JP2020055751A - Novel compound and taste-improving agent containing that compound - Google Patents

Abstract

To provide a novel compound capable of imparting a sweet taste preferable to food by enhancing the sweetness of a sweetener such as sucrose.SOLUTION: The invention provides a compound represented by the general formula (I) in the figure or a salt thereof.SELECTED DRAWING: None

Description

  The present invention relates to a low molecular weight organic compound having a specific structure, a food composition containing the compound, a taste improving agent containing the compound, a food or drink containing the compound, a production intermediate of the food or drink, and a food or drink. The present invention relates to a method for producing goods or food and drink.

In recent years, diversification of eating habits and the like have increased consumer interest and demand for tastes such as five basic tastes represented by sweet, salty, sour, bitter, and umami.
At the same time, in response to growing interest in health, sweetened foods have been developed using low-calorie, high-sweetness sweeteners. At present, the sweetness is not sufficiently satisfactory.
On the other hand, Patent Document 1 discloses a compound containing a heterocyclic ring represented by the formula (IA), a composition that can be ingested into the body containing the compound, and a composition that enhances sweetness containing the compound. Patent Document 2 also discloses a compound similar to the compound of Patent Document 1. Patent Literature 3 discloses a compound containing a heterocycle represented by the formula (IB) and a sweet taste enhancing composition containing the compound. Patent Document 4 discloses a compound similar to the compound of Patent Document 3. Patent Literatures 1 to 4 describe that the compounds of the above general formulas have little sweetness by themselves, but can enhance the sweetness of sucralose and sucrose.

Japanese Patent No. 5931033 JP-T-2005-530370 Japanese Patent No. 5988506 Japanese Patent No. 5985640

However, Patent Documents 1 to 4 do not disclose the structures of the compounds used in the sensory evaluation in the examples, and it is unclear what specific structure of the compound has the above-mentioned sweetness. Further, the compounds described in Patent Documents 1 to 4 each have a bicyclic fused ring as a basic skeleton, and compounds having a chemical structure other than these and exhibiting a sweetness enhancing effect of food and drink are disclosed. It has not been.
The present invention has been made in view of the above points, and has an object to provide a novel compound having a chemical structure different from that of the compounds described in the above-mentioned patent documents and capable of enhancing the sweetness of food and drink. Aim.

（式中、
Ｒ₁、Ｒ₂はそれぞれ独立して、水素原子、ハロゲン原子、置換基を有してもよいＣ_1-6アルキル基又は置換基を有してもよいＣ_1-6アルコキシ基を表し、
Ｒ₃及びＲ₄は、それぞれ独立して、水素原子、又は置換基を有していてもよいＣ_1-6アルキル基を表し、
Ｒ₅は、置換基を有していてもよいＣ_1-12アルキル基、置換基を有していてもよい３〜１４員の脂環式基、置換基を有していてもよい３〜１４員の複素環式基、置換基を有していてもよい６〜１４員のアリール基、置換基を有していてもよい５〜１４員のヘテロアリール基、又は置換基を有していてもよいアミノ基を表し、
Ａは、ＮＨＣＯ、ＣＯＮＨ、単結合、ビニレン基、置換基を有していてもよい６〜１４員のアリーレン基、置換基を有していてもよい５〜１４員のヘテロアリーレン基、置換基を有していてもよい３〜１４員の二価の脂環式基、又は置換基を有していてもよい３〜１４員の二価の複素環式基を表し、
Ｄは、単結合、置換基を有していてもよいＣ_1-12アルキレン基、置換式を有していてもよい３〜１４員の二価の脂環式基、又は置換式を有していてもよい３〜１４員の二価の複素環式基を表し、且つ
Ｅは、単結合又は下記式（ＩＩ）：

（式中、＊は、隣接するＤへの結合を表し、
＊＊は隣接する窒素原子への結合を表し、
Ｒ₆及びＲ₇は、それぞれ独立して、水素原子、置換基を有していてもよいＣ_1-12アルキル基、置換基を有していてもよい３〜１４員の脂環式基、置換基を有していてもよい３〜１４員の複素環式基、置換基を有していてもよい６〜１４員のアリール基、又は置換基を有していてもよい５〜１４員のヘテロアリール基を表し、或いはＲ₆とＲ₇はこれらの基が結合する炭素原子とともに置換基を有していてもよい３〜８員の環を形成してもよく、或いはＲ₆とＲ₄はこれらの基が結合する炭素原子及び窒素原子とともに置換基を有していてもよい４〜８員の環を形成してもよい。）で表される基であり、
但し、Ａ、Ｄ及びＥが同時に単結合ではないことを条件とする。）
〔２〕 ＡがＮＨＣＯ、単結合、ビニレン基、ベンゼン環から２個の水素を除いた２価の基、フラン環から２個の水素を除いた２価の基、又はピラゾール環から２個の水素を除いた２価の基を表す、〔１〕に記載の化合物、その互変異性体若しくは立体異性体又はそれらの塩。
〔３〕 Ｒ₅が、下記式（ＩＩＩ）又は（ＩＶ）で表される基である、〔１〕又は〔２〕に記載の化合物、その互変異性体若しくは立体異性体又はそれらの塩。

（式中、Ｒ₈は、水素原子、置換基を有していてもよいＣ_1-8アルキル基又は置換基を有していてもよいＣ_1-8アルキルカルボニル基を表し、
Ｒ₉は、水素原子、置換基を有していてもよい３〜１４員の脂環式基、置換基を有していてもよい３〜１４員の複素環式基、置換基を有していてもよい６〜１４員のアリール基、置換基を有していてもよい５〜１４員のヘテロアリール基、又は置換基を有していてもよいＣ_1-8アルキル基を表し、且つ
＊＊＊は、隣接する炭素原子への結合を表す。）
〔４〕 下記一般式（Ｖ）〜（ＩＸ）のいずれかで表される化合物又はその塩である、〔１〕〜〔３〕のいずれかに記載の化合物、その互変異性体若しくは立体異性体又はそれらの塩。

（式中、Ｒ₅、Ｄ及びＥは、請求項１〜３のいずれか１項に記載した通りである。）
〔５〕 Ｄが単結合又は直鎖状のＣ_1-6アルキレン基である、〔１〕〜〔４〕のいずれかに記載の化合物、その互変異性体若しくは立体異性体又はそれらの塩。
〔６〕 一般式（Ｉ）中の下記式（Ｘ）：

（式中、＊＊＊＊は、隣接するピリジン環への結合を表し、＊＊＊＊＊は隣接するＣ＝Ｏの炭素原子への結合を表す）
で表される部分構造が、下記から成る群から選択される構造である、〔１〕〜〔５〕のいずれかに記載の化合物、その互変異性体若しくは立体異性体又はそれらの塩。

〔７〕 一般式（Ｉ）中の下記式（ＸＩ）：

（式中、＊＊＊＊＊＊は、隣接する窒素原子への結合部位を表す。）
で表される部分構造が、下記から成る群から選択される構造である、〔１〕〜〔６〕のいずれかに記載の化合物、その互変異性体若しくは立体異性体又はそれらの塩。

〔８〕 下記からなる群から選択される化合物又はその塩である、〔１〕に記載の化合物、その互変異性体若しくは立体異性体又はそれらの塩：
４−アミノ−５−[５−（Ｌ−シクロヘキシルグリシルアミノ）−ペンタノイルアミノ]−ニコチン酸
４−アミノ−５−［［３−［［（２Ｓ）−２−アミノ−２−シクロヘキシル−アセチル］アミノ］−３−メチル−ブタノイル］アミノ］ピリジン−３−カルボン酸
４−アミノ−５−［［３−［（２−シクロヘキシルアセチル）アミノ］−３−メチル−ブタノイル］アミノ］ピリジン−３−カルボン酸
４−アミノ−５−［５−［［［（２Ｓ）−２−アミノ−２−シクロヘキシル−アセチル］アミノ］メチル］−２−フリル］ピリジン−３−カルボン酸
４−アミノ−５−［（Ｅ）−４−［［（２Ｓ）−２−アミノ−２−シクロヘキシル−アセチル］アミノ］ブタ−１−エニル］ピリジン−３−カルボン酸
４−アミノ−５−［４−［［（２Ｓ）−２−アミノ−２−シクロヘキシル−アセチル］アミノ］ブチル］ピリジン−３−カルボン酸
４−アミノ−５−[[３−[[(２Ｓ)−２−［［(２Ｓ)−２−アミノ−３−メチル−ペンタノイル]アミノ］−２−シクロヘキシル−アセチル]アミノ]−３−メチル−ブタノイル]アミノ]ピリジン−３−カルボン酸
４−アミノ−５−［［（３Ｒ）−３−［［（２Ｓ）−２−アミノ−２−シクロヘキシル−アセチル］アミノ］−３−フェニル−プロパノイル］アミノ］ピリジン−３−カルボン酸
４−アミノ−５−［５−［（２−シクロヘキシルアセチル）アミノ］ペンタノイルアミノ］ピリジン−３−カルボン酸
４−アミノ−５−[[３−[[（２Ｓ，３Ｓ)−２−アミノ−３−メチル−ペンタノイル]アミノ]−３−メチル−ブタノイル]アミノ]ピリジン−３−カルボン酸
４−アミノ−５−[[３−[[（２Ｓ)−２−[[（２Ｓ)−２−アミノ−２−シクロヘキシル−アセチル]アミノ] −２−シクロヘキシル−アセチル]アミノ]−３−メチル−ブタノイル]アミノ]ピリジン−３−カルボン酸
４−アミノ−５−[[３−[[(２Ｓ)−２−[(２−アミノアセチル)アミノ]−２−シクロヘキシル−アセチル]アミノ]−３−メチル−ブタノイル]アミノ]ピリジン−３−カルボン酸
４−アミノ−５−[[３−[[(２Ｓ)−２−アミノ−３−メチル−ブタノイル]アミノ]−２−シクロヘキシル−アセチル]アミノ]−３−メチル−ブタノイル]アミノ]ピリジン−３−カルボン酸
４−アミノ−５−[[３−[[(２Ｓ)−２−[[(２Ｓ)−２−アミノ−４−メチル−ペンタノイル]アミノ]−２−シクロヘキシル−アセチル]アミノ]−３−メチル−ブタノイル]アミノ]ピリジン−３−カルボン酸
４−アミノ−５−［５−［［［（２Ｓ）−２−アミノ−３−メチル−ブタノイル］アミノ］メチル］−２−フリル］ピリジン−３−カルボン酸
４−アミノ−５−［５−［［［（２Ｓ）−２−アミノ−４−メチル−ペンタノイル］アミノ］メチル］−２−フリル］ピリジン−３−カルボン酸。
〔９〕 下記からなる群から選択される化合物又はその塩である、〔１〕に記載の化合物、その互変異性体若しくは立体異性体又はそれらの塩。

〔１０〕 前記塩が、塩酸塩、硫酸塩、リン酸塩、硝酸塩、臭化水素酸塩、酢酸塩、トリフルオロ酢酸塩、クエン酸塩、安息香酸塩、マレイン酸塩、フマル酸塩、酒石酸塩、コハク酸塩、タンニン酸塩、酪酸塩、ヒベンズ酸塩、パモ酸塩、エナント酸塩、デカン酸塩、テオクル酸塩、サリチル酸塩、乳酸塩、シュウ酸塩、マンデル酸塩、リンゴ酸塩、メタンスルホン酸塩、ベンゼンスルホン酸塩、ｐ−トルエンスルホン酸塩、グルタミン酸塩、アスパラギン酸塩、ナトリウム塩、カリウム塩、マグネシウム塩、カルシウム塩、リジン塩、オルニチン塩、アルギニン塩及びヒスチジン塩からなる群から選ばれる、〔１〕〜〔９〕のいずれかに記載の化合物、その互変異性体又はその立体異性体の塩。
〔１１〕 〔１〕〜〔１０〕のいずれかに記載の化合物、その互変異性体若しくは立体異性体又はそれらの塩を含有する食品組成物。
〔１２〕 〔１〕〜〔１０〕のいずれかに記載の化合物、その互変異性体若しくは立体異性体又はそれらの塩を含有する呈味改善剤。
〔１３〕 〔１〕〜〔１０〕のいずれかに記載の化合物、その互変異性体若しくは立体異性体又はそれらの塩を飲食品原料に添加する工程を含む、飲食品の製造方法。
〔１４〕 〔１〕〜〔１０〕のいずれかに記載の化合物、その互変異性体若しくは立体異性体又はそれらの塩を飲食品原料又は飲食品に添加する工程を含む、飲食品の甘味を増強する方法。 As a result of intensive efforts, the present inventors have found that the above-mentioned problems can be solved by a novel low-molecular-weight organic compound having a specific 4-aminonicotinic acid structure or a salt thereof. The present invention includes the following inventions.
[1] A compound represented by the following general formula (I), a tautomer or stereoisomer thereof, or a salt thereof.

(Where
R ₁ and R ₂ each independently represent a hydrogen atom, a halogen atom, a C _1-6 alkyl group which may have a substituent or a C _1-6 alkoxy group which may have a substituent,
R ₃ and R ₄ each independently represent a hydrogen atom or a C _1-6 alkyl group which may have a substituent,
R ₅ is a C _1-12 alkyl group which may have a substituent, a 3- to 14-membered alicyclic group which may have a substituent, or a 3- to 5-membered group which may have a substituent. A 14-membered heterocyclic group, a 6- to 14-membered aryl group which may have a substituent, a 5- to 14-membered heteroaryl group which may have a substituent, or a substituent Represents an amino group which may be
A is NHCO, CONH, a single bond, a vinylene group, a 6-14 membered arylene group which may have a substituent, a 5-14 membered heteroarylene group which may have a substituent, Represents a 3 to 14 membered divalent alicyclic group which may have, or a 3 to 14 membered divalent heterocyclic group which may have a substituent,
D has a single bond, a C _1-12 alkylene group which may have a substituent, a 3- to 14-membered divalent alicyclic group which may have a substituent, or a substituent. Represents a 3- to 14-membered divalent heterocyclic group, and E represents a single bond or the following formula (II):

(In the formula, * represents a bond to an adjacent D,
** represents a bond to an adjacent nitrogen atom,
R ₆ and R ₇ are each independently a hydrogen atom, a C _1-12 alkyl group which may have a substituent, a 3- to 14-membered alicyclic group which may have a substituent, A 3- to 14-membered heterocyclic group which may have a substituent, a 6- to 14-membered aryl group which may have a substituent, or a 5- to 14-membered which may have a substituent of represents a heteroaryl group, or R ₆ and R ₇ may form these groups is 3 to 8 membered which may have a substituent together with the carbon atom bonded ring, or R ₆ and R ₄ may form a 4- to 8-membered ring which may have a substituent together with a carbon atom and a nitrogen atom to which these groups are bonded. ) Is a group represented by
Provided that A, D and E are not simultaneously a single bond. )
[2] A is NHCO, a single bond, a vinylene group, a divalent group obtained by removing two hydrogens from a benzene ring, a divalent group obtained by removing two hydrogens from a furan ring, or two The compound according to [1], which represents a divalent group exclusive of hydrogen, a tautomer or stereoisomer thereof, or a salt thereof.
[3] The compound according to [1] or [2], wherein R ₅ is a group represented by the following formula (III) or (IV), a tautomer or stereoisomer or a salt thereof.

(Wherein, R ₈ represents a hydrogen atom, a C _1-8 alkyl group which may have a substituent or a C _1-8 alkylcarbonyl group which may have a substituent,
R ₉ has a hydrogen atom, a 3- to 14-membered alicyclic group which may have a substituent, a 3- to 14-membered heterocyclic group which may have a substituent, and a substituent An optionally substituted 6-14 membered aryl group, an optionally substituted 5-14 membered heteroaryl group, or an optionally substituted C _1-8 alkyl group, and *** represents a bond to an adjacent carbon atom. )
[4] The compound according to any one of [1] to [3], which is a compound represented by any of the following formulas (V) to (IX) or a salt thereof, a tautomer or stereoisomer thereof Body or their salts.

(In the formula, R ₅ , D, and E are as described in any one of claims 1 to 3.)
[5] The compound according to any one of [1] to [4], wherein D is a single bond or a linear C _1-6 alkylene group, a tautomer or stereoisomer thereof, or a salt thereof.
[6] The following formula (X) in the general formula (I):

(Wherein **** represents a bond to an adjacent pyridine ring, and **** represents a bond to an adjacent C 炭素 O carbon atom)
The compound according to any one of [1] to [5], wherein the partial structure represented by is a structure selected from the group consisting of the following, a tautomer or stereoisomer thereof, or a salt thereof.

[7] The following formula (XI) in the general formula (I):

(In the formula, **** represents a bonding site to an adjacent nitrogen atom.)
The compound according to any one of [1] to [6], wherein the partial structure represented by is a structure selected from the group consisting of the following, a tautomer or stereoisomer or a salt thereof.

[8] The compound according to [1], which is a compound selected from the group consisting of the following or a salt thereof, a tautomer or stereoisomer thereof, or a salt thereof:
4-amino-5- [5- (L-cyclohexylglycylamino) -pentanoylamino] -nicotinic acid 4-amino-5-[[3-[[(2S) -2-amino-2-cyclohexyl-acetyl] ] Amino] -3-methyl-butanoyl] amino] pyridine-3-carboxylic acid 4-amino-5-[[3-[(2-cyclohexylacetyl) amino] -3-methyl-butanoyl] amino] pyridine-3- Carboxylic acid 4-amino-5- [5-[[[(2S) -2-amino-2-cyclohexyl-acetyl] amino] methyl] -2-furyl] pyridine-3-carboxylic acid 4-amino-5- [ (E) -4-[[(2S) -2-amino-2-cyclohexyl-acetyl] amino] but-1-enyl] pyridine-3-carboxylic acid 4-amino-5- [4-[[(2S) − 2-Amino-2-cyclohexyl-acetyl] amino] butyl] pyridine-3-carboxylic acid 4-amino-5-[[3-[[(2S) -2-[[(2S) -2-amino-3- Methyl-pentanoyl] amino] -2-cyclohexyl-acetyl] amino] -3-methyl-butanoyl] amino] pyridine-3-carboxylic acid 4-amino-5-[[(3R) -3-[[(2S)- 2-amino-2-cyclohexyl-acetyl] amino] -3-phenyl-propanoyl] amino] pyridine-3-carboxylic acid 4-amino-5- [5-[(2-cyclohexylacetyl) amino] pentanoylamino] pyridine -3-Carboxylic acid 4-amino-5-[[3-[[(2S, 3S) -2-amino-3-methyl-pentanoyl] amino] -3-methyl-butanoyl] amino] pyridine-3-carbo 4-Amino-5-[[3-[[(2S) -2-[[(2S) -2-amino-2-cyclohexyl-acetyl] amino] -2-cyclohexyl-acetyl] amino] -3-methyl acid -Butanoyl] amino] pyridine-3-carboxylic acid 4-amino-5-[[3-[[(2S) -2-[(2-aminoacetyl) amino] -2-cyclohexyl-acetyl] amino] -3- Methyl-butanoyl] amino] pyridine-3-carboxylic acid 4-amino-5-[[3-[[(2S) -2-amino-3-methyl-butanoyl] amino] -2-cyclohexyl-acetyl] amino]- 3-Methyl-butanoyl] amino] pyridine-3-carboxylic acid 4-amino-5-[[3-[[(2S) -2-[[(2S) -2-amino-4-methyl-pentanoyl] amino] -2-cyclohexyl-acetyl] amino] -3-methyl-butanoyl] amino] pi Gin-3-carboxylic acid 4-amino-5- [5-[[[(2S) -2-amino-3-methyl-butanoyl] amino] methyl] -2-furyl] pyridine-3-carboxylic acid 4-amino -5- [5-[[[(2S) -2-amino-4-methyl-pentanoyl] amino] methyl] -2-furyl] pyridine-3-carboxylic acid.
[9] The compound according to [1], which is a compound selected from the group consisting of the following or a salt thereof, a tautomer or stereoisomer thereof, or a salt thereof.

[10] The salt is hydrochloride, sulfate, phosphate, nitrate, hydrobromide, acetate, trifluoroacetate, citrate, benzoate, maleate, fumarate, tartaric acid Salt, succinate, tannate, butyrate, hibenzate, pamoate, enanthate, decanoate, theoclate, salicylate, lactate, oxalate, mandelate, malate Consisting of methanesulfonate, benzenesulfonate, p-toluenesulfonate, glutamate, aspartate, sodium salt, potassium salt, magnesium salt, calcium salt, lysine salt, ornithine salt, arginine salt and histidine salt The compound according to any one of [1] to [9], a tautomer thereof or a salt of a stereoisomer thereof selected from the group.
[11] A food composition comprising the compound according to any one of [1] to [10], a tautomer or stereoisomer thereof, or a salt thereof.
[12] A taste improver containing the compound according to any one of [1] to [10], a tautomer or stereoisomer thereof, or a salt thereof.
[13] A method for producing a food or drink, comprising a step of adding the compound according to any one of [1] to [10], a tautomer or stereoisomer or a salt thereof to a food or drink raw material.
[14] The method according to any one of [1] to [10], comprising the step of adding a tautomer or stereoisomer or a salt thereof to a food or drink raw material or a food or drink, to enhance the sweetness of the food or drink. How to strengthen.

  When the compound of the present invention or a salt thereof is added to a food or drink raw material or food or drink, the sweetness of the food or drink can be enhanced.

In the present specification and claims, the “alkyl group” includes linear and branched ones. As the alkyl group, straight-chain and branched alkyl groups having 1 to 12 carbon atoms are preferable, and straight-chain and branched alkyl groups having 1 to 8 carbon atoms are more preferable. A branched alkyl group having 1 to 6 carbon atoms is still more preferred, and a linear or branched alkyl group having 1 to 4 carbon atoms is still more preferred. Alkyl groups of numbers 1 to 4 are even more preferred, and linear and branched alkyl groups of 1 to 3 carbon atoms are even more preferred. Examples of the alkyl group include methyl, ethyl, isopropyl, butyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, and 2,3-dimethylpropyl. Hexyl group.
The “alkylene group” includes linear and branched ones. The alkylene group is preferably a linear or branched alkylene group having 1 to 12 carbon atoms, more preferably a linear or branched alkylene group having 1 to 8 carbon atoms, and is preferably a linear or branched alkylene group. Even more preferred are chained alkylene groups of 1 to 6 carbon atoms, even more preferred are straight-chain and branched alkylene groups of 1 to 4 carbon atoms, Even more preferred are alkylene groups of 1-3. Examples of alkylene groups include methylene group, ethylene group, n- propylene group _{(- (CH 2) 3 -} ), n- butylene _{(- (CH 2) 4 -} ), n- pentylene (- (CH ₂ ) ₅ -), n-hexylene _{(- (CH 2) 6 -} ), isopropylene group, isobutylene group, and an isopentylene group.
“Alkenyl group” refers to a linear or branched alkenyl group having 2 to 6 carbon atoms including each isomer. As the alkenyl group, a linear or branched alkenyl group having 2 to 6 carbon atoms is preferable, and a linear or branched alkenyl group having 2 to 4 carbon atoms is more preferable. Examples of alkenyl groups include vinyl, allyl, propenyl, butenyl, pentenyl and hexenyl.
“Alkynyl group” refers to a linear or branched alkynyl group having 2 to 6 carbon atoms including each isomer. As the alkynyl group, a linear or branched alkynyl group having 2 to 6 carbon atoms is preferable, and a linear or branched alkynyl group having 2 to 4 carbon atoms is more preferable. Examples of the alkynyl group include an ethynyl group, a 1-propynyl group, a 2-propynyl group, a 2-butynyl group, a 3-butynyl group, and a pentynyl group.

As the "aryl group", a 6-14 membered aryl group is preferable, a 6-12 membered aryl group is more preferable, a 6-10 membered aryl group is still more preferable, and a 6-8 membered aryl group is even more preferable. Preferably, a 6-membered aryl group is particularly preferred. In the aryl group, for example, a 6 to 14 membered aryl group can be rephrased as an aryl group having 6 to 14 carbon atoms. Examples of the aryl group include a phenyl group, a naphthyl group, and a 2,3-dihydroxyindenyl group.
As the "arylene group", a 6-14 membered arylene group is preferable, a 6-12 membered arylene group is more preferable, a 6-10 membered arylene group is still more preferable, and a 6-8 membered arylene group is even more preferable. Preferably, a 6-membered arylene group is particularly preferred. Examples of the arylene group include a phenylene group and a naphthylene group.
“Heteroaryl group” means a group having at least one heteroatom selected from the group consisting of nitrogen, oxygen and sulfur as atoms constituting a ring of the aryl group. The heteroaryl group is preferably a 5- to 14-membered heteroaryl group, more preferably a 5- to 14-membered heteroaryl group, still more preferably a 5- to 10-membered heteroaryl group, and a 5- to 6-membered heteroaryl group. Particularly preferred. The number of hetero atoms present in the heteroaryl group is not limited as long as a heteroaryl group can be formed, but the number of hetero atoms constituting the ring of the heteroaryl group is preferably 1 to 3, and is preferably 1 to 2. Is more preferable, and one is even more preferable. Examples of the heteroaryl group include a furanyl group, a pyrrolyl group, an oxazolyl group, an imidazolyl group, a pyrazolyl group, a pyranyl group, an indenyl group, a thiophenyl group, a pyridinyl group, an indolyl group, a quinolinyl group, and a thiazolyl group.
“Heteroarylene group” refers to a group in which one hydrogen atom has been further removed from a heteroaryl group.

“Alicyclic group” refers to a cyclic saturated or unsaturated aliphatic hydrocarbon group. The alicyclic group is preferably a 3- to 14-membered alicyclic group, more preferably a 3- to 8-membered alicyclic group, still more preferably a 5- to 8-membered alicyclic group, and more preferably a 5- to 6-membered alicyclic group. Are still more preferred. The alicyclic group may be any of a saturated aliphatic hydrocarbon group and an unsaturated aliphatic hydrocarbon group, but is preferably a saturated aliphatic hydrocarbon group. A saturated aliphatic hydrocarbon group can be referred to as a cycloalkyl group. Examples of the alicyclic group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cyclohexenyl group, a cycloheptyl group, and the like.
“Heterocyclic group” refers to a group having at least one heteroatom selected from the group consisting of nitrogen, oxygen and sulfur as atoms constituting a ring of an alicyclic group. As the heterocyclic group, a 3- to 14-membered heterocyclic group is preferable, a 3- to 8-membered heterocyclic group is preferable, a 5- to 8-membered heterocyclic group is more preferable, and a 5- to 6-membered heterocyclic group is more preferable. Cyclic groups are even more preferred. The number of heteroatoms present in the heterocyclic group is not limited as long as a heterocyclic group can be formed, but the number of heteroatoms constituting the ring of the heterocyclic group is preferably 1 to 3, and 1 ~ 2 are more preferred and 1 is even more preferred. Examples of the heterocyclic group include a pyrrolidinyl group, a piperidinyl group, a pyrazinyl group, a morpholinyl group, a tetrahydrofuranyl group, a tetrahydropyranyl group, a tetrahydrothiophenyl group, and the like.
The divalent alicyclic group refers to a divalent group obtained by further removing one hydrogen atom from the alicyclic group.
The divalent heterocyclic group refers to a divalent group in which one hydrogen atom is further removed from the heterocyclic group.

  As the “acyl group” in the “acyl group”, “acylamino group”, and “acyloxy group”, an acyl group having a linear or branched or cyclic alkyl group or alkenyl group having 1 to 6 carbon atoms is preferable. Preferably, a lower acyl group, that is, an acyl group having 1 to 4 carbon atoms is used. For example, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, acryloyl, methacryloyl, crotonoyl, isocrotonoyl, cyclopropanoyl, cyclobutanoyl, cyclopentanoyl A noyl group and a cyclohexanoyl group.

The "acylamino group" is a group in which a nitrogen atom is bonded to the carbon atom of the carbonyl group in the aforementioned acyl group, and the acyl group is preferably a lower acyl group, that is, an acyl group having 1 to 4 carbon atoms. For example, an acetylamino group, a propionylamino group and the like can be mentioned.
The “acyloxy group” is a group in which an oxygen atom is bonded to a carbon atom of the carbonyl group in the aforementioned acyl group, and the acyl group is preferably a lower acyl group, that is, an acyl group having 1 to 4 carbon atoms. For example, an acetyloxy group, a propionyloxy group, a butyryloxy group and the like can be mentioned.
The “alkylamino group” refers to an amino group that is monosubstituted with the aforementioned alkyl group. For example, a methylamino group, an ethylamino group, a propylamino group, an isopropylamino group and the like can be mentioned.
The “dialkylamino group” refers to an amino group disubstituted with the aforementioned alkyl group. Examples thereof include a dimethylamino group, a diethylamino group, a dipropylamino group, a diisopropylamino group, and an ethylmethylamino group, or a ring group in which two alkyl groups are combined to form an alkylene group having 2 to 5 carbon atoms. There may be.
“Alkylthio group” refers to an alkylthio group having an alkyl group having 1 to 6 carbon atoms. For example, a methylthio group, an ethylthio group, an n-propylthio group and the like can be mentioned.
The term “alkylcarbamoyl group” refers to a carbamoyl group substituted with the above-mentioned alkyl group.

As the “alkoxy group”, an alkoxy group having 1 to 6 carbon atoms is preferable. Specifically, methoxy, ethoxy, 1-propoxy, 2-propoxy, n-butoxy, i-butoxy, sec-butoxy, t-butoxy, 1-pentyloxy, 2-pentyloxy, 3-pentyloxy, 2-pentyloxy Methyl-1-butyloxy, 3-methyl-1-butyloxy, 2-methyl-2-butyloxy, 3-methyl-2-butyloxy, 2,2-dimethyl-1-propyloxy, 1-hexyloxy, 2-hexyloxy , 3-hexyloxy and the like. Preferably it is a C1-C3 alkoxy group.
“Alkoxycarbonyl group” refers to a carbonyl group substituted with the aforementioned alkoxy group.
The “alkoxyalkyl group” refers to an alkyl group substituted with the above-described alkoxy group, and is preferably an alkyl group having 1 to 3 carbon atoms substituted with an alkoxy group having 1 to 3 carbon atoms. Specific examples include a methoxymethyl group, a methoxyethyl group, an ethoxymethyl group, an ethoxyethyl group and the like.
"Halogen atom" includes fluorine, chlorine, bromine, iodine atom and the like. Of these, fluorine and chlorine are preferred.
The expression “may have a substituent” means that one or more hydrogen atoms present in the target group may be replaced by a substituent other than hydrogen. The number of substituents is not particularly limited as long as the structure of the group to be substituted is possible, but the number of substituents is preferably 1 to 5, more preferably 1 to 4, and still more preferably 1 to 3. Preferably, one or two are even more preferred, and one is even more preferred.

（式中、
Ｒ₁、Ｒ₂はそれぞれ独立して、水素原子、ハロゲン原子、置換基を有してもよいＣ_1-6アルキル基又は置換基を有してもよいＣ_1-6アルコキシ基を表し、
Ｒ₃及びＲ₄は、それぞれ独立して、水素原子、又は置換基を有していてもよいＣ_1-6アルキル基を表し、
Ｒ₅は、置換基を有していてもよいＣ_1-12アルキル基、置換基を有していてもよい３〜１４員の脂環式基、置換基を有していてもよい３〜１４員の複素環式基、置換基を有していてもよい６〜１４員のアリール基、置換基を有していてもよい５〜１４員のヘテロアリール基、又は置換基を有していてもよいアミノ基を表し、
Ａは、ＮＨＣＯ、ＣＯＮＨ、単結合、ビニレン基、置換基を有していてもよい６〜１４員のアリーレン基、置換基を有していてもよい５〜１４員のヘテロアリーレン基、置換基を有していてもよい３〜１４員の二価の脂環式基、又は置換基を有していてもよい３〜１４員の二価の複素環式基を表し、
Ｄは、単結合、置換基を有していてもよいＣ_1-12アルキレン基、置換式を有していてもよい３〜１４員の二価の脂環式基、又は置換式を有していてもよい３〜１４員の二価の複素環式基を表し、且つ
Ｅは、単結合又は下記式（ＩＩ）：

（式中、＊は、隣接するＤへの結合を表し、
＊＊は隣接する窒素原子への結合を表し、
Ｒ₆及びＲ₇は、それぞれ独立して、水素原子、置換基を有していてもよいＣ_1-12アルキル基、置換基を有していてもよい３〜１４員の脂環式基、置換基を有していてもよい３〜１４員の複素環式基、置換基を有していてもよい６〜１４員のアリール基、又は置換基を有していてもよい５〜１４員のヘテロアリール基を表し、或いはＲ₆とＲ₇はこれらの基が結合する炭素原子とともに置換基を有していてもよい３〜８員の環を形成してもよく、或いはＲ₆とＲ₄はこれらの基が結合する炭素原子及び窒素原子とともに置換基を有していてもよい４〜８員の環を形成してもよい。）で表される基であり、
但し、Ａ、Ｄ及びＥが同時に単結合ではないことを条件とする。） <Compound>
The compound of the present invention, its tautomer or stereoisomer or a salt thereof is a compound having a structure represented by the following general formula (I), its tautomer or stereoisomer or a salt thereof. . In the present specification, the compound represented by the general formula (I), a tautomer or stereoisomer thereof, or a salt thereof may be simply referred to as the compound of the present invention.

(Where
R ₁ and R ₂ each independently represent a hydrogen atom, a halogen atom, a C _1-6 alkyl group which may have a substituent or a C _1-6 alkoxy group which may have a substituent,
R ₃ and R ₄ each independently represent a hydrogen atom or a C _1-6 alkyl group which may have a substituent,
R ₅ is a C _1-12 alkyl group which may have a substituent, a 3- to 14-membered alicyclic group which may have a substituent, or a 3- to 5-membered group which may have a substituent. A 14-membered heterocyclic group, a 6- to 14-membered aryl group which may have a substituent, a 5- to 14-membered heteroaryl group which may have a substituent, or a substituent Represents an amino group which may be
A is NHCO, CONH, a single bond, a vinylene group, a 6-14 membered arylene group which may have a substituent, a 5-14 membered heteroarylene group which may have a substituent, Represents a 3 to 14 membered divalent alicyclic group which may have, or a 3 to 14 membered divalent heterocyclic group which may have a substituent,
D has a single bond, a C _1-12 alkylene group which may have a substituent, a 3- to 14-membered divalent alicyclic group which may have a substituent, or a substituent. Represents a 3- to 14-membered divalent heterocyclic group, and E represents a single bond or the following formula (II):

(In the formula, * represents a bond to an adjacent D,
** represents a bond to an adjacent nitrogen atom,
R ₆ and R ₇ are each independently a hydrogen atom, a C _1-12 alkyl group which may have a substituent, a 3- to 14-membered alicyclic group which may have a substituent, A 3- to 14-membered heterocyclic group which may have a substituent, a 6- to 14-membered aryl group which may have a substituent, or a 5- to 14-membered which may have a substituent of represents a heteroaryl group, or R ₆ and R ₇ may form these groups is 3 to 8 membered which may have a substituent together with the carbon atom bonded ring, or R ₆ and R ₄ may form a 4- to 8-membered ring which may have a substituent together with a carbon atom and a nitrogen atom to which these groups are bonded. ) Is a group represented by
Provided that A, D and E are not simultaneously a single bond. )

In the general formula (I), R ₁ represents a hydrogen atom, a halogen atom, a C _1-6 alkyl group which may have a substituent or a C _1-6 alkoxy group which may have a substituent. R ₁ is preferably a hydrogen atom, a halogen atom, or an optionally substituted C _1-6 alkyl group, and is preferably a hydrogen atom, an optionally substituted C _1-6 alkyl group. More preferably, it is even more preferably a hydrogen atom.
In the general formula (I), R ₂ represents a hydrogen atom, a halogen atom, a C _1-6 alkyl group which may have a substituent or a C _1-6 alkoxy group which may have a substituent. R ₂ is preferably a hydrogen atom, a halogen atom or an optionally substituted C _1-6 alkyl group, and is preferably a hydrogen atom or an optionally substituted C _1-6 alkyl group. More preferably, it is even more preferably a hydrogen atom.
In the general formula (I), R ₃ represents a hydrogen atom or a C _1-6 alkyl group which may have a substituent. R ₃ is preferably a hydrogen atom.
In the general formula (I), R ₄ represents a hydrogen atom or a C _1-6 alkyl group which may have a substituent. R ₄ is preferably a hydrogen atom or a C _1-3 alkyl group which may have a substituent, more preferably a hydrogen atom or a C _1-3 alkyl group having an amino group, and a hydrogen atom Is even more preferred.
As the substituent which the C _1-6 alkyl group or C _1-6 alkoxy group in R ₁ , R ₂ , R ₃ and R ₄ may have, a halogen atom, a hydroxyl group, a thiol group, a cyano group, an amino group Group, cycloalkyl group, aryl group, arylalkyl group, heteroaryl group, alkoxy group, aryloxy group, arylthio group, arylamino group, alkenyl group, alkynyl group, acyl group, carboxyl group, sulfo group, phosphono group, alkyl Examples include an amino group, a dialkylamino group, an alkylthio group, an acyloxy group, an acylamino group, an alkoxycarbonyl group, a carbamoyl group, an alkylcarbamoyl group, and a guanidino group. Among these, a halogen atom, an amino group, a cycloalkyl group and an aryl group are preferred, a halogen atom and an amino group are more preferred, and a halogen atom is even more preferred.

In the general formula (I), A is NHCO, CONH, a single bond, a vinylene group, an optionally substituted 6 to 14-membered arylene group, or an optionally substituted 5 to 14-membered group. Represents a 3- to 14-membered divalent alicyclic group which may have a substituent or a 3- to 14-membered divalent heterocyclic group which may have a substituent. .
A has NHCO, a single bond, a vinylene group, a 6- to 10-membered arylene group which may have a substituent, a 5- to 10-membered heteroarylene group which may have a substituent, and a substituent. It is preferably a 5- to 10-membered divalent alicyclic group which may be substituted or a 5- to 10-membered divalent heterocyclic group which may have a substituent, NHCO, a single bond, A vinylene group, a 6-membered arylene group optionally having a substituent, a 5- to 6-membered heteroarylene group optionally having a substituent, a 5- to 6-membered optionally substituted substituent It is more preferably a divalent alicyclic group or a 5- to 6-membered divalent heterocyclic group which may have a substituent, and two or more of NHCO, a single bond, a vinylene group, and a benzene ring A divalent group from which hydrogen has been removed, a divalent group from which two hydrogens have been removed from the furan ring, or two Is even more preferable, and is more preferably NHCO, a divalent group obtained by removing two hydrogens from a furan ring, a vinylene group or a single bond, and more preferably NHCO. Particularly preferred. These groups may or may not have a substituent, but preferably do not have a substituent.
Examples of the substituent which each group as A may have include a C _1-6 alkyl group. Among these, a C _1-4 alkyl group is preferred as a substituent, a methyl group and an ethyl group are more preferred, and a methyl group is even more preferred.

In the general formula (I), D represents a single bond, a C _1-12 alkylene group which may have a substituent, or a 3- to 14-membered divalent alicyclic group which may have a substituent. And a 3- to 14-membered divalent heterocyclic group which may have a substituent. D is preferably a single bond or a C _1-12 alkylene group which may have a substituent, more preferably a single bond or a C _1-8 alkylene group, and more preferably a C _1-12 alkylene group which may have a single bond or a substituent. _{A 1-6} alkylene group is still more preferred, and a C _1-4 alkylene group which may have a single bond or a substituent is even more preferred. The alkylene group may be linear or branched, but is preferably linear.
Examples of the substituent which each group as D may have include a C _1-6 alkyl group, an alkoxy group, an alkylthio group, an alkylamino group, a dialkylamino group, an alkylcarbamoyl group, an alkoxycarbonyl group, and a halogen atom. Is mentioned. Among these, a C _1-4 alkyl group is preferred, a methyl group and an ethyl group are more preferred, and a methyl group is even more preferred. Each group as D may or may not have a substituent, but preferably does not have a substituent.

（式中、＊は、隣接するＤへの結合を表し、
＊＊は隣接する窒素原子への結合を表し、
Ｒ₆及びＲ₇は、それぞれ独立して、水素原子、置換基を有していてもよいＣ_1-12アルキル基、置換基を有していてもよい３〜１４員の脂環式基、置換基を有していてもよい３〜１４員の複素環式基、置換基を有していてもよい６〜１４員のアリール基、又は置換基を有していてもよい５〜１４員のヘテロアリール基を表し、或いはＲ₆とＲ₇はこれらの基が結合する炭素原子とともに置換基を有していてもよい３〜８員の環を形成してもよく、或いはＲ₆とＲ₄はこれらの基が結合する炭素原子及び窒素原子とともに置換基を有していてもよい４〜８員の環を形成してもよい。）
Ｒ₆及びＲ₇は、それぞれ独立して、水素原子、Ｃ_1-6アルキル基、シクロアルキル基、シクロアルキルアルキル基、アルキルシクロアルキル基、アリール基、アリールアルキル基、アルキルアリール基であることが好ましく、水素原子、Ｃ_1-6アルキル基、アリール基、アリールアルキル基、アルキルアリール基であることがより好ましく、水素原子、Ｃ_1-4アルキル基、フェニル基、３−メチルフェニル基、ベンジル基であることがさらにより好ましく、水素原子又はＣ_1-4アルキル基であることがさらにより好ましく、メチル基であることがさらにより好ましい。また、Ｒ₆とＲ₇の少なくとも一方がメチル基であることが好ましく、Ｒ₆とＲ₇がいずれもメチル基であることも好ましい。また、Ｒ₆及びＲ₇の少なくとも一方が水素原子でないことが好ましい。上記Ｒ₆及び／又はＲ₇の各基は置換基を有していても有していなくてもよいが、置換基を有していないことが好ましい。
Ｒ₆及び／又はＲ₇としての各基が有していていもよい置換基としては、アルキル基、脂環式基、複素環式基、アリール基、ヘテロアリール基、アルコキシ基、アルキルチオ基、アルキルアミノ基、ジアルキルアミノ基、アルキルカルバモイル基、アルコキシカルボニル基、ハロゲン原子が挙げられる。これらの中でも、アルキル基、脂環式基、複素環式基、アリール基、ヘテロアリール基、アルコキシ基、アルキルチオ基、ジアルキルアミノ基、アルキルカルバモイル基が好ましく、アルキル基、脂環式基、複素環式基、アリール基、ヘテロアリール基、アルコキシ基、アルキルチオ基、ジアルキルアミノ基がより好ましく、アルキル基、脂環式基、複素環式基、アリール基、ヘテロアリール基、アルコキシ基、アルキルチオ基がさらにより好ましく、アルキル基、脂環式基、複素環式基、アリール基、ヘテロアリール基がさらにより好ましく、アルキル基、脂環式基、アリール基がさらにより好ましい。
なお、式（ＩＩ）中に不斉炭素が存在する場合、その立体化学は（Ｒ）、（Ｓ），（ＲＳ）のいずれであってもよい。
一般式（Ｉ）中、Ａ、Ｄ及びＥは同時に単結合でない。すなわち、Ａ、Ｄ及びＥのうち、少なくとも１つは単結合ではない。これらの中でも、Ａ及びＤのいずれか一方が単結合でないことが好ましい。また、Ａが単結合でないことが好ましく、Ａ及びＤがいずれも単結合でないことが好ましく、Ａ、Ｄ及びＥがいずれも単結合ではないことが特に好ましい。 In the general formula (I), E is a single bond or a group represented by the following formula (II).

(In the formula, * represents a bond to an adjacent D,
** represents a bond to an adjacent nitrogen atom,
R ₆ and R ₇ are each independently a hydrogen atom, a C _1-12 alkyl group which may have a substituent, a 3- to 14-membered alicyclic group which may have a substituent, A 3- to 14-membered heterocyclic group which may have a substituent, a 6- to 14-membered aryl group which may have a substituent, or a 5- to 14-membered which may have a substituent of represents a heteroaryl group, or R ₆ and R ₇ may form these groups is 3 to 8 membered which may have a substituent together with the carbon atom bonded ring, or R ₆ and R ₄ may form a 4- to 8-membered ring which may have a substituent together with a carbon atom and a nitrogen atom to which these groups are bonded. )
R ₆ and R ₇ are each independently a hydrogen atom, a C _1-6 alkyl group, a cycloalkyl group, a cycloalkylalkyl group, an alkylcycloalkyl group, an aryl group, an arylalkyl group, or an alkylaryl group. preferably, hydrogen atom, C _1-6 alkyl group, aryl group, arylalkyl group, more preferably an alkyl aryl group, a hydrogen atom, C _1-4 alkyl group, a phenyl group, 3-methylphenyl group, a benzyl group Is still more preferable, a hydrogen atom or a C _1-4 alkyl group is still more preferable, and a methyl group is still more preferable. Further, it is preferable that at least one of R ₆ and R ₇ are methyl groups, it is also preferable R ₆ and R ₇ are a methyl group. Further, it is preferable that at least one of R ₆ and R ₇ is not a hydrogen atom. Each of the groups R ₆ and / or R ₇ may or may not have a substituent, but preferably does not have a substituent.
Examples of the substituent which each group as R ₆ and / or R ₇ may have include an alkyl group, an alicyclic group, a heterocyclic group, an aryl group, a heteroaryl group, an alkoxy group, an alkylthio group, and an alkyl group. Examples include an amino group, a dialkylamino group, an alkylcarbamoyl group, an alkoxycarbonyl group, and a halogen atom. Among these, an alkyl group, an alicyclic group, a heterocyclic group, an aryl group, a heteroaryl group, an alkoxy group, an alkylthio group, a dialkylamino group, and an alkylcarbamoyl group are preferable, and an alkyl group, an alicyclic group, and a heterocyclic group are preferable. Formula groups, aryl groups, heteroaryl groups, alkoxy groups, alkylthio groups, dialkylamino groups are more preferred, and alkyl groups, alicyclic groups, heterocyclic groups, aryl groups, heteroaryl groups, alkoxy groups, and alkylthio groups are further preferred. More preferably, an alkyl group, an alicyclic group, a heterocyclic group, an aryl group, and a heteroaryl group are still more preferable, and an alkyl group, an alicyclic group, and an aryl group are still more preferable.
When an asymmetric carbon is present in the formula (II), its stereochemistry may be any of (R), (S) and (RS).
In the general formula (I), A, D and E are not simultaneously a single bond. That is, at least one of A, D, and E is not a single bond. Among these, it is preferable that one of A and D is not a single bond. Further, it is preferable that A is not a single bond, it is preferable that all of A and D are not a single bond, and it is particularly preferable that all of A, D and E are not a single bond.

（式中、Ｒ₈は、水素原子、置換基を有していてもよいＣ_1-8アルキル基又は置換基を有していてもよいＣ_1-8アルキルカルボニル基を表し、
Ｒ₉は、水素原子、置換基を有していてもよい３〜１４員の脂環式基、置換基を有していてもよい３〜１４員の複素環式基、置換基を有していてもよい６〜１４員のアリール基、置換基を有していてもよい５〜１４員のヘテロアリール基、又は置換基を有していてもよいＣ_1-8アルキル基を表し、且つ
＊＊＊は、隣接する炭素原子への結合を表す。） In the general formula (I), R ₅ represents a C _1-12 alkyl group which may have a substituent, a 3- to 14-membered alicyclic group which may have a substituent, or a substituent. A 3- to 14-membered heterocyclic group which may be substituted, a 6- to 14-membered aryl group which may have a substituent, a 5- to 14-membered heteroaryl group which may have a substituent, Represents an amino group which may have a substituent.
Examples of the substituent which each group as R ₅ may have include an amino group, a 3- to 14-membered alicyclic group, a 3- to 14-membered heterocyclic group, a 6- to 14-membered aryl group, and a 5- to 5-membered aryl group. 14-membered heteroaryl group, -NHCO-alkyl group, -NHCO-alkoxy group, alkylamino group, dialkylamino group, hydroxyl group, vinyl group, alkoxy group, alkylthio group, alkylcarbamoyl group, alkoxycarbonyl group, halogen atom, Examples include a halogenated alkyl group and a carboxyl group. Each of these groups is, when structurally possible, an amino group, an alkyl group, a halogenated alkyl group, a 3- to 14-membered alicyclic group, or a 3- to 14-membered group. A heterocyclic group, a 6 to 14 membered aryl group, a 5 to 14 membered heteroaryl group, a -NHCO-alkyl group, a -NHCO-alkoxy group, a -NHCO-alkylene- OOH, a carboxyl group, a hydroxyl group, a vinyl group, may be further substituted by a halogen atom. Among these, the substituent which each group as R ₅ may have may be an amino group, a 3- to 14-membered alicyclic group, a 3- to 14-membered heterocyclic group, or an amino group. -NHCO-alkyl group which may be substituted is preferable, and an amino group, a 5- to 8-membered alicyclic group, and -NHCO-alkyl group which may be substituted with an amino group are more preferable, and an amino group and a 5- to 8-membered Alicyclic groups are even more preferred, amino groups and / or heterohexyl groups are even more preferred. That is, R ₅ preferably contains one or two selected from an amino group and a heterohexyl group as a substituent.
Further, R ₅ is preferably a group represented by the following formula (III) or (IV).

(Wherein, R ₈ represents a hydrogen atom, a C _1-8 alkyl group which may have a substituent or a C _1-8 alkylcarbonyl group which may have a substituent,
R ₉ has a hydrogen atom, a 3- to 14-membered alicyclic group which may have a substituent, a 3- to 14-membered heterocyclic group which may have a substituent, and a substituent An optionally substituted 6-14 membered aryl group, an optionally substituted 5-14 membered heteroaryl group, or an optionally substituted C _1-8 alkyl group, and *** represents a bond to an adjacent carbon atom. )

R ₈ is preferably a hydrogen atom, a C _1-6 alkyl group or a C _1-8 alkylcarbonyl group, more preferably a hydrogen atom or a C _1-6 alkylcarbonyl group, and more preferably a hydrogen atom Is even more preferred. These groups may or may not have a substituent.
Examples of the substituent which each group as R ₈ may have include an amino group, a 3 to 14 membered alicyclic group, a 3 to 14 membered heterocyclic group, a 6 to 14 membered aryl group, A 14-membered heteroaryl group, -NHCO-alkoxy group, carboxyl group, hydroxyl group, alkenyl group, alkoxy group, alkylthio group, alkylamino group, dialkylamino group, alkylcarbamoyl group, alkoxycarbonyl group, and halogen atom. . Among these, as a substituent, an amino group, a 3-14 membered alicyclic group, a 3-14 membered heterocyclic group, a 6-14 membered aryl group, a 5-14 membered heteroaryl group,- An NHCO-alkoxy group, a carboxyl group, a hydroxyl group, and a vinyl group are preferred, an amino group, a cyclohexyl group, and an -NHCO-alkoxy group are still more preferred, and an amino group and a cyclohexyl group are even more preferred.
R ₉ is a hydrogen atom, a 3-14 membered alicyclic group, a 3-14 membered heterocyclic group, a 6-14 membered aryl group, a 5-14 membered heteroaryl group, a C _1-8 alkyl group And an alkyl group substituted with a 6 to 14-membered aryl group, more preferably a hydrogen atom, a cyclohexyl group, a phenyl group, a C _1-6 alkyl group or a benzyl group, and a cyclohexyl group or a C _1-4 alkyl group. Even more preferably a cyclohexyl group.
Examples of the substituent which each group as R ₉ may have include an alkyl group, an alkenyl group, a hydroxyl group, an alkoxy group, an alkylthio group, an alkylamino group, a dialkylamino group, an alkylcarbamoyl group, an alkoxycarbonyl group, and a halogen atom. Examples include an atom, an aryl group, a heteroaryl group, an alicyclic group, and a heterocyclic group. Among these, the substituent is preferably an alkyl group, an alkenyl group, a hydroxyl group, an alkoxy group, an alkylthio group, a dialkylamino group, an alkylcarbamoyl group, an aryl group, a heteroaryl group, an alicyclic group, or a heterocyclic group. , An alkyl group, an alkenyl group, a hydroxyl group, an alkoxy group, an alkylthio group, a dialkylamino group, an aryl group, a heteroaryl group, an alicyclic group, and a heterocyclic group are more preferable, and an alkyl group, an alkenyl group, a hydroxyl group, an alkoxy group Groups, alkylthio groups, aryl groups, heteroaryl groups, alicyclic groups, heterocyclic groups are even more preferred, alkyl groups, alkenyl groups, hydroxyl groups, aryl groups, heteroaryl groups, alicyclic groups, heterocyclic groups Groups are even more preferred.
When an asymmetric carbon is present in the formula (III) and / or the formula (IV), its stereochemistry may be any of (R), (S) and (RS).

（式中、Ｒ₅、Ｄ及びＥは、上記の通りである。） More specifically, the compound represented by the general formula (I) or a salt thereof is preferably a compound represented by any of the following general formulas (V) to (IX) or a salt thereof. The compound represented by (V), (VI), (VIII) or (IX) is more preferred, and the compound represented by formula (V) or (VI) is still more preferred. Still more preferably, it is a compound represented by the formula (V).

(In the formula, R ₅ , D and E are as described above.)

（式中、＊＊＊＊は、隣接するピリジン環への結合を表し、＊＊＊＊＊は隣接するＣ＝Ｏの炭素原子への結合を表す）
で表される部分構造が、下記から成る群から選択される構造であることが好ましい。なお、式中に不斉炭素が存在する場合、その立体化学は（Ｒ）、（Ｓ）、（ＲＳ）のいずれであってもよい。

Further, the compound of the present invention is represented by the following formula (X) in the general formula (I):

(Wherein **** represents a bond to an adjacent pyridine ring, and **** represents a bond to an adjacent C 炭素 O carbon atom)
The partial structure represented by is preferably a structure selected from the group consisting of: When an asymmetric carbon is present in the formula, its stereochemistry may be any of (R), (S), and (RS).

Among these, the partial structure represented by the formula (X) is more preferably a structure selected from the group consisting of:

（式中、＊＊＊＊＊＊は、隣接する窒素原子への結合部位を表す。）
で表される部分構造が、下記から成る群から選択される構造であることが好ましい。なお、式中に不斉炭素が存在する場合、その立体化学は（Ｒ）、（Ｓ）、（ＲＳ）のいずれであってもよい。

Further, the compound of the present invention is represented by the following formula (XI) in the general formula (I):

(In the formula, **** represents a bonding site to an adjacent nitrogen atom.)
The partial structure represented by is preferably a structure selected from the group consisting of: When an asymmetric carbon is present in the formula, its stereochemistry may be any of (R), (S), and (RS).

Among them, the partial structure represented by the formula (XI) is more preferably a structure selected from the group consisting of:

Specific examples of preferable compounds of the present invention include the following compounds.
4-amino-5- [5- (L-cyclohexylglycylamino) -pentanoylamino] -nicotinic acid 4-amino-5-[[3-[[(2S) -2-amino-2-cyclohexyl-acetyl] ] Amino] -3-methyl-butanoyl] amino] pyridine-3-carboxylic acid 4-amino-5-[[3-[(2-cyclohexylacetyl) amino] -3-methyl-butanoyl] amino] pyridine-3- Carboxylic acid 4-amino-5- [5-[[[(2S) -2-amino-2-cyclohexyl-acetyl] amino] methyl] -2-furyl] pyridine-3-carboxylic acid 4-amino-5- [ (E) -4-[[(2S) -2-amino-2-cyclohexyl-acetyl] amino] but-1-enyl] pyridine-3-carboxylic acid 4-amino-5- [4-[[(2S) − 2-Amino-2-cyclohexyl-acetyl] amino] butyl] pyridine-3-carboxylic acid 4-amino-5-[[3-[[(2S) -2-[[(2S) -2-amino-3- Methyl-pentanoyl] amino] -2-cyclohexyl-acetyl] amino] -3-methyl-butanoyl] amino] pyridine-3-carboxylic acid 4-amino-5-[[(3R) -3-[[(2S)- 2-amino-2-cyclohexyl-acetyl] amino] -3-phenyl-propanoyl] amino] pyridine-3-carboxylic acid 4-amino-5- [5-[(2-cyclohexylacetyl) amino] pentanoylamino] pyridine -3-Carboxylic acid 4-amino-5-[[3-[[(2S, 3S) -2-amino-3-methyl-pentanoyl] amino] -3-methyl-butanoyl] amino] pyridine-3-carbo 4-Amino-5-[[3-[[(2S) -2-[[(2S) -2-amino-2-cyclohexyl-acetyl] amino] -2-cyclohexyl-acetyl] amino] -3-methyl acid -Butanoyl] amino] pyridine-3-carboxylic acid 4-amino-5-[[3-[[(2S) -2-[(2-aminoacetyl) amino] -2-cyclohexyl-acetyl] amino] -3- Methyl-butanoyl] amino] pyridine-3-carboxylic acid 4-amino-5-[[3-[[(2S) -2-amino-3-methyl-butanoyl] amino] -2-cyclohexyl-acetyl] amino]- 3-Methyl-butanoyl] amino] pyridine-3-carboxylic acid 4-amino-5-[[3-[[(2S) -2-[[(2S) -2-amino-4-methyl-pentanoyl] amino] -2-cyclohexyl-acetyl] amino] -3-methyl-butanoyl] amino] pi Gin-3-carboxylic acid 4-amino-5- [5-[[[(2S) -2-amino-3-methyl-butanoyl] amino] methyl] -2-furyl] pyridine-3-carboxylic acid 4-amino -5- [5-[[[(2S) -2-amino-4-methyl-pentanoyl] amino] methyl] -2-furyl] pyridine-3-carboxylic acid Among these, from the viewpoint of sweetness enhancing effect, The following compounds are particularly preferred.
4-amino-5- [5- (L-cyclohexylglycylamino) -pentanoylamino] -nicotinic acid 4-amino-5-[[3-[[(2S) -2-amino-2-cyclohexyl-acetyl] ] Amino] -3-methyl-butanoyl] amino] pyridine-3-carboxylic acid 4-amino-5- [5-[[[(2S) -2-amino-2-cyclohexyl-acetyl] amino] methyl] -2 -Furyl] pyridine-3-carboxylic acid 4-amino-5-[[3-[[(2S) -2-[[(2S) -2-amino-2-cyclohexyl-acetyl] amino] -2-cyclohexyl- Acetyl] amino] -3-methyl-butanoyl] amino] pyridine-3-carboxylic acid 4-amino-5- [5-[[[(2S) -2-amino-3-methyl-butanoyl] amino] methyl]- 2-furyl] pili Down-3-carboxylic acid 4-amino -5- [5 - [[[(2S) -2- amino-4-methyl - pentanoyl] amino] methyl] -2-furyl] pyridine-3-carboxylic acid

Further, from the comprehensive viewpoint of the sweetness enhancing effect and the sweetness quality, the following compounds are particularly preferable as the compound of the present invention.

  The compounds of the present invention also include solvates of the compounds represented by the general formula (I), such as hydrates and alcohol adducts.

<Isomer of compound>
In the present invention, the compound represented by the general formula (I) includes its tautomers and / or stereoisomers (enantiomers, diastereomers), and a plurality of tautomers and / or Alternatively, when a stereoisomer may exist, any of them may be used.
<Compound salt>
In the present invention, the salt of the compound represented by the general formula (I) (including isomers) may be any as long as it is acceptable as a food additive. For the acidic groups, salts with inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, hydrobromic acid, acetic acid, trifluoroacetic acid, citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid, succinic acid , Tannic acid, butyric acid, hibenzic acid, pamoic acid, enanthic acid, decanoic acid, theocleic acid, salicylic acid, salts with organic carboxylic acids such as lactic acid, oxalic acid, mandelic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, Examples thereof include salts with organic sulfonic acids such as p-toluenesulfonic acid, and salts with acidic amino acids such as glutamic acid and aspartic acid. Among these, trifluoroacetate, hydrochloride, acetate, and oxalate are preferred.
When an acidic group is present in the formula, a salt with an inorganic base such as sodium, potassium, magnesium, or calcium, or a salt with a basic amino acid such as lysine, ornithine, arginine, or histidine is used. No. Among these, sodium salts, potassium salts and calcium salts are preferred.
Among these, as the salt of the compound represented by the general formula (I), trifluoroacetate, hydrochloride, and sodium salt are preferable, trifluoroacetate and hydrochloride are more preferable, and trifluoroacetate is still more preferable. preferable.
The salt can be formed by mixing the compound represented by the general formula (I) with a necessary acid or base in an appropriate amount ratio in a solvent or a dispersant.

（式中、Ｒ₁₀は水素原子、炭素数１から４のアルキル基、またはベンジル基を表し、Ｒ₁からＲ₃は前記定義した通りである。）
一般式（ＸＶＩ）で表される化合物は、一般式（ＸＩＩ）で表される４−アミノ−５−ブロモ−３−ピリジンカルボン酸誘導体（ハロゲン化アリール）と、一般式（ＸＩＶ）で表される有機ホウ素化合物又は一般式（ＸＶ）で表されるアルケンを、パラジウム触媒を用いるクロスカップリング反応に付した後に、脱保護を行うことによって得ることができる。クロスカップリング反応としては、鈴木−宮浦カップリング反応やヘック反応が挙げられるが、これらの反応は定法に従って公知の反応条件を用いて行えばよい。

（式中、Ｒ₁₀は炭素数１から４のアルキル基、またはベンジル基を表し、Ａ、D、E、Ｒ₁からＲ₄は前記定義した通りである。Ｒ₁₁、Ｒ₁₂は水素原子または一緒になって１，１，２，２−テトラメチルエチレン基を表し、Ｒ₁₃はｔｅｒｔ−ブトキシカルボニル基、ベンジルオキシカルボニル基を表す。） <Production method>
The method for producing the compound represented by formula (I) of the present invention is not particularly limited, and the compound can be produced by a known method. For example, as a compound represented by the general formula (I), a compound represented by the following general formula (XVII) can be easily produced by the following method.
(General production method 1: N-terminal extension method)
First, a compound represented by the general formula (XIII) or a compound represented by the general formula (XVI) is prepared.
As the compound represented by the general formula (XIII), a commercially available compound may be used, or a 4-amino-5-bromo-3-pyridinecarboxylic acid derivative represented by the general formula (XII) may be obtained by a conventional method. It may be produced by subjecting it to a nitration, esterification, or reduction reaction under known reaction conditions.

(In the formula, R ₁₀ represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, or a benzyl group, and R ₁ to R ₃ are as defined above.)
The compound represented by the general formula (XVI) includes a 4-amino-5-bromo-3-pyridinecarboxylic acid derivative (aryl halide) represented by the general formula (XII) and a compound represented by the general formula (XIV). By subjecting the organic boron compound or the alkene represented by the general formula (XV) to a cross-coupling reaction using a palladium catalyst, followed by deprotection. Examples of the cross-coupling reaction include a Suzuki-Miyaura coupling reaction and a Heck reaction, and these reactions may be performed using known reaction conditions according to a conventional method.

(Wherein, R ₁₀ represents an alkyl group having 1 to 4 carbon atoms or a benzyl group, and A, D, E, and R ₁ to R ₄ are as defined above. R ₁₁ and R ₁₂ represent a hydrogen atom or Together, they represent a 1,1,2,2-tetramethylethylene group, and R ₁₃ represents a tert-butoxycarbonyl group or a benzyloxycarbonyl group.)

（式中、Ｒ₁₀は炭素数１から４のアルキル基、またはベンジル基を表し、Ａ、Ｄ、Ｅ、Ｒ₁からＲ₄、Ｒ₈、及びＲ₉は前記定義した通りである。） Next, 1 to 3 N-tert-butoxycarbonyl amino acids are sequentially dehydrated and condensed to the N-terminal of the compound represented by the general formula (XIII) or (XVI) to deprotect the tert-butoxycarbonyl group. Hydrolyze the ester bond, or sequentially dehydrate and condense one or two N-tert-butoxycarbonyl amino acids or one carboxylic acid compound to the N-terminal to hydrolyze the ester bond. Thereby, the compound represented by the general formula (XVII) can be obtained.

(In the formula, R ₁₀ represents an alkyl group having 1 to 4 carbon atoms or a benzyl group, and A, D, E, R ₁ to R ₄ , R ₈ , and R ₉ are as defined above.)

（式中、Ａ、Ｄ、Ｅ、Ｒ₁からＲ₄、Ｒ₈、およびＲ₉は前記定義した通りである。） (General production method 2: C-terminal extension method)
To the N-tert-butoxycarbonyl amino acid, N-tert-butoxycarbonyl dipeptide, or N-acyl amino acid C-terminal represented by the formula (XVIII), the amino acid and / or the formula (XIII), (XVI) ) Are successively dehydrated and condensed, and then the ester bond is hydrolyzed, and if necessary, the tert-butoxycarbonyl group is deprotected. Thereby, the compound represented by the general formula (XVII) can be obtained.

(Where A, D, E, R ₁ to R ₄ , R ₈ , and R ₉ are as defined above)

  The carboxylic acid component used in the dehydration condensation reaction performed in the general production method 1 may be a salt such as a dicyclohexylamine salt, and the amine component may be a free form or a salt such as a hydrochloride or p-toluenesulfonic acid salt. When the carboxylic acid component is a salt such as a dicyclohexylamine salt, an acid such as hydrochloric acid is added at the time of condensation, and when the amine component is a salt such as a hydrochloride, the ratio with triethyl is not limited during the condensation reaction, In order to carry out the reaction with high yield, the amine component or the amine component may be used in an amount of 0.8 to 1.2 equivalents per equivalent of the carboxylic acid component. The amount of the acid used for neutralizing the salt is 0.8 to 2.0 equivalents, preferably 1.0 to 1.5 equivalents to the carboxylic acid component. The amount of the base used for neutralization of the salt is 0.8 to 2.0 equivalents, preferably 1.0 to 1.5 equivalents to the amine component.

  The solvent used in the dehydration condensation reaction of the above General Production Method 1 is not particularly limited as long as it does not react with a carboxylic acid component or an amine component. For example, dichloromethane (DCM), N, N′-dimethylformamide (DMF) ), Chloroform, dimethylsulfoxide (DMSO), N-methylpyrrolidone (NMP), acetonitrile, ethyl acetate, tetrahydrofuran (THF), or a mixed solvent thereof. Of these, dichloromethane and N, N'-dimethylformamide are preferred. The amount of the solvent is 10 to 500 times, preferably 15 to 100 times the weight of the amine component.

As the dehydrating condensing agent used in the dehydrating condensation reaction of the above-mentioned general production method 1, a general condensing agent used in peptide synthesis or the like may be used. -Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSC.HCl), 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate ( HBTU) is used. At that time, a condensation promoting agent such as 1-hydroxybenzotriazole monohydrate (HOBt · H ₂ O) is used. The amount of the dehydrating condensing agent to be used is 1.0 to 2.0 equivalents, preferably 1.05 to 1.20 equivalents, based on the carboxylic acid component. The amount of the condensation accelerator used is 0.5 to 3.0 equivalents, preferably 1.0 to 1.5 equivalents, based on the carboxylic acid component.
The reaction time is preferably about 3 to 24 hours, which depends on the reaction temperature, and the range is preferably 5 to 35C.

The ester may be hydrolyzed by a deprotection method generally used in peptide synthesis. In the case of an alkyl ester or benzyl ester other than t-butyl ester, alkali hydrolysis with a base such as sodium hydroxide, potassium hydroxide, or lithium hydroxide; in the case of t-butyl ester, hydrochloric acid, trifluoroacetic acid (TFA); Acid hydrolysis with methanesulfonic acid, p-toluenesulfonic acid or the like, and hydrogenolysis with a palladium carbon catalyst or the like in the case of benzyl ester can be performed.
For example, in the case of an alkyl ester or benzyl ester other than t-butyl ester, the amount of the base to be used is not limited. Amount, preferably 1.2 to 3.0 equivalents. As the solvent used at the time of the hydrolysis reaction, water or a mixed solvent of water and an organic solvent such as methanol, ethanol, acetonitrile, and tetrahydrofuran is used in an amount of 10 to 500 times, preferably 15 to 100 times the weight of the ester component. good. The reaction time is preferably about 1 to 24 hours, which depends on the reaction temperature, and the range is preferably from 5 to 100 ° C.

  Regarding the deprotection, the tert-butoxycarbonyl group (Boc group) as a protecting group can be removed using an acid such as hydrochloric acid, trifluoroacetic acid (TFA), methanesulfonic acid, and p-toluenesulfonic acid. The amount of the acid used for removing the tert-butoxycarbonyl group is not limited. However, in order to carry out the reaction with a high yield, the acid is used in an amount of 1.0 to 1.0 with respect to the component from which the tert-butoxycarbonyl group is to be removed. Up to 30 equivalents, preferably 2.0 to 10 equivalents may be used. As a solvent used in the reaction, water or an organic solvent such as tetrahydrofuran (THF), dioxane, methanol, ethanol, acetonitrile, ethyl acetate, or a mixture thereof may be used. In the case of trifluoroacetic acid, it may be used as it is. The amount of the solvent may be 10 to 500 times, preferably 15 to 100 times the weight of the component from which the tert-butoxycarbonyl group is to be removed. The reaction time is preferably about 1 to 24 hours, which depends on the reaction temperature, and the range is preferably from 0 to 100 ° C.

The carboxylic acid component serving as a raw material of the active ester used in the general production method 2 may be a salt such as a dicyclohexylamine salt. When the carboxylic acid component is a salt such as a dicyclohexylamine salt, the reaction may be carried out by adding an acid such as hydrochloric acid during the condensation.
To obtain an active ester component from a carboxylic acid component, a dehydrating condensing agent such as DCC or WSC.HCl, N-hydroxysuccinimide (HOSu), 1-hydroxybenzotriazole monohydrate (HOBt.H ₂ O), nitrophenol And an active esterifying agent such as pentafluorophenol may be reacted under the reaction conditions for performing a normal peptide synthesis reaction.
The ratio between the carboxylic acid component and the active esterifying agent used is not limited, but in order to make the reaction with good yield, 0.8 to 1.2 equivalents of the active esterifying agent is used per 1 equivalent of the carboxylic acid component. I just need. When an acid is required for neutralizing the salt, the amount of the acid used is 0.8 to 2.0 equivalents, preferably 1.0 to 1.5 equivalents to the carboxylic acid component.

The solvent used in preparing the active ester component in the general production method 2 is not particularly limited as long as it does not react with the carboxylic acid component or the active esterifying agent. For example, dichloromethane (DCM), N, N -Dimethylformamide (DMF), chloroform, dimethylsulfoxide (DMSO), N-methylpyrrolidone (NMP), acetonitrile, ethyl acetate, tetrahydrofuran (THF) or a mixed solvent thereof can be used. Among them, dichloromethane, N, N'-dimethylformamide, acetonitrile and ethyl acetate are preferred. The amount of the solvent is 10 to 500 times the weight of the carboxylic acid component, preferably 15 to 100 times the weight.
As a dehydrating condensing agent for preparing the active ester component, a general condensing agent used in peptide synthesis or the like may be used. As described above, for example, DCC or WSC.HCl is used. The amount of the dehydrating condensing agent to be used is 1.0 to 2.0 equivalents, preferably 1.05 to 1.20 equivalents, based on the carboxylic acid component.
The reaction time is preferably about 3 to 24 hours, which depends on the reaction temperature, and the range is preferably 5 to 35C.

In the condensation reaction step of the active ester component and the amine component performed in the general production method 2, the ratio of the active ester component to the amine component to be used is not limited. The amine component may be used in an amount of 0.8 to 1.2 equivalents with respect to 1 equivalent of the component.
The solvent used is not particularly limited as long as it does not react with the active ester component or the amine component. For example, dichloromethane (DCM), N, N′-dimethylformamide (DMF), chloroform, dimethyl sulfoxide (DMSO), N -Methylpyrrolidone (NMP), acetonitrile, ethyl acetate, tetrahydrofuran (THF) or a mixed solvent thereof can be used. Among them, dichloromethane, N, N'-dimethylformamide, acetonitrile and ethyl acetate are preferred. The amount of the solvent is 10 to 500 times, preferably 15 to 100 times the weight of the active ester component.
The reaction time is preferably about 3 to 24 hours, which depends on the reaction temperature, and the range is preferably 5 to 35C.

In the above-mentioned each reaction and the synthesis of each reaction component, if desired, a known deprotection reaction, acylation reaction, alkylation reaction, hydrogenation reaction, oxidation reaction, reduction reaction, carbon chain extension reaction or substituent exchange reaction, Each substituent can be converted by performing it alone or in combination of two or more thereof.
In each of the above reactions, when the starting compound has an amino group, a carboxyl group, a hydroxy group, or a carbonyl group as a substituent, a protecting group generally used in peptide chemistry or the like may be introduced into these groups. The desired compound can be obtained by removing the protecting group after the reaction, if necessary.
The above-described method for removing the protecting group is based on a known method, for example, a method described in Protective Groups in Organic Synthesis, Third Edition, published by John Wiley and Sons (1999). Can be done.

The resulting compound represented by the general formula (I) or a salt thereof can be isolated and purified by a conventional method. For example, when purification is performed by crystallization, as a solvent, ethyl acetate, isopropyl acetate, ethanol, methanol, acetonitrile, acetone, diethyl ether, chloroform, dichloromethane, n-hexane, n-heptane, or the like, or a mixed solvent thereof is used. be able to. As a purification method by chromatography, preparative thin-layer chromatography (PTLC) or silica gel column chromatography can be used. As the developing solvent at that time, the solvents mentioned above as the crystallization solvent can be used.
As the starting material used for producing the compound represented by the formula (I), a commercially available starting material may be purchased or used, or may be synthesized and produced by itself.

The compound represented by the general formula (I) of the present invention, a tautomer or stereoisomer thereof, or a salt thereof (hereinafter, simply referred to as the compound of the present invention) is limited to physical properties such as a dry powder, a paste, and a solution. Can be used in any form without.
The compound of the present invention can be used as a component of a taste improver, particularly a sweet taste improver or a sweetness enhancer. Taste improvers include the compounds of the present invention. The taste improving agent may consist of only the compound of the present invention, may consist essentially of only the compound of the present invention, or may contain components other than the compound of the present invention. Other components include taste improvers other than the compound of the present invention. Examples of the taste improver other than the compound of the present invention include flavors such as fruit flavors and masking flavors, thickening polysaccharides such as carrageenan, inorganic salts such as potassium chloride, sweeteners other than the present invention, and salty tastes other than sweetness. And the like.

The compound of the present invention can be used as a component of a food composition. Food compositions include the compounds of the present invention. Examples of the food composition include various foods and beverages such as foods, beverages, and seasonings.
The amount of the compound of the present invention in the food composition is not particularly limited as long as the desired effect can be obtained, but is about 0.1 ppb to about 99.9% by mass based on the total mass of the food composition. It is preferably about 1 ppb to 10% by mass, and more preferably about 0.01 ppm to 1% by mass.
The food composition containing the compound of the present invention may further contain any solid or liquid carrier that is food- and food-acceptable, a suitable seasoning material, and the like.
Examples of the carrier include glucose, lactose, sucrose, starch, mannitol, dextrin, fatty acid glyceride, polyethylene glycol, hydroxyethyl starch, ethylene glycol, polyoxyethylene sorbitan fatty acid ester, gelatin, albumin, amino acid, water, and physiological saline. Water and the like.
The above-mentioned seasoning ingredients may be any seasoning ingredients used in the art, and are not particularly limited. For example, flavors, sugars, sweeteners, dietary fibers, vitamins, amino acids such as sodium glutamate (MSG) Nucleic acids such as inoline-phosphate (IMP); inorganic salts such as sodium chloride; organic acids such as citric acid; natural seasonings such as protein hydrolysates; and fermented seasonings such as miso and soy sauce.
The content of any of the above-mentioned carriers and other seasoning ingredients is not particularly limited.
Of the seasoning ingredients, yeast extract is not particularly limited, and any yeast extract can be used. It may have been subjected to a chemical treatment or the like.

In addition, the present invention can provide a method for enhancing the sweetness of a food or drink comprising a step of adding the compound of the present invention to a food or drink raw material or food or drink.
The method for enhancing the sweetness of the food or drink of the present invention includes a step of adding the compound of the present invention to a food or drink raw material or a food or drink. After adding the compound of the present invention to a food or drink raw material or food or drink, it is preferable to mix these components. Further, the method may further include a step of cooking a mixture of the compound of the present invention and a food or drink raw material obtained by mixing.
The compound of the present invention is preferably added to the finished food or drink so as to be contained in an amount of 0.005 to 30 ppm by weight, and is added so as to be contained in an amount of 0.05 to 10 ppm. Is more preferred.
The present invention can also provide a method for producing a food or drink comprising a step of adding the compound of the present invention to a food or drink raw material. At this time, the compound of the present invention is preferably added to the food or drink raw material, preferably in an amount of 0.01 to 50% by weight. After adding the compound of the present invention to a food or drink raw material or food or drink, it is preferable to mix these components. Further, the method may further include a step of cooking a mixture of the compound of the present invention and a food or drink raw material obtained by mixing.
The compound of the present invention is preferably added to the finished food or drink so as to be contained in an amount of 0.005 to 30 ppm by weight, and is added so as to be contained in an amount of 0.05 to 10 ppm. Is more preferred.
The food and drink are not particularly limited, but powdered food, for example, beverage powder such as instant coffee is preferable. Also preferred are solution drinks, such as coffee, juice, carbonated drinks, and the like.
Food and drink ingredients include excipients, seasonings, anti-caking agents, defoamers, disintegrants, lubricants, binders, isotonic agents, buffers, solubilizing agents, preservatives, antioxidants, Examples of additives that can be used in foods, such as coloring agents, flavoring agents, coagulants, pH buffers, and food raw materials such as milk and fruits.
Hereinafter, the present invention will be described in more detail with reference to examples, but these examples do not limit the present invention.

  Hereinafter, the usefulness of the present invention will be specifically described with reference to Examples and Test Examples. However, the present invention is not limited by these. Compounds 1 to 64 were produced according to the method described in the representative synthetic examples described below. In the following production examples, the structure of the synthesized compound was identified by a nuclear magnetic resonance spectrum (Bruker AVANCE 400) and an ESI-MS spectrum.

Synthesis of methyl 4,5-diaminopyridine-3-carboxylate (intermediate)

4-Aminopyridine-3-carboxylic acid (5.00 g, 36.2 mmol) is dissolved in sulfuric acid (40.0 mL), and potassium nitrate (3.66 g, 36.2 mmol) is added by ice cooling, and the mixture is heated at 75 ° C. for 5 hours. Stirred. After returning to room temperature, methanol (100 mL) was added, and the mixture was stirred at 60 ° C. overnight. The reaction solution was slowly added to an aqueous solution of potassium acetate (145 g) and water (271 mL) under ice-cooling, and the precipitated crystals were filtered. The crystals are dissolved in ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, the organic layer is dried over magnesium sulfate, filtered, the solvent is distilled off, and methyl 4-amino-5-nitro-pyridine-3-carboxylate ( (2.36 g, 12.0 mmol).
Methanol (20.0 mL) was added to methyl 4-amino-5-nitro-pyridine-3-carboxylate (2.36 g, 12.0 mmol) and palladium carbon (100 mg), and the atmosphere in the flask was replaced with argon. The balloon was charged and replaced with hydrogen, followed by stirring at room temperature for 3 hours. After the atmosphere in the flask was replaced with argon again, the mixture was filtered and the solvent was distilled off to obtain methyl 4,5-diaminopyridine-3-carboxylate (1.87 g, 11.2 mmol).
If ethanol is used instead of methanol, ethyl 4-amino-5-nitro-pyridine-3-carboxylate can be obtained.

Ｂｏｃ−Ｌ−シクロヘキシルグリシン（５．１６ｇ、２０．０ｍｍｏｌ）、Ｎ−ヒドロキシコハク酸イミド（２．３ｇ、２０．０ｍｍｏｌ）を酢酸エチルに溶解し、Ｎ，Ｎ‘−ジシクロヘキシルカルボジイミド（４．１２ｇ、２０．０ｍｍｏｌ）の酢酸エチル溶液を加えて室温で一晩撹拌した。析出したＮ，Ｎ’−ジシクロヘキシル尿素をろ過により分離し、母液の酢酸エチル層を５％炭酸水素ナトリウム水溶液、水で洗浄後、減圧濃縮により溶媒を留去、残渣にｎ−ヘキサン、酢酸エチルを加えて晶析、分離、減圧乾燥しＢｏｃ−Ｌ−シクロヘキシルグリシン−Ｎ−コハク酸イミドエステル（５．７６ｇ、１６．３ｍｍｏｌ）を得た。
５-アミノペンタン酸（０．２５ｇ、２．１ｍｍｏｌ）、炭酸水素ナトリウム０．１７ｇ（２．０ｍｍｏｌ）、を水に溶解し１Ｍ水酸化ナトリウム水溶液（２．１ｍＬ、２．１ｍｍｏｌ）、アセトニトリルを加えて撹拌、Ｂｏｃ−Ｌ−シクロヘキシルグリシン−Ｎ−コハク酸イミドエステル（０．７１ｇ、２．０ｍｍｏｌ）を加えて室温で一晩撹拌した。アセトニトリルを減圧下留去し、酢酸エチル、水を加え、６Ｍ塩酸でｐＨ１．５に調整して抽出した。有機層を水で洗浄し減圧下溶媒を留去、乾燥し５−Ｂｏｃ−Ｌ−シクロヘキシルグリシルアミノペンタン酸（０．７２ｇ、２．０ｍｍｏｌ）を得た。
５−Ｂｏｃ−Ｌ−シクロヘキシルグリシルアミノペンタン酸（０．７１ｇ、２．０ｍｍｏｌ）、４、５−ジアミノニコチン酸エチルエステル（０．３５ｇ、１．９ｍｍｏｌ）をＤＭＦに溶解し、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（０．４２ｇ、２．１ｍｍｏｌ）を加えて一晩撹拌した。５％炭酸水素ナトリウム水溶液、水を加えて晶析し、分離、減圧乾燥して４−アミノ−５−[７−（Ｂｏｃ−Ｌ−シクロヘキシルグリシルアミノ）−ペンタノイルアミノ]−ニコチン酸エチルエステル（０．９２ｇ、１．７７ｍｍｏｌ）を得た。
４−アミノ−５−[５−（Ｂｏｃ−Ｌ−シクロヘキシルグリシルアミノ）−ペンタノイルアミノ]−ニコチン酸エチルエステル（０．９２ｇ、１．７７ｍｍｏｌ）をＴＨＦ、水を加えて溶解し、１Ｍ水酸化ナトリウム水溶液（２．１２ｍＬ、２．１２ｍｍｏｌ）を加えて室温で一晩撹拌した。水および１Ｍ塩酸（２．１２ｍＬ、２．１２ｍｍｏｌ）を加えて晶析、分離、乾燥して４−アミノ−５−[５−（Ｂｏｃ−Ｌ−シクロヘキシルグリシルアミノ）−ペンタノイルアミノ]−ニコチン酸（０．６６ｇ、１．３５ｍｍｏｌ）を得た。
４−アミノ−５−[５−（Ｂｏｃ−Ｌ−シクロヘキシルグリシルアミノ）−ペンタノイルアミノ]−ニコチン酸（０．６６ｇ、１．３５ｍｍｏｌ）トリフルオロ酢酸を加えて室温で４時間撹拌した。トリフルオロ酢酸を減圧下留去し、アセトニトリルを加えて晶析、分離、乾燥して４−アミノ−５−[５−（Ｌ−シクロヘキシルグリシルアミノ）−ペンタノイルアミノ]−ニコチン酸．２ＴＦＡ塩（ＩＮ４１５０、０．８５ｇ、１．３５ｍｍｏｌ）を得た。
4-Amino-5-[5-((S)-cyclohexylglycylamino)-pentanoylamino]-nicotinic acid
４−アミノ−５−[５−（(S)−シクロヘキシルグリシルアミノ）−ペンタノイルアミノ]−ニコチン酸
¹H NMR (400 MHz, DMSO-d₆) δ 9.57 (s, 1H), 8.72 (s, 1H), 8.53 (s, 1H), 8.42 (t, J = 5.6 Hz, 1H), 8.11 - 8.05 (m, 2H), 3.25 (dd, J = 13.3, 6.5 Hz, 5H), 3.08 (dq, J = 12.6, 6.4 Hz, 2H), 2.44 (t, J = 7.3 Hz, 2H), 1.75 - 1.56 (m, 8H), 1.49 (p, J = 7.0 Hz, 2H), 1.13 (ddd, J = 32.9, 15.8, 7.6 Hz, 3H).
MS(ESI) m/z: 392.1 (M+H)⁺. Example 1 Synthesis of 2-amino-5- [5- (L-cyclohexylglycylamino) -pentanoylamino] -nicotinic acid 2TFA salt (Compound 1)

Boc-L-cyclohexylglycine (5.16 g, 20.0 mmol) and N-hydroxysuccinimide (2.3 g, 20.0 mmol) were dissolved in ethyl acetate, and N, N′-dicyclohexylcarbodiimide (4.12 g, (20.0 mmol) in ethyl acetate and stirred overnight at room temperature. The precipitated N, N'-dicyclohexylurea was separated by filtration, and the ethyl acetate layer of the mother liquor was washed with a 5% aqueous solution of sodium hydrogen carbonate and water, and the solvent was distilled off under reduced pressure, and n-hexane and ethyl acetate were added to the residue. In addition, crystallization, separation and drying under reduced pressure gave Boc-L-cyclohexylglycine-N-succinimide ester (5.76 g, 16.3 mmol).
5-Aminopentanoic acid (0.25 g, 2.1 mmol) and sodium hydrogen carbonate 0.17 g (2.0 mmol) are dissolved in water, and a 1 M aqueous sodium hydroxide solution (2.1 mL, 2.1 mmol) and acetonitrile are added. Then, Boc-L-cyclohexylglycine-N-succinimide ester (0.71 g, 2.0 mmol) was added, and the mixture was stirred at room temperature overnight. Acetonitrile was distilled off under reduced pressure, ethyl acetate and water were added, and the mixture was adjusted to pH 1.5 with 6M hydrochloric acid and extracted. The organic layer was washed with water, the solvent was distilled off under reduced pressure, and dried to obtain 5-Boc-L-cyclohexylglycylaminopentanoic acid (0.72 g, 2.0 mmol).
5-Boc-L-cyclohexylglycylaminopentanoic acid (0.71 g, 2.0 mmol) and ethyl 4-, 5-diaminonicotinic acid (0.35 g, 1.9 mmol) were dissolved in DMF, and 1-ethyl- 3- (3-Dimethylaminopropyl) carbodiimide hydrochloride (0.42 g, 2.1 mmol) was added and stirred overnight. A 5% aqueous solution of sodium hydrogencarbonate and water are added for crystallization, separated, dried under reduced pressure and 4-amino-5- [7- (Boc-L-cyclohexylglycylamino) -pentanoylamino] -nicotinic acid ethyl ester (0.92 g, 1.77 mmol).
4-Amino-5- [5- (Boc-L-cyclohexylglycylamino) -pentanoylamino] -nicotinic acid ethyl ester (0.92 g, 1.77 mmol) was dissolved by adding THF and water, and 1M water was added. An aqueous sodium oxide solution (2.12 mL, 2.12 mmol) was added, and the mixture was stirred at room temperature overnight. Water and 1 M hydrochloric acid (2.12 mL, 2.12 mmol) are added for crystallization, separation and drying, followed by drying with 4-amino-5- [5- (Boc-L-cyclohexylglycylamino) -pentanoylamino] -nicotine. The acid (0.66 g, 1.35 mmol) was obtained.
4-Amino-5- [5- (Boc-L-cyclohexylglycylamino) -pentanoylamino] -nicotinic acid (0.66 g, 1.35 mmol) trifluoroacetic acid was added, and the mixture was stirred at room temperature for 4 hours. The trifluoroacetic acid was distilled off under reduced pressure, and acetonitrile was added for crystallization, separation, and drying. 4-amino-5- [5- (L-cyclohexylglycylamino) -pentanoylamino] -nicotinic acid. 2TFA salt (IN4150, 0.85 g, 1.35 mmol) was obtained.
4-Amino-5- [5-((S) -cyclohexylglycylamino) -pentanoylamino] -nicotinic acid
4-amino-5- [5-((S) -cyclohexylglycylamino) -pentanoylamino] -nicotinic acid
¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.57 (s, 1H), 8.72 (s, 1H), 8.53 (s, 1H), 8.42 (t, J = 5.6 Hz, 1H), 8.11-8.05 ( m, 2H), 3.25 (dd, J = 13.3, 6.5 Hz, 5H), 3.08 (dq, J = 12.6, 6.4 Hz, 2H), 2.44 (t, J = 7.3 Hz, 2H), 1.75-1.56 (m , 8H), 1.49 (p, J = 7.0 Hz, 2H), 1.13 (ddd, J = 32.9, 15.8, 7.6 Hz, 3H).
MS (ESI) m / z: 392.1 (M + H) ⁺ .

４−アミノ−５−[５−（Ｂｏｃ−Ｌ−シクロヘキシルグリシルアミノ）−ペンタノイルアミノ]−ニコチン酸（０．０２５ｇ、０．０５ｍｍｏｌ）に酢酸エチル（２ｍＬ）、４Ｍ塩酸―酢酸エチル溶液（０．５ｍＬ）を加えて室温で２時間撹拌した。酢酸エチルを減圧下留去し、酢酸エチルを加えて晶析、分離、乾燥して４−アミノ−５−[５−（Ｌ−シクロヘキシルグリシルアミノ）−ペンタノイルアミノ]−ニコチン酸．２ＨＣｌ塩（０．０２１ｇ、０．０４５ｍｍｏｌ）を得た。 Example 2 Synthesis of 4-amino-5- [5- (L-cyclohexylglycylamino) -pentanoylamino] -nicotinic acid 2HCl salt (Compound 2)

4-Amino-5- [5- (Boc-L-cyclohexylglycylamino) -pentanoylamino] -nicotinic acid (0.025 g, 0.05 mmol) in ethyl acetate (2 mL), 4 M hydrochloric acid-ethyl acetate solution ( 0.5 mL) and stirred at room temperature for 2 hours. Ethyl acetate was distilled off under reduced pressure, and ethyl acetate was added for crystallization, separation and drying, followed by drying. The 2HCl salt (0.021 g, 0.045 mmol) was obtained.

４−アミノ−５−[５−（Ｌ−シクロヘキシルグリシルアミノ）−ペンタノイルアミノ]−ニコチン酸．２ＴＦＡ塩（０．０６２ｇ、０．１ｍｍｏｌ）に水（２ｍＬ）加えて１Ｍ水酸化ナトリウム水溶液２００μＬを加えて室温で一晩撹拌した。析出した結晶を分離、４０℃で一晩減圧乾燥性し４−アミノ−５−[５−（Ｌ−シクロヘキシルグリシルアミノ）−ペンタノイルアミノ]−ニコチン酸を得た。（１４ｍｇ、０．０３６ｍｍｏｌ） Example 3 Synthesis of 4-amino-5- [5- (L-cyclohexylglycylamino) -pentanoylamino] -nicotinic acid (Compound 3)

4-amino-5- [5- (L-cyclohexylglycylamino) -pentanoylamino] -nicotinic acid. Water (2 mL) was added to 2TFA salt (0.062 g, 0.1 mmol), 200 μL of a 1 M aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature overnight. The precipitated crystals were separated and dried under reduced pressure at 40 ° C. overnight to obtain 4-amino-5- [5- (L-cyclohexylglycylamino) -pentanoylamino] -nicotinic acid. (14 mg, 0.036 mmol)

４−アミノ−５−[５−（Ｌ−シクロヘキシルグリシルアミノ）−ペンタノイルアミノ]−ニコチン酸．２ＴＦＡ塩（０．０６２ｇ、０．１ｍｍｏｌ）にメタノール（４ｍＬ）加えて８Ｍ水酸化ナトリウム水溶液４３μＬを加えて室温で一晩撹拌した。反応液を減圧下濃縮しアセトン（１５ｍＬ）加えて晶析した。析出した結晶を分離、４０℃で一晩減圧乾燥性し４−アミノ−５−[５−（Ｌ−シクロヘキシルグリシルアミノ）−ペンタノイルアミノ]−ニコチン酸Ｎａ塩を得た。（４１ｍｇ、０．０1ｍｍｏｌ） (Example 4) Synthesis of Na salt of 4-amino-5- [5- (L-cyclohexylglycylamino) -pentanoylamino] -nicotinic acid (compound 4)

4-amino-5- [5- (L-cyclohexylglycylamino) -pentanoylamino] -nicotinic acid. Methanol (4 mL) was added to 2TFA salt (0.062 g, 0.1 mmol), 43 μL of an 8 M aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and acetone (15 mL) was added for crystallization. The precipitated crystals were separated and dried under reduced pressure at 40 ° C. overnight to obtain sodium 4-amino-5- [5- (L-cyclohexylglycylamino) -pentanoylamino] -nicotinic acid salt. (41 mg, 0.01 mmol)

３−（ｔｅｒｔ−ブトキシカルボニルアミノ）−３−メチルーブタン酸（６５２ｍｇ， ３．００ｍｍｏｌ）、ＣＯＭＵ（１．４１ｇ， ３．３０ｍｍｏｌ）をＤＭＦ（１５．０ｍＬ）に溶解し、ＤＩＰＥＡ（５６１μＬ， ３．３０ｍｍｏｌ）を加え室温で１０分攪拌した。その後、４，５−ジアミノピリジン−３−カルボン酸メチル（５００ｍｇ， ３．００ｍｍｏｌ）加え室温で終夜攪拌した。反応液を酢酸エチルで希釈し、炭酸水素ナトリウム水溶液および飽和食塩水で洗浄後、有機層を無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた残渣を塩基性シリカゲルクロマトグラフィー（ヘキサン／酢酸エチル）にて精製することで４−アミノ−５−［［３−（ｔｅｒｔ−ブトキシカルボニルアミノ）−３−メチル−ブタノイル］アミノ］ピリジン−３−カルボン酸メチル（６１７ｍｇ， １．６８ｍｍｏｌ）を得た。
４−アミノ−５−［［３−（ｔｅｒｔ−ブトキシカルボニルアミノ）−３−メチル−ブタノイル］アミノ］ピリジン−３−カルボン酸メチル（６１７ｍｇ， １．６８ｍｍｏｌ）をジクロロメタン（２．００ｍＬ）に懸濁し、トリフルオロ酢酸（２．００ｍｌ）を加えて室温で２時間撹拌した。減圧下溶媒を留去して得られた残渣を水に溶解し、凍結乾燥することにより、４−アミノ−５−［（３−アミノ−３−メチル−ブタノイル）アミノ］ピリジン−３−カルボン酸メチル トリフルオロ酢酸塩（５９０ｍｇ， １．６２ｍｍｏｌ）を得た。
４−アミノ−５−［（３−アミノ−３−メチル−ブタノイル）アミノ］ピリジン−３−カルボン酸メチル トリフルオロ酢酸塩（１５９．０ｍｇ，０．５９８ｍｍｏｌ）、Ｎ−（ｔｅｒｔ−ブトキシカルボニル）−Ｌ−２−シクロヘキシルグリシン（１５４．０ｍｇ，０．５９８ｍｍｏｌ）、ＷＳＣＩ（１１６．０ｍｇ，０．５９８ｍｍｏｌ）およびＨＯＢｔ（８２．０ｍｇ，０．５９８ｍｍｏｌ）をジクロロメタン（２ｍＬ）に懸濁し、ＤＩＰＥＡ（０．５０ｍＬ，１．７９４ｍｍｏｌ）を加えて室温で２時間撹拌した。酢酸エチルで希釈し、炭酸水素ナトリウム水溶液および飽和食塩水で洗浄後、有機層を無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた残渣をメタノール（１ｍＬ）の溶媒に溶解し、氷冷下２Ｍ 水酸化ナトリウム水溶液（１．００ｍＬ）を加えて室温で２時間撹拌した。反応液に氷冷下で２Ｍ トリフルオロ酢酸水溶液（１．００ｍＬ）を加え、減圧下濃縮して得られた残渣を、オクタドデシル基化学結合型シリカゲルを充填剤とする逆相高速液体クロマトグラフィーに付し、トリフルオロ酢酸を０．０５％含有する（ｖ／ｖ）、水とアセトニトリルの混合溶液で溶出し目的のフラクションを凍結乾燥することにより、４−アミノ−５−［［３−［［（２Ｓ）−２−（ｔｅｒｔ−ブトキシカルボニルアミノ）−２−シクロヘキシル−アセチル］アミノ］−３−メチル−ブタノイル］アミノ］ピリジン−３−カルボン酸 トリフルオロ酢酸塩（２０９．２ｍｇ，０．４２６ｍｍｏｌ）を得た。
４−アミノ−５−［［３−［［（２Ｓ）−２−（ｔｅｒｔ−ブトキシカルボニルアミノ）−２−シクロヘキシル−アセチル］アミノ］−３−メチル−ブタノイル］アミノ］ピリジン−３−カルボン酸 トリフルオロ酢酸塩（２０９．２ｍｇ，０．４２６ｍｍｏｌ）をジクロロメタン１ｍＬに溶解し、トリフルオロ酢酸１ｍＬを加えて１時間撹拌した。減圧下溶媒を留去した後、凍結乾燥を行うことで４−アミノ−５−［［３−［［（２Ｓ）−２−アミノ−２−シクロヘキシル−アセチル］アミノ］−３−メチル−ブタノイル］アミノ］ピリジン−３−カルボン酸 二トリフルオロ酢酸塩（１６５．４ｍｇ，０．４２３ｍｍｏｌ）を得た。
4-amino-5-[[3-[[(2S)-2-amino-2-cyclohexyl-acetyl]amino]-3-methyl-butanoyl]amino]pyridine-3-carboxylic acid ditrifluoroacetate
４−アミノ−５−［［３−［［（２Ｓ）−２−アミノ−２−シクロヘキシル−アセチル］アミノ］−３−メチル−ブタノイル］アミノ］ピリジン−３−カルボン酸 二トリフルオロ酢酸塩
¹H NMR ((CD₃)₂SO) δ= 9.41 (s, 1H), 8.62 (s, 1H), 8.38 (s, 1H), 8.06 (s, 1H), 7.93 (s, 2H), 2.91 - 2.73 (m, 2H), 1.57 (dq, J = 23.5, 12.5, 11.5 Hz, 6H), 1.36 (d, J = 7.8 Hz, 6H), 1.03 (dtd, J = 45.5, 23.9, 23.3, 14.4 Hz, 6H).
MS(ESI) m/z: 392.2 (M+H)⁺. Example 5 4-Amino-5-[[3-[[(2S) -2-amino-2-cyclohexyl-acetyl] amino] -3-methyl-butanoyl] amino] pyridine-3-carboxylic acid Synthesis of Fluoroacetate (Compound 5)

3- (tert-Butoxycarbonylamino) -3-methylbutanoic acid (652 mg, 3.00 mmol) and COMU (1.41 g, 3.30 mmol) were dissolved in DMF (15.0 mL), and DIPEA (561 μL, 3.30 mmol). ) And stirred at room temperature for 10 minutes. Thereafter, methyl 4,5-diaminopyridine-3-carboxylate (500 mg, 3.00 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution and saturated saline, and then the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue is purified by basic silica gel chromatography (hexane / ethyl acetate) to give 4-amino-5-[[3- (tert-butoxycarbonylamino) -3-methyl-butanoyl] amino] pyridine-. Methyl 3-carboxylate (617 mg, 1.68 mmol) was obtained.
Methyl 4-amino-5-[[3- (tert-butoxycarbonylamino) -3-methyl-butanoyl] amino] pyridine-3-carboxylate (617 mg, 1.68 mmol) was suspended in dichloromethane (2.00 mL). , Trifluoroacetic acid (2.00 ml) was added, and the mixture was stirred at room temperature for 2 hours. The residue obtained by evaporating the solvent under reduced pressure was dissolved in water and lyophilized to give 4-amino-5-[(3-amino-3-methyl-butanoyl) amino] pyridine-3-carboxylic acid. Methyl trifluoroacetate (590 mg, 1.62 mmol) was obtained.
4-Amino-5-[(3-amino-3-methyl-butanoyl) amino] pyridine-3-carboxylic acid methyl trifluoroacetate (159.0 mg, 0.598 mmol), N- (tert-butoxycarbonyl)- L-2-cyclohexylglycine (154.0 mg, 0.598 mmol), WSCI (116.0 mg, 0.598 mmol) and HOBt (82.0 mg, 0.598 mmol) were suspended in dichloromethane (2 mL), and DIPEA (0. (50 mL, 1.794 mmol) and stirred at room temperature for 2 hours. After diluting with ethyl acetate and washing with an aqueous sodium hydrogen carbonate solution and saturated saline, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in a solvent of methanol (1 mL), a 2M aqueous sodium hydroxide solution (1.00 mL) was added under ice cooling, and the mixture was stirred at room temperature for 2 hours. A 2M aqueous solution of trifluoroacetic acid (1.00 mL) was added to the reaction mixture under ice-cooling, and the resulting residue was concentrated under reduced pressure. The mixture was eluted with a mixed solution of water and acetonitrile containing 0.05% trifluoroacetic acid (v / v), and the desired fraction was lyophilized to give 4-amino-5-[[3-[[ (2S) -2- (tert-Butoxycarbonylamino) -2-cyclohexyl-acetyl] amino] -3-methyl-butanoyl] amino] pyridine-3-carboxylic acid trifluoroacetate (209.2 mg, 0.426 mmol) I got
4-Amino-5-[[3-[[(2S) -2- (tert-butoxycarbonylamino) -2-cyclohexyl-acetyl] amino] -3-methyl-butanoyl] amino] pyridine-3-carboxylic acid tri Fluoroacetate (209.2 mg, 0.426 mmol) was dissolved in dichloromethane (1 mL), trifluoroacetic acid (1 mL) was added, and the mixture was stirred for 1 hour. After evaporating the solvent under reduced pressure, the residue is freeze-dried to give 4-amino-5-[[3-[[(2S) -2-amino-2-cyclohexyl-acetyl] amino] -3-methyl-butanoyl]. Amino] pyridine-3-carboxylic acid ditrifluoroacetate (165.4 mg, 0.423 mmol) was obtained.
4-amino-5-[[3-[[(2S) -2-amino-2-cyclohexyl-acetyl] amino] -3-methyl-butanoyl] amino] pyridine-3-carboxylic acid ditrifluoroacetate
4-amino-5-[[3-[[(2S) -2-amino-2-cyclohexyl-acetyl] amino] -3-methyl-butanoyl] amino] pyridine-3-carboxylic acid ditrifluoroacetate
¹ H NMR ((CD ₃ ) ₂ SO) δ = 9.41 (s, 1H), 8.62 (s, 1H), 8.38 (s, 1H), 8.06 (s, 1H), 7.93 (s, 2H), 2.91- 2.73 (m, 2H), 1.57 (dq, J = 23.5, 12.5, 11.5 Hz, 6H), 1.36 (d, J = 7.8 Hz, 6H), 1.03 (dtd, J = 45.5, 23.9, 23.3, 14.4 Hz, 6H).
MS (ESI) m / z: 392.2 (M + H) ⁺ .

上記の点以外は実施例５と同様にして化合物６を調製した。 Example 6 4-Amino-5-[[3-[[(2S) -2-amino-2-cyclohexyl-acetyl] amino] -3-methyl-butanoyl] amino] pyridine-3-carboxylic acid dihydrochloride Synthesis of salt (compound 6)

Compound 6 was prepared in the same manner as in Example 5 except for the above.

４−アミノ−５−［（３−アミノ−３−メチル−ブタノイル）アミノ］ピリジン−３−カルボン酸メチル トリフルオロ酢酸塩（３０．０ｍｇ， ０．１２０ｍｍｏｌ）、２−シクロヘキシル酢酸（１７．０ｍｇ， ０．１２０ｍｍｏｌ）、ＨＯＢｔ（１５．０ｍｇ， ０．１３０ｍｍｏｌ）、ＷＳＣＩ（２５．０ｍｇ， ０．１３０ｍｍｏｌ）、ＤＩＰＥＡ（２２μＬ， ０．１３０ｍｍｏｌ）をＤＭＦ（２．００ｍＬ）に溶解し室温で終夜攪拌した。反応液を酢酸エチルで希釈し、炭酸水素ナトリウム水溶液および飽和食塩水で洗浄後、有機層を無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた残渣を塩基性シリカゲルクロマトグラフィー（ヘキサン／酢酸エチル）にて精製することで、４−アミノ−５−［［３−［（２−シクロヘキシルアセチル）アミノ］−３−メチル−ブタノイル］アミノ］ピリジン−３−カルボン酸メチル（１５．０ｍｇ， ０．０３８４ｍｍｏｌ）得た。
４−アミノ−５−［［３−［（２−シクロヘキシルアセチル）アミノ］−３−メチル−ブタノイル］アミノ］ピリジン−３−カルボン酸メチル（１５．０ｍｇ， ０．０３８４ｍｍｏｌ）をメタノール（１．００ｍＬ）に溶解し、２Ｍ 水酸化ナトリウム水溶液（５０μＬ）を加え室温で終夜攪拌した。反応液に、酸性イオン交換樹脂を入れ中和し濾過を行い、減圧下溶媒を留去して得られた残渣を水に溶解し、凍結乾燥することにより、４−アミノ−５−［［３−［（２−シクロヘキシルアセチル）アミノ］−３−メチル−ブタノイル］アミノ］ピリジン−３−カルボン酸 トリフルオロ酢酸塩（１２．０ｍｇ，０．０３１９ｍｍｏｌ）得た。
4-amino-5-[[3-[(2-cyclohexylacetyl)amino]-3-methyl-butanoyl]amino]pyridine-3-carboxylic acid trifluoroacetate
４−アミノ−５−［［３−［（２−シクロヘキシルアセチル）アミノ］−３−メチル−ブタノイル］アミノ］ピリジン−３−カルボン酸 トリフルオロ酢酸塩
¹H NMR (CH₃OD) δ= 8.61 (s, 1H), 8.20 (s, 1H), 2.92 (s, 2H), 2.01 (d, J = 7.0 Hz, 2H), 1.72 - 1.62 (m, 5H), 1.47 (s, 6H), 1.32 - 1.06 (m, 4H), 1.00 - 0.86 (m, 2H).
MS(ESI) m/z: 377.2 (M+H)⁺. Example 7 Synthesis of 4-amino-5-[[3-[(2-cyclohexylacetyl) amino] -3-methyl-butanoyl] amino] pyridine-3-carboxylic acid trifluoroacetate (Compound 7)

4-Amino-5-[(3-amino-3-methyl-butanoyl) amino] pyridine-3-carboxylate methyl trifluoroacetate (30.0 mg, 0.120 mmol), 2-cyclohexylacetic acid (17.0 mg, 0.120 mmol), HOBt (15.0 mg, 0.130 mmol), WSCI (25.0 mg, 0.130 mmol) and DIPEA (22 μL, 0.130 mmol) were dissolved in DMF (2.00 mL) and stirred at room temperature overnight. . The reaction solution was diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution and saturated saline, and then the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue is purified by basic silica gel chromatography (hexane / ethyl acetate) to give 4-amino-5-[[3-[(2-cyclohexylacetyl) amino] -3-methyl-butanoyl] amino. ] Methyl pyridine-3-carboxylate (15.0 mg, 0.0384 mmol) was obtained.
Methyl 4-amino-5-[[3-[(2-cyclohexylacetyl) amino] -3-methyl-butanoyl] amino] pyridine-3-carboxylate (15.0 mg, 0.0384 mmol) in methanol (1.00 mL) ), 2M aqueous sodium hydroxide solution (50 μL) was added, and the mixture was stirred at room temperature overnight. The reaction solution was neutralized with an acidic ion exchange resin, filtered, and the solvent was distilled off under reduced pressure. The residue obtained was dissolved in water and lyophilized to give 4-amino-5-[[3 -[(2-Cyclohexylacetyl) amino] -3-methyl-butanoyl] amino] pyridine-3-carboxylic acid trifluoroacetate (12.0 mg, 0.0319 mmol) was obtained.
4-amino-5-[[3-[(2-cyclohexylacetyl) amino] -3-methyl-butanoyl] amino] pyridine-3-carboxylic acid trifluoroacetate
4-amino-5-[[3-[(2-cyclohexylacetyl) amino] -3-methyl-butanoyl] amino] pyridine-3-carboxylic acid trifluoroacetate
¹ H NMR (CH ₃ OD) δ = 8.61 (s, 1H), 8.20 (s, 1H), 2.92 (s, 2H), 2.01 (d, J = 7.0 Hz, 2H), 1.72-1.62 (m, 5H ), 1.47 (s, 6H), 1.32-1.06 (m, 4H), 1.00-0.86 (m, 2H).
MS (ESI) m / z: 377.2 (M + H) ⁺ .

４−アミノ−５−ブロモニコチン酸（０．４ｇ、１．８６ｍｍｏｌ）を硫酸１ｍＬ、メタノール４ｍＬ中で混合し、７５℃で１２時間攪拌を行った。反応終了後、酢酸エチルで希釈し、重層水及び飽和食塩水で有機層を洗浄した。有機層を硫酸マグネシウムで乾燥後、ろ過し、溶媒を留去し、シリカゲルカラムクロマトグラフィーを行うことでメチル−４−アミノ−５−ブロモニコチン酸（０．３９ｇ、１．７２ｍｍｏｌ）を得た。 Synthesis of methyl-4-amino-5-bromonicotinic acid (intermediate)

4-Amino-5-bromonicotinic acid (0.4 g, 1.86 mmol) was mixed in 1 mL of sulfuric acid and 4 mL of methanol, and stirred at 75 ° C for 12 hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate, and the organic layer was washed with an aqueous layer solution and saturated saline. The organic layer was dried over magnesium sulfate, filtered, the solvent was distilled off, and silica gel column chromatography was performed to obtain methyl-4-amino-5-bromonicotinic acid (0.39 g, 1.72 mmol).

４−アミノ−５−ブロモピリジン−３−カルボン酸メチル（７８６ｍｇ，３．４０ｍｍｏｌ）、［５−［（ｔｅｒｔ−ブトキシカルボニルアミノ）メチル］−２−フリル］ボロン酸（１．１５ｇ，４．７７ｍｍｏｌ）、炭酸ナトリウム（９０１ｍｇ，８．５０ｍｍｏｌ）および［１，１’−ビス（ジフェニルホスフィノ）フェロセン］ジクロロパラジウム（II）（１２４ｍｇ，０．１７ｍｍｏｌ）を１，４−ジオキサン（２４ｍＬ）／水（８ｍＬ）の混合溶媒中１０５℃で１．５時間撹拌した。反応溶液を減圧下濃縮し、酢酸エチルおよび炭酸水素ナトリウム水溶液を加え、セライトを用いて不溶物を濾別した。濾液を酢酸エチルで抽出し、有機層を無水硫酸マグネシウムで乾燥後、減圧下溶媒を留去して得られた残渣を塩基性シリカゲルクロマトグラフィー（ヘキサン／酢酸エチル）にて精製することによって４−アミノ−５−［５−［（ｔｅｒｔ−ブトキシカルボニルアミノ）メチル］−２−フリル］ピリジン−３−カルボン酸メチル（８１３ｍｇ，２．３４ｍｍｏｌ）を得た。MS (ESI) m/z: 348 [M+H]⁺.
４−アミノ−５−［５−［（ｔｅｒｔ−ブトキシカルボニルアミノ）メチル］−２−フリル］ピリジン−３−カルボン酸メチル（８１３ｍｇ，２．３４ｍｍｏｌ）を１，４−ジオキサン（５ｍＬ）に溶解し、４Ｎ 塩酸／１，４−ジオキサン溶液（２５ｍＬ）を加え室温で一晩撹拌した。減圧下溶媒を留去し乾燥することにより、４−アミノ−５−［５−（アミノメチル）−２−フリル］ピリジン−３−カルボン酸メチル 二塩酸塩（７５０ｍｇ，２．３４ｍｍｏｌ）を得た。MS (ESI) m/z: 248 [M+H]⁺
４−アミノ−５−［５−（アミノメチル）−２−フリル］ピリジン−３−カルボン酸メチル 二塩酸塩（３８．４ｍｇ，０．１２０ｍｍｏｌ）、Ｎ−（ｔｅｒｔ−ブトキシカルボニル）−Ｌ−２−シクロヘキシルグリシン（３４．０ｍｇ，０．１３２ｍｍｏｌ）、ＷＳＣＩ（２５．３ｍｇ，０．１３２ｍｍｏｌ）およびＨＯＢｔ（１７．８ｍｇ，０．１３２ｍｍｏｌ）をジクロロメタン（２ｍＬ）に懸濁し、氷冷下トリエチルアミン（０．０５０ｍＬ，０．３６ｍｍｏｌ）を加えて室温で一晩撹拌した。反応液を減圧下濃縮した後、酢酸エチルで希釈し、炭酸水素ナトリウム水溶液および飽和食塩水で洗浄後、有機層を無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた残渣をＴＨＦ（１ｍＬ）／メタノール（１ｍＬ）の混合溶媒に溶解し、氷冷下１Ｍ 水酸化リチウム水溶液（０．６００ｍＬ）を加えて室温で２時間撹拌した。反応液に氷冷下で２Ｍ トリフルオロ酢酸水溶液（０．３００ｍＬ）を加え、減圧下濃縮して得られた残渣を逆相高速液体クロマトグラフィーで精製することにより、４−アミノ−５−［５−［［［（２Ｓ）−２−（ｔｅｒｔ−ブトキシカルボニルアミノ）−２−シクロヘキシル−アセチル］アミノ］メチル］−２−フリル］ピリジン−３−カルボン酸 トリフルオロ酢酸塩（４７．６ｍｇ，０．０８１２ｍｍｏｌ）を得た。MS (ESI) m/z: 473 [M+H]⁺
４−アミノ−５−［５−［［［（２Ｓ）−２−（ｔｅｒｔ−ブトキシカルボニルアミノ）−２−シクロヘキシル−アセチル］アミノ］メチル］−２−フリル］ピリジン−３−カルボン酸 トリフルオロ酢酸塩（３３．６ｍｇ，０．０５７３ｍｍｏｌ）をジクロロメタン（２ｍＬ）に懸濁し、トリフルオロ酢酸（２ｍＬ）を加えて室温で２時間撹拌した。減圧下溶媒を留去して得られた残渣を水に溶解し、凍結乾燥することにより、４−アミノ−５−［５−［［［（２Ｓ）−２−アミノ−２−シクロヘキシル−アセチル］アミノ］メチル］−２−フリル］ピリジン−３−カルボン酸 二トリフルオロ酢酸塩（３６．０ｍｇ， ０．０６００ｍｍｏｌ）を得た。
４−アミノ−５−［５−［［［（２Ｓ）−２−アミノ−２−シクロヘキシル−アセチル］アミノ］メチル］−２−フリル］ピリジン−３−カルボン酸 二トリフルオロ酢酸塩（１１０ｍｇ， ０．１８３ｍｍｏｌ）に４Ｎ 塩酸／酢酸エチル溶液（１０ｍＬ）を加えて室温で３０分撹拌した後、減圧下溶媒を留去した。更に４Ｎ 塩酸／酢酸エチル溶液（１０ｍＬ）を加え、減圧下溶媒を留去して得られた残渣を水に溶解し、凍結乾燥することにより、４−アミノ−５−［５−［［［（２Ｓ）−２−アミノ−２−シクロヘキシル−アセチル］アミノ］メチル］−２−フリル］ピリジン−３−カルボン酸 二塩酸塩（８１．０ｍｇ，０．１８２ｍｍｏｌ）を得た。
4-amino-5-[5-[[[(2S)-2-amino-2-cyclohexyl-acetyl]amino]methyl]-2-furyl]pyridine-3-carboxylic acid dihydrochloride
４−アミノ−５−［５−［［［（２Ｓ）−２−アミノ−２−シクロヘキシル−アセチル］アミノ］メチル］−２−フリル］ピリジン−３−カルボン酸 二塩酸塩
¹H NMR (CD₃OD) δ= 8.71 (d, J = 1.1 Hz, 1H), 8.38 (d, J = 1.1 Hz, 1H), 6.87 (d, J = 3.5 Hz, 1H), 6.46 (d, J = 3.5 Hz, 1H), 4.62 - 4.30 (m, 2H), 3.57 (d, J = 6.2 Hz, 1H), 1.80 - 1.48 (m, 6H), 1.25 - 0.90 (m, 5H). Example 8 4-amino-5- [5-[[[(2S) -2-amino-2-cyclohexyl-acetyl] amino] methyl] -2-furyl] pyridine-3-carboxylic acid dihydrochloride ( Synthesis of compound 8)

Methyl 4-amino-5-bromopyridine-3-carboxylate (786 mg, 3.40 mmol), [5-[(tert-butoxycarbonylamino) methyl] -2-furyl] boronic acid (1.15 g, 4.77 mmol) ), Sodium carbonate (901 mg, 8.50 mmol) and [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) (124 mg, 0.17 mmol) were treated with 1,4-dioxane (24 mL) / water ( (8 mL) in a mixed solvent at 105 ° C. for 1.5 hours. The reaction solution was concentrated under reduced pressure, ethyl acetate and an aqueous solution of sodium hydrogen carbonate were added, and insolubles were filtered off using celite. The filtrate was extracted with ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue obtained was purified by basic silica gel chromatography (hexane / ethyl acetate) to give 4- Amino-5- [5-[(tert-butoxycarbonylamino) methyl] -2-furyl] pyridine-3-carboxylate (813 mg, 2.34 mmol) was obtained. MS (ESI) m / z: 348 [M + H] ⁺ .
Methyl 4-amino-5- [5-[(tert-butoxycarbonylamino) methyl] -2-furyl] pyridine-3-carboxylate (813 mg, 2.34 mmol) was dissolved in 1,4-dioxane (5 mL). A 4N hydrochloric acid / 1,4-dioxane solution (25 mL) was added, and the mixture was stirred at room temperature overnight. The solvent was distilled off under reduced pressure and dried to obtain methyl 4-amino-5- [5- (aminomethyl) -2-furyl] pyridine-3-carboxylate dihydrochloride (750 mg, 2.34 mmol). . MS (ESI) m / z: 248 [M + H] ⁺
Methyl 4-amino-5- [5- (aminomethyl) -2-furyl] pyridine-3-carboxylate dihydrochloride (38.4 mg, 0.120 mmol), N- (tert-butoxycarbonyl) -L-2 -Cyclohexylglycine (34.0 mg, 0.132 mmol), WSCI (25.3 mg, 0.132 mmol) and HOBt (17.8 mg, 0.132 mmol) are suspended in dichloromethane (2 mL), and triethylamine (0. 050 mL, 0.36 mmol) and stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution and saturated saline, and then the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in a mixed solvent of THF (1 mL) / methanol (1 mL), a 1 M aqueous lithium hydroxide solution (0.600 mL) was added under ice cooling, and the mixture was stirred at room temperature for 2 hours. A 2M aqueous trifluoroacetic acid solution (0.300 mL) was added to the reaction mixture under ice-cooling, and the residue obtained by concentration under reduced pressure was purified by reversed-phase high-performance liquid chromatography to give 4-amino-5- [5 -[[[(2S) -2- (tert-butoxycarbonylamino) -2-cyclohexyl-acetyl] amino] methyl] -2-furyl] pyridine-3-carboxylic acid trifluoroacetate (47.6 mg, 0.1 mg). 0812 mmol). MS (ESI) m / z: 473 [M + H] ⁺
4-amino-5- [5-[[[(2S) -2- (tert-butoxycarbonylamino) -2-cyclohexyl-acetyl] amino] methyl] -2-furyl] pyridine-3-carboxylic acid trifluoroacetic acid The salt (33.6 mg, 0.0573 mmol) was suspended in dichloromethane (2 mL), trifluoroacetic acid (2 mL) was added, and the mixture was stirred at room temperature for 2 hours. The residue obtained by evaporating the solvent under reduced pressure was dissolved in water and freeze-dried to give 4-amino-5- [5-[[[(2S) -2-amino-2-cyclohexyl-acetyl]. Amino] methyl] -2-furyl] pyridine-3-carboxylic acid ditrifluoroacetate (36.0 mg, 0.0600 mmol) was obtained.
4-Amino-5- [5-[[[(2S) -2-amino-2-cyclohexyl-acetyl] amino] methyl] -2-furyl] pyridine-3-carboxylic acid ditrifluoroacetate (110 mg, 0 .183 mmol), a 4N hydrochloric acid / ethyl acetate solution (10 mL) was added, and the mixture was stirred at room temperature for 30 minutes, and then the solvent was distilled off under reduced pressure. Further, a 4N hydrochloric acid / ethyl acetate solution (10 mL) was added, and the residue obtained by evaporating the solvent under reduced pressure was dissolved in water and lyophilized to give 4-amino-5- [5-[[[( 2S) -2-Amino-2-cyclohexyl-acetyl] amino] methyl] -2-furyl] pyridine-3-carboxylic acid dihydrochloride (81.0 mg, 0.182 mmol) was obtained.
4-amino-5- [5-[[[[(2S) -2-amino-2-cyclohexyl-acetyl] amino] methyl] -2-furyl] pyridine-3-carboxylic acid dihydrochloride
4-amino-5- [5-[[[(2S) -2-amino-2-cyclohexyl-acetyl] amino] methyl] -2-furyl] pyridine-3-carboxylic acid dihydrochloride
¹ H NMR (CD ₃ OD) δ = 8.71 (d, J = 1.1 Hz, 1H), 8.38 (d, J = 1.1 Hz, 1H), 6.87 (d, J = 3.5 Hz, 1H), 6.46 (d, J = 3.5 Hz, 1H), 4.62-4.30 (m, 2H), 3.57 (d, J = 6.2 Hz, 1H), 1.80-1.48 (m, 6H), 1.25-0.90 (m, 5H).

上記の点以外は実施例８と同様にして化合物９を調製した。 Example 9 4-amino-5- [5-[[[(2S) -2-amino-2-cyclohexyl-acetyl] amino] methyl] -2-furyl] pyridine-3-carboxylic acid (Compound 9) Synthesis of

Compound 9 was prepared in the same manner as in Example 8 except for the above.

４−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）−１Ｈ−ピラゾール（１９４ｍｇ，１．００ｍｍｏｌ）および炭酸カリウム（２７６ｍｇ，２．００ｍｍｏｌ）をＤＭＦ（１．５ｍＬ）に懸濁し、氷冷下２−（ｔｅｒｔ−ブトキシカルボニルアミノ）エチルブロミド（２２４ｍｇ，１．００ｍｍｏｌ）を加えて室温で３日間撹拌した。減圧下濃縮後、酢酸エチルで希釈し、１Ｎ 塩酸および飽和塩化アンモニウム水溶液で洗浄後、有機層を無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去することにより、Ｎ−［２−［４−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）ピラゾール−１−イル］エチル］カルバミン酸 ｔｅｒｔ−ブチルの粗生成物（２４５ｍｇ）を得た。
４−アミノ−５−ブロモピリジン−３−カルボン酸メチル（１１４ｍｇ，０．４９３ｍｍｏｌ）、Ｎ−［２−［４−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）ピラゾール−１−イル］エチル］カルバミン酸 ｔｅｒｔ−ブチルの粗生成物（２００ｍｇ）、炭酸ナトリウム（１３１ｍｇ，１．２３ｍｍｏｌ）および［１，１’−ビス（ジフェニルホスフィノ）フェロセン］ジクロロパラジウム（II）（１８ｍｇ，０．０２４７ｍｍｏｌ）を１，４−ジオキサン（３ｍＬ）／水（１ｍＬ）の混合溶媒中１０５℃で２時間撹拌した。反応溶液を減圧下濃縮し、酢酸エチルおよび炭酸水素ナトリウム水溶液を加え、セライトを用いて不溶物を濾別した。濾液を酢酸エチルで抽出し、有機層を無水硫酸マグネシウムで乾燥後、減圧下溶媒を留去して得られた残渣を塩基性シリカゲルクロマトグラフィー（ヘキサン／酢酸エチル）にて精製することによって４−アミノ−５−［１−［２−（ｔｅｒｔ−ブトキシカルボニルアミノ）エチル］ピラゾール−４−イル］ピリジン−３−カルボン酸メチル（１１０ｍｇ，０．３０４ｍｍｏｌ）を得た。
MS (ESI) m/z: 362 [M+H]⁺.
４−アミノ−５−［１−［２−（ｔｅｒｔ−ブトキシカルボニルアミノ）エチル］ピラゾール−４−イル］ピリジン−３−カルボン酸メチル（１１０ｍｇ，０．３０４ｍｍｏｌ）を１，４−ジオキサン（２ｍＬ）に溶解し、４Ｎ 塩酸／１，４−ジオキサン（６ｍＬ）を加えて室温で２．５時間撹拌した。減圧下溶媒を留去することにより、４−アミノ−５−［１−（２−アミノエチル）ピラゾール−４−イル］ピリジン−３−カルボン酸メチル 塩酸塩の粗結晶（１２０ｍｇ）を得た。
MS (ESI) m/z: 262 [M+H]⁺.
４−アミノ−５−［１−（２−アミノエチル）ピラゾール−４−イル］ピリジン−３−カルボン酸メチル 塩酸塩（６０．０ｍｇ，０．１８０ｍｍｏｌ）、Ｎ−（ｔｅｒｔ−ブトキシカルボニル）−Ｌ−２−シクロヘキシルグリシン（５１．０ｍｇ，０．１９８ｍｍｏｌ）、ＷＳＣＩ（３８．０ｍｇ，０．１９８ｍｍｏｌ）およびＨＯＢｔ（２６．８ｍｇ，０．１９８ｍｍｏｌ）をジクロロメタン（２ｍＬ）に懸濁し、氷冷下トリエチルアミン（０．０７７８ｍＬ，０．５５８ｍｍｏｌ）を加えて室温で一晩撹拌した。反応液を減圧下濃縮した後、酢酸エチルで希釈し、炭酸水素ナトリウム水溶液および飽和食塩水で洗浄後、有機層を無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた残渣をＴＨＦ（２ｍＬ）／メタノール（２ｍＬ）の混合溶媒に溶解し、氷冷下１Ｍ 水酸化リチウム水溶液（０．８００ｍＬ）を加えて室温で２時間撹拌した。反応液に氷冷下で２Ｍ トリフルオロ酢酸水溶液（０．４００ｍＬ）を加え、減圧下濃縮して得られた残渣を逆相高速液体クロマトグラフィーで精製することにより、４−アミノ−５−［１−［２−［［（２Ｓ）−２−（ｔｅｒｔ−ブトキシカルボニルアミノ）−２−シクロヘキシル−アセチル］アミノ］エチル］ピラゾール−４−イル］ピリジン−３−カルボン酸 トリフルオロ酢酸塩（４３．９ｍｇ，０．０７３１ｍｍｏｌ）を得た。
MS (ESI) m/z: 487 [M+H]⁺.
４−アミノ−５−［１−［２−［［（２Ｓ）−２−（ｔｅｒｔ−ブトキシカルボニルアミノ）−２−シクロヘキシル−アセチル］アミノ］エチル］ピラゾール−４−イル］ピリジン−３−カルボン酸 トリフルオロ酢酸塩（４３．９ｍｇ，０．０７３１ｍｍｏｌ））をジクロロメタン（４ｍＬ）に懸濁し、トリフルオロ酢酸（１ｍＬ）を加えて室温で１時間撹拌した。減圧下溶媒を留去して得られた残渣を水に溶解し、凍結乾燥することにより、４−アミノ−５−［１−［２−［［（２Ｓ）−２−アミノ−２−シクロヘキシル−アセチル］アミノ］エチル］ピラゾール−４−イル］ピリジン−３−カルボン酸 二トリフルオロ酢酸塩（４７．８ｍｇ，０．０７７８ｍｍｏｌ）を得た。
4-amino-5-[1-[2-[[(2S)-2-amino-2-cyclohexyl-acetyl]amino]ethyl]pyrazol-4-yl]pyridine-3-carboxylic acid ditrifluoroacetate
４−アミノ−５−［１−［２−［［（２Ｓ）−２−アミノ−２−シクロヘキシル−アセチル］アミノ］エチル］ピラゾール−４−イル］ピリジン−３−カルボン酸 二トリフルオロ酢酸塩
¹H NMR ((CD₃)₂SO) δ= 8.73 (s, 1H), 8.50 (t, J = 5.8 Hz, 1H), 8.12 (s, 1H), 8.06 (s, 1H), 8.03 - 7.92 (m, 3H), 7.70 (s, 1H), 4.29 - 4.11 (m, 2H), 3.78 - 3.64 (m, 2H), 3.45 - 3.41 (m, 1H), 1.62 - 1.32 (m, 6H), 1.10 - 0.74 (m, 5H).
MS (ESI) m/z: 387 [M+H]⁺. Example 10 4-Amino-5- [1- [2-[[(2S) -2-amino-2-cyclohexyl-acetyl] amino] ethyl] pyrazol-4-yl] pyridine-3-carboxylic acid Synthesis of trifluoroacetate (compound 10)

4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole (194 mg, 1.00 mmol) and potassium carbonate (276 mg, 2.00 mmol) were added to DMF ( 1.5 (mL), 2- (tert-butoxycarbonylamino) ethyl bromide (224 mg, 1.00 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 3 days. After concentration under reduced pressure, the mixture was diluted with ethyl acetate, washed with 1N hydrochloric acid and a saturated aqueous solution of ammonium chloride, and the organic layer was dried over anhydrous magnesium sulfate. By evaporating the solvent under reduced pressure, N- [2- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyrazol-1-yl] ethyl] A crude product of tert-butyl carbamate (245 mg) was obtained.
Methyl 4-amino-5-bromopyridine-3-carboxylate (114 mg, 0.493 mmol), N- [2- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane- Crude tert-butyl 2-yl) pyrazol-1-yl] ethyl] carbamate (200 mg), sodium carbonate (131 mg, 1.23 mmol) and [1,1′-bis (diphenylphosphino) ferrocene] dichloro Palladium (II) (18 mg, 0.0247 mmol) was stirred in a mixed solvent of 1,4-dioxane (3 mL) / water (1 mL) at 105 ° C. for 2 hours. The reaction solution was concentrated under reduced pressure, ethyl acetate and an aqueous solution of sodium hydrogen carbonate were added, and insolubles were filtered off using celite. The filtrate was extracted with ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue obtained was purified by basic silica gel chromatography (hexane / ethyl acetate) to give 4- Methyl amino-5- [1- [2- (tert-butoxycarbonylamino) ethyl] pyrazol-4-yl] pyridine-3-carboxylate (110 mg, 0.304 mmol) was obtained.
MS (ESI) m / z: 362 [M + H] ⁺ .
Methyl 4-amino-5- [1- [2- (tert-butoxycarbonylamino) ethyl] pyrazol-4-yl] pyridine-3-carboxylate (110 mg, 0.304 mmol) in 1,4-dioxane (2 mL) And 4N hydrochloric acid / 1,4-dioxane (6 mL) was added thereto, followed by stirring at room temperature for 2.5 hours. The solvent was distilled off under reduced pressure to obtain crude crystals of methyl 4-amino-5- [1- (2-aminoethyl) pyrazol-4-yl] pyridine-3-carboxylate hydrochloride (120 mg).
MS (ESI) m / z: 262 [M + H] ⁺ .
Methyl 4-amino-5- [1- (2-aminoethyl) pyrazol-4-yl] pyridine-3-carboxylate hydrochloride (60.0 mg, 0.180 mmol), N- (tert-butoxycarbonyl) -L -2-Cyclohexylglycine (51.0 mg, 0.198 mmol), WSCI (38.0 mg, 0.198 mmol) and HOBt (26.8 mg, 0.198 mmol) were suspended in dichloromethane (2 mL), and triethylamine ( 0.0778 mL, 0.558 mmol) and stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution and saturated saline, and then the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in a mixed solvent of THF (2 mL) / methanol (2 mL), a 1 M aqueous lithium hydroxide solution (0.800 mL) was added under ice cooling, and the mixture was stirred at room temperature for 2 hours. A 2M aqueous trifluoroacetic acid solution (0.400 mL) was added to the reaction mixture under ice-cooling, and the residue obtained by concentration under reduced pressure was purified by reversed-phase high-performance liquid chromatography to give 4-amino-5- [1 -[2-[[(2S) -2- (tert-butoxycarbonylamino) -2-cyclohexyl-acetyl] amino] ethyl] pyrazol-4-yl] pyridine-3-carboxylic acid trifluoroacetate (43.9 mg , 0.0731 mmol).
MS (ESI) m / z: 487 [M + H] ⁺ .
4-amino-5- [1- [2-[[(2S) -2- (tert-butoxycarbonylamino) -2-cyclohexyl-acetyl] amino] ethyl] pyrazol-4-yl] pyridine-3-carboxylic acid Trifluoroacetic acid salt (43.9 mg, 0.0731 mmol) was suspended in dichloromethane (4 mL), trifluoroacetic acid (1 mL) was added, and the mixture was stirred at room temperature for 1 hour. The residue obtained by evaporating the solvent under reduced pressure was dissolved in water and lyophilized to give 4-amino-5- [1- [2-[[(2S) -2-amino-2-cyclohexyl- [Acetyl] amino] ethyl] pyrazol-4-yl] pyridine-3-carboxylic acid ditrifluoroacetate (47.8 mg, 0.0778 mmol) was obtained.
4-amino-5- [1- [2-[[(2S) -2-amino-2-cyclohexyl-acetyl] amino] ethyl] pyrazol-4-yl] pyridine-3-carboxylic acid ditrifluoroacetate
4-amino-5- [1- [2-[[(2S) -2-amino-2-cyclohexyl-acetyl] amino] ethyl] pyrazol-4-yl] pyridine-3-carboxylic acid ditrifluoroacetate
¹ H NMR ((CD ₃ ) ₂ SO) δ = 8.73 (s, 1H), 8.50 (t, J = 5.8 Hz, 1H), 8.12 (s, 1H), 8.06 (s, 1H), 8.03-7.92 ( m, 3H), 7.70 (s, 1H), 4.29-4.11 (m, 2H), 3.78-3.64 (m, 2H), 3.45-3.41 (m, 1H), 1.62-1.32 (m, 6H), 1.10- 0.74 (m, 5H).
MS (ESI) m / z: 387 [M + H] ⁺ .

４−アミノ−５−ブロモピリジン−３−カルボン酸メチル（６９３ｍｇ，３．００ｍｍｏｌ）のＤＭＦ溶液（１５ｍＬ）に、テトラキス（トリフェニルホスフィン）パラジウム（０）（５２０ｍｇ，０．４５０ｍｍｏｌ）、Ｎ−ブタ−３−エニルカルバミン酸 ｔｅｒｔ−ブチル（０．６９１ｍＬ，３．７５ｍｏｌ）およびＤＩＰＥＡ（０．６３８ｍＬ，３．７５ｍｍｏｌ）を加えて１２０℃で一晩撹拌した。反応液に酢酸エチルおよび炭酸水素ナトリウム水溶液を加えて撹拌し、不溶物を濾別後した後、濾液を酢酸エチルで抽出した。有機層を無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去して得られた残渣を、塩基性シリカゲルクロマトグラフィー（ヘキサン／酢酸エチル）で精製することにより、４−アミノ−５−［（Ｅ）−４−（ｔｅｒｔ−ブトキシカルボニルアミノ）ブタ−１−エニル］ピリジン−３−カルボン酸メチル（１９０ｍｇ，０．５９１ｍｍｏｌ）を得た。
MS (ESI) m/z: 322 [M+H]⁺.
４−アミノ−５−［（Ｅ）−４−（ｔｅｒｔ−ブトキシカルボニルアミノ）ブタ−１−エニル］ピリジン−３−カルボン酸メチル（１８８ｍｇ，０５８５ｍｍｏｌ）を１，４−ジオキサン（２ｍＬ）に溶解し、４Ｎ 塩酸／１，４−ジオキサン溶液（８ｍＬ）を加え室温で一晩撹拌した。減圧下溶媒を留去し乾燥することにより、４−アミノ−５−［（Ｅ）−４−アミノブタ−１−エニル］ピリジン−３−カルボン酸メチル 二塩酸塩（１７２ｍｇ，０．５８５ｍｍｏｌ）を得た。
MS (ESI) m/z: 222 [M+H]⁺.
４−アミノ−５−［（Ｅ）−４−アミノブタ−１−エニル］ピリジン−３−カルボン酸メチル 二塩酸塩（１７２ｍｇ，０．５８５ｍｍｏｌ）、Ｎ−（ｔｅｒｔ−ブトキシカルボニル）−Ｌ−２−シクロヘキシルグリシン（１６６ｍｇ，０．６４４ｍｍｏｌ）、ＷＳＣＩ（１２３ｍｇ，０．６４４ｍｍｏｌ）およびＨＯＢｔ（８７．０ｍｇ，０．６４４ｍｍｏｌ）をジクロロメタン（１０ｍＬ）に懸濁し、氷冷下トリエチルアミン（０．２７０ｍＬ，１．９３ｍｍｏｌ）を加えて室温で一晩撹拌した。反応液を減圧下濃縮した後、酢酸エチルで希釈し、炭酸水素ナトリウム水溶液および飽和食塩水で洗浄後、有機層を無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。得られた残渣をヘキサン／酢酸エチルの混合溶媒で洗浄し、濾取することで４−アミノ−５−［（Ｅ）−４−［［（２Ｓ）−２−（ｔｅｒｔ−ブトキシカルボニルアミノ）−２−シクロヘキシル−アセチル］アミノ］ブタ−１−エニル］ピリジン−３−カルボン酸メチル（１５９ｍｇ，０．３４５ｍｍｏｌ）を得た。
MS (ESI) m/z: 461 [M+H]⁺.
４−アミノ−５−［（Ｅ）−４−［［（２Ｓ）−２−（ｔｅｒｔ−ブトキシカルボニルアミノ）−２−シクロヘキシル−アセチル］アミノ］ブタ−１−エニル］ピリジン−３−カルボン酸メチル（２０９ｍｇ，０．４５４ｍｍｏｌ）をＴＨＦ（４ｍＬ）／メタノール（４ｍＬ）の混合溶媒に溶解し、氷冷下１Ｍ 水酸化リチウム水溶液（１．８ｍＬ）を加えて室温で一晩撹拌した。反応液に氷冷下で２Ｍ トリフルオロ酢酸水溶液（０．９００ｍＬ）を加え、減圧下濃縮して得られた残渣を０．０５％トリフルオロ酢酸水溶液／アセトニトリルで洗浄し、固体を濾取後凍結乾燥することにより、４−アミノ−５−［（Ｅ）−４−［［（２Ｓ）−２−（ｔｅｒｔ−ブトキシカルボニルアミノ）−２−シクロヘキシル−アセチル］アミノ］ブタ−１−エニル］ピリジン−３−カルボン酸 トリフルオロ酢酸塩（２２０ｍｇ，０．３９２ｍｍｏｌ）を得た。
MS (ESI) m/z: 4447 [M+H]⁺.
４−アミノ−５−［（Ｅ）−４−［［（２Ｓ）−２−（ｔｅｒｔ−ブトキシカルボニルアミノ）−２−シクロヘキシル−アセチル］アミノ］ブタ−１−エニル］ピリジン−３−カルボン酸 トリフルオロ酢酸塩（２１７ｍｇ，０．３８７ｍｍｏｌ）をジクロロメタン（４ｍＬ）に懸濁し、トリフルオロ酢酸（１ｍＬ）を加えて室温で１時間撹拌した。減圧下溶媒を留去して得られた残渣を水に溶解し、凍結乾燥することにより、４−アミノ−５−［（Ｅ）−４−［［（２Ｓ）−２−アミノ−２−シクロヘキシル−アセチル］アミノ］ブタ−１−エニル］ピリジン−３−カルボン酸 二トリフルオロ酢酸塩（２４０ｍｇ，０．４１８ｍｍｏｌ）を得た。
4-amino-5-[(E)-4-[[(2S)-2-amino-2-cyclohexyl-acetyl]amino]but-1-enyl]pyridine-3-carboxylic acid ditrifluoroacetate
４−アミノ−５−［（Ｅ）−４−［［（２Ｓ）−２−アミノ−２−シクロヘキシル−アセチル］アミノ］ブタ−１−エニル］ピリジン−３−カルボン酸 二トリフルオロ酢酸塩
¹H NMR ((CD₃)₂SO) δ= 9.02 (br s, 1H), 8.76 (s, 1H), 8.70 - 8.40 (m, 2H), 8.26 (s, 1H), 8.10 (s, 3H), 6.59 (d, J = 15.5 Hz, 1H), 6.29 (dt, J = 15.5, 6.7 Hz, 1H), 3.54 - 3.38 (m, 2H), 3.28 - 3.16 (m, 1H), 2.46 - 2.35 (m, 2H), 1.81 - 1.46 (m, 6H), 1.21 - 0.85 (m, 5H).
MS (ESI) m/z: 347 [M+H]⁺. Example 11 4-Amino-5-[(E) -4-[[(2S) -2-amino-2-cyclohexyl-acetyl] amino] but-1-enyl] pyridine-3-carboxylic acid Method for synthesizing fluoroacetate (compound 11)

To a DMF solution (15 mL) of methyl 4-amino-5-bromopyridine-3-carboxylate (693 mg, 3.00 mmol) was added tetrakis (triphenylphosphine) palladium (0) (520 mg, 0.450 mmol), N-butadiene. Tert-butyl-3-enylcarbamate (0.691 mL, 3.75 mol) and DIPEA (0.638 mL, 3.75 mmol) were added, and the mixture was stirred at 120 ° C overnight. Ethyl acetate and an aqueous solution of sodium hydrogen carbonate were added to the reaction solution, and the mixture was stirred. After insoluble matter was filtered off, the filtrate was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the residue obtained by evaporating the solvent under reduced pressure was purified by basic silica gel chromatography (hexane / ethyl acetate) to give 4-amino-5-[(E ) -4- (tert-Butoxycarbonylamino) but-1-enyl] pyridine-3-carboxylate (190 mg, 0.591 mmol).
MS (ESI) m / z: 322 [M + H] ⁺ .
Methyl 4-amino-5-[(E) -4- (tert-butoxycarbonylamino) but-1-enyl] pyridine-3-carboxylate (188 mg, 0585 mmol) was dissolved in 1,4-dioxane (2 mL). A 4N hydrochloric acid / 1,4-dioxane solution (8 mL) was added, and the mixture was stirred at room temperature overnight. The solvent was distilled off under reduced pressure and dried to obtain methyl 4-amino-5-[(E) -4-aminobut-1-enyl] pyridine-3-carboxylate dihydrochloride (172 mg, 0.585 mmol). Was.
MS (ESI) m / z: 222 [M + H] ⁺ .
Methyl 4-amino-5-[(E) -4-aminobut-1-enyl] pyridine-3-carboxylate dihydrochloride (172 mg, 0.585 mmol), N- (tert-butoxycarbonyl) -L-2- Cyclohexylglycine (166 mg, 0.644 mmol), WSCI (123 mg, 0.644 mmol) and HOBt (87.0 mg, 0.644 mmol) are suspended in dichloromethane (10 mL), and triethylamine (0.270 mL, 1.93 mmol) is cooled under ice-cooling. ) And stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution and saturated saline, and then the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was washed with a mixed solvent of hexane / ethyl acetate, and collected by filtration to give 4-amino-5-[(E) -4-[[(2S) -2- (tert-butoxycarbonylamino)-]. Methyl 2-cyclohexyl-acetyl] amino] but-1-enyl] pyridine-3-carboxylate (159 mg, 0.345 mmol) was obtained.
MS (ESI) m / z: 461 [M + H] ⁺ .
Methyl 4-amino-5-[(E) -4-[[(2S) -2- (tert-butoxycarbonylamino) -2-cyclohexyl-acetyl] amino] but-1-enyl] pyridine-3-carboxylate (209 mg, 0.454 mmol) was dissolved in a mixed solvent of THF (4 mL) / methanol (4 mL), a 1 M aqueous lithium hydroxide solution (1.8 mL) was added under ice cooling, and the mixture was stirred at room temperature overnight. A 2M aqueous trifluoroacetic acid solution (0.900 mL) was added to the reaction mixture under ice-cooling, and the residue obtained by concentration under reduced pressure was washed with a 0.05% aqueous trifluoroacetic acid solution / acetonitrile, and the solid was collected by filtration and frozen. By drying, 4-amino-5-[(E) -4-[[(2S) -2- (tert-butoxycarbonylamino) -2-cyclohexyl-acetyl] amino] but-1-enyl] pyridine- 3-Carboxylic acid trifluoroacetate (220 mg, 0.392 mmol) was obtained.
MS (ESI) m / z: 4447 [M + H] ⁺ .
4-Amino-5-[(E) -4-[[(2S) -2- (tert-butoxycarbonylamino) -2-cyclohexyl-acetyl] amino] but-1-enyl] pyridine-3-carboxylic acid tri Fluoroacetate (217 mg, 0.387 mmol) was suspended in dichloromethane (4 mL), trifluoroacetic acid (1 mL) was added, and the mixture was stirred at room temperature for 1 hour. The residue obtained by evaporating the solvent under reduced pressure was dissolved in water and lyophilized to give 4-amino-5-[(E) -4-[[(2S) -2-amino-2-cyclohexyl]. -Acetyl] amino] but-1-enyl] pyridine-3-carboxylic acid ditrifluoroacetate (240 mg, 0.418 mmol) was obtained.
4-amino-5-[(E) -4-[[(2S) -2-amino-2-cyclohexyl-acetyl] amino] but-1-enyl] pyridine-3-carboxylic acid ditrifluoroacetate
4-amino-5-[(E) -4-[[(2S) -2-amino-2-cyclohexyl-acetyl] amino] but-1-enyl] pyridine-3-carboxylic acid ditrifluoroacetate
¹ H NMR ((CD ₃ ) ₂ SO) δ = 9.02 (br s, 1H), 8.76 (s, 1H), 8.70-8.40 (m, 2H), 8.26 (s, 1H), 8.10 (s, 3H) , 6.59 (d, J = 15.5 Hz, 1H), 6.29 (dt, J = 15.5, 6.7 Hz, 1H), 3.54-3.38 (m, 2H), 3.28-3.16 (m, 1H), 2.46-2.35 (m , 2H), 1.81-1.46 (m, 6H), 1.21-0.85 (m, 5H).
MS (ESI) m / z: 347 [M + H] ⁺ .

４−アミノ−５−［（Ｅ）−４−［［（２Ｓ）−２−アミノ−２−シクロヘキシル−アセチル］アミノ］ブタ−１−エニル］ピリジン−３−カルボン酸 二トリフルオロ酢酸塩（３３．２ｍｇ，０．０５６８ｍｍｌ）を水（５ｍＬ）に溶解し、触媒量の５％ パラジウム−炭素を加えて水素雰囲気下室温で２時間撹拌した。不溶物を濾別し、濾液を凍結乾燥することにより、４−アミノ−５−［４−［［（２Ｓ）−２−アミノ−２−シクロヘキシル−アセチル］アミノ］ブチル］ピリジン−３−カルボン酸 二トリフルオロ酢酸塩（２９．７ｍｇ，０．０５１５ｍｍｏｌ）を得た。
4-amino-5-[4-[[(2S)-2-amino-2-cyclohexyl-acetyl]amino]butyl]pyridine-3-carboxylic acid ditrifluoroacetate
４−アミノ−５−［４−［［（２Ｓ）−２−アミノ−２−シクロヘキシル−アセチル］アミノ］ブチル］ピリジン−３−カルボン酸 二トリフルオロ酢酸塩
¹H NMR ((CD₃)₂SO) δ= 13.90 (br s, 1H), 9.14 ( br s, 1H), 8.73 (s, 1H), 8.43 (t, J = 5.7 Hz, 1H), 8.21 - 7.91 (m, 4H), 7.63 (br s, 1H), 3.58 - 3.44 (m, 2H), 3.31 - 3.24 (m, 2H), 3.14 - 3.02 (m, 1H), 2.65 - 2.56 (m, 2H), 1.80 - 1.39 (m, 8H), 1.27 - 0.90 (m, 5H).
MS (ESI) m/z: 349 [M+H]⁺. Example 12 4-amino-5- [4-[[(2S) -2-amino-2-cyclohexyl-acetyl] amino] butyl] pyridine-3-carboxylic acid ditrifluoroacetate (Compound 12) Synthesis

4-amino-5-[(E) -4-[[(2S) -2-amino-2-cyclohexyl-acetyl] amino] but-1-enyl] pyridine-3-carboxylic acid ditrifluoroacetate (33 .2 mg, 0.0568 mmol) was dissolved in water (5 mL), a catalytic amount of 5% palladium-carbon was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. The insolubles were separated by filtration and the filtrate was freeze-dried to give 4-amino-5- [4-[[(2S) -2-amino-2-cyclohexyl-acetyl] amino] butyl] pyridine-3-carboxylic acid The ditrifluoroacetate salt (29.7 mg, 0.0515 mmol) was obtained.
4-amino-5- [4-[[(2S) -2-amino-2-cyclohexyl-acetyl] amino] butyl] pyridine-3-carboxylic acid ditrifluoroacetate
4-amino-5- [4-[[(2S) -2-amino-2-cyclohexyl-acetyl] amino] butyl] pyridine-3-carboxylic acid ditrifluoroacetate
¹ H NMR ((CD ₃ ) ₂ SO) δ = 13.90 (br s, 1H), 9.14 (br s, 1H), 8.73 (s, 1H), 8.43 (t, J = 5.7 Hz, 1H), 8.21- 7.91 (m, 4H), 7.63 (br s, 1H), 3.58-3.44 (m, 2H), 3.31-3.24 (m, 2H), 3.14-3.02 (m, 1H), 2.65-2.56 (m, 2H) , 1.80-1.39 (m, 8H), 1.27-0.90 (m, 5H).
MS (ESI) m / z: 349 [M + H] ⁺ .

メチル４−アミノ−５−[[３−[[(２Ｓ)−２−（ｔｅｒｔ−ブトキシカルボニルアミノ）−２−シクロヘキシル−アセチル]アミノ]−３−メチル−ブタノイル]アミノ]ピリジン−３−カルボキシレート（０．１６３ｇ、０．３２ｍｍｏｌ）を１，４−ジオキサン２．０ｍＬに溶解し４Ｎ塩酸／ジオキサン溶液２．０ｍＬを加えて一晩撹拌した。反応液を減圧濃縮して得られたペースト状の残渣０．１６８ｇをそのまま次の反応に用いた。
メチル４−アミノ−５−[[３−[[(２Ｓ)−２−アミノ−２−シクロヘキシル−アセチル]アミノ]−３−メチル−ブタノイル]アミノ]ピリジン−３−カルボキシレート・２塩酸塩（０．０３７ｇ、０．０７７ｍｍｏｌ）をＮ，Ｎ−ジメチルホルムアミド３．０ｍＬに溶解し、（２Ｓ）−２−（ｔｅｒｔ−ブトキシカルボニルアミノ）−３−メチルペンタン酸（０．０２０ｇ、０．０８６ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール（０．０１２ｇ、０．０９０ｍｍｏｌ）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（０．０１８ｇ、０．０９２ｍｏｌ）、トリエチルアミン（０．１２１ｍＬ、０．８７ｍｍｏｌ）を加えて一晩撹拌した。反応液に１０％重曹水２．０ｍＬ、飽和食塩水４．０ｍＬ、水４．０ｍＬの混合液と酢酸エチル２０ｍＬを加えて抽出した。有機層を１０％重曹水２．０ｍＬと飽和食塩水８．０ｍＬで洗浄後、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィーで精製し目的物のメチル４−アミノ−５−[[３−[[(２Ｓ)−２−［［(２Ｓ)−２−（ｔｅｒｔ−ブトキシカルボニルアミノ）−３−メチル−ペンタノイル]アミノ］−２−シクロヘキシル−アセチル]アミノ]−３−メチル−ブタノイル]アミノ]ピリジン−３−カルボキシレート０．０４２ｇを得た（ＤＭＦ残存のため純度７９％、０．０５３ｍｍｏｌ）。
メチル４−アミノ−５−[[３−[[(２Ｓ)−２−［［(２Ｓ)−２−（ｔｅｒｔ−ブトキシカルボニルアミノ）−３−メチル−ペンタノイル]アミノ］−２−シクロヘキシル−アセチル]アミノ]−３−メチル−ブタノイル]アミノ]ピリジン−３−カルボキシレート（０．０３１ｇ、０．０５１ｍｍｏｌ）をテトラヒドロフラン０．５ｍＬとメタノール０．５ｍＬに溶解し、氷冷下１Ｍ水酸化リチウム水溶液０．６ｍＬを加えた。室温に戻し３時間撹拌し後、ＬＣＭＳにて原料の消失を確認した。２Ｍトリフルオロ酢酸水溶液０．３ｍＬで中和した後、反応液を減圧濃縮した。得られた残渣を０．０５％トリフルオロ酢酸−アセトニトリル溶液に溶解し、そのうちの約８０％を逆相高速液体クロマトグラフィーにて精製した。目的物を含むフラクションを回収・濃縮してアセトニトリルを除去した後、水溶液を凍結乾燥することで目的物の４−アミノ−５−[[３−[[(２Ｓ)−２−［［(２Ｓ)−２−（ｔｅｒｔ−ブトキシカルボニルアミノ）−３−メチル−ペンタノイル]アミノ］−２−シクロヘキシル−アセチル]アミノ]−３−メチル−ブタノイル]アミノ]ピリジン−３−カルボキシレート・トリフルオロ酢酸塩（０．０２１ｇ、０．０２９ｍｍｏｌ）を得た。
４−アミノ−５−[[３−[[(２Ｓ)−２−［［(２Ｓ)−２−（ｔｅｒｔ−ブトキシカルボニルアミノ）−３−メチル−ペンタノイル]アミノ］−２−シクロヘキシル−アセチル]アミノ]−３−メチル−ブタノイル]アミノ]ピリジン−３−カルボキシレート・トリフルオロ酢酸塩（０．０１４ｇ、０．０２０ｍｍｏｌ）をジクロロメタン１．５ｍＬに懸濁し、トリフルオロ酢酸１．５ｍＬを加えた。室温で３時間撹拌後、ＬＣＭＳにて原料の消失を確認、反応液を減圧濃縮した。得られた残渣を水５．０ｍＬで希釈して凍結乾燥を行い目的の４−アミノ−５−[[３−[[(２Ｓ)−２−［［(２Ｓ)−２−アミノ−３−メチル−ペンタノイル]アミノ］−２−シクロヘキシル−アセチル]アミノ]−３−メチル−ブタノイル]アミノ]ピリジン−３−カルボン酸・２トリフルオロ酢酸塩（０．０１５ｇ、０．０２０ｍｍｏｌ）を得た。
4-amino-5-[[3-[[(2S)-2-[[(2S)-2-amino-3-methyl-pentanoyl]amino]-2-cyclohexyl-acetyl]amino]-3-methyl-butanoyl]amino]pyridine-3-carboxylic acid (trifluoroacetic acid salt)
４−アミノ−５−[[３−[[(２Ｓ)−２−[[(２Ｓ)−２−アミノ−３−メチル−ペンタノイル]アミノ]−２−シクロヘキシル−アセチル]アミノ]−３−メチル−ブタノイル]アミノ]ピリジン−３−カルボン酸（２トリフルオロ酢酸塩）
¹H NMR (CD₃OD) δ= 8.78 (d, J = 1.2 Hz, 1H), 8.47 (d, J = 1.1 Hz, 1H), 4.17 (d, J = 8.2 Hz, 1H), 3.78 (d, J = 5.6 Hz, 1H), 3.09 - 2.73 (m, 2H), 1.97 - 1.62 (m, 8H), 1.50 (d, J = 14.5 Hz, 6H), 1.30 - 1.07 (m, 6H), 1.02 (d, J = 6.9 Hz, 3H), 0.95 (t, J = 7.4 Hz, 3H)
MS(ESI) m/z: 505.5 (M+H)⁺. Example 13 4-Amino-5-[[3-[[(2S) -2-[[(2S) -2-amino-3-methyl-pentanoyl] amino] -2-cyclohexyl-acetyl] amino] Synthesis of -3-methyl-butanoyl] amino] pyridine-3-carboxylic acid 2-trifluoroacetate (Compound 13)

Methyl 4-amino-5-[[3-[[(2S) -2- (tert-butoxycarbonylamino) -2-cyclohexyl-acetyl] amino] -3-methyl-butanoyl] amino] pyridine-3-carboxylate (0.163 g, 0.32 mmol) was dissolved in 2.0 mL of 1,4-dioxane, and 2.0 mL of a 4N hydrochloric acid / dioxane solution was added thereto, followed by stirring overnight. The reaction solution was concentrated under reduced pressure, and 0.168 g of a paste-like residue obtained was directly used in the next reaction.
Methyl 4-amino-5-[[3-[[(2S) -2-amino-2-cyclohexyl-acetyl] amino] -3-methyl-butanoyl] amino] pyridine-3-carboxylate dihydrochloride (0 0.037 g, 0.077 mmol) was dissolved in 3.0 mL of N, N-dimethylformamide, and (2S) -2- (tert-butoxycarbonylamino) -3-methylpentanoic acid (0.020 g, 0.086 mmol), 1-hydroxybenzotriazole (0.012 g, 0.090 mmol) 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.018 g, 0.092 mol), triethylamine (0.121 mL, 0.87 mmol) Was added and stirred overnight. The reaction solution was extracted by adding a mixed solution of 2.0 mL of 10% aqueous sodium hydrogen carbonate, 4.0 mL of saturated saline, 4.0 mL of water and 20 mL of ethyl acetate. The organic layer was washed with 2.0 mL of 10% aqueous sodium bicarbonate and 8.0 mL of saturated saline, and then concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography, and the intended product, methyl 4-amino-5-[[3-[[(2S) -2-[[(2S) -2- (tert-butoxycarbonylamino)-] is obtained. 0.042 g of 3-methyl-pentanoyl] amino] -2-cyclohexyl-acetyl] amino] -3-methyl-butanoyl] amino] pyridine-3-carboxylate was obtained (purity 79%, 0.053 mmol because DMF remains). ).
Methyl 4-amino-5-[[3-[[(2S) -2-[[(2S) -2- (tert-butoxycarbonylamino) -3-methyl-pentanoyl] amino] -2-cyclohexyl-acetyl] Amino] -3-methyl-butanoyl] amino] pyridine-3-carboxylate (0.031 g, 0.051 mmol) was dissolved in 0.5 mL of tetrahydrofuran and 0.5 mL of methanol, and 0.1M aqueous solution of lithium hydroxide was added under ice cooling. 6 mL was added. After returning to room temperature and stirring for 3 hours, disappearance of the raw materials was confirmed by LCMS. After neutralization with 0.3 mL of a 2M aqueous trifluoroacetic acid solution, the reaction solution was concentrated under reduced pressure. The obtained residue was dissolved in a 0.05% trifluoroacetic acid-acetonitrile solution, and about 80% of the solution was purified by reversed-phase high-performance liquid chromatography. After collecting and concentrating the fraction containing the target substance to remove acetonitrile, the aqueous solution was freeze-dried to obtain the target substance, 4-amino-5-[[3-[[(2S) -2-[[(2S) -2- (tert-butoxycarbonylamino) -3-methyl-pentanoyl] amino] -2-cyclohexyl-acetyl] amino] -3-methyl-butanoyl] amino] pyridine-3-carboxylate trifluoroacetate (0 .021 g, 0.029 mmol).
4-amino-5-[[3-[[(2S) -2-[[(2S) -2- (tert-butoxycarbonylamino) -3-methyl-pentanoyl] amino] -2-cyclohexyl-acetyl] amino ] -3-Methyl-butanoyl] amino] pyridine-3-carboxylate trifluoroacetate (0.014 g, 0.020 mmol) was suspended in 1.5 mL of dichloromethane, and 1.5 mL of trifluoroacetic acid was added. After stirring at room temperature for 3 hours, disappearance of the raw materials was confirmed by LCMS, and the reaction solution was concentrated under reduced pressure. The obtained residue was diluted with 5.0 mL of water, lyophilized, and then subjected to 4-amino-5-[[3-[[(2S) -2-[[(2S) -2-amino-3-methyl]. -Pentanoyl] amino] -2-cyclohexyl-acetyl] amino] -3-methyl-butanoyl] amino] pyridine-3-carboxylic acid · 2 trifluoroacetate (0.015 g, 0.020 mmol) was obtained.
4-amino-5-[[3-[[(2S) -2-[[(2S) -2-amino-3-methyl-pentanoyl] amino] -2-cyclohexyl-acetyl] amino] -3-methyl- butanoyl] amino] pyridine-3-carboxylic acid (trifluoroacetic acid salt)
4-amino-5-[[3-[[(2S) -2-[[(2S) -2-amino-3-methyl-pentanoyl] amino] -2-cyclohexyl-acetyl] amino] -3-methyl- Butanoyl] amino] pyridine-3-carboxylic acid (2 trifluoroacetate)
¹ H NMR (CD ₃ OD) δ = 8.78 (d, J = 1.2 Hz, 1H), 8.47 (d, J = 1.1 Hz, 1H), 4.17 (d, J = 8.2 Hz, 1H), 3.78 (d, J = 5.6 Hz, 1H), 3.09-2.73 (m, 2H), 1.97-1.62 (m, 8H), 1.50 (d, J = 14.5 Hz, 6H), 1.30-1.07 (m, 6H), 1.02 (d , J = 6.9 Hz, 3H), 0.95 (t, J = 7.4 Hz, 3H)
MS (ESI) m / z: 505.5 (M + H) ⁺ .

4-amino-5-[[(3R)-3-[[(2S)-2-amino-2-cyclohexyl-acetyl]amino]-3-phenyl-propanoyl]amino]pyridine-3-carboxylic acid ditrifluoroacetate
４−アミノ−５−［［（３Ｒ）−３−［［（２Ｓ）−２−アミノ−２−シクロヘキシル−アセチル］アミノ］−３−フェニル−プロパノイル］アミノ］ピリジン−３−カルボン酸 二トリフルオロ酢酸塩
¹H NMR ((CD₃)₂SO) δ= 9.50 (s, 1H), 8.85 (d, J = 8.3 Hz, 1H), 8.60 (d, J = 6.7 Hz, 1H), 8.19 (s, 1H), 7.92 (s, 2H), 7.38 - 7.28 (m, 4H), 7.26 - 7.19 (m, 1H), 5.34 (q, J = 8.3 Hz, 1H), 3.48 (s, 1H), 2.93 - 2.70 (m, 2H), 1.65 - 1.38 (m, 7H), 1.13 - 0.82 (m, 2H).
MS(ESI) m/z: 440.2 (M+H)⁺. (Examples 14 to 64) Synthesis of compounds 14 to 64 The following compounds 14 to 64 were synthesized according to the above method.
(Compound 14)

4-amino-5-[[(3R) -3-[[(2S) -2-amino-2-cyclohexyl-acetyl] amino] -3-phenyl-propanoyl] amino] pyridine-3-carboxylic acid ditrifluoroacetate
4-amino-5-[[(3R) -3-[[(2S) -2-amino-2-cyclohexyl-acetyl] amino] -3-phenyl-propanoyl] amino] pyridine-3-carboxylic acid ditrifluoro Acetate
¹ H NMR ((CD ₃ ) ₂ SO) δ = 9.50 (s, 1H), 8.85 (d, J = 8.3 Hz, 1H), 8.60 (d, J = 6.7 Hz, 1H), 8.19 (s, 1H) , 7.92 (s, 2H), 7.38-7.28 (m, 4H), 7.26-7.19 (m, 1H), 5.34 (q, J = 8.3 Hz, 1H), 3.48 (s, 1H), 2.93-2.70 (m , 2H), 1.65-1.38 (m, 7H), 1.13-0.82 (m, 2H).
MS (ESI) m / z: 440.2 (M + H) ⁺ .

4-amino-5-[5-[(2-cyclohexylacetyl)amino]pentanoylamino]pyridine-3-carboxylic acid trifluoroacetate
４−アミノ−５−［５−［（２−シクロヘキシルアセチル）アミノ］ペンタノイルアミノ］ピリジン−３−カルボン酸 トリフルオロ酢酸塩
¹H NMR ((CD₃)₂SO) δ= 9.45 (s, 1H), 8.64 (s, 1H), 8.48 (s, 1H), 7.71 (t, J = 5.8 Hz, 1H), 2.99 (q, J = 6.6 Hz, 2H), 2.35 (t, J = 7.4 Hz, 2H), 1.86 (d, J = 6.9 Hz, 2H), 1.54 (dh, J = 15.1, 7.6, 5.9 Hz, 8H), 1.37 (p, J = 7.3 Hz, 2H), 1.19 - 0.96 (m, 3H), 0.89 - 0.75 (m, 2H).
MS(ESI) m/z: 377.2 (M+H)⁺. (Compound 15)

4-amino-5- [5-[(2-cyclohexylacetyl) amino] pentanoylamino] pyridine-3-carboxylic acid trifluoroacetate
4-amino-5- [5-[(2-cyclohexylacetyl) amino] pentanoylamino] pyridine-3-carboxylic acid trifluoroacetate
¹ H NMR ((CD ₃ ) ₂ SO) δ = 9.45 (s, 1H), 8.64 (s, 1H), 8.48 (s, 1H), 7.71 (t, J = 5.8 Hz, 1H), 2.99 (q, J = 6.6 Hz, 2H), 2.35 (t, J = 7.4 Hz, 2H), 1.86 (d, J = 6.9 Hz, 2H), 1.54 (dh, J = 15.1, 7.6, 5.9 Hz, 8H), 1.37 ( p, J = 7.3 Hz, 2H), 1.19-0.96 (m, 3H), 0.89-0.75 (m, 2H).
MS (ESI) m / z: 377.2 (M + H) ⁺ .

4-amino-5-[[3-[[(2S,3S)-2-amino-3-methyl-pentanoyl]amino]-3-methyl-butanoyl]amino]pyridine-3-carboxylic acid ditrifluoroacetate
４−アミノ−５−[[３−[[（２Ｓ，３Ｓ)−２−アミノ−３−メチル−ペンタノイル]アミノ]−３−メチル−ブタノイル]アミノ]ピリジン−３−カルボン酸 二トリフルオロ酢酸塩
¹H NMR (400 MHz, DMSO-d₆) δ 9.49 (s, 1H), 8.71 (s, 1H), 8.49 (s, 1H), 8.21 (s, 1H), 8.10 - 7.99 (m, 4H), 3.70 (s, 1H), 2.94 (d, J = 14.2 Hz, 1H), 2.81 (d, J = 14.3 Hz, 1H), 1.72 - 1.31 (m, 9H), 0.97 - 0.77 (m, 6H).
MS(ESI) m/z: 366.2 (M+H)⁺. (Compound 16)

4-amino-5-[[3-[[(2S, 3S) -2-amino-3-methyl-pentanoyl] amino] -3-methyl-butanoyl] amino] pyridine-3-carboxylic acid ditrifluoroacetate
4-amino-5-[[3-[[(2S, 3S) -2-amino-3-methyl-pentanoyl] amino] -3-methyl-butanoyl] amino] pyridine-3-carboxylic acid ditrifluoroacetate
¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.49 (s, 1H), 8.71 (s, 1H), 8.49 (s, 1H), 8.21 (s, 1H), 8.10-7.99 (m, 4H), 3.70 (s, 1H), 2.94 (d, J = 14.2 Hz, 1H), 2.81 (d, J = 14.3 Hz, 1H), 1.72-1.31 (m, 9H), 0.97-0.77 (m, 6H).
MS (ESI) m / z: 366.2 (M + H) ⁺ .

4-amino-5-[[3-[[(2S)-2-[[(2S)-2-amino-2-cyclohexyl-acetyl]amino]-2-cyclohexyl-acetyl]amino]-3-methyl-butanoyl]amino]pyridine-3-carboxylic acid ditrifluoroacetate
４−アミノ−５−[[３−[[（２Ｓ)−２−[[（２Ｓ)−２−アミノ−２−シクロヘキシル−アセチル]アミノ] −２−シクロヘキシル−アセチル]アミノ]−３−メチル−ブタノイル]アミノ]ピリジン−３−カルボン酸 二トリフルオロ酢酸塩
¹H NMR (400 MHz, DMSO-d₆) δ 9.49 (s, 1H), 8.72 (s, 1H), 8.50 (s, 1H), 8.28 (d, J = 8.9 Hz, 1H), 8.13 - 7.95 (m, 3H), 7.89 (s, 1H), 4.16 (t, J = 8.4 Hz, 1H), 3.69 (s, 1H), 2.86 (q, J = 14.3 Hz, 2H), 1.61 (dt, J = 40.0, 9.0 Hz, 15H), 1.38 (s, 3H), 1.37 (s, 3H), 1.06 (p, J = 13.3 Hz, 12H).
MS(ESI) m/z: 531.3 (M+H)⁺. (Compound 17)

4-amino-5-[[3-[[(2S) -2-[[(2S) -2-amino-2-cyclohexyl-acetyl] amino] -2-cyclohexyl-acetyl] amino] -3-methyl- butanoyl] amino] pyridine-3-carboxylic acid ditrifluoroacetate
4-amino-5-[[3-[[(2S) -2-[[(2S) -2-amino-2-cyclohexyl-acetyl] amino] -2-cyclohexyl-acetyl] amino] -3-methyl- Butanoyl] amino] pyridine-3-carboxylic acid ditrifluoroacetate
¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.49 (s, 1H), 8.72 (s, 1H), 8.50 (s, 1H), 8.28 (d, J = 8.9 Hz, 1H), 8.13-7.95 ( m, 3H), 7.89 (s, 1H), 4.16 (t, J = 8.4 Hz, 1H), 3.69 (s, 1H), 2.86 (q, J = 14.3 Hz, 2H), 1.61 (dt, J = 40.0 , 9.0 Hz, 15H), 1.38 (s, 3H), 1.37 (s, 3H), 1.06 (p, J = 13.3 Hz, 12H).
MS (ESI) m / z: 531.3 (M + H) ⁺ .

4-amino-5-[[3-[[(2S)-2-[(2-aminoacetyl)amino]-2-cyclohexyl-acetyl]amino]-3-methyl-butanoyl]amino]pyridine-3-carboxylic acid (trifluoroacetic acid salt)
４−アミノ−５−[[３−[[(２Ｓ)−２−[(２−アミノアセチル)アミノ]−２−シクロヘキシル−アセチル]アミノ]−３−メチル−ブタノイル]アミノ]ピリジン−３−カルボン酸（２トリフルオロ酢酸塩）
¹H NMR (CD₃OD) δ= 8.74 (d, J = 1.3 Hz, 1H), 8.41 (d, J = 1.3 Hz, 1H), 4.18 (d, J = 6.9 Hz, 1H), 3.72 (d, J = 2.3 Hz, 2H), 3.06 - 2.77 (m, 2H), 1.74-1.65 (m, 6H), 1.48 (d, J = 13.2 Hz, 6H), 1.25-1.04 (m, 5H)
MS(ESI) m/z: 449.4 (M+H)⁺. (Compound 18)

4-amino-5-[[3-[[(2S) -2-[(2-aminoacetyl) amino] -2-cyclohexyl-acetyl] amino] -3-methyl-butanoyl] amino] pyridine-3-carboxylic acid (trifluoroacetic acid salt)
4-Amino-5-[[3-[[(2S) -2-[(2-aminoacetyl) amino] -2-cyclohexyl-acetyl] amino] -3-methyl-butanoyl] amino] pyridine-3-carboxylic Acid (2 trifluoroacetate)
¹ H NMR (CD ₃ OD) δ = 8.74 (d, J = 1.3 Hz, 1H), 8.41 (d, J = 1.3 Hz, 1H), 4.18 (d, J = 6.9 Hz, 1H), 3.72 (d, J = 2.3 Hz, 2H), 3.06-2.77 (m, 2H), 1.74-1.65 (m, 6H), 1.48 (d, J = 13.2 Hz, 6H), 1.25-1.04 (m, 5H)
MS (ESI) m / z: 449.4 (M + H) ⁺ .

4-amino-5-[[3-[[(2S)-2-[[(2S)-2-amino-3-methyl-butanoyl]amino]-2-cyclohexyl-acetyl]amino]-3-methyl-butanoyl]amino]pyridine-3-carboxylic acid (trifluoroacetic acid salt)
４−アミノ−５−[[３−[[(２Ｓ)−２−アミノ−３−メチル−ブタノイル]アミノ]−２−シクロヘキシル−アセチル]アミノ]−３−メチル−ブタノイル]アミノ]ピリジン−３−カルボン酸（２トリフルオロ酢酸塩）
¹H NMR (CD₃OD) δ= 8.74 (s, 1H), 8.43 (s, 1H), 4.15 (d, J = 8.0 Hz, 1H), 3.72 (d, J = 5.6 Hz, 1H), 3.02 - 2.80 (m, 2H), 2.17-2.13 (m, 1H), 1.82-1.68 (m, 6H), 1.48 (d, J = 16.8 Hz, 6H), 1.29 - 0.98 (m, 11H)
MS(ESI) m/z: 491.4 (M+H)⁺. (Compound 19)

4-amino-5-[[3-[[((2S) -2-[[(2S) -2-amino-3-methyl-butanoyl] amino] -2-cyclohexyl-acetyl] amino] -3-methyl- butanoyl] amino] pyridine-3-carboxylic acid (trifluoroacetic acid salt)
4-amino-5-[[3-[[(2S) -2-amino-3-methyl-butanoyl] amino] -2-cyclohexyl-acetyl] amino] -3-methyl-butanoyl] amino] pyridine-3- Carboxylic acid (2 trifluoroacetate)
¹ H NMR (CD ₃ OD) δ = 8.74 (s, 1H), 8.43 (s, 1H), 4.15 (d, J = 8.0 Hz, 1H), 3.72 (d, J = 5.6 Hz, 1H), 3.02- 2.80 (m, 2H), 2.17-2.13 (m, 1H), 1.82-1.68 (m, 6H), 1.48 (d, J = 16.8 Hz, 6H), 1.29-0.98 (m, 11H)
MS (ESI) m / z: 491.4 (M + H) ⁺ .

4-amino-5-[[3-[[(2S)-2-[[(2S)-2-amino-4-methyl-pentanoyl]amino]-2-cyclohexyl-acetyl]amino]-3-methyl-butanoyl]amino]pyridine-3-carboxylic acid (trifluoroacetic acid salt)
４−アミノ−５−[[３−[[(２Ｓ)−２−[[(２Ｓ)−２−アミノ−４−メチル−ペンタノイル]アミノ]−２−シクロヘキシル−アセチル]アミノ]−３−メチル−ブタノイル]アミノ]ピリジン−３−カルボン酸（２トリフルオロ酢酸塩）
¹H NMR (CD₃OD) δ= 8.78 (d, J = 1.1 Hz, 1H), 8.45 (s, 1H), 4.17 (d, J = 7.9 Hz, 1H), 4.03 - 3.82 (m, 1H), 3.07 - 2.77 (m, 2H), 1.87 - 1.60 (m, 9H), 1.50 (d, J = 18.9 Hz, 6H), 1.31 - 1.03 (m, 5H), 0.98 (d, J = 4.8 Hz, 6H)
MS(ESI) m/z: 505.4 (M+H)⁺. (Compound 20)

4-amino-5-[[3-[[((2S) -2-[[(2S) -2-amino-4-methyl-pentanoyl] amino] -2-cyclohexyl-acetyl] amino] -3-methyl- butanoyl] amino] pyridine-3-carboxylic acid (trifluoroacetic acid salt)
4-amino-5-[[3-[[(2S) -2-[[(2S) -2-amino-4-methyl-pentanoyl] amino] -2-cyclohexyl-acetyl] amino] -3-methyl- Butanoyl] amino] pyridine-3-carboxylic acid (2 trifluoroacetate)
¹ H NMR (CD ₃ OD) δ = 8.78 (d, J = 1.1 Hz, 1H), 8.45 (s, 1H), 4.17 (d, J = 7.9 Hz, 1H), 4.03-3.82 (m, 1H), 3.07-2.77 (m, 2H), 1.87-1.60 (m, 9H), 1.50 (d, J = 18.9 Hz, 6H), 1.31-1.03 (m, 5H), 0.98 (d, J = 4.8 Hz, 6H)
MS (ESI) m / z: 505.4 (M + H) ⁺ .

4-Amino-5-[7-((S)-cyclohexylglycylamino)-heptanoylamino]-nicotinic acid (trifluoroacetic acid salt)
４−アミノ−５−[７−（(S)−シクロヘキシルグリシルアミノ）−ヘプタノイルアミノ]−ニコチン酸（２トリフルオロ酢酸塩）
¹H NMR (400 MHz, DMSO-d₆) δ 9.56 (s, 1H), 8.71 (s, 1H), 8.55 (s, 1H), 8.38 (t, J = 5.6 Hz, 1H), 8.07 (s, 2H), 3.22 (dt, J = 13.1, 6.6 Hz, 2H), 3.03 (dq, J = 12.8, 6.5 Hz, 2H), 2.42 (t, J = 7.5 Hz, 2H), 1.73 (s, 1H), 1.70 (s, 2H), 1.60 (d, J = 6.3 Hz, 3H), 1.44 (d, J = 6.9 Hz, 2H), 1.32 (s, 3H), 1.22 - 1.09 (m, 3H), 1.02 (t, J = 14.0 Hz, 2H).
MS(ESI) m/z: 420.1 (M+H)⁺. (Compound 21)

4-Amino-5- [7-((S) -cyclohexylglycylamino) -heptanoylamino] -nicotinic acid (trifluoroacetic acid salt)
4-amino-5- [7-((S) -cyclohexylglycylamino) -heptanoylamino] -nicotinic acid (2-trifluoroacetate)
¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.56 (s, 1H), 8.71 (s, 1H), 8.55 (s, 1H), 8.38 (t, J = 5.6 Hz, 1H), 8.07 (s, 2H), 3.22 (dt, J = 13.1, 6.6 Hz, 2H), 3.03 (dq, J = 12.8, 6.5 Hz, 2H), 2.42 (t, J = 7.5 Hz, 2H), 1.73 (s, 1H), 1.70 (s, 2H), 1.60 (d, J = 6.3 Hz, 3H), 1.44 (d, J = 6.9 Hz, 2H), 1.32 (s, 3H), 1.22-1.09 (m, 3H), 1.02 (t , J = 14.0 Hz, 2H).
MS (ESI) m / z: 420.1 (M + H) ⁺ .

4-amino-5-[3-[[(2S)-2-amino-2-cyclohexyl-acetyl]amino]propanoylamino]pyridine-3-carboxylic acid ditrifluoroacetate
４−アミノ−５−［３−［［（２Ｓ）−２−アミノ−２−シクロヘキシル−アセチル］アミノ］プロパノイルアミノ］ピリジン−３−カルボン酸 二トリフルオロ酢酸塩
¹H NMR ((CD₃)₂SO) δ= 9.55 (s, 1H), 8.65 (s, 1H), 8.48 (t, J = 5.6 Hz, 1H), 8.36 (s, 1H), 8.01 (d, J = 5.3 Hz, 2H), 3.52 (dq, J = 13.1, 6.5 Hz, 1H), 3.42 (s, 2H), 2.58 (q, J = 6.9, 5.8 Hz, 2H), 1.70 - 1.45 (m, 6H), 0.99 (dt, J = 45.1, 13.3 Hz, 5H).
MS(ESI) m/z: 364.2 (M+H)⁺. (Compound 22)

4-amino-5- [3-[[((2S) -2-amino-2-cyclohexyl-acetyl] amino] propanoylamino] pyridine-3-carboxylic acid ditrifluoroacetate
4-amino-5- [3-[[(2S) -2-amino-2-cyclohexyl-acetyl] amino] propanoylamino] pyridine-3-carboxylic acid ditrifluoroacetate
¹ H NMR ((CD ₃ ) ₂ SO) δ = 9.55 (s, 1H), 8.65 (s, 1H), 8.48 (t, J = 5.6 Hz, 1H), 8.36 (s, 1H), 8.01 (d, J = 5.3 Hz, 2H), 3.52 (dq, J = 13.1, 6.5 Hz, 1H), 3.42 (s, 2H), 2.58 (q, J = 6.9, 5.8 Hz, 2H), 1.70-1.45 (m, 6H ), 0.99 (dt, J = 45.1, 13.3 Hz, 5H).
MS (ESI) m / z: 364.2 (M + H) ⁺ .

4-amino-5-[4-[[(2S)-2-amino-2-cyclohexyl-acetyl]amino]butanoylamino]pyridine-3-carboxylic acid ditrifluoroacetate
４−アミノ−５−［４−［［（２Ｓ）−２−アミノ−２−シクロヘキシル−アセチル］アミノ］ブタノイルアミノ］ピリジン−３−カルボン酸 二トリフルオロ酢酸塩
¹H NMR ((CD₃)₂SO) δ= 9.84 (s, 1H), 8.82 (t, J = 5.7 Hz, 1H), 8.74 (s, 1H), 8.42 (s, 1H), 8.16 (s, 2H), 4.22 (dd, J = 16.9, 5.9 Hz, 1H), 4.05 (dd, J = 16.9, 5.2 Hz, 1H), 3.69 (s, 1H), 1.72 (d, J = 9.4 Hz, 5H), 1.62 (d, J = 11.3 Hz, 1H), 1.13 (dt, J = 25.5, 15.3 Hz, 5H).
MS(ESI) m/z: 350.2 (M+H)⁺. (Compound 23)

4-amino-5- [4-[[(2S) -2-amino-2-cyclohexyl-acetyl] amino] butanoylamino] pyridine-3-carboxylic acid ditrifluoroacetate
4-amino-5- [4-[[(2S) -2-amino-2-cyclohexyl-acetyl] amino] butanoylamino] pyridine-3-carboxylic acid ditrifluoroacetate
¹ H NMR ((CD ₃ ) ₂ SO) δ = 9.84 (s, 1H), 8.82 (t, J = 5.7 Hz, 1H), 8.74 (s, 1H), 8.42 (s, 1H), 8.16 (s, 2H), 4.22 (dd, J = 16.9, 5.9 Hz, 1H), 4.05 (dd, J = 16.9, 5.2 Hz, 1H), 3.69 (s, 1H), 1.72 (d, J = 9.4 Hz, 5H), 1.62 (d, J = 11.3 Hz, 1H), 1.13 (dt, J = 25.5, 15.3 Hz, 5H).
MS (ESI) m / z: 350.2 (M + H) ⁺ .

4-Amino-5-[5-((S)-phenylalanylamino)-pentanoylamino]-nicotinic acid ditrifluoroacetate
４−アミノ−５−[７−（(S)−フェニルアラニルアミノ）−ペンタノイルアミノ]−ニコチン酸 二トリフルオロ酢酸塩
¹H NMR (400 MHz, DMSO-d₆) δ 9.58 (s, 1H), 8.72 (d, J = 1.0 Hz, 1H), 8.54 (s, 1H), 8.35 (t, J = 5.6 Hz, 1H), 8.22 (s, 2H), 7.54 - 6.89 (m, 5H), 3.92 (s, 1H), 3.16 (dq, J = 13.0, 6.6 Hz, 2H), 2.99 (dt, J = 9.3, 4.8 Hz, 2H), 2.39 (t, J = 7.3 Hz, 2H), 1.47 (q, J = 8.3, 7.0 Hz, 2H), 1.34 (m, 2H).
MS(ESI) m/z: 400.0 (M+H)⁺. (Compound 24)

4-Amino-5- [5-((S) -phenylalanylamino) -pentanoylamino] -nicotinic acid ditrifluoroacetate
4-amino-5- [7-((S) -phenylalanylamino) -pentanoylamino] -nicotinic acid ditrifluoroacetate
¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.58 (s, 1H), 8.72 (d, J = 1.0 Hz, 1H), 8.54 (s, 1H), 8.35 (t, J = 5.6 Hz, 1H) , 8.22 (s, 2H), 7.54-6.89 (m, 5H), 3.92 (s, 1H), 3.16 (dq, J = 13.0, 6.6 Hz, 2H), 2.99 (dt, J = 9.3, 4.8 Hz, 2H ), 2.39 (t, J = 7.3 Hz, 2H), 1.47 (q, J = 8.3, 7.0 Hz, 2H), 1.34 (m, 2H).
MS (ESI) m / z: 400.0 (M + H) ⁺ .

4-Amino-5-[5-((R)-cyclohexylglycylamino)-pentanoylamino]-nicotinic acid ditrifluoroacetate
４−アミノ−５−[７−（(Ｒ)−シクロヘキシルグリシルアミノ）−ペンタノイルアミノ]−ニコチン酸 二トリフルオロ酢酸塩
¹H NMR (400 MHz, DMSO-d₆) δ 9.58 (s, 1H), 8.72 (d, J = 1.0 Hz, 1H), 8.55 (s, 1H), 8.42 (t, J = 5.6 Hz, 1H), 8.08 (s, 2H), 3.25 (dq, J = 13.0, 6.6 Hz, 2H), 3.08 (dq, J = 12.7, 6.5 Hz, 2H), 2.45 (t, J = 7.3 Hz, 2H), 1.70 (t, J = 13.8 Hz, 4H), 1.61 (q, J = 8.3 Hz, 4H), 1.50 (q, J = 7.2 Hz, 2H), 1.13 (q, J = 10.2, 8.5 Hz, 3H), 1.06 (s, 1H), 1.02 (t, J = 11.3 Hz, 2H).
MS(ESI) m/z: 391.1 (M+H)⁺. (Compound 25)

4-Amino-5- [5-((R) -cyclohexylglycylamino) -pentanoylamino] -nicotinic acid ditrifluoroacetate
4-amino-5- [7-((R) -cyclohexylglycylamino) -pentanoylamino] -nicotinic acid ditrifluoroacetate
¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.58 (s, 1H), 8.72 (d, J = 1.0 Hz, 1H), 8.55 (s, 1H), 8.42 (t, J = 5.6 Hz, 1H) , 8.08 (s, 2H), 3.25 (dq, J = 13.0, 6.6 Hz, 2H), 3.08 (dq, J = 12.7, 6.5 Hz, 2H), 2.45 (t, J = 7.3 Hz, 2H), 1.70 ( t, J = 13.8 Hz, 4H), 1.61 (q, J = 8.3 Hz, 4H), 1.50 (q, J = 7.2 Hz, 2H), 1.13 (q, J = 10.2, 8.5 Hz, 3H), 1.06 ( s, 1H), 1.02 (t, J = 11.3 Hz, 2H).
MS (ESI) m / z: 391.1 (M + H) ⁺ .

4-amino-5-[5-[[(2S)-2-amino-3-methyl-pentanoyl]amino]pentanoylamino]pyridine-3-carboxylic acid ditrifluoroacetate
４−アミノ−５−［５−［［（２Ｓ）−２−アミノ−３−メチル−ペンタノイル］アミノ］ペンタノイルアミノ］ピリジン−３−カルボン酸 二トリフルオロ酢酸塩
¹H NMR ((CD₃)₂SO) δ= 9.46 (s, 1H), 8.67 (s, 1H), 8.55 - 8.33 (m, 2H), 8.08 (s, 2H), 3.77 - 3.50 (m, 2H), 3.07 (dq, J = 12.7, 6.5 Hz, 1H), 2.43 (t, J = 7.3 Hz, 2H), 1.79 (dtd, J = 10.0, 6.5, 3.6 Hz, 1H), 1.70 - 1.40 (m, 5H), 1.21 - 1.03 (m, 1H), 0.99 - 0.76 (m, 6H).
MS(ESI) m/z: 366.2 (M+H)⁺. (Compound 26)

4-amino-5- [5-[[(2S) -2-amino-3-methyl-pentanoyl] amino] pentanoylamino] pyridine-3-carboxylic acid ditrifluoroacetate
4-amino-5- [5-[[(2S) -2-amino-3-methyl-pentanoyl] amino] pentanoylamino] pyridine-3-carboxylic acid ditrifluoroacetate
¹ H NMR ((CD ₃ ) ₂ SO) δ = 9.46 (s, 1H), 8.67 (s, 1H), 8.55-8.33 (m, 2H), 8.08 (s, 2H), 3.77-3.50 (m, 2H ), 3.07 (dq, J = 12.7, 6.5 Hz, 1H), 2.43 (t, J = 7.3 Hz, 2H), 1.79 (dtd, J = 10.0, 6.5, 3.6 Hz, 1H), 1.70-1.40 (m, 5H), 1.21-1.03 (m, 1H), 0.99-0.76 (m, 6H).
MS (ESI) m / z: 366.2 (M + H) ⁺ .

4-amino-5-[5-[[(2S)-2-amino-4-methyl-pentanoyl]amino]pentanoylamino]pyridine-3-carboxylic acid ditrifluoroacetate
４−アミノ−５−［５−［［（２Ｓ）−２−アミノ−４−メチル−ペンタノイル］アミノ］ペンタノイルアミノ］ピリジン−３−カルボン酸 二トリフルオロ酢酸塩
¹H NMR ((CD₃)₂SO) δ= 9.49 (s, 1H), 8.69 (s, 1H), 8.48 (d, J = 4.2 Hz, 2H), 8.10 (s, 2H), 3.68 (s, 2H), 3.10 (dq, J = 12.8, 6.4 Hz, 1H), 2.44 (t, J = 7.3 Hz, 2H), 1.71 - 1.40 (m, 7H), 0.90 (t, J = 6.4 Hz, 6H).
MS(ESI) m/z: 366.2 (M+H)⁺. (Compound 27)

4-amino-5- [5-[[(2S) -2-amino-4-methyl-pentanoyl] amino] pentanoylamino] pyridine-3-carboxylic acid ditrifluoroacetate
4-amino-5- [5-[[(2S) -2-amino-4-methyl-pentanoyl] amino] pentanoylamino] pyridine-3-carboxylic acid ditrifluoroacetate
¹ H NMR ((CD ₃ ) ₂ SO) δ = 9.49 (s, 1H), 8.69 (s, 1H), 8.48 (d, J = 4.2 Hz, 2H), 8.10 (s, 2H), 3.68 (s, 2H), 3.10 (dq, J = 12.8, 6.4 Hz, 1H), 2.44 (t, J = 7.3 Hz, 2H), 1.71-1.40 (m, 7H), 0.90 (t, J = 6.4 Hz, 6H).
MS (ESI) m / z: 366.2 (M + H) ⁺ .

4-amino-5-[[(4R)-4-[[(2S)-2-amino-2-cyclohexyl-acetyl]amino]-5-methyl-heptanoyl]amino]pyridine-3-carboxylic acid ditrifluoroacetate
４−アミノ−５−［［（４Ｒ）−４−［［（２Ｓ）−２−アミノ−２−シクロヘキシル−アセチル］アミノ］−５−メチル−ヘプタノイル］アミノ］ピリジン−３−カルボン酸 二トリフルオロ酢酸塩
¹H NMR ((CD₃)₂SO) δ= 9.49 (s, 1H), 8.69 (s, 1H), 8.43 (s, 1H), 8.18 (d, J = 8.8 Hz, 1H), 8.04 (d, J = 5.2 Hz, 2H), 3.83 - 3.69 (m, 1H), 3.57 (s, 2H), 2.45 - 2.29 (m, 2H), 1.94 - 1.38 (m, 6H), 1.29 - 0.97 (m, 6H), 0.89 (t, J = 7.4 Hz, 6H).
MS(ESI) m/z: 434.3 (M+H)⁺. (Compound 28)

4-amino-5-[[(4R) -4-[[(2S) -2-amino-2-cyclohexyl-acetyl] amino] -5-methyl-heptanoyl] amino] pyridine-3-carboxylic acid ditrifluoroacetate
4-amino-5-[[(4R) -4-[[(2S) -2-amino-2-cyclohexyl-acetyl] amino] -5-methyl-heptanoyl] amino] pyridine-3-carboxylic acid ditrifluoro Acetate
¹ H NMR ((CD ₃ ) ₂ SO) δ = 9.49 (s, 1H), 8.69 (s, 1H), 8.43 (s, 1H), 8.18 (d, J = 8.8 Hz, 1H), 8.04 (d, J = 5.2 Hz, 2H), 3.83-3.69 (m, 1H), 3.57 (s, 2H), 2.45-2.29 (m, 2H), 1.94-1.38 (m, 6H), 1.29-0.97 (m, 6H) , 0.89 (t, J = 7.4 Hz, 6H).
MS (ESI) m / z: 434.3 (M + H) ⁺ .

4-amino-5-[[4-[[(2S)-2-amino-2-cyclohexyl-acetyl]amino]cyclohexanecarbonyl]amino]pyridine-3-carboxylic acid ditrifluoroacetate
４−アミノ−５−［［４−［［（２Ｓ）−２−アミノ−２−シクロヘキシル−アセチル］アミノ］シクロヘキサンカルボニル］アミノ］ピリジン−３−カルボン酸 二トリフルオロ酢酸塩
¹H NMR ((CD₃)₂SO) δ= 9.42 (s, 1H), 8.64 (s, 1H), 8.44 (s, 1H), 8.25 (d, J = 7.2 Hz, 1H), 8.07 - 7.89 (m, 3H), 3.92 - 3.78 (m, 1H), 3.59 - 3.50 (m, 1H), 2.56 - 2.47 (m, 1H), 1.90 - 1.36 (m, 13H), 1.24 - 0.83 (m, 6H).
MS (ESI) m/z: 418 [M+H]⁺. (Compound 29)

4-amino-5-[[4-[[(2S) -2-amino-2-cyclohexyl-acetyl] amino] cyclohexanecarbonyl] amino] pyridine-3-carboxylic acid ditrifluoroacetate
4-amino-5-[[4-[[(2S) -2-amino-2-cyclohexyl-acetyl] amino] cyclohexanecarbonyl] amino] pyridine-3-carboxylic acid ditrifluoroacetate
¹ H NMR ((CD ₃ ) ₂ SO) δ = 9.42 (s, 1H), 8.64 (s, 1H), 8.44 (s, 1H), 8.25 (d, J = 7.2 Hz, 1H), 8.07-7.89 ( m, 3H), 3.92-3.78 (m, 1H), 3.59-3.50 (m, 1H), 2.56-2.47 (m, 1H), 1.90-1.36 (m, 13H), 1.24-0.83 (m, 6H).
MS (ESI) m / z: 418 [M + H] ⁺ .

4-amino-5-[[(4R)-4-[[(2S)-2-amino-2-cyclohexyl-acetyl]amino]-5-phenyl-pentanoyl]amino]pyridine-3-carboxylic acid ditrifluoroacetate
４−アミノ−５−［［（４Ｒ）−４−［［（２Ｓ）−２−アミノ−２−シクロヘキシル−アセチル］アミノ］−５−フェニル−ペンタノイル］アミノ］ピリジン−３−カルボン酸 二トリフルオロ酢酸塩
¹H NMR ((CD₃)₂SO) δ= 9.51 (s, 1H), 8.69 (s, 1H), 8.41 (d, J = 6.9 Hz, 2H), 8.07 (s, 2H), 7.37 - 7.18 (m, 5H), 2.91 - 2.81 (m, 1H), 2.42 (p, J = 8.5, 8.0 Hz, 1H), 1.89 - 1.56 (m, 11H), 1.13 (tt, J = 23.8, 12.1 Hz, 6H).
MS(ESI) m/z: 468.2 (M+H)⁺. (Compound 30)

4-amino-5-[[(4R) -4-[[(2S) -2-amino-2-cyclohexyl-acetyl] amino] -5-phenyl-pentanoyl] amino] pyridine-3-carboxylic acid ditrifluoroacetate
4-amino-5-[[(4R) -4-[[(2S) -2-amino-2-cyclohexyl-acetyl] amino] -5-phenyl-pentanoyl] amino] pyridine-3-carboxylic acid ditrifluoro Acetate
¹ H NMR ((CD ₃ ) ₂ SO) δ = 9.51 (s, 1H), 8.69 (s, 1H), 8.41 (d, J = 6.9 Hz, 2H), 8.07 (s, 2H), 7.37-7.18 ( m, 5H), 2.91-2.81 (m, 1H), 2.42 (p, J = 8.5, 8.0 Hz, 1H), 1.89-1.56 (m, 11H), 1.13 (tt, J = 23.8, 12.1 Hz, 6H) .
MS (ESI) m / z: 468.2 (M + H) ⁺ .

4-amino-5-[[(4R)-4-[[(2S)-2-amino-2-cyclohexyl-acetyl]amino]-5-methyl-hexanoyl]amino]pyridine-3-carboxylic acid ditrifluoroacetate
４−アミノ−５−［［（４Ｒ）−４−［［（２Ｓ）−２−アミノ−２−シクロヘキシル−アセチル］アミノ］−５−メチル−ヘキサノイル］アミノ］ピリジン−３−カルボン酸 二トリフルオロ酢酸塩
¹H NMR ((CD₃)₂SO) δ= 9.55 (s, 1H), 8.71 (s, 1H), 8.49 (s, 1H), 8.13 (d, J = 8.9 Hz, 1H), 8.10 - 8.00 (m, 2H), 3.74 - 3.55 (m, 1H), 2.39 (t, J = 7.8 Hz, 2H), 1.91 - 1.54 (m, 10H), 1.29 - 1.00 (m, 5H), 0.90 (dd, J = 6.9, 1.5 Hz, 6H).
MS(ESI) m/z: 420.3 (M+H)⁺. (Compound 31)

4-amino-5-[[(4R) -4-[[(2S) -2-amino-2-cyclohexyl-acetyl] amino] -5-methyl-hexanoyl] amino] pyridine-3-carboxylic acid ditrifluoroacetate
4-Amino-5-[[(4R) -4-[[(2S) -2-amino-2-cyclohexyl-acetyl] amino] -5-methyl-hexanoyl] amino] pyridine-3-carboxylic acid ditrifluoro Acetate
¹ H NMR ((CD ₃ ) ₂ SO) δ = 9.55 (s, 1H), 8.71 (s, 1H), 8.49 (s, 1H), 8.13 (d, J = 8.9 Hz, 1H), 8.10-8.00 ( m, 2H), 3.74-3.55 (m, 1H), 2.39 (t, J = 7.8 Hz, 2H), 1.91-1.54 (m, 10H), 1.29-1.00 (m, 5H), 0.90 (dd, J = (6.9, 1.5 Hz, 6H).
MS (ESI) m / z: 420.3 (M + H) ⁺ .

4-amino-5-[[(3S)-3-[[(2S)-2-amino-2-cyclohexyl-acetyl]amino]butanoyl]amino]pyridine-3-carboxylic acid ditrifluoroacetate
４−アミノ−５−［［（３Ｓ）−３−［［（２Ｓ）−２−アミノ−２−シクロヘキシル−アセチル］アミノ］ブタノイル］アミノ］ピリジン−３−カルボン酸 二トリフルオロ酢酸塩
¹H NMR ((CD₃)₂SO) δ= 9.53 (s, 1H), 8.61 (s, 1H), 8.37 (d, J = 8.0 Hz, 1H), 8.34 (s, 1H), 8.04 - 7.94 (m, 2H), 4.25 (p, J = 7.0 Hz, 1H), 2.51 (d, J = 7.1 Hz, 2H), 1.49 (q, J = 15.8, 14.7 Hz, 7H), 1.12 (d, J = 6.6 Hz, 3H), 0.94 (ddt, J = 27.4, 16.5, 8.1 Hz, 5H).
MS(ESI) m/z: 378.2 (M+H)⁺. (Compound 32)

4-amino-5-[[(3S) -3-[[(2S) -2-amino-2-cyclohexyl-acetyl] amino] butanoyl] amino] pyridine-3-carboxylic acid ditrifluoroacetate
4-amino-5-[[(3S) -3-[[(2S) -2-amino-2-cyclohexyl-acetyl] amino] butanoyl] amino] pyridine-3-carboxylic acid ditrifluoroacetate
¹ H NMR ((CD ₃ ) ₂ SO) δ = 9.53 (s, 1H), 8.61 (s, 1H), 8.37 (d, J = 8.0 Hz, 1H), 8.34 (s, 1H), 8.04-7.94 ( m, 2H), 4.25 (p, J = 7.0 Hz, 1H), 2.51 (d, J = 7.1 Hz, 2H), 1.49 (q, J = 15.8, 14.7 Hz, 7H), 1.12 (d, J = 6.6 Hz, 3H), 0.94 (ddt, J = 27.4, 16.5, 8.1 Hz, 5H).
MS (ESI) m / z: 378.2 (M + H) ⁺ .

4-amino-5-[[3-[[(2S)-2-amino-4-methyl-pentanoyl]amino]-3-methyl-butanoyl]amino]pyridine-3-carboxylic acid ditrifluoroacetate
４−アミノ−５［［３−［［（２Ｓ）−２−アミノ−４−メチル−ペンタノイル］アミノ］−３−メチル−ブタノイル］アミノ］ピリジン−３−カルボン酸 二トリフルオロ酢酸塩
¹H NMR ((CD₃)₂SO) δ= 9.49 (s, 1H), 8.71 (s, 1H), 8.49 (s, 1H), 8.21 (s, 1H), 8.11 - 7.99 (m, 4H), 3.70 (s, 1H), 2.94 (d, J = 14.2 Hz, 1H), 2.81 (d, J = 14.3 Hz, 1H), 1.69 - 1.31 (m, 9H), 0.93 - 0.80 (m, 6H).
MS(ESI) m/z: 365.2 (M+H)⁺. (Compound 33)

4-amino-5-[[3-[[(2S) -2-amino-4-methyl-pentanoyl] amino] -3-methyl-butanoyl] amino] pyridine-3-carboxylic acid ditrifluoroacetate
4-amino-5 [[3-[[(2S) -2-amino-4-methyl-pentanoyl] amino] -3-methyl-butanoyl] amino] pyridine-3-carboxylic acid ditrifluoroacetate
¹ H NMR ((CD ₃ ) ₂ SO) δ = 9.49 (s, 1H), 8.71 (s, 1H), 8.49 (s, 1H), 8.21 (s, 1H), 8.11-7.99 (m, 4H), 3.70 (s, 1H), 2.94 (d, J = 14.2 Hz, 1H), 2.81 (d, J = 14.3 Hz, 1H), 1.69-1.31 (m, 9H), 0.93-0.80 (m, 6H).
MS (ESI) m / z: 365.2 (M + H) ⁺ .

4-amino-5-[[3-[[(2S)-2-[[(2S)-2-amino-2-cyclohexyl-acetyl]amino]-3-methyl-pentanoyl]amino]-3-methyl-butanoyl]amino]pyridine-3-carboxylic acid (trifluoroacetic acid salt)
４−アミノ−５−[[３−[[(２Ｓ)−２−[[(２Ｓ)−２−アミノ−２−シクロヘキシル−アセチル]アミノ]−３−メチル−ペンタノイル]アミノ]−３−メチル−ブタノイル]アミノ]ピリジン−３−カルボン酸（２トリフルオロ酢酸塩）
¹H NMR (CD₃OD) δ= 8.72 (d, J = 1.2 Hz, 1H), 8.39 (d, J = 1.2 Hz, 1H), 4.17 (d, J = 8.5 Hz, 1H), 3.69 (d, J = 5.9 Hz, 1H), 2.92 (d, J = 2.4 Hz, 2H), 1.94 - 1.55 (m, 8H), 1.48 (d, J = 10.8 Hz, 6H), 1.33 - 1.03 (m, 6H), 1.00 - 0.75 (m, 6H)
MS(ESI) m/z: 505.5 (M+H)⁺. (Compound 34)

4-amino-5-[[3-[[(2S) -2-[[(2S) -2-amino-2-cyclohexyl-acetyl] amino] -3-methyl-pentanoyl] amino] -3-methyl- butanoyl] amino] pyridine-3-carboxylic acid (trifluoroacetic acid salt)
4-amino-5-[[3-[[(2S) -2-[[(2S) -2-amino-2-cyclohexyl-acetyl] amino] -3-methyl-pentanoyl] amino] -3-methyl- Butanoyl] amino] pyridine-3-carboxylic acid (2 trifluoroacetate)
¹ H NMR (CD ₃ OD) δ = 8.72 (d, J = 1.2 Hz, 1H), 8.39 (d, J = 1.2 Hz, 1H), 4.17 (d, J = 8.5 Hz, 1H), 3.69 (d, J = 5.9 Hz, 1H), 2.92 (d, J = 2.4 Hz, 2H), 1.94-1.55 (m, 8H), 1.48 (d, J = 10.8 Hz, 6H), 1.33-1.03 (m, 6H), 1.00-0.75 (m, 6H)
MS (ESI) m / z: 505.5 (M + H) ⁺ .

4-amino-5-[[3-[[(2S)-2-[[(2S)-2-amino-2-cyclohexyl-acetyl]amino]-4-methyl-pentanoyl]amino]-3-methyl-butanoyl]amino]pyridine-3-carboxylic acid (trifluoroacetic acid salt)
４−アミノ−５−[[３−[[(２Ｓ)−２−[[(２Ｓ)−２−アミノ−２−シクロヘキシル−アセチル]アミノ]−４−メチル−ペンタノイル]アミノ]−３−メチル−ブタノイル]アミノ]ピリジン−３−カルボン酸（２トリフルオロ酢酸塩）
¹H NMR (CD₃OD) δ= 8.74 (d, J = 1.3 Hz, 1H), 8.44 (s, 1H), 4.41 (t, J = 7.5 Hz, 1H), 3.64 (d, J = 5.8 Hz, 1H), 2.99 (d, J = 14.5 Hz, 1H), 2.86 (d, J = 14.5 Hz, 1H), 1.93 - 1.59 (m, 7H), 1.59 - 1.40 (m, 8H), 1.37 - 1.01 (m, 5H), 0.91 (t, J = 6.6 Hz, 6H)
MS(ESI) m/z: 505.5 (M+H)⁺. (Compound 35)

4-amino-5-[[3-[[(2S) -2-[[(2S) -2-amino-2-cyclohexyl-acetyl] amino] -4-methyl-pentanoyl] amino] -3-methyl- butanoyl] amino] pyridine-3-carboxylic acid (trifluoroacetic acid salt)
4-amino-5-[[3-[[(2S) -2-[[(2S) -2-amino-2-cyclohexyl-acetyl] amino] -4-methyl-pentanoyl] amino] -3-methyl- Butanoyl] amino] pyridine-3-carboxylic acid (2 trifluoroacetate)
¹ H NMR (CD ₃ OD) δ = 8.74 (d, J = 1.3 Hz, 1H), 8.44 (s, 1H), 4.41 (t, J = 7.5 Hz, 1H), 3.64 (d, J = 5.8 Hz, 1H), 2.99 (d, J = 14.5 Hz, 1H), 2.86 (d, J = 14.5 Hz, 1H), 1.93-1.59 (m, 7H), 1.59-1.40 (m, 8H), 1.37-1.01 (m , 5H), 0.91 (t, J = 6.6 Hz, 6H)
MS (ESI) m / z: 505.5 (M + H) ⁺ .

4-amino-5-[[(3R)-3-[[(2S)-2-amino-2-cyclohexyl-acetyl]amino]-3-(m-tolyl)propanoyl]amino]pyridine-3-carboxylic acid ditrifluoroacetate
４−アミノ−５−［［（３Ｒ）−３−［［（２Ｓ）−２−アミノ−２−シクロヘキシル−アセチル］アミノ］−３−（ｍ−トリル）プロパノイル］アミノ］ピリジン−３−カルボン酸 二トリフルオロ酢酸塩
¹H NMR ((CD₃)₂SO) δ= 9.69 (s, 1H), 8.93 (d, J = 8.3 Hz, 1H), 8.70 (s, 1H), 8.34 (s, 1H), 8.11 - 7.90 (m, 3H), 7.32 - 7.15 (m, 3H), 7.10 (d, J = 7.4 Hz, 1H), 5.45 - 5.29 (m, 1H), 3.60 - 3.52 (m, 1H), 2.99 - 2.78 (m, 2H), 2.32 (s, 3H), 1.76 - 1.40 (m, 6H), 1.16 - 0.84 (m, 5H).
MS (ESI) m/z: 454 [M+H]⁺. (Compound 36)

4-amino-5-[[(3R) -3-[[(2S) -2-amino-2-cyclohexyl-acetyl] amino] -3- (m-tolyl) propanoyl] amino] pyridine-3-carboxylic acid ditrifluoroacetate
4-amino-5-[[(3R) -3-[[(2S) -2-amino-2-cyclohexyl-acetyl] amino] -3- (m-tolyl) propanoyl] amino] pyridine-3-carboxylic acid Ditrifluoroacetate
¹ H NMR ((CD ₃ ) ₂ SO) δ = 9.69 (s, 1H), 8.93 (d, J = 8.3 Hz, 1H), 8.70 (s, 1H), 8.34 (s, 1H), 8.11-7.90 ( m, 3H), 7.32-7.15 (m, 3H), 7.10 (d, J = 7.4 Hz, 1H), 5.45-5.29 (m, 1H), 3.60-3.52 (m, 1H), 2.99-2.78 (m, 2H), 2.32 (s, 3H), 1.76-1.40 (m, 6H), 1.16-0.84 (m, 5H).
MS (ESI) m / z: 454 [M + H] ⁺ .

4-amino-5-[[3-[[(2S)-2-cyclohexyl-2-hydroxy-acetyl]amino]-3-methyl-butanoyl]amino]pyridine-3-carboxylic acid trifluoroacetate
４−アミノ−５−［［３−［［（２Ｓ）−２−シクロヘキシル−２−ヒドロキシ−アセチル］アミノ］−３−メチル−ブタノイル］アミノ］ピリジン−３−カルボン酸 トリフルオロ酢酸塩
¹H NMR ((CD₃)₂SO) δ= 9.32 (s, 1H), 8.53 (s, 1H), 8.14 (s, 1H), 7.65 (s, 1H), 5.38 (s, 1H), 3.57 (d, J = 3.4 Hz, 1H), 2.69 (d, J = 2.4 Hz, 2H), 1.61 (td, J = 29.0, 27.8, 12.9 Hz, 6H), 1.43 (d, J = 3.7 Hz, 6H), 1.26 - 0.98 (m, 5H).
MS(ESI) m/z: 393.2 (M+H)⁺. (Compound 37)

4-amino-5-[[3-[[(2S) -2-cyclohexyl-2-hydroxy-acetyl] amino] -3-methyl-butanoyl] amino] pyridine-3-carboxylic acid trifluoroacetate
4-amino-5-[[3-[[(2S) -2-cyclohexyl-2-hydroxy-acetyl] amino] -3-methyl-butanoyl] amino] pyridine-3-carboxylic acid trifluoroacetate
¹ H NMR ((CD ₃ ) ₂ SO) δ = 9.32 (s, 1H), 8.53 (s, 1H), 8.14 (s, 1H), 7.65 (s, 1H), 5.38 (s, 1H), 3.57 ( d, J = 3.4 Hz, 1H), 2.69 (d, J = 2.4 Hz, 2H), 1.61 (td, J = 29.0, 27.8, 12.9 Hz, 6H), 1.43 (d, J = 3.7 Hz, 6H), 1.26-0.98 (m, 5H).
MS (ESI) m / z: 393.2 (M + H) ⁺ .

4-amino-5-[[3-[[(2S)-2-(tert-butoxycarbonylamino)-2-cyclohexyl-acetyl]amino]-3-methyl-butanoyl]amino]pyridine-3-carboxylic acid
４−アミノ−５−［［３−［［（２Ｓ）−２−（ｔｅｒｔ−ブトキシカルボニルアミノ）−２−シクロヘキシル−アセチル］アミノ］−３−メチル−ブタノイル］アミノ］ピリジン−３−カルボン酸
MS(ESI) m/z: 492.3 (M+H)⁺. (Compound 38)

4-amino-5-[[3-[[(2S) -2- (tert-butoxycarbonylamino) -2-cyclohexyl-acetyl] amino] -3-methyl-butanoyl] amino] pyridine-3-carboxylic acid
4-amino-5-[[3-[[(2S) -2- (tert-butoxycarbonylamino) -2-cyclohexyl-acetyl] amino] -3-methyl-butanoyl] amino] pyridine-3-carboxylic acid
MS (ESI) m / z: 492.3 (M + H) ⁺ .

4-Amino-5-[5-(N-t-butoxycabonyl-(S)-cyclohexylglycylamino)-pentanoylamino]-nicotinic acid
４−アミノ−５−[５−（Ｎ−ｔ−ブトキシカルボニル−(Ｓ)−シクロヘキシルグリシルアミノ）−ペンタノイルアミノ]−ニコチン酸
¹H NMR (400 MHz, DMSO-d₆) δ 9.20 (s, 1H), 8.53 (s, 1H), 8.22 (s, 1H), 7.86 (s, 1H), 6.57 (d, J = 9.0 Hz, 1H), 3.74 (t, J = 8.2 Hz, 1H), 3.09 (ddt, J = 29.2, 12.9, 6.5 Hz, 3H), 2.37 (t, J = 7.3 Hz, 2H), 1.64 (s, 2H), 1.58 (d, J = 8.3 Hz, 4H), 1.54 - 1.40 (m, 4H), 1.37 (s, 9H), 1.09 (d, J = 8.2 Hz, 3H), 0.97 (dt, J = 21.1, 10.5 Hz, 2H).
MS(ESI) m/z: 420.1 (M+H)⁺. (Compound 39)

4-Amino-5- [5- (Nt-butoxycabonyl- (S) -cyclohexylglycylamino) -pentanoylamino] -nicotinic acid
4-amino-5- [5- (Nt-butoxycarbonyl- (S) -cyclohexylglycylamino) -pentanoylamino] -nicotinic acid
¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.20 (s, 1H), 8.53 (s, 1H), 8.22 (s, 1H), 7.86 (s, 1H), 6.57 (d, J = 9.0 Hz, 1H), 3.74 (t, J = 8.2 Hz, 1H), 3.09 (ddt, J = 29.2, 12.9, 6.5 Hz, 3H), 2.37 (t, J = 7.3 Hz, 2H), 1.64 (s, 2H), 1.58 (d, J = 8.3 Hz, 4H), 1.54-1.40 (m, 4H), 1.37 (s, 9H), 1.09 (d, J = 8.2 Hz, 3H), 0.97 (dt, J = 21.1, 10.5 Hz , 2H).
MS (ESI) m / z: 420.1 (M + H) ⁺ .

4-amino-5-[[3-[[(2S)-2-[(2-(tert-butoxycarbonylamino)acetyl]amino]-2-cyclohexyl-acetyl]amino]-3-methyl-butanoyl]amino]pyridine-3-carboxylic acid (trifluoroacetic acid salt)
４−アミノ−５−[[３−[[(２Ｓ)−２−[(２−(ｔｅｒｔ−ブトキシカルボニルアミノ)アセチル]アミノ]−２−シクロヘキシル−アセチル]アミノ]−３−メチル−ブタノイル]アミノ]ピリジン−３−カルボン酸（トリフルオロ酢酸塩）
¹H NMR (400 MHz, Methanol-d₄) δ 8.76 (d, J = 1.1 Hz, 1H), 8.40 (s, 1H), 4.07 (d, J = 7.1 Hz, 1H), 3.66 (s, 2H), 3.07 (d, J = 14.2 Hz, 1H), 2.76 (d, J = 14.1 Hz, 1H), 1.74-1.65 (m, 6H), 1.52 (s, 3H), 1.45 (s, 3H), 1.43 (s, 9H), 1.31 - 0.80 (m, 5H).
MS(ESI) m/z: 549.5 (M+H)⁺. (Compound 40)

4-amino-5-[[3-[[(2S) -2-[(2- (tert-butoxycarbonylamino) acetyl] amino] -2-cyclohexyl-acetyl] amino] -3-methyl-butanoyl] amino] pyridine -3-carboxylic acid (trifluoroacetic acid salt)
4-amino-5-[[3-[[(2S) -2-[(2- (tert-butoxycarbonylamino) acetyl] amino] -2-cyclohexyl-acetyl] amino] -3-methyl-butanoyl] amino ] Pyridine-3-carboxylic acid (trifluoroacetate)
¹ H NMR (400 MHz, Methanol-d ₄ ) δ 8.76 (d, J = 1.1 Hz, 1H), 8.40 (s, 1H), 4.07 (d, J = 7.1 Hz, 1H), 3.66 (s, 2H) , 3.07 (d, J = 14.2 Hz, 1H), 2.76 (d, J = 14.1 Hz, 1H), 1.74-1.65 (m, 6H), 1.52 (s, 3H), 1.45 (s, 3H), 1.43 ( s, 9H), 1.31-0.80 (m, 5H).
MS (ESI) m / z: 549.5 (M + H) ⁺ .

4-amino-5-[[3-[[(2S)-2-[[(2S)-2-(tert-butoxycarbonylamino)-3-methyl-pentanoyl]amino]-2-cyclohexyl-acetyl]amino]-3-methyl-butanoyl]amino]pyridine-3-carboxylic acid(trifluoroacetic acid salt)
４−アミノ−５−[[３−[[(２Ｓ)−２−[[(２Ｓ)−２−(ｔｅｒｔ−ブトキシカルボニルアミノ)−３−メチル−ペンタノイル]アミノ]−２−シクロヘキシル−アセチル]アミノ]−３−メチル−ブタノイル]アミノ]ピリジン−３−カルボン酸（トリフルオロ酢酸塩）
¹H NMR (400 MHz, Methanol-d₄) δ 8.74 (d, J = 1.1 Hz, 1H), 8.42 (s, 1H), 4.06 (t, J = 7.6 Hz, 1H), 3.81 (d, J = 7.5 Hz, 1H), 3.05 (d, J = 14.0 Hz 1H), 2.81 (d, J = 14.2 Hz, 1H), 1.88 - 1.57 (m, 7H), 1.50 (s, 3H), 1.44 (s, 12H), 1.27 - 0.99 (m, 7H), 0.88-0.84 (m, 6H).
MS(ESI) m/z: 605.5 (M+H)⁺. (Compound 41)

4-amino-5-[[3-[[(2S) -2-[[(2S) -2- (tert-butoxycarbonylamino) -3-methyl-pentanoyl] amino] -2-cyclohexyl-acetyl] amino]- 3-methyl-butanoyl] amino] pyridine-3-carboxylic acid (trifluoroacetic acid salt)
4-amino-5-[[3-[[(2S) -2-[[(2S) -2- (tert-butoxycarbonylamino) -3-methyl-pentanoyl] amino] -2-cyclohexyl-acetyl] amino ] -3-Methyl-butanoyl] amino] pyridine-3-carboxylic acid (trifluoroacetate)
¹ H NMR (400 MHz, Methanol-d ₄ ) δ 8.74 (d, J = 1.1 Hz, 1H), 8.42 (s, 1H), 4.06 (t, J = 7.6 Hz, 1H), 3.81 (d, J = 7.5 Hz, 1H), 3.05 (d, J = 14.0 Hz 1H), 2.81 (d, J = 14.2 Hz, 1H), 1.88-1.57 (m, 7H), 1.50 (s, 3H), 1.44 (s, 12H ), 1.27-0.99 (m, 7H), 0.88-0.84 (m, 6H).
MS (ESI) m / z: 605.5 (M + H) ⁺ .

4-amino-5-[[3-[[(2S)-2-[[(2S)-2-(tert-butoxycarbonylamino)-3-methyl-butanoyl]amino]-2-cyclohexyl-acetyl]amino]-3-methyl-butanoyl]amino]pyridine-3-carboxylic acid (trifluoroacetic acid salt)
４−アミノ−５−[[３−[[(２Ｓ)−２−[[(２Ｓ)−２−(ｔｅｒｔ−ブトキシカルボニルアミノ)−３−メチル−ブタノイル]アミノ]−２−シクロヘキシル−アセチル]アミノ]−３−メチル−ブタノイル]アミノ]ピリジン−３−カルボン酸（トリフルオロ酢酸塩）
¹H NMR (400 MHz, Methanol-d₄) δ 8.74 (d, J = 1.1 Hz, 1H), 8.42 (s, 1H), 4.07 (t, J = 7.1 Hz, 1H), 3.78 (d, J = 7.0 Hz, 1H), 3.06 (d, J = 14.3 Hz, 1H), 2.80 (d, J = 14.3 Hz, 1H), 1.98 (q, J = 7.1 Hz, 1H), 1.88 - 1.57 (m, 6H), 1.50 (s, 3H), 1.43 (s, 12H), 1.28-0.94 (m, 5H), 0.89 (d, J = 7.1 Hz , 6H)
MS(ESI) m/z: 590.7 (M+H)⁺. (Compound 42)

4-amino-5-[[3-[[(2S) -2-[[(2S) -2- (tert-butoxycarbonylamino) -3-methyl-butanoyl] amino] -2-cyclohexyl-acetyl] amino]- 3-methyl-butanoyl] amino] pyridine-3-carboxylic acid (trifluoroacetic acid salt)
4-amino-5-[[3-[[(2S) -2-[[(2S) -2- (tert-butoxycarbonylamino) -3-methyl-butanoyl] amino] -2-cyclohexyl-acetyl] amino ] -3-Methyl-butanoyl] amino] pyridine-3-carboxylic acid (trifluoroacetate)
¹ H NMR (400 MHz, Methanol-d ₄ ) δ 8.74 (d, J = 1.1 Hz, 1H), 8.42 (s, 1H), 4.07 (t, J = 7.1 Hz, 1H), 3.78 (d, J = 7.0 Hz, 1H), 3.06 (d, J = 14.3 Hz, 1H), 2.80 (d, J = 14.3 Hz, 1H), 1.98 (q, J = 7.1 Hz, 1H), 1.88-1.57 (m, 6H) , 1.50 (s, 3H), 1.43 (s, 12H), 1.28-0.94 (m, 5H), 0.89 (d, J = 7.1 Hz, 6H)
MS (ESI) m / z: 590.7 (M + H) ⁺ .

4-amino-5-[[3-[[(2S)-2-[[(2S)-2-(tert-butoxycarbonylamino)-4-methyl-pentanoyl]amino]-2-cyclohexyl-acetyl]amino]-3-methyl-butanoyl]amino]pyridine-3-carboxylic acid (trifluoroacetic acid salt)
４−アミノ−５−[[３−[[(２Ｓ)−２−[[(２Ｓ)−２−(ｔｅｒｔ−ブトキシカルボニルアミノ)−４−メチル−ペンタノイル]アミノ]−２−シクロヘキシル−アセチル]アミノ]−３−メチル−ブタノイル]アミノ]ピリジン−３−カルボン酸（トリフルオロ酢酸塩）
¹H NMR (400 MHz, Methanol-d₄) δ 8.75 (d, J = 1.2 Hz, 1H), 8.38 (s, 1H), 4.02 (dt, J = 30.6, 7.7 Hz, 2H), 3.07 (d, J = 14.1 Hz, 1H), 2.76 (d, J = 14.2 Hz, 1H), 1.78-1.60 (m, 8H), 1.51 (s, 3H), 1.44 (s, 13H), 1.27-0.99 (m, 5H), 0.90 (d, J = 6.4 Hz, 3H), 0.87 (d, J = 6.4 Hz, 3H).
MS(ESI) m/z: 605.5 (M+H)⁺. (Compound 43)

4-amino-5-[[3-[[((2S) -2-[[(2S) -2- (tert-butoxycarbonylamino) -4-methyl-pentanoyl] amino] -2-cyclohexyl-acetyl] amino]- 3-methyl-butanoyl] amino] pyridine-3-carboxylic acid (trifluoroacetic acid salt)
4-amino-5-[[3-[[(2S) -2-[[(2S) -2- (tert-butoxycarbonylamino) -4-methyl-pentanoyl] amino] -2-cyclohexyl-acetyl] amino ] -3-Methyl-butanoyl] amino] pyridine-3-carboxylic acid (trifluoroacetate)
¹ H NMR (400 MHz, Methanol-d ₄ ) δ 8.75 (d, J = 1.2 Hz, 1H), 8.38 (s, 1H), 4.02 (dt, J = 30.6, 7.7 Hz, 2H), 3.07 (d, J = 14.1 Hz, 1H), 2.76 (d, J = 14.2 Hz, 1H), 1.78-1.60 (m, 8H), 1.51 (s, 3H), 1.44 (s, 13H), 1.27-0.99 (m, 5H ), 0.90 (d, J = 6.4 Hz, 3H), 0.87 (d, J = 6.4 Hz, 3H).
MS (ESI) m / z: 605.5 (M + H) ⁺ .

4-amino-5-[[3-[[(2S)-2-[[(2S)-2-(tert-butoxycarbonylamino)-2-cyclohexyl-acetyl]amino]-4-methyl-pentanoyl]amino]-3-methyl-butanoyl]amino]pyridine-3-carboxylic acid(trifluoroacetic acid salt)
４−アミノ−５−[[３−[[(２Ｓ)−２−[[(２Ｓ)−２−(ｔｅｒｔ−ブトキシカルボニルアミノ)−２−シクロヘキシル−アセチル]アミノ]−４−メチル−ペンタノイル]アミノ]−３−メチル−ブタノイル]アミノ]ピリジン−３−カルボン酸（トリフルオロ酢酸塩）
¹H NMR (400 MHz, Methanol-d₄) δ 8.75 (d, J = 1.1 Hz, 1H), 8.44 (s, 1H), 4.30 (m, 1H), 3.78 (d, J = 7.1 Hz, 1H), 2.98 (d, J = 14.1 Hz, 1H), 2.85 (d, J = 14.2 Hz, 1H), 1.71-1.51 (m, 9H)1.48 (s, 3H), 1.45 (s, 3H), 1.43 (s, 9H), 1.23-1.12 (m, 5H), 0.93 (d, J = 4.0 Hz, 3H), 0.88 (d, J = 8.0 Hz, 3H) .
MS(ESI) m/z: 605.5 (M+H)⁺. (Compound 44)

4-amino-5-[[3-[[(2S) -2-[[(2S) -2- (tert-butoxycarbonylamino) -2-cyclohexyl-acetyl] amino] -4-methyl-pentanoyl] amino]- 3-methyl-butanoyl] amino] pyridine-3-carboxylic acid (trifluoroacetic acid salt)
4-amino-5-[[3-[[(2S) -2-[[(2S) -2- (tert-butoxycarbonylamino) -2-cyclohexyl-acetyl] amino] -4-methyl-pentanoyl] amino ] -3-Methyl-butanoyl] amino] pyridine-3-carboxylic acid (trifluoroacetate)
¹ H NMR (400 MHz, Methanol-d ₄ ) δ 8.75 (d, J = 1.1 Hz, 1H), 8.44 (s, 1H), 4.30 (m, 1H), 3.78 (d, J = 7.1 Hz, 1H) , 2.98 (d, J = 14.1 Hz, 1H), 2.85 (d, J = 14.2 Hz, 1H), 1.71-1.51 (m, 9H) 1.48 (s, 3H), 1.45 (s, 3H), 1.43 (s , 9H), 1.23-1.12 (m, 5H), 0.93 (d, J = 4.0 Hz, 3H), 0.88 (d, J = 8.0 Hz, 3H).
MS (ESI) m / z: 605.5 (M + H) ⁺ .

4-amino-5-[[3-[[(2S)-2-[[(2S)-2-(tert-butoxycarbonylamino)-2-cyclohexyl-acetyl]amino]-3-methyl-pentanoyl]amino]-3-methyl-butanoyl]amino]pyridine-3-carboxylic acid (trifluoroacetic acid salt)
４−アミノ−５−[[３−[[(２Ｓ)−２−[[(２Ｓ)−２−(ｔｅｒｔ−ブトキシカルボニルアミノ)−２−シクロヘキシル−アセチル]アミノ]−３−メチル−ペンタノイル]アミノ]−３−メチル−ブタノイル]アミノ]ピリジン−３−カルボン酸（トリフルオロ酢酸塩）
¹H NMR (400 MHz, Methanol-d₄) δ 8.75 (d, J = 1.2 Hz, 1H), 8.40 (s, 1H), 4.10 (t, J = 8.0 Hz, 1H), 3.78 (d, J = 7.1 Hz, 1H), 3.05 (d, J = 14.2 Hz, 1H), 2.78 (d, J = 14.2 Hz, 1H), 1.82 (m, 1H), 1.76 - 1.52 (m, 8H), 1.50 (s, 3H), 1.45 (s, 3H), 1.43 (s, 9H), 1.22-0.99 (m, 5H), 0.93 (d, J = 8.0 Hz, 3H), 0.88 (d, J = 8.0 Hz, 1H).
MS(ESI) m/z: 605.5 (M+H)⁺. (Compound 45)

4-amino-5-[[3-[[(2S) -2-[[(2S) -2- (tert-butoxycarbonylamino) -2-cyclohexyl-acetyl] amino] -3-methyl-pentanoyl] amino]- 3-methyl-butanoyl] amino] pyridine-3-carboxylic acid (trifluoroacetic acid salt)
4-amino-5-[[3-[[(2S) -2-[[(2S) -2- (tert-butoxycarbonylamino) -2-cyclohexyl-acetyl] amino] -3-methyl-pentanoyl] amino ] -3-Methyl-butanoyl] amino] pyridine-3-carboxylic acid (trifluoroacetate)
¹ H NMR (400 MHz, Methanol-d ₄ ) δ 8.75 (d, J = 1.2 Hz, 1H), 8.40 (s, 1H), 4.10 (t, J = 8.0 Hz, 1H), 3.78 (d, J = 7.1 Hz, 1H), 3.05 (d, J = 14.2 Hz, 1H), 2.78 (d, J = 14.2 Hz, 1H), 1.82 (m, 1H), 1.76-1.52 (m, 8H), 1.50 (s, 3H), 1.45 (s, 3H), 1.43 (s, 9H), 1.22-0.99 (m, 5H), 0.93 (d, J = 8.0 Hz, 3H), 0.88 (d, J = 8.0 Hz, 1H).
MS (ESI) m / z: 605.5 (M + H) ⁺ .

4-amino-5-[5-[[[(2S)-2-amino-3-methyl-butanoyl]amino]methyl]-2-furyl]pyridine-3-carboxylic acid ditrifluoroacetate
４−アミノ−５−［５−［［［（２Ｓ）−２−アミノ−３−メチル−ブタノイル］アミノ］メチル］−２−フリル］ピリジン−３−カルボン酸 二トリフルオロ酢酸塩
¹H NMR ((CD₃)₂SO) δ= 8.95 (t, J = 5.6 Hz, 1H), 8.72 (s, 1H), 8.44 (s, 1H), 8.07 (br s, 3H), 6.94 (d, J = 3.4 Hz, 1H), 6.47 (d, J = 3.4 Hz, 1H), 4.49 - 4.29 (m, 2H), 3.60 - 3.41 (m, 1H), 2.06 - 1.91 (m, 1H), 0.83 (d, J = 6.9 Hz, 6H).
MS (ESI) m/z: 333 [M+H]⁺. (Compound 46)

4-amino-5- [5-[[[(2S) -2-amino-3-methyl-butanoyl] amino] methyl] -2-furyl] pyridine-3-carboxylic acid ditrifluoroacetate
4-amino-5- [5-[[[(2S) -2-amino-3-methyl-butanoyl] amino] methyl] -2-furyl] pyridine-3-carboxylic acid ditrifluoroacetate
¹ H NMR ((CD ₃ ) ₂ SO) δ = 8.95 (t, J = 5.6 Hz, 1H), 8.72 (s, 1H), 8.44 (s, 1H), 8.07 (br s, 3H), 6.94 (d , J = 3.4 Hz, 1H), 6.47 (d, J = 3.4 Hz, 1H), 4.49-4.29 (m, 2H), 3.60-3.41 (m, 1H), 2.06-1.91 (m, 1H), 0.83 ( d, J = 6.9 Hz, 6H).
MS (ESI) m / z: 333 [M + H] ⁺ .

4-amino-5-[5-[[[(2S)-2-amino-4-methyl-pentanoyl]amino]methyl]-2-furyl]pyridine-3-carboxylic acid ditrifluoroacetate
４−アミノ−５−［５−［［［（２Ｓ）−２−アミノ−４−メチル−ペンタノイル］アミノ］メチル］−２−フリル］ピリジン−３−カルボン酸 二トリフルオロ酢酸塩
¹H NMR ((CD₃)₂SO) δ= 9.09 (t, J = 5.6 Hz, 1H), 8.79 (s, 1H), 8.51 (s, 1H), 8.17 (br s, 3H), 6.99 (d, J = 3.4 Hz, 1H), 6.54 (d, J = 3.4 Hz, 1H), 4.54 - 4.38 (m, 2H), 3.82 - 3.73 (m, 1H), 1.69 - 1.50 (m, 3H), 0.88 (dd, J = 8.5, 6.0 Hz, 6H).
MS (ESI) m/z: 347 [M+H]⁺. (Compound 47)

4-amino-5- [5-[[[(2S) -2-amino-4-methyl-pentanoyl] amino] methyl] -2-furyl] pyridine-3-carboxylic acid ditrifluoroacetate
4-Amino-5- [5-[[[(2S) -2-amino-4-methyl-pentanoyl] amino] methyl] -2-furyl] pyridine-3-carboxylic acid ditrifluoroacetate
¹ H NMR ((CD ₃ ) ₂ SO) δ = 9.09 (t, J = 5.6 Hz, 1H), 8.79 (s, 1H), 8.51 (s, 1H), 8.17 (br s, 3H), 6.99 (d , J = 3.4 Hz, 1H), 6.54 (d, J = 3.4 Hz, 1H), 4.54-4.38 (m, 2H), 3.82-3.73 (m, 1H), 1.69-1.50 (m, 3H), 0.88 ( dd, J = 8.5, 6.0 Hz, 6H).
MS (ESI) m / z: 347 [M + H] ⁺ .

4-amino-5-[5-[[[(2S)-2-aminohexanoyl]amino]methyl]-2-furyl]pyridine-3-carboxylic acid dihydrochloride
４−アミノ−５−［５−［［［（２Ｓ）−２−アミノヘキサノイル］アミノ］メチル］−２−フリル］ピリジン−３−カルボン酸 二塩酸塩
¹H NMR ((CD₃)₂SO) δ= 9.40 (t, J = 5.5 Hz, 1H), 9.28 (br s, 1H), 8.84 (d, J = 1.0 Hz, 1H), 8.65 (d, J = 1.0 Hz, 1H), 8.55 - 8.23 (m, 4H), 7.13 (d, J = 3.4 Hz, 1H), 6.64 (d, J = 3.4 Hz, 1H), 4.60 - 4.43 (m, 2H), 3.95 - 3.83 (m, 1H), 1.88 - 1.69 (m, 2H), 1.38 - 1.21 (m, 4H), 0.85 (t, J = 6.6 Hz, 3H).
MS (ESI) m/z: 347 [M+H]⁺. (Compound 48)

4-amino-5- [5-[[[(2S) -2-aminohexanoyl] amino] methyl] -2-furyl] pyridine-3-carboxylic acid dihydrochloride
4-amino-5- [5-[[[(2S) -2-aminohexanoyl] amino] methyl] -2-furyl] pyridine-3-carboxylic acid dihydrochloride
¹ H NMR ((CD ₃ ) ₂ SO) δ = 9.40 (t, J = 5.5 Hz, 1H), 9.28 (br s, 1H), 8.84 (d, J = 1.0 Hz, 1H), 8.65 (d, J = 1.0 Hz, 1H), 8.55-8.23 (m, 4H), 7.13 (d, J = 3.4 Hz, 1H), 6.64 (d, J = 3.4 Hz, 1H), 4.60-4.43 (m, 2H), 3.95 -3.83 (m, 1H), 1.88-1.69 (m, 2H), 1.38-1.21 (m, 4H), 0.85 (t, J = 6.6 Hz, 3H).
MS (ESI) m / z: 347 [M + H] ⁺ .

4-amino-5-[5-[[[(2S)-2-amino-3,3-dimethyl-butanoyl]amino]methyl]-2-furyl]pyridine-3-carboxylic acid dihydrochloride
４−アミノ−５−「５−［［［（２Ｓ）−２−アミノ−３，３−ジメチル−ブタノイル］アミノ］メチル］−２−フリル」ピリジン−３−カルボン酸 二塩酸塩
¹H NMR ((CD₃)₂SO) δ= 9.32 (t, J = 5.5 Hz, 1H), 9.12 (br s, 1H), 8.77 (d, J = 0.9 Hz, 1H), 8.57 (d, J = 0.9 Hz, 1H), 8.49 - 7.94 (m, 4H), 7.05 (d, J = 3.4 Hz, 1H), 6.61 (d, J = 3.4 Hz, 1H), 4.54 - 4.38 (m, 2H), 3.66 - 3.60 (m, 1H), 0.99 (s, 9H).
MS (ESI) m/z: 347 [M+H]⁺. (Compound 49)

4-amino-5- [5-[[[[(2S) -2-amino-3,3-dimethyl-butanoyl] amino] methyl] -2-furyl] pyridine-3-carboxylic acid dihydrochloride
4-amino-5- "5-[[[(2S) -2-amino-3,3-dimethyl-butanoyl] amino] methyl] -2-furyl" pyridine-3-carboxylic acid dihydrochloride
¹ H NMR ((CD ₃ ) ₂ SO) δ = 9.32 (t, J = 5.5 Hz, 1H), 9.12 (br s, 1H), 8.77 (d, J = 0.9 Hz, 1H), 8.57 (d, J = 0.9 Hz, 1H), 8.49-7.94 (m, 4H), 7.05 (d, J = 3.4 Hz, 1H), 6.61 (d, J = 3.4 Hz, 1H), 4.54-4.38 (m, 2H), 3.66 -3.60 (m, 1H), 0.99 (s, 9H).
MS (ESI) m / z: 347 [M + H] ⁺ .

4-amino-5-[5-[[[(2S)-2-amino-2-phenyl-acetyl]amino]methyl]-2-furyl]pyridine-3-carboxylic acid dihydrochloride
４−アミノ−５−［５−［［［（２Ｓ）−２−アミノ−２−フェニル−アセチル］アミノ］メチル］−２−フリル］ピリジン−３−カルボン酸 二塩酸塩
¹H NMR ((CD₃)₂SO) δ= 9.30 (t, J = 5.6 Hz, 1H), 8.84 - 8.58 (m, 4H), 8.42 (s, 1H), 7.59 - 7.45 (m, 2H), 7.43 - 7.27 (m, 3H), 6.87 (d, J = 3.4 Hz, 1H), 6.34 (d, J = 3.4 Hz, 1H), 5.05 - 4.93 (m, 1H), 4.34 (qd, J = 15.8, 5.6 Hz, 2H).
MS (ESI) m/z: 367 [M+H]⁺. (Compound 50)

4-amino-5- [5-[[[(2S) -2-amino-2-phenyl-acetyl] amino] methyl] -2-furyl] pyridine-3-carboxylic acid dihydrochloride
4-amino-5- [5-[[[(2S) -2-amino-2-phenyl-acetyl] amino] methyl] -2-furyl] pyridine-3-carboxylic acid dihydrochloride
¹ H NMR ((CD ₃ ) ₂ SO) δ = 9.30 (t, J = 5.6 Hz, 1H), 8.84-8.58 (m, 4H), 8.42 (s, 1H), 7.59-7.45 (m, 2H), 7.43-7.27 (m, 3H), 6.87 (d, J = 3.4 Hz, 1H), 6.34 (d, J = 3.4 Hz, 1H), 5.05-4.93 (m, 1H), 4.34 (qd, J = 15.8, 5.6 Hz, 2H).
MS (ESI) m / z: 367 [M + H] ⁺ .

4-amino-5-[5-[[[(2S)-2-(carboxymethylamino)-2-cyclohexyl-acetyl]amino]methyl]-2-furyl]pyridine-3-carboxylic acid ditrifluoroacid ditrifluoroacetate
４−アミノ−５−［５−［［［（２Ｓ）−２−（カルボメチルアミノ）−２−シクロヘキシルアセチル］アミノ］メチル］−２−フリル］ピリジン−３−カルボン酸 二トリフルオロ酢酸塩
¹H NMR ((CD₃)₂SO) δ= 8.96 (t, J = 5.6 Hz, 1H), 8.69 (s, 1H), 8.41 (s, 1H), 6.90 (d, J = 3.4 Hz, 1H), 6.46 (d, J = 3.4 Hz, 1H), 4.56 - 4.25 (m, 2H), 3.77 - 3.60 (m, 2H), 3.52 (d, J = 17.1 Hz, 1H), 1.61 (ddt, J = 40.1, 28.7, 15.3 Hz, 7H), 1.22 - 0.82 (m, 4H).
MS(ESI) m/z: 431.2 (M+H)⁺. (Compound 51)

4-amino-5- [5-[[[[(2S) -2- (carboxymethylamino) -2-cyclohexyl-acetyl] amino] methyl] -2-furyl] pyridine-3-carboxylic acid ditrifluoroacid ditrifluoroacetate
4-amino-5- [5-[[[(2S) -2- (carbomethylamino) -2-cyclohexylacetyl] amino] methyl] -2-furyl] pyridine-3-carboxylic acid ditrifluoroacetate
¹ H NMR ((CD ₃ ) ₂ SO) δ = 8.96 (t, J = 5.6 Hz, 1H), 8.69 (s, 1H), 8.41 (s, 1H), 6.90 (d, J = 3.4 Hz, 1H) , 6.46 (d, J = 3.4 Hz, 1H), 4.56-4.25 (m, 2H), 3.77-3.60 (m, 2H), 3.52 (d, J = 17.1 Hz, 1H), 1.61 (ddt, J = 40.1 , 28.7, 15.3 Hz, 7H), 1.22-0.82 (m, 4H).
MS (ESI) m / z: 431.2 (M + H) ⁺ .

4-amino-5-[5-[[[(2S)-2-cyclohexyl-2-hydroxy-acetyl]amino]methyl]-2-furyl]pyridine-3-carboxylic acid trifluoroacetate
４−アミノ−５−［５−［［［（２Ｓ）−２−シクロヘキシル−２−ヒドロキシ−アセチル］アミノ］メチル］−２−フリル］ピリジン−３−カルボン酸 トリフルオロ酢酸塩
¹H NMR ((CD₃)₂SO) δ= 9.10 (br s, 1H), 8.72 (d, J = 1.0 Hz, 1H), 8.45 (d, J = 1.0 Hz, 1H), 8.36 - 7.86 (m, 2H), 6.94 (d, J = 3.4 Hz, 1H), 6.37 (d, J = 3.4 Hz, 1H), 5.36 (br s, 1H), 4.38 - 4.24 (m, 2H), 3.65 (d, J = 3.9 Hz, 1H), 1.67 - 1.27 (m, 6H), 1.20 - 0.88 (m, 5H).
MS (ESI) m/z: 374 [M+H]⁺. (Compound 52)

4-amino-5- [5-[[[[(2S) -2-cyclohexyl-2-hydroxy-acetyl] amino] methyl] -2-furyl] pyridine-3-carboxylic acid trifluoroacetate
4-Amino-5- [5-[[[(2S) -2-cyclohexyl-2-hydroxy-acetyl] amino] methyl] -2-furyl] pyridine-3-carboxylic acid trifluoroacetate
¹ H NMR ((CD ₃ ) ₂ SO) δ = 9.10 (br s, 1H), 8.72 (d, J = 1.0 Hz, 1H), 8.45 (d, J = 1.0 Hz, 1H), 8.36-7.86 (m , 2H), 6.94 (d, J = 3.4 Hz, 1H), 6.37 (d, J = 3.4 Hz, 1H), 5.36 (br s, 1H), 4.38-4.24 (m, 2H), 3.65 (d, J = 3.9 Hz, 1H), 1.67-1.27 (m, 6H), 1.20-0.88 (m, 5H).
MS (ESI) m / z: 374 [M + H] ⁺ .

4-amino-5-[5-[[[(2R)-2-amino-2-cyclohexyl-acetyl]amino]methyl]-2-furyl]pyridine-3-carboxylic acid ditrifluoroacetate
４−アミノ−５−［５−［［［（２Ｒ）−２−アミノ−２−シクロヘキシル−アセチル］アミノ］メチル］−２−フリル］ピリジン−３−カルボン酸 二トリフルオロ酢酸塩
¹H NMR ((CD₃)₂SO) δ= 9.02 (t, J = 5.6 Hz, 1H), 8.81 (s, 1H), 8.52 (s, 1H), 8.16 (br s, 3H), 7.02 (d, J = 3.4 Hz, 1H), 6.55 (d, J = 3.4 Hz, 1H), 4.58 - 4.34 (m, 2H), 3.62 - 3.54 (m, 1H), 1.81 - 1.49 (m, 6H), 1.24 - 0.89 (m, 5H).
MS (ESI) m/z: 373 [M+H]⁺. (Compound 53)

4-amino-5- [5-[[[(2R) -2-amino-2-cyclohexyl-acetyl] amino] methyl] -2-furyl] pyridine-3-carboxylic acid ditrifluoroacetate
4-amino-5- [5-[[[(2R) -2-amino-2-cyclohexyl-acetyl] amino] methyl] -2-furyl] pyridine-3-carboxylic acid ditrifluoroacetate
¹ H NMR ((CD ₃ ) ₂ SO) δ = 9.02 (t, J = 5.6 Hz, 1H), 8.81 (s, 1H), 8.52 (s, 1H), 8.16 (br s, 3H), 7.02 (d , J = 3.4 Hz, 1H), 6.55 (d, J = 3.4 Hz, 1H), 4.58-4.34 (m, 2H), 3.62-3.54 (m, 1H), 1.81-1.49 (m, 6H), 1.24- 0.89 (m, 5H).
MS (ESI) m / z: 373 [M + H] ⁺ .

4-amino-5-[5-[[[(2S,3R)-2-amino-3-hydroxy-3-phenyl-propanoyl]amino]methyl]-2-furyl]pyridine-3-carboxylic acid ditrifluoroacetate
and
4-amino-5-[5-[[[(2R,3S)-2-amino-3-hydroxy-3-phenyl-propanoyl]amino]methyl]-2-furyl]pyridine-3-carboxylic acid ditrifluoroacetate
４−アミノ−５−［５−［［［（２Ｓ，３Ｒ）−２−アミノ−３−ヒドロキシ−３−フェニル−プロパノイル］アミノ］メチル］−２−フリル］ピリジン−３−カルボン酸 二トリフルオロ酢酸塩
及び
４−アミノ−５−［５−［［［（２Ｒ，３Ｓ）−２−アミノ−３−ヒドロキシ−３−フェニル−プロパノイル］アミノ］メチル］−２−フリル］ピリジン−３−カルボン酸 二トリフルオロ酢酸塩
¹H NMR ((CD₃)₂SO) δ= 8.75 (s, 1H), 8.73 - 8.66 (m, 1H), 8.51 - 8.38 (m, 1H), 8.33 - 7.98 (m, 3H), 7.29 - 7.11 (m, 5H), 6.89 (d, J = 3.4 Hz, 1H), 6.40 - 6.16 (m, 1H), 6.12 (d, J = 3.4 Hz, 1H), 4.91 - 4.71 (m, 1H), 4.44 - 4.12 (m, 2H), 3.94 - 3.74 (m, 1H).
MS (ESI) m/z: 397 [M+H]⁺. (Compound 54)

4-amino-5- [5-[[[(2S, 3R) -2-amino-3-hydroxy-3-phenyl-propanoyl] amino] methyl] -2-furyl] pyridine-3-carboxylic acid ditrifluoroacetate
and
4-amino-5- [5-[[[[(2R, 3S) -2-amino-3-hydroxy-3-phenyl-propanoyl] amino] methyl] -2-furyl] pyridine-3-carboxylic acid ditrifluoroacetate
4-Amino-5- [5-[[[(2S, 3R) -2-amino-3-hydroxy-3-phenyl-propanoyl] amino] methyl] -2-furyl] pyridine-3-carboxylic acid ditrifluoro Acetate and 4-amino-5- [5-[[[(2R, 3S) -2-amino-3-hydroxy-3-phenyl-propanoyl] amino] methyl] -2-furyl] pyridine-3-carboxylic acid Ditrifluoroacetate
¹ H NMR ((CD ₃ ) ₂ SO) δ = 8.75 (s, 1H), 8.73-8.66 (m, 1H), 8.51-8.38 (m, 1H), 8.33-7.98 (m, 3H), 7.29-7.11 (m, 5H), 6.89 (d, J = 3.4 Hz, 1H), 6.40-6.16 (m, 1H), 6.12 (d, J = 3.4 Hz, 1H), 4.91-4.71 (m, 1H), 4.44- 4.12 (m, 2H), 3.94-3.74 (m, 1H).
MS (ESI) m / z: 397 [M + H] ⁺ .

4-amino-5-[5-[[[(2S)-2-amino-2-cyclohexyl-acetyl]-(2-aminoethyl)amino]methyl]-2-furyl]pyridine-3-carboxylic acid tritrifluoroacetate
４−アミノ−５−［５−［［［（２Ｓ）−２−アミノ−２−シクロヘキシル−アセチル］−２−（２−アミノエチル）アミノ］メチル］−２−フリル］ピリジン−３−カルボン酸 三トリフルオロ酢酸塩
¹H NMR ((CD₃)₂SO) δ= 8.70 (d, J = 6.0 Hz, 1H), 8.41 (d, J = 2.5 Hz, 1H), 8.13 (s, 3H), 7.98 - 7.72 (m, 3H), 6.99 - 6.87 (m, 1H), 6.69 - 6.48 (m, 1H), 4.94 - 4.62 (m, 2H), 4.45 - 4.05 (m, 2H), 3.73 - 3.49 (m, 1H), 3.07 - 2.80 (m, 2H), 1.81 - 1.38 (m, 6H), 1.18 - 0.83 (m, 5H).
MS (ESI) m/z: 416 [M+H]⁺. (Compound 55)

4-amino-5- [5-[[[(2S) -2-amino-2-cyclohexyl-acetyl]-(2-aminoethyl) amino] methyl] -2-furyl] pyridine-3-carboxylic acid tritrifluoroacetate
4-amino-5- [5-[[[(2S) -2-amino-2-cyclohexyl-acetyl] -2- (2-aminoethyl) amino] methyl] -2-furyl] pyridine-3-carboxylic acid Tritrifluoroacetate
¹ H NMR ((CD ₃ ) ₂ SO) δ = 8.70 (d, J = 6.0 Hz, 1H), 8.41 (d, J = 2.5 Hz, 1H), 8.13 (s, 3H), 7.98-7.72 (m, 3H), 6.99-6.87 (m, 1H), 6.69-6.48 (m, 1H), 4.94-4.62 (m, 2H), 4.45-4.05 (m, 2H), 3.73-3.49 (m, 1H), 3.07- 2.80 (m, 2H), 1.81-1.38 (m, 6H), 1.18-0.83 (m, 5H).
MS (ESI) m / z: 416 [M + H] ⁺ .

4-amino-5-[5-[[[(2S)-piperidine-2-carbonyl]amino]methyl]-2-furyl]pyridine-3-carboxylic acid ditrifluoroacetate
４−アミノ−５−［５−［［［（２Ｓ）−ピペリジン−２−カルボニル］アミノ］メチル］−２−フリル］ピリジン−３−カルボン酸 二トリフルオロ酢酸塩
¹H NMR (CD₃OD) δ= 8.83 (d, J = 1.2 Hz, 1H), 8.48 (d, J = 1.2 Hz, 1H), 6.98 (d, J = 3.4 Hz, 1H), 6.56 (d, J = 3.4 Hz, 1H), 4.56 (s, 2H), 3.84 (dd, J = 11.8, 3.3 Hz, 1H), 3.42 (d, J = 12.8 Hz, 1H), 3.03 (m, 1H), 2.21 (d, J = 13.1 Hz, 1H), 2.03 - 1.81 (m, 2H), 1.75-1.63 (m, 3H).
MS(ESI) m/z: 344.6 (M+H)⁺. (Compound 56)

4-amino-5- [5-[[[[(2S) -piperidine-2-carbonyl] amino] methyl] -2-furyl] pyridine-3-carboxylic acid ditrifluoroacetate
4-amino-5- [5-[[[(2S) -piperidine-2-carbonyl] amino] methyl] -2-furyl] pyridine-3-carboxylic acid ditrifluoroacetate
¹ H NMR (CD ₃ OD) δ = 8.83 (d, J = 1.2 Hz, 1H), 8.48 (d, J = 1.2 Hz, 1H), 6.98 (d, J = 3.4 Hz, 1H), 6.56 (d, J = 3.4 Hz, 1H), 4.56 (s, 2H), 3.84 (dd, J = 11.8, 3.3 Hz, 1H), 3.42 (d, J = 12.8 Hz, 1H), 3.03 (m, 1H), 2.21 ( d, J = 13.1 Hz, 1H), 2.03-1.81 (m, 2H), 1.75-1.63 (m, 3H).
MS (ESI) m / z: 344.6 (M + H) ⁺ .

4-amino-5-[5-[[(1-aminocyclohexanecarbonyl)amino]methyl]-2-furyl]pyridine-3-carboxylic acid ditrifluoroacetate
４−アミノ−５−［５−［［（１−アミノシクロヘキサンカルボニル）アミノ］メチル］−２−フリル］ピリジン−３−カルボン酸 二トリフルオロ酢酸塩
¹H NMR ((CD₃)₂SO) δ= 8.95 (t, J = 5.4 Hz, 1H), 8.81 (s, 1H), 8.52 (s, 1H), 8.18 (s, 3H), 7.02 (d, J = 3.4 Hz, 1H), 6.50 (d, J = 3.4 Hz, 1H), 4.47 (d, J = 5.4 Hz, 2H), 2.06 - 1.90 (m, 2H), 1.81 - 1.66 (m, 2H), 1.66 - 1.46 (m, 5H), 1.39 - 1.26 (m, 1H).
MS (ESI) m/z: 359 [M+H]⁺. (Compound 57)

4-amino-5- [5-[[(1-aminocyclohexanecarbonyl) amino] methyl] -2-furyl] pyridine-3-carboxylic acid ditrifluoroacetate
4-amino-5- [5-[[(1-aminocyclohexanecarbonyl) amino] methyl] -2-furyl] pyridine-3-carboxylic acid ditrifluoroacetate
¹ H NMR ((CD ₃ ) ₂ SO) δ = 8.95 (t, J = 5.4 Hz, 1H), 8.81 (s, 1H), 8.52 (s, 1H), 8.18 (s, 3H), 7.02 (d, J = 3.4 Hz, 1H), 6.50 (d, J = 3.4 Hz, 1H), 4.47 (d, J = 5.4 Hz, 2H), 2.06-1.90 (m, 2H), 1.81-1.66 (m, 2H), 1.66-1.46 (m, 5H), 1.39-1.26 (m, 1H).
MS (ESI) m / z: 359 [M + H] ⁺ .

4-amino-5-[5-[[[(2S)-2-cyclohexyl-2-[(4-hydroxy-4-oxo-butyl)amino]acetyl]amino]methyl]-2-furyl]pyridine-3-carboxylic acid ditrifluoroacetate
４−アミノ−５−［５−［［［（２Ｓ）−２−シクロヘキシル−２−［（４−ヒドロキシ−４−オキソ−ブチル）アミノ］アセチル］アミノ］メチル］−２−フリル］ピリジン−３−カルボン酸 二トリフルオロ酢酸塩
¹H NMR ((CD₃)₂SO) δ= 9.07 (t, J = 5.6 Hz, 1H), 8.72 (s, 1H), 8.44 (s, 1H), 6.94 (d, J = 3.4 Hz, 1H), 6.48 (d, J = 3.4 Hz, 1H), 4.43 (ddd, J = 53.6, 15.8, 5.5 Hz, 2H), 3.58 (d, J = 5.1 Hz, 1H), 2.77 (d, J = 11.1 Hz, 2H), 2.22 (t, J = 7.2 Hz, 2H), 1.86 - 1.44 (m, 8H), 1.20 - 0.83 (m, 5H).
MS(ESI) m/z: 459.2 (M+H)⁺. (Compound 58)

4-amino-5- [5-[[[[(2S) -2-cyclohexyl-2-[(4-hydroxy-4-oxo-butyl) amino] acetyl] amino] methyl] -2-furyl] pyridine-3 -carboxylic acid ditrifluoroacetate
4-amino-5- [5-[[[(2S) -2-cyclohexyl-2-[(4-hydroxy-4-oxo-butyl) amino] acetyl] amino] methyl] -2-furyl] pyridine-3 -Carboxylic acid ditrifluoroacetate
¹ H NMR ((CD ₃ ) ₂ SO) δ = 9.07 (t, J = 5.6 Hz, 1H), 8.72 (s, 1H), 8.44 (s, 1H), 6.94 (d, J = 3.4 Hz, 1H) , 6.48 (d, J = 3.4 Hz, 1H), 4.43 (ddd, J = 53.6, 15.8, 5.5 Hz, 2H), 3.58 (d, J = 5.1 Hz, 1H), 2.77 (d, J = 11.1 Hz, 2H), 2.22 (t, J = 7.2 Hz, 2H), 1.86-1.44 (m, 8H), 1.20-0.83 (m, 5H).
MS (ESI) m / z: 459.2 (M + H) ⁺ .

4-amino-5-[5-[[[(1S,2R)-2-aminocyclopentyl]carbamoylamino]methyl]-2-furyl]pyridine-3-carboxylic acid ditrifluoroacetate
４−アミノ−５−［５−［［［（１Ｓ，２Ｒ）−２−アミノシクロペンチル］カルバモイルアミノ］メチル］−２−フリル］ピリジン−３−カルボン酸 二トリフルオロ酢酸塩
¹H NMR ((CD₃)₂SO) δ= 8.71 (s, 1H), 8.46 (s, 1H), 7.61 (br s, 3H), 6.92 (d, J = 3.4 Hz, 1H), 6.62 (t, J = 5.8 Hz, 1H), 6.41 (d, J = 3.4 Hz, 1H), 6.24 (d, J = 6.3 Hz, 1H), 4.38 - 4.16 (m, 2H), 3.99 - 3.89 (m, 1H), 3.43 - 3.37 (m, 1H), 1.98 - 1.74 (m, 2H), 1.73 - 1.59 (m, 1H), 1.59 - 1.39 (m, 3H). (Compound 59)

4-amino-5- [5-[[[[(1S, 2R) -2-aminocyclopentyl] carbamoylamino] methyl] -2-furyl] pyridine-3-carboxylic acid ditrifluoroacetate
4-Amino-5- [5-[[[(1S, 2R) -2-aminocyclopentyl] carbamoylamino] methyl] -2-furyl] pyridine-3-carboxylic acid ditrifluoroacetate
¹ H NMR ((CD ₃ ) ₂ SO) δ = 8.71 (s, 1H), 8.46 (s, 1H), 7.61 (br s, 3H), 6.92 (d, J = 3.4 Hz, 1H), 6.62 (t , J = 5.8 Hz, 1H), 6.41 (d, J = 3.4 Hz, 1H), 6.24 (d, J = 6.3 Hz, 1H), 4.38-4.16 (m, 2H), 3.99-3.89 (m, 1H) , 3.43-3.37 (m, 1H), 1.98-1.74 (m, 2H), 1.73-1.59 (m, 1H), 1.59-1.39 (m, 3H).

4-amino-5-[5-[[[(2S)-2-aminopent-4-enoyl]amino]methyl]-2-furyl]pyridine-3-carboxylic acid ditrifluoroacetate
４−アミノ−５−［５−［［［（２Ｓ）−２−アミノペンタ−４−エノイル］アミノ］メチル］−２−フリル］ピリジン−３−カルボン酸 二トリフルオロ酢酸塩
¹H NMR ((CD₃)₂SO) δ= 9.01 (t, J = 5.7 Hz, 1H), 8.80 (s, 1H), 8.52 (s, 1H), 8.19 (br s, 3H), 7.00 (d, J = 3.4 Hz, 1H), 6.54 (d, J = 3.4 Hz, 1H), 5.79 - 5.63 (m, 1H), 5.19 - 5.05 (m, 2H), 4.54 - 4.38 (m, 2H), 3.93 - 3.82 (m, 1H), 2.55 - 2.52 (m, 2H).
MS (ESI) m/z: 331 [M+H]⁺. (Compound 60)

4-amino-5- [5-[[[(2S) -2-aminopent-4-enoyl] amino] methyl] -2-furyl] pyridine-3-carboxylic acid ditrifluoroacetate
4-amino-5- [5-[[[(2S) -2-aminopenta-4-enoyl] amino] methyl] -2-furyl] pyridine-3-carboxylic acid ditrifluoroacetate
¹ H NMR ((CD ₃ ) ₂ SO) δ = 9.01 (t, J = 5.7 Hz, 1H), 8.80 (s, 1H), 8.52 (s, 1H), 8.19 (br s, 3H), 7.00 (d , J = 3.4 Hz, 1H), 6.54 (d, J = 3.4 Hz, 1H), 5.79-5.63 (m, 1H), 5.19-5.05 (m, 2H), 4.54-4.38 (m, 2H), 3.93- 3.82 (m, 1H), 2.55-2.52 (m, 2H).
MS (ESI) m / z: 331 [M + H] ⁺ .

4-amino-5-[5-[[[(2S,3R,4S)-2-amino-4-hydroxy-3-methyl-pentanoyl]amino]methyl]-2-furyl]pyridine-3-carboxylic acid ditrifluoroacetate
４−アミノ−５−［５−［［［（２Ｓ，３Ｒ，４Ｓ）−２−アミノ−４−ヒドロキシ−３−メチル−ペンタノイル］アミノ］メチル］−２−フリル］ピリジン−３−カルボン酸 二トリフルオロ酢酸塩
¹H NMR ((CD₃)₂SO) δ= 8.85 - 8.70 (m, 2H), 8.51 (s, 1H), 8.22 - 8.04 (m, 3H), 7.00 (d, J = 3.4 Hz, 1H), 6.56 (d, J = 3.4 Hz, 1H), 5.35 (br s, 1H), 4.59 - 4.35 (m, 2H), 3.88 - 3.81 (m, 1H), 3.59 - 3.52 (m, 1H), 1.85 - 1.71 (m, 1H), 1.10 (d, J = 6.1 Hz, 3H), 0.78 (d, J = 6.9 Hz, 3H).
MS (ESI) m/z: 363 [M+H]⁺. (Compound 61)

4-amino-5- [5-[[[(2S, 3R, 4S) -2-amino-4-hydroxy-3-methyl-pentanoyl] amino] methyl] -2-furyl] pyridine-3-carboxylic acid ditrifluoroacetate
4-Amino-5- [5-[[[(2S, 3R, 4S) -2-amino-4-hydroxy-3-methyl-pentanoyl] amino] methyl] -2-furyl] pyridine-3-carboxylic acid Trifluoroacetate
¹ H NMR ((CD ₃ ) ₂ SO) δ = 8.85-8.70 (m, 2H), 8.51 (s, 1H), 8.22-8.04 (m, 3H), 7.00 (d, J = 3.4 Hz, 1H), 6.56 (d, J = 3.4 Hz, 1H), 5.35 (br s, 1H), 4.59-4.35 (m, 2H), 3.88-3.81 (m, 1H), 3.59-3.52 (m, 1H), 1.85-1.71 (m, 1H), 1.10 (d, J = 6.1 Hz, 3H), 0.78 (d, J = 6.9 Hz, 3H).
MS (ESI) m / z: 363 [M + H] ⁺ .

4-amino-5-[5-[[[(1S,2S)-2-aminocyclopentyl]carbamoylamino]methyl]-2-furyl]pyridine-3-carboxylic acid ditrifluoroacetate
４−アミノ−５−［５−［［［（１Ｓ，２Ｓ）−２−アミノシクロペンチル］カルバモイルアミノ］メチル］−２−フリル］ピリジン−３−カルボン酸 二トリフルオロ酢酸塩
¹H NMR ((CD₃)₂SO) δ= 8.71 (s, 1H), 8.45 (s, 1H), 7.89 (br s, 3H), 6.92 (d, J = 3.4 Hz, 1H), 6.64 (t, J = 5.7 Hz, 1H), 6.50 (d, J = 6.0 Hz, 1H), 6.38 (d, J = 3.4 Hz, 1H), 4.26 (qd, J = 15.9, 5.7 Hz, 2H), 3.74 (p, J = 7.6 Hz, 1H), 3.17 - 3.07 (m, 1H), 2.01 - 1.82 (m, 2H), 1.68 - 1.30 (m, 4H).
MS (ESI) m/z: 360 [M+H]⁺. (Compound 62)

4-amino-5- [5-[[[[(1S, 2S) -2-aminocyclopentyl] carbamoylamino] methyl] -2-furyl] pyridine-3-carboxylic acid ditrifluoroacetate
4-amino-5- [5-[[[(1S, 2S) -2-aminocyclopentyl] carbamoylamino] methyl] -2-furyl] pyridine-3-carboxylic acid ditrifluoroacetate
¹ H NMR ((CD ₃ ) ₂ SO) δ = 8.71 (s, 1H), 8.45 (s, 1H), 7.89 (br s, 3H), 6.92 (d, J = 3.4 Hz, 1H), 6.64 (t , J = 5.7 Hz, 1H), 6.50 (d, J = 6.0 Hz, 1H), 6.38 (d, J = 3.4 Hz, 1H), 4.26 (qd, J = 15.9, 5.7 Hz, 2H), 3.74 (p , J = 7.6 Hz, 1H), 3.17-3.07 (m, 1H), 2.01-1.82 (m, 2H), 1.68-1.30 (m, 4H).
MS (ESI) m / z: 360 [M + H] ⁺ .

4-amino-5-[5-[[[(3S)-3-amino-4-phenyl-butanoyl]amino]methyl]-2-furyl]pyridine-3-carboxylic acid ditrifluoroacetate
４−アミノ−５−］５−［［［（３Ｓ）−３−アミノ−４−フェニル−ブタノイル］アミノ］メチル］−２−フリル］ピリジン−３−カルボン酸 二トリフルオロ酢酸塩
¹H NMR ((CD₃)₂SO) δ= 8.79 (s, 1H), 8.72 (t, J = 5.5 Hz, 1H), 8.51 (s, 1H), 7.96 (br s, 3H), 7.38 - 7.18 (m, 5H), 6.99 (d, J = 3.4 Hz, 1H), 6.50 (d, J = 3.4 Hz, 1H), 4.37 (d, J = 5.5 Hz, 2H), 3.76 - 3.67 (m, 1H), 3.03 - 2.91 (m, 1H), 2.82 - 2.72 (m, 1H), 2.47 - 2.40 (m, 2H).
MS (ESI) m/z: 395 [M+H]⁺. (Compound 63)

4-amino-5- [5-[[[[(3S) -3-amino-4-phenyl-butanoyl] amino] methyl] -2-furyl] pyridine-3-carboxylic acid ditrifluoroacetate
4-amino-5-] 5-[[[(3S) -3-amino-4-phenyl-butanoyl] amino] methyl] -2-furyl] pyridine-3-carboxylic acid ditrifluoroacetate
¹ H NMR ((CD ₃ ) ₂ SO) δ = 8.79 (s, 1H), 8.72 (t, J = 5.5 Hz, 1H), 8.51 (s, 1H), 7.96 (br s, 3H), 7.38-7.18 (m, 5H), 6.99 (d, J = 3.4 Hz, 1H), 6.50 (d, J = 3.4 Hz, 1H), 4.37 (d, J = 5.5 Hz, 2H), 3.76-3.67 (m, 1H) , 3.03-2.91 (m, 1H), 2.82-2.72 (m, 1H), 2.47-2.40 (m, 2H).
MS (ESI) m / z: 395 [M + H] ⁺ .

4-amino-5-[5-[[[(1R,2S)-2-aminocyclohexanecarbonyl]amino]methyl]-2-furyl]pyridine-3-carboxylic acid ditrifluoroacetate
and
4-amino-5-[5-[[[(1S,2R)-2-aminocyclohexanecarbonyl]amino]methyl]-2-furyl]pyridine-3-carboxylic acid ditrifluoroacetate
４−アミノ−５−［５−［［［（１Ｒ，２Ｓ）−２−アミノシクロヘキサンカルボニル］アミノ］メチル］−２−フリル］ピリジン−３−カルボン酸 二トリフルオロ酢酸塩
及び
４−アミノ−５−［５−［［［（１Ｓ，２Ｒ）−２−アミノシクロヘキサンカルボニル］アミノ］メチル］−２−フリル］ピリジン−３−カルボン酸 二トリフルオロ酢酸塩
¹H NMR ((CD₃)₂SO) δ= 8.80 (s, 1H), 8.75 (t, J = 5.6 Hz, 1H), 8.53 (s, 1H), 7.83 (s, 3H), 7.01 (d, J = 3.4 Hz, 1H), 6.51 (d, J = 3.4 Hz, 1H), 4.52 - 4.30 (m, 2H), 3.46 - 3.35 (m, 1H), 2.77 - 2.64 (m, 1H), 2.00 - 1.82 (m, 2H), 1.74 - 1.53 (m, 3H), 1.53 - 1.28 (m, 3H).
MS (ESI) m/z: 359 [M+H]⁺. (Compound 64)

4-amino-5- [5-[[[[(1R, 2S) -2-aminocyclohexanecarbonyl] amino] methyl] -2-furyl] pyridine-3-carboxylic acid ditrifluoroacetate
and
4-amino-5- [5-[[[(1S, 2R) -2-aminocyclohexanecarbonyl] amino] methyl] -2-furyl] pyridine-3-carboxylic acid ditrifluoroacetate
4-amino-5- [5-[[[(1R, 2S) -2-aminocyclohexanecarbonyl] amino] methyl] -2-furyl] pyridine-3-carboxylic acid ditrifluoroacetate and 4-amino-5 -[5-[[[(1S, 2R) -2-aminocyclohexanecarbonyl] amino] methyl] -2-furyl] pyridine-3-carboxylic acid ditrifluoroacetate
¹ H NMR ((CD ₃ ) ₂ SO) δ = 8.80 (s, 1H), 8.75 (t, J = 5.6 Hz, 1H), 8.53 (s, 1H), 7.83 (s, 3H), 7.01 (d, J = 3.4 Hz, 1H), 6.51 (d, J = 3.4 Hz, 1H), 4.52-4.30 (m, 2H), 3.46-3.35 (m, 1H), 2.77-2.64 (m, 1H), 2.00-1.82 (m, 2H), 1.74-1.53 (m, 3H), 1.53-1.28 (m, 3H).
MS (ESI) m / z: 359 [M + H] ⁺ .

(Test Example 1) Evaluation method of activity of sweet taste receptor:
The activity of the sweet taste receptor was evaluated using the method described in Example 6 of JP-A-2015-192664.
HEK293E cells maintained using a DMEM / Ham's F-12 (Nacalai Tesque) medium containing 10% Fetal bovine serum (Nichirei) and 1% Pen Strep (GIBCO) were treated with D-PBS (-) (Nacalai Tesque). After washing, cells were collected from the flask using 0.25% Trypsin EDTA (GIBCO). The supernatant was removed by centrifugation (1,200 rpm, 3 min) and suspended in 5% FBS DMEM / Ham's F-12 to 0.75 × 10 7 cells / mL. This was inoculated into a 150 cm ³ flask (IWAKI) at 10 mL and cultured overnight (37 ° C., 5% CO ₂ ). On the next day, the medium was replaced with 30 mL of Opti-MEM (Invitrogen, Life Technologies), and a sweet receptor gene mixture gene-αr-Gr-Gr and a G-rtan-Gr-t solution of a gene for the receptor for Receptor gene prepared by using Opti-MEM and Lipofectamine 2000 (Invitrogen, Life Technologies). The T1R2 chimeric gene and the T1R3 chimeric gene (63.8 μg in total) were slowly added to the cell suspension, and the genes were introduced by culturing for 6 hours (37 ° C., 5% CO ₂ ).

  After gene transfer, the cells were washed with D-PBS (-), and the cells were peeled off from the flask using 0.25% Trypsin EDTA (GIBCO) and collected. After counting the number of cells, the cells were suspended in 5% FBS DMEM (2.78 mM glucose, GIBCO) medium to a concentration of 0.5 × 10 6 cells / mL. This cell suspension was inoculated to each well of a D-Lysine coat 96-well plate (BD Bioscience) so as to have a density of 7.0 × 104 cells, and cultured overnight.

  After the culturing, all the 96-well culture media were completely diluted with a buffer for Assay (20 mM HEPES, 146 mM NaCl, 1 mM MgSO4, 1.39 mM glucose, 1 mM CaCl2, 2.5 mM Probenecid, 0.05% Bovine serum albumin). 200 μL of a staining solution for measuring intracellular calcium ion (Calcium assay kit Express (Molecular Device)) diluted with the above was added, and the mixture was allowed to stand at 37 ° C. for 30 minutes and at room temperature for 45 minutes to perform staining. After staining, 50 μL of a stimulus (sweet substance) prepared as described below was added using FDSS μCELL (Hamamatsu Photonics), and the fluorescence value up to 120 seconds after stimulation was measured. By measuring the fluorescence value (Ex480: Em540) before and after stimulation, the change in intracellular free calcium ion concentration caused via the sweet receptor by the addition of the stimulant was quantitatively examined. The measurement and analysis of the fluorescence value were performed using software (FDSS7000EX) attached to FDSS μCELL, and the ΔF / F value was calculated by the following method and used for evaluation.

Stimulants (sweet substances):
Each compound described in Table 1 was dissolved in dimethyl sulfoxide at a concentration of 100 mM. Thereafter, the final concentration of each compound is 100 μM, 50.0 μM, 25.0 μM, 12.5 μM, 6.25 μM, 3.13 μM, 1.56 μM, 0.781 μM, and the final concentration of sucrose or glucose is 20 mM. The concentration was adjusted using the buffer for Assay as described above, and this was used as a stimulant (sweet substance).

Using the ΔF / F value obtained when each stimulus was added, an activity index was calculated as follows. Specifically, first, for each concentration of the compound, a value obtained by subtracting the ΔF / F value when the stimulant containing the compound and glucose is added from the ΔF / F value when the stimulus containing the compound and sucrose is added. Was calculated. Thereafter, the values calculated at each of the above concentrations were summed, and the sum was used as an activity index of the compound.
The compound of Reference Example 1 described below is a compound described in Example 5 of Patent Document 2. The activity index of this compound was also determined, and the ratio of the activity index to Reference Example 1 was determined by “(activity index of each compound / activity index of Reference Example 1) × 100”. Table 1 shows the results.

(Test Example 2) Sensory evaluation Evaluation method:
<Method for confirming the presence or absence of sweetness of compound alone>
The taste of the compound was confirmed as follows. Each compound used was dissolved in ethanol for food use at a concentration of 10,000 ppm. An aqueous solution of the compound having a final concentration of 10 ppm was prepared, and the solution was dispensed into a 2.5 oz sample cup in 25 mL portions and presented to the subject at room temperature. The subjects contained the sample in the oral cavity and compared them with the 0%, 0.5%, 1.0%, and 1.5% aqueous sucrose solutions, and scored them with numerical values considered to be equivalent sweetness. The evaluation was performed by a method of discharging the sample. After evaluating one sample, the subject rinsed the inside of the oral cavity with ion-exchanged water, and evaluated the sample within the given volume. This evaluation was carried out by three or four expert panelists for sensory evaluation of sweetness, and the average value of the scores for each sample was taken as the equivalent concentration of sucrose alone. By subtracting the sweetness of the compound alone, the sweetness enhancement factor can be accurately calculated.

<Calculation method of sweetness enhancement factor>
The measurement of the sweetness enhancement of the compound was carried out as follows. Each compound used was dissolved in ethanol for food use at a concentration of 10,000 ppm. A 5% aqueous solution of sucrose having a final concentration of 10 ppm of the compound was prepared, and the solution was dispensed into a 2.5 oz sample cup in 25 mL portions and presented to the subject at room temperature. The subject contained the sample in the oral cavity, and compared with the 5%, 6%, 7%, 8%, 9%, 10%, 11%, and 12% aqueous sucrose solutions, a value considered to be equivalent in sweetness Scored on. The evaluation was performed by a method of discharging the sample. After evaluating one sample, the subject rinsed the mouth with ion-exchanged water, and evaluated the sample within the given volume. This evaluation was carried out by 3 to 4 expert panels of sensory evaluation of sweetness, and the average value of the scores for each sample was taken as the equivalent sucrose concentration. Using the equivalent sucrose concentration, the sweetness enhancement factor with respect to the 5% aqueous sucrose solution was calculated for each sample (see formula 1 below). However, when the compound alone had sweetness, the sweetness of the compound alone was subtracted in advance, and then the sweetness enhancement factor was calculated (see the following formula 2).
Formula 1: equivalent sucrose concentration (%) / 5
Formula 2: (Equivalent sucrose concentration (%)-equivalent sucrose concentration of simple substance (%)) / 5
In addition, Reference Example 1 was similarly evaluated. Table 2 shows the results.

(Test Example 3) Time-Intensity (TI) Evaluation The TI evaluation is a method for recording a time-series change in perceived taste intensity, and the TI evaluation of a compound was performed as follows. Each compound used was dissolved in ethanol for food use at a concentration of 10,000 ppm. A 5% aqueous solution of sucrose having a final concentration of 10 ppm of the compound was prepared, and the solution was dispensed into a 2.5 oz sample cup in 25 mL portions and presented to the subject at room temperature. The subject contained the sample in the oral cavity, and compared the 10% aqueous sucrose solution, the 0.1% aqueous aspartame solution, and the 0.000492% aqueous advantame solution to evaluate the sweetness peak position of each compound. The evaluation was performed by a method of discharging the sample. After evaluating one sample, the subject rinsed the inside of the oral cavity with ion-exchanged water, and evaluated the sample within the given volume. Regarding the sweetness peak of the compound, the earlier the peak is, the middle is later and the later is the same as compared with the time of the sweetness peak of aspartame (about 3.2 seconds after ingestion).
This evaluation was performed by 3 to 4 expert panelists for sensory evaluation of sweetness.
In addition, Reference Example 1 was similarly evaluated. Table 2 shows the results.

(Note 1) Since the sweetness was evaluated by adding the compound to a 5% aqueous sucrose solution, the sweetness enhancement factor was calculated by (AB) # 5.
(Note 2) Compared to the peak time of aspartame sweetness (approximately 3.2 seconds after ingestion), the earlier the peak is, the earlier it is equal, and the later it is later. . The time when the sweetness peak of sucrose is about 2.2 seconds after being contained in the mouth, and the sweetness peak is earlier than aspartame. Thus, compounds whose peak is “earlier” have a sweetness peak close to sucrose.

As shown in Table 2, the compound of the present invention or a salt thereof enhanced the sweetness intensity of a 5% aqueous sucrose solution by 1.49 times or more. Among them, Compound 46, Compound 47, Compound 9, Compound 2, Compound 6, Compound 17, and Compound 4 enhanced the sweetness intensity by 1.90 times or more.
As for the sweetness, the sweetness peak positions of compound 46, compound 47, compound 9, compound 8, compound 11, compound 12, compound 2, compound 3, compound 7, and compound 20 are closer to sucrose than aspartame, It has been shown to be a preferred sweetness.

(Test Example 4) Evaluation of heating stability A test substance was dissolved in a buffer solution (pH 3.0 and pH 6.5) so as to be 0.01 wt% (100 ppm), and heated at 90 ° C for 24 hours in a sealed vial. . The amount of the test substance remaining after 24 hours was measured by reversed-phase high-performance liquid chromatography, and the residual ratio was calculated based on the amount at the start of the test and the remaining amount after 24 hours. Three tests were performed for one compound, and the average value was calculated. Table 3 shows the results.
Preparation of pH3 citrate buffer:
It was prepared by adding a 25 mM sodium citrate solution to a 25 mM citric acid solution.
Preparation of pH 6.5 buffer:
It was prepared by adding a 25 mM aqueous sodium hydroxide solution to a 25 mM aqueous hydrochloric acid solution.
HPLC measurement conditions:
Column: SHISEIDO CAPCELL CORE C18, 3.0 mm × 100 mm, 3 μm
Measurement temperature: 40 ° C
Detection: UV 210 nm
Flow rate: 0.5 mL / min
Sample injection volume: 10 μL
_{Eluent: A: 10mM NaH 2 PO 4} (pH4.7); B: acetonitrile Gradient: 0-4 min: 1% B; 4 to 11 minutes: 40% B; 11 to 14 min: 70% B;. 14 to 20 minutes: 1% B

  As a result of the test, all of the compounds were stable at pH 3.0 and 6.5 after heating at 90 ° C. for 24 hours, with a residual ratio of about 90% or more.

Claims (14)

A compound represented by the following general formula (I), a tautomer or stereoisomer thereof, or a salt thereof.

(Where
R ₁ and R ₂ each independently represent a hydrogen atom, a halogen atom, a C _1-6 alkyl group which may have a substituent or a C _1-6 alkoxy group which may have a substituent,
R ₃ and R ₄ each independently represent a hydrogen atom or a C _1-6 alkyl group which may have a substituent,
R ₅ is a C _1-12 alkyl group which may have a substituent, a 3- to 14-membered alicyclic group which may have a substituent, or a 3- to 5-membered group which may have a substituent. A 14-membered heterocyclic group, a 6- to 14-membered aryl group which may have a substituent, a 5- to 14-membered heteroaryl group which may have a substituent, or a substituent Represents an amino group which may be
A is NHCO, CONH, a single bond, a vinylene group, a 6-14 membered arylene group which may have a substituent, a 5-14 membered heteroarylene group which may have a substituent, Represents a 3 to 14 membered divalent alicyclic group which may have, or a 3 to 14 membered divalent heterocyclic group which may have a substituent,
D has a single bond, a C _1-12 alkylene group which may have a substituent, a 3- to 14-membered divalent alicyclic group which may have a substituent, or a substituent. Represents a 3- to 14-membered divalent heterocyclic group, and E represents a single bond or the following formula (II):

(In the formula, * represents a bond to an adjacent D,
** represents a bond to an adjacent nitrogen atom,
R ₆ and R ₇ are each independently a hydrogen atom, a C _1-12 alkyl group which may have a substituent, a 3- to 14-membered alicyclic group which may have a substituent, A 3- to 14-membered heterocyclic group which may have a substituent, a 6- to 14-membered aryl group which may have a substituent, or a 5- to 14-membered which may have a substituent of represents a heteroaryl group, or R ₆ and R ₇ may form these groups is 3 to 8 membered which may have a substituent together with the carbon atom bonded ring, or R ₆ and R ₄ may form a 4- to 8-membered ring which may have a substituent together with a carbon atom and a nitrogen atom to which these groups are bonded. ) Is a group represented by
Provided that A, D and E are not simultaneously a single bond. )   A is NHCO, a single bond, a vinylene group, a divalent group in which two hydrogen atoms have been removed from a benzene ring, a divalent group in which two hydrogen atoms have been removed from a furan ring, or two hydrogen atoms have been removed from a pyrazole ring. The compound according to claim 1, which represents a divalent group, a tautomer or stereoisomer thereof, or a salt thereof. 3. The compound according to claim 1, wherein R ₅ is a group represented by the following formula (III) or (IV), a tautomer or stereoisomer thereof, or a salt thereof.

(Wherein, R ₈ represents a hydrogen atom, a C _1-8 alkyl group which may have a substituent or a C _1-8 alkylcarbonyl group which may have a substituent,
R ₉ has a hydrogen atom, a 3- to 14-membered alicyclic group which may have a substituent, a 3- to 14-membered heterocyclic group which may have a substituent, and a substituent An optionally substituted 6-14 membered aryl group, an optionally substituted 5-14 membered heteroaryl group, or an optionally substituted C _1-8 alkyl group, and *** represents a bond to an adjacent carbon atom. ) The compound according to any one of claims 1 to 3, which is a compound represented by any of the following formulas (V) to (IX) or a salt thereof, a tautomer or stereoisomer thereof, or a compound thereof. Salt.

(In the formula, R ₅ , D, and E are as described in any one of claims 1 to 3.) The compound according to claim 1, wherein D is a single bond or a linear C _1-6 alkylene group, a tautomer or stereoisomer thereof, or a salt thereof. The following formula (X) in the general formula (I):

(Wherein **** represents a bond to an adjacent pyridine ring, and **** represents a bond to an adjacent C 炭素 O carbon atom)
The compound according to any one of claims 1 to 5, wherein the partial structure represented by is a structure selected from the group consisting of the following, a tautomer or stereoisomer thereof, or a salt thereof.

The following formula (XI) in the general formula (I):

(In the formula, **** represents a bonding site to an adjacent nitrogen atom.)
The compound according to any one of claims 1 to 6, wherein the partial structure represented by is a structure selected from the group consisting of the following, a tautomer or stereoisomer thereof, or a salt thereof.

The compound according to claim 1, which is a compound selected from the group consisting of or a salt thereof, a tautomer or stereoisomer thereof, or a salt thereof:
4-amino-5- [5- (L-cyclohexylglycylamino) -pentanoylamino] -nicotinic acid 4-amino-5-[[3-[[(2S) -2-amino-2-cyclohexyl-acetyl] ] Amino] -3-methyl-butanoyl] amino] pyridine-3-carboxylic acid 4-amino-5-[[3-[(2-cyclohexylacetyl) amino] -3-methyl-butanoyl] amino] pyridine-3- Carboxylic acid 4-amino-5- [5-[[[(2S) -2-amino-2-cyclohexyl-acetyl] amino] methyl] -2-furyl] pyridine-3-carboxylic acid 4-amino-5- [ (E) -4-[[(2S) -2-amino-2-cyclohexyl-acetyl] amino] but-1-enyl] pyridine-3-carboxylic acid 4-amino-5- [4-[[(2S) − 2-Amino-2-cyclohexyl-acetyl] amino] butyl] pyridine-3-carboxylic acid 4-amino-5-[[3-[[(2S) -2-[[(2S) -2-amino-3- Methyl-pentanoyl] amino] -2-cyclohexyl-acetyl] amino] -3-methyl-butanoyl] amino] pyridine-3-carboxylic acid 4-amino-5-[[(3R) -3-[[(2S)- 2-amino-2-cyclohexyl-acetyl] amino] -3-phenyl-propanoyl] amino] pyridine-3-carboxylic acid 4-amino-5- [5-[(2-cyclohexylacetyl) amino] pentanoylamino] pyridine -3-Carboxylic acid 4-amino-5-[[3-[[(2S, 3S) -2-amino-3-methyl-pentanoyl] amino] -3-methyl-butanoyl] amino] pyridine-3-carbo 4-Amino-5-[[3-[[(2S) -2-[[(2S) -2-amino-2-cyclohexyl-acetyl] amino] -2-cyclohexyl-acetyl] amino] -3-methyl acid -Butanoyl] amino] pyridine-3-carboxylic acid 4-amino-5-[[3-[[(2S) -2-[(2-aminoacetyl) amino] -2-cyclohexyl-acetyl] amino] -3- Methyl-butanoyl] amino] pyridine-3-carboxylic acid 4-amino-5-[[3-[[(2S) -2-amino-3-methyl-butanoyl] amino] -2-cyclohexyl-acetyl] amino]- 3-Methyl-butanoyl] amino] pyridine-3-carboxylic acid 4-amino-5-[[3-[[(2S) -2-[[(2S) -2-amino-4-methyl-pentanoyl] amino] -2-cyclohexyl-acetyl] amino] -3-methyl-butanoyl] amino] pi Gin-3-carboxylic acid 4-amino-5- [5-[[[(2S) -2-amino-3-methyl-butanoyl] amino] methyl] -2-furyl] pyridine-3-carboxylic acid 4-amino -5- [5-[[[(2S) -2-amino-4-methyl-pentanoyl] amino] methyl] -2-furyl] pyridine-3-carboxylic acid. The compound according to claim 1, which is a compound selected from the group consisting of the following or a salt thereof, a tautomer or stereoisomer thereof, or a salt thereof.

  The salt is hydrochloride, sulfate, phosphate, nitrate, hydrobromide, acetate, trifluoroacetate, citrate, benzoate, maleate, fumarate, tartrate, succinate Acid salt, tannate, butyrate, hibenzate, pamoate, enanthate, decanoate, teocrate, salicylate, lactate, oxalate, mandelate, malate, methanesulfone Acid salt, benzenesulfonate, p-toluenesulfonate, glutamate, aspartate, sodium salt, potassium salt, magnesium salt, calcium salt, lysine salt, ornithine salt, arginine salt and histidine salt 10. A salt of the compound according to any one of claims 1 to 9, a tautomer or a stereoisomer thereof.   A food composition comprising the compound according to any one of claims 1 to 10, a tautomer or stereoisomer thereof, or a salt thereof.   A taste improver comprising the compound according to any one of claims 1 to 10, a tautomer or stereoisomer thereof, or a salt thereof.   A method for producing a food or drink, comprising a step of adding the compound according to any one of claims 1 to 10, a tautomer or stereoisomer thereof, or a salt thereof to a food or drink raw material.   A method for enhancing the sweetness of a food or drink, comprising a step of adding the compound according to any one of claims 1 to 10, a tautomer or stereoisomer thereof, or a salt thereof to a food or drink raw material or a food or drink. .