (CDCl_Three, 400MHz) δ0.87 (3H, d, J = 5.9 Hz), 0.94 (3H, d, J = 5.9 Hz), 0.96 (3H, t, J = 7.3 Hz), 1.48 (9H, s), 1.53- 1.73 (5H, m), 3.11-3.22 (2H, m), 4.02-4.10 (2H, m), 4.38 (2H, s), 5.33 (1H, d, J = 2.2 Hz), 5.71 (1H, br s ), 6.24 (1H, d, J = 2.2 Hz), 6.53 (2H, d, J = 8.8 Hz), 6.73 (2H, d, J = 8.8 Hz), 7.14 (1H, br s), 7.38-7.43 ( 3H, m), 7.69-7.71 (2H, m);
HRMS (FAB): 600.3064 [M + Na]^{+ ・} (calcd 600.3040 for C₃₃H₄₃N_ThreeO₆Na)

Example 32 {4-[((2S) -2-{[N- (morpholin-4-ylcarbonyl) -L-leucyl] amino} butyl) amino] phenoxy} acetic acid hydrochloride (Exemplified Compound No. 5- 19)
  Tert-Butyl {4-[((2S) -2-{[N- (morpholin-4-ylcarbonyl) -L-leucyl] amino} butyl) amino] phenoxy} acetate prepared in Example 30 (30b) To a solution of 643 mg (1.23 mmol) in methylene chloride (5 mL) was added trifluoroacetic acid (5 mL) under ice-cooling, and the mixture was further stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and a 4 M hydrochloric acid dioxane solution (3 mL) was added to the residue. After evaporating the solvent under reduced pressure, the obtained residue was triturated from ether (20 mL), and filtered and washed with ether to obtain the title compound (571 mg, yield 93%).
IR (KBr) ν_max 3264, 2961, 1740, 1607, 1512, 1444, 1263, 1199, 1118, 1072, 833 cm^-1;
¹H NMR (CD_ThreeOD, 400MHz) δ0.89-0.97 (9H, m), 1.55-1.74 (5H, m), 3.30-3.64 (10H, m), 3.84-3.92 (1H, m), 4.06-4.09 (1H, m) , 4.70 (2H, s), 7.06 (2H, d, J = 8.8 Hz), 7.40 (2H, d, J = 8.8 Hz);
HRMS (FAB): 465.2700 [M + H]^{+ ・} (calcd 465.2728 for C_{twenty three}H₃₇N_FourO₆)

Example 33 N- [1-({[(1S) -1-({[4- (benzyloxy) phenyl] amino} methyl) propyl] amino} carbonyl) cyclohexyl] -1-benzofuran-2-carboxamide (Exemplified Compound No. 5-21)
(33a) tert-butyl 1-{[(9H-fluoren-9-ylmethoxy) carbonyl] amino} cyclohexanecarboxylate
  N, N'-diisopropylcarbodiimide (36 g, 285 mmol), tert-butyl alcohol (23.3 g, 314 mmol), and copper (I) chloride (303 mg, 3.0 mmol) are stirred at room temperature for 5 days. The solution was diluted with 100 ml of methylene chloride, 1-{[(9H-fluoren-9-ylmethoxy) carbonyl] amino} cyclohexanecarboxylic acid (15.3 g, 42 mmol) was added, and the mixture was stirred at the same temperature for 45 minutes. The resulting precipitate (N, N'-diisopropylurea) was removed, and the filtrate was concentrated. The residue was purified by column chromatography to give the title compound (15.6 g, 88%) as a colorless solid.
¹H NMR (CDCl_Three, 400 MHz) δ1.30-1.50 (4H, m), 1.42 (9H, s), 1.57-1.68 (2H, m), 1.75-2.06 (4H, m), 4.23-4.27 (1H, br), 4.34 -4.45 (2H, br), 4.84-4.92 (1H, br), 7.32 (2H, t, J = 7.3Hz), 7.40 (2H, t, J = 7.3Hz), 7.62 (2H, d, J = 7.3 Hz), 7.77 (2H, d, J = 7.3Hz).
 
(33b) tert-butyl 1-aminocyclohexanecarboxylate
  The tert-butyl ester (15.6 g, 37 mmol) produced in Example 33 (33a) was dissolved in tetrahydrofuran (100 ml), pyrrolidine (3.7 ml, 44.4 mmol) was added, and the mixture was stirred at room temperature for 14 hours. The reaction solution was concentrated, and the residue was purified by column chromatography to obtain the title compound (7.37 g, 99%) as an oil.
¹H NMR (CDCl_Three, 400 MHz) δ 1.38 (9H, s), 1.42-1.46 (4H, m), 1.52-1.58 (2H, m), 1.74-1.82 (4H, m).

(33c) tert-butyl 1-[(1-benzofuran-2-ylcarbonyl) amino] cyclohexanecarboxylate
  Tert-Butyl 1-aminocyclohexanecarboxylate (7.37 g, 37 mmol), benzofuran-2-carboxylic acid (7.13 g, 44 mmol) prepared in Example 33 (33b), 1-ethyl-3- (3-dimethyl (Aminopropyl) -carbodiimide hydrochloride (8.4 g, 44 mmol) and 1-hydroxybenzotriazole monohydrate (6.74 g, 44 mmol) were dissolved in N, N-dimethylformamide (200 ml), and the mixture was dissolved at room temperature. And stirred for 14 hours. The reaction solution was poured into water and extracted with ether. The ether layer was washed with water and saturated saline, dried over magnesium sulfate, and concentrated. The residue was purified by column chromatography to give the title compound (12.7 g, 99%) as an oil.
¹H NMR (CDCl_Three, 400 MHz) δ1.34-1.60 (4H, m), 1.45 (9H, s), 1.63-1.77 (2H, m), 1.87-1.97 (2H, m), 2.15-2.22 (2H, m), 5.68 (1H, s), 7.29 (1H, t, J = 8.0Hz), 7.42 (1H, t, J = 8.0Hz), 7.45 (1H, s), 7.53 (1H, d, J = 8.0Hz), 7.67 (1H, d, J = 7.3Hz).

(33d) 1-[(1-benzofuran-2-ylcarbonyl) amino] cyclohexanecarboxylic acid
  The tert-butyl 1-[(1-benzofuran-2-ylcarbonyl) amino] cyclohexanecarboxylate (12.7 g, 37 mmol) prepared in Example 33 (33c) was dissolved in methylene chloride (150 ml) and cooled on ice. Then, trifluoroacetic acid (14 ml) was added dropwise, and the mixture was further stirred at room temperature for 24 hours. After concentration of the reaction solution, the title compound (10.4 g, 98%) was obtained as a colorless solid.
M.p. 220-224 ℃
IR (KBr) ν_max2937, 1740, 1596, 1518, 746 cm^-1;
¹H NMR (CDCl_Three, 400MHz) δ1.35-2.07 (6H, m), 1.99-2.07 (2H, m), 2.24-2.31 (2H, m), 6.77 (1H, brs), 7.32 (1H, dd, J = 7.0, 7.5 Hz), 7.45 (1H, dd, J = 7.0, 8.2 Hz), 7.53 (1H, s), 7.54 (1H, d, J = 8.2 Hz), 7.69 (1H, dd, J = 7.5 Hz);
MS (EI⁺) m / z: 287 [M⁺], 243, 161, 145;
Anal. Calcd for C₁₆H₁₇NO_Four·0.1 H_TwoO: C, 66.47; H, 6.00; N, 4.84. Found: C, 66.30; H, 5.99; N, 4.80.

(33e) N- [1-({[(1S) -1-({[4- (benzyloxy) phenyl] amino} methyl) propyl] amino} carbonyl) cyclohexyl] -1-benzofuran-2-carboxamide
  According to the method described in Example 28 (28c), instead of N- (morpholin-4-ylcarbonyl) -L-leucine, 1-[(1-benzofuran-2-yl) produced in Example 33 (33d). The title compound (1398 mg, yield 85%) was obtained using carbonyl) amino] cyclohexanecarboxylic acid (868 mg, 3.05 mmol).
M.p. 112-114 ° C
IR (KBr) ν_max3345, 2932, 1659, 1592, 1512, 1448, 1296, 1228, 1177, 1025, 820, 749, 6966 cm^-1;
¹H NMR (CDCl_Three, 400MHz) δ0.95 (3H, t, J = 7.4 Hz), 1.35-1.74 (8H, m), 2.01 (2H, dq, J = 3.9, 13.3 Hz), 2.24 (2H, dt, J = 2.7, 13.7 Hz), 3.03 (1H, dd, J = 7.8, 12.5 Hz), 3.23 (1H, dd, J = 4.3, 12.5 Hz), 4.00-4.10 (1H, m), 4.90 (2H, s), 6.55 ( 2H, d, J = 8.6 Hz), 6.61 (1H, s), 6.72-6.77 (3H, m), 7.26-7.43 (8H, m), 7.50 (1H, d, J = 7.8 Hz), 7,64 (1H, d, J = 7.4 Hz);
HRMS (FAB): 540.2854 [M + H]^{+ ・} (calcd 540.2869 for C₃₃H₃₈N_ThreeO_Four)

Example 34 tert-butyl [4-({(2S) -2-[({1-[(1-benzofuran-2-ylcarbonyl) amino] cyclohexyl} carbonyl) amino] butyl} amino) phenoxyacetate ( Exemplified compound number 5-22)
(34a) N- (1-{[((1S) -1-{[(4-hydroxyphenyl) amino] methyl} propyl) amino] carbonyl} cyclohexyl) -1-benzofuran-2-carboxamide
  N- [1-({[(1S) -1-({[4- (benzyloxy) phenyl] amino} methyl) propyl] amino} carbonyl) cyclohexyl] -1-benzofuran prepared in Example 33 (33e) 2-Carboxamide (1398 mg, 2.59 mmol) was dissolved in acetic acid (30 ml), concentrated hydrochloric acid (15 ml) was added, and the mixture was heated under reflux for 10 minutes. Ethyl acetate (50 ml) and water (50 ml) were added to the reaction solution. After liquid separation, the organic phase was washed with water (20 mL × 5) and saturated saline (50 ml), dried over sodium sulfate, and the solvent was removed under reduced pressure. Distilled off. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate, 1: 1) to give the title compound (789 mg, yield 68%).
M.p. 185-188 oC
IR (KBr) ν_max3315, 2934, 1657, 1593, 1515, 1296, 1244, 1178, 823, 749 cm^-1;
¹H NMR (CD_ThreeOD, 400MHz) δ0.93 (3H, d, J = 7.4 Hz), 1.41-1.75 (8H, m), 1.93 (2H, dq, J = 3.9, 11.7 Hz), 2.21 (2H, t, J = 14.5 Hz), 2.93 (1H, dd, J = 8.6, 12.5 Hz), 3.16 (1H, dd, J = 4.3, 12.5 Hz), 3.97-4.02 (1H, m), 6.60 (2H, d, J = 9.0 Hz) ), 6.64 (2H, d, J = 9.0 Hz), 7.32 (1H, t, J = 8.2 Hz), 7.47 (1H, d, J = 8.2 Hz), 7.51 (1H, s), 7.62 (1H, d , J = 8.2 Hz), 7.71 (1H, d, J = 8.2 Hz);
HRMS (FAB): 450.2385 [M + H]^{+ ・} (calcd 450.2402 for C₂₆H₃₂N_ThreeO_Four)

(34b) tert-butyl [4-({(2S) -2-[({1-[(1-benzofuran-2-ylcarbonyl) amino] cyclohexyl} carbonyl) amino] butyl} amino) phenoxyacetate
  According to the method described in Example 30 (30b), N¹-((1S) -1-{[(4-hydroxyphenyl) amino] methyl} propyl) -N²Instead of-(morpholin-4-ylcarbonyl) -L-leucinamide, N- (1-{[((1S) -1-} [(4-hydroxyphenyl) amino] produced in Example 34 (34a)). Methyl {propyl) amino] carbonyl {cyclohexyl) -1-benzofuran-2-carboxamide (690 mg, 1.53 mmol) was used to obtain the title compound (614 mg, yield 71%).
M.p. 145-148 oC
IR (KBr) ν_max3358, 2933, 1660, 1593, 1513, 1447, 1368, 1297, 1257, 1215, 1154, 1082, 822, 750 cm^-1;
¹H NMR (CDCl_Three, 400MHz) δ0.95 (3H, d, J = 7.0 Hz), 1.34-1.75 (17H, m), 1.95-2.07 (2H, m), 2.20-2.29 (2H, m), 3.02 (1H, dd, J = 8.2, 12.5 Hz), 3.23 (1H, dd, J = 4.3, 12.5 Hz), 4.00-4.09 (1H, m), 4.33 (2H, s), 6.53 (2H, d, J = 8.6 Hz), 6.61 (1H, s), 6.68 (2H, d, J = 8.6 Hz), 6.77 (1H, d, J = 8.2 Hz), 7.29 (1H, t, J = 7.2 Hz), 7.41 (1H, s), 7.42 (1H, t, J = 8.2 Hz), 7.51 (1H, d, J = 8.2 Hz), 7.66 (1H, d, J = 8.2 Hz);
HRMS (FAB): 564.3064 [M + H]^{+ ・} (calcd 564.3081 for C₃₂H₄₂N_ThreeO₆)

Example 35 [4-({(2S) -2-[({1-[(1-benzofuran-2-ylcarbonyl) amino] cyclohexyl} carbonyl) amino] butyl} amino) phenoxyacetic acid hydrochloride (exemplary) Compound No. 5-15)
  Following the procedure described in Example 32, tert-butyl {4-[((2S) -2-{[N- (morpholin-4-ylcarbonyl) -L-leucyl] amino} butyl) amino] phenoxy} acetate Alternatively, tert-butyl [4-({(2S) -2-[({1-[(1-benzofuran-2-ylcarbonyl) amino] cyclohexyl} carbonyl) amino] produced in Example 34 (34b). The title compound (515 mg, yield 88%) was obtained using (butyl @ amino) phenoxyacetate (604 mg, 1.07 mmol).
IR (KBr) ν_max 3273, 2935, 1640, 1953, 1511, 1447, 1182, 835, 751 cm^-1;
¹H NMR (CD_ThreeOD, 400MHz) δ0.99 (3H, t, J = 7.4 Hz), 1.50-1.84 (8H, m), 2.00-2.24 (4H, m), 3.25 (1H, t, J = 12.5 Hz), 3.60 ( 1H, dd, J = 2.7, 12.5 Hz), 4.21-4.26 (1H, m), 4.77 (2H, s), 7.14 (2H, d, J = 9.0 Hz), 7.35 (1H, t, J = 8.1 Hz) ), 7.50 (1H, t, J = 8.1 Hz), 7.54 (1H, s), 7.58 (2H, d, J = 9.0 Hz), 7.65 (1H, d, J = 8.1 Hz), 7,75 (1H , d, J = 8.1 Hz), 8.00 (1H, d, J = 9.0 Hz), 8.41 (1H, s);
HRMS (FAB): 508.2460 [M + H]^{+ ・} (calcd 508.2436 for C₂₈H₃₄N_ThreeO₆)

Example 36 {4-[((2S) -2-{[N- (2-oxo-6-phenyl-2H-pyran-4-yl) -L-leucyl] amino} butyl) amino] phenoxy} Acetic acid (Exemplified Compound No. 5-16)
  Tert-Butyl {4-[((2S) -2-} [N- (2-oxo-6-phenyl-2H-pyran-4-yl) -L-leucyl] amino prepared in Example 31 (31b) Trifluoroacetic acid (5 mL) was added to a solution of [{butyl) amino] phenoxy} acetate (943 mg, 1.63 mmol) in methylene chloride (5 mL) under ice-cooling, and the mixture was further stirred at room temperature for 2 hours. The residue obtained by evaporating the solvent under reduced pressure was purified by high-performance liquid chromatography (40% acetonitrile, 0.06% triethylamine, acetic acid) to obtain the title compound (395 mg, yield 46%).
IR (KBr) ν_max 3262, 3065, 2960, 1664, 1548, 1511, 1201, 1068, 830, 769, 692 cm^-1;
¹H NMR (CD_ThreeOD, 400MHz) δ0.97 (3H, d, J = 6.7 Hz), 1.00 (3H, t, J = 6.3 Hz), 1.02 (3H, d, J = 6.7 Hz), 1.59-1.84 (5H, m) , 3.40 (2H, brs), 4.00-4.09 (2H, m), 4.65 (2H, s), 5.14 (1H, s), 6.66 (1H, s), 6.99 (2H, d, J = 8.6 Hz), 7.18 (2H, br s), 7.45-7.49 (3H, m), 7.78-7.80 (2H, m);
HRMS (FAB): 522.2594 [M + H]^{+ ・} (calcd 522.2613 for C₂₉H₃₆N_ThreeO₆)

Example 37 Benzyl (2E) -3- (4-{[(2S) -2-({[1- (1,1′-biphenyl-3-ylamino) cyclohexyl] carbonyl} amino} butyl] amino} Phenoxy) acrylate (Exemplary Compound No. 5-17)
  1- (1,1′-biphenyl-3-ylamino) -N-((1S) -1-{[(4-hydroxyphenyl) amino] methyl} propyl) cyclohexanecarboxamide (prepared in Example 20 (20a)) 90 mg, 0.20 mmol) was dissolved in tetrahydrofuran (3 ml), N-methylmorpholine (55 μl, 0.50 mmol) and benzyl propiolate (80 mg, 0.50 mmol) were added under a nitrogen atmosphere, and the mixture was stirred at room temperature for 30 hours. The residue obtained by evaporating the solvent under reduced pressure was purified by thin-layer chromatography (hexane / ethyl acetate, 3: 1) to obtain the title compound (82 mg, yield 66%).
IR (KBr) ν_max3374, 2935, 1705, 1645, 1509, 1320, 1287, 1208, 1116, 828, 757, 699 cm^-1;
¹H NMR (CDCl_Three, 400MHz): δ0.89 (3H, d, J = 7.4 Hz), 1.24-1.66 (8H, m), 1.93-2.04 (4H, m), 2.99-3.04 (1H, m), 3.13-3.16 (1H , m), 4.03-4.09 (1H, m), 5.17 (2H, s), 5.44 (1H, d, J = 12.1 Hz), 6.41 (2H, d, J = 9.0 Hz), 6.58 (1H, d, J = 7.1 Hz), 6.81 (2H, d, J = 9.0 Hz), 6.85 (1H, s), 7.03 (2H, t, J = 7.8 Hz), 7.10 (1H, t, J = 7.1 Hz), 7.80 -7.86 (8H, m), 7.51 (2H, d, J = 7.1 Hz), 7.76 (1H, d, J = 12.1);
HRMS (FAB): 618.3337 [M + H]^{+ ・} (calcd 618.3329 for C₃₉H₄₄N_ThreeO_Four)

Example 38 Methyl (2E) -3- (4-{[(2S) -2-({[1- (1,1'-biphenyl-3-ylamino) cyclohexyl] carbonyl} amino) butyl] amino} Phenoxy) acrylate (Exemplary Compound No. 5-25)
  1- (1,1′-biphenyl-3-ylamino) -N-((1S) -1-{[(4-hydroxyphenyl) amino] methyl} propyl) cyclohexanecarboxamide (prepared in Example 20 (20a)) 81 mg, 0.18 mmol) was dissolved in tetrahydrofuran (3 ml), N-methylmorpholine (40 μl, 0.36 mmol) and methyl propiolate (32 μl, 0.36 mmol) were added under a nitrogen atmosphere, and the mixture was stirred at room temperature for 30 hours. The residue obtained by evaporating the solvent under reduced pressure was purified by thin-layer chromatography (hexane / ethyl acetate, 2: 1) to obtain the title compound (63 mg, yield 64%).
IR (KBr) ν_max3371, 2933, 1709, 1646, 1509, 1210, 1123, 828, 758, 701 cm^-1;
¹H NMR (CDCl_Three, 400MHz): δ0.89 (3H, d, J = 7.4 Hz), 1.30-1.67 (8H, m), 1.92-2.04 (4H, m), 3.01 (1H, dd, J = 8.2, 12.1 Hz), 3.14 (1H, dd, J = 4.3, 12.1 Hz), 3.70 (3H, s), 4.02-4.08 (1H, m), 5.40 (1H, d, J = 12.1 Hz), 6.40 (2H, d, J = 9.0 Hz), 6.56 (1H, d, J = 9.0 Hz), 6.80 (2H, d, J = 8.6 Hz), 6.82 (1H, d, J = 5.9 Hz), 7.01 (2H, t, J = 5.9 Hz) ), 7.08 (1H, t, J = 7.8 Hz), 7.28-7.35 (8H, m), 7.49 (2H, d, J = 8.6 Hz), 7.71 (1H, d, J = 12.1);
HRMS (FAB): 542.3016 [M + H]^{+ ・} (calcd 542.3019 for C₃₃H₄₀N_ThreeO_Four)

Example 39 3- (4-{[(2S) -2-({[1- (1,1′-biphenyl-3-ylamino) cyclohexyl] carbonyl} amino) butyl] amino} phenoxy) propanoic acid ( Exemplified compound number 5-27)
  Benzyl (2E) -3- (4-{[(2S) -2-({[1- (1,1'-biphenyl-3-ylamino) cyclohexyl] carbonyl} amino) butyl] amino prepared in Example 37 Hydrogenolysis of @phenoxy) acrylate (68 mg, 0.11 mmol) in a hydrogen atmosphere (1 atm) in the presence of a 10% palladium on carbon catalyst (12 mg, 0.011 mmol) in an ethanol (5 ml) solvent at room temperature for 20 hours did. After removing the catalyst, the solvent was distilled off, and the obtained residue was purified by thin-layer chromatography (hexane / ethyl acetate, 1: 1) to give the title compound (22 mg, yield 37%). Obtained.
IR (KBr) ν_max3369, 2933, 1650, 1602, 1513, 1229, 758, 701 cm^-1;
¹H NMR (CDCl_Three, 400MHz) δ0.98 (3H, d, J = 7.4 Hz), 1.32-1.65 (8H, m), 1.95-2.04 (4H, m), 2.78 (2H, t, J = 6.3 Hz), 3.01 (1H , dd, J = 10.1, 12.5 Hz), 3.13 (1H, dd, J = 4.3, 12.5 Hz), 4.02-4.09 (1H, m), 4.16 (2H, t, J = 6.3 Hz), 6.42 (2H, d, J = 8.6 Hz), 6.59 (1H, d, J = 8.2 Hz), 6.72 (2H, d, J = 8.6 Hz), 6.85 (1H, s), 7.02 (1H, d, J = 7.8 Hz) , 7.07 (1H, d, J = 7.8 Hz), 7.12 (1H, t, J = 7.8 Hz), 7.31 (1H, d, J = 7.0 Hz), 7.37 (2H, t, J = 7.0 Hz), 7.52 (2H, d, J = 7.0 Hz);
HRMS (FAB): 530.3009 [M + H]^{+ ・} (calcd 530.3027 for C₃₂H₄₀N_ThreeO_Four)

[Example 40] N¹-((1S) -1-{[(4-methoxyphenyl) amino] methyl} propyl) -N²-(5-Phenylisoxazol-3-yl) -L-leucinamide (Exemplary Compound No. 5-3)
(40a) N-[(1Z) -1- (methylthio) -3-oxo-3-phenylprop-1-enyl] -L-leucine
  (L) -Leucine (4.84 g, 36.8 mmol) and sodium hydroxide (1.50 g, 37.3 mmol) were suspended in 90% ethanol (150 mL) and heated under reflux for 1 hour. Further, 3,3-bis (methylthio) -1-phenylprop-2-en-1-one (Bull. Chem. Soc. Jpn., Vol. 64, 1991, 3727-3728) (4.18 g, 18.6 mmol) was added. In addition, the mixture was heated under reflux for 24 hours. After evaporating the solvent, ethyl acetate (100 mL) and water (100 mL) were added to the residue, and the separated aqueous layer was acidified with 1N hydrochloric acid (30 mL). Extracted with ethyl acetate (100 mL) and dried over sodium sulfate. The solvent was distilled off to obtain the title compound as crystals (4.01 g, yield 70%).
IR (KBr) ν_max 2959, 1721, 1561, 1472, 1280, 756 cm^-1;
¹H NMR (CDCl_Three, 400 MHz) δ 0.90 (3H, d, J = 6.2 Hz), 0.91 (3H, d, J = 6.2 Hz), 1.77 (2H, dd, J = 6.1, 12.6 Hz), 1.78-1.85 (1H, m ), 2.39 (3H, s), 4.33 (1H, br s), 5.60 (1H, s), 7.28-7.41 (3H, m), 7.75-7.80 (2H, m);
MS (FAB) m / z: 308.13 [M + H]⁺;

(40b) N- (5-phenylisoxazol-3-yl) -L-leucine
  (N-[(1Z) -1- (methylthio) -3-oxo-3-phenylprop-1-enyl] -L-leucine (1.86 g, 6.07 mmol) prepared in Example 40 (40a) and Sodium hydroxide (1.50 g, 37.3 mmol) was suspended in ethanol (50 mL), and hydroxylamine hydrochloride (1.69 g, 24.4 mmol) and potassium hydroxide (1.37 g, 24.4 mmol) were added to water. , And the mixture was added to the reaction solution and heated under reflux for 4.5 hours.The solvent was distilled off, and ethyl acetate (100 mL) and water (100 mL) were added to the residue, and the separated organic layer was dried over sodium sulfate. The solvent was distilled off to obtain the title compound as crystals (1.27 g, yield 76%).
IR (KBr) ν_max 3362, 2958, 1723, 1625, 1579, 1561, 1450, 1209, 762, 688 cm^-1;
¹H NMR (CDCl_Three, 400 MHz) δ 0.98 (6H, t, J = 6.4 Hz), 1.63-1.94 (3H, m), 4.26 (1H, dd, J = 5.1, 8.8 Hz), 4.53 (1H, br s), 6.06 ( 1H, s), 7.39-7.44 (3H, m), 7.67-7.71 (2H, m);
MS (FAB) m / z: 275.13 [M + H]⁺;

(40c) N¹-((1S) -1-{[(4-methoxyphenyl) amino] methyl} propyl) -N²-(5-Phenylisoxazol-3-yl) -L-leucinamide
  Tert-Butyl (1S) -1-{[(4-methoxyphenyl) amino] methyl} propylcarbamate (2.14 g, 7.28 mmol) produced in Example 2 (2a) was added to 1,4-dioxane (60 mL). And 4N hydrochloric acid-dioxane (40 mL) was added, followed by stirring for 12 hours. After the solvent was distilled off, the residue was dried under vacuum to obtain a white crude product. To the obtained crude product, N- (5-phenylisoxazol-3-yl) -L-leucine (2.21 g, 8.06 mmol) produced in Example 40 (40b), 1-ethyl -3- (3-Dimethylaminopropyl) -carbodiimide hydrochloride (1.53 g, 8.03 mmol), 1-hydroxybenzotriazole monohydrate (1.08 g, 8.03 mmol), methylene chloride (200 mL) ) Was added, and triethylamine (2.24 mL, 16.06 mmol) was added dropwise, followed by stirring for 20 hours. The organic layer was washed with saturated saline (2 × 80 mL), dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (methylene chloride / methanol, 99: 1) to give the title compound (2.20 g, yield 67%).
Mp 165-167 ° C;
IR (KBr) ν_max 3278, 3065, 1649, 1556, 1512, 1235, 1039, 820, 761, 690 cm^-1;
¹H NMR (CDCl_Three, 400 MHz) δ 0.92 (3H, d, J = 7.4 Hz), 0.97 (3H, d, J = 7.4 Hz), 1.43-1.55 (1H, m), 1.58-1.71 (2H, m), 1.74-1.86 (2H, m), 3.01 (1H, dd, J = 8.3, 12.3 Hz), 3.19 (1H, dd, J = 4.3, 12.3 Hz), 3.70 (3H, s), 3.95-4.01 (1H, m), 4.03-4.12 (1H, m), 4.51 (1H, d, J = 6.3 Hz), 6.06 (1H, s), 6.49-6.55 (3H, m), 6.66-6.72 (2H, m), 7.34-7.41 ( 3H, m), 7.55-7.60 (2H, m);
MS (FAB) m / z: 451.27 [M + H]⁺;

[Example 41] N¹-[(1S) -1-({[4- (benzyloxy) phenyl] amino} methyl) propyl] -N²-(5-Phenylisoxazol-3-yl) -L-leucinamide (Exemplary Compound No. 5-23)
  Tert-Butyl (1S) -1-({[4- (benzyloxy) phenyl] amino} methyl) propylcarbamate (904 mg, 2.43 mmol) prepared in Example 19 (19b) was added to 4N hydrochloric acid-dioxane (14 mL). Was added and stirred for 12 hours. After evaporating the solvent, ethyl acetate (40 mL) and saturated aqueous sodium hydrogen carbonate (30 mL) were added to the residue, and the separated aqueous layer was extracted with ethyl acetate (40 mL). The combined organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was dissolved in N, N-dimethylformamide (20 mL) and N- (5-phenylisoxazol-3-yl) -L-leucine (prepared in Example 40 (40b)) was used. 666 mg, 2.42 mmol), 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (542 mg, 2.83 mmol), 1-hydroxybenzotriazol monohydrate (367 mg, 2.71 mmol) ) And stirred for 20 hours. The organic layer was washed with saturated saline (2 × 80 mL), dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane, 1: 1) to obtain the title compound (1.04 g, 1.97 mmol, yield 81%).
Mp 184-186 ° C;
IR (KBr) ν_max 3279, 2960, 1645, 1511, 1231, 1025, 816, 762, 692 cm^-1;
¹H NMR (CDCl_Three, 400 MHz) δ 0.93 (3H, t, J = 7.4 Hz), 0.95 (3H, d, J = 6.1 Hz), 0.98 (3H, d, J = 6.1 Hz), 1.42-1.70 (3H, m), 1.74-1.83 (2H, m), 3.00 (1H, dd, J = 8.5, 12.2 Hz), 3.19 (1H, dd, J = 4.2, 12.2 Hz), 3.54 (1H, br s), 3.80 (1H, br) s), 3.92-3.99 (1H, m), 4.01-4.12 (1H, m), 4.31 (1H, d, J = 5.8 Hz), 4.92 (2H, s), 6.04 (1H, s), 6.41 (1H , d, J = 9.1 Hz), 6.50 (2H, d, J = 8.9 Hz), 6.75 (2H, d, J = 8.9 Hz), 7.25-7.41 (8H, m), 7.53-7.58 (2H, m) ;
MS (FAB) m / z: 527.30 [M + H]⁺;

Example 42 tert-butyl {4-[((2S) -2-{[N- (5-phenylisoxazol-3-yl) -L-leucyl] amino} butyl) amino] phenoxy} Acetate (Exemplified Compound No. 5-24)
(42a) N¹-((1S) -1-{[(4-hydroxyphenyl) amino] methyl} propyl) -N²-(5-Phenylisoxazol-3-yl) -L-leucinamide
  N produced in Example 41¹-[(1S) -1-({[4- (benzyloxy) phenyl] amino} methyl) propyl] -N²-(5-Phenylisoxazol-3-yl) -L-leucinamide (1.13 mg, 2.15 mmol) was dissolved in acetic acid (5 mL), concentrated hydrochloric acid (2.5 mL) was added, and the solution was added for 15 hours. Heated to reflux for a minute. After cooling to room temperature, ethyl acetate (70 mL) and saturated aqueous sodium hydrogen carbonate (70 mL) were added to the solution, and the separated organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane, 1: 1) to give the title compound (522 mg, 1.20 mmol, yield 56%).
Mp 197-198 ° C;
IR (KBr) ν_max 3297, 2961, 1649, 1626, 1515, 1240, 819, 761, 690 cm^-1;
¹H NMR (CDCl_Three, 400 MHz) δ 0.89 (3H, t, J = 7.4 Hz), 0.91 (3H, d, J = 6.0 Hz), 0.95 (3H, d, J = 6.0 Hz), 1.40-1.51 (1H, m), 1.56-1.66 (2H, m), 1.70-1.82 (2H, m), 2.98 (1H, dd, J = 8.2, 12.5 Hz), 3.14 (1H, dd, J = 4.3, 12.5 Hz), 3.93-4.07 ( 2H, m), 4.56 (1H, d, J = 6.3 Hz), 6.02 (1H, s), 6.42 (2H, d, J = 8.6 Hz), 6.57 (1H, d, J = 8.2 Hz), 6.60 ( 2H, d, J = 8.6 Hz), 7.32-7.37 (3H, m), 7.52-7.57 (2H, m);
MS (FAB) m / z: 436.26 [M⁺];

(42b) N produced in Example 42 (42a)¹-((1S) -1-{[(4-hydroxyphenyl) amino] methyl} propyl) -N²To a solution of-(5-phenylisoxazol-3-yl) -L-leucinamide (522 mg, 1.20 mmol) in tetrahydrofuran (15 mL) was added sodium hydride (55% oily) (63 mg, 1.44 mmol), and a solution of bromoacetic acid t-butyl ester (0.21 mL, 1.44 mmol) in N, N-dimethylformamide (2 mL) was added dropwise. After returning the reaction temperature to room temperature, the reaction solution was further stirred for 2 hours. Under ice cooling, water (50 mL) was added to the reaction solution, and the aqueous layer was extracted with ethyl acetate (2 × 70 mL). The organic layer was dried over sodium sulfate and the residue obtained by evaporating the solvent was purified by silica gel column chromatography (hexane / ethyl acetate, 3: 1) to give the title compound (370 mg, 0.67 mmol, yield). 56%).
IR (KBr) ν_max 3275, 2961, 1753, 1648, 1557, 1511, 1214, 1155, 820, 763, 690 cm^-1;
¹H NMR (CDCl_Three, 400 MHz) δ 0.90 (3H, t, J = 7.4 Hz), 0.93 (3H, d, J = 6.3 Hz), 0.96 (3H, d, J = 6.3 Hz), 1.47 (9H, s), 1.56- 1.70 (2H, m), 1.74-1.84 (2H, m), 2.99 (1H, dd, J = 8.2, 12.1 Hz), 3.16 (1H, dd, J = 4.3, 12.1 Hz), 3.86 (1H, br s ), 3.97-4.07 (2H, m), 4.35 (2H, s), 4.91 (1H, br s), 6.06 (1H, s), 6.47 (2H, d, J = 8.6 Hz), 6.67 (2H, d , J = 8.6 Hz), 7.32-7.38 (3H, m), 7.53-7.58 (2H, m);
MS (FAB) m / z: 551.32 [M + H]⁺;

Example 43 {4-[((2S) -2-{[N- (5-phenylisoxazol-3-yl) -L-leucyl] amino} butyl) amino] phenoxy} acetic acid dihydrochloride Salt (Exemplary Compound No. 5-26)
  Tert-Butyl {4-[((2S) -2-{[N- (5-phenylisoxazol-3-yl) -L-leucyl] amino} butyl) prepared in Example 42 (42b) To a solution of [amino] phenoxy diacetate (166 mg, 0.30 mmol) in methylene chloride (3 mL) was added trifluoroacetic acid (3 mL) under ice-cooling, and the mixture was further stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and a 4N hydrochloric acid-dioxane solution (4 mL) was added to the residue. After evaporating the solvent under reduced pressure, the obtained residue was triturated from ether (20 mL), and filtered and washed with ether to obtain the title compound (147 mg, 0.26 mmol, yield 86%).
IR (KBr) ν_max 3265, 2961, 1740, 1625, 1546, 1511, 1198, 1075, 832, 763, 690 cm^-1;
¹H NMR (CD_ThreeOD, 400 MHz) δ 0.96 (3H, t, J = 6.7 Hz), 1.00 (3H, d, J = 6.3 Hz), 1.05 (3H, d, J = 6.3 Hz), 1.58-1.68 (2H, m) , 1.69-1.76 (2H, m), 1.84-1.94 (1H, m), 3.31 (1H, d, J = 6.3 Hz), 3.48 (1H, d, J = 6.3 Hz), 4.00 (1H, br s) , 4.65 (2H, s), 6.38 (1H, s), 7.00 (2H, d, J = 8.6 Hz), 7.33 (2H, d, J = 8.6 Hz), 7.41-7.49 (3H, m), 7.59- 7.67 (2H, m));
MS (FAB) m / z: 495.26 [M + H]⁺;

Example 44 N- (1-{[((1S) -1-{[(4-methoxyphenyl) amino] methyl} propyl) amino] carbonyl} cyclohexyl) -1-benzofuran-2-carboxamide (exemplified compound No. 4-10)
  To 4% hydrochloric acid-dioxane (1 mL) was added to tert-butyl (1S) -1-{[(4-methoxyphenyl) amino] methyl} propylcarbamate (147 mg, 0.5 mmol) produced in Example 2 (2a), and Stirred for hours. After evaporating the solvent, the obtained crude product was dissolved in N, N-dimethylformamide (2 mL) and 1-[(1-benzofuran-2-ylcarbonyl) amino] produced in Example 33 (33d). Cyclohexanecarboxylic acid (158 mg, 0.55 mmol), 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (105 mg, 0.55 mmol), 1-hydroxybenzotriazole monohydrate (84 mg) , 0.55 mmol) and triethylamine (0.21 mL, 1.5 mmol) and stirred for 3 hours. The reaction solution was partitioned between ethyl acetate (50 mL) and water (50 mL), and the organic layer was washed with saturated aqueous sodium hydrogen carbonate (30 mL), dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude crystals were recrystallized from a mixed solvent of hexane / ethyl acetate (1: 1) (4 mL) to give the title compound (159 mg, yield 69%).
Mp 131-134 ° C;
IR (KBr) ν_max3328, 1657, 1514, 1235, 821, 750 cm^-1;
¹H NMR (CDCl_Three, 400MHz) δ 0.95 (3H, t, J = 7.4 Hz), 1.35-2.29 (12H, m), 3.02 (1H, dd, J = 7.9, 12.5 Hz), 3.23 (1H, dd, J = 4.4, 12.5 Hz), 3.66 (3H, s), 3.95 (1H, br), 4.02-4.08 (1H, m), 6.55 (2H, d, J = 8.9 Hz), 6.61 (1H, brs), 6.67 (2H, d , J = 8.9 Hz), 6.76 (1H, brd, J = 8.6 Hz), 7.29 (1H, dd, J = 7.2, 7.7 Hz), 7.41 (1H, brs), 7.42 (1H, dd, J = 7.2, 8.2 Hz), 7.50 (1H, d, J = 8.2 Hz), 7.65 (1H, d, J = 7.7 Hz);
MS (FAB) m / z: 464 [M + H]⁺, 238.
Anal. Calcd for C₃₅H₄₅N_ThreeO_Four·0.6 H_TwoO: C, 68.36; H, 7.27; N, 8.86. Found: C, 68.39; H, 6.99; N, 8.76.

[Example 45] N²-(1-benzofuran-2-carbonyl) -N¹-((1S) -1-{[(4-methoxyphenyl) amino] methyl} propyl) -L-leucinamide (Exemplary Compound No. 3-10)
(45a) N²-(Tert-butoxycarbonyl) -N¹-((1S) -1-{[(4-methoxyphenyl) amino] methyl} propyl) -L-leucinamide
  To tert-butyl (1S) -1-{[(4-methoxyphenyl) amino] methyl} propylcarbamate (589 mg, 2.0 mmol) produced in Example 2 (2a) was added 4N hydrochloric acid-dioxane (4 mL), and Stirred for hours. After evaporating the solvent, the obtained crude product was dissolved in N, N-dimethylformamide (5 mL), and N- (tert-butoxycarbonyl) -L-leucine monohydrate (548 mg, 2.2 mmol) was added. 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (422 mg, 2.2 mmol), 1-hydroxybenzotriazole monohydrate (337 mg, 2.2 mmol), triethylamine (0.84 mL) , 6.0 mmol) and stirred for 15 hours. The reaction solution was partitioned between ethyl acetate (100 mL) and water (100 mL), and the organic layer was washed with saturated aqueous sodium hydrogen carbonate (50 mL), dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate, 2: 1) to give the title compound (330 mg, yield 40%).
Mp 142-144 ° C;
IR (KBr) ν_max3354, 1682, 1651, 1517, 1237, 1174, 819 cm^-1;
¹H NMR (CDCl_Three, 400MHz) δ 0.91 (3H, d, J = 6.2 Hz), 0.92 (3H, d, J = 6.2 Hz), 0.95 (3H, t, J = 7.4 Hz), 1.42 (9H, s), 1.44-1.69 (5H, m), 3.06 (1H, dd, J = 7.5, 12.7 Hz), 3.18 (1H, dd, J = 4.6, 12.7 Hz), 3.71 (1H, br), 3.74 (3H, s), 3.98- 4.06 (1H, m), 4.81 (1H, br), 6.05 (1H, brd, J = 7.9 Hz), 6.58 (2H, d, J = 8.9 Hz), 6.76 (2H, d, J = 8.9 Hz);
MS (FAB) m / z: 464 [M + H]⁺, 408.
Anal. Calcd for C_{twenty two}H₃₇N_ThreeO_Four: C, 64.84; H, 9.15; N, 10.31. Found: C, 64.82; H, 8.84; N, 10.17.

(45b) N²-(1-benzofuran-2-carbonyl) -N¹-((1S) -1-{[(4-methoxyphenyl) amino] methyl} propyl) -L-leucinamide
N produced in Example 45 (45a)²-(Tert-butoxycarbonyl) -N¹Trifluoroacetic acid (4 mL) was added to-((1S) -1-{[(4-methoxyphenyl) amino] methyl} propyl) -L-leucinamide (0.32 g, 0.8 mmol), and the mixture was stirred for 1 hour. After the mixture was concentrated, saturated aqueous sodium hydrogen carbonate (50 mL) was added to the obtained residue, and the mixture was extracted with ethyl acetate (50 mL). After the extract was dried over sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was dissolved in N, N-dimethylformamide (3 mL), and benzofuran-2-carboxylic acid (0.15 g, 0.9 mmol) was dissolved. ), 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (0.17 g, 0.9 mmol), 1-hydroxybenzotriazole monohydrate (0.14 g, 0.9 mmol) Was added and stirred for 5 hours. The reaction solution was partitioned between ethyl acetate (50 mL) and water (50 mL). The organic layer was washed with saturated aqueous sodium hydrogen carbonate (30 mL), dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate, 1: 1) to give the title compound (0.21 g, yield 59%).
IR (KBr) ν_max3289, 1642, 1514, 1235, 820, 749 cm^-1;
¹H NMR (CDCl_Three, 400MHz) δ0.88 (3H, t, J = 7.4 Hz), 0.94 (3H, d, J = 5.8 Hz), 0.95 (3H, d, J = 5.8 Hz), 1.43-1.79 (5H, m), 3.13 (1H, dd, J = 7.6, 12.5 Hz), 3.22 (1H, dd, J = 4.7, 12.5 Hz), 3.73 (3H, s), 3.82 (1H, br), 4.03-4.11 (1H, m) , 4.76-4.78 (1H, m), 6.59 (2H, d, J = 8.9 Hz), 6.76 (2H, d, J = 8.9 Hz), 6.81-6.86 (1H, m), 7.26-7.29 (2H, m ), 7.40 (1H, dd, J = 7.3, 8.3 Hz), 7.43 (1H, brs), 7.48 (1H, d, J = 8.3 Hz), 7.59 (1H, d, J = 7.3 Hz);
MS (FAB) m / z: 464 [M + H]⁺, 452.
Anal. Calcd for C_{twenty two}H₃₇N_ThreeO_Four·0.2 H_TwoO: C, 68.61; H, 7.40; N, 9.23. Found: C, 68.46; H, 7.43; N, 9.41.

[Example 46] N¹-((1S) -1-{[(4-methoxyphenyl) amino] methyl} propyl) -N²-(Morpholin-4-ylcarbonyl) -L-leucinamide (Exemplary Compound No. 5-10)
(46a) allyl (2S) -2-[(tert-butoxycarbonyl) amino] butyl ((4-methoxyphenyl) carbamate
  Tert-Butyl (1S) -1-{[(4-methoxyphenyl) amino] methyl} propylcarbamate (3.06 g, 10.4 mmol) produced in Example 2 (2a) and pyridine (1.1 ml, 13.2 g). Allyloxycarbonyl chloride (1.1 ml, 13.5 mmol) was added dropwise to a solution of 5 mmol) in methylene chloride (100 mL) under ice-cooling. After returning the reaction temperature to room temperature, the reaction solution was further stirred for 2 hours. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane / ethyl acetate, 1: 1) to obtain the title compound (3.93 g, yield 100%).
¹H NMR (CDCl_Three, 400MHz) δ 0.89 (3H, t, J = 7.3 Hz), 1.43 (9H, s), 1.31-1.48 (2H, m), 3.29-3.32 (1H, m), 3.71-3.75 (1H, m), 3.80 (3H, s), 3.84-3.85 (1H, m), 4.51-4.61 (2H, m), 4.78-4.79 (1H, m), 5.10 (2H, d, J = 9.5 Hz), 5.82 (1H, br s), 6.88 (2H, d, J = 8.8 Hz), 7.14 (2H, d, J = 8.8 Hz);

(46b) Allyl (2S) -2-[(1-[(1S) -1-[(tert-butoxycarbonyl) amino] -3-methylbutyl] vinyl) amino] butyl (4-methoxyphenyl) carbamate
  Allyl (2S) -2-[(tert-butoxycarbonyl) amino] butyl ((4-methoxyphenyl) carbamate (2.06 g, 5.43 mmol) produced in Example 46 (46a) was treated with a 4 M hydrochloric acid-dioxane solution ( 10 ml), and the mixture was stirred at room temperature for 2 hours.The solvent was distilled off under reduced pressure, and the obtained residue was dissolved in N, N-dimethylformamide (80 ml), and tert-butoxycarbonyl-L-leucine hydrate ( 1.49 g, 5.97 mmol), triethylamine (0.91 ml, 6.52 mmol), hydroxybenzotriazole monohydrate (0.88 g, 6.52 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) Carbodiimide hydrochloride (1.25 g, 6.52 mmol) was added and the mixture was stirred at room temperature for 9 hours. Ethyl acid (20 ml) and water (20 mL) were added, and after liquid separation, the organic phase was washed with water (20 ml × 5) and brine (20 ml), dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate, 2: 1) to obtain the title compound (2.67 g, yield 100%).
¹H NMR (CDCl_Three, 400MHz) δ 0.86 (3H, t, J = 7.3 Hz), 0.93 (6H, t, J = 7.3 Hz), 1.44 (9H, s), 1.38-1.59 (5H, m), 3.29-3.30 (1H, m), 3.80 (3H, s), 3.98-4.03 (3H, m), 4.50-4.61 (2H, m), 4.89-5.09 (3H, m), 5.79 (1H, br s), 6.28 (1H, br) s), 6.88 (2H, d, J = 8.8 Hz), 7.08 (2H, d, J = 8.8 Hz);

(46c) allyl 4-methoxyphenyl {(2S) -2-[(1-{(1S) -3-methyl-1-[(morpholin-4-ylcarbonyl) amino] butyl} vinyl) amino] butyl} carbamate
  Allyl (2S) -2-[(1-[(1S) -1-[(tert-butoxycarbonyl) amino] -3-methylbutyl] vinyl) amino] butyl] (4-methoxy) prepared in Example 46 (46b) (Phenyl) carbamate (147 mg, 0.30 mmol) was dissolved in a 4 M hydrochloric acid-dioxane solution (2 ml) and stirred at room temperature for 2 hours. The residue obtained by evaporating the solvent under reduced pressure was dissolved in methylene chloride (5 ml), and triethylamine (125 µl, 0.90 mmol) and morpholine-4-carbonyl chloride (70 µl, 0.60 mmol) were added. Stirred. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (ethyl acetate / methanol, 20: 1) to obtain the title compound (147 mg, yield 98%).
¹H NMR (CDCl_Three, 400MHz) δ 0.85 (3H, t, J = 7.3 Hz), 0.93 (3H, d, J = 6.6 Hz), 0.96 (3H, d, J = 5.9 Hz), 1.39-1.73 (5H, m), 3.34 -3.38 (5H, m), 3.67 (4H, t, J = 4.4 Hz), 3.80 (3H, s), 3.98-4.05 (2H, m), 4.32-4.61 (3H, m), 5.05-5.10 (3H , m), 5.79 (1H, br s), 6.35 (1H, br s), 6.88 (2H, d, J = 8.8 Hz), 7.09 (2H, d, J = 8.8 Hz);

(46d) N¹-((1S) -1-{[(4-methoxyphenyl) amino] methyl} propyl) -N²-(Morpholin-4-ylcarbonyl) -L-leucinamide
  Allyl 4-methoxyphenyl {(2S) -2-[(1-{(1S) -3-methyl-1-[(morpholin-4-ylcarbonyl) amino] butyl} vinyl} prepared in Example 46 (46c) ) Amino] butyl} carbamate (147 mg, 0.29 mmol) in tetrahydrofuran (5 ml) under a nitrogen atmosphere under a nitrogen atmosphere, pyrrolidine (240 μl, 2.9 mmol), tris (dibenzylideneacetone) dipalladium (0) (13 mg, 0.1 g). 015 mmol) and 1,3-bis (diphenylphosphino) propane (12 mg, 0.029 mmol) were added, and the mixture was stirred at room temperature for 18 hours. The residue obtained by evaporating the solvent under reduced pressure was purified by thin-layer chromatography (100% ethyl acetate) to obtain the title compound (89 mg, yield 73%).
IR (KBr) ν_max 3284, 2957, 1623, 1515, 1239, 1119, 820 cm^-1;
¹H NMR (CDCl_Three, 400MHz) δ 0.91-0.96 (9H, m), 1.47-1.70 (5H, m), 3.09 (1H, dd, J = 7.3, 12.5 Hz), 3.19 (1H, dd, J = 5.1, 12.5 Hz), 3.33-3.36 (4H, m), 3.66 (4H, t, J = 4.4 Hz), 3.74 (3H, s), 3.99-4.02 (1H, m), 4.25-4.29 (1H, m), 4.84 (1H, d, J = 8.1 Hz), 6.17 (1H, d, J = 8.1 Hz), 6.58 (2H, d, J = 8.8 Hz), 6.77 (2H, d, J = 8.8 Hz);
HRMS (FAB): 421.2801 [M + H]⁺ (calcd 421.2815 for C_{twenty two}H₃₇N_FourO_Four)

[Example 47] N¹-((1S) -1-{[(4-methoxyphenyl) amino] methyl} propyl) -N²-[4- (4-Methylpiperazin-1-yl) benzoyl] -L-leucinamide (Exemplary Compound No. 3-274)
(47a) N¹-((1S) -1-{[[(allyloxy) carbonyl] (4-methoxyphenyl) amino] methyl} propyl) -N²-[4- (4-methylpiperazin-1-yl) benzoyl] -L-leucinamide
  Allyl (2S) -2-[(1-[(1S) -1-[(tert-butoxycarbonyl) amino] -3-methylbutyl] vinyl) amino] butyl] (4-methoxy) prepared in Example 46 (46b) (Phenyl) carbamate (157 mg, 0.32 mmol) was dissolved in a 4 M hydrochloric acid-dioxane solution (2 ml) and stirred at room temperature for 2 hours. The residue obtained by evaporating the solvent under reduced pressure was dissolved in N, N-dimethylformamide (5 ml), and 4- (4-methylpiperazin-1-yl) benzoic acid (70 mg, 0.32 mmol), triethylamine ( 54 μl, 0.38 mmol), hydroxybenzotriazole monohydrate (53 mg, 0.38 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (74 mg, 0.38 mmol), and the mixture was added at room temperature. Stirred for 2 days. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate / methanol, 20: 1) to obtain the title compound (163 mg, yield 86%).
¹H NMR (CDCl_Three, 400MHz) δ 0.71 (3H, t, J = 7.3 Hz), 0.94 (3H, d, J = 5.9 Hz), 0.98 (3H, d, J = 5.1 Hz), 1.42-1.73 (5H, m), 2.35 (3H, s), 2.55 (4H, t, J = 4.4 Hz), 3.15-3.27 (1H, m), 3.30 (4H, t, J = 4.4 Hz), 3.80 (3H, s), 4.02-4.06 ( 2H, m), 4.42-4.61 (3H, m), 5.03-5.07 (2H, m), 5.76 (1H, br s), 6.52 (2H, br s), 6.88 (2H, d, J = 8.8 Hz) , 6.89 (2H, d, J = 8.8 Hz), 7.10 (2H, d, J = 8.1 Hz), 7.71 (2H, d, J = 8.1 Hz);

(47b) N¹-((1S) -1-{[(4-methoxyphenyl) amino] methyl} propyl) -N²-[4- (4-Methylpiperazin-1-yl) benzoyl] -L-leucinamide
  N produced in Example 47 (47a)¹-((1S) -1-{[[(allyloxy) carbonyl] (4-methoxyphenyl) amino] methyl} propyl) -N²To a solution of-[4- (4-methylpiperazin-1-yl) benzoyl] -L-leucinamide (163 mg, 0.27 mmol) in tetrahydrofuran (5 ml), under a nitrogen atmosphere, pyrrolidine (230 µl, 2.7 mmol), tetrakis ( Triphenylphosphine) palladium (0) (31 mg, 0.027 mmol) and triphenylphosphine (14 mg, 0.054 mmol) were added, and the mixture was stirred for 18 hours. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (ethyl acetate) to obtain the title compound (130 mg, yield 94%).
IR (KBr) ν_max 3316, 2959, 1626, 1513, 1237 cm^-1;
¹H NMR (CDCl_Three, 400MHz) δ 0.89 (3H, t, J = 7,3 Hz), 0.94 (6H, t, J = 5.9 Hz), 1.42-1.79 (5H, m), 2.35 (3H, s), 2.56 (4H, t, J = 5.1 Hz), 3.10 (1H, dd, J = 8.1, 12.5 Hz), 3.19 (1H, dd, J = 5.1, 12.5 Hz), 3.32 (4H, t, J = 5.1 Hz), 3.74 ( 3H, s), 3.99-4.04 (1H, m), 4.54-4.60 (1H, m), 6.33 (2H, t, J = 8.1 Hz), 6.59 (2H, d, J = 8.8 Hz), 6.77 (2H , d, J = 8.8 Hz), 6.88 (2H, d, J = 8.8 Hz), 7.67 (2H, d, J = 8.8 Hz);
HRMS (FAB): 510.3431 [M + H]⁺ (calcd 510.3444 for C₂₉H₄₄N_ThreeO_Five)

[Example 48] N¹-((1S) -1-{[(4-methoxyphenyl) amino] methyl} propyl) -N²-[4-morpholin-4-ylbenzoyl] -L-leucinamide (Exemplary Compound No. 3-270)
(48a) N¹-((1S) -1-{[[(allyloxy) carbonyl] (4-methoxyphenyl) amino] methyl} propyl) -N²-(4-morpholin-4-ylbenzoyl) -L-leucinamide
  Allyl (2S) -2-[(1-[(1S) -1-[(tert-butoxycarbonyl) amino] -3-methylbutyl] vinyl) amino] butyl] (4-methoxy) prepared in Example 46 (46b) (Phenyl) carbamate (128 mg, 0.26 mmol) was dissolved in a 4 M hydrochloric acid-dioxane solution (2 ml) and stirred at room temperature for 2 hours. The residue obtained by evaporating the solvent under reduced pressure was dissolved in N, N-dimethylformamide (5 ml), and 4-morpholin-4-ylbenzoic acid (53 mg, 0.26 mmol), triethylamine (43 μl, 0.31 mmol) , Hydroxybenzotriazole monohydrate (42 mg, 0.31 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (60 mg, 0.31 mmol) were added, and the mixture was stirred at room temperature for 1 day. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (ethyl acetate) to obtain the title compound (148 mg, yield 98%).
¹H NMR (CDCl_Three, 400MHz) δ 0.81 (3H, t, J = 7.4 Hz), 0.94 (3H, d, J = 6.3 Hz), 0.98 (3H, d, J = 5.9 Hz), 1.41-1.74 (5H, m), 3.23 (4H, t, J = 4.7 Hz), 3.29-3.39 (1H, m), 3.79 (3H, s), 3.84 (4H, t, J = 5.1 Hz), 3.98-4.04 (2H, m), 4.40- 4.61 (3H, m), 5.01-5.04 (2H, m), 5.75 (1H, br s), 6.48-6.51 (2H, br s), 6.85 (2H, d, J = 8.2 Hz), 6.86 (2H, d, J = 8.6 Hz), 7.08 (2H, d, J = 8.2 Hz), 7.71 (2H, d, J = 8.6 Hz);

(48b) N¹-((1S) -1-{[(4-methoxyphenyl) amino] methyl} propyl) -N²-[4-morpholin-4-ylbenzoyl] -L-leucinamide
  According to the method described in Example 46 (46d), allyl 4-methoxyphenyl} (2S) -2-[(1-{(1S) -3-methyl-1-[(morpholin-4-ylcarbonyl) amino] Instead of butyl {vinyl) amino] butyl} carbamate, the N prepared in Example 48 (48a)¹-((1S) -1-{[[(allyloxy) carbonyl] (4-methoxyphenyl) amino] methyl} propyl) -N²The title compound (122 mg, 98% yield) was obtained using-(4-morpholin-4-ylbenzoyl) -L-leucinamide (147 mg, 0.25 mmol).
IR (KBr) ν_max 3324, 2960, 1627, 1513, 1234, 1125, 928, 817 cm^-1;
¹H NMR (CDCl_Three, 400MHz) δ 0.87 (3H, t, J = 7,3 Hz), 0.94 (6H, t, J = 5.1 Hz), 1.43-1.78 (5H, m), 3.09 (1H, dd, J = 7.3, 12.5 Hz), 3.18 (1H, dd, J = 5.1, 12.5 Hz), 3.24 (4H, t, J = 5.1 Hz), 3.74 (3H, s), 3.84 (4H t, J = 4.4 Hz), 3.98-4.02 (1H, m), 4.60-4.66 (1H, m), 6.54-6.59 (4H, m), 6.77 (2H, d, J = 8.8 Hz), 6.85 (2H, d, J = 8.8 Hz), 7.70 ( 2H, d, J = 8.8 Hz);
HRMS (FAB): 497.3116 [M + H]⁺ (calcd 497.3128 for C₂₈H₄₁N_FourO_Four)

[Example 49] N¹-((1S) -1-{[(4-methoxyphenyl) amino] methyl} propyl) -N²-(Piperidin-1-ylcarbonyl) -L-leucinamide (Exemplary Compound No. 5-11)
(49a) allyl 4-methoxyphenyl {(2S) -2-[(1-{(1S) -3-methyl-1-[(piperidin-1-ylcarbonyl) amino] butyl} vinyl) amino] butyl} carbamate
  Allyl (2S) -2-[(1-[(1S) -1-[(tert-butoxycarbonyl) amino] -3-methylbutyl] vinyl) amino] amino] butyl (4-methoxy) prepared in Example 46 (46b) (Phenyl) carbamate (177 mg, 0.36 mmol) was dissolved in a 4 M hydrochloric acid-dioxane solution (2 ml) and stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure, and the obtained residue was dissolved in methylene chloride (5 ml). Stirred. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane / ethyl acetate, 1: 1) to obtain the title compound (181 mg, yield 100%).
¹H NMR (CDCl_Three, 400MHz) δ 0.84 (3H, t, J = 7.4 Hz), 0.92 (3H, d, J = 6.6 Hz), 0.95 (3H, d, J = 6.6 Hz), 1.38-1.72 (11H, m), 3.31 -3.33 (5H, m), 3.79 (3H, s), 3.94-4.03 (2H, m), 4.28-4.59 (3H, m), 4.88-5.08 (3H, m), 5.77 (1H, br s), 6.37 (1H, br s), 6.86 (2H, d, J = 8.8 Hz), 7.07 (2H, d, J = 8.8 Hz);

(49b) N¹-((1S) -1-{[(4-methoxyphenyl) amino] methyl} propyl) -N²-(Piperidin-1-ylcarbonyl) -L-leucinamide
  According to the method described in Example 46 (46d), allyl 4-methoxyphenyl} (2S) -2-[(1-{(1S) -3-methyl-1-[(morpholin-4-ylcarbonyl) amino] Instead of butyl {vinyl) amino] butyl} carbamate, allyl 4-methoxyphenyl} (2S) -2-[(1-{(1S) -3-methyl-1- [produced in Example 49 (49a). The title compound (126 mg, yield 83%) was obtained using (piperidin-1-ylcarbonyl) amino] butyl {vinyl) amino] butyl} carbamate (181 mg, 0.36 mmol).
IR (KBr) ν_max 3275, 29 34, 1619, 1514, 1237, 1040, 817 cm^-1;
¹H NMR (CDCl_Three, 400MHz) δ 0.90-0.95 (9H, m), 1.46-1.68 (11H, m), 3.08 (1H, dd, J = 8.1, 12.5 Hz), 3.18 (1H, dd, J = 4.4, 12.5 Hz), 3.31 (4H, t, J = 5.1 Hz), 3.73 (3H, s), 3.80 (1H, br s), 3.96-4.01 (1H, m), 4.24-4.30 (1H, m), 4.83 (1H, d , J = 8.1 Hz), 6.55 (1H, d, J = 8.8 Hz), 6.58 (2H, d, J = 8.8 Hz), 6.76 (2H, d, J = 8.8 Hz);
HRMS (FAB): 419.3049 [M + H]⁺ (calcd 419.3022 for C_{twenty three}H₃₉N_FourO_Three)

[Example 50] N¹-((1S) -1-{[(4-methoxyphenyl) amino] methyl} propyl) -N²-(4-Piperidin-1-ylbenzoyl) -L-leucinamide (Exemplary Compound No. 3-266)
(50a) N¹-((1S) -1-{[[(allyloxy) carbonyl] (4-methoxyphenyl) amino] methyl} propyl) -N²-(4-piperidin-1-ylbenzoyl) -L-leucinamide
  Allyl (2S) -2-[(1-[(1S) -1-[(tert-butoxycarbonyl) amino] -3-methylbutyl] vinyl) amino] butyl] (4-methoxy) prepared in Example 46 (46b) (Phenyl) carbamate (147 mg, 0.30 mmol) was dissolved in a 4 M hydrochloric acid-dioxane solution (2 ml) and stirred at room temperature for 2 hours. The residue obtained by evaporating the solvent under reduced pressure was dissolved in N, N-dimethylformamide (5 ml), and 4-piperidin-1-ylbenzoic acid (62 mg, 0.30 mmol), triethylamine (50 μl, 0.36 mmol) , Hydroxybenzotriazole monohydrate (49 mg, 0.36 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (69 mg, 0.36 mmol) were added, and the mixture was stirred at room temperature for 1 day. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane / ethyl acetate, 1: 1) to obtain the title compound (171 mg, yield 98%).
¹H NMR (CDCl_Three, 400MHz) δ 0.80 (3H, t, J = 7.3 Hz), 0.94 (3H, d, J = 5.9 Hz), 0.98 (3H, d, J = 5.9 Hz), 1.41-1.74 (11, m), 3.27 (4H, t, J = 5.9 Hz), 3.33 (1H, br s), 3.80 (3H, s), 4.00-4.02 (2H, m), 4.43-4.61 (3H, m), 5.05-5.07 (2H, m), 5.76 (1H, br s), 6.50-6.52 (2H, br s), 6.85 (2H, d, J = 8.8 Hz), 6.88 (2H, d, J = 8.8 Hz), 7.11 (2H, d , J = 8.1 Hz), 7.69 (2H, d, J = 8.1 Hz);

(50b) N¹-((1S) -1-{[(4-methoxyphenyl) amino] methyl} propyl) -N²-(4-piperidin-1-ylbenzoyl) -L-leucinamide
  According to the method described in Example 46 (46d), allyl 4-methoxyphenyl} (2S) -2-[(1-{(1S) -3-methyl-1-[(morpholin-4-ylcarbonyl) amino] Instead of butyl {vinyl) amino] butyl} carbamate, the N prepared in Example 50 (50a)¹-((1S) -1-{[[(allyloxy) carbonyl] (4-methoxyphenyl) amino] methyl} propyl) -N²The title compound (134 mg, yield 93%) was obtained using-(4-piperidin-1-ylbenzoyl) -L-leucinamide (170 mg, 0.29 mmol).
M.p. 152-154 oC
IR (KBr) ν_max 3324, 2936, 1625, 1512, 1236, 1125, 1041 cm^-1;
¹H NMR (CDCl_Three, 400MHz) δ 0.88 (3H, t, J = 7.4 Hz), 0.94 (6H, t, J = 6.3 Hz), 1.45-1.78 (11H, m), 3.11 (1H, dd, J = 7.8, 12.5 Hz) , 3.18 (1H, dd, J = 5.1, 12.5 Hz), 3.28 (4H, t, J = 5.9 Hz), 3.73 (3H, s), 3.97-4.03 (1H, m), 4.53-4.59 (1H, m ), 6.34 (1H, d, J = 7.8 Hz), 6.45 (1H, d, J = 7.8 Hz), 6.61 (2H, d, J = 9.0 Hz), 6.75 (2H, d, J = 9.0 Hz), 6.83 (2H, d, J = 8.6 Hz), 7.63 (2H, d, J = 8.6 Hz);
HRMS (FAB): 495.3327 [M + H]⁺ (calcd 495.3335 for C₂₉H₄₃N_FourO_Three)

[Example 51] N¹-((1S) -1-{[(4-methoxyphenyl) amino] methyl} propyl) -N²-[(4-Methylpiperazin-1-yl) carbonyl] -L-leucinamide (Exemplary Compound No. 5-20)
(51a) benzyl N-[(4-methylpiperazin-1-yl) carbonyl] -L-leucinate
  The compound was synthesized by the following method with reference to the method of a literature (J. Med. Chem. Soc., Vol 40, 1997, 3820).

トリホスゲン（１４２ｍｇ，０．４８ｍｍｏｌ）の塩化メチレン（２ｍｌ）溶液にロイシン ベンジルエステル ｐ−トルエンスルホネート（３９４ｍｇ，１ｍｍｏｌ）及びジイソプロピルエチルアミン（３７４μｌ，２．２ｍｍｏｌ）の塩化メチレン（１０ｍｌ）溶液を２．５時間滴下した。さらに１−メチルピペラジン及びジイソプロピルエチルアミン（３７４μｌ，２．２ｍｍｏｌ）の塩化メチレン（２ｍｌ）溶液を滴下し，室温で１時間撹拌した。溶媒を減圧下留去し得られた残渣をシリカゲルカラムクロマトグラフィー（１００％酢酸エチル）を用いて精製し，標記目的化合物（２４８ｍｇ，収率７２％）を得た。
¹H NMR (CDCl₃, 400MHz) δ 0.92 (3H, d, J = 6.7 Hz), 0.93 (3H, d, J=6.3 Hz), 1.48-1.70 (3H, m), 2.29 (3H, s), 2.38 (4H, t, J=5.1 Hz), 3.40(4H, t, J=5.9 Hz), 4.56 (1H, dt, J=5.1, 8.6 Hz), 4.79 (1H, d, J=8.2 Hz), 5.11 (1H, d, J=12.1 Hz), 5.19 (1H, d, J=12.1 Hz), 7.80-7.86 (5H, m);

（５１ｂ） Ｎ−［（４−メチルピペラジン−１−イル）カルボニル］−Ｌ−ロイシン
実施例５１（５１ａ）で製造したベンジル Ｎ−［（４−メチルピペラジン−１−イル）カルボニル］−Ｌ−ロイシネート（２４８ｍｇ，０．７１ｍｍｏｌ）を水素雰囲気下（１気圧）、１０％パラジウム炭素触媒（３８ｍｇ，０．０３６ｍｍｏｌ）存在下に、エタノール（１０ｍｌ）溶媒中、室温で２時間水素化分解した。触媒を除去したのち、溶媒を留去して粗製の標記目的化合物を得た。
¹H NMR (CD₃OD, 400MHz) δ 0.93 (3H, d, J = 6.7 Hz), 0.95 (3H, d, J=6.7 Hz), 1.61 (2H, t, J=7.8 Hz), 1.67-1.76 (1H, m), 2.56 (3H, s), 2.77-2.80 (4H, m), 3.54(4H, t, J=5.1 Hz), 4.26 (1H, t, J=7.8 Hz);

（５１ｃ） Ｎ^１−（（１Ｓ）−１−｛［（４−メトキシフェニル）アミノ］メチル｝プロピル）−Ｎ^２−［（４−メチルピペラジン−１−イル）カルボニル］−Ｌ−ロイシナミド
実施例２（２ａ）で製造したｔｅｒｔ−ブチル （１Ｓ）−１−｛［（４−メトキシフェニル）アミノ］メチル｝プロピルカーバメート（２０９ｍｇ，０．７１ｍｍｏｌ）を４Ｍ塩酸−ジオキサン溶液（５ｍｌ）に溶解し、室温で２時間撹拌した。溶媒を減圧下留去し得られた残渣をＮ，Ｎ−ジメチルホルムアミド（５ｍｌ）に溶解し、実施例５１（５１ｂ）で製造したＮ−［（４−メチルピペラジン−１−イル）カルボニル］−Ｌ−ロイシン（１８４ｍｇ，０．７１ｍｍｏｌ）、トリエチルアミン（１２０μｌ，０．８５ｍｍｏｌ），ヒドロキシベンゾトリアゾール １水和物（１１５ｍｇ，０．８５ｍｍｏｌ）及び１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩（１３６ｍｇ，０．８５ｍｍｏｌ）を加え、室温で２日間撹拌した。溶媒を減圧下留去し得られた残渣を高速液体クロマトグラフィー（３０％アセトニトリル，１％トリエチルアミン酢酸）を用いて精製し、標記目的化合物（１９ｍｇ，収率６％）を得た。
IR(film) ν_max3278, 2936, 1620, 1546, 1514, 1462, 1238, 1003, 819 cm^-1;
¹H NMR (CDCl₃, 400MHz) δ0.88-0.94 (9H, m), 1.42-1.68 (5H, m), 2.27 (3H, s), 2.34 (4H, t, J=5.1 Hz), 3.07(1H, dd, J=7.4, 12.1 Hz), 3.17 (1H, dd, J=4.7, 12.1 Hz), 3.37 (4H, t, J=5.5 Hz), 3.72 (3H, s), 3.94-4.00 (1H, m), 4.23-4.28 (1H, m), 4.93 (1H, t, J=7.8 Hz), 6.44 (1H, t, J=8.6 Hz), 6.55 (2H, d, J=8.8 Hz), 6.74 (2H, d, J=8.8 Hz);
HRMS(FAB): 434.3129 [M+H]^+・ (calcd 434.3131 for C₂₃H₄₀N₅O₃)

［実施例５２］ Ｎ−（（１Ｓ）−１−｛［（４−メトキシフェニル）アミノ］メチル｝プロピル）−１−［（４’−メチル−１，１’−ビフェニル−３−イル）アミノ］シクロヘキサンカルボキサミド（例示化合物番号２−５）
実施例１５（１５ｃ）に記載された反応と同様にして、ｍ−トリルホウ酸に代えてｐ−トリルホウ酸を用いて標記化合物を得た。収率９５％。
Mp 68-75 ℃;
IR (KBr) ν_max 3368, 1652, 1605, 1513, 1234, 820, 780 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 0.89 (3H, t, J = 7.4 Hz), 1.25-2.10 (12H, m), 2.37 (3H, s), 3.02 (1H, dd, J = 7.7, 12.2 Hz), 3.13 (1H, dd, J = 4.5, 12.2 Hz), 3.66 (1H, brs), 3.73 (3H, s), 4.00-4.10 (2H, m), 6.43 (2H, d, J = 8.9 Hz), 6.57 (1H, dd, J = 2.0, 8.0 Hz), 6.71 (2H, d, J = 8.9 Hz), 6.84 (1H, t, J = 2.0 Hz), 7.01 (1H, brd, J = 8.0 Hz), 7.04 (1H, brd, J = 8.8 Hz), 7.11 (1H, t, J = 8.0 Hz), 7.16 (2H, d, J = 8.0 Hz), 7.42 (2H, d, J = 8.0 Hz);
MS (FAB) m/z: 486 [M+H]⁺;

［実施例５３］ Ｎ−（（１Ｓ）−１−｛［（４−メトキシフェニル）アミノ］メチル｝プロピル）−１−［（２’−メチル−１，１’−ビフェニル−３−イル）アミノ］シクロヘキサンカルボキサミド（例示化合物番号２−３）
実施例１５（１５ｃ）に記載された反応と同様にして、ｍ−トリルホウ酸に代えてＯ−トリルホウ酸を用いて標記化合物を得た。収率９９％。
IR (KBr) ν_max 3366, 1651, 1601, 1513, 1235, 1038, 821, 759 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 0.88 (3H, t, J = 7.4 Hz), 1.24-2.01 (12H, m), 2.24 (3H, s), 3.02 (1H, dd, J = 7.7, 12.2 Hz), 3.13 (1H, dd, J = 4.6, 12.2 Hz), 3.64 (1H, brs), 3.73 (3H, s), 3.99-4.05 (2H, m), 6.45 (2H, d, J = 8.9 Hz), 6.58-6.60 (2H, m), 6.71-6.75 (1H, m), 6.72 (2H, d, J = 8.9 Hz), 7.05 (1H, brd, J = 8.8 Hz), 7.07-7.22 (5H, m);
MS (FAB) m/z: 486 [M+H]⁺;

［実施例５４］ Ｎ−（（１Ｓ）−１−｛［（４−メトキシフェニル）アミノ］メチル｝プロピル）−１−［（４’−メチルスルホニル−１，１’−ビフェニル−３−イル）アミノ］シクロヘキサンカルボキサミド（例示化合物番号５−４）
実施例１５（１５ｃ）に記載された反応と同様にして、ｍ−トリルホウ酸に代えてｐ−メタンスルホニルフェニルホウ酸を用いて標記化合物を得た。収率９５％。
IR (KBr) ν_max 3372, 1655, 1594, 1514, 1311, 1235, 1150, 776 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 0.89 (3H, t, J = 7.4 Hz), 1.24-2.06 (12H, m), 3.02 (1H, dd, J = 8.0, 12.0 Hz), 3.05 (3H, s), 3.13 (1H, dd, J = 4.3, 12.0 Hz), 3.75 (3H, s), 4.05-4.11 (1H, m), 6.45 (2H, d, J = 8.8 Hz), 6.69 (1H, dd, J = 2.3, 7.9 Hz), 6.73 (2H, d, J = 8.8 Hz), 6.84 (1H, t, J = 1.8 Hz), 7.00 (1H, brt, J = 7.9 Hz), 7.02 (1H, brd, J = 7.9 Hz), 7.18 (1H, t, J = 7.9 Hz), 7.67 (2H, d, J = 8.4 Hz), 7.83 (2H, d, J = 8.4 Hz);
MS (FAB) m/z: 550 [M+H]⁺;
Anal. Calcd for C₃₁H₃₉N₃SO₄・0.5EtOAc: C,66.75; H,7.30; N,7.08; S,5.40. Found: C,66.65; H,7.05; N,7.20; Cl,5.56.

［製剤例］
［製剤例１］ 散剤
実施例１３の化合物 ５ｇ、乳糖 ８９５ｇおよびトウモロコシデンプン １００ｇをブレンダーで混合することにより、散剤をえることができる。
［製剤例２］ 顆粒剤
実施例１４の化合物 ５ｇ、乳糖 ８６５ｇおよび低置換度ヒドロキシプロピルセルロース １００ｇを混合した後、１０％ヒドロキシプロピルセルロース水溶液 ３００ｇを加えて練合する。これを押し出し造粒機を用いて造粒し、乾燥すると顆粒剤が得られる。
［製剤例３］ 錠剤
実施例１５の化合物 ５ｇ、乳糖 ９０ｇ、トウモロコシデンプン ３４ｇ、結晶セルロース ２０ｇおよびステアリン酸マグネシウム １ｇをブレンダーで混合した後、錠剤機で打錠することにより、錠剤が得られる。

［試験例］
［試験例１］ カテプシンＫ阻害活性の測定
ヒトカテプシンKを用いた酵素阻害実験は，特願平９−１５１８０４に記載の方法に準じて行った。To a solution of triphosgene (142 mg, 0.48 mmol) in methylene chloride (2 ml) was added a solution of leucine benzyl ester p-toluenesulfonate (394 mg, 1 mmol) and diisopropylethylamine (374 μl, 2.2 mmol) in methylene chloride (10 ml) for 2.5 hours. It was dropped. Further, a solution of 1-methylpiperazine and diisopropylethylamine (374 μl, 2.2 mmol) in methylene chloride (2 ml) was added dropwise, and the mixture was stirred at room temperature for 1 hour. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (100% ethyl acetate) to obtain the title compound (248 mg, yield 72%).
¹ H NMR (CDCl₃ , 400 MHz) δ 0.92 (3H, d, J = 6.7 Hz), 0.93 (3H, d, J = 6.3 Hz), 1.48-1.70 (3H, m), 2.29 (3H, s), 2.38 (4H, t, J = 5.1 Hz), 3.40 (4H, t, J = 5.9 Hz), 4.56 (1H, dt, J = 5.1, 8.6 Hz), 4.79 (1H, d, J = 8.2 Hz), 5.11 (1H, d, J = 12.1 Hz), 5.19 (1H, d, J = 12.1 Hz), 7.80-7.86 (5H, m);

(51b) N-[(4-methylpiperazin-1-yl) carbonyl] -L-leucine Benzyl N-[(4-methylpiperazin-1-yl) carbonyl] -L- produced in Example 51 (51a). Leucinate (248 mg, 0.71 mmol) was hydrogenolyzed in an ethanol (10 ml) solvent at room temperature for 2 hours in a hydrogen atmosphere (1 atm) in the presence of a 10% palladium carbon catalyst (38 mg, 0.036 mmol). After removing the catalyst, the solvent was distilled off to obtain a crude title compound.
¹ H NMR (CD₃ OD, 400 MHz) δ 0.93 (3H, d, J = 6.7 Hz), 0.95 (3H, d, J = 6.7 Hz), 1.61 (2H, t, J = 7.8 Hz), 1.67-1.76 (1H, m), 2.56 (3H, s), 2.77-2.80 (4H, m), 3.54 (4H, t, J = 5.1 Hz), 4.26 (1H, t, J = 7.8 Hz);

^{(51c) N 1 - ((} 1S) -1 - {[(4- methoxyphenyl) amino] methyl}^propyl) -N 2 - [(4- methylpiperazin-l-yl) carbonyl] -L- Roishinamido Example The tert-butyl (1S) -1-{[(4-methoxyphenyl) amino] methyl} propylcarbamate (209 mg, 0.71 mmol) produced in 2 (2a) was dissolved in a 4 M hydrochloric acid-dioxane solution (5 ml), Stirred at room temperature for 2 hours. The residue obtained by evaporating the solvent under reduced pressure was dissolved in N, N-dimethylformamide (5 ml), and N-[(4-methylpiperazin-1-yl) carbonyl]-produced in Example 51 (51b) was used. L-leucine (184 mg, 0.71 mmol), triethylamine (120 μl, 0.85 mmol), hydroxybenzotriazole monohydrate (115 mg, 0.85 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride Salt (136 mg, 0.85 mmol) was added, and the mixture was stirred at room temperature for 2 days. The residue obtained by evaporating the solvent under reduced pressure was purified by high-performance liquid chromatography (30% acetonitrile, 1% triethylamineacetic acid) to obtain the title compound (19 mg, yield 6%).
IR (film) ν_max 3278, 2936, 1620, 1546, 1514, 1462, 1238, 1003, 819 cm^-1 ;
_{^{1 H NMR (CDCl 3, 400MHz}} ) δ0.88-0.94 (9H, m), 1.42-1.68 (5H, m), 2.27 (3H, s), 2.34 (4H, t, J = 5.1 Hz), 3.07 ( 1H, dd, J = 7.4, 12.1 Hz), 3.17 (1H, dd, J = 4.7, 12.1 Hz), 3.37 (4H, t, J = 5.5 Hz), 3.72 (3H, s), 3.94-4.00 (1H , m), 4.23-4.28 (1H, m), 4.93 (1H, t, J = 7.8 Hz), 6.44 (1H, t, J = 8.6 Hz), 6.55 (2H, d, J = 8.8 Hz), 6.74 (2H, d, J = 8.8 Hz);
HRMS (FAB): 434.3129 [M + H]^{+ ・} (calcd 434.3131 for C₂₃ H₄₀ N₅ O₃ )

Example 52 N-((1S) -1-{[(4-methoxyphenyl) amino] methyl} propyl) -1-[(4′-methyl-1,1′-biphenyl-3-yl) amino Cyclohexanecarboxamide (Exemplary Compound No. 2-5)
In the same manner as in the reaction described in Example 15 (15c), the title compound was obtained using p-tolylboric acid instead of m-tolylboric acid. 95% yield.
Mp 68-75 ° C;
IR (KBr) ν_max 3368, 1652, 1605, 1513, 1234, 820, 780 cm^-1 ;
¹ H NMR (CDCl₃ , 400 MHz) δ 0.89 (3H, t, J = 7.4 Hz), 1.25-2.10 (12H, m), 2.37 (3H, s), 3.02 (1H, dd, J = 7.7, 12.2 Hz), 3.13 (1H, dd, J = 4.5, 12.2 Hz), 3.66 (1H, brs), 3.73 (3H, s), 4.00-4.10 (2H, m), 6.43 (2H, d, J = 8.9 Hz) ), 6.57 (1H, dd, J = 2.0, 8.0 Hz), 6.71 (2H, d, J = 8.9 Hz), 6.84 (1H, t, J = 2.0 Hz), 7.01 (1H, brd, J = 8.0 Hz) ), 7.04 (1H, brd, J = 8.8 Hz), 7.11 (1H, t, J = 8.0 Hz), 7.16 (2H, d, J = 8.0 Hz), 7.42 (2H, d, J = 8.0 Hz);
MS (FAB) m / z: 486 [M + H]⁺ ;

Example 53 N-((1S) -1-{[(4-methoxyphenyl) amino] methyl} propyl) -1-[(2′-methyl-1,1′-biphenyl-3-yl) amino Cyclohexanecarboxamide (Exemplary Compound No. 2-3)
In the same manner as in the reaction described in Example 15 (15c), the title compound was obtained using O-tolylboric acid instead of m-tolylboric acid. Yield 99%.
IR (KBr) ν_max 3366, 1651, 1601, 1513, 1235, 1038, 821, 759 cm^-1 ;
¹ H NMR (CDCl₃ , 400 MHz) δ 0.88 (3H, t, J = 7.4 Hz), 1.24-2.01 (12H, m), 2.24 (3H, s), 3.02 (1H, dd, J = 7.7, 12.2 Hz), 3.13 (1H, dd, J = 4.6, 12.2 Hz), 3.64 (1H, brs), 3.73 (3H, s), 3.99-4.05 (2H, m), 6.45 (2H, d, J = 8.9 Hz ), 6.58-6.60 (2H, m), 6.71-6.75 (1H, m), 6.72 (2H, d, J = 8.9 Hz), 7.05 (1H, brd, J = 8.8 Hz), 7.07-7.22 (5H, m);
MS (FAB) m / z: 486 [M + H]⁺ ;

Example 54 N-((1S) -1-{[(4-methoxyphenyl) amino] methyl} propyl) -1-[(4′-methylsulfonyl-1,1′-biphenyl-3-yl) Amino] cyclohexanecarboxamide (Exemplary Compound No. 5-4)
In the same manner as in the reaction described in Example 15 (15c), the title compound was obtained using p-methanesulfonylphenylboric acid instead of m-tolylboric acid. 95% yield.
IR (KBr) ν_max 3372, 1655, 1594, 1514, 1311, 1235, 1150, 776 cm^-1 ;
¹ H NMR (CDCl₃ , 400 MHz) δ 0.89 (3H, t, J = 7.4 Hz), 1.24-2.06 (12H, m), 3.02 (1H, dd, J = 8.0, 12.0 Hz), 3.05 (3H, s), 3.13 (1H, dd, J = 4.3, 12.0 Hz), 3.75 (3H, s), 4.05-4.11 (1H, m), 6.45 (2H, d, J = 8.8 Hz), 6.69 (1H, dd) , J = 2.3, 7.9 Hz), 6.73 (2H, d, J = 8.8 Hz), 6.84 (1H, t, J = 1.8 Hz), 7.00 (1H, brt, J = 7.9 Hz), 7.02 (1H, brd , J = 7.9 Hz), 7.18 (1H, t, J = 7.9 Hz), 7.67 (2H, d, J = 8.4 Hz), 7.83 (2H, d, J = 8.4 Hz);
MS (FAB) m / z: 550 [M + H]⁺ ;
Anal.Calcd for C₃₁ H₃₉ N₃ SO₄・ 0.5EtOAc: C, 66.75; H, 7.30; N, 7.08; S, 5.40. Found: C, 66.65; H, 7.05; N, 7.20; Cl, 5.56.

[Formulation example]
[Formulation Example 1] Powder A powder can be obtained by mixing 5 g of the compound of Example 13, lactose 895 g, and corn starch 100 g with a blender.
[Formulation Example 2] Granules 5 g of the compound of Example 14, 865 g of lactose and 100 g of low-substituted hydroxypropylcellulose are mixed, and 300 g of a 10% aqueous solution of hydroxypropylcellulose is added and kneaded. This is granulated using an extrusion granulator and dried to obtain a granule.
[Formulation Example 3] Tablet A tablet is obtained by mixing 5 g of the compound of Example 15, 90 g of lactose, 34 g of corn starch, 20 g of crystalline cellulose, and 1 g of magnesium stearate with a blender and tableting with a tablet machine.

[Test example]
[Test Example 1] Measurement of cathepsin K inhibitory activity An enzyme inhibition experiment using human cathepsin K was carried out according to the method described in Japanese Patent Application No. 9-151804.

ヒト−カテプシンＫ ｃＤＮＡの全翻訳領域を既報（Biochem.Biophys.Res.Commun., vol. 206, 89-96, 1995）のヒトカテプシンＫの塩基配列を基に，Ｑｕｉｃｋ−Ｓｃｒｅｅｎ^ＴＭ Ｈｕｍａｎ ｃＤＮＡ Ｌｉｂｒａｒｙ Ｐａｎｅｌ（クローンテク・ラボラトリー社製）に含まれるヒト肺ｃＤＮＡ（λｇｔ１１）を鋳型としてポリメラーゼ連鎖反応（Ｐｏｌｙｍｅｒａｓｅ Ｃｈａｉｎ Ｒｅａｃｔｉｏｎ：以下ＰＣＲ）法によりクローニングした。このｃＤＮＡよりプロ成熟体に相当する領域をＰＣＲ法により増幅してサブクローニングを行い、大腸菌の発現ベクターｐＴｒｃＨｉｓＢ（ストラタゲン社製）に挿入して発現プラスミドを作成した。このプラスミドを用いて大腸菌Ｍ１５［ｐＲＥＰ４］株（キアゲン社製）を形質転換してヒトカテプシンＫを発現させた。精製後にリフォールディングを行い、さらにｐＨを４．０に下げ、自己消化（オートプロセシング）を行わせ、活性型のヒトカテプシンＫを得た。Human cathepsin K cDNA of the entire coding region previously reported (Biochem.Biophys.Res.Commun., Vol. 206, 89-96, 1995) based on the nucleotide sequence of human cathepsin K^{of, Quick-Screen TM Human cDNA Library} Panel The clone was cloned by a polymerase chain reaction (hereinafter, PCR) method using human lung cDNA (λgt11) contained in (Clontech Laboratories) as a template. From this cDNA, a region corresponding to a pro-mature was amplified by PCR and subcloned, and inserted into an E. coli expression vector pTrcHisB (Stratagen) to prepare an expression plasmid. Escherichia coli M15 [pREP4] strain (manufactured by Qiagen) was transformed with this plasmid to express human cathepsin K. After the purification, refolding was performed, the pH was further lowered to 4.0, and autodigestion (autoprocessing) was performed to obtain active human cathepsin K.

活性型ヒトカテプシンＫに基質として終濃度８ＭのＺ−フェニルアラニン−アルギニン−アミノメチルクマリン（Ｚ−Ｐｈｅ−Ａｒｇ−ＡＭＣ（ペプチド研究所製）と試験化合物を加え、３７℃で３０分間反応した。反応停止液（１Ｍ Ｔｒｉｓ−ＨＣｌ(ｐＨ＝１０．０)）を加え、蛍光測定器（ＡＲＶＯ_ｓｘ１４２０（ワラック社製）を用いて遊離したアミノメチルクマリンの蛍光（励起波長３５５ｎｍ，蛍光波長４６０ｎｍ）を測定した。対照としては試験化合物の溶液の代わりに試験化合物を溶解するために用いた溶媒を加え、このときの酵素活性を１００％とした。試験化合物を添加したときの酵素活性及び対照の酵素活性から、試験化合物のカテプシンＫ阻害活性を算出した。
表１に実施例化合物のカテプシンＫ阻害活性を示す。To the activated human cathepsin K, a test compound and Z-phenylalanine-arginine-aminomethylcoumarin (Z-Phe-Arg-AMC (manufactured by Peptide Research Laboratories)) having a final concentration of 8 M were added as substrates, and reacted at 37 ° C. for 30 minutes. stop solution (1M Tris-HCl (pH = 10.0)) was added, the fluorescence measuring apparatus_{(fluorescence} of the liberated aminomethylcoumarin using ARVO sx 1420 (Wallac, Inc.) (excitation wavelength: 355 nm, fluorescence wavelength 460 nm) As a control, a solvent used for dissolving the test compound was added instead of the test compound solution, and the enzyme activity at this time was set to 100%. The cathepsin K inhibitory activity of the test compound was calculated from the activity.
Table 1 shows the cathepsin K inhibitory activity of the compounds of the examples.

_（表１_）
---------------------------------------
試験化合物 阻害率（％、2μM）
---------------------------------------
実施例１の化合物 90
実施例２の化合物 93
実施例３の化合物 86
実施例４の化合物 91
実施例５の化合物 89
実施例６の化合物 80
実施例７の化合物 91
実施例８の化合物 93
実施例９の化合物 91
実施例１０の化合物 89
実施例１１の化合物 85
実施例１２の化合物 80
実施例１３の化合物 97
実施例１４の化合物 97
実施例１５の化合物 97
実施例１６の化合物 93
実施例１７の化合物 83
実施例１８の化合物 89
---------------------------------------
₍ Table 1₎
---------------------------------------
Test compound inhibition rate (%, 2 μM)
---------------------------------------
Compound of Example 1 90
Compound 93 of Example 2
Compound of Example 3 86
Compound of Example 4 91
Compound of Example 5 89
Compound of Example 6 80
Compound of Example 7 91
Compound 93 of Example 8
Compound of Example 9 91
Compound of Example 10 89
Compound of Example 11 85
Compound of Example 12 80
Compound 97 of Example 13
Compound of Example 14 97
Compound of Example 15 97
Compound 93 of Example 16
Compound of Example 17 83
Compound of Example 18 89
---------------------------------------

本発明の化合物は、カテプシンＫを阻害するので、カテプシンＫ阻害剤（特に、骨粗鬆症又は変形性関節症の予防剤又は治療剤）として有用である。  Since the compound of the present invention inhibits cathepsin K, it is useful as a cathepsin K inhibitor (particularly, a prophylactic or therapeutic agent for osteoporosis or osteoarthritis).

Claims (27)

Translated fromJapanese

下記一般式（Ｉ）

｛式中、
Ｒ^１及びＲ^２は、同一若しくは異なって、それぞれ、水素原子又はＣ_１−Ｃ_８アルキル基を示すか、或いは、Ｒ^１及びＲ^２は、それらが結合している炭素原子と一緒になって、置換基群αから選択される基で置換されていてもよいＣ_３−Ｃ_８シクロアルキル基を形成し、
Ｒ^３は、水素原子；置換基群βから選択される少なくとも１個の基で置換されたＣ_１−Ｃ_６アルキル基；置換基群βから選択される少なくとも１個の基で置換されたＣ_１−Ｃ_６アルコキシ基；置換基群αから選択される基で置換されていてもよいＣ_６−Ｃ_１０アリール基；置換基群αから選択される基で置換されていてもよい、硫黄原子、酸素原子及び／又は窒素原子を１乃至３個含む５乃至７員ヘテロアリール基；置換基群αから選択される基で置換されていてもよいＣ_３−Ｃ_８シクロアルキル基；置換基群αから選択される基で置換されていてもよい、硫黄原子、酸素原子及び／又は窒素原子を１乃至３個含む５乃至７員ヘテロシクリル基；置換基群αから選択される基で置換されていてもよいＣ_６−Ｃ_１０アリールオキシ基；置換基群αから選択される基で置換されていてもよい、硫黄原子、酸素原子及び／又は窒素原子を１乃至３個含む５乃至７員ヘテロアリールオキシ基；置換基群αから選択される基で置換されていてもよいＣ_３−Ｃ_８シクロアルキルオキシ基；或いは、置換基群αから選択される基で置換されていてもよい、硫黄原子、酸素原子及び／又は窒素原子を１乃至３個含む５乃至７員ヘテロシクリルオキシ基を示し、
Ｒ^４は、Ｃ_１−Ｃ_８アルキル基、置換基群αから選択される基で置換されていてもよいＣ_６−Ｃ_１０アリール基、又は下記一般式（ＩＩ）
Ｒ^５−（ＣＨ_２）_ｍ− （ＩＩ）
［式中、
ｍは１乃至８の整数を示し、
Ｒ^５は、置換基群αから選択される基で置換されていてもよいＣ_６−Ｃ_１０アリール基；置換基群αから選択される基で置換されていてもよい、硫黄原子、酸素原子及び／又は窒素原子を１乃至３個含む５乃至７員ヘテロアリール基；置換基群αから選択される基で置換されていてもよいＣ_３−Ｃ_８シクロアルキル基；カルバモイル基；アミノ基；Ｃ_１−Ｃ_６アルキルアミノ基；ジ（Ｃ_１−Ｃ_６アルキル）アミノ基；グアニジル基；或いは、式Ｒ^６−Ｏ−、Ｒ^６−Ｓ−又はＲ^６−Ｏ−ＣＯ−（式中、Ｒ^６は、水素原子、置換基群βから選択される基で置換されていてもよいＣ_１−Ｃ_６アルキル基、又は置換基群αから選択される基で置換されていてもよいＣ_６−Ｃ_１０アリール基を示す。）で表される基を示す。］
で表される基を示し、
Ａｒは、置換基群α、置換基群β及び置換基群γから選択される基で置換されていてもよいＣ_６−Ｃ_１０アリール基；或いは、置換基群α、置換基群β及び置換基群γから選択される基で置換されていてもよい、硫黄原子、酸素原子及び／又は窒素原子を１乃至３個含む５乃至７員ヘテロアリール基を示し、
Ｘは、単結合、−ＮＨ−、−Ｏ−、−Ｓ−、−ＣＯＮＨ−、−ＳＯ_２ＮＨ−、−ＳＯＮＨ−、又は−Ｏ−ＣＯＮＨ−を示し、
Ｚは、置換基群βから選択される少なくとも１個の基で置換されたＣ_１−Ｃ_６アルキル基；置換基群αから選択される基で置換されていてもよいＣ_６−Ｃ_１０アリール基；置換基群αから選択される基で置換されていてもよい、硫黄原子、酸素原子及び／又は窒素原子を１乃至３個含む５乃至７員ヘテロアリール基；置換基群αから選択される基で置換されていてもよいＣ_３−Ｃ_８シクロアルキル基；或いは、置換基群αから選択される基で置換されていてもよい、硫黄原子、酸素原子及び／又は窒素原子を１乃至３個含む５乃至７員ヘテロシクリル基を示し、
置換基群αは、ハロゲン原子、Ｃ_１−Ｃ_６アルキル基、Ｃ_１−Ｃ_６ハロゲン化アルキル基、ホルミル基、（Ｃ_１−Ｃ_６アルキル）カルボニル基、（Ｃ_１−Ｃ_６ハロゲン化アルキル）カルボニル基、ニトロ基、シアノ基、アミノ基、Ｃ_１−Ｃ_６アルキルアミノ基、ジ（Ｃ_１−Ｃ_６アルキル）アミノ基、Ｃ_１−Ｃ_６アルコキシ基、Ｃ_１−Ｃ_６ハロゲン化アルコキシ基、Ｃ_１−Ｃ_６アルキルチオ基、Ｃ_１−Ｃ_６アルキルスルホニル基、Ｃ_１−Ｃ_６ヒドロキシアルキル基、Ｃ_１−Ｃ_６アルコキシＣ_１−Ｃ_６アルキル基、Ｃ_１−Ｃ_６アルキレンジオキシ基、Ｃ_１−Ｃ_６アミノアルキル基、Ｃ_２−Ｃ_６アミノアルコキシ基、式−ＣＯ−Ｒ^７（式中、Ｒ^７は、水酸基、Ｃ_１−Ｃ_６アルコキシ基、Ｃ_６−Ｃ_１０アリールオキシ基、Ｃ_６−Ｃ_１０アリールＣ_１−Ｃ_６アルコキシ基、アミノ基、Ｃ_１−Ｃ_６アルキルアミノ基、ジ（Ｃ_１−Ｃ_６アルキル）アミノ基を示す）で表される基、及びテトラゾリル基からなる群を示し、
置換基群βは、置換基群αから選択される基で置換されていてもよいＣ_６−Ｃ_１０アリール基；置換基群αから選択される基で置換されていてもよい、硫黄原子、酸素原子及び／又は窒素原子を１乃至３個含む５乃至７員ヘテロアリール基；置換基群αから選択される基で置換されていてもよいＣ_３−Ｃ_８シクロアルキル基；置換基群αから選択される基で置換されていてもよい、硫黄原子、酸素原子及び／又は窒素原子を１乃至３個含む５乃至７員ヘテロシクリル基；置換基群αから選択される基で置換されていてもよいＣ_６−Ｃ_１０アリールオキシ基；置換基群αから選択される基で置換されていてもよい、硫黄原子、酸素原子及び／又は窒素原子を１乃至３個含む５乃至７員ヘテロアリールオキシ基；置換基群αから選択される基で置換されていてもよいＣ_３−Ｃ_８シクロアルキルオキシ基；並びに、置換基群αから選択される基で置換されていてもよい、硫黄原子、酸素原子及び／又は窒素原子を１乃至３個含む５乃至７員ヘテロシクリルオキシ基からなる群を示し、
置換基群γは、置換基群α及び置換基群βから選択される基で置換されていてもよいＣ_１−Ｃ_６アルキル基、置換基群α及び置換基群βから選択される基で置換されていてもよいＣ_１−Ｃ_６アルコキシ基、置換基群α及び置換基群βから選択される基で置換されていてもよいＣ_２−Ｃ_６アルケニル基、並びに、置換基群α及び置換基群βから選択される基で置換されていてもよいＣ_２−Ｃ_６アルケニルオキシ基からなる群を示す。｝
を有する化合物又はその薬理上許容される塩。
The following general formula (I)

中
R¹ and R² are the same or different and each represent a hydrogen atom or a C₁ -C₈ alkyl group, or R¹ and R² together with the carbon atom to which they are attached Forming a C₃ -C₈ cycloalkyl group which may be substituted with a group selected from substituent group α,
R³ represents a hydrogen atom; a C₁ -C₆ alkyl group substituted with at least one group selected from substituent group β; a C₁ -C₆ alkyl group substituted with at least one group selected from substituent group β.₁ -C₆ alkoxy groups; optionally substituted with a group selected from substituent group α C₆ -C₁₀ aryl group; optionally substituted with a group selected from substituent group alpha, a sulfur atom A 5- to 7-membered heteroaryl group containing 1 to 3 oxygen atoms and / or nitrogen atoms; a C₃ -C₈ cycloalkyl group optionally substituted with a group selected from the substituent group α; a 5- to 7-membered heterocyclyl group containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms, which may be substituted with a group selected from α; substituted with a group selected from substituent group α which may be_C 6_{-C 10} aryloxy group; location A 5- to 7-membered heteroaryloxy group containing 1 to 3 sulfur, oxygen and / or nitrogen atoms, which may be substituted with a group selected from group α; a group selected from substituent group α in an optionally substituted C₃ -C₈ cycloalkyloxy group; or optionally substituted with a group selected from substituent group alpha, a sulfur atom, an oxygen atom and / or nitrogen atoms from 1 to 3 Represents a 5- to 7-membered heterocyclyloxy group,
R⁴ is a C₁ -C₈ alkyl group, a C₆ -C₁₀ aryl group which may be substituted with a group selected from substituent group α, or the following general formula (II)
R^5- (CH₂ )_m- (II)
[Where,
m represents an integer of 1 to 8,
R⁵ is a C₆ -C₁₀ aryl group which may be substituted with a group selected from substituent group α; a sulfur atom, an oxygen atom which may be substituted with a group selected from substituent group α. And / or a 5- to 7-membered heteroaryl group containing 1 to 3 nitrogen atoms; a C₃ -C₈ cycloalkyl group optionally substituted with a group selected from substituent group α; a carbamoyl group; an amino group; A C₁ -C₆ alkylamino group; a di (C₁ -C₆ alkyl) amino group; a guanidyl group; or a compound represented by the formula R⁶ —O—, R⁶ —S— or R⁶ —O—CO— R⁶ is a hydrogen atom, it may be substituted with a group selected from the substituent group beta C₁ -C₆ alkyl group, or optionally substituted with a group selected from substituent group alpha C₆ -C shows a₁₀ aryl group.) a group represented by. ]
Represents a group represented by
Ar is a C₆ -C₁₀ aryl group which may be substituted with a group selected from substituent group α, substituent group β and substituent group γ; or, substituent group α, substituent group β and substituent A 5- to 7-membered heteroaryl group containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms, which may be substituted with a group selected from group γ,
X is a single bond, -NH -, - O -, - S -, - CONH -, - SO 2 NH -, - SONH-, or indicates -O-CONH-,
Z is a C₁ -C₆ alkyl group substituted with at least one group selected from substituent group β; C₆ -C₁₀ aryl optionally substituted with a group selected from substituent group α. A 5- to 7-membered heteroaryl group containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms, which may be substituted with a group selected from substituent group α; selected from substituent group α A C₃ -C₈ cycloalkyl group which may be substituted with a group selected from the group consisting of a sulfur atom, an oxygen atom and / or a nitrogen atom which may be substituted with a group selected from the substituent group α. A 5- to 7-membered heterocyclyl group containing 3
Substituent group α is a halogen atom, a C₁ -C₆ alkyl group, a C₁ -C₆ halogenated alkyl group, a formyl group, a (C₁ -C₆ alkyl) carbonyl group, a (C₁ -C₆ halogenated alkyl) ) Carbonyl, nitro, cyano, amino, C₁ -C₆ alkylamino, di (C₁ -C₆ alkyl) amino, C₁ -C₆ alkoxy, C₁ -C₆ halogenated alkoxy Group, C₁ -C₆ alkylthio group, C₁ -C₆ alkylsulfonyl group, C₁ -C₆ hydroxyalkyl group, C₁ -C₆ alkoxy C₁ -C₆ alkyl group, C₁ -C₆ alkylenedioxy_group, C 1 -C₆ aminoalkyl_group, C 2 -C₆ aminoalkoxy groups, wherein^{-CO-R 7} (wherein,^{R 7} is_hydroxyl, C 1 -C₆ alkoxy_group, C 6_{-C 10} arylene Oxy_group, C 6_{-C 10} aryl_C 1 -C₆ alkoxy group, amino_group, C 1 -C₆ alkylamino group, a group represented by di showing a_(C 1 -C₆ alkyl) amino group) and, A group consisting of a tetrazolyl group,
Substituent group β is a C₆ -C₁₀ aryl group which may be substituted with a group selected from substituent group α; a sulfur atom which may be substituted with a group selected from substituent group α, oxygen atom and / or nitrogen atoms from 1 to 3 5 to 7-membered containing heteroaryl group; which may be substituted with a group selected from the substituent group alpha C₃ -C₈ cycloalkyl group; substituent group alpha A 5- to 7-membered heterocyclyl group containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms, which may be substituted with a group selected from the group consisting of: A C₆ -C₁₀ aryloxy group; a 5- to 7-membered heteroaryl containing 1 to 3 sulfur, oxygen and / or nitrogen atoms which may be substituted with a group selected from the substituent group α. An oxy group; a group selected from the substituent group α Optionally substituted C₃ -C₈ cycloalkyloxy group; and 1 to 3 sulfur, oxygen and / or nitrogen atoms which may be substituted with a group selected from substituent group α. A group consisting of a 5- to 7-membered heterocyclyloxy group,
Substituent group γ is a C₁ -C₆ alkyl group which may be substituted with a group selected from substituent group α and substituent group β, and a group selected from substituent group α and substituent group β. A C₁ -C₆ alkoxy group which may be substituted, a C₂ -C₆ alkenyl group which may be substituted with a group selected from substituent group α and substituent group β, and substituent group α and shows a group consisting of optionally substituted C₂ -C₆ alkenyloxy group with a group selected from the substituent group beta. ｝
Or a pharmacologically acceptable salt thereof.
請求項１において、一般式（Ｉ）が、下記一般式（Ｉ’）であり、Ｒ^１が水素原子であり、Ｒ^２がＣ_１−Ｃ_８アルキル基であるか、或いは、Ｒ^１及びＲ^２が、それらが結合している炭素原子と一緒になって、置換基群αから選択される基で置換されていてもよいＣ_３−Ｃ_８シクロアルキル基を形成している化合物又はその薬理上許容される塩。

2. The method according to claim 1, wherein the general formula (I) is the following general formula (I ′), R¹ is a hydrogen atom, R² is a C₁ -C₈ alkyl group, or R¹ and R² is a compound or a pharmacological compound thereof, which together with the carbon atom to which they are bonded form a C₃ -C₈ cycloalkyl group which may be substituted with a group selected from the substituent group α. Above acceptable salts.

請求項１又は請求項２において、Ｒ^１が水素原子であり、Ｒ^２がＣ_１−Ｃ_４アルキル基であるか、或いは、Ｒ^１及びＲ^２が、それらが結合している炭素原子と一緒になって、置換基群αから選択される基で置換されていてもよいＣ_５−Ｃ_６シクロアルキル基を形成している化合物又はその薬理上許容される塩。3. The method according to claim 1, wherein R¹ is a hydrogen atom, R² is a C₁ -C₄ alkyl group, or R¹ and R² are the same as the carbon atom to which they are bonded. A compound forming a C₅ -C₆ cycloalkyl group which may be substituted with a group selected from the substituent group α, or a pharmaceutically acceptable salt thereof.請求項１又は請求項２において、Ｒ^１が水素原子であり、Ｒ^２がイソブチルであるか、或いは、Ｒ^１及びＲ^２が、それらが結合している炭素原子と一緒になって、シクロヘキシルを形成している化合物又はその薬理上許容される塩。
In claim 1 or claim 2, R¹ is a hydrogen atom and R² is isobutyl, or R¹ and R² together with the carbon atom to which they are attached form cyclohexyl. A compound being formed or a pharmacologically acceptable salt thereof.
請求項１乃至請求項４から選択されるいずれか１項において、Ｒ^３が、置換基群αから選択される基で置換されていてもよいＣ_６−Ｃ_１０アリール基；置換基群αから選択される基で置換されていてもよい、硫黄原子、酸素原子及び／又は窒素原子を１乃至３個含む５乃至７員ヘテロアリール基；置換基群αから選択される基で置換されていてもよいＣ_３−Ｃ_８シクロアルキル基；置換基群αから選択される基で置換されていてもよい、硫黄原子、酸素原子及び／又は窒素原子を１乃至３個含む５乃至７員ヘテロシクリル基；置換基群αから選択される基で置換されていてもよいＣ_６−Ｃ_１０アリールオキシ基；置換基群αから選択される基で置換されていてもよい、硫黄原子、酸素原子及び／又は窒素原子を１乃至３個含む５乃至７員ヘテロアリールオキシ基；置換基群αから選択される基で置換されていてもよいＣ_３−Ｃ_８シクロアルキルオキシ基；或いは、置換基群αから選択される基で置換されていてもよい、硫黄原子、酸素原子及び／又は窒素原子を１乃至３個含む５乃至７員ヘテロシクリルオキシ基である化合物又はその薬理上許容される塩。5. The method according to claim 1, wherein R³ is a C₆ -C₁₀ aryl group optionally substituted with a group selected from the substituent group α; 5. A 5- to 7-membered heteroaryl group containing 1 to 3 sulfur, oxygen and / or nitrogen atoms, which may be substituted with a selected group; substituted with a group selected from substituent group α which may C₃ -C₈ cycloalkyl group; optionally substituted with a group selected from substituent group alpha, a sulfur atom, an oxygen atom and / or nitrogen atoms from 1 to 3 containing 5 to 7-membered heterocyclyl group A C₆ -C₁₀ aryloxy group optionally substituted with a group selected from substituent group α; a sulfur atom, an oxygen atom, and / or a group optionally substituted with a group selected from substituent group α. Or a 5-7 member containing 1 to 3 nitrogen atoms. A t3-aryloxy group; a C₃ -C₈ cycloalkyloxy group optionally substituted with a group selected from substituent group α; or, optionally, a group selected from substituent group α. A 5- to 7-membered heterocyclyloxy group containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms, or a pharmaceutically acceptable salt thereof.請求項１乃至請求項４から選択されるいずれか１項において、Ｒ^３が、置換基群αから選択される基で置換されていてもよいＣ_６−Ｃ_１０アリール基；置換基群αから選択される基で置換されていてもよい、硫黄原子、酸素原子及び／又は窒素原子を１乃至３個含む５乃至７員ヘテロアリール基；置換基群αから選択される基で置換されていてもよいＣ_３−Ｃ_８シクロアルキル基；或いは、置換基群αから選択される基で置換されていてもよい、硫黄原子、酸素原子及び／又は窒素原子を１乃至３個含む５乃至７員ヘテロシクリル基；置換基群αから選択される基で置換されていてもよいＣ_６−Ｃ_１０アリールオキシ基である化合物又はその薬理上許容される塩。5. The method according to claim 1, wherein R³ is a C₆ -C₁₀ aryl group which may be substituted with a group selected from the substituent group α; 5. A 5- to 7-membered heteroaryl group containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms, which may be substituted with a selected group; substituted with a group selected from substituent group α A C₃ -C₈ cycloalkyl group; or a 5- to 7-membered group containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms, which may be substituted with a group selected from substituent group α. Heterocyclyl group; a compound which is a C₆ -C₁₀ aryloxy group which may be substituted with a group selected from substituent group α, or a pharmaceutically acceptable salt thereof.請求項１乃至請求項４から選択されるいずれか１項において、Ｒ^３が、置換基群αから選択される基で置換されていてもよいＣ_６−Ｃ_１０アリール基；或いは、置換基群αから選択される基で置換されていてもよい、硫黄原子、酸素原子及び／又は窒素原子を１乃至３個含む５乃至７員ヘテロアリール基である化合物又はその薬理上許容される塩。5. The method according to claim 1, wherein R³ is a C₆ -C₁₀ aryl group which may be substituted with a group selected from the substituent group α; or a substituent group. A compound or a pharmacologically acceptable salt thereof, which is a 5- to 7-membered heteroaryl group containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms, which may be substituted with a group selected from α.請求項１乃至請求項４から選択されるいずれか１項において、Ｒ^３が、フェニル；メチル、メトキシ、フッ素原子、塩素原子、トリフロロメチル、トリフロロメトキシ、水酸基、ヒドロキシメチル及びアミノ基からなる群から選択される１個の基で置換されたフェニル；チエニル又はフリルである化合物又はその薬理上許容される塩。5. The method according to claim 1, wherein R³ is phenyl; methyl, methoxy, fluorine, chlorine, trifluoromethyl, trifluoromethoxy, hydroxyl, hydroxymethyl and amino. A compound or a pharmaceutically acceptable salt thereof, which is phenyl substituted with one group selected from the group; thienyl or furyl.請求項１乃至請求項４から選択されるいずれか１項において、Ｒ^３が、フェニル、２−メチルフェニル、３−メチルフェニル、４−メチルフェニル、２−メトキシフェニル、３−メトキシフェニル、４−メトキシフェニル、２−フロロフェニル、３−フロロフェニル、４−フロロフェニル、２−クロロフェニル、３−クロロフェニル、４−クロロフェニル、３−トリフロロメチルフェニル、４−トリフロロメチルフェニル、３−トリフロロメトキシフェニル、４−トリフロロメトキシフェニル、３−ヒドロキシフェニル、４−ヒドロキシフェニル、３−ヒドロキシメチルフェニル、４−ヒドロキシメチルフェニル、３−アミノフェニル又は４−アミノフェニルである化合物又はその薬理上許容される塩。
The method according to any one of claims 1 to 4, wherein R³ is phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, Methoxyphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3-trifluoromethoxyphenyl , 4-trifluoromethoxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 3-hydroxymethylphenyl, 4-hydroxymethylphenyl, 3-aminophenyl or 4-aminophenyl or a pharmaceutically acceptable salt thereof .
請求項１乃至請求項９から選択されるいずれか１項において、Ｒ^４が、Ｃ_１−Ｃ_８アルキル基、４−アミノブチル、３−グアニジルプロピル、又は下記一般式（ＩＩ）
Ｒ^５−（ＣＨ_２）_ｍ− （ＩＩ）
（式中、ｍは１又は２を示す。）で表される基である化合物又はその薬理上許容される塩。10. The method according to claim 1, wherein R⁴ is a C₁ -C₈ alkyl group, 4-aminobutyl, 3-guanidylpropyl, or the following general formula (II): 11.
R^5- (CH₂ )_m- (II)
(Wherein m represents 1 or 2) or a pharmacologically acceptable salt thereof.請求項１乃至請求項９から選択されるいずれか１項において、Ｒ^４が、Ｃ_１−Ｃ_４アルキル基、ベンジル、フェネチル、シクロヘキシルメチル、シクロヘキシルエチル、ヒドロキシメチル、ベンジルオキシメチル、メルカプトメチル、メチルチオエチル、ベンジルチオメチル、カルボキシメチル、カルボキシエチル、カルバモイルメチル、カルバモイルエチル、アミノブチル、グアニジルプロピル、イミダゾール−４−イルメチル又はインドール−３−イルメチルである化合物又はその薬理上許容される塩。10. In any one of claims 1 to 9, wherein R⁴ is a C₁ -C₄ alkyl group, benzyl, phenethyl, cyclohexylmethyl, cyclohexylethyl, hydroxymethyl, benzyloxymethyl, mercaptomethyl, methylthio A compound which is ethyl, benzylthiomethyl, carboxymethyl, carboxyethyl, carbamoylmethyl, carbamoylethyl, aminobutyl, guanidylpropyl, imidazol-4-ylmethyl or indol-3-ylmethyl, or a pharmaceutically acceptable salt thereof.請求項１乃至請求項９から選択されるいずれか１項において、Ｒ^４が、Ｃ_１−Ｃ_４アルキル基である化合物又はその薬理上許容される塩。
The compound according to any one of claims 1 to 9, wherein R⁴ is a C₁ -C₄ alkyl group, or a pharmaceutically acceptable salt thereof.
請求項１乃至請求項１２から選択されるいずれか１項において、Ａｒが、置換基群α、置換基群β及び置換基群γから選択される基で置換されていてもよいＣ_６−Ｃ_１０アリール基である化合物又はその薬理上許容される塩。13. The C₆ -C according to any one of claims 1 to 12, wherein Ar is optionally substituted with a group selected from the group of substituents α, β and γ._A compound having₁₀ aryl groups or a pharmacologically acceptable salt thereof.請求項１乃至請求項１２から選択されるいずれか１項において、Ａｒが、置換基群α及び置換基群βから選択される基で置換されていてもよいＣ_１−Ｃ_６アルコキシ基で置換されたＣ_６−Ｃ_１０アリール基である化合物又はその薬理上許容される塩。Substituted at any one selected from claims 1 to 12, Ar is, in optionally substituted C₁ -C₆ alkoxy group with a group selected from Substituent group α and Substituent group β Or a pharmacologically acceptable salt thereof, wherein the compound is a C₆ -C₁₀ aryl group.請求項１乃至請求項１２から選択されるいずれか１項において、Ａｒが、パラ位に、置換基群α及び置換基群βから選択される基で置換されていてもよいＣ_１−Ｃ_６アルコキシ基を有するフェニルである化合物又はその薬理上許容される塩。13. The compound according to claim 1, wherein Ar is substituted at the para-position with C₁ -C₆ which may be substituted with a group selected from substituent group α and substituent group β. A compound which is phenyl having an alkoxy group or a pharmacologically acceptable salt thereof.請求項１乃至請求項１２から選択されるいずれか１項において、Ａｒが、ｐ−メトキシフェニル、ｐ−ベンジルオキシフェニル、ｐ−カルボキシメチルオキシフェニル又はｐ−（ｔ−ブトキシカルボニルメチル）フェニルである化合物又はその薬理上許容される塩。
In any one of the claims 1 to 12, Ar is p-methoxyphenyl, p-benzyloxyphenyl, p-carboxymethyloxyphenyl or p- (t-butoxycarbonylmethyl) phenyl A compound or a pharmacologically acceptable salt thereof.
請求項１乃至請求項１６から選択されるいずれか１項において、Ｘが、単結合、−ＮＨ−、−Ｏ−、−ＣＯＮＨ−、−ＳＯ_２ＮＨ−、又は−Ｏ−ＣＯＮＨ−である化合物又はその薬理上許容される塩。In any one selected from claims 1 to 16, X is a single bond, -NH -, - O -, - CONH -, - SO 2 NH-, or -O-CONH-, compound Or a pharmacologically acceptable salt thereof.請求項１乃至請求項１６から選択されるいずれか１項において、Ｘが、−ＮＨ−、−ＣＯＮＨ−、又は−ＳＯ_２ＮＨ−である化合物又はその薬理上許容される塩。In any one selected from claims 1 to 16, X is, -NH -, - CONH-, or a compound or a pharmacologically acceptable salt thereof is a_-SO 2 NH-.請求項１乃至請求項１６から選択されるいずれか１項において、Ｘが、−ＮＨ−である化合物又はその薬理上許容される塩。
17. The compound according to any one of claims 1 to 16, wherein X is -NH-, or a pharmaceutically acceptable salt thereof.
請求項１乃至請求項１９から選択されるいずれか１項において、Ｚが、置換基群βから選択される少なくとも１個の基で置換されたＣ_１−Ｃ_６アルキル基；置換基群αから選択される基で置換されていてもよいＣ_６−Ｃ_１０アリール基；或いは、置換基群αから選択される基で置換されていてもよい、硫黄原子、酸素原子及び／又は窒素原子を１乃至３個含む５乃至７員ヘテロアリール基である化合物又はその薬理上許容される塩。20. The method according to claim 1, wherein Z is a C₁ -C₆ alkyl group substituted with at least one group selected from a substituent group β; A C₆ -C₁₀ aryl group which may be substituted with a selected group; or a sulfur atom, an oxygen atom and / or a nitrogen atom which may be substituted with a group selected from a substituent group α. Or a pharmacologically acceptable salt thereof, which is a 5- to 7-membered heteroaryl group containing 1 to 3 members.請求項１乃至請求項１９から選択されるいずれか１項において、Ｚが、置換基群αから選択される基で置換されていてもよいＣ_６−Ｃ_１０アリール基；或いは、置換基群αから選択される基で置換されていてもよい、硫黄原子、酸素原子及び／又は窒素原子を１乃至３個含む５乃至７員ヘテロアリール基である化合物又はその薬理上許容される塩。In any one selected from claims 1 to 19, Z is, which may be C₆ -C₁₀ aryl group substituted with a group selected from substituent group alpha; or substituent group alpha A 5- to 7-membered heteroaryl group containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms, or a pharmacologically acceptable salt thereof, which may be substituted with a group selected from the group consisting of:請求項１乃至請求項２１から選択されるいずれか１項において、Ｚが、置換基群αから選択される基で置換されていてもよいＣ_６−Ｃ_１０アリール基である化合物又はその薬理上許容される塩。In any one selected from claims 1 to 21, Z is optionally substituted with a group selected from substituent group α is also good C₆ -C₁₀ aryl group compound or a pharmacologically Acceptable salt.請求項１乃至請求項２１から選択されるいずれか１項において、Ｚが、置換基群αから選択される基で置換されていてもよい１，３−フェニレンである化合物又はその薬理上許容される塩。
The compound according to any one of claims 1 to 21, wherein Z is 1,3-phenylene which may be substituted with a group selected from the substituent group α, or a pharmacologically acceptable compound thereof. Salt.
請求項１において、下記から選択される1つの化合物又はその薬理上許容される塩：
・Ｎ^２−１，１’−ビフェニル−３−イル−Ｎ^１−（（１Ｓ）−１−｛［（４−メトキシフェニル）アミノ］メチル｝プロピル）−Ｌ−ロイシンアミド、
・Ｎ^２−１，１’−ビフェニル−３−イル−Ｎ^１−（（１Ｓ）−１−｛［（４−メトキシフェニル）アミノ］メチル｝ブチル）−Ｌ−ロイシンアミド
・Ｎ^２−１，１’−ビフェニル−３−イル−Ｎ^１−（（１Ｓ）−１−｛［（４−メトキシフェニル）アミノ］メチル｝ペンチル）−Ｌ−ロイシンアミド
・Ｎ^１−（（１Ｓ）−１−｛［（４−ベンジルオキシフェニル）アミノ］メチル｝プロピル）−Ｎ^２−（１，１‘−ビフェニル−３−イル）−L−ロイシナミド、
・１−（１，１’−ビフェニル−３−イルアミノ）−Ｎ−（（１Ｓ）−１−｛［（４−メトキシフェニル）アミノ］メチル｝プロピル）シクロヘキサンカルボキサミド、
・１−（１，１’−ビフェニル−３−イルアミノ）−Ｎ−（（１Ｓ）−１−｛［（４−メトキシフェニル）アミノ］メチル｝ブチル）シクロヘキサンカルボキサミド、
・１−（１，１’−ビフェニル−３−イルアミノ）−Ｎ−（（１Ｓ）−１−｛［（４−メトキシフェニル）アミノ］メチル｝ペンチル）シクロヘキサンカルボキサミド、
・１−（１，１‘−ビフェニル−３−イルアミノ）−Ｎ−（（１Ｓ）−１−｛［（４−ベンジルオキシフェニル）アミノ］メチル｝プロピル）シクロヘキサンカルボキサミド、
・ｔｅｒｔ−ブチル （４−｛[（２Ｓ）−２−（｛[１−（１，１‘−ビフェニル−３−イルアミノ）シクロヘキシル]カルボニル｝アミノ）ブチル]アミノ｝フェノキシ）アセテート、
・（４−｛[（２Ｓ）−２−（｛[１−（１，１‘−ビフェニル−３−イルアミノ）シクロヘキシル]カルボニル｝アミノ）ブチル]アミノ｝フェノキシ）酢酸、
・［４−（｛（２Ｓ）−２−［（Ｎ−１，１‘−ビフェニル−３−イル−Ｌ−ロイシル）アミノ］ブチル｝アミノ）フェノキシ］酢酸 ｔｅｒｔ−ブチル、及び
・［４−（｛（２Ｓ）−２−［（Ｎ−１，１‘−ビフェニル−３−イル−Ｌ−ロイシル）アミノ］ブチル｝アミノ）フェノキシ］酢酸。
2. The compound according to claim 1, wherein the compound is selected from the group consisting of:
·^N 2-1,1'-biphenyl-3-yl^{-N 1 - ((1S) -1} - {[(4- methoxyphenyl) amino] methyl} propyl) -L- leucinamide,
·^N 2-1,1'-biphenyl-3-yl^{-N 1 - ((1S) -1} - {[(4- methoxyphenyl) amino] methyl} butyl) -L- leucinamide^· N 2 -1, 1′-biphenyl-3-yl-N¹ -((1S) -1-{[(4-methoxyphenyl) amino] methyl} pentyl) -L-leucinamide / N¹ -((1S) -1-} [(4-benzyloxyphenyl) amino] methyl} propyl) -N^2- (1,1′-biphenyl-3-yl) -L-leucinamide,
1- (1,1′-biphenyl-3-ylamino) -N-((1S) -1-{[(4-methoxyphenyl) amino] methyl} propyl) cyclohexanecarboxamide;
1- (1,1'-biphenyl-3-ylamino) -N-((1S) -1-{[(4-methoxyphenyl) amino] methyl} butyl) cyclohexanecarboxamide;
1- (1,1′-biphenyl-3-ylamino) -N-((1S) -1-{[(4-methoxyphenyl) amino] methyl} pentyl) cyclohexanecarboxamide;
1- (1,1′-biphenyl-3-ylamino) -N-((1S) -1-{[(4-benzyloxyphenyl) amino] methyl} propyl) cyclohexanecarboxamide;
-Tert-butyl (4-{[(2S) -2-({[1- (1,1'-biphenyl-3-ylamino) cyclohexyl] carbonyl} amino) butyl] amino} phenoxy) acetate,
-(4-{[(2S) -2-({[1- (1,1'-biphenyl-3-ylamino) cyclohexyl] carbonyl} amino) butyl] amino} phenoxy) acetic acid,
Tert-butyl [4-({(2S) -2-[(N-1,1′-biphenyl-3-yl-L-leucyl) amino] butyl} amino) phenoxy] acetate; {(2S) -2-[(N-1,1′-biphenyl-3-yl-L-leucyl) amino] butyl} amino) phenoxy] acetic acid.
請求項１乃至請求項２４から選択されるいずれか１項に記載された化合物又はその薬理上許容される塩を有効成分として含有する医薬。A medicament comprising the compound according to any one of claims 1 to 24 or a pharmacologically acceptable salt thereof as an active ingredient.請求項１乃至請求項２４から選択されるいずれか１項に記載された化合物又はその薬理上許容される塩を有効成分として含有する、カテプシンＫ阻害剤。25. A cathepsin K inhibitor comprising the compound according to any one of claims 1 to 24 or a pharmaceutically acceptable salt thereof as an active ingredient.請求項１乃至請求項２４から選択されるいずれか１項に記載された化合物又はその薬理上許容される塩を有効成分として含有する、骨粗鬆症又は変形性関節症の予防若しくは治療剤）An agent for preventing or treating osteoporosis or osteoarthritis, comprising as an active ingredient the compound according to any one of claims 1 to 24 or a pharmacologically acceptable salt thereof.