RU2780491C2 - Double-headed protease inhibitor - Google Patents

Abstract

FIELD: pharmaceutics.

SUBSTANCE: group of inventions relates to inhibitors of enteropeptidase and/or trypsin. A compound or its pharmaceutically acceptable salt is claimed, having the following general formula (I):

, where: A¹ and A², each independently, are a residue of an inhibitor having at least one type of activity selected from enteropeptidase-inhibiting activity and trypsin-inhibiting activity; Z is a bridge, which connects A¹ to A², and which is a simple bond, C₆-C₁₂ arylene group, -(CH₂-CH₂-O)_m-CH₂-CH₂-, -(CH₂-O-CH₂)_m-, -(CH₂)_m-(C₆-C₁₂arylene)-(CH₂)_m-, or -(CH₂)_n-; m is an integer from 1 to 6; and n is an integer from 2 to 12; A¹ and A² have certain structures. A pharmaceutical composition for inhibition of enteropeptidase and/or inhibition of trypsin is also disclosed.

EFFECT: group of inventions provides for the expansion of the arsenal of means of a specific purpose.

25 cl, 23 tbl, 37 ex

Description

The field of technology to which the invention belongs

The present invention relates to new biceps compounds having protease-inhibiting activity that can be used as medicines and pharmaceutical compositions containing them, in particular new compounds and pharmaceutical compositions containing them, intended for the prevention, mitigation and/or treatment of diseases, the symptoms of which become less pronounced with inhibition of enteropeptidase and/or inhibition of trypsin, as well as methods for obtaining such compounds.

Prior Art

Dietary proteins are broken down by digestive enzymes and eventually converted into amino acids or peptides that are absorbed by the body. Trypsin is the main protease. Enteropeptidase is a serine protease that is secreted by mucosal cells in the duodenum and converts trypsinogen secreted by the pancreas from food proteins into trypsin. Trypsin is also known to act on protease precursors such as chymotrypsinogen, procarboxypeptidase, proelastase, and procolipase, activating various enzymes. Accordingly, it is believed that a compound that inhibits enteropeptidase and/or trypsin will result in inhibition of protein breakdown and absorption, inhibition of lipid absorption, and reduction of sugar digestion capacity, and thus can be used as an anti-obesity therapeutic drug and as an anti-diabetic drug. funds.

Patent Document 1 discloses that compounds that inhibit both enteropeptidase and trypsin have an anti-obesity effect. Patent Document 2 discloses that compounds which have an inhibitory effect on enteropeptidase, trypsin, plasmin, kallikrein, and the like have an anti-obesity effect. Patent Document 3 discloses that administration of enteropeptidase inhibitors has an anti-obesity effect and improves type 2 diabetes. As a compound having trypsin-inhibiting activity and suitable for use in the prevention, alleviation and/or treatment of pancreatitis and reflux esophagitis, Patent Document 4 discloses camostat mesylate having the following formula, which is clinically used in the treatment of chronic pancreatitis and reflux esophagitis.

As compounds having trypsin-inhibiting activity and suitable for use in the prevention, mitigation and/or treatment of kidney diseases and diseases involving trypsin, Patent Documents 5 and 6 disclose guanidinobenzoic acid compounds, but they do not disclose two-headed compounds according to the present invention. As compounds having enteropeptidase inhibitory activity and suitable for use in the prevention, alleviation and/or treatment of obesity and diseases caused by impaired fat metabolism, Patent Document 2 discloses boron-containing peptides, but does not disclose the two-headed compounds of the present invention. As compounds having serine protease inhibitory activity, especially enteropeptidase inhibitory activity and trypsin inhibitory activity, and suitable for use in the prevention, mitigation and/or treatment of obesity, diabetes, and the like, Patent Documents 7-9 disclose ester derivatives of heteroarylcarboxylic acid, but they do not disclose the two-headed compounds of the present invention. As compounds having enteropeptidase inhibitory activity and suitable for use in the prevention, mitigation and/or treatment of obesity, diabetes and the like, Patent Documents 3 and 10-12 disclose heterocyclic compounds, but they do not disclose biceps compounds according to the present invention.

List of cited literature

Patent Documents

Patent document 1: WO 2006/050999 abstract

Patent document 2: WO 2009/071601 abstract

Patent document 3: WO 2015/122187 abstract

Patent Document 4: JP S52-089640 A

Patent document 5: WO 2013/039187 abstract

Patent document 6: WO 2014/142219 abstract

Patent document 7: WO 2011/071048 abstract

Patent document 8: WO 2012/169579 abstract

Patent document 9: WO 2013/187533 abstract

Patent document 10: WO 2015/122188 abstract

Patent document 11: WO 2016/104630 abstract

Patent document 12: WO 2016/158788 abstract

Brief description of the invention

Problems to be solved by the invention

The present invention relates to novel biceps compounds useful in the prevention, amelioration and/or treatment of diseases ameliorated by enteropeptidase inhibition and/or trypsin inhibition, pharmaceutical compositions with such compounds, and processes for their preparation.

Ways to solve the tasks

The inventors of the present invention conscientiously investigated compounds having enteropeptidase inhibitory activity and/or trypsin inhibitory activity, and showed that after oral administration, there is a very small amount of them in the blood. As a result, the present inventors have found that biceps compounds or pharmaceutically acceptable salts thereof, in which two inhibitor molecules having at least one activity selected from an enteropeptidase inhibitory activity and a trypsin inhibitory activity, are connected by a single bond or a suitable bridge, have excellent enteropeptidase-inhibiting activity and/or trypsin-inhibiting activity, actively inhibit enteropeptidase and/or trypsin in the intestine after oral administration, are contained in the blood in very small amounts, and can be used to prevent, alleviate and/or treat diseases whose symptoms become less pronounced with enteropeptidase inhibition and/or trypsin inhibition, especially for the prevention, mitigation and/or treatment of obesity, which ultimately led to the present invention.

In the present invention, the following items [1]-[29] are described.

[1] A compound having the following general formula (I):

where:

A ¹ and A ² are each independently an inhibitor residue having at least one activity selected from an enteropeptidase inhibitory activity and a trypsin inhibitory activity; and

Z is the bridge that connects A ¹ to A ² ]

or a pharmaceutically acceptable salt thereof.

[2] The compound of [1] or a pharmaceutically acceptable salt thereof, wherein

A ¹ and A ² are each independently an inhibitor residue obtained by removing any hydrogen atom or any hydroxy group from an inhibitor molecule selected from the following group of inhibitor molecules:

or an inhibitor molecule having the following general formula (II)

where:

Ring B and Ring C are each independently an aryl group or a heteroaryl group;

R ¹ each independently represents a hydrogen atom or -COO-(C ₁ -C ₄ alkyl group);

W represents a single bond or a C ₁ -C ₄ alkylene group;

X is -C(=O)-, -OC(=O)- or -NG-SO ₂ -;

G represents a hydrogen atom, a C ₁ -C ₄ alkyl group, or —COOR ² ;

R ² is a C ₁ -C ₄ alkyl group optionally substituted with 1-5 aryl groups;

Y is -NG ² G ⁴ , -NG ² -L ¹ -COOH, -NG ² -L ¹ -C(=O)-NH ₂ , -NG ² -L ¹ -C(=O)-NG ³ - L ² -COOH, -NG ² -L ¹ -C(=O)-NG ³ -L ² -C(=O)-NG ³ -L ² -COOH, -NG ² -L ¹ -C(=O) -NG ³ -L ² -C(=O)-NH ₂ , -NG ² -L ³ -OH or -NG ² -(CH ₂ -CH ₂ -O) _q -CH ₂ -CH ₂ -COOH;

q is an integer from 1 to 6;

G ² and G ³ are each independently a hydrogen atom or a C ₁ -C ₆ alkyl group optionally substituted with 1-5 substituents independently selected from the group consisting of a phenyl group optionally substituted with 1-5 -COOR ³ groups, and -COOR ³ groups;

G ⁴ represents a hydrogen atom, a C ₁ -C ₄ alkyl group or a C ₁ -C ₄ alkoxy-C ₁ -C ₄ alkyl group;

R ³ each independently represents a hydrogen atom or a C ₁ -C ₄ alkyl group optionally substituted with 1-5 aryl groups;

L ¹ and L ² are each independently a C ₁ -C ₆ alkylene group optionally substituted with 1-5 C ₁ -C ₆ alkyl groups optionally substituted with 1-5 -COOR ⁴ groups, a C ₁ -C ₆ alkylene group substituted with C a ₇ -C ₁₂ aralkyl group optionally substituted with 1-5 substituents independently selected from the group consisting of a hydroxy group and a carboxyl group, a C ₁ -C ₄ alkylene-phenylene group, or a phenylene-C ₁ -C ₄ alkylene group;

L ³ represents a C ₁ -C ₄ alkylene-phenylene group, where the phenylene fragment is optionally substituted with 1-3 -COOR ⁴ groups;

R ⁴ each independently represents a hydrogen atom or a C ₁ -C ₄ alkyl group optionally substituted with 1-5 substituents independently selected from the group consisting of an aryl group and a trimethylsilyl group;

R ⁵ and R ⁶ are each independently a hydrogen atom, a halogen atom, a C ₁ -C ₄ alkyl group, a C ₁ -C ₄ alkoxy group, a carboxyl group, or -C(=O)-NG ² G ⁴ ;

s and t are each independently an integer from 1 to 4;

two or more R ⁵ and/or two or more R ⁶ may be the same or different from each other;

or any of R ⁵ and any of R ⁶ may be combined with each other to form a C ₁ -C ₄ alkyleneoxy group; and

Z represents a single bond, an arylene group, a heteroarylene group, or a C ₂ -C ₃₀ alkylene group (provided that one or more methylene groups in the chain of said alkylene group may be replaced by a group(s) independently selected from a group consisting of -C(=O)-, -NR ⁷ -, -O-, -SiR ⁸ R ⁹ -, -SO _r -, an arylene group and a heteroarylene group, R ⁷ represents a hydrogen atom or C ₁ -C ₄ alkyl group, R ⁸ and R ⁹ are each independently a C ₁ -C ₄ alkyl group, and r is an integer from 0 to 2).

[3] The compound of [2] or a pharmaceutically acceptable salt thereof, wherein

A ¹ and A ² are each independently an inhibitor residue obtained by removing any hydrogen atom or any hydroxy group from an inhibitor molecule having the general formula (II).

[4] The connection according to any one of paragraphs. [2]-[3] or a pharmaceutically acceptable salt thereof, wherein

A ¹ has the structure represented by the formula

or

,

,

A ² has the structure represented by the formula

or

,

,

where:

ring B ¹ , ring B ² , ring C ¹ and ring C ² are each independently an aryl group;

R ¹ each independently represents a hydrogen atom or -COO-(C ₁ -C ₄ alkyl group);

W ¹ and W ² are each independently a single bond or a C ₁ -C ₄ alkylene group;

X ¹ is -C(=O)-, -OC(=O)- or -NG ¹¹ -SO ₂ -;

X ^1' is -NG ^Z -SO ₂ -;

X ² is -C(=O)-, -C(=O)-O- or -SO ₂ -NG ¹² -;

X ^2' is -SO ₂ -NG ^Z -;

G ¹¹ and G ¹² are each independently a hydrogen atom, a C ₁ -C ₄ alkyl group, or —COOR ² ;

G ^Z is a single bond that connects X ^1' or X ^2' to Z;

R ² is a C ₁ -C ₄ alkyl group optionally substituted with 1-5 aryl groups;

Y ¹ is -NG ²¹ -, -NG ²¹ -L ¹¹ -C(=O)-, -NG ²¹ -L ¹¹ -C(=O)-NH-, -NG ²¹ -L ¹¹ -C(=O )-NG ³¹ -L ²¹ -C(=O)-, -NG ²¹ -L ¹¹ -C(=O)-NG ³¹ -L ²¹ -C(=O)-NH-, -NG ²¹ -L ³ - O- or -NG ²¹ -G ^4' -;

Y ^1' is -NG ²¹ H, -NG ²¹ -L ¹¹ -COOH or -NG ²¹ -L ¹¹ -C(=O)-NG ³¹ -L ²¹ -COOH;

Y ² is -NG ²² -, -C(=O)-L ¹² -NG ²² -, -NH-C(=O) -L ¹² -NG ²² -, -C(=O) -L ²² -NG ³² -C(=O)-L ¹² -NG ²² -, -NH-C(=O)-L ²² -NG ³² -C(=O)-L ¹² -NG ²² -, -OL ³ -NG ²² - or -G ^4' -NG ²² -;

Y ^2' is HNG ²² -, HOOC-L ¹² -NG ²² - or HOOC-L ²² -NG ³² -C(=O) -L ¹² -NG ²² -;

G ²¹ , G ³¹ , G ²² and G ³² are each independently a hydrogen atom or a C ₁ -C ₆ alkyl group optionally substituted with 1-5 substituents independently selected from the group consisting of a phenyl group optionally substituted with 1-5 -COOR ³ groups, and -COOR ³ groups;

G ^4' represents a C ₁ -C ₄ alkylene group or a C ₁ -C ₄ alkyleneoxy-C ₁ -C ₄ alkylene group;

R ³ each independently represents a hydrogen atom or a C ₁ -C ₄ alkyl group optionally substituted with 1-5 aryl groups;

L ¹¹ , L ²¹ , L ¹² and L ²² are each independently a C ₁ -C ₆ alkylene group optionally substituted with 1-5 C ₁ -C ₆ alkyl groups optionally substituted with 1-5 -COOR ⁴ groups, C ₁ -C ₄ alkylene-phenylene group or phenylene-C ₁ -C ₄ alkylene group;

L ³ represents a C ₁ -C ₄ alkylene-phenylene group, where the phenylene fragment is optionally substituted with 1-3 -COOR ⁴ groups;

R ⁴ each independently represents a hydrogen atom or a C ₁ -C ₄ alkyl group optionally substituted with 1-5 substituents independently selected from the group consisting of an aryl group and a trimethylsilyl group;

R ⁵ and R ⁶ are each independently a hydrogen atom, a halogen atom, a C ₁ -C ₄ alkyl group, or a C ₁ -C ₄ alkoxy group;

s and t are each independently an integer from 1 to 4;

two or more R ⁵ and/or two or more R ⁶ may be the same or different from each other;

or any of R ⁵ and any of R ⁶ may be combined with each other to form a C ₁ -C ₄ alkyleneoxy group; and

означает точку присоединения к Z; иsymbol

means the point of attachment to Z; and

Z represents a single bond, an arylene group, a heteroarylene group, or a C ₂ -C ₃₀ alkylene group (provided that one or more methylene groups in the chain of said alkylene group may be replaced by a group(s) independently selected from a group consisting of -C(=O)-, -NR ⁷ -, -O-, an arylene group and a heteroarylene group, and R ⁷ is a hydrogen atom or a C ₁ -C ₄ alkyl group).

[5] A compound according to [4] or a pharmaceutically acceptable salt thereof, wherein

A ¹ has the structure represented by the formula

or

,

,

A ² has the structure represented by the formula

or

,

,

Z represents a single bond, C ₆ -C ₁₂ arylene group, -(CH ₂ -CH ₂ -O) _m -CH ₂ -CH ₂ -, -(CH ₂ -O-CH ₂ ) _m -, -(CH ₂ ) _m -(C ₆ -C ₁₂ arylene)-(CH ₂ ) _m - or -(CH ₂ ) _n -;

m is an integer from 1 to 6; and

n is an integer from 2 to 12.

[6] The connection according to any one of paragraphs. [4]-[5] or a pharmaceutically acceptable salt thereof, wherein

A ¹ has the structure represented by the formula

or

, и

, and

A ² has the structure represented by the formula

or

.

.

[7] The connection according to any one of paragraphs. [4]-[6] or a pharmaceutically acceptable salt thereof, wherein

A ¹ has the structure represented by the formula

,

,

and

A ² has the structure represented by the formula

.

.

[8] The connection according to any one of paragraphs. [4]-[7] having the following general formula (III):

or the general formula (IV) shown below:

or a pharmaceutically acceptable salt thereof.

[9] The compound according to [8] or a pharmaceutically acceptable salt thereof, wherein

R ¹ each independently represents a hydrogen atom or a tert-butoxycarbonyl group;

W ¹ and W ² are each independently a single bond or a C ₁ -C ₄ alkylene group;

X ¹ is -C(=O)-, -OC(=O)- or -NG ¹¹ -SO ₂ -;

X ^1' is -NG ^Z -SO ₂ -;

X ² is -C(=O)-, -C(=O)-O- or -SO ₂ -NG ¹² -;

X ^2' is -SO ₂ -NG ^Z -;

G ¹¹ and G ¹² are each independently a hydrogen atom, a C ₁ -C ₄ alkyl group, or —COOR ² ;

G ^Z is a single bond that connects X ^1' or X ^2' to Z;

R ² is a C ₁ -C ₄ alkyl group optionally substituted with 1-5 aryl groups;

Y ¹ is -NG ²¹ -, -NG ²¹ -L ¹¹ -C(=O)-, -NG ²¹ -L ¹¹ -C(=O)-NH-, -NG ²¹ -L ¹¹ -C(=O )-NG ³¹ -L ²¹ -C(=O)-, -NG ²¹ -L ¹¹ -C(=O)-NG ³¹ -L ²¹ -C(=O)-NH-, -NG ²¹ -L ³ - O- or -NG ²¹ -G ^4' -;

Y ^1' is -NG ²¹ H, -NG ²¹ -L ¹¹ -COOH or -NG ²¹ -L ¹¹ -C(=O)-NG ³¹ -L ²¹ -COOH;

Y ² is -NG ²² -, -C(=O)-L ¹² -NG ²² -, -NH-C(=O) -L ¹² -NG ²² -, -C(=O) -L ²² -NG ³² -C(=O)-L ¹² -NG ²² -, -NH-C(=O)-L ²² -NG ³² -C(=O)-L ¹² -NG ²² -, -OL ³ -NG ²² - or -G ^4' -NG ²² -;

Y ^2' is HNG ²² -, HOOC-L ¹² -NG ²² - or HOOC-L ²² -NG ³² -C(=O) -L ¹² -NG ²² -;

G ²¹ , G ³¹ , G ²² and G ³² are each independently a hydrogen atom or a C ₁ -C ₆ alkyl group optionally substituted with 1-5 substituents independently selected from the group consisting of a phenyl group optionally substituted with 1-5 -COOR ³ groups, and -COOR ³ groups;

G ^4' represents a C ₁ -C ₄ alkylene group or a C ₁ -C ₄ alkyleneoxy-C ₁ -C ₄ alkylene group;

R ³ each independently represents a hydrogen atom, a benzyl group or a tert-butyl group;

L ¹¹ , L ²¹ , L ¹² and L ²² are each independently a C ₁ -C ₆ alkylene group optionally substituted with 1-5 C ₁ -C ₆ alkyl groups optionally substituted with 1-5 -COOR ⁴ groups, C ₁ -C ₄ alkylene-phenylene group or phenylene-C ₁ -C ₄ alkylene group;

L ³ represents a C ₁ -C ₄ alkylene-phenylene group, where the phenylene fragment is optionally substituted with 1-3 -COOR ⁴ groups;

R ⁴ each independently represents a hydrogen atom, a benzyl group, a 2-(trimethylsilyl)ethyl group, or a tert-butyl group;

R ⁵ and R ⁶ are each independently a hydrogen atom, a halogen atom, a C ₁ -C ₄ alkyl group, or a C ₁ -C ₄ alkoxy group;

all R ⁵ may be the same or different from each other;

Z represents a single bond, C ₆ -C ₁₂ arylene group, -(CH ₂ -CH ₂ -O) _m -CH ₂ -CH ₂ -, -(CH ₂ -O-CH ₂ ) _m -, -(CH ₂ ) _m -(C ₆ -C ₁₂ arylene)-(CH ₂ ) _m - or -(CH ₂ ) _n -;

m is an integer from 1 to 6; and

n is an integer from 2 to 12.

[10] The compound according to [9] or a pharmaceutically acceptable salt thereof, wherein

R ¹ each independently represents a hydrogen atom or a tert-butoxycarbonyl group;

W ¹ and W ² are each independently a single bond or a C ₁ -C ₄ alkylene group;

X ¹ is -C(=O)-, -OC(=O)- or -NG ¹¹ -SO ₂ -;

X ^1' is -NG ^Z -SO ₂ -;

X ² is -C(=O)-, -C(=O)-O- or -SO ₂ -NG ¹² -;

X ^2' is -SO ₂ -NG ^Z -;

G ¹¹ and G ¹² are each independently a hydrogen atom, a C ₁ -C ₄ alkyl group, or —COOR ² ;

G ^Z is a single bond that connects X ^1' or X ^2' to Z;

R ² is a C ₁ -C ₄ alkyl group optionally substituted with 1-3 aryl groups;

Y ¹ is -NG ²¹ -, -NG ²¹ -L ¹¹ -C(=O)-, -NG ²¹ -L ¹¹ -C(=O)-NH-, -NG ²¹ -L ¹¹ -C(=O )-NG ³¹ -L ²¹ -C(=O)-, -NG ²¹ -L ¹¹ -C(=O)-NG ³¹ -L ²¹ -C(=O)-NH- or -NG ²¹ -L ³ - O-;

Y ^1' is -NG ²¹ H, -NG ²¹ -L ¹¹ -COOH or -NG ²¹ -L ¹¹ -C(=O)-NG ³¹ -L ²¹ -COOH;

Y ² is -NG ²² -, -C(=O)-L ¹² -NG ²² -, -NH-C(=O) -L ¹² -NG ²² -, -C(=O) -L ²² -NG ³² -C(=O)-L ¹² -NG ²² -, -NH-C(=O)-L ²² -NG ³² -C(=O)-L ¹² -NG ²² - or -OL ³ -NG ²² - ;

Y ^2' is HNG ²² -, HOOC-L ¹² -NG ²² - or HOOC-L ²² -NG ³² -C(=O) -L ¹² -NG ²² -;

G ²¹ , G ³¹ , G ²² and G ³² are each independently a hydrogen atom or a C ₁ -C ₆ alkyl group optionally substituted with 1-3 substituents independently selected from the group consisting of a phenyl group optionally substituted with 1-3 -COOR ³ groups, and -COOR ³ groups;

R ³ each independently represents a hydrogen atom, a benzyl group or a tert-butyl group;

L ¹¹ , L ²¹ , L ¹² and L ²² are each independently a C ₁ -C ₆ alkylene group optionally substituted with 1-5 C ₁ -C ₆ alkyl groups optionally substituted with 1-5 -COOR ⁴ groups, C ₁ -C ₄ alkylene-phenylene group or phenylene-C ₁ -C ₄ alkylene group;

L ³ represents a C ₁ -C ₂ alkylene-phenylene group, where the phenylene fragment is optionally substituted with 1-2 -COOR ⁴ groups;

R ⁴ each independently represents a hydrogen atom, a benzyl group, a 2-(trimethylsilyl)ethyl group, or a tert-butyl group;

R ⁵ and R ⁶ are each independently a hydrogen atom, a halogen atom, a C ₁ -C ₄ alkyl group, or a C ₁ -C ₄ alkoxy group;

all R ⁵ may be the same or different from each other;

Z is a single bond, a biphenylene group, -(CH ₂ -CH ₂ -O) _m -CH ₂ -CH ₂ -, -(CH ₂ -O-CH ₂ ) _m -, -(CH ₂ ) _m -biphenylene- (CH ₂ ) _m - or -(CH ₂ ) _n -;

m is an integer from 1 to 6; and

n is an integer from 2 to 12.

[11] The compound according to [10] or a pharmaceutically acceptable salt thereof, wherein

R ¹ each represents a hydrogen atom;

W ¹ and W ² are each independently a single bond or a C ₁ -C ₄ alkylene group;

X ¹ is -C(=O)- or -NG ¹¹ -SO ₂ -;

X ^1' is -NG ^Z -SO ₂ -;

X ² represents -C(=O)- or -SO ₂ -NG ¹² -;

X ^2' is -SO ₂ -NG ^Z -;

G ¹¹ and G ¹² are each independently a hydrogen atom or —COOR ² ;

G ^Z is a single bond that connects X ^1' or X ^2' to Z;

R ² is a C ₁ -C ₄ alkyl group optionally substituted with one phenyl group;

Y ¹ is -NG ²¹ -;

Y ^1' is -NG ²¹ H;

Y ² is -NG ²² -;

Y ^2' is HNG ²² -;

G ²¹ and G ²² are each independently a hydrogen atom or a C ₁ -C ₃ alkyl group substituted with 1-3 carboxyl groups;

R ⁵ and R ⁶ are each independently a hydrogen atom, a fluorine atom, a methyl group, or a methoxy group;

all R ⁵ may be the same or different from each other;

Z is a single bond, [1,1'-biphenyl]-3,3'-diyl, -(CH ₂ -CH ₂ -O) _m -CH ₂ -CH ₂ -, -(CH ₂ -O-CH ₂ ) _m -, -(CH ₂ ) _m -([1,1'-biphenyl]-3,3'-diyl)-(CH ₂ ) _m - or -(CH ₂ ) _n -;

m is an integer from 1 to 6; and

n is an integer from 2 to 12.

[12] The connection according to any one of paragraphs. [4]-[7] having the following general formula (V):

where:

R ¹ each independently represents a hydrogen atom or -COO-(C ₁ -C ₄ alkyl group);

W ¹ and W ² are each independently a single bond or a C ₁ -C ₄ alkylene group;

X ¹ is -C(=O)- or -NG ¹¹ -SO ₂ -;

X ² represents -C(=O)- or -SO ₂ -NG ¹² -;

G ¹¹ and G ¹² are each independently a hydrogen atom, a C ₁ -C ₄ alkyl group, or —COOR ² ;

R ² is a C ₁ -C ₄ alkyl group optionally substituted with 1-5 aryl groups;

Y ¹ is -NG ²¹ -, -NG ²¹ -L ¹¹ -C(=O)-, -NG ²¹ -L ¹¹ -C(=O)-NH-, -NG ²¹ -L ¹¹ -C(=O )-NG ³¹ -L ²¹ -C(=O)-, -NG ²¹ -L ¹¹ -C(=O)-NG ³¹ -L ²¹ -C(=O)-NH-, -NG ²¹ -L ³ - O- or -NG ²¹ -G ^4' -;

Y ² is -NG ²² -, -C(=O)-L ¹² -NG ²² -, -NH-C(=O) -L ¹² -NG ²² -, -C(=O) -L ²² -NG ³² -C(=O)-L ¹² -NG ²² -, -NH-C(=O)-L ²² -NG ³² -C(=O)-L ¹² -NG ²² -, -OL ³ -NG ²² - or -G ^4' -NG ²² -;

G ²¹ , G ³¹ , G ²² and G ³² are each independently a hydrogen atom or a C ₁ -C ₆ alkyl group optionally substituted with 1-5 substituents independently selected from the group consisting of a phenyl group optionally substituted with 1-5 -COOR ³ groups, and -COOR ³ groups;

G ^4' represents a C ₁ -C ₄ alkylene group or a C ₁ -C ₄ alkyleneoxy-C ₁ -C ₄ alkylene group;

R ³ each independently represents a hydrogen atom or a C ₁ -C ₄ alkyl group optionally substituted with 1-5 aryl groups;

L ¹¹ , L ²¹ , L ¹² and L ²² are each independently a C ₁ -C ₆ alkylene group optionally substituted with 1-5 C ₁ -C ₆ alkyl groups optionally substituted with 1-5 -COOR ⁴ groups, C ₁ -C ₄ alkylene-phenylene group or phenylene-C ₁ -C ₄ alkylene group;

L ³ represents a C ₁ -C ₄ alkylene-phenylene group, where the phenylene fragment is optionally substituted with 1-3 -COOR ⁴ groups;

R ⁴ each independently represents a hydrogen atom or a C ₁ -C ₄ alkyl group optionally substituted with 1-5 substituents independently selected from the group consisting of an aryl group and a trimethylsilyl group;

R ⁵ each independently represents a hydrogen atom, a halogen atom, a C ₁ -C ₄ alkyl group, or a C ₁ -C ₄ alkoxy group;

Z represents a single bond, C ₆ -C ₁₂ arylene group, -(CH ₂ -CH ₂ -O) _m -CH ₂ -CH ₂ -, -(CH ₂ -O-CH ₂ ) _m -, -(CH ₂ ) _m -(C ₆ -C ₁₂ arylene)-(CH ₂ ) _m - or -(CH ₂ ) _n -;

m is an integer from 1 to 6; and

n is an integer from 2 to 12;

or a pharmaceutically acceptable salt thereof.

[13] The compound of [12] having the general formula (VI) shown below:

or a pharmaceutically acceptable salt thereof.

[14] The compound according to [13] or a pharmaceutically acceptable salt thereof, wherein

R ¹ each independently represents a hydrogen atom or a tert-butoxycarbonyl group;

W ¹ and W ² are each independently a single bond or a C ₁ -C ₂ alkylene group;

X ¹ is -C(=O)- or -NG ¹¹ -SO ₂ -;

X ² represents -C(=O)- or -SO ₂ -NG ¹² -;

G ¹¹ and G ¹² each represents a hydrogen atom;

Y ¹ is -NG ²¹ -, -NG ²¹ -L ¹¹ -C(=O)-, -NG ²¹ -L ¹¹ -C(=O)-NH-, -NG ²¹ -L ¹¹ -C(=O )-NG ³¹ -L ²¹ -C(=O)-, -NG ²¹ -L ¹¹ -C(=O)-NG ³¹ -L ²¹ -C(=O)-NH-, -NG ²¹ -L ³ - O- or -NG ²¹ -G ^4' -;

Y ² is -NG ²² -, -C(=O)-L ¹² -NG ²² -, -NH-C(=O) -L ¹² -NG ²² -, -C(=O) -L ²² -NG ³² -C(=O)-L ¹² -NG ²² -, -NH-C(=O)-L ²² -NG ³² -C(=O)-L ¹² -NG ²² -, -OL ³ -NG ²² - or -G ^4' -NG ²² -;

G ²¹ , G ³¹ , G ²² and G ³² are each independently a hydrogen atom or a C ₁ -C ₃ alkyl group optionally substituted with 1-3 -COOR ³ groups;

G ^4' represents a C ₁ -C ₂ alkylene group or a C ₁ -C ₂ alkyleneoxy-C ₁ -C ₂ alkylene group;

R ³ each independently represents a hydrogen atom or a tert-butyl group;

L ¹¹ , L ²¹ , L ¹² and L ²² are each independently a C ₁ -C ₂ alkylene group;

L ³ represents a C ₁ -C ₄ alkylene-phenylene group, where the phenylene fragment is optionally substituted with 1-3 -COOR ⁴ groups;

R ⁴ each independently represents a hydrogen atom or a C ₁ -C ₄ alkyl group optionally substituted with 1-5 substituents independently selected from the group consisting of an aryl group and a trimethylsilyl group;

R ⁵ each independently represents a hydrogen atom, a halogen atom, a C ₁ -C ₄ alkyl group, or a C ₁ -C ₄ alkoxy group;

Z is a single bond, a biphenylene group, -(CH ₂ -CH ₂ -O) _m -CH ₂ -CH ₂ -, -(CH ₂ -O-CH ₂ ) _m -, -(CH ₂ ) _m -biphenylene- (CH ₂ ) _m - or -(CH ₂ ) _n -;

m is an integer from 1 to 6; and

n is an integer from 2 to 12.

[15] A compound according to [14] or a pharmaceutically acceptable salt thereof, wherein

R ¹ each represents a hydrogen atom;

W ¹ and W ² are each a single bond;

X ¹ represents -C(=O)-;

X ² is -C(=O)-;

Y ¹ is -NG ²¹ -, -NG ²¹ -L ³ -O- or -NG ²¹ -G ^4' -;

Y ² is -NG ²² -, -OL ³ -NG ²² - or -G ^4' -NG ²² -;

G ²¹ and G ²² are each independently a C ₁ -C ₃ alkyl group substituted with 1-3 carboxyl groups;

G ^4' represents a C ₁ -C ₂ alkylene group or a C ₁ -C ₂ alkyleneoxy-C ₁ -C ₂ alkylene group;

L ³ represents a C ₁ -C ₂ alkylene-phenylene group, where the phenylene fragment is optionally substituted with 1-2 -COOR ⁴ groups;

R ⁴ each independently represents a hydrogen atom or a C ₁ -C ₄ alkyl group optionally substituted with 1-5 substituents independently selected from the group consisting of an aryl group and a trimethylsilyl group;

R ⁵ each independently represents a hydrogen atom, a fluorine atom, a methyl group or a methoxy group;

Z is a single bond, [1,1'-biphenyl]-3,3'-diyl, -(CH ₂ -CH ₂ -O) _m -CH ₂ -CH ₂ -, -(CH ₂ -O-CH ₂ ) _m -, -(CH ₂ ) _m -([1,1'-biphenyl]-3,3'-diyl)-(CH ₂ ) _m - or -(CH ₂ ) _n -;

m is an integer from 1 to 6; and

n is an integer from 2 to 12.

[16] The connection according to any one of paragraphs. [1]-[6] or a pharmaceutically acceptable salt thereof, wherein

A ¹ has the structure represented by the formula

,

,

A ² has the structure represented by the formula

,

,

where:

R ¹ each independently represents a hydrogen atom or -COO-(C ₁ -C ₄ alkyl group);

W ¹ and W ² are each independently a single bond or a C ₁ -C ₄ alkylene group;

X ¹ is -C(=O)-, -OC(=O)- or -NG ¹¹ -SO ₂ -;

X ² is -C(=O)-, -C(=O)-O- or -SO ₂ -NG ¹² -;

G ¹¹ and G ¹² are each independently a hydrogen atom or —COOR ² ;

R ² is a C ₁ -C ₄ alkyl group optionally substituted with 1-5 aryl groups;

Y ¹ is -NG ²¹ -, -NG ²¹ -L ¹¹ -C(=O)-NH- or -NG ²¹ -L ¹¹ -C(=O)-NG ³¹ -L ²¹ -C(=O)- NH-;

Y ² is -NG ²² -, -NH-C(=O)-L ¹² -NG ²² - or -NH-C(=O)-L ²² -NG ³² -C(=O)-L ¹² -NG ^22- ;

G ²¹ , G ³¹ , G ²² and G ³² are each independently a hydrogen atom or a C ₁ -C ₆ alkyl group optionally substituted with 1-5 substituents independently selected from the group consisting of a phenyl group optionally substituted with 1-5 -COOR ³ groups, and -COOR ³ groups;

R ³ each independently represents a hydrogen atom or a C ₁ -C ₄ alkyl group optionally substituted with 1-5 aryl groups;

L ¹¹ , L ²¹ , L ¹² and L ²² are each independently a C ₁ -C ₆ alkylene group optionally substituted with 1-5 C ₁ -C ₆ alkyl groups optionally substituted with 1-5 -COOR ⁴ groups, C ₁ -C ₄ alkylene-phenylene group or phenylene-C ₁ -C ₄ alkylene group;

R ⁴ each independently represents a hydrogen atom or a C ₁ -C ₄ alkyl group optionally substituted with 1-5 aryl groups;

R ⁵ and R ⁶ are each independently a hydrogen atom, a C ₁ -C ₄ alkyl group or a C ₁ -C ₄ alkoxy group, or R ⁵ and R ⁶ may be combined with each other to form a C ₁ -C ₄ alkyleneoxy groups; and

symbol

means the point of attachment to Z; and

Z is -(CH ₂ -CH ₂ -O) _m -CH ₂ -CH ₂ - or -(CH ₂ ) _n -;

m is an integer from 1 to 6; and

n is an integer from 2 to 12.

[17] The compound according to [16] or a pharmaceutically acceptable salt thereof, wherein

A ¹ has the structure represented by the formula

,

,

and

A ² has the structure represented by the formula

.

.

[18] The connection according to any one of paragraphs. [1] and [16]-[17], which has the following general formula (VII):

where:

R ¹ each independently represents a hydrogen atom or -COO-(C ₁ -C ₄ alkyl group);

W ¹ and W ² are each independently a single bond or a C ₁ -C ₄ alkylene group;

X ¹ is -OC(=O)- or -NG ¹¹ -SO ₂ -;

X ² is -C(=O)-O- or -SO ₂ -NG ¹² -;

G ¹¹ and G ¹² are each independently a hydrogen atom or —COOR ² ;

R ² is a C ₁ -C ₄ alkyl group optionally substituted with 1-5 aryl groups;

Y ¹ is -NG ²¹ -, -NG ²¹ -L ¹¹ -C(=O)-NH- or -NG ²¹ -L ¹¹ -C(=O)-NG ³¹ -L ²¹ -C(=O)- NH-;

Y ² is -NG ²² -, -NH-C(=O)-L ¹² -NG ²² - or -NH-C(=O)-L ²² -NG ³² -C(=O)-L ¹² -NG ^22- ;

G ²¹ , G ³¹ , G ²² and G ³² are each independently a hydrogen atom or a C ₁ -C ₆ alkyl group optionally substituted with 1-5 substituents independently selected from the group consisting of a phenyl group optionally substituted with 1-5 -COOR ³ groups, and -COOR ³ groups;

R ³ each independently represents a hydrogen atom or a C ₁ -C ₄ alkyl group optionally substituted with 1-5 aryl groups;

L ¹¹ , L ²¹ , L ¹² and L ²² are each independently a C ₁ -C ₆ alkylene group optionally substituted with 1-5 C ₁ -C ₆ alkyl groups optionally substituted with 1-5 -COOR ⁴ groups, C ₁ -C ₄ alkylene-phenylene group or phenylene-C ₁ -C ₄ alkylene group;

R ⁴ each independently represents a hydrogen atom or a C ₁ -C ₄ alkyl group optionally substituted with 1-5 aryl groups;

Z is -(CH ₂ -CH ₂ -O) _m -CH ₂ -CH ₂ - or -(CH ₂ ) _n -;

m is an integer from 1 to 6; and

n is an integer from 2 to 12]

or a pharmaceutically acceptable salt thereof.

[19] The compound according to [18] or a pharmaceutically acceptable salt thereof, wherein

R ¹ each independently represents a hydrogen atom or a tert-butoxycarbonyl group;

W ¹ and W ² each represents a C ₁ -C ₄ alkylene group;

X ¹ is -OC(=O)- or -NG ¹¹ -SO ₂ -;

X ² is -C(=O)-O- or -SO ₂ -NG ¹² -;

G ¹¹ and G ¹² are each independently a hydrogen atom or —COOR ² ;

R ² is a C ₁ -C ₄ alkyl group optionally substituted with 1-3 phenyl groups;

Y ¹ is -NG ²¹ -, -NG ²¹ -L ¹¹ -C(=O)-NH- or -NG ²¹ -L ¹¹ -C(=O)-NG ³¹ -L ²¹ -C(=O)- NH-;

Y ² is -NG ²² -, -NH-C(=O)-L ¹² -NG ²² - or -NH-C(=O)-L ²² -NG ³² -C(=O)-L ¹² -NG ^22- ;

G ²¹ , G ³¹ , G ²² and G ³² are each independently a hydrogen atom or a C ₁ -C ₆ alkyl group optionally substituted with 1-3 substituents independently selected from the group consisting of a phenyl group optionally substituted with 1-3 -COOR ³ groups, and -COOR ³ groups;

R ³ each independently represents a hydrogen atom, a benzyl group or a tert-butyl group;

L ¹¹ , L ²¹ , L ¹² and L ²² are each independently a C ₁ -C ₆ alkylene group optionally substituted with 1-5 C ₁ -C ₆ alkyl groups optionally substituted with 1-5 -COOR ⁴ groups, C ₁ -C ₄ alkylene-phenylene group or phenylene-C ₁ -C ₄ alkylene group;

R ⁴ each independently represents a hydrogen atom, a benzyl group or a tert-butyl group;

Z is -(CH ₂ -CH ₂ -O) _m -CH ₂ -CH ₂ - or -(CH ₂ ) _n -;

m is an integer from 1 to 6; and

n is an integer from 2 to 12.

[20] A compound according to [19] or a pharmaceutically acceptable salt thereof, wherein

R ¹ each independently represents a hydrogen atom or a tert-butoxycarbonyl group;

W ¹ and W ² each represents a C ₁ -C ₂ alkylene group;

X ¹ is -OC(=O)- or -NG ¹¹ -SO ₂ -;

X ² is -C(=O)-O- or -SO ₂ -NG ¹² -;

G ¹¹ and G ¹² are each independently a hydrogen atom or —COOR ² ;

R ² is a C ₁ -C ₄ alkyl group optionally substituted with one phenyl group;

Y ¹ is -NG ²¹ -, -NG ²¹ -L ¹¹ -C(=O)-NH- or -NG ²¹ -L ¹¹ -C(=O)-NG ³¹ -L ²¹ -C(=O)- NH-;

Y ² is -NG ²² -, -NH-C(=O)-L ¹² -NG ²² - or -NH-C(=O)-L ²² -NG ³² -C(=O)-L ¹² -NG ^22- ;

G ²¹ , G ³¹ , G ²² and G ³² are each independently a hydrogen atom or a C ₁ -C ₃ alkyl group optionally substituted with 1-3 substituents independently selected from the group consisting of a phenyl group optionally substituted with one —COOR ³ group , and -COOR ³ groups;

R ³ each independently represents a hydrogen atom or a tert-butyl group;

L ¹¹ , L ²¹ , L ¹² and L ²² are each independently a C ₁ -C ₂ alkylene group optionally substituted with 1-2 C ₁ -C ₂ alkyl groups optionally substituted with 1-2 -COOR ⁴ groups, C ₁ -C ₂ alkylene-phenylene group or phenylene-C ₁ -C ₂ alkylene group;

R ⁴ each independently represents a hydrogen atom or a tert-butyl group;

Z is -(CH ₂ -CH ₂ -O) _m -CH ₂ -CH ₂ - or -(CH ₂ ) _n -;

m is an integer from 1 to 6; and

n is an integer from 2 to 12.

[21] A compound according to [20] or a pharmaceutically acceptable salt thereof, wherein

R ¹ each represents a hydrogen atom;

W ¹ and W ² each represents a C ₁ -C ₂ alkylene group;

X ¹ is -NG ¹¹ -SO ₂ -;

X ² is -SO ₂ -NG ¹² -;

G ¹¹ and G ¹² are each independently a hydrogen atom or —COOR ² ;

R ² is a C ₁ -C ₄ alkyl group optionally substituted with one phenyl group;

Y ¹ is -NG ²¹ -;

Y ² is -NG ²² -;

G ²¹ and G ²² are each independently a C ₁ -C ₃ alkyl group substituted with 1-3 substituents independently selected from the group consisting of a phenyl group substituted with one carboxyl group and a carboxyl group;

Z is -(CH ₂ -CH ₂ -O) _m -CH ₂ -CH ₂ - or -(CH ₂ ) _n -;

m is an integer from 1 to 6; and

n is an integer from 2 to 12.

[22] The connection according to any one of paragraphs. [1] and [16]-[17], having the following general formula (VIII):

where:

R ¹ each independently represents a hydrogen atom or -COO-(C ₁ -C ₄ alkyl group);

W ¹ and W ² are each independently a single bond or a C ₁ -C ₄ alkylene group;

X ¹ is -C(=O)- or -NG ¹¹ -SO ₂ -;

X ² represents -C(=O)- or -SO ₂ -NG ¹² -;

G ¹¹ and G ¹² are each independently a hydrogen atom or —COOR ² ;

R ² is a C ₁ -C ₄ alkyl group optionally substituted with 1-5 aryl groups;

Y ¹ is -NG ²¹ -, -NG ²¹ -L ¹¹ -C(=O)-NH- or -NG ²¹ -L ¹¹ -C(=O)-NG ³¹ -L ²¹ -C(=O)- NH-;

Y ² is -NG ²² -, -NH-C(=O)-L ¹² -NG ²² - or -NH-C(=O)-L ²² -NG ³² -C(=O)-L ¹² -NG ^22- ;

G ²¹ , G ³¹ , G ²² and G ³² are each independently a hydrogen atom or a C ₁ -C ₆ alkyl group optionally substituted with 1-5 substituents independently selected from the group consisting of a phenyl group optionally substituted with 1-5 -COOR ³ groups, and -COOR ³ groups;

R ³ each independently represents a hydrogen atom or a C ₁ -C ₄ alkyl group optionally substituted with 1-5 aryl groups;

L ¹¹ , L ²¹ , L ¹² and L ²² are each independently a C ₁ -C ₆ alkylene group optionally substituted with 1-5 C ₁ -C ₆ alkyl groups optionally substituted with 1-5 -COOR ⁴ groups, C ₁ -C ₄ alkylene-phenylene group or phenylene-C ₁ -C ₄ alkylene group;

R ⁴ each independently represents a hydrogen atom or a C ₁ -C ₄ alkyl group optionally substituted with 1-5 aryl groups;

Z is -(CH ₂ -CH ₂ -O) _m -CH ₂ -CH ₂ - or -(CH ₂ ) _n -;

m is an integer from 1 to 6; and

n is an integer from 2 to 12]

or a pharmaceutically acceptable salt thereof.

[23] A compound according to [22] or a pharmaceutically acceptable salt thereof, wherein

R ¹ each independently represents a hydrogen atom or a tert-butoxycarbonyl group;

W ¹ and W ² are each independently a single bond or a C ₁ -C ₂ alkylene group;

X ¹ is -C(=O)- or -NG ¹¹ -SO ₂ -;

X ² represents -C(=O)- or -SO ₂ -NG ¹² -;

G ¹¹ and G ¹² each represents a hydrogen atom;

Y ¹ is -NG ²¹ -, -NG ²¹ -L ¹¹ -C(=O)-NH- or -NG ²¹ -L ¹¹ -C(=O)-NG ³¹ -L ²¹ -C(=O)- NH-;

Y ² is -NG ²² -, -NH-C(=O)-L ¹² -NG ²² - or -NH-C(=O)-L ²² -NG ³² -C(=O)-L ¹² -NG ^22- ;

G ²¹ , G ³¹ , G ²² and G ³² are each independently a hydrogen atom or a C ₁ -C ₃ alkyl group optionally substituted with 1-3 -COOR ³ groups;

R ³ each independently represents a hydrogen atom or a tert-butyl group;

L ¹¹ , L ²¹ , L ¹² and L ²² are each independently a C ₁ -C ₂ alkylene group;

Z is -(CH ₂ -CH ₂ -O) _m -CH ₂ -CH ₂ - or -(CH ₂ ) _n -;

m is an integer from 1 to 6; and

n is an integer from 2 to 12.

[24] A compound according to [23] or a pharmaceutically acceptable salt thereof, wherein

R ¹ each represents a hydrogen atom;

W ¹ and W ² are each a single bond;

X ¹ represents -C(=O)-;

X ² is -C(=O)-;

Y ¹ is -NG ²¹ -;

Y ² is -NG ²² -;

G ²¹ and G ²² are each independently a C ₁ -C ₃ alkyl group substituted with 1-3 carboxyl groups;

Z is -(CH ₂ -CH ₂ -O) _m -CH ₂ -CH ₂ -; and

m is an integer from 1 to 6.

[25] The connection according to any one of paragraphs. [1]-[7] selected from the group consisting of the following compounds:

(2S,2'S)-2,2'-((oxybis(ethane-2,1-diyl))bis((N-(4-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl)azandiyl))succinic acid;

(2S,13S)-3,12-bis(N-(4-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl)-6,9-dioxa-3,12-diazatetradecane-1,2,13,14- tetracarboxylic acid;

(2S,16S)-3,15-bis(N-(4-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl)-6,9,12-trioxa-3,15-diazaheptadecan-1,2,16, 17-tetracarboxylic acid;

(2S,19S)-3,18-bis(N-(4-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl)-6,9,12,15-tetraoxa-3,18-diazaicosan-1,2, 19,20-tetracarboxylic acid;

(2S,22S)-3,21-bis(N-(4-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl)-6,9,12,15,18-pentaoxa-3,21-diazatricosan-1, 2,22,23-tetracarboxylic acid;

(2S,25S)-3,24-bis(N-(4-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl)-6,9,12,15,18,21-hexaoxa-3,24-diazahexacosan- 1,2,25,26-tetracarboxylic acid;

(2S,2'S)-2,2'-(propane-1,3-diylbis((N-(4-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl)azandiyl))succinic acid;

(2S,2'S)-2,2'-(butane-1,4-diylbis((N-(4-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl)azandiyl))succinic acid;

(2S,2'S)-2,2'-(pentane-1,5-diylbis((N-(4-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl)azandiyl))disuccinic acid:

3,18-bis(((4-((4-guanidinobenzoyl)oxy)benzyl)oxy)carbonyl)-6,9,12,15-tetraoxa-3,18-diazaicosan-1,2,19,20-tetracarboxylic acid;

2,2'-(1,20-bis(4-((4-guanidinobenzoyl)oxy)phenyl)-3,18-dioxo-2,19-dioxa-4,17-diazaicosan-4,17-diyl)disuccinic acid;

(3S,6S,25S,28S)-6,25-bis(carboxymethyl)-3,28-bis((((4-((4-guanidinobenzoyl)oxy)benzyl)oxy)carbonyl)amino)-4.7 ,24,27-tetraoxo-11,14,17,20-tetraoxa-5,8,23,26-tetraazatriacontane-1,30-dioic acid;

(3S,6S,23S,26S)-6,23-bis(carboxymethyl)-3,26-bis((((4-((4-guanidinobenzoyl)oxy)benzyl)oxy)carbonyl)amino)-4.7 ,22,25-tetraoxo-5,8,21,24-tetraazaoctacosan-1,28-dioic acid;

(3S,22S)-3,22-bis(2-((3-carboxybenzyl)(((4-((4-guanidinobenzoyl)oxy)benzyl)oxy)carbonyl)amino)acetamido)-4,21-dioxo- 8,11,14,17-tetraoxa-5,20-diazatetracosan-1,24-dioic acid;

(4S,7S,26S,29S)-4,7,26,29-tetrakis(carboxymethyl)-3,30-bis(((4-((4-guanidinobenzoyl)oxy)benzyl)oxy)carbonyl)-5, 8,25,28-tetraoxo-12,15,18,21-tetraoxa-3,6,9,24,27,30-hexaazadotriacontane-1,32-dioic acid;

(3S,22S)-3,22-bis((3-carboxybenzyl)(((4-((4-guanidinobenzoyl)oxy)benzyl)oxy)carbonyl)amino)-4,21-dioxo-8,11,14 ,17-tetraoxa-5,20-diazatetracosan-1,24-dioic acid;

(2S,2'S)-2,2'-((((5,8,11,14-tetraoxa-2,17-diazaoctadecan-1,18-dioyl)bis(3,1-phenylene))bis(methylene) )bis((((4-((4-guanidinobenzoyl)oxy)benzyl)oxy)carbonyl)azandiyl))succinic acid;

(2S,2'S)-2,2'-((((5,8,11,14-tetraoxa-2,17-diazaoctadecan-1,18-dioyl)bis(3,1-phenylene))bis(methylene) )bis((N-(4-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl)azandiyl))succinic acid;

3,12-bis(10-guanidino-13-oxo-6,7,8,13-tetrahydrodibenzo[b,f][1,4] dioxecine-4-carbonyl)-6,9-dioxa-3,12- diasatetradecane-1,2,13,14-tetracarboxylic acid;

(2S,13S)-3,12-bis(10-guanidino-13-oxo-6,7,8,13-tetrahydrodibenzo[b,f] [1,4]dioxecine-4-carbonyl)-6,9- dioxa-3,12-diazatetradecane-1,2,13,14-tetracarboxylic acid;

(2R,13R)-3,12-bis(10-guanidino-13-oxo-6,7,8,13-tetrahydrodibenzo[b,f] [1,4]dioxecine-4-carbonyl)-6,9- dioxa-3,12-diazatetradecane-1,2,13,14-tetracarboxylic acid;

(2S,13S)-3,12-bis(N-(4-((4-guanidinobenzoyl)oxy)benzyl)-N-methylsulfamoyl)-6,9-dioxa-3,12-diazatetradecane-1,2,13 ,14-tetracarboxylic acid;

3,3'-(((ethane-1,2-diylbis(oxy))bis(ethane-2,1-diyl))bis((N-(4-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl) azandiyl))dipentanedioic acid;

(2S,2'S)-2,2'-((1,12-bis(4-((4-guanidinobenzoyl)oxy)phenyl)-5,8-dioxa-2,11-diazadecanedisulfonyl)bis(azandiyl))disuccinic acid;

(2S,13S)-3,12-bis(N-(3-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl)-6,9-dioxa-3,12-diazatetradecane-1,2,13,14- tetracarboxylic acid;

(2S,2'S)-2,2'-((oxybis(ethane-2,1-diyl))bis((10-guanidino-13-oxo-6,7,8,13-tetrahydrodibenzo[b,f][ 1,4]dioxecin-4-carbonyl)azandiyl))succinic acid;

(2S,16S)-3,15-bis(10-guanidino-13-oxo-6,7,8,13-tetrahydrodibenzo[b,f] [1,4]dioxecine-4-carbonyl)-6,9, 12-trioxa-3,15-diazaheptadecan-1,2,16,17-tetracarboxylic acid;

(2S,2'S)-2,2'-(([1,1'-biphenyl]-3,3'-diylbis(methylene))bis((10-guanidino-13-oxo-6,7,8,13 -tetrahydrodibenzo[b,f][1,4]dioxecine-4-carbonyl)azandiyl)) disuccinic acid;

(2S,2'S)-2,2'-(((((oxybis(ethane-2,1-diyl))bis(oxy))bis(3-carboxy-5,1-phenylene))bis(methylene)) bis((10-guanidino-13-oxo-6,7,8,13-tetrahydrodibenzo[b,f][1,4]dioxecine-4-carbonyl)azandiyl))succinic acid; and

(2S,2'S)-2,2'-((oxybis(ethane-2,1-diyl))bis((3-((4-guanidinobenzoyl)oxy)benzoyl)azandiyl))disuccinic acid

or a pharmaceutically acceptable salt thereof.

[26] The connection according to any one of paragraphs. [1]-[7] selected from the group consisting of the following compounds:

(2S,2'S)-2,2'-((oxybis(ethane-2,1-diyl))bis((N-(4-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl)azandiyl))succinic acid;

(2S,13S)-3,12-bis(N-(4-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl)-6,9-dioxa-3,12-diazatetradecane-1,2,13,14- tetracarboxylic acid;

(2S,2'S)-2,2'-(butane-1,4-diylbis((N-(4-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl)azandiyl))succinic acid;

(2S,13S)-3,12-bis(10-guanidino-13-oxo-6,7,8,13-tetrahydrodibenzo[b,f] [1,4]dioxecine-4-carbonyl)-6,9- dioxa-3,12-diazatetradecane-1,2,13,14-tetracarboxylic acid;

(2S,2'S)-2,2'-((oxybis(ethane-2,1-diyl))bis((10-guanidino-13-oxo-6,7,8,13-tetrahydrodibenzo[b,f][ 1,4]dioxecin-4-carbonyl)azandiyl))succinic acid;

(2S,16S)-3,15-bis(10-guanidino-13-oxo-6,7,8,13-tetrahydrodibenzo[b,f] [1,4]dioxecine-4-carbonyl)-6,9, 12-trioxa-3,15-diazaheptadecan-1,2,16,17-tetracarboxylic acid;

(2S,2'S)-2,2'-(([1,1'-biphenyl]-3,3'-diylbis(methylene))bis((10-guanidino-13-oxo-6,7,8,13 -tetrahydrodibenzo[b,f][1,4]dioxecine-4-carbonyl)azandiyl)) disuccinic acid; and

(2S,2'S)-2,2'-(((((oxybis(ethane-2,1-diyl))bis(oxy))bis(3-carboxy-5,1-phenylene))bis(methylene)) bis((10-guanidino-13-oxo-6,7,8,13-tetrahydrodibenzo[b,f][1,4]dioxecine-4-carbonyl)azandiyl))succinic acid

or a pharmaceutically acceptable salt thereof.

[27] The connection according to any one of paragraphs. [1]-[26] or a pharmaceutically acceptable salt thereof, having a molecular weight of 1000 or more.

[28] A pharmaceutical composition containing a compound according to any one of paragraphs. [1]-[27] or a pharmaceutically acceptable salt thereof.

[29] The pharmaceutical composition according to [28] for the prevention, mitigation and/or treatment of obesity.

Invention Effect

Compounds having the general formula (I) or pharmaceutically acceptable salts thereof of the present invention have excellent enteropeptidase inhibitory activity and/or excellent trypsin inhibitory activity, and have pharmacokinetic properties to effectively inhibit enteropeptidase and/or trypsin in the intestine after oral administration. and are present in the blood in very small quantities. Therefore, compounds having the general formula (I), or pharmaceutically acceptable salts thereof, can be used as agents for the prevention, mitigation and/or treatment of various diseases whose symptoms are ameliorated by enteropeptidase inhibition and/or trypsin inhibition, such as obesity. The compounds of the present invention can also be used as drugs with a high degree of safety and less pronounced side effects caused by blood levels.

Ways of practical implementation of the invention

Embodiments of the present invention are described below. In the present text, "a compound having the general formula (I)" and the like. also referred to as "Compound (I)" and the like, respectively. Various substituents, as defined or illustrated below, may optionally be selected and combined with each other. Embodiments created by optionally selecting or combining any of the embodiments described below are also within the scope of the present invention.

The following are definitions of each term used in this application.

The term "inhibitor" in the terms "inhibitor", "inhibitor molecule" and "inhibitor moiety" as used herein means a compound having at least one activity selected from an enteropeptidase inhibitory activity and a trypsin inhibitory activity.

The term "halogen atom" as used herein means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom. Preferred examples of the halogen atom include a fluorine atom and a chlorine atom.

The term "C ₁ -C ₄ alkyl group" when used in the present text means a linear or branched saturated hydrocarbon group containing 1-4 carbon atoms. Examples of the C ₁ -C ₄ alkyl group include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, and a tert-butyl group. Its preferred examples include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, and a tert-butyl group.

Also, the term "C ₁ -C ₆ alkyl group" when used in the present text means a linear or branched saturated hydrocarbon group containing 1-6 carbon atoms. Examples of the C ₁ -C ₆ alkyl group include those encompassed by the "C ₁ -C ₄ alkyl group" described above, as well as an n-pentyl group, an isopentyl group, an n-hexyl group, and an isohexyl group. Its preferred examples include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a t-butyl group, an n-pentyl group, and an n-hexyl group.

Examples of the more preferred "C ₁ -C ₄ alkyl group" and "C ₁ -C ₆ alkyl group" include a C ₁ -C ₃ alkyl group (namely, a methyl group, an ethyl group, an n-propyl group, and an isopropyl group, preferably a methyl group, an ethyl group and an n-propyl group), and a C ₁ -C ₂ alkyl group (namely, a methyl group and an ethyl group, preferably a methyl group).

The term "C ₁ -C ₄ alkylene group" as used herein means a divalent group formed when any hydrogen atom is removed from the "C ₁ -C ₄ alkyl group" described above. Examples of the C ₁ -C ₄ alkylene group include a methylene group, an ethylene group, a methylmethylene group, a trimethylene group, an ethylmethylene group, a dimethylmethylene group, and a tetramethylene group. Its preferred examples include a methylene group, an ethylene group, a methylmethylene group, a trimethylene group, and a tetramethylene group.

The term "C ₁ -C ₆ alkylene group" as used herein means a divalent group formed when any hydrogen atom is removed from the "C ₁ -C ₆ alkyl group" described above. Examples of the C ₁ -C ₆ alkylene group include the groups covered by the "C ₁ -C ₄ alkylene group" described above, as well as the pentamethylene group and the hexamethylene group. Its preferred examples include a methylene group, an ethylene group, a methylmethylene group, a trimethylene group, a tetramethylene group, a pentamethylene group, and a hexamethylene group.

Examples of the more preferred "C ₁ -C ₄ alkylene group" and "C ₁ -C ₆ alkylene group" include a C ₁ -C ₂ alkylene group (namely, a methylene group and an ethylene group, preferably a methylene group).

The term "C ₂ -C ₃₀ alkylene group (provided that one or more methylene groups in the chain of said alkylene group can be replaced by a group(s) independently selected from the group consisting of -C(=O) -, -NR ⁷ -, -O-, -SiR ⁸ R ⁹ -, -SO _r -, arylene group and heteroarylene group, R ⁷ represents a hydrogen atom or a C ₁ -C ₄ alkyl group, R ⁸ and R ⁹ each are independently a C ₁ -C ₄ alkyl group, and r is an integer from 0 to 2)" when used herein means a divalent group formed when any hydrogen atom is removed from a linear or branched saturated hydrocarbon group containing 2-30 carbon atoms, where one or more methylene groups in the chain can be replaced by a group(s) independently selected from the group consisting of -C(=O)-, -NR ⁷ -, -O-, -SiR ⁸ R ⁹ -, -SO _r -, an arylene group and a heteroarylene group, and examples thereof include -(CH ₂ -CH ₂ -C(=O)) _M -CH ₂ -CH ₂ - (where e M is an integer from 1 to 9), -(CH ₂ -CH ₂ -NR ⁷ ) _M -CH ₂ -CH ₂ - (where M is an integer from 1 to 9), -(CH ₂ -CH ₂ -O) _M -CH ₂ -CH ₂ - (where M is an integer from 1 to 9), -(CH ₂ -CH ₂ -SiR ⁸ R ⁹ ) _M -CH ₂ -CH ₂ - (where M represents is an integer from 1 to 9), -(CH ₂ -CH ₂ -SO _r ) _M -CH ₂ -CH ₂ - (where M is an integer from 1 to 9), -(CH ₂ -CH ₂ -arylene ) _M -CH ₂ -CH ₂ - (where M is an integer from 1 to 9), -(CH ₂ -CH ₂ -heteroarylene) _M -CH ₂ -CH ₂ - (where M is an integer from 1 to 9) and -(CH ₂ ) _N - (where N is an integer from 2 to 30). Its preferred examples include -(CH ₂ -CH ₂ -O) _m -CH ₂ -CH ₂ - (where m is an integer from 1 to 6), -(CH ₂ -O-CH ₂ ) _m - (where m is an integer from 1 to 6), -(CH ₂ ) _m -(C ₆ -C ₁₂ arylene) -(CH ₂ ) _m - (where m is an integer from 1 to 6), and -(CH ₂ ) _n - (where n is an integer from 2 to 12). Preferred examples of -(CH ₂ ) _m -(C ₆ -C ₁₂ arylene) -(CH ₂ ) _m - (where m is an integer from 1 to 6) include -(CH ₂ ) _m -biphenylene-(CH ₂ ) _m - (where m is an integer from 1 to 6), and more preferred examples include -(CH ₂ ) _m -([1,1'-biphenyl]-3,3'-diyl)-(CH ₂ ) _m - (where m is an integer from 1 to 6).

The term "phenylene group" as used herein means a divalent group formed when any hydrogen atom is removed from a phenyl group. Examples of the phenylene group include an o-phenylene group, an m-phenylene group, and a p-phenylene group. The term "biphenylene group" as used herein means a divalent group formed by linking two phenylene groups with a single bond. Examples of the biphenylene group include [1,1'-biphenyl]-2,2'-diyl group, [1,1'-biphenyl]-3,3'-diyl group, and [1,1'-biphenyl]-4,4 '-diyl group, and preferred examples include [1,1'-biphenyl]-3,3'-diyl group.

The term "aryl group" as used herein means a monocyclic or bicyclic aromatic hydrocarbon group containing 6-12 ring carbon atoms (C ₆ -C ₁₂ ), eg C ₆ -C ₁₁ . Examples thereof include monocyclic aryl groups such as a phenyl group; and optionally partially saturated bicyclic aryl groups containing 9-12 carbon atoms in the ring (C ₉ -C ₁₂ ), such as C ₉ -C ₁₁ , such as naphthyl group, tetrahydronaphthyl group, indenyl group and indanyl group. Preferred examples of the aryl group include a phenyl group and a naphthyl group, and more preferred examples thereof include a phenyl group.

The term "arylene group" or "C ₆ -C ₁₂ arylene group" as used herein means a divalent group formed by the removal of any hydrogen atom from the "aryl group" described above.

The term "heteroaryl group" as used herein means a 5-11 membered monocyclic or bicyclic aromatic heterocyclic group containing 1-4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom other than carbon atoms, and examples thereof include 5 -6-membered monocyclic heteroaryl groups containing 1-4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom other than carbon atoms, such as a pyrrolyl group, a furyl group, a thienyl group, a pyrazolyl group, an imidazolyl group, an oxazolyl group, an isoxazolyl group, a thiazolyl group, an isothiazolyl group, a thiadiazolyl group, a pyridyl group, a pyrazinyl group, a pyrimidinyl group, a pyridazinyl group, and a triazinyl group; 8-11-membered bicyclic heteroaryl groups containing 1-4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom other than carbon atoms, such as indolyl group, indolinyl group, isoindolinyl group, indazolyl group, tetrahydroindazolyl group, benzofuranyl group , dihydrobenzofuranyl group, dihydroisobenzofuranyl group, benzothiophenyl group, dihydrobenzothiophenyl group, dihydroisobenzothiophenyl group, benzoxazolyl group, dihydrobenzoxazolyl group, benzothiazolyl group, dihydrobenzothiazolyl group, quinolyl group, tetrahydroquinolyl group, isoquinolyl group, tetrahydroisoquinolyl group, naphthyridinyl group, tetrahydronaphthyridinoxinyl group group; and a quinazolinyl group. Its preferred examples include a pyrrolyl group, a furyl group, a thienyl group, a pyrazolyl group, an imidazolyl group, an oxazolyl group, an isoxazolyl group, a thiazolyl group, an isothiazolyl group, a thiadiazolyl group, a pyridyl group, a pyrazinyl group, a pyrimidinyl group, a pyridazinyl group, and a triazinyl group, and more preferred examples thereof include a pyrrolyl group, a furyl group and a thienyl group.

The term "heteroarylene group" as used herein means a divalent group formed when any hydrogen atom is removed from the "heteroaryl group" described above.

The term "C ₁ -C ₄ alkoxy group" when used in the present text means a monovalent group, where the above-described C ₁ -C ₄ alkyl group is linked to an oxy group. Examples of the C ₁ -C ₄ alkoxy group include a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, a sec-butoxy group, and a tert-butoxy group. Its preferred examples include a methoxy group, an ethoxy group, and an n-propoxy group.

The term "C ₁ -C ₄ alkoxy-C ₁ -C ₄ alkyl group" when used in the present text means a group where the C ₁ -C ₄ alkyl group described above is substituted with a C ₁ -C ₄ alkoxy group. Examples of the C ₁ -C ₄ alkoxy-C ₁ -C ₄ alkyl group include methoxymethyl group, methoxyethyl group, ethoxymethyl group, ethoxyethyl group, n-propoxymethyl group, isopropoxymethyl group, n-butoxymethyl group, isobutoxymethyl group, sec-butoxymethyl group and t -butoxymethyl group. Its preferred examples include a methoxymethyl group, a methoxyethyl group, an ethoxymethyl group, and an ethoxyethyl group.

The term "C ₁ -C ₄ alkyleneoxy group" as used herein means a divalent group wherein the C ₁ -C ₄ alkylene group described above is bonded to an oxy group. Examples of the C ₁ -C ₄ alkyleneoxy group include a methyleneoxy group, an ethyleneoxy group, a methylmethyleneoxy group, trimethyleneoxy groups, an ethylmethyleneoxy group, a dimethylmethyleneoxy group, and a tetramethyleneoxy group. Its preferred examples include an ethyleneoxy group, a trimethyleneoxy group, and a tetramethyleneoxy group.

The term "C ₇ -C ₁₂ aralkyl group" as used herein means a group where the C ₁ -C ₆ alkyl group described above is substituted by the aryl group described above. Examples of the C ₇ -C ₁₂ aralkyl group include a benzyl group and a phenethyl group. Its preferred examples include a benzyl group.

The term "any hydrogen atom" in the term "a group resulting from the removal of any hydrogen atom or any hydroxy group" as used herein means any hydrogen atom bonded to a carbon atom, a nitrogen atom, or an oxygen atom.

The term "any hydroxy group" in the term "a group resulting from the removal of any hydrogen atom or any hydroxy group" as used herein means a hydroxy group or a hydroxy group within a carboxyl group.

The term "at room temperature" when used in this text means a temperature in the range from 1 to 30°C, preferably from 10 to 30°C.

Compound (I)

One embodiment of the present invention is a compound having the general formula (I) shown below, or a pharmaceutically acceptable salt thereof.

In the general formula (I),

A ¹ and A ² are each independently an inhibitor residue having at least one activity selected from an enteropeptidase inhibitory activity and a trypsin inhibitory activity; and

Z is a bridge that connects A ¹ to A ² and also includes a single bond.

In the above definition, the term "inhibitor residue" means an inhibitor residue in which a hydrogen atom or a hydroxy group is removed from an inhibitor molecule having at least one activity selected from an enteropeptidase inhibitory activity and a trypsin inhibitory activity. Examples of such an inhibitor include, but are not limited to, the compounds disclosed in Patent Documents 1-12 and the compounds synthesized herein.

In addition, the term "bridge" means a structure that connects two residues, and examples include linkers.

In Compound (I), A ¹ and A ² may have the same structure or different structures from each other.

In one embodiment of the present invention,

A ¹ and A ² are each independently an inhibitor residue obtained by removing any hydrogen atom or any hydroxy group from an inhibitor molecule selected from the following group of inhibitor molecules:

or an inhibitor molecule having the following general formula (II)

where:

Ring B and Ring C are each independently an aryl group or a heteroaryl group;

R ¹ each independently represents a hydrogen atom or -COO-(C ₁ -C ₄ alkyl group);

W represents a single bond or a C ₁ -C ₄ alkylene group;

X is -C(=O)-, -OC(=O)- or -NG-SO ₂ -;

G represents a hydrogen atom, a C ₁ -C ₄ alkyl group, or —COOR ² ;

R ² is a C ₁ -C ₄ alkyl group optionally substituted with 1-5 aryl groups;

Y is -NG ² G ⁴ , -NG ² -L ¹ -COOH, -NG ² -L ¹ -C(=O)-NH ₂ , -NG ² -L ¹ -C(=O)-NG ³ - L ² -COOH, -NG ² -L ¹ -C(=O)-NG ³ -L ² -C(=O)-NG ³ -L ² -COOH, -NG ² -L ¹ -C(=O) -NG ³ -L ² -C(=O)-NH ₂ , -NG ² -L ³ -OH or -NG ² -(CH ₂ -CH ₂ -O) _q -CH ₂ -CH ₂ -COOH;

q is an integer from 1 to 6;

G ² and G ³ are each independently a hydrogen atom or a C ₁ -C ₆ alkyl group optionally substituted with 1-5 substituents independently selected from the group consisting of a phenyl group optionally substituted with 1-5 -COOR ³ groups, and -COOR ³ groups;

G ⁴ represents a hydrogen atom, a C ₁ -C ₄ alkyl group or a C ₁ -C ₄ alkoxy-C ₁ -C ₄ alkyl group;

R ³ each independently represents a hydrogen atom or a C ₁ -C ₄ alkyl group optionally substituted with 1-5 aryl groups;

L ¹ and L ² are each independently a C ₁ -C ₆ alkylene group optionally substituted with 1-5 C ₁ -C ₆ alkyl groups optionally substituted with 1-5 -COOR ⁴ groups, a C ₁ -C ₆ alkylene group substituted with C a ₇ -C ₁₂ aralkyl group optionally substituted with 1-5 substituents independently selected from the group consisting of a hydroxy group and a carboxyl group, a C ₁ -C ₄ alkylene-phenylene group, or a phenylene-C ₁ -C ₄ alkylene group;

L ³ represents a C ₁ -C ₄ alkylene-phenylene group, where the phenylene fragment is optionally substituted with 1-3 -COOR ⁴ groups;

R ⁴ each independently represents a hydrogen atom or a C ₁ -C ₄ alkyl group optionally substituted with 1-5 substituents independently selected from the group consisting of an aryl group and a trimethylsilyl group;

R ⁵ and R ⁶ are each independently a hydrogen atom, a halogen atom, a C ₁ -C ₄ alkyl group, a C ₁ -C ₄ alkoxy group, a carboxyl group, or -C(=O)-NG ² G ⁴ ;

s and t are each independently an integer from 1 to 4;

two or more R ⁵ and/or two or more R ⁶ may be the same or different from each other;

or any of R ⁵ and any of R ⁶ may be combined with each other to form a C ₁ -C ₄ alkyleneoxy group; and

Z represents a single bond, an arylene group, a heteroarylene group, or a C ₂ -C ₃₀ alkylene group (provided that one or more methylene groups in the chain of said alkylene group may be replaced by a group(s) independently selected from a group consisting of -C(=O)-, -NR ⁷ -, -O-, -SiR ⁸ R ⁹ -, -SO _r -, an arylene group and a heteroarylene group, R ⁷ represents a hydrogen atom or C ₁ -C ₄ alkyl group, R ⁸ and R ⁹ are each independently a C ₁ -C ₄ alkyl group, and r is an integer from 0 to 2).

In one embodiment of the present invention, A ¹ and A ² are each independently an inhibitor residue obtained by removing any hydrogen atom or any hydroxy group from an inhibitor molecule having the general formula (II).

In one embodiment of the present invention,

A ¹ has the structure represented by the formula

or

:

:

A ² has the structure represented by the formula

or

:

:

where:

ring B ¹ , ring B ² , ring C ¹ and ring C ² are each independently an aryl group;

R ¹ each independently represents a hydrogen atom or -COO-(C ₁ -C ₄ alkyl group);

W ¹ and W ² are each independently a single bond or a C ₁ -C ₄ alkylene group;

X ¹ is -C(=O)-, -OC(=O)- or -NG ¹¹ -SO ₂ -;

X ^1' is -NG ^Z -SO ₂ -;

X ² is -C(=O)-, -C(=O)-O- or -SO ₂ -NG ¹² -;

X ^2' is -SO ₂ -NG ^Z -;

G ¹¹ and G ¹² are each independently a hydrogen atom, a C ₁ -C ₄ alkyl group, or —COOR ² ;

G ^Z is a single bond that connects X ^1' or X ^2' to Z;

R ² is a C ₁ -C ₄ alkyl group optionally substituted with 1-5 aryl groups;

Y ¹ is -NG ²¹ -, -NG ²¹ -L ¹¹ -C(=O)-, -NG ²¹ -L ¹¹ -C(=O)-NH-, -NG ²¹ -L ¹¹ -C(=O )-NG ³¹ -L ²¹ -C(=O)-, -NG ²¹ -L ¹¹ -C(=O)-NG ³¹ -L ²¹ -C(=O)-NH-, -NG ²¹ -L ³ - O- or -NG ²¹ -G ^4' -;

Y ^1' is -NG ²¹ H, -NG ²¹ -L ¹¹ -COOH or -NG ²¹ -L ¹¹ -C(=O)-NG ³¹ -L ²¹ -COOH;

Y ² is -NG ²² -, -C(=O)-L ¹² -NG ²² -, -NH-C(=O) -L ¹² -NG ²² -, -C(=O) -L ²² -NG ³² -C(=O)-L ¹² -NG ²² -, -NH-C(=O)-L ²² -NG ³² -C(=O)-L ¹² -NG ²² -, -OL ³ -NG ²² - or -G ^4' -NG ²² -;

Y ^2' is HNG ²² -, HOOC-L ¹² -NG ²² - or HOOC-L ²² -NG ³² -C(=O) -L ¹² -NG ²² -;

G ²¹ , G ³¹ , G ²² and G ³² are each independently a hydrogen atom or a C ₁ -C ₆ alkyl group optionally substituted with 1-5 substituents independently selected from the group consisting of a phenyl group optionally substituted with 1-5 -COOR ³ groups, and -COOR ³ groups;

G ^4' represents a C ₁ -C ₄ alkylene group or a C ₁ -C ₄ alkyleneoxy-C ₁ -C ₄ alkylene group;

R ³ each independently represents a hydrogen atom or a C ₁ -C ₄ alkyl group optionally substituted with 1-5 aryl groups;

L ¹¹ , L ²¹ , L ¹² and L ²² are each independently a C ₁ -C ₆ alkylene group optionally substituted with 1-5 C ₁ -C ₆ alkyl groups optionally substituted with 1-5 -COOR ⁴ groups, C ₁ -C ₄ alkylene-phenylene group or phenylene-C ₁ -C ₄ alkylene group;

L ³ represents a C ₁ -C ₄ alkylene-phenylene group, where the phenylene fragment is optionally substituted with 1-3 -COOR ⁴ groups;

R ⁴ each independently represents a hydrogen atom or a C ₁ -C ₄ alkyl group optionally substituted with 1-5 substituents independently selected from the group consisting of an aryl group and a trimethylsilyl group;

R ⁵ and R ⁶ are each independently a hydrogen atom, a halogen atom, a C ₁ -C ₄ alkyl group, or a C ₁ -C ₄ alkoxy group;

s and t are each independently an integer from 1 to 4;

two or more R ⁵ and/or two or more R ⁶ may be the same or different from each other;

or any of R ⁵ and any of R ⁶ may be combined with each other to form a C ₁ -C ₄ alkyleneoxy group; and

symbol

means the point of attachment to Z; and

Z represents a single bond, an arylene group, a heteroarylene group, or a C ₂ -C ₃₀ alkylene group (provided that one or more methylene groups in the chain of said alkylene group may be replaced by a group(s) independently selected from a group consisting of -C(=O)-, -NR ⁷ -, -O-, an arylene group and a heteroarylene group, and R ⁷ is a hydrogen atom or a C ₁ -C ₄ alkyl group).

Embodiments of each substituent in Compound (I) are described below.

In one embodiment, the aryl group on Ring B and Ring C are each independently a C ₆ -C ₁₂ aryl group, preferably a phenyl group or a naphthyl group, more preferably a phenyl group.

In one embodiment, the heteroaryl group in Ring B and Ring C are each independently a 5-11 membered monocyclic or bicyclic aromatic heterocyclic group containing 1-4 heteroatoms selected from an oxygen atom, a sulfur atom, and a nitrogen atom other than carbon atoms. , preferably a pyrrolyl group, a furyl group and a thienyl group, more preferably a thienyl group.

In one embodiment, Ring B and Ring C are each independently an aryl group, preferably each is a phenyl group.

In one embodiment, ring B and ring C are each independently a phenyl group, a naphthyl group, or a thienyl group, preferably ring B and ring C are each a phenyl group.

In one embodiment, ring B ¹ , ring B ² , ring C ¹ and ring C ² are each independently a phenyl group or a naphthyl group, preferably ring B ¹ , ring B ² , ring C ¹ and ring C ² are each phenyl group.

In one embodiment, the C ₁ -C ₄ alkyl group in "-COO-(C ₁ -C ₄ alkyl group)" in R ¹ is a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group or a tert-butyl group.

In one embodiment, R ¹ is a hydrogen atom or a t-butoxycarbonyl group, preferably a hydrogen atom.

In one embodiment, W is a C ₁ -C ₄ alkylene group, eg a methylene group, an ethylene group, a trimethylene group, or a tetramethylene group, preferably a C ₁ -C ₂ alkylene group, eg a methylene group. In another embodiment, W is a single bond or a C ₁ -C ₂ alkylene group, preferably a single bond or a methylene group.

In one embodiment, W ¹ is a C ₁ -C ₄ alkylene group, eg a methylene group, an ethylene group, a trimethylene group, or a tetramethylene group, preferably a C ₁ -C ₂ alkylene group, eg a methylene group. In another embodiment, W ¹ is a single bond or a C ₁ -C ₄ alkylene group, preferably a single bond or a C ₁ -C ₂ alkylene group, more preferably a single bond or a methylene group, even more preferably a single bond.

In one embodiment, W ² is a C ₁ -C ₄ alkylene group, eg a methylene group, an ethylene group, a trimethylene group, or a tetramethylene group, preferably a C ₁ -C ₂ alkylene group, eg a methylene group. In another embodiment, W ² is a single bond or a C ₁ -C ₄ alkylene group, preferably a single bond or a C ₁ -C ₂ alkylene group, more preferably a single bond or a methylene group, even more preferably a single bond.

In one embodiment, X is -OC(=O)- or -NG-SO ₂ -, preferably -NG-SO ₂ -. In another embodiment, X is -C(=O)- or -NG-SO ₂ -, preferably -C(=O)-.

In one embodiment, X ¹ is -OC(=O)- or -NG ¹¹ -SO ₂ -, preferably -NG ¹¹ -SO ₂ -. In another embodiment, X ¹ is -C(=O)- or -NG ¹¹ -SO ₂ -, preferably -C(=O)-.

In one embodiment, X ² is -C(=O)-O- or -SO ₂ -NG ¹² -, preferably -SO ₂ -NG ¹² -. In another embodiment, X ² is -C(=O)- or -SO ₂ -NG ¹² -, preferably -C(=O)-.

In one embodiment, the "C ₁ -C ₄ alkyl group" in G is a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, or a t-butyl group, preferably a methyl group or an ethyl group.

In one embodiment, R ² in the "-COOR ² group" in G is a C ₁ -C ₄ alkyl group optionally substituted with 1-3 phenyl groups, e.g., methyl group, ethyl group, n-propyl group, isopropyl group, n -butyl group, tert-butyl group or benzyl group, preferably C ₁ -C ₄ alkyl group, optionally substituted with one phenyl group, more preferably tert-butyl group or benzyl group.

In one embodiment, G is a hydrogen atom, a methyl group, a t-butoxycarbonyl group, or a benzyloxycarbonyl group, preferably a hydrogen atom, a methyl group, or a benzyloxycarbonyl group, more preferably a hydrogen atom or a methyl group.

In one embodiment, the "C ₁ -C ₄ alkyl group" in G ¹¹ and G ¹² is a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, or a t-butyl group, preferably a methyl group or ethyl group.

In one embodiment, R ² in the "-COOR ² group" in G ¹¹ and G ¹² is a C ₁ -C ₄ alkyl group, such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a tert-butyl group or a benzyl group optionally substituted with 1-3 aryl groups, for example phenyl groups, preferably a C ₁ -C ₄ alkyl group optionally substituted with one phenyl group, more preferably a tert-butyl group or a benzyl group.

In one embodiment, G ¹¹ is a hydrogen atom, a methyl group, a t-butoxycarbonyl group, or a benzyloxycarbonyl group, preferably a hydrogen atom, a methyl group, or a benzyloxycarbonyl group, more preferably a hydrogen atom or a methyl group. In another embodiment, G ¹¹ is a hydrogen atom or —COOR ² , preferably a hydrogen atom, a t-butoxycarbonyl group or a benzyloxycarbonyl group, more preferably a hydrogen atom or a benzyloxycarbonyl group, even more preferably a hydrogen atom.

In one embodiment, G ¹² is a hydrogen atom, a methyl group, a t-butoxycarbonyl group, or a benzyloxycarbonyl group, preferably a hydrogen atom, a methyl group, or a benzyloxycarbonyl group, more preferably a hydrogen atom or a methyl group. In another embodiment, G ¹² is a hydrogen atom or —COOR ² , preferably a hydrogen atom, a t-butoxycarbonyl group or a benzyloxycarbonyl group, more preferably a hydrogen atom or a benzyloxycarbonyl group, even more preferably a hydrogen atom.

In one embodiment, Y is -NG ² G ⁴ , -NG ² -L ¹ -COOH, -NG ² -L ¹ -C(=O)-NH ₂ , -NG ² -L ¹ -C(=O )-NG ³ -L ² -COOH, -NG ² -L ¹ -C(=O)-NG ³ -L ² -C(=O)-NH ₂ , -NG ² -L ³ -OH or -NG ² -(CH ₂ -CH ₂ -O) _q -CH ₂ -CH ₂ -COOH, preferably -NG ² G ⁴ , -NG ² -L ¹ -COOH, -NG ² -L ¹ -C(=O)-NH ₂ , -NG ² -L ¹ -C(=O)-NG ³ -L ² -COOH, -NG ² -L ¹ -C(=O)-NG ³ -L ² -C(=O)-NH ₂ or -NG ² -L ³ -OH, more preferably -NG ² G ⁴ .

In one embodiment, Y ¹ is -NG ²¹ -, -NG ²¹ -L ¹¹ -C(=O)-, -NG ²¹ -L ¹¹ -C(=O)-NH-, -NG ²¹ -L ¹¹ -C(=O)-NG ³¹ -L ²¹ -C(=O)-, -NG ²¹ -L ¹¹ -C(=O)-NG ³¹ -L ²¹ -C(=O)-NH- or -NG ²¹ -L ³ -O-. In another embodiment, Y ¹ is -NG ²¹ -, -NG ²¹ -L ³ -O- or -NG ²¹ -G ^4' -. Preferably Y ¹ is -NG ²¹ -.

In one embodiment, Y ^1' is -NG ²¹ H.

In one embodiment, Y ² is -NG ²² -, -C(=O)-L ¹² -NG ²² -, -NH-C(=O)-L ¹² -NG ²² -, -C(=O) -L ²² -NG ³² -C(=O)-L ¹² -NG ²² -, -NH-C(=O)-L ²² -NG ³² -C(=O)-L ¹² -NG ²² - or -OL ³ -NG ^22- . In another embodiment, Y ² is -NG ²² -, -OL ³ -NG ²² - or -G ^4' -NG ²² -. Preferably Y ² is -NG ²² -.

In one embodiment, Y ^2' is HNG ²² -.

In one embodiment, q is an integer from 1 to 4, preferably an integer from 1 to 3, more preferably an integer from 1 to 2.

In one embodiment, the "phenyl group optionally substituted with 1-5 -COOR ³ groups" in G ² and G ³ is preferably a phenyl group optionally substituted with 1-3 -COOR ³ groups, more preferably a phenyl group optionally substituted with one - COOR ³ group, for example 2-(COOR ³ )-phenyl group, 3-(COOR ³ )-phenyl group, 4-(COOR ³ )-phenyl group, and the like.

In one embodiment, R ³ in the "-COOR ³ group" in G ² and G ³ are each independently a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a t-butyl group or a benzyl group, preferably a hydrogen atom, a benzyl group or a t-butyl group, more preferably a hydrogen atom or a t-butyl group, even more preferably a hydrogen atom.

In one embodiment, G ² is a hydrogen atom or a C ₁ -C ₆ alkyl group optionally substituted with 1-3 substituents independently selected from the group consisting of a phenyl group optionally substituted with 1-3 -COOR ³ groups, and -COOR ³ groups, preferably a hydrogen atom or a C ₁ -C ₃ alkyl group optionally substituted with 1-3 substituents independently selected from the group consisting of a phenyl group optionally substituted with one -COOR ³ group and -COOR ³ groups, more preferably C ₁ -C ₃ alkyl group substituted with 1-3 substituents independently selected from the group consisting of a phenyl group substituted with one carboxyl group and a carboxyl group.

In another embodiment, G ² is a hydrogen atom or a C ₁ -C ₃ alkyl group optionally substituted with 1-3 -COOR ³ groups, preferably a C ₁ -C ₃ alkyl group substituted with 1-3 carboxyl groups.

In one embodiment, G ³ is a hydrogen atom or a C ₁ -C ₆ alkyl group optionally substituted with 1-3 substituents independently selected from the group consisting of a phenyl group optionally substituted with 1-3 -COOR ³ groups, and -COOR ³ groups, preferably a hydrogen atom or a C ₁ -C ₃ alkyl group optionally substituted with 1-3 substituents independently selected from the group consisting of a phenyl group optionally substituted with one -COOR ³ group, and -COOR ³ groups, more preferably a hydrogen atom .

In another embodiment, G ³ is a hydrogen atom or a C ₁ -C ₃ alkyl group optionally substituted with 1-3 -COOR ³ groups, preferably a hydrogen atom.

In one embodiment, the "phenyl group optionally substituted with 1-5 -COOR ³ groups" in G ²¹ , G ³¹ , G ²² and G ³² is preferably a phenyl group optionally substituted with 1-3 -COOR ³ groups, more preferably phenyl a group optionally substituted with one -COOR ³ group, such as 2-(COOR ³ )-phenyl group, 3-(COOR ³ )-phenyl group, 4-(COOR ³ )-phenyl group, and the like.

In one embodiment, R ³ in the "-COOR ³ group" in G ²¹ , G ³¹ , G ²² and G ³² are each independently hydrogen atom, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl a group, a t-butyl group or a benzyl group, preferably a hydrogen atom, a benzyl group or a t-butyl group, more preferably a hydrogen atom or a t-butyl group, even more preferably a hydrogen atom.

In one embodiment, G ²¹ is a hydrogen atom or a C ₁ -C ₆ alkyl group optionally substituted with 1-3 substituents independently selected from the group consisting of a phenyl group optionally substituted with 1-3 -COOR ³ groups, and -COOR ³ groups, preferably a hydrogen atom or a C ₁ -C ₃ alkyl group optionally substituted with 1-3 substituents independently selected from the group consisting of a phenyl group optionally substituted with one -COOR ³ group and -COOR ³ groups, more preferably C ₁ -C ₃ alkyl group substituted with 1-3 substituents independently selected from the group consisting of a phenyl group substituted with one carboxyl group and a carboxyl group.

In another embodiment, G ²¹ is a hydrogen atom or a C ₁ -C ₃ alkyl group optionally substituted with 1-3 -COOR ³ groups, preferably a hydrogen atom or a C ₁ -C ₃ alkyl group substituted with 1-3 carboxyl groups, more preferably a C ₁ -C ₃ alkyl group substituted with 1-3 carboxyl groups.

In one embodiment, G ³¹ is a hydrogen atom or a C ₁ -C ₆ alkyl group optionally substituted with 1-3 substituents independently selected from the group consisting of a phenyl group optionally substituted with 1-3 -COOR ³ groups, and -COOR ³ groups, preferably a hydrogen atom or a C ₁ -C ₃ alkyl group optionally substituted with 1-3 substituents independently selected from the group consisting of a phenyl group optionally substituted with one -COOR ³ group, and -COOR ³ groups, more preferably a hydrogen atom .

In another embodiment, G ³¹ is a hydrogen atom or a C ₁ -C ₃ alkyl group optionally substituted with 1-3 -COOR ³ groups, preferably a hydrogen atom.

In one embodiment, G ²² is a hydrogen atom or a C ₁ -C ₆ alkyl group optionally substituted with 1-3 substituents independently selected from the group consisting of a phenyl group optionally substituted with 1-3 -COOR ³ groups, and -COOR ³ groups, preferably a hydrogen atom or a C ₁ -C ₃ alkyl group optionally substituted with 1-3 substituents independently selected from the group consisting of a phenyl group optionally substituted with one -COOR ³ group and -COOR ³ groups, more preferably C ₁ -C ₃ alkyl group substituted with 1-3 substituents independently selected from the group consisting of a phenyl group substituted with one carboxyl group and a carboxyl group.

In another embodiment, G ²² is a hydrogen atom or a C ₁ -C ₃ alkyl group optionally substituted with 1-3 -COOR ³ groups, preferably a hydrogen atom or a C ₁ -C ₃ alkyl group substituted with 1-3 carboxyl groups, more preferably a C ₁ -C ₃ alkyl group substituted with 1-3 carboxyl groups.

In one embodiment, G ³² is a hydrogen atom or a C ₁ -C ₆ alkyl group optionally substituted with 1-3 substituents independently selected from the group consisting of a phenyl group optionally substituted with 1-3 -COOR ³ groups, and -COOR ³ groups, preferably a hydrogen atom or a C ₁ -C ₃ alkyl group optionally substituted with 1-3 substituents independently selected from the group consisting of a phenyl group optionally substituted with one -COOR ³ group, and -COOR ³ groups, more preferably a hydrogen atom .

In another embodiment, G ³² is a hydrogen atom or a C ₁ -C ₃ alkyl group optionally substituted with 1-3 -COOR ³ groups, preferably a hydrogen atom.

In one embodiment, G ⁴ is a hydrogen atom, a C ₁ -C ₂ alkyl group, or a C ₁ -C ₂ alkoxy-C ₁ -C ₂ alkyl group, preferably a methyl group, an ethyl group, or a methoxyethyl group, more preferably a methyl group, or methoxyethyl group.

In one embodiment, G ^4' is a C ₁ -C ₂ alkylene group or a C ₁ -C ₂ alkyleneoxy-C ₁ -C ₂ alkylene group, preferably a methylene group, an ethylene group, or a methyleneoxyethylene group, more preferably a methylene group or a methyleneoxyethylene group .

In one embodiment, R ⁴ in the "-COOR ⁴ group" in L ¹ and L ² are each independently a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a t-butyl group or a benzyl group, preferably a hydrogen atom, a t-butyl group or a benzyl group, more preferably a hydrogen atom or a t-butyl group, even more preferably a hydrogen atom.

In one embodiment, L ¹ is a C ₁ -C ₆ alkylene group optionally substituted with 1-2 C ₁ -C ₆ alkyl groups optionally substituted with 1-2 -COOR ⁴ groups, a C ₁ -C ₄ alkylene group substituted with benzyl a group wherein the phenyl moiety is optionally substituted with 1-2 substituents independently selected from the group consisting of a hydroxy group and a carboxyl group, a C ₁ -C ₄ alkylene-phenylene group or a phenylene-C ₁ -C ₄ alkylene group, preferably a methylene group, optionally substituted with a C ₁ -C ₆ alkyl group, optionally substituted with a -COOR ⁴ group, a methylenephenylene group, or a phenylenemethylene group.

In another embodiment, L ¹ is a C ₁ -C ₂ alkylene group, preferably a methylene group.

In another embodiment, L ¹ is a C ₁ -C ₂ alkylene group optionally substituted with 1-2 C ₁ -C ₂ alkyl groups, optionally substituted with 1-2 -COOR ⁴ groups, a C ₁ -C ₂ alkylene-phenylene group, or phenylene-C ₁ -C ₂ alkylene group.

In one embodiment, L ² is a C ₁ -C ₆ alkylene group optionally substituted with 1-2 C ₁ -C ₆ alkyl groups optionally substituted with 1-2 -COOR ⁴ groups, a C ₁ -C ₄ alkylene group substituted with benzyl a group wherein the phenyl moiety is optionally substituted with 1-2 substituents independently selected from the group consisting of a hydroxy group and a carboxyl group, a C ₁ -C ₄ alkylene-phenylene group or a phenylene-C ₁ -C ₄ alkylene group, preferably a methylene group, optionally substituted with a C ₁ -C ₆ alkyl group, optionally substituted with a -COOR ⁴ group.

In another embodiment, L ² is a C ₁ -C ₂ alkylene group, preferably a methylene group.

In another embodiment, L ² is a C ₁ -C ₂ alkylene group optionally substituted with 1-2 C ₁ -C ₂ alkyl groups, optionally substituted with 1-2 -COOR ⁴ groups, a C ₁ -C ₂ alkylene-phenylene group, or phenylene-C ₁ -C ₂ alkylene group.

In one embodiment, R ⁴ in the "-COOR ⁴ group" in L ¹¹ , L ²¹ , L ¹² and L ²² are each independently hydrogen atom, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl a group, a t-butyl group or a benzyl group, preferably a hydrogen atom, a t-butyl group or a benzyl group, more preferably a hydrogen atom or a t-butyl group, even more preferably a hydrogen atom.

In one embodiment, L ¹¹ is a C ₁ -C ₆ alkylene group optionally substituted with 1-2 C ₁ -C ₆ alkyl groups optionally substituted with 1-2 -COOR ⁴ groups, a C ₁ -C ₄ alkylene group substituted with benzyl a group wherein the phenyl moiety is optionally substituted with 1-2 substituents independently selected from the group consisting of a hydroxy group and a carboxyl group, a C ₁ -C ₄ alkylene-phenylene group or a phenylene-C ₁ -C ₄ alkylene group, preferably a C ₁ - C ₆ alkylene group optionally substituted with 1-2 C ₁ -C ₆ alkyl groups optionally substituted with 1-2 -COOR ⁴ groups, C ₁ -C ₄ alkylene-phenylene group or phenylene-C ₁ -C ₄ alkylene group, more preferably C ₁ -C ₆ alkylene group optionally substituted with 1-2 C ₁ -C ₆ alkyl groups optionally substituted with 1-2 -COOR ⁴ groups, or C ₁ -C ₄ alkylene-phenylene group, even more preferably methylene group, optionally substituted C ₁ -C ₆ alkyl group npoy, optionally substituted with a -COOR ⁴ group, or a methylenephenylene group.

In another embodiment, L ¹¹ is a C ₁ -C ₂ alkylene group, preferably a methylene group.

In another embodiment, L ¹¹ is a C ₁ -C ₂ alkylene group optionally substituted with 1-2 C ₁ -C ₂ alkyl groups optionally substituted with 1-2 -COOR ⁴ groups, or a C ₁ -C ₂ alkylene-phenylene group .

In one embodiment, L ²¹ is a C ₁ -C ₆ alkylene group optionally substituted with 1-2 C ₁ -C ₆ alkyl groups optionally substituted with 1-2 -COOR ⁴ groups, a C ₁ -C ₄ alkylene group substituted with benzyl a group wherein the phenyl moiety is optionally substituted with 1-2 substituents independently selected from the group consisting of a hydroxy group and a carboxyl group, a C ₁ -C ₄ alkylene-phenylene group or a phenylene-C ₁ -C ₄ alkylene group, preferably a C ₁ - C ₆ alkylene group optionally substituted with 1-2 C ₁ -C ₆ alkyl groups optionally substituted with 1-2 -COOR ⁴ groups, C ₁ -C ₄ alkylene-phenylene group or phenylene-C ₁ -C ₄ alkylene group, more preferably C ₁ -C ₆ alkylene group optionally substituted with 1-2 C ₁ -C ₆ alkyl groups optionally substituted with 1-2 -COOR ⁴ groups, or C ₁ -C ₄ alkylene-phenylene group, even more preferably methylene group, optionally substituted C ₁ -C ₆ alkyl group npoy, optionally substituted with -COOR ⁴ group.

In another embodiment, L ²¹ is a C ₁ -C ₂ alkylene group, preferably a methylene group.

In another embodiment, L ²¹ is a C ₁ -C ₂ alkylene group optionally substituted with 1-2 C ₁ -C ₂ alkyl groups optionally substituted with 1-2 -COOR ⁴ groups, or a C ₁ -C ₂ alkylene-phenylene group .

In one embodiment, L ¹² is a C ₁ -C ₆ alkylene group optionally substituted with 1-2 C ₁ -C ₆ alkyl groups optionally substituted with 1-2 -COOR ⁴ groups, a C ₁ -C ₄ alkylene group substituted with benzyl a group wherein the phenyl moiety is optionally substituted with 1-2 substituents independently selected from the group consisting of a hydroxy group and a carboxyl group, a C ₁ -C ₄ alkylene-phenylene group or a phenylene-C ₁ -C ₄ alkylene group, preferably a C ₁ - C ₆ alkylene group optionally substituted with 1-2 C ₁ -C ₆ alkyl groups optionally substituted with 1-2 -COOR ⁴ groups, C ₁ -C ₄ alkylene-phenylene group or phenylene-C ₁ -C ₄ alkylene group, more preferably a C ₁ -C ₆ alkylene group optionally substituted with 1-2 C ₁ -C ₆ alkyl groups optionally substituted with 1-2 -COOR ⁴ groups, or a phenylene-C ₁ -C ₄ alkylene group, even more preferably a methylene group, optionally substituted C ₁ -C ₆ alkyl group npoy optionally substituted with a -COOR ⁴ group, or a phenylenemethylene group.

In another embodiment, L ¹² is a C ₁ -C ₂ alkylene group, preferably a methylene group.

In another embodiment, L ¹² is a C ₁ -C ₂ alkylene group optionally substituted with 1-2 C ₁ -C ₂ alkyl groups optionally substituted with 1-2 -COOR ⁴ groups, or a phenylene-C ₁ -C ₂ alkylene group .

In one embodiment, L ²² is a C ₁ -C ₆ alkylene group optionally substituted with 1-2 C ₁ -C ₆ alkyl groups optionally substituted with 1-2 -COOR ⁴ groups, a C ₁ -C ₄ alkylene group substituted with benzyl a group wherein the phenyl moiety is optionally substituted with 1-2 substituents independently selected from the group consisting of a hydroxy group and a carboxyl group, a C ₁ -C ₄ alkylene-phenylene group or a phenylene-C ₁ -C ₄ alkylene group, preferably a C ₁ - C ₆ alkylene group optionally substituted with 1-2 C ₁ -C ₆ alkyl groups optionally substituted with 1-2 -COOR ⁴ groups, C ₁ -C ₄ alkylene-phenylene group or phenylene-C ₁ -C ₄ alkylene group, more preferably a C ₁ -C ₆ alkylene group optionally substituted with 1-2 C ₁ -C ₆ alkyl groups optionally substituted with 1-2 -COOR ⁴ groups, or a phenylene-C ₁ -C ₄ alkylene group, even more preferably a methylene group, optionally substituted C ₁ -C ₆ alkyl group npoy, optionally substituted with -COOR ⁴ group.

In another embodiment, L ²² is a C ₁ -C ₂ alkylene group, preferably a methylene group.

In another embodiment, L ²² is a C ₁ -C ₂ alkylene group optionally substituted with 1-2 C ₁ -C ₂ alkyl groups optionally substituted with 1-2 -COOR ⁴ groups, or a phenylene-C ₁ -C ₂ alkylene group .

In one embodiment, R ⁴ in the "-COOR ⁴ group" in L ³ is each independently a hydrogen atom or a C ₁ -C ₄ alkyl group optionally substituted with one trimethylsilyl group, preferably a hydrogen atom or a 2-(trimethylsilyl)ethyl group, more preferably a hydrogen atom.

In one embodiment, L ³ is a C ₁ -C ₂ alkylene-phenylene group, where the phenylene moiety is optionally substituted with 1-2 -COOR ⁴ groups, preferably a methylenephenylene group, where the phenylene moiety is optionally substituted with one -COOR ⁴ group.

In one embodiment, R ⁵ and R ⁶ are each independently a hydrogen atom, a halogen atom, a C ₁ -C ₄ alkyl group, or a C ₁ -C ₄ alkoxy group, preferably a hydrogen atom, a fluorine atom, a methyl group, or a methoxy group. ; more preferably R ⁵ and R ⁶ each represents a hydrogen atom.

In another embodiment, any of R ⁵ and any of R ⁶ may be combined with each other to form a C ₁ -C ₄ alkyleneoxy group, preferably a trimethyleneoxy group.

In one embodiment, s and t are each independently an integer from 1 to 3, preferably an integer from 1 to 2, more preferably each is 1.

In one embodiment, at least one of R ¹ , R ³ , R ⁴ and G is a hydrogen atom. In another embodiment, at least one of R ¹ and R ⁴ is a hydrogen atom. In another embodiment, R ¹ , R ³ , R ⁴ and G each represents a hydrogen atom.

In one embodiment, at least one of R ¹ , R ³ , R ⁴ , G ¹¹ and G ¹² is a hydrogen atom. In another embodiment, at least one of R ¹ and R ⁴ is a hydrogen atom. In another embodiment, R ¹ , R ³ , R ⁴ , G ¹¹ and G ¹² each represents a hydrogen atom.

In one embodiment, Z is an arylene group, a heteroarylene group, a single bond, or a C ₂ -C ₃₀ alkylene group (provided that one or more methylene groups in the chain of said alkylene group may be replaced by a group(s) independently selected (s) from the group consisting of -C(=O)-, -NR ⁷ -, -O-, an arylene group and a heteroarylene group, and R ⁷ represents a hydrogen atom or a C ₁ -C ₄ alkyl group).

In another embodiment, Z is a single bond, a C ₆ -C ₁₂ arylene group, -(CH ₂ -CH ₂ -O) _m -CH ₂ -CH ₂ -, -(CH ₂ -O-CH ₂ ) _m - , -(CH ₂ ) _m -(C ₆ -C ₁₂ arylene) -(CH ₂ ) _m - or -(CH ₂ ) _n -, preferably a single bond, a biphenylene group, -(CH ₂ -CH ₂ -O) _m -CH ₂ -CH ₂ -, -(CH ₂ -O-CH ₂ ) _m -, -(CH ₂ ) _m -biphenylene-(CH ₂ ) _m - or -(CH ₂ ) _n -, more preferably a single bond, [1,1'-biphenyl]-3,3'-diyl, -(CH ₂ -CH ₂ -O) _m -CH ₂ -CH ₂ -, -(CH ₂ -O-CH ₂ ) _m -, -( CH ₂ ) _m -([1,1'-biphenyl]-3,3'-diyl)-(CH ₂ ) _m - or -(CH ₂ ) _n -, even more preferably -(CH ₂ -CH ₂ -O ) _m -CH ₂ -CH ₂ - or -(CH ₂ ) _n -, particularly preferably -(CH ₂ -CH ₂ -O) _m -CH ₂ -CH ₂ -.

In one embodiment, m is an integer from 1 to 6 and n is an integer from 2 to 12, preferably m is an integer from 1 to 4 and n is an integer from 2 to 6.

In another embodiment, m is an integer from 1 to 6 and n is an integer from 2 to 12, preferably m is an integer from 1 to 4.

In one embodiment, "a group obtained by removing any hydrogen atom or any hydroxy group from a compound having the general formula (II)" is a group obtained by removing any hydrogen atom or any hydroxy group present in X or Y of the compound, having the general formula (II). "Any hydrogen atom" is preferably a hydrogen atom that is bonded to any nitrogen atom or any oxygen atom, more preferably a hydrogen atom that is bonded to any nitrogen atom. "Any hydroxy group" is a hydroxy group present in any hydroxy group or any carboxyl group, more preferably a hydroxy group present in any carboxyl group.

In one embodiment of Compound (I),

A ¹ has the structure represented by the formula

or

:

:

A ² has the structure represented by the formula

or

:

:

Z represents a single bond, C ₆ -C ₁₂ arylene group, -(CH ₂ -CH ₂ -O) _m -CH ₂ -CH ₂ -, -(CH ₂ -O-CH ₂ ) _m -, -(CH ₂ ) _m -(C ₆ -C ₁₂ arylene)-(CH ₂ ) _m - or -(CH ₂ ) _n -;

m is an integer from 1 to 6; and

n is an integer from 2 to 12.

In one embodiment of Compound (I),

A ¹ has the structure represented by the formula

: и

: and

A ² has the structure represented by the formula

.

.

In one embodiment of Compound (I),

A ¹ has the structure represented by the formula

: и

: and

A ² has the structure represented by the formula

.

.

In one embodiment of Compound (I),

A ¹ has the structure represented by the formula

: и

: and

A ² has the structure represented by the formula

.

.

In one embodiment of Compound (I),

A ¹ has the structure represented by the formula

: и

: and

A ² has the structure represented by the formula

.

.

In one embodiment of Compound (I),

A ¹ has the structure represented by the formula

or

: и

: and

A ² has the structure represented by the formula

or

.

.

In one embodiment of Compound (I),

A ¹ has the structure represented by the formula

:

:

and

A ² has the structure represented by the formula

.

.

Compound (III) and Compound (IV)

In one embodiment, Compound (I) has the structure represented by the following general formula (III):

or the general formula (IV) shown below:

.

.

In one embodiment of Compound (III) and Compound (IV), a compound or a pharmaceutically acceptable salt thereof is described, wherein

R ¹ each independently represents a hydrogen atom or a tert-butoxycarbonyl group;

W ¹ and W ² are each independently a single bond or a C ₁ -C ₄ alkylene group;

X ¹ is -C(=O)-, -OC(=O)- or -NG ¹¹ -SO ₂ -;

X ^1' is -NG ^Z -SO ₂ -;

X ² is -C(=O)-, -C(=O)-O- or -SO ₂ -NG ¹² -;

X ^2' is -SO ₂ -NG ^Z -;

G ¹¹ and G ¹² are each independently a hydrogen atom, a C ₁ -C ₄ alkyl group, or —COOR ² ;

G ^Z is a single bond that connects X ^1' or X ^2' to Z;

R ² is a C ₁ -C ₄ alkyl group optionally substituted with 1-5 aryl groups;

Y ¹ is -NG ²¹ -, -NG ²¹ -L ¹¹ -C(=O)-, -NG ²¹ -L ¹¹ -C(=O)-NH-, -NG ²¹ -L ¹¹ -C(=O )-NG ³¹ -L ²¹ -C(=O)-, -NG ²¹ -L ¹¹ -C(=O)-NG ³¹ -L ²¹ -C(=O)-NH-, -NG ²¹ -L ³ - O- or -NG ²¹ -G ^4' -;

Y ^1' is -NG ²¹ H, -NG ²¹ -L ¹¹ -COOH or -NG ²¹ -L ¹¹ -C(=O)-NG ³¹ -L ²¹ -COOH;

Y ² is -NG ²² -, -C(=O)-L ¹² -NG ²² -, -NH-C(=O) -L ¹² -NG ²² -, -C(=O) -L ²² -NG ³² -C(=O)-L ¹² -NG ²² -, -NH-C(=O)-L ²² -NG ³² -C(=O)-L ¹² -NG ²² -, -OL ³ -NG ²² - or -G ^4' -NG ²² -;

Y ^2' is HNG ²² -, HOOC-L ¹² -NG ²² - or HOOC-L ²² -NG ³² -C(=O) -L ¹² -NG ²² -;

G ²¹ , G ³¹ , G ²² and G ³² are each independently a hydrogen atom or a C ₁ -C ₆ alkyl group optionally substituted with 1-5 substituents independently selected from the group consisting of a phenyl group optionally substituted with 1-5 -COOR ³ groups, and -COOR ³ groups;

G ^4' represents a C ₁ -C ₄ alkylene group or a C ₁ -C ₄ alkyleneoxy-C ₁ -C ₄ alkylene group;

R ³ each independently represents a hydrogen atom, a benzyl group or a tert-butyl group;

L ¹¹ , L ²¹ , L ¹² and L ²² are each independently a C ₁ -C ₆ alkylene group optionally substituted with 1-5 C ₁ -C ₆ alkyl groups optionally substituted with 1-5 -COOR ⁴ groups, C ₁ -C ₄ alkylene-phenylene group or phenylene-C ₁ -C ₄ alkylene group;

L ³ represents a C ₁ -C ₄ alkylene-phenylene group, where the phenylene fragment is optionally substituted with 1-3 -COOR ⁴ groups;

R ⁴ each independently represents a hydrogen atom, a benzyl group, a 2-(trimethylsilyl)ethyl group, or a tert-butyl group;

R ⁵ and R ⁶ are each independently a hydrogen atom, a halogen atom, a C ₁ -C ₄ alkyl group, or a C ₁ -C ₄ alkoxy group;

each R ⁵ may be the same or different from each other;

Z represents a single bond, C ₆ -C ₁₂ arylene group, -(CH ₂ -CH ₂ -O) _m -CH ₂ -CH ₂ -, -(CH ₂ -O-CH ₂ ) _m -, -(CH ₂ ) _m -(C ₆ -C ₁₂ arylene)-(CH ₂ ) _m - or -(CH ₂ ) _n -;

m is an integer from 1 to 6; and

n is an integer from 2 to 12

In one embodiment of Compound (III) and Compound (IV), a compound or a pharmaceutically acceptable salt thereof is described, wherein

R ¹ each represents a hydrogen atom;

W ¹ and W ² are each independently a single bond or a C ₁ -C ₄ alkylene group;

X ¹ is -C(=O)-, -OC(=O)- or -NG ¹¹ -SO ₂ -;

X ^1' is -NG ^Z -SO ₂ -;

X ² is -C(=O)-, -C(=O)-O- or -SO ₂ -NG ¹² -;

X ^2' is -SO ₂ -NG ^Z -;

G ¹¹ and G ¹² are each independently a hydrogen atom, a C ₁ -C ₄ alkyl group, or —COOR ² ;

G ^Z is a single bond that connects X ^1' or X ^2' to Z;

R ² is a C ₁ -C ₄ alkyl group optionally substituted with 1-5 aryl groups;

Y ¹ is -NG ²¹ -, -NG ²¹ -L ¹¹ -C(=O)-, -NG ²¹ -L ¹¹ -C(=O)-NH-, -NG ²¹ -L ¹¹ -C(=O )-NG ³¹ -L ²¹ -C(=O)-, -NG ²¹ -L ¹¹ -C(=O)-NG ³¹ -L ²¹ -C(=O)-NH-, -NG ²¹ -L ³ - O- or -NG ²¹ -G ^4' -;

Y ^1' is -NG ²¹ H, -NG ²¹ -L ¹¹ -COOH or -NG ²¹ -L ¹¹ -C(=O)-NG ³¹ -L ²¹ -COOH;

Y ² is -NG ²² -, -C(=O)-L ¹² -NG ²² -, -NH-C(=O) -L ¹² -NG ²² -, -C(=O) -L ²² -NG ³² -C(=O)-L ¹² -NG ²² -, -NH-C(=O)-L ²² -NG ³² -C(=O)-L ¹² -NG ²² -, -OL ³ -NG ²² - or -G ^4' -NG ²² -;

Y ^2' is HNG ²² -, HOOC-L ¹² -NG ²² - or HOOC-L ²² -NG ³² -C(=O) -L ¹² -NG ²² -;

G ²¹ , G ³¹ , G ²² and G ³² are each independently a hydrogen atom or a C ₁ -C ₆ alkyl group optionally substituted with 1-5 substituents independently selected from the group consisting of a phenyl group optionally substituted with 1-5 -COOR ³ groups, and -COOR ³ groups;

G ^4' represents a C ₁ -C ₄ alkylene group or a C ₁ -C ₄ alkyleneoxy-C ₁ -C ₄ alkylene group;

R ³ each independently represents a hydrogen atom, a benzyl group or a tert-butyl group;

L ¹¹ , L ²¹ , L ¹² and L ²² are each independently a C ₁ -C ₆ alkylene group optionally substituted with 1-5 C ₁ -C ₆ alkyl groups optionally substituted with 1-5 -COOR ⁴ groups, C ₁ -C ₄ alkylene-phenylene group or phenylene-C ₁ -C ₄ alkylene group;

L ³ represents a C ₁ -C ₄ alkylene-phenylene group, where the phenylene fragment is optionally substituted with 1-3 -COOR ⁴ groups;

R ⁴ each represents a hydrogen atom;

R ⁵ and R ⁶ are each independently a hydrogen atom, a halogen atom, a C ₁ -C ₄ alkyl group, or a C ₁ -C ₄ alkoxy group;

all R ⁵ may be the same or different from each other;

Z represents a single bond, C ₆ -C ₁₂ arylene group, -(CH ₂ -CH ₂ -O) _m -CH ₂ -CH ₂ -, -(CH ₂ -O-CH ₂ ) _m -, -(CH ₂ ) _m -(C ₆ -C ₁₂ arylene)-(CH ₂ ) _m - or -(CH ₂ ) _n -;

m is an integer from 1 to 6; and

n is an integer from 2 to 12

[0080]

In one embodiment of Compound (III) and Compound (IV), a compound or a pharmaceutically acceptable salt thereof is described, wherein

R ¹ each represents a hydrogen atom;

W ¹ and W ² are each independently a single bond or a C ₁ -C ₄ alkylene group;

X ¹ is -C(=O)-, -OC(=O)- or -NG ¹¹ -SO ₂ -;

X ^1' is -NG ^Z -SO ₂ -;

X ² is -C(=O)-, -C(=O)-O- or -SO ₂ -NG ¹² -;

X ^2' is -SO ₂ -NG ^Z -;

G ¹¹ and G ¹² each represents a hydrogen atom;

G ^Z is a single bond that connects X ^1' or X ^2' to Z;

Y ¹ is -NG ²¹ -, -NG ²¹ -L ¹¹ -C(=O)-, -NG ²¹ -L ¹¹ -C(=O)-NH-,
-NG ²¹ -L ¹¹ -C(=O)-NG ³¹ -L ²¹ -C(=O)-, -NG ²¹ -L ¹¹ -C(=O)-NG ³¹ -L ²¹ -C(=O) -NH-,
-NG ²¹ -L ³ -O- or -NG ²¹ -G ^4' -;

Y ^1' is -NG ²¹ H, -NG ²¹ -L ¹¹ -COOH or -NG ²¹ -L ¹¹ -C(=O)-NG ³¹ -L ²¹ -COOH;

Y ² is -NG ²² -, -C(=O)-L ¹² -NG ²² -, -NH-C(=O)-L ¹² -NG ²² -,
-C(=O)-L ²² -NG ³² -C(=O)-L ¹² -NG ²² -, -NH-C(=O)-L ²² -NG ³² -C(=O)-L ¹² - NG ²² -, -OL ³ -NG ²² - or -G ^4' -NG ²² -;

Y ^2' is HNG ²² -, HOOC-L ¹² -NG ²² - or HOOC-L ²² -NG ³² -C(=O) -L ¹² -NG ²² -;

G ²¹ , G ³¹ , G ²² and G ³² are each independently a hydrogen atom or a C ₁ -C ₆ alkyl group optionally substituted with 1-5 substituents independently selected from the group consisting of a phenyl group optionally substituted with 1-5 -COOR ³ groups, and -COOR ³ groups;

G ^4' represents a C ₁ -C ₄ alkylene group or a C ₁ -C ₄ alkyleneoxy-C ₁ -C ₄ alkylene group;

R ³ each represents a hydrogen atom;

L ¹¹ , L ²¹ , L ¹² and L ²² are each independently a C ₁ -C ₆ alkylene group optionally substituted with 1-5 C ₁ -C ₆ alkyl groups optionally substituted with 1-5 -COOR ⁴ groups, C ₁ -C ₄ alkylene-phenylene group or phenylene-C ₁ -C ₄ alkylene group;

L ³ represents a C ₁ -C ₄ alkylene-phenylene group, where the phenylene fragment is optionally substituted with 1-3 -COOR ⁴ groups;

R ⁴ each represents a hydrogen atom;

R ⁵ and R ⁶ are each independently a hydrogen atom, a halogen atom, a C ₁ -C ₄ alkyl group, or a C ₁ -C ₄ alkoxy group;

all R ⁵ may be the same or different from each other;

Z represents a single bond, C ₆ -C ₁₂ arylene group, -(CH ₂ -CH ₂ -O) _m -CH ₂ -CH ₂ -, -(CH ₂ -O-CH ₂ ) _m -, -(CH ₂ ) _m -(C ₆ -C ₁₂ arylene)-(CH ₂ ) _m - or -(CH ₂ ) _n -;

m is an integer from 1 to 6; and

n is an integer from 2 to 12

In another embodiment of Compound (III) and Compound (IV), a compound or a pharmaceutically acceptable salt thereof is described, wherein

R ¹ each independently represents a hydrogen atom or a tert-butoxycarbonyl group;

W ¹ and W ² are each independently a single bond or a C ₁ -C ₄ alkylene group;

X ¹ is -C(=O)-, -OC(=O)- or -NG ¹¹ -SO ₂ -;

X ^1' is -NG ^Z -SO ₂ -;

X ² is -C(=O)-, -C(=O)-O- or -SO ₂ -NG ¹² -;

X ^2' is -SO ₂ -NG ^Z -;

G ¹¹ and G ¹² are each independently a hydrogen atom, a C ₁ -C ₄ alkyl group, or —COOR ² ;

G ^Z is a single bond that connects X ^1' or X ^2' to Z;

R ² is a C ₁ -C ₄ alkyl group optionally substituted with 1-3 aryl groups;

Y ¹ is -NG ²¹ -, -NG ²¹ -L ¹¹ -C(=O)-, -NG ²¹ -L ¹¹ -C(=O)-NH-, -NG ²¹ -L ¹¹ -C(=O )-NG ³¹ -L ²¹ -C(=O)-, -NG ²¹ -L ¹¹ -C(=O)-NG ³¹ -L ²¹ -C(=O)-NH- or -NG ²¹ -L ³ - O-;

Y ^1' is -NG ²¹ H, -NG ²¹ -L ¹¹ -COOH or -NG ²¹ -L ¹¹ -C(=O)-NG ³¹ -L ²¹ -COOH;

Y ² is -NG ²² -, -C(=O)-L ¹² -NG ²² -, -NH-C(=O) -L ¹² -NG ²² -, -C(=O) -L ²² -NG ³² -C(=O)-L ¹² -NG ²² -, -NH-C(=O)-L ²² -NG ³² -C(=O)-L ¹² -NG ²² - or -OL ³ -NG ²² - ;

Y ^2' is HNG ²² -, HOOC-L ¹² -NG ²² - or HOOC-L ²² -NG ³² -C(=O) -L ¹² -NG ²² -;

G ²¹ , G ³¹ , G ²² and G ³² are each independently a hydrogen atom or a C ₁ -C ₆ alkyl group optionally substituted with 1-3 substituents independently selected from the group consisting of a phenyl group optionally substituted with 1-3 -COOR ³ groups, and -COOR ³ groups;

R ³ each independently represents a hydrogen atom, a benzyl group or a tert-butyl group;

L ¹¹ , L ²¹ , L ¹² and L ²² are each independently a C ₁ -C ₆ alkylene group optionally substituted with 1-5 C ₁ -C ₆ alkyl groups optionally substituted with 1-5 -COOR ⁴ groups, C ₁ -C ₄ alkylene-phenylene group or phenylene-C ₁ -C ₄ alkylene group;

L ³ represents a C ₁ -C ₂ alkylene-phenylene group, where the phenylene fragment is optionally substituted with 1-2 -COOR ⁴ groups;

R ⁴ each independently represents a hydrogen atom, a benzyl group, a 2-(trimethylsilyl)ethyl group, or a tert-butyl group;

R ⁵ and R ⁶ are each independently a hydrogen atom, a halogen atom, a C ₁ -C ₄ alkyl group, or a C ₁ -C ₄ alkoxy group;

all R ⁵ may be the same or different from each other;

Z is a single bond, a biphenylene group, -(CH ₂ -CH ₂ -O) _m -CH ₂ -CH ₂ -, -(CH ₂ -O-CH ₂ ) _m -, -(CH ₂ ) _m -biphenylene- (CH ₂ ) _m - or -(CH ₂ ) _n -;

m is an integer from 1 to 6; and

n is an integer from 2 to 12

In another embodiment of Compound (III) and Compound (IV), a compound or a pharmaceutically acceptable salt thereof is described, wherein

R ¹ each represents a hydrogen atom;

W ¹ and W ² are each independently a single bond or a C ₁ -C ₄ alkylene group;

X ¹ is -C(=O)-, -OC(=O)- or -NG ¹¹ -SO ₂ -;

X ^1' is -NG ^Z -SO ₂ -;

X ² is -C(=O)-, -C(=O)-O- or -SO ₂ -NG ¹² -;

X ^2' is -SO ₂ -NG ^Z -;

G ¹¹ and G ¹² are each independently a hydrogen atom, a C ₁ -C ₄ alkyl group, or —COOR ² ;

G ^Z is a single bond that connects X ^1' or X ^2' to Z;

R ² is a C ₁ -C ₄ alkyl group optionally substituted with 1-3 phenyl groups;

Y ¹ is -NG ²¹ -, -NG ²¹ -L ¹¹ -C(=O)-, -NG ²¹ -L ¹¹ -C(=O)-NH-, -NG ²¹ -L ¹¹ -C(=O )-NG ³¹ -L ²¹ -C(=O)-, -NG ²¹ -L ¹¹ -C(=O)-NG ³¹ -L ²¹ -C(=O)-NH- or -NG ²¹ -L ³ - O-;

Y ^1' is -NG ²¹ H, -NG ²¹ -L ¹¹ -COOH or -NG ²¹ -L ¹¹ -C(=O)-NG ³¹ -L ²¹ -COOH;

Y ² is -NG ²² -, -C(=O)-L ¹² -NG ²² -, -NH-C(=O) -L ¹² -NG ²² -, -C(=O) -L ²² -NG ³² -C(=O)-L ¹² -NG ²² -, -NH-C(=O)-L ²² -NG ³² -C(=O)-L ¹² -NG ²² - or -OL ³ -NG ²² - ;

Y ^2' is HNG ²² -, HOOC-L ¹² -NG ²² - or HOOC-L ²² -NG ³² -C(=O) -L ¹² -NG ²² -;

G ²¹ , G ³¹ , G ²² and G ³² are each independently a hydrogen atom or a C ₁ -C ₆ alkyl group optionally substituted with 1-3 substituents independently selected from the group consisting of a phenyl group optionally substituted with 1-3 -COOR ³ groups, and -COOR ³ groups;

R ³ each represents a hydrogen atom;

L ¹¹ , L ²¹ , L ¹² and L ²² are each independently a C ₁ -C ₆ alkylene group optionally substituted with 1-2 C ₁ -C ₆ alkyl groups optionally substituted with 1-2 -COOR ⁴ groups, C ₁ -C ₄ alkylene-phenylene group or phenylene-C ₁ -C ₄ alkylene group;

L ³ represents a C ₁ -C ₂ alkylene-phenylene group, where the phenylene fragment is optionally substituted with 1-2 -COOR ⁴ groups;

R ⁴ each represents a hydrogen atom;

R ⁵ and R ⁶ are each independently a hydrogen atom, a fluorine atom, a methyl group, or a methoxy group;

each R ⁵ may be the same or different from each other;

Z is a single bond, a biphenylene group, -(CH ₂ -CH ₂ -O) _m -CH ₂ -CH ₂ -, -(CH ₂ -O-CH ₂ ) _m -, -(CH ₂ ) _m -biphenylene- (CH ₂ ) _m - or -(CH ₂ ) _n -;

m is an integer from 1 to 6; and

n is an integer from 2 to 12

In another embodiment of Compound (III) and Compound (IV), a compound or a pharmaceutically acceptable salt thereof is described, wherein

R ¹ each represents a hydrogen atom;

W ¹ and W ² are each independently a single bond or a C ₁ -C ₄ alkylene group;

X ¹ is -C(=O)-, -OC(=O)- or -NG ¹¹ -SO ₂ -;

X ^1' is -NG ^Z -SO ₂ -;

X ² is -C(=O)-, -C(=O)-O- or -SO ₂ -NG ¹² -;

X ^2' is -SO ₂ -NG ^Z -;

G ¹¹ and G ¹² each represents a hydrogen atom;

G ^Z is a single bond that connects X ^1' or X ^2' to Z;

Y ¹ is -NG ²¹ -, -NG ²¹ -L ¹¹ -C(=O)-, -NG ²¹ -L ¹¹ -C(=O)-NH-, -NG ²¹ -L ¹¹ -C(=O )-NG ³¹ -L ²¹ -C(=O)-, -NG ²¹ -L ¹¹ -C(=O)-NG ³¹ -L ²¹ -C(=O)-NH- or -NG ²¹ -L ³ - O-;

Y ^1' is -NG ²¹ H, -NG ²¹ -L ¹¹ -COOH or -NG ²¹ -L ¹¹ -C(=O)-NG ³¹ -L ²¹ -COOH;

Y ² is -NG ²² -, -C(=O)-L ¹² -NG ²² -, -NH-C(=O) -L ¹² -NG ²² -, -C(=O) -L ²² -NG ³² -C(=O)-L ¹² -NG ²² -, -NH-C(=O)-L ²² -NG ³² -C(=O)-L ¹² -NG ²² - or -OL ³ -NG ²² - ;

Y ^2' is HNG ²² -, HOOC-L ¹² -NG ²² - or HOOC-L ²² -NG ³² -C(=O) -L ¹² -NG ²² -;

G ²¹ , G ³¹ , G ²² and G ³² are each independently a hydrogen atom or a C ₁ -C ₆ alkyl group optionally substituted with 1-3 substituents independently selected from the group consisting of a phenyl group optionally substituted with 1-3 -COOR ³ groups, and -COOR ³ groups;

R ³ each represents a hydrogen atom;

L ¹¹ , L ²¹ , L ¹² and L ²² are each independently a C ₁ -C ₆ alkylene group optionally substituted with 1-2 C ₁ -C ₆ alkyl groups optionally substituted with 1-2 -COOR ⁴ groups, C ₁ -C ₄ alkylene-phenylene group or phenylene-C ₁ -C ₄ alkylene group;

L ³ represents a C ₁ -C ₂ alkylene-phenylene group, where the phenylene fragment is optionally substituted with 1-2 -COOR ⁴ groups;

R ⁴ each represents a hydrogen atom;

R ⁵ and R ⁶ are each independently a hydrogen atom, a fluorine atom, a methyl group, or a methoxy group;

all R ⁵ may be the same or different from each other;

Z is a single bond, a biphenylene group, -(CH ₂ -CH ₂ -O) _m -CH ₂ -CH ₂ -, -(CH ₂ -O-CH ₂ ) _m -, -(CH ₂ ) _m -biphenylene- (CH ₂ ) _m - or -(CH ₂ ) _n -;

m is an integer from 1 to 6; and

n is an integer from 2 to 12

In another embodiment of Compound (III) and Compound (IV), a compound or a pharmaceutically acceptable salt thereof is described, wherein

R ¹ each represents a hydrogen atom;

W ¹ and W ² are each independently a single bond or a C ₁ -C ₄ alkylene group;

X ¹ is -C(=O)-, -OC(=O)- or -NG ¹¹ -SO ₂ -;

X ^1' is -NG ^Z -SO ₂ -;

X ² is -C(=O)-, -C(=O)-O- or -SO ₂ -NG ¹² -;

X ^2' is -SO ₂ -NG ^Z -;

G ¹¹ and G ¹² are each independently a hydrogen atom, a C ₁ -C ₄ alkyl group, or —COOR ² ;

G ^Z is a single bond that connects X ^1' or X ^2' to Z;

R ² is a C ₁ -C ₄ alkyl group optionally substituted with one phenyl group;

Y ¹ is -NG ²¹ -, -NG ²¹ -L ¹¹ -C(=O)-, -NG ²¹ -L ¹¹ -C(=O)-NH-, -NG ²¹ -L ¹¹ -C(=O )-NG ³¹ -L ²¹ -C(=O)-, -NG ²¹ -L ¹¹ -C(=O)-NG ³¹ -L ²¹ -C(=O)-NH- or -NG ²¹ -L ³ - O-;

Y ^1' is -NG ²¹ H, -NG ²¹ -L ¹¹ -COOH or -NG ²¹ -L ¹¹ -C(=O)-NG ³¹ -L ²¹ -COOH;

Y ² is -NG ²² -, -C(=O)-L ¹² -NG ²² -, -NH-C(=O) -L ¹² -NG ²² -, -C(=O) -L ²² -NG ³² -C(=O)-L ¹² -NG ²² -, -NH-C(=O)-L ²² -NG ³² -C(=O)-L ¹² -NG ²² - or -OL ³ -NG ²² - ;

Y ^2' is HNG ²² -, HOOC-L ¹² -NG ²² - or HOOC-L ²² -NG ³² -C(=O) -L ¹² -NG ²² -;

G ²¹ and G ²² are each independently a hydrogen atom or a C ₁ -C ₃ alkyl group substituted with 1-3 carboxyl groups;

G ³¹ and G ³² each represents a hydrogen atom;

L ¹¹ and L ²¹ are each independently a C ₁ -C ₆ alkylene group optionally substituted with 1-2 C ₁ -C ₆ alkyl groups optionally substituted with 1-2 -COOR ⁴ groups, or a C ₁ -C ₄ alkylene-phenylene group ;

L ¹² and L ²² are each independently a C ₁ -C ₆ alkylene group optionally substituted with 1-2 C ₁ -C ₆ alkyl groups optionally substituted with 1-2 -COOR ⁴ groups, or a phenylene-C ₁ -C ₄ alkylene group ;

L ³ represents a methylenephenylene group, where the phenylene moiety is optionally substituted with one —COOR ⁴ group;

R ⁴ represents a hydrogen atom;

R ⁵ and R ⁶ are each independently a hydrogen atom, a fluorine atom, a methyl group, or a methoxy group;

each R ⁵ may be the same or different from each other;

Z is a single bond, [1,1'-biphenyl]-3,3'-diyl, -(CH ₂ -CH ₂ -O) _m -CH ₂ -CH ₂ -, -(CH ₂ -O-CH ₂ ) _m -, -(CH ₂ ) _m -([1,1'-biphenyl]-3,3'-diyl)-(CH ₂ ) _m - or -(CH ₂ ) _n -;

m is an integer from 1 to 6; and

n is an integer from 2 to 12

In another embodiment of Compound (III) and Compound (IV), a compound or a pharmaceutically acceptable salt thereof is described, wherein

R ¹ each represents a hydrogen atom;

W ¹ and W ² are each independently a single bond or a C ₁ -C ₄ alkylene group;

X ¹ is -C(=O)-, -OC(=O)- or -NG ¹¹ -SO ₂ -;

X ^1' is -NG ^Z -SO ₂ -;

X ² is -C(=O)-, -C(=O)-O- or -SO ₂ -NG ¹² -;

X ^2' is -SO ₂ -NG ^Z -;

G ¹¹ and G ¹² each represents a hydrogen atom;

G ^Z is a single bond that connects X ^1' or X ^2' to Z;

Y ¹ is -NG ²¹ -, -NG ²¹ -L ¹¹ -C(=O)-, -NG ²¹ -L ¹¹ -C(=O)-NH-, -NG ²¹ -L ¹¹ -C(=O )-NG ³¹ -L ²¹ -C(=O)-, -NG ²¹ -L ¹¹ -C(=O)-NG ³¹ -L ²¹ -C(=O)-NH- or -NG ²¹ -L ³ - O-;

Y ^1' is -NG ²¹ H, -NG ²¹ -L ¹¹ -COOH or -NG ²¹ -L ¹¹ -C(=O)-NG ³¹ -L ²¹ -COOH;

Y ² is -NG ²² -, -C(=O)-L ¹² -NG ²² -, -NH-C(=O) -L ¹² -NG ²² -, -C(=O) -L ²² -NG ³² -C(=O)-L ¹² -NG ²² -, -NH-C(=O)-L ²² -NG ³² -C(=O)-L ¹² -NG ²² - or -OL ³ -NG ²² - ;

Y ^2' is HNG ²² -, HOOC-L ¹² -NG ²² - or HOOC-L ²² -NG ³² -C(=O) -L ¹² -NG ²² -;

G ²¹ and G ²² are each independently a hydrogen atom or a C ₁ -C ₃ alkyl group substituted with 1-3 carboxyl groups;

G ³¹ and G ³² each represents a hydrogen atom;

L ¹¹ and L ²¹ are each independently a C ₁ -C ₆ alkylene group optionally substituted with 1-2 C ₁ -C ₆ alkyl groups optionally substituted with 1-2 -COOR ⁴ groups, or a C ₁ -C ₄ alkylene-phenylene group ;

L ¹² and L ²² are each independently a C ₁ -C ₆ alkylene group optionally substituted with 1-2 C ₁ -C ₆ alkyl groups optionally substituted with 1-2 -COOR ⁴ groups, or a phenylene-C ₁ -C ₄ alkylene group ;

L ³ represents a methylenephenylene group, where the phenylene moiety is optionally substituted with one —COOR ⁴ group;

R ⁴ represents a hydrogen atom;

R ⁵ and R ⁶ are each independently a hydrogen atom, a fluorine atom, a methyl group, or a methoxy group;

all R ⁵ may be the same or different from each other;

Z is a single bond, [1,1'-biphenyl]-3,3'-diyl, -(CH ₂ -CH ₂ -O) _m -CH ₂ -CH ₂ -, -(CH ₂ -O-CH ₂ ) _m -, -(CH ₂ ) _m -([1,1'-biphenyl]-3,3'-diyl)-(CH ₂ ) _m - or -(CH ₂ ) _n -;

m is an integer from 1 to 6; and

n is an integer from 2 to 12

In another embodiment of Compound (III) and Compound (IV), a compound or a pharmaceutically acceptable salt thereof is described, wherein

R ¹ each represents a hydrogen atom;

W ¹ and W ² are each independently a single bond or a C ₁ -C ₄ alkylene group;

X ¹ is -C(=O)- or -NG ¹¹ -SO ₂ -;

X ^1' is -NG ^Z -SO ₂ -;

X ² represents -C(=O)- or -SO ₂ -NG ¹² -;

X ^2' is -SO ₂ -NG ^Z -;

G ¹¹ and G ¹² are each independently a hydrogen atom or
-COOR ² ;

G ^Z is a single bond that connects X ^1' or X ^2' to Z;

R ² is a C ₁ -C ₄ alkyl group optionally substituted with one phenyl group;

Y ¹ is -NG ²¹ -;

Y ^1' is -NG ²¹ H;

Y ² is -NG ²² -;

Y ^2' is HNG ²² -;

G ²¹ and G ²² are each independently a hydrogen atom or a C ₁ -C ₃ alkyl group substituted with 1-3 carboxyl groups;

R ⁵ and R ⁶ are each independently a hydrogen atom, a fluorine atom, a methyl group, or a methoxy group;

each R ⁵ may be the same or different from each other;

Z is a single bond, [1,1'-biphenyl]-3,3'-diyl, -(CH ₂ -CH ₂ -O) _m -CH ₂ -CH ₂ -, -(CH ₂ -O-CH ₂ ) _m -, -(CH ₂ ) _m -([1,1'-biphenyl]-3,3'-diyl)-(CH ₂ ) _m - or -(CH ₂ ) _n -;

m is an integer from 1 to 6; and

n is an integer from 2 to 12.

In another embodiment of Compound (III) and Compound (IV), a compound or a pharmaceutically acceptable salt thereof is described, wherein

R ¹ each represents a hydrogen atom;

W ¹ and W ² are each independently a single bond or a C ₁ -C ₄ alkylene group;

X ¹ is -C(=O)- or -NG ¹¹ -SO ₂ -;

X ^1' is -NG ^Z -SO ₂ -;

X ² represents -C(=O)- or -SO ₂ -NG ¹² -;

X ^2' is -SO ₂ -NG ^Z -;

G ¹¹ and G ¹² each represents a hydrogen atom;

G ^Z is a single bond that connects X ^1' or X ^2' to Z;

Y ¹ is -NG ²¹ -;

Y ^1' is -NG ²¹ H;

Y ² is -NG ²² -;

Y ^2' is HNG ²² -;

G ²¹ and G ²² are each independently a hydrogen atom or a C ₁ -C ₃ alkyl group substituted with 1-3 carboxyl groups;

R ⁵ and R ⁶ are each independently a hydrogen atom, a fluorine atom, a methyl group, or a methoxy group;

each R ⁵ may be the same or different from each other;

Z is a single bond, [1,1'-biphenyl]-3,3'-diyl, -(CH ₂ -CH ₂ -O) _m -CH ₂ -CH ₂ -, -(CH ₂ -O-CH ₂ ) _m -, -(CH ₂ ) _m -([1,1'-biphenyl]-3,3'-diyl)-(CH ₂ ) _m - or -(CH ₂ ) _n -;

m is an integer from 1 to 6; and

n is an integer from 2 to 12

In another embodiment of Compound (III) and Compound (IV), a compound or a pharmaceutically acceptable salt thereof is described, wherein

R ¹ each represents a hydrogen atom;

W ¹ and W ² are each independently a single bond or a C ₁ -C ₂ alkylene group;

X ¹ is -C(=O)- or -NG ¹¹ -SO ₂ -;

X ^1' is -NG ^Z -SO ₂ -;

X ² represents -C(=O)- or -SO ₂ -NG ¹² -;

X ^2' is -SO ₂ -NG ^Z -;

G ¹¹ and G ¹² each represents a hydrogen atom;

G ^Z is a single bond that connects X ^1' or X ^2' to Z;

Y ¹ is -NG ²¹ -;

Y ^1' is -NG ²¹ H;

Y ² is -NG ²² -;

Y ^2' is HNG ²² -;

G ²¹ and G ²² are each independently a C ₁ -C ₃ alkyl group substituted with 1-3 carboxyl groups;

R ⁵ and R ⁶ each represents a hydrogen atom;

Z is a single bond, [1,1'-biphenyl]-3,3'-diyl, -(CH ₂ -CH ₂ -O) _m -CH ₂ -CH ₂ -, -(CH ₂ -O-CH ₂ ) _m -, -(CH ₂ ) _m -([1,1'-biphenyl]-3,3'-diyl)-(CH ₂ ) _m - or -(CH ₂ ) _n -;

m is an integer from 1 to 6; and

n is an integer from 2 to 12.

Compound (V) and Compound (VI)

In one embodiment, Compound (I) has the structure represented by the following general formula (V):

where:

R ¹ each independently represents a hydrogen atom or -COO-(C ₁ -C ₄ alkyl group);

W ¹ and W ² are each independently a single bond or a C ₁ -C ₄ alkylene group;

X ¹ is -C(=O)- or -NG ¹¹ -SO ₂ -;

X ² represents -C(=O)- or -SO ₂ -NG ¹² -;

G ¹¹ and G ¹² are each independently a hydrogen atom, a C ₁ -C ₄ alkyl group, or —COOR ² ;

R ² is a C ₁ -C ₄ alkyl group optionally substituted with 1-5 aryl groups;

Y ¹ is -NG ²¹ -, -NG ²¹ -L ¹¹ -C(=O)-, -NG ²¹ -L ¹¹ -C(=O)-NH-, -NG ²¹ -L ¹¹ -C(=O )-NG ³¹ -L ²¹ -C(=O)-, -NG ²¹ -L ¹¹ -C(=O)-NG ³¹ -L ²¹ -C(=O)-NH-, -NG ²¹ -L ³ - O- or -NG ²¹ -G ^4' -;

Y ² is -NG ²² -, -C(=O)-L ¹² -NG ²² -, -NH-C(=O) -L ¹² -NG ²² -, -C(=O) -L ²² -NG ³² -C(=O)-L ¹² -NG ²² -, -NH-C(=O)-L ²² -NG ³² -C(=O)-L ¹² -NG ²² -, -OL ³ -NG ²² - or -G ^4' -NG ²² -;

G ²¹ , G ³¹ , G ²² and G ³² are each independently a hydrogen atom or a C ₁ -C ₆ alkyl group optionally substituted with 1-5 substituents independently selected from the group consisting of a phenyl group optionally substituted with 1-5 -COOR ³ groups, and -COOR ³ groups;

G ^4' represents a C ₁ -C ₄ alkylene group or a C ₁ -C ₄ alkyleneoxy-C ₁ -C ₄ alkylene group;

R ³ each independently represents a hydrogen atom or a C ₁ -C ₄ alkyl group optionally substituted with 1-5 aryl groups;

L ¹¹ , L ²¹ , L ¹² and L ²² are each independently a C ₁ -C ₆ alkylene group optionally substituted with 1-5 C ₁ -C ₆ alkyl groups optionally substituted with 1-5 -COOR ⁴ groups, C ₁ -C ₄ alkylene-phenylene group or phenylene-C ₁ -C ₄ alkylene group;

L ³ represents a C ₁ -C ₄ alkylene-phenylene group, where the phenylene fragment is optionally substituted with 1-3 -COOR ⁴ groups;

R ⁴ each independently represents a hydrogen atom or a C ₁ -C ₄ alkyl group optionally substituted with 1-5 substituents independently selected from the group consisting of an aryl group and a trimethylsilyl group;

R ⁵ each independently represents a hydrogen atom, a halogen atom, a C ₁ -C ₄ alkyl group, or a C ₁ -C ₄ alkoxy group;

Z represents a single bond, C ₆ -C ₁₂ arylene group, -(CH ₂ -CH ₂ -O) _m -CH ₂ -CH ₂ -, -(CH ₂ -O-CH ₂ ) _m -, -(CH ₂ ) _m -(C ₆ -C ₁₂ arylene)-(CH ₂ ) _m - or -(CH ₂ ) _n -;

m is an integer from 1 to 6; and

n is an integer from 2 to 12].

In one embodiment of Compound (V), a compound or a pharmaceutically acceptable salt thereof is described, wherein

R ¹ each represents a hydrogen atom;

W ¹ and W ² are each independently a single bond or a C ₁ -C ₄ alkylene group;

X ¹ is -C(=O)- or -NG ¹¹ -SO ₂ -;

X ² represents -C(=O)- or -SO ₂ -NG ¹² -;

G ¹¹ and G ¹² are each independently a hydrogen atom, a C ₁ -C ₄ alkyl group, or —COOR ² ;

R ² is a C ₁ -C ₄ alkyl group optionally substituted with 1-5 aryl groups;

Y ¹ is -NG ²¹ -, -NG ²¹ -L ¹¹ -C(=O)-, -NG ²¹ -L ¹¹ -C(=O)-NH-, -NG ²¹ -L ¹¹ -C(=O )-NG ³¹ -L ²¹ -C(=O)-, -NG ²¹ -L ¹¹ -C(=O)-NG ³¹ -L ²¹ -C(=O)-NH-, -NG ²¹ -L ³ - O- or -NG ²¹ -G ^4' -;

Y ² is -NG ²² -, -C(=O)-L ¹² -NG ²² -, -NH-C(=O) -L ¹² -NG ²² -, -C(=O) -L ²² -NG ³² -C(=O)-L ¹² -NG ²² -, -NH-C(=O)-L ²² -NG ³² -C(=O)-L ¹² -NG ²² -, -OL ³ -NG ²² - or -G ^4' -NG ²² -;

G ²¹ , G ³¹ , G ²² and G ³² are each independently a hydrogen atom or a C ₁ -C ₆ alkyl group optionally substituted with 1-5 substituents independently selected from the group consisting of a phenyl group optionally substituted with 1-5 -COOR ³ groups, and -COOR ³ groups;

G ^4' represents a C ₁ -C ₄ alkylene group or a C ₁ -C ₄ alkyleneoxy-C ₁ -C ₄ alkylene group;

R ³ each independently represents a hydrogen atom or a C ₁ -C ₄ alkyl group optionally substituted with 1-5 aryl groups;

L ¹¹ , L ²¹ , L ¹² and L ²² are each independently a C ₁ -C ₆ alkylene group optionally substituted with 1-5 C ₁ -C ₆ alkyl groups optionally substituted with 1-5 -COOR ⁴ groups, C ₁ -C ₄ alkylene-phenylene group or phenylene-C ₁ -C ₄ alkylene group;

L ³ represents a C ₁ -C ₄ alkylene-phenylene group, where the phenylene fragment is optionally substituted with 1-3 -COOR ⁴ groups;

R ⁴ each represents a hydrogen atom;

R ⁵ each independently represents a hydrogen atom, a halogen atom, a C ₁ -C ₄ alkyl group, or a C ₁ -C ₄ alkoxy group;

Z represents a single bond, C ₆ -C ₁₂ arylene group, -(CH ₂ -CH ₂ -O) _m -CH ₂ -CH ₂ -, -(CH ₂ -O-CH ₂ ) _m -, -(CH ₂ ) _m -(C ₆ -C ₁₂ arylene)-(CH ₂ ) _m - or -(CH ₂ ) _n -;

m is an integer from 1 to 6; and

n is an integer from 2 to 12

In another embodiment of Compound (V), a compound or a pharmaceutically acceptable salt thereof is described, wherein

R ¹ each represents a hydrogen atom;

W ¹ and W ² are each independently a single bond or a C ₁ -C ₄ alkylene group;

X ¹ is -C(=O)- or -NG ¹¹ -SO ₂ -;

X ² represents -C(=O)- or -SO ₂ -NG ¹² -;

G ¹¹ and G ¹² each represents a hydrogen atom;

Y ¹ is -NG ²¹ -, -NG ²¹ -L ¹¹ -C(=O)-, -NG ²¹ -L ¹¹ -C(=O)-NH-, -NG ²¹ -L ¹¹ -C(=O )-NG ³¹ -L ²¹ -C(=O)-, -NG ²¹ -L ¹¹ -C(=O)-NG ³¹ -L ²¹ -C(=O)-NH-, -NG ²¹ -L ³ - O- or -NG ²¹ -G ^4' -;

Y ² is -NG ²² -, -C(=O)-L ¹² -NG ²² -, -NH-C(=O) -L ¹² -NG ²² -, -C(=O) -L ²² -NG ³² -C(=O)-L ¹² -NG ²² -, -NH-C(=O)-L ²² -NG ³² -C(=O)-L ¹² -NG ²² -, -OL ³ -NG ²² - or -G ^4' -NG ²² -;

G ²¹ , G ³¹ , G ²² and G ³² are each independently a hydrogen atom or a C ₁ -C ₆ alkyl group optionally substituted with 1-5 substituents independently selected from the group consisting of a phenyl group optionally substituted with 1-5 -COOR ³ groups, and -COOR ³ groups;

G ^4' represents a C ₁ -C ₄ alkylene group or a C ₁ -C ₄ alkyleneoxy-C ₁ -C ₄ alkylene group;

R ³ each represents a hydrogen atom;

L ¹¹ , L ²¹ , L ¹² and L ²² are each independently a C ₁ -C ₆ alkylene group optionally substituted with 1-5 C ₁ -C ₆ alkyl groups optionally substituted with 1-5 -COOR ⁴ groups, C ₁ -C ₄ alkylene-phenylene group or phenylene-C ₁ -C ₄ alkylene group;

L ³ represents a C ₁ -C ₄ alkylene-phenylene group, where the phenylene fragment is optionally substituted with 1-3 -COOR ⁴ groups;

R ⁴ each represents a hydrogen atom;

R ⁵ each independently represents a hydrogen atom, a halogen atom, a C ₁ -C ₄ alkyl group, or a C ₁ -C ₄ alkoxy group;

Z represents a single bond, C ₆ -C ₁₂ arylene group, -(CH ₂ -CH ₂ -O) _m -CH ₂ -CH ₂ -, -(CH ₂ -O-CH ₂ ) _m -, -(CH ₂ ) _m -(C ₆ -C ₁₂ arylene)-(CH ₂ ) _m - or -(CH ₂ ) _n -;

m is an integer from 1 to 6; and

n is an integer from 2 to 12

In one embodiment, Compound (V) has the structure represented by the following general formula (VI):

В одном варианте Соединения (VI), описано соединение или его фармацевтически приемлемая соль, где

In one embodiment of Compound (VI), a compound or a pharmaceutically acceptable salt thereof is described, wherein

R ¹ each independently represents a hydrogen atom or a tert-butoxycarbonyl group;

W ¹ and W ² are each independently a single bond or a C ₁ -C ₂ alkylene group;

X ¹ is -C(=O)- or -NG ¹¹ -SO ₂ -;

X ² represents -C(=O)- or -SO ₂ -NG ¹² -;

G ¹¹ and G ¹² each represents a hydrogen atom;

Y ¹ is -NG ²¹ -, -NG ²¹ -L ¹¹ -C(=O)-, -NG ²¹ -L ¹¹ -C(=O)-NH-, -NG ²¹ -L ¹¹ -C(=O )-NG ³¹ -L ²¹ -C(=O)-, -NG ²¹ -L ¹¹ -C(=O)-NG ³¹ -L ²¹ -C(=O)-NH-, -NG ²¹ -L ³ - O- or -NG ²¹ -G ^4' -;

Y ² is -NG ²² -, -C(=O)-L ¹² -NG ²² -, -NH-C(=O) -L ¹² -NG ²² -, -C(=O) -L ²² -NG ³² -C(=O)-L ¹² -NG ²² -, -NH-C(=O)-L ²² -NG ³² -C(=O)-L ¹² -NG ²² -, -OL ³ -NG ²² - or -G ^4' -NG ²² -;

G ²¹ , G ³¹ , G ²² and G ³² are each independently a hydrogen atom or a C ₁ -C ₃ alkyl group optionally substituted with 1-3 -COOR ³ groups;

G ^4' represents a C ₁ -C ₂ alkylene group or a C ₁ -C ₂ alkyleneoxy-C ₁ -C ₂ alkylene group;

R ³ each independently represents a hydrogen atom or a tert-butyl group;

L ¹¹ , L ²¹ , L ¹² and L ²² are each independently a C ₁ -C ₂ alkylene group;

L ³ represents a C ₁ -C ₄ alkylene-phenylene group, where the phenylene fragment is optionally substituted with 1-3 -COOR ⁴ groups;

R ⁴ each independently represents a hydrogen atom or a C ₁ -C ₄ alkyl group optionally substituted with 1-5 substituents independently selected from the group consisting of an aryl group and a trimethylsilyl group;

R ⁵ each independently represents a hydrogen atom, a halogen atom, a C ₁ -C ₄ alkyl group, or a C ₁ -C ₄ alkoxy group;

Z is a single bond, a biphenylene group, -(CH ₂ -CH ₂ -O) _m -CH ₂ -CH ₂ -, -(CH ₂ -O-CH ₂ ) _m -, -(CH ₂ ) _m -biphenylene- (CH ₂ ) _m - or -(CH ₂ ) _n -;

m is an integer from 1 to 6; and

n is an integer from 2 to 12.

In another embodiment of Compound (VI), a compound or a pharmaceutically acceptable salt thereof is described, wherein

R ¹ each represents a hydrogen atom;

W ¹ and W ² are each independently a single bond or a C ₁ -C ₂ alkylene group;

X ¹ is -C(=O)- or -NG ¹¹ -SO ₂ -;

X ² represents -C(=O)- or -SO ₂ -NG ¹² -;

G ¹¹ and G ¹² each represents a hydrogen atom;

Y ¹ is -NG ²¹ -, -NG ²¹ -L ¹¹ -C(=O)-, -NG ²¹ -L ¹¹ -C(=O)-NH-, -NG ²¹ -L ¹¹ -C(=O )-NG ³¹ -L ²¹ -C(=O)-, -NG ²¹ -L ¹¹ -C(=O)-NG ³¹ -L ²¹ -C(=O)-NH-, -NG ²¹ -L ³ - O- or -NG ²¹ -G ^4' -;

Y ² is -NG ²² -, -C(=O)-L ¹² -NG ²² -, -NH-C(=O) -L ¹² -NG ²² -, -C(=O) -L ²² -NG ³² -C(=O)-L ¹² -NG ²² -, -NH-C(=O)-L ²² -NG ³² -C(=O)-L ¹² -NG ²² -, -OL ³ -NG ²² - or -G ^4' -NG ²² -;

G ²¹ , G ³¹ , G ²² and G ³² are each independently a hydrogen atom or a C ₁ -C ₃ alkyl group optionally substituted with 1-3 -COOR ³ groups;

G ^4' represents a C ₁ -C ₂ alkylene group or a C ₁ -C ₂ alkyleneoxy-C ₁ -C ₂ alkylene group;

R ³ each represents a hydrogen atom;

L ¹¹ , L ²¹ , L ¹² and L ²² are each independently a C ₁ -C ₂ alkylene group;

L ³ represents a C ₁ -C ₂ alkylene-phenylene group, where the phenylene fragment is optionally substituted with 1-2 -COOR ⁴ groups;

R ⁴ each independently represents a hydrogen atom or a C ₁ -C ₄ alkyl group optionally substituted with 1-5 substituents independently selected from the group consisting of an aryl group and a trimethylsilyl group;

R ⁵ each independently represents a hydrogen atom, a fluorine atom, a methyl group or a methoxy group;

Z is a single bond, [1,1'-biphenyl]-3,3'-diyl, -(CH ₂ -CH ₂ -O) _m -CH ₂ -CH ₂ -, -(CH ₂ -O-CH ₂ ) _m -, -(CH ₂ ) _m -([1,1'-biphenyl]-3,3'-diyl)-(CH ₂ ) _m - or -(CH ₂ ) _n -;

m is an integer from 1 to 6; and

n is an integer from 2 to 12

In another embodiment of Compound (VI), a compound or a pharmaceutically acceptable salt thereof is described, wherein

R ¹ each represents a hydrogen atom;

W ¹ and W ² are each independently a single bond or a C ₁ -C ₂ alkylene group;

X ¹ is -C(=O)- or -NG ¹¹ -SO ₂ -;

X ² represents -C(=O)- or -SO ₂ -NG ¹² -;

G ¹¹ and G ¹² each represents a hydrogen atom;

Y ¹ is -NG ²¹ -, -NG ²¹ -L ¹¹ -C(=O)-, -NG ²¹ -L ¹¹ -C(=O)-NH-, -NG ²¹ -L ¹¹ -C(=O )-NG ³¹ -L ²¹ -C(=O)-, -NG ²¹ -L ¹¹ -C(=O)-NG ³¹ -L ²¹ -C(=O)-NH-, -NG ²¹ -L ³ - O- or -NG ²¹ -G ^4' -;

Y ² is -NG ²² -, -C(=O)-L ¹² -NG ²² -, -NH-C(=O) -L ¹² -NG ²² -, -C(=O) -L ²² -NG ³² -C(=O)-L ¹² -NG ²² -, -NH-C(=O)-L ²² -NG ³² -C(=O)-L ¹² -NG ²² -, -OL ³ -NG ²² - or -G ^4' -NG ²² -;

G ²¹ , G ³¹ , G ²² and G ³² are each independently a hydrogen atom or a C ₁ -C ₃ alkyl group optionally substituted with 1-3 -COOR ³ groups;

G ^4' represents a C ₁ -C ₂ alkylene group or a C ₁ -C ₂ alkyleneoxy-C ₁ -C ₂ alkylene group;

R ³ each represents a hydrogen atom;

L ¹¹ , L ²¹ , L ¹² and L ²² are each independently a C ₁ -C ₂ alkylene group;

L ³ represents a C ₁ -C ₂ alkylene-phenylene group, where the phenylene fragment is optionally substituted with 1-2 -COOR ⁴ groups;

R ⁴ each represents a hydrogen atom;

R ⁵ each independently represents a hydrogen atom, a fluorine atom, a methyl group or a methoxy group;

Z is a single bond, [1,1'-biphenyl]-3,3'-diyl, -(CH ₂ -CH ₂ -O) _m -CH ₂ -CH ₂ -, -(CH ₂ -O-CH ₂ ) _m -, -(CH ₂ ) _m -([1,1'-biphenyl]-3,3'-diyl)-(CH ₂ ) _m - or -(CH ₂ ) _n -;

m is an integer from 1 to 6; and

n is an integer from 2 to 12.

In another embodiment of Compound (VI), a compound or a pharmaceutically acceptable salt thereof is described, wherein

R ¹ each represents a hydrogen atom;

W ¹ and W ² are each independently a single bond or a C ₁ -C ₂ alkylene group;

X ¹ is -C(=O)- or -NG ¹¹ -SO ₂ -;

X ² represents -C(=O)- or -SO ₂ -NG ¹² -;

G ¹¹ and G ¹² each represents a hydrogen atom;

Y ¹ is -NG ²¹ -, -NG ²¹ -L ¹¹ -C(=O)-, -NG ²¹ -L ¹¹ -C(=O)-NH-, -NG ²¹ -L ¹¹ -C(=O )-NG ³¹ -L ²¹ -C(=O)-, -NG ²¹ -L ¹¹ -C(=O)-NG ³¹ -L ²¹ -C(=O)-NH-, -NG ²¹ -L ³ - O- or -NG ²¹ -G ^4' -;

Y ² is -NG ²² -, -C(=O)-L ¹² -NG ²² -, -NH-C(=O) -L ¹² -NG ²² -, -C(=O) -L ²² -NG ³² -C(=O)-L ¹² -NG ²² -, -NH-C(=O)-L ²² -NG ³² -C(=O)-L ¹² -NG ²² -, -OL ³ -NG ²² - or -G ^4' -NG ²² -;

G ²¹ and G ²² are each independently a hydrogen atom or a C ₁ -C ₃ alkyl group optionally substituted with 1-3 -COOR ³ groups;

G ³¹ and G ³² each represents a hydrogen atom;

G ^4' represents a C ₁ -C ₂ alkylene group or a C ₁ -C ₂ alkyleneoxy-C ₁ -C ₂ alkylene group;

R ³ each represents a hydrogen atom;

L ¹¹ , L ²¹ , L ¹² and L ²² are each independently a C ₁ -C ₂ alkylene group;

L ³ represents a C ₁ -C ₂ alkylene-phenylene group, where the phenylene fragment is optionally substituted with 1-2 -COOR ⁴ groups;

R ⁴ each independently represents a hydrogen atom or a C ₁ -C ₄ alkyl group optionally substituted with 1-5 substituents independently selected from the group consisting of an aryl group and a trimethylsilyl group;

R ⁵ each independently represents a hydrogen atom, a fluorine atom, a methyl group or a methoxy group;

Z is a single bond, [1,1'-biphenyl]-3,3'-diyl, -(CH ₂ -CH ₂ -O) _m -CH ₂ -CH ₂ -, -(CH ₂ -O-CH ₂ ) _m -, -(CH ₂ ) _m -([1,1'-biphenyl]-3,3'-diyl)-(CH ₂ ) _m - or -(CH ₂ ) _n -;

m is an integer from 1 to 6; and

n is an integer from 2 to 12.

In another embodiment of Compound (VI), a compound or a pharmaceutically acceptable salt thereof is described, wherein

R ¹ each represents a hydrogen atom;

W ¹ and W ² are each independently a single bond or a C ₁ -C ₂ alkylene group;

X ¹ is -C(=O)- or -NG ¹¹ -SO ₂ -;

X ² represents -C(=O)- or -SO ₂ -NG ¹² -;

G ¹¹ and G ¹² each represents a hydrogen atom;

Y ¹ is -NG ²¹ -, -NG ²¹ -L ¹¹ -C(=O)-, -NG ²¹ -L ¹¹ -C(=O)-NH-, -NG ²¹ -L ¹¹ -C(=O )-NG ³¹ -L ²¹ -C(=O)-, -NG ²¹ -L ¹¹ -C(=O)-NG ³¹ -L ²¹ -C(=O)-NH-, -NG ²¹ -L ³ - O- or -NG ²¹ -G ^4' -;

Y ² is -NG ²² -, -C(=O)-L ¹² -NG ²² -, -NH-C(=O) -L ¹² -NG ²² -, -C(=O) -L ²² -NG ³² -C(=O)-L ¹² -NG ²² -, -NH-C(=O)-L ²² -NG ³² -C(=O)-L ¹² -NG ²² -, -OL ³ -NG ²² - or -G ^4' -NG ²² -;

G ²¹ and G ²² are each independently a hydrogen atom or a C ₁ -C ₃ alkyl group optionally substituted with 1-3 -COOR ³ groups;

G ³¹ and G ³² each represents a hydrogen atom;

G ^4' represents a C ₁ -C ₂ alkylene group or a C ₁ -C ₂ alkyleneoxy-C ₁ -C ₂ alkylene group;

R ³ each represents a hydrogen atom;

L ¹¹ , L ²¹ , L ¹² and L ²² are each independently a C ₁ -C ₂ alkylene group;

L ³ represents a C ₁ -C ₂ alkylene-phenylene group, where the phenylene fragment is optionally substituted with 1-2 -COOR ⁴ groups;

R ⁴ each represents a hydrogen atom;

Z is a single bond, [1,1'-biphenyl]-3,3'-diyl, -(CH ₂ -CH ₂ -O) _m -CH ₂ -CH ₂ -, -(CH ₂ -O-CH ₂ ) _m -, -(CH ₂ ) _m -([1,1'-biphenyl]-3,3'-diyl)-(CH ₂ ) _m - or -(CH ₂ ) _n -;

m is an integer from 1 to 6; and

n is an integer from 2 to 12.

In one embodiment of Compound (VI), a compound or a pharmaceutically acceptable salt thereof is described, wherein

R ¹ each represents a hydrogen atom;

W ¹ and W ² are each a single bond;

X ¹ represents -C(=O)-;

X ² is -C(=O)-;

Y ¹ is -NG ²¹ -, -NG ²¹ -L ³ -O- or -NG ²¹ -G ^4' -;

Y ² is -NG ²² -, -OL ³ -NG ²² - or -G ^4' -NG ²² -;

G ²¹ and G ²² are each independently a C ₁ -C ₃ alkyl group substituted with 1-3 carboxyl groups;

G ^4' represents a C ₁ -C ₂ alkylene group or a C ₁ -C ₂ alkyleneoxy-C ₁ -C ₂ alkylene group;

L ³ represents a C ₁ -C ₂ alkylene-phenylene group, where the phenylene fragment is optionally substituted with 1-2 -COOR ⁴ groups;

R ⁴ each independently represents a hydrogen atom or a C ₁ -C ₄ alkyl group optionally substituted with 1-5 substituents independently selected from the group consisting of an aryl group and a trimethylsilyl group;

R ⁵ each independently represents a hydrogen atom, a fluorine atom, a methyl group or a methoxy group;

Z is a single bond, [1,1'-biphenyl]-3,3'-diyl, -(CH ₂ -CH ₂ -O) _m -CH ₂ -CH ₂ -, -(CH ₂ -O-CH ₂ ) _m -, -(CH ₂ ) _m -([1,1'-biphenyl]-3,3'-diyl)-(CH ₂ ) _m - or -(CH ₂ ) _n -;

m is an integer from 1 to 6; and

n is an integer from 2 to 12.

In one embodiment of Compound (VI), a compound or a pharmaceutically acceptable salt thereof is described, wherein

R ¹ each represents a hydrogen atom;

W ¹ and W ² are each a single bond;

X ¹ represents -C(=O)-;

X ² is -C(=O)-;

Y ¹ is -NG ²¹ -, -NG ²¹ -L ³ -O- or -NG ²¹ -G ^4' -;

Y ² is -NG ²² -, -OL ³ -NG ²² - or -G ^4' -NG ²² -;

G ²¹ and G ²² are each independently a C ₁ -C ₃ alkyl group substituted with 1-3 carboxyl groups;

G ^4' represents a C ₁ -C ₂ alkylene group or a C ₁ -C ₂ alkyleneoxy-C ₁ -C ₂ alkylene group;

L ³ represents a C ₁ -C ₂ alkylene-phenylene group, where the phenylene fragment is optionally substituted with 1-2 -COOR ⁴ groups;

R ⁴ each represents a hydrogen atom;

R ⁵ each represents a hydrogen atom;

Z is a single bond, [1,1'-biphenyl]-3,3'-diyl, -(CH ₂ -CH ₂ -O) _m -CH ₂ -CH ₂ -, -(CH ₂ -O-CH ₂ ) _m -, -(CH ₂ ) _m -([1,1'-biphenyl]-3,3'-diyl)-(CH ₂ ) _m - or -(CH ₂ ) _n -;

m is an integer from 1 to 6; and

n is an integer from 2 to 12.

In one embodiment of the present invention,

A ¹ has the structure represented by the formula

:

:

A ² has the structure represented by the formula

:

:

where:

R ¹ each independently represents a hydrogen atom or -COO-(C ₁ -C ₄ alkyl group);

W ¹ and W ² are each independently a single bond or a C ₁ -C ₄ alkylene group;

X ¹ is -C(=O)-, -OC(=O)- or -NG ¹¹ -SO ₂ -;

X ² is -C(=O)-, -C(=O)-O- or -SO ₂ -NG ¹² -;

G ¹¹ and G ¹² are each independently a hydrogen atom or —COOR ² ;

R ² is a C ₁ -C ₄ alkyl group optionally substituted with 1-5 aryl groups;

Y ¹ is -NG ²¹ -, -NG ²¹ -L ¹¹ -C(=O)-NH- or -NG ²¹ -L ¹¹ -C(=O)-NG ³¹ -L ²¹ -C(=O)- NH-;

Y ² is -NG ²² -, -NH-C(=O)-L ¹² -NG ²² - or -NH-C(=O)-L ²² -NG ³² -C(=O)-L ¹² -NG ^22- ;

G ²¹ , G ³¹ , G ²² and G ³² are each independently a hydrogen atom or a C ₁ -C ₆ alkyl group optionally substituted with 1-5 substituents independently selected from the group consisting of a phenyl group optionally substituted with 1-5 -COOR ³ groups, and -COOR ³ groups;

R ³ each independently represents a hydrogen atom or a C ₁ -C ₄ alkyl group optionally substituted with 1-5 aryl groups;

L ¹¹ , L ²¹ , L ¹² and L ²² are each independently a C ₁ -C ₆ alkylene group optionally substituted with 1-5 C ₁ -C ₆ alkyl groups optionally substituted with 1-5 -COOR ⁴ groups, C ₁ -C ₄ alkylene-phenylene group or phenylene-C ₁ -C ₄ alkylene group;

R ⁴ each independently represents a hydrogen atom or a C ₁ -C ₄ alkyl group optionally substituted with 1-5 aryl groups;

R ⁵ and R ⁶ are each independently a hydrogen atom, a C ₁ -C ₄ alkyl group or a C ₁ -C ₄ alkoxy group, or R ⁵ and R ⁶ may be combined with each other to form a C ₁ -C ₄ alkyleneoxy Group; and

symbol

means the point of attachment to Z;

Z is -(CH ₂ -CH ₂ -O) _m -CH ₂ -CH ₂ - or -(CH ₂ ) _n -;

m is an integer from 1 to 6; and

n is an integer from 2 to 12.

In another embodiment of the present invention, a compound or a pharmaceutically acceptable salt thereof is described, wherein

A ¹ has the structure represented by the formula

:

:

A ² has the structure represented by the formula

:

:

where:

R ¹ each represents a hydrogen atom;

W ¹ and W ² are each independently a single bond or a C ₁ -C ₄ alkylene group;

X ¹ is -C(=O)-, -OC(=O)- or -NG ¹¹ -SO ₂ -;

X ² is -C(=O)-, -C(=O)-O- or -SO ₂ -NG ¹² -;

G ¹¹ and G ¹² are each independently a hydrogen atom or —COOR ² ;

R ² is a C ₁ -C ₄ alkyl group optionally substituted with 1-5 aryl groups;

Y ¹ is -NG ²¹ -, -NG ²¹ -L ¹¹ -C(=O)-NH- or -NG ²¹ -L ¹¹ -C(=O)-NG ³¹ -L ²¹ -C(=O)- NH-;

Y ² is -NG ²² -, -NH-C(=O)-L ¹² -NG ²² - or -NH-C(=O)-L ²² -NG ³² -C(=O)-L ¹² -NG ^22- ;

G ²¹ , G ³¹ , G ²² and G ³² are each independently a hydrogen atom or a C ₁ -C ₆ alkyl group optionally substituted with 1-5 substituents independently selected from the group consisting of a phenyl group optionally substituted with 1-5 -COOR ³ groups, and -COOR ³ groups;

R ³ each independently represents a hydrogen atom or a C ₁ -C ₄ alkyl group optionally substituted with 1-5 aryl groups;

L ¹¹ , L ²¹ , L ¹² and L ²² are each independently a C ₁ -C ₆ alkylene group optionally substituted with 1-5 C ₁ -C ₆ alkyl groups optionally substituted with 1-5 -COOR ⁴ groups, C ₁ -C ₄ alkylene-phenylene group or phenylene-C ₁ -C ₄ alkylene group;

R ⁴ each represents a hydrogen atom;

R ⁵ and R ⁶ are each independently a hydrogen atom, a C ₁ -C ₄ alkyl group or a C ₁ -C ₄ alkoxy group, or R ⁵ and R ⁶ may be combined with each other to form a C ₁ -C ₄ alkyleneoxy Group; and

symbol

means the point of attachment to Z;

Z is -(CH ₂ -CH ₂ -O) _m -CH ₂ -CH ₂ - or -(CH ₂ ) _n -;

m is an integer from 1 to 6; and

n is an integer from 2 to 12.

In another embodiment of the present invention, a compound or a pharmaceutically acceptable salt thereof is described, wherein

A ¹ has the structure represented by the formula

:

:

A ² has the structure represented by the formula

:

:

where:

R ¹ each represents a hydrogen atom;

W ¹ and W ² are each independently a single bond or a C ₁ -C ₄ alkylene group;

X ¹ is -C(=O)-, -OC(=O)- or -NG ¹¹ -SO ₂ -;

X ² is -C(=O)-, -C(=O)-O- or -SO ₂ -NG ¹² -;

G ¹¹ and G ¹² each represents a hydrogen atom;

Y ¹ is -NG ²¹ -, -NG ²¹ -L ¹¹ -C(=O)-NH- or -NG ²¹ -L ¹¹ -C(=O)-NG ³¹ -L ²¹ -C(=O)- NH-;

Y ² is -NG ²² -, -NH-C(=O)-L ¹² -NG ²² - or -NH-C(=O)-L ²² -NG ³² -C(=O)-L ¹² -NG ^22- ;

G ²¹ , G ³¹ , G ²² and G ³² are each independently a hydrogen atom or a C ₁ -C ₆ alkyl group optionally substituted with 1-5 substituents independently selected from the group consisting of a phenyl group optionally substituted with 1-5 -COOR ³ groups, and -COOR ³ groups;

R ³ each represents a hydrogen atom;

L ¹¹ , L ²¹ , L ¹² and L ²² are each independently a C ₁ -C ₆ alkylene group optionally substituted with 1-5 C ₁ -C ₆ alkyl groups optionally substituted with 1-5 -COOR ⁴ groups, C ₁ -C ₄ alkylene-phenylene group or phenylene-C ₁ -C ₄ alkylene group;

R ⁴ each represents a hydrogen atom;

R ⁵ and R ⁶ are each independently a hydrogen atom, a C ₁ -C ₄ alkyl group or a C ₁ -C ₄ alkoxy group, or R ⁵ and R ⁶ may be combined with each other to form a C ₁ -C ₄ alkyleneoxy Group; and

symbol

means the point of attachment to Z;

Z is -(CH ₂ -CH ₂ -O) _m -CH ₂ -CH ₂ - or -(CH ₂ ) _n -;

m is an integer from 1 to 6; and

n is an integer from 2 to 12.

In one embodiment of Compound (I),

A ¹ has the structure represented by the formula

,

,

and

A ² has the structure represented by the formula

In another embodiment of Compound (I),

A ¹ has the structure represented by the formula

, и

, and

A ² has the structure represented by the formula

.

.

In another embodiment of Compound (I),

A ¹ has the structure represented by the formula

, и

, and

A ² has the structure represented by the formula

.

.

In another embodiment of Compound (I),

A ¹ has the structure represented by the formula

, и

, and

A ² has the structure represented by the formula

.

.

In another embodiment of Compound (I),

A ¹ has the structure represented by the formula

, и

, and

A ² has the structure represented by the formula

.

.

Compound (VII)

In one embodiment of the present invention, Compound (I), or a pharmaceutically acceptable salt thereof, is a compound having the general formula (VII) shown below:

where:

R ¹ each independently represents a hydrogen atom or -COO-(C ₁ -C ₄ alkyl group);

W ¹ and W ² are each independently a single bond or a C ₁ -C ₄ alkylene group;

X ¹ is -OC(=O)- or -NG ¹¹ -SO ₂ -;

X ² is -C(=O)-O- or -SO ₂ -NG ¹² -;

G ¹¹ and G ¹² are each independently a hydrogen atom or
-COOR ² ;

R ² is a C ₁ -C ₄ alkyl group optionally substituted with 1-5 aryl groups;

Y ¹ is -NG ²¹ -, -NG ²¹ -L ¹¹ -C(=O)-NH- or -NG ²¹ -L ¹¹ -C(=O)-NG ³¹ -L ²¹ -C(=O)- NH-;

Y ² is -NG ²² -, -NH-C(=O)-L ¹² -NG ²² - or -NH-C(=O)-L ²² -NG ³² -C(=O)-L ¹² -NG ^22- ;

G ²¹ , G ³¹ , G ²² and G ³² are each independently a hydrogen atom or a C ₁ -C ₆ alkyl group optionally substituted with 1-5 substituents independently selected from the group consisting of a phenyl group optionally substituted with 1-5 -COOR ³ groups, and -COOR ³ groups;

R ³ each independently represents a hydrogen atom or a C ₁ -C ₄ alkyl group optionally substituted with 1-5 aryl groups;

L ¹¹ , L ²¹ , L ¹² and L ²² are each independently a C ₁ -C ₆ alkylene group optionally substituted with 1-5 C ₁ -C ₆ alkyl groups optionally substituted with 1-5 -COOR ⁴ groups, C ₁ -C ₄ alkylene-phenylene group or phenylene-C ₁ -C ₄ alkylene group;

R ⁴ each independently represents a hydrogen atom or a C ₁ -C ₄ alkyl group optionally substituted with 1-5 aryl groups;

Z is -(CH ₂ -CH ₂ -O) _m -CH ₂ -CH ₂ - or -(CH ₂ ) _n -;

m is an integer from 1 to 6; and

n is an integer from 2 to 12]

or a pharmaceutically acceptable salt thereof.

Examples of variants of each substituent in Compound (VII) include those listed below, in addition to the variants listed above of each substituent in Compound (I).

In one embodiment, the C ₁ -C ₄ alkyl group in "-COO-(C ₁ -C ₄ alkyl group)" in R ¹ is a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group or a tert-butyl group.

In one embodiment, R ¹ is a hydrogen atom or a t-butoxycarbonyl group, preferably a hydrogen atom.

In one embodiment, W ¹ is a C ₁ -C ₄ alkylene group, eg a methylene group, an ethylene group, a trimethylene group, or a tetramethylene group, preferably a C ₁ -C ₂ alkylene group, eg a methylene group.

In one embodiment, W ² is a C ₁ -C ₄ alkylene group, eg a methylene group, an ethylene group, a trimethylene group, or a tetramethylene group, preferably a C ₁ -C ₂ alkylene group, eg a methylene group.

In one embodiment, X ¹ is -NG ¹¹ -SO ₂ -.

In one embodiment, X ² is -SO ₂ -NG ¹² -.

In one embodiment, R ² in the "-COOR ² group" in G ¹¹ and G ¹² is a C ₁ -C ₄ alkyl group optionally substituted with 1-3 phenyl groups, e.g., a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a t-butyl group or a benzyl group, preferably a C ₁ -C ₄ alkyl group optionally substituted with one phenyl group, more preferably a t-butyl group or a benzyl group.

In one embodiment, G ¹¹ is a hydrogen atom, a t-butoxycarbonyl group or a benzyloxycarbonyl group, preferably a hydrogen atom or a benzyloxycarbonyl group, more preferably a hydrogen atom.

In one embodiment, G ¹² is a hydrogen atom, a t-butoxycarbonyl group, or a benzyloxycarbonyl group, preferably a hydrogen atom or a benzyloxycarbonyl group, more preferably a hydrogen atom.

In one embodiment, Y ¹ is -NG ²¹ -.

In one embodiment, Y ² is -NG ²² -.

In one embodiment, the "phenyl group optionally substituted with 1-5-COOR ³ groups" in G ²¹ , G ³¹ , G ²² and G ³² is a 2-(COOR ³ )-phenyl group, 3-(COOR ³ )- a phenyl group, a 4-(COOR ³ )-phenyl group, and the like.

In one embodiment, R ³ in the "-COOR ³ group" in G ²¹ , G ³¹ , G ²² and G ³² are each independently hydrogen atom, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl a group, a t-butyl group or a benzyl group, preferably a hydrogen atom, a benzyl group or a t-butyl group, more preferably a hydrogen atom or a t-butyl group, even more preferably a hydrogen atom.

In one embodiment, G ²¹ is a hydrogen atom or a C ₁ -C ₆ alkyl group optionally substituted with 1-3 substituents independently selected from the group consisting of a phenyl group optionally substituted with 1-3 -COOR ³ groups, and -COOR ³ groups, preferably a hydrogen atom or a C ₁ -C ₃ alkyl group optionally substituted with 1-3 substituents independently selected from the group consisting of a phenyl group optionally substituted with one -COOR ³ group and -COOR ³ groups, more preferably C ₁ -C ₃ alkyl group substituted with 1-3 substituents independently selected from the group consisting of a phenyl group substituted with one carboxyl group and a carboxyl group.

In one embodiment, G ³¹ is a hydrogen atom or a C ₁ -C ₆ alkyl group optionally substituted with 1-3 substituents independently selected from the group consisting of a phenyl group optionally substituted with 1-3 -COOR ³ groups, and -COOR ³ groups, preferably a hydrogen atom or a C ₁ -C ₃ alkyl group optionally substituted with 1-3 substituents independently selected from the group consisting of a phenyl group optionally substituted with one -COOR ³ group, and -COOR ³ groups, more preferably a hydrogen atom .

In one embodiment, G ²² is a hydrogen atom or a C ₁ -C ₆ alkyl group optionally substituted with 1-3 substituents independently selected from the group consisting of a phenyl group optionally substituted with 1-3 -COOR ³ groups, and -COOR ³ groups, preferably a hydrogen atom or a C ₁ -C ₃ alkyl group optionally substituted with 1-3 substituents independently selected from the group consisting of a phenyl group optionally substituted with one -COOR ³ group and -COOR ³ groups, more preferably C ₁ -C ₃ alkyl group substituted with 1-3 substituents independently selected from the group consisting of a phenyl group substituted with one carboxyl group and a carboxyl group.

In one embodiment, G ³² is a hydrogen atom or a C ₁ -C ₆ alkyl group optionally substituted with 1-3 substituents independently selected from the group consisting of a phenyl group optionally substituted with 1-3 -COOR ³ groups, and -COOR ³ groups, preferably a hydrogen atom or a C ₁ -C ₃ alkyl group optionally substituted with 1-3 substituents independently selected from the group consisting of a phenyl group optionally substituted with one -COOR ³ group, and -COOR ³ groups, more preferably a hydrogen atom .

In one embodiment, R ⁴ in the "-COOR ⁴ group" in L ¹¹ , L ²¹ , L ¹² and L ²² are each independently hydrogen atom, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl a group, a t-butyl group or a benzyl group, preferably a hydrogen atom, a t-butyl group or a benzyl group, more preferably a hydrogen atom or a t-butyl group, even more preferably a hydrogen atom.

In one embodiment, L ¹¹ is a C ₁ -C ₆ alkylene group optionally substituted with 1-2 C ₁ -C ₆ alkyl groups optionally substituted with 1-2 -COOR ⁴ groups, or a C ₁ -C ₄ alkylene-phenylene group , preferably a methylene group optionally substituted with a C ₁ -C ₆ alkyl group optionally substituted with a -COOR ⁴ group, or a methylenephenylene group.

In another embodiment, L ¹¹ is a C ₁ -C ₂ alkylene group optionally substituted with 1-2 C ₁ -C ₂ alkyl groups optionally substituted with 1-2 -COOR ⁴ groups, or a C ₁ -C ₂ alkylene-phenylene group .

In one embodiment, L ²¹ is a C ₁ -C ₆ alkylene group optionally substituted with 1-2 C ₁ -C ₆ alkyl groups optionally substituted with 1-2 -COOR ⁴ groups, or a C ₁ -C ₄ alkylene-phenylene group , preferably a methylene group, optionally substituted with a C ₁ -C ₆ alkyl group, optionally substituted with a -COOR ⁴ group.

In another embodiment, L ²¹ is a C ₁ -C ₂ alkylene group optionally substituted with 1-2 C ₁ -C ₂ alkyl groups optionally substituted with 1-2 -COOR ⁴ groups, or a C ₁ -C ₂ alkylene-phenylene group .

In one embodiment, L ¹² is a C ₁ -C ₆ alkylene group optionally substituted with 1-2 C ₁ -C ₆ alkyl groups optionally substituted with 1-2 -COOR ⁴ groups, or a phenylene-C ₁ -C ₄ alkylene group , preferably a methylene group optionally substituted with a C ₁ -C ₆ alkyl group optionally substituted with a —COOR ⁴ group, or a phenylene methylene group.

In another embodiment, L ¹² is a C ₁ -C ₂ alkylene group optionally substituted with 1-2 C ₁ -C ₂ alkyl groups optionally substituted with 1-2 -COOR ⁴ groups, or a phenylene-C ₁ -C ₂ alkylene group .

In one embodiment, L ²² is a C ₁ -C ₆ alkylene group optionally substituted with 1-2 C ₁ -C ₆ alkyl groups optionally substituted with 1-2 -COOR ⁴ groups, or a phenylene-C ₁ -C ₄ alkylene group , preferably a methylene group, optionally substituted with a C ₁ -C ₆ alkyl group, optionally substituted with a -COOR ⁴ group.

In another embodiment, L ²² is a C ₁ -C ₂ alkylene group optionally substituted with 1-2 C ₁ -C ₂ alkyl groups optionally substituted with 1-2 -COOR ⁴ groups, or a phenylene-C ₁ -C ₂ alkylene group .

In one embodiment, at least one of R ¹ , R ³ , R ⁴ , G ¹¹ and G ¹² is a hydrogen atom. In another embodiment, at least one of R ¹ and R ⁴ is a hydrogen atom. In another embodiment, R ¹ , R ³ , R ⁴ , G ¹¹ and G ¹² each represents a hydrogen atom.

In one embodiment, Z is -(CH ₂ -CH ₂ -O) _m -CH ₂ -CH ₂ - or -(CH ₂ ) _n -, preferably -(CH ₂ -CH ₂ -O) _m -CH ₂ -CH2- _.

In one embodiment, m is an integer from 1 to 6 and n is an integer from 2 to 12, preferably m is an integer from 1 to 4 and n is an integer from 2 to 6.

In one embodiment of Compound (VII), a compound or a pharmaceutically acceptable salt thereof is described, wherein

R ¹ each represents a hydrogen atom;

W ¹ and W ² are each independently a single bond or a C ₁ -C ₄ alkylene group;

X ¹ is -OC(=O)- or -NG ¹¹ -SO ₂ -;

X ² is -C(=O)-O- or -SO ₂ -NG ¹² -;

G ¹¹ and G ¹² are each independently a hydrogen atom or
-COOR ² ;

R ² is a C ₁ -C ₄ alkyl group optionally substituted with 1-5 aryl groups;

Y ¹ is -NG ²¹ -, -NG ²¹ -L ¹¹ -C(=O)-NH- or -NG ²¹ -L ¹¹ -C(=O)-NG ³¹ -L ²¹ -C(=O)- NH-;

Y ² is -NG ²² -, -NH-C(=O)-L ¹² -NG ²² - or -NH-C(=O)-L ²² -NG ³² -C(=O)-L ¹² -NG ^22- ;

G ²¹ , G ³¹ , G ²² , and G ³² are each independently a hydrogen atom or a C ₁ -C ₆ alkyl group optionally substituted with 1-5 substituents independently selected from the group consisting of a phenyl group optionally substituted with 1-5 - COOR ³ groups, and -COOR ³ groups;

R ³ each independently represents a hydrogen atom or a C ₁ -C ₄ alkyl group optionally substituted with 1-5 aryl groups;

L ¹¹ , L ²¹ , L ¹² and L ²² are each independently a C ₁ -C ₆ alkylene group optionally substituted with 1-5 C ₁ -C ₆ alkyl groups optionally substituted with 1-5 -COOR ⁴ groups, C ₁ -C ₄ alkylene-phenylene group or phenylene-C ₁ -C ₄ alkylene group;

R ⁴ each represents a hydrogen atom;

Z is -(CH ₂ -CH ₂ -O) _m -CH ₂ -CH ₂ - or -(CH ₂ ) _n -;

m is an integer from 1 to 6; and

n is an integer from 2 to 12.

In one embodiment of Compound (VII), a compound or a pharmaceutically acceptable salt thereof is described, wherein

R ¹ each represents a hydrogen atom;

W ¹ and W ² are each independently a single bond or a C ₁ -C ₄ alkylene group;

X ¹ is -OC(=O)- or -NG ¹¹ -SO ₂ -;

X ² is -C(=O)-O- or -SO ₂ -NG ¹² -;

G ¹¹ and G ¹² each represents a hydrogen atom;

Y ¹ is -NG ²¹ -, -NG ²¹ -L ¹¹ -C(=O)-NH- or -NG ²¹ -L ¹¹ -C(=O)-NG ³¹ -L ²¹ -C(=O)- NH-;

Y ² is -NG ²² -, -NH-C(=O)-L ¹² -NG ²² - or -NH-C(=O)-L ²² -NG ³² -C(=O)-L ¹² -NG ^22- ;

G ²¹ , G ³¹ , G ²² and G ³² are each independently a hydrogen atom or a C ₁ -C ₆ alkyl group optionally substituted with 1-5 substituents independently selected from the group consisting of a phenyl group optionally substituted with 1-5 -COOR ³ groups, and -COOR ³ groups;

R ³ each represents a hydrogen atom;

L ¹¹ , L ²¹ , L ¹² and L ²² are each independently a C ₁ -C ₆ alkylene group optionally substituted with 1-5 C ₁ -C ₆ alkyl groups optionally substituted with 1-5 -COOR ⁴ groups, C ₁ -C ₄ alkylene-phenylene group or phenylene-C ₁ -C ₄ alkylene group;

R ⁴ each represents a hydrogen atom;

Z is -(CH ₂ -CH ₂ -O) _m -CH ₂ -CH ₂ - or -(CH ₂ ) _n -;

m is an integer from 1 to 6; and

n is an integer from 2 to 12.

In another embodiment of Compound (VII), a compound or a pharmaceutically acceptable salt thereof is described, wherein

R ¹ each independently represents a hydrogen atom or a tert-butoxycarbonyl group;

W ¹ and W ² each represents a C ₁ -C ₄ alkylene group;

X ¹ is -OC(=O)- or -NG ¹¹ -SO ₂ -;

X ² is -C(=O)-O- or -SO ₂ -NG ¹² -;

G ¹¹ and G ¹² are each independently a hydrogen atom or
-COOR ² ;

R ² is a C ₁ -C ₄ alkyl group optionally substituted with 1-3 phenyl groups;

Y ¹ is -NG ²¹ -, -NG ²¹ -L ¹¹ -C(=O)-NH- or -NG ²¹ -L ¹¹ -C(=O)-NG ³¹ -L ²¹ -C(=O)- NH-;

Y ² is -NG ²² -, -NH-C(=O)-L ¹² -NG ²² - or -NH-C(=O)-L ²² -NG ³² -C(=O)-L ¹² -NG ^22- ;

G ²¹ , G ³¹ , G ²² and G ³² are each independently a hydrogen atom or a C ₁ -C ₆ alkyl group optionally substituted with 1-3 substituents independently selected from the group consisting of a phenyl group optionally substituted with 1-3 -COOR ³ groups, and -COOR ³ groups;

R ³ each independently represents a hydrogen atom, a benzyl group or a tert-butyl group;

L ¹¹ , L ²¹ , L ¹² and L ²² are each independently a C ₁ -C ₆ alkylene group optionally substituted with 1-5 C ₁ -C ₆ alkyl groups optionally substituted with 1-5 -COOR ⁴ groups, C ₁ -C ₄ alkylene-phenylene group or phenylene-C ₁ -C ₄ alkylene group;

R ⁴ each independently represents a hydrogen atom, a benzyl group or a tert-butyl group;

Z is -(CH ₂ -CH ₂ -O) _m -CH ₂ -CH ₂ - or -(CH ₂ ) _n -;

m is an integer from 1 to 6; and

n is an integer from 2 to 12.

In another embodiment of Compound (VII), a compound or a pharmaceutically acceptable salt thereof is described, wherein

R ¹ each represents a hydrogen atom;

W ¹ and W ² each represents a C ₁ -C ₄ alkylene group;

X ¹ is -OC(=O)- or -NG ¹¹ -SO ₂ -;

X ² is -C(=O)-O- or -SO ₂ -NG ¹² -;

G ¹¹ and G ¹² are each independently a hydrogen atom or
-COOR ² ;

R ² is a C ₁ -C ₄ alkyl group optionally substituted with 1-3 phenyl groups;

Y ¹ is -NG ²¹ -, -NG ²¹ -L ¹¹ -C(=O)-NH- or -NG ²¹ -L ¹¹ -C(=O)-NG ³¹ -L ²¹ -C(=O)- NH-;

Y ² is -NG ²² -, -NH-C(=O)-L ¹² -NG ²² - or -NH-C(=O)-L ²² -NG ³² -C(=O)-L ¹² -NG ^22- ;

G ²¹ , G ³¹ , G ²² and G ³² are each independently a hydrogen atom or a C ₁ -C ₆ alkyl group optionally substituted with 1-3 substituents independently selected from the group consisting of a phenyl group optionally substituted with 1-3 -COOR ³ groups, and -COOR ³ groups;

R ³ each independently represents a hydrogen atom, a benzyl group or a tert-butyl group;

L ¹¹ , L ²¹ , L ¹² and L ²² are each independently a C ₁ -C ₆ alkylene group optionally substituted with 1-5 C ₁ -C ₆ alkyl groups optionally substituted with 1-5 -COOR ⁴ groups, C ₁ -C ₄ alkylene-phenylene group or phenylene-C ₁ -C ₄ alkylene group;

R ⁴ each represents a hydrogen atom;

Z is -(CH ₂ -CH ₂ -O) _m -CH ₂ -CH ₂ - or -(CH ₂ ) _n -;

m is an integer from 1 to 6; and

n is an integer from 2 to 12.

In another embodiment of Compound (VII), a compound or a pharmaceutically acceptable salt thereof is described, wherein

R ¹ each represents a hydrogen atom;

W ¹ and W ² each represents a C ₁ -C ₄ alkylene group;

X ¹ is -OC(=O)- or -NG ¹¹ -SO ₂ -;

X ² is -C(=O)-O- or -SO ₂ -NG ¹² -;

G ¹¹ and G ¹² each represents a hydrogen atom;

Y ¹ is -NG ²¹ -, -NG ²¹ -L ¹¹ -C(=O)-NH- or -NG ²¹ -L ¹¹ -C(=O)-NG ³¹ -L ²¹ -C(=O)- NH-;

Y ² is -NG ²² -, -NH-C(=O)-L ¹² -NG ²² - or -NH-C(=O)-L ²² -NG ³² -C(=O)-L ¹² -NG ^22- ;

G ²¹ , G ³¹ , G ²² and G ³² are each independently a hydrogen atom or a C ₁ -C ₆ alkyl group optionally substituted with 1-3 substituents independently selected from the group consisting of a phenyl group optionally substituted with 1-3 -COOR ³ groups, and -COOR ³ groups;

R ³ each represents a hydrogen atom;

L ¹¹ , L ²¹ , L ¹² and L ²² are each independently a C ₁ -C ₆ alkylene group optionally substituted with 1-5 C ₁ -C ₆ alkyl groups optionally substituted with 1-5 -COOR ⁴ groups, C ₁ -C ₄ alkylene-phenylene group or phenylene-C ₁ -C ₄ alkylene group;

R ⁴ each represents a hydrogen atom;

Z is -(CH ₂ -CH ₂ -O) _m -CH ₂ -CH ₂ - or -(CH ₂ ) _n -;

m is an integer from 1 to 6; and

n is an integer from 2 to 12.

In one embodiment of Compound (VII), a compound or a pharmaceutically acceptable salt thereof is described, wherein

R ¹ each independently represents a hydrogen atom or a tert-butoxycarbonyl group;

W ¹ and W ² each represents a C ₁ -C ₂ alkylene group;

X ¹ is -OC(=O)- or -NG ¹¹ -SO ₂ -;

X ² is -C(=O)-O- or -SO ₂ -NG ¹² -;

G ¹¹ and G ¹² are each independently a hydrogen atom or —COOR ² ;

R ² is a C ₁ -C ₄ alkyl group optionally substituted with one phenyl group;

Y ¹ is -NG ²¹ -, -NG ²¹ -L ¹¹ -C(=O)-NH- or -NG ²¹ -L ¹¹ -C(=O)-NG ³¹ -L ²¹ -C(=O)- NH-;

Y ² is -NG ²² -, -NH-C(=O)-L ¹² -NG ²² - or -NH-C(=O)-L ²² -NG ³² -C(=O)-L ¹² -NG ^22- ;

G ²¹ , G ³¹ , G ²² and G ³² are each independently a hydrogen atom or a C ₁ -C ₃ alkyl group optionally substituted with 1-3 substituents independently selected from the group consisting of a phenyl group optionally substituted with one —COOR ³ group , and -COOR ³ groups;

R ³ each independently represents a hydrogen atom or a tert-butyl group;

L ¹¹ , L ²¹ , L ¹² and L ²² are each independently a C ₁ -C ₂ alkylene group optionally substituted with 1-2 C ₁ -C ₂ alkyl groups optionally substituted with 1-2 -COOR ⁴ groups, C ₁ -C ₂ alkylene-phenylene group or phenylene-C ₁ -C ₂ alkylene group;

R ⁴ each independently represents a hydrogen atom or a tert-butyl group;

Z is -(CH ₂ -CH ₂ -O) _m -CH ₂ -CH ₂ - or -(CH ₂ ) _n -;

m is an integer from 1 to 6; and

n is an integer from 2 to 12.

In one embodiment of Compound (VII), a compound or a pharmaceutically acceptable salt thereof is described, wherein

R ¹ each represents a hydrogen atom;

W ¹ and W ² each represents a C ₁ -C ₂ alkylene group;

X ¹ is -OC(=O)- or -NG ¹¹ -SO ₂ -;

X ² is -C(=O)-O- or -SO ₂ -NG ¹² -;

G ¹¹ and G ¹² are each independently a hydrogen atom or —COOR ² ;

R ² is a C ₁ -C ₄ alkyl group optionally substituted with one phenyl group;

Y ¹ is -NG ²¹ -, -NG ²¹ -L ¹¹ -C(=O)-NH- or -NG ²¹ -L ¹¹ -C(=O)-NG ³¹ -L ²¹ -C(=O)- NH-;

Y ² is -NG ²² -, -NH-C(=O)-L ¹² -NG ²² - or -NH-C(=O)-L ²² -NG ³² -C(=O)-L ¹² -NG ^22- ;

G ²¹ and G ²² are each independently a hydrogen atom or a C ₁ -C ₃ alkyl group optionally substituted with 1-3 substituents independently selected from the group consisting of a phenyl group optionally substituted with one -COOR ³ group, and a -COOR ³ group ;

G ³¹ and G ³² each represents a hydrogen atom;

R ³ each represents a hydrogen atom;

L ¹¹ , L ²¹ , L ¹² and L ²² are each independently a C ₁ -C ₂ alkylene group optionally substituted with 1-2 C ₁ -C ₂ alkyl groups optionally substituted with 1-2 -COOR ⁴ groups, C ₁ -C ₂ alkylene-phenylene group or phenylene-C ₁ -C ₂ alkylene group;

R ⁴ each represents a hydrogen atom;

Z is -(CH ₂ -CH ₂ -O) _m -CH ₂ -CH ₂ - or -(CH ₂ ) _n -;

m is an integer from 1 to 6; and

n is an integer from 2 to 12.

In one embodiment of Compound (VII), a compound or a pharmaceutically acceptable salt thereof is described, wherein

R ¹ each represents a hydrogen atom;

W ¹ and W ² each represents a C ₁ -C ₂ alkylene group;

X ¹ is -OC(=O)- or -NG ¹¹ -SO ₂ -;

X ² is -C(=O)-O- or -SO ₂ -NG ¹² -;

G ¹¹ and G ¹² are each independently a hydrogen atom or
-COOR ² ;

R ² is a C ₁ -C ₄ alkyl group optionally substituted with one phenyl group;

Y ¹ is -NG ²¹ -, -NG ²¹ -L ¹¹ -C(=O)-NH- or -NG ²¹ -L ¹¹ -C(=O)-NG ³¹ -L ²¹ -C(=O)- NH-;

Y ² is -NG ²² -, -NH-C(=O)-L ¹² -NG ²² - or -NH-C(=O)-L ²² -NG ³² -C(=O)-L ¹² -NG ^22- ;

G ²¹ and G ²² are each independently a hydrogen atom or a C ₁ -C ₃ alkyl group optionally substituted with 1-3 substituents independently selected from the group consisting of a phenyl group optionally substituted with one -COOR ³ group, and a -COOR ³ group ;

G ³¹ and G ³² each represents a hydrogen atom;

R ³ each represents a hydrogen atom;

L ¹¹ and L ²¹ are each independently a C ₁ -C ₂ alkylene group optionally substituted with 1-2 C ₁ -C ₂ alkyl groups optionally substituted with 1-2 -COOR ⁴ groups, or a C ₁ -C ₂ alkylene-phenylene group ;

L ¹² and L ²² are each independently a C ₁ -C ₂ alkylene group optionally substituted with 1-2 C ₁ -C ₂ alkyl groups optionally substituted with 1-2 -COOR ⁴ groups, or a phenylene-C ₁ -C ₂ alkylene group ;

R ⁴ each represents a hydrogen atom;

Z is -(CH ₂ -CH ₂ -O) _m -CH ₂ -CH ₂ - or -(CH ₂ ) _n -;

m is an integer from 1 to 6; and

n is an integer from 2 to 12.

In one embodiment of Compound (VII), a compound or a pharmaceutically acceptable salt thereof is described, wherein

R ¹ each represents a hydrogen atom;

W ¹ and W ² each represents a C ₁ -C ₂ alkylene group;

X ¹ is -OC(=O)- or -NG ¹¹ -SO ₂ -;

X ² is -C(=O)-O- or -SO ₂ -NG ¹² -;

G ¹¹ and G ¹² each represents a hydrogen atom;

Y ¹ is -NG ²¹ -, -NG ²¹ -L ¹¹ -C(=O)-NH- or -NG ²¹ -L ¹¹ -C(=O)-NG ³¹ -L ²¹ -C(=O)- NH-;

Y ² is -NG ²² -, -NH-C(=O)-L ¹² -NG ²² - or -NH-C(=O)-L ²² -NG ³² -C(=O)-L ¹² -NG ^22- ;

G ²¹ and G ²² are each independently a hydrogen atom or a C ₁ -C ₃ alkyl group optionally substituted with 1-3 substituents independently selected from the group consisting of a phenyl group optionally substituted with one -COOR ³ group, and a -COOR ³ group ;

G ³¹ and G ³² each represents a hydrogen atom;

R ³ each represents a hydrogen atom;

L ¹¹ and L ²¹ are each independently a C ₁ -C ₂ alkylene group optionally substituted with 1-2 C ₁ -C ₂ alkyl groups optionally substituted with 1-2 -COOR ⁴ groups, or a C ₁ -C ₂ alkylene-phenylene group ;

L ¹² and L ²² are each independently a C ₁ -C ₂ alkylene group optionally substituted with 1-2 C ₁ -C ₂ alkyl groups optionally substituted with 1-2 -COOR ⁴ groups, or a phenylene-C ₁ -C ₂ alkylene group ;

R ⁴ each represents a hydrogen atom;

Z is -(CH ₂ -CH ₂ -O) _m -CH ₂ -CH ₂ - or -(CH ₂ ) _n -;

m is an integer from 1 to 6; and

n is an integer from 2 to 12.

In one embodiment of Compound (VII), a compound or a pharmaceutically acceptable salt thereof is described, wherein

R ¹ each represents a hydrogen atom;

W ¹ and W ² each represents a C ₁ -C ₂ alkylene group;

X ¹ is -NG ¹¹ -SO ₂ -;

X ² is -SO ₂ -NG ¹² -;

G ¹¹ and G ¹² are each independently a hydrogen atom or —COOR ² ;

R ² is a C ₁ -C ₄ alkyl group optionally substituted with one phenyl group;

Y ¹ is -NG ²¹ -;

Y ² is -NG ²² -;

G ²¹ and G ²² are each independently a C ₁ -C ₃ alkyl group substituted with 1-3 substituents independently selected from the group consisting of a phenyl group substituted with one carboxyl group and a carboxyl group;

Z is -(CH ₂ -CH ₂ -O) _m -CH ₂ -CH ₂ - or -(CH ₂ ) _n -;

m is an integer from 1 to 6; and

n is an integer from 2 to 12.

In one embodiment of Compound (VII), a compound or a pharmaceutically acceptable salt thereof is described, wherein

R ¹ each represents a hydrogen atom;

W ¹ and W ² each represents a C ₁ -C ₂ alkylene group;

X ¹ is -NG ¹¹ -SO ₂ -;

X ² is -SO ₂ -NG ¹² -;

G ¹¹ and G ¹² each represents a hydrogen atom;

Y ¹ is -NG ²¹ -;

Y ² is -NG ²² -;

G ²¹ and G ²² are each independently a C ₁ -C ₃ alkyl group substituted with 1-3 substituents independently selected from the group consisting of a phenyl group substituted with one carboxyl group and a carboxyl group;

Z is -(CH ₂ -CH ₂ -O) _m -CH ₂ -CH ₂ - or -(CH ₂ ) _n -;

m is an integer from 1 to 6; and

n is an integer from 2 to 12.

Compound (VIII)

In one embodiment of the present invention, Compound (I), or a pharmaceutically acceptable salt thereof, is a compound having the general formula (VIII) shown below:

where:

R ¹ each independently represents a hydrogen atom or -COO-(C ₁ -C ₄ alkyl group);

W ¹ and W ² are each independently a single bond or a C ₁ -C ₄ alkylene group;

X ¹ is -C(=O)- or -NG ¹¹ -SO ₂ -;

X ² represents -C(=O)- or -SO ₂ -NG ¹² -;

G ¹¹ and G ¹² are each independently a hydrogen atom or
-COOR ² ;

R ² is a C ₁ -C ₄ alkyl group optionally substituted with 1-5 aryl groups;

Y ¹ is -NG ²¹ -, -NG ²¹ -L ¹¹ -C(=O)-NH- or -NG ²¹ -L ¹¹ -C(=O)-NG ³¹ -L ²¹ -C(=O)- NH-;

Y ² is -NG ²² -, -NH-C(=O)-L ¹² -NG ²² - or -NH-C(=O)-L ²² -NG ³² -C(=O)-L ¹² -NG ^22- ;

G ²¹ , G ³¹ , G ²² , and G ³² are each independently a hydrogen atom or a C ₁ -C ₆ alkyl group optionally substituted with 1-5 substituents independently selected from the group consisting of a phenyl group optionally substituted with 1-5 - COOR ³ groups, and -COOR ³ groups;

R ³ each independently represents a hydrogen atom or a C ₁ -C ₄ alkyl group optionally substituted with 1-5 aryl groups;

L ¹¹ , L ²¹ , L ¹² and L ²² are each independently a C ₁ -C ₆ alkylene group optionally substituted with 1-5 C ₁ -C ₆ alkyl groups optionally substituted with 1-5 -COOR ⁴ groups, C ₁ -C ₄ alkylene-phenylene group or phenylene-C ₁ -C ₄ alkylene group;

R ⁴ each independently represents a hydrogen atom or a C ₁ -C ₄ alkyl group optionally substituted with 1-5 aryl groups;

Z is -(CH ₂ -CH ₂ -O) _m -CH ₂ -CH ₂ - or -(CH ₂ ) _n -;

m is an integer from 1 to 6; and

n is an integer from 2 to 12;

or a pharmaceutically acceptable salt thereof.

Exemplary variants of each substituent in Compound (VIII) include those listed below, in addition to the variants listed above for each substituent in Compound (I).

In one embodiment, the C ₁ -C ₄ alkyl group in "-COO-(C ₁ -C ₄ alkyl group)" in R ¹ is a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group or a tert-butyl group.

In one embodiment, R ¹ is a hydrogen atom or a t-butoxycarbonyl group, preferably a hydrogen atom.

In one embodiment, W ¹ is a single bond or a C ₁ -C ₂ alkylene group, preferably a single bond.

In one embodiment, W ² is a single bond or a C ₁ -C ₂ alkylene group, preferably a single bond.

In one embodiment, X ¹ is -C(=O)- or
-NG ¹¹ -SO ₂ -, preferably -C(=O)-.

In one embodiment, X ² is -C(=O)- or -SO ₂ -NG ¹² -, preferably -C(=O)-.

In one embodiment, R ² in the "-COOR ² group" in G ¹¹ and G ¹² is a C ₁ -C ₄ alkyl group optionally substituted with 1-3 phenyl groups, preferably a C ₁ -C ₄ alkyl group optionally substituted with one a phenyl group, more preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a t-butyl group, or a benzyl group.

In one embodiment, G ¹¹ is a hydrogen atom, a t-butoxycarbonyl group or a benzyloxycarbonyl group, preferably a hydrogen atom or a benzyloxycarbonyl group, more preferably a hydrogen atom.

In one embodiment, G ¹² is a hydrogen atom, a t-butoxycarbonyl group, or a benzyloxycarbonyl group, preferably a hydrogen atom or a benzyloxycarbonyl group, more preferably a hydrogen atom.

In one embodiment, Y ¹ is -NG ²¹ -.

In one embodiment, Y ² is -NG ²² -.

In one embodiment, the "phenyl group optionally substituted with 1-5-COOR ³ groups" in G ²¹ , G ³¹ , G ²² and G ³² is a 2-(COOR ³ )-phenyl group, 3-(COOR ³ )- a phenyl group, a 4-(COOR ³ )-phenyl group, and the like.

In one embodiment, R ³ in the "-COOR ³ group" in G ²¹ , G ³¹ , G ²² and G ³² are each independently hydrogen atom, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl a group, a t-butyl group or a benzyl group, preferably a hydrogen atom, a benzyl group or a t-butyl group, more preferably a hydrogen atom or a t-butyl group, even more preferably a hydrogen atom.

In one embodiment, G ²¹ is a hydrogen atom or a C ₁ -C ₃ alkyl group optionally substituted with 1-3 -COOR ³ groups, preferably a C ₁ -C ₃ alkyl group substituted with 1-3 carboxyl groups.

In one embodiment, G ³¹ is a hydrogen atom or a C ₁ -C ₃ alkyl group optionally substituted with 1-3 -COOR ³ groups, preferably a hydrogen atom.

In one embodiment, G ²² is a hydrogen atom or a C ₁ -C ₃ alkyl group optionally substituted with 1-3 -COOR ³ groups, preferably a C ₁ -C ₃ alkyl group substituted with 1-3 carboxyl groups.

In one embodiment, G ³² is a hydrogen atom or a C ₁ -C ₃ alkyl group optionally substituted with 1-3 -COOR ³ groups, preferably a hydrogen atom.

In one embodiment, R ⁴ in the "-COOR ⁴ group" in L ¹¹ , L ¹² , L ²¹ and L ²² are each independently hydrogen atom, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl a group, a t-butyl group or a benzyl group, preferably a hydrogen atom, a t-butyl group or a benzyl group, more preferably a hydrogen atom or a t-butyl group, even more preferably a hydrogen atom.

In one embodiment, L ¹¹ is a C ₁ -C ₂ alkylene group, preferably a methylene group.

In one embodiment, L ¹² is a C ₁ -C ₂ alkylene group, preferably a methylene group.

In one embodiment, L ²¹ is a C ₁ -C ₂ alkylene group, preferably a methylene group.

In one embodiment, L ²² is a C ₁ -C ₂ alkylene group, preferably a methylene group.

In one embodiment, at least one of R ¹ , R ³ , R ⁴ , G ¹¹ and G ¹² is a hydrogen atom. In another embodiment, at least one of R ¹ and R ⁴ is a hydrogen atom. In another embodiment, R ¹ , R ³ , R ⁴ , G ¹¹ and G ¹² each represents a hydrogen atom.

In one embodiment, Z is -(CH ₂ -CH ₂ -O) _m -CH ₂ -CH ₂ - or -(CH ₂ ) _n -, preferably -(CH ₂ -CH ₂ -O) _m -CH ₂ -CH2- _.

In one embodiment, m is an integer from 1 to 6 and n is an integer from 2 to 12, preferably m is an integer from 1 to 4 and n is an integer from 2 to 6.

In one embodiment of Compound (VIII), a compound or a pharmaceutically acceptable salt thereof is described, wherein

R ¹ each represents a hydrogen atom;

W ¹ and W ² are each independently a single bond or a C ₁ -C ₄ alkylene group;

X ¹ is -C(=O)- or -NG ¹¹ -SO ₂ -;

X ² represents -C(=O)- or -SO ₂ -NG ¹² -;

G ¹¹ and G ¹² are each independently a hydrogen atom or
-COOR ² ;

R ² is a C ₁ -C ₄ alkyl group optionally substituted with 1-5 aryl groups;

Y ¹ is -NG ²¹ -, -NG ²¹ -L ¹¹ -C(=O)-NH- or -NG ²¹ -L ¹¹ -C(=O)-NG ³¹ -L ²¹ -C(=O)- NH-;

Y ² is -NG ²² -, -NH-C(=O)-L ¹² -NG ²² - or -NH-C(=O)-L ²² -NG ³² -C(=O)-L ¹² -NG ^22- ;

G ²¹ , G ³¹ , G ²² and G ³² are each independently a hydrogen atom or a C ₁ -C ₆ alkyl group optionally substituted with 1-5 substituents independently selected from the group consisting of a phenyl group optionally substituted with 1-5 -COOR ³ groups, and -COOR ³ groups;

R ³ each independently represents a hydrogen atom or a C ₁ -C ₄ alkyl group optionally substituted with 1-5 aryl groups;

L ¹¹ , L ²¹ , L ¹² and L ²² are each independently a C ₁ -C ₆ alkylene group optionally substituted with 1-5 C ₁ -C ₆ alkyl groups optionally substituted with 1-5 -COOR ⁴ groups, C ₁ -C ₄ alkylene-phenylene group or phenylene-C ₁ -C ₄ alkylene group;

R ⁴ each represents a hydrogen atom;

Z is -(CH ₂ -CH ₂ -O) _m -CH ₂ -CH ₂ - or -(CH ₂ ) _n -;

m is an integer from 1 to 6; and

n is an integer from 2 to 12.

In another embodiment of Compound (VIII), a compound or a pharmaceutically acceptable salt thereof is described, wherein

R ¹ each represents a hydrogen atom;

W ¹ and W ² are each independently a single bond or a C ₁ -C ₄ alkylene group;

X ¹ is -C(=O)- or -NG ¹¹ -SO ₂ -;

X ² represents -C(=O)- or -SO ₂ -NG ¹² -;

G ¹¹ and G ¹² each represents a hydrogen atom;

Y ¹ is -NG ²¹ -, -NG ²¹ -L ¹¹ -C(=O)-NH- or -NG ²¹ -L ¹¹ -C(=O)-NG ³¹ -L ²¹ -C(=O)- NH-;

Y ² is -NG ²² -, -NH-C(=O)-L ¹² -NG ²² - or -NH-C(=O)-L ²² -NG ³² -C(=O)-L ¹² -NG ^22- ;

G ²¹ , G ³¹ , G ²² and G ³² are each independently a hydrogen atom or a C ₁ -C ₆ alkyl group optionally substituted with 1-5 substituents independently selected from the group consisting of a phenyl group optionally substituted with 1-5 -COOR ³ groups, and -COOR ³ groups;

R ³ each represents a hydrogen atom;

L ¹¹ , L ²¹ , L ¹² and L ²² are each independently a C ₁ -C ₆ alkylene group optionally substituted with 1-5 C ₁ -C ₆ alkyl groups optionally substituted with 1-5 -COOR ⁴ groups, C ₁ -C ₄ alkylene-phenylene group or phenylene-C ₁ -C ₄ alkylene group;

R ⁴ each represents a hydrogen atom;

Z is -(CH ₂ -CH ₂ -O) _m -CH ₂ -CH ₂ - or -(CH ₂ ) _n -;

m is an integer from 1 to 6; and

n is an integer from 2 to 12.

In another embodiment of Compound (VIII), a compound or a pharmaceutically acceptable salt thereof is described, wherein

R ¹ each independently represents a hydrogen atom or a tert-butoxycarbonyl group;

W ¹ and W ² are each independently a single bond or a C ₁ -C ₂ alkylene group;

X ¹ is -C(=O)- or -NG ¹¹ -SO ₂ -;

X ² represents -C(=O)- or -SO ₂ -NG ¹² -;

G ¹¹ and G ¹² each represents a hydrogen atom;

Y ¹ is -NG ²¹ -, -NG ²¹ -L ¹¹ -C(=O)-NH- or -NG ²¹ -L ¹¹ -C(=O)-NG ³¹ -L ²¹ -C(=O)- NH-;

Y ² is -NG ²² -, -NH-C(=O)-L ¹² -NG ²² - or -NH-C(=O)-L ²² -NG ³² -C(=O)-L ¹² -NG ^22- ;

G ²¹ , G ³¹ , G ²² and G ³² are each independently a hydrogen atom or a C ₁ -C ₃ alkyl group optionally substituted with 1-3 -COOR ³ groups;

R ³ each independently represents a hydrogen atom or a tert-butyl group;

L ¹¹ , L ²¹ , L ¹² and L ²² are each independently a C ₁ -C ₂ alkylene group;

Z is -(CH ₂ -CH ₂ -O) _m -CH ₂ -CH ₂ - or -(CH ₂ ) _n -;

m is an integer from 1 to 6; and

n is an integer from 2 to 12.

In another embodiment of Compound (VIII), a compound or a pharmaceutically acceptable salt thereof is described, wherein

R ¹ each represents a hydrogen atom;

W ¹ and W ² are each independently a single bond or a C ₁ -C ₂ alkylene group;

X ¹ is -C(=O)- or -NG ¹¹ -SO ₂ -;

X ² represents -C(=O)- or -SO ₂ -NG ¹² -;

G ¹¹ and G ¹² each represents a hydrogen atom;

Y ¹ is -NG ²¹ -, -NG ²¹ -L ¹¹ -C(=O)-NH- or -NG ²¹ -L ¹¹ -C(=O)-NG ³¹ -L ²¹ -C(=O)- NH-;

Y ² is -NG ²² -, -NH-C(=O)-L ¹² -NG ²² - or -NH-C(=O)-L ²² -NG ³² -C(=O)-L ¹² -NG ^22- ;

G ²¹ , G ³¹ , G ²² and G ³² are each independently a hydrogen atom or a C ₁ -C ₃ alkyl group optionally substituted with 1-3 -COOR ³ groups;

R ³ each independently represents a hydrogen atom or a tert-butyl group;

L ¹¹ , L ²¹ , L ¹² and L ²² are each independently a C ₁ -C ₂ alkylene group;

Z is -(CH ₂ -CH ₂ -O) _m -CH ₂ -CH ₂ - or -(CH ₂ ) _n -;

m is an integer from 1 to 6; and

n is an integer from 2 to 12.

In another embodiment of Compound (VIII), a compound or a pharmaceutically acceptable salt thereof is described, wherein

R ¹ each represents a hydrogen atom;

W ¹ and W ² are each independently a single bond or a C ₁ -C ₂ alkylene group;

X ¹ is -C(=O)- or -NG ¹¹ -SO ₂ -;

X ² represents -C(=O)- or -SO ₂ -NG ¹² -;

G ¹¹ and G ¹² each represents a hydrogen atom;

Y ¹ is -NG ²¹ -, -NG ²¹ -L ¹¹ -C(=O)-NH- or -NG ²¹ -L ¹¹ -C(=O)-NG ³¹ -L ²¹ -C(=O)- NH-;

Y ² is -NG ²² -, -NH-C(=O)-L ¹² -NG ²² - or -NH-C(=O)-L ²² -NG ³² -C(=O)-L ¹² -NG ^22- ;

G ²¹ and G ²² are each independently a hydrogen atom or a C ₁ -C ₃ alkyl group optionally substituted with 1-3 -COOR ³ groups;

G ³¹ and G ³² each represents a hydrogen atom;

R ³ each represents a hydrogen atom;

L ¹¹ , L ²¹ , L ¹² and L ²² are each independently a C ₁ -C ₂ alkylene group;

Z is -(CH ₂ -CH ₂ -O) _m -CH ₂ -CH ₂ - or -(CH ₂ ) _n -;

m is an integer from 1 to 6; and

n is an integer from 2 to 12.

In another embodiment of Compound (VIII), a compound or a pharmaceutically acceptable salt thereof is described, wherein

R ¹ each represents a hydrogen atom;

W ¹ and W ² are each a single bond;

X ¹ represents -C(=O)-;

X ² is -C(=O)-;

Y ¹ is -NG ²¹ -;

Y ² is -NG ²² -;

G ²¹ and G ²² are each independently a C ₁ -C ₃ alkyl group substituted with 1-3 carboxyl groups;

Z is -(CH ₂ -CH ₂ -O) _m -CH ₂ -CH ₂ -; and

m is an integer from 1 to 6.

In one embodiment of the present invention, A ¹ and A ² are each independently an inhibitor residue obtained by removing any hydrogen atom or any hydroxy group from an inhibitor molecule selected from the following group of inhibitor molecules.

In one embodiment of the present invention, A ¹ and A ² are each independently an inhibitor residue selected from the following group.

where symbol

means the point of attachment to Z.

Connection examples

In one embodiment of the present invention, Compound (I), or a pharmaceutically acceptable salt thereof, is a compound selected from the group consisting of the following compounds:

(2S,2'S)-tetra-tert-butyl 2,2'-((oxybis(ethane-2,1-diyl))bis((N-((benzyloxy)carbonyl)-N-(4-((4- (2,3-bis(tert-butoxycarbonyl)guanidino)benzoyl)oxy)benzyl)sulfamoyl)azandiyl))disuccinate;

(2S,2'S)-2,2'-((oxybis(ethane-2,1-diyl))bis((N-(4-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl)azandiyl))succinic acid;

(2S,13S)-tetra-tert-butyl 3,12-bis(N-((benzyloxy)carbonyl)-N-(4-((4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoyl) hydroxy)benzyl)sulfamoyl)-6,9-dioxa-3,12-diazatetradecane-1,2,13,14-tetracarboxylate;

(2S,13S)-3,12-bis(N-(4-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl)-6,9-dioxa-3,12-diazatetradecane-1,2,13,14- tetracarboxylic acid;

(2S,16S)-tetra-tert-butyl 3,15-bis(N-((benzyloxy)carbonyl)-N-(4-((4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoyl) hydroxy)benzyl)sulfamoyl)-6,9,12-trioxa-3,15-diazaheptadecan-1,2,16,17-tetracarboxylate;

(2S,16S)-3,15-bis(N-(4-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl)-6,9,12-trioxa-3,15-diazaheptadecan-1,2,16, 17-tetracarboxylic acid;

(2S,19S)-tetra-tert-butyl 3,18-bis(N-((benzyloxy)carbonyl)-N-(4-((4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoyl) hydroxy)benzyl)sulfamoyl)-6,9,12,15-tetraoxa-3,18-diazaicosan-1,2,19,20-tetracarboxylate;

(2S,19S)-3,18-bis(N-(4-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl)-6,9,12,15-tetraoxa-3,18-diazaicosan-1,2, 19,20-tetracarboxylic acid;

(2S,22S)-tetra-tert-butyl 3,21-bis(N-((benzyloxy)carbonyl)-N-(4-((4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoyl) hydroxy)benzyl)sulfamoyl)-6,9,12,15,18-pentaoxa-3,21-diazatricosan-1,2,22,23-tetracarboxylate;

(2S,22S)-3,21-bis(N-(4-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl)-6,9,12,15,18-pentaoxa-3,21-diazatricosan-1, 2,22,23-tetracarboxylic acid;

(2S,25S)-tetra-tert-butyl 3,24-bis(N-((benzyloxy)carbonyl)-N-(4-((4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoyl) hydroxy)benzyl)sulfamoyl)-6,9,12,15,18,21-hexaoxa-3,24-diazahexacosan-1,2,25,26-tetracarboxylate;

(2S,25S)-3,24-bis(N-(4-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl)-6,9,12,15,18,21-hexaoxa-3,24-diazahexacosan- 1,2,25,26-tetracarboxylic acid;

(2S,2'S)-tetra-tert-butyl 2,2'-(propane-1,3-diylbis((N-((benzyloxy)carbonyl)-N-(4-((4-(2,3-bis (tert-butoxycarbonyl)guanidino)benzoyl)oxy)benzyl)sulfamoyl)azandiyl))disuccinate;

(2S,2'S)-2,2'-(propane-1,3-diylbis((N-(4-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl)azandiyl))succinic acid;

(2S,2'S)-tetra-tert-butyl 2,2'-(butane-1,4-diylbis((N-((benzyloxy)carbonyl)-N-(4-((4-(2,3-bis (tert-butoxycarbonyl)guanidino)benzoyl)oxy)benzyl)sulfamoyl)azandiyl))disuccinate;

(2S,2'S)-2,2'-(butane-1,4-diylbis((N-(4-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl)azandiyl))succinic acid;

(2S,2'S)-tetra-tert-butyl 2,2'-(pentane-1,5-diylbis((N-((benzyloxy)carbonyl)-N-(4-((4-(2,3-bis (tert-butoxycarbonyl)guanidino)benzoyl)oxy)benzyl)sulfamoyl)azandiyl))disuccinate;

(2S,2'S)-2,2'-(pentane-1,5-diylbis((N-(4-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl)azandiyl))succinic acid;

tetra-tert-butyl 3,18-bis(((4-((4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoyl)oxy)benzyl)oxy)carbonyl)-6,9,12,15 -tetraoxa-3,18-diazaicosan-1,2,19,20-tetracarboxylate;

3,18-bis(((4-((4-guanidinobenzoyl)oxy)benzyl)oxy)carbonyl)-6,9,12,15-tetraoxa-3,18-diazaicosan-1,2,19,20-tetracarboxylic acid;

tetra-tert-butyl 2,2'-(1,20-bis(4-((4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoyl)oxy)phenyl)-3,18-dioxo-2 ,19-dioxa-4,17-diazaicosan-4,17-diyl)disuccinate;

2,2'-(1,20-bis(4-((4-guanidinobenzoyl)oxy)phenyl)-3,18-dioxo-2,19-dioxa-4,17-diazaicosan-4,17-diyl)disuccinic acid;

(3S,6S,25S,28S)-di-tert-butyl 3,28-bis((((4-((4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoyl)oxy)benzyl)oxy )carbonyl)amino)-6,25-bis(2-(tert-butoxy)-2-oxoethyl)-4,7,24,27-tetraoxo-11,14,17,20-tetraoxa-5,8,23 ,26-tetraazatriacontane-1,30-dioate;

(3S,6S,25S,28S)-6,25-bis(carboxymethyl)-3,28-bis((((4-((4-guanidinobenzoyl)oxy)benzyl)oxy)carbonyl)amino)-4.7 ,24,27-tetraoxo-11,14,17,20-tetraoxa-5,8,23,26-tetraazatriacontane-1,30-dioic acid;

(3S,6S,23S,26S)-di-tert-butyl 3,26-bis((((4-((4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoyl)oxy)benzyl)oxy )carbonyl)amino)-6,23-bis(2-(tert-butoxy)-2-oxoethyl)-4,7,22,25-tetraoxo-5,8,21,24-tetraazaoctacosan-1,28-dioate ;

(3S,6S,23S,26S)-6,23-bis(carboxymethyl)-3,26-bis((((4-((4-guanidinobenzoyl)oxy)benzyl)oxy)carbonyl)amino)-4.7 ,22,25-tetraoxo-5,8,21,24-tetraazaoctacosan-1,28-dioic acid;

(3S,22S)-di-tert-butyl 3,22-bis(2-((((4-((4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoyl)oxy)benzyl)oxy) carbonyl)(3-(tert-butoxycarbonyl)benzyl)amino)acetamido)-4,21-dioxo-8,11,14,17-tetraoxa-5,20-diazatetracosan-1,24-dioate;

(3S,22S)-3,22-bis(2-((3-carboxybenzyl)(((4-((4-guanidinobenzoyl)oxy)benzyl)oxy)carbonyl)amino)acetamido)-4,21-dioxo- 8,11,14,17-tetraoxa-5,20-diazatetracosan-1,24-dioic acid;

(4S,7S,26S,29S)-di-tert-butyl 3,30-bis(((4-((4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoyl)oxy)benzyl)oxy) carbonyl)-4,7,26,29-tetrakis(2-(tert-butoxy)-2-oxoethyl)-5,8,25,28-tetraoxo-12,15,18,21-tetraoxa-3,6, 9,24,27,30-hexaazadotriacontane-1,32-dioate;

(4S,7S,26S,29S)-4,7,26,29-tetrakis(carboxymethyl)-3,30-bis(((4-((4-guanidinobenzoyl)oxy)benzyl)oxy)carbonyl)-5, 8,25,28-tetraoxo-12,15,18,21-tetraoxa-3,6,9,24,27,30-hexaazadotriacontane-1,32-dioic acid;

(3S,22S)-di-tert-butyl 3,22-bis((((4-((4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoyl)oxy)benzyl)oxy)carbonyl)( 3-(tert-butoxycarbonyl)benzyl)amino)-4,21-dioxo-8,11,14,17-tetraoxa-5,20-diazatetracosan-1,24-dioate;

(3S,22S)-3,22-bis((3-carboxybenzyl)(((4-((4-guanidinobenzoyl)oxy)benzyl)oxy)carbonyl)amino)-4,21-dioxo-8,11,14 ,17-tetraoxa-5,20-diazatetracosan-1,24-dioic acid;

(2S,2'S)-tetra-tert-butyl 2,2'-((((5,8,11,14-tetraoxa-2,17-diazaoctadecan-1,18-dioyl)bis(3,1-phenylene) )bis(methylene))bis((((4-((4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoyl)oxy)benzyl)oxy)carbonyl)azandiyl)) disuccinate;

(2S,2'S)-2,2'-((((5,8,11,14-tetraoxa-2,17-diazaoctadecan-1,18-dioyl)bis(3,1-phenylene))bis(methylene) )bis((((4-((4-guanidinobenzoyl)oxy)benzyl)oxy)carbonyl)azandiyl))succinic acid;

(2S,2'S)-tetra-tert-butyl 2,2'-((((5,8,11,14-tetraoxa-2,17-diazaoctadecan-1,18-dioyl)bis(3,1-phenylene) )bis(methylene))bis((N-((benzyloxy)carbonyl)-N-(4-((4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoyl)oxy)benzyl)sulfamoyl)azandiyl) )disuccinate;

(2S,2'S)-2,2'-((((5,8,11,14-tetraoxa-2,17-diazaoctadecan-1,18-dioyl)bis(3,1-phenylene))bis(methylene) )bis((N-(4-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl)azandiyl))succinic acid;

tetra-tert-butyl 3,12-bis(10-(2,3-bis(tert-butoxycarbonyl)guanidino)-13-oxo-6,7,8,13-tetrahydrodibenzo[b,f][1,4] dioxecine-4-carbonyl)-6,9-dioxa-3,12-diazatetradecane-1,2,13,14-tetracarboxylate;

3,12-bis(10-guanidino-13-oxo-6,7,8,13-tetrahydrodibenzo[b,f][1,4] dioxecine-4-carbonyl)-6,9-dioxa-3,12- diasatetradecane-1,2,13,14-tetracarboxylic acid;

(2S,13S)-tetra-tert-butyl 3,12-bis(10-(2,3-bis(tert-butoxycarbonyl)guanidino)-13-oxo-6,7,8,13-tetrahydrodibenzo[b,f ][1,4]dioxecin-4-carbonyl)-6,9-dioxa-3,12-diazatetradecane-1,2,13,14-tetracarboxylate;

(2S,13S)-3,12-bis(10-guanidino-13-oxo-6,7,8,13-tetrahydrodibenzo[b,f] [1,4]dioxecine-4-carbonyl)-6,9- dioxa-3,12-diazatetradecane-1,2,13,14-tetracarboxylic acid;

(2R,13R)-tetra-tert-butyl 3,12-bis(10-(2,3-bis(tert-butoxycarbonyl)guanidino)-13-oxo-6,7,8,13-tetrahydrodibenzo[b,f ][1,4]dioxecin-4-carbonyl)-6,9-dioxa-3,12-diazatetradecane-1,2,13,14-tetracarboxylate;

(2R,13R)-3,12-bis(10-guanidino-13-oxo-6,7,8,13-tetrahydrodibenzo[b,f] [1,4]dioxecine-4-carbonyl)-6,9- dioxa-3,12-diazatetradecane-1,2,13,14-tetracarboxylic acid;

(2S,13S)-3,12-bis(N-(4-((4-guanidinobenzoyl)oxy)benzyl)-N-methylsulfamoyl)-6,9-dioxa-3,12-diazatetradecane-1,2,13 ,14-tetracarboxylic acid;

tetrabenzyl 3,3'-(((ethane-1,2-diylbis(oxy))bis(ethane-2,1-diyl))bis((N-((benzyloxy)carbonyl)-N-(4-(( 4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoyl)oxy)benzyl)sulfamoyl)azandiyl))dipentanedioate;

3,3'-(((ethane-1,2-diylbis(oxy))bis(ethane-2,1-diyl))bis((N-(4-((4-(2,3-bis(tert -butoxycarbonyl)guanidino)benzoyl)oxy)benzyl)sulfamoyl)azandiyl))dipentanedioic acid;

3,3'-(((ethane-1,2-diylbis(oxy))bis(ethane-2,1-diyl))bis((N-(4-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl) azandiyl))dipentanedioic acid;

(2S,2'S)-2,2'-((1,12-bis(4-((4-guanidinobenzoyl)oxy)phenyl)-5,8-dioxa-2,11-diazadecanedisulfonyl)bis(azandiyl))disuccinic acid;

(2S,13S)-tetra-tert-butyl 3,12-bis(N-((benzyloxy)carbonyl)-N-(3-(((4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoyl )hydroxy))benzyl)sulfamoyl)-6,9-dioxa-3,12-diazatetradecane-1,2,13,14-tetracarboxylate;

(2S,13S)-3,12-bis(N-(3-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl)-6,9-dioxa-3,12-diazatetradecane-1,2,13,14- tetracarboxylic acid;

(2S,2'S)-tetra-tert-butyl 2,2'-((oxybis(ethane-2,1-diyl))bis((10-(2,3-bis(tert-butoxycarbonyl)guanidino)-13- oxo-6,7,8,13-tetrahydrodibenzo[b,f][1,4]dioxecine-4-carbonyl)azandiyl))disuccinate;

(2S,2'S)-2,2'-((oxybis(ethane-2,1-diyl))bis((10-guanidino-13-oxo-6,7,8,13-tetrahydrodibenzo[b,f][ 1,4]dioxecin-4-carbonyl)azandiyl))succinic acid;

(2S,16S)-tetra-tert-butyl 3,15-bis(10-(2,3-bis(tert-butoxycarbonyl)guanidino)-13-oxo-6,7,8,13-tetrahydrodibenzo[b,f ][1,4]dioxecine-4-carbonyl)-6,9,12-trioxa-3,15-diazaheptadecan-1,2,16,17-tetracarboxylate;

(2S,16S)-3,15-bis(10-guanidino-13-oxo-6,7,8,13-tetrahydrodibenzo[b,f] [1,4]dioxecine-4-carbonyl)-6,9, 12-trioxa-3,15-diazaheptadecan-1,2,16,17-tetracarboxylic acid;

(2S,2'S)-tetrabenzyl 2,2'-(([1,1'-biphenyl]-3,3'-diylbis(methylene))bis((10-(2,3-bis(tert-butoxycarbonyl)guanidino )-13-oxo-6,7,8,13-tetrahydrodibenzo[b,f][1,4]dioxecine-4-carbonyl)azandiyl))disuccinate;

(2S,2'S)-tetrabenzyl 2,2'-(([1,1'-biphenyl]-3,3'-diylbis(methylene))bis((10-guanidino-13-oxo-6,7,8, 13-tetrahydrodibenzo[b,f][1,4]dioxecine-4-carbonyl)azandiyl))disuccinate;

(2S,2'S)-2,2'-(([1,1'-biphenyl]-3,3'-diylbis(methylene))bis((10-guanidino-13-oxo-6,7,8,13 -tetrahydrodibenzo[b,f][1,4]dioxecine-4-carbonyl)azandiyl)) disuccinic acid;

(2S,2'S)-tetra-tert-butyl 2,2'-(((((oxybis(ethane-2,1-diyl))bis(oxy))bis(3-((2-(trimethylsilyl)ethoxy) carbonyl)-5,1-phenylene))bis(methylene))bis((10-(2,3-bis(tert-butoxycarbonyl)guanidino)-13-oxo-6,7,8,13-tetrahydrodibenzo[b, f] [1,4]dioxecine-4-carbonyl)azandiyl))disuccinate;

(S)-5,5'-((oxybis(ethane-2,1-diyl))bis(oxy))bis(3-((10-(2,3-bis(tert-butoxycarbonyl)guanidino)-N -((S)-1,4-di-tert-butoxy-1,4-dioxobutan-2-yl)-13-oxo-6,7,8,13-tetrahydrodibenzo[b,f][1,4] dioxecine-4-carboxamide) methyl) benzoic acid);

(2S,2'S)-2,2'-(((((oxybis(ethane-2,1-diyl))bis(oxy))bis(3-carboxy-5,1-phenylene))bis(methylene)) bis((10-guanidino-13-oxo-6,7,8,13-tetrahydrodibenzo[b,f][1,4]dioxecine-4-carbonyl)azandiyl))succinic acid; and

(2S,2'S)-2,2'-((oxybis(ethane-2,1-diyl))bis((3-((4-guanidinobenzoyl)oxy)benzoyl)azandiyl))disuccinic acid

or a pharmaceutically acceptable salt thereof.

In one embodiment of the present invention, Compound (I), or a pharmaceutically acceptable salt thereof, is a compound selected from the group consisting of the following compounds:

(2S,2'S)-2,2'-((oxybis(ethane-2,1-diyl))bis((N-(4-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl)azandiyl))succinic acid;

(2S,13S)-3,12-bis(N-(4-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl)-6,9-dioxa-3,12-diazatetradecane-1,2,13,14- tetracarboxylic acid;

(2S,16S)-3,15-bis(N-(4-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl)-6,9,12-trioxa-3,15-diazaheptadecan-1,2,16, 17-tetracarboxylic acid;

(2S,19S)-3,18-bis(N-(4-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl)-6,9,12,15-tetraoxa-3,18-diazaicosan-1,2, 19,20-tetracarboxylic acid;

(2S,22S)-3,21-bis(N-(4-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl)-6,9,12,15,18-pentaoxa-3,21-diazatricosan-1, 2,22,23-tetracarboxylic acid;

(2S,25S)-3,24-bis(N-(4-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl)-6,9,12,15,18,21-hexaoxa-3,24-diazahexacosan- 1,2,25,26-tetracarboxylic acid;

(2S,2'S)-2,2'-(propane-1,3-diylbis((N-(4-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl)azandiyl))succinic acid;

(2S,2'S)-2,2'-(butane-1,4-diylbis((N-(4-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl)azandiyl))succinic acid;

(2S,2'S)-2,2'-(pentane-1,5-diylbis((N-(4-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl)azandiyl))disuccinic acid:

3,18-bis(((4-((4-guanidinobenzoyl)oxy)benzyl)oxy)carbonyl)-6,9,12,15-tetraoxa-3,18-diazaicosan-1,2,19,20-tetracarboxylic acid;

2,2'-(1,20-bis(4-((4-guanidinobenzoyl)oxy)phenyl)-3,18-dioxo-2,19-dioxa-4,17-diazaicosan-4,17-diyl)disuccinic acid;

(3S,6S,25S,28S)-6,25-bis(carboxymethyl)-3,28-bis((((4-((4-guanidinobenzoyl)oxy)benzyl)oxy)carbonyl)amino)-4.7 ,24,27-tetraoxo-11,14,17,20-tetraoxa-5,8,23,26-tetraazatriacontane-1,30-dioic acid;

(3S,6S,23S,26S)-6,23-bis(carboxymethyl)-3,26-bis((((4-((4-guanidinobenzoyl)oxy)benzyl)oxy)carbonyl)amino)-4.7 ,22,25-tetraoxo-5,8,21,24-tetraazaoctacosan-1,28-dioic acid;

(3S,22S)-3,22-bis(2-((3-carboxybenzyl)(((4-((4-guanidinobenzoyl)oxy)benzyl)oxy)carbonyl)amino)acetamido)-4,21-dioxo- 8,11,14,17-tetraoxa-5,20-diazatetracosan-1,24-dioic acid;

(4S,7S,26S,29S)-4,7,26,29-tetrakis(carboxymethyl)-3,30-bis(((4-((4-guanidinobenzoyl)oxy)benzyl)oxy)carbonyl)-5, 8,25,28-tetraoxo-12,15,18,21-tetraoxa-3,6,9,24,27,30-hexaazadotriacontane-1,32-dioic acid;

(3S,22S)-3,22-bis((3-carboxybenzyl)(((4-((4-guanidinobenzoyl)oxy)benzyl)oxy)carbonyl)amino)-4,21-dioxo-8,11,14 ,17-tetraoxa-5,20-diazatetracosan-1,24-dioic acid;

(2S,2'S)-2,2'-((((5,8,11,14-tetraoxa-2,17-diazaoctadecan-1,18-dioyl)bis(3,1-phenylene))bis(methylene) )bis((((4-((4-guanidinobenzoyl)oxy)benzyl)oxy)carbonyl)azandiyl))succinic acid;

(2S,2'S)-2,2'-((((5,8,11,14-tetraoxa-2,17-diazaoctadecan-1,18-dioyl)bis(3,1-phenylene))bis(methylene) )bis((N-(4-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl)azandiyl))succinic acid;

3,12-bis(10-guanidino-13-oxo-6,7,8,13-tetrahydrodibenzo[b,f][1,4] dioxecine-4-carbonyl)-6,9-dioxa-3,12- diasatetradecane-1,2,13,14-tetracarboxylic acid;

(2S,13S)-3,12-bis(10-guanidino-13-oxo-6,7,8,13-tetrahydrodibenzo[b,f] [1,4]dioxecine-4-carbonyl)-6,9- dioxa-3,12-diazatetradecane-1,2,13,14-tetracarboxylic acid;

(2R,13R)-3,12-bis(10-guanidino-13-oxo-6,7,8,13-tetrahydrodibenzo[b,f] [1,4]dioxecine-4-carbonyl)-6,9- dioxa-3,12-diazatetradecane-1,2,13,14-tetracarboxylic acid;

(2S,13S)-3,12-bis(N-(4-((4-guanidinobenzoyl)oxy)benzyl)-N-methylsulfamoyl)-6,9-dioxa-3,12-diazatetradecane-1,2,13 ,14-tetracarboxylic acid;

3,3'-(((ethane-1,2-diylbis(oxy))bis(ethane-2,1-diyl))bis((N-(4-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl) azandiyl))dipentanedioic acid;

(2S,2'S)-2,2'-((1,12-bis(4-((4-guanidinobenzoyl)oxy)phenyl)-5,8-dioxa-2,11-diazadecanedisulfonyl)bis(azandiyl))disuccinic acid;

(2S,13S)-3,12-bis(N-(3-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl)-6,9-dioxa-3,12-diazatetradecane-1,2,13,14- tetracarboxylic acid;

(2S,2'S)-2,2'-((oxybis(ethane-2,1-diyl))bis((10-guanidino-13-oxo-6,7,8,13-tetrahydrodibenzo[b,f][ 1,4]dioxecin-4-carbonyl)azandiyl))succinic acid;

(2S,16S)-3,15-bis(10-guanidino-13-oxo-6,7,8,13-tetrahydrodibenzo[b,f] [1,4]dioxecine-4-carbonyl)-6,9, 12-trioxa-3,15-diazaheptadecan-1,2,16,17-tetracarboxylic acid;

(2S,2'S)-2,2'-(([1,1'-biphenyl]-3,3'-diylbis(methylene))bis((10-guanidino-13-oxo-6,7,8,13 -tetrahydrodibenzo[b,f][1,4]dioxecine-4-carbonyl)azandiyl)) disuccinic acid;

(2S,2'S)-2,2'-(((((oxybis(ethane-2,1-diyl))bis(oxy))bis(3-carboxy-5,1-phenylene))bis(methylene)) bis((10-guanidino-13-oxo-6,7,8,13-tetrahydrodibenzo[b,f][1,4]dioxecine-4-carbonyl)azandiyl))succinic acid; and

(2S,2'S)-2,2'-((oxybis(ethane-2,1-diyl))bis((3-((4-guanidinobenzoyl)oxy)benzoyl)azandiyl))disuccinic acid,

or a pharmaceutically acceptable salt thereof.

In one embodiment of the present invention, Compound (I) or a pharmaceutically acceptable salt thereof is a compound selected from the group consisting of the following compounds

(2S,2'S)-2,2'-((oxybis(ethane-2,1-diyl))bis((N-(4-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl)azandiyl))succinic acid;

(2S,13S)-3,12-bis(N-(4-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl)-6,9-dioxa-3,12-diazatetradecane-1,2,13,14- tetracarboxylic acid;

(2S,2'S)-2,2'-(butane-1,4-diylbis((N-(4-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl)azandiyl))succinic acid;

(2S,13S)-3,12-bis(10-guanidino-13-oxo-6,7,8,13-tetrahydrodibenzo[b,f] [1,4]dioxecine-4-carbonyl)-6,9- dioxa-3,12-diazatetradecane-1,2,13,14-tetracarboxylic acid;

(2S,2'S)-2,2'-((oxybis(ethane-2,1-diyl))bis((10-guanidino-13-oxo-6,7,8,13-tetrahydrodibenzo[b,f][ 1,4]dioxecin-4-carbonyl)azandiyl))succinic acid;

(2S,16S)-3,15-bis(10-guanidino-13-oxo-6,7,8,13-tetrahydrodibenzo[b,f] [1,4]dioxecine-4-carbonyl)-6,9, 12-trioxa-3,15-diazaheptadecan-1,2,16,17-tetracarboxylic acid;

(2S,2'S)-2,2'-(([1,1'-biphenyl]-3,3'-diylbis(methylene))bis((10-guanidino-13-oxo-6,7,8,13 -tetrahydrodibenzo[b,f][1,4]dioxecine-4-carbonyl)azandiyl)) disuccinic acid; and

(2S,2'S)-2,2'-(((((oxybis(ethane-2,1-diyl))bis(oxy))bis(3-carboxy-5,1-phenylene))bis(methylene)) bis((10-guanidino-13-oxo-6,7,8,13-tetrahydrodibenzo[b,f][1,4]dioxecine-4-carbonyl)azandiyl))succinic acid,

or a pharmaceutically acceptable salt thereof.

Compound (II)

The present invention describes a compound having the following general formula (II)

where:

Ring B and Ring C are each independently an aryl group or a heteroaryl group;

R ¹ each independently represents a hydrogen atom or -COO-(C ₁ -C ₄ alkyl group);

W represents a single bond or a C ₁ -C ₄ alkylene group;

X is -C(=O)-, -OC(=O)- or -NG-SO ₂ -;

G represents a hydrogen atom, a C ₁ -C ₄ alkyl group, or —COOR ² ;

R ² is a C ₁ -C ₄ alkyl group optionally substituted with 1-5 aryl groups;

Y is -NG ² G ⁴ , -NG ² -L ¹ -COOH, -NG ² -L ¹ -C(=O)-NH ₂ , -NG ² -L ¹ -C(=O)-NG ³ - L ² -COOH, -NG ² -L ¹ -C(=O)-NG ³ -L ² -C(=O)-NG ³ -L ² -COOH, -NG ² -L ¹ -C(=O) -NG ³ -L ² -C(=O)-NH ₂ , -NG ² -L ³ -OH or -NG ² -(CH ₂ -CH ₂ -O) _q -CH ₂ -CH ₂ -COOH;

q is an integer from 1 to 6;

G ² and G ³ are each independently a hydrogen atom or a C ₁ -C ₆ alkyl group optionally substituted with 1-5 substituents independently selected from the group consisting of a phenyl group optionally substituted with 1-5 -COOR ³ groups, and -COOR ³ groups;

G ⁴ represents a hydrogen atom, a C ₁ -C ₄ alkyl group or a C ₁ -C ₄ alkoxy-C ₁ -C ₄ alkyl group;

R ³ each independently represents a hydrogen atom or a C ₁ -C ₄ alkyl group optionally substituted with 1-5 aryl groups;

L ¹ and L ² are each independently a C ₁ -C ₆ alkylene group optionally substituted with 1-5 C ₁ -C ₆ alkyl groups optionally substituted with 1-5 -COOR ⁴ groups, a C ₁ -C ₆ alkylene group substituted with C a ₇ -C ₁₂ aralkyl group optionally substituted with 1-5 substituents independently selected from the group consisting of a hydroxy group and a carboxyl group, a C ₁ -C ₄ alkylene-phenylene group, or a phenylene-C ₁ -C ₄ alkylene group;

L ³ represents a C ₁ -C ₄ alkylene-phenylene group, where the phenylene fragment is optionally substituted with 1-3 -COOR ⁴ groups;

R ⁴ each independently represents a hydrogen atom or a C ₁ -C ₄ alkyl group optionally substituted with 1-5 substituents independently selected from the group consisting of an aryl group and a trimethylsilyl group;

R ⁵ and R ⁶ are each independently a hydrogen atom, a halogen atom, a C ₁ -C ₄ alkyl group, a C ₁ -C ₄ alkoxy group, a carboxyl group, or -C(=O)-NG ² G ⁴ ;

s and t are each independently an integer from 1 to 4;

two or more R ⁵ and/or two or more R ⁶ may be the same or different from each other;

or a pharmaceutically acceptable salt thereof.

In one embodiment, the aryl group on Ring B and Ring C are each independently a C ₆ -C ₁₂ aryl group, preferably a phenyl group or a naphthyl group, more preferably a phenyl group.

In one embodiment, the heteroaryl group in Ring B and Ring C are each independently a 5-11 membered monocyclic or bicyclic aromatic heterocyclic group containing 1-4 heteroatoms selected from an oxygen atom, a sulfur atom, and a nitrogen atom other than carbon atoms. , preferably a pyrrolyl group, a furyl group and a thienyl group, more preferably a thienyl group.

In one embodiment, Ring B and Ring C are each independently an aryl group, preferably each is a phenyl group.

In one embodiment, ring B and ring C are each independently a phenyl group, a naphthyl group, or a thienyl group, preferably ring B and ring C are each a phenyl group.

In one embodiment, the C ₁ -C ₄ alkyl group in "-COO-(C ₁ -C ₄ alkyl group)" in R ¹ is a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group or a tert-butyl group.

In one embodiment, R ¹ is a hydrogen atom or a t-butoxycarbonyl group, preferably a hydrogen atom.

In one embodiment, W is a C ₁ -C ₄ alkylene group, eg a methylene group, an ethylene group, a trimethylene group, or a tetramethylene group, preferably a C ₁ -C ₂ alkylene group, eg a methylene group. In another embodiment, W is a single bond or a C ₁ -C ₂ alkylene group, preferably a single bond or a methylene group.

In one embodiment, X is -OC(=O)- or -NG-SO ₂ -, preferably -NG-SO ₂ -. In another embodiment, X is -C(=O)- or -NG-SO ₂ -, preferably -C(=O)-.

In one embodiment, the "C ₁ -C ₄ alkyl group" in G is a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, or a t-butyl group, preferably a methyl group or an ethyl group.

In one embodiment, R ² in the "-COOR ² group" in G is a C ₁ -C ₄ alkyl group optionally substituted with 1-3 phenyl groups, e.g., methyl group, ethyl group, n-propyl group, isopropyl group, n -butyl group, tert-butyl group or benzyl group, preferably C ₁ -C ₄ alkyl group, optionally substituted with one phenyl group, more preferably tert-butyl group or benzyl group.

In one embodiment, G is a hydrogen atom, a methyl group, a t-butoxycarbonyl group, or a benzyloxycarbonyl group, preferably a hydrogen atom, a methyl group, or a benzyloxycarbonyl group, more preferably a hydrogen atom or a methyl group.

In one embodiment, Y is -NG ² G ⁴ , -NG ² -L ¹ -COOH, -NG ² -L ¹ -C(=O)-NH ₂ , -NG ² -L ¹ -C(=O )-NG ³ -L ² -COOH, -NG ² -L ¹ -C(=O)-NG ³ -L ² -C(=O)-NH ₂ , -NG ² -L ³ -OH or -NG ² -(CH ₂ -CH ₂ -O) _q -CH ₂ -CH ₂ -COOH, preferably -NG ² G ⁴ , -NG ² -L ¹ -COOH, -NG ² -L ¹ -C(=O)-NH ₂ , -NG ² -L ¹ -C(=O)-NG ³ -L ² -COOH, -NG ² -L ¹ -C(=O)-NG ³ -L ² -C(=O)-NH ₂ or -NG ² -L ³ -OH, more preferably -NG ² G ⁴ .

In another embodiment, Y is -NG ² G ⁴ , -NG ² -L ³ -OH or -NG ² -(CH ₂ -CH ₂ -O) _q -CH ₂ -CH ₂ -COOH.

In another embodiment, Y is -NG ² G ⁴ , -NG ² -L ¹ -C(=O)-NH ₂ , -NG ² -L ¹ -C(=O)-NG ³ -L ² -C (=O)-NH ₂ or -NG ² -(CH ₂ -CH ₂ -O) _q -CH ₂ -CH ₂ -COOH.

In another embodiment, Y is -NG ² G ⁴ , -NG ² -L ¹ -C(=O)-NH ₂ or -NG ² -L ¹ -C(=O)-NG ³ -L ² -C (=O)-NH ₂ .

In one embodiment, q is an integer from 1 to 4, preferably an integer from 1 to 3, more preferably an integer from 1 to 2.

In one embodiment, the "phenyl group optionally substituted with 1-5 -COOR ³ groups" in G ² and G ³ is preferably a phenyl group optionally substituted with 1-3 -COOR ³ groups, more preferably a phenyl group optionally substituted with one - COOR ³ group, such as 2-(COOR ³ )-phenyl group, 3-(COOR ³ )-phenyl group, 4-(COOR ³ )-phenyl group and the like.

In one embodiment, R ³ in the "-COOR ³ group" in G ² and G ³ are each independently a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a t-butyl group or a benzyl group, preferably a hydrogen atom, a benzyl group or a t-butyl group, more preferably a hydrogen atom or a t-butyl group, even more preferably a hydrogen atom.

In one embodiment, G ² is a hydrogen atom or a C ₁ -C ₆ alkyl group optionally substituted with 1-3 substituents independently selected from the group consisting of a phenyl group optionally substituted with 1-3 -COOR ³ groups, and -COOR ³ groups, preferably a hydrogen atom or a C ₁ -C ₃ alkyl group optionally substituted with 1-3 substituents independently selected from the group consisting of a phenyl group optionally substituted with one -COOR ³ group, and a -COOR ³ group, more preferably C ₁ -C ₃ alkyl group substituted with 1-3 substituents independently selected from the group consisting of a phenyl group substituted with one carboxyl group and a carboxyl group.

In another embodiment, G ² is a hydrogen atom or a C ₁ -C ₃ alkyl group optionally substituted with 1-3 -COOR ³ groups, preferably a C ₁ -C ₃ alkyl group substituted with 1-3 carboxyl groups.

In one embodiment, G ³ is a hydrogen atom or a C ₁ -C ₆ alkyl group optionally substituted with 1-3 substituents independently selected from the group consisting of a phenyl group optionally substituted with 1-3 -COOR ³ groups, and -COOR ³ groups, preferably a hydrogen atom or a C ₁ -C ₃ alkyl group optionally substituted with 1-3 substituents independently selected from the group consisting of a phenyl group optionally substituted with one -COOR ³ group, and a -COOR ³ group, more preferably a hydrogen atom .

In another embodiment, G ³ is a hydrogen atom or a C ₁ -C ₃ alkyl group optionally substituted with 1-3 -COOR ³ groups, preferably a hydrogen atom.

In one embodiment, G ⁴ is a hydrogen atom, a C ₁ -C ₂ alkyl group, or a C ₁ -C ₂ alkoxy-C ₁ -C ₂ alkyl group, preferably an ethyl group or a methoxyethyl group, more preferably a methoxyethyl group.

In one embodiment, R ⁴ in the "-COOR ⁴ group" in L ¹ and L ² are each independently a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a t-butyl group or a benzyl group, preferably a hydrogen atom, a t-butyl group or a benzyl group, more preferably a hydrogen atom or a t-butyl group, even more preferably a hydrogen atom.

In one embodiment, L ¹ is a C ₁ -C ₆ alkylene group optionally substituted with 1-2 C ₁ -C ₆ alkyl groups optionally substituted with 1-2 -COOR ⁴ groups, a C ₁ -C ₄ alkylene group substituted with benzyl a group wherein the phenyl moiety is optionally substituted with 1-2 substituents independently selected from the group consisting of a hydroxy group and a carboxyl group, a C ₁ -C ₄ alkylene-phenylene group or a phenylene-C ₁ -C ₄ alkylene group, preferably a methylene group, optionally substituted with a C ₁ -C ₆ alkyl group, optionally substituted with a -COOR ⁴ group, a methylenephenylene group, or a phenylenemethylene group.

In another embodiment, L ¹ is a C ₁ -C ₂ alkylene group, preferably a methylene group.

In another embodiment, L ¹ is a C ₁ -C ₂ alkylene group optionally substituted with 1-2 C ₁ -C ₂ alkyl groups, optionally substituted with 1-2 -COOR ⁴ groups, a C ₁ -C ₂ alkylene-phenylene group, or phenylene-C ₁ -C ₂ alkylene group.

In one embodiment, L ² is a C ₁ -C ₆ alkylene group optionally substituted with 1-2 C ₁ -C ₆ alkyl groups optionally substituted with 1-2 -COOR ⁴ groups, a C ₁ -C ₄ alkylene group substituted with benzyl a group wherein the phenyl moiety is optionally substituted with 1-2 substituents independently selected from the group consisting of a hydroxy group and a carboxyl group, a C ₁ -C ₄ alkylene-phenylene group or a phenylene-C ₁ -C ₄ alkylene group, preferably a methylene group, optionally substituted with a C ₁ -C ₆ alkyl group, optionally substituted with a -COOR ⁴ group.

In another embodiment, L ² is a C ₁ -C ₂ alkylene group, preferably a methylene group.

In another embodiment, L ² is a C ₁ -C ₂ alkylene group optionally substituted with 1-2 C ₁ -C ₂ alkyl groups, optionally substituted with 1-2 -COOR ⁴ groups, a C ₁ -C ₂ alkylene-phenylene group, or phenylene-C ₁ -C ₂ alkylene group.

In one embodiment, R ⁴ in the "-COOR ⁴ group" in L ³ is each independently a hydrogen atom or a C ₁ -C ₄ alkyl group optionally substituted with one trimethylsilyl group, preferably a hydrogen atom or a 2-(trimethylsilyl)ethyl group, more preferably a hydrogen atom.

In one embodiment, L ³ is a C ₁ -C ₂ alkylene-phenylene group, where the phenylene moiety is optionally substituted with 1-2 -COOR ⁴ groups, preferably a methylenephenylene group, where the phenylene moiety is optionally substituted with one -COOR ⁴ group.

In one embodiment, R ⁵ and R ⁶ are each independently a hydrogen atom, a halogen atom, a C ₁ -C ₄ alkyl group, or a C ₁ -C ₄ alkoxy group, preferably a hydrogen atom, a fluorine atom, a methyl group, or a methoxy group. , more preferably R ⁵ and R ⁶ each represents a hydrogen atom.

In one embodiment, s and t are each independently an integer from 1 to 3, preferably an integer from 1 to 2, more preferably each is 1.

In one embodiment, at least one of R ¹ , R ³ , R ⁴ and G is a hydrogen atom. In another embodiment, at least one of R ¹ and R ⁴ is a hydrogen atom. In another embodiment, R ¹ , R ³ , R ⁴ and G each represents a hydrogen atom.

In one embodiment, Compound (II) has the structure represented by the formula

.

.

In one embodiment, Compound (II) has the structure represented by the formula

.

.

In one embodiment, Compound (II) has the structure represented by the formula

In one embodiment, Compound (II) has the structure represented by the following general formula (II'):

.

.

In one embodiment of Compound (II'), a compound or a pharmaceutically acceptable salt thereof is described, wherein

R ¹ each independently represents a hydrogen atom or a tert-butoxycarbonyl group;

W represents a single bond or a C ₁ -C ₄ alkylene group;

X is -C(=O)-, -OC(=O)- or -NG-SO ₂ -;

G represents a hydrogen atom, a C ₁ -C ₄ alkyl group, or
-COOR ² ;

R ² is a C ₁ -C ₄ alkyl group optionally substituted with 1-5 aryl groups;

Y is -NG ² G ⁴ , -NG ² -L ¹ -COOH, -NG ² -L ¹ -C(=O)-NG ³ -L ² -COOH, -NG ² -L ³ -OH or -NG ² -(CH ₂ -CH ₂ -O) _q -CH ₂ -CH ₂ -COOH;

q is an integer from 1 to 6;

G ² and G ³ are each independently a hydrogen atom or a C ₁ -C ₆ alkyl group optionally substituted with 1-5 substituents independently selected from the group consisting of a phenyl group optionally substituted with 1-5 -COOR ³ groups, and -COOR ³ groups;

G ⁴ represents a hydrogen atom, a C ₁ -C ₄ alkyl group or a C ₁ -C ₄ alkoxy-C ₁ -C ₄ alkyl group;

R ³ each independently represents a hydrogen atom, a benzyl group or a tert-butyl group;

L ¹ and L ² are each independently a C ₁ -C ₆ alkylene group optionally substituted with 1-5 C ₁ -C ₆ alkyl groups optionally substituted with 1-5 -COOR ⁴ groups, a C ₁ -C ₆ alkylene group substituted with C a ₇ -C ₁₂ aralkyl group optionally substituted with 1-5 substituents independently selected from the group consisting of a hydroxy group and a carboxyl group, a C ₁ -C ₄ alkylene-phenylene group, or a phenylene-C ₁ -C ₄ alkylene group;

L ³ represents a C ₁ -C ₄ alkylene-phenylene group, where the phenylene fragment is optionally substituted with 1-3 -COOR ⁴ groups;

R ⁴ each independently represents a hydrogen atom, a benzyl group or a tert-butyl group; and

R ⁵ and R ⁶ are each independently a hydrogen atom, a halogen atom, a C ₁ -C ₄ alkyl group, or a C ₁ -C ₄ alkoxy group.

In another embodiment of Compound (II'), a compound or a pharmaceutically acceptable salt thereof is described, wherein

R ¹ each independently represents a hydrogen atom or a tert-butoxycarbonyl group;

W represents a single bond or a C ₁ -C ₄ alkylene group;

X represents -OC(=O)- or -NG-SO ₂ -;

G represents a hydrogen atom, a C ₁ -C ₄ alkyl group, or
-COOR ² ;

R ² is a C ₁ -C ₄ alkyl group optionally substituted with 1-3 aryl groups;

Y is -NG ² G ⁴ , -NG ² -L ¹ -COOH, -NG ² -L ¹ -C(=O)-NG ³ -L ² -COOH or -NG ² -(CH ₂ -CH ₂ - O) _q -CH ₂ -CH ₂ -COOH;

q is an integer from 1 to 6;

G ² and G ³ are each independently a hydrogen atom or a C ₁ -C ₆ alkyl group optionally substituted with 1-3 substituents independently selected from the group consisting of a phenyl group optionally substituted with 1-3 -COOR ³ groups, and -COOR ³ groups;

G ⁴ represents a hydrogen atom, a C ₁ -C ₄ alkyl group or a C ₁ -C ₄ alkoxy-C ₁ -C ₄ alkyl group;

R ³ each independently represents a hydrogen atom, a benzyl group or a tert-butyl group;

L ¹ and L ² are each independently a C ₁ -C ₆ alkylene group optionally substituted with 1-5 C ₁ -C ₆ alkyl groups, optionally substituted with 1-5 -COOR ⁴ groups, a C ₁ -C ₄ alkylene-phenylene group, or phenylene-C ₁ -C ₄ alkylene group;

L ³ represents a C ₁ -C ₂ alkylene-phenylene group, where the phenylene fragment is optionally substituted with 1-2 -COOR ⁴ groups;

R ⁴ each independently represents a hydrogen atom, a benzyl group or a tert-butyl group; and

R ⁵ and R ⁶ are each independently a hydrogen atom, a halogen atom, a C ₁ -C ₄ alkyl group, or a C ₁ -C ₄ alkoxy group.

In another embodiment of Compound (II'), a compound or a pharmaceutically acceptable salt thereof is described, wherein

R ¹ each represents a hydrogen atom;

W represents a C ₁ -C ₄ alkylene group;

X represents -OC(=O)- or -NG-SO ₂ -;

G represents a hydrogen atom;

Y is -NG ² G ⁴ , -NG ² -L ¹ -COOH, -NG ² -L ¹ -C(=O)-NG ³ -L ² -COOH or -NG ² -(CH ₂ -CH ₂ - O) _q -CH ₂ -CH ₂ -COOH;

q is an integer from 1 to 6;

G ² represents a hydrogen atom or a C ₁ -C ₃ alkyl group substituted with 1-3 carboxyl groups;

G ³ represents a hydrogen atom;

G ⁴ represents a hydrogen atom, a C ₁ -C ₂ alkyl group or a C ₁ -C ₂ alkoxy-C ₁ -C ₂ alkyl group;

L ¹ and L ² are each independently a C ₁ -C ₆ alkylene group optionally substituted with 1-2 C ₁ -C ₆ alkyl groups optionally substituted with 1-2 -COOR ⁴ groups, or a C ₁ -C ₄ alkylene-phenylene group ;

L ³ represents a methylenephenylene group, where the phenylene moiety is optionally substituted with one —COOR ⁴ group;

R ⁴ represents a hydrogen atom; and

R ⁵ and R ⁶ are each independently a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group, or a methoxy group.

In one embodiment, Compound (II) has the structure represented by the following general formula (II''):

.

.

In one embodiment of Compound (II''), a compound or a pharmaceutically acceptable salt thereof is described, wherein

R ¹ each independently represents a hydrogen atom or a tert-butoxycarbonyl group;

W represents a single bond or a C ₁ -C ₄ alkylene group;

X is -C(=O)-, -OC(=O)- or -NG-SO ₂ -;

G represents a hydrogen atom, a C ₁ -C ₄ alkyl group, or
-COOR ² ;

R ² is a C ₁ -C ₄ alkyl group optionally substituted with 1-5 aryl groups;

Y is -NG ² G ⁴ , -NG ² -L ¹ -COOH, -NG ² -L ¹ -C(=O)-NG ³ -L ² -COOH, -NG ² -L ³ -OH or -NG ² -(CH ₂ -CH ₂ -O) _q -CH ₂ -CH ₂ -COOH;

q is an integer from 1 to 6;

G ² and G ³ are each independently a hydrogen atom or a C ₁ -C ₆ alkyl group optionally substituted with 1-5 substituents independently selected from the group consisting of a phenyl group optionally substituted with 1-5 -COOR ³ groups, and -COOR ³ groups;

G ⁴ represents a hydrogen atom, a C ₁ -C ₄ alkyl group or a C ₁ -C ₄ alkoxy-C ₁ -C ₄ alkyl group;

R ³ each independently represents a hydrogen atom, a benzyl group or a tert-butyl group;

L ¹ and L ² are each independently a C ₁ -C ₆ alkylene group optionally substituted with 1-5 C ₁ -C ₆ alkyl groups optionally substituted with 1-5 -COOR ⁴ groups, a C ₁ -C ₆ alkylene group substituted with C a ₇ -C ₁₂ aralkyl group optionally substituted with 1-5 substituents independently selected from the group consisting of a hydroxy group and a carboxyl group, a C ₁ -C ₄ alkylene-phenylene group, or a phenylene-C ₁ -C ₄ alkylene group;

L ³ represents a C ₁ -C ₄ alkylene-phenylene group, where the phenylene fragment is optionally substituted with 1-3 -COOR ⁴ groups;

R ⁴ each independently represents a hydrogen atom, a benzyl group or a tert-butyl group; and

R ⁵ and R ⁶ are each independently a hydrogen atom, a halogen atom, a C ₁ -C ₄ alkyl group, a C ₁ -C ₄ alkoxy group, a carboxyl group, or -C(=O)-NG ² G ⁴ .

In another embodiment of Compound (II''), a compound or a pharmaceutically acceptable salt thereof is described, wherein

R ¹ each independently represents a hydrogen atom or a tert-butoxycarbonyl group;

W represents a single bond or a C ₁ -C ₄ alkylene group;

X represents -OC(=O)- or -NG-SO ₂ -;

G represents a hydrogen atom, a C ₁ -C ₄ alkyl group, or —COOR ² ;

R ² is a C ₁ -C ₄ alkyl group optionally substituted with 1-3 aryl groups;

Y is -NG ² G ⁴ , -NG ² -L ¹ -COOH, -NG ² -L ¹ -C(=O)-NG ³ -L ² -COOH or -NG ² -(CH ₂ -CH ₂ - O) _q -CH ₂ -CH ₂ -COOH;

q is an integer from 1 to 6;

G ² and G ³ are each independently a hydrogen atom or a C ₁ -C ₆ alkyl group optionally substituted with 1-3 substituents independently selected from the group consisting of a phenyl group optionally substituted with 1-3 -COOR ³ groups, and -COOR ³ groups;

G ⁴ represents a hydrogen atom, a C ₁ -C ₄ alkyl group or a C ₁ -C ₄ alkoxy-C ₁ -C ₄ alkyl group;

R ³ each independently represents a hydrogen atom, a benzyl group or a tert-butyl group;

L ¹ and L ² are each independently a C ₁ -C ₆ alkylene group optionally substituted with 1-5 C ₁ -C ₆ alkyl groups, optionally substituted with 1-5 -COOR ⁴ groups, a C ₁ -C ₄ alkylene-phenylene group, or phenylene-C ₁ -C ₄ alkylene group;

L ³ represents a C ₁ -C ₂ alkylene-phenylene group, where the phenylene fragment is optionally substituted with 1-2 -COOR ⁴ groups;

R ⁴ each independently represents a hydrogen atom, a benzyl group or a tert-butyl group; and

R ⁵ and R ⁶ are each independently a hydrogen atom, a halogen atom, a C ₁ -C ₄ alkyl group, a C ₁ -C ₄ alkoxy group, a carboxyl group, or -C(=O)-NG ² G ⁴ .

In another embodiment of Compound (II''), a compound or a pharmaceutically acceptable salt thereof is described, wherein

R ¹ each represents a hydrogen atom;

W represents a C ₁ -C ₄ alkylene group;

X represents -OC(=O)- or -NG-SO ₂ -;

G represents a hydrogen atom;

Y is -NG ² G ⁴ , -NG ² -L ¹ -COOH, -NG ² -L ¹ -C(=O)-NG ³ -L ² -COOH or -NG ² -(CH ₂ -CH ₂ - O) _q -CH ₂ -CH ₂ -COOH;

q is an integer from 1 to 6;

G ² represents a hydrogen atom or a C ₁ -C ₃ alkyl group substituted with 1-3 carboxyl groups;

G ³ represents a hydrogen atom;

G ⁴ represents a hydrogen atom, a C ₁ -C ₂ alkyl group or a C ₁ -C ₂ alkoxy-C ₁ -C ₂ alkyl group;

L ¹ and L ² are each independently a C ₁ -C ₆ alkylene group optionally substituted with 1-2 C ₁ -C ₆ alkyl groups optionally substituted with 1-2 -COOR ⁴ groups, or a C ₁ -C ₄ alkylene-phenylene group ;

L ³ represents a methylenephenylene group, where the phenylene moiety is optionally substituted with one —COOR ⁴ group;

R ⁴ represents a hydrogen atom; and

R ⁵ and R ⁶ are each independently a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group, a methoxy group, a carboxyl group, or -C(=O)-NG ² G ⁴ .

In one embodiment, Compound (II) has the structure represented by the formula:

.

.

In one embodiment, Compound (II) is a compound having the general formula (II''') shown below:

where:

R ¹ each independently represents a hydrogen atom or -COO-(C ₁ -C ₄ alkyl group);

W represents a single bond or a C ₁ -C ₄ alkylene group;

X represents -OC(=O)- or -NG-SO ₂ -;

G represents a hydrogen atom or -COOR ² ;

R ² is a C ₁ -C ₄ alkyl group optionally substituted with 1-5 aryl groups;

Y is -NG ² G ⁴ , -NG ² -L ¹ -C(=O)-NH ₂ , -NG ² -L ¹ -C(=O)-NG ³ -L ² -C(=O)- NH ₂ or -NG ² -(CH ₂ -CH ₂ -O) _q -CH ₂ -CH ₂ -COOH;

q is an integer from 1 to 6;

G ² and G ³ are each independently a hydrogen atom or a C ₁ -C ₆ alkyl group optionally substituted with 1-5 substituents independently selected from the group consisting of a phenyl group optionally substituted with 1-5 -COOR ³ groups, and -COOR ³ groups;

G ⁴ represents a hydrogen atom, a C ₁ -C ₄ alkyl group or a C ₁ -C ₄ alkoxy-C ₁ -C ₄ alkyl group;

R ³ each independently represents a hydrogen atom or a C ₁ -C ₄ alkyl group optionally substituted with 1-5 aryl groups;

L ¹ and L ² are each independently a C ₁ -C ₆ alkylene group optionally substituted with 1-5 C ₁ -C ₆ alkyl groups, optionally substituted with 1-5 -COOR ⁴ groups, a C ₁ -C ₄ alkylene-phenylene group, or phenylene-C ₁ -C ₄ alkylene group; and

R ⁴ each independently represents a hydrogen atom or a C ₁ -C ₄ alkyl group optionally substituted with 1-5 aryl groups;

or a pharmaceutically acceptable salt thereof.

In another embodiment of Compound (II'''), a compound or a pharmaceutically acceptable salt thereof is described, wherein

R ¹ each independently represents a hydrogen atom or a tert-butoxycarbonyl group;

W represents a C ₁ -C ₄ alkylene group;

X represents -OC(=O)- or -NG-SO ₂ -;

G represents a hydrogen atom or -COOR ² ;

R ² is a C ₁ -C ₄ alkyl group optionally substituted with 1-3 phenyl groups;

Y is -NG ² G ⁴ , -NG ² -L ¹ -C(=O)-NH ₂ , -NG ² -L ¹ -C(=O)-NG ³ -L ² -C(=O)- NH ₂ or -NG ² -(CH ₂ -CH ₂ -O) _q -CH ₂ -CH ₂ -COOH;

q is an integer from 1 to 6;

G ² and G ³ are each independently a hydrogen atom or a C ₁ -C ₆ alkyl group optionally substituted with 1-3 substituents independently selected from the group consisting of a phenyl group optionally substituted with 1-3 -COOR ³ groups, and -COOR ³ groups;

G ⁴ represents a hydrogen atom, a C ₁ -C ₂ alkyl group or a C ₁ -C ₂ alkoxy-C ₁ -C ₂ alkyl group;

R ³ each independently represents a hydrogen atom, a benzyl group or a tert-butyl group;

L ¹ and L ² are each independently a C ₁ -C ₆ alkylene group optionally substituted with 1-5 C ₁ -C ₆ alkyl groups, optionally substituted with 1-5 -COOR ⁴ groups, a C ₁ -C ₄ alkylene-phenylene group, or phenylene-C ₁ -C ₄ alkylene group; and

R ⁴ each independently represents a hydrogen atom, a benzyl group or a tert-butyl group.

In another embodiment of Compound (II'''), a compound or a pharmaceutically acceptable salt thereof is described, wherein

R ¹ each represents a hydrogen atom;

W represents a C ₁ -C ₂ alkylene group;

X is -NG-SO ₂ -;

G represents a hydrogen atom;

Y is -NG ² G ⁴ ;

G ² is a C ₁ -C ₃ alkyl group substituted with 1-3 substituents independently selected from the group consisting of a phenyl group substituted with one carboxyl group and a carboxyl group; and

G ⁴ represents a hydrogen atom, a C ₁ -C ₂ alkyl group, or a C ₁ -C ₂ alkoxy-C ₁ -C ₂ alkyl group.

Process for the Preparation of Compound (I)

In one embodiment, the present invention describes a method for obtaining Compound (I). In one embodiment, the process for preparing Compound (I) comprises reacting a compound having the general formula shown below (I-A-1)

where A is a structure formed by removing -WXY- from A ¹ or A ² ;

or a salt thereof with a compound having the general formula shown below (I-A-2')

where the symbols have the above meanings;

or its salt under conditions suitable for obtaining Compound (I).

In one embodiment, Compound (I-A-2') is reacted with Compound (I-A-1) in a solvent (e.g., ethers such as tetrahydrofuran and 1,4-dioxane; aromatic hydrocarbons such as toluene; nitriles such as as acetonitrile; and mixtures thereof), and in the presence of an azodicarboxylic acid derivative (for example, azodicarboxylic acid dialkyl esters such as diethyl azodicarboxylate and diisopropyl azodicarboxylate; and azodicarboxamides such as 1,1'-azobis(N,N-dimethylformamide)) and phosphine (for example, triarylphosphines such as triphenylphosphine; and trialkylphosphines such as tributylphosphine) to give Compound (I).

Compound (I), Compound (II), Compound (III), Compound (IV), Compound (V), Compound (VI), Compound (VII) or Compound (VIII) of the present invention may exist in the form of a tautomer or a mixture thereof . Compound (I), Compound (II), Compound (III), Compound (IV), Compound (V), Compound (VI), Compound (VII) or Compound (VIII) of the present invention may exist in the form of a stereoisomer such as enantiomer or diastereomer, or mixtures thereof. Compound (I), Compound (II), Compound (III), Compound (IV), Compound (V), Compound (VI), Compound (VII) or Compound (VIII) of the present invention includes a mixture of tautomers or stereoisomers, and also each pure or substantially pure isomer.

When the Compound (I), Compound (II), Compound (III), Compound (IV), Compound (V), Compound (VI), Compound (VII) or Compound (VIII) of the present invention is obtained in the form of a diastereomer or enantiomer, it can be isolated by conventional methods known in the art, such as chromatography or crystallization.

The Compound (I), Compound (II), Compound (III), Compound (IV), Compound (V), Compound (VI), Compound (VII) or Compound (VIII) of the present invention includes isotopically labeled compounds (for example, ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ F, ³² P, ³⁵ S and ¹²⁵ I), etc., as well as deuterated products.

Examples of pharmaceutically acceptable salts of Compound (I), Compound (II), Compound (III), Compound (IV), Compound (V), Compound (VI), Compound (VII) or Compound (VIII) include alkali metal salts such as salts of lithium, sodium and potassium; alkaline earth metal salts such as magnesium and calcium salts; salts of aluminum and zinc; salts with amines such as ammonia, choline, diethanolamine, lysine, ethylenediamine, t-butylamine, t-octylamine, tris(hydroxymethyl)aminomethane, N-methyl-glucosamine, triethanolamine and dehydroabietylamine; salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid and phosphoric acid; salts with organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid and benzenesulfonic acid; and salts with amino acids such as aspartic acid and glutamic acid.

In addition, a pharmaceutically acceptable salt of Compound (I), Compound (II), Compound (III), Compound (IV), Compound (V), Compound (VI), Compound (VII) or Compound (VIII) includes internal acids, their hydrates and solvates.

The term "pharmaceutically acceptable" in relation to the ingredients in this application means that they are not harmful to the subject to whom the introduction is carried out and are compatible with each other in the preparation of a pharmaceutical composition, and include ingredients suitable for use in human medicines, as well as ingredients suitable for veterinary use.

Application

Compound (I), Compound (II), Compound (III), Compound (IV), Compound (V), Compound (VI), Compound (VII) or Compound (VIII), or a pharmaceutically acceptable salt thereof of the present invention described in each of the above embodiments and combinations thereof, all can be used as active ingredients in a pharmaceutical composition, and all of the compounds described in each of the above embodiments and combinations thereof can be administered to a subject (preferably a human). In one embodiment, Compound (I), Compound (II), Compound (III), Compound (IV), Compound (V), Compound (VI), Compound (VII), or Compound (VIII), or a pharmaceutically thereof, is administered to the subject. a suitable salt wherein the protecting groups such as the tert-butoxycarbonyl group and the benzyloxycarbonyl group are partially or completely removed.

In one embodiment, Compound (I) or Compound (II), or a pharmaceutically acceptable salt thereof, is administered to the subject, wherein at least one of R ¹ , R ³ , R ⁴ and G is a hydrogen atom in any of the above embodiments and their combinations. In another embodiment, Compound (I) or Compound (II), or a pharmaceutically acceptable salt thereof, is administered to the subject, wherein at least one of R ¹ and R ⁴ is a hydrogen atom in any of the above embodiments and combinations thereof. In another embodiment, Compound (I) or Compound (II), or a pharmaceutically acceptable salt thereof, is administered to the subject, wherein R ¹ , R ³ , R ⁴ and G each represents a hydrogen atom in any of the above embodiments and combinations thereof.

In one embodiment, the subject is administered Compound (I), Compound (III), Compound (IV), Compound (V), Compound (VI), Compound (VII) or Compound (VIII), or a pharmaceutically acceptable salt thereof, wherein at least one of R ¹ , R ³ , R ⁴ , G ¹¹ and G ¹² is a hydrogen atom in any of the above embodiments and combinations thereof. In another embodiment, Compound (I), Compound (III), Compound (IV), Compound (V), Compound (VI), Compound (VII), or Compound (VIII), or a pharmaceutically acceptable salt thereof, is administered to the subject, wherein at least one of R ¹ and R ⁴ is a hydrogen atom in any of the above embodiments and combinations thereof. In another embodiment, the subject is administered Compound (I), Compound (III), Compound (IV), Compound (V), Compound (VI), Compound (VII), or Compound (VIII), or a pharmaceutically acceptable salt thereof, wherein R ¹ , R ³ , R ⁴ , G ¹¹ and G ¹² each represents a hydrogen atom in any of the above embodiments and combinations thereof.

Compound (I), Compound (II), Compound (III), Compound (IV), Compound (V), Compound (VI), Compound (VII) or Compound (VIII), or a pharmaceutically acceptable salt thereof of the present invention can be orally or parenterally administered alone or as a pharmaceutical composition containing it and a pharmaceutically acceptable carrier. Preferably, the pharmaceutical composition of the present invention contains Compound (I), Compound (II), Compound (III), Compound (IV), Compound (V), Compound (VI), Compound (VII) or Compound (VIII), or its a pharmaceutically acceptable salt of the present invention; and a pharmaceutically acceptable carrier. A pharmaceutically acceptable carrier may be any carrier commonly used in the art and examples include diluents, binders (e.g. syrup, gum arabic, gelatin, sorbitol, gum tragacanth and polyvinylpyrrolidone), excipients (e.g. lactose, sucrose, corn starch, potassium phosphate, sorbitol, and glycine), lubricants (eg, magnesium stearate, talc, polyethylene glycol, and silica gel), disintegrants (eg, potato starch), and wetting agents (eg, sodium lauryl sulfate). The dosage form of the pharmaceutical composition is also not limited to any particular form, and the pharmaceutical composition can be used in conventional pharmaceutical preparations such as tablet, granule, capsule, powder, injection, inhalation and suppository.

Dose (i.e., effective amount) of Compound (I), Compound (II), Compound (III), Compound (IV), Compound (V), Compound (VI), Compound (VII) or Compound (VIII), or its pharmaceutically acceptable salt of the present invention varies depending on the route of administration, age, body weight and condition of the patient and the like, and is usually 0.001 to 500 mg/kg/day, particularly preferably 0.01 to 10 mg/kg /day, and is administered as a single dose or as 2-4 divided doses.

Compound (I), Compound (II), Compound (III), Compound (IV), Compound (V), Compound (VI), Compound (VII) or Compound (VIII), or a pharmaceutically acceptable salt thereof of the present invention has at least one activity selected from an enteropeptidase inhibitory activity and a trypsin inhibitory activity, and can be used to prevent, alleviate and/or treat diseases whose symptoms are ameliorated by enteropeptidase inhibition and/or trypsin inhibition. Examples of such diseases include obesity, obesity-related conditions or diseases, diabetes, complications of diabetes, renal disease, coronary artery disease, bone and joint disease, metabolic syndrome, hypertension, hyperuricemia, fatty liver (including non-alcoholic steatohepatitis), drug resistance syndrome. insulin, glucose intolerance, cerebral infarction, Parkinson's disease, muscular dystrophy, Alzheimer's disease, eating disorders, hyperinsulinemia, acute or chronic diarrhea, inflammatory diseases, osteoporosis and various types of cancer. Compound (I), Compound (II), Compound (III), Compound (IV), Compound (V), Compound (VI), Compound (VII) or Compound (VIII), or a pharmaceutically acceptable salt thereof of the present invention, in the features can be used to prevent, mitigate and/or treat obesity.

One embodiment of the present invention relates to a pharmaceutical composition comprising Compound (I), Compound (II), Compound (III), Compound (IV), Compound (V), Compound (VI), Compound (VII) or Compound (VIII), or a pharmaceutically acceptable salt thereof according to the present invention, and a pharmaceutically acceptable carrier(s). In a preferred embodiment, the above pharmaceutical composition is used for the prevention, mitigation and/or treatment of diseases whose symptoms are ameliorated by enteropeptidase inhibition and/or trypsin inhibition. In a more preferred embodiment, the above pharmaceutical composition is used for the prevention, mitigation and/or treatment of obesity.

One embodiment of the present invention relates to the use of Compound (I), Compound (II), Compound (III), Compound (IV), Compound (V), Compound (VI), Compound (VII) or Compound (VIII), or its pharmaceutical acceptable salt of the present invention, in the manufacture of a medicinal product. In a preferred embodiment, the above drug is used to prevent, alleviate and / or treat diseases, the symptoms of which become less pronounced with enteropeptidase inhibition and / or trypsin inhibition. In a more preferred embodiment, the above drug is used to prevent, alleviate and /or treatment of obesity.

One embodiment of the present invention relates to the use of Compound (I), Compound (II), Compound (III), Compound (IV), Compound (V), Compound (VI), Compound (VII) or Compound (VIII), or its pharmaceutical acceptable salt of the present invention, for prevention, mitigation and/or treatment. A preferred embodiment of the present invention relates to Compound (I), Compound (II), Compound (III), Compound (IV), Compound (V), Compound (VI), Compound (VII) or Compound (VIII), or a pharmaceutically acceptable salts of the present invention, for the prevention, mitigation and/or treatment of diseases whose symptoms are relieved by inhibition of enteropeptidase and/or inhibition of trypsin. A more preferred embodiment of the present invention relates to Compound (I), Compound (II), Compound (III), Compound (IV), Compound (V), Compound (VI), Compound (VII) or Compound (VIII), or its pharmaceutical acceptable salt of the present invention, for the prevention, mitigation and/or treatment of obesity.

One embodiment of the present invention relates to a method for preventing, alleviating and/or treating diseases whose symptoms are ameliorated by inhibition of enteropeptidase and/or inhibition of trypsin, which method comprises administering Compound (I), Compound (II), Compound (III) , Compound (IV), Compound (V), Compound (VI), Compound (VII) or Compound (VIII), or its pharmaceutically acceptable salt of the present invention. A more preferred embodiment of the present invention relates to a method for preventing, alleviating and/or treating obesity, which method comprises administering Compound (I), Compound (II), Compound (III), Compound (IV), Compound (V), Compound ( VI), Compound (VII) or Compound (VIII), or a pharmaceutically acceptable salt thereof according to the present invention.

Compound (I), Compound (II), Compound (III), Compound (IV), Compound (V), Compound (VI), Compound (VII) or Compound (VIII), or a pharmaceutically acceptable salt thereof, can be prepared as described below ways, not limited to them. Also, each step in the preparation methods described below can be carried out by combining them with each other in an appropriate way.

When a functional group in a compound needs to be protected at any of the following steps in the preparation of Compound (I), Compound (II), Compound (III), Compound (IV), Compound (V), Compound (VI), Compound (VII), or Compound (VIII), such protection can be appropriately provided by the special methods described below or well-known methods. For a general description of protecting groups and their uses, see T. W. Greene et al., “Protective Groups in Organic Synthesis”, John Wiley & Sons, New York, Fifth Edition. The protecting group can be removed in a subsequent step by the specific methods described below, or by conventional methods. In addition, any conversion of a carboxylic acid to or from its salt, or an amine compound to or from its salt, can be carried out by the specific methods described below, or by conventional methods for preparing salts and converting the salts back to the parent compounds.

Production Method A

Of the compounds having formula (I), Compound (IA) wherein X ¹ is -NG ¹¹ -SO ₂ -, X ² is -SO ₂ -NG ¹² -, Y ¹ is -NG ²¹ -, Y ² represents -NG ²² -, and G ¹¹ and G ¹² each independently represent a hydrogen atom or a benzyloxycarbonyl group, can be obtained according to, for example, the following scheme.

where P ¹ represents a protective group such as 2-nitrobenzenesulfonyl group; Cbz is a benzyloxycarbonyl group; G ^11' and G ^12' are each independently a hydrogen atom or a benzyloxycarbonyl group; and the rest of the characters have the same meanings as above.

Stage 1

Compound (I-A-6) may be a commercially available substance, or may be obtained by known methods from commercially available substances.

Compound (I-A-6) is reacted with Compound (I-A-5) in a solvent and in the presence of an azodicarboxylic acid derivative and a phosphine derivative to give Compound (I-A-4).

Any solvents that do not interfere with the reaction may be used, and examples thereof include ethers such as tetrahydrofuran and dioxane; halogenated aliphatic hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as toluene; nitriles such as acetonitrile; and their mixtures.

Examples of the azodicarboxylic acid derivative include azodicarboxylic acid dialkyl esters such as diethyl azodicarboxylate and diisopropyl azodicarboxylate; and azodicarboxamides such as 1,1'-azobis(N,N-dimethylformamide).

Examples of the phosphine derivative include triarylphosphines such as triphenylphosphine; and trialkylphosphines such as tributylphosphine.

The amount of Compound (I-A-5) used may be 1.8-5.0 mole equivalents, preferably 1.8-3.0 mole equivalents, relative to Compound (I-A-6).

The amount of azodicarboxylic acid derivative used may be 2.0-6.0 mole equivalents, preferably 2.0-5.0 mole equivalents, relative to Compound (I-A-6).

The amount of phosphine derivative used may be 2.0-6.0 mole equivalents, preferably 2.0-5.0 mole equivalents, relative to Compound (I-A-6).

The reaction can be carried out at room temperature to elevated, for example at room temperature to 100°C, preferably at room temperature.

Stage 2

Compound (I-A-4) can be reacted in a solvent and in the presence of a thiol and a base to give Compound (I-A-3).

Any solvents that do not interfere with the reaction may be used, and examples thereof include amides such as N-methylpyrrolidone and N,N-dimethylformamide (hereinafter also referred to as dimethylformamide); ethers such as tetrahydrofuran and dioxane; nitriles such as acetonitrile; dimethyl sulfoxide; and their mixtures.

Examples of the thiol include thiophenols such as 4-tert-butylthiophenol; alkylthiols such as 1-dodecanethiol; and thiosalicylic acid.

Examples of bases include alkali metal carbonates such as cesium carbonate, potassium carbonate, sodium carbonate and sodium hydrogen carbonate; alkali metal phosphates such as tribasic potassium phosphate, sodium phosphate and sodium hydrogen phosphate; alkylamines such as triethylamine and N,N-diisopropylethylamine; organic bases such as pyridines such as pyridine and 4-dimethylaminopyridine and 1,8-diazabicyclo[5.4.0]-7-undecene; and alkali metal fluorides such as cesium fluoride and potassium fluoride.

The amount of thiol used may be 2.0-7.0 mole equivalents, preferably 2.0-5.0 mole equivalents, relative to Compound (I-A-4).

The amount of base used may be 2.0-10.0 mole equivalents, preferably 2.5-7.0 mole equivalents, relative to Compound (I-A-4).

The reaction can be carried out at room temperature to elevated, for example at room temperature to 100°C, preferably at room temperature.

Stage 3

Compound (I-A-3) can be reacted in a solvent in the presence of a base and benzyl chlorosulfonyl carbamate, which is a compound obtained by reacting chlorosulfonyl isocyanate (CSI) with benzyl alcohol (BnOH), to give Compound (I-A-2).

Any solvents that do not interfere with the reaction can be used, and examples include amides such as N,N-dimethylformamide; ethers such as tetrahydrofuran and dioxane; halogenated aliphatic hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as toluene; nitriles such as acetonitrile; and their mixtures.

Examples of bases include alkylamines such as triethylamine and N,N-diisopropylethylamine; and organic bases such as pyridines such as pyridine and 4-dimethylaminopyridine, and 1,8-diazabicyclo[5.4.0]-7-undecene.

The amount of base used may be 2.0-10.0 mole equivalents, preferably 2.0-7.0 mole equivalents, relative to Compound (I-A-3).

The amount of chlorosulfonyl isocyanate used may be 2.0-5.0 mole equivalents, preferably 2.0-3.0 mole equivalents, relative to Compound (I-A-3).

The amount of benzyl alcohol used may be 2.0-5.0 mole equivalents, preferably 2.0-3.0 mole equivalents, relative to Compound (I-A-3).

When benzyl chlorosulfonylcarbamate is used directly, its amount may be 2.0-5.0 mole equivalents, preferably 2.0-3.0 mole equivalents, relative to Compound (I-A-3).

The reaction can be carried out at temperatures ranging from ice bath cooling to elevated temperatures, for example at temperatures ranging from ice bath cooling to 100° C., preferably at temperatures ranging from 0° C. to room temperature.

Stage 4

Compound (I-A-2) is reacted with Compound (I-A-1) in a solvent and in the presence of an azodicarboxylic acid derivative and a phosphine derivative to give Compound (I-A).

Any solvents that do not interfere with the reaction may be used, and examples thereof include ethers such as tetrahydrofuran and dioxane; aromatic hydrocarbons such as toluene; nitriles such as acetonitrile; and their mixtures.

Examples of the azodicarboxylic acid derivative include azodicarboxylic acid dialkyl esters such as diethyl azodicarboxylate and diisopropyl azodicarboxylate; and azodicarboxamides such as 1,1'-azobis(N,N-dimethylformamide).

Examples of the phosphine derivative include triarylphosphines such as triphenylphosphine; and trialkylphosphines such as tributylphosphine.

The amount of Compound (I-A-1) used may be 2.0-5.0 mole equivalents, preferably 2.0-3.0 mole equivalents, relative to Compound (I-A-2).

The amount of azodicarboxylic acid derivative used may be 2.0-5.0 mole equivalents, preferably 2.0-3.5 mole equivalents, relative to Compound (I-A-2).

The amount of phosphine derivative used may be 2.0-5.0 mole equivalents, preferably 2.0-3.5 mole equivalents, relative to Compound (I-A-2).

The reaction can be carried out at room temperature to elevated, for example at room temperature to 100°C, preferably at room temperature.

Stage 5

The protecting groups present in Compound (I-A) can be removed.

Stage 5-1

For example, Compound (I-A) can be reacted with an acid in a solvent, and with or without a reducing agent, to remove a protecting group such as a t-butyl group and a t-butoxycarbonyl group.

Any solvents that do not interfere with the reaction can be used and examples include esters such as ethyl acetate; ethers such as tetrahydrofuran and dioxane; amides such as N,N-dimethylformamide; halogenated aliphatic hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as toluene; nitriles such as acetonitrile; carboxylic acids such as acetic acid; water; and their mixtures.

Examples of the acid include formic acid, hydrochloric acid and trifluoroacetic acid.

Examples of the reducing agent include trialkylsilanes such as triethylsilane.

The amount of acid used may be 10.0-600 mole equivalents, preferably 15.0-500 mole equivalents, relative to the Compound (I-A).

The amount of reducing agent used may be 3.0-20 mole equivalents, preferably 5.0-10 mole equivalents, relative to Compound (I-A).

The reaction can be carried out at room temperature to elevated, for example at room temperature to 100°C, preferably at room temperature.

Stage 5-2

For example, Compound (I-A) is reacted with a catalyst in a solvent and under a hydrogen atmosphere to remove a protecting group such as a benzyloxycarbonyl group and a benzyl group.

Any solvents that do not interfere with the reaction may be used, and examples thereof include ethers such as tetrahydrofuran and dioxane; alcohols such as methanol, ethanol and isopropanol; aromatic hydrocarbons such as toluene; nitriles such as acetonitrile; carboxylic acids such as acetic acid; water; and their mixtures.

Examples of the catalyst include palladium on carbon.

The amount of catalyst used may be 0.01-20.0 mole equivalents, preferably 0.01-10.0 mole equivalents, relative to Compound (I-A).

The reaction can be carried out at room temperature to elevated, for example at room temperature to 100°C, preferably at room temperature.

Stage 5-1 can be carried out simultaneously with Stage 5-2.

The compound obtained in Step 4 or Step 5 can be reacted with an acid such as hydrochloric acid and trifluoroacetic acid according to known procedures to give acid addition salts such as hydrochloride and trifluoroacetate.

The amount of acid used may be 2.0-20.0 mole equivalents, preferably 2.0-15.0 mole equivalents, relative to the compound obtained in Step 4 or Step 5.

Preparation method A-1 (preparation of intermediate)

Compound (I-A-5) can be obtained according to, for example, the following scheme.

where V ¹ represents a halogen atom, such as a chlorine atom; and the rest of the characters have the same meanings as above.

Compound (I-A-7) and Compound (I-A-8) may be commercially available substances, or they can be obtained by known methods from commercially available substances. Also, Compound (I-A-8) may be in the form of a salt such as a hydrochloride.

Compound (I-A-8) is reacted with Compound (I-A-7) in a solvent and in the presence of a base to give Compound (I-A-5).

Any solvents that do not interfere with the reaction can be used, and examples include amides such as N,N-dimethylformamide; ethers such as tetrahydrofuran and dioxane; halogenated aliphatic hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as toluene; nitriles such as acetonitrile; and their mixtures.

Examples of bases include alkylamines such as triethylamine and N,N-diisopropylethylamine; and organic bases such as pyridines such as pyridine and 4-dimethylaminopyridine, and 1,8-diazabicyclo[5.4.0]-7-undecene.

The amount of Compound (I-A-7) used may be 1.0-5.0 mole equivalents, preferably 1.0-2.0 mole equivalents, relative to Compound (I-A-8).

The amount of base used may be 1.0-5.0 mole equivalents, preferably 2.0-3.0 mole equivalents, relative to Compound (I-A-4).

The reaction can be carried out at room temperature to elevated, for example at room temperature to 100°C, preferably at room temperature.

Preparation method A-2 (preparation of intermediate)

Of Connections (I-A-1), Connection (I-A-1’)

where the symbols have the meanings given above.]

can be obtained according to, for example, the following scheme.

where the symbols have the meanings given above.

Stage 1

The compound (I-A-1'-5) may be a commercially available substance, or may be obtained by known methods from commercially available substances.

Compound (I-A-1'-5) is reacted with Compound (I-A-1'-4) in a solvent and in the presence of a base to give Compound (I-A-1'-3).

Any solvents that do not interfere with the reaction may be used, and examples thereof include ethers such as tetrahydrofuran and dioxane; alcohols such as methanol, ethanol and isopropanol; aromatic hydrocarbons such as toluene; nitriles such as acetonitrile; water; and their mixtures.

Examples of bases include alkali metal carbonates such as cesium carbonate, potassium carbonate, sodium carbonate and sodium hydrogen carbonate; alkali metal phosphates such as tribasic potassium phosphate, sodium phosphate and sodium hydrogen phosphate; amines such as triethylamine and N,N-diisopropylethylamine; and alkali metal fluorides such as cesium fluoride and potassium fluoride.

The amount of Compound (I-A-1'-4) used may be 1.0-5.0 mole equivalents, preferably 1.0-2.0 mole equivalents, relative to Compound (I-A-1'-5).

The amount of base used may be 1.0-5.0 mole equivalents, preferably 2.0-3.0 mole equivalents, relative to Compound (I-A-1'-5).

The reaction can be carried out at room temperature to elevated, for example at room temperature to 100°C, preferably at room temperature.

Stage 2

Compound (I-A-1'-3) is reacted with Compound (I-A-1'-2) in a solvent, with or without a base, and in the presence of a condensing agent to give Compound (I-A-1'-1).

Any solvents that do not interfere with the reaction can be used, and examples include amides such as N,N-dimethylformamide; ethers such as tetrahydrofuran and dioxane; halogenated aliphatic hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as toluene; nitriles such as acetonitrile; and their mixtures.

Examples of bases include alkali metal hydrogen carbonates such as sodium hydrogen carbonate; alkali metal carbonates such as potassium carbonate; inorganic bases such as alkali metal hydroxides such as sodium hydroxide; alkylamines such as triethylamine and N,N-diisopropylethylamine; and organic bases such as pyridines such as pyridine and 4-dimethylaminopyridine, and 1,8-diazabicyclo[5.4.0]-7-undecene.

Examples of the condensing agent include O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.

The amount of Compound (I-A-1'-2) used may be 1.0-5.0 mole equivalents, preferably 1.0-2.0 mole equivalents, relative to Compound (I-A-1'-3).

The amount of base used may be 0.1-3.0 mole equivalents, preferably 0.1-1.0 mole equivalents, relative to Compound (I-A-1'-3).

The amount of condensing agent used may be 1.0-5.0 mole equivalents, preferably 1.0-2.0 mole equivalents, relative to Compound (I-A-1'-3).

The reaction can be carried out at room to elevated temperature, for example at room temperature to 100° C., preferably at room temperature.

Stage 3

Compound (I-A-1'-1) can be reacted with a reducing agent in a solvent and with or without an acid to give Compound (I-A-1').

Any solvents that do not interfere with the reaction can be used, and examples include amides such as N,N-dimethylformamide; ethers such as tetrahydrofuran and dioxane; halogenated aliphatic hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as toluene; nitriles such as acetonitrile; carboxylic acids such as acetic acid; and their mixtures.

Examples of the acid include acetic acid.

Examples of the reducing agent include sodium triacetoxyborohydride and sodium borohydride.

The amount of acid used may be 1.0-5.0 mole equivalents, preferably 1.0-4.0 mole equivalents, relative to Compound (I-A-1'-1).

The amount of reducing agent used may be 1.0-5.0 mole equivalents, preferably 1.0-4.0 mole equivalents, relative to Compound (I-A-1'-1).

The reaction can be carried out at room to elevated temperature, for example at room temperature to 100° C., preferably at room temperature.

Preparation method A-3 (preparation of intermediate compound)

Compound (I-A-4') can also be used instead of Compound (I-A-4).

where P ¹ represents a protecting group such as tert-butoxycarbonyl group, and the remaining symbols have the same meanings as above.

Connection (I-A-4') can be obtained according to the following scheme.

where the symbols have the meanings given above.

Stage 1

Compound (1-A-4'-4) may be a commercially available substance, or may be obtained by known methods from commercially available substances.

Compound (1-A-4'-4) is reacted with Compound (1-A-4'-3) in a solvent and in the presence of an acid and a reducing agent to give Compound (1-A-4'-2).

Any solvents that do not interfere with the reaction can be used and examples include amides such as 1M,1M-dimethylformamide; ethers such as tetrahydrofuran and dioxane; halogenated aliphatic hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as toluene; nitriles such as acetonitrile; carboxylic acids such as acetic acid; and their mixtures.

Examples of the acid include acetic acid.

Examples of the reducing agent include sodium triacetoxyborohydride and sodium borohydride.

The amount of Compound (I-A-4'-3) used may be 0.4-1.0 mole equivalents, preferably 0.5-0.8 mole equivalents, relative to Compound (I-A-4'-4).

The amount of acid used may be 2.0-5.0 mole equivalents, preferably 2.0-3.0 mole equivalents, relative to Compound (I-A-4'-4).

The amount of reducing agent used may be 2.0-5.0 mole equivalents, preferably 2.0-3.0 mole equivalents, relative to Compound (I-A-4'-4).

The reaction can be carried out at room temperature to elevated, for example at room temperature to 100°C, preferably at room temperature.

Stage 2

Compound (I-A-4'-2) is reacted with Compound (I-A-4'-1) in a solvent to give Compound (I-A'-4).

Any solvents that do not interfere with the reaction can be used, and examples include amides such as N,N-dimethylformamide; ethers such as tetrahydrofuran and dioxane; halogenated aliphatic hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as toluene; nitriles such as acetonitrile; carboxylic acids such as acetic acid; and their mixtures.

The amount of Compound (I-A-4'-1) used may be 2.0-5.0 molar equivalents, preferably 2.0-3.0 molar equivalents, relative to Compound (I-A-4'-2).

The reaction can be carried out at room temperature to elevated, for example at room temperature to 100°C, preferably at room temperature.

Production Method B

Of the compounds having formula (I), Compound (IB) wherein X ¹ is -OC(=O)-, X ² is -C(=O)-O-, Y ¹ is -NG ²¹ - , Y ² is -NG ²² -, G ²¹ is -CH(COOR ³ )-CH ₂ -COOR ³ , and G ²² is -CH(COOR ³ )-CH ₂ -COOR ³ can be obtained according to, for example , the following diagram.

where the symbols have the meanings given above.

Stage 1

Compound (I-B-3) and Compound (I-B-4) may be commercially available substances, or they can be obtained by known methods from commercially available substances.

Compound (I-B-4) is reacted with Compound (I-B-3) in a solvent and in the presence of a base or without a base to give Compound (I-B-2).

Any solvents that do not interfere with the reaction may be used, and examples thereof include ethers such as tetrahydrofuran and dioxane; aromatic hydrocarbons such as toluene; nitriles such as acetonitrile; and their mixtures.

Examples of bases include alkylamines such as triethylamine and N,N-diisopropylethylamine; organic bases such as pyridines such as pyridine and 4-dimethylaminopyridine and 1,8-diazabicyclo[5.4.0]-7-undecene; and inorganic bases such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate and sodium hydride.

The amount of Compound (I-B-3) used may be 2.0-5.0 mole equivalents, preferably 2.0-3.0 mole equivalents, relative to Compound (I-B-4).

The amount of base used may be 0.5-5.0 mole equivalents, preferably 0.5-2.0 mole equivalents, relative to Compound (I-B-4).

The reaction can be carried out at room temperature to elevated, for example at room temperature to 100°C, preferably at room temperature.

Stage 2

Compound (I-B-2) is reacted with Compound (I-B-1) in a solvent and in the presence of a base or without a base to give Compound (I-B).

Any solvents that do not interfere with the reaction can be used, and examples include amides such as N,N-dimethylformamide; halogenated aliphatic hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as toluene; nitriles such as acetonitrile; carboxylic acids such as acetic acid; water; and their mixtures.

Examples of bases include alkylamines such as triethylamine and N,N-diisopropylethylamine; and organic bases such as pyridines such as pyridine and 4-dimethylaminopyridine, and 1,8-diazabicyclo[5.4.0]-7-undecene.

The amount of Compound (I-B-1) used may be 2.0-5.0 mole equivalents, preferably 2.0-3.0 mole equivalents, relative to Compound (I-B-2).

The amount of base used may be 2.0-10.0 mole equivalents, preferably 2.0-4.0 mole equivalents, relative to Compound (I-B-2).

The reaction can be carried out at room temperature to elevated, for example at room temperature to 100°C, preferably at room temperature.

Stage 3

When a protecting group(s) is present(s) in Compound (I-B), the protecting group(s) may be removed by procedures similar to those described for Step 5-1 and/or Step 5-2 in the Preparation Method. A.

The compound obtained in Step 2 or Step 3 can be reacted with an acid such as hydrochloric acid and trifluoroacetic acid according to known procedures to give acid addition salts such as hydrochloride and trifluoroacetate.

The amount of acid used may be 2.0-20.0 mole equivalents, preferably 2.0-15.0 mole equivalents, relative to the compound obtained in Step 2 or Step 3.

Preparation method B-1 (preparation of an intermediate)

Compound (I-B-1) can be obtained according to, for example, the following scheme.

where the symbols have the meanings given above.

Stage 1

Compound (I-B-6) can be obtained in the same manner as Compound (I-A-1).

Compound (I-B-6) can be reacted with 1,1'-carbonyldiimidazole (CDI) in a solvent and in the presence of a base or without a base to give Compound (I-B-5).

Any solvents that do not interfere with the reaction can be used, and examples include amides such as N,N-dimethylformamide; halogenated aliphatic hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as toluene; nitriles such as acetonitrile; carboxylic acids such as acetic acid; water; and their mixtures.

Examples of bases include alkylamines such as triethylamine and N,N-diisopropylethylamine; organic bases such as pyridines such as pyridine and 4-dimethylaminopyridine and 1,8-diazabicyclo[5.4.0]-7-undecene; and metal hydrides such as sodium hydride.

The amount of 1,1'-carbonyldiimidazole used may be 1.0-5.0 mole equivalents, preferably 1.0-2.0 mole equivalents, relative to Compound (I-B-6).

The amount of base used can be 0.1-3.0 mole equivalents, preferably 0.1-1.0 mole equivalents, relative to Compound (I-B-6).

The reaction can be carried out at room temperature to elevated, for example at room temperature to 100°C, preferably at room temperature.

Stage 2

Compound (I-B-5) can be reacted with methyl trifluoromethanesulfonate (MeOTf) in a solvent to give Compound (I-B-1).

Any solvents that do not interfere with the reaction can be used, and examples include amides such as N,N-dimethylformamide; ethers such as tetrahydrofuran and dioxane; halogenated aliphatic hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as toluene; nitriles such as acetonitrile; carboxylic acids such as acetic acid; and their mixtures.

The amount of methyl trifluoromethanesulfonate used may be 1.0-5.0 mole equivalents, preferably 1.0-2.0 mole equivalents, relative to Compound (I-B-5).

The reaction can be carried out at room temperature to elevated, for example at room temperature to 100°C, preferably at room temperature.

Way to get C

Of the compounds having formula (I), Compound (IC) wherein X ¹ is -OC(=O)-, X ² is -C(=O)-O-, Y ¹ is -NG ²¹ - L ¹¹ -C(=O)-NG ³¹ -L ²¹ -C(=O)-, and Y ² is -C(=O)-L ²² -NG ³² -C(=O)-L ¹² -NG ²² - can be obtained according to, for example, the following scheme.

where P ² and P ³ each independently represent a protective group such as a benzyloxycarbonyl group; and the rest of the characters have the same meanings as above.

Stage 1

Compound (I-C-7) and Compound (I-C-8) may be commercially available substances, or they can be obtained by known methods from commercially available substances.

Compound (I-C-8) is reacted with Compound (I-C-7) in a solvent, with or without a base, and in the presence of a condensing agent to give Compound (I-C-6).

Any solvents that do not interfere with the reaction can be used, and examples include amides such as N,N-dimethylformamide; ethers such as tetrahydrofuran and dioxane; halogenated aliphatic hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as toluene; nitriles such as acetonitrile; carboxylic acids such as acetic acid; water; and their mixtures.

Examples of bases include alkali metal carbonates such as cesium carbonate, potassium carbonate, sodium carbonate and sodium hydrogen carbonate; alkali metal phosphates such as tribasic potassium phosphate, sodium phosphate and sodium hydrogen phosphate; amines such as triethylamine and N,N-diisopropylethylamine; and alkali metal fluorides such as cesium fluoride and potassium fluoride.

Examples of the condensing agent include O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, and (1-cyano-2-ethoxy -2-oxoethylideneaminooxy)dimethylamino(morpholino)carbenium hexafluorophosphate (COMU).

The amount of Compound (I-C-7) used may be 2.0-5.0 mole equivalents, preferably 2.0-3.5 mole equivalents, relative to Compound (I-C-8).

The amount of base used may be 2.0-5.0 mole equivalents, preferably 2.0-4.0 mole equivalents, relative to Compound (I-C-8).

The amount of condensing agent used may be 2.0-5.0 mole equivalents, preferably 2.0-4.0 mole equivalents, relative to Compound (I-C-8).

The reaction can be carried out at room temperature to elevated, for example at room temperature to 100°C, preferably at room temperature.

Stage 2

Compound (I-C-6) can be reacted in a manner similar to Step 5-2 of Production Method A to give Compound (I-C-5).

Stage 3

Compound (I-C-5) and Compound (I-C-4) can be reacted in a manner similar to Step 1 to give Compound (I-C-3).

Stage 4

Compound (I-C-3) can be reacted in a manner similar to Step 5-2 of Production Method A to give Compound (I-C-2).

Stage 5

Compound (I-C-2) and Compound (I-C-1) can be reacted in a manner similar to Step 2 of Production Method B to give Compound (I-C). Compound (I-C-1) can be obtained in the same manner as Compound (I-B-1).

Stage 6

When a protecting group(s) is present in Compound (I-C), the protecting group(s) may be removed by procedures similar to those described for Step 5-1 and/or Step 5-2 of Preparation Method A .

The compound obtained in Step 5 or Step 6 can be reacted with an acid such as hydrochloric acid and trifluoroacetic acid according to known procedures to give acid addition salts such as hydrochloride and trifluoroacetate.

The amount of acid used may be 2.0-20.0 mole equivalents, preferably 2.0-15.0 mole equivalents, relative to the compound obtained in Step 5 or Step 6.

Method of obtaining D

Of the compounds having formula (I), Compound (ID) wherein X ¹ is -OC(=O)-, X ² is -C(=O)-O-, Y ¹ is -NG ²¹ - L ¹¹ -C(=O)-NG ³¹ -L ²¹ -C(=O)-, and Y ² is -C(=O)-L ²² -NG ³² -C(=O)-L ¹² -NG ²² - can also be obtained, for example, according to the following scheme.

where the symbols have the meanings given above.

Stage 1

Compound (I-D-2) can be obtained in the same manner as Compound (I-C-5).

Compound (I-D-2) is reacted with Compound (I-D-1) in a solvent, with or without a base, in the presence of a condensing agent, and with or without an activating agent, to give Compound (I-D).

Any solvents that do not interfere with the reaction can be used, and examples include amides such as N,N-dimethylformamide; ethers such as tetrahydrofuran and dioxane; halogenated aliphatic hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as toluene; nitriles such as acetonitrile; carboxylic acids such as acetic acid; water; and their mixtures.

Examples of bases include alkali metal carbonates such as cesium carbonate, potassium carbonate, sodium carbonate and sodium hydrogen carbonate; alkali metal phosphates such as tribasic potassium phosphate, sodium phosphate and sodium hydrogen phosphate; amines such as triethylamine and N,N-diisopropylethylamine; and alkali metal fluorides such as cesium fluoride and potassium fluoride.

Examples of the condensing agent include O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, (1-cyano-2-ethoxy -2-oxoethylideneaminooxy)dimethylamino(morpholino)carbenium hexafluorophosphate (COMU), and mixtures thereof.

Examples of the activating agent include t-butyl peroxide, 1-hydroxy-7-azabenzotriazole (HOAt), 1-hydroxybenzotriazole (HOBt), and 4-dimethylaminopyridine.

The amount of Compound (I-D-1) used may be 2.0-5.0 mole equivalents, preferably 2.0-3.0 mole equivalents, relative to Compound (I-D-2).

The amount of base used may be 2.0-6.0 mole equivalents, preferably 2.0-5.0 mole equivalents, relative to Compound (I-D-2).

The amount of condensing agent used may be 2.0-5.0 mole equivalents, preferably 2.0-3.0 mole equivalents, relative to Compound (I-D-2).

The amount of activating agent used may be 2.0-5.0 mole equivalents, preferably 2.0-3.0 mole equivalents, relative to Compound (I-D-2).

The reaction can be carried out at room temperature to elevated, for example at room temperature to 100°C, preferably at room temperature.

Stage 2

When a protecting group(s) are present in Compound (I-D), the protecting group(s) may be removed by procedures similar to those described for Step 5-1 and/or Step 5-2 of Preparation Method A .

The compound obtained in Step 1 or Step 2 can be reacted with an acid such as hydrochloric acid and trifluoroacetic acid according to known procedures to give acid addition salts such as hydrochloride and trifluoroacetate.

The amount of acid used may be 2.0-20.0 mole equivalents, preferably 2.0-15.0 mole equivalents, relative to the compound obtained in Step 1 or Step 2.

Preparation method D-1 (preparation of intermediate)

Connection (I-D-1) can be obtained according to, for example, the following scheme.

where P ⁴ represents a protective group such as 2-trimethylsilylethyl group; and the rest of the characters have the same meanings as above.

Stage 1

Compound (I-D-5) can be obtained in the same manner as Compound (I-B-1).

Compound (I-D-5) is reacted with Compound (I-D-4) in a solvent and in the presence of a base or without a base to give Compound (I-D-3).

Any solvents that do not interfere with the reaction can be used, and examples include amides such as N,N-dimethylformamide; halogenated aliphatic hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as toluene; nitriles such as acetonitrile; carboxylic acids such as acetic acid; water; and their mixtures.

Examples of bases include alkylamines such as triethylamine and N,N-diisopropylethylamine; and organic bases such as pyridines such as pyridine and 4-dimethylaminopyridine, and 1,8-diazabicyclo[5.4.0]-7-undecene.

The amount of Compound (I-D-4) used may be 1.0-5.0 mole equivalents, preferably 1.0-3.0 mole equivalents, relative to Compound (I-D-5).

The amount of base used may be 1.0-5.0 mole equivalents, preferably 1.0-2.0 mole equivalents, relative to Compound (I-D-5).

The reaction can be carried out at room temperature to elevated, for example at room temperature to 100°C, preferably at room temperature.

Stage 2

Compound (I-D-3) can be reacted with tetrabutylammonium fluoride in a solvent to give Compound (I-D-1).

Any solvents that do not interfere with the reaction may be used, and examples thereof include ethers such as tetrahydrofuran and dioxane; aromatic hydrocarbons such as toluene; nitriles such as acetonitrile; and their mixtures.

The amount of tetrabutylammonium fluoride used may be 1.0-20.0 mole equivalents, preferably 1.0-15.0 mole equivalents, relative to Compound (I-D-3).

The reaction can be carried out at room temperature to elevated, for example at room temperature to 100°C, preferably at room temperature.

Preparation method D-2 (preparation of intermediate)

Connection (I-D-4) can be obtained according to, for example, the following scheme.

where V ² represents a halogen atom, such as a chlorine atom; and the rest of the characters have the same meanings as above.

Compound (I-D-6) may be a commercially available substance, or may be obtained by known methods from commercially available substances.

Compound (I-D-7) is reacted with Compound (I-D-6) in a solvent and in the presence of a base to give Compound (I-D-4).

Any solvents that do not interfere with the reaction can be used, and examples include amides such as N,N-dimethylformamide; ethers such as tetrahydrofuran and dioxane; halogenated aliphatic hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as toluene; nitriles such as acetonitrile; and their mixtures.

Examples of bases include alkali metal carbonates such as cesium carbonate, potassium carbonate, sodium carbonate and sodium hydrogen carbonate; alkali metal phosphates such as tribasic potassium phosphate, sodium phosphate and sodium hydrogen phosphate; amines such as triethylamine and N,N-diisopropylethylamine; and alkali metal fluorides such as cesium fluoride and potassium fluoride.

The amount of Compound (I-D-6) used may be 1.0-5.0 molar equivalents, preferably 1.0-2.0 molar equivalents, relative to Compound (I-D-7).

The amount of base used may be 1.0-5.0 mole equivalents, preferably 2.0-4.0 mole equivalents, relative to Compound (I-D-7).

The reaction can be carried out at room to elevated temperature, for example at room temperature to 150°C, preferably at 50 to 100°C.

Preparation method D-3 (preparation of intermediate)

Among Compounds (ID-4), a compound wherein G ² is a C ₁ -C ₆ alkyl group substituted with one phenyl group optionally substituted with 1-5 -COOR ³ groups can also be prepared, for example, according to the following scheme.

where o is an integer from 1 to 5; p is an integer from 0 to 5; and the rest of the characters have the same meanings as above.

Compound (I-D-6') may be a commercially available substance, or may be obtained by known methods from commercially available substances.

Compound (I-D-7) is reacted with Compound (I-D-6') in a solvent, in the presence of a dehydrating agent or without a dehydrating agent, and in the presence of sodium acetate or without sodium acetate, and then a reaction can be carried out with a reducing agent in the presence of an acid or without acid to give Compound (I-D-4').

Any solvents that do not interfere with the reaction can be used, and examples include amides such as N,N-dimethylformamide; halogenated aliphatic hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as toluene; nitriles such as acetonitrile; and their mixtures.

Examples of the dehydrating agent include magnesium sulfate and molecular sieves.

Examples of the acid include acetic acid.

Examples of the reducing agent include sodium triacetoxyborohydride and sodium borohydride.

The amount of Compound (I-D-6') used may be 0.5-5.0 mole equivalents, preferably 0.8-2.0 mole equivalents, relative to Compound (I-D-7).

The amount of dehydrating agent used may be 1.0-5.0 mole equivalents, preferably 1.0-2.0 mole equivalents, relative to Compound (I-D-7).

The amount of sodium acetate used may be 1.0-5.0 mole equivalents, preferably 1.0-2.0 mole equivalents, relative to Compound (I-D-7).

The amount of acid used may be 1.0-5.0 mole equivalents, preferably 1.0-2.0 mole equivalents, relative to Compound (I-D-7).

The amount of reducing agent used may be 1.0-5.0 mole equivalents, preferably 1.0-2.0 mole equivalents, relative to Compound (I-D-7).

The reaction can be carried out at room temperature to elevated, for example at room temperature to 150°C, preferably at room temperature.

Preparation method D-4 (preparation of intermediate)

Connection (I-D-7) can be obtained according to, for example, the following scheme.

where P ⁵ is a protecting group such as a benzyloxycarbonyl group; and the rest of the characters have the same meanings as above.

Stage 1

Compound (I-D-9) and Compound (I-D-10) may be commercially available substances, or they can be obtained by known methods from commercially available substances.

Compound (I-D-10) is reacted with Compound (I-D-9) in a solvent, with or without a base, and in the presence of a condensing agent to give Compound (I-D-8).

Any solvents that do not interfere with the reaction can be used, and examples include amides such as N,N-dimethylformamide; ethers such as tetrahydrofuran and dioxane; halogenated aliphatic hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as toluene; nitriles such as acetonitrile; carboxylic acids such as acetic acid; water; and their mixtures.

Examples of bases include alkali metal hydrogen carbonates such as sodium hydrogen carbonate; alkali metal carbonates such as potassium carbonate; inorganic bases such as alkali metal hydroxides such as sodium hydroxide; alkylamines such as triethylamine and N,N-diisopropylethylamine; and organic bases such as pyridines such as pyridine and 4-dimethylaminopyridine.

Examples of the condensing agent include O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, (1-cyano-2-ethoxy -2-oxoethylideneaminooxy)dimethylamino(morpholino)carbenium hexafluorophosphate (COMU), and mixtures thereof.

The amount of Compound (I-D-9) used may be 1.0-5.0 mole equivalents, preferably 1.0-2.0 mole equivalents, relative to Compound (I-D-10).

The amount of base used may be 0.1-5.0 mole equivalents, preferably 0.1-2.0 mole equivalents, relative to Compound (I-D-10).

The amount of condensing agent used may be 1.0-5.0 mole equivalents, preferably 1.0-2.0 mole equivalents, relative to Compound (I-D-10).

The reaction can be carried out at room temperature to elevated, for example at room temperature to 100°C, preferably at room temperature.

Stage 2

Compound (I-D-8) can be reacted in a manner similar to Step 5-2 of Production Method A to give Compound (I-D-7).

Method of obtaining E

Of the compounds having formula (I), Compound (IE) wherein X ¹ is -OC(=O)-, X ² is -C(=O)-O-, Y ¹ is -NG ²¹ - L ¹¹ -C(=O)-, and Y ² is -C(=O)-L ¹² -NG ²² - can also be obtained, for example, according to the following scheme.

where the symbols have the meanings given above.

Stage 1

Compound (I-E-2) and Compound (I-E-1) can be reacted in a manner similar to Step 1 of Production Method D to give Compound (I-E). Compound (I-E-2) may be a commercially available substance, or may be obtained by known methods from commercially available substances.

Stage 2

When a protecting group(s) is present in Compound (I-E), the protecting group(s) may be removed by procedures similar to those described for Step 5-1 and/or Step 5-2 of Production Method A .

The resulting compound can be reacted with an acid such as hydrochloric acid and trifluoroacetic acid according to known procedures to give acid addition salts such as hydrochloride and trifluoroacetate.

The amount of acid used may be 2.0-20.0 mole equivalents, preferably 2.0-15.0 mole equivalents, relative to the compound obtained in Step 1 or Step 2.

Production method E-1 (preparation of an intermediate)

Compound (IE-1) can be obtained in the same way as Compound (ID-1) in a manner similar to Production Method D-1. Among Compounds (ID-4), Compound (IE-3) wherein L ¹ is a C ₁ -C ₄ alkylene-phenylene group can be obtained according to, for example, the following scheme.

where q is an integer from 0 to 3; and the rest of the characters have the same meanings as above.

Stage 1

Compound (I-E-7) and Compound (I-E-6) may be commercially available substances, or they can be obtained by known methods from commercially available substances.

Compound (I-E-7) can be reacted with a chlorinating agent in a solvent with or without a catalyst, and then reacted with Compound (I-E-6) with or without a base to give Compound (I-E-5).

Any solvents that do not interfere with the reaction can be used, and examples include amides such as N,N-dimethylformamide; ethers such as tetrahydrofuran and dioxane; halogenated aliphatic hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as toluene; nitriles such as acetonitrile; and their mixtures.

Examples of the catalyst include dimethylformamide.

Examples of the chlorinating agent include oxalyl chloride.

Examples of bases include alkylamines such as triethylamine and N,N-diisopropylethylamine; and organic bases such as pyridines such as pyridine and 4-dimethylaminopyridine, and 1,8-diazabicyclo[5.4.0]-7-undecene.

The amount of Compound (I-E-6) used may be 1.0-5.0 molar equivalents, preferably 1.0-2.0 molar equivalents, relative to Compound (I-E-7).

The amount of catalyst used may be 0.01-0.1 mole equivalents, preferably 0.03-0.06 mole equivalents, relative to Compound (I-E-7).

The amount of chlorinating agent used may be 1.0-5.0 mole equivalents, preferably 1.0-2.0 mole equivalents, relative to Compound (I-E-7).

The amount of base used may be 1.0-5.0 mole equivalents, preferably 1.0-2.0 mole equivalents, relative to Compound (I-E-7).

The reaction can be carried out at room temperature to elevated, for example at room temperature to 100°C, preferably at room temperature.

Stage 2

The compound (I-E-4) may be a commercially available substance, or may be obtained from commercially available substances according to known methods, or may also be in the form of a salt such as hydrochloride.

Compound (I-E-5) is reacted with Compound (I-E-4) in a solvent, in the presence of a dehydrating agent or without a dehydrating agent, and in the presence of sodium acetate or without sodium acetate, and then can be reacted with a reducing agent with or without an acid acids to give Compound (I-E-3).

Any solvents that do not interfere with the reaction can be used, and examples include amides such as N,N-dimethylformamide; halogenated aliphatic hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as toluene; nitriles such as acetonitrile; and their mixtures.

Examples of the dehydrating agent include magnesium sulfate and molecular sieves.

Examples of the acid include acetic acid.

Examples of the reducing agent include sodium triacetoxyborohydride and sodium borohydride.

The amount of Compound (I-E-4) used may be 1.0-5.0 molar equivalents, preferably 1.0-2.0 molar equivalents, relative to Compound (I-E-5).

The amount of dehydrating agent used may be 1.0-5.0 mole equivalents, preferably 1.0-2.0 mole equivalents, relative to Compound (I-E-5).

The amount of sodium acetate used may be 1.0-5.0 mole equivalents, preferably 1.0-2.0 mole equivalents, relative to Compound (I-E-5).

The amount of acid used may be 1.0-5.0 mole equivalents, preferably 1.0-2.0 mole equivalents, relative to Compound (I-E-5).

The amount of reducing agent used may be 1.0-5.0 mole equivalents, preferably 1.0-2.0 mole equivalents, relative to Compound (I-E-5).

The reaction can be carried out at room temperature to elevated, for example at room temperature to 150°C, preferably at room temperature.

Method of obtaining F

Of the compounds having formula (I), Compound (IF) wherein X ¹ is -NG ¹¹ -SO ₂ -, X ² is -SO ₂ -NG ¹² -, Y ¹ is -NG ²¹ -L ¹¹ -C(=O)-, and Y ² is -C(=O)-L ¹² -NG ²² - can also be obtained, for example, according to the following scheme.

where the symbols have the meanings given above.

Stage 1

Compound (I-F-2) may be a commercially available substance, or may be obtained by known methods from commercially available substances.

Compound (I-F-2) is reacted with Compound (I-F-1) in a solvent, with or without a base, in the presence of a condensing agent, and with or without an activating agent, to give Compound (I-F).

Any solvents that do not interfere with the reaction can be used, and examples include amides such as N,N-dimethylformamide; halogenated aliphatic hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as toluene; nitriles such as acetonitrile; carboxylic acids such as acetic acid; water; and their mixtures.

Examples of bases include alkali metal carbonates such as cesium carbonate, potassium carbonate, sodium carbonate and sodium hydrogen carbonate; alkali metal phosphates such as tribasic potassium phosphate, sodium phosphate and sodium hydrogen phosphate; amines such as triethylamine and N,N-diisopropylethylamine; and alkali metal fluorides such as cesium fluoride and potassium fluoride.

Examples of the condensing agent include O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, (1-cyano-2-ethoxy -2-oxoethylideneaminooxy)dimethylamino(morpholino)carbenium hexafluorophosphate (COMU), and mixtures thereof.

Examples of the activating agent include t-butyl peroxide, 1-hydroxy-7-azabenzotriazole (HOAt), 1-hydroxybenzotriazole (HOBt), and 4-dimethylaminopyridine.

The amount of Compound (I-F-1) used may be 2.0-5.0 mole equivalents, preferably 2.0-3.0 mole equivalents, relative to Compound (I-F-2).

The amount of base used may be 2.0-6.0 mole equivalents, preferably 2.0-4.0 mole equivalents, relative to Compound (I-F-2).

The amount of condensing agent used may be 2.0-5.0 mole equivalents, preferably 2.0-3.0 mole equivalents, relative to Compound (I-F-2).

The amount of activating agent used may be 2.0-5.0 mole equivalents, preferably 2.0-3.0 mole equivalents, relative to Compound (I-F-2).

The reaction can be carried out at room temperature to elevated, for example at room temperature to 100°C, preferably at room temperature.

Stage 2

When a protecting group(s) is present in Compound (I-F), the protecting group(s) may be removed by procedures similar to those described for Step 5-1 and/or Step 5-2 of Preparation Method A .

The compound obtained in Step 1 or Step 2 can be reacted with an acid such as hydrochloric acid and trifluoroacetic acid according to known procedures to give acid addition salts such as hydrochloride and trifluoroacetate.

The amount of acid used may be 2.0-20.0 mole equivalents, preferably 2.0-15.0 mole equivalents, relative to the compound obtained in Step 1 or Step 2.

Production method F-1 (preparation of an intermediate)

Of Connections (I-F-1), Connection (I-F-1’)

where the symbols have the meanings given above.

can be obtained according to, for example, the following scheme.

where P ⁶ represents a protective group such as 2-trimethylsilylethyl group; and the rest of the characters have the same meanings as above.

Stage 1

Compound (1-F-1'-4) can be obtained in the same manner as Compound (1-D-4).

Compound (1-F-1'-4) is reacted in a solvent in the presence of a base and benzyl N-chlorosulfonylcarbamate, which is a compound obtained by reacting chlorosulfonyl isocyanate (CSI) with benzyl alcohol (BnOH), to give Compound (1-F- 1'-3).

Any solvents that do not interfere with the reaction can be used, and examples include amides such as N,N-dimethylformamide; ethers such as tetrahydrofuran and dioxane; halogenated aliphatic hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as toluene; nitriles such as acetonitrile; and their mixtures.

Examples of bases include alkylamines such as triethylamine and N,N-diisopropylethylamine; and organic bases such as pyridines such as pyridine and 4-dimethylaminopyridine, and 1,8-diazabicyclo[5.4.0]-7-undecene.

The amount of base used may be 1.0-5.0 mole equivalents, preferably 1.0-3.5 mole equivalents, relative to Compound (1-F-1'-4).

The amount of chlorosulfonyl isocyanate used may be 1.0-5.0 mole equivalents, preferably 1.0-2.0 mole equivalents, relative to Compound (1-F-1'-4).

The amount of benzyl alcohol used may be 1.0-5.0 mole equivalents, preferably 1.0-2.0 mole equivalents, relative to Compound (1-F-1'-4).

The reaction can be carried out at room temperature to elevated, for example at room temperature to 100°C, preferably at room temperature.

Stage 2

Compound (1-F-1'-2) can be obtained in the same manner as Compound (I-A-1').

Compound (1-F-1'-3) is reacted with Compound (1-F-1'-2) in a solvent and in the presence of an azodicarboxylic acid derivative and a phosphine derivative to give Compound (1-F-1'-1) .

Any solvents that do not interfere with the reaction may be used, and examples thereof include ethers such as tetrahydrofuran and dioxane; aromatic hydrocarbons such as toluene; nitriles such as acetonitrile; and their mixtures.

Examples of the azodicarboxylic acid derivative include azodicarboxylic acid dialkyl esters such as diethyl azodicarboxylate and diisopropyl azodicarboxylate; and azodicarboxamides such as 1,1'-azobis(N,N-dimethylformamide).

Examples of the phosphine derivative include triarylphosphines such as triphenylphosphine; and trialkylphosphines such as tributylphosphine.

The amount of Compound (1-F-1'-2) used may be 1.0-5.0 mole equivalents, preferably 1.0-2.0 mole equivalents, relative to Compound (1-F-1'-3).

The amount of azodicarboxylic acid derivative used may be 1.0-5.0 mole equivalents, preferably 1.0-2.0 mole equivalents, relative to Compound (1-F-1'-3).

The amount of phosphine derivative used may be 1.0-5.0 mole equivalents, preferably 1.0-2.0 mole equivalents, relative to Compound (1-F-1'-3).

The reaction can be carried out at room temperature to elevated, for example at room temperature to 100°C, preferably at room temperature.

Stage 3

Compound (1-F-1'-1) can be reacted in a manner similar to Step 2 of Preparation Method D-1 to give Compound (1-F-1').

Method of obtaining G

Of the compounds having formula (I), Compound (IG) wherein X ¹ is -C(=O)-, X ² is -C(=O)-, Y ¹ is -NG ²¹ -, and Y ² is -NG ²² - can be obtained according to, for example, the following scheme.

where the symbols have the meanings given above.

Stage 1

Compound (I-G-2) can be obtained in the same manner as Compound (I-A-3).

Compound (I-G-2) is reacted with Compound (I-G-1) in a solvent, with or without a base, in the presence of a condensing agent, and with or without an activating agent, to give Compound (I-G).

Any solvents that do not interfere with the reaction can be used, and examples include amides such as N,N-dimethylformamide; ethers such as tetrahydrofuran and dioxane; halogenated aliphatic hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as toluene; nitriles such as acetonitrile; carboxylic acids such as acetic acid; water; and their mixtures.

Examples of bases include alkali metal carbonates such as cesium carbonate, potassium carbonate, sodium carbonate and sodium hydrogen carbonate; alkali metal phosphates such as tribasic potassium phosphate, sodium phosphate and sodium hydrogen phosphate; amines such as triethylamine and N,N-diisopropylethylamine; and alkali metal fluorides such as cesium fluoride and potassium fluoride.

Examples of the condensing agent include O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, (1-cyano-2-ethoxy -2-oxoethylideneaminooxy)dimethylamino(morpholino)carbenium hexafluorophosphate (COMU), and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride.

Examples of the activating agent include t-butyl peroxide, 1-hydroxy-7-azabenzotriazole (HOAt), 1-hydroxybenzotriazole (HOBt), and 4-dimethylaminopyridine.

The amount of Compound (I-G-1) used may be 2.0-5.0 molar equivalents, preferably 2.0-3.5 molar equivalents, relative to Compound (I-G-2).

The amount of base used may be 2.0-10.0 mole equivalents, preferably 2.0-7.0 mole equivalents, relative to Compound (I-G-2).

The amount of condensing agent used may be 2.0-10.0 mole equivalents, preferably 2.0-7.0 mole equivalents, relative to Compound (I-G-2).

The amount of activating agent used may be 2.0-5.0 mole equivalents, preferably 2.0-3.0 mole equivalents, relative to Compound (I-G-2).

The reaction can be carried out at room temperature to elevated, for example at room temperature to 100°C, preferably at room temperature.

Stage 2

When a protecting group(s) is present in Compound (I-G), the protecting group(s) may be removed by procedures similar to those described for Step 5-1 and/or Step 5-2 of Preparation Method A .

The compound obtained in Step 1 or Step 2 can be reacted with an acid such as hydrochloric acid, formic acid and trifluoroacetic acid according to known procedures to give acid addition salts such as hydrochloride, formate and trifluoroacetate.

The amount of acid used may be 2.0-20.0 mole equivalents, preferably 2.0-15.0 mole equivalents, relative to the compound obtained in Step 1 or Step 2.

Method for obtaining G (alternative method)

Compound (I-G) can also be obtained by reacting Compound (I-G-2) with Compound (I-G'-1) in a manner similar to Step 1 to obtain Compound (I-G'), and then Compound (I-G') can be react according to procedures similar to Steps 4 and 5 of Method H described below.

where the symbols have the meanings given above.

Compound (I-G-1') may be a commercially available substance, or may be obtained by known methods from commercially available substances.

Preparation method G-1 (preparation of intermediate compound)

Of Connections (I-G-1), Connection (I-G-1’)

where s' and t' are each independently an integer from 0 to 3; and the rest of the characters have the same meanings as above,

can be obtained according to, for example, the following scheme.

where P ⁷ represents a protective group such as tert-butoxycarbonyl group; P ⁸ is a protecting group such as a benzyl group; P ⁹ is a protecting group such as a benzyl group; P ¹⁰ is a protecting group such as a 2-trimethylsilylethyl group; and the rest of the characters have the same meanings as above.

Stage 1

Compound (I-G-1'-8) is reacted with Compound (I-G-1'-7) in a solvent and in the presence of an azodicarboxylic acid derivative and a phosphine derivative to give Compound (I-G-1'-6).

Any solvents that do not interfere with the reaction may be used, and examples thereof include ethers such as tetrahydrofuran and dioxane; aromatic hydrocarbons such as toluene; nitriles such as acetonitrile; and their mixtures.

Examples of the azodicarboxylic acid derivative include azodicarboxylic acid dialkyl esters such as diethyl azodicarboxylate and diisopropyl azodicarboxylate; and azodicarboxamides such as 1,1'-azobis(N,N-dimethylformamide).

Examples of the phosphine derivative include triarylphosphines such as triphenylphosphine; and trialkylphosphines such as tributylphosphine.

The amount of Compound (I-G-1'-7) used may be 0.9-5.0 mole equivalents, preferably 0.9-2.0 mole equivalents, relative to Compound (I-G-1'-8).

The amount of azodicarboxylic acid derivative used may be 1.0-5.0 mole equivalents, preferably 1.0-3.0 mole equivalents, relative to Compound (I-G-1'-8).

The amount of phosphine derivative used may be 1.0-5.0 mole equivalents, preferably 1.0-3.0 mole equivalents, relative to Compound (I-G-1'-8).

The reaction can be carried out at room to elevated temperature, for example at room temperature to 100° C., preferably at room temperature.

Stage 2

Compound (I-G-1'-6) can be reacted in a manner similar to Step 5-2 of Production Method A to give Compound (I-G-1'-5).

Stage 3

Compound (I-G-1'-5) can be reacted with a condensing agent in a solvent and in the presence of a base or without a base to give Compound (I-G-1'-4).

Any solvents that do not interfere with the reaction can be used, and examples include amides such as N,N-dimethylformamide; ethers such as tetrahydrofuran and dioxane; halogenated aliphatic hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as toluene; heterocyclic aromatic compounds such as pyridine; nitriles such as acetonitrile; carboxylic acids such as acetic acid; water; and their mixtures.

Examples of bases include alkali metal hydrogen carbonates such as sodium hydrogen carbonate; alkali metal carbonates such as potassium carbonate; inorganic bases such as alkali metal hydroxides such as sodium hydroxide; alkylamines such as triethylamine and N,N-diisopropylethylamine; and organic bases such as pyridines such as pyridine and 4-dimethylaminopyridine, and 1,8-diazabicyclo[5.4.0]-7-undecene.

Examples of the condensing agent include O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.

The amount of base used may be 1.0-5.0 mole equivalents, preferably 1.0-2.0 mole equivalents, relative to the Compound (I-G-1'-5).

The amount of condensing agent used may be 1.0-5.0 mole equivalents, preferably 1.0-2.0 mole equivalents, relative to Compound (I-G-1'-5).

The reaction can be carried out at room temperature to elevated, for example at room temperature to 100°C, preferably at room temperature.

Stage 4

Compound (I-G-1'-4) can be reacted in a manner similar to Step 2 of Preparation Method D-1 to give Compound (I-G-1'-3).

Stage 5

Compound (I-G-1'-3) can be reacted with an acid in a solvent to give Compound (I-G-1'-2). Compound (I-G-1'-2) may also be in the form of a salt such as a hydrochloride.

Any solvents that do not interfere with the reaction may be used, and examples thereof include ethers such as tetrahydrofuran and dioxane; aromatic hydrocarbons such as toluene; nitriles such as acetonitrile; and their mixtures.

Examples of the acid include a solution of hydrogen chloride in cyclopentyl methyl ether.

The amount of acid used may be 1-20 mole equivalents, preferably 5-15 mole equivalents, relative to the Compound (I-G-1'-3).

Stage 6

Compound (I-G-1'-1) may be a commercially available substance, or may be obtained by known methods from commercially available substances.

Compound (I-G-1'-2) is reacted with Compound (I-G-1'-1) in a solvent and in the presence of a base to give Compound (I-G-1').

Any solvents that do not interfere with the reaction may be used, and examples thereof include ethers such as tetrahydrofuran, dioxane, and cyclopentyl methyl ether; alcohols such as methanol, ethanol, isopropanol and t-butyl alcohol; aromatic hydrocarbons such as toluene; nitriles such as acetonitrile; water; and their mixtures.

Examples of bases include alkali metal carbonates such as cesium carbonate, potassium carbonate, sodium carbonate and sodium hydrogen carbonate; alkali metal phosphates such as tribasic potassium phosphate, sodium phosphate and sodium hydrogen phosphate; amines such as triethylamine and N,N-diisopropylethylamine; and alkali metal fluorides such as cesium fluoride and potassium fluoride.

The amount of Compound (I-G-1'-1) used may be 1.0-10.0 mole equivalents, preferably 2.0-5.0 mole equivalents, relative to Compound (I-G-1'-2).

The amount of base used may be 1.0-10.0 mole equivalents, preferably 3.0-7.0 mole equivalents, relative to Compound (I-G-1'-2).

The reaction can be carried out at room temperature to elevated, for example at room temperature to 100°C, preferably at room temperature.

Method for obtaining G-2 (preparation of intermediate compound)

Connection (I-G-1'-8) can be obtained according to, for example, the following scheme.

where V ³ represents a halogen atom, such as a bromine atom; and the rest of the characters have the same meanings as above.

Stage 1

Compound (I-G-1'-13) and Compound (I-G-1'-14) may be commercially available substances, or they can be obtained by known methods from commercially available substances.

Compound (I-G-1'-14) is reacted with Compound (I-G-1'-13) in a solvent in the presence of a base, and with or without a catalyst to give Compound (I-G-1'-12).

Any solvents that do not interfere with the reaction can be used, and examples include amides such as N,N-dimethylformamide; ethers such as tetrahydrofuran and dioxane; halogenated aliphatic hydrocarbons such as chloroform and dichloromethane; alcohols such as methanol, ethanol and isopropanol; ketones such as acetone, methyl ethyl ketone and cyclohexanone; aromatic hydrocarbons such as toluene; nitriles such as acetonitrile; dimethyl sulfoxide; dimethylacetamide; and their mixtures.

Examples of bases include alkali metal carbonates such as cesium carbonate, potassium carbonate, sodium carbonate and sodium hydrogen carbonate; alkali metal phosphates such as tribasic potassium phosphate, sodium phosphate and sodium hydrogen phosphate; amines such as triethylamine and N,N-diisopropylethylamine; and alkali metal fluorides such as cesium fluoride and potassium fluoride.

Examples of the catalyst include tetrabutylammonium bromide.

The amount of Compound (I-G-1'-13) used may be 2.0-5.0 molar equivalents, preferably 2.0-3.0 molar equivalents, relative to Compound (I-G-1'-14).

The amount of base used may be 2.0-5.0 mole equivalents, preferably 3.0-4.0 mole equivalents, relative to Compound (I-G-1'-14).

The amount of catalyst used may be 0.01-1.0 mole equivalents, preferably 0.01-0.1 mole equivalents, relative to Compound (I-G-1'-14).

The reaction can be carried out at room temperature to elevated, for example at room temperature to 100°C, preferably at room temperature.

Stage 2

Compound (I-G-1'-12) is treated with a base in a solvent to give Compound (I-G-1'-11).

Any solvents that do not interfere with the reaction may be used, and examples thereof include ethers such as tetrahydrofuran and dioxane; alcohols such as methanol, ethanol and isopropanol; aromatic hydrocarbons such as toluene; nitriles such as acetonitrile; water; and their mixtures.

Examples of bases include alkali metal hydrogen carbonates such as sodium hydrogen carbonate; alkali metal carbonates such as potassium carbonate; inorganic bases such as alkali metal hydroxides such as sodium hydroxide; alkylamines such as triethylamine and N,N-diisopropylethylamine; and organic bases such as pyridines such as pyridine and 4-dimethylaminopyridine.

The amount of base used may be 1.0-5.0 mole equivalents, preferably 2.0-3.0 mole equivalents, relative to Compound (I-G-1'-12).

The reaction can be carried out at room temperature to elevated, for example at room temperature to 100°C, preferably from 40°C to 100°C.

Stage 3

Compound (I-G-1'-11) is treated with an amine in a solvent to give Compound (I-G-1'-10).

Any solvents that do not interfere with the reaction may be used, and examples thereof include amides such as N-methylpyrrolidone and N,N-dimethylformamide (hereinafter also referred to as dimethylformamide); ethers such as tetrahydrofuran; nitriles such as acetonitrile; dimethyl sulfoxide; dimethylacetamide; and their mixtures.

Examples of the amine include pyrrolidine, piperidine and morpholine.

The amount of amine used may be 1.0-10.0 mole equivalents, preferably 3.0-6.0 mole equivalents, relative to Compound (I-G-1'-11).

The reaction can be carried out at room temperature to elevated, for example at room temperature to 200°C, preferably from 100°C to 200°C.

Stage 4

Compound (I-G-1'-10) is reacted with Compound (I-G-1'-9) in a solvent and in the presence of an azodicarboxylic acid derivative and a phosphine derivative to give Compound (I-G-1'-8).

Any solvents that do not interfere with the reaction may be used, and examples thereof include ethers such as tetrahydrofuran and dioxane; aromatic hydrocarbons such as toluene; nitriles such as acetonitrile; and their mixtures.

Examples of the azodicarboxylic acid derivative include azodicarboxylic acid dialkyl esters such as diethyl azodicarboxylate and diisopropyl azodicarboxylate; and azodicarboxamides such as 1,1'-azobis(N,N-dimethylformamide).

Examples of the phosphine derivative include triarylphosphines such as triphenylphosphine; and trialkylphosphines such as tributylphosphine.

The amount of Compound (I-G-1'-9) used may be 1.0-5.0 mole equivalents, preferably 2.0-3.0 mole equivalents, relative to Compound (I-G-1'-10).

The amount of azodicarboxylic acid derivative used may be 1.0-5.0 mole equivalents, preferably 2.0-3.0 mole equivalents, relative to Compound (I-G-1'-10).

The amount of phosphine derivative used may be 1.0-5.0 mole equivalents, preferably 2.0-3.0 mole equivalents, relative to Compound (I-G-1'-10).

The reaction can be carried out at room temperature to elevated, for example at room temperature to 100°C, preferably at room temperature.

Preparation method G-3 (preparation of intermediate compound)

Connection (I-G-1'-7) can be obtained according to, for example, the following scheme.

where LG is a leaving group such as a halogen atom such as a bromine atom; V ⁴ represents a halogen atom such as a bromine atom; and the rest of the characters have the same meanings as above.

Stage 1

Compound (I-G-1'-20) and Compound (I-G-1'-21) may be commercially available substances, or they can be obtained by known methods from commercially available substances.

Compound (I-G-1'-21) is reacted with Compound (I-G-1'-20) in a solvent, in the presence of a base, in the presence of a catalyst 1, in the presence or absence of an organic phosphine compound, and in the presence of a catalyst 2, to give Compound (I-G-1'-19).

Any solvents that do not interfere with the reaction can be used, and examples include amides such as N,N-dimethylformamide; ethers such as tetrahydrofuran and dioxane; halogenated aliphatic hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as toluene; nitriles such as acetonitrile; and their mixtures.

Examples of bases include alkali metal carbonates such as cesium carbonate, potassium carbonate, sodium carbonate and sodium hydrogen carbonate; alkali metal phosphates such as tribasic potassium phosphate, sodium phosphate and sodium hydrogen phosphate; amines such as triethylamine and N,N-diisopropylethylamine; and alkali metal fluorides such as cesium fluoride and potassium fluoride.

Examples of catalyst 1 include palladium catalysts such as palladium(II) acetate, dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium, dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium dichloromethane adduct, tris( dibenzylideneacetone)dipalladium(0), tetrakistriphenylphosphinepalladium and bis(triphenylphosphine)palladium dichloride.

Examples of the organic phosphine compound include triarylphosphines such as triphenylphosphine and tri(o-tolyl)phosphine; trialkylphosphines such as tri-tert-butylphosphine and tricyclohexylphosphine; and bidentate phosphines such as 1,1'-bis(diphenylphosphino)ferrocene and 4,5'-bis(diphenylphosphino)-9,9'-dimethylxanthene.

Examples of catalyst 2 include copper(I) iodide and iron(III) acetylacetonate.

The amount of Compound (I-G-1'-20) used may be 1.0-5.0 mole equivalents, preferably 2.0-3.0 mole equivalents, relative to Compound (I-G-1'-21).

The amount of base used may be 1.0-5.0 mole equivalents, preferably 1.0-2.0 mole equivalents, relative to Compound (I-G-1'-21).

The amount of catalyst 1 used may be 0.01-1.0 mole equivalents, preferably 0.01-0.1 mole equivalents, relative to Compound (I-G-1'-21).

The amount of organic phosphine compound used may be 0.01-1.0 mole equivalents, preferably 0.01-0.1 mole equivalents, relative to Compound (I-G-1'-21).

The amount of catalyst 2 used may be 0.01-1.0 mole equivalents, preferably 0.01-0.1 mole equivalents, relative to Compound (I-G-1'-21).

The reaction can be carried out at room temperature to elevated, for example at room temperature to 200°C, preferably at room temperature to 100°C.

Stage 2

Compound (I-G-1'-19) is reacted with a catalyst in a solvent and under a hydrogen atmosphere to give Compound (I-G-1'-18).

Any solvents that do not interfere with the reaction may be used, and examples thereof include ethers such as tetrahydrofuran and dioxane; alcohols such as methanol, ethanol and isopropanol; aromatic hydrocarbons such as toluene; nitriles such as acetonitrile; carboxylic acids such as acetic acid; water; and their mixtures.

Examples of the catalyst include palladium on carbon.

The amount of catalyst used may be 0.01-20.0 mole equivalents, preferably 0.01-10.0 mole equivalents, relative to Compound (I-G-1'-19).

The reaction can be carried out at room temperature to elevated, for example at room temperature to 100°C, preferably at room temperature.

Stage 3

Compound (I-G-1'-18) is reacted with a base and Compound (I-G-1'-17) in a solvent to give Compound (I-G-1'-16).

Any solvents that do not interfere with the reaction may be used, and examples thereof include ethers such as tetrahydrofuran and dioxane; alcohols such as methanol, ethanol and isopropanol; aromatic hydrocarbons such as toluene; nitriles such as acetonitrile; water; and their mixtures.

Examples of bases include alkali metal hydrogen carbonates such as sodium hydrogen carbonate; alkali metal carbonates such as potassium carbonate; inorganic bases such as alkali metal hydroxides such as sodium hydroxide.

The amount of Compound (I-G-1'-17) used may be 1.0-5.0 molar equivalents, preferably 2.0-3.0 molar equivalents, relative to Compound (I-G-1'-18).

The amount of base used may be 1.0-5.0 mole equivalents, preferably 2.0-3.0 mole equivalents, relative to Compound (I-G-1'-18).

The reaction can be carried out at room temperature to elevated, for example at room temperature to 100°C, preferably at room temperature to 60°C.

Stage 4

Compound (I-G-1'-16) is reacted with Compound (I-G-1'-15) in a solvent and in the presence of a base to give Compound (I-G-1'-7).

Any solvents that do not interfere with the reaction can be used, and examples include amides such as N,N-dimethylformamide; ethers such as tetrahydrofuran and dioxane; halogenated aliphatic hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as toluene; nitriles such as acetonitrile; carboxylic acids such as acetic acid; water; and their mixtures.

Examples of bases include alkali metal hydrogen carbonates such as sodium hydrogen carbonate; alkali metal carbonates such as potassium carbonate; inorganic bases such as alkali metal hydroxides such as sodium hydroxide; alkylamines such as triethylamine and N,N-diisopropylethylamine; and organic bases such as pyridines such as pyridine and 4-dimethylaminopyridine.

The amount of Compound (I-G-1'-15) used may be 1.0-5.0 mole equivalents, preferably 1.0-2.0 mole equivalents, relative to Compound (I-G-1'-16).

The amount of base used may be 1.0-5.0 mole equivalents, preferably 2.0-3.0 mole equivalents, relative to Compound (I-G-1'-16).

The reaction can be carried out at room temperature to elevated, for example at room temperature to 100°C, preferably at room temperature.

How to obtain H

Of the compounds having formula (I), Compound (IH) wherein R ¹ is each a hydrogen atom, X ¹ is -NG ¹¹ -SO ₂ -, X ² is -SO ₂ -NG ¹² -, Y ¹ represents -NG ²¹ -, and Y ² represents -NG ²² -, can be obtained according to, for example, the following scheme.

where P ¹¹ is a protecting group such as a benzyloxycarbonyl group; and the rest of the characters have the same meanings as above.

Stage 1

Compound (I-H-7) can be obtained in the same manner as Compound (I-A-2).

Compound (I-H-6) may be a commercially available substance, or may be obtained by known methods from commercially available substances.

Compound (I-H-7) is reacted with Compound (I-H-6) in a solvent and in the presence of an azodicarboxylic acid derivative and a phosphine derivative to give Compound (I-H-5).

Any solvents that do not interfere with the reaction may be used, and examples thereof include ethers such as tetrahydrofuran and dioxane; aromatic hydrocarbons such as toluene; nitriles such as acetonitrile; and their mixtures.

Examples of the azodicarboxylic acid derivative include azodicarboxylic acid dialkyl esters such as diethyl azodicarboxylate and diisopropyl azodicarboxylate; and azodicarboxamides such as 1,1'-azobis(N,N-dimethylformamide).

Examples of the phosphine derivative include triarylphosphines such as triphenylphosphine; and trialkylphosphines such as tributylphosphine.

The amount of Compound (I-H-6) used may be 2.0-5.0 molar equivalents, preferably 2.0-3.0 molar equivalents, relative to Compound (I-H-7).

The amount of azodicarboxylic acid derivative used may be 2.0-6.0 mole equivalents, preferably 2.0-5.0 mole equivalents, relative to Compound (I-H-7).

The amount of phosphine derivative used may be 2.0-6.0 mole equivalents, preferably 2.0-5.0 mole equivalents, relative to Compound (I-H-7).

The reaction can be carried out at room temperature to elevated, for example at room temperature to 100°C, preferably at room temperature.

Stage 2

Compound (I-H-5) can be reacted in a manner similar to Step 5-2 of Production Method A to give Compound (I-H-4).

Stage 3

Compound (I-H-3) may be a commercially available substance, or may be obtained by known methods from commercially available substances.

Compound (I-H-4) is reacted with Compound (I-H-3) in a solvent and in the presence of an azodicarboxylic acid derivative and a phosphine derivative to give Compound (I-H-2).

Any solvents that do not interfere with the reaction may be used, and examples thereof include ethers such as tetrahydrofuran and dioxane; aromatic hydrocarbons such as toluene; nitriles such as acetonitrile; and their mixtures.

Examples of the azodicarboxylic acid derivative include azodicarboxylic acid dialkyl esters such as diethyl azodicarboxylate and diisopropyl azodicarboxylate; and azodicarboxamides such as 1,1'-azobis(N,N-dimethylformamide).

Examples of the phosphine derivative include triarylphosphines such as triphenylphosphine; and trialkylphosphines such as tributylphosphine.

The amount of Compound (I-H-3) used may be 2.0-5.0 molar equivalents, preferably 2.0-3.0 molar equivalents, relative to Compound (I-H-4).

The amount of azodicarboxylic acid derivative used may be 2.0-6.0 mole equivalents, preferably 2.0-5.0 mole equivalents, relative to Compound (I-H-4).

The amount of phosphine derivative used may be 2.0-6.0 mole equivalents, preferably 2.0-5.0 mole equivalents, relative to Compound (I-H-4).

The reaction can be carried out at room temperature to elevated, for example at room temperature to 100°C, preferably at room temperature.

Stage 4-1

Compound (I-H-2) can be reacted in a manner similar to Step 2 of Production Method G-3 to give Compound (I-H-1).

Stage 4-2

Compound (I-H-1) can be converted to the hydrochloride, if necessary.

For example, Compound (I-H-1) can be reacted with a solution of hydrogen chloride in cyclopentyl methyl ether or with a solution of hydrogen chloride in dioxane to convert it to the hydrochloride.

When the reaction is followed by deprotection of the tert-butoxycarbonyl groups in G ²¹ and G ²² in Compound (IH-1), the amount of hydrogen chloride used may be 10-150 mole equivalents, preferably 20-100 mole equivalents, relative to Compound (IH-1).

The reaction can be carried out at room temperature to elevated, for example at room temperature to 100°C, preferably at room temperature.

Stage 5

Compound (I-H-1) can be reacted with cyanamide in a solvent and in the presence of an acid to give Compound (I-H).

Any solvents that do not interfere with the reaction may be used, and examples thereof include ethers such as tetrahydrofuran and dioxane; alcohols such as methanol, ethanol, isopropanol and t-butanol; aromatic hydrocarbons such as toluene; nitriles such as acetonitrile; carboxylic acids such as acetic acid; water; and their mixtures.

Examples of the acid include a solution of hydrogen chloride in dioxane and a solution of hydrogen chloride in cyclopentyl methyl ether.

The amount of cyanamide used may be 3.0-15.0 mole equivalents, preferably 3.0-10.0 mole equivalents, relative to Compound (I-H-1).

The amount of acid used may be 2.0-15.0 mole equivalents, preferably 2.0-10.0 mole equivalents, relative to Compound (I-H-1).

The reaction can be carried out at room to elevated temperature, for example at room temperature to 100°C, preferably at 50 to 100°C.

Production Method I

Of the compounds having formula (I), Compound (II) wherein each R ¹ is a hydrogen atom, X ^1' is -NG ^Z -SO ₂ -, X ^2' is -SO ₂ -NG ^Z -, Y ^1' is -NG ²¹ H and Y ^2' is HNG ²² - can be obtained according to, for example, the following scheme.

where P ¹² is a protecting group such as a benzyloxycarbonyl group; P ¹³ is a protecting group such as t-butoxycarbonyl group; and the rest of the characters have the same meanings as above.

Stage 1

Compound (I-I-8) is reacted with Compound (I-I-7) in a solvent and in the presence of a base to give Compound (I-I-6).

Any solvents that do not interfere with the reaction can be used, and examples include amides such as N,N-dimethylformamide; ethers such as tetrahydrofuran and dioxane; halogenated aliphatic hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as toluene; nitriles such as acetonitrile; and their mixtures.

Examples of bases include alkylamines such as triethylamine and N,N-diisopropylethylamine; and organic bases such as pyridines such as pyridine and 4-dimethylaminopyridine, and 1,8-diazabicyclo[5.4.0]-7-undecene.

The amount of Compound (I-I-7) used can be 1.0-5.0 mole equivalents, preferably 1.0-3.0 mole equivalents, relative to Compound (I-I-8).

The amount of base used may be 2.0-5.0 mole equivalents, preferably 2.5-3.5 mole equivalents, relative to Compound (I-I-8).

The reaction can be carried out at room temperature to elevated, for example at room temperature to 100°C, preferably at room temperature.

Stage 2

Compound (I-I-6) can be reacted in a manner similar to Step 5-2 of Production Method A to give Compound (I-I-5).

Stage 3

Compound (I-I-5) and Compound (I-I-4) can be reacted in a manner similar to Step 3 of Production Method H to give Compound (I-I-3).

Stage 4

Compound (I-I-3) can be reacted in a manner similar to Step 2 of Production Method G-3 to give Compound (I-I-2).

Stage 5

Compound (I-I-2) can be reacted in a manner similar to Step 4-2 of Production Method H to give Compound (I-I-1).

Stage 6

Compound (I-I-1) can be reacted in a manner similar to Step 5 of Production Method H to give Compound (I-I).

Preparation method I-1 (preparation of an intermediate)

Compound (I-I-8) can be obtained according to, for example, the following scheme.

where the symbols have the meanings given above.

Compound (I-I-9) may be the same compound as Compound (I-A-6).

Compound (I-I-10) is reacted with Compound (I-I-9) in a solvent and in the presence of an azodicarboxylic acid derivative and a phosphine derivative to give Compound (I-I-8).

Any solvents that do not interfere with the reaction may be used, and examples thereof include ethers such as tetrahydrofuran and dioxane; aromatic hydrocarbons such as toluene; nitriles such as acetonitrile; and their mixtures.

Examples of the azodicarboxylic acid derivative include azodicarboxylic acid dialkyl esters such as diethyl azodicarboxylate and diisopropyl azodicarboxylate; and azodicarboxamides such as 1,1'-azobis(N,N-dimethylformamide).

Examples of the phosphine derivative include triarylphosphines such as triphenylphosphine; and trialkylphosphines such as tributylphosphine.

The amount of Compound (I-I-9) used may be 0.3-0.5 mole equivalents, preferably 0.4-0.5 mole equivalents, relative to Compound (I-I-10).

The amount of azodicarboxylic acid derivative used may be 1.0-3.0 mole equivalents, preferably 1.0-2.0 mole equivalents, relative to Compound (I-I-10).

The amount of phosphine derivative used may be 1.0-3.0 mole equivalents, preferably 1.0-2.0 mole equivalents, relative to Compound (I-I-10).

The reaction can be carried out at room temperature to elevated, for example at room temperature to 100°C, preferably at room temperature.

Preparation method I-2 (preparation of intermediate compound)

Among the Compounds (II-10), the Compound (II-10'), where P ¹² represents a benzyloxycarbonyl group, can be obtained according to, for example, the following scheme.

where the symbols have the meanings given above.]

Compound (I-I-11) may be a commercially available substance, or may be obtained by known methods from commercially available substances. Also, Compound (I-I-11) may be in the form of a salt such as a hydrochloride.

Compound (I-I-11) can be reacted with chlorosulfonyl isocyanate (CSI) and benzyl alcohol (BnOH) in a solvent and in the presence of a base to give Compound (I-I-10').

Any solvents that do not interfere with the reaction can be used, and examples include amides such as N,N-dimethylformamide; ethers such as tetrahydrofuran and dioxane; halogenated aliphatic hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as toluene; nitriles such as acetonitrile; and their mixtures.

Examples of bases include alkylamines such as triethylamine and N,N-diisopropylethylamine; and organic bases such as pyridines such as pyridine and 4-dimethylaminopyridine, and 1,8-diazabicyclo[5.4.0]-7-undecene.

The amount of base used may be 1.0-5.0 mole equivalents, preferably 2.0-3.0 mole equivalents, relative to Compound (I-I-11).

The amount of chlorosulfonyl isocyanate used may be 1.0-3.0 mole equivalents, preferably 1.0-1.5 mole equivalents, relative to Compound (I-I-11).

The amount of benzyl alcohol used may be 1.0-3.0 mole equivalents, preferably 1.0-1.5 mole equivalents, relative to Compound (I-I-11).

The reaction can be carried out at room temperature to elevated, for example at room temperature to 100°C, preferably at room temperature.

Method of obtaining J

Of the compounds having formula (I), Compound (IJ) wherein X ¹ is -C(=O)-, X ² is -C(=O)-, Y ¹ is -NG ²¹ -L ³ -O-, and Y ² is -OL ³ -NG ²² - can be obtained according to, for example, the following scheme.

where L ⁴ represents a C ₁ -C ₄ alkylene group; P ¹⁴ and P ¹⁵ are each independently a protecting group such as a benzyl group; u is an integer from 0 to 3; and the rest of the characters have the same meanings as above.

Stage 1

Compound (I-J-7) may be the same compound as Compound (I-G-1).

Compound (I-J-8) is reacted with Compound (I-J-7) in a solvent, with or without a base, and in the presence of a condensing agent to give Compound (I-J-6).

Any solvents that do not interfere with the reaction can be used, and examples include amides such as N,N-dimethylformamide; ethers such as tetrahydrofuran and dioxane; halogenated aliphatic hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as toluene; nitriles such as acetonitrile; carboxylic acids such as acetic acid; water; and their mixtures.

Examples of bases include alkali metal carbonates such as cesium carbonate, potassium carbonate, sodium carbonate and sodium hydrogen carbonate; alkali metal phosphates such as tribasic potassium phosphate, sodium phosphate and sodium hydrogen phosphate; amines such as triethylamine and N,N-diisopropylethylamine; and alkali metal fluorides such as cesium fluoride and potassium fluoride.

Examples of the condensing agent include O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, (1-cyano-2-ethoxy -2-oxoethylideneaminooxy)dimethylamino(morpholino)carbenium hexafluorophosphate (COMU) and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride.

The amount of Compound (I-J-7) used may be 1.0-3.0 molar equivalents, preferably 1.0-2.0 molar equivalents, relative to Compound (I-J-8).

The amount of base used may be 1.0-5.0 mole equivalents, preferably 2.0-4.0 mole equivalents, relative to Compound (I-J-8).

The amount of condensing agent used may be 1.0-5.0 mole equivalents, preferably 1.0-3.0 mole equivalents, relative to Compound (I-J-8).

The reaction can be carried out at room temperature to elevated, for example at room temperature to 100°C, preferably at room temperature.

Stage 2

Compound (I-J-6) can be reacted in a manner similar to Step 5-2 of Production Method A to give Compound (I-J-5).

Stage 3

Compound (I-J-4) may be a commercially available substance, or may be obtained by known methods from commercially available substances.

Compound (I-J-5) is reacted with Compound (I-J-4) in a solvent and in the presence of an azodicarboxylic acid derivative and a phosphine derivative to give Compound (I-J-3).

Any solvents that do not interfere with the reaction may be used, and examples thereof include ethers such as tetrahydrofuran and dioxane; halogenated aliphatic hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as toluene; nitriles such as acetonitrile; and their mixtures.

Examples of the azodicarboxylic acid derivative include azodicarboxylic acid dialkyl esters such as diethyl azodicarboxylate and diisopropyl azodicarboxylate; and azodicarboxamides such as 1,1'-azobis(N,N-dimethylformamide).

Examples of the phosphine derivative include triarylphosphines such as triphenylphosphine; and trialkylphosphines such as tributylphosphine.

The amount of Compound (I-J-4) used may be 1.0-5.0 mole equivalents, preferably 1.0-2.0 mole equivalents, relative to Compound (I-J-5).

The amount of azodicarboxylic acid derivative used may be 1.0-5.0 mole equivalents, preferably 1.0-3.0 mole equivalents, relative to Compound (I-J-5).

The amount of phosphine derivative used may be 1.0-5.0 mole equivalents, preferably 1.0-3.0 mole equivalents, relative to Compound (I-J-5).

The reaction can be carried out at room temperature to elevated, for example at room temperature to 100°C, preferably at room temperature.

Stage 4

Compound (I-J-3) can be reacted in a manner similar to Step 5-2 of Production Method A to give Compound (I-J-2).

Stage 5

Compound (I-J-1) may be the same compound as Compound (I-J-5).

Compound (I-J-2) is reacted with Compound (I-J-1) in a solvent and in the presence of an azodicarboxylic acid derivative and a phosphine derivative to give Compound (I-J). The compound (I-J) may also be in the form of a salt such as a hydrochloride.

Any solvents that do not interfere with the reaction may be used, and examples thereof include ethers such as tetrahydrofuran and dioxane; halogenated aliphatic hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as toluene; nitriles such as acetonitrile; and their mixtures.

Examples of the azodicarboxylic acid derivative include azodicarboxylic acid dialkyl esters such as diethyl azodicarboxylate and diisopropyl azodicarboxylate; and azodicarboxamides such as 1,1'-azobis(N,N-dimethylformamide).

Examples of the phosphine derivative include triarylphosphines such as triphenylphosphine; and trialkylphosphines such as tributylphosphine.

The amount of Compound (I-J-1) used may be 1.0-5.0 molar equivalents, preferably 1.0-2.0 molar equivalents, relative to Compound (I-J-2).

The amount of azodicarboxylic acid derivative used may be 1.0-5.0 mole equivalents, preferably 1.0-3.0 mole equivalents, relative to Compound (I-J-2).

The amount of phosphine derivative used may be 1.0-5.0 mole equivalents, preferably 1.0-3.0 mole equivalents, relative to Compound (I-J-2).

The reaction can be carried out at room temperature to elevated, for example at room temperature to 100°C, preferably at room temperature.

Stage 6

The protecting groups present in the Compound (I-J) can be removed. For example, Compound (I-J) can be reacted in a manner similar to Step 5-1 of Production Method A or Step 2 of Production Method D-1 to remove a protecting group such as a t-butoxycarbonyl group and a 2-trimethylsilylethyl group.

Production method J-1 (preparation of an intermediate)

Among Compounds (IJ-8), Compound (IJ-8') containing a COOR ⁴ group, where R ⁴ is a 2-trimethylsilylethyl group, can be obtained according to, for example, the following scheme.

where L ⁵ represents a single bond or a C ₁ -C ₃ alkylene group; R ¹⁰ represents a methyl group or an ethyl group; v is an integer from 0 to 2; P ¹⁶ is a protecting group such as t-butoxycarbonyl group; and the rest of the characters have the same meanings as above.

Stage 1

Compound (I-J-8'-7) and Compound (I-J-8'-8) may be commercially available substances, or may be obtained from commercially available substances by known methods, or may also be in the form of a salt such as hydrochloride.

Compound (I-J-8'-8) is reacted with Compound (I-J-8'-7) in a solvent, in the presence of a base, in the presence of an acid, and in the presence of a reducing agent, to give Compound (I-J-8'-6).

Any solvents that do not interfere with the reaction can be used, and examples include amides such as N,N-dimethylformamide; halogenated aliphatic hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as toluene; nitriles such as acetonitrile; and their mixtures.

Examples of bases include alkali metal carbonates such as cesium carbonate, potassium carbonate, sodium carbonate and sodium hydrogen carbonate; alkali metal phosphates such as tribasic potassium phosphate, sodium phosphate and sodium hydrogen phosphate; alkylamines such as triethylamine and N,N-diisopropylethylamine; organic bases such as pyridines such as pyridine and 4-dimethylaminopyridine and 1,8-diazabicyclo[5.4.0]-7-undecene; and alkali metal fluorides such as cesium fluoride and potassium fluoride.

Examples of the acid include acetic acid.

Examples of the reducing agent include sodium triacetoxyborohydride and sodium borohydride.

The amount of Compound (I-J-8'-7) used may be 1.0-5.0 mole equivalents, preferably 1.0-3.0 molar equivalents, relative to Compound (I-J-8'-8).

The amount of base used may be 1.0-5.0 mole equivalents, preferably 2.0-4.0 mole equivalents, relative to the Compound (I-J-8'-8).

The amount of acid used may be 1.0-5.0 mole equivalents, preferably 2.0-4.0 mole equivalents, relative to the Compound (I-J-8'-8).

The amount of reducing agent used may be 1.0-5.0 mole equivalents, preferably 2.0-4.0 mole equivalents, relative to the Compound (I-J-8'-8).

The reaction can be carried out at room temperature to elevated, for example at room temperature to 150°C, preferably at room temperature.

Stage 2

Compound (I-J-8'-5) and Compound (I-J-8'-6) can be reacted in a manner similar to Step 1 of Preparation Method I to give Compound (I-J-8'-4).

Stage 3

Compound (I-J-8'-4) can be reacted with a base or acid in a solvent to give Compound (I-J-8'-3).

Any solvents that do not interfere with the reaction may be used, and examples thereof include ethers such as tetrahydrofuran and dioxane; alcohols such as methanol, ethanol and isopropanol; water; and their mixtures.

Examples of bases include sodium hydroxide.

Examples of the acid include hydrochloric acid.

The amount of base used may be 1.0-10.0 mole equivalents, preferably 2.0-5.0 mole equivalents, relative to Compound (I-J-8'-4).

The amount of acid used may be 1.0-10.0 mole equivalents, preferably 2.0-5.0 mole equivalents, relative to the Compound (I-J-8'-4).

The reaction can be carried out at room temperature to elevated, for example at room temperature to 150°C, preferably at room temperature.

Stage 4

Compound (I-J-8'-3) is reacted with Compound (I-J-8'-2) in a solvent, with or without a base, and in the presence of a condensing agent to give Compound (I-J-8'-1).

Any solvents that do not interfere with the reaction can be used, and examples include amides such as N,N-dimethylformamide; ethers such as tetrahydrofuran and dioxane; halogenated aliphatic hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as toluene; nitriles such as acetonitrile; and their mixtures.

Examples of bases include alkali metal hydrogen carbonates such as sodium hydrogen carbonate; alkali metal carbonates such as potassium carbonate; inorganic bases such as alkali metal hydroxides such as sodium hydroxide; alkylamines such as triethylamine and N,N-diisopropylethylamine; and organic bases such as pyridines such as pyridine and 4-dimethylaminopyridine, and 1,8-diazabicyclo[5.4.0]-7-undecene.

Examples of the condensing agent include O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.

The amount of Compound (I-J-8'-2) used may be 1.0-5.0 molar equivalents, preferably 1.0-2.0 molar equivalents, relative to Compound (I-J-8'-3).

The amount of base used may be 0.1-3.0 mole equivalents, preferably 0.1-1.0 mole equivalents, relative to the Compound (I-J-8'-3).

The amount of condensing agent used may be 1.0-5.0 mole equivalents, preferably 1.0-2.0 mole equivalents, relative to the Compound (I-J-8'-3).

The reaction can be carried out at room temperature to elevated, for example at room temperature to 100°C, preferably at room temperature.

Stage 5

Compound (I-J-8'-1) can be reacted in a manner similar to Step 5-1 of Production Method A to give Compound (I-J-8').

The target compound obtained can be isolated or purified, if necessary, by combining, as appropriate, well-known methods such as recrystallization, precipitation, filtration, evaporation and drying, or methods commonly used in the isolation or purification of organic compounds (for example, column chromatography).

The compounds of the present invention and intermediates can be prepared according to the Preparation Methods described above, as well as the methods described below in the Examples and Comparative Examples. In addition, the compounds of the present invention and intermediates can be converted to other target compounds and intermediates by the Preparation Methods described above, the methods described in the Examples and Comparative Examples below, and/or known methods or a combination thereof. Examples of such methods include those described in items (1) to (5) below.

(1) Conversion of an alkoxycarbonyl group to a benzyloxycarbonyl group

A compound containing an alkoxycarbonyl group is reacted with benzyl alcohol by heating to convert it into a benzyloxycarbonyl group.

(2) Conversion of an alkoxycarbonyl group to a carboxyl group

A compound containing an alkoxycarbonyl group is reacted with a base (eg, sodium hydroxide) or an acid (eg, sulfuric acid) in a solvent (eg, tetrahydrofuran and methanol) to give a compound containing a carboxyl group.

(3) Conversion of a carboxyl group to an alkoxycarbonyl group

A compound containing a carboxyl group is reacted with an alcohol (eg, methanol and ethanol) in the presence of an acid (eg, sulfuric acid) or a base (eg, sodium hydroxide) to give an alkoxycarbonyl group-containing compound.

(4) Conversion of a carboxyl group to a benzyloxycarbonyl group

A compound containing a carboxyl group is reacted with benzyl alcohol in a solvent (eg chloroform), in the presence of an activating agent (eg 4-dimethylaminopyridine) and in the presence of a condensing agent (eg 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride) to give a compound containing a benzyloxycarbonyl group. Alternatively, a compound containing a carboxyl group is reacted with a benzyl halide (eg, benzyl bromide) in a solvent (eg, dimethylformamide) and in the presence of a base (eg, cesium carbonate) to give a compound containing a benzyloxycarbonyl group.

(5) Interesterification reaction of alkoxycarbonyl group

A compound containing an alkoxycarbonyl group is reacted with an alcohol (eg, methanol and ethanol) in the presence of an acid (eg, sulfuric acid) or a base (eg, sodium hydroxide) to give a compound containing another alkoxycarbonyl group.

In addition, other compounds of the present invention or intermediates can be obtained by using other starting compounds other than the starting compounds described in the Methods of Use above and below in Examples and Comparative Examples, and using the preparation methods described above, the methods described below in Examples and Comparative Examples, and/or known methods or combinations thereof.

Examples

Hereinafter, the present invention is illustrated in more detail using the compounds in Examples, Comparative Examples and Pharmacological Test Examples, or pharmaceutically acceptable salts thereof, according to embodiments of the present invention. These Examples are provided for a better understanding of the present invention and do not limit the scope of the present invention in any way.

"DIOL silica gel" in the description of silica gel column chromatography means CHROMATOREX (trade name) DIOL manufactured by Fuji Silysia Chemical Ltd.

"DNH silica gel" in the description of silica gel column chromatography means CHROMATOREX (trade name) DNH manufactured by Fuji Silysia Chemical Ltd.

"DUIS" in the description of the ionization mode in mass spectrometry means mixed mode of ESI and APCI.

Unless otherwise indicated, ¹ H-NMR data are given with chemical shifts (δ) relative to tetramethylsilane as an internal standard (0 ppm) and spin-spin coupling constants (J-value) in hertz (Hz). Signal multiplicity abbreviations: s: singlet, d: doublet, broad: broad, m: multiplet.

When a configuration is indicated in the name or structure of a compound in the following Examples or Comparative Examples, said compound is a compound having the configuration indicated in the Example or Comparative Example, its enanathiomer or diastereomer, or a mixture of enantiomers.

Abbreviations in the Examples, Comparative Examples and Chemical Structures have the meanings commonly used in organic chemistry and pharmaceuticals. In particular, the decoding of some abbreviations is given below.

Boc: tert-butoxycarbonyl group

Cbz: benzyloxycarbonyl group

t-Bu: tert-butyl group

Bn: benzyl group

Ns: 2-nitrobenzenesulfonyl group

TMS: trimethylsilyl group

TFA: trifluoroacetic acid

tert-: tertiary

n.: normality

M: molar concentration

COMU: (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino(morpholino)carbenium hexafluorophosphate

ESI: electrospray ionization

APCI: atmospheric pressure chemical ionization

Examples

Example 1

Example 1-(a)

Preparation of (2S,2'S)-tetra-tert-butyl 2,2'-((oxybis(ethane-2,1-diyl))bis((N-((benzyloxy)carbonyl)-N-(4-((4 -(2,3-bis(tert-butoxycarbonyl)guanidino)benzoyl)oxy)benzyl)sulfamoyl)azandiyl))disuccinate

Into a solution of (2S,2'S)-tetra-tert-butyl 2,2'-((oxybis(ethane-2,1-diyl))bis((N-((benzyloxy)carbonyl)sulfamoyl)azandiyl))disuccinate (10.74 d) obtained by the same procedure as described for Comparative Example 1-(d), in tetrahydrofuran (100 ml) in a 300 ml round bottom flask was added 4-(hydroxymethyl)phenyl 4-(2,3-bis(tert- butoxycarbonyl)guanidino)benzoate (11.52 g) prepared in the same manner as described for Comparative Example 1-(g), diisopropyl azodicarboxylate (1.9M solution in toluene) (12.60 ml) and triphenylphosphine (6.42 g) at room temperature in argon atmosphere with stirring, and the resulting mixture was stirred at room temperature for 1 hour. After completion of the reaction, the solution was evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (14.47 g) as a white foam.

Mass spectrum (DUIS, m/z): 962 [M+2H] ²⁺ .

¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ: 11.62 (s, 2H), 10.63 (s, 2H), 8.19-8.12 (m, 4H), 7.84-7.77 (m, 4H), 7.42-7.23 (m, 14H), 7.15-7.09 (m, 4H), 5.22-5.12 (m, 4H), 5.00-4.90 (m, 4H), 4.68 (dd, J = 6.3, 7.9 Hz, 2H), 3.75-3.60 (m, 2H), 3.58-3.44 (m, 4H), 3.39-3.26 (m, 2H), 2.87 (dd, J = 7.9, 16.6 Hz, 2H), 2.64 (dd, J = 6.3, 16.6 Hz, 2H ), 1.55 (s, 18H), 1.53 (s, 18H), 1.46 (s, 18H), 1.45 (s, 18H).

Example 1-(b)

Preparation of (2S,2'S)-2,2'-((oxybis(ethane-2,1-diyl))bis((N-(4-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl)azandiyl))succinic acid

In a solution of (2S,2'S)-tetra-tert-butyl 2,2'-((oxybis(ethane-2,1-diyl))bis((N-((benzyloxy)carbonyl)-N-(4-(( 4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoyl)oxy)benzyl)sulfamoyl)azandiyl))disuccinate (14.47g) obtained in Example 1-(a) in dichloromethane (80ml) in 500- trifluoroacetic acid (20 ml) was added to a milliliter round bottom flask at room temperature under argon with stirring, and the resulting mixture was stirred at room temperature for 24 hours. The reaction solution was evaporated under reduced pressure. Dichloromethane (40 ml) and trifluoroacetic acid (10 ml) were added to the evaporation residue, and the resulting mixture was stirred at room temperature for 2 hours. The reaction solution was evaporated under reduced pressure, reducing the volume to about 20 ml, diisopropyl ether (10 ml) was added, the precipitate formed was filtered off and dried under reduced pressure. To a solution of the obtained solid in tetrahydrofuran (80 ml)/water (40 ml) in a 200 ml round bottom flask was added 5% palladium on carbon (moisture content 54.28%, STD-type manufactured by NE CHEMCAT Corporation) (3.5 g) at room temperature. temperature in an argon atmosphere with stirring, and the resulting mixture was stirred at room temperature in a hydrogen atmosphere for 8 hours. After completion of the reaction, the precipitate formed was filtered off and washed with a tetrahydrofuran/water mixture. Tetrahydrofuran was distilled off under reduced pressure, acetonitrile was added to the resulting mixture to obtain a homogeneous solution, and then the resulting solution was lyophilized. The resulting residue was purified by preparative chromatography at medium pressure (ODS silica gel, elution solvent: water with 0.1% trifluoroacetic acid : acetonitrile with 0.1% trifluoroacetic acid), 10% aqueous ammonium acetate was added dropwise to the fractions with the target compound at room temperature with stirring, adjusting the pH to 4. The precipitate that formed was collected by filtration, washed with water and dried under reduced pressure to give the title Compound (5.86 g) as a white solid.

Mass Spectrum (ESI, m/z): 515 [M+2H] ²⁺ .

¹ H-NMR spectrum (400 MHz, DMSO-d ₆ + D ₂ O) δ: 7.87-7.77 (m, 4H), 7.28-7.18 (m, 8H), 7.07-6.99 (m, 4H), 4.51 ( dd, J = 5.0, 9.1 Hz, 2H), 4.22 (broad.d, J = 14.5 Hz, 2H), 4.14 (broad.d, J = 14.5 Hz, 2H), 3.89–3.20 (m, 8H), 2.96 (broad.dd, J = 9.1, 15.7 Hz, 2H), 2.64–2.31 (m, 2H).

Example 2

Example 2-(a)

Preparation of (2S,13S)-tetra-tert-butyl 3,12-bis(N-((benzyloxy)carbonyl)-N-(4-((4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoyl )hydroxy)benzyl)sulfamoyl)-6,9-dioxa-3,12-diazatetradecane-1,2,13,14-tetracarboxylate

To a solution of 4-(hydroxymethyl)phenyl 4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoate (2.67 g) prepared in the same manner as described for Comparative Example 1-(g), (2S,13S )-tetra-tert-butyl 3,12-bis(N-((benzyloxy)carbonyl)sulfamoyl)-6,9-dioxa-3,12-diazatetradecane-1,2,13,14-tetracarboxylate (2.70 g), prepared by the same procedure as described for Comparative Example 2-(c) and triphenylphosphine (2.05 g) in anhydrous tetrahydrofuran (20 ml) diisopropyl azodicarboxylate (1.9M solution in toluene) (4.15 ml) was added to a 200 ml round bottom flask at room temperature under argon atmosphere with stirring, and the resulting mixture was stirred at room temperature for 16 hours. After completion of the reaction, the solution was evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (4.68 g) as a white foam.

Mass Spectrum (ESI, m/z): 984 [M+2H] ²⁺ .

¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ: 11.63 (s, 2H), 10.64 (s, 2H), 8.19-8.12 (m, 4H), 7.84-7.75 (m, 4H), 7.43-7.23 (m, 14H), 7.15-7.09 (m, 4H), 5.20 (d, J = 11.9 Hz, 2H), 5.15 (d, J = 11.9 Hz, 2H), 5.10-4.87 (m, 4H), 4.68 ( dd, J = 6.2, 8.0 Hz, 2H), 3.79–3.63 (m, 2H), 3.61–3.43 (m, 8H), 3.42–3.27 (m, 2H), 2.90 (dd, J = 8.0, 16.7 Hz, 2H), 2.66 (dd, J = 6.2, 16.7 Hz, 2H), 1.55 (s, 18H), 1.53 (s, 18H), 1.45 (s, 36H).

Example 2-(b)

Preparation of (2S,13S)-3,12-bis(N-(4-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl)-6,9-dioxa-3,12-diazatetradecane-1,2,13,14 -tetracarboxylic acid trifluoroacetate

In a solution of (2S,13S)-tetra-tert-butyl 3,12-bis(N-((benzyloxy)carbonyl)-N-(4-((4-(2,3-bis(tert-butoxycarbonyl)guanidino) benzoyl)oxy)benzyl)sulfamoyl)-6,9-dioxa-3,12-diazatetradecane-1,2,13,14-tetracarboxylate (4.68 g) obtained in Example 2-(a) in anhydrous dichloromethane (15 ml ) in a 200 ml round bottom flask was added trifluoroacetic acid (5.00 ml) while cooling in an ice bath under argon atmosphere with stirring, and the resulting mixture was stirred at room temperature for 16 hours. The reaction solution was evaporated under reduced pressure. To a solution of the resulting evaporation residue in anhydrous dichloromethane (6 ml) was added trifluoroacetic acid (5.00 ml) at room temperature under argon atmosphere with stirring, the mixture was stirred at room temperature for 2 hours, and then the reaction solution was evaporated under reduced pressure. To a solution of the obtained evaporation residue in methanol (6 ml) was added 10% palladium-carbon (moisture content about 55%, manufactured by Tokyo Chemical Industry Co., Ltd.) (350 mg), the reaction system was filled with hydrogen, and then the resulting mixture was stirred at room temperature for 4 hours. After completion of the reaction, the atmosphere in the reaction system was changed to nitrogen, and the reaction solution was filtered through celite. The separated solid was washed with a mixture of methanol and acetonitrile (1:1 (v/v)), and the filtrate was evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (ODS silica gel, elution solvent: water with 0.1% trifluoroacetic acid: acetonitrile with 0.1% trifluoroacetic acid), and fractions with the title compound were freeze-dried to give the title Compound (1.65 g) in form of a white solid.

Mass Spectrum (ESI, m/z): 537 [M+2H] ²⁺ .

¹ H-NMR spectrum (400 MHz, DMSO-d ₆ + D ₂ O) δ: 8.20-8.14 (m, 4H), 7.47-7.38 (m, 8H), 7.26-7.21 (m, 4H), 4.61 ( dd, J = 5.6, 8.4 Hz, 2H), 4.11 (d, J = 15.1 Hz, 2H), 4.06 (d, J = 15.1 Hz, 2H), 3.64-3.24 (m, 12H), 2.96 (dd, J = 8.4, 16.6 Hz, 2H), 2.68 (dd, J = 5.6, 16.6 Hz, 2H).

Example 2-(c)

Preparation of (2S,13S)-3,12-bis(N-(4-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl)-6,9-dioxa-3,12-diazatetradecane-1,2,13,14 -tetracarboxylic acid

In a solution of (2S,13S)-3,12-bis(N-(4-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl)-6,9-dioxa-3,12-diazatetradecan-1,2,13, 14-tetracarboxylic acid trifluoroacetate (1.00 g) obtained in Example 2-(b), in a mixture of water (24.0 ml)/acetonitrile (6.00 ml) in a 100 ml round-bottom flask, saturated aqueous ammonium acetate was added with stirring, adjusting the pH up to 4.0. The resulting mixture was stirred at room temperature for 1 hour, the precipitate formed was filtered off and dried under reduced pressure to give the title Compound (756 mg) as a white solid.

Mass Spectrum (ESI, m/z): 537 [M+2H] ²⁺ .

¹ H-NMR spectrum (400 MHz, DMSO-d ₆ + D ₂ O) δ: 7.90-7.79 (m, 4H), 7.34-7.19 (m, 8H), 7.12-7.06 (m, 4H), 4.57- 4.47 (m, 2H), 4.26 (d, J = 14.9 Hz, 2H), 4.19 (d, J = 14.9 Hz, 2H), 3.66-3.12 (m, 12H), 3.00-2.87 (m, 2H), 2.59 -2.30 (m, 2H).

Example 3

Example 3-(a)

Preparation of (2S,16S)-tetra-tert-butyl 3,15-bis(N-((benzyloxy)carbonyl)-N-(4-((4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoyl )hydroxy)benzyl)sulfamoyl)-6,9,12-trioxa-3,15-diazaheptadecan-1,2,16,17-tetracarboxylate

To a solution of 4-(hydroxymethyl)phenyl 4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoate (1.68 g) prepared in the same manner as that described for Comparative Example 1-(g), (2S,16S )-tetra-tert-butyl 3,15-bis(N-((benzyloxy)carbonyl)sulfamoyl)-6,9,12-trioxa-3,15-diazaheptadecan-1,2,16,17-tetracarboxylate (1.69 g ) obtained by the same procedure as described for Comparative Example 3-(c), and triphenylphosphine (1.07 g) in tetrahydrofuran (30 ml) in a 200 ml round bottom flask was added diisopropyl azodicarboxylate (1.9M solution in toluene) (2.15 ml ) at room temperature under argon atmosphere with stirring, and the resulting mixture was stirred at room temperature for 2 hours. Additionally, triphenylphosphine (165 mg) and diisopropyl azodicarboxylate (1.9M solution in toluene) (330 μl) were added at room temperature, and the resulting mixture was stirred at room temperature for 1 hour. After completion of the reaction, the solution was evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate), and fractions with the title compound were evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: dichloroethane:ethyl acetate) to give the title Compound (3.21 g) as a white foam.

Mass spectrum (ESI, m/z): 1006 [M+2H] ²⁺ .

¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ: 11.63 (s, 2H), 10.64 (s, 2H), 8.19-8.13 (m, 4H), 7.85-7.77 (m, 4H), 7.43-7.22 (m, 14H), 7.15-7.08 (m, 4H), 5.19 (d, J = 12.2 Hz, 2H), 5.15 (d, J = 12.2 Hz, 2H), 5.08-4.89 (m, 4H), 4.68 ( dd, J = 6.1, 8.3 Hz, 2H), 3.80–3.67 (m, 2H), 3.63–3.49 (m, 12H), 3.40–3.25 (m, 2H), 2.91 (dd, J = 8.3, 16.8 Hz, 2H), 2.66 (dd, J = 6.1, 16.8 Hz, 2H), 1.55 (s, 18H), 1.53 (s, 18H), 1.45 (s, 36H).

Example 3-(b)

Preparation of (2S,16S)-3,15-bis(N-(4-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl)-6,9,12-trioxa-3,15-diazaheptadecan-1,2,16 ,17-tetracarboxylic acid trifluoroacetate

In a solution of (2S,16S)-tetra-tert-butyl 3,15-bis(N-((benzyloxy)carbonyl)-N-(4-((4-(2,3-bis(tert-butoxycarbonyl)guanidino) benzoyl)oxy)benzyl)sulfamoyl)-6,9,12-trioxa-3,15-diazaheptadecan-1,2,16,17-tetracarboxylate (300 mg) obtained in Example 3-(a) in dichloromethane (2.5 ml) in a 30-ml cylindrical flask was added trifluoroacetic acid (500 μl) at 0°C under argon atmosphere with stirring, and the resulting mixture was stirred at room temperature for 15 hours. The reaction solution was evaporated under reduced pressure. To a solution of the resulting evaporation residue in dichloromethane (1 ml) was added trifluoroacetic acid (1 ml) at room temperature, and the resulting mixture was stirred at room temperature for 3 hours. The reaction solution was evaporated under reduced pressure. To a solution of the resulting evaporation residue in methanol (3 ml) was added 5% palladium on carbon (moisture content 54.28%, STD-type manufactured by NE CHEMCAT Corporation) (106 mg), the reaction system was filled with hydrogen, and then the resulting mixture was stirred at room temperature within 30 minutes. After completion of the reaction, the solution was filtered through Celite, and the resulting filtrate was evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (ODS silica gel, elution solvent: water with 0.1% trifluoroacetic acid: acetonitrile with 0.1% trifluoroacetic acid), and fractions with the target compound were freeze-dried. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: acetonitrile with 0.1% trifluoroacetic acid: water with 0.1% trifluoroacetic acid), and fractions with the target compound were freeze-dried. A saturated aqueous solution of ammonium acetate was added to a solution of the obtained residue in a mixture of acetonitrile with 0.1% trifluoroacetic acid (3 ml)/water with 0.1% trifluoroacetic acid (3 ml), adjusting the pH to 4.0, and the resulting mixture was stirred at room temperature for 30 minutes. The reaction solution was evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: acetonitrile with 0.1% trifluoroacetic acid: water with 0.1% trifluoroacetic acid), and fractions with the title compound were freeze-dried to give the title Compound (78 mg) as white solid.

Mass Spectrum (ESI, m/z): 559 [M+2H] ²⁺ .

¹ H-NMR spectrum (400 MHz, DMSO-d ₆ + D ₂ O) δ: 8.21-8.13 (m, 4H), 7.47-7.38 (m, 8H), 7.28-7.19 (m, 4H), 4.65- 4.54 (m, 2H), 4.11 (d, J = 15.2 Hz, 2H), 4.06 (d, J = 15.2 Hz, 2H), 3.68-3.19 (m, 16H), 2.95 (dd, J = 8.3, 16.6 Hz , 2H), 2.75–2.63 (m, 2H).

Example 3-(c)

Preparation of (2S,16S)-3,15-bis(N-(4-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl)-6,9,12-trioxa-3,15-diazaheptadecan-1,2,16 ,17-tetracarboxylic acid hydrochloride

In a solution of (2S,16S)-tetra-tert-butyl 3,15-bis(N-((benzyloxy)carbonyl)-N-(4-((4-(2,3-bis(tert-butoxycarbonyl)guanidino) benzoyl)oxy)benzyl)sulfamoyl)-6,9,12-trioxa-3,15-diazaheptadecan-1,2,16,17-tetracarboxylate (6.77 g) prepared in the same manner as described for Example 3-( a), in dichloromethane (40 ml) in a 300 ml round bottom flask, trifluoroacetic acid (20 ml) was added at 0° C. under argon with stirring, and the resulting mixture was stirred at room temperature for 15 hours. The reaction solution was evaporated under reduced pressure. To a solution of the resulting evaporation residue in a mixture of tetrahydrofuran (45 ml)/water (15 ml) was added 5% palladium on carbon (moisture content 54.28%, STD-type manufactured by NE CHEMCAT Corporation) (1.20 g), the reaction system was filled with hydrogen, and then the resulting mixture was stirred at room temperature for 2 hours. After completion of the reaction, the solution was filtered through Celite, and the resulting filtrate was evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: acetonitrile with 0.1% trifluoroacetic acid: water with 0.1% trifluoroacetic acid), and fractions with the target compound were evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (ODS silica gel, elution solvent: water with 0.1% trifluoroacetic acid: acetonitrile with 0.1% trifluoroacetic acid), and fractions with the target compound were freeze-dried. A solution of the resulting residue in 0.1N. hydrochloric acid solution (168 ml) was lyophilized to give the title Compound (1.36 g) as a white solid.

Mass Spectrum (ESI, m/z): 559 [M+2H] ²⁺ .

¹ H-NMR spectrum (400 MHz, DMSO-d ₆ + D ₂ O) δ: 8.21-8.13 (m, 4H), 7.48-7.38 (m, 8H), 7.27-7.20 (m, 4H), 4.60 ( dd, J = 5.5, 8.4 Hz, 2H), 4.11 (d, J = 15.4 Hz, 2H), 4.06 (d, J = 15.4 Hz, 2H), 3.71–3.21 (m, 16H), 2.96 (dd, J = 8.4, 16.6 Hz, 2H), 2.73-2.65 (m, 2H).

Example 4

Example 4-(a)

Preparation of (2S,19S)-tetra-tert-butyl 3,18-bis(N-((benzyloxy)carbonyl)-N-(4-((4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoyl )hydroxy)benzyl)sulfamoyl)-6,9,12,15-tetraoxa-3,18-diazaicosan-1,2,19,20-tetracarboxylate

Into a solution of (2S,19S)-tetra-tert-butyl 3,18-bis(N-((benzyloxy)carbonyl)sulfamoyl)-6,9,12,15-tetraoxa-3,18-diazaicosan-1,2, 19,20-tetracarboxylate (1.30 g) prepared in the same manner as that described for Comparative Example 4-(c), 4-(hydroxymethyl)phenyl 4-(2,3-bis(t-butoxycarbonyl)guanidino)benzoate ( 1.31 g) obtained by the same procedure as described for Comparative Example 1-(g) and triphenylphosphine (0.88 g) in tetrahydrofuran (20 ml) in a 100 ml round bottom flask was added diisopropyl azodicarboxylate (1.9M solution in toluene) ( 1.80 ml) at room temperature under argon flow with stirring, and the resulting mixture was stirred at room temperature for 2 hours. After completion of the reaction, the solution was evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (2.00 g) as a white foam.

Mass spectrum (ESI, m/z): 1028 [M+2H] ²⁺ .

¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ: 11.61 (s, 2H), 10.64 (s, 2H), 8.19-8.12 (m, 4H), 7.84-7.77 (m, 4H), 7.43-7.21 (m, 14H), 7.15-7.09 (m, 4H), 5.19 (d, J = 12.1 Hz, 2H), 5.15 (d, J = 12.1 Hz, 2H), 5.03-4.89 (m, 4H), 4.68 ( dd, J = 6.0, 8.3 Hz, 2H), 3.78–3.67 (m, 2H), 3.65–3.51 (m, 16H), 3.39–3.27 (m, 2H), 2.91 (dd, J = 8.3, 16.7 Hz, 2H), 2.66 (dd, J = 6.0, 16.7 Hz, 2H), 1.55 (s, 18H), 1.53 (s, 18H), 1.45 (s, 36H).

Example 4-(b)

Preparation of (2S,19S)-3,18-bis(N-(4-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl)-6,9,12,15-tetraoxa-3,18-diazaicosan-1,2 ,19,20-tetracarboxylic acid trifluoroacetate

In a solution of (2S,19S)-tetra-tert-butyl 3,18-bis(N-((benzyloxy)carbonyl)-N-(4-((4-(2,3-bis(tert-butoxycarbonyl)guanidino) benzoyl)oxy)benzyl)sulfamoyl)-6,9,12,15-tetraoxa-3,18-diazaicosan-1,2,19,20-tetracarboxylate (2.00 g) obtained in Example 4-(a) in dichloromethane (15 ml) in a 50 ml round bottom flask was added trifluoroacetic acid (15 ml) at room temperature under argon with stirring, and the resulting mixture was stirred at room temperature for 90 hours. The reaction solution was evaporated under reduced pressure. The evaporation residue was dissolved in dichloromethane (15 ml), trifluoroacetic acid (15 ml) was added and the resulting mixture was stirred at room temperature for 4 hours. The reaction solution was evaporated under reduced pressure. To a solution of the obtained evaporation residue in methanol (20 ml) was added 5% palladium on carbon (moisture content 54.28%, STD-type manufactured by NE CHEMCAT Corporation) (1.03 g) at room temperature under argon atmosphere with stirring, and the resulting mixture was stirred at room temperature in a hydrogen atmosphere for 2 hours. After completion of the reaction, the solution was filtered through celite, washed with methanol, and the resulting filtrate was evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (ODS silica gel, elution solvent: water with 0.1% trifluoroacetic acid: acetonitrile with 0.1% trifluoroacetic acid), and fractions with the target compound were freeze-dried to give the title Compound (710 mg) in form of a white solid.

Mass spectrum (ESI, m/z): 1161 [M+H] ⁺ .

¹ H-NMR spectrum (400 MHz, DMSO-d ₆ + D ₂ O) δ: 8.20-8.13 (m, 4H), 7.47-7.38 (m, 8H), 7.27-7.20 (m, 4H), 4.60 ( dd, J = 5.5, 8.4 Hz, 2H), 4.11 (d, J = 15.3 Hz, 2H), 4.06 (d, J = 15.3 Hz, 2H), 3.66-3.22 (m, 20H), 2.96 (dd, J = 8.4, 16.6 Hz, 2H), 2.74-2.64 (m, 2H).

Example 4-(c)

Preparation of (2S,19S)-3,18-bis(N-(4-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl)-6,9,12,15-tetraoxa-3,18-diazaicosan-1,2 ,19,20-tetracarboxylic acid hydrochloride

(2S,19S)-3,18-bis(N-(4-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl)-6,9,12,15-tetraoxa-3,18-diazaicosan-1,2, 19,20-tetracarboxylic acid trifluoroacetate (4.60 g) prepared in the same manner as described for Example 4-(b) in a 1000 ml round bottom flask was dissolved in acetonitrile (40 ml) and 0.1M hydrochloric acid solution (150 ml) , and the resulting solution was lyophilized to give the title Compound (4.02 g) as a white solid.

Mass spectrum (ESI, m/z): 1161 [M+H] ⁺ .

¹ H-NMR spectrum (400 MHz, DMSO-d ₆ + D ₂ O) δ: 8.20-8.14 (m, 4H), 7.47-7.39 (m, 8H), 7.26-7.20 (m, 4H), 4.60 ( dd, J = 5.4, 8.5 Hz, 2H), 4.12 (d, J = 15.3 Hz, 2H), 4.06 (d, J = 15.3 Hz, 2H), 3.77-3.21 (m, 20H), 2.96 (dd, J = 8.5, 16.7 Hz, 2H), 2.69 (dd, J = 5.4, 16.7 Hz, 2H).

Example 5

Example 5-(a)

Preparation of (2S,22S)-tetra-tert-butyl 3,21-bis(N-((benzyloxy)carbonyl)-N-(4-((4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoyl )oxy)benzyl)sulfamoyl)-6,9,12,15,18-pentaoxa-3,21-diazatricosan-1,2,22,23-tetracarboxylate

Into a solution of (2S,22S)-tetra-tert-butyl 3,21-bis(N-((benzyloxy)carbonyl)sulfamoyl)-6,9,12,15,18-pentaoxa-3,21-diazatricosan-1, 2,22,23-tetracarboxylate (443 mg) obtained in Comparative Example 5-(c), 4-(hydroxymethyl)phenyl 4-(2,3-bis(t-butoxycarbonyl)guanidino)benzoate (390 mg) obtained diisopropyl azodicarboxylate (1.9M solution in toluene) (0.450 ml) was added in a 100 ml round bottom flask using the same procedure as described for Comparative Example 1-(g) and triphenylphosphine (225 mg) in tetrahydrofuran (10 ml) at room temperature temperature under argon atmosphere with stirring, and the resulting mixture was stirred at room temperature for 30 minutes. After completion of the reaction, the solution was evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (591 mg) as a white foam.

Mass spectrum (ESI, m/z): 2121 [M+Na] ⁺ .

¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ: 11.63 (s, 2H), 10.64 (s, 2H), 8.19-8.12 (m, 4H), 7.85-7.77 (m, 4H), 7.42-7.21 (m, 14H), 7.15-7.09 (m, 4H), 5.19 (d, J = 12.0 Hz, 2H), 5.15 (d, J = 12.0 Hz, 2H), 4.97 (d, J = 16.1 Hz, 2H) , 4.94 (d, J = 16.1 Hz, 2H), 4.68 (dd, J = 6.0, 8.2 Hz, 2H), 3.78–3.47 (m, 22H), 3.38–3.26 (m, 2H), 2.91 (dd, J = 8.2, 16.7 Hz, 2H), 2.66 (dd, J = 6.0, 16.7 Hz, 2H), 1.55 (s, 18H), 1.53 (s, 18H), 1.45 (s, 36H).

Example 5-(b)

Preparation of (2S,22S)-3,21-bis(N-(4-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl)-6,9,12,15,18-pentaoxa-3,21-diazatricosan-1 ,2,22,23-tetracarboxylic acid trifluoroacetate

In a solution of (2S,22S)-tetra-tert-butyl 3,21-bis(N-((benzyloxy)carbonyl)-N-(4-((4-(2,3-bis(tert-butoxycarbonyl)guanidino) benzoyl)oxy)benzyl)sulfamoyl)-6,9,12,15,18-pentaoxa-3,21-diazatricosan-1,2,22,23-tetracarboxylate (591 mg) obtained in Example 5-(a), in dichloromethane (5 ml) in a 50 ml round bottom flask was added trifluoroacetic acid (5 ml) at room temperature under argon with stirring, and the resulting mixture was stirred at room temperature for 4 hours. The reaction solution was evaporated under reduced pressure. To a solution of the resulting evaporation residue in ethanol (10 ml) was added 5% palladium-carbon (moisture content 54.28%, STD-type manufactured by NE CHEMCAT Corporation) (200 mg) at room temperature under argon with stirring, and the resulting mixture was stirred at room temperature in a hydrogen atmosphere for 40 minutes. After completion of the reaction, the solution was filtered through Celite and the separated solid was washed with ethanol. The resulting filtrate was evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (ODS silica gel, elution solvent: acetonitrile with 0.1% trifluoroacetic acid: water with 0.1% trifluoroacetic acid), and fractions with the title compound were freeze-dried to give the title Compound (167 mg) in form of a white solid.

Mass spectrum (ESI, m/z): 603 [M+2H] ²⁺ .

¹ H-NMR spectrum (400 MHz, DMSO-d ₆ + D ₂ O) δ: 8.20-8.12 (m, 4H), 7.46-7.39 (m, 8H), 7.26-7.20 (m, 4H), 4.64- 4.52 (m, 2H), 4.20-4.04 (m, 4H), 3.76-3.23 (m, 24H), 3.02-2.89 (m, 2H), 2.75-2.42 (m, 2H).

Example 5-(c)

Preparation of (2S,22S)-3,21-bis(N-(4-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl)-6,9,12,15,18-pentaoxa-3,21-diazatricosan-1 ,2,22,23-tetracarboxylic acid hydrochloride

In a solution of (2S,22S)-tetra-tert-butyl 3,21-bis(N-((benzyloxy)carbonyl)-N-(4-((4-(2,3-bis(tert-butoxycarbonyl)guanidino) benzoyl)oxy)benzyl)sulfamoyl)-6,9,12,15,18-pentaoxa-3,21-diazatricosan-1,2,22,23-tetracarboxylate (3.36 g), obtained by the same method as described for Example 5-(a), in dichloromethane (25 ml) in a 300 ml round bottom flask was added trifluoroacetic acid (12.5 ml) at 0°C under argon with stirring, and the resulting mixture was stirred at room temperature for 14 hours. The reaction solution was evaporated under reduced pressure. To a solution of the resulting evaporation residue in ethanol (40 ml) was added 5% palladium on carbon (moisture content 54.28%, STD-type manufactured by NE CHEMCAT Corporation) (1.12 g), the reaction system was filled with hydrogen, and then the resulting mixture was stirred at room temperature within 2 hours. After completion of the reaction, the solution was filtered through Celite, and the resulting filtrate was evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: acetonitrile with 0.1% trifluoroacetic acid: water with 0.1% trifluoroacetic acid), and fractions with the target compound were evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (ODS silica gel, elution solvent: acetonitrile with 0.1% trifluoroacetic acid: water with 0.1% trifluoroacetic acid), and fractions with the target compound were freeze-dried. A solution of the resulting residue in 0.1N. hydrochloric acid solution (160 ml) was lyophilized to give the title Compound (1.29 g) as a white solid.

Mass spectrum (ESI, m/z): 603 [M+2H] ²⁺ .

¹ H-NMR spectrum (400 MHz, DMSO-d ₆ + D ₂ O) δ: 8.20-8.13 (m, 4H), 7.47-7.39 (m, 8H), 7.27-7.20 (m, 4H), 4.61 ( dd, J = 5.3, 8.5 Hz, 2H), 4.12 (d, J = 15.3 Hz, 2H), 4.06 (d, J = 15.3 Hz, 2H), 3.71-3.21 (m, 24H), 2.96 (dd, J = 8.5, 16.7 Hz, 2H), 2.69 (dd, J = 5.3, 16.7 Hz, 2H).

Example 6

Example 6-(a)

Preparation of (2S,25S)-tetra-tert-butyl 3,24-bis(N-((benzyloxy)carbonyl)-N-(4-((4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoyl )oxy)benzyl)sulfamoyl)-6,9,12,15,18,21-hexaoxa-3,24-diazahexacosan-1,2,25,26-tetracarboxylate

Into a solution of (2S,25S)-tetra-tert-butyl 3,24-bis(N-((benzyloxy)carbonyl)sulfamoyl)-6,9,12,15,18,21-hexaoxa-3,24-diazahexacosan- 1,2,25,26-tetracarboxylate (2.50 g) obtained in Comparative Example 6-(c),4-(hydroxymethyl)phenyl 4-(2,3-bis(t-butoxycarbonyl)guanidino)benzoate (2.21 g) , obtained by the same procedure as described for Comparative example 1-(g), and triphenylphosphine (1.41 g) in tetrahydrofuran (30 ml) in a 200 ml round bottom flask was added diisopropyl azodicarboxylate (1.9M solution in toluene) (2.83 ml) at room temperature under argon atmosphere with stirring, and the resulting mixture was stirred at room temperature for 2 hours. After completion of the reaction, the solution was evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (3.84 g) as a colorless oil.

Mass spectrum (ESI, m/z): 1072 [M+2H] ²⁺ .

¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ: 11.63 (s, 2H), 10.64 (s, 2H), 8.19-8.13 (m, 4H), 7.85-7.78 (m, 4H), 7.43-7.23 (m, 14H), 7.16-7.10 (m, 4H), 5.19 (d, J = 12.0 Hz, 2H), 5.15 (d, J = 12.0 Hz, 2H), 4.97 (d, J = 16.1 Hz, 2H) , 4.94 (d, J = 16.1 Hz, 2H), 4.68 (dd, J = 6.0, 8.3 Hz, 2H), 3.79–3.47 (m, 26H), 3.39–3.25 (m, 2H), 2.91 (dd, J = 8.3, 16.7 Hz, 2H), 2.66 (dd, J = 6.0, 16.7 Hz, 2H), 1.55 (s, 18H), 1.53 (s, 18H), 1.45 (s, 36H).

Example 6-(b)

Preparation of (2S,25S)-3,24-bis(N-(4-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl)-6,9,12,15,18,21-hexaoxa-3,24-diazahexacosan -1,2,25,26-tetracarboxylic acid trifluoroacetate

In a solution of (2S,25S)-tetra-tert-butyl 3,24-bis(N-((benzyloxy)carbonyl)-N-(4-((4-(2,3-bis(tert-butoxycarbonyl)guanidino) benzoyl)oxy)benzyl)sulfamoyl)-6,9,12,15,18,21-hexaoxa-3,24-diazahexacosan-1,2,25,26-tetracarboxylate (300 mg) obtained in Example 6-(a ), in dichloromethane (2.5 ml) in a 30 ml cylindrical flask was added trifluoroacetic acid (0.43 ml) at 0°C under argon with stirring, and the resulting mixture was stirred at room temperature for 14 hours. The reaction solution was evaporated under reduced pressure. To a solution of the resulting evaporation residue in dichloromethane (1 ml) was added trifluoroacetic acid (1 ml) at room temperature, and the resulting mixture was stirred at room temperature for 3 hours. The reaction solution was evaporated under reduced pressure. To a solution of the resulting evaporation residue in methanol (3 ml) was added 5% palladium on carbon (moisture content 54.28%, STD-type manufactured by NE CHEMCAT Corporation) (100 mg), the reaction system was filled with hydrogen, and then the resulting mixture was stirred at room temperature within 2 hours. After completion of the reaction, the solution was filtered through Celite, and the resulting filtrate was evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (ODS silica gel, elution solvent: water with 0.1% trifluoroacetic acid: acetonitrile with 0.1% trifluoroacetic acid), and fractions with the title compound were freeze-dried to give the title Compound (115.3 mg) in form of a white solid.

Mass spectrum (ESI, m/z): 625 [M+2H] ²⁺ .

¹ H-NMR spectrum (400 MHz, DMSO-d ₆ + D ₂ O) δ: 8.20-8.14 (m, 4H), 7.47-7.39 (m, 8H), 7.27-7.20 (m, 4H), 4.60 ( dd, J = 5.4, 8.5 Hz, 2H), 4.11 (d, J = 15.2 Hz, 2H), 4.06 (d, J = 15.2 Hz, 2H), 3.67-3.21 (m, 28H), 2.96 (dd, J = 8.5, 16.6 Hz, 2H), 2.74-2.64 (m, 2H).

Example 6-(c)

Preparation of (2S,25S)-3,24-bis(N-(4-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl)-6,9,12,15,18,21-hexaoxa-3,24-diazahexacosan -1,2,25,26-tetracarboxylic acid hydrochloride

In a solution of (2S,25S)-tetra-tert-butyl 3,24-bis(N-((benzyloxy)carbonyl)-N-(4-((4-(2,3-bis(tert-butoxycarbonyl)guanidino) benzoyl)oxy)benzyl)sulfamoyl)-6,9,12,15,18,21-hexaoxa-3,24-diazahexacosan-1,2,25,26-tetracarboxylate (3.23 g) obtained in Example 6-(a ), in dichloromethane (24 ml) in a 100 ml round bottom flask was added trifluoroacetic acid (12 ml) at 0° C. under argon with stirring, and the resulting mixture was stirred at room temperature for 8 hours. The reaction solution was evaporated under reduced pressure. To a solution of the resulting evaporation residue in a mixture of tetrahydrofuran (20 ml)/water (20 ml) was added 5% palladium on carbon (moisture content 54.28%, STD-type manufactured by NE CHEMCAT Corporation) (1.00 g), the reaction system was filled with hydrogen, and then the resulting mixture was stirred at room temperature for 30 minutes. After completion of the reaction, the solution was filtered through Celite, and the resulting filtrate was evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (ODS silica gel, elution solvent: water with 0.1% trifluoroacetic acid: acetonitrile with 0.1% trifluoroacetic acid), and fractions with the target compound were freeze-dried. The resulting residue was purified by preparative medium pressure chromatography (silica gel, acetonitrile with 0.1% trifluoroacetic acid: water with 0.1% trifluoroacetic acid), and fractions with the target compound were evaporated under reduced pressure. A solution of the resulting residue in a mixture of 0.1N. a solution of hydrochloric acid (100 ml)/acetonitrile (20 ml) was subjected to lyophilization. A solution of the resulting residue in acetonitrile (20 ml) was lyophilized to give the title Compound (1.23 g) as a white solid.

Mass spectrum (ESI, m/z): 625 [M+2H] ²⁺ .

¹ H-NMR spectrum (400 MHz, DMSO-d ₆ + D ₂ O) δ: 8.21-8.13 (m, 4H), 7.47-7.38 (m, 8H), 7.27-7.20 (m, 4H), 4.60 ( dd, J = 5.6, 8.5 Hz, 2H), 4.12 (d, J = 15.2 Hz, 2H), 4.06 (d, J = 15.2 Hz, 2H), 3.80-3.19 (m, 28H), 2.96 (dd, J = 8.5, 16.6 Hz, 2H), 2.69 (dd, J = 5.6, 16.6 Hz, 2H).

Example 7

Example 7-(a)

Preparation of (2S,2'S)-tetra-tert-butyl 2,2'-(propane-1,3-diylbis((N-((benzyloxy)carbonyl)-N-(4-((4-(2,3- bis(tert-butoxycarbonyl)guanidino)benzoyl)oxy)benzyl)sulfamoyl)azandiyl))disuccinate

To a solution of 4-(hydroxymethyl)phenyl 4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoate (2.24 g) prepared in the same manner as described for Comparative Example 1-(g), (2S,2'S )-tetra-tert-butyl 2,2'-(propane-1,3-diylbis((N-((benzyloxy)carbonyl)sulfamoyl)azandiyl))disuccinate (2.10g) obtained in Comparative Example 7-(c) , and triphenylphosphine (1.40 g) in anhydrous tetrahydrofuran (12 ml) diisopropyl azodicarboxylate (1.9M solution in toluene) (2.80 ml) was added to a 100 ml round bottom flask under cooling in an ice bath under argon atmosphere with stirring, and the resulting mixture was stirred at room temperature for 16 hours. After completion of the reaction, the solution was evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (3.13 g) as a white foam.

Mass spectrum (ESI, m/z): 947 [M+2H] ²⁺ .

¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ: 11.62 (s, 2H), 10.63 (s, 2H), 8.19-8.12 (m, 4H), 7.85-7.77 (m, 4H), 7.43-7.23 (m, 14H), 7.15-7.10 (m, 4H), 5.19 (d, J = 12.0 Hz, 2H), 5.15 (d, J = 12.0 Hz, 2H), 5.04-4.89 (m, 4H), 4.61 ( dd, J = 5.8, 8.6 Hz, 2H), 3.43–3.28 (m, 2H), 3.10–2.97 (m, 2H), 2.87 (dd, J = 8.6, 16.4 Hz, 2H), 2.58 (dd, J = 5.8, 16.4 Hz, 2H), 1.99-1.85 (m, 2H), 1.55 (s, 18H), 1.53 (s, 18H), 1.45 (s, 18H), 1.45 (s, 18H).

Example 7-(b)

Preparation of (2S,2'S)-2,2'-(propane-1,3-diylbis((N-(4-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl)azandiyl))succinic acid

In a solution of (2S,2'S)-tetra-tert-butyl 2,2'-(propane-1,3-diylbis((N-((benzyloxy)carbonyl)-N-(4-((4-(2,3 -bis(tert-butoxycarbonyl)guanidino)benzoyl)oxy)benzyl)sulfamoyl)azandiyl))disuccinate (3.13g) obtained in Example 7-(a) in anhydrous dichloromethane (15ml) in a 200ml round bottom flask was added trifluoroacetic acid (5.00 ml) under cooling in an ice bath under argon atmosphere with stirring, and the resulting mixture was stirred at room temperature for 16 hours. The reaction solution was evaporated under reduced pressure. To a solution of the resulting evaporation residue in ethanol (10 ml) was added 10% palladium-carbon (moisture content about 55%, manufactured by Tokyo Chemical Industry Co., Ltd.) (200 mg), the reaction system was filled with hydrogen, and the resulting mixture was stirred at room temperature for 5 hours. After completion of the reaction, the atmosphere in the reaction system was changed to nitrogen, and the solution was filtered through celite. The separated solid was washed with a mixture of ethanol and acetonitrile (1:1 (v/v)), and the resulting filtrate was evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (ODS silica gel, elution solvent: water with 0.1% trifluoroacetic acid: acetonitrile with 0.1% trifluoroacetic acid), fractions with the target compound were combined, and a saturated aqueous ammonium acetate solution was added, adjusting the pH to 4.0. The resulting mixture was stirred at room temperature for 1 hour, the precipitate formed was filtered off and dried under reduced pressure to give the title Compound (925 mg) as a white solid.

Mass spectrum (ESI, m/z): 999 [M+H] ⁺ .

¹ H-NMR spectrum (400 MHz, DMSO-d ₆ + D ₂ O) δ: 7.72-7.52 (m, 4H), 7.25-7.16 (m, 4H), 7.02-6.90 (m, 8H), 4.50- 4.31 (m, 4H), 3.97-3.74 (m, 2H), 3.70-2.78 (m, 6H), 2.59-2.29 (m, 2H), 2.15-1.99 (m, 2H).

Example 8

Example 8-(a)

Preparation of (2S,2'S)-tetra-tert-butyl 2,2'-(butane-1,4-diylbis((N-((benzyloxy)carbonyl)-N-(4-((4-(2,3- bis(tert-butoxycarbonyl)guanidino)benzoyl)oxy)benzyl)sulfamoyl)azandiyl))disuccinate

To a solution of 4-(hydroxymethyl)phenyl 4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoate (2.90 g) prepared in the same manner as described for Comparative Example 1-(g), (2S,2'S )-tetra-tert-butyl 2,2'-(butane-1,4-diylbis((N-((benzyloxy)carbonyl)sulfamoyl)azandiyl))disuccinate (2.72g) obtained in Comparative Example 8-(c) , and triphenylphosphine (1.80 g) in anhydrous tetrahydrofuran (15 ml) diisopropyl azodicarboxylate (1.9M solution in toluene) (3.60 ml) was added to a 100 ml round bottom flask under cooling in an ice bath under argon atmosphere with stirring, and the resulting mixture was stirred under room temperature for 2 hours. After completion of the reaction, the solution was evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (3.23 g) as a white foam.

Mass spectrum (DUIS, m/z): 954 [M+2H] ²⁺ .

¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ: 11.62 (s, 2H), 10.63 (s, 2H), 8.20-8.12 (m, 4H), 7.85-7.77 (m, 4H), 7.45-7.23 (m, 14H), 7.15-7.10 (m, 4H), 5.19 (d, J = 12.0 Hz, 2H), 5.15 (d, J = 12.0 Hz, 2H), 5.03-4.89 (m, 4H), 4.60 ( dd, J = 5.6, 8.8 Hz, 2H), 3.43–3.28 (m, 2H), 3.11–2.96 (m, 2H), 2.83 (dd, J = 8.8, 16.4 Hz, 2H), 2.56 (dd, J = 5.6, 16.4 Hz, 2H), 1.55 (s, 18H), 1.53 (s, 18H), 1.45 (s, 18H), 1.45 (s, 18H), 1.73-1.19 (m, 4H).

Example 8-(b)

Preparation of (2S,2'S)-2,2'-(butane-1,4-diylbis((N-(4-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl)azandiyl))disuccinic acid trifluoroacetate

In a solution of (2S,2'S)-tetra-tert-butyl 2,2'-(butane-1,4-diylbis((N-((benzyloxy)carbonyl)-N-(4-((4-(2,3 -bis(tert-butoxycarbonyl)guanidino)benzoyl)oxy)benzyl)sulfamoyl)azandiyl))disuccinate (3.23g) obtained in Example 8-(a) in anhydrous dichloromethane (15ml) in a 200ml round bottom flask was added trifluoroacetic acid (5.00 ml) under cooling in an ice bath under argon atmosphere with stirring, and the resulting mixture was stirred at room temperature for 16 hours. The reaction solution was evaporated under reduced pressure. To a solution of the obtained evaporation residue in ethanol (10 ml) was added 10% palladium-carbon (moisture content about 55%, manufactured by Tokyo Chemical Industry Co., Ltd.) (210 mg), the reaction system was filled with hydrogen, and then the resulting mixture was stirred at room temperature for 4 hours. After completion of the reaction, the atmosphere in the reaction system was changed to nitrogen, and the solution was filtered through celite. The separated solid was washed with a mixture of ethanol and acetonitrile (1:1 (v/v)), and the resulting filtrate was evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (ODS silica gel, elution solvent: water with 0.1% trifluoroacetic acid: acetonitrile with 0.1% trifluoroacetic acid), fractions with the target compound were combined, and a saturated aqueous ammonium acetate solution was added, adjusting the pH to 4.0. The resulting mixture was stirred at room temperature for 1 hour, the precipitate formed was filtered off and dried under reduced pressure to give the title Compound (1.25 g) as a white solid.

Mass Spectrum (ESI, m/z): 1011 [MH] ^- .

¹ H-NMR spectrum (400 MHz, DMSO-d ₆ + D ₂ O) δ: 7.86-7.74 (m, 4H), 7.30-7.15 (m, 8H), 7.06-6.97 (m, 4H), 4.58- 4.42 (m, 2H), 4.30-4.10 (m, 4H), 3.94-2.79 (m, 6H), 2.63-2.29 (m, 2H), 1.68-1.44 (m, 4H).

Example 8-(c)

Preparation of (2S,2'S)-2,2'-(butane-1,4-diylbis((N-(4-((4-guanidinobenzoyl)oxy) benzyl)sulfamoyl)azandiyl))disuccinic acid hydrochloride

(2S,2'S)-2,2'-(butane-1,4-diylbis((N-(4-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl)azandiyl))disuccinic acid trifluoroacetate (730mg) obtained in Example 8-(b), in a 300 ml round bottom flask was dissolved in acetonitrile (10 ml) and 0.1M hydrochloric acid solution (31 ml), and the resulting solution was lyophilized to give the title Compound (731 mg) as white solid.

Mass Spectrum (ESI, m/z): 1011 [MH] ^- .

¹ H-NMR spectrum (400 MHz, DMSO-d ₆ + D ₂ O) δ: 8.20-8.13 (m, 4H), 7.47-7.39 (m, 8H), 7.26-7.20 (m, 4H), 4.56- 4.46 (m, 2H), 4.14 (d, J = 15.2 Hz, 2H), 4.09 (d, J = 15.2 Hz, 2H), 3.30-3.03 (m, 4H), 2.97 (dd, J = 9.2, 16.5 Hz , 2H), 2.62 (broad.dd, J = 4.8, 16.5 Hz, 2H), 1.65–1.46 (m, 4H).

Example 9

Example 9-(a)

Preparation of (2S,2'S)-tetra-tert-butyl 2,2'-(pentane-1,5-diylbis((N-((benzyloxy)carbonyl)-N-(4-((4-(2,3- bis(tert-butoxycarbonyl)guanidino)benzoyl)oxy)benzyl)sulfamoyl)azandiyl))disuccinate

To a solution of (2S,2'S)-tetra-tert-butyl 2,2'-(pentane-1,5-diylbis((N-((benzyloxy)carbonyl)sulfamoyl)azandiyl))disuccinate (505 mg) obtained in Comparative Example 9-(c), in tetrahydrofuran (10 ml) in a 100 ml round bottom flask was added 4-(hydroxymethyl)phenyl 4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoate (524 mg) prepared according to the same procedure as that described for Comparative Example 1-(g), triphenylphosphine (308 mg) and diisopropyl azodicarboxylate (1.9M solution in toluene) (0.595 ml) at room temperature under argon with stirring, and the resulting mixture was stirred at room temperature in during the night. After completion of the reaction, water was added to the solution, and the resulting solution was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (388.1 mg) as a white foam.

Mass spectrum (ESI, m/z): 961 [M+2H] ²⁺ .

¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ: 11.62 (s, 2H), 10.63 (s, 2H), 8.19-8.13 (m, 4H), 7.84-7.77 (m, 4H), 7.45-7.22 (m, 14H), 7.16-7.10 (m, 4H), 5.19 (d, J = 12.2 Hz, 2H), 5.15 (d, J = 12.2 Hz, 2H), 4.97 (d, J = 16.0 Hz, 2H) , 4.92 (d, J = 16.0 Hz, 2H), 4.61 (dd, J = 5.7, 8.8 Hz, 2H), 3.42–3.31 (m, 2H), 3.09–2.96 (m, 2H), 2.83 (dd, J = 8.8, 16.4 Hz, 2H), 2.55 (dd, J = 5.7, 16.4 Hz, 2H), 1.53 (s, 18H), 1.45 (s, 18H), 1.45 (s, 18H), 1.74-1.19 (m, 22H), 1.00-0.82 (m, 2H).

Example 9-(b)

Preparation of (2S,2'S)-2,2'-(pentane-1,5-diylbis((N-(4-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl)azandiyl))disuccinic acid

In a solution of (2S,2'S)-tetra-tert-butyl 2,2'-(pentane-1,5-diylbis((N-((benzyloxy)carbonyl)-N-(4-((4-(2,3 -bis(tert-butoxycarbonyl)guanidino)benzoyl)oxy)benzyl)sulfamoyl)azandiyl))disuccinate (388mg) obtained in Example 9-(a) in dichloromethane (10ml) in a 100ml round bottom flask was added trifluoroacetic acid (3.56 ml) at 0°C in air with stirring, and the resulting mixture was stirred at room temperature overnight. The reaction solution was evaporated under reduced pressure. To a solution of the resulting evaporation residue in ethanol (10 ml) was added 5% palladium on carbon (moisture content 55.32%, STD-type manufactured by NE CHEMCAT Corporation) (181 mg) at room temperature under air with stirring, and the resulting mixture was stirred at room temperature in a hydrogen atmosphere for 3 hours. After completion of the reaction, the solution was filtered through Celite, washed with a mixture of ethanol and acetonitrile (1:1 (v/v)), and the resulting filtrate was evaporated under reduced pressure. The evaporation residue was purified by preparative medium pressure chromatography (ODS silica gel, elution solvent: water with 0.1% trifluoroacetic acid: acetonitrile with 0.1% trifluoroacetic acid), and fractions with the target compound were freeze-dried. The resulting solid was dissolved in water (4 ml) and acetonitrile (1 ml), and a saturated aqueous ammonium acetate solution was added to the resulting solution, adjusting the pH to 4.0. The resulting mixture was stirred at room temperature for 1 hour, the precipitate formed was filtered off and dried to give the title Compound (50.7 mg) as a white solid.

Mass Spectrum (ESI, m/z): 1025 [MH] ^- .

¹ H-NMR spectrum (400 MHz, DMSO-d ₆ + D ₂ O) δ: 7.94-7.77 (m, 4H), 7.41-6.93 (m, 12H), 4.60-4.39 (m, 2H), 4.35- 4.00 (m, 4H), 3.74-2.77 (m, 6H), 2.62-2.26 (m, 2H), 1.79-1.43 (m, 4H), 1.32-1.09 (m, 2H).

Example 10

Example 10-(a)

Preparation of tetra-tert-butyl 3,18-bis(((4-((4-(2,3-bis(tert-butoxycarbonyl) guanidino)benzoyl)oxy)benzyl)oxy)carbonyl)-6,9,12, 15-tetraoxa-3,18-diazaicosan-1,2,19,20-tetracarboxylate

To a solution of tetra-tert-butyl 6,9,12,15-tetraoxa-3,18-diazaicosan-1,2,19,20-tetracarboxylate (403 mg) obtained in Comparative Example 10-(c) in dichloromethane ( 15 ml) in a 100 ml round bottom flask was added 1-(((4-((4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoyl)oxy)benzyl)oxy)carbonyl)-3-methyl-1H -imidazol-3-ium trifluoromethanesulfonate (1.03 g) prepared in the same manner as that described in Comparative Example 10-(b) at room temperature under argon with stirring, the resulting mixture was stirred at room temperature for 24 hours, and left to stand for 15 hours. After completion of the reaction, the solution was evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (235.1 mg) as a colorless oil.

Mass spectrum (ESI, m/z): 1738 [M+Na] ⁺ .

¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ: 11.62 (s, 2H), 10.64 (s, 2H), 8.19-8.12 (m, 4H), 7.84-7.78 (m, 4H), 7.44-7.38 (m, 4H), 7.22-7.16 (m, 4H), 5.27-5.02 (m, 4H), 4.62-4.41 (m, 2H), 3.76-3.52 (m, 18H), 3.50-3.35 (m, 2H) , 3.15-2.95 (m, 2H), 2.79-2.64 (m, 2H), 1.61-1.49 (m, 36H), 1.46-1.33 (m, 36H).

Example 10-(b)

Preparation of 3,18-bis(((4-((4-guanidinobenzoyl)oxy)benzyl)oxy)carbonyl)-6,9,12,15-tetraoxa-3,18-diazaicosan-1,2,19,20- tetracarboxylic acid trifluoroacetate

Into a solution of tetra-tert-butyl 3,18-bis(((4-((4-(2,3-bis(tert-butoxycarbonyl) guanidino)benzoyl)oxy)benzyl)oxy)carbonyl)-6,9,12 ,15-tetraoxa-3,18-diazaicosan-1,2,19,20-tetracarboxylate (1.50 g) obtained by the same procedure as described for Example 10-(a) in dichloromethane (21.4 ml) in 100- trifluoroacetic acid (5.35 ml) was added to a milliliter round bottom flask at 0° C. under argon with stirring, and the resulting mixture was stirred at room temperature for 15 hours. After completion of the reaction, the solution was evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: acetonitrile with 0.1% trifluoroacetic acid: water with 0.1% trifluoroacetic acid), and fractions with the target compound were evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (ODS silica gel, elution solvent: water with 0.1% trifluoroacetic acid: acetonitrile with 0.1% trifluoroacetic acid), and fractions with the target compound were freeze-dried to give the title Compound (790 mg) in form of a white solid.

Mass spectrum (ESI, m/z): 1091 [M+H] ⁺ .

¹ H-NMR spectrum (400 MHz, CD ₃ CN/D ₂ O = 1/1) δ: 8.26-8.17 (m, 4H), 7.52-7.41 (m, 8H), 7.30-7.22 (m, 4H) , 5.18-5.08 (m, 4H), 4.62-4.48 (m, 2H), 3.66-3.48 (m, 20H), 3.19-3.00 (m, 2H), 2.89-2.76 (m, 2H).

Example 11

Example 11-(a)

Preparation of tetra-tert-butyl 2,2'-(1,20-bis(4-((4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoyl)oxy)phenyl)-3,18-dioxo- 2,19-dioxa-4,17-diazaicosan-4,17-diyl)disuccinate

To a solution of tetra-tert-butyl 2,2'-(dodecane-1,12-diylbis(azandiyl)) disuccinate (0.920 g) obtained in Comparative Example 11-(a) in acetonitrile (30 ml) in a 200 ml 1-(((4-((4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoyl)oxy)benzyl)oxy)carbonyl)-3-methyl-1H-imidazol-3-ium trifluoromethanesulfonate was added to a round bottom flask (2.5 g) prepared in the same manner as that described for Comparative Example 10-(b) at room temperature under argon with stirring, and the resulting mixture was stirred at room temperature for 71 hours. After completion of the reaction, the solution was evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (1.64 g) as a colorless oil.

Mass Spectrum (ESI, m/z): 1702 [M+Na] ⁺ .

¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ: 11.62 (s, 2H), 10.64 (s, 2H), 8.18-8.14 (m, 4H), 7.85-7.77 (m, 4H), 7.48-7.37 (m, 4H), 7.29-7.16 (m, 4H), 5.28-5.00 (m, 4H), 4.47-4.31 (m, 2H), 3.56-3.36 (m, 2H), 3.18-2.98 (m, 4H) , 2.73-2.43 (m, 2H), 1.72-1.18 (m, 92H).

Example 11-(b)

Preparation of 2,2'-(1,20-bis(4-((4-guanidinobenzoyl)oxy)phenyl)-3,18-dioxo-2,19-dioxa-4,17-diazaicosan-4,17-diyl) disuccinic acid trifluoroacetate

Into a solution of tetra-tert-butyl 2,2'-(1,20-bis(4-((4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoyl)oxy)phenyl)-3,18-dioxo -2,19-dioxa-4,17-diazaicosan-4,17-diyl)disuccinate (260 mg) prepared in the same manner as described for Example 11-(a) in dichloromethane (4 ml) in 100- trifluoroacetic acid (0.947 ml) was added to a milliliter round bottom flask at 0°C under argon with stirring, and the resulting mixture was stirred at room temperature for 14 hours. After completion of the reaction, the solution was evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (ODS silica gel, elution solvent: water with 0.1% trifluoroacetic acid: acetonitrile with 0.1% trifluoroacetic acid), and fractions with the target compound were freeze-dried. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: acetonitrile with 0.1% trifluoroacetic acid: water with 0.1% trifluoroacetic acid), and fractions with the title compound were freeze-dried to give the title compound (117.6 mg) as white solid.

Mass spectrum (ESI, m/z): 1055 [M+H] ⁺ .

¹ H-NMR spectrum (400 MHz, CD ₃ CN/D ₂ O = 1/1) δ: 8.28-8.12 (m, 4H), 7.51-7.39 (m, 8H), 7.29-7.19 (m, 4H) , 5.17-5.02 (m, 4H), 4.51-4.42 (m, 2H), 3.46-3.29 (m, 2H), 3.27-2.99 (m, 4H), 2.77-2.60 (m, 2H), 1.61-1.40 ( m, 4H), 1.32–1.09 (m, 16H).

Example 11-(c)

Preparation of 2,2'-(1,20-bis(4-((4-guanidinobenzoyl)oxy)phenyl)-3,18-dioxo-2,19-dioxa-4,17-diazaicosan-4,17-diyl) disuccinic acid

Into a solution of tetra-tert-butyl 2,2'-(1,20-bis(4-((4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoyl)oxy)phenyl)-3,18-dioxo -2,19-dioxa-4,17-diazaicosan-4,17-diyl)disuccinate (1.64 g) obtained in Example 11-(a) in dichloromethane (24 ml) in a 200 ml round bottom flask was added trifluoroacetic acid ( 6.00 ml) at 0°C under argon atmosphere with stirring, and the resulting mixture was stirred at room temperature for 19 hours. After completion of the reaction, the solution was evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: acetonitrile with 0.1% trifluoroacetic acid: water with 0.1% trifluoroacetic acid), and fractions with the target compound were evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (ODS silica gel, elution solvent: water with 0.1% trifluoroacetic acid: acetonitrile with 0.1% trifluoroacetic acid), and fractions with the target compound were evaporated under reduced pressure. The concentrated suspension was stirred at room temperature for 30 minutes, the precipitate formed was filtered off and dried under reduced pressure to give the title Compound (497 mg) as a white solid.

Mass spectrum (ESI, m/z): 1055 [M+H] ⁺ .

¹ H-NMR spectrum (400 MHz, DMSO-d ₆ + D ₂ O) δ: 8.13-8.00 (m, 4H), 7.51-7.32 (m, 8H), 7.23-6.86 (m, 4H), 5.21- 4.77 (m, 4H), 4.39-3.94 (m, 2H), 3.79-2.78 (m, 6H), 2.60-2.38 (m, 2H), 1.52-0.69 (m, 20H).

Example 12

Example 12-(a)

Preparation of (3S,6S,25S,28S)-di-tert-butyl 3,28-bis((((4-((4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoyl)oxy)benzyl) hydroxy)carbonyl)amino)-6,25-bis(2-(tert-butoxy)-2-oxoethyl)-4,7,24,27-tetraoxo-11,14,17,20-tetraoxa-5,8, 23,26-tetraazatriacontane-1,30-dioate

Into a solution of (3S,6S,25S,28S)-di-tert-butyl 3,28-diamino-6,25-bis(2-(tert-butoxy)-2-oxoethyl)-4,7,24,27- tetraoxo-11,14,17,20-tetraoxa-5,8,23,26-tetraazatriacontane-1,30-dioate (1.50 g) obtained by the same procedure as described for Comparative Example 12-(d), in dichloromethane (30 ml) in a 200 ml round bottom flask was added 1-(((4-((4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoyl)oxy)benzyl)oxy)carbonyl)-3-methyl -1H-imidazol-3-ium trifluoromethanesulfonate (2.91 g) prepared in the same manner as in Comparative Example 10-(b) at room temperature under argon with stirring, and the resulting mixture was stirred at room temperature for 20 hours . After completion of the reaction, the solution was evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (DIOL silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (1.79 g) as a white foam.

Mass spectrum (ESI, m/z): 973 [M+2H] ²⁺ .

¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ: 11.62 (s, 2H), 10.64 (s, 2H), 8.19-8.13 (m, 4H), 7.85-7.78 (m, 4H), 7.55 (d , J = 8.5 Hz, 2H), 7.46-7.38 (m, 4H), 7.23-7.18 (m, 4H), 7.15-7.06 (m, 2H), 5.93 (d, J = 8.3 Hz, 2H), 5.17 ( d, J = 12.4 Hz, 2H), 5.11 (d, J = 12.4 Hz, 2H), 4.80-4.66 (m, 2H), 4.58-4.42 (m, 2H), 3.70-3.33 (m, 20H), 2.95 -2.81 (m, 4H), 2.72 (dd, J = 6.4, 16.8 Hz, 2H), 2.61 (dd, J = 6.0, 16.8 Hz, 2H), 1.55 (s, 18H), 1.53 (s, 18H), 1.44 (s, 18H), 1.43 (s, 18H).

Example 12-(b)

Preparation of (3S,6S,25S,28S)-6,25-bis(carboxymethyl)-3,28-bis((((4-((4-guanidinobenzoyl)oxy)benzyl)oxy)carbonyl)amino)-4, 7,24,27-tetraoxo-11,14,17,20-tetraoxa-5,8,23,26-tetraazatriacontane-1,30-dioic acid trifluoroacetate

In a solution of (3S,6S,25S,28S)-di-tert-butyl 3,28-bis((((4-((4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoyl)oxy)benzyl )oxy)carbonyl)amino)-6,25-bis(2-(tert-butoxy)-2-oxoethyl)-4,7,24,27-tetraoxo-11,14,17,20-tetraoxa-5,8 ,23,26-tetraazatriacontane-1,30-dioate (1.79 g) obtained in Example 12-(a), in dichloromethane (12 ml) in a 200 ml round bottom flask was added trifluoroacetic acid (3 ml) at 0°C in argon atmosphere with stirring, and the resulting mixture was stirred at room temperature for 15 hours. The reaction solution was evaporated under reduced pressure. Dichloromethane (5 ml) and trifluoroacetic acid (10 ml) were added to the evaporation residue at room temperature, and the resulting mixture was stirred at room temperature for 3 hours. After completion of the reaction, the solution was evaporated under reduced pressure. To a solution of the resulting residue in water (15 ml)/acetonitrile (10 ml) was added a saturated aqueous ammonium acetate solution, adjusting the pH to 4.0. The reaction solution was evaporated under reduced pressure, and the concentrated solution was stirred at room temperature for 1 hour. Methanol was added to the reaction solution, and the resulting mixture was left at room temperature for 2 days. Trifluoroacetic acid (80 μl) was added to the reaction solution, adjusting the pH to 4.0. The reaction solution was evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (ODS silica gel, elution solvent: water with 0.1% trifluoroacetic acid: acetonitrile with 0.1% trifluoroacetic acid), and fractions with the target compound were freeze-dried to give the title Compound (900 mg) in form of a white solid.

Mass spectrum (ESI, m/z): 660 [M+2H] ²⁺ .

¹ H-NMR spectrum (400 MHz, CD ₃ CN/D ₂ O = 1/1) δ: 8.26-8.17 (m, 4H), 7.52-7.41 (m, 8H), 7.30-7.22 (m, 4H) , 5.20-5.07 (m, 4H), 4.70-4.59 (m, 2H), 4.52-4.45 (m, 2H), 3.65-3.45 (m, 16H), 3.37-3.25 (m, 4H), 2.92-2.65 ( m, 8H).

Example 12-(c)

Preparation of (3S,6S,25S,28S)-6,25-bis(carboxymethyl)-3,28-bis((((4-((4-guanidinobenzoyl)oxy)benzyl)oxy)carbonyl)amino)-4, 7,24,27-tetraoxo-11,14,17,20-tetraoxa-5,8,23,26-tetraazatriacontane-1,30-dioic acid

In a solution of (3S,6S,25S,28S)-di-tert-butyl 3,28-bis((((4-((4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoyl)oxy)benzyl )oxy)carbonyl)amino)-6,25-bis(2-(tert-butoxy)-2-oxoethyl)-4,7,24,27-tetraoxo-11,14,17,20-tetraoxa-5,8 Trifluoroacetic acid (283 μl) at 0°C under argon atmosphere with stirring, and the resulting mixture was stirred at room temperature for 14 hours. After completion of the reaction, the solution was evaporated under reduced pressure. A saturated aqueous ammonium acetate solution was added to a solution of the resulting residue in a water (1.5 ml)/acetonitrile (0.75 ml) mixture, adjusting the pH to 4.0. The resulting mixture was stirred at room temperature for 1 hour, the precipitate formed was filtered off and dried under reduced pressure to give the title Compound (72 mg) as a white solid.

Mass spectrum (ESI, m/z): 660 [M+2H] ²⁺ .

¹ H-NMR spectrum (400 MHz, DMSO-d ₆ + D ₂ O) δ: 8.12-7.94 (m, 4H), 7.47-7.26 (m, 8H), 7.21-7.11 (m, 4H), 5.18- 4.90 (m, 4H), 4.45-4.17 (m, 4H), 3.71-3.25 (m, 16H), 3.23-3.02 (m, 4H), 2.65-2.32 (m, 8H).

Example 13

Example 13-(a)

Preparation of (3S,6S,23S,26S)-di-tert-butyl 3,26-bis((((4-((4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoyl)oxy)benzyl) hydroxy)carbonyl)amino)-6,23-bis(2-(tert-butoxy)-2-oxoethyl)-4,7,22,25-tetraoxo-5,8,21,24-tetraazaoctacosan-1,28- dioate

Into a solution of (3S,6S,23S,26S)-di-tert-butyl 3,26-diamino-6,23-bis(2-(tert-butoxy)-2-oxoethyl)-4,7,22,25- 1-((( 4-((4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoyl)oxy)benzyl)oxy)carbonyl)-3-methyl-1H-imidazol-3-ium trifluoromethanesulfonate (1.80 g), obtained according to this the same procedure as that described for Comparative Example 10-(b) at room temperature under argon atmosphere with stirring, and the resulting mixture was stirred at room temperature for 1 hour. After completion of the reaction, the solution was evaporated under reduced pressure. Hexane (120 ml) was added to the concentrated solution, the resulting mixture was stirred at room temperature for 10 minutes, the precipitate formed was collected by filtration and dried under reduced pressure to give the title Compound (1.60 g) as a white solid.

Mass spectrum (ESI, m/z): 955 [M+2H] ²⁺ .

¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ: 11.62 (s, 2H), 10.64 (s, 2H), 8.19-8.13 (m, 4H), 7.85-7.78 (m, 4H), 7.50 (broad .d, J = 8.7 Hz, 2H), 7.46–7.39 (m, 4H), 7.24–7.18 (m, 4H), 6.89–6.77 (m, 2H), 5.77 (broad.d, J = 8.2 Hz, 2H ), 5.17 (d, J = 12.2 Hz, 2H), 5.12 (d, J = 12.2 Hz, 2H), 4.76-4.65 (m, 2H), 4.55-4.38 (m, 2H), 3.27-3.13 (m, 4H), 3.00 (broad dd, J = 4.0, 17.2 Hz, 2H), 2.86 (dd, J = 5.0, 17.2 Hz, 2H), 2.76 (dd, J = 6.8, 17.0 Hz, 2H), 2.54 (dd , J = 6.0, 17.0 Hz, 2H), 1.55 (s, 18H), 1.53 (s, 18H), 1.44 (s, 18H), 1.43 (s, 18H), 1.72–1.35 (m, 4H), 1.33– 1.18 (m, 16H).

Example 13-(b)

Preparation of (3S,6S,23S,26S)-6,23-bis(carboxymethyl)-3,26-bis((((4-((4-guanidinobenzoyl)oxy)benzyl)oxy)carbonyl)amino)-4, 7,22,25-tetraoxo-5,8,21,24-tetraazaoctacosan-1,28-dioic acid trifluoroacetate

In a solution of (3S,6S,23S,26S)-di-tert-butyl 3,26-bis((((4-((4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoyl)oxy)benzyl )oxy)carbonyl)amino)-6,23-bis(2-(tert-butoxy)-2-oxoethyl)-4,7,22,25-tetraoxo-5,8,21,24-tetraazaoctacosan-1,28 -dioate (228.4 mg), obtained by the same procedure as described for Example 13-(a), in dichloromethane (3 ml) in a 30 ml round bottom flask was added trifluoroacetic acid (733 μl) at 0°C in an argon atmosphere at stirring, and the resulting mixture was stirred at room temperature for 17 hours. After completion of the reaction, the solution was evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (ODS silica gel, elution solvent: water with 0.1% trifluoroacetic acid: acetonitrile with 0.1% trifluoroacetic acid), and fractions with the title compound were freeze-dried to give the title Compound (137.7 mg) in form of a white solid.

Mass Spectrum (ESI, m/z): 640 [M-2H] ^2- .

¹ H-NMR spectrum (400 MHz, DMSO-d ₆ + D ₂ O) δ: 8.24-8.13 (m, 4H), 7.50-7.41 (m, 8H), 7.30-7.21 (m, 4H), 5.14- 5.00 (m, 4H), 4.55-4.43 (m, 2H), 4.42-4.27 (m, 2H), 3.10-2.93 (m, 4H), 2.77-2.43 (m, 8H), 1.42-1.29 (m, 4H ), 1.27-1.14 (m, 16H).

Example 13-(c)

Preparation of (3S,6S,23S,26S)-6,23-bis(carboxymethyl)-3,26-bis((((4-((4-guanidinobenzoyl)oxy)benzyl)oxy)carbonyl)amino)-4, 7,22,25-tetraoxo-5,8,21,24-tetraazaoctacosan-1,28-dioic acid

In a solution of (3S,6S,23S,26S)-di-tert-butyl 3,26-bis((((4-((4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoyl)oxy)benzyl )oxy)carbonyl)amino)-6,23-bis(2-(tert-butoxy)-2-oxoethyl)-4,7,22,25-tetraoxo-5,8,21,24-tetraazaoctacosan-1,28 -dioate (1.60 g) obtained in Example 13-(a) in dichloromethane (20 ml) in a 100 ml round bottom flask was added trifluoroacetic acid (10 ml) at 0°C under argon atmosphere with stirring, and the resulting mixture was stirred at room temperature for 15 hours. After completion of the reaction, the solution was evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: acetonitrile with 0.1% trifluoroacetic acid: water with 0.1% trifluoroacetic acid), and fractions with the target compound were evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (ODS silica gel, elution solvent: water with 0.1% trifluoroacetic acid: acetonitrile with 0.1% trifluoroacetic acid), and fractions with the target compound were evaporated under reduced pressure. The concentrated suspension was stirred at room temperature for 30 minutes, the precipitate formed was filtered off and dried under reduced pressure to give the title Compound (583 mg) as a white solid.

Mass Spectrum (ESI, m/z): 640 [M-2H] ^2- .

¹ H-NMR spectrum (400 MHz, DMSO-d ₆ + D ₂ O) δ: 8.12-7.97 (m, 4H), 7.48-7.29 (m, 8H), 7.21-7.10 (m, 4H), 5.23- 4.91 (m, 4H), 4.46-4.30 (m, 2H), 4.26-4.14 (m, 2H), 3.08-2.82 (m, 4H), 2.71-2.30 (m, 8H), 1.33-0.89 (m, 20H) ).

Example 14

Example 14-(a)

Preparation of (3S,22S)-di-tert-butyl 3,22-bis(2-(((4-((4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoyl)oxy)benzyl)oxy )carbonyl)(3-(tert-butoxycarbonyl)benzyl)amino)acetamido)-4,21-dioxo-8,11,14,17-tetraoxa-5,20-diazatetracosan-1,24-dioate

In a solution of 2-((((4-((4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoyl)oxy)benzyl)oxy)carbonyl)(3-(tert-butoxycarbonyl)benzyl)amino)acetic acid (3.83 g) obtained in Comparative example 14-(e), in anhydrous dichloromethane (10 ml) in a 200 ml round bottom flask was added 1-hydroxybenzotriazole (0.700 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.00 g) and N,N-diisopropylethylamine (1.70 ml) while cooling in an ice bath under argon atmosphere with stirring, then a solution of (3S,22S)-di-tert-butyl 3,22-diamino-4,21-dioxo was added -8,11,14,17-tetraoxa-5,20-diazatetracosan-1,24-dioate (1.36 g) obtained in Comparative Example 12-(b) in anhydrous dichloromethane (5 ml) with stirring while cooling on ice bath, and the resulting mixture was stirred at room temperature for 16 hours. After completion of the reaction, a saturated ammonium chloride aqueous solution was added to the solution, and the resulting solution was extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and water, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (DIOL silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (3.17 g) as a white foam.

Mass spectrum (ESI, m/z): 1049 [M+2H] ²⁺ .

¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ: 11.62 (s, 2H), 10.64 (s, 2H), 8.19-8.12 (m, 4H), 7.94-7.78 (m, 8H), 7.53-6.95 (m, 16H), 5.27-5.16 (m, 4H), 4.80-4.54 (m, 6H), 3.97-3.81 (m, 4H), 3.67-3.32 (m, 20H), 2.97-2.38 (m, 4H) , 1.76-1.30 (m, 72H).

Example 14-(b)

Preparation of (3S,22S)-3,22-bis(2-((3-carboxybenzyl)(((4-((4-guanidinobenzoyl)oxy)benzyl)oxy)carbonyl)amino)acetamido)-4,21-dioxo -8,11,14,17-tetraoxa-5,20-diazatetracosan-1,24-dioic acid trifluoroacetate

In a solution of (3S,22S)-di-tert-butyl 3,22-bis(2-((((4-((4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoyl)oxy)benzyl) hydroxy)carbonyl)(3-(tert-butoxycarbonyl)benzyl)amino)acetamido)-4,21-dioxo-8,11,14,17-tetraoxa-5,20-diazatetracosan-1,24-dioate (3.17 g) , obtained in Example 14-(a), in anhydrous dichloromethane (8 ml) in a 200 ml round bottom flask was added trifluoroacetic acid (2.00 ml) while cooling in an ice bath under argon atmosphere with stirring, and the resulting mixture was stirred at room temperature for 16 hours. The reaction solution was evaporated under reduced pressure. To a solution of the resulting evaporation residue in anhydrous dichloromethane (8 ml) was added trifluoroacetic acid (2.00 ml) at room temperature under argon with stirring, and the resulting mixture was stirred at room temperature for 5 hours. The reaction solution was evaporated under reduced pressure. To a solution of the resulting evaporation residue in anhydrous dichloromethane (8 ml) was added trifluoroacetic acid (2.00 ml) at room temperature under argon with stirring, and the resulting mixture was stirred at room temperature for 30 minutes. After completion of the reaction, the solution was evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (ODS silica gel, elution solvent: water with 0.1% trifluoroacetic acid: acetonitrile with 0.1% trifluoroacetic acid), and fractions with the title compound were freeze-dried to give the title Compound (1.23 g) in form of a white solid.

Mass spectrum (ESI, m/z): 736 [M+2H] ²⁺ .

¹ H-NMR spectrum (400 MHz, CD ₃ CN + D ₂ O) δ: 8.24-8.18 (m, 4H), 7.95-7.87 (m, 4H), 7.71-7.34 (m, 12H), 7.28-7.11 (m, 4H), 5.18 (s, 4H), 4.71-4.53 (m, 6H), 4.03-3.89 (m, 4H), 3.62-2.90 (m, 20H), 2.83-2.57 (m, 4H).

Example 15

Example 15-(a)

Preparation of (4S,7S,26S,29S)-di-tert-butyl 3,30-bis(((4-((4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoyl)oxy)benzyl)oxy )carbonyl)-4,7,26,29-tetrakis(2-(tert-butoxy)-2-oxoethyl)-5,8,25,28-tetraoxo-12,15,18,21-tetraoxa-3,6 ,9,24,27,30-hexaazadotriacontane-1,32-dioate

In a solution of (S)-2-((((4-((4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoyl)oxy)benzyl)oxy)carbonyl)(2-(tert-butoxy)- COMU (62 mg) and N,N-diisopropylethylamine (27 μl) at room temperature under argon atmosphere with stirring, and the resulting mixture was stirred at room temperature for 30 minutes. Then a solution of (3S,22S)-di-tert-butyl 3,22-diamino-4,21-dioxo-8,11,14,17-tetraoxa-5,20-diazatetracosan-1,24-dioate (35 mg ) obtained in Comparative Example 12-(b) in dichloromethane (2 ml) with stirring at room temperature, and the resulting mixture was stirred at room temperature for 30 minutes. After completion of the reaction, the solution was evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (DIOL silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (110.9 mg) as a colorless oil.

Mass spectrum (ESI, m/z): 1087 [M+2H] ²⁺ .

¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ: 11.62 (broad s, 2H), 10.64 (s, 2H), 8.73-8.24 (m, 2H), 8.19-8.13 (m, 4H), 7.85 -7.78 (m, 4H), 7.44-7.33 (m, 4H), 7.24-7.15 (m, 4H), 7.12-6.92 (m, 2H), 5.26-5.06 (m, 4H), 4.69-4.59 (m, 2H), 4.58-4.25 (m, 2H), 4.17-3.86 (m, 4H), 3.69-3.28 (m, 20H), 3.24-3.01 (m, 2H), 2.88-2.57 (m, 6H), 1.91- 1.33 (m, 90H).

Example 15-(b)

Preparation of (4S,7S,26S,29S)-4,7,26,29-tetrakis(carboxymethyl)-3,30-bis(((4-((4-guanidinobenzoyl)oxy)benzyl)oxy)carbonyl)-5 ,8,25,28-tetraoxo-12,15,18,21-tetraoxa-3,6,9,24,27,30-hexaazadotriacontane-1,32-dioic acid trifluoroacetate

In a solution of (4S,7S,26S,29S)-di-tert-butyl 3,30-bis(((4-((4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoyl)oxy)benzyl) hydroxy)carbonyl)-4,7,26,29-tetrakis(2-(tert-butoxy)-2-oxoethyl)-5,8,25,28-tetraoxo-12,15,18,21-tetraoxa-3, 6,9,24,27,30-hexaazadotriacontane-1,32-dioate (110 mg) obtained in Example 15-(a) in dichloromethane (1.2 ml) in a 30 ml cylindrical flask was added trifluoroacetic acid (310 μl) at 0°C under argon atmosphere with stirring, and the resulting mixture was stirred at room temperature for 21 hours. After completion of the reaction, the solution was evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (ODS silica gel, elution solvent: water with 0.1% trifluoroacetic acid: acetonitrile with 0.1% trifluoroacetic acid), and fractions with the target compound were freeze-dried to give the title Compound (31 mg) in form of a white solid.

Mass spectrum (ESI, m/z): 716 [M-2H] ^2- .

¹ H-NMR spectrum (400 MHz, CD ₃ CN/D ₂ O = 1/1) δ: 8.27-8.17 (m, 4H), 7.52-7.40 (m, 8H), 7.30-7.21 (m, 4H) , 5.22-5.05 (m, 4H), 4.65-3.93 (m, 8H), 3.64-3.47 (m, 16H), 3.36-3.28 (m, 4H), 3.19-3.08 (m, 2H), 2.86-2.51 ( m, 6H).

Example 16

Example 16-(a)

Preparation of (3S,22S)-di-tert-butyl 3,22-bis((((4-((4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoyl)oxy)benzyl)oxy)carbonyl) (3-(tert-butoxycarbonyl)benzyl)amino)-4,21-dioxo-8,11,14,17-tetraoxa-5,20-diazatetracosan-1,24-dioate

In a solution of (S)-2-((((4-((4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoyl)oxy)benzyl)oxy)carbonyl)(3-(tert-butoxycarbonyl)benzyl )amino)-4-(tert-butoxy)-4-oxobutanoic acid (230 mg) obtained in Comparative Example 16-(c) in anhydrous dichloromethane (2 ml) in a 30 ml cylindrical flask was added COMU (120 mg) and N,N-diisopropylethylamine (0.100 ml) under ice bath cooling under argon atmosphere with stirring, and the resulting mixture was stirred under ice bath cooling for 30 minutes. Then, a solution of 3,6,9,12-tetraoxatetradecane-1,14-diamine (30 mg) in anhydrous dichloromethane (2 ml) was added with stirring while cooling in an ice bath, and the resulting mixture was stirred at room temperature for 3 days. After completion of the reaction, the solution was evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (67 mg) as a colorless oil.

Mass spectrum (ESI, m/z): 992 [M+2H] ²⁺ .

¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ: 11.62 (s, 2H), 10.64 (s, 2H), 8.18-8.11 (m, 4H), 7.97-7.77 (m, 8H), 7.61-7.04 (m, 12H), 6.68-6.57 & 6.18-5.99 (m, 2H total), 5.32-4.26 (m, 10H), 3.71-2.84 (m, 22H), 2.60-2.42 (m, 2H), 1.64-1.50 (m, 54H), 1.43-1.33 (m, 18H).

Example 16-(b)

Preparation of (3S,22S)-3,22-bis((3-carboxybenzyl)(((4-((4-guanidinobenzoyl)oxy)benzyl)oxy)carbonyl)amino)-4,21-dioxo-8.11, 14,17-tetraoxa-5,20-diazatetracosan-1,24-dioic acid trifluoroacetate

In a solution of (3S,22S)-di-tert-butyl 3,22-bis((((4-((4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoyl)oxy)benzyl)oxy)carbonyl )(3-(tert-butoxycarbonyl)benzyl)amino)-4,21-dioxo-8,11,14,17-tetraoxa-5,20-diazatetracosan-1,24-dioate (67 mg) obtained in Example 16 -(a), in anhydrous dichloromethane (1 ml) in a 50 ml round bottom flask was added trifluoroacetic acid (0.250 ml) under ice bath cooling under argon atmosphere with stirring, and the resulting mixture was stirred at room temperature for 16 hours. The reaction solution was evaporated under reduced pressure. To a solution of the resulting evaporation residue in anhydrous dichloromethane (2 ml) was added trifluoroacetic acid (0.250 ml) at room temperature under argon with stirring, and the resulting mixture was stirred at room temperature for 5 hours. After completion of the reaction, the solution was evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (ODS silica gel, elution solvent: water with 0.1% trifluoroacetic acid: acetonitrile with 0.1% trifluoroacetic acid), and fractions with the target compound were freeze-dried to give the title Compound (15 mg) in form of a white solid.

Mass spectrum (ESI, m/z): 679 [M+2H] ²⁺ .

¹ H-NMR spectrum (400 MHz, DMSO-d ₆ + D ₂ O) δ: 8.21-8.01 (m, 6H), 7.89-7.79 (m, 4H), 7.55-7.37 (m, 10H), 7.32- 7.15 (m, 6H), 5.26-5.07 (m, 4H), 4.98-4.76 (m, 2H), 4.62-4.41 (m, 4H), 3.52-3.21 (m, 16H), 3.15-3.03 (m, 4H ), 2.87-2.77 (m, 2H), 2.57-2.44 (m, 2H).

Example 17

Example 17-(a)

Preparation of (2S,2'S)-tetra-tert-butyl 2,2'-((((5,8,11,14-tetraoxa-2,17-diazaoctadecan-1,18-dioyl)bis(3,1-phenylene ))bis(methylene))bis((((4-((4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoyl)oxy)benzyl)oxy)carbonyl)azandiyl))disuccinate

In a solution of (S)-3-(((((4-((4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoyl)oxy)benzyl)oxy)carbonyl)(1,4-di-tert -butoxy-1,4-dioxobutan-2-yl)amino)methyl)benzoic acid (401 mg) obtained in Comparative Example 17-(d) in anhydrous dichloromethane (2 ml) in a 50 ml round bottom flask was added COMU ( 202 mg) and N,N-diisopropylethylamine (0.160 ml) while cooling in an ice bath under argon atmosphere with stirring, and the resulting mixture was stirred while cooling in an ice bath for 30 minutes. Then, a solution of 3,6,9,12-tetraoxatetradecane-1,14-diamine (50 mg) in anhydrous dichloromethane (2 ml) was added with stirring while cooling in an ice bath, and the resulting mixture was stirred at room temperature for 16 hours. After completion of the reaction, the solution was evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (160 mg) as a colorless oil.

Mass spectrum (ESI, m/z): 992 [M+2H] ²⁺ .

¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ: 11.62 (broad s, 2H), 10.64 (s, 2H), 8.21-8.08 (m, 4H), 7.86-7.76 (m, 6H), 7.74 -7.69 (m, 2H), 7.56-6.98 (m, 14H), 5.37-5.04 (m, 4H), 4.91-4.71 (m, 2H), 4.60-4.27 (m, 4H), 3.78-3.50 (m, 20H), 3.18-2.95 (m, 2H), 2.69-2.52 (m, 2H), 1.69-1.16 (m, 72H).

Example 17-(b)

Preparation of (2S,2'S)-2,2'-((((5,8,11,14-tetraoxa-2,17-diazaoctadecan-1,18-dioyl)bis(3,1-phenylene))bis(methylene ))bis((((4-((4-guanidinobenzoyl)oxy)benzyl)oxy)carbonyl)azandiyl))disuccinic acid trifluoroacetate

In a solution of (2S,2'S)-tetra-tert-butyl 2,2'-((((5,8,11,14-tetraoxa-2,17-diazaoctadecan-1,18-dioyl)bis(3,1- phenylene))bis(methylene))bis((((4-((4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoyl)oxy)benzyl)oxy)carbonyl)azandiyl))disuccinate (160 mg) , obtained in Example 17-(a), in anhydrous dichloromethane (4 ml) in a 50 ml round bottom flask was added trifluoroacetic acid (1.00 ml) while cooling in an ice bath under argon atmosphere with stirring, and the resulting mixture was stirred at room temperature for 16 hours. The reaction solution was evaporated under reduced pressure. Trifluoroacetic acid (1.00 ml) was further added to a solution of the resulting evaporation residue in anhydrous dichloromethane (2 ml) at room temperature under argon with stirring, and the resulting mixture was stirred at room temperature for 3 hours. After completion of the reaction, the solution was evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (ODS silica gel, elution solvent: water with 0.1% trifluoroacetic acid: acetonitrile with 0.1% trifluoroacetic acid), and fractions with the title compound were freeze-dried to give the title Compound (65 mg) in form of a white solid.

Mass spectrum (ESI, m/z): 679 [M+2H] ²⁺ .

¹ H-NMR spectrum (400 MHz, CD ₃ CN + D ₂ O) δ: 8.25-8.16 (m, 4H), 7.77-7.73 (m, 2H), 7.70-7.64 (m, 2H), 7.51-7.07 (m, 16H), 5.22-5.07 (m, 4H), 4.73-4.45 (m, 6H), 3.62-3.43 (m, 20H), 3.12-2.52 (m, 4H).

Example 18

Example 18-(a)

Preparation of (2S,2'S)-tetra-tert-butyl 2,2'-((((5,8,11,14-tetraoxa-2,17-diazaoctadecan-1,18-dioyl)bis(3,1-phenylene ))bis(methylene))bis((N-((benzyloxy)carbonyl)-N-(4-((4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoyl)oxy)benzyl)sulfamoyl)azandiyl ))disuccinate

In a solution of (S)-3-(((N-((benzyloxy)carbonyl)-N-(4-((4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoyl)oxy)benzyl)sulfamoyl) (1,4-di-tert-butoxy-1,4-dioxobutan-2-yl)amino)methyl)benzoic acid (205 mg) obtained in Comparative Example 18-(c), 3,6,9,12- tetraoxatetradecane-1,14-diamine (22.1 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (39.0 mg) and triethylamine (40 μl) in dichloromethane (5 ml) in a 50 ml round bottom flask was added 1-hydroxybenzotriazole (28.5 mg) at room temperature under argon flow with stirring, and the resulting mixture was stirred at room temperature for 18 hours. After the completion of the reaction, 1N sodium hydroxide was added to the solution. hydrochloric acid solution, and the resulting solution was extracted with dichloromethane. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (190 mg) as a white foam.

Mass spectrum (ESI, m/z): 1161 [M+2H] ²⁺ .

¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ: 11.62 (s, 2H), 10.64 (s, 2H), 8.19-8.11 (m, 4H), 7.84-7.77 (m, 4H), 7.74-7.65 (m, 4H), 7.45-7.23 (m, 18H), 7.14-7.09 (m, 4H), 7.07-6.99 (m, 2H), 5.21 (s, 4H), 4.91-4.69 (m, 8H), 4.29 (d, J = 16.8 Hz, 2H), 3.67–3.56 (m, 20H), 2.58 (dd, J = 8.8, 16.7 Hz, 2H), 2.43 (dd, J = 5.2, 16.7 Hz, 2H), 1.55 ( s, 18H), 1.53 (s, 18H), 1.44 (s, 18H), 1.36 (s, 18H).

Example 18-(b)

Preparation of (2S,2'S)-2,2'-((((5,8,11,14-tetraoxa-2,17-diazaoctadecan-1,18-dioyl)bis(3,1-phenylene))bis(methylene ))bis((N-(4-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl)azandiyl))disuccinic acid trifluoroacetate

In a solution of (2S,2'S)-tetra-tert-butyl 2,2'-((((5,8,11,14-tetraoxa-2,17-diazaoctadecan-1,18-dioyl)bis(3,1- phenylene))bis(methylene))bis((N-((benzyloxy)carbonyl)-N-(4-((4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoyl)oxy)benzyl)sulfamoyl) azandiyl))disuccinate (190 mg) prepared in the same manner as described for Example 18-(a), in dichloromethane (3 ml) in a 50 ml round bottom flask, trifluoroacetic acid (3 ml) was added at room temperature under argon with stirring, and the resulting mixture was stirred at room temperature for 18 hours. The reaction solution was evaporated under reduced pressure. To a solution of the obtained evaporation residue in methanol (5 ml) was added 5% palladium on carbon (moisture content 54.28%, STD-type manufactured by NE CHEMCAT Corporation) (51 mg) at room temperature under argon atmosphere with stirring, and the resulting mixture was stirred at room temperature in a hydrogen atmosphere for 2 hours. After completion of the reaction, the solution was filtered through Celite. The separated solid was washed with methanol and the resulting filtrate was evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (ODS silica gel, elution solvent: acetonitrile with 0.1% trifluoroacetic acid: water with 0.1% trifluoroacetic acid), and fractions with the target compound were freeze-dried to give the title Compound (80 mg) in form of a white solid.

Mass spectrum (ESI, m/z): 714 [M+2H] ²⁺ .

¹ H-NMR spectrum (400 MHz, DMSO-d ₆ + D ₂ O) δ: 8.20-8.13 (m, 4H), 7.90-7.85 (m, 2H), 7.79-7.73 (m, 2H), 7.64- 7.57 (m, 2H), 7.49-7.38 (m, 10H), 7.26-7.20 (m, 4H), 4.57 (d, J = 15.9 Hz, 2H), 4.40-4.09 (m, 8H), 3.66-3.29 ( m, 20H), 2.83 (dd, J = 9.8, 16.5 Hz, 2H), 2.61 (dd, J = 3.6, 16.5 Hz, 2H).

Example 19

Example 19-(a)

Preparation of tetra-tert-butyl 3,12-bis(10-(2,3-bis(tert-butoxycarbonyl)guanidino)-13-oxo-6,7,8,13-tetrahydrodibenzo[b,f][1,4 ]dioxecin-4-carbonyl)-6,9-dioxa-3,12-diazatetradecane-1,2,13,14-tetracarboxylate

To a solution of tetra-tert-butyl 6,9-dioxa-3,12-diazatetradecane-1,2,13,14-tetracarboxylate (1.44 g) obtained in Comparative Example 19-(q) and 10-(2.3 -bis(tert-butoxycarbonyl)guanidino)-13-oxo-6,7,8,13-tetrahydrodibenzo[b,f][1,4]dioxecine-4-carboxylic acid (3.00 g) obtained in Comparative Example 19- (n), N,N-diisopropylethylamine (1.15 ml) and COMU (2.53 g) were added in dimethylformamide (20 ml) in a 100 ml round bottom flask at room temperature under air with stirring, and the resulting mixture was stirred at room temperature for night. After completion of the reaction, a saturated sodium hydrogen carbonate aqueous solution was added to the solution, and the resulting solution was extracted with ethyl acetate. The organic layer was washed successively with a 0.02M hydrochloric acid solution and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (2.10 g) as a light yellow foam.

Mass spectrum (ESI, m/z): 1680 [M+H] ⁺ .

¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ: 11.62-11.51 (m, 2H), 10.58-10.36 (m, 2H), 8.12-7.70 (m, 4H), 7.65-7.51 (m, 2H) , 7.49-7.40 (m, 2H), 7.35-6.91 (m, 4H), 4.70-2.53 (m, 26H), 2.39-0.78 (m, 76H).

Example 19-(b)

Preparation of 3,12-bis(10-guanidino-13-oxo-6,7,8,13-tetrahydrodibenzo[b,f][1,4] dioxecine-4-carbonyl)-6,9-dioxa-3,12 -diazatetradecane-1,2,13,14-tetracarboxylic acid trifluoroacetate

Into a solution of tetra-tert-butyl 3,12-bis(10-(2,3-bis(tert-butoxycarbonyl)guanidino)-13-oxo-6,7,8,13-tetrahydrodibenzo[b,f][1, 4]dioxecin-4-carbonyl)-6,9-dioxa-3,12-diazatetradecane-1,2,13,14-tetracarboxylate (2.10 g) obtained in Example 19-(a) in dichloromethane (8 ml) in a 100 ml round bottom flask, trifluoroacetic acid (2.0 ml) was added at 0° C. under air with stirring, and the resulting mixture was stirred at room temperature for 16 hours. Additional trifluoroacetic acid (2.0 ml) was added with stirring at room temperature, and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, the solution was evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: water with 0.1% trifluoroacetic acid: acetonitrile with 0.1% trifluoroacetic acid), and fractions with the target compound were freeze-dried. The resulting residue was purified by preparative medium pressure chromatography (ODS silica gel, elution solvent: water with 0.1% trifluoroacetic acid: acetonitrile with 0.1% trifluoroacetic acid), and fractions with the target compound were freeze-dried. The resulting solid was dissolved in water/acetonitrile and the solution was lyophilized to give the title Compound (377 mg) as a white solid.

Mass spectrum (ESI, m/z): 1055 [M+H] ⁺ .

¹ H-NMR spectrum (500 MHz, DMSO-d ₆ + D ₂ O) δ: 7.92-7.81 (m, 2H), 7.58-7.47 (m, 2H), 7.36-7.05 (m, 8H), 4.61- 2.36 (m, 26H), 2.12-1.65 (m, 4H).

Example 19-(c)

Preparation of 3,12-bis(10-guanidino-13-oxo-6,7,8,13-tetrahydrodibenzo[b,f][1,4] dioxecine-4-carbonyl)-6,9-dioxa-3,12 -diazatetradecane-1,2,13,14-tetracarboxylic acid hydrochloride

Solution 3,12-bis(10-guanidino-13-oxo-6,7,8,13-tetrahydrodibenzo[b,f][1,4] dioxecine-4-carbonyl)-6,9-dioxa-3,12 -diazatetradecane-1,2,13,14-tetracarboxylic acid trifluoroacetate (344 mg) obtained in Example 19-(b) in 0.1M hydrochloric acid solution (30 ml)/acetonitrile (8 ml) in a 300 ml round bottom the flask was lyophilized to give the title Compound (288.5 mg) as a white solid.

Mass spectrum (ESI, m/z): 1055 [M+H] ⁺ .

¹ H-NMR spectrum (400 MHz, DMSO-d ₆ + D ₂ O) δ: 7.94-7.81 (m, 2H), 7.61-7.47 (m, 2H), 7.36-7.05 (m, 8H), 4.58- 4.41 (m, 2H), 4.04-2.43 (m, 24H), 2.13-1.71 (m, 4H).

Example 20

Example 20-(a)

Preparation of (2S,13S)-tetra-tert-butyl 3,12-bis(10-(2,3-bis(tert-butoxycarbonyl)guanidino)-13-oxo-6,7,8,13-tetrahydrodibenzo[b, f][1,4]dioxecin-4-carbonyl)-6,9-dioxa-3,12-diazatetradecane-1,2,13,14-tetracarboxylate

Into a suspension of 10-(2,3-bis(tert-butoxycarbonyl)guanidino)-13-oxo-6,7,8,13-tetrahydrodibenzo[b,f][1,4]dioxecine-4-carboxylic acid (2.20 g ) obtained by the same procedure as described for Comparative Example 19-(n), N,N-diisopropylethylamine (1.00 ml) and COMU (1.85 g) were added in anhydrous dimethylformamide (10 ml) in a 200 ml round bottom flask with cooling in an ice bath under argon atmosphere with stirring, and the resulting mixture was stirred while cooling in an ice bath for 30 minutes. Then a solution of (2S,13S)-tetra-tert-butyl 6,9-dioxa-3,12-diazatetradecane-1,2,13,14-tetracarboxylate (1.10 g) obtained by the same procedure as described for Comparative example 2-(b), in anhydrous dimethylformamide (5 ml) with stirring while cooling in an ice bath, and the resulting mixture was stirred at room temperature for 16 hours. After completion of the reaction, a saturated sodium hydrogen carbonate aqueous solution was added to the solution, and the resulting solution was extracted with ethyl acetate. The organic layer was washed successively with 0.1M hydrochloric acid and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (DIOL silica gel, elution solvent: hexane:ethyl acetate), and fractions with the title compound were evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (2.09 g) as a yellow oil.

Mass Spectrum (ESI, m/z): 1678 [MH] ^- .

¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ: 11.62 (s, 2H), 10.54 (s, 2H), 8.01-7.91 (m, 2H), 7.86-7.77 (m, 2H), 7.65-7.50 (m, 2H), 7.49-7.40 (m, 2H), 7.29-6.98 (m, 4H), 4.66-4.34 (m, 2H), 4.22-2.57 (m, 24H), 2.21-1.29 (m, 76H) .

Example 20-(b)

Preparation of (2S,13S)-3,12-bis(10-guanidino-13-oxo-6,7,8,13-tetrahydrodibenzo[b,f][1,4]dioxecine-4-carbonyl)-6,9 -dioxa-3,12-diazatetradecane-1,2,13,14-tetracarboxylic acid trifluoroacetate

In a solution of (2S,13S)-tetra-tert-butyl 3,12-bis(10-(2,3-bis(tert-butoxycarbonyl)guanidino)-13-oxo-6,7,8,13-tetrahydrodibenzo[b ,f][1,4] dioxecine-4-carbonyl)-6,9-dioxa-3,12-diazatetradecane-1,2,13,14-tetracarboxylate (2.09 g) obtained in Example 20-(a), in anhydrous dichloromethane (9 ml) in a 200 ml round bottom flask was added trifluoroacetic acid (3.00 ml) under ice bath cooling under argon atmosphere with stirring, and the resulting mixture was stirred at room temperature for 2 hours. The reaction solution was evaporated under reduced pressure. To a solution of the resulting evaporation residue in anhydrous dichloromethane (9 ml) was added trifluoroacetic acid (3.00 ml) at room temperature under argon with stirring, and the resulting mixture was stirred at room temperature for 16 hours. The reaction solution was evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: acetonitrile with 0.1% trifluoroacetic acid: water with 0.1% trifluoroacetic acid), and fractions with the target compound were freeze-dried. The resulting residue was purified by preparative medium pressure chromatography (ODS silica gel, elution solvent: water with 0.1% trifluoroacetic acid: acetonitrile with 0.1% trifluoroacetic acid), and fractions with the target compound were freeze-dried. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: acetonitrile with 0.1% trifluoroacetic acid: water with 0.1% trifluoroacetic acid), and fractions with the target compound were freeze-dried. The resulting solid was dissolved in a mixed solvent of water with 0.1% trifluoroacetic acid and acetonitrile with 0.1% trifluoroacetic acid (4:1 (v/v)), and the resulting solution was lyophilized. The resulting solid was dissolved in a mixture of water and acetonitrile (4:1 (v/v)), and the resulting solution was lyophilized to give the title Compound (589 mg) as a white solid.

Mass spectrum (ESI, m/z): 1055 [M+H] ⁺ .

¹ H-NMR spectrum (400 MHz, DMSO-d ₆ + D ₂ O) δ: 7.94-7.81 (m, 2H), 7.60-7.46 (m, 2H), 7.36-7.03 (m, 8H), 4.56- 4.34 (m, 2H), 4.22-2.40 (m, 24H), 2.10-1.71 (m, 4H).

Example 20-(c)

Preparation of (2S,13S)-3,12-bis(10-guanidino-13-oxo-6,7,8,13-tetrahydrodibenzo[b,f][1,4]dioxecine-4-carbonyl)-6,9 -dioxa-3,12-diazatetradecane-1,2,13,14-tetracarboxylic acid hydrochloride

(2S,13S)-3,12-bis(10-guanidino-13-oxo-6,7,8,13-tetrahydrodibenzo[b,f][1,4]dioxecine-4-carbonyl)-6,9 solution -dioxa-3,12-diazatetradecane-1,2,13,14-tetracarboxylic acid trifluoroacetate (533 mg) obtained in Example 20-(b) in acetonitrile (11.5 ml)/0.1M hydrochloric acid solution (46.0 ml ) in a 300 ml round bottom flask was lyophilized to give the title Compound (421 mg) as a white solid.

Mass spectrum (ESI, m/z): 1055 [M+H] ⁺ .

¹ H-NMR spectrum (400 MHz, DMSO-d ₆ + D ₂ O) δ: 7.94-7.81 (m, 2H), 7.61-7.46 (m, 2H), 7.36-7.04 (m, 8H), 4.57- 4.38 (m, 2H), 4.04-2.45 (m, 24H), 2.12-1.70 (m, 4H).

Example 20-(d)

Preparation of (2S,13S)-3,12-bis(10-guanidino-13-oxo-6,7,8,13-tetrahydrodibenzo[b,f][1,4]dioxecine-4-carbonyl)-6,9 -dioxa-3,12-diazatetradecane-1,2,13,14-tetracarboxylic acid

K (2S,13S)-tetra-tert-butyl 3,12-bis(10-(2,3-bis(tert-butoxycarbonyl)guanidino)-13-oxo-6,7,8,13-tetrahydrodibenzo[b, f][1,4]dioxecin-4-carbonyl)-6,9-dioxa-3,12-diazatetradecane-1,2,13,14-tetracarboxylate (6.98 g) prepared in the same manner as described for Example 20-(a), a 4M solution of hydrogen chloride in dioxane (40 ml) was added to a 200 ml round bottom flask at room temperature, and the resulting mixture was stirred at room temperature for 15 hours. After completion of the reaction, the solution was evaporated under reduced pressure. Toluene was added to the evaporation residue and the resulting mixture was subjected to azeotropic distillation. Then acetonitrile was added to the evaporation residue, and the resulting mixture was subjected to azeotropic distillation. A solution of the resulting residue in acetonitrile (10 ml)/water (20 ml)/trifluoroacetic acid (0.5 ml) was purified by preparative medium pressure chromatography (ODS silica gel, elution solvent: water with 0.1% trifluoroacetic acid : acetonitrile with 0.1% trifluoroacetic acid ), and fractions with the target compound were freeze-dried. A solution of the resulting residue in acetonitrile (40 ml)/water (5.5 ml) was purified by preparative medium pressure chromatography (ODS silica gel, elution solvent: water with 0.1% trifluoroacetic acid : acetonitrile with 0.1% trifluoroacetic acid), and fractions with the target compound subjected to freeze drying. To a solution of the resulting residue in a mixture of water (75 ml)/acetonitrile (25 ml) was added a saturated aqueous solution of ammonium acetate with stirring, bringing the pH to 4.2. The resulting mixture was stirred at room temperature for 7 hours, the precipitate formed was filtered off and dried under reduced pressure to give the title Compound (3.16 g) as a white solid.

Mass spectrum (ESI, m/z): 1055 [M+H] ⁺ .

¹ H-NMR spectrum (400 MHz, DMSO-d ₆ + D ₂ O) δ: 7.83-7.64 (m, 2H), 7.53-7.36 (m, 2H), 7.29-7.00 (m, 8H), 4.62- 2.37 (m, 26H), 2.05-1.65 (m, 4H).

Example 21

Example 21-(a)

Preparation of (2R,13R)-tetra-tert-butyl 3,12-bis(10-(2,3-bis(tert-butoxycarbonyl)guanidino)-13-oxo-6,7,8,13-tetrahydrodibenzo[b, f][1,4]dioxecin-4-carbonyl)-6,9-dioxa-3,12-diazatetradecane-1,2,13,14-tetracarboxylate

Into a suspension of 10-(2,3-bis(tert-butoxycarbonyl)guanidino)-13-oxo-6,7,8,13-tetrahydrodibenzo[b,f][1,4]dioxecine-4-carboxylic acid (2.20 g ) obtained by the same procedure as described for Comparative Example 19-(n), N,N-diisopropylethylamine (1.00 ml) and COMU (1.85 g) were added in anhydrous dimethylformamide (10 ml) in a 200 ml round bottom flask with cooling in an ice bath under argon atmosphere with stirring, and the resulting mixture was stirred while cooling in an ice bath for 30 minutes. Then, a solution of (2R,13R)-tetra-tert-butyl 6,9-dioxa-3,12-diazatetradecane-1,2,13,14-tetracarboxylate (1.25 g) obtained in Comparative Example 21-(b) was added, in anhydrous dimethylformamide (5 ml) with stirring while cooling in an ice bath, and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, a saturated sodium hydrogen carbonate aqueous solution was added to the solution, and the resulting solution was extracted with ethyl acetate. The organic layer was washed successively with 0.1M hydrochloric acid and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (2.16 g) as a yellow foam.

Mass Spectrum (ESI, m/z): 1678 [MH] ^- .

¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ: 11.62 (s, 2H), 10.54 (s, 2H), 8.01-7.92 (m, 2H), 7.86-7.78 (m, 2H), 7.65-7.50 (m, 2H), 7.49-7.40 (m, 2H), 7.31-6.97 (m, 4H), 4.67-4.35 (m, 2H), 4.22-2.56 (m, 24H), 2.22-1.29 (m, 76H) .

Example 21-(b)

Preparation of (2R,13R)-3,12-bis(10-guanidino-13-oxo-6,7,8,13-tetrahydrodibenzo[b,f][1,4]dioxecine-4-carbonyl)-6,9 -dioxa-3,12-diazatetradecane-1,2,13,14-tetracarboxylic acid trifluoroacetate

In a solution of (2R,13R)-tetra-tert-butyl 3,12-bis(10-(2,3-bis(tert-butoxycarbonyl)guanidino)-13-oxo-6,7,8,13-tetrahydrodibenzo[b ,f][1,4] dioxecine-4-carbonyl)-6,9-dioxa-3,12-diazatetradecane-1,2,13,14-tetracarboxylate (2.16 g) obtained in Example 21-(a), in dichloromethane (9 ml) in a 200 ml round bottom flask was added trifluoroacetic acid (3 ml) under ice bath cooling under argon atmosphere with stirring, and the resulting mixture was stirred at room temperature overnight. The reaction solution was evaporated under reduced pressure. The evaporation residue was dissolved in dichloromethane (9 ml), trifluoroacetic acid (3 ml) was added under ice bath cooling under argon atmosphere with stirring, and the resulting mixture was stirred at room temperature for 6 hours. After completion of the reaction, the solution was evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: water with 0.1% trifluoroacetic acid: acetonitrile with 0.1% trifluoroacetic acid), and fractions with the target compound were freeze-dried. The resulting residue was purified by preparative medium pressure chromatography (ODS silica gel, elution solvent: water with 0.1% trifluoroacetic acid : acetonitrile with 0.1% trifluoroacetic acid), and fractions with the target compound were freeze-dried to give the title Compound (0.757 g) in form of a white solid.

Mass Spectrum (ESI, m/z): 1053 [MH] ^- .

¹ H-NMR spectrum (500 MHz, DMSO-d ₆ + D ₂ O) δ: 7.92-7.82 (m, 2H), 7.58-7.44 (m, 2H), 7.33-7.06 (m, 8H), 4.63- 4.38 (m, 2H), 4.17-2.43 (m, 24H), 2.17-1.71 (m, 4H).

Example 21-(c)

Preparation of (2R,13R)-3,12-bis(10-guanidino-13-oxo-6,7,8,13-tetrahydrodibenzo[b,f][1,4]dioxecine-4-carbonyl)-6,9 -dioxa-3,12-diazatetradecane-1,2,13,14-tetracarboxylic acid hydrochloride

(2R,13R)-3,12-bis(10-guanidino-13-oxo-6,7,8,13-tetrahydrodibenzo[b,f][1,4]dioxecin-4-carbonyl)-6,9 solution -dioxa-3,12-diazatetradecane-1,2,13,14-tetracarboxylic acid trifluoroacetate (734 mg) obtained in Example 21-(b) in 0.1M hydrochloric acid solution (63.0 ml)/acetonitrile (16 ml ) in a 300 ml round bottom flask was lyophilized to give the title Compound (640 mg) as a white solid.

Mass spectrum (ESI, m/z): 1055 [M+H] ⁺ .

¹ H-NMR spectrum (400 MHz, DMSO-d ₆ + D ₂ O) δ: 7.94-7.81 (m, 2H), 7.60-7.48 (m, 2H), 7.35-7.04 (m, 8H), 4.56- 4.40 (m, 2H), 4.04-2.43 (m, 24H), 2.11-1.70 (m, 4H).

Example 22-(a)

Preparation of (2S,13S)-3,12-bis(N-(4-((4-guanidinobenzoyl)oxy)benzyl)-N-methylsulfamoyl)-6,9-dioxa-3,12-diazatetradecane-1,2, 13,14-tetracarboxylic acid trifluoroacetate

In suspension (2S,13S)-3,12-bis(N-(4-((4-aminobenzoyl)oxy)benzyl)-N-methylsulfamoyl)-6,9-dioxa-3,12-diazatetradecan-1,2 ,13,14-tetracarboxylic acid hydrochloride (51.6 mg) obtained in Comparative Example 22-(e) in tert-butanol (1.0 ml) in a 30 ml cylindrical flask was added cyanamide (12.6 mg) and a 4M solution of hydrogen chloride in dioxane ( 71 μl) at room temperature under argon flow with stirring, and the resulting mixture was stirred at 60°C for 5 hours. After completion of the reaction, water (5 ml) was added to the solution. Then, a 10% ammonium acetate aqueous solution was added to adjust the pH to 4, and the resulting mixture was stirred at room temperature for 1 hour. The precipitate that formed was separated by filtration, washed with water, and dried under reduced pressure. The resulting solid was purified by preparative medium pressure chromatography (ODS silica gel, elution solvent: water with 0.1% trifluoroacetic acid: acetonitrile with 0.1% trifluoroacetic acid), and the resulting mixture was lyophilized to give the title Compound (13.4 mg) as white solid.

Mass spectrum (ESI, m/z): 1101 [M+H] ⁺ .

¹ H-NMR spectrum (400 MHz, DMSO-d ₆ + D ₂ O) δ: 8.22-8.13 (m, 4H), 7.49-7.38 (m, 8H), 7.32-7.22 (m, 4H), 4.57 ( dd, J = 5.5, 8.3 Hz, 2H), 4.38 (d, J = 15.8 Hz, 2H), 4.34 (d, J = 15.8 Hz, 2H), 3.91–3.49 (m, 12H), 2.98 (dd, J = 8.3, 16.6 Hz, 2H), 2.77-2.64 (m, 8H).

Example 23-(a)

Preparation of tetrabenzyl 3,3'-(((ethane-1,2-diylbis(oxy))bis(ethane-2,1-diyl))bis((N-((benzyloxy)carbonyl)-N-(4-( (4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoyl)oxy)benzyl)sulfamoyl)azandiyl))dipentanedioate

To a solution of tetrabenzyl 3,3'-(((ethane-1,2-diylbis(oxy))bis(ethane-2,1-diyl))bis((N-((benzyloxy)carbonyl)sulfamoyl)azandiyl))dipentanedioate (1.47 g) obtained in Comparative Example 23-(e) and 4-(hydroxymethyl)phenyl 4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoate (1.26 g) obtained by the same procedure as described for Comparative Example 1-(g), in anhydrous tetrahydrofuran (30 ml) in a 300 ml round bottom flask, triphenylphosphine (0.90 g) was added at room temperature under argon with stirring, and the resulting mixture was stirred at room temperature. Then, diisopropyl azodicarboxylate (1.9M solution in toluene) (1.80 ml) was added at room temperature while cooling on a water bath, and the resulting mixture was stirred at room temperature for 4 hours. After completion of the reaction, the solution was diluted with ethyl acetate (100 ml), a 1% aqueous potassium hydrogen sulfate solution (50 ml) and a saturated aqueous sodium chloride solution (50 ml) were added, and the resulting solution was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution (100 ml), saturated aqueous sodium hydrogen carbonate solution (50 ml) and saturated aqueous sodium chloride solution (50 ml), dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate), and fractions with the title compound were evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: dichloromethane:ethyl acetate), and fractions with the title compound were evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: toluene:ethyl acetate) to give the title Compound (0.68 g) as a white foam.

Mass spectrum (ESI, m/z): 1066 [M+2H] ²⁺ .

¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ: 11.62 (broad s, 2H), 10.63 (s, 2H), 8.18-8.12 (m, 4H), 7.83-7.78 (m, 4H), 7.39 -7.06 (m, 38H), 5.15-5.10 (m, 4H), 5.10-5.01 (m, 8H), 4.91 (s, 4H), 4.50-4.39 (m, 2H), 3.56-3.36 (m, 12H) , 2.81 (dd, J = 6.5, 16.4 Hz, 4H), 2.69 (dd, J = 7.3, 16.4 Hz, 4H), 1.60–1.49 (m, 36H).

Example 23-(b)

Preparation of 3,3'-(((ethane-1,2-diylbis(oxy))bis(ethane-2,1-diyl))bis((N-(4-((4-(2,3-bis( tert-Butoxycarbonyl)guanidino)benzoyl)oxy)benzyl)sulfamoyl)azandiyl))dipentanedioic acid

In a solution of tetrabenzyl 3,3'-(((ethane-1,2-diylbis(oxy))bis(ethane-2,1-diyl))bis((N-((benzyloxy)carbonyl)-N-(4- ((4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoyl)oxy)benzyl)sulfamoyl)azandiyl))dipentanedioate (326.7mg) obtained in Example 23-(a) in ethanol (5ml) /tetrahydrofuran (2 ml) in a 30 ml cylindrical flask was added ASCA-2 (water content 52%, manufactured by NE CHEMCAT Corporation) (213.3 mg) at room temperature under nitrogen atmosphere, and the resulting mixture was stirred at room temperature under hydrogen atmosphere for 2 hours. After completion of the reaction, the solution was filtered and washed with ethanol. The resulting filtrate and washing solution were combined and evaporated under reduced pressure. The obtained residue was purified by preparative medium pressure chromatography (DIOL silica gel, elution solvent: ethyl acetate:acetic acid), fractions with the target compound were washed with water (five times) and saturated aqueous sodium chloride solution (once), dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (DIOL silica gel, elution solvent: ethyl acetate:acetic acid), and fractions with the title compound were evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (DIOL silica gel, elution solvent: ethyl acetate:acetic acid), and fractions with the title compound were evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (DIOL silica gel, elution solvent: ethyl acetate:acetic acid), and fractions with the title compound were evaporated under reduced pressure. The evaporation residue was diluted with ethyl acetate, washed with water (three times) and saturated aqueous sodium chloride solution (once), dried over anhydrous magnesium sulfate, filtered, evaporated under reduced pressure, hexane was added, and the resulting mixture was evaporated under reduced pressure, obtaining specified in title Compound (85.6 mg) as a white solid.

Mass spectrum (ESI, m/z): 752 [M+2H] ²⁺ .

¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ: 11.66 (brs, 2H), 10.60 (brs, 2H), 8.14-8.09 (m, 4H), 7.77-7.72 (m, 4H) , 7.42-7.34 (m, 4H), 7.19-7.11 (m, 4H), 5.57-5.34 (m, 2H), 4.37-4.06 (m, 6H), 3.50-3.27 (m, 12H), 2.96 (dd, J = 7.0, 16.4 Hz, 4H), 2.70 (dd, J = 6.4, 16.4 Hz, 4H), 1.53 (s, 36H).

Example 23-(c)

Preparation of 3,3'-(((ethane-1,2-diylbis(oxy))bis(ethane-2,1-diyl))bis((N-(4-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl )azandiyl))dipentanedioic acid

K 3,3'-(((ethane-1,2-diylbis(oxy))bis(ethane-2,1-diyl))bis((N-(4-((4-(2,3-bis( tert-butoxycarbonyl)guanidino)benzoyl)oxy)benzyl)sulfamoyl)azandiyl))dipentanedioic acid (85.6mg) obtained in Example 23-(b), in a 50ml round bottom flask was added a 4M solution of hydrogen chloride in dioxane (5ml), and the resulting mixture was stirred at room temperature for 19 hours. After completion of the reaction, the solution was evaporated under reduced pressure. Cyclohexane was added to the evaporation residue and the resulting mixture was evaporated under reduced pressure. Anhydrous diethyl ether was added to the evaporation residue, the resulting mixture was kept in an ultrasonic bath, stirred at room temperature for 1 hour, the resulting solid was separated by filtration and washed with diethyl ether. The resulting solid was isolated by preparative supercritical liquid chromatography (column: Torus DEA OBD Prep column (trade name, manufactured by Waters Corporation), elution solvent: carbon dioxide: methanol), and fractions with the target compound were freeze-dried to give the title Compound (2.0 mg) as a white solid.

Mass spectrum (DUIS, m/z): 551 [M+2H] ²⁺ .

¹ H-NMR spectrum (500 MHz, (CF ₃ ) ₂ CDOD + D ₂ O) δ: 8.27 (d, J = 7.9 Hz, 4H), 7.49 (d, J = 7.9 Hz, 4H), 7.38 (d , J = 8.0 Hz, 4H), 7.16 (d, J = 8.0 Hz, 4H), 4.69-4.56 (m, 2H), 4.35-4.27 (m, 4H), 3.83-3.42 (m, 12H), 2.88- 2.59 (m, 8H).

Example 24-(a)

Preparation of (2S,2'S)-2,2'-((1,12-bis(4-((4-guanidinobenzoyl)oxy)phenyl)-5,8-dioxa-2,11-diazadecanedisulfonyl)bis(azandiyl)) disuccinic acid

In suspension (2S,2'S)-2,2'-((1,12-bis(4-((4-aminobenzoyl)oxy)phenyl)-5,8-dioxa-2,11-diazadecanedisulfonyl)bis(azandiyl) )succinic acid hydrochloride (0.83 g) obtained in Comparative Example 24-(g) in tert-butanol (7 ml) cyanamide (0.20 g) and a 4M solution of hydrogen chloride in dioxane (1.17 ml) were added in a 100 ml round bottom flask at room temperature in a stream of argon with stirring, and the resulting mixture was stirred at 60°C for 5 hours. After completion of the reaction, the solution was evaporated under reduced pressure. The evaporation residue was subjected to a single azeotropic distillation with toluene and then once with acetonitrile. The resulting residue was dissolved in acetonitrile (2.0 ml)/water (4.0 ml)/trifluoroacetic acid (0.06 ml), the resulting solution was purified by preparative medium pressure chromatography (ODS silica gel, elution solvent: water with 0.1% trifluoroacetic acid : acetonitrile with 0.1 % trifluoroacetic acid), and fractions with the target compound were freeze-dried. The resulting residue was dissolved in acetonitrile (8 ml)/water (32 ml), a saturated aqueous ammonium acetate solution was added to the resulting solution with stirring, adjusting the pH to 4.17, and the resulting mixture was stirred at room temperature for 17 hours. The precipitate that formed was collected by filtration, washed with water and dried under reduced pressure to give the title Compound (0.20 g) as a white solid.

Mass Spectrum (ESI, m/z): 537 [M+2H] ²⁺ .

¹ H-NMR spectrum (400 MHz, DMSO-d ₆ + D ₂ O) δ: 8.09-8.00 (m, 4H), 7.40-7.29 (m, 4H), 7.27-7.17 (m, 4H), 7.13- 7.03 (m, 4H), 4.40-4.18 (m, 4H), 3.97-3.84 (m, 2H), 3.40-3.07 (m, 12H), 2.67-2.40 (m, 4H).

Example 25-(a)

Preparation of (2S,13S)-tetra-tert-butyl 3,12-bis(N-((benzyloxy)carbonyl)-N-(3-(((4-(2,3-bis(tert-butoxycarbonyl)guanidino) benzoyl)oxy)benzyl)sulfamoyl)-6,9-dioxa-3,12-diazatetradecane-1,2,13,14-tetracarboxylate

(1) To a solution of (2S,13S)-tetra-tert-butyl 3,12-bis(N-((benzyloxy)carbonyl)sulfamoyl)-6,9-dioxa-3,12-diazatetradecane-1,2,13 ,14-tetracarboxylate (206.4 mg) obtained in the same manner as described for Comparative Example 2-(c) and 3-(hydroxymethyl)phenyl 4-(2,3-bis(tert-butoxycarbonyl)guanidino) benzoate ( 203.8 mg) obtained by the same procedure as described for Comparative Example 1-(g)-14, triphenylphosphine (146.9 mg) was added in anhydrous tetrahydrofuran (2 ml) in a 10 ml two-necked flask at room temperature under argon flow with stirring . Then, diisopropyl azodicarboxylate (1.9M solution in toluene) (295 μl) was added dropwise at room temperature over 5 minutes, and the resulting mixture was stirred for 5 hours.

(2) To a solution of (2S,13S)-tetra-tert-butyl 3,12-bis(N-((benzyloxy)carbonyl)sulfamoyl)-6,9-dioxa-3,12-diazatetradecane-1,2,13 ,14-tetracarboxylate (2.14 g) obtained in the same manner as described for Comparative Example 2-(c) and 3-(hydroxymethyl)phenyl 4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoate ( 2.11 g) prepared by the same procedure as that described for Comparative Example 1-(g)-14, triphenylphosphine (1.53 g) was added in anhydrous tetrahydrofuran (20 ml) in a 100 ml three-necked flask at room temperature under argon flow with stirring . Then, diisopropyl azodicarboxylate (1.9M solution in toluene) (3.05 ml) was added dropwise at room temperature over 10 minutes, and the resulting mixture was stirred for 4 hours.

The reaction solution from (1) and the reaction solution from (2) were combined, water (40 ml) was added, and the resulting solution was extracted with ethyl acetate (100 ml). The organic layer was washed with saturated aqueous sodium chloride solution (40 ml), dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate), and fractions with the title compound were evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: toluene:ethyl acetate) to give the title Compound (3.51 g) as a white foam.

Mass Spectrum (ESI, m/z): 984 [M+2H] ²⁺ .

¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ: 11.61 (s, 2H), 10.62 (s, 2H), 8.18-8.11 (m, 4H), 7.86-7.77 (m, 4H), 7.36-7.10 (m, 18H), 5.18 (d, J = 12.1 Hz, 2H), 5.14 (d, J = 12.1 Hz, 2H), 5.00–4.90 (m, 4H), 4.69 (dd, J = 6.2, 8.1 Hz, 2H), 3.77-3.66 (m, 2H), 3.60-3.44 (m, 8H), 3.40-3.28 (m, 2H), 2.90 (dd, J = 8.1, 16.7 Hz, 2H), 2.66 (dd, J = 6.2, 16.7 Hz, 2H), 1.56 (s, 18H), 1.53 (s, 18H), 1.44 (s, 18H), 1.44 (s, 18H).

Example 25-(b)

Preparation of (2S,13S)-3,12-bis(N-(3-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl)-6,9-dioxa-3,12-diazatetradecane-1,2,13,14 -tetracarboxylic acid

In a solution of (2S,13S)-tetra-tert-butyl 3,12-bis(N-((benzyloxy)carbonyl)-N-(3-(((4-(2,3-bis(tert-butoxycarbonyl)guanidino )benzoyl)oxy)benzyl)sulfamoyl)-6,9-dioxa-3,12-diazatetradecane-1,2,13,14-tetracarboxylate (3.50 g) obtained in Example 25-(a) in anhydrous toluene (13.5 ml) in a 300 ml round bottom flask was added trifluoroacetic acid (13.5 ml) at room temperature with stirring, and the resulting mixture was stirred at 50°C for 15 hours. with toluene (25 ml) and then with acetonitrile (25 ml) four times and dried under reduced pressure to give (2S,13S)-3,12-bis(N-((benzyloxy)carbonyl)-N-(3-( (4-guanidinobenzoyl)oxy)benzyl)-sulfamoyl)-6,9-dioxa-3,12-diazatetradecane-1,2,13,14-tetracarboxylic acid trifluoroacetate in the form of a white foam. 3,12-bis(N-((benzyloxy)carbonyl)-N-(3-((4-guanidinobenzoyl)oxy)benzyl )sulfamoyl)-6,9-dioxa-3,12-diazatetradecane-1,2,13,14-tetracarboxylic acid trifluoroacetate (2.39 g) in acetic acid (20 ml)/water (4 ml) in a 500 ml round bottom ASCA-2 (water content 52%, manufactured by NE CHEMCAT Corporation) (360.3 mg) was added to the flask at room temperature, the reaction system was filled with hydrogen, and then the resulting mixture was stirred at room temperature for 5 hours. After completion of the reaction, the solution was filtered through celite, washed with acetic acid/water, and evaporated under reduced pressure. The resulting residue was isolated by preparative high performance liquid chromatography (column: XSelect CSH C18 OBD Prep Column (trade name, manufactured by Waters Corporation), elution solvent: water with 0.1% formic acid : acetonitrile with 0.1% formic acid), and fractions with the target compound were subjected to lyophilization. drying. A mixture of acetonitrile (50 ml)/water (50 ml) and dilute aqueous ammonium acetate and dilute aqueous acetic acid were added to the resulting residue, adjusting the pH to 4.20. The reaction solution was evaporated under reduced pressure until a white solid precipitated. The resulting mixture was stirred at room temperature for 14 hours, cooled with ice water, stirred for a while, the precipitate formed was collected by filtration, washed with cold water and dried under reduced pressure to give the title Compound (0.91 g) as a white solid.

Mass spectrum (DUIS, m/z): 537 [M+2H] ²⁺ .

¹ H-NMR spectrum (400 MHz, (CF ₃ ) ₂ CDOD) δ: 8.30 (d, J = 8.5 Hz, 4H), 7.50 (dd, J = 7.9 Hz, J = 7.9 Hz, 2H), 7.43- 7.34 (m, 6H), 7.26-7.20 (m, 2H), 7.17-7.10 (m, 2H), 4.66-4.55 (m, 2H), 4.37-4.31 (m, 4H), 3.84-3.41 (m, 12H ), 3.33 (dd, J = 9.9, 16.2 Hz, 2H), 2.95–2.79 (m, 2H).

Example 26-(a)

Preparation of (2S,2'S)-tetra-tert-butyl 2,2'-((oxybis(ethane-2,1-diyl))bis((10-(2,3-bis(tert-butoxycarbonyl)guanidino)-13 -oxo-6,7,8,13-tetrahydrodibenzo[b,f] [1,4]dioxecine-4-carbonyl)azandiyl))disuccinate

Into a suspension of 10-(2,3-bis(tert-butoxycarbonyl)guanidino)-13-oxo-6,7,8,13-tetrahydrodibenzo[b,f][1,4]dioxecine-4-carboxylic acid (6.25 g ) obtained by the same procedure as described for Comparative Example 19-(n), COMU (5.19 g) and N,N-diisopropylethylamine (2.8 ml) were added in dimethylformamide (46 ml) in a 200 ml round bottom flask at 0° C in a stream of argon with stirring, and the resulting mixture was stirred at 0°C for 10 minutes. Then a solution of (2S,2'S)-tetra-tert-butyl 2,2'-((oxybis(ethane-2,1-diyl))bis(azandiyl))disuccinate (3.01 g) obtained by the same procedure as described for Comparative Example 1-(c), in dimethylformamide (8 ml) dropwise with stirring at 0°C, and the resulting mixture was stirred at room temperature for 19 hours. After completion of the reaction, a saturated sodium hydrogen carbonate aqueous solution was added to the solution, and the resulting solution was extracted with toluene. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (5.63 g) as a slightly yellow solid.

Mass spectrum (ESI, m/z): 819 [M+2H] ²⁺ .

¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 11.47-11.13 (m, 2H), 10.38-10.03 (m, 2H), 7.94-7.70 (m, 4H), 7.65-7.38 (m, 4H), 7.35-6.92 (m, 4H), 4.59-4.29 (m, 2H), 4.17-2.37 (m, 20H), 2.18-0.99 (m, 76H).

Example 26-(b)

Preparation of (2S,2'S)-2,2'-((oxybis(ethane-2,1-diyl))bis((10-guanidino-13-oxo-6,7,8,13-tetrahydrodibenzo[b,f] [1,4]dioxecin-4-carbonyl)azandiyl))disuccinic acid

K (2S,2'S)-tetra-tert-butyl 2,2'-((oxybis(ethane-2,1-diyl))bis((10-(2,3-bis(tert-butoxycarbonyl)guanidino)-13 -oxo-6,7,8,13-tetrahydrodibenzo[b,f][1,4]dioxecin-4-carbonyl)azandiyl))disuccinate (6.7g) obtained in Example 26-(a) in a 200ml A 4M solution of hydrogen chloride in dioxane (34 ml) was added to a round bottom flask at room temperature under argon flow with stirring, and the resulting mixture was stirred at room temperature for 16 hours. After completion of the reaction, the solution was evaporated under reduced pressure. The evaporation residue was subjected to a single azeotropic distillation with toluene, and then once with acetonitrile. The resulting residue was dissolved in acetonitrile (17 ml)/water (17 ml)/trifluoroacetic acid (340 μl), the resulting solution was purified by preparative medium pressure chromatography (ODS silica gel, elution solvent: water with 0.1% trifluoroacetic acid: acetonitrile with 0.1 % trifluoroacetic acid), and fractions with the target compound were freeze-dried. The resulting residue was dissolved in acetonitrile (37 ml)/water (2 ml)/trifluoroacetic acid (390 μl), the resulting solution was purified by preparative medium pressure chromatography (silica gel, elution solvent: water with 0.1% trifluoroacetic acid; acetonitrile with 0.1% trifluoroacetic acid), and fractions with the target compound were freeze-dried. The resulting residue was dissolved in a mixture of water (70 ml)/acetonitrile (20 ml), and a saturated aqueous ammonium acetate solution was added with stirring, bringing the pH to 4.2. Water (15 ml) was added and the resulting mixture was stirred at room temperature for 8 hours. The precipitate that formed was collected by filtration, washed with water and dried under reduced pressure to give the title Compound (3.25 g) as a white solid.

Mass spectrum (ESI, m/z): 1011 [M+H] ⁺ .

¹ H-NMR spectrum (500 MHz, (CF ₃ ) ₂ CDOD) δ: 8.02-7.48 (m, 4H), 7.47-6.92 (m, 8H), 5.54-2.50 (m, 22H), 2.44-1.61 ( m, 4H).

Example 27-(a)

Preparation of (2S,16S)-tetra-tert-butyl 3,15-bis(10-(2,3-bis(tert-butoxycarbonyl)guanidino)-13-oxo-6,7,8,13-tetrahydrodibenzo[b, f][1,4]dioxecine-4-carbonyl)-6,9,12-trioxa-3,15-diazaheptadecan-1,2,16,17-tetracarboxylate

Into a solution of 10-(2,3-bis(tert-butoxycarbonyl)guanidino)-13-oxo-6,7,8,13-tetrahydrodibenzo[b,f][1,4]dioxecine-4-carboxylic acid (5.65 g ) obtained by the same procedure as described for Comparative Example 19-(n), N,N-diisopropylethylamine (2.42 ml) and COMU (4.46 g) were added in dimethylformamide (30 ml) in a 200 ml round bottom flask at 0° C in a stream of argon with stirring, and the resulting mixture was stirred at 0°C for 30 minutes. Then a solution of (2S,16S)-tetra-tert-butyl 6,9,12-trioxa-3,15-diazaheptadecan-1,2,16,17-tetracarboxylate (3.01 g) was added, obtained by the same procedure as described for Comparative Example 3-(b), in dimethylformamide (15 ml) with stirring at 0°C, and the resulting mixture was stirred at room temperature for 19 hours. After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added to the solution, and the resulting solution was extracted with toluene. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (6.18 g) as a yellow foam.

Mass Spectrum (ESI, m/z): 863 [M+2H] ²⁺ .

¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 11.36-11.21 (m, 2H), 10.26-10.14 (m, 2H), 7.91-7.76 (m, 4H), 7.62-7.40 (m, 4H), 7.33-6.99 (m, 4H), 4.50-4.36 (m, 2H), 3.96-2.42 (m, 28H), 2.11-1.70 (m, 4H), 1.51 (s, 18H), 1.45-1.38 ( m, 54H).

Example 27-(b)

Preparation of (2S,16S)-3,15-bis(10-guanidino-13-oxo-6,7,8,13-tetrahydrodibenzo[b,f][1,4]dioxecine-4-carbonyl)-6,9 ,12-trioxa-3,15-diazaheptadecan-1,2,16,17-tetracarboxylic acid

K (2S,16S)-tetra-tert-butyl 3,15-bis(10-(2,3-bis(tert-butoxycarbonyl)guanidino)-13-oxo-6,7,8,13-tetrahydrodibenzo[b, f][1,4]dioxecin-4-carbonyl)-6,9,12-trioxa-3,15-diazaheptadecan-1,2,16,17-tetracarboxylate (6.9 g) obtained in Example 27-(a) , in a 300 ml round bottom flask was added a 4M solution of hydrogen chloride in dioxane (35 ml) at room temperature in a stream of argon with stirring, and the resulting mixture was stirred at room temperature for 16 hours. After completion of the reaction, the solution was evaporated under reduced pressure. The evaporation residue was subjected to a single azeotropic distillation with toluene, and then once with acetonitrile. The residue was dissolved in acetonitrile (8.0 ml)/water (12.0 ml)/trifluoroacetic acid (0.02 ml), the resulting solution was purified by preparative medium pressure chromatography (ODS, elution solvent: water with 0.1% trifluoroacetic acid : acetonitrile with 0.1% trifluoroacetic acid acids), and fractions with the target compound were subjected to freeze drying. The residue was dissolved in acetonitrile (30 ml)/water (3 ml), the resulting solution was purified by preparative medium pressure chromatography (silica gel, elution solvent: water with 0.1% trifluoroacetic acid : acetonitrile with 0.1% trifluoroacetic acid), and fractions with the desired compound was subjected to freeze drying. The residue was dissolved in acetonitrile (14 ml)/water (56 ml), saturated aqueous ammonium acetate was added with stirring to adjust the pH to 4.1, and the resulting mixture was stirred at room temperature for 17 hours. The precipitate that formed was collected by filtration, washed with water and dried under reduced pressure to give the title Compound (2.83 g) as a white solid.

Mass Spectrum (ESI, m/z): 550 [M+2H] ²⁺ .

¹ H-NMR spectrum (500 MHz, (CF ₃ ) ₂ CDOD) δ: 7.93-7.69 (m, 2H), 7.65-7.50 (m, 2H), 7.43-7.00 (m, 8H), 5.20-2.65 ( m, 30H), 2.34-1.74 (m, 4H).

Example 28-(a)

Preparation of (2S,2'S)-tetrabenzyl 2,2'-(([1,1'-biphenyl]-3,3'-diylbis(methylene))bis ((10-(2,3-bis(tert-butoxycarbonyl) guanidino)-13-oxo-6,7,8,13-tetrahydrodibenzo[b,f][1,4]dioxecine-4-carbonyl)azandiyl))disuccinate

Into a suspension of 10-(2,3-bis(tert-butoxycarbonyl)guanidino)-13-oxo-6,7,8,13-tetrahydrodibenzo[b,f][1,4]dioxecine-4-carboxylic acid (234.8 mg ) obtained by the same procedure as described for Comparative Example 19-(n), and (2S,2'S)-tetrabenzyl 2,2'-(([1,1'-biphenyl]-3,3'-diylbis( methylene))bis(azandiyl))disuccinate (153.5mg) obtained in Comparative Example 28-(c) in dimethylformamide (1.5ml) in a 20ml cylindrical flask was added 4-(4,6-dimethoxy-1,3, 5-triazin-2-yl)-4-methylmorpholinium chloride n-hydrate (159.1 mg) at room temperature under argon flow with stirring, and the resulting mixture was stirred at room temperature for 19 hours. Additionally, 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride n-hydrate (177.2 mg) was added at room temperature with stirring, and the resulting mixture was stirred at room temperature for 99.5 hours. After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added to the solution, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (221.0 mg) as a white foam.

Mass spectrum (ESI, m/z): 941 [M+2H] ²⁺ .

¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 11.78-10.84 (m, 2H), 10.69-9.93 (m, 2H), 8.15-6.58 (m, 40H), 5.32-0.69 (m, 66H).

Example 28-(b)

Preparation of (2S,2'S)-tetrabenzyl 2,2'-(([1,1'-biphenyl]-3,3'-diylbis(methylene))bis ((10-guanidino-13-oxo-6,7,8 ,13-tetrahydrodibenzo[b,f][1,4]dioxecine-4-carbonyl)azandiyl)) formate disuccinate

In a solution of (2S,2'S)-tetrabenzyl 2,2'-(([1,1'-biphenyl]-3,3'-diylbis(methylene)) bis((10-(2,3-bis(tert-butoxycarbonyl )guanidino)-13-oxo-6,7,8,13-tetrahydrodibenzo[b,f][1,4]dioxecin-4-carbonyl)azandiyl))disuccinate (221 mg) obtained in Example 28-(a) , in toluene (0.5 ml) in a 100 ml round bottom flask was added formic acid (0.5 ml) at room temperature in a stream of argon with stirring, and the resulting mixture was stirred at room temperature for 44 hours. After completion of the reaction, the solution was evaporated under reduced pressure. The evaporation residue was subjected to azeotropic distillation with toluene twice. tert-Butyl methyl ether was added to the evaporation residue, the precipitate was separated by filtration through a membrane filter, washed with tert-butyl methyl ether and dried under reduced pressure to give the title Compound (127.9 mg) as a white solid.

Mass spectrum (DUIS, m/z): 1480 [M+H] ⁺ .

¹ H-NMR spectrum (400 MHz, DMSO-d ₆ + D ₂ O) δ: 8.40 (s, 2H), 8.03-6.82 (m, 40H), 5.31-4.22 (m, 14H), 4.22-0.72 ( m, 16H).

Example 28-(c)

Preparation of (2S,2'S)-2,2'-(([1,1'-biphenyl]-3,3'-diylbis(methylene))bis(((10-guanidino-13-oxo-6,7,8 ,13-Tetrahydrodibenzo[b,f][1,4]dioxecine-4-carbonyl) azandiyl)) disuccinic acid

In a solution of (2S,2'S)-tetrabenzyl 2,2'-(([1,1'-biphenyl]-3,3'-diylbis(methylene)) bis((10-guanidino-13-oxo-6,7, 8,13-tetrahydrodibenzo[b,f][1,4]dioxecin-4-carbonyl)azandiyl))disuccinate formate (127.9mg) prepared in Example 28-(b) in acetic acid (0.7mL)/water (0.14 ml) in a 20 ml cylindrical flask was added ASCA-2 (water content 54.29%, ASCA-2 manufactured by NE CHEMCAT Corporation) (19.6 mg) at room temperature, and the resulting mixture was stirred at room temperature under a hydrogen atmosphere for 4.5 hours . ASCA-2 (water content 54.29%, manufactured by NE CHEMCAT Corporation) (26.1 mg) was further added with stirring at room temperature, and the resulting mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. After completion of the reaction, the solution was filtered through celite, washed with acetic acid, and the resulting filtrate was evaporated under reduced pressure. The evaporation residue was subjected to a single azeotropic distillation with toluene, and then once with acetonitrile. The resulting residue was dissolved in acetonitrile (5.7 ml)/water (0.3 ml)/trifluoroacetic acid (60 μl), the resulting solution was purified by preparative medium pressure chromatography (silica gel, elution solvent: water with 0.1% trifluoroacetic acid : acetonitrile with 0.1% trifluoroacetic acid), and fractions with the target compound were freeze-dried. The resulting residue was dissolved in water (5 ml)/acetonitrile (1 ml)/trifluoroacetic acid (50 μl), and saturated aqueous ammonium acetate was added with stirring, adjusting the pH to 4.1. Water (3 ml) was added and the resulting mixture was stirred at room temperature for 6 hours. The precipitate that formed was collected by filtration, washed with water and dried under reduced pressure to give the title Compound (27.8 mg) as a white solid.

Mass Spectrum (ESI, m/z): 1117 [MH] ^- .

¹ H-NMR spectrum (400 MHz, DMSO-d ₆ + D ₂ O) δ: 8.10-6.84 (m, 20H), 5.56-1.32 (m, 22H).

Example 29-(a)

Preparation of (2S,2'S)-tetra-tert-butyl 2,2'-(((((oxybis(ethane-2,1-diyl))bis(oxy))bis(3-((2-(trimethylsilyl)ethoxy )carbonyl)-5,1-phenylene))bis(methylene))bis((10-(2,3-bis(tert-butoxycarbonyl)guanidino)-13-oxo-6,7,8,13-tetrahydrodibenzo [b ,f][1,4]dioxecin-4-carbonyl)azandiyl))disuccinate

(1) A solution of (S)-di-tert-butyl 2-(10-(2,3-bis(tert-butoxycarbonyl)guanidino)-N-(3-(2-(2-hydroxyethoxy)ethoxy)-5- ((2-(trimethylsilyl)ethoxy)carbonyl)benzyl)-13-oxo-6,7,8,13-tetrahydrodibenzo[b,f][1,4]dioxecin-4-carboxamide)succinate (416.2 mg) obtained in Comparative Example 29-(h),(S)-di-t-butyl 2-(10-(2,3-bis(t-butoxycarbonyl)guanidino)-N-(3-hydroxy-5-((2- (trimethylsilyl)ethoxy)carbonyl)benzyl)-13-oxo-6,7,8,13-tetrahydrodibenzo[b,f][1,4]dioxecine-4-carboxamide)succinate (380.4 mg) obtained by the same method as described for Comparative Example 29-(f) and triphenylphosphine (148.8 mg) in anhydrous dichloromethane (2 ml) in a 50 ml round bottom flask was stirred at room temperature under argon and cooled in an ice bath. Then, diisopropyl azodicarboxylate (1.9M solution in toluene) (0.30 ml) was added dropwise, and after completion of the addition, the mixture was stirred under cooling in an ice bath for 0.2 hours and at room temperature for 3 hours. After completion of the reaction, the solution was purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate), and fractions with the target compound were evaporated under reduced pressure.

(2) A solution of (S)-di-tert-butyl 2-(10-(2,3-bis(tert-butoxycarbonyl)guanidino)-N-(3-(2-(2-hydroxyethoxy)ethoxy)-5- ((2-(trimethylsilyl)ethoxy)carbonyl)benzyl)-13-oxo-6,7,8,13-tetrahydrodibenzo[b,f][1,4]dioxetin-4-carboxamide)succinate (375 mg) obtained in Comparative Example 29-(h),(S)-di-t-butyl 2-(10-(2,3-bis(t-butoxycarbonyl)guanidino)-N-(3-hydroxy-5-((2- (trimethylsilyl)ethoxy)carbonyl)benzyl)-13-oxo-6,7,8,13-tetrahydrodibenzo[b,f][1,4]dioxecine-4-carboxamide)succinate (348 mg) obtained by the same method as described for Comparative Example 29-(f) and triphenylphosphine (145.1 mg) in anhydrous dichloromethane (2 ml) in a 50 ml round bottom flask was stirred at room temperature under argon and cooled in an ice bath. Then, diisopropyl azodicarboxylate (1.9M solution in toluene) (0.30 ml) was added dropwise, and after completion of the addition, the mixture was stirred under cooling in an ice bath for 0.1 hour and at room temperature for 1.5 hours. Triphenylphosphine (104 mg) and diisopropyl azodicarboxylate (1.9M solution in toluene) (150 μl) were added and the resulting mixture was stirred at room temperature for 1 hour. After completion of the reaction, the solution was diluted with dichloromethane, purified by preparative chromatography at medium pressure (silica gel, elution solvent: hexane:ethyl acetate), and fractions with the target compound were evaporated under reduced pressure.

The obtained residue from (1) and the obtained residue from (2) were combined, purified by preparative high performance liquid chromatography (Column; XSelect CSH Fluoro Phenyl OBD prep Column (trade name, manufactured by Waters Corporation), elution solvent: water with 0.1% formic acid: acetonitrile with 0.1% formic acid), and fractions with the target compound were evaporated under reduced pressure. Ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the evaporation residue, and the resulting mixture was stirred at room temperature and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure to give the title Compound (0.57 g) as a white foam.

Mass spectrum (DUIS, m/z): 1069 [M+2H] ²⁺ .

¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ: 11.61 (s, 2H), 10.55 (s, 2H), 8.05-7.91 (m, 2H), 7.88-7.78 (m, 2H), 7.69-7.38 (m, 8H), 7.34-7.04 (m, 6H), 4.65-2.40 (m, 30H), 2.32-1.71 (m, 4H), 1.65-1.21 (m, 72H), 1.18-1.06 (m, 4H) , 0.07 (s, 18H).

Example 29-(b)

Preparation of (S)-5,5'-((oxybis(ethane-2,1-diyl))bis(oxy))bis(3-((10-(2,3-bis(tert-butoxycarbonyl)guanidino)- N-((S)-1,4-di-tert-butoxy-1,4-dioxobutan-2-yl)-13-oxo-6,7,8,13-tetrahydrodibenzo[b,f][1,4 ]dioxecine-4-carboxamide)methyl)benzoic acid)

In a solution of (2S,2'S)-tetra-tert-butyl 2,2'-(((((oxybis(ethane-2,1-diyl))bis(oxy))bis(3-((2-(trimethylsilyl) ethoxy)carbonyl)-5,1-phenylene))bis(methylene))bis((10-(2,3-bis(tert-butoxycarbonyl)guanidino)-13-oxo-6,7,8,13-tetrahydrodibenzo[ b,f][1,4]dioxecin-4-carbonyl)azandiyl))disuccinate (789.8mg) obtained by the same procedure as described for Example 29-(a) in anhydrous tetrahydrofuran (4ml) in 100- tetrabutylammonium fluoride (1.0M solution in tetrahydrofuran) (4 ml) was added to a milliliter round bottom flask at room temperature under argon with stirring, and the resulting mixture was stirred at room temperature for 3.5 hours. After completion of the reaction, the solution was diluted with toluene (50 ml), then washed with saturated aqueous ammonium chloride solution (25 ml) twice, with 5% aqueous potassium hydrogen sulfate solution (25 ml) twice, and with saturated sodium chloride solution (25 ml), dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure to give the title Compound (730.5 mg) as a white foam.

Mass spectrum (DUIS, m/z): 968 [M+2H] ²⁺ .

¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ: 11.62 (broad s, 2H), 10.54 (s, 2H), 8.08-7.90 (m, 2H), 7.89-7.75 (m, 2H), 7.71 -7.35 (m, 8H), 7.33-7.01 (m, 6H), 4.68-2.41 (m, H), 2.34-1.68 (m, 4H), 1.68-1.18 (m, 72H).

Example 29-(c)

Preparation of (2S,2'S)-2,2'-(((((oxybis(ethane-2,1-diyl))bis(oxy))bis(3-carboxy-5,1-phenylene))bis(methylene) )bis((10-guanidino-13-oxo-6,7,8,13-tetrahydrodibenzo[b,f][1,4]dioxecine-4-carbonyl)azandiyl))disuccinic acid hydrochloride

K (S)-5,5'-((oxybis(ethane-2,1-diyl))bis(oxy))bis(3-((10-(2,3-bis(tert-butoxycarbonyl)guanidino)- N-((S)-1,4-di-tert-butoxy-1,4-dioxobutan-2-yl)-13-oxo-6,7,8,13-tetrahydrodibenzo[b,f][1,4 ]dioxecin-4-carboxamide)methyl) benzoic acid) (725 mg) prepared in Example 29-(b) was added to a 100 ml round bottom flask with a 4M solution of hydrogen chloride in dioxane (15 ml) at room temperature under nitrogen atmosphere, and the resulting mixture was stirred at room temperature for 14 hours. After completion of the reaction, the liquid component was removed from the reaction solution, and the resulting residue was washed with anhydrous diethyl ether. Anhydrous diethyl ether was then added and the resulting mixture was kept in an ultrasonic bath. The resulting mixture was stirred at room temperature for 1 hour, the solid was separated by filtration, washed with anhydrous diethyl ether and dried under reduced pressure. Ethanol (15 ml) was added to the resulting solid, and the mixture was evaporated under reduced pressure. A small amount of ethanol was added to the evaporation residue to obtain a homogeneous solution, ethyl acetate was added, the resulting mixture was kept in an ultrasonic bath and stirred at room temperature for 1 hour. The solid was collected by filtration, washed with ethyl acetate and dried under reduced pressure to give the title Compound (461.4 mg) as a white solid.

Mass spectrum (DUIS, m/z): 656 [M+2H] ²⁺ .

¹ H-NMR spectrum (500 MHz, (CF ₃ ) ₂ CDOD) δ: 8.02-7.90 (m, 2H), 7.84-7.51 (m, 6H), 7.46-7.11 (m, 10H), 4.77-2.74 ( m, 26H), 2.46-2.24 (m, 2H), 2.06-1.85 (m, 2H).

Example 30-(a)

Preparation of (2S,2'S)-2,2'-((oxybis(ethane-2,1-diyl))bis((3-((4-guanidinobenzoyl)oxy)benzoyl)azandiyl))succinic acid

In a solution of (2S,2'S)-2,2'-((oxybis(ethane-2,1-diyl))bis((3-((4-aminobenzoyl)oxy)benzoyl)azandiyl))disuccinic acid hydrochloride (1.35 g ) obtained in Comparative Example 30-(c) in tert-butanol (5.5 ml) in a 200 ml round bottom flask was added 4 M hydrogen chloride in cyclopentyl methyl ether (1.14 ml) and cyanamide (247.5 mg) at room temperature under argon flow with stirring, and the resulting mixture was stirred at 60°C for 3 hours. After completion of the reaction, the solution was evaporated under reduced pressure. The evaporation residue was subjected to a single azeotropic distillation with toluene, and then once with acetonitrile. The resulting residue was dissolved in acetonitrile (3.5 ml)/water (3.5 ml)/trifluoroacetic acid (70 μl), the solution was purified by preparative medium pressure chromatography (ODS silica gel, elution solvent: water with 0.1% trifluoroacetic acid : acetonitrile with 0.1% trifluoroacetic acid), and fractions with the target compound were freeze-dried. The resulting residue was dissolved in acetonitrile (5.7 ml)/water (0.3 ml)/trifluoroacetic acid (60 µl), the solution was purified by preparative chromatography at medium pressure (silica gel, elution solvent: water with 0.1% trifluoroacetic acid : acetonitrile with 0.1% trifluoroacetic acid acids), and fractions with the target compound were freeze-dried. The resulting residue was dissolved in a mixture of water (8 ml)/acetonitrile (2 ml), and a saturated aqueous ammonium acetate solution was added to the solution with stirring, bringing the pH to 4.2. Water (10 ml) was added and the mixture was stirred at room temperature for 6 hours. The precipitate that formed was separated by filtration, washed with water, and dried under reduced pressure. The resulting solid was isolated by preparative HPLC (column: XSelect CSH C18 OBD Prep Column (trade name, manufactured by Waters Corporation), elution solvent: water with 0.1% formic acid : acetonitrile with 0.1% formic acid), in fractions with the target compound were added saturated ammonium acetate aqueous solution was added dropwise to pH 4.2, and the resulting mixture was lyophilized. The resulting residue was then dissolved in a mixture of water (8 ml)/acetonitrile (2 ml)/trifluoroacetic acid (0.1 ml), and a saturated aqueous ammonium acetate solution was added to the solution with stirring, adjusting the pH to 4.2. Was added water (5 ml), the mixture was stirred at room temperature for 6 hours, and the solid precipitate was separated by filtration. Water (8 ml) and acetonitrile (8 ml) were added to the obtained solid, the mixture was stirred at room temperature for 6 hours, and the precipitate was separated by filtration. Water (8 ml) and acetonitrile (8 ml) were added to the resulting solid, the mixture was stirred at room temperature for 6 hours, the precipitate was filtered off and dried under reduced pressure to give the title Compound (51.4 mg) as a white solid .

Mass Spectrum (ESI, m/z): 897 [MH] ^- .

¹ H-NMR spectrum (400 MHz, DMSO-d ₆ + D ₂ O) δ: 8.44-6.95 (m, 16H), 4.67-4.22 (m, 2H), 4.21-2.24 (m, 12H).

Comparative examples

Comparative Example 1-(a)

Preparation of (S)-di-tert-butyl 2-(2-nitrophenylsulfonamide)succinate

To a solution of L-aspartic acid di-tert-butyl ester hydrochloride (20 g) and N,N-diisopropylethylamine (31 ml) in dichloromethane (200 ml) in a 500 ml three-necked argon atmosphere with stirring so that the internal temperature did not exceed 5°C, and the resulting mixture was stirred at room temperature for 2 hours. After completion of the reaction, the solution was washed with 5% aqueous citric acid solution (200 ml) twice, water (200 ml) and saturated aqueous sodium chloride solution (200 ml), dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. To a solution of the resulting evaporation residue in dichloromethane (70 ml) was added hexane (490 ml), the mixture was stirred at room temperature for 10 minutes, the precipitate was separated by filtration and dried under reduced pressure to give the title Compound (18.19 g) as white solid.

Mass Spectrum (ESI, m/z): 429 [MH] ^- .

Comparative Example 1-(b)

Preparation of (2S,2'S)-tetra-tert-butyl 2,2'-((oxybis(ethane-2,1-diyl))bis(((2-nitrophenyl)sulfonyl)azandiyl))disuccinate

To a solution of (S)-di-tert-butyl 2-(2-nitrophenylsulfonamide)succinate (20.0 g) prepared in the same manner as described for Comparative Example 1-(a), 2,2'-oxydiethanol (2.41 g ) and 1,1'-azobis(N,N-dimethylformamide) (11.60 g) in tetrahydrofuran (50 ml) in a 200 ml round bottom flask was added tributylphosphine (16.60 ml) at room temperature under argon with stirring, and the resulting mixture was stirred at room temperature for 20 hours. After completion of the reaction, water was added to the solution and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (16.80 g) as a light yellow foam.

¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ: 8.16-8.05 (m, 2H), 7.75-7.65 (m, 4H), 7.64-7.57 (m, 2H), 4.97-4.90 (m, 2H) , 3.73-3.53 (m, 6H), 3.32-3.21 (m, 2H), 2.98 (dd, J = 7.3, 16.4 Hz, 2H), 2.71 (dd, J = 6.8, 16.4 Hz, 2H), 1.46 (s , 18H), 1.31 (s, 18H).

Comparative example 1-(c)

Preparation of (2S,2'S)-tetra-tert-butyl 2,2'-((oxybis(ethane-2,1-diyl))bis(azandiyl))disuccinate

Into a suspension of (2S,2'S)-tetra-tert-butyl 2,2'-((oxybis(ethane-2,1-diyl))bis(((2-nitrophenyl)sulfonyl)azandiyl))disuccinate (16.80 g), obtained in Comparative Example 1-(b) and potassium carbonate (7.52 g) in dimethylformamide (100 ml) in a 500 ml round bottom flask, 4-tert-butylthiophenol (9.10 ml) was added at room temperature under argon with stirring, and the resulting the mixture was stirred at room temperature for 16 hours. After completion of the reaction, water was added to the solution and extracted with tert-butyl methyl ether. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (DIOL silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (8.10 g) as a yellowish oil.

Mass spectrum (ESI, m/z): 561 [M+H] ⁺ .

Comparative Example 1-(d)

Preparation of (2S,2'S)-tetra-tert-butyl 2,2'-((oxybis(ethane-2,1-diyl))bis((N-((benzyloxy)carbonyl)sulfamoyl)azandiyl))disuccinate

To a solution of chlorosulfonyl isocyanate (0.81 ml) in dichloromethane (20 ml) in a 100 ml round bottom flask was added benzyl alcohol (0.975 ml) at 0°C under argon with stirring, and the resulting mixture was stirred at 0°C for 15 minutes. Then triethylamine (1.55 ml) and (2S,2'S)-tetra-tert-butyl 2,2'-((oxybis(ethane-2,1-diyl))bis(azandiyl))disuccinate (2.5g) obtained in Comparative Example 1-(c), with stirring at 0°C, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the solution was evaporated under reduced pressure. In the residue from evaporation was added 1N. hydrochloric acid solution, and the resulting solution was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (3.30 g) as a yellowish foam.

¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ: 8.39 (broad s, 2H), 7.40-7.29 (m, 10H), 5.19 (d, J = 12.2 Hz, 2H), 5.14 (d, J = 12.2 Hz, 2H), 4.91-4.84 (m, 2H), 3.69-3.58 (m, 2H), 3.56-3.46 (m, 4H), 3.45-3.32 (m, 2H), 2.92 (dd, J = 6.8 , 16.7 Hz, 2H), 2.76 (dd, J = 7.3, 16.7 Hz, 2H), 1.45 (s, 18H), 1.45 (s, 18H).

Comparative Example 1-(e)

Preparation of 4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoic acid

To a solution of 4-aminobenzoic acid (442 mg) and tert-butyl (((tert-butoxycarbonyl)imino)(1H-pyrazol-1-yl)methyl)carbamate (1.00 g) in methanol (10 ml) in a 100 ml round bottom triethylamine (988 μl) was added to the flask at room temperature under argon atmosphere with stirring, the resulting mixture was stirred at room temperature for 173 hours, left at room temperature for 38 hours, and stirred at room temperature for 9 hours. After completion of the reaction, 10% citric acid solution (10 ml) and methanol (10 ml) were added to the solution, and the resulting mixture was stirred at room temperature for 15 hours. The precipitate that formed was filtered off and dried under reduced pressure to give the title Compound (986.9 mg) as a white solid.

Mass spectrum (ESI, m/z): 380 [M+H] ⁺ .

[0473]

Comparative Example 1-(e)-2 and Comparative Example 1-(e)-3 were prepared in a similar manner to Comparative Example 1-(e).

Comparative example 1-(f)

Preparation of 4-formylphenyl 4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoate

To a suspension of 4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoic acid (5.00 g) obtained in the same manner as described for Comparative Example 1-(e) in anhydrous dichloromethane (50 ml) in 200 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.80 g) and 4-dimethylaminopyridine (0.500 g) were added to a -milliliter round bottom flask at room temperature under argon with stirring, and the resulting mixture was stirred at room temperature for 30 minutes. Then 4-hydroxybenzaldehyde (1.77 g) was added with stirring at room temperature, and the resulting mixture was stirred at room temperature for 5.5 hours. Silica gel (50 g) (DAISOGEL IR-60-40/63-W (trade name) manufactured by Osaka Soda Co., Ltd.) was added to the reaction solution, the resulting mixture was stirred, and then filtered. The filter cake was washed with dichloromethane (50 ml) and ethyl acetate (50 ml)/hexane (50 ml). The resulting filtrate was evaporated under reduced pressure to give the title Compound (5.90 g) as a pink solid.

Mass spectrum (ESI, m/z): 484 [M+H] ⁺ .

Comparative Example 1-(f)-2-Comparative Example 1-(f)-12 was prepared in a similar manner to Comparative Example 1-(f).

Comparative example 1-(g)

Preparation of 4-(hydroxymethyl)phenyl 4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoate

To a solution of 4-formylphenyl 4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoate (5.90 g) obtained in Comparative Example 1-(f) in anhydrous dichloromethane (60 ml) in a 500 ml round bottom flask was added acetic acid (0.840 ml) under argon with stirring, then sodium triacetoxyborohydride (3.90 g) was added in portions while cooling in an ice bath, and the resulting mixture was stirred at room temperature for 16 hours. Sodium triacetoxyborohydride (3.90 g) was then added in portions while cooling in an ice bath, and the mixture was stirred at room temperature for 48 hours. Sodium triacetoxyborohydride (1.30 g) was then added in portions while cooling in an ice bath, and the resulting mixture was stirred at room temperature for 72 hours. After completion of the reaction, water was added to the solution, and the solution was extracted with dichloromethane. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give the title Compound (5.36 g) as a brown solid.

Mass spectrum (ESI, m/z): 486 [M+H] ⁺ .

Comparative Example 1-(g) was also prepared as follows.

To a solution of 4-hydroxybenzenemethanol (2.00 g) in anhydrous dimethylformamide (10 ml) in a 100 ml round bottom flask was added tert-butylchlorodimethylsilane (2.67 g) and imidazole (2.20 g) while cooling in an ice bath in an argon atmosphere with stirring, and the resulting mixture stirred at room temperature for 16 hours. After completion of the reaction, the solution was diluted with ethyl acetate, a 0.1M hydrochloric acid solution was added, and the solution was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate) to give 4-(((t-butyldimethylsilyl)oxy)methyl)phenol (3.67 g) as a colorless oil.

To a solution of the obtained 4-(((tert-butyldimethylsilyl)oxy)methyl)phenol (1.00 g) in anhydrous dichloromethane (15 ml) in a 100-ml round-bottom flask was added 4-(2,3-bis(tert-butoxycarbonyl)guanidino) benzoic acid (1.50 g) prepared in the same manner as described for Comparative Example 1-(e), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.910 g) and 4-dimethylaminopyridine (0.145 g) at room temperature under argon atmosphere with stirring, and the resulting mixture was stirred at room temperature for 17 hours. After completion of the reaction, water was added to the solution, and the solution was extracted with dichloromethane and ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate) to give 4-(((t-butyldimethylsilyl)oxy)methyl)phenyl 4-(2,3-bis(t-butoxycarbonyl)guanidino) benzoate (1.34 g) as a white solid.

To a solution of the obtained 4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl 4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoate (1.34 g) in anhydrous tetrahydrofuran (10 ml) in a 100 ml round bottom flask tetrabutylammonium fluoride (1.0M solution in tetrahydrofuran) (3.50 ml) was added while cooling in an ice bath under argon atmosphere with stirring, and the resulting mixture was stirred at room temperature for 1 hour. After completion of the reaction, water was added to the solution, and the solution was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: dichloroethane:methanol) to give the title Compound (968 mg) as a white solid.

Mass spectrum (ESI, m/z): 486 [M+H] ⁺ .

Comparative Example 1-(g)-2 and Comparative Example 1-(g)-3 were prepared in a similar manner to Comparative Example 1-(g).

Comparative example 1-(g)-4

Preparation of 4-(hydroxymethyl)phenyl 4-(2,3-bis(tert-butoxycarbonyl)guanidino)-2-fluorobenzoate

To a solution of 4-formylphenyl 4-(2,3-bis(tert-butoxycarbonyl)guanidino)-2-fluorobenzoate (3.43 g) obtained in Comparative Example 1-(f)-2 in tetrahydrofuran (35 ml) in 200- To a milliliter four-necked flask, sodium borohydride (385 mg) and acetic acid (468 μl) were added at 0° C. with stirring, and the resulting mixture was stirred at room temperature for 1 hour. After completion of the reaction, water was added to the solution, and the solution was extracted with dichloromethane. The organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give the title Compound (3.28 g).

Mass spectrum (ESI, m/z): 504 [M+H] ⁺ .

Comparative Example 1-(g)-5-Comparative Example 1-(g)-14 was prepared in a similar manner to Comparative Example 1-(g)-4.

Comparative Example 2-(a)

Preparation of (2S,13S)-tetra-tert-butyl 3,12-bis((2-nitrophenyl)sulfonyl)-6,9-dioxa-3,12-diazatetradecane-1,2,13,14-tetracarboxylate

Triethylene glycol ( 0.740 ml), tributylphosphine (3.30 ml) and 1,1'-azobis(N,N-dimethylformamide) (2.30 g) while cooling in an ice bath under argon atmosphere with stirring, and the resulting mixture was stirred at room temperature for 20 hours. After completion of the reaction, water was added to the solution, and the solution was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (5.64 g) as a light yellow oil.

Mass spectrum (ESI, m/z): 997 [M+Na] ⁺ .

Comparative Example 2-(b)

Preparation of (2S,13S)-tetra-tert-butyl 6,9-dioxa-3,12-diazatetradecane-1,2,13,14-tetracarboxylate

Into a solution of (2S,13S)-tetra-tert-butyl 3,12-bis((2-nitrophenyl)sulfonyl)-6,9-dioxa-3,12-diazatetradecane-1,2,13,14-tetracarboxylate (5.64 d) obtained in Comparative Example 2-(a), in anhydrous dimethylformamide (20 ml) in a 300 ml round bottom flask, potassium carbonate (2.40 g) and 4-tert-butylthiophenol (2.45 ml) were added at room temperature under argon atmosphere under stirring, and the resulting mixture was stirred at room temperature for 2 hours. After completion of the reaction, a saturated sodium hydrogen carbonate aqueous solution was added to the solution, and the resulting solution was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (DIOL silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (3.45 g) as a yellow oil.

Mass spectrum (ESI, m/z): 605 [M+H] ⁺ .

Comparative example 2-(c)

Preparation of (2S,13S)-tetra-tert-butyl 3,12-bis(N-((benzyloxy)carbonyl)sulfamoyl)-6,9-dioxa-3,12-diazatetradecane-1,2,13,14-tetracarboxylate

To a solution of chlorosulfonyl isocyanate (1.20 ml) in anhydrous dichloromethane (20 ml) in a 200 ml round bottom flask was added benzyl alcohol (1.41 ml) while cooling in an ice bath under argon atmosphere with stirring, and the resulting mixture was stirred while cooling in an ice bath for 30 minutes . Then triethylamine (3.20 ml) and a solution of (2S,13S)-tetra-tert-butyl 6,9-dioxa-3,12-diazatetradecane-1,2,13,14-tetracarboxylate (3.45 g) obtained in Comparative Example were added. 2-(b) in anhydrous dichloromethane (6 ml) with stirring while cooling in an ice bath, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, a saturated sodium hydrogen carbonate aqueous solution was added to the solution, and the resulting solution was extracted with dichloromethane. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (3.93 g) as a yellowish oil.

Mass Spectrum (ESI, m/z): 1053 [M+Na] ⁺ .

Comparative Example 3-(a)

Preparation of (2S,16S)-tetra-tert-butyl 3,15-bis((2-nitrophenyl)sulfonyl)-6,9,12-trioxa-3,15-diazaheptadecan-1,2,16,17-tetracarboxylate

In a solution of 2,2'-((oxybis(ethane-2,1-diyl))bis(oxy))diethanol (1.24 g), (S)-di-tert-butyl 2-(2-nitrophenylsulfonamide)succinate (5 d) prepared in the same manner as described for Comparative Example 1-(a) and 1,1'-azobis(N,N-dimethylformamide) (2.60 g) in tetrahydrofuran (50 ml) in a 300 ml round bottom flask tributylphosphine (3.73 ml) was added at room temperature under argon with stirring, and the resulting mixture was stirred at room temperature for 15 hours. Additionally, 1,1'-azobis(N,N-dimethylformamide) (1.00 g) and tributylphosphine (1.44 ml) were added at room temperature, and the mixture was stirred at room temperature for 23 hours. After completion of the reaction, water was added to the solution, and the resulting solution was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (2.88 g) as a yellow oil.

Mass spectrum (ESI, m/z): 1036 [M+NH ₄ ] ⁺ .

Comparative Example 3-(b)

Preparation of (2S,16S)-tetra-tert-butyl 6,9,12-trioxa-3,15-diazaheptadecan-1,2,16,17-tetracarboxylate

To a suspension of (2S,16S)-tetra-tert-butyl 3,15-bis((2-nitrophenyl)sulfonyl)-6,9,12-trioxa-3,15-diazaheptadecan-1,2,16,17-tetracarboxylate (2.88 g) obtained in Comparative Example 3-(a) and potassium carbonate (1.18 g) in dimethylformamide (30 ml) in a 300 ml round bottom flask were added 4-tert-butylthiophenol (1.19 ml) at room temperature under argon atmosphere with stirring, and the resulting mixture was stirred at room temperature for 3 hours. After completion of the reaction, water was added to the solution, and the solution was extracted with t-butyl methyl ether. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (DIOL silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (1.82 g) as a yellow oil.

Mass spectrum (ESI, m/z): 649 [M+H] ⁺ .

Comparative Example 3-(c)

Preparation of (2S,16S)-tetra-tert-butyl 3,15-bis(N-((benzyloxy)carbonyl)sulfamoyl)-6,9,12-trioxa-3,15-diazaheptadecan-1,2,16,17 -tetracarboxylate

To a solution of chlorosulfonyl isocyanate (605 μl) in dichloromethane (20 ml) in a 100 ml round bottom flask was added benzyl alcohol (722 μl) at 0°C under argon with stirring, and the resulting mixture was stirred at 0°C for 30 minutes. Then triethylamine (1.56 ml) and a solution of (2S,16S)-tetra-tert-butyl 6,9,12-trioxa-3,15-diazaheptadecan-1,2,16,17-tetracarboxylate (1.82 g) obtained in Comparative Example 3-(b), in dichloromethane (20 ml) with stirring at 0°C, and the reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, a saturated ammonium chloride aqueous solution was added to the solution, and the resulting solution was extracted with dichloromethane. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (710 mg) as a yellowish oil.

Mass spectrum (ESI, m/z): 1097 [M+Na] ⁺ .

Comparative Example 4-(a)

Preparation of (2S,19S)-tetra-tert-butyl 3,18-bis((2-nitrophenyl)sulfonyl)-6,9,12,15-tetraoxa-3,18-diazaicosan-1,2,19,20- tetracarboxylate

Into a solution of 1,1'-azobis(N,N-dimethylformamide) (0.80 g), 3,6,9,12-tetraoxatetradecan-1,14-diol (0.45 ml), and (S)-di-tert-butyl 2-(2-nitrophenylsulfonamide)succinate (2.01 g) obtained in the same manner as described for Comparative Example 1-(a), in tetrahydrofuran (20 ml) in a 100 ml round bottom flask was added tributylphosphine (1.15 ml) at room temperature in a stream of argon with stirring, and the reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the solution was evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (1.56 g) as a white foam.

Mass spectrum (ESI, m/z): 1085 [M+Na] ⁺ .

Comparative Example 4-(b)

Preparation of (2S,19S)-tetra-tert-butyl 6,9,12,15-tetraoxa-3,18-diazaicosan-1,2,19,20-tetracarboxylate

In a solution of (2S,19S)-tetra-tert-butyl 3,18-bis((2-nitrophenyl)sulfonyl)-6,9,12,15-tetraoxa-3,18-diazaicosan-1,2,19,20 -tetracarboxylate (1.56 g) obtained in Comparative Example 4-(a) in dimethylformamide (20 ml) in a 100 ml round bottom flask was added potassium carbonate (0.62 g) and 4-tert-butylthiophenol (0.620 ml) at room temperature in argon atmosphere with stirring, and the reaction mixture was stirred at room temperature for 24 hours. After completion of the reaction, a saturated sodium hydrogen carbonate aqueous solution was added to the solution, and the resulting solution was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (DIOL silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (0.93 g) as a colorless oil.

Mass spectrum (ESI, m/z): 693 [M+H] ⁺ .

Comparative Example 4-(c)

Preparation of (2S,19S)-tetra-tert-butyl 3,18-bis(N-((benzyloxy)carbonyl)sulfamoyl)-6,9,12,15-tetraoxa-3,18-diazaicosan-1,2,19 ,20-tetracarboxylate

To a solution of chlorosulfonyl isocyanate (0.290 ml) in dichloromethane (10 ml) in a 100 ml round bottom flask was added benzyl alcohol (0.350 ml) at 0°C under argon with stirring, and the reaction mixture was stirred at 0°C for 30 minutes. Then triethylamine (0.560 ml) and a solution of (2S,19S)-tetra-tert-butyl 6,9,12,15-tetraoxa-3,18-diazaicosan-1,2,19,20-tetracarboxylate (0.93 g) were added, obtained in Comparative Example 4-(b) in dichloromethane (10 ml) with stirring at 0°C, and the resulting mixture was stirred at room temperature for 4 hours. After completion of the reaction, a saturated aqueous sodium hydrogencarbonate solution was added to the solution, and the solution was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (680 mg) as a colorless oil.

Mass spectrum (ESI, m/z): 1141 [M+Na] ⁺ .

Comparative Example 5-(a)

Preparation of (2S,22S)-tetra-tert-butyl 3,21-bis((2-nitrophenyl)sulfonyl)-6,9,12,15,18-pentaoxa-3,21-diazatricosan-1,2,22, 23-tetracarboxylate

To a solution of (S)-di-tert-butyl 2-(2-nitrophenylsulfonamide)succinate (3.01 g) prepared in the same manner as described for Comparative Example 1-(a), 3,6,9,12,15 tributylphosphine (2.10 ml) was added to temperature under argon atmosphere with stirring, and the reaction mixture was stirred at room temperature for 4 hours. Additionally, 1,1'-azobis(N,N-dimethylformamide) (1.44 g) and tributylphosphine (2.10 ml) were added three times every hour. After completion of the reaction, the precipitate formed was filtered off, washed with tert-butyl methyl ether, and the filtrate was evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (1.30 g) as an orange solid.

¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ: 8.14-8.07 (m, 2H), 7.72-7.66 (m, 4H), 7.63-7.57 (m, 2H), 4.97-4.89 (m, 2H) , 3.77-3.53 (m, 22H), 3.35-3.23 (m, 2H), 3.02 (dd, J = 7.7, 16.5 Hz, 2H), 2.74 (dd, J = 6.5, 16.5 Hz, 2H), 1.46 (s , 18H), 1.30 (s, 18H).

Comparative Example 5-(b)

Preparation of (2S,22S)-tetra-tert-butyl 6,9,12,15,18-pentaoxa-3,21-diazatricosan-1,2,22,23-tetracarboxylate

In suspension (2S,22S)-tetra-tert-butyl 3,21-bis((2-nitrophenyl)sulfonyl)-6,9,12,15,18-pentaoxa-3,21-diazatricosan-1,2,22 ,23-tetracarboxylate (1.30 g) obtained in Comparative Example 5-(a) and potassium carbonate (492 mg) in dimethylformamide (15 ml) in a 100 ml round bottom flask were added 4-tert-butylthiophenol (0.500 ml) at room temperature under argon atmosphere with stirring, and the reaction mixture was stirred at room temperature for 3 hours. Additional 4-tert-butylthiophenol (0.500 ml) was added and the reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, water was added to the solution, and the resulting solution was extracted with tert-butyl methyl ether. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (DIOL silica gel, elution solvent: dichloroethane: methanol) to give the title Compound (310 mg) as a yellowish oil.

Mass Spectrum (ESI, m/z): 759 [M+Na] ⁺ .

Comparative Example 5-(c)

Preparation of (2S,22S)-tetra-tert-butyl 3,21-bis(N-((benzyloxy)carbonyl)sulfamoyl)-6,9,12,15,18-pentaoxa-3,21-diazatricosan-1,2 ,22,23-tetracarboxylate

To a solution of chlorosulfonyl isocyanate (0.195 ml) in dichloromethane (10 ml) in a 100 ml round bottom flask was added benzyl alcohol (0.110 ml) at 0°C under argon with stirring, and the reaction mixture was stirred at 0°C for 10 minutes. Then triethylamine (0.180 ml) and (2S,22S)-tetra-tert-butyl 6,9,12,15,18-pentaoxa-3,21-diazatricosan-1,2,22,23-tetracarboxylate (310 mg) were added obtained in Comparative Example 5-(b) with stirring at 0°C, and the reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, a saturated sodium hydrogen carbonate aqueous solution was added to the solution, and the resulting solution was extracted with dichloromethane. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: dichloroethane:methanol) to give the title Compound (443 mg) as a yellowish foam.

Mass spectrum (ESI, m/z): 1185 [M+Na] ⁺ .

Comparative Example 6-(a)

Preparation of (2S,25S)-tetra-tert-butyl 3,24-bis((2-nitrophenyl)sulfonyl)-6,9,12,15,18,21-hexaoxa-3,24-diazahexacosan-1,2, 25,26-tetracarboxylate

In a solution of 3,6,9,12,15,18-hexaoxaicosan-1,20-diol (1.89 g), (S)-di-tert-butyl 2-(2-nitrophenylsulfonamide)succinate (4.94 g), obtained by tributylphosphine (3.70 ml ) at room temperature under argon with stirring, and the reaction mixture was stirred at room temperature for 30 hours. After completion of the reaction, water was added to the solution, and the resulting solution was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (5.52 g) as a yellow oil.

Mass spectrum (ESI, m/z): 1173 [M+Na] ⁺ .

Comparative Example 6-(b)

Preparation of (2S,25S)-tetra-tert-butyl 6,9,12,15,18,21-hexaoxa-3,24-diazahexacosan-1,2,25,26-tetracarboxylate

In a solution of (2S,25S)-tetra-tert-butyl 3,24-bis((2-nitrophenyl)sulfonyl)-6,9,12,15,18,21-hexaoxa-3,24-diazahexacosan-1,2 ,25,26-tetracarboxylate (5.52 g) obtained in Comparative Example 6-(a) in dimethylformamide (50 ml), potassium carbonate (3.98 g) and 4-tert-butylthiophenol (3.22 ml) were added in a 300 ml round bottom flask at room temperature under argon with stirring, and the reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, water was added to the solution, and the resulting solution was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (DIOL silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (2.98 g) as a yellowish oil.

Mass spectrum (ESI, m/z): 782 [M+H] ⁺ .

Comparative Example 6-(c)

Preparation of (2S,25S)-tetra-tert-butyl 3,24-bis(N-((benzyloxy)carbonyl)sulfamoyl)-6,9,12,15,18,21-hexaoxa-3,24-diazahexacosan-1 ,2,25,26-tetracarboxylate

To a solution of chlorosulfonyl isocyanate (823 µl) in dichloromethane (30 ml) in a 200 ml round bottom flask was added benzyl alcohol (982 µl) at 0°C under argon with stirring, and the reaction mixture was stirred at 0°C for 30 minutes. Then triethylamine (2.13 ml) and a solution of (2S,25S)-tetra-tert-butyl 6,9,12,15,18,21-hexaoxa-3,24-diazahexacosan-1,2,25,26-tetracarboxylate ( 2.98 g) obtained in Comparative Example 6-(b) in dichloromethane (30 ml) with stirring at 0°C, and the reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, a saturated sodium hydrogen carbonate aqueous solution was added to the solution, and the resulting solution was extracted with dichloromethane. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: dichloroethane:methanol), and fractions with the title compound were evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: dichloroethane:ethyl acetate) to give the title Compound (3.60 g) as a colorless oil.

Mass spectrum (ESI, m/z): 1230 [M+Na] ⁺ .

Comparative Example 7-(a)

Preparation of (2S,2'S)-tetra-tert-butyl 2,2'-(propane-1,3-diylbis(((2-nitrophenyl)sulfonyl)azandiyl))disuccinate

To a solution of (S)-di-tert-butyl 2-(2-nitrophenylsulfonamide)succinate (1.90 g) obtained in the same manner as described for Comparative Example 1-(a) in anhydrous tetrahydrofuran (20 ml) in 200 Trimethylene glycol (0.150 ml), tributylphosphine (1.25 ml) and 1,1'-azobis(N,N-dimethylformamide) (870 mg) were added to a -milliliter round-bottom flask while cooling in an ice bath under argon atmosphere with stirring, and the reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, water was added to the solution, and the resulting solution was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (1.86 g) as a white foam.

Mass spectrum (ESI, m/z): 923 [M+Na] ⁺ .

Comparative Example 7-(b)

Preparation of (2S,2'S)-tetra-tert-butyl 2,2'-(propane-1,3-diylbis(azandiyl)) disuccinate

In a solution of (2S,2'S)-tetra-tert-butyl 2,2'-(propane-1,3-diylbis(((2-nitrophenyl)sulfonyl)azandiyl))disuccinate (2.04 g) obtained by the same method, as described for Comparative Example 7-(a), in anhydrous dimethylformamide (20 ml) in a 100 ml round bottom flask, potassium carbonate (940 mg) and 4-tert-butylthiophenol (0.95 ml) were added at room temperature under argon atmosphere with stirring, and the reaction mixture was stirred at room temperature for 5 hours. After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added to the solution, and the resulting solution was extracted with tert-butyl methyl ether. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (DIOL silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (1.10 g) as a yellowish oil.

Mass spectrum (ESI, m/z): 531 [M+H] ⁺ .

Comparative Example 7-(c)

Preparation of (2S,2'S)-tetra-tert-butyl 2,2'-(propane-1,3-diylbis((N-((benzyloxy)carbonyl)sulfamoyl)azandiyl))disuccinate

To a solution of chlorosulfonyl isocyanate (0.430 ml) in anhydrous dichloromethane (10 ml) in a 100 ml round bottom flask was added benzyl alcohol (0.515 ml) while cooling in an ice bath under argon atmosphere with stirring, and the reaction mixture was stirred while cooling in an ice bath for 30 minutes . Then, triethylamine (1.20 ml) and a solution of (2S,2'S)-tetra-tert-butyl 2,2'-(propane-1,3-diylbis(azandiyl))disuccinate (1.10g) prepared in Comparative Example 7-( b) in anhydrous dichloromethane (10 ml) with stirring while cooling in an ice bath, and the reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, a saturated sodium hydrogen carbonate aqueous solution was added to the solution, and the resulting solution was extracted with dichloromethane. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: dichloroethane: ethyl acetate) to give the title Compound (2.10 g) as a yellowish oil.

Mass spectrum (ESI, m/z): 979 [M+Na] ⁺ .

Comparative Example 8-(a)

Preparation of (2S,2'S)-tetra-tert-butyl 2,2'-(butane-1,4-diylbis(((2-nitrophenyl)sulfonyl)azandiyl))disuccinate

To a solution of (S)-di-tert-butyl 2-(2-nitrophenylsulfonamide)succinate (7.50 g) obtained in the same manner as described for Comparative Example 1-(a) in anhydrous tetrahydrofuran (50 ml) in 200 Butane-1,4-diol (0.750 ml), tributylphosphine (5.15 ml) and 1,1'-azobis(N,N-dimethylformamide) (3.60 g) were added to a -milliliter round bottom flask while cooling in an ice bath under argon atmosphere with stirring , and the reaction mixture was stirred at room temperature for 16 hours. Additional butane-1,4-diol (1.15 ml), tributylphosphine (7.20 ml) and 1,1'-azobis(N,N-dimethylformamide) (5.00 g) were added at room temperature, and the reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, water was added to the solution, and the resulting solution was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (2.70 g) as an orange oil.

Mass spectrum (ESI, m/z): 932 [M+NH ₄ ] ⁺ .

Comparative Example 8-(b)

Preparation of (2S,2'S)-tetra-tert-butyl 2,2'-(butane-1,4-diylbis(azandiyl)) disuccinate

In a solution of (2S,2'S)-tetra-tert-butyl 2,2'-(butan-1,4-diylbis(((2-nitrophenyl)sulfonyl)azandiyl))disuccinate (3.26 g) obtained by the same method, as described for Comparative Example 8-(a), in anhydrous dimethylformamide (20 ml) in a 200 ml round bottom flask, potassium carbonate (1.50 g) and 4-tert-butylthiophenol (1.50 ml) were added at room temperature under argon atmosphere with stirring, and the reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added to the solution, and the resulting solution was extracted with tert-butyl methyl ether. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (1.56 g) as a yellowish oil.

Mass spectrum (ESI, m/z): 545 [M+H] ⁺ .

Comparative Example 8-(c)

Preparation of (2S,2'S)-tetra-tert-butyl 2,2'-(butane-1,4-diylbis((N-((benzyloxy)carbonyl)sulfamoyl)azandiyl))disuccinate

To a solution of chlorosulfonyl isocyanate (0.600 ml) in anhydrous dichloromethane (10 ml) in a 100 ml round bottom flask was added benzyl alcohol (0.710 ml) while cooling in an ice bath under argon atmosphere with stirring, and the reaction mixture was stirred while cooling in an ice bath for 30 minutes . Triethylamine (1.60 ml) and a solution of (2S,2'S)-tetra-tert-butyl 2,2'-(butan-1,4-diylbis(azandiyl))disuccinate (1.56g) obtained in Comparative Example 8-( b) in anhydrous dichloromethane (10 ml) with stirring while cooling in an ice bath, and the reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, a saturated sodium hydrogen carbonate aqueous solution was added to the solution, and the resulting solution was extracted with dichloromethane. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: dichloroethane:ethyl acetate) to give the title Compound (2.74 g) as a colorless oil.

Mass spectrum (ESI, m/z): 988 [M+NH ₄ ] ⁺ .

Comparative Example 9-(a)

Preparation of (2S,2'S)-tetra-tert-butyl 2,2'-(pentane-1,5-diylbis(((2-nitrophenyl)sulfonyl)azandiyl))disuccinate

To a solution of (S)-di-tert-butyl 2-(2-nitrophenylsulfonamide)succinate (2.03 g) obtained in the same manner as described for Comparative Example 1-(a) in tetrahydrofuran (15 ml) in 100- Pentan-1,5-diol (0.235 ml), tributylphosphine (1.32 ml) and 1,1'-azobis(N,N-dimethylformamide) (0.917 g) were added to a milliliter round-bottom flask while cooling in an ice bath in an argon atmosphere with stirring, and the reaction mixture was stirred at room temperature for 21.5 hours. Additionally, tributylphosphine (1.32 ml) and 1,1'-azobis(N,N-dimethylformamide) (0.915 g) were added with stirring at room temperature, and the resulting mixture was stirred at room temperature for 6 hours. After completion of the reaction, water was added to the solution, and the resulting solution was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (881.4 mg) as a light yellow oil.

Mass Spectrum (ESI, m/z): 927 [MH] ^- .

Comparative Example 9-(b)

Preparation of (2S,2'S)-tetra-tert-butyl 2,2'-(pentane-1,5-diylbis(azandiyl)) disuccinate

To a solution of (2S,2'S)-tetra-tert-butyl 2,2'-(pentane-1,5-diylbis(((2-nitrophenyl)sulfonyl)azandiyl))disuccinate (881 mg) obtained in Comparative Example 9- (a), in dimethylformamide (3 ml) in a 30 ml cylindrical flask, potassium carbonate (393 mg) and 4-tert-butylthiophenol (0.394 ml) were added at room temperature under argon with stirring, and the reaction mixture was stirred at room temperature in during the night. After completion of the reaction, water was added to the solution, and the resulting solution was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (443.0 mg) as a light yellow oil.

Mass spectrum (ESI, m/z): 559 [M+H] ⁺ .

Comparative Example 9-(c)

Preparation of (2S,2'S)-tetra-tert-butyl 2,2'-(pentane-1,5-diylbis((N-((benzyloxy)carbonyl)sulfamoyl)azandiyl))disuccinate

To a solution of chlorosulfonyl isocyanate (0.165 mL) in dichloromethane (10 mL) in a 100 mL round bottom flask was added benzyl alcohol (0.200 mL) at 0°C under argon with stirring, and the reaction mixture was stirred at 0°C for 1 hour. Then triethylamine (0.445 ml) and a solution of (2S,2'S)-tetra-tert-butyl 2,2'-(pentan-1,5-diylbis(azandiyl)) disuccinate (443 mg) prepared in Comparative Example 9-( b), in dichloromethane (6 ml) with stirring at 0°C, and the reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, a saturated sodium hydrogen carbonate aqueous solution was added to the solution, and the resulting solution was extracted with dichloromethane. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate and then ethyl acetate:methanol) to give the title Compound (505.3 mg) as a light yellow oil.

Mass Spectrum (ESI, m/z): 983 [MH] ^- .

Comparative Example 10-(a)

Preparation of 4-((4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoyl)oxy)benzyl 1H-imidazole-1-carboxylate

To a solution of 4-(hydroxymethyl)phenyl 4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoate (904.2 mg) prepared in the same manner as described for Comparative Example 1-(g) in dichloromethane (9 ml) in a 100 ml round bottom flask, 1,1'-carbonyldiimidazole (374.9 mg) and 4-dimethylaminopyridine (51.7 mg) were added at room temperature under argon with stirring, and the reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, water was added to the solution, and the resulting solution was extracted with dichloromethane. The organic layer was washed with 5% aqueous sodium hydrosulfite and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (1.0039 g) as a white solid.

Mass spectrum (ESI, m/z): 580 [M+H] ⁺ .

Comparative Example 10-(b)

Preparation of 1-(((4-((4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoyl)oxy)benzyl)oxy)carbonyl)-3-methyl-1H-imidazol-3-ium trifluoromethanesulfonate

To a solution of 4-((4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoyl)oxy)benzyl 1H-imidazole-1-carboxylate (1.00 g) obtained in Comparative Example 10-(a) in dichloromethane (10 ml) in a 100 ml round bottom flask was added methyl trifluoromethanesulfonate (208 μl) at 0°C under argon with stirring, and the reaction mixture was stirred at 0°C for 2 hours. After the reaction was completed, diethyl ether (20 ml) was added to the solution, the resulting mixture was stirred at room temperature for 1 hour, the precipitate formed was collected by filtration and dried under reduced pressure to give the title Compound (1.09 g) as a white solid.

Mass spectrum (ESI, m/z): 594 [M-CF ₃ SO ₃ ] ⁺ .

Comparative Example 10-(c)

Preparation of tetra-tert-butyl 6,9,12,15-tetraoxa-3,18-diazaicosan-1,2,19,20-tetracarboxylate

1,8-Diazabicyclo [5.4.0]-7-undecene (319 µl) at room temperature under argon with stirring, and the reaction mixture was stirred at room temperature for 22 hours. After completion of the reaction, the solution was evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (DIOL silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (993.2 mg) as a colorless oil.

Mass spectrum (ESI, m/z): 693 [M+H] ⁺ .

Comparative Example 10-(c)-2-Comparative Example 10-(c)-7 was prepared in a similar manner to Comparative Example 10-(c).

Comparative Example 11-(a)

Preparation of tetra-tert-butyl 2,2'-(dodecane-1,12-diylbis(azandiyl))disuccinate

1,8-Diazabicyclo[5.4.0]-7- undecene (1.13 ml) at room temperature under argon with stirring, and the reaction mixture was stirred at room temperature for 22 hours. After completion of the reaction, the solution was evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (4.1 g) as a colorless oil.

¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ: 3.48-3.42 (m, 2H), 2.68-2.55 (m, 4H), 2.53-2.44 (m, 4H), 1.53-1.37 (m, 40H) , 1.34-1.20 (m, 16H).

Comparative Example 12-(a)

Preparation of (3S,22S)-di-tert-butyl 3,22-bis(((benzyloxy)carbonyl)amino)-4,21-dioxo-8,11,14,17-tetraoxa-5,20-diazatetracosan-1 ,24-dioate

COMU (19.6 d) and N,N-diisopropylethylamine (8.62 ml) at room temperature under argon with stirring, and the reaction mixture was stirred at room temperature for 1 hour. Then a solution of 3,6,9,12-tetraoxatetradecane-1,14-diamine (3 g) in dichloromethane (30 ml) was added with stirring at room temperature, and the reaction mixture was stirred at room temperature for 22 hours. After completion of the reaction, the solution was evaporated under reduced pressure. Ethyl acetate was added to the evaporation residue, the resulting solution was washed with a saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (DIOL silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (8.84 g) as a yellowish oil.

Mass Spectrum (ESI, m/z): 869 [M+Na] ⁺ .

Comparative Example 12-(a)-2-Comparative Example 12-(a)-6 was prepared in a similar manner to Comparative Example 12-(a).

Comparative Example 12-(b)

Preparation of (3S,22S)-di-tert-butyl 3,22-diamino-4,21-dioxo-8,11,14,17-tetraoxa-5,20-diazatetracosan-1,24-dioate

In a solution of (3S,22S)-di-tert-butyl 3,22-bis(((benzyloxy)carbonyl)amino)-4,21-dioxo-8,11,14,17-tetraoxa-5,20-diazatetracosan- 1,24-dioate (6.52 g) obtained by the same procedure as described for Comparative Example 12-(a), in ethanol (40 ml) in a 300 ml round bottom flask was added 10% palladium on carbon (water content 54.51% , PE-type manufactured by NE CHEMCAT Corporation) (652 mg) at room temperature under an argon atmosphere with stirring, the reaction system was filled with hydrogen, and then the resulting mixture was stirred at room temperature for 2 hours. After the reaction was completed, ethyl acetate and celite were added to the solution, the resulting mixture was filtered, and the filtrate was evaporated under reduced pressure to give the title Compound (4.63 g) as a yellowish oil.

Mass spectrum (ESI, m/z): 579 [M+H] ⁺ .

Comparative Example 12-(b)-2-Comparative Example 12-(b)-5 was prepared in a similar manner to Comparative Example 12-(b).

Comparative Example 12-(c)

Preparation of (3S,6S,25S,28S)-di-tert-butyl 3,28-bis(((benzyloxy)carbonyl)amino)-6,25-bis(2-(tert-butoxy)-2-oxoethyl)- 4,7,24,27-tetraoxo-11,14,17,20-tetraoxa-5,8,23,26-tetraazatriacontane-1,30-dioate

COMU (8.45 d) and N,N-diisopropylethylamine (3.71 ml) at room temperature under argon flow with stirring, and the reaction mixture was stirred at room temperature for 1 hour. Then a solution of (3S,22S)-di-tert-butyl 3,22-diamino-4,21-dioxo-8,11,14,17-tetraoxa-5,20-diazatetracosan-1,24-dioate (3.16 g ) obtained by the same procedure as described for Comparative Example 12-(b) in dichloromethane (20 ml) with stirring at room temperature, and the reaction mixture was stirred at room temperature for 15 hours. After completion of the reaction, the solution was evaporated under reduced pressure. Ethyl acetate was added to the evaporation residue, the resulting solution was washed with a saturated aqueous sodium hydrogen carbonate solution three times, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (DNH silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (5.18 g) as a white foam.

Mass Spectrum (ESI, m/z): 1212 [M+Na] ⁺ .

Comparative Example 12-(d)

Preparation of (3S,6S,25S,28S)-di-tert-butyl 3,28-diamino-6,25-bis(2-(tert-butoxy)-2-oxoethyl)-4,7,24,27-tetraoxo -11,14,17,20-tetraoxa-5,8,23,26-tetraazatriacontane-1,30-dioate

In a solution of (3S,6S,25S,28S)-di-tert-butyl 3,28-bis(((benzyloxy)carbonyl)amino)-6,25-bis(2-(tert-butoxy)-2-oxoethyl) -4,7,24,27-tetraoxo-11,14,17,20-tetraoxa-5,8,23,26-tetraazatriacontane-1,30-dioate (400 mg) obtained in Comparative Example 12-(c) , in a mixture of ethanol (8 ml)/tetrahydrofuran (4 ml) in a 100 ml round bottom flask was added 10% palladium on carbon (water content 54.51%, PE-type manufactured by NE CHEMCAT Corporation) (40.5 mg) at room temperature under argon atmosphere while stirring, the reaction system was filled with hydrogen, and then the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, ethyl acetate and celite were added to the solution, the resulting mixture was filtered, and the filtrate was evaporated under reduced pressure to give the title Compound (329.2 mg) as a colorless oil.

Mass spectrum (ESI, m/z): 922 [M+H] ⁺ .

Comparative Example 13-(a)

Preparation of (5S,22S)-tert-butyl 22-(((benzyloxy)carbonyl)amino)-5-(2-(tert-butoxy)-2-oxoethyl)-3,6,21-trioxo-1-phenyl- 2-oxa-4,7,20-triazatetracosan-24-oate

COMU (5.13 d) and N,N-diisopropylethylamine (2.26 ml) at room temperature under argon with stirring, and the reaction mixture was stirred at room temperature for 1 hour. Then a solution of dodecane-1,12-diamine (1.00 g) in dichloromethane (10 ml) was added with stirring at room temperature, and the reaction mixture was stirred at room temperature for 3.5 hours. Additionally, (S)-2-(((benzyloxy)carbonyl)amino)-4-(tert-butoxy)-4-oxobutanoic acid (1.29 g), COMU (1.92 g) and N,N-diisopropylethylamine (869 μl) were added at room temperature, and the reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, the solution was evaporated under reduced pressure. Ethyl acetate was added to the evaporation residue, the resulting solution was washed with a saturated aqueous sodium hydrogen carbonate solution three times, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate), and fractions with the title compound were evaporated under reduced pressure. Tert-butyl methyl ether and dichloromethane were added to the evaporation residue and the resulting solution was evaporated under reduced pressure to give the title Compound (4.09 g) as a light yellow semi-solid.

Mass spectrum (ESI, m/z): 811 [M+H] ⁺ .

Comparative Example 13-(b)

Preparation of (3S,3'S)-di-tert-butyl 4,4'-(dodecane-1,12-diylbis(azandiyl))bis(3-amino-4-oxobutanoate)

In a solution of (5S,22S)-tert-butyl 22-(((benzyloxy)carbonyl)amino)-5-(2-(tert-butoxy)-2-oxoethyl)-3,6,21-trioxo-1-phenyl -2-oxa-4,7,20-triazatetracosan-24-oate (4.09 g) obtained in Comparative Example 13-(a) in a mixture of ethanol (20 ml) and tetrahydrofuran (20 ml) in a 200 ml round bottom flask 10% palladium-carbon (water content 54.51%, PE-type manufactured by NE CHEMCAT Corporation) (400 mg) was added at room temperature under argon atmosphere with stirring, the reaction system was filled with hydrogen, and then the resulting mixture was stirred at room temperature for 3 hours . After the reaction was completed, ethyl acetate and celite were added to the solution, the resulting mixture was filtered, and the filtrate was evaporated under reduced pressure to give the title Compound (2.35 g) as a white solid.

¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ: 7.41-7.28 (m, 2H), 3.64 (dd, J = 3.8, 8.5 Hz, 2H), 3.31-3.16 (m, 4H), 2.86 (dd , J = 3.8, 16.6 Hz, 2H), 2.49 (dd, J = 8.5, 16.7 Hz, 2H), 1.45 (s, 18H), 1.55–1.39 (m, 4H), 1.36–1.22 (m, 16H).

Comparative Example 13-(c)

Preparation of (3S,6S,23S,26S)-di-tert-butyl 3,26-bis(((benzyloxy)carbonyl)amino)-6,23-bis(2-(tert-butoxy)-2-oxoethyl)- 4,7,22,25-tetraoxo-5,8,21,24-tetraazaoctacosan-1,28-dioate

COMU (2.85 d) and N,N-diisopropylethylamine (1.25 ml) at room temperature under argon with stirring, and the reaction mixture was stirred at room temperature for 1 hour. Then, a solution of (3S,3'S)-di-tert-butyl 4,4'-(dodecane-1,12-diylbis(azandiyl))bis(3-amino-4-oxobutanoate) (1.00 g) obtained in Comparative Example was added. 13-(b) in dichloromethane (10 ml) with stirring at room temperature, and the reaction mixture was stirred at room temperature for 3.5 hours. After completion of the reaction, the solution was evaporated under reduced pressure. Ethyl acetate was added to the evaporation residue, the resulting solution was washed with a saturated aqueous sodium hydrogen carbonate solution three times, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate), and fractions with the title compound were evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (DNH silica gel, hexane:ethyl acetate) to give the title Compound (1.93 g) as a white solid.

Mass spectrum (ESI, m/z): 1176 [M+Na] ⁺ .

Comparative Example 13-(d)

Preparation of (3S,6S,23S,26S)-di-tert-butyl 3,26-diamino-6,23-bis(2-(tert-butoxy)-2-oxoethyl)-4,7,22,25-tetraoxo -5,8,21,24-tetraazaoctacosan-1,28-dioate

In a solution of (3S,6S,23S,26S)-di-tert-butyl 3,26-bis(((benzyloxy)carbonyl)amino)-6,23-bis(2-(tert-butoxy)-2-oxoethyl) -4,7,22,25-tetraoxo-5,8,21,24-tetraazaoctacosan-1,28-dioate (1.93 g) obtained in Comparative Example 13-(c) in ethanol (20 ml) and tetrahydrofuran ( 20 ml) in a 200 ml round bottom flask was added 10% palladium on carbon (water content 54.51%, PE-type manufactured by NE CHEMCAT Corporation) (193 mg) at room temperature in an argon atmosphere with stirring, the reaction system was filled with hydrogen, and then the resulting the mixture was stirred at room temperature for 1 hour. After the reaction was completed, ethyl acetate and celite were added to the solution, the resulting mixture was filtered, and the filtrate was evaporated under reduced pressure to give the title Compound (1.48 g) as a white solid.

¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ: 8.17 (d, J = 8.4 Hz, 2H), 6.80-6.62 (m, 2H), 4.71-4.63 (m, 2H), 3.66-3.59 (m , 2H), 3.29-3.10 (m, 4H), 2.90 (dd, J = 4.6, 16.8 Hz, 2H), 2.82 (dd, J = 4.9, 16.8 Hz, 2H), 2.67-2.52 (m, 4H), 1.45 (s, 18H), 1.45 (s, 18H), 1.53-1.39 (m, 4H), 1.32-1.20 (m, 16H).

Comparative Example 14-(a)

Preparation of 2-(trimethylsilyl)ethyl 2-(((benzyloxy)carbonyl)amino)acetate

To a suspension of N-carbobenzyloxyglycine (5.00 g) in anhydrous dichloromethane (100 ml) in a 300 ml round bottom flask was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.05 g), (trimethylsilyl)ethanol (3.75 ml) under ice bath cooling under argon atmosphere with stirring, and the reaction mixture was stirred at room temperature for 5 days. After completion of the reaction, a saturated sodium hydrogen carbonate aqueous solution was added to the solution, and the resulting solution was extracted with dichloromethane. The organic layer was washed with water, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (6.42 g) as a colorless oil.

Mass spectrum (ESI, m/z): 332 [M+Na] ⁺ .

Comparative Example 14-(b)

Preparation of 2-(trimethylsilyl)ethyl 2-aminoacetate

To a solution of 2-(trimethylsilyl)ethyl 2-(((benzyloxy)carbonyl)amino)acetate (6.42 g) obtained in Comparative Example 14-(a) in ethanol (40 ml) in a 200 ml round bottom flask was added 10% palladium-carbon (moisture content about 55%, manufactured by Tokyo Chemical Industry Co., Ltd.) (600 mg), the reaction system was filled with hydrogen, and then the resulting mixture was stirred at room temperature for 2 hours. After completion of the reaction, the atmosphere in the reaction system was changed to nitrogen, and the reaction solution was filtered through celite. The separated solid was washed with ethyl acetate, and then the resulting filtrate was evaporated under reduced pressure to give the title Compound (3.57 g) as a brown oil.

¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ: 4.26-4.19 (m, 2H), 3.40 (s, 2H), 1.07-0.93 (m, 2H), 0.05 (s, 9H).

Comparative Example 14-(c)

Preparation of tert-butyl 3-(((2-oxo-2-(2-(trimethylsilyl)ethoxy)ethyl)amino)methyl)benzoate

Magnesium sulfate (1.52 g), sodium acetate (1.20 g), and 2-(trimethylsilyl)ethyl 2-aminoacetate ( 1.87 g) obtained in Comparative Example 14-(b) by cooling in an ice bath under argon atmosphere with stirring, and the reaction mixture was stirred at room temperature for 16 hours. Then acetic acid (0.850 ml), sodium triacetoxyborohydride (3.10 g) were added in portions with stirring while cooling in an ice bath, and the reaction mixture was stirred at room temperature for 4 hours. After completion of the reaction, the solution was filtered, a saturated aqueous sodium hydrogen carbonate solution was added to the resulting filtrate, and the solution was extracted with dichloromethane. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (2.37 g) as a colorless oil.

Mass spectrum (ESI, m/z): 366 [M+H] ⁺ .

Comparative Example 14-(c)-2 was prepared in a similar manner to Comparative Example 14-(c).

Comparative Example 14-(d)

Preparation of tert-butyl 3-((((4-((4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoyl)oxy)benzyl)oxy)carbonyl)(2-oxo-2-(2- (trimethylsilyl)ethoxy)ethyl)amino)methyl)benzoate

Into a suspension of 1-(((4-((4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoyl)oxy)benzyl)oxy)carbonyl)-3-methyl-1H-imidazol-3-ium trifluoromethanesulfonate ( 3.70 g) obtained by the same procedure as described for Comparative Example 10-(b), in anhydrous acetonitrile (10 ml) in a 100 ml round bottom flask was added a solution of tert-butyl 3-(((2-oxo-2- (2-(trimethylsilyl)ethoxy)-ethyl)amino)methyl)benzoate (2.37 g) obtained in Comparative Example 14-(c) in anhydrous acetonitrile (5 ml) at room temperature under argon with stirring, and the reaction mixture stirred at room temperature for 16 hours. After completion of the reaction, the solution was evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (4.71 g) as a colorless oil.

Mass spectrum (ESI, m/z): 877 [M+H] ⁺ .

Comparative Example 14-(e)

Preparation of 2-((((4-((4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoyl)oxy)benzyl)oxy)carbonyl)(3-(tert-butoxycarbonyl)benzyl)amino)acetic acid

In a solution of tert-butyl 3-((((4-((4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoyl)oxy)benzyl)oxy)carbonyl)(2-oxo-2-(2 -(trimethylsilyl)ethoxy)ethyl)amino)methyl)benzoate (4.71 g) obtained in Comparative Example 14-(d) in anhydrous tetrahydrofuran (20 ml) in a 100 ml round bottom flask was added tetrabutylammonium fluoride (1.0M solution in tetrahydrofuran ) (7.00 ml) under cooling in an ice bath under argon atmosphere with stirring, and the reaction mixture was stirred at room temperature for 21 hours. After completion of the reaction, a saturated ammonium chloride aqueous solution was added to the solution, and the resulting solution was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give the title Compound (3.98 g) as a white foam.

Mass spectrum (ESI, m/z): 777 [M+H] ⁺ .

Comparative Example 15-(a)

Preparation of (S)-4-tert-butyl 1-(2-(trimethylsilyl)ethyl) 2-(((benzyloxy)carbonyl)amino)succinate

1-( 3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.26 g) and 4-dimethylaminopyridine (573 mg) at room temperature under argon with stirring, and the reaction mixture was stirred at room temperature for 20 minutes. Then 2-(trimethylsilyl)ethanol (2.42 ml) was added with stirring at room temperature, and the reaction mixture was stirred at room temperature for 15 hours. Additionally, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.29 g) and 4-dimethylaminopyridine (561.5 mg) were added at room temperature, and the reaction mixture was stirred at room temperature for 23 hours. After completion of the reaction, a saturated ammonium chloride aqueous solution was added to the solution, and the resulting solution was extracted with dichloromethane. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (5.32 g) as a colorless oil.

Mass spectrum (ESI, m/z): 424 [M+H] ⁺ .

Comparative Example 15-(b)

Preparation of (S)-4-tert-butyl 1-(2-(trimethylsilyl)ethyl) 2-aminosuccinate

To a solution of (S)-4-tert-butyl 1-(2-(trimethylsilyl)ethyl) 2-(((benzyloxy)carbonyl)amino)succinate (5.32 g) obtained in Comparative Example 15-(a) in ethanol (25 ml) and tetrahydrofuran (25 ml) in a 300 ml round bottom flask was added 10% palladium on carbon (water content 54.51%, PE-type manufactured by NE CHEMCAT Corporation) (558.5 mg) at room temperature in an argon atmosphere with stirring, the reaction the system was filled with hydrogen, and then the resulting mixture was stirred at room temperature for 1 hour. After completion of the reaction, ethyl acetate and celite were added to the solution, the resulting mixture was filtered, and the filtrate was evaporated under reduced pressure to give the title Compound (3.49 g) as a colorless oil.

Mass spectrum (CI, m/z): 290 [M+H] ⁺ .

Comparative Example 15-(c)

Preparation of (S)-4-tert-butyl 1-(2-(trimethylsilyl)ethyl) 2-((2-(tert-butoxy)-2-oxoethyl)amino)succinate

To a solution of (S)-4-tert-butyl 1-(2-(trimethylsilyl)ethyl) 2-aminosuccinate (2.0 g) prepared in the same manner as that described in Comparative Example 15-(b) and potassium carbonate ( 1.99 g) in acetonitrile (50 ml) in a 200 ml round bottom flask was added tert-butyl bromoacetate (1.15 ml) at room temperature under argon with stirring, and the reaction mixture was stirred at 70°C for 2 hours. After completion of the reaction, the solution was filtered, the separated solid was washed with ethyl acetate, and the filtrate was evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (2.12 g) as a colorless oil.

Mass spectrum (ESI, m/z): 404 [M+H] ⁺ .

Comparative Example 15-(c)-2-Comparative Example 15-(c)-9 was prepared in a similar manner to Comparative Example 15-(c).

Comparative Example 15-(d)

Preparation of (S)-4-tert-butyl 1-(2-(trimethylsilyl)ethyl) 2-((((4-((4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoyl)oxy)benzyl )oxy)carbonyl)(2-(tert-butoxy)-2-oxoethyl)amino)succinate

Into a solution of 1-(((4-((4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoyl)oxy)benzyl)oxy)carbonyl)-3-methyl-1H-imidazol-3-ium trifluoromethanesulfonate ( 462.5 mg) obtained by the same procedure as described for Comparative Example 10-(b), in acetonitrile (6 ml) in a 100 ml round bottom flask was added (S)-4-tert-butyl 1-(2-(trimethylsilyl )ethyl) 2-((2-(tert-butoxy)-2-oxoethyl)amino)succinate (309.5 mg) prepared in the same manner as in Comparative Example 15-(c) at room temperature under argon while stirring, the reaction mixture was stirred at room temperature for 4 hours, left at room temperature for 12 days and stirred at room temperature for 57 hours. After completion of the reaction, the solution was evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (268.3 mg) as a colorless oil.

Mass spectrum (ESI, m/z): 915 [M+H] ⁺ .

Comparative Example 15-(e)

Preparation of (S)-2-((((4-((4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoyl)oxy)benzyl)oxy)carbonyl)(2-(tert-butoxy)-2 -oxoethyl)amino)-4-(tert-butoxy)-4-oxobutanoic acid

To a solution of (S)-4-tert-butyl 1-(2-(trimethylsilyl)ethyl) 2-((((4-((4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoyl)oxy) benzyl)oxy)carbonyl)(2-(tert-butoxy)-2-oxoethyl)amino)succinate (268 mg) obtained in Comparative Example 15-(d) in anhydrous tetrahydrofuran (5 ml) in a 100 ml round bottom flask was added tetrabutylammonium fluoride (1.0M solution in tetrahydrofuran) (288 μl) at 0°C in an argon atmosphere with stirring, and the reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, a saturated ammonium chloride aqueous solution was added to the solution, and the resulting solution was extracted with dichloromethane. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: dichloroethane:methanol), and fractions with the title compound were evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: ethyl acetate:methanol) to give the title Compound (110 mg) as a colorless oil.

Mass spectrum (ESI, m/z): 815 [M+H] ⁺ .

Comparative Example 16-(a)

Preparation of (S)-4-tert-butyl 1-(2-(trimethylsilyl)ethyl)2-((3-(tert-butoxycarbonyl)benzyl)amino)succinate

To a solution of (S)-4-tert-butyl 1-(2-(trimethylsilyl)ethyl) 2-aminosuccinate (500 mg) prepared in the same manner as in Comparative Example 15-(b) in anhydrous acetonitrile ( 10 ml) in a 100 ml round bottom flask was added anhydrous potassium carbonate (500 mg) and tert-butyl 3-(chloromethyl)benzoate (430 mg) at room temperature under argon with stirring, and the reaction mixture was stirred at 60°C for 7 o'clock. Additionally, tert-butyl 3-(chloromethyl)benzoate (315 mg) and anhydrous potassium carbonate (360 mg) were added with stirring at room temperature, and the reaction mixture was stirred at 60° C. for 3 hours. After completion of the reaction, the solution was allowed to cool to room temperature and filtered. The separated solid was washed with ethyl acetate and the resulting filtrate was evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (332 mg) as a colorless oil.

Mass spectrum (ESI, m/z): 480 [M+H] ⁺ .

Comparative Example 16-(b)

Preparation of (S)-4-tert-butyl 1-(2-(trimethylsilyl)ethyl)2-((((4-((4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoyl)oxy)benzyl )oxy)carbonyl)(3-(tert-butoxycarbonyl)benzyl)amino)succinate

Into a suspension of 1-(((4-((4-(2,3-bis(tert-butoxycarbonyl)guanidino) benzoyl)oxy)benzyl)oxy)carbonyl)-3-methyl-1H-imidazol-3-ium trifluoromethanesulfonate ( 430 mg) obtained by the same procedure as described for Comparative Example 10-(b), in anhydrous acetonitrile (4 ml) in a 50 ml round bottom flask was added a solution of (S)-4-tert-butyl 1-(2- (trimethylsilyl)ethyl)2-((3-(tert-butoxycarbonyl)benzyl)amino)succinate (332 mg) obtained in Comparative Example 16-(a) in anhydrous acetonitrile (2 ml) at room temperature under argon atmosphere under stirring, and the reaction mixture was stirred at room temperature for 6 days. After completion of the reaction, the solution was evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (223 mg) as a white foam.

Mass spectrum (ESI, m/z): 991 [M+H] ⁺ .

Comparative Example 16-(c)

Preparation of (S)-2-((((4-((4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoyl)oxy) benzyl)oxy)carbonyl)(3-(tert-butoxycarbonyl)benzyl) amino)-4-(tert-butoxy)-4-oxobutanoic acid

To a solution of (S)-4-tert-butyl 1-(2-(trimethylsilyl)ethyl)2-((((4-((4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoyl)oxy) benzyl)oxy)carbonyl)(3-(tert-butoxycarbonyl)benzyl)amino)succinate (223 mg) obtained in Comparative Example 16-(b) in anhydrous tetrahydrofuran (2 ml) in a 50 ml round bottom flask was added tetrabutylammonium fluoride (1.0M solution in tetrahydrofuran) (0.270 ml) under ice bath cooling under argon atmosphere with stirring, and the reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, a saturated ammonium chloride aqueous solution was added to the solution, and the resulting solution was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give the title Compound (230 mg) as a white foam.

Mass spectrum (ESI, m/z): 891 [M+H] ⁺ .

Comparative Example 17-(a)

Obtaining 2-(trimethylsilyl)ethyl 3-formylbenzoate

(1) To a suspension of m-formylbenzoic acid (2.00 g) in anhydrous dichloromethane (30 ml) in a 200 ml round bottom flask was added oxalyl chloride (1.20 ml) and dimethylformamide (50 μl) under ice bath cooling under argon atmosphere with stirring, and the reaction mixture was stirred at room temperature for 3 hours. After completion of the reaction, the solution was evaporated under reduced pressure.

(2) To a solution of 2-(trimethylsilyl)ethanol (2.10 ml) and pyridine (1.10 ml) in anhydrous dichloromethane (30 ml) in a 200 ml round bottom flask was added dropwise a solution of the evaporation residue from (1) in dichloromethane (30 ml ) while cooling in an ice bath under argon atmosphere with stirring, and the reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the solution was evaporated under reduced pressure. Water was added to the evaporation residue and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (3.00 g) as a colorless oil.

Mass spectrum (CI, m/z): 251 [M+H] ⁺ .

Comparative Example 17-(b)

Preparation of (S)-di-tert-butyl 2-((3-((2-(trimethylsilyl)ethoxy)carbonyl)benzyl)amino)succinate

Magnesium sulfate (1.00 g), sodium acetate ( 0.740 g) and L-aspartic acid di-tert-butyl ester hydrochloride (2.03 g) while cooling in an ice bath under argon atmosphere with stirring, and the reaction mixture was stirred at room temperature for 16 hours. Then acetic acid (0.520 ml) was added, sodium triacetoxyborohydride (1.90 g) was added in portions with stirring while cooling in an ice bath, and the reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, a saturated sodium hydrogen carbonate aqueous solution was added to the solution, and the resulting solution was extracted with dichloromethane. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (2.68 g) as a colorless oil.

Mass spectrum (ESI, m/z): 480 [M+H] ⁺ .

Comparative Example 17-(c)

Preparation of (S)-di-tert-butyl 2-((((4-((4-(2,3-bis(tert-butoxycarbonyl) guanidino)benzoyl)oxy)benzyl)oxy)carbonyl)(3-(( 2-(trimethylsilyl)ethoxy)carbonyl)benzyl)amino)succinate

Into a suspension of 1-(((4-((4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoyl)oxy)benzyl)oxy)carbonyl)-3-methyl-1H-imidazol-3-ium trifluoromethanesulfonate ( 570 mg) obtained by the same procedure as described for Comparative Example 10-(b), in anhydrous acetonitrile (4 ml) in a 100 ml round bottom flask was added a solution of (S)-di-tert-butyl 2-((3 -((2-(trimethylsilyl)ethoxy)carbonyl)benzyl)amino)succinate (880 mg) obtained in Comparative Example 17-(b) in anhydrous acetonitrile (2 ml) at room temperature under argon with stirring, and reaction the mixture was stirred at room temperature for 3 days. After completion of the reaction, the solution was evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (391 mg) as a colorless oil.

Mass spectrum (ESI, m/z): 991 [M+H] ⁺ .

Comparative Example 17-(d)

Preparation of (S)-3-(((((4-((4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoyl)oxy)benzyl)oxy)carbonyl)(1,4-di-tert- butoxy-1,4-dioxobutan-2-yl)amino)methyl)benzoic acid

Into a solution of (S)-di-tert-butyl 2-((((4-((4-(2,3-bis(tert-butoxycarbonyl) guanidino)benzoyl)oxy)benzyl)oxy)carbonyl)(3-( (2-(trimethylsilyl)ethoxy)carbonyl)benzyl)amino)succinate (391 mg) obtained in Comparative Example 17-(c) in anhydrous tetrahydrofuran (4 ml) in a 100 ml round bottom flask was added tetrabutylammonium fluoride (1.0M solution in tetrahydrofuran) (0.480 ml) while cooling in an ice bath under argon atmosphere with stirring, and the reaction mixture was stirred at room temperature for 25 hours. Additionally, tetrabutylammonium fluoride (1.0M solution in tetrahydrofuran) (0.160 ml) was added with stirring at room temperature, and the reaction mixture was stirred at room temperature for 4 hours. After completion of the reaction, a saturated ammonium chloride aqueous solution was added to the solution, and the resulting solution was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The resulting filtrate was evaporated under reduced pressure to give the title Compound (401 mg) as a white foam.

Mass spectrum (ESI, m/z): 891 [M+H] ⁺ .

Comparative Example 18-(a)

Preparation of (S)-di-tert-butyl 2-((N-((benzyloxy)carbonyl)sulfamoyl)(3-((2-(trimethylsilyl)ethoxy)carbonyl)benzyl)amino)succinate

To a solution of chlorosulfonyl isocyanate (60 μl) in dichloromethane (10 ml) in a 50 ml round bottom flask was added benzyl alcohol (70 μl) at 0°C under argon with stirring, and the reaction mixture was stirred at 0°C for 15 minutes. Then, triethylamine (180 μl) and (S)-di-tert-butyl 2-((3-((2-(trimethylsilyl)ethoxy)carbonyl)benzyl)amino)succinate (290mg) obtained in Comparative Example 17- (b), with stirring at 0°C, and the reaction mixture was stirred at room temperature for 18 hours. After completion of the reaction, a saturated sodium hydrogen carbonate aqueous solution was added to the solution, and the resulting solution was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (240.5 mg) as a yellowish foam.

Mass Spectrum (ESI, m/z): 691 [MH] ^- .

Comparative Example 18-(a)-2-Comparative Example 18-(a)-4 was prepared in a similar manner to Comparative Example 18-(a).

By the same procedure as Comparative Example 18-(a), except that tert-butanol was used instead of benzyl alcohol, Comparative Example 18-(a)-5-Comparative Example 18-(a)-14 was prepared.

Comparative Example 18-(b)

Preparation of (S)-di-tert-butyl 2-((N-((benzyloxy)carbonyl)-N-(4-((4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoyl)oxy)benzyl )sulfamoyl)(3-((2-(trimethylsilyl)ethoxy)carbonyl)benzyl)amino)succinate

To a solution of (S)-di-tert-butyl 2-((N-((benzyloxy)carbonyl)sulfamoyl)(3-((2-(trimethylsilyl)ethoxy)carbonyl)benzyl)amino)succinate (240 mg) obtained in the same manner as that described for Comparative Example 18-(a), 4-(hydroxymethyl)phenyl 4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoate (188 mg) prepared in the same manner as described for Comparative Example 1-(g), and triphenylphosphine (111 mg) in tetrahydrofuran (10 ml) diisopropyl azodicarboxylate (81 μl) was added to a 50 ml round bottom flask at room temperature under argon with stirring, and the reaction mixture was stirred at room temperature. temperature for 30 minutes. After completion of the reaction, the solution was evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (352.3 mg) as a white foam.

Mass spectrum (ESI, m/z): 1161 [M+H] ⁺ .

Comparative Example 18-(c)

Preparation of (S)-3-(((N-((benzyloxy)carbonyl)-N-(4-((4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoyl)oxy)benzyl)sulfamoyl)( 1,4-di-tert-butoxy-1,4-dioxobutan-2-yl)amino)methyl)benzoic acid

To a solution of (S)-di-tert-butyl 2-((N-((benzyloxy)carbonyl)-N-(4-((4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoyl)oxy) benzyl)sulfamoyl)(3-((2-(trimethylsilyl)ethoxy)carbonyl)benzyl)amino)succinate (350mg) obtained in Comparative Example 18-(b) in tetrahydrofuran (10ml) in a 50ml round bottom flask tetrabutylammonium fluoride (1.0M solution in tetrahydrofuran) (0.450 ml) was added at room temperature under argon atmosphere with stirring, and the reaction mixture was stirred at room temperature for 2 hours. Additional tetrabutylammonium fluoride (1.0M solution in tetrahydrofuran) (0.450 ml) was added and the reaction mixture was stirred at room temperature for 18 hours. After completion of the reaction, a saturated ammonium chloride aqueous solution was added to the solution, and the resulting solution was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (205 mg) as a white foam.

Mass spectrum (ESI, m/z): 1060 [M+H] ⁺ .

Comparative Example 19-(a)

Preparation of methyl 2,3-bis(benzyloxy)benzoate

To a suspension of methyl 2,3-dihydroxybenzoate (15.4 g), potassium carbonate (41.2 g), and tetrabutylammonium bromide (1.53 g) in acetone (150 ml) in a 500 ml round bottom flask was added benzyl bromide (24.3 ml) a stream of argon with stirring, and the reaction mixture was stirred at room temperature for 5 hours. After completion of the reaction, the solution was evaporated under reduced pressure. Water (40 ml) was added to the evaporation residue at 0° C., the mixture was stirred and the resulting solution was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure to give the title Compound (38.9 g) as a colorless oil.

Mass spectrum (ESI, m/z): 371 [M+Na] ⁺ .

Comparative Example 19-(b)

Preparation of 2,3-bis(benzyloxy)benzoic acid

To a solution of methyl 2,3-bis(benzyloxy)benzoate (38.9 g) obtained in Comparative Example 19-(a) in tetrahydrofuran (70 ml)/methanol (70 ml) in a 500 ml round bottom flask was added 5 M aqueous sodium hydroxide solution (45.0 ml) at room temperature under air with stirring, and the reaction mixture was stirred at 50°C for 2 hours. After completion of the reaction, 6M hydrochloric acid solution (52.0 ml) and water (100 ml) were added to the reaction solution cooled in an ice bath. The resulting mixture was stirred at room temperature for 1 hour, the precipitate formed was filtered off and dried under reduced pressure to give the title Compound (31.0 g) as a white solid.

Mass Spectrum (ESI, m/z): 333 [MH] ^- .

Comparative Example 19-(c)

Preparation of 3-(benzyloxy)-2-hydroxybenzoic acid

To a solution of 2,3-bis(benzyloxy)benzoic acid (15 g) obtained in Comparative Example 19-(b) in N,N-dimethylacetamide (24 ml) in a 200 ml round bottom flask was added piperidine (18.0 ml) at room temperature in a stream of argon with stirring, and the reaction mixture was stirred at 150°C for 7.75 hours. After the completion of the reaction, the solution was poured into hydrochloric acid, adjusting the pH to 2–3, and the precipitate that formed was separated by filtration. The resulting solid was dissolved in ethyl acetate, the resulting solution was washed successively with water, 1M hydrochloric acid and saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and evaporated under reduced pressure to give the title Compound (9.483 g) as a white solid.

Mass spectrum (ESI, m/z): 267 [M+Na] ⁺ .

Comparative Example 19-(d)

Preparation of 2-(trimethylsilyl)ethyl 3-(benzyloxy)-2-hydroxybenzoate

To a solution of 3-(benzyloxy)-2-hydroxybenzoic acid (5.05 g) obtained in Comparative Example 19-(c), 2-(trimethylsilyl)ethanol (3.21 ml) and triphenylphosphine (6.43 g) in tetrahydrofuran (30 ml) in Diisopropyl azodicarboxylate (1.9M solution in toluene) (12.9 ml) was added to a 200 ml round bottom flask at room temperature under argon with stirring, and the reaction mixture was stirred at room temperature for 16.5 hours. Additionally, 2-(trimethylsilyl)ethanol (3.21 ml), triphenylphosphine (6.51 g) and diisopropyl azodicarboxylate (1.9M solution in toluene) (13.0 ml) were added with stirring at room temperature, and the reaction mixture was stirred at room temperature for 2.5 hours. After completion of the reaction, water was added to the solution, and the resulting solution was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (2.980 g) as a yellow oil.

Mass Spectrum (ESI, m/z): 343 [MH] ^- .

Comparative Example 19-(e)

Preparation of methyl 2-(3-hydroxyprop-1-yn-1-yl)-4-nitrobenzoate

Propargyl alcohol (2.90 ml), triethylamine (5.60 ml), copper(I) iodide (40 mg) and dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium adduct with dichloromethane (165 mg) at room temperature under argon atmosphere with stirring, the resulting mixture was stirred at 45°C for 8 hours, stirred at room temperature for 14 hours, stirred at 45°C for 10 hours, stirred at room temperature for 13 hours and stirred at 45°C for 7 hours. After completion of the reaction, ethyl acetate and celite were added to the solution, the resulting mixture was filtered, and the filtrate was evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (4.35 g) as an orange solid.

Mass spectrum (CI, m/z): 236 [M+H] ⁺ .

Comparative Example 19-(f)

Preparation of methyl 4-amino-2-(3-hydroxypropyl)benzoate

To a solution of methyl 2-(3-hydroxyprop-1-yn-1-yl)-4-nitrobenzoate (1.50 g) obtained in Comparative Example 19-(e) in ethanol (15 ml)/tetrahydrofuran (15 ml) 10% palladium on carbon (water content 54.51%, PE-type manufactured by NE CHEMCAT Corporation) (161.3 mg) was added to a 300 ml round bottom flask at room temperature under argon atmosphere with stirring, the reaction system was filled with hydrogen, and then the resulting mixture was stirred at room temperature for 8 hours. Ethyl acetate and celite were added to the reaction solution, the resulting mixture was filtered, the filtrate was evaporated under reduced pressure, and left at room temperature for 2 days. To a solution of the resulting evaporation residue in an ethanol (15 ml)/tetrahydrofuran (15 ml) mixture was added 10% palladium on carbon (water content 54.51%, PE-type manufactured by NE CHEMCAT Corporation) (480 mg) under argon with stirring, the reaction the system was filled with hydrogen, and then the resulting mixture was stirred at room temperature for 8 hours. After completion of the reaction, ethyl acetate and celite were added to the solution, the resulting mixture was filtered, and the filtrate was evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (902.6 mg) as a colorless oil.

Mass spectrum (ESI, m/z): 210 [M+H] ⁺ .

Comparative Example 19-(g)

Preparation of 4-((tert-butoxycarbonyl)amino)-2-(3-hydroxypropyl)benzoic acid

To a solution of methyl 4-amino-2-(3-hydroxypropyl)benzoate (900 mg) obtained in Comparative Example 19-(f) in methanol (9 ml) in a 100 ml round bottom flask was added 1N. an aqueous solution of sodium hydroxide (9 ml) at room temperature under argon atmosphere with stirring, and the reaction mixture was stirred at 50°C for 5 hours. Di-tert-butyl dicarbonate (1.92 g) was then added with stirring at 0°C, and the resulting mixture was stirred at room temperature for 16 hours. After completion of the reaction, water (9 ml) and 1N. hydrochloric acid solution (18 ml) and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure to give the title Compound (1.33 g) as a brown foam.

Mass Spectrum (ESI, m/z): 294 [MH] ^- .

Comparative Example 19-(h)

Preparation of benzyl 4-((tert-butoxycarbonyl)amino)-2-(3-hydroxypropyl)benzoate

To a solution of 4-((tert-butoxycarbonyl)amino)-2-(3-hydroxypropyl)benzoic acid (1.33 g) obtained in Comparative Example 19-(g) in dimethylformamide (13 ml) in a 200 ml round bottom flask was added benzyl bromide (642 μl) and N,N-diisopropylethylamine (1.57 ml) at room temperature under argon with stirring, and the reaction mixture was stirred at room temperature for 18 hours. After completion of the reaction, water was added to the solution, and the resulting solution was extracted with tert-butyl methyl ether. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate) to give the title compound (1.32 g) as a colorless oil.

Mass spectrum (ESI, m/z): 386 [M+H] ⁺ .

Comparative Example 19-(i)

Preparation of 2-(trimethylsilyl)ethyl 3-(benzyloxy)-2-(3-(2-((benzyloxy)carbonyl)-5-((tert-butoxycarbonyl)amino)phenyl)propoxy)benzoate

Benzyl 4-(( tert-butoxycarbonyl)amino)-2-(3-hydroxypropyl)benzoate (2.32 g) prepared in the same manner as in Comparative Example 19-(h), tributylphosphine (3.40 ml) and 1,1'-azobis( N,N-dimethylformamide) (2.40 g) under cooling in an ice bath under argon atmosphere with stirring, and the reaction mixture was stirred at room temperature overnight. After completion of the reaction, water was added to the solution, and the resulting solution was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (3.131 g) as a yellow oil.

Mass spectrum (ESI, m/z): 734 [M+Na] ⁺ .

Comparative Example 19-(i)-2-Comparative Example 19-(i)-4 was prepared in a similar manner to Comparative Example 19-(i).

Comparative Example 19-(j)

Preparation of 4-((tert-butoxycarbonyl)amino)-2-(3-(2-hydroxy-6-((2-(trimethylsilyl)ethoxy)carbonyl)phenoxy)propyl)benzoic acid

Into a solution of 2-(trimethylsilyl)ethyl 3-(benzyloxy)-2-(3-(2-((benzyloxy)carbonyl)-5-((tert-butoxycarbonyl)amino)phenyl)propoxy)benzoate (3.13 g) obtained in Comparative Example 19-(i), in a mixture of tetrahydrofuran (10 ml)/ethanol (10 ml) in a 200 ml round bottom flask, 10% palladium-carbon (moisture content about 55%, manufactured by Tokyo Chemical Industry Co., Ltd.) was added. ) (0.938 g) at room temperature under air with stirring, and the resulting mixture was stirred at room temperature under hydrogen atmosphere for 2.5 hours. After completion of the reaction, the solution was filtered through Celite and evaporated under reduced pressure to give the title Compound (2.166 g) as a colorless oil.

Mass Spectrum (ESI, m/z): 530 [MH] ^- .

Comparative Example 19-(j)-2

Preparation of 4-((tert-butoxycarbonyl)amino)-2-(3-(2-(((tert-butyldimethylsilyl)oxy)methyl)-6-hydroxyphenoxy)propyl)benzoic acid

In a solution of benzyl 2-(3-(2-(benzyloxy)-6-(((tert-butyldimethylsilyl)oxy) methyl)phenoxy)propyl)-4-((tert-butoxycarbonyl)amino)benzoate (100 mg), obtained in Comparative Example 19-(i)-2, BNA-5D (water content 52.97%, manufactured by NE CHEMCAT Corporation) (20 mg) was added in ethyl acetate (4.00 ml) in a 50 ml round bottom flask at room temperature, the reaction system was filled with hydrogen , and then the resulting mixture was stirred at room temperature for 4 hours. After completion of the reaction, the solution was filtered through Celite, washed with ethyl acetate, and the resulting filtrate was evaporated under reduced pressure to give the title Compound (84 mg) as a brown oil.

Mass Spectrum (ESI, m/z): 530 [MH] ^- .

By the same procedure as Comparative Example 19-(j)-2, Comparative Example 19-(j)-3 and Comparative Example 19-(j)-4 were prepared.

Comparative Example 19-(k)

Preparation of 2-(trimethylsilyl)ethyl 10-((tert-butoxycarbonyl)amino)-13-oxo-6,7,8,13-tetrahydrodibenzo[b,f][1,4]dioxecine-4-carboxylate

In a solution of 4-((tert-butoxycarbonyl)amino)-2-(3-(2-hydroxy-6-((2-(trimethylsilyl)ethoxy)carbonyl)phenoxy)propyl)benzoic acid (1.18 g) obtained in the Comparative example 19-(j), and 4-dimethylaminopyridine (0.015 g) in pyridine (10 ml) 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.641 g) was added at room temperature under argon flow in a 100 ml round bottom flask with stirring, and the reaction mixture was stirred at room temperature overnight. After completion of the reaction, water was added to the solution, and the resulting solution was extracted with ethyl acetate. The organic layer was washed successively with 0.5M hydrochloric acid and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (0.732 g) as a colorless oil.

Mass Spectrum (ESI, m/z): 512 [MH] ^- .

Comparative Example 19-(k)-2-Comparative Example 19-(k)-4 was prepared in a similar manner to Comparative Example 19-(k).

Comparative Example 19-(l)

Preparation of 10-((tert-butoxycarbonyl)amino)-13-oxo-6,7,8,13-tetrahydrodibenzo[b,f][1,4]dioxecine-4-carboxylic acid

Into a solution of 2-(trimethylsilyl)ethyl 10-((tert-butoxycarbonyl)amino)-13-oxo-6,7,8,13-tetrahydrodibenzo[b,f][1,4]dioxecine-4-carboxylate (0.500 g ) obtained by the same procedure as described for Comparative Example 19-(k), in tetrahydrofuran (3 ml) in a 30 ml cylindrical flask was added tetrabutylammonium fluoride (1.95 ml) (1.0M solution in tetrahydrofuran) at room temperature in an atmosphere air with stirring, and the reaction mixture was stirred at room temperature overnight. After completion of the reaction, water was added to the solution, and the resulting solution was extracted with ethyl acetate. The organic layer was washed successively with 0.1N. hydrochloric acid solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure to give the title Compound (0.455 g) as a light yellow foam.

Mass Spectrum (ESI, m/z): 412 [MH] ^- .

Comparative Example 19-(l)-2-Comparative Example 19-(l)-4 was prepared in a similar manner to Comparative Example 19-(l).

Comparative Example 19-(m)

Preparation of 10-amino-13-oxo-6,7,8,13-tetrahydrodibenzo[b,f][1,4]dioxecine-4-carboxylic acid hydrochloride

In a solution of 10-((tert-butoxycarbonyl)amino)-13-oxo-6,7,8,13-tetrahydrodibenzo[b,f][1,4]dioxecine-4-carboxylic acid (2.52 g) obtained according to this In the same manner as described for Comparative Example 19-(l), in tetrahydrofuran (5 ml) in a 30 ml cylindrical flask was added a 4M solution of hydrogen chloride in cyclopentyl methyl ether (14.93 ml) at room temperature under a stream of argon with stirring, and the reaction mixture was stirred at 50°C for 5 hours. After completion of the reaction, the solution was allowed to cool to room temperature and hexane and diisopropyl ether were added. The precipitate that formed was filtered off, washed with hexane and diisopropyl ether, and air dried overnight to give the title Compound (2.073 g) as a white solid.

Mass spectrum (ESI, m/z): 314 [M+H] ⁺ .

Comparative Example 19-(m)-2-Comparative Example 19-(m)-4 was prepared in a similar manner to Comparative Example 19-(m).

Comparative Example 19-(n)

Preparation of 10-(2,3-bis(tert-butoxycarbonyl)guanidino)-13-oxo-6,7,8,13-tetrahydrodibenzo[b,f][1,4]dioxecine-4-carboxylic acid

Into a solution of 10-amino-13-oxo-6,7,8,13-tetrahydrodibenzo[b,f][1,4]dioxecin-4-carboxylic acid hydrochloride (2.07 g) obtained by the same procedure as described for Comparative Example 19-(m), and triethylamine (4.10 ml) in tert-butanol (10 ml), tert-butyl (((tert-butoxycarbonyl)imino)(1H-pyrazol-1-yl) was added in a 100 ml round bottom flask methyl)carbamate (5.53 g) at room temperature under argon flow with stirring, and the reaction mixture was stirred at room temperature for 5 days. After completion of the reaction, the solution was evaporated under reduced pressure, methanol (300 ml) and 10% citric acid solution (175 ml) were added, and the resulting mixture was stirred at room temperature for 1 hour. The precipitate that formed was separated by filtration, washed with a mixture of methanol and water (1:2 (v/v)) (100 ml), air-dried overnight, dried under reduced pressure at 50°C for 6 hours, and additionally dried in air overnight to give the title Compound (3.243 g) as a white solid.

Mass spectrum (ESI, m/z): 556 [M+H] ⁺ .

Comparative Example 19-(o)

Preparation of (R)-di-tert-butyl 2-(2-nitrophenylsulfonamide)succinate

To a solution of (R)-di-tert-butyl 2-aminosuccinate hydrochloride (14.0 g) and N,N-diisopropylethylamine (21.7 ml) in dichloromethane (60 ml) in a 300 ml round bottom flask was added portionwise 2-nitrobenzenesulfonyl chloride (11.5 g ) at 0°C under argon atmosphere with stirring, and the resulting mixture was stirred at room temperature for 1.5 hours. After completion of the reaction, water was added to the solution, and the resulting solution was extracted with dichloromethane. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The evaporation residue was dissolved in dichloromethane, filtered through celite and the filtrate was evaporated under reduced pressure. Acetone (30 ml), water (60 ml) and ethanol (6 ml) were added to the resulting residue, and the resulting mixture was stirred at room temperature for 1 hour. The precipitate that formed was filtered off and air dried to give the title Compound (19.74 g) as a white solid.

Mass Spectrum (ESI, m/z): 429 [MH] ^- .

Comparative Example 19-(p)

Preparation of tetra-tert-butyl 3,12-bis((2-nitrophenyl)sulfonyl)-6,9-dioxa-3,12-diazatetradecane-1,2,13,14-tetracarboxylate

To a solution of (S)-di-tert-butyl 2-(2-nitrophenylsulfonamide)succinate (4.53 g) prepared in the same manner as described for Comparative Example 1-(a) and (R)-di-tert- butyl 2-(2-nitrophenylsulfonamide)succinate (4.51 g) obtained in Comparative Example 19-(o) in tetrahydrofuran (40 ml), triethylene glycol (1.45 ml), tributylphosphine (5.90 ml) and 1 ,1'-azobis(N,N-dimethylformamide) (4.11 g) under cooling in an ice bath under argon atmosphere with stirring, and the resulting mixture was stirred at room temperature overnight. Additional tributylphosphine (5.92 ml) and 1,1'-azobis(N,N-dimethylformamide) (4.10 g) were added with stirring while cooling in an ice bath, and the reaction mixture was stirred at room temperature overnight. After completion of the reaction, water was added to the solution, and the resulting solution was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (4.66 g) as a light yellow oil.

Mass spectrum (ESI, m/z): 997 [M+Na] ⁺ .

Comparative Example 19-(q)

Preparation of tetra-tert-butyl 6,9-dioxa-3,12-diazatetradecane-1,2,13,14-tetracarboxylate

Into a solution of tetra-tert-butyl 3,12-bis((2-nitrophenyl)sulfonyl)-6,9-dioxa-3,12-diazatetradecane-1,2,13,14-tetracarboxylate (4.66 g) obtained in Comparative example 19-(p), in dimethylformamide (30 ml) in a 300 ml round bottom flask were added potassium carbonate (2.00 g) and 4-tert-butylthiophenol (2.01 ml) at room temperature under argon with stirring, and the reaction mixture was stirred at room temperature overnight. After the completion of the reaction, 1N sodium hydroxide was added to the solution. hydrochloric acid solution, and the resulting mixture was washed with ethyl acetate. In the aqueous layer was added 1N. an aqueous solution of sodium hydroxide, and the resulting solution was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate and then ethyl acetate:methanol) to give the title Compound (2.442 g) as a light yellow oil.

Mass spectrum (ESI, m/z): 605 [M+H] ⁺ .

Comparative Example 21-(a)

Preparation of (2R,13R)-tetra-tert-butyl 3,12-bis((2-nitrophenyl)sulfonyl)-6,9-dioxa-3,12-diazatetradecane-1,2,13,14-tetracarboxylate

Triethylene glycol (1.33 ml), tributylphosphine (5.42 ml) and 1,1'-azobis(N,N-dimethylformamide) (3.78 g) while cooling in an ice bath under argon atmosphere with stirring, and the reaction mixture was stirred for 30 minutes, then stirred at room temperature in during the night. After completion of the reaction, water was added to the solution, and the resulting solution was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (6.47 g) as a light yellow oil.

Mass spectrum (ESI, m/z): 992 [M+NH ₄ ] ⁺ .

Comparative Example 21-(b)

Preparation of (2R,13R)-tetra-tert-butyl 6,9-dioxa-3,12-diazatetradecane-1,2,13,14-tetracarboxylate

Into a solution of (2R,13R)-tetra-tert-butyl 3,12-bis((2-nitrophenyl)sulfonyl)-6,9-dioxa-3,12-diazatetradecane-1,2,13,14-tetracarboxylate (6.47 d) obtained in Comparative Example 21-(a), in dimethylformamide (50 ml) in a 200 ml round bottom flask were added potassium carbonate (2.78 g) and 4-tert-butylthiophenol (2.80 ml) at room temperature under argon atmosphere with stirring , and the reaction mixture was stirred at room temperature overnight. After the completion of the reaction, 1N sodium hydroxide was added to the solution. hydrochloric acid solution, and the resulting mixture was washed with ethyl acetate. In the aqueous layer was added 1N. an aqueous solution of sodium hydroxide, and the resulting solution was extracted with tert-butyl methyl ether. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give the title Compound (3.287 g) as a yellowish oil.

Mass spectrum (ESI, m/z): 605 [M+H] ⁺ .

Comparative Example 22-(a)

Preparation of (2S,13S)-tetra-tert-butyl 3,12-bis(N-((benzyloxy)carbonyl)-N-methylsulfamoyl)-6,9-dioxa-3,12-diazatetradecan-1,2,13, 14-tetracarboxylate

In a solution of (2S,13S)-tetra-tert-butyl 3,12-bis(N-((benzyloxy)carbonyl)sulfamoyl)-6,9-dioxa-3,12-diazatetradecan-1,2,13,14- tetracarboxylate (1.96 g) obtained by the same procedure as described for Comparative Example 2-(c), in anhydrous tetrahydrofuran (15 ml) in a 50 ml three-necked flask, methanol (170 μl) was added at room temperature under argon atmosphere with stirring . Then tributylphosphine (1.40 ml) and 1,1'-azobis(N,N-dimethylformamide) (982.3 mg) were added successively, and the reaction mixture was stirred at room temperature for 20 hours. After completion of the reaction, the solution was poured into water (20 ml) and the resulting solution was extracted with ethyl acetate (60 ml). The organic layer was washed with saturated aqueous sodium chloride (20 ml), dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (1.71 g) as a colorless oil.

Mass spectrum (ESI, m/z): 1081 [M+Na] ⁺ .

Comparative Example 22-(b)

Preparation of (2S,13S)-tetra-tert-butyl 3,12-bis(N-methylsulfamoyl)-6,9-dioxa-3,12-diazatetradecane-1,2,13,14-tetracarboxylate

In a solution of (2S,13S)-tetra-tert-butyl 3,12-bis(N-((benzyloxy)carbonyl)-N-methylsulfamoyl)-6,9-dioxa-3,12-diazatetradecan-1,2,13 ,14-tetracarboxylate (1.71 g) obtained in Comparative Example 22-(a) in ethanol (20 ml) in a 200 ml round bottom flask was added 5% palladium on carbon (moisture content 54.28%, STD-type manufactured by NE CHEMCAT Corporation ) (345.1 mg) at room temperature, and the resulting mixture was degassed under reduced pressure. Then, after the atmosphere in the system was changed to hydrogen, the mixture was stirred at room temperature for 7 hours. After completion of the reaction, the solution was filtered through Celite, washed with ethyl acetate, and evaporated under reduced pressure to give the title Compound (1.25 g) as a colorless oil.

Mass Spectrum (ESI, m/z): 789 [MH] ^- .

Comparative Example 22-(c)

Preparation of (2S,13S)-tetra-tert-butyl 3,12-bis(N-methyl-N-(4-((4-nitrobenzoyl)oxy)benzyl)sulfamoyl)-6,9-dioxa-3,12- diazatetradecane-1,2,13,14-tetracarboxylate

In a solution of (2S,13S)-tetra-tert-butyl 3,12-bis(N-methylsulfamoyl)-6,9-dioxa-3,12-diazatetradecane-1,2,13,14-tetracarboxylate (79.0 mg), obtained in Comparative Example 22-(b), 4-(hydroxymethyl)phenyl 4-nitrobenzoate (60.1 mg) was added in anhydrous tetrahydrofuran (1.5 ml) in a 10 ml two-necked flask at room temperature under argon atmosphere with stirring. Tributylphosphamide (61.5 mg) and 1,1'-azobis(N,N-dimethylformamide) (52.3 mg) were then added successively, and the resulting mixture was stirred at room temperature for 17 hours. After completion of the reaction, the solution was poured into water (15 ml) and extracted with ethyl acetate (40 ml). The organic layer was washed with saturated aqueous sodium chloride (15 ml), dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (94.8 mg) as a white foam.

Mass spectrum (ESI, m/z): 1324 [M+Na] ⁺ .

Comparative Example 22-(d)

Preparation of (2S,13S)-tetra-tert-butyl 3,12-bis(N-(4-((4-aminobenzoyl)oxy) benzyl)-N-methylsulfamoyl)-6,9-dioxa-3,12-diazatetradecane -1,2,13,14-tetracarboxylate

In a solution of (2S,13S)-tetra-tert-butyl 3,12-bis(N-methyl-N-(4-((4-nitrobenzoyl)oxy)benzyl)sulfamoyl)-6,9-dioxa-3,12 -diazatetradecane-1,2,13,14-tetracarboxylate (91.3 mg) obtained in Comparative Example 22-(c), 5% palladium was added to ethanol (1 ml)/tetrahydrofuran (1 ml) in a 30 ml cylindrical flask on carbon (containing 48.57% water, AER-type manufactured by NE CHEMCAT Corporation) (9.8 mg) at room temperature, and the resulting mixture was degassed under reduced pressure. Then, after the atmosphere in the system was changed to hydrogen, the mixture was stirred at room temperature for 11 hours. After completion of the reaction, the solution was filtered through celite, washed with ethyl acetate and then evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (64.7 mg) as a white foam.

Mass spectrum (ESI, m/z): 1264 [M+Na] ⁺ .

Comparative Example 22-(e)

Preparation of (2S,13S)-3,12-bis(N-(4-((4-aminobenzoyl)oxy)benzyl)-N-methylsulfamoyl)-6,9-dioxa-3,12-diazatetradecan-1,2, 13,14-tetracarboxylic acid hydrochloride

K (2S,13S)-tetra-tert-butyl 3,12-bis(N-(4-((4-aminobenzoyl)oxy)benzyl)-N-methylsulfamoyl)-6,9-dioxa-3,12-diazatetradecane -1,2,13,14-tetracarboxylate (59.6 mg) obtained in Comparative Example 22-(d), a 4M solution of hydrogen chloride in cyclopentylmethyl ether (1.0 ml) was added to a 30 ml cylindrical flask, and the reaction mixture was stirred at room temperature within 23 hours. After completion of the reaction, the solution was evaporated under reduced pressure. Dichloromethane (3 ml) was added to the evaporation residue and the mixture was evaporated under reduced pressure. This procedure was repeated three times to give the title Compound (53.7 mg) as a white solid.

Mass spectrum (ESI, m/z): 1017 [M+H] ⁺ .

Comparative Example 23-(a)

Preparation of dibenzyl 3-oxo-pentanedioate

Dimethyl 3-oxo-pentanedioate (24.82 g) and phenylmethanol (30.0 ml) were placed into a 100-mL round-bottom flask with a Dean-Stark trap, and the resulting mixture was stirred at 180°C under argon for 0.75 h. After completion of the reaction, the solution was purified by column chromatography (silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (9.32 g) as a colorless oil.

Mass spectrum (ESI, m/z): 327 [M+H] ⁺ .

Comparative Example 23-(b)

Preparation of dibenzyl 3,14-bis(2-(benzyloxy)-2-oxoethyl)-7,10-dioxa-4,13-diazahexadecanedioate

A solution of dibenzyl 3-oxopentanedioate (7.18 g) obtained in Comparative Example 23-(a) in dichloromethane (35 ml) in a 500 ml round bottom flask was cooled in an ice bath, and acetic acid (3.36 g) was added under argon. Then a solution of 2,2'-(ethane-1,2-diylbis(oxy))diethanamine (1.63 g) in dichloromethane (35 ml) was added with stirring, and the reaction mixture was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (11.96 g) was then added and the mixture was stirred at room temperature for 65 hours. After completion of the reaction, the solution was diluted with ethyl acetate, poured into saturated aqueous sodium hydrogen carbonate solution (300 ml), the resulting mixture was stirred and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give the title Compound (8.56 g) as a light yellow liquid.

Mass spectrum (ESI, m/z): 769 [M+H] ⁺ .

Comparative Example 23-(c)

Preparation of tetrabenzyl 3,3'-(2,2,17,17-tetramethyl-4,15-dioxo-3,8,11,16-tetraoxa-5,14-diazaoctadecan-5,14-diyl)dipentanedioate

To a solution of dibenzyl 3,14-bis(2-(benzyloxy)-2-oxoethyl)-7,10-dioxa-4,13-diazahexadecanedioate (8.56 g) obtained in Comparative Example 23-(b) in anhydrous dichloromethane ( 70 ml) in a 500 ml round bottom flask was added di-tert-butyl dicarbonate (6.10 ml) at room temperature under argon with stirring, the reaction mixture was stirred at room temperature for 25 hours and left at room temperature for 72 hours. After completion of the reaction, the solution was evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (3.42 g) as a colorless oil.

Mass spectrum (ESI, m/z): 991 [M+Na] ⁺ .

Comparative Example 23-(d)

Preparation of dibenzyl 3,14-bis(2-(benzyloxy)-2-oxoethyl)-7,10-dioxa-4,13-diazahexadecane-1,16-dioate

(1) To a solution of tetrabenzyl 3,3'-(2,2,17,17-tetramethyl-4,15-dioxo-3,8,11,16-tetraoxa-5,14-diazaoctadecan-5,14-diyl) dipentanedioate (0.49 g) prepared in the same manner as in Comparative Example 23-(c) in anhydrous ethyl acetate (30 ml) in a 100 ml round bottom flask was added a 4 M solution of hydrogen chloride in cyclopentyl methyl ether (0.5 ml) at room temperature under nitrogen atmosphere with stirring, and the reaction mixture was stirred at room temperature for 2 hours. Additionally, a 4 M solution of hydrogen chloride in cyclopentylmethyl ether (1.0 ml) was added at room temperature, the reaction mixture was stirred at room temperature for 3.8 hours, stirred at 60°C for 3.3 hours and left at room temperature overnight. An additional 4 M solution of hydrogen chloride in cyclopentylmethyl ether (1.0 ml) was added and the reaction mixture was stirred at 60° C. for 6 hours. After completion of the reaction, the solution was evaporated under reduced pressure, anhydrous diethyl ether was added, and the resulting mixture was kept in an ultrasonic bath. The supernatant solution was removed while cooling in an ice bath, anhydrous diethyl ether was added to the resulting residue, and the mixture was kept in an ultrasonic bath. The resulting residue was dried under reduced pressure.

(2) To a solution of tetrabenzyl 3,3'-(2,2,17,17-tetramethyl-4,15-dioxo-3,8,11,16-tetraoxa-5,14-diazaoctadecan-5,14-diyl) dipentanedioate (3.42 g) obtained in Comparative Example 23-(c) in anhydrous ethyl acetate (30 ml) in a 500 ml round bottom flask was added a 4 M solution of hydrogen chloride in cyclopentyl methyl ether (15 ml) at room temperature under nitrogen atmosphere with stirring, and the reaction mixture was stirred at 60°C for 5 hours. After completion of the reaction, the solution was evaporated under reduced pressure, anhydrous diethyl ether was added, and the mixture was kept in an ultrasonic bath. The supernatant solution was removed while cooling in an ice bath, anhydrous diethyl ether was added to the resulting residue, and the mixture was kept in an ultrasonic bath. The resulting residue was dried under reduced pressure.

The obtained residue from (1) and the obtained residue from (2) were combined, ethyl acetate (100 ml) was added, the mixture was washed successively with saturated aqueous sodium hydrogen carbonate solution (100 ml) and saturated aqueous sodium chloride solution (50 ml), dried over anhydrous sodium sulfate , filtered, and the filtrate was evaporated under reduced pressure to give the title Compound (1.40 g) as a yellowish oil.

Mass spectrum (ESI, m/z): 769 [M+H] ⁺ .

Comparative Example 23-(e)

Preparation of tetrabenzyl 3,3'-(((ethane-1,2-diylbis(oxy))bis(ethane-2,1-diyl))bis((N-((benzyloxy)carbonyl)sulfamoyl)azandiyl))dipentanedioate

To a solution of dibenzyl 3,14-bis(2-(benzyloxy)-2-oxoethyl)-7,10-dioxa-4,13-diazahexadecane-1,16-dioate (1.40 g) obtained in Comparative Example 23-(d )-2, in anhydrous dichloromethane (10 ml) in a 300 ml round bottom flask was added dropwise a solution of benzyl chlorosulfonylcarbamate (1.00 g) in dichloromethane (5 ml) at 0°C under argon atmosphere with stirring, the reaction mixture was washed with anhydrous dichloromethane (5 ml) and stirred at 0°C for 2.5 hours. After completion of the reaction, the solution was evaporated under reduced pressure. The evaporation residue was diluted with ethyl acetate and washed successively with 5% aqueous potassium hydrogen sulfate solution (50 ml) and saturated aqueous sodium chloride solution (50 ml x twice). The organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (1.47 g) as an anhydrous viscous oil.

Mass spectrum (ESI, m/z): 1217 [M+Na] ⁺ .

Comparative Example 24-(a)

Preparation of (S)-di-tert-butyl 2-((N-((benzyloxy)carbonyl)sulfamoyl)amino)succinate

To a solution of chlorosulfonyl isocyanate (5.53 g) in dichloromethane (100 ml) in a 300 ml three-necked flask was added dropwise benzyl alcohol (4.06 ml) at 0°C under argon flow with stirring, and the reaction mixture was stirred at 0°C for 1 hours. Then L-aspartic acid di-tert-butyl ester hydrochloride (10.00 g) and a solution of triethylamine (10.88 ml) in dichloromethane (50.0 ml) were added with stirring at 0°C, and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, a saturated sodium hydrogen carbonate aqueous solution was added to the solution, and the resulting solution was extracted with dichloromethane. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (7.516 g) as a white solid.

Mass spectrum (ESI, m/z): 457 [M-H]-.

Comparative Example 24-(b)

Preparation of (2S,2'S)-tetra-tert-butyl 2,2'-((3,14-dioxo-1,16-diphenyl-2,7,10,15-tetraoxa-4,13-diazahexadecanedisulfonyl)bis(azandiyl ))disuccinate

To a solution of (S)-di-tert-butyl 2-((N-((benzyloxy)carbonyl)sulfamoyl)amino)succinate (3.21g) obtained in Comparative Example 24-(a) in tetrahydrofuran (15ml) in Triethylene glycol (0.44 ml), diisopropyl azodicarboxylate (1.9M solution in toluene) (4.21 ml) and triphenylphosphine (2.10 g) were added successively to a 100 ml round bottom flask at room temperature under argon flow with stirring, and the reaction mixture was stirred at room temperature for 4 hours. (S)-di-tert-butyl 2-((N-((benzyloxy)carbonyl)sulfamoyl)amino)succinate (0.80g), triphenylphosphine (1.05g) and diisopropyl azodicarboxylate (1.9M solution in toluene) (4.21ml) was added at room temperature, and the reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, water was added to the solution, and the resulting solution was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (2.78 g) as a colorless oil.

Mass spectrum (ESI, m/z): 1029 [M-H]-.

Comparative Example 24-(c)

Preparation of (2S,2'S)-tetra-tert-butyl 2,2'-((3,14-dioxo-1,16-diphenyl-2,7,10,15-tetraoxa-4,13-diazahexadecanedisulfonyl)bis(( tert-butoxycarbonyl)azandiyl))disuccinate

In a solution of (2S,2'S)-tetra-tert-butyl 2,2'-((3,14-dioxo-1,16-diphenyl-2,7,10,15-tetraoxa-4,13-diazahexadecanedisulfonyl)bis( azandiyl))disuccinate (1.65 g) obtained in Comparative Example 24-(b) in dichloromethane (10 ml) in a 100 ml round bottom flask were added di-tert-butyl dicarbonate (0.81 ml) and 4-dimethylaminopyridine (0.10 g) at room temperature in a stream of argon with stirring, and the reaction mixture was stirred at room temperature for 2.5 hours. Then triethylamine (0.45 ml) and 4-dimethylaminopyridine (0.10 g) were added and the resulting mixture was stirred at room temperature for 16 hours. After completion of the reaction, the solution was evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (1.05 g) as a white foam.

Mass spectrum (ESI, m/z): 1253 [M+Na] ⁺ .

Comparative Example 24-(d)

Preparation of (2S,2'S)-tetra-tert-butyl 2,2'-((((2-(2-(2-(hydrosulfonylamino) ethoxy)ethoxy)ethyl)amino)sulfonyl)bis((tert-butoxycarbonyl)azandiyl )) disuccinate

In a solution of (2S,2'S)-tetra-tert-butyl 2,2'-((3,14-dioxo-1,16-diphenyl-2,7,10,15-tetraoxa-4,13-diazahexadecanedisulfonyl)bis( (tert-butoxycarbonyl) azandiyl)) disuccinate (0.62 g) obtained in Comparative Example 24-(c) in ethanol (6 ml)/tetrahydrofuran (2 ml) in a 100 ml round bottom flask was added 5% palladium on charcoal ( contains 51.65% water, AER-type manufactured by NE CHEMCAT Corporation) (0.11 g) at room temperature, the reaction system was filled with hydrogen, and then the resulting mixture was stirred at room temperature for 2.5 hours. After completion of the reaction, the solution was filtered through Celite and the resulting filtrate was evaporated under reduced pressure to give the title Compound (0.48 g) as a white foam.

Mass spectrum (ESI, m/z): 985 [M+Na] ⁺ .

Comparative Example 24-(e)

Preparation of (2S,2'S)-tetra-tert-butyl 2,2'-((1,12-bis(4-((4-nitrobenzoyl)oxy)phenyl)-5,8-dioxa-2,11-diazadecanedisulfonyl) bis((tert-butoxycarbonyl)azandiyl))disuccinate

(1) To a solution of (2S,2'S)-tetra-tert-butyl 2,2'-((((2-(2-(2-(hydrosulfonylamino)ethoxy)ethoxy)ethyl)amino)sulfonyl)bis((tert -butoxycarbonyl)azandiyl))disuccinate (0.47g) obtained in Comparative Example 24-(d) in tetrahydrofuran (5ml) in a 100ml round bottom flask was added 4-(hydroxymethyl)phenyl 4-nitrobenzoate (0.30g), tributylphosphine (0.30 ml) and 1,1'-azobis(N,N-dimethylformamide) (0.21 g) at room temperature under argon flow with stirring, and the reaction mixture was stirred at room temperature for 7.5 hours. Tributylphosphine (0.150 ml) and 1,1'-azobis(N,N-dimethylformamide) (0.10 g) were added at room temperature and the reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, water was added to the solution, and the resulting solution was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure.

(2) To a solution of (2S,2'S)-tetra-tert-butyl 2,2'-((((2-(2-(2-(hydrosulfonylamino)ethoxy)ethoxy)ethyl)amino)sulfonyl)bis((tert -butoxycarbonyl)azandiyl))disuccinate (0.81g) obtained in Comparative Example 24-(d) in tetrahydrofuran (8.5ml) in a 100ml round bottom flask was added 4-(hydroxymethyl)phenyl 4-nitrobenzoate (0.51g), tributylphosphine (0.50 ml) and 1,1'-azobis(N,N-dimethylformamide) (0.35 g) at room temperature under argon flow with stirring, and the reaction mixture was stirred at room temperature for 2 hours. Tributylphosphine (0.25 ml) and 1,1'-azobis(N,N-dimethylformamide) (0.17 g) were added at room temperature and the reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, water was added to the solution, and the resulting solution was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure.

The obtained residue from (1) and the obtained residue from (2) were combined and purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (1.49 g) as a white foam.

Mass spectrum (ESI, m/z): 1495 [M+Na] ⁺ .

Comparative Example 24-(f)

Preparation of (2S,2'S)-tetra-tert-butyl 2,2'-((1,12-bis(4-((4-aminobenzoyl)oxy)phenyl)-5,8-dioxa-2,11-diazadecanedisulfonyl) bis((tert-butoxycarbonyl)azandiyl))disuccinate

In a solution of (2S,2'S)-tetra-tert-butyl 2,2'-((1,12-bis(4-((4-nitrobenzoyl)oxy)phenyl)-5,8-dioxa-2,11-diazadecanedisulfonyl )bis((tert-butoxycarbonyl)azandiyl))disuccinate (1.46g) obtained in Comparative Example 24-(e) in ethanol (10ml) in a 100ml round bottom flask was added 5% palladium on carbon (containing 51.65% water , AER-type manufactured by NE CHEMCAT Corporation) (0.22 g) at room temperature under an argon atmosphere, the reaction system was filled with hydrogen, and then the resulting mixture was stirred at room temperature for 4 hours. After completion of the reaction, the solution was filtered through Celite, and the filtrate was evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate), and fractions with the title compound were evaporated under reduced pressure to give the title Compound (1.12 g) as a white foam.

Mass spectrum (ESI, m/z): 1435 [M+Na] ⁺ .

Comparative Example 24-(g)

Preparation of (2S,2'S)-2,2'-((1,12-bis(4-((4-aminobenzoyl)oxy)phenyl)-5,8-dioxa-2,11-diazadecanedisulfonyl)bis(azandiyl)) disuccinic acid hydrochloride

K (2S,2'S)-tetra-tert-butyl 2,2'-((1,12-bis(4-((4-aminobenzoyl)oxy)phenyl)-5,8-dioxa-2,11-diazadecanedisulfonyl) bis((tert-butoxycarbonyl)azandiyl))disuccinate (1.11g) obtained in Comparative Example 24-(f) was added to a 100ml round bottom flask with a 4M solution of hydrogen chloride in cyclopentylmethyl ether (5.0ml) at room temperature, and the reaction the mixture was stirred at room temperature for 28.5 hours. After completion of the reaction, the solution was evaporated under reduced pressure. Dichloromethane was added to the evaporation residue and the resulting mixture was evaporated under reduced pressure. The resulting residue was dried under reduced pressure to give the title Compound (0.84 g) as a white solid.

Mass spectrum (ESI, m/z): 989 [M+H] ⁺ .

Comparative Example 28-(a)

Preparation of (S)-dibenzyl 2-(2-nitrophenylsulfonamide)succinate

To a solution of L-aspartic acid dibenzyl ester hydrochloride (5.06 g) in dichloromethane (30 ml) in a 200-ml round-bottomed flask was added N,N-diisopropylethylamine (6.0 ml) and 2-nitrobenzenesulfonyl chloride (3.55 g) at 0 argon with stirring, the resulting mixture was stirred at 0°C for 10 minutes and at room temperature for 2 hours. After completion of the reaction, dichloromethane (50 ml) was added to the solution, the mixture was washed with a 5% aqueous citric acid solution (80 ml) and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate), and fractions with the title compound were evaporated under reduced pressure. Hexane was added to a solution of the resulting residue in ethyl acetate, the resulting mixture was stirred at room temperature for 10 minutes, the precipitate formed was collected by filtration and dried under reduced pressure to give the title Compound (5.92 g) as a slightly yellow solid.

Mass spectrum (ESI, m/z): 521 [M+Na] ⁺ .

Comparative Example 28-(b)

Preparation of (2S,2'S)-tetrabenzyl 2,2'-(([1,1'-biphenyl]-3,3'-diylbis(methylene)) bis(((2-nitrophenyl)sulfonyl)azandiyl))disuccinate

Into a 200 ml four-necked flask was placed (S)-dibenzyl 2-(2-nitrophenylsulfonamide)succinate (8.9 g) prepared in the same manner as described in Comparative Example 28-(a), [1,1'-biphenyl] -3,3'-diyldimethanol (1.82 g) and dichloromethane (40 ml), triphenylphosphine (5.35 g) was added at 7° C. under nitrogen with stirring. Then, diisopropyl azodicarboxylate (1.9M solution in toluene) (10.7 ml) was added dropwise at 4 to 11°C over 15 minutes, and then the resulting mixture was stirred at room temperature for 4 hours. After completion of the reaction, water (40 ml) was added to the solution, and the solution was extracted with dichloromethane (40 ml). The organic layer was washed with saturated sodium chloride solution (40 ml), dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (7.1 g) as a yellow foam.

Mass spectrum (ESI, m/z): 1197 [M+Na] ⁺ .

Comparative Example 28-(c)

Preparation of (2S,2'S)-tetrabenzyl 2,2'-(([1,1'-biphenyl]-3,3'-diylbis(methylene))bis(azandiyl))disuccinate

In a 500 ml four-neck flask was placed (2S,2'S)-tetrabenzyl 2,2'-(([1,1'-biphenyl]-3,3'-diylbis(methylene))bis(((2-nitrophenyl)sulfonyl) azandiyl))disuccinate (7.1 g) obtained in Comparative Example 28-(b), potassium carbonate (4.17 g), thiosalicylic acid (3.73 g) and acetonitrile (90 ml) under nitrogen atmosphere, and the resulting mixture was stirred at 80°C in a nitrogen atmosphere for 7 hours. Potassium carbonate (0.74 g), thiosalicylic acid (0.66 g) and acetonitrile (20 ml) were added and the mixture was stirred for 3 hours. After completion of the reaction, water (150 ml) was added to the solution, and the resulting solution was extracted with ethyl acetate (100 ml) twice. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution (150 ml) twice and saturated sodium chloride solution (200 ml), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The resulting residue was purified by column chromatography (NH silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (4.18 g) as a yellow oil.

Mass spectrum (ESI, m/z): 805 [M+H] ⁺ .

Comparative Example 29-(a)

Preparation of (S)-di-tert-butyl 2-((3-(benzyloxy)-5-(methoxycarbonyl)benzyl)(tert-butoxycarbonyl)amino)succinate

To a solution of methyl 3-(benzyloxy)-5-formylbenzoate (2.08 g) and L-aspartic acid di-tert-butyl ester hydrochloride (2.18 g) in dichloromethane (40 ml) in a 500 ml round bottom flask was added N,N-diisopropylethylamine (4.00 ml) and then acetic acid (1.20 ml) at room temperature under argon, and the reaction mixture was stirred at room temperature for 16.5 hours. Then sodium triacetoxyborohydride (4.10 g) was added at room temperature, the resulting mixture was stirred at room temperature under argon for 34 hours and left at room temperature for 72 hours. After completion of the reaction, the solution was diluted with ethyl acetate, a saturated aqueous sodium hydrogen carbonate solution (100 ml) was added, the resulting mixture was stirred at room temperature for 1 hour and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give (S)-di-tert-butyl 2-((3-(benzyloxy)-5-(methoxycarbonyl)benzyl)amino) succinate. Di-tert-butyl dicarbonate (2.00 ml ) at room temperature under argon atmosphere with stirring, and the resulting mixture was stirred at room temperature for 66.5 hours. After completion of the reaction, the solution was evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (4.02 g) as an anhydrous viscous oil.

Mass spectrum (ESI, m/z): 622 [M+Na] ⁺ .

Comparative Example 29-(b)

Preparation of (S)-3-(benzyloxy)-5-(((tert-butoxycarbonyl)(1,4-di-tert-butoxy-1,4-dioxobutan-2-yl)amino)methyl)benzoic acid

To a solution of (S)-di-tert-butyl 2-((3-(benzyloxy)-5-(methoxycarbonyl)benzyl) (tert-butoxycarbonyl)amino)succinate (9.54 g) obtained in Comparative Example 29-(a) , in a mixture of tetrahydrofuran (90 ml)/methanol (45 ml) in a 500 ml round bottom flask was added 1 M aqueous sodium hydroxide solution (50 ml) at 0°C under argon atmosphere with stirring, and the reaction mixture was stirred at room temperature for 6 hours. 1M hydrochloric acid solution (50 ml) was added at room temperature, the reaction mixture was stirred for some time, ethyl acetate (200 ml), 5% aqueous potassium hydrogensulfate solution (10 ml) and saturated aqueous sodium chloride solution (75 ml) were added, and the resulting solution was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution (100 ml), dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure to give the title Compound (8.95 g) as a white foam.

Mass spectrum (ESI, m/z): 608 [M+Na] ⁺ .

Comparative Example 29-(c)

Preparation of (S)-di-tert-butyl 2-((3-(benzyloxy)-5-((2-(trimethylsilyl)ethoxy)carbonyl)benzyl)(tert-butoxycarbonyl)amino)succinate

To a solution of (S)-3-(benzyloxy)-5-(((tert-butoxycarbonyl)(1,4-di-tert-butoxy-1,4-dioxobutan-2-yl)amino)methyl)benzoic acid (8.95 d) obtained in Comparative Example 29-(b), 2-(trimethylsilyl)ethanol (2.21 g) and 4-dimethylaminopyridine (0.19 g) in anhydrous dichloromethane (270 ml) in a 500 ml round bottom flask were added 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.55 g) at room temperature under argon atmosphere with water bath cooling with stirring, and the reaction mixture was stirred at room temperature for 3.5 hours. Additional 4-dimethylaminopyridine (0.30 g) was added with stirring at room temperature, and the mixture was stirred at room temperature for 15 hours. After completion of the reaction, the solution was evaporated under reduced pressure. Ethyl acetate (250 ml) was added to the evaporation residue, the resulting mixture was washed successively with a mixture of 5% aqueous potassium hydrogen sulfate solution (200 ml) and saturated aqueous sodium chloride solution (50 ml), saturated aqueous sodium chloride solution (100 ml), saturated aqueous sodium hydrogen carbonate solution (50 ml) and saturated aqueous sodium chloride solution (50 ml), dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate), and fractions with the title compound were evaporated under reduced pressure to give the title Compound (9.09 g) as a colorless oil.

Mass spectrum (ESI, m/z): 708 [M+Na] ⁺ .

Comparative Example 29-(d)

Preparation of (S)-di-tert-butyl 2-((3-(benzyloxy)-5-((2-(trimethylsilyl)ethoxy)carbonyl)benzyl)amino)succinate

To (S)-di-tert-butyl 2-((3-(benzyloxy)-5-((2-(trimethylsilyl)ethoxy)carbonyl)benzyl)(tert-butoxycarbonyl)amino)succinate (8.91 g) obtained in Comparative Example 29-(c), a 1M solution of hydrogen chloride in ethyl acetate (200 ml) was added to a 500 ml round bottom flask at room temperature under nitrogen, and the resulting mixture was stirred at room temperature for 6 hours. After completion of the reaction, the solution was poured into a saturated aqueous sodium hydrogen carbonate solution (300 ml), the resulting mixture was stirred for 1 hour, a saturated aqueous sodium chloride solution (300 ml) was added, and the resulting solution was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. Diethyl ether was added to the evaporation residue, indissolved substances were removed by filtration, washed with diethyl ether, the resulting filtrate and washing solution were combined and evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (DIOL silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (3.72 g) as an anhydrous viscous oil. Another fraction was evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (DIOL silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (1.02 g) as an anhydrous viscous oil.

Mass spectrum (ESI, m/z): 608 [M+Na] ⁺ .

Comparative Example 29-(e)

Preparation of (S)-di-tert-butyl 2-(N-(3-(benzyloxy)-5-((2-(trimethylsilyl)ethoxy)carbonyl)benzyl)-10-(2,3-bis(tert-butoxycarbonyl) )guanidino)-13-oxo-6,7,8,13-tetrahydrodibenzo[b,f][1,4]dioxecine-4-carboxamide)succinate

Into a solution of 10-(2,3-bis(tert-butoxycarbonyl)guanidino)-13-oxo-6,7,8,13-tetrahydrodibenzo[b,f][1,4]dioxecine-4-carboxylic acid (0.97 g ) obtained by the same procedure as described for Comparative Example 19-(n), in anhydrous dimethylformamide (10 ml) in a 100 ml round bottom flask was added COMU (0.91 g) at room temperature under argon atmosphere with stirring, and the resulting mixture stirred at room temperature for 1 hour. Then N,N-diisopropylethylamine (0.46 ml) was added at room temperature, the mixture was cooled with ice water and stirred for 0.5 hour. Then, a solution of (S)-di-tert-butyl 2-((3-(benzyloxy)-5-((2-(trimethylsilyl)ethoxy)carbonyl)benzyl)amino)succinate (1.02 g) obtained in Comparative Example 29 was added. -(d), in anhydrous dimethylformamide (10 ml) with stirring and cooling in an ice bath, and the resulting mixture was stirred at room temperature for 1 hour. Additional N,N-diisopropylethylamine (0.16 ml) was added and the mixture was stirred for 45.5 hours. Additional COMU (0.31 g) and N,N-diisopropylethylamine (0.20 ml) were added at room temperature and the mixture was stirred at room temperature for 7 hours. After completion of the reaction, the solution was diluted with toluene (100 ml), poured into a saturated aqueous sodium hydrogen carbonate solution (100 ml), the resulting mixture was thoroughly stirred, left, and the resulting solution was extracted with toluene. The organic layer was washed with water (100 ml). Saturated aqueous sodium chloride solution (100 ml) and ethyl acetate were added to the organic layer, the resulting mixture was shaken, allowed to stand and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (1.05 g) as a yellowish foam.

Mass spectrum (DUIS, m/z): 1123 [M+H] ⁺ .

Comparative Example 29-(f)

Preparation of (S)-di-tert-butyl 2-(10-(2,3-bis(tert-butoxycarbonyl)guanidino)-N-(3-hydroxy-5-((2-(trimethylsilyl)ethoxy)carbonyl)benzyl )-13-oxo-6,7,8,13-tetrahydrodibenzo[b,f][1,4]dioxecine-4-carboxamide)succinate

In a solution of (S)-di-tert-butyl 2-(N-(3-(benzyloxy)-5-((2-(trimethylsilyl) ethoxy)carbonyl)benzyl)-10-(2,3-bis(tert- butoxycarbonyl)guanidino)-13-oxo-6,7,8,13-tetrahydrodibenzo[b,f][1,4]dioxecine-4-carboxamide)succinate (3.23 g) obtained in Comparative Example 29-(e), in a mixture of ethanol (40 ml)/tetrahydrofuran (20 ml) in a 500 ml round bottom flask was added ASCA-2 (water content 52%, manufactured by NE CHEMCAT Corporation) (0.60 g) at room temperature under nitrogen atmosphere, and the reaction mixture was stirred at room temperature in a hydrogen atmosphere for 3 hours. After completion of the reaction, the solution was filtered through celite, washed with ethanol, the resulting filtrate and washing solution were combined and evaporated under reduced pressure. The evaporation residue was diluted with ethyl acetate and the resulting mixture was evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (0.40 g) as a slightly yellow solid.

Mass spectrum (DUIS, m/z): 1033 [M+H] ⁺ .

Comparative Example 29-(g)

Preparation of (S)-di-tert-butyl 2-(N-(3-(2-(2-(benzyloxy)ethoxy)ethoxy)-5-((2-(trimethylsilyl)ethoxy)carbonyl)benzyl)-10- (2,3-bis(tert-butoxycarbonyl)guanidino)-13-oxo-6,7,8,13-tetrahydrodibenzo[b,f][1,4]dioxecine-4-carboxamide) succinate

Solution of 2-(2-(benzyloxy)ethoxy)ethan-1-ol (0.1 ml), (S)-di-tert-butyl 2-(10-(2,3-bis(tert-butoxycarbonyl)guanidino)-N -(3-hydroxy-5-((2-(trimethylsilyl)ethoxy)carbonyl)benzyl)-13-oxo-6,7,8,13-tetrahydrodibenzo[b,f] [1,4]dioxecine-4-carboxamide )succinate (504.8 mg) obtained in Comparative Example 29-(f) and triphenylphosphine (161.6 mg) in anhydrous dichloromethane (2 ml) in a 20 ml cylindrical flask were stirred at room temperature under argon and cooled in an ice bath. Then, diisopropyl azodicarboxylate (1.9M solution in toluene) (0.32 ml) was added dropwise, and after the addition was complete, the mixture was stirred under cooling in an ice bath for 0.2 hours and at room temperature for 2.5 hours. Triphenylphosphine (27.8 mg) was further added at room temperature, diisopropyl azodicarboxylate (1.9M solution in toluene) (0.07 ml) was further added under ice-bath cooling, and the resulting mixture was stirred at room temperature for 15 hours. After completion of the reaction, the solution was purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (452.8 mg) as a white foam.

Mass spectrum (DUIS, m/z): 1211 [M+H] ⁺ .

Comparative Example 29-(h)

Preparation of (S)-di-tert-butyl 2-(10-(2,3-bis(tert-butoxycarbonyl)guanidino)-N-(3-(2-(2-hydroxyethoxy)ethoxy)-5-((2 -(trimethylsilyl)ethoxy)carbonyl)benzyl)-13-oxo-6,7,8,13-tetrahydrodibenzo[b,f][1,4]dioxecine-4-carboxamide)succinate

To a solution of (S)-di-tert-butyl 2-(N-(3-(2-(2-(benzyloxy)ethoxy)ethoxy)-5-((2-(trimethylsilyl)ethoxy)carbonyl)benzyl)-10 - (2,3-bis (tert-butoxycarbonyl) guanidino) -13-oxo-6,7,8,13-tetrahydrodibenzo[b,f][1,4]dioxetin-4-carboxamide) succinate (448.7 mg), obtained in Comparative Example 29-(g), ASCA-2 (52% water content, manufactured by NE CHEMCAT Corporation) (83.4 mg) was added to ethanol (5 ml)/tetrahydrofuran (2.5 ml) in a 100 ml round bottom flask at room temperature under a nitrogen atmosphere, and the resulting mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. After completion of the reaction, the solution was filtered through celite, washed with ethanol, the resulting filtrate and washing solution were combined and evaporated under reduced pressure. The evaporation residue was diluted with ethyl acetate and evaporated under reduced pressure to give the title Compound (420.2 mg) as a white foam.

Mass spectrum (DUIS, m/z): 1121 [M+H] ⁺ .

Comparative Example 30-(a)

Preparation of (2S,2'S)-tetra-tert-butyl 2,2'-((oxybis(ethane-2,1-diyl))bis((3-((4-nitrobenzoyl)oxy)benzoyl)azandiyl))disuccinate

COMU (2.52 g) and N,N-diisopropylethylamine (1.32 ml) were added to a solution of 3-((4-nitrobenzoyl)oxy)benzoic acid (1.50 g) in dimethylformamide (18 ml) at 0°C in a stream of argon with stirring, and the reaction mixture was stirred at 0°C for 10 minutes. Then a solution of (2S,2'S)-tetra-tert-butyl 2,2'-((oxybis(ethane-2,1-diyl))bis(azandiyl))disuccinate (1.41 g) obtained by the same procedure as described for Comparative Example 1-(c), in dimethylformamide (6.00 ml) dropwise with stirring at 0°C, and the mixture was stirred at room temperature for 5 hours. Additionally, 3-((4-nitrobenzoyl)oxy)benzoic acid (0.76 g) and COMU (2.52 g) were added with stirring at room temperature, and the resulting mixture was stirred at room temperature for 24 hours. After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added to the solution and extracted with toluene. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate), and fractions with the title compound were evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (1.40 g) as a yellowish foam.

Mass spectrum (ESI, m/z): 1121 [M+Na] ⁺ .

Comparative Example 30-(b)

Preparation of (2S,2'S)-tetra-tert-butyl 2,2'-((oxybis(ethane-2,1-diyl))bis((3-((4-aminobenzoyl)oxy)benzoyl)azandiyl))disuccinate

Into a solution of (2S,2'S)-tetra-tert-butyl 2,2'-((oxybis(ethane-2,1-diyl))bis((3-((4-nitrobenzoyl)oxy)benzoyl)azandiyl))disuccinate (1.4 g) obtained in Comparative Example 30-(a) in ethanol (10 ml) in a 200 ml round bottom flask was added 5% palladium on carbon (containing 48.57% water, AER-type manufactured by NE CHEMCAT Corporation) (147.1 mg ) at room temperature, and the resulting mixture was stirred at room temperature under a hydrogen atmosphere for 4 hours. The reaction mixture was filtered through celite, washed with ethyl acetate, and the resulting filtrate was evaporated under reduced pressure to give (2S,2'S)-tetra-tert-butyl 2,2'-((oxybis(ethane-2,1-diyl))bis(( 3-((4-(hydroxyamino)benzoyl)oxy)benzoyl)azandiyl))disuccinate (1.45 g). In a solution of the resulting tetra-tert-butyl 2,2'-((oxybis(ethane-2,1-diyl)) bis((3-((4-(hydroxyamino)benzoyl)oxy)benzoyl)azandiyl))(2S, 2'S)-disuccinate (1.45 g) in ethanol (10 ml) was added 5% palladium-carbon (contains 48.57% water, AER-type manufactured by NE CHEMCAT Corporation) (0.73 g) at room temperature, and the reaction mixture was stirred at room temperature in hydrogen atmosphere for 2 hours. After completion of the reaction, the mixture was filtered through Celite, washed with ethyl acetate, and the resulting filtrate was evaporated under reduced pressure to give the title Compound (1.27 g) as a yellowish foam.

Mass spectrum (DUIS, m/z): 1039 [M+H] ⁺ .

Comparative Example 30-(c)

Preparation of (2S,2'S)-2,2'-((oxybis(ethane-2,1-diyl))bis((3-((4-aminobenzoyl)oxy)benzoyl)azandiyl))disuccinic acid hydrochloride

Into a solution of (2S,2'S)-tetra-tert-butyl 2,2'-((oxybis(ethane-2,1-diyl))bis((3-((4-aminobenzoyl)oxy)benzoyl)azandiyl))disuccinate (1.27 g) obtained in Comparative Example 30-(b) in dioxane (20 ml) in a 200 ml round bottom flask was added dropwise with a 4M solution of hydrogen chloride in dioxane (10 ml) at room temperature under argon flow with stirring, and the resulting the mixture was stirred at room temperature for 0.5 hours. Additionally, a 4M solution of hydrogen chloride in dioxane (10 ml) and dioxane (20 ml) were added with stirring at room temperature, and the resulting mixture was stirred at room temperature for 18 hours. Additionally, a 4M solution of hydrogen chloride in dioxane (10 ml) and dioxane (20 ml) were added. After completion of the reaction, the solution was evaporated under reduced pressure. The evaporation residue was azeotroped once with toluene to give the title Compound (1.35 g) as a slightly yellow solid.

Mass spectrum (ESI, m/z): 813 [MH] ⁺ .

Comparative Example 31-(a)

Preparation of (S)-di-tert-butyl 2-((((4-((4-(2,3-bis(tert-butoxycarbonyl) guanidino)benzoyl)oxy)benzyl)oxy)carbonyl)amino)succinate

(1) A solution of bis(trichloromethyl) carbonate (1.16 d) in anhydrous dichloromethane (10 ml) at -20°C under argon flow with stirring, and the resulting mixture was stirred at -20°C for 2 hours.

(2) To a suspension of 4-(hydroxymethyl)phenyl 4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoate (3.14 g) prepared in the same manner as described for Comparative Example 1-(g), and N,N-diisopropylethylamine (5.00 ml) in anhydrous dichloromethane (20 ml) in a 300 ml round bottom flask was added to the reaction solution obtained in (1) while cooling in an ice bath under argon atmosphere with stirring, and the reaction mixture was stirred at room temperature within 16 hours. The reaction solution was evaporated under reduced pressure. A solution of the evaporation residue in anhydrous dimethylformamide (50 ml) was stirred at 65°C for 1 hour, at 75°C for 2 hours and at 65°C for 2 hours. After completion of the reaction, a saturated sodium hydrogen carbonate aqueous solution was added to the solution, and the resulting solution was extracted with dichloromethane. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (1.46 g) as a white solid.

Mass spectrum (ESI, m/z): 757 [M+H] ⁺ .

Comparative Example 31-(b)

Preparation of (S)-2-((((4-((4-guanidinobenzoyl)oxy)benzyl)oxy)carbonyl)amino)succinic acid trifluoroacetate

Into a solution of (S)-di-tert-butyl 2-((((4-((4-(2,3-bis(tert-butoxycarbonyl) guanidino)benzoyl)oxy)benzyl)oxy)carbonyl)amino)succinate ( 1.46 g) obtained in Comparative Example 31-(a) in anhydrous dichloromethane (15 ml) in a 500 ml round bottom flask was added trifluoroacetic acid (3.00 ml) while cooling in an ice bath under argon atmosphere with stirring, and the resulting mixture was stirred under cooling in an ice bath for 3 hours. The reaction solution was evaporated under reduced pressure. To a solution of the resulting evaporation residue in anhydrous dichloromethane (15 ml) was added trifluoroacetic acid (3.00 ml) under ice-bath cooling under argon with stirring, and the mixture was stirred at room temperature for 3 hours. Additional trifluoroacetic acid (3.00 ml) was added with stirring at room temperature, and the resulting mixture was stirred at room temperature for 1 hour. After completion of the reaction, the solution was evaporated under reduced pressure. The evaporation residue was dissolved in a mixture of water and acetonitrile (1:1 (v/v)), and the solution was subjected to lyophilization. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: acetonitrile with 0.1% trifluoroacetic acid: water with 0.1% trifluoroacetic acid), and fractions with the target compound were evaporated under reduced pressure. The evaporation residue was dissolved in a mixture of water and acetonitrile (1:1 (v/v)), and the solution was lyophilized to give the title Compound (1.17 g) as a white solid.

Mass spectrum (ESI, m/z): 445 [M+H] ⁺ .

Comparative Example 31-(c)

Preparation of (S)-2-((((4-((4-guanidinobenzoyl)oxy)benzyl)oxy)carbonyl)amino)succinic acid hydrochloride

To a solution of (S)-2-((((4-((4-guanidinobenzoyl)oxy)benzyl)oxy)carbonyl)amino)succinic acid trifluoroacetate (220 mg) obtained in Comparative Example 31-(b) in a mixture acetonitrile (1.5 ml)/water (1 ml) in a 50 ml round bottom flask was added 1N. hydrochloric acid solution (0.430 ml) at room temperature with stirring, and the resulting mixture was lyophilized to give the title Compound (180 mg) as a white solid.

Mass spectrum (ESI, m/z): 445 [M+H] ⁺ .

Comparative Example 32-(a)

Preparation of (S)-di-tert-butyl 2-(((4-(benzyloxy)phenoxy)carbonyl)amino)succinate

To a solution of 4-(benzyloxy)phenol (0.99 g) in ethyl acetate (25 ml) in 100 ml was added 1,1'-carbonyldiimidazole (2.05 g) at room temperature in an argon atmosphere with stirring, and the reaction mixture was stirred at room temperature for 1 hour . Then, acetic acid (1.70 ml) and L-aspartic acid di-tert-butyl ester hydrochloride (2.03 g) were added with stirring at room temperature, and the resulting mixture was stirred at room temperature for 120 hours. After the completion of the reaction, 1N sodium hydroxide was added to the solution. hydrochloric acid solution, and the resulting solution was extracted with ethyl acetate. The organic layer was washed successively with a saturated aqueous sodium hydrogen carbonate solution and an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and evaporated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (0.43 g) as a white solid.

Mass Spectrum (ESI, m/z): 470 [MH] ^- .

By a method similar to Comparative Example 32-(a), Comparative Example 33-(a) and Comparative Example 34-(a) were prepared.

Comparative Example 32-(b)

Preparation of (S)-di-tert-butyl 2-(((4-hydroxyphenoxy)carbonyl)amino)succinate

To a solution of (S)-di-tert-butyl 2-(((4-(benzyloxy)phenoxy)carbonyl)amino)succinate (0.43 g) prepared in the same manner as described for Comparative Example 32-(a), in ethanol (20 ml) in a 100 ml round bottom flask was added 10% palladium on carbon (water content 54.51%, PE-type manufactured by NE CHEMCAT Corporation) (42 mg) at room temperature in an argon atmosphere with stirring, the reaction system was filled with hydrogen, and then the resulting mixture was stirred at room temperature for 3 hours. After the completion of the reaction, the atmosphere in the reaction system was replaced with argon, the reaction solution was filtered through Celite, washed with ethanol, and the filtrate was evaporated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (350.5 mg) as a white solid.

Mass Spectrum (ESI, m/z): 380 [MH] ^- .

By a method similar to Comparative Example 32-(b), Comparative Example 33-(b) and Comparative Example 34-(b) were prepared.

Comparative Example 32-(c)

Preparation of (S)-di-tert-butyl 2-(((4-((4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoyl)oxy)phenoxy)carbonyl)amino)succinate

To a suspension of (S)-di-tert-butyl 2-(((4-hydroxyphenoxy)carbonyl)amino)succinate (350 mg) obtained in Comparative Example 32-(b), 4-(2,3-bis(tert -butoxycarbonyl)guanidino)benzoic acid (458 mg) prepared in the same manner as described in Comparative Example 1-(e) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (262 mg) in dichloromethane (10 ml) in a 50 ml round bottom flask was added 4-dimethylaminopyridine (57 mg) at room temperature under argon with stirring, and the reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, silica gel was added to the solution, the resulting mixture was eluted with ethyl acetate/hexane, and the eluate was evaporated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (447.1 mg) as a white solid.

Mass spectrum (ESI, m/z): 743 [M+H] ⁺ .

By a method similar to Comparative Example 32-(c), Comparative Example 33-(c) and Comparative Example 34-(c) were prepared.

Comparative Example 32-(d)

Preparation of (S)-2-(((4-((4-guanidinobenzoyl)oxy)phenoxy)carbonyl)amino)succinic acid trifluoroacetate

In a solution of (S)-di-tert-butyl 2-(((4-((4-(2,3-bis(tert-butoxycarbonyl) guanidino) benzoyl) oxy) phenoxy) carbonyl) amino) succinate (440 mg) obtained in Comparative Example 32-(c), in dichloromethane (6 ml) in a 50 ml round bottom flask was added trifluoroacetic acid (3 ml) at room temperature under argon atmosphere with stirring, and the resulting mixture was stirred at room temperature for 5 hours . After completion of the reaction, the solution was evaporated under reduced pressure. Dichloromethane was added to the evaporation residue and the resulting mixture was azeotropically distilled off three times. Then acetonitrile was added to the evaporation residue and the resulting mixture was azeotropically distilled three times. The evaporation residue was dissolved in water/acetonitrile and the resulting solution was lyophilized to give the title Compound (295 mg) as a white solid.

Mass spectrum (ESI, m/z): 431 [M+H] ⁺ .

Comparative Example 33-(d)

Preparation of (S)-2-(((4-((4-guanidinobenzoyl)oxy)phenetoxy)carbonyl)amino)succinic acid trifluoroacetate

The title compound was prepared using Comparative Example 33-(c) in the same manner as Comparative Example 32-(d).

Mass spectrum (ESI, m/z): 459 [M+H] ⁺ .

Comparative Example 34-(d)

Preparation of (S)-2-(((3-(4-((4-guanidinobenzoyl)oxy)phenyl)propoxy)carbonyl)amino)succinic acid

To a solution of (S)-di-tert-butyl 2-(((3-(4-((4-(2,3-bis(tert-butoxycarbonyl) guanidino)benzoyl)oxy)phenyl)propoxy)carbonyl)amino) succinate (340 mg) obtained in Comparative Example 34-(c) in dichloromethane (6 ml) in a 50 ml round bottom flask was added trifluoroacetic acid (3 ml) at room temperature under argon atmosphere with stirring, and the resulting mixture was stirred at room temperature. temperature for 18 hours. The reaction solution was evaporated under reduced pressure. Dichloromethane was added to the evaporation residue and the mixture was azeotroped three times. The evaporation residue was dissolved in a mixture of water and acetonitrile (1:1 (v/v)), and the resulting solution was subjected to lyophilization. Dichloromethane (5 ml) and trifluoroacetic acid (5 ml) were added to the evaporation residue and the resulting mixture was stirred overnight. After completion of the reaction, the solution was evaporated under reduced pressure. The evaporation residue was dissolved in a mixture of water and acetonitrile (1:1 (v/v)), and the resulting solution was subjected to lyophilization. The resulting residue was isolated by preparative high performance liquid chromatography (column: XBridge BEH C18 OBD Prep Column, elution solvent: water with 0.1% trifluoroacetic acid : acetonitrile with 0.1% trifluoroacetic acid), and fractions with the target compound were evaporated under reduced pressure. The precipitate that formed was filtered off and dried under reduced pressure to give the title Compound (145.2 mg) as a white solid.

Mass spectrum (ESI, m/z): 473 [M+H] ⁺ .

Comparative Example 35-(a)

Preparation of tri-tert-butyl 3-(((4-((4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoyl)oxy)benzyl)oxy)carbonyl)-6,9,12,15,18 ,21-hexaoxa-3-azatricosan-1,2,23-tricarboxylate

Into a suspension of 1-(((4-((4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoyl)oxy)benzyl)oxy)carbonyl)-3-methyl-1H-imidazol-3-ium trifluoromethanesulfonate ( 400 mg) obtained by the same procedure as described for Comparative Example 10-(b), in anhydrous dichloromethane (4 ml) in a 50 ml round bottom flask was added tri-tert-butyl 6,9,12,15,18, 21-hexaoxa-3-azatricosan-1,2,23-tricarboxylate (415 mg) obtained in Comparative Example 10-(c)-2 at room temperature under argon with stirring, and the resulting mixture was stirred at room temperature for 6 days. After completion of the reaction, the solution was evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (264 mg) as a colorless oil.

Mass spectrum (ESI, m/z): 1150 [M+H] ⁺ .

Comparative Example 36-(a)-Comparative Example 51-(a) was prepared in a similar manner to Comparative Example 35-(a).

Comparative Example 35-(b)

Preparation of 3-(((4-((4-guanidinobenzoyl)oxy)benzyl)oxy)carbonyl)-6,9,12,15,18,21-hexaoxa-3-azatricosan-1,2,23-tricarboxylic acid

In a solution of tri-tert-butyl 3-(((4-((4-(2,3-bis(tert-butoxycarbonyl) guanidino) benzoyl) oxy) benzyl) oxy) carbonyl) -6,9,12,15, Trifluoroacetic acid (1.00 ml) while cooling in an ice bath under argon atmosphere with stirring, and the resulting mixture was stirred at room temperature for 6 hours. The reaction solution was evaporated under reduced pressure. To a solution of the evaporation residue in anhydrous dichloromethane (2 ml) was added trifluoroacetic acid (1.00 ml) at room temperature under argon with stirring, and the resulting mixture was stirred at room temperature for 18 hours. After completion of the reaction, the solution was evaporated under reduced pressure. To a solution of the resulting residue in a mixture of water (8 ml)/acetonitrile (2 ml)/trifluoroacetic acid was added a saturated aqueous solution of ammonium acetate, bringing the pH to 4.0. The resulting solution was purified by preparative medium pressure chromatography (ODS silica gel, elution solvent: water:acetonitrile:methanol), and fractions with the target compound were evaporated under reduced pressure. The evaporation residue was freeze-dried to give the title Compound (144 mg) as a white solid.

Mass spectrum (ESI, m/z): 781 [M+H] ⁺ .

Comparative Example 36-(b)

Preparation of 3-(((4-((4-guanidinobenzoyl)oxy)benzyl)oxy)carbonyl)-6,9,12,15,18-pentaoxa-3-azaicosan-1,2,20-tricarboxylic acid

The title compound was prepared using Comparative Example 36-(a) in the same manner as Comparative Example 35-(b).

Mass spectrum (ESI, m/z): 737 [M+H] ⁺ .

Comparative Example 37-(b)

Preparation of 3-(((4-((4-guanidinobenzoyl)oxy)benzyl)oxy)carbonyl)-6,9,12,15-tetraoxa-3-azaheptadecan-1,2,17-tricarboxylic acid

In a solution of tri-tert-butyl 3-(((4-((4-(2,3-bis(tert-butoxycarbonyl) guanidino) benzoyl) oxy) benzyl) oxy) carbonyl) -6,9,12,15- tetraoxa-3-azaheptadecan-1,2,17-tricarboxylate (264 mg) obtained in Comparative Example 37-(a) in dichloromethane (3.2 ml) in a 50 ml round bottom flask was added trifluoroacetic acid (800 μl) at room temperature in a stream of argon with stirring, and the resulting mixture was stirred at room temperature for 15 hours. The reaction solution was evaporated under reduced pressure. Dichloromethane (800 μl) and trifluoroacetic acid (800 μl) were added to the evaporation residue at room temperature, and the resulting mixture was stirred at room temperature for 3 hours. After completion of the reaction, the solution was evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: acetonitrile with 0.1% trifluoroacetic acid: water with 0.1% trifluoroacetic acid), and fractions with the title compound were evaporated under reduced pressure to give a white foam (330 mg). Water (2 ml) and acetonitrile (200 μl) were added to a portion of the resulting white foam (114 mg), and the resulting solution was evaporated under reduced pressure. A saturated aqueous solution of ammonium acetate was added to the resulting residue, adjusting the pH to 4.0. The resulting solution was purified with Bond Elut C18 (eluting solvent: water:acetonitrile:methanol) and the target compound fractions were evaporated under reduced pressure. The evaporation residue was dissolved in water/acetonitrile and the resulting solution was lyophilized to give the title Compound (57 mg) as a white solid.

Mass spectrum (ESI, m/z): 693 [M+H] ⁺ .

Comparative Example 38-(b)

Preparation of 3-(((4-((4-guanidinobenzoyl)oxy)benzyl)oxy)carbonyl)-6,9,12-trioxa-3-azatetradecane-1,2,14-tricarboxylic acid

The title compound was prepared using Comparative Example 38-(a) in the same manner as Comparative Example 37-(b).

Mass spectrum (ESI, m/z): 649 [M+H] ⁺ .

Comparative Example 39-(b)

Preparation of 2-((2-(2-(2-carboxyethoxy)ethoxy)ethyl)(((4-((4-guanidinobenzoyl)oxy)benzyl)oxy)carbonyl)amino)succinic acid

The title compound was prepared using Comparative Example 39-(a) in the same manner as Comparative Example 37-(b).

Mass spectrum (ESI, m/z): 605 [M+H] ⁺ .

Comparative Example 40-(b)

Preparation of 2-((2-(2-carboxyethoxy)ethyl)(((4-((4-guanidinobenzoyl)oxy)benzyl)oxy)carbonyl)amino)succinic acid

The title compound was prepared using Comparative Example 40-(a) in a similar manner to Comparative Example 37-(b).

Mass spectrum (ESI, m/z): 561 [M+H] ⁺ .

Comparative Example 41-(b)

Preparation of (2S)-2-(3-carboxy-2-((((4-((4-guanidinobenzoyl)oxy)benzyl)oxy) carbonyl)amino)propanamide)succinic acid trifluoroacetate

In a solution of (2S)-di-tert-butyl 2-(2-(((4-((4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoyl)oxy)benzyl)oxy)carbonyl)amino )-4-(tert-butoxy)-4-oxobutanamide)succinate (395 mg) prepared in the same manner as described for Comparative Example 41-(a) in anhydrous dichloromethane (2 ml) in a 100 ml round bottom flask trifluoroacetic acid (0.500 ml) was added while cooling in an ice bath under argon atmosphere with stirring, and the resulting mixture was stirred at room temperature for 16 hours. The reaction solution was evaporated under reduced pressure. To a solution of the resulting evaporation residue in anhydrous dichloromethane (2 ml) was added trifluoroacetic acid (0.500 ml) at room temperature under argon with stirring, and the resulting mixture was stirred at room temperature for 5 hours. After completion of the reaction, the solution was evaporated under reduced pressure. The evaporation residue was dissolved in a mixture of water and acetonitrile (1:1 (v/v)), and the resulting solution was subjected to lyophilization. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: acetonitrile with 0.1% trifluoroacetic acid: water with 0.1% trifluoroacetic acid), and fractions with the target compound were evaporated under reduced pressure. The evaporation residue was dissolved in a mixture of water and acetonitrile (1:1 (v/v)), and the resulting solution was lyophilized to give the title Compound (292 mg) as a white solid.

Mass spectrum (ESI, m/z): 560 [M+H] ⁺ .

Comparative Example 41-(c)

Preparation of (2S)-2-(3-carboxy-2-((((4-((4-guanidinobenzoyl)oxy)benzyl)oxy)carbonyl)amino)propanamide)succinic acid

In a solution of (2S)-di-tert-butyl 2-(2-(((4-((4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoyl)oxy)benzyl)oxy)carbonyl)amino )-4-(tert-butoxy)-4-oxobutanamide)succinate (1.79 g) prepared in the same manner as described for Comparative Example 41-(a) in anhydrous dichloromethane (10 ml) in a 200 ml round bottom flask trifluoroacetic acid (2.50 ml) was added while cooling in an ice bath under argon atmosphere with stirring, and the resulting mixture was stirred at room temperature for 16 hours. After completion of the reaction, the solution was evaporated under reduced pressure. To a solution of the resulting evaporation residue in anhydrous dichloromethane (10 ml) was added trifluoroacetic acid (2.50 ml) at room temperature under argon with stirring, and the resulting mixture was stirred at room temperature for 6 hours. The reaction solution was evaporated under reduced pressure. Saturated ammonium acetate aqueous solution was added to a solution of the resulting residue in water (20 ml)/acetonitrile (5 ml)/trifluoroacetic acid (1 ml), adjusting the pH to 4.0, and the mixture was stirred at room temperature for 16 hours. The reaction solution was purified by preparative medium pressure chromatography (ODS silica gel, elution solvent: water:(acetonitrile:methanol = 1:1 (v/v))), and fractions with the target compound were evaporated under reduced pressure. The evaporation residue was dissolved in a mixture of water and acetonitrile (1:1 (v/v)), and the resulting solution was lyophilized to give the title Compound (855 mg) as a white solid.

Mass spectrum (ESI, m/z): 560 [M+H] ⁺ .

Comparative Example 42-(b)

Preparation of (S)-2-((S)-3-carboxy-2-((S)-3-carboxy-2-((((4-((4-guanidinobenzoyl)oxy)benzyl)oxy)carbonyl)amino )propanamide)propanamide)succinic acid trifluoroacetate

In a solution of (S)-di-tert-butyl 2-((S)-2-((S)-2-((((4-((4-(2,3-bis(tert-butoxycarbonyl)guanidino) benzoyl)oxy)benzyl)oxy)carbonyl)amino)-4-(tert-butoxy)-4-oxobutanamide)-4-(tert-butoxy)-4-oxobutanamide)succinate (570 mg) obtained in Comparative Example 42- (a), in dichloromethane (5 ml) in a 50 ml round bottom flask, trifluoroacetic acid (5 ml) was added at room temperature under argon with stirring, and the resulting mixture was stirred at room temperature for 40 hours. After completion of the reaction, the solution was evaporated under reduced pressure. A saturated aqueous solution of ammonium acetate was added to a solution of the resulting residue in an acetonitrile/water mixture, adjusting the pH to 4.0. The resulting residue was purified by preparative medium pressure chromatography (ODS silica gel, elution solvent: water with 0.1% trifluoroacetic acid : acetonitrile with 0.1% trifluoroacetic acid), and fractions with the target compound were freeze-dried to give the title Compound (304.2 mg) in form of a white solid.

Mass spectrum (ESI, m/z): 675 [M+H] ⁺ .

Comparative Example 43-(b)

Preparation of (S)-2-(2-((3-carboxybenzyl)(((4-((4-guanidinobenzoyl)oxy)benzyl)oxy)carbonyl)amino)acetamido)succinic acid

In a solution of (S)-di-tert-butyl 2-(2-((((4-((4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoyl)oxy)benzyl)oxy)carbonyl)( 3-(tert-butoxycarbonyl)benzyl)amino)acetamido)succinate (2.34g) obtained in Comparative Example 43-(a) in anhydrous dichloromethane (8ml) in a 200ml round bottom flask was added trifluoroacetic acid (2.00ml) at cooling in an ice bath under argon atmosphere with stirring, and the resulting mixture was stirred at room temperature for 16 hours. The reaction solution was evaporated under reduced pressure. To a solution of the evaporation residue in anhydrous dichloromethane (8 ml) was added trifluoroacetic acid (2.00 ml) at room temperature under argon with stirring, and the resulting mixture was stirred at room temperature for 5 hours. After completion of the reaction, the solution was evaporated under reduced pressure. A mixture of water (36 ml)/acetonitrile (12 ml) was added to the residue, then a saturated aqueous ammonium acetate solution was added, adjusting the pH to 4.0. The resulting mixture was stirred at room temperature for 1 hour, the precipitate formed was filtered off and dried under reduced pressure to give the title Compound (1.36 g) as a white solid.

Mass spectrum (ESI, m/z): 636 [M+H] ⁺ .

Comparative Example 44-(b)

Preparation of (2S)-2-(3-carboxy-2-((carboxymethyl)(((4-((4-guanidinobenzoyl)oxy) benzyl)oxy)carbonyl)amino)propanamide)succinic acid

In a solution of (2S)-di-tert-butyl 2-(2-(((4-((4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoyl)oxy)benzyl)oxy)carbonyl)( 2-(tert-butoxy)-2-oxoethyl)amino)-4-(tert-butoxy)-4-oxobutanamide)succinate (189 mg) obtained in Comparative Example 44-(a) in anhydrous dichloromethane (4 ml) in a 50 ml round bottom flask, trifluoroacetic acid (1.00 ml) was added under ice bath cooling under argon atmosphere with stirring, and the resulting mixture was stirred at room temperature for 6 hours. The reaction solution was evaporated under reduced pressure. To a solution of the resulting evaporation residue in anhydrous dichloromethane (2 ml) was added trifluoroacetic acid (1.00 ml) at room temperature under argon with stirring, and the resulting mixture was stirred at room temperature for 18 hours. After completion of the reaction, the solution was evaporated under reduced pressure. To a solution of the resulting residue in a mixture of water (10 ml)/acetonitrile (3 ml)/trifluoroacetic acid (1 ml) was added a saturated aqueous solution of ammonium acetate, bringing the pH to 4.0. The reaction solution was purified by preparative medium pressure chromatography (ODS silica gel, elution solvent: water:(acetonitrile:methanol = 1:1 (v/v))), and fractions with the target compound were freeze-dried to give the title Compound (92 mg) as a white solid.

Mass spectrum (ESI, m/z): 618 [M+H] ⁺ .

Comparative Example 45-(b)

Preparation of 3-(((carboxymethyl)(((4-((4-guanidinobenzoyl)oxy)benzyl)oxy)carbonyl)amino)methyl)benzoic acid trifluoroacetate

The title compound was prepared using Comparative Example 45-(a) in the same manner as Comparative Example 32-(d).

Mass spectrum (ESI, m/z): 521 [M+H] ⁺ .

Comparative Example 46-(b)

Preparation of 3-(((4-((4-guanidinobenzoyl)oxy)benzyl)oxy)carbonyl)-6,9,12,15-tetraoxa-3-azaoctadecane-1,18-dioic acid trifluoroacetate

The title compound was prepared using Comparative Example 46-(a) in the same manner as Comparative Example 31-(b).

Mass spectrum (ESI, m/z): 635 [M+H] ⁺ .

Comparative Example 46-(c)

Preparation of 3-(((4-((4-guanidinobenzoyl)oxy)benzyl)oxy)carbonyl)-6,9,12,15-tetraoxa-3-azaoctadecane-1,18-dioic acid hydrochloride

The title compound was prepared using Comparative Example 46-(b) in the same manner as Comparative Example 31-(c).

Mass spectrum (ESI, m/z): 635 [M+H] ⁺ .

Comparative Example 46-(c)

Preparation of 3-(((4-((4-guanidinobenzoyl)oxy)benzyl)oxy)carbonyl)-6,9,12,15-tetraoxa-3-azaoctadecane-1,18-dioic acid hydrochloride

The title compound was prepared using Comparative Example 46-(b) in the same manner as Comparative Example 31-(c).

Mass spectrum (ESI, m/z): 635 [M+H] ⁺ .

Comparative Example 46-(d)

Preparation of 3-(((4-((4-guanidinobenzoyl)oxy)benzyl)oxy)carbonyl)-6,9,12,15-tetraoxa-3-azaoctadecane-1,18-dioic acid

The title compound was prepared using Comparative Example 46-(a) in the same manner as Comparative Example 35-(b).

Mass spectrum (ESI, m/z): 635 [M+H] ⁺ .

Comparative Example 47-(b)

Preparation of 4-(3-carboxybenzyl)-1-(4-((4-guanidinobenzoyl)oxy)phenyl)-3-oxo-2,7,10,13,16-pentaoxa-4-azanonedecane-19-acid trifluoroacetate

The title compound was prepared using Comparative Example 47-(a) in the same manner as Comparative Example 31-(b).

Comparative Example 48-(b)

Preparation of (S)-2-((carboxymethyl)(((4-((4-guanidinobenzoyl)oxy)benzyl)oxy) carbonyl)amino)succinic acid trifluoroacetate

Into a solution of (S)-di-tert-butyl 2-((((4-((4-(2,3-bis(tert-butoxycarbonyl) guanidino)benzoyl)oxy)benzyl)oxy)carbonyl)(2-( tert-butoxy)-2-oxoethyl) amino) succinate (270 mg) obtained in Comparative Example 48-(a) in dichloromethane (2.85 ml) in a 100 ml round bottom flask was added trifluoroacetic acid (712 μl) at room temperature in a stream of argon with stirring, and the resulting mixture was stirred at room temperature for 15 hours. The reaction solution was evaporated under reduced pressure. Trifluoroacetic acid (1424 μl) and dichloromethane (1424 μl) were added to the evaporation residue, and the resulting mixture was stirred at room temperature for 2.5 hours. After completion of the reaction, the solution was evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: acetonitrile with 0.1% trifluoroacetic acid: water with 0.1% trifluoroacetic acid), and fractions with the target compound were evaporated under reduced pressure. The precipitate that formed was filtered off and dried under reduced pressure to give the title Compound (124.3 mg) as a white solid.

Mass spectrum (ESI, m/z): 503 [M+H] ⁺ .

Comparative Example 48-(c)

Preparation of (S)-2-((carboxymethyl)(((4-((4-guanidinobenzoyl)oxy)benzyl)oxy)carbonyl)amino)succinic acid

Into a solution of (S)-di-tert-butyl 2-((((4-((4-(2,3-bis(tert-butoxycarbonyl) guanidino)benzoyl)oxy)benzyl)oxy)carbonyl)(2-( tert-Butoxy)-2-oxoethyl)amino)succinate (1.566 g) obtained in Comparative Example 48-(a) in dichloromethane (10 ml) in a 100 ml round bottom flask was added trifluoroacetic acid (2.5 ml) at 0°C in a stream of argon with stirring, and the resulting mixture was stirred at room temperature for 15 hours. The reaction solution was evaporated under reduced pressure. Dichloromethane (2.50 ml) and trifluoroacetic acid (2.50 ml) were added to the evaporation residue at room temperature, and the resulting mixture was stirred at room temperature for 3 hours. After completion of the reaction, the solution was evaporated under reduced pressure. Dichloromethane (2 ml) was added at room temperature and the resulting mixture was stirred at room temperature for 1 hour. The reaction solution was evaporated under reduced pressure. A saturated aqueous solution of ammonium acetate was added to a solution of the resulting residue in a water (10 ml)/acetonitrile (2 ml) mixture, adjusting the pH to 3.9. The resulting mixture was stirred in an ice bath for 30 minutes, the precipitate that formed was separated by filtration and dried under reduced pressure. The resulting solid was purified by preparative medium pressure chromatography (silica gel, elution solvent: acetonitrile with 0.1% trifluoroacetic acid: water with 0.1% trifluoroacetic acid), and fractions with the target compound were evaporated under reduced pressure. The precipitate that formed was filtered off and dried under reduced pressure to give solids. To a solution of the resulting solid in water (3 ml)/trifluoroacetic acid (1 ml) was added a saturated aqueous ammonium acetate solution, adjusting the pH to 4.0. the mixture was stirred at room temperature for 30 minutes, the precipitate was separated by filtration and dried under reduced pressure to give the title Compound (503 mg) as a white solid.

Mass spectrum (ESI, m/z): 503 [M+H] ⁺ .

Comparative Example 49-(b)

Preparation of (S)-2-((3-carboxybenzyl)(((4-((4-guanidinobenzoyl)oxy)benzyl)oxy) carbonyl)amino)succinic acid trifluoroacetate

Into a solution of (S)-di-tert-butyl 2-((((4-((4-(2,3-bis(tert-butoxycarbonyl) guanidino)benzoyl)oxy)benzyl)oxy)carbonyl)(3-( tert-butoxycarbonyl) benzyl) amino) succinate (167 mg) obtained by the same procedure as described for Comparative Example 49-(a), trifluoroacetic acid (0.500 ml ) while cooling in an ice bath under argon atmosphere with stirring, and the resulting mixture was stirred at room temperature for 16 hours. The reaction solution was evaporated under reduced pressure. To a solution of the resulting evaporation residue in anhydrous dichloromethane (2 ml) was added trifluoroacetic acid (0.500 ml) at room temperature under argon with stirring, and the resulting mixture was stirred at room temperature for 5 hours. After completion of the reaction, the solution was evaporated under reduced pressure. The evaporation residue was dissolved in a mixture of water and acetonitrile (1:1 (v/v)), and the resulting solution was lyophilized to give the title Compound (125 mg) as a white solid.

Mass spectrum (ESI, m/z): 579 [M+H] ⁺ .

Comparative Example 49-(c)

Preparation of (S)-2-((3-carboxybenzyl)(((4-((4-guanidinobenzoyl)oxy)benzyl)oxy)carbonyl)amino)succinic acid

Into a solution of (S)-di-tert-butyl 2-((((4-((4-(2,3-bis(tert-butoxycarbonyl) guanidino)benzoyl)oxy)benzyl)oxy)carbonyl)(3-( trifluoroacetic acid (5.00 ml ) while cooling in an ice bath under argon atmosphere with stirring, and the resulting mixture was stirred at room temperature for 15 hours. After completion of the reaction, the solution was evaporated under reduced pressure. To a solution of the resulting residue in anhydrous dichloromethane (20 ml) was added trifluoroacetic acid (5.00 ml) at room temperature under argon with stirring, and the mixture was stirred at room temperature for 5 hours. The reaction solution was evaporated under reduced pressure. A mixture of water (25 ml)/acetonitrile (5 ml) was added to the evaporation residue, then a saturated aqueous ammonium acetate solution was added, adjusting the pH to 4.0, and the resulting mixture was stirred at room temperature for 30 minutes. Part of the reaction solution (29 ml) was stirred at room temperature for 24 hours, the precipitate was separated by filtration and dried under reduced pressure to give the title Compound (1.07 g) as a white solid.

Mass spectrum (ESI, m/z): 579 [M+H] ⁺ .

Comparative Example 50-(b)

Preparation of (S)-2-(2-(((S)-1,2-dicarboxyethyl)(((4-((4-guanidinobenzoyl)oxy) benzyl)oxy)carbonyl)amino)acetamido)succinic acid

The title compound was prepared using Comparative Example 50-(a) in the same manner as Comparative Example 43-(b).

Mass spectrum (ESI, m/z): 618 [M+H] ⁺ .

Comparative Example 51-(b)

Preparation of (S)-2-((5-carboxypentyl)(((4-((4-guanidinobenzoyl)oxy)benzyl)oxy)carbonyl)amino)succinic acid

The title compound was prepared using Comparative Example 51-(a) in the same manner as Comparative Example 48-(c).

Mass spectrum (ESI, m/z): 559 [M+H] ⁺ .

Comparative Example 52-(a)

Preparation of (S)-di-tert-butyl 2-((N-((benzyloxy)carbonyl)-N-(4-((4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoyl)oxy)benzyl )sulfamoyl)(3-(tert-butoxycarbonyl)benzyl)amino)succinate

To a solution of 4-(hydroxymethyl)phenyl 4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoate (2.56 g) prepared in the same manner as described for Comparative Example 1-(g), and (S) -di-tert-butyl 2-((N-((benzyloxy)carbonyl)sulfamoyl)(3-(tert-butoxycarbonyl)benzyl)amino)succinate (3.07 g) obtained in Comparative Example 18-(a)-2, triphenylphosphine (1.51 g) and diisopropyl azodicarboxylate (1.9M solution in toluene) (3.00 ml) were added in tetrahydrofuran (10 ml) in a 100 ml round bottom flask at 0°C under argon flow with stirring, and the reaction mixture was stirred at room temperature 1 hour. After completion of the reaction, the solution was evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (1.52 g) as a white foam.

Mass spectrum (ESI, m/z): 1116 [M+H] ⁺ .

Comparative Example 53-(a)-Comparative Example 83-(a) was prepared in a similar manner to Comparative Example 52-(a).

Comparative Example 52-(b)

Preparation of (S)-2-((3-carboxybenzyl)(N-(4-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl)amino)succinic acid trifluoroacetate

To a solution of (S)-di-tert-butyl 2-((N-((benzyloxy)carbonyl)-N-(4-((4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoyl)oxy) benzyl)sulfamoyl)(3-(tert-butoxycarbonyl)benzyl)amino)succinate (2.42 g) prepared in the same manner as that described in Comparative Example 52-(a) in dichloromethane (20 ml) in a 100 ml round bottom the flask was added trifluoroacetic acid (20 ml) at room temperature under argon with stirring, and the resulting mixture was stirred at room temperature for 4 hours. The reaction solution was evaporated under reduced pressure. To a solution of the resulting evaporation residue in methanol (20 ml) was added 10% palladium-carbon (moisture content about 55%, manufactured by Tokyo Chemical Industry Co., Ltd.) (484 mg) at room temperature under argon atmosphere with stirring, the reaction system filled with hydrogen and stirred at room temperature for 2 hours. After completion of the reaction, the solution was filtered through celite, washed with methanol, and the filtrate was evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (ODS silica gel, elution solvent: water with 0.1% trifluoroacetic acid: acetonitrile with 0.1% trifluoroacetic acid), and fractions with the title compound were freeze-dried to give the title Compound (1.10 g) in form of a white solid.

Mass spectrum (ESI, m/z): 614 [M+H] ⁺ .

Comparative Example 52-(c)

Preparation of (S)-2-((3-carboxybenzyl)(N-(4-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl)amino)succinic acid

To a solution of (S)-di-tert-butyl 2-((N-((benzyloxy)carbonyl)-N-(4-((4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoyl)oxy) benzyl)sulfamoyl)(3-(tert-butoxycarbonyl)benzyl)amino)succinate (106 mg) prepared in the same manner as that described for Comparative Example 52-(a) in dichloromethane (1.5 ml) in a 20 ml cylindrical trifluoroacetic acid (1.5 ml) was added to the flask at room temperature under argon with stirring, and the resulting mixture was stirred at room temperature for 2 hours. The reaction solution was evaporated under reduced pressure. To a solution of the resulting evaporation residue in methanol (2 ml) was added 5% palladium on charcoal (moisture content 54.28%, STD-type manufactured by NE CHEMCAT Corporation) (80 mg) at room temperature in an argon atmosphere with stirring, the reaction system was filled with hydrogen and stirred at room temperature for 1 hour. After completion of the reaction, the solution was filtered through Celite, and the filtrate was evaporated under reduced pressure. A saturated aqueous solution of ammonium acetate was added to a solution of the resulting residue in a water/acetonitrile mixture, adjusting the pH to 4.0. The resulting mixture was stirred at room temperature for 1 hour, the precipitate formed was filtered off and dried under reduced pressure to give the title Compound (34 mg) as a white solid.

Mass spectrum (ESI, m/z): 614 [M+H] ⁺ .

Comparative Example 53-(b)

Preparation of (S)-2-((5-carboxypentyl)(N-(4-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl)amino)succinic acid trifluoroacetate

The title compound was prepared using Comparative Example 53-(a) in the same manner as Comparative Example 52-(b).

Mass spectrum (ESI, m/z): 594 [M+H] ⁺ .

Comparative Example 54-(b)

Preparation of (S)-2-((N-(4-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl)(methyl)amino)succinic acid

To a solution of (S)-di-tert-butyl 2-((N-((benzyloxy)carbonyl)-N-(4-((4-(2,3-bis(tert-butoxycarbonyl)guanidino)benzoyl)oxy) benzyl)sulfamoyl)(methyl)amino)succinate (614mg) prepared in the same manner as that described for Comparative Example 54-(a), trifluoroacetic acid (2.00 ml) while cooling in an ice bath under argon atmosphere with stirring, and the resulting mixture was stirred at room temperature for 16 hours. The reaction solution was evaporated under reduced pressure. To a solution of the obtained evaporation residue in methanol (6 ml) was added 10% palladium-carbon (moisture content about 55%, manufactured by Tokyo Chemical Industry Co., Ltd.) (50 mg) at room temperature under argon atmosphere with stirring, the reaction system filled with hydrogen and stirred at room temperature for 2 hours. After completion of the reaction, the solution was filtered through Celite, washed with a mixture of methanol and acetonitrile (1:1 (v/v)), and the filtrate was evaporated under reduced pressure. To a solution of the obtained residue in a mixture of water (10 ml)/acetonitrile (4 ml)/trifluoroacetic acid was added a saturated aqueous solution of ammonium acetate, bringing the pH to 4.0. The resulting mixture was stirred at room temperature for 1 hour, and filtered, separating the solid fraction. The separated solid was purified by preparative medium pressure chromatography (ODS silica gel, elution solvent: water with 0.1% trifluoroacetic acid: acetonitrile with 0.1% trifluoroacetic acid), and fractions with the target compound were evaporated under reduced pressure. A saturated aqueous solution of ammonium acetate was added to the resulting residue, adjusting the pH to 4.0. The resulting mixture was stirred at room temperature for 1 hour, the precipitate formed was filtered off and dried under reduced pressure to give the title Compound (198 mg) as a white solid.

Mass spectrum (ESI, m/z): 494 [M+H] ⁺ .

Comparative Example 55-(b)

Preparation of (S)-2-((N-(4-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl)amino)succinic acid

In a solution of (S)-di-tert-butyl 2-((N-(4-((4-(2,3-bis(tert-butoxycarbonyl) guanidino)benzoyl)oxy)benzyl)-N-(tert-butoxycarbonyl )sulfamoyl)amino)succinate (370mg) prepared in the same manner as that described for Comparative Example 55-(a) in dichloromethane (1.5mL) in a 30mL cylindrical flask was added trifluoroacetic acid (1.500mL) at room temperature in a stream of argon with stirring, and the resulting mixture was stirred at room temperature for 14 hours. The reaction solution was evaporated under reduced pressure. Trifluoroacetic acid (1.5 ml) was added to the evaporation residue and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, the solution was evaporated under reduced pressure. A saturated aqueous solution of ammonium acetate was added to a solution of the obtained residue in water (4 ml) at room temperature, adjusting the pH to 3.97. The resulting mixture was stirred at room temperature for 2 hours, the precipitate formed was filtered off and dried under reduced pressure to give the title Compound (177.3 mg) as a white solid.

Mass spectrum (ESI, m/z): 480 [M+H] ⁺ .

Comparative Example 56-(b)

Preparation of (S)-2-((carboxymethyl)(N-(4-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl)amino)succinic acid

In a solution of (S)-di-tert-butyl 2-((N-(4-((4-(2,3-bis(tert-butoxycarbonyl) guanidino)benzoyl)oxy)benzyl)-N-(tert-butoxycarbonyl )sulfamoyl)(2-(tert-butoxy)-2-oxoethyl)amino)succinate (450 mg) obtained in Comparative Example 56-(a) in dichloromethane (5 ml) in a 50 ml round bottom flask was added trifluoroacetic acid ( 5.00 ml) at room temperature under argon atmosphere with stirring, and the resulting mixture was stirred at room temperature for 18 hours. The reaction solution was evaporated under reduced pressure. Dichloromethane (5 ml) and trifluoroacetic acid (5.00 ml) were added to the evaporation residue, and the reaction mixture was stirred at room temperature for 24 hours. After completion of the reaction, the solution was evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (ODS silica gel, elution solvent: water with 0.1% trifluoroacetic acid: acetonitrile with 0.1% trifluoroacetic acid), and fractions with the target compound were evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (ODS silica gel, elution solvent: water with 0.1% trifluoroacetic acid: acetonitrile with 0.1% trifluoroacetic acid), and fractions with the target compound were evaporated under reduced pressure. The precipitate that formed was collected by filtration and dried under reduced pressure to give the title Compound (36 mg) as a white solid.

Mass spectrum (ESI, m/z): 538 [M+H] ⁺ .

Comparative Example 57-(b)

Preparation of (S)-2-((N-(4-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl)amino)pentanedioic acid

In a solution of (S)-di-tert-butyl 2-((N-(4-((4-(2,3-bis(tert-butoxycarbonyl) guanidino)benzoyl)oxy)benzyl)-N-(tert-butoxycarbonyl )sulfamoyl)amino)pentanedioate (550mg) obtained in Comparative Example 57-(a) in anhydrous dichloromethane (6mL) in a 50mL round-bottomed flask was added trifluoroacetic acid (2.00mL) while cooling in an ice bath under argon at stirring, and the resulting mixture was stirred at room temperature for 16 hours. The reaction solution was evaporated under reduced pressure. To a solution of the resulting evaporation residue in anhydrous dichloromethane (6 ml) was added trifluoroacetic acid (2.00 ml) at room temperature under argon with stirring, and the reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, the solution was evaporated under reduced pressure. To a solution of the resulting evaporation residue in a mixture of water (8 ml)/acetonitrile (2 ml) was added a saturated aqueous solution of ammonium acetate, bringing the pH to 4.0. The resulting mixture was stirred at room temperature for 1 hour and filtered. The filter cake was purified by preparative medium pressure chromatography (ODS silica gel, elution solvent: water with 0.1% trifluoroacetic acid: acetonitrile with 0.1% trifluoroacetic acid), fractions with the target compound were combined, and acetonitrile was distilled off under reduced pressure. A saturated aqueous ammonium acetate solution was added to the evaporation residue, adjusting the pH to 4.0. The resulting mixture was stirred at room temperature for 1 hour, the precipitate formed was filtered off and dried under reduced pressure to give the title Compound (227 mg) as a white solid.

Mass spectrum (ESI, m/z): 494 [M+H] ⁺ .

Comparative Example 58-(b)

Preparation of (S)-4-(2-carboxy-2-((N-(4-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl)amino)ethyl)benzoic acid

The title compound was prepared using Comparative Example 58-(a) in the same manner as Comparative Example 43-(b).

Mass spectrum (ESI, m/z): 556 [M+H] ⁺ .

Comparative Example 59-(b)

Preparation of (S)-4-(((N-(1-(tert-butoxy)-3-(4-hydroxyphenyl)-1-oxopropan-2-yl)sulfamoyl)(tert-butoxycarbonyl)amino)methyl)phenyl 4 -(2,3-bis(tert-butoxycarbonyl)guanidino)benzoate

In a solution of (S)-4-(((N-(1-(tert-butoxy)-3-(4-((tert-butyldimethylsilyl)oxy) phenyl)-1-oxopropan-2-yl)sulfamoyl)(tert -butoxycarbonyl)amino)methyl)phenyl 4-(2,3-bis(t-butoxycarbonyl)guanidino)benzoate (359 mg) obtained in Comparative Example 59-(a) in anhydrous tetrahydrofuran (4.00 ml) in 100 ml Tetrabutylammonium fluoride (1.0M solution in tetrahydrofuran) (0.500 ml) was added to a round-bottomed flask while cooling in an ice bath under argon atmosphere with stirring, and the reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, a saturated ammonium chloride aqueous solution was added to the solution, and the resulting solution was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (296 mg) as a white foam.

Mass spectrum (ESI, m/z): 884 [M+H] ⁺ .

Comparative Example 59-(c)

Preparation of (S)-2-((N-(4-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl)amino)-3-(4-hydroxyphenyl)propanoic acid trifluoroacetate

The title compound was prepared using Comparative Example 59-(b) in the same manner as Comparative Example 42-(b).

Mass spectrum (ESI, m/z): 528 [M+H] ⁺ .

Comparative Example 60-(b)

Preparation of (S)-2-((N-(4-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl)amino)-3-phenylpropanoic acid

The title compound was prepared using Comparative Example 60-(a) in the same manner as Comparative Example 43-(b).

Mass spectrum (ESI, m/z): 512 [M+H] ⁺ .

Comparative Example 61-(b)

Preparation of 6-((N-(4-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl)amino)hexanoic acid

The title compound was prepared using Comparative Example 61-(a) in the same manner as Comparative Example 57-(b).

Mass spectrum (ESI, m/z): 478 [M+H] ⁺ .

Comparative Example 62-(b)

Preparation of 2-((N-(4-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl)amino)acetic acid

The title compound was prepared using Comparative Example 62-(a) in the same manner as Comparative Example 57-(b).

Mass spectrum (ESI, m/z): 422 [M+H] ⁺ .

Comparative Example 63-(b)

Preparation of (S)-2-((N-(4-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl)amino)propanoic acid

The title compound was prepared using Comparative Example 63-(a) in the same manner as Comparative Example 43-(b).

Mass spectrum (ESI, m/z): 436 [M+H] ⁺ .

Comparative Example 64-(b)

Preparation of 4-(((N-methylsulfamoyl)amino)methyl)phenyl 4-guanidinobenzoate trifluoroacetate

The title compound was prepared using Comparative Example 64-(a) in the same manner as Comparative Example 32-(d).

Mass spectrum (ESI, m/z): 378 [M+H] ⁺ .

Comparative Example 65-(b)

Preparation of (S)-2-((N-(3-fluoro-4-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl)amino)succinic acid trifluoroacetate

The title compound was prepared using Comparative Example 65-(a) in the same manner as Comparative Example 43-(b).

Mass spectrum (ESI, m/z): 498 [M+H] ⁺ .

Comparative Example 66-(b)

Preparation of (S)-2-((N-(3-chloro-4-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl)amino)succinic acid trifluoroacetate

The title compound was prepared using Comparative Example 66-(a) in the same manner as Comparative Example 42-(b).

Mass spectrum (ESI, m/z): 514 [M+H] ⁺ .

Comparative Example 67-(b)

Preparation of (S)-2-((N-(4-((4-guanidinobenzoyl)oxy)-3-methoxybenzyl)sulfamoyl)amino)succinic acid trifluoroacetate

The title compound was prepared using Comparative Example 67-(a) in the same manner as Comparative Example 42-(b).

Mass spectrum (ESI, m/z): 510 [M+H] ⁺ .

Comparative Example 68-(b)

Preparation of (S)-2-((N-(4-((4-guanidinobenzoyl)oxy)-3-methylbenzyl)sulfamoyl)amino)succinic acid

The title compound was prepared using Comparative Example 68-(a) in the same manner as Comparative Example 43-(b).

Mass spectrum (ESI, m/z): 494 [M+H] ⁺ .

Comparative Example 69-(b)

Preparation of (S)-2-((N-(2-fluoro-4-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl)amino)succinic acid

The title compound was prepared using Comparative Example 69-(a) in the same manner as Comparative Example 43-(b).

Comparative Example 70-(b)

Preparation of (S)-2-((N-(2-chloro-4-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl)amino)succinic acid

The title compound was prepared using Comparative Example 70-(a) in a similar manner to Comparative Example 56-(b).

Mass spectrum (ESI, m/z): 514 [M+H] ⁺ .

Comparative Example 71-(b)

Preparation of (S)-2-((N-(4-((4-guanidinobenzoyl)oxy)-2-methoxybenzyl)sulfamoyl)amino)succinic acid trifluoroacetate

The title compound was prepared using Comparative Example 71-(a) in the same manner as Comparative Example 42-(b).

Mass spectrum (ESI, m/z): 510 [M+H] ⁺ .

Comparative Example 72-(b)

Preparation of (S)-2-((N-(4-((4-guanidinobenzoyl)oxy)-2-methylbenzyl)sulfamoyl)amino)succinic acid

The title compound was prepared using Comparative Example 72-(a) in the same manner as Comparative Example 43-(b).

Mass spectrum (ESI, m/z): 494 [M+H] ⁺ .

Comparative Example 73-(b)

Preparation of (S)-2-((N-(3-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl)amino)succinic acid trifluoroacetate

In a solution of (S)-di-tert-butyl 2-((N-(3-((4-(2,3-bis(tert-butoxycarbonyl) guanidino)benzoyl)oxy)benzyl)-N-(tert-butoxycarbonyl )sulfamoyl)amino)succinate (351mg) prepared in the same manner as that described for Comparative Example 73-(a) in anhydrous dichloromethane (6mL) in a 50mL round bottom flask was added trifluoroacetic acid (2.00mL) with cooling in an ice bath under argon atmosphere with stirring, and the reaction mixture was stirred at room temperature for 16 hours. The reaction solution was evaporated under reduced pressure. To a solution of the resulting evaporation residue in anhydrous dichloromethane (6 ml) was added trifluoroacetic acid (2.00 ml) at room temperature under argon with stirring, and the resulting mixture was stirred at room temperature for 1 hour. After completion of the reaction, the solution was evaporated under reduced pressure. Saturated ammonium acetate aqueous solution was added to a solution of the resulting residue in a mixture of water (8 ml)/acetonitrile (2 ml), adjusting the pH to 4.0, and trifluoroacetic acid was added to the resulting suspension to obtain a solution. The resulting solution was purified by preparative medium pressure chromatography (ODS silica gel, elution solvent: water with 0.1% trifluoroacetic acid: acetonitrile with 0.1% trifluoroacetic acid), and fractions with the target compound were freeze-dried to give the title Compound (210 mg) in form of a white solid.

Mass spectrum (ESI, m/z): 480 [M+H] ⁺ .

Comparative Example 74-(b)

Preparation of (S)-2-((N-(4-((2-fluoro-4-guanidinobenzoyl)oxy)benzyl)sulfamoyl)amino)succinic acid

The title compound was prepared using Comparative Example 74-(a) in the same manner as Comparative Example 43-(b).

Mass spectrum (ESI, m/z): 498 [M+H] ⁺ .

Comparative Example 75-(b)

Preparation of (S)-2-((N-(4-((4-guanidino-2-methylbenzoyl)oxy)benzyl)sulfamoyl)amino)succinic acid

The title compound was prepared using Comparative Example 75-(a) in the same manner as Comparative Example 43-(b).

Mass spectrum (ESI, m/z): 494 [M+H] ⁺ .

Comparative Example 76-(b)

Preparation of (S)-2-((N-(2-carboxy-4-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl)amino)succinic acid

The title compound was prepared using Comparative Example 76-(a) in the same manner as Comparative Example 57-(b).

Mass spectrum (ESI, m/z): 524 [M+H] ⁺ .

Comparative Example 77-(b)

Preparation of (S)-2-((N-(2-(((S)-1,2-dicarboxyethyl)carbamoyl)-4-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl)amino)succinic acid trifluoroacetate

The title compound was prepared using Comparative Example 77-(a) in the same manner as Comparative Example 42-(b).

Mass spectrum (ESI, m/z): 639 [M+H] ⁺ .

Comparative Example 78-(b)

Preparation of 2-((N-(2-chloro-4-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl)amino)acetic acid

The title compound was prepared using Comparative Example 78-(a) in the same manner as Comparative Example 57-(b).

Mass spectrum (ESI, m/z): 456 [M+H] ⁺ .

Comparative Example 79-(b)

Preparation of 2-(((N-(carboxymethyl)sulfamoyl)amino)methyl)-5-((4-guanidinobenzoyl)oxy)benzoic acid

The title compound was prepared using Comparative Example 79-(a) in a similar manner to Comparative Example 57-(b).

Mass spectrum (ESI, m/z): 466 [M+H] ⁺ .

Comparative Example 80-(b)

Preparation of (S)-2-(2-(((N-(carboxymethyl)sulfamoyl)amino)methyl)-5-((4-guanidinobenzoyl)oxy)benzamide)succinic acid trifluoroacetate

The title compound was prepared using Comparative Example 80-(a) in the same manner as Comparative Example 42-(b).

Mass spectrum (ESI, m/z): 581 [M+H] ⁺ .

Comparative Example 81-(b)

Preparation of (S)-2-((N-((10-guanidino-13-oxo-6,7,8,13-tetrahydrodibenzo[b,f][1,4]dioxecin-4-yl)methyl)sulfamoyl) amino)succinic acid trifluoroacetate

In suspension (S)-2-((N-((10-amino-13-oxo-6,7,8,13-tetrahydrodibenzo[b,f] [1,4]dioxecin-4-yl)methyl)sulfamoyl )amino)succinic acid hydrochloride (1.46g) obtained in Comparative Example 19-(m)-2 in tert-butanol (1mL) in a 30mL round bottom flask was added 4M hydrogen chloride in cyclopentylmethyl ether (85µl) and cyanamide (17.5 mg) at room temperature under argon flow with stirring, and the reaction mixture was stirred at 50°C for 30 hours. After completion of the reaction, the solution was evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: acetonitrile with 0.1% trifluoroacetic acid: water with 0.1% trifluoroacetic acid), and fractions with the title compound were freeze-dried to give the title Compound (43.5 mg) as white solid.

Mass spectrum (ESI, m/z): 536 [M+H] ⁺ .

Comparative Example 82-(b)

Preparation of (S)-2-((N-((10-guanidino-13-oxo-6,7,8,13-tetrahydrodibenzo[b,f][1,4]dioxecin-3-yl)methyl)sulfamoyl) amino)succinic acid trifluoroacetate

The title compound was prepared using Comparative Example 19-(m)-3 in the same manner as Comparative Example 81-(b).

Mass spectrum (ESI, m/z): 536 [M+H] ⁺ .

Comparative Example 83-(b)

Preparation of (S)-2-((N-((10-guanidino-13-oxo-6,7,8,13-tetrahydrodibenzo[b,f][1,4]dioxecin-2-yl)methyl)sulfamoyl) amino)succinic acid trifluoroacetate

The title compound was prepared using Comparative Example 19-(m)-4 in the same manner as Comparative Example 81-(b).

Mass spectrum (ESI, m/z): 536 [M+H] ⁺ .

Comparative Example 84-(a)

Preparation of (4-(benzyloxy)-2-bromophenyl)methanol

Sodium borohydride (1.03 g) was added to a solution of 4-(benzyloxy)-2-bromobenzaldehyde (7.17 g) in an ethanol (35 ml)/tetrahydrofuran (35 ml) mixture in a 300 ml round bottom flask at 0°C under argon with stirring , and the reaction mixture was stirred at 0°C for 15 minutes. After completion of the reaction, water was added to the solution, and the resulting solution was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure to give the title Compound (7.06 g) as a white solid.

Mass spectrum (ESI, m/z): 291 [MH] ⁺ .

Comparative Example 84-(a)-2 was prepared in a similar manner to Comparative Example 84-(a).

Table 22

Comparative Example Connection name
Structural formula
mass spectrum 84-(a)-2

(ESI, m/z): 229 [M-H]⁺.2-(benzyloxy)-4-(hydroxymethyl)phenol

(ESI, m/z): 229 [MH] ⁺ .

Comparative Example 84-(b)

Preparation of ((4-(benzyloxy)-2-bromobenzyl)oxy)(tert-butyl)dimethylsilane

Imidazole (1.97 g) and t- butyldimethylchlorosilane (4.00 g) at room temperature under argon flow with stirring, and the reaction mixture was stirred at room temperature for 30 minutes. After completion of the reaction, water (70 ml) was added to the solution, and the resulting solution was extracted with tert-butyl methyl ether (70 ml). The organic layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (9.08 g) as a colorless foam.

Mass spectrum (ESI, m/z): 405 [MH] ⁺ .

Comparative Example 84-(b)-2-84-(b)-4 was prepared in a similar manner to Comparative Example 84-(b).

Table 23

Comparative Example Connection name
Structural formula 84-(b)-2

(ESI, m/z): 343 [M-H]⁺.2-(benzyloxy)-6-(((tert-butyldimethylsilyl)oxy)methyl)phenol

(ESI, m/z): 343 [MH] ⁺ . 84-(b)-3 2-(benzyloxy)-5-(((tert-butyldimethylsilyl)oxy)methyl)phenol

(ESI, m/z): 343 [MH] ⁺ . 84-(b)-4 2-(benzyloxy)-4-(((tert-butyldimethylsilyl)oxy)methyl)phenol

(ESI, m/z): 343 [MH] ⁺ .

Comparative Example 84-(c)

Preparation of tert-butyl 5-(benzyloxy)-2-(((tert-butyldimethylsilyl)oxy)methyl) benzoate

To a solution of ((4-(benzyloxy)-2-bromobenzyl)oxy)(tert-butyl)dimethylsilane (2.87 g) obtained in Comparative Example 84-(b) in tetrahydrofuran (30 ml) in a 300 ml three-necked flask was added dropwise n-butyl lithium (1.6 M solution in hexane) (5.28 ml) in a stream of argon with stirring so that the temperature does not exceed -60°C, and the reaction mixture was stirred at -70°C for 50 minutes. Then, a solution of di-tert-butyl dicarbonate (1.86 g) in tetrahydrofuran (10 ml) was added dropwise with stirring so that the temperature did not exceed -60°C, the resulting mixture was stirred at -70°C for 1 hour and at room temperature. temperature for 40 minutes. After completion of the reaction, a saturated ammonium chloride aqueous solution was added to the solution, and the resulting solution was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (1.13 g) as a colorless oil.

Mass spectrum (ESI, m/z): 451 [M+Na] ⁺ .

Comparative Example 84-(d)

Preparation of tert-butyl 2-(((tert-butyldimethylsilyl)oxy)methyl)-5-hydroxybenzoate

To a solution of tert-butyl 5-(benzyloxy)-2-(((tert-butyldimethylsilyl)oxy)methyl)benzoate (1.126 g) obtained in Comparative Example 84-(c) in ethyl acetate (12 ml) in a 100 ml BNA-5D (water content 52.97%, manufactured by NE CHEMCAT Corporation) (225 mg) was added to a round bottom flask at room temperature under argon flow with stirring, the reaction system was filled with hydrogen, and then the resulting mixture was stirred at room temperature for 30 minutes. After completion of the reaction, the solution was filtered through celite, washed with ethyl acetate, and the filtrate was evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (500 mg) as a colorless oil.

Mass spectrum (CI, m/z): 339 [M+H] ⁺ .

Comparative Example 85-(a)

Preparation of 5-(benzyloxy)-2-(((tert-butyldimethylsilyl)oxy)methyl)benzoic acid

To a solution of ((4-(benzyloxy)-2-bromobenzyl)oxy)(tert-butyl)dimethylsilane (3.00 g) obtained in Comparative Example 84-(b) in tetrahydrofuran (30 ml) in a 300 ml three-necked flask was added dropwise n-butyl lithium (1.6 M solution in hexane) (5.06 ml) in a stream of argon with stirring so that the temperature does not exceed -60°C, and the resulting mixture was stirred at -70°C for 30 minutes. Dry ice (32.4 g) was then added with stirring at -70°C, the mixture was stirred at -70°C for 1 hour and at room temperature for 30 minutes. After completion of the reaction, water was added to the solution, then 1N. hydrochloric acid solution, adjusting the pH to 2, and the resulting solution was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (DIOL silica gel, elution solvent: hexane:ethyl acetate). Hexane (30 ml) was added to the evaporation residue, the mixture was stirred at room temperature, the precipitate formed was filtered off and dried under reduced pressure to give the title Compound (750 mg) as a white solid.

Mass spectrum (ESI, m/z): 371 [MH] ⁺ .

Comparative Example 85-(b)

Preparation of (S)-di-tert-butyl 2-(5-(benzyloxy)-2-(((tert-butyldimethylsilyl)oxy)methyl)benzamide)succinate

(1) To a solution of ((4-(benzyloxy)-2-bromobenzyl)oxy)(tert-butyl)dimethylsilane (48 mg) obtained in Comparative Example 85-(a) in dimethylformamide (500 µl) in a 300 ml di-tert-butyl ester of L-aspartic acid hydrochloride (43.3 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (30.8 mg), 1-hydroxybenzotriazole (20.1 mg) and N,N-diisopropylethylamine ( 26 μl) at room temperature under argon flow with stirring, and the resulting mixture was stirred at room temperature for 2 hours.

(2) To a solution of ((4-(benzyloxy)-2-bromobenzyl)oxy)(tert-butyl)dimethylsilane (500 mg) obtained in Comparative Example 85-(a) in dimethylformamide (5 ml) in a 50 ml L-aspartic acid tert-butyl ester dihydrochloride (418 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (271.5 mg), 1-hydroxybenzotriazole (191 mg), and N,N-diisopropylethylamine ( 257 μl) at room temperature under argon flow with stirring, and the resulting mixture was stirred at room temperature for 3 hours.

The reaction solution from (1) and the reaction solution from (2) were combined, water was added, and the resulting solution was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (618.9 mg) as a colorless oil.

Mass spectrum (CI, m/z): 600 [M+H] ⁺ .

Comparative Example 85-(c)

Preparation of (S)-di-tert-butyl 2-(2-(((tert-butyldimethylsilyl)oxy)methyl)-5-hydroxybenzamide)succinate

The title compound was prepared using Comparative Example 85-(b) in the same manner as Comparative Example 84-(d).

Mass spectrum (CI, m/z): 510 [M+H] ⁺ .

Comparative Example 86-(a)

Preparation of (S)-di-tert-butyl 2-(N-methyl-2-nitrophenylsulfonamide)succinate

To a solution of (S)-di-tert-butyl 2-(2-nitrophenylsulfonamide)succinate (503.1 mg) obtained in the same manner as described for Comparative Example 1-(a) in dimethylformamide (2.5 ml) in 30 potassium carbonate (324 mg) and iodomethane (291 μl) were added to a milliliter cylindrical flask at room temperature under argon with stirring, and the reaction mixture was stirred at room temperature for 1.5 hours. After completion of the reaction, water was added to the solution, and the resulting solution was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (522.4 mg) as a colorless foam.

Mass spectrum (ESI, m/z): 467 [M+Na] ⁺ .

Comparative Example 86-(b)

Obtaining (S)-di-tert-butyl 2-(methylamino)succinate

The title compound was prepared using Comparative Example 86-(a) in the same manner as Comparative Example 1-(c).

Mass spectrum (ESI, m/z): 260 [M+H] ⁺ .

Comparative Example 87-(a)

Preparation of (S)-dibenzyl 2-(3-hydroxybenzamide)succinate

(1) To a solution of 3-((tert-butyldimethylsilyl)oxy)benzoic acid in anhydrous dimethylformamide (5 ml) in a 20 ml two-necked flask was added N,N-diisopropylethylamine (390 µl) and COMU (467.2 mg) at 0°C in a stream of argon with stirring, and the reaction mixture was stirred at 0°C for 40 minutes. Then (S)-dibenzyl 2-aminosuccinate hydrochloride (350.1 mg) was added at 0°C and the mixture was stirred at room temperature for 6 hours. After completion of the reaction, the solution was poured into cold water (20 ml) and the resulting solution was extracted with toluene (50 ml). The organic layer was washed with water (20 ml) and saturated aqueous sodium chloride solution (20 ml), dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate) to give (S)-dibenzyl 2-(3-((tert-butyldimethylsilyl)oxy)benzamide)succinate (302.9 mg) as light rose oil.

Tetrabutylammonium fluoride (1.0M solution in tetrahydrofuran ) (235 μl) at 0°C under argon flow with stirring, and the reaction mixture was stirred at room temperature for 16 hours.

(2) To a solution of 3-((tert-butyldimethylsilyl)oxy)benzoic acid (252.2 mg) in anhydrous dimethylformamide (5 ml) in a 20 ml two-necked flask was added (S)-dibenzyl 2-aminosuccinate hydrochloride (367.4 mg) and N ,N-diisopropylethylamine (345 µl) at 0°C under argon with stirring. Then 1-hydroxybenzotriazole (148.3 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (211.2 mg) were added at 0°C, and the reaction mixture was stirred at room temperature for 18 hours. After completion of the reaction, the solution was poured into water (20 ml) and the resulting solution was extracted with toluene (50 ml). The organic layer was washed with water (20 ml) and saturated aqueous sodium chloride solution (20 ml), dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure.

Tetrabutylammonium fluoride (1.0 M solution in tetrahydrofuran) (1.5 ml) was added to a solution of the residue obtained from evaporation in anhydrous tetrahydrofuran (10 ml) in a 100-ml round-bottom flask at 0°C in a stream of argon with stirring, the resulting mixture was stirred at 0°C for 30 minutes and at room temperature for 1 hour.

The reaction solution from (1) and the reaction solution from (2) were combined, poured into a saturated ammonium chloride aqueous solution (20 ml), and the resulting solution was extracted with ethyl acetate (50 ml). The organic layer was washed with saturated sodium chloride solution (20 ml), dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (580.5 mg) as a colorless oil.

Mass spectrum (ESI, m/z): 434 [M+H] ⁺ .

Comparative Example 87-(b)

Preparation of (S)-dibenzyl 2-(3-((4-nitrobenzoyl)oxy)benzamide)succinate

N,N-diisopropylethylamine ( 350 μl) and 4-nitrobenzoyl chloride (227.2 mg) at 0°C under argon flow with stirring, the resulting mixture was stirred at 0°C for 30 minutes and at room temperature for 30 minutes. After completion of the reaction, the solution was poured into water (20 ml) and the solution was extracted with dichloromethane (50 ml). The organic layer was washed with saturated aqueous sodium chloride (20 ml), dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (561.7 mg) as a yellowish oil.

Mass spectrum (ESI, m/z): 583 [M+H] ⁺ .

Comparative Example 87-(c)

Preparation of (S)-2-(3-((4-aminobenzoyl)oxy)benzamide)succinic acid

To a solution of (S)-dibenzyl 2-(3-((4-nitrobenzoyl)oxy)benzamide)succinate (557.8 mg) obtained in Comparative Example 87-(b) in ethanol (7.5 ml)/tetrahydrofuran (7.5 ml ) in a 200 ml round bottom flask was added 5% palladium on carbon (containing 48.57% water, AER-type manufactured by NE CHEMCAT Corporation) (56.2 mg) at room temperature, the reaction system was filled with hydrogen, and then the resulting mixture was stirred at room temperature for 8 ocloc'k. After completion of the reaction, the solution was filtered through Celite, washed with tetrahydrofuran, and the filtrate was evaporated under reduced pressure to give the title Compound (369.3 mg) as a slightly yellow solid.

Mass spectrum (ESI, m/z): 373 [M+H] ⁺ .

Comparative Example 87-(d)

Preparation of (S)-2-(3-((4-guanidinobenzoyl)oxy)benzamide)succinic acid

(1) To a suspension of (S)-2-(3-((4-aminobenzoyl)oxy)benzamide)succinic acid (63.5 mg) prepared in the same manner as that described for Comparative Example 87-(c) in tert -butanol (1.0 ml) in a 30 ml cylindrical flask was added cyanamide (21.9 mg) and a 4M solution of hydrogen chloride in dioxane (130 μl) at room temperature in a stream of argon with stirring, and the resulting mixture was stirred at 60°C for 4 hours.

(2) To a suspension of (S)-2-(3-((4-aminobenzoyl)oxy)benzamide)succinic acid (365.4 mg) obtained in Comparative Example 87-(c) in tert-butanol (5.0 ml) in Cyanamide (124.3 mg) and 4M hydrogen chloride in dioxane (735 µl) were added to a 50 ml round bottom flask at room temperature under argon flow with stirring, the reaction mixture was stirred at 60°C for 4 hours and at room temperature for 16 hours.

The reaction solution from (1) and the reaction solution from (2) were combined, toluene (30 ml) was added, and the resulting solution was extracted with water (20 ml). The organic layer was extracted with water (10 ml). The aqueous layers were combined and filtered. A 10% aqueous solution of ammonium acetate was added to the filtrate, bringing the pH value to 4.0. The resulting mixture was stirred at room temperature for 2 hours, the precipitate formed was filtered off and dried under reduced pressure to give the title Compound (457.1 mg) as an off-white solid.

Mass spectrum (ESI, m/z): 415 [M+H] ⁺ .

Comparative Example 88-(a)

Preparation of (S)-3-(benzyloxy)-5-((10-(2,3-bis(tert-butoxycarbonyl)guanidino)-N-(1,4-di-tert-butoxy-1,4-dioxobutan- 2-yl)-13-oxo-6,7,8,13-tetrahydrodibenzo[b,f][1,4]dioxecine-4-carboxamide)methyl)benzoic acid

In a solution of (S)-di-tert-butyl 2-(N-(3-(benzyloxy)-5-((2-(trimethylsilyl) ethoxy)carbonyl)benzyl)-10-(2,3-bis(tert- butoxycarbonyl)guanidino)-13-oxo-6,7,8,13-tetrahydrodibenzo[b,f][1,4]dioxecin-4-carboxamide)succinate (200.0 mg) obtained by the same procedure as described for Comparative example 29-(e), in anhydrous tetrahydrofuran (5 ml) in a 20 ml cylindrical flask was added tetrabutylammonium fluoride (1.0M solution in tetrahydrofuran) (0.55 ml) at room temperature in an argon atmosphere with stirring, and the reaction mixture was stirred at room temperature within 20 hours. After completion of the reaction, toluene (5 ml) was added to the solution, the resulting mixture was washed with saturated aqueous ammonium chloride solution (5 ml) twice, with water (5 ml) and with saturated sodium chloride solution (5 ml), dried over anhydrous magnesium sulfate, filtered, and evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure chromatography (DIOL silica gel, elution solvent: hexane:ethyl acetate) to give the title Compound (110.2 mg) as a light brown foam.

Mass spectrum (ESI, m/z): 1023 [M+H] ⁺ .

Comparative Example 88-(b)

Preparation of (S)-2-(N-(3-(benzyloxy)-5-carboxybenzyl)-10-guanidino-13-oxo-6,7,8,13-tetrahydrodibenzo[b,f][1,4]dioxecine -4-carboxamide)succinic acid hydrochloride

K (S)-3-(benzyloxy)-5-((10-(2,3-bis(tert-butoxycarbonyl)guanidino)-N-(1,4-di-tert-butoxy-1,4-dioxobutan- 2-yl)-13-oxo-6,7,8,13-tetrahydrodibenzo[b,f][1,4]dioxecin-4-carboxamide)methyl)benzoic acid (104.4 mg) obtained in Comparative Example 88-( a), in a 30 ml pear-shaped flask, a 4M solution of hydrogen chloride in dioxane (2 ml) was added at room temperature under nitrogen with stirring, and the reaction mixture was stirred at room temperature for 23 hours. After completion of the reaction, diethyl ether was added to the solution, and the resulting mixture was evaporated under reduced pressure. This evaporation under reduced pressure was repeated twice. Diethyl ether was added to the evaporation residue, and the resulting mixture was kept in an ultrasonic bath. The solid was filtered off and dried under reduced pressure to give the title Compound (72.3 mg) as a beige solid.

Mass spectrum (DUIS, m/z): 711 [M+H] ⁺ .

Comparative Example 88-(c)

Preparation of (S)-2-(N-(3-carboxy-5-hydroxybenzyl)-10-guanidino-13-oxo-6,7,8,13-tetrahydrodibenzo[b,f][1,4]dioxetin-4 -carboxamide)succinic acid hydrochloride

To a solution of (S)-2-(N-(3-(benzyloxy)-5-carboxybenzyl)-10-guanidino-13-oxo-6,7,8,13-tetrahydrodibenzo[b,f][1,4] dioxecine-4-carboxamide)succinic acid hydrochloride (69.9 mg) obtained in Comparative Example 88-(b) in ethanol (2 ml)/tetrahydrofuran (1 ml) in a 30 ml cylindrical flask was added ASCA-2 (water content 52%, manufactured by NE CHEMCAT Corporation) (77.6 mg) at room temperature under nitrogen atmosphere, the reaction system was filled with hydrogen, and then the resulting mixture was stirred at room temperature for 2 hours. After completion of the reaction, the solution was filtered through Celite, washed with ethanol, and the resulting filtrate was evaporated under reduced pressure. Diethyl ether was added to the evaporation residue, the mixture was kept in an ultrasonic bath and stirred at room temperature for 1 hour. The solid was filtered off and dried under reduced pressure to give the title Compound (51.1 mg) as a white solid.

Mass spectrum (DUIS, m/z): 621 [M+H] ⁺ .

Examples of pharmacological tests

(Test Example 1): Human Enteropeptidase Inhibition

Recombinant human enteropeptidase (manufactured by BIO Vision Inc., catalog number: 7529-50) was diluted with assay buffer (50 mM tricine (pH8.0), 0.01 w/v% Tween 20, 10 mM CaCl ₂ ) to give an enzyme solution with concentration of 8 ng/ml. Then 5FAM-Abu-Gly-Asp-Asp-Lys-Ile-Val-Gly-Gly-Lys(CPQ2)-Lys-Lys-NH ₂ (manufactured by CHINESE PEPTIDE COMPANY, purity: 94.5%) was added and diluted with assay buffer to obtain a 1.5 μM substrate solution. Each test compound was dissolved in DMSO, then diluted with assay buffer 100-fold, and diluted with the correct amount of assay buffer containing 1% DMSO to give a solution of each compound. 10 µl of compound solution, 15 µl of assay buffer and 50 µl of substrate solution were added to a 96-well black plate (manufactured by Thermo Fisher Scientific Inc., code no.: 9502867), mixed, then 25 µl of enzyme solution was added and mixed by initiating start of the reaction. Fluorescence intensity at length was measured at an excitation wavelength of 485 nm and a florescence wavelength of 535 nm using a fluorescence plate reader (Flex station 3) (Study Compound Addition Group). In addition, reactions were carried out similar to those described above, but without addition of test compound (Group without addition of test compound). Additionally, reactions were carried out similar to those described above, but without the addition of the test compound and enzyme (Control group). The inhibition coefficient was calculated according to the equation below from the fluorescence intensity 20 minutes after the start of the reaction.

Inhibition Ratio (%) = (1-(fluorescence intensity in the Test Compound Added Group-fluorescence intensity in the Control Group) ÷ (fluorescence intensity in the Group without test compound added-fluorescence intensity in the Control Group)) × 100

In the present test, each compound of the present invention showed excellent enteropeptidase inhibitory activity. For example, all compounds from Examples 1-(b), 2-(b), 3-(b), 4-(b), 5-(b), 6-(b), 7-(b), 8- (b), 9-(b), 10-(b), 11-(b), 12-(c), 13-(b), 14-(b), 15-(b), 16-(b ), 17-(b), 18-(b), 19-(b), 20-(b), 21-(b), 23-(c), 24-(a), 25-(b), 27-(b), 28-(c), 29-(c) and 30-(a) showed an inhibition ratio of 50% or more at a compound concentration of 100 nM, all compounds from Examples 1-(b), 2-(b ), 3-(b), 4-(b), 5-(b), 6-(b), 7-(b), 8-(b), 9-(b), 10-(b), 11-(b), 12-(c), 13-(b), 14-(b), 15-(b), 16-(b), 17-(b), 18-(b), 19- (b), 20-(b), 21-(b), 22-(a), 23-(c), 24-(a), 25-(b), 26-(b), 27-(b ), 28-(c), 29-(c) and 30-(a) also showed an inhibition ratio of 50% or more at a compound concentration of 10 nM, and all compounds from Examples 1-(b), 2-(b), 3-(b), 7-(b), 8-(b), 9-(b), 15-(b), 19-(b), 20-(b), 21-(b), 22- (a), 25-(b), 26-(b), 27-(b), 28-(c), 29-(c), and 30-(a) also showed an inhibition ratio of 50% or more at compound concentration 1 nM.

In addition, each monomeric compound constituting each two-headed compound of the present invention, namely, each compound corresponding to A ¹ or A ² in Compound (I), also showed excellent enteropeptidase inhibitory activity. For example, all compounds from Comparative Examples 31-(b), 41-(b), 49-(b), 52-(b), 55-(b), 73-(b) and 87-(d) showed a coefficient inhibition of 50% or more at a compound concentration of 100 nM.

(Test Example 2): Human Trypsin Inhibition

Recombinant human trypsin (manufactured by Wako Pure Chemical Industries, Ltd., code no.: 206-17171) was diluted with assay buffer (0.1 M Tris-HCl (pH8.0), 0.15 M NaCl, 10 mM CaCl ₂ , 0.05% Brij35 ) to give an enzyme solution at a concentration of 10 ng/mL. Boc-Phe-Ser-Arg-MCA (manufactured by PEPTIDE INSTITUTE, INC., code no.: 3107-v) was then added and diluted with assay buffer to obtain a 40 μM substrate solution. Each test compound was dissolved in DMSO, then diluted with assay buffer 100-fold, and diluted with the correct amount of assay buffer containing 1% DMSO to give a solution of each compound. 10 µl of compound solution, 15 µl of assay buffer and 50 µl of substrate solution were added to a 96-well black plate (manufactured by Thermo Fisher Scientific Inc., code no.: 9502867), mixed, then 25 µl of enzyme solution was added and mixed by initiating start of the reaction. Fluorescence intensity at length was measured at an excitation wavelength of 355 nm and a florescence wavelength of 460 nm using a fluorescence plate reader (Flex station 3) (Study Compound Addition Group). In addition, reactions were carried out similar to those described above, but without addition of test compound (Group without addition of test compound). Additionally, reactions were carried out similar to those described above, but without the addition of the test compound and enzyme (Control group). The inhibition coefficient was calculated according to the equation below from the fluorescence intensity 20 minutes after the start of the reaction.

Inhibition Ratio (%) = (1-(fluorescence intensity in the Test Compound Added Group-fluorescence intensity in the Control Group) ÷ (fluorescence intensity in the Group without test compound added-fluorescence intensity in the Control Group)) × 100

In this test, each compound of the present invention showed excellent trypsin inhibitory activity. For example, all compounds from Examples 1-(b), 2-(b), 3-(b), 4-(b), 5-(b), 6-(b), 7-(b), 8- (b), 9-(b), 10-(b), 11-(b), 12-(c), 13-(b), 14-(b), 15-(b), 16-(b ), 17-(b), 18-(b), 19-(b), 20-(b), 21-(b), 22-(a), 23-(c), 24-(a), 25-(b), 27-(b), 28-(c), 29-(c) and 30-(a) showed an inhibition ratio of 50% or more at a compound concentration of 100 nM, all compounds from Examples 1-(b ), 2-(b), 3-(b), 4-(b), 5-(b), 6-(b), 7-(b), 8-(b), 9-(b), 10-(b), 11-(b), 12-(c), 13-(b), 14-(b), 15-(b), 16-(b), 17-(b), 18- (b), 19-(b), 20-(b), 21-(b), 22-(a), 23-(c), 24-(a), 25-(b), 26-(b ), 27-(b), 28-(c) and 30-(a) also showed an inhibition ratio of 50% or more at a compound concentration of 10 nM, and all compounds from Examples 1-(b), 2-(b), 3-(b), 5-(b), 7-(b), 8-(b), 9-(b), 12-(c), 14-(b), 17-(b), 18- (b), 19-(b), 20-(b), 22-(a), 23-(c), 24-(a), 26-(b) and 30-(a) also showed an inhibition coefficient of 50 % or more at a compound concentration of 1 nM.

In addition, each monomeric compound constituting each two-headed compound of the present invention, namely, each compound corresponding to A ¹ or A ² in Compound (I), also showed excellent trypsin-inhibiting activity. For example, all compounds from Comparative Examples 31-(b), 41-(b), 49-(b), 52-(b), 55-(b), 73-(b) and 87-(d) showed a coefficient inhibition of 50% or more at a compound concentration of 100 nM.

(Test Example 3): Increase in Fecal Protein Concentration at Single Administration to Mice on a High Fat Diet

Mice on a high fat diet (D-12492 diet, male, ICR, 6 weeks of age) were orally administered with a 0.5 w/v% methylcellulose suspension containing each test compound (Compound Administration Group, 4 or 5 mice per group), or 0.5 w/v% methylcellulose suspension (Group without compound administration, 5, 6, or 7 mice per group) and all faeces from the day were collected. Dried faeces were dissolved in 0.5N. aqueous sodium hydroxide solution, then centrifuged at 3500 rpm. Then, the protein concentration in the supernatant was determined (Lowry's method), and the faecal protein concentration increase factor was calculated according to the equation below from the protein concentration in 1 g feces (mg/g feces).

Faecal Protein Concentration Elevation Factor = (Mean Fecal Protein Concentration for the Compound Treatment Group) ÷ (Mean Fecal Protein Concentration for the No Compound Group)

In this test, each compound of the present invention showed an excellent effect of increasing fecal protein concentration. For example, an increase in fecal protein concentration of 1.3 or more times was shown by the compound of Example 4-(b) at a dosage of 100 mg/kg, the compound of Example 17-(b) at a dosage of 91 mg/kg, the compound of Example 14-( b) at a dosage of 89 mg/kg, the compound from Example 18-(b) at a dosage of 87 mg/kg, the compound from Example 2-(b) at a dosage of 86 mg/kg, the compound from Example 10-(b) at a dosage of 79 mg/kg, all compounds from Examples 26-(b), 27-(b), 28-(c) and 29-(c) at a dosage of 50 mg/kg, and all compounds from Examples 1-(b), 2 -(c), 3-(b), 5-(b), 6-(b), 7-(b), 8-(c), 9-(b), 12-(c), 13-( b), 19-(b), 20-(b) and 21-(b) at 30 mg/kg.

(Test Example 4): Anti-Obesity Action in Dietary Obese Mice

Nutritionally obese mice (D-12492 diet, male, C57BL-DIO, 26-28 weeks of age) were orally administered a 0.5 w/v% methylcellulose suspension containing each test compound (Compound Administration Group, 5 or 6 mice per group), or 0.5 w/v% methylcellulose suspension (No compound group, 6 mice per group) n once a day for 2 weeks. The weight loss coefficient was calculated according to the following equation.

Weight Loss Rate (%) for each Compound Treatment Group = (1 - Average Last Test Day Weight for each Compound Treatment Group/Average Last Test Day Weight for No Compound Group) × 100

In this test, each compound of the present invention showed an anti-obesity effect. For example, a weight loss ratio of 4% or more was shown by all compounds of Examples 3-(c), 5-(c), 6-(c), 7-(b), 8-(b) and 9-(b) in 100 mg/kg, all compounds from Examples 12-(b), 14-(b) and 18-(b) at 90 mg/kg, compound from Example 17-(b) at 88 mg/kg, compound from Example 10-(b) at a dosage of 87 mg/kg, the compound from Example 4-(b) at a dosage of 86 mg/kg, all compounds from Examples 20-(d), 24-(a), 25-(b) , 26-(b), 27-(b), 28-(c) and 29-(c) at 50 mg/kg, all compounds from Examples 1-(b), 2-(c) and 19-( b) at a dosage of 30 mg/kg, and all compounds from Examples 20-(b) and 21-(b) at a dosage of 25 mg/kg.

(Test Example 5): Pharmacokinetic Study (Plasma Concentration after Compound Oral Administration)

Each test compound was suspended in a 0.5 w/v% methylcellulose 400 solution and the resulting suspension was orally administered to 7-8 week old male SD rats (weight: 180 to 250 g). At 0.25, 0.5, 1, 2, 4, 8 and 24 hours after the administration of each test compound, blood was collected (blood with the addition of EDTA) from the jugular vein under isoflurane inhalation anesthesia. The blood samples were centrifuged at 4°C and 6000 g for 10 minutes, obtaining the plasma of each blood sample. Acetonitrile, a mixture of acetonitrile and water (1:1 (v/v)) or a mixture of acetonitrile and 0.1M hydrochloric acid solution (1:1 (v/v)) were added to the resulting plasma, then the mixture was stirred at 750 rpm for 3 minutes in a shaker and subjected to separation in a centrifuge at 3700 rpm for 2 minutes to separate proteins. The resulting sample was analyzed by LC (liquid chromatography)/MS (mass spectrometry) under the following conditions.

The plasma concentration of each compound at each time point of blood sampling was calculated according to the internal standard method, and the area under the plasma concentration-time curve (AUCall (area under the curve)) was calculated using the trapezoidal method.

The following LC and MS systems were used in this test.

LC: HPLC system LC20 or LC30 manufactured by Shimadzu Corporation

Column: Phenomenex Kinetex C18 (50 x 2.1 mm, 2.6 µm)

Column temperature: 40°C

Flow rate: 0.3 ml/min

Mobile phase A: water with 0.1% formic acid, Mobile phase B: 50% acetonitrile/methanol solution with 0.1% formic acid

Gradient: 0-2 min: A/B = 90/10 → 10/90; 2-3 min: A/B = 10/90; 3-3.01 min: A/B = 10/90 → 90/10.

MS: Q-Trap3200 manufactured by SCIEX

Ionization: ESI

Mode: Positively charged ions

In this test, each compound of the present invention showed a very low blood concentration. For example, an AUCall of 100 ng⋅h/mL or less for the compound of Example 10-(b) at a dosage of 8 mg/kg, for all compounds of Examples 11-(b), 12-(c), 15-(b), 16-(b), 17-(b) and 18-(b) at a dosage of 9 mg/kg, for all compounds from Examples 2-(c), 3-(c), 4-(b), 5-( c), 6-(c), 7-(b), 8-(b), 9-(b), 13-(b), 19-(b), 20-(c), 21-(c) , 26-(b), 28-(c), 29-(c) and 30-(a) at a dosage of 10 mg/kg, and for the compound of Example 1-(b) at a dosage of 100 mg/kg.

(Test example 6): Stability test in solution 1 for disintegration test (pH 1.2) and in solution 2 for disintegration test (pH 6.8)

A 1 mM solution of each test compound in DMSO was added to disintegration test solution 1 (pH 1.2) or to disintegration test solution 2 (pH 6.8) so that the final concentration was 10 μM, and the stability test was started. A sample of the solution was taken immediately after the start of the test, then after 20 minutes and 1 hour after the start of the test, 3 times the volume of acetonitrile was added and the resulting solution was stirred. The sample thus prepared was examined by LC (liquid chromatography)/UV (ultraviolet absorption) under the conditions described below.

The peak area of the test compound immediately after the start of the test was taken as the residual content of 100%, and the remaining values of the residual content (%) were calculated as the ratio of the peak area of the test compound after 20 minutes or 1 hour after the start of the test to the peak area of the test compound immediately after the start of the test.

The following LC and UV systems were used in this test.

LC: HPLC system LC20 or LC30 manufactured by Shimadzu Corporation

Column: Phenomenex Kinetex C18 (100 x 2.1 mm, 2.6 µm)

Column temperature: 40°C

Flow rate: 0.25 ml/min

Mobile phase A: water with 0.1% formic acid, Mobile phase B: 50% acetonitrile/methanol solution with 0.1% formic acid

Gradient: 0-3 min: A/B = 90/10; 3-11 min: A/B = 90/10 × 5/95; 11-15 min: A/B = 5/95, 15-15.1 min: A/B = 5/95 → 90/10.

Detector Wavelength: 200-350nM

UV Analyzer Wavelength: 265nM

In this test, each compound of the present invention showed excellent stability in Disintegration Test Solution 1 (pH 1.2) and Disintegration Test Solution 2 (pH 6.8). For example, a residual content of 95% or more after 20 minutes was shown by all compounds from Examples 5-(b) and 9-(b), and a residual content by 95% or more after 1 hour was shown by all compounds from Examples 22-(a) and 27 -(b).

(Test Example 7): Stability Test in Small Intestine Contents of DIO Mice

Mice (D-12492 diet, male, C57BL-DIO, 28-30 weeks of age) fed in a similar manner to the anti-obesity test of DIO mice in Test Example 4 were laparotomized under isoflurane inhalation anesthesia and the contents of the small intestine were collected. Fluid extruded from the contents of the small intestine was used as a source of enzymes (undiluted solution of the contents of the small intestine) to determine the stability of each test compound.

A 10-fold volume of distilled water was added to the resulting undiluted solution of the contents of the small intestine, the resulting mixture was placed in a tube (MatrixD) for the FastPrep-24 instrument (MP Biomedicals) and processed in the FastPrep-24 instrument (rotation speed: 6.5, 30 seconds), obtaining suspension of the contents of the small intestine. A 1 mM solution of each test compound in DMSO was added to a suspension of the contents of the small intestine heated to 37° C. so that the final concentration was 10 μM, and the stability test was started. Incubated at 37°C. A sample of the solution was taken immediately after the start of the test and 20 minutes after the start of the test, a 3-fold volume of acetonitrile, a mixture of acetonitrile/methanol (1/1) or a mixture of acetonitrile/distilled water (1/1) was added, the resulting mixture was stirred, centrifuged at 13300 rpm for 3 minutes (table centrifuge manufactured by Labnet International, Inc.) and then filtered through a syringe filter (GL Chromatodisc 0.2 μm 13P, GL Sciences Inc.). The resulting filtered samples were analyzed by LC (liquid chromatography)/UV (ultraviolet absorption) under the conditions described below.

The peak area of the test compound immediately after the start of the test was taken as the residual content of 100%, and the remaining values of the residual content (%) were calculated as the ratio of the peak area of the test compound 20 minutes after the start of the test to the peak area of the test compound immediately after the start of the test.

The following LC/UV systems were used in this test.

HPLC system LC20 or LC30 manufactured by Shimadzu Corporation

Column: Phenomenex Kinetex C18 (100 x 2.1 mm, 2.6 µm)

Column temperature: 40°C

Flow rate: 0.25 ml/min

Mobile phase A: water with 0.1% formic acid, Mobile phase B: 50% acetonitrile/methanol solution with 0.1% formic acid

Gradient: 0-3 min: A/B = 90/10; 3-11 min: A/B = 90/10 → 5/95; 11-15 min: A/B = 5/95, 15-15.1 min: A/B = 5/95 → 90/10.

Detector Wavelength: 200-350nM

UV Analyzer Wavelength: 265nM

In this test, each compound of the present invention confirmed its excellent metabolic stability.

Industrial Applicability

The compound having the general formula (I) or pharmaceutically acceptable salts thereof of the present invention has excellent enteropeptidase inhibitory activity and/or excellent trypsin inhibitory activity, and has pharmacokinetic properties to effectively inhibit enteropeptidase and/or trypsin in the intestine after oral administration. and are present in the blood in very small quantities. According to the present invention, drugs can be obtained that have a high degree of safety with less pronounced side effects caused by blood levels of compounds, and can be used as agents for the prevention, mitigation and/or treatment of various diseases such as obesity by inhibition of enteropeptidase and/or trypsin inhibition.

Claims (380)

1. A compound having the general formula (I) shown below, or a pharmaceutically acceptable salt thereof:

where: A ¹ and A ² are each independently an inhibitor residue having at least one activity selected from an enteropeptidase inhibitory activity and a trypsin inhibitory activity; and Z is a bridge that connects A ¹ to A ² and means a single bond, C ₆ -C ₁₂ arylene group, -(CH ₂ -CH ₂ -O) _m -CH ₂ -CH ₂ -, -(CH ₂ - O-CH ₂ ) _m -, -(CH ₂ ) _m -(C ₆ -C ₁₂ arylene)-(CH ₂ ) _m - or -(CH ₂ ) _n -; m is an integer from 1 to 6; and n is an integer from 2 to 12; A ¹ has the structure represented by the formula

or

; A ² has the structure represented by the formula

or

, where: R ¹ each independently represents a hydrogen atom or -COO-(C ₁ -C ₄ alkyl group); W ¹ and W ² are each independently a single bond or a C ₁ -C ₄ alkylene group; X ¹ is -C(=O)-, -OC(=O)- or -NG ¹¹ -SO ₂ -; X ^1' is -NG ^Z -SO ₂ -; X ² is -C(=O)-, -C(=O)-O- or -SO ₂ -NG ¹² -; X ^2' is -SO ₂ -NG ^Z -; G ¹¹ and G ¹² are each independently a hydrogen atom, a C ₁ -C ₄ alkyl group, or —COOR ² ; G ^Z is a single bond that connects X ^1' or X ^2' to Z; R ² is a C ₁ -C ₄ alkyl group optionally substituted with 1-5 aryl groups; Y ¹ is -NG ²¹ -, -NG ²¹ -L ¹¹ -C(=O)-, -NG ²¹ -L ¹¹ -C(=O)-NH-, -NG ²¹ -L ¹¹ -C(=O)-NG ³¹ -L ²¹ -C(=O)-, -NG ²¹ -L ¹¹ -C(=O)-NG ³¹ -L ²¹ -C(=O) -NH-, -NG ²¹ -L ³ -O- or -NG ²¹ -G ^4' -; Y ^1' is -NG ²¹ H, -NG ²¹ -L ¹¹ -COOH or -NG ²¹ -L ¹¹ -C(=O)-NG ³¹ -L ²¹ -COOH; Y ² is -NG ²² -, -C(=O)-L ¹² -NG ²² -, -NH-C(=O)-L ¹² -NG ²² -, -C(=O)-L ²² -NG ³² -C(=O)-L ¹² -NG ²² -, -NH-C(=O)-L ²² -NG ³² -C(=O)-L ¹² - NG ²² -, -OL ³ -NG ²² - or -G ^4' -NG ²² -; Y ^2' is HNG ²² -, HOOC-L ¹² -NG ²² - or HOOC-L ²² -NG ³² -C(=O) -L ¹² -NG ²² -; G ²¹ , G ³¹ , G ²² and G ³² are each independently a hydrogen atom or a C ₁ -C ₆ alkyl group optionally substituted with 1-5 substituents independently selected from the group consisting of a phenyl group optionally substituted with 1-5 -COOR ³ groups, and -COOR ³ groups; G ^4' represents a C ₁ -C ₄ alkylene group or a C ₁ -C ₄ alkyleneoxy-C ₁ -C ₄ alkylene group; R ³ each independently represents a hydrogen atom or a C ₁ -C ₄ alkyl group optionally substituted with 1-5 aryl groups; L ¹¹ , L ²¹ , L ¹² and L ²² are each independently a C ₁ -C ₆ alkylene group optionally substituted with 1-5 C ₁ -C ₆ alkyl groups optionally substituted with 1-5 -COOR ⁴ groups, C ₁ -C ₄ alkylene-phenylene group or phenylene-C ₁ -C ₄ alkylene group; L ³ represents a C ₁ -C ₄ alkylene-phenylene group, where the phenylene fragment is optionally substituted with 1-3 -COOR ⁴ groups; R ⁴ each independently represents a hydrogen atom or a C ₁ -C ₄ alkyl group optionally substituted with 1-5 substituents independently selected from the group consisting of an aryl group and a trimethylsilyl group; R ⁵ and R ⁶ are each independently a hydrogen atom, a halogen atom, a C ₁ -C ₄ alkyl group, or a C ₁ -C ₄ alkoxy group; s and t are each independently an integer from 1 to 4; two or more R ⁵ and/or two or more R ⁶ may be the same or different from each other; or any of R ⁵ and any of R ⁶ may be combined with each other to form a C ₁ -C ₄ alkyleneoxy group; and symbol

means the point of attachment to Z. 2. The compound according to p. 1 or its pharmaceutically acceptable salt, where A ¹ has the structure represented by the formula

or

, and A ² has the structure represented by the formula

or

. 3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, where A ¹ has the structure represented by the formula

, and A ² has the structure represented by the formula

. 4. The connection according to any one of paragraphs. 1-3 having the general formula (III) shown below:

or the general formula (IV) shown below:

or a pharmaceutically acceptable salt thereof. 5. The compound according to claim 4 or a pharmaceutically acceptable salt thereof, where R ¹ each independently represents a hydrogen atom or a tert-butoxycarbonyl group; W ¹ and W ² are each independently a single bond or a C ₁ -C ₄ alkylene group; X ¹ is -C(=O)-, -OC(=O)- or -NG ¹¹ -SO ₂ -; X ^1' is -NG ^Z -SO ₂ -; X ² is -C(=O)-, -C(=O)-O- or -SO ₂ -NG ¹² -; X ^2' is -SO ₂ -NG ^Z -; G ¹¹ and G ¹² are each independently a hydrogen atom, a C ₁ -C ₄ alkyl group, or —COOR ² ; G ^Z is a single bond that connects X ^1' or X ^2' to Z; R ² is a C ₁ -C ₄ alkyl group optionally substituted with 1-5 aryl groups; Y ¹ is -NG ²¹ -, -NG ²¹ -L ¹¹ -C(=O)-, -NG ²¹ -L ¹¹ -C(=O)-NH-, -NG ²¹ -L ¹¹ -C(=O)-NG ³¹ -L ²¹ -C(=O)-, -NG ²¹ -L ¹¹ -C(=O)-NG ³¹ -L ²¹ -C(=O) -NH-, -NG ²¹ -L ³ -O- or -NG ²¹ -G ^4' -; Y ^1' is -NG ²¹ H, -NG ²¹ -L ¹¹ -COOH or -NG ²¹ -L ¹¹ -C(=O)-NG ³¹ -L ²¹ -COOH; Y ² is -NG ²² -, -C(=O)-L ¹² -NG ²² -, -NH-C(=O)-L ¹² -NG ²² -, -C(=O)-L ²² -NG ³² -C(=O)-L ¹² -NG ²² -, -NH-C(=O)-L ²² -NG ³² -C(=O)-L ¹² - NG ²² -, -OL ³ -NG ²² - or -G ^4' -NG ²² -; Y ^2' is HNG ²² -, HOOC-L ¹² -NG ²² - or HOOC-L ²² -NG ³² -C(=O) -L ¹² -NG ²² -; G ²¹ , G ³¹ , G ²² and G ³² are each independently a hydrogen atom or a C ₁ -C ₆ alkyl group optionally substituted with 1-5 substituents independently selected from the group consisting of a phenyl group optionally substituted with 1-5 -COOR ³ groups, and -COOR ³ groups; G ^4' represents a C ₁ -C ₄ alkylene group or a C ₁ -C ₄ alkyleneoxy-C ₁ -C ₄ alkylene group; R ³ each independently represents a hydrogen atom, a benzyl group or a tert-butyl group; L ¹¹ , L ²¹ , L ¹² and L ²² are each independently a C ₁ -C ₆ alkylene group optionally substituted with 1-5 C ₁ -C ₆ alkyl groups optionally substituted with 1-5 -COOR ⁴ groups, C ₁ -C ₄ alkylene-phenylene group or phenylene-C ₁ -C ₄ alkylene group; L ³ represents a C ₁ -C ₄ alkylene-phenylene group, where the phenylene fragment is optionally substituted with 1-3 -COOR ⁴ groups; R ⁴ each independently represents a hydrogen atom, a benzyl group, a 2-(trimethylsilyl)ethyl group, or a tert-butyl group; R ⁵ and R ⁶ are each independently a hydrogen atom, a halogen atom, a C ₁ -C ₄ alkyl group, or a C ₁ -C ₄ alkoxy group; all R ⁵ may be the same or different from each other; Z represents a single bond, C ₆ -C ₁₂ arylene group, -(CH ₂ -CH ₂ -O) _m -CH ₂ -CH ₂ -, -(CH ₂ -O-CH ₂ ) _m -, -(CH ₂ ) _m -(C ₆ -C ₁₂ arylene)-(CH ₂ ) _m - or -(CH ₂ ) _n -; m is an integer from 1 to 6; and n is an integer from 2 to 12. 6. The compound according to claim. 5 or its pharmaceutically acceptable salt, where R ¹ each independently represents a hydrogen atom or a tert-butoxycarbonyl group; W ¹ and W ² are each independently a single bond or a C ₁ -C ₄ alkylene group; X ¹ is -C(=O)-, -OC(=O)- or -NG ¹¹ -SO ₂ -; X ^1' is -NG ^Z -SO ₂ -; X ² is -C(=O)-, -C(=O)-O- or -SO ₂ -NG ¹² -; X ^2' is -SO ₂ -NG ^Z -; G ¹¹ and G ¹² are each independently a hydrogen atom, a C ₁ -C ₄ alkyl group, or —COOR ² ; G ^Z is a single bond that connects X ^1' or X ^2' to Z; R ² is a C ₁ -C ₄ alkyl group optionally substituted with 1-3 aryl groups; Y ¹ is -NG ²¹ -, -NG ²¹ -L ¹¹ -C(=O)-, -NG ²¹ -L ¹¹ -C(=O)-NH-, -NG ²¹ -L ¹¹ -C(=O )-NG ³¹ -L ²¹ -C(=O)-, -NG ²¹ -L ¹¹ -C(=O)-NG ³¹ -L ²¹ -C(=O)-NH- or -NG ²¹ -L ³ - O-; Y ^1' is -NG ²¹ H, -NG ²¹ -L ¹¹ -COOH or -NG ²¹ -L ¹¹ -C(=O)-NG ³¹ -L ²¹ -COOH; Y ² is -NG ²² -, -C(=O)-L ¹² -NG ²² -, -NH-C(=O)-L ¹² -NG ²² -, -C(=O)-L ²² -NG ³² -C(=O)-L ¹² -NG ²² -, -NH-C(=O)-L ²² -NG ³² -C(=O)-L ¹² - NG ²² - or -OL ³ -NG ²² -; Y ^2' is HNG ²² -, HOOC-L ¹² -NG ²² - or HOOC-L ²² -NG ³² -C(=O) -L ¹² -NG ²² -; G ²¹ , G ³¹ , G ²² and G ³² are each independently a hydrogen atom or a C ₁ -C ₆ alkyl group optionally substituted with 1-3 substituents independently selected from the group consisting of a phenyl group optionally substituted with 1-3 -COOR ³ groups, and -COOR ³ groups; R ³ each independently represents a hydrogen atom, a benzyl group or a tert-butyl group; L ¹¹ , L ²¹ , L ¹² and L ²² are each independently a C ₁ -C ₆ alkylene group optionally substituted with 1-5 C ₁ -C ₆ alkyl groups optionally substituted with 1-5 -COOR ⁴ groups, C ₁ -C ₄ alkylene-phenylene group or phenylene-C ₁ -C ₄ alkylene group; L ³ represents a C ₁ -C ₂ alkylene-phenylene group, where the phenylene fragment is optionally substituted with 1-2 -COOR ⁴ groups; R ⁴ each independently represents a hydrogen atom, a benzyl group, a 2-(trimethylsilyl)ethyl group, or a tert-butyl group; R ⁵ and R ⁶ are each independently a hydrogen atom, a halogen atom, a C ₁ -C ₄ alkyl group, or a C ₁ -C ₄ alkoxy group; each R ⁵ may be the same or different from each other; Z is a single bond, a biphenylene group, -(CH ₂ -CH ₂ -O) _m -CH ₂ -CH ₂ -, -(CH ₂ -O-CH ₂ ) _m -, -(CH ₂ ) _m -biphenylene- (CH ₂ ) _m - or -(CH ₂ ) _n -; m is an integer from 1 to 6; and n is an integer from 2 to 12. 7. The compound according to claim. 6 or its pharmaceutically acceptable salt, where R ¹ each represents a hydrogen atom; W ¹ and W ² are each independently a single bond or a C ₁ -C ₄ alkylene group; X ¹ is -C(=O)- or -NG ¹¹ -SO ₂ -; X ^1' is -NG ^Z -SO ₂ -; X ² represents -C(=O)- or -SO ₂ -NG ¹² -; X ^2' is -SO ₂ -NG ^Z -; G ¹¹ and G ¹² are each independently a hydrogen atom or —COOR ² ; G ^Z is a single bond that connects X ^1' or X ^2' to Z; R ² is a C ₁ -C ₄ alkyl group optionally substituted with one phenyl group; Y ¹ is -NG ²¹ -; Y ^1' is -NG ²¹ H; Y ² is -NG ²² -; Y ^2' is HNG ²² -; G ²¹ and G ²² are each independently a hydrogen atom or a C ₁ -C ₃ alkyl group substituted with 1-3 carboxyl groups; R ⁵ and R ⁶ are each independently a hydrogen atom, a fluorine atom, a methyl group or a methoxy group; all R ⁵ may be the same or different from each other; Z is a single bond, [1,1'-biphenyl]-3,3'-diyl, -(CH ₂ -CH ₂ -O) _m -CH ₂ -CH ₂ -, -(CH ₂ -O-CH ₂ ) _m -, -(CH ₂ ) _m -([1,1'-biphenyl]-3,3'-diyl)-(CH ₂ ) _m - or -(CH ₂ ) _n -; m is an integer from 1 to 6; and n is an integer from 2 to 12. 8. Connection according to any one of paragraphs. 1-3 having the general formula (V) shown below:

where: R ¹ each independently represents a hydrogen atom or -COO-(C ₁ -C ₄ alkyl group); W ¹ and W ² are each independently a single bond or a C ₁ -C ₄ alkylene group; X ¹ is -C(=O)- or -NG ¹¹ -SO ₂ -; X ² represents -C(=O)- or -SO ₂ -NG ¹² -; G ¹¹ and G ¹² are each independently a hydrogen atom, a C ₁ -C ₄ alkyl group, or —COOR ² ; R ² is a C ₁ -C ₄ alkyl group optionally substituted with 1-5 aryl groups; Y ¹ is -NG ²¹ -, -NG ²¹ -L ¹¹ -C(=O)-, -NG ²¹ -L ¹¹ -C(=O)-NH-, -NG ²¹ -L ¹¹ -C(=O)-NG ³¹ -L ²¹ -C(=O)-, -NG ²¹ -L ¹¹ -C(=O)-NG ³¹ -L ²¹ -C(=O) -NH-, -NG ²¹ -L ³ -O- or -NG ²¹ -G ^4' -; Y ² is -NG ²² -, -C(=O)-L ¹² -NG ²² -, -NH-C(=O)-L ¹² -NG ²² -, -C(=O)-L ²² -NG ³² -C(=O)-L ¹² -NG ²² -, -NH-C(=O)-L ²² -NG ³² -C(=O)-L ¹² - NG ²² -, -OL ³ -NG ²² - or -G ^4' -NG ²² -; G ²¹ , G ³¹ , G ²² and G ³² are each independently a hydrogen atom or a C ₁ -C ₆ alkyl group optionally substituted with 1-5 substituents independently selected from the group consisting of a phenyl group optionally substituted with 1-5 -COOR ³ groups, and -COOR ³ groups; G ^4' represents a C ₁ -C ₄ alkylene group or a C ₁ -C ₄ alkyleneoxy-C ₁ -C ₄ alkylene group; R ³ each independently represents a hydrogen atom or a C ₁ -C ₄ alkyl group optionally substituted with 1-5 aryl groups; L ¹¹ , L ²¹ , L ¹² and L ²² are each independently a C ₁ -C ₆ alkylene group optionally substituted with 1-5 C ₁ -C ₆ alkyl groups optionally substituted with 1-5 -COOR ⁴ groups, C ₁ -C ₄ alkylene-phenylene group or phenylene-C ₁ -C ₄ alkylene group; L ³ represents a C ₁ -C ₄ alkylene-phenylene group, where the phenylene fragment is optionally substituted with 1-3 -COOR ⁴ groups; R ⁴ each independently represents a hydrogen atom or a C ₁ -C ₄ alkyl group optionally substituted with 1-5 substituents independently selected from the group consisting of an aryl group and a trimethylsilyl group; R ⁵ each independently represents a hydrogen atom, a halogen atom, a C ₁ -C ₄ alkyl group, or a C ₁ -C ₄ alkoxy group; Z represents a single bond, C ₆ -C ₁₂ arylene group, -(CH ₂ -CH ₂ -O) _m -CH ₂ -CH ₂ -, -(CH ₂ -O-CH ₂ ) _m -, -(CH ₂ ) _m -(C ₆ -C ₁₂ arylene)-(CH ₂ ) _m - or -(CH ₂ ) _n -; m is an integer from 1 to 6; and n is an integer from 2 to 12; or a pharmaceutically acceptable salt thereof. 9. The compound according to claim 8, having the general formula (VI) shown below:

or a pharmaceutically acceptable salt thereof. 10. The compound according to claim 9 or its pharmaceutically acceptable salt, where R ¹ each independently represents a hydrogen atom or a tert-butoxycarbonyl group; W ¹ and W ² are each independently a single bond or a C ₁ -C ₂ alkylene group; X ¹ is -C(=O)- or -NG ¹¹ -SO ₂ -; X ² represents -C(=O)- or -SO ₂ -NG ¹² -; G ¹¹ and G ¹² each represents a hydrogen atom; Y ¹ is -NG ²¹ -, -NG ²¹ -L ¹¹ -C(=O)-, -NG ²¹ -L ¹¹ -C(=O)-NH-, -NG ²¹ -L ¹¹ -C(=O)-NG ³¹ -L ²¹ -C(=O)-, -NG ²¹ -L ¹¹ -C(=O)-NG ³¹ -L ²¹ -C(=O) -NH-, -NG ²¹ -L ³ -O- or -NG ²¹ -G ^4' -; Y ² is -NG ²² -, -C(=O)-L ¹² -NG ²² -, -NH-C(=O)-L ¹² -NG ²² -, -C(=O)-L ²² -NG ³² -C(=O)-L ¹² -NG ²² -, -NH-C(=O)-L ²² -NG ³² -C(=O)-L ¹² - NG ²² -, -OL ³ -NG ²² - or -G ^4' -NG ²² -; G ²¹ , G ³¹ , G ²² and G ³² are each independently a hydrogen atom or a C ₁ -C ₃ alkyl group optionally substituted with 1-3 -COOR ³ groups; G ^4' represents a C ₁ -C ₂ alkylene group or a C ₁ -C ₂ alkyleneoxy-C ₁ -C ₂ alkylene group; R ³ each independently represents a hydrogen atom or a tert-butyl group; L ¹¹ , L ²¹ , L ¹² and L ²² are each independently a C ₁ -C ₂ alkylene group; L ³ represents a C ₁ -C ₄ alkylene-phenylene group, where the phenylene fragment is optionally substituted with 1-3 -COOR ⁴ groups; R ⁴ each independently represents a hydrogen atom or a C ₁ -C ₄ alkyl group optionally substituted with 1-5 substituents independently selected from the group consisting of an aryl group and a trimethylsilyl group; R ⁵ each independently represents a hydrogen atom, a halogen atom, a C ₁ -C ₄ alkyl group, or a C ₁ -C ₄ alkoxy group; Z is a single bond, a biphenylene group, -(CH ₂ -CH ₂ -O) _m -CH ₂ -CH ₂ -, -(CH ₂ -O-CH ₂ ) _m -, -(CH ₂ ) _m -biphenylene- (CH ₂ ) _m - or -(CH ₂ ) _n -; m is an integer from 1 to 6; and n is an integer from 2 to 12. 11. The compound according to claim 10 or its pharmaceutically acceptable salt, where R ¹ each represents a hydrogen atom; W ¹ and W ² are each a single bond; X ¹ represents -C(=O)-; X ² is -C(=O)-; Y ¹ is -NG ²¹ -, -NG ²¹ -L ³ -O- or -NG ²¹ -G ^4' -; Y ² is -NG ²² -, -OL ³ -NG ²² - or -G ^4' -NG ²² -; G ²¹ and G ²² are each independently a C ₁ -C ₃ alkyl group substituted with 1-3 carboxyl groups; G ^4' represents a C ₁ -C ₂ alkylene group or a C ₁ -C ₂ alkyleneoxy-C ₁ -C ₂ alkylene group; L ³ represents a C ₁ -C ₂ alkylene-phenylene group, where the phenylene fragment is optionally substituted with 1-2 -COOR ⁴ groups; R ⁴ each independently represents a hydrogen atom or a C ₁ -C ₄ alkyl group optionally substituted with 1-5 substituents independently selected from the group consisting of an aryl group and a trimethylsilyl group; R ⁵ each independently represents a hydrogen atom, a fluorine atom, a methyl group or a methoxy group; Z is a single bond, [1,1'-biphenyl]-3,3'-diyl, -(CH ₂ -CH ₂ -O) _m -CH ₂ -CH ₂ -, -(CH ₂ -O-CH ₂ ) _m -, -(CH ₂ ) _m -([1,1'-biphenyl]-3,3'-diyl)-(CH ₂ ) _m - or -(CH ₂ ) _n -; m is an integer from 1 to 6; and n is an integer from 2 to 12. 12. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, where A ¹ has the structure represented by the formula

, and A ² has the structure represented by the formula

, where: R ¹ each independently represents a hydrogen atom or -COO-(C ₁ -C ₄ alkyl group); W ¹ and W ² are each independently a single bond or a C ₁ -C ₄ alkylene group; X ¹ is -C(=O)-, -OC(=O)- or -NG ¹¹ -SO ₂ -; X ² is -C(=O)-, -C(=O)-O- or -SO ₂ -NG ¹² -; G ¹¹ and G ¹² are each independently a hydrogen atom or —COOR ² ; R ² is a C ₁ -C ₄ alkyl group optionally substituted with 1-5 aryl groups; Y ¹ is -NG ²¹ -, -NG ²¹ -L ¹¹ -C(=O)-NH- or -NG ²¹ -L ¹¹ -C(=O)-NG ³¹ -L ²¹ -C(=O)- NH-; Y ² is -NG ²² -, -NH-C(=O)-L ¹² -NG ²² - or -NH-C(=O)-L ²² -NG ³² -C(=O)-L ¹² -NG ^22- ; G ²¹ , G ³¹ , G ²² and G ³² are each independently a hydrogen atom or a C ₁ -C ₆ alkyl group optionally substituted with 1-5 substituents independently selected from the group consisting of a phenyl group optionally substituted with 1-5 -COOR ³ groups, and -COOR ³ groups; R ³ each independently represents a hydrogen atom or a C ₁ -C ₄ alkyl group optionally substituted with 1-5 aryl groups; L ¹¹ , L ²¹ , L ¹² and L ²² are each independently a C ₁ -C ₆ alkylene group optionally substituted with 1-5 C ₁ -C ₆ alkyl groups optionally substituted with 1-5 -COOR ⁴ groups, C ₁ -C ₄ alkylene-phenylene group or phenylene-C ₁ -C ₄ alkylene group; R ⁴ each independently represents a hydrogen atom or a C ₁ -C ₄ alkyl group optionally substituted with 1-5 aryl groups; R ⁵ and R ⁶ each independently represent a hydrogen atom, a C ₁ -C ₄ alkyl group or a C ₁ -C ₄ alkoxy group, or R ⁵ and R ⁶ may be combined with each other to form a C ₁ -C ₄ alkyleneoxy group; and symbol

means the point of attachment to Z; Z is -(CH ₂ -CH ₂ -O) _m -CH ₂ -CH ₂ - or -(CH ₂ ) _n -; m is an integer from 1 to 6; and n is an integer from 2 to 12. 13. The compound according to claim 12 or a pharmaceutically acceptable salt thereof, where A ¹ has the structure represented by the formula

, and A ² has the structure represented by the formula

. 14. Connection according to any one of paragraphs. 1 and 12, 13 having the general formula (VII) shown below:

where: R ¹ each independently represents a hydrogen atom or -COO-(C ₁ -C ₄ alkyl group); W ¹ and W ² are each independently a single bond or a C ₁ -C ₄ alkylene group; X ¹ is -OC(=O)- or -NG ¹¹ -SO ₂ -; X ² is -C(=O)-O- or -SO ₂ -NG ¹² -; G ¹¹ and G ¹² are each independently a hydrogen atom or —COOR ² ; R ² is a C ₁ -C ₄ alkyl group optionally substituted with 1-5 aryl groups; Y ¹ is -NG ²¹ -, -NG ²¹ -L ¹¹ -C(=O)-NH- or -NG ²¹ -L ¹¹ -C(=O)-NG ³¹ -L ²¹ -C(=O)- NH-; Y ² is -NG ²² -, -NH-C(=O)-L ¹² -NG ²² - or -NH-C(=O)-L ²² -NG ³² -C(=O)-L ¹² -NG ^22- ; G ²¹ , G ³¹ , G ²² and G ³² are each independently a hydrogen atom or a C ₁ -C ₆ alkyl group optionally substituted with 1-5 substituents independently selected from the group consisting of a phenyl group optionally substituted with 1-5 -COOR ³ groups, and -COOR ³ groups; R ³ each independently represents a hydrogen atom or a C ₁ -C ₄ alkyl group optionally substituted with 1-5 aryl groups; L ¹¹ , L ²¹ , L ¹² and L ²² are each independently a C ₁ -C ₆ alkylene group optionally substituted with 1-5 C ₁ -C ₆ alkyl groups optionally substituted with 1-5 -COOR ⁴ groups, C ₁ -C ₄ alkylene-phenylene group or phenylene-C ₁ -C ₄ alkylene group; R ⁴ each independently represents a hydrogen atom or a C ₁ -C ₄ alkyl group optionally substituted with 1-5 aryl groups; Z is -(CH ₂ -CH ₂ -O) _m -CH ₂ -CH ₂ - or -(CH ₂ ) _n -; m is an integer from 1 to 6; and n is an integer from 2 to 12; or a pharmaceutically acceptable salt thereof. 15. The compound according to claim 14 or a pharmaceutically acceptable salt thereof, where R ¹ each independently represents a hydrogen atom or a tert-butoxycarbonyl group; W ¹ and W ² each represents a C ₁ -C ₄ alkylene group; X ¹ is -OC(=O)- or -NG ¹¹ -SO ₂ -; X ² is -C(=O)-O- or -SO ₂ -NG ¹² -; G ¹¹ and G ¹² are each independently a hydrogen atom or —COOR ² ; R ² is a C ₁ -C ₄ alkyl group optionally substituted with 1-3 phenyl groups; Y ¹ is -NG ²¹ -, -NG ²¹ -L ¹¹ -C(=O)-NH- or -NG ²¹ -L ¹¹ -C(=O)-NG ³¹ -L ²¹ -C(=O)- NH-; Y ² is -NG ²² -, -NH-C(=O)-L ¹² -NG ²² - or -NH-C(=O)-L ²² -NG ³² -C(=O)-L ¹² -NG ^22- ; G ²¹ , G ³¹ , G ²² and G ³² are each independently a hydrogen atom or a C ₁ -C ₆ alkyl group optionally substituted with 1-3 substituents independently selected from the group consisting of a phenyl group optionally substituted with 1-3 -COOR ³ groups, and -COOR ³ groups; R ³ each independently represents a hydrogen atom, a benzyl group or a tert-butyl group; L ¹¹ , L ²¹ , L ¹² and L ²² are each independently a C ₁ -C ₆ alkylene group optionally substituted with 1-5 C ₁ -C ₆ alkyl groups optionally substituted with 1-5 -COOR ⁴ groups, C ₁ -C ₄ alkylene-phenylene group or phenylene-C ₁ -C ₄ alkylene group; R ⁴ each independently represents a hydrogen atom, a benzyl group or a tert-butyl group; Z is -(CH ₂ -CH ₂ -O) _m -CH ₂ -CH ₂ - or -(CH ₂ ) _n -; m is an integer from 1 to 6; and n is an integer from 2 to 12. 16. The compound according to claim 15 or a pharmaceutically acceptable salt thereof, where R ¹ each independently represents a hydrogen atom or a tert-butoxycarbonyl group; W ¹ and W ² each represents a C ₁ -C ₂ alkylene group; X ¹ is -OC(=O)- or -NG ¹¹ -SO ₂ -; X ² is -C(=O)-O- or -SO ₂ -NG ¹² -; G ¹¹ and G ¹² are each independently a hydrogen atom or —COOR ² ; R ² is a C ₁ -C ₄ alkyl group optionally substituted with one phenyl group; Y ¹ is -NG ²¹ -, -NG ²¹ -L ¹¹ -C(=O)-NH- or -NG ²¹ -L ¹¹ -C(=O)-NG ³¹ -L ²¹ -C(=O)- NH-; Y ² is -NG ²² -, -NH-C(=O)-L ¹² -NG ²² - or -NH-C(=O)-L ²² -NG ³² -C(=O)-L ¹² -NG ^22- ; G ²¹ , G ³¹ , G ²² and G ³² are each independently a hydrogen atom or a C ₁ -C ₃ alkyl group optionally substituted with 1-3 substituents independently selected from the group consisting of a phenyl group optionally substituted with one —COOR ³ group , and -COOR ³ groups; R ³ each independently represents a hydrogen atom or a tert-butyl group; L ¹¹ , L ²¹ , L ¹² and L ²² are each independently a C ₁ -C ₂ alkylene group optionally substituted with 1-2 C ₁ -C ₂ alkyl groups optionally substituted with 1-2 -COOR ⁴ groups, C ₁ -C ₂ alkylene-phenylene group or phenylene-C ₁ -C ₂ alkylene group; R ⁴ each independently represents a hydrogen atom or a tert-butyl group; Z is -(CH ₂ -CH ₂ -O) _m -CH ₂ -CH ₂ - or -(CH ₂ ) _n -; m is an integer from 1 to 6; and n is an integer from 2 to 12. 17. The compound according to claim 16 or a pharmaceutically acceptable salt thereof, where R ¹ each represents a hydrogen atom; W ¹ and W ² each represents a C ₁ -C ₂ alkylene group; X ¹ is -NG ¹¹ -SO ₂ -; X ² is -SO ₂ -NG ¹² -; G ¹¹ and G ¹² are each independently a hydrogen atom or —COOR ² ; R ² is a C ₁ -C ₄ alkyl group optionally substituted with one phenyl group; Y ¹ is -NG ²¹ -; Y ² is -NG ²² -; G ²¹ and G ²² are each independently a C ₁ -C ₃ alkyl group substituted with 1-3 substituents independently selected from the group consisting of a phenyl group substituted with one carboxyl group and a carboxyl group; Z is -(CH ₂ -CH ₂ -O) _m -CH ₂ -CH ₂ - or -(CH ₂ ) _n -; m is an integer from 1 to 6; and n is an integer from 2 to 12. 18. A compound according to claim 12 or 13 having the general formula (VIII) shown below:

where: R ¹ each independently represents a hydrogen atom or -COO-(C ₁ -C ₄ alkyl group); W ¹ and W ² are each independently a single bond or a C ₁ -C ₄ alkylene group; X ¹ is -C(=O)- or -NG ¹¹ -SO ₂ -; X ² represents -C(=O)- or -SO ₂ -NG ¹² -; G ¹¹ and G ¹² are each independently a hydrogen atom or —COOR ² ; R ² is a C ₁ -C ₄ alkyl group optionally substituted with 1-5 aryl groups; Y ¹ is -NG ²¹ -, -NG ²¹ -L ¹¹ -C(=O)-NH- or -NG ²¹ -L ¹¹ -C(=O)-NG ³¹ -L ²¹ -C(=O)- NH-; Y ² is -NG ²² -, -NH-C(=O)-L ¹² -NG ²² - or -NH-C(=O)-L ²² -NG ³² -C(=O)-L ¹² -NG ^22- ; G ²¹ , G ³¹ , G ²² and G ³² are each independently a hydrogen atom or a C ₁ -C ₆ alkyl group optionally substituted with 1-5 substituents independently selected from the group consisting of a phenyl group optionally substituted with 1-5 -COOR ³ groups, and -COOR ³ groups; R ³ each independently represents a hydrogen atom or a C ₁ -C ₄ alkyl group optionally substituted with 1-5 aryl groups; L ¹¹ , L ²¹ , L ¹² and L ²² are each independently a C ₁ -C ₆ alkylene group optionally substituted with 1-5 C ₁ -C ₆ alkyl groups optionally substituted with 1-5 -COOR ⁴ groups, C ₁ -C ₄ alkylene-phenylene group or phenylene-C ₁ -C ₄ alkylene group; R ⁴ each independently represents a hydrogen atom or a C ₁ -C ₄ alkyl group optionally substituted with 1-5 aryl groups; Z is -(CH ₂ -CH ₂ -O) _m -CH ₂ -CH ₂ - or -(CH ₂ ) _n -; m is an integer from 1 to 6; and n is an integer from 2 to 12; or a pharmaceutically acceptable salt thereof. 19. A compound according to claim 18, or a pharmaceutically acceptable salt thereof, wherein R ¹ each independently represents a hydrogen atom or a tert-butoxycarbonyl group; W ¹ and W ² are each independently a single bond or a C ₁ -C ₂ alkylene group; X ¹ is -C(=O)- or -NG ¹¹ -SO ₂ -; X ² represents -C(=O)- or -SO ₂ -NG ¹² -; G ¹¹ and G ¹² each represents a hydrogen atom; Y ¹ is -NG ²¹ -, -NG ²¹ -L ¹¹ -C(=O)-NH- or -NG ²¹ -L ¹¹ -C(=O)-NG ³¹ -L ²¹ -C(=O)- NH-; Y ² is -NG ²² -, -NH-C(=O)-L ¹² -NG ²² - or -NH-C(=O)-L ²² -NG ³² -C(=O)-L ¹² -NG ^22- ; G ²¹ , G ³¹ , G ²² and G ³² are each independently a hydrogen atom or a C ₁ -C ₃ alkyl group optionally substituted with 1-3 -COOR ³ groups; R ³ each independently represents a hydrogen atom or a tert-butyl group; L ¹¹ , L ²¹ , L ¹² and L ²² are each independently a C ₁ -C ₂ alkylene group; Z is -(CH ₂ -CH ₂ -O) _m -CH ₂ -CH ₂ - or -(CH ₂ ) _n -; m is an integer from 1 to 6; and n is an integer from 2 to 12. 20. The compound according to claim 19 or a pharmaceutically acceptable salt thereof, where R ¹ each represents a hydrogen atom; W ¹ and W ² are each a single bond; X ¹ represents -C(=O)-; X ² is -C(=O)-; Y ¹ is -NG ²¹ -; Y ² is -NG ²² -; G ²¹ and G ²² are each independently a C ₁ -C ₃ alkyl group substituted with 1-3 carboxyl groups; Z is -(CH ₂ -CH ₂ -O) _m -CH ₂ -CH ₂ -; and m is an integer from 1 to 6. 21. Connection according to any one of paragraphs. 1-3 selected from the group consisting of the following compounds: (2S,2'S)-2,2'-((oxybis(ethane-2,1-diyl))bis((N-(4-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl)azandiyl))succinic acid; (2S,13S)-3,12-bis(N-(4-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl)-6,9-dioxa-3,12-diazatetradecane-1,2,13,14- tetracarboxylic acid; (2S,16S)-3,15-bis(N-(4-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl)-6,9,12-trioxa-3,15-diazaheptadecan-1,2,16, 17-tetracarboxylic acid; (2S,19S)-3,18-bis(N-(4-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl)-6,9,12,15-tetraoxa-3,18-diazaicosan-1,2, 19,20-tetracarboxylic acid; (2S,22S)-3,21-bis(N-(4-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl)-6,9,12,15,18-pentaoxa-3,21-diazatricosan-1, 2,22,23-tetracarboxylic acid; (2S,25S)-3,24-bis(N-(4-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl)-6,9,12,15,18,21-hexaoxa-3,24-diazahexacosan- 1,2,25,26-tetracarboxylic acid; (2S,2'S)-2,2'-(propane-1,3-diylbis((N-(4-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl)azandiyl))succinic acid; (2S,2'S)-2,2'-(butane-1,4-diylbis((N-(4-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl)azandiyl))succinic acid; (2S,2'S)-2,2'-(pentane-1,5-diylbis((N-(4-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl)azandiyl))succinic acid; 3,18-bis(((4-((4-guanidinobenzoyl)oxy)benzyl)oxy)carbonyl)-6,9,12,15-tetraoxa-3,18-diazaicosan-1,2,19,20-tetracarboxylic acid; 2,2'-(1,20-bis(4-((4-guanidinobenzoyl)oxy)phenyl)-3,18-dioxo-2,19-dioxa-4,17-diazaicosan-4,17-diyl)disuccinic acid; (3S,6S,25S,28S)-6,25-bis(carboxymethyl)-3,28-bis((((4-((4-guanidinobenzoyl)oxy)benzyl)oxy)carbonyl)amino)-4.7 ,24,27-tetraoxo-11,14,17,20-tetraoxa-5,8,23,26-tetraazatriacontane-1,30-dioic acid; (3S,6S,23S,26S)-6,23-bis(carboxymethyl)-3,26-bis((((4-((4-guanidinobenzoyl)oxy)benzyl)oxy)carbonyl)amino)-4.7 ,22,25-tetraoxo-5,8,21,24-tetraazaoctacosan-1,28-dioic acid; (3S,22S)-3,22-bis(2-((3-carboxybenzyl)(((4-((4-guanidinobenzoyl)oxy)benzyl)oxy)carbonyl)amino)acetamido)-4,21-dioxo- 8,11,14,17-tetraoxa-5,20-diazatetracosan-1,24-dioic acid; (4S,7S,26S,29S)-4,7,26,29-tetrakis(carboxymethyl)-3,30-bis(((4-((4-guanidinobenzoyl)oxy)benzyl)oxy)carbonyl)-5, 8,25,28-tetraoxo-12,15,18,21-tetraoxa-3,6,9,24,27,30-hexaazadotriacontane-1,32-dioic acid; (3S,22S)-3,22-bis((3-carboxybenzyl)(((4-((4-guanidinobenzoyl)oxy)benzyl)oxy)carbonyl)amino)-4,21-dioxo-8,11,14 ,17-tetraoxa-5,20-diazatetracosan-1,24-dioic acid; (2S,2'S)-2,2'-((((5,8,11,14-tetraoxa-2,17-diazaoctadecan-1,18-dioyl)bis(3,1-phenylene))bis(methylene) )bis((((4-((4-guanidinobenzoyl)oxy)benzyl)oxy)carbonyl)azandiyl))succinic acid; (2S,2'S)-2,2'-((((5,8,11,14-tetraoxa-2,17-diazaoctadecan-1,18-dioyl)bis(3,1-phenylene))bis(methylene) )bis((N-(4-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl)azandiyl))succinic acid; 3,12-bis(10-guanidino-13-oxo-6,7,8,13-tetrahydrodibenzo[b,f][1,4]dioxecine-4-carbonyl)-6,9-dioxa-3,12- diasatetradecane-1,2,13,14-tetracarboxylic acid; (2S,13S)-3,12-bis(10-guanidino-13-oxo-6,7,8,13-tetrahydrodibenzo[b,f][1,4]dioxecine-4-carbonyl)-6,9- dioxa-3,12-diazatetradecane-1,2,13,14-tetracarboxylic acid; (2R,13R)-3,12-bis(10-guanidino-13-oxo-6,7,8,13-tetrahydrodibenzo[b,f][1,4]dioxecine-4-carbonyl)-6,9- dioxa-3,12-diazatetradecane-1,2,13,14-tetracarboxylic acid; (2S,13S)-3,12-bis(N-(4-((4-guanidinobenzoyl)oxy)benzyl)-N-methylsulfamoyl)-6,9-dioxa-3,12-diazatetradecane-1,2,13 ,14-tetracarboxylic acid; 3,3'-(((ethane-1,2-diylbis(oxy))bis(ethane-2,1-diyl))bis((N-(4-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl) azandiyl))dipentanedioic acid; (2S,2'S)-2,2'-((1,12-bis(4-((4-guanidinobenzoyl)oxy)phenyl)-5,8-dioxa-2,11-diazadecanedisulfonyl)bis(azandiyl))disuccinic acid; (2S,13S)-3,12-bis(N-(3-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl)-6,9-dioxa-3,12-diazatetradecane-1,2,13,14- tetracarboxylic acid; (2S,2'S)-2,2'-((oxybis(ethane-2,1-diyl))bis((10-guanidino-13-oxo-6,7,8,13-tetrahydrodibenzo[b,f][ 1,4]dioxecin-4-carbonyl)azandiyl))succinic acid; (2S,16S)-3,15-bis(10-guanidino-13-oxo-6,7,8,13-tetrahydrodibenzo[b,f][1,4]dioxecine-4-carbonyl)-6,9, 12-trioxa-3,15-diazaheptadecan-1,2,16,17-tetracarboxylic acid; (2S,2'S)-2,2'-(([1,1'-biphenyl]-3,3'-diylbis(methylene))bis((10-guanidino-13-oxo-6,7,8,13 -tetrahydrodibenzo[b,f][1,4]dioxecine-4-carbonyl)azandiyl)) disuccinic acid; (2S,2'S)-2,2'-(((((oxybis(ethane-2,1-diyl))bis(oxy))bis(3-carboxy-5,1-phenylene))bis(methylene)) bis((10-guanidino-13-oxo-6,7,8,13-tetrahydrodibenzo[b,f][1,4]dioxecine-4-carbonyl)azandiyl))succinic acid; and (2S,2'S)-2,2'-((oxybis(ethane-2,1-diyl))bis((3-((4-guanidinobenzoyl)oxy)benzoyl)azandiyl))disuccinic acid, or a pharmaceutically acceptable salt thereof. 22. Connection according to any one of paragraphs. 1-3 selected from the group consisting of the following compounds: (2S,2'S)-2,2'-((oxybis(ethane-2,1-diyl))bis((N-(4-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl)azandiyl))succinic acid; (2S,13S)-3,12-bis(N-(4-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl)-6,9-dioxa-3,12-diazatetradecane-1,2,13,14- tetracarboxylic acid; (2S,2'S)-2,2'-(butane-1,4-diylbis((N-(4-((4-guanidinobenzoyl)oxy)benzyl)sulfamoyl)azandiyl))succinic acid; (2S,13S)-3,12-bis(10-guanidino-13-oxo-6,7,8,13-tetrahydrodibenzo[b,f][1,4]dioxecine-4-carbonyl)-6,9- dioxa-3,12-diazatetradecane-1,2,13,14-tetracarboxylic acid; (2S,2'S)-2,2'-((oxybis(ethane-2,1-diyl))bis((10-guanidino-13-oxo-6,7,8,13-tetrahydrodibenzo[b,f][ 1,4]dioxecin-4-carbonyl)azandiyl))succinic acid; (2S,16S)-3,15-bis(10-guanidino-13-oxo-6,7,8,13-tetrahydrodibenzo[b,f][1,4]dioxecine-4-carbonyl)-6,9, 12-trioxa-3,15-diazaheptadecan-1,2,16,17-tetracarboxylic acid; (2S,2'S)-2,2'-(([1,1'-biphenyl]-3,3'-diylbis(methylene))bis((10-guanidino-13-oxo-6,7,8,13 -tetrahydrodibenzo[b,f][1,4]dioxecine-4-carbonyl)azandiyl))succinic acid; and (2S,2'S)-2,2'-(((((oxybis(ethane-2,1-diyl))bis(oxy))bis(3-carboxy-5,1-phenylene))bis(methylene)) bis((10-guanidino-13-oxo-6,7,8,13-tetrahydrodibenzo[b,f][1,4]dioxecine-4-carbonyl)azandiyl))succinic acid, or a pharmaceutically acceptable salt thereof. 23. Connection according to any one of paragraphs. 1-22 or a pharmaceutically acceptable salt thereof having a molecular weight of 1000 or greater. 24. Pharmaceutical composition for inhibition of enteropeptidase and/or inhibition of trypsin, containing an effective amount of a compound according to any one of paragraphs. 1-23 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 25. A pharmaceutical composition according to claim 24 for use in the prevention, mitigation and/or treatment of obesity.