RU2828218C9 - Polypeptide having mmr-2 inhibitory action - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to a substituted polypeptide of formula I'-B, where AA¹-AA⁵, W^C, R^C are defined in the claims, or a pharmaceutically acceptable salt thereof, which has the inhibitory effect of MMP2. Also disclosed is a pharmaceutical preparation, an MMP2 inhibitor and a drug having MMP2 inhibitory activity.

EFFECT: disclosed is a polypeptide having mmr-2 inhibitory action.

5 cl, 53 tbl, 9 ex

Description

AREA OF TECHNOLOGY

The present invention relates to a substituted polypeptide compound having an effect of inhibiting matrix metalloprotease 2 (hereinafter appropriately abbreviated as “MMP2”).

LEVEL OF TECHNOLOGY

Matrix metalloprotease is a zinc-active site endopeptidase for which 24 genes are known. MMPs degrade the extracellular matrix, including collagen and gelatin, thus participating not only in physiological responses such as bone remodeling and wound healing, but also in pathological processes such as inflammation and cancer progression (see NPTL 1).

Clinical trials of several MMP inhibitors have previously been conducted with an emphasis on the anticancer effect of MMP inhibition, but were terminated due to side effects such as skeletal muscle pain and possible promotion of cancer metastasis, which are thought to be caused by inhibitory effects that are relatively non-selective for MMP subtypes (see NPTL 2 and 3).

MMP2 activation has been reported to play an important role in cancer cell infiltration and metastasis. Cancer cell infiltration and metastasis are key factors associated with malignant tumor prognosis, and inhibition of MMP2 activity may serve as an effective therapeutic agent for cancer control. Cancer growth is suppressed in MMP2 gene knockout animals, and MMP2 has been reported to play an important role in cancer growth (see NPTL 4). In addition, MMP2 has been reported to be associated with the progression of pathological condition in patients with various cancers, such as breast cancer, pancreatic cancer, bladder cancer, colorectal cancer, ovarian cancer, prostate cancer, brain tumor, gastric cancer, hepatocellular carcinoma, head and neck cancer, melanoma, uterine cancer, esophageal cancer, renal cell carcinoma, lung cancer and glioma (see NPTL 5 and 6). In addition, MMP2 has been described to be involved in the formation of pathological conditions even in non-neoplastic diseases.

In chronic kidney disease, MMP2 has been reported to induce renal tubular epithelial-mesenchymal transition by remodeling the tubular basement membrane structure, causing tubular atrophy, fibrogenesis and renal dysfunction (see NPTL 7). Blood concentrations of MMP2 have been detected in patients with chronic kidney disease (see NPTL 8 and 9). Furthermore, renal fibrosis induced by unilateral ureteral obstruction has been reported to be suppressed in MMP2 gene knockout animals (see NPTL 10 and 11). In light of this, inhibition of MMP2 activity to regulate the progression of the pathological state of chronic kidney disease may serve as an effective therapeutic agent.

Increased expression of MMP2 has been detected in alveolar epithelial cells, fibroblasts and macrophages in idiopathic pulmonary fibrosis, and in particular, increased expression of MMP2 in alveolar lavage fluid has been detected in patients with rapidly progressive idiopathic pulmonary fibrosis (see NPTL 12 and 13). Furthermore, the effect of a non-selective MMP inhibitor on the reduction of lung collagen content in mice with bleomycin-induced pulmonary fibrosis (see NPTL 14) and on the prevention of TGFβ-induced transformation of lung parenchymal fibroblasts (see NPTL 15) has been described. In light of this, inhibition of MMP2 activity to regulate the progression of the pathological condition of idiopathic pulmonary fibrosis may serve as an effective therapeutic option.

Additionally, an association between MMP2 and non-neoplastic diseases has been reported, where non-neoplastic diseases include multiple sclerosis, cerebral infarction, atherosclerosis, abdominal aortic aneurysm, peritoneal sclerosis, myocardial infarction, acute kidney injury, diabetic nephropathy, nephrosclerosis, glomerulonephritis, polycystic kidney disease, polycystic liver disease, alcoholic liver disease, non-alcoholic steatohepatitis, cholestatic liver disease, chronic obstructive pulmonary disease, interstitial pneumonia, diabetic retinopathy, age-related macular degeneration, Sjogren's syndrome, meningitis, muscular dystrophy, scleroderma, inflammatory bowel disease, and tuberculosis (see NPTL 16).

In light of the issues described above, finding agents to selectively inhibit MMP2 represents an approach with a high probability of creating an effective therapeutic method for diseases in which MMP2 is involved.

A hydroxamic acid or carboxylic acid compound introduced as a zinc chelator has been described as a small molecule compound having an MMP2 inhibitory effect, however, no compound having a selective MMP2 inhibitory effect was known (e.g., see NPTL 17 and 18).

It has been reported that "β-amyloid precursor protein (APP-IP, IIe-Ser-Tyr-Gly-Asn-Asp-Ala-Leu-Met-Pro)", a peptide compound consisting of 10 natural amino acids, exhibits a selective inhibitory effect on MMP2 (see NPTL 19). However, peptide compounds are generally rapidly metabolized and excreted in vivo, so it is known that even when the peptide compound is administered, the expected pharmacological effect is not maintained.

LIST OF QUOTES

NON-PATENT LITERATURE

NPL 1: H. J. Ra and W. C. Parks Matrix Biol., 2007, 26(8), 587-596.

NPL 2: A. H. Drummond et al. Ann N Y Acad Sci., 1999, 878, 228-235.

NPL 3: A. D. Baxter et al. Bioorg Med Chem Lett., 2001, 11, 1465-1468.

NPL 4: T. Itoh et al. Cancer Res., 1998, 58, 1048-1051.

NPL 5: R. Roy et al. J Clin Oncol., 2009, 27, 5287-5297.

NPL 6: T. Turpeenniemi-Hujanen Biochimie., 2005, 87, 287-297.

NPL 7: S. Cheng et al. FASEB J., 2006, 20, 1898-1900.

NPL 8: K. Pawlak et al. Clin Biochem., 2011, 44, 838-843.

NPL 9: H. R. Chang et al. Clin Chim Acta., 2006, 366, 243-248.

NPL 10: X. Du et al. Lab Invest., 2012, 92, 1149-1160.

NPL 11: M. K. Tveitaras et al. PLoS One., 2015, 10, e0143390.

NPL 12: M. Selman et al. Am J Physiol Lung Cell Mol Physiol., 2000, 279, L562-L574.

NPL 13: M. Suga et al. Am J Respir Crit Care Med., 2000, 162, 1949-1956.

NPL 14: M. Corbel et al. J Pathol., 2001, 193, 538-545.

NPL 15: J. Michael et al. Am J Respir Cell Mol Biol., 2009, 41, 731-741.

NPL 16: A. Tokito et al. Int J Mol Sci., 2016, 17, E1178.

NPL 17: D. E. Levy et al. J Med Chem., 1998, 41, 199-223.

NPL 18: Y. Tamura et al. J Med Chem., 1998, 41, 640-649.

NPL 19: S. Higashi et al. J Biol Chem., 2003, 278, 14020-14028.

ESSENCE OF THE INVENTION

TECHNICAL PROBLEM

The object of the present invention is to provide a novel MMP2 inhibitor.

SOLVING THE PROBLEM

The present inventors carefully studied to achieve the object and found that the compound represented by the formula [I'] (hereinafter sometimes referred to as compound [I']) has an effect of inhibiting MMP2.

The present invention is described in detail below.

More specifically, embodiments of the present invention are as follows.

(1) As an embodiment of the present invention, there is provided a substituted polypeptide represented by formula [I']:

or a pharmaceutically acceptable salt thereof,

Where

AA ¹ represents:

Asp,

β-Asp, β-(d)-Asp, γ-Glu or γ-(d)-Glu;

AA ² is one group selected from the group consisting of:

Ala,

a group represented by any of the formulas [IV-7], [IV-8], [IV-9], [IV-11], [IV-12] and [IV-13]:

[IV-7], [IV-8], [IV-9], [IV-11], [IV-12], [IV-13]

group represented by formula [IV-27]:

[IV-27]

Pro and the group represented by any of the formulas [II-1] and [II-2]:

[II-1], [II-2]

where R ^AA2 is hydroxy or amino; or

AA ¹ and AA ² can be taken together to form the structure of formula [IV-32]:

[IV-32];

AA ³ is one group selected from the group consisting of:

Val, Leu, Ile, group represented by the formula [IV-2]:

[IV-2]

Phe, Trp,

Tyr, Lys, a group represented by any of the formulas [IV-3], [IV-4] and [IV-5]:

[IV-3], [IV-4], [IV-5]

And

group represented by formula [IV-9]:

[IV-9];

AA ⁴ is one group selected from the group consisting of:

single bond,

Gly, (d)-Ala, (N-Me)Ala, (N-Me)Val, (N-Me)Leu, (N-Me)Ile,

Pro, (d)-Pro,

(N-Me)Phe, (d)-Phe,

(N-Me)Tyr, (d)-Tyr,

(N-Me)Ser, (d)-Ser, homoSer, (d)-Thr,

Met, (N-Me)Met,

(N-Me)Asp, Glu, (N-Me)Glu, (d)-(N-Me)Glu, homoGlu,

(N-Me)Asn,

(N-Me)Arg, (d)-Arg,

group represented by any of the formulas [IV-7], [IV-9] and [IV-13]:

[IV-7], [IV-9], [IV-13]

Lys and (N-Me)Lys,

where if AA ⁴ is Lys, then

the amino on the Lys side chain is optionally substituted with a C _2-16 alkylcarbonyl substituted at the carboxy end;

AA ⁵ is one group selected from the group consisting of:

single bond,

Ala, a group represented by the formula [IV-1]:

[IV-1]

group represented by any of the formulas [IV-27], [IV-28] and [IV-29]:

[IV-27], [IV-28], [IV-29]

Pro, (d)-Pro, β-homoPro, homoPro, group represented by the formula [II-1']:

[II-1']

Phe, His,

Th,

Arg, (d)-Arg,

group represented by any of the formulas [IV-7], [IV-9] and [IV-13]:

[IV-7], [IV-9], [IV-13]

Lys, (d)-Lys,

β-Ala, (N-Me)-β-Ala, GABA, Ape, Acp,

group represented by any of the formulas [III-6] and [III-13]:

[III-6], [III-7], [III-8], [III-9], [III-10], [III-11], [III-12], [III-13]

And

group represented by any of the formulas [IV-25] and [IV-26]:

[IV-25], [IV-26];

W ¹ is -L ¹ - or -L ¹ '-L ¹ "-; where

L ¹ represents a single bond; and

L ¹ ' represents one group selected from the group consisting of:

single bond,

β-Ala, GABA, (N-Me)GABA, Ape, Acp,

a group represented by any of the formulas [III-6] to [III-13]

[III-6], [III-7], [III-8], [III-9], [III-10], [III-11], [III-12], [III-13]

And

group represented by any of the formulas [IV-23] and [IV-24]:

[IV-23], [IV-24];

And

L ¹ " represents one group selected from the group consisting of:

single bond,

Gly, (N-Me)Gly,

Ala, (N-Me)Ala, (d)-Ala, Val, (N-Me)Val, (N-Me)Leu, (N-Me)Ile,

group represented by formula [IV-27]:

[IV-27]

Pro, (d)-Pro, homoPro, Phe, (N-Me)Phe, (d)-Phe,

His, (d)-His, Trp, (N-Me)Trp, (d)-Trp,

Tyr, (N-Me)Tyr, (d)-Tyr,

(d)-Ser, homoSer, Thr, (N-Me)Thr, (d)-Thr,

Cys, (d)-Cys, Met, (N-Me)Met,

(N-Me)Asp, Glu, (N-Me)Glu, (d)-Glu,

Asn, (N-Me)Asn, (d)-Asn, Gln, (N-Me)Gln, (d)-Gln,

Arg, (N-Me)Arg, (d)-Arg, Cit, (d)-Cit,

group represented by any of the formulas [IV-7], [IV-9], [IV-10] and [IV-13]:

[IV-7], [IV-9], [IV-10],

[IV-13]

Lys, (N-Me)Lys, (d)-Lys, a group represented by formula [IV-14]:

[IV-14]

β-Ala,

β-Asp, β-(d)-Asp, and

group represented by any of the formulas [III-6] and [III-7]:

[III-6], [III-7];

where if L ¹ " is Lys or (d)-Lys, then

amino on the side chain of Lys or (d)-Lys is optionally substituted with a group represented by formula [VII-1]:

FA ^N -AA ^N5 -AA ^N4 -AA ^N3 -AA ^N2 -AA ^N1 - [VII-1]

Where

FA ^N is C _2-16 alkylcarbonyl substituted at the end with carboxy;

AA ^N5 represents:

single bond,

Arg, (d)-Arg,

Lys, (d)-Lys,

γ-Glu, or

the group represented by formula [IV-24]:

[IV-24];

AA ^N4 represents:

single bond,

Arg, (d)-Arg,

Lys, (d)-Lys, or

the group represented by formula [IV-24]:

[IV-24];

AA ^N3 represents:

single bond,

Arg, (d)-Arg,

Lys, (d)-Lys,

γ-Glu, or

the group represented by formula [IV-24]:

[IV-24];

AA ^N2 is:

single bond, or

(d)-Lys; and

AA ^N1 represents:

single bond, or

(d)-Lys;

where if L ¹ " is Glu and AA ³ is Lys, then

the compound represented by the formula [I'] can be taken together with L ³ attached to each of the functional groups on the side chains of two amino acids to form a cyclic structure as represented by the formula [I'-α]:

[I'-α]

where L ³ is Gly, β-Ala or GABA;

L ^N1 represents the formula -C(=O)- or the formula -S(=O) ₂ -;

L ^N2 is:

single bond,

C _1-3 alkanediyl,

C _2-3 alkenediyl,

ethyndiyl,

formula -O-,

formula -C(=O)-, formula -C(=O)-NH-, or

triazolediyl;

L ² is a single bond;

ring A is an aromatic ring or a heteroaromatic ring;

R ^A1 and R ^A2 each independently represent:

hydrogen atom,

halogen atom,

C _1-6 alkyl, or

C _1-6 alkoxy;

Ring B represents:

aryl or heteroaryl;

R ^B1 , R ^B2 and R ^B3 each independently represent:

hydrogen atom,

carbamoyl,

cyano,

halogen atom,

C _1-6 alkyl optionally substituted with one hydroxy, halogen C _1-6 alkyl,

C _1-6 alkoxy optionally substituted with one hydroxy, halogen C _1-6 alkoxy,

C _1-6 alkylcarbonyl,

C _1-6 alkylcarbonylamino,

mono C _1-6 alkylaminocarbonyl, di C _1-6 alkylaminocarbonyl, wherein the alkyl in each of the mono C _1-6 alkylaminocarbonyl and di C _1-6 alkylaminocarbonyl is optionally substituted with one group selected from the group consisting of hydroxy, carboxy, carbamoyl and amino,

C _1-6 alkylsulfonyl, or

aryl;

W ^C is a single bond or linker consisting of one to three amino acids, wherein the one to three amino acids forming the linker are the same or different and each is selected from the group consisting of:

Gly,

Pro,

Arg, (d)-Arg,

Lys, (d)-Lys,

β-Ala, GABA and Ape,

where if Lys or (d)-Lys is included in the group represented by W ^C , then

amino on the side chain of Lys or (d)-Lys is optionally substituted:

C _2-16 alkylcarbonyl substituted at the end by carboxy,

Lys, wherein the amino on the side chain of Lys is optionally substituted with a C _2-16 alkylcarbonyl substituted at the end of a carboxy, or

(d)-Lys, wherein the amino on the side chain of (d)-Lys is optionally substituted with a C _2-16 alkylcarbonyl substituted at the carboxy end; and

R ^C is:

formula -OH, formula -NH ₂ ,

C _1-6 alkylamino, wherein the C _1-6 alkyl of the C _1-6 alkylamino is optionally substituted with one group selected from the group consisting of hydroxy, amino, C _1-6 alkoxy and a four- to seven-membered saturated heterocyclyl containing one nitrogen atom and optionally another containing one heteroatom, or

four to seven membered saturated heterocyclyl containing one nitrogen atom and optionally another containing one heteroatom, wherein the four to seven membered saturated heterocyclyl containing one nitrogen atom and optionally another containing one heteroatom is optionally substituted with one group selected from the group consisting of hydroxy, amino and C _1-6 alkyl, wherein the C _1-6 alkyl is optionally substituted with one carbamoyl; and two carbon atoms in the four to seven membered saturated heterocyclyl containing one nitrogen atom and optionally another containing one heteroatom are optionally crosslinked with C _1-4 alkanediyl.

(2) As another embodiment of the present invention, there is provided a substituted polypeptide or a pharmaceutically acceptable salt thereof according to (1), wherein

W ^C represents:

single bond,

Pro,

Arg, (d)-Arg,

Lys, (d)-Lys,

β-Ala, GABA, Ape,

Gly-(d)-Lys, Gly-(d)-Lys-(d)-Lys, Gly-(d)-Lys-(d)-Arg, Gly-(d)-Arg-(d)-Lys,

Lys-Lys, (d)-Lys-(d)-Lys, (d)-Lys-(d)-Lys-(d)-Lys,

Arg-Arg, (d)-Arg-(d)-Arg, (d)-Arg-(d)-Lys,

Lys-(d)-Lys-(d)-Lys, (d)-Lys-Lys-(d)-Lys, (d)-Lys-(d)-Lys-Lys,

β-Ala-(d)-Lys, β-Ala-(d)-Lys-(d)-Arg, β-Ala-(d)-Arg-(d)-Lys or β-Ala-(d)- Arg-(d)-Arg

where if Lys is contained in the group represented by W ^C ,

then the amino on the side chain of Lys is optionally substituted:

C _2-16 alkylcarbonyl substituted at the end with carboxy, or

(d)-Lys, wherein the amino on the side chain of (d)-Lys is optionally substituted with a C _2-16 alkylcarbonyl substituted at the carboxy end.

(3) As another embodiment of the present invention, there is provided a substituted polypeptide or a pharmaceutically acceptable salt thereof according to (1) or (2), wherein

ring A is a benzene ring, thiophene ring or pyridine ring;

R ^A1 and R ^A2 each independently represent:

hydrogen atom, or

halogen atom;

Ring B represents:

phenyl, oxazolyl, thiadiazolyl, pyridyl or benzofuranyl;

R ^B1 , R ^B2 and R ^B3 each independently represent:

hydrogen atom,

carbamoyl,

cyano,

halogen atom,

C _1-6 alkyl, wherein C _1-6 alkyl is optionally substituted with one hydroxy,

halogen C _1-6 alkyl,

C _1-6 alkoxy, wherein C _1-6 alkoxy is optionally substituted with one hydroxy,

halogen C _1-6 alkoxy,

C _1-6 alkylcarbonyl,

mono C _1-6 alkylaminocarbonyl, di C _1-6 alkylaminocarbonyl, wherein the alkyl in each of the mono C _1-6 alkylaminocarbonyl and di C _1-6 alkylaminocarbonyl is optionally substituted with one group selected from the group consisting of hydroxy, carboxy, carbamoyl and amino, or

C _1-6 alkylsulfonyl; and

R ^C is:

formula -OH, formula -NH ₂ ,

C _1-6 alkylamino, wherein the C _1-6 alkyl of the C _1-6 alkylamino is optionally substituted with one group selected from the group consisting of hydroxy, amino, C _1-6 alkoxy and morpholinyl, or

azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl or piperazinyl, wherein azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl or piperazinyl is optionally substituted with one group selected from the group consisting of hydroxy, amino and C _1-6 alkyl, wherein C _1-6 alkyl is optionally substituted with one carbamoyl, wherein

two carbon atoms in azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl or piperazinyl are optionally cross-linked to a C _1-4 alkanediyl.

(4) As another embodiment of the present invention, there is provided a substituted polypeptide or a pharmaceutically acceptable salt thereof according to any one of (1) to (3), wherein in the substituted polypeptide represented by formula [I'],

Ring A is a benzene ring;

ring B is phenyl;

L ¹ " represents one group selected from the group consisting of:

single bond,

Gly, (N-Me)Gly,

Ala, (N-Me)Ala, (d)-Ala, Val, (N-Me)Val, (N-Me)Leu, (N-Me)Ile,

group represented by formula [IV-27]:

[IV-27]

Pro, (d)-Pro, homoPro, Phe, (N-Me)Phe, (d)-Phe,

His, (d)-His, Trp, (N-Me)Trp, (d)-Trp,

Tyr, (N-Me)Tyr, (d)-Tyr,

(d)-Ser, homoSer, Thr, (N-Me)Thr, (d)-Thr,

Cys, (d)-Cys, Met, (N-Me)Met,

(N-Me)Asp, Glu, (N-Me)Glu, (d)-Glu,

Asn, (N-Me)Asn, (d)-Asn, Gln, (N-Me)Gln, (d)-Gln,

Arg, (N-Me)Arg, (d)-Arg, Cit, (d)-Cit,

group represented by any of the formulas [IV-7], [IV-9], [IV-10] and [IV-13]:

[IV-7], [IV-9], [IV-10], [IV-13]

Lys, (N-Me)Lys, (d)-Lys, a group represented by formula [IV-14]:

[IV-14]

β-Ala,

β-Asp, β-(d)-Asp, and

group represented by any of the formulas [III-6] and [III-7]:

[III-6], [III-7];

And

W ^C represents:

single bond,

Pro,

Arg, (d)-Arg,

Lys, (d)-Lys,

β-Ala, GABA, Ape,

Gly-(d)-Lys, Gly-(d)-Lys-(d)-Lys, Gly-(d)-Lys-(d)-Arg, Gly-(d)-Arg-(d)-Lys,

Lys-Lys, (d)-Lys-(d)-Lys, (d)-Lys-(d)-Lys-(d)-Lys,

Arg-Arg, (d)-Arg-(d)-Arg, (d)-Arg-(d)-Lys,

Lys-(d)-Lys-(d)-Lys, (d)-Lys-Lys-(d)-Lys, (d)-Lys-(d)-Lys-Lys,

β-Ala-(d)-Lys, β-Ala-(d)-Lys-(d)-Arg,

β-Ala-(d)-Arg-(d)-Lys or β-Ala-(d)-Arg-(d)-Arg.

(5) As another embodiment of the present invention, there is provided a substituted polypeptide or a pharmaceutically acceptable salt thereof according to any one of (1) to (4), wherein in the substituted polypeptide represented by formula [I'],

AA ² is one group selected from the group consisting of:

group represented by formula [II-1]:

[II-1]

And

a group represented by any of the formulas [IV-7], [IV-8], [IV-9], [IV-11] and [IV-12]:

[IV-7], [IV-8], [IV-9], [IV-11], [IV-12]

where R ^AA2 is amino;

AA ³ is Val, Leu, Ile, Phe, or Trp;

AA ⁴ is (N-Me)Val, (N-Me)Leu, (N-Me)Ile, (N-Me)Asp, or (N-Me)Glu;

AA ⁵ is β-Ala, GABA, Ape, Acp, Pro, (d)-Pro, or β-homoPro;

W ^C represents a single bond, Arg, (d)-Arg, Lys, or (d)-Lys; and

R ^C represents the formula -OH or the formula -NH ₂ .

(6) As another embodiment of the present invention, there is provided a substituted polypeptide or a pharmaceutically acceptable salt thereof according to any one of (1) to (5), wherein in the substituted polypeptide represented by formula [I'],

W ¹ represents -L ¹ '-L ¹ "-;

L ² is a single bond;

AA ¹ represents Asp;

L ¹ ' represents one group selected from the group consisting of β-Ala, GABA, Ape, Acp and a group represented by any one of formulas [IV-23] and [IV-24]:

[IV-23], [IV-24];

L ¹ " represents a single bond, Asn, (d)-Ser, (d)-Thr or Glu;

L ^N1 represents the formula -C(=O)- or the formula -S(=O) ₂ -;

L ^N2 represents the formula -O- or the formula -C(=O)-NH-;

R ^A1 and R ^A2 each represent a hydrogen atom; and

R ^B1 , R ^B2 and R ^B3 each independently represent a hydrogen atom, carbamoyl, a halogen atom, C _1-6 alkoxy or halogen C _1-6 alkoxy.

(7) As another embodiment of the present invention, there is provided a substituted polypeptide or a pharmaceutically acceptable salt thereof according to any one of (1) to (5), wherein in the substituted polypeptide represented by formula [I'],

W ¹ represents -L ¹ -, where L ¹ represents a single bond;

L ² is a single bond;

AA ¹ is β-Asp, β-(d)-Asp, γ-Glu or γ-(d)-Glu;

AA ² is one group selected from the group consisting of:

group represented by formula [II-1]:

[II-1]

And

a group represented by any of the formulas [IV-7], [IV-8], [IV-9], [IV-11] and [IV-12]:

[IV-7], [IV-8], [IV-9], [IV-11], [IV-12]

where R ^AA2 is amino;

AA ³ is Val, Leu, Ile, Phe, or Trp;

AA ⁴ is (N-Me)Val, (N-Me)Leu, (N-Me)Ile, (N-Me)Asp, or (N-Me)Glu;

AA ⁵ is β-Ala, GABA, Ape, Acp, or β-homoPro;

L ^N1 represents the formula -C(=O)- or the formula -S(=O) ₂ -;

L ^N2 represents a single bond, formula -O- or formula -C(=O)-NH-;

R ^A1 and R ^A2 each represent a hydrogen atom; and

R ^B1 , R ^B2 and R ^B3 each independently represent a hydrogen atom, carbamoyl, a halogen atom, C _1-6 alkoxy or halogen C _1-6 alkoxy.

(8) As another embodiment of the present invention, there is provided a substituted polypeptide or a pharmaceutically acceptable salt thereof according to any one of (1) to (4), wherein the substituted polypeptide represented by formula [I'] is a substituted polypeptide represented by formula [1]:

[1]

Where

AA ¹ is β-Asp, γ-Glu, or γ-(d)-Glu;

AA ² is a group represented by formula [II-1] or formula [II-2]:

[II-1], [II-2]

where R ^AA2 is hydroxy or amino;

AA ³ is Val, Leu, Ile, Phe, or Trp;

AA ⁴ represents a single bond, Pro, (N-Me)Ala, (N-Me)Val, (N-Me)Leu, (N-Me)Ile, (N-Me)Phe, (N-Me)Tyr, (N-Me)Ser, (N-Me)Asp, or (N-Me)Glu;

AA ⁵ is a single bond, Pro, (d)-Pro, β-homoPro, Arg, (d)-Arg, Lys, (d)-Lys, β-Ala, GABA, Ape, or Acp;

L ¹ represents a single bond;

L ² is a single bond;

L ^N1 represents the formula -C(=O)- or the formula -S(=O) ₂ -;

L ^N2 represents a single bond, C _1-3 alkanediyl, formula -O- or formula -C(=O)-NH-;

R ^A represents a hydrogen atom, a halogen atom, C _1-6 alkyl or C _1-6 alkoxy;

R ^B represents a hydrogen atom, carbamoyl, a halogen atom, C _1-6 alkyl or C _1-6 alkoxy;

L ^C represents a single bond, Pro, Arg, (d)-Arg, Lys, (d)-Lys, or (d)-Lys-(d)-Lys; and

R ^C represents the formula -OH or the formula -NH ₂ .

(9) As another embodiment of the present invention, there is provided a substituted polypeptide or a pharmaceutically acceptable salt thereof according to any one of (1) to (5), wherein in the substituted polypeptide represented by formula [I'],

AA ¹ is Asp, β-(d)-Asp, or γ-(d)-Glu;

AA ² is one group selected from the group consisting of:

group represented by formula [II-1]:

[II-1]

And

group represented by any of the formulas [IV-7] and [IV-9]:

[IV-7], [IV-9]

where R ^AA2 is amino;

AA ³ represents Val, Leu or Ile;

AA ⁴ is (N-Me)Ile or (N-Me)Glu;

AA ⁵ is Ape or β-homoPro;

W ¹ represents -L ¹ - or -L ¹ '-L ¹ "-,

Where

L ¹ is a single bond,

L ¹ ' represents GABA or Ape, and

L ¹ " is Asn, (d)-Ser, (d)-Thr or Glu;

L ^N1 represents the formula -C(=O)- or the formula -S(=O) ₂ -;

L ^N2 represents the formula -O- or the formula -C(=O)-NH-;

R ^A1 and R ^A2 each represent a hydrogen atom;

R ^B1 , R ^B2 and R ^B3 each independently represent a hydrogen atom, carbamoyl, a halogen atom, C _1-6 alkoxy or halogen C _1-6 alkoxy;

W ^C represents a single bond or (d)-Lys; and

R ^C represents the formula -NH ₂ .

(10) As another embodiment of the present invention, there is provided a substituted polypeptide or a pharmaceutically acceptable salt thereof according to any one of (1) to (5), wherein the substituted polypeptide is selected from the compounds shown in the following:

(11) As another embodiment of the present invention, there is provided a pharmaceutical preparation comprising a substituted polypeptide or a pharmaceutically acceptable salt thereof according to any one of (1) to (10) as an active ingredient.

(12) As another embodiment of the present invention, there is provided an MMP2 inhibitor comprising a substituted polypeptide or a pharmaceutically acceptable salt thereof according to any one of (1) to (10) as an active ingredient.

(13) As another embodiment of the present invention, there is provided an agent for suppressing the growth, infiltration or metastasis of cancer cells, comprising a substituted polypeptide or a pharmaceutically acceptable salt thereof according to any one of (1) to (10) as an active ingredient.

(14) As another embodiment of the present invention, there is provided an agent for suppressing fibrogenesis comprising a substituted polypeptide or a pharmaceutically acceptable salt thereof according to any one of (1) to (10) as an active ingredient.

(15) As another embodiment of the present invention, there is provided a medicament for the prevention or treatment of cancer or organ fibrosis, or a symptom associated with cancer or organ fibrosis, comprising a substituted polypeptide or a pharmaceutically acceptable salt thereof according to any one of (1) to (10) as an active ingredient.

ADVANTAGES OF THE INVENTION

The compounds of the present invention (hereinafter sometimes referred to as "the compounds of the present invention") have an MMP2 inhibiting effect. Some of the compounds of the present invention have a selective MMP2 inhibiting effect.

DESCRIPTION OF IMPLEMENTATION OPTIONS

The present invention provides a substituted polypeptide represented by formula [I'] or a pharmaceutically acceptable salt thereof having an MMP2 inhibiting effect.

The compounds of the present invention will be described in more detail below, but the present invention is not limited to the compounds exemplified.

In this document, "amino acid" in a broad sense means an organic compound having two functional groups: amino and carboxy, in a narrow sense (particularly in the field of biochemistry) "amino acid" means "α-amino acid". (An α-amino acid is an amino acid in which the amino group is bonded to a carbon atom to which a carboxy (α carbon) is bonded), which serves as a constituent unit of biogenic proteins.

Examples of amino acids in the present description include naturally occurring proteogenic L-amino acids; naturally occurring non-proteogenic amino acids; and amino acids of non-natural origin. Examples of non-naturally occurring amino acids include D-forms of naturally occurring proteogenic L-amino acids; chemically modified amino acids such as amino acid variants and derivatives; and chemically synthesized compounds having properties characteristic of amino acids and known in the art.

In this document, when an "amino acid" is represented by its name without an abbreviation, such as a three-letter code or a one-letter code, where the name indicates the amino acid in the L-form, the D-form, or both forms.

In this document, when "amino acid" is represented as an abbreviation, such as in a three-letter code or a one-letter code, the abbreviation means the amino acid is in the L-form. "L" or "l" is sometimes added immediately before "amino acid" to clearly indicate that the amino acid is in the L-form.

In this document, "D" or "d" added immediately before "amino acid" indicates that the amino acid is in the D-form.

As used herein, a “natural proteogenic L-amino acid” is a naturally occurring amino acid in the L-form that makes up proteins, and examples thereof include Gly, Ala, Val, Leu, Ile, Pro, Phe, His, Trp, Tyr, Ser, Thr, Met, Cys, Asp, Glu, Asn, Gln, Lys, and Arg.

In this document, "D-form of natural proteogenic L-amino acid" refers to an enantiomer of a natural proteogenic L-amino acid. Each of the natural proteogenic L-amino acids, except glycine, has at least one asymmetric carbon, so they are optically active. Amino acids are classified into L-forms and D-forms based on the structure of the L-form and D-form of glyceraldehyde.

Amino acids other than the natural proteogenic L-amino acids can also have D-forms.

In this document, “natural non-proteogenic amino acid” is a naturally occurring amino acid that does not form proteins, and examples thereof include L-norleucine (hereinafter also referred to as Nle; hereinafter, the “code following in brackets” indicates the abbreviation), β-alanine (β-Ala), and L-ornithine (Orn).

If a natural non-proteogenic amino acid has an asymmetric carbon, then there is an L-form and a D-form for the amino acid. There may also be L-forms and D-forms for amino acids other than natural non-proteogenic amino acids.

In this document, "non-naturally occurring amino acid" refers to an amino acid that does not constitute proteins and is mainly produced artificially, being an amino acid not included in the "natural proteogenic L-amino acid and natural non-proteogenic amino acid" described above. Examples of non-naturally occurring amino acids include D-forms of natural proteogenic L-amino acids (such as D-Cys, D-Ser); α-methyl amino acids (such as 2-aminoisobutyric acid (Aib)); amino acids with excess methylene in the side chain ("homo" amino acids such as L-β-homoproline (β-Hep or β-homoPro), L-homoserine (Hes or homoSer), L-homocysteine (Hec or homoCys), L-homoproline (homoPro), L-homoglutamic acid (homoGlu)); amino acids in which the side chain of the amino acid with a carboxylic acid functional group is replaced by a sulfonic acid group (for example, L-cysteine); chemically modified amino acids, such as amino acid variants and derivatives (such as hydroxyproline, L-2,3-diaminopropionic acid (Dap), L-2,4-diaminobutyric acid (Dab), N-methylglycine); and chemically synthesized compounds having properties characteristic of amino acids and known in the art (such as 4-aminobenzoic acid).

If an amino acid that is not naturally occurring has an asymmetric carbon, there is an L-form and a D-form of the amino acid.

Specific examples of "non-naturally occurring amino acid" as used herein include the following:

- (d)-Pro, (d)-Ser, (d)-Thr, (d)-Asp, (d)-Glu, (d)-Arg, (d)-Lys

- β-homoPro

- β-Ala, GABA, Ape, Acp

- (N-Me)Ala, (N-Me)Val, (N-Me)Leu, (N-Me)Ile, (N-Me)Phe, (N-Me)Tyr, (N-Me)Ser, (N-Me) Asp, (N-Me) Glu

- a group represented by formula [II-1] or formula [II-2]:

[II-1], [II-2]

where R ^AA2 is hydroxy or amino; and

- amino acids listed below in Table 1 and Table 2

The nitrogen atom involved in the peptide bond in any amino acid in the present specification may be alkylated. In this case, the amino acid is also called an "N-alkyl amino acid". Examples of alkyl include methyl and ethyl.

As used herein, the expression "β-Asp" means aspartic acid participating in the amide linkage of the main chain via the carboxy in the side chain, as shown in the structure represented by formula [III-1]. Similarly, the expressions "β-(d)-Asp", "γ-Glu" and "γ-(d)-Glu" mean the structures represented by formula [III-2] to formula [III-4].

[III-1], [III-2], [III-3], [III-4].

The expression “(N-Me)Glu(OtBu)” means the N-methyl form of the amino acid (Glu(OtBu)), as shown in the structure represented by formula [III-5].

[III-5]

The expression “(2S,4S)-(4-amino)Pro” in structure corresponding to AA ² means the structure represented by the formula [II-3]. Similarly, the expressions “(2S,4R)-(4-amino)Pro”, “(2S,4S)-(4-hydroxy)Pro”, and “(2S,4R)-(4-hydroxy)Pro” mean the structures represented by the formulas [II-4] to [II-6]. In addition, the expression “(S)-piperazine” means the structure represented by the formula [II-2].

[II-3], [II-4], [II-5], [II-6], [II-2]

In this document, "n" denotes normal, "i" denotes iso, "s" denotes secondary, "t" and "tert" each denote tertiary, "c" denotes cyclo, "o" denotes ortho, "m" denotes meta, and "p" denotes para.

"Halogen atom" refers to a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

"C _1-6 alkyl" refers to a straight or branched alkyl containing from one to six carbon atoms. Examples of "C _1-6 alkyl" include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, and n-hexyl.

"Halogen C _1-6 alkyl" refers to a linear or branched alkyl having from one to six carbon atoms and substituted with a halogen atom. The preferred number of halogen atoms is from one to five, and the preferred halogen atom is a fluorine atom. Examples of "halogen C _1-6 alkyl" include monofluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 1,1-difluoroethyl, 1,1,2,2-tetrafluoroethyl, 1,1,2,2,2-pentafluoroethyl, 2-fluoroethyl, 2-fluoro-2-methylpropyl, 2,2-difluoropropyl, 1-fluoro-2-methylpropan-2-yl, 1,1-difluoro-2-methylpropan-2-yl, 1-fluoropentyl, 1-fluorohexyl and 2,2,2-trifluoro-1-methylethyl.

"Aryl" refers to a monocyclic aromatic hydrocarbon group or a fused polycyclic aromatic hydrocarbon group having from 6 to 14 carbon atoms. Examples of "aryl" include phenyl, naphthyl, and anthryl.

"Aromatic ring" refers to a monocyclic aromatic hydrocarbon group or a fused polycyclic aromatic hydrocarbon group having 6 to 14 carbon atoms. Examples of "aromatic ring" include benzene ring, naphthalene ring, and anthracene ring.

Partially saturated aryl is also included in the term "aryl". The same applies to aromatic rings. "Partially saturated aryl" and the corresponding aromatic ring, "partially saturated aromatic ring" refer to a group in which a monocyclic aromatic hydrocarbon group or a fused polycyclic aromatic hydrocarbon group containing from 6 to 14 carbon atoms is partially saturated, and the ring has such a structure, for example, dihydroindenyl and dihydroindene ring.

"Heteroaryl" refers to a five- to seven-membered monocyclic aromatic heterocyclic group consisting of one to six carbon atoms and one or more atoms, identical or different, selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom, or a fused polycyclic aromatic heterocyclic group consisting of 9 to 14 atoms, in particular consisting of 1 to 13 carbon atoms and one or more atoms, identical or different, selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom. Examples of "heteroaryl" include imidazolyl, pyrazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isooxazolyl, oxadiazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, indolyl, benzopyrazolyl, benzotriazolyl, benzofuranyl, benzothiophenyl, quinolyl, isoquinolyl, and quinoxalyl.

"Heteroaromatic ring" refers to a five- to seven-membered monocyclic aromatic heterocycle consisting of one to six carbon atoms and one or more atoms, identical or different, selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom, or a fused polycyclic aromatic heterocycle consisting of 9 to 14 atoms, in particular consisting of 1 to 13 carbon atoms and one or more atoms, identical or different, selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom. Examples of the "heteroaromatic ring" include imidazole ring, pyrazole ring, thiophene ring, thiazole ring, isothiazole ring, thiadiazole ring, oxazole ring, isoxazole ring, oxadiazole ring, pyrrole ring, triazole ring, terazole ring, pyridine ring, pyrimidine ring, pyrazine ring, pyridazine ring, triazine ring, indole ring, benzopyrazole ring, benzotriazole ring, benzofuran ring, benzothiophene ring, quinoline ring, isoquinoline ring, and quinoxaline ring.

Partially saturated heteroaryl is also included in the term "heteroaryl". The same applies to heteroaromatic rings. "Partially saturated heteroaryl" and the corresponding heteroaromatic ring, "partially saturated heteroaromatic ring" refers to a five- to seven-membered partially saturated monocyclic heterocyclic group consisting of one to six carbon atoms and one or more atoms, identical or different, and selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom, or a partially saturated condensed polycyclic heterocyclic group consisting of 9 to 14 atoms, in particular consisting of 1 to 13 carbon atoms and one or more atoms, identical or different, and selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom, and a ring having such a structure. Examples of such compounds include oxazolidinyl, thiazolinyl, dihydropyridinyl, dihydrobenzofuranyl, chromanyl, dihydropyranopyridinyl, dihydrofuropyridinyl, tetrahydroquinolyl, dihydrobenzodioxinyl, tetrahydrotriazoloazepinyl, oxazolidine ring, thiazoline ring, dihydropyridine ring, dihydrobenzofuran ring, chroman ring, dihydropyranopyridine ring, dihydrofuropyridine ring, tetrahydroquinoline ring, tetrahydroquinoline ring, dihydrobenzodioxine ring and tetrahydrotriazoloazepine ring.

"Four- to seven-membered saturated heterocyclyl containing a nitrogen atom" refers to a four- to seven-membered monocyclic saturated heterocyclic group consisting of one nitrogen atom and three to six carbon atoms, and may further contain, in addition to the nitrogen atom, one atom selected from the group consisting of an oxygen atom, a sulfur atom, and a nitrogen atom. Examples of the "four- to seven-membered saturated heterocyclyl containing a nitrogen atom" include azetidinyl, pyrolidinyl, piperidinyl, azepanyl, morpholinyl, thiomorpholinyl, and piperazinyl.

"Four- to seven-membered saturated heterocyclyl containing one nitrogen atom and optionally further containing one heteroatom" refers to a four- to seven-membered monocyclic saturated heterocyclic group consisting of one nitrogen atom and three to six carbon atoms, and may further contain, in addition to the nitrogen atom, one atom selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom. Examples of "four- to seven-membered saturated heterocyclyl containing one nitrogen atom and optionally further containing one heteroatom" include azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, morpholinyl, thiomorpholinyl and piperazinyl.

Examples of "four- to seven-membered saturated heterocyclyl containing one nitrogen atom and optionally further containing one heteroatom, and optionally cross-linked with a C _1-4 alkanediyl" include 8-oxa-3-azabicyclo[3,2,1]octan-3-yl (a group represented by formula [VI-16]) and 3,8-diazabicyclo[3,2,1]octan-3-yl (a group represented by formula [VI-18]):

[VI-16], [VI-18]

"C _1-6 alkoxy" refers to a linear or branched alkoxy having from one to six carbon atoms. Examples of "C _1-6 alkoxy" include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, and n-hexyloxy.

"Halogen C _1-6 alkoxy" refers to a linear or branched alkoxy containing from one to six carbon atoms and substituted with a halogen atom. The preferred number of halogen atoms as substituents is from one to five, and the preferred halogen atom is a fluorine atom. Examples of "halogen C _1-6 alkoxy" include monofluoromethoxy, difluoromethoxy, trifluoromethoxy, 1-fluoroethoxy, 1,1-difluoroethoxy, 1,1,2,2-tetrafluoroethoxy, 2-fluoroethoxy, 2,2,2-trifluoroethoxy, 3,3,3-trifluoropropoxy, 1,3-difluoropropan-2-yloxy, 2-fluoro-2-methylpropoxy, 2,2-difluoropropoxy, 1-fluoro-2-methylpropan-2-yloxy, 1,1-difluoro-2-methylpropoxy-2-yloxy and 4,4,4-trifluorobutoxy.

"C _1-6 alkylcarbonyl" refers to a group in which the "C _1-6 alkyl" described above and carbonyl are bonded together. Examples of "C _1-6 alkylcarbonyl" include methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl, tert-butylcarbonyl, n-pentylcarbonyl, and n-hexylcarbonyl.

"C _1-6 alkylcarbonylamino" refers to a group in which the "C _1-6 alkylcarbonyl" described above and an amino group are bonded together. Examples of "C _1-6 alkylcarbonylamino" include methylcarbonylamino, ethylcarbonylamino, n-propylcarbonylamino, isopropylcarbonylamino, n-butylcarbonylamino, isobutylcarbonylamino, sec-butylcarbonylamino, tert-butylcarbonylamino, n-pentylcarbonylamino and n-hexylcarbonylamino.

"C _1-6 alkylamino" refers to an amino group having one or two "C _1-6 alkyl" described above as substituents, which are the same or different. Examples of "C _1-6 alkylamino" include methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, sec-butylamino, tert-butylamino, n-pentylamino, n-hexylamino, dimethylamino, diethylamino, di(n-propyl)amino, di(isopropyl)amino, ethylmethylamino and methyl(n-propyl)amino.

"Mono C _1-6 alkylamino" refers to an amino having one "C _1-6 alkyl" as described above as a replacement. Examples of "mono C _1-6 alkylamino" include methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, sec-butylamino, tert-butylamino, n-pentylamino, and n-hexylamino.

"DiC _1-6 alkylamino" refers to an amino having two "C _1-6 alkyl" described above as substituents, which are the same or different. Examples of "diC _1-6 alkylamino" include dimethylamino, diethylamino, di(n-propyl)amino, di(isopropyl)amino, ethylmethylamino, and methyl(n-propyl)amino.

"Mono C _1-6 alkylaminocarbonyl" refers to a group in which the "mono C _1-6 alkylamino" described above and carbonyl are bonded together. Examples of "mono C _1-6 alkylaminocarbonyl" include methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, isopropylaminocarbonyl, n-butylaminocarbonyl, isobutylaminocarbonyl, n-pentylaminocarbonyl and n-hexylaminocarbonyl.

"Di-C _1-6 alkylaminocarbonyl" refers to a group in which the "di-C _1-6 alkylamino" described above and carbonyl are bonded together. Examples of "di-C _1-6 alkylaminocarbonyl" include dimethylaminocarbonyl, diethiaminocabinyl, di(n-propyl)aminocarbonyl, di(isopropyl)aminocarbonyl, ethylmethylaminocarbonyl, and methyl(n-propyl)aminocarbonyl.

"C _1-6 alkylcarbonyl" refers to a group in which the "C _1-6 alkyl" described above and carbonyl are bonded together. Examples of "C _1-6 alkylcarbonyl" include methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl, tert-butylcarbonyl, n-pentylcarbonyl, and n-hexylcarbonyl.

"C _2-16 alkylcarbonyl" refers to a group in which a straight or branched alkyl having from 2 to 16 carbon atoms and a carbonyl are linked together. Examples of "C _2-16 alkylcarbonyl" include ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl, tert-butylcarbonyl, n-decylcarbonyl (undecanoyl), n-dodecylcarbonyl (tridecanoyl), and n-tetradecylcarbonyl (pentadecanoyl).

"C _2-16 alkylcarbonyl terminally substituted with carboxy" refers to a group in which the terminal of the "C _2-16 alkyl" in the "C _2-16 alkylcarbonyl" described above is substituted with carboxy. Examples of the "C _2-16 alkylcarbonyl terminally substituted with carboxy" include 11-carboxyundecanoyl, 13-carboxytridecanoyl, and 15-carboxypentadecanoyl.

"C _1-6 alkylsulfonyl" refers to a group in which the "C _1-6 alkyl" described above and sulfonyl are bonded to each other. Examples of "C _1-6 alkylsulfonyl" include methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl, n-pentylsulfonyl and n-hexylsulfonyl.

"C _1-3 alkanediyl" refers to a divalent hydrocarbon formed by the removal of one hydrogen atom from an alkyl group containing from one to three carbon atoms. Examples of "C _1-3 alkanediyl" include methanediyl, ethane-1,1-diyl, ethane-1,2-diyl, propane-1,1-diyl, propane-1,3-diyl, and propane-2,2-diyl.

"C _1-4 alkanediyl" refers to a divalent hydrocarbon formed by the removal of one hydrogen atom from an alkyl group containing from one to four carbon atoms. Examples of "C _1-4 alkanediyl" include methanediyl, ethane-1,1-diyl, ethane-1,2-diyl, propane-1,1-diyl, propane-1,3-diyl, propane-2,2-diyl, and butane-1,4-diyl.

"C _2-3 alkenediyl" refers to a divalent unsaturated hydrocarbon formed by the removal of one hydrogen atom from an alkenyl having two or three carbon atoms. Examples of "C _2-3 alkenediyl" include ethene-1,1-diyl, ethene-1,2-diyl, prop-1-ene-1,1-diyl, prop-2-ene-1,1-diyl, prop-1-ene-1,3-diyl, prop-2-ene-1,3-diyl, and prop-1-ene-2,2-diyl.

"Triazolediyl" refers to a divalent triazole formed by removing two hydrogen atoms from the triazole ring. Examples of "triazolediyl" include structures represented by formulas [VIII-1] through [VIII-5]:

[VIII-1], [VIII-2], [VIII-3], [VIII-4], [VIII-5]

The abbreviations used in this document refer to the structures listed in Table 1 through Table 4.

[Table 1-1]

[Table 2-1]

[Table 2-2]

[Table 2-3]

[Table 2-4]

[Table 3-1]

[Table 4-1]

[Table 4-2]

Preferred embodiments of the substituted polypeptide represented by formula [I'] or a pharmaceutically acceptable salt thereof according to the present invention are as follows.

Preferably, AA ¹ is Asp, β-Asp, β-(d)-Asp, γ-Glu or γ-(d)-Glu,

more preferably, AA ¹ is β-Asp, γ-Glu or γ-(d)-Glu,

where even more preferably, AA ¹ is γ-(d)-Glu,

in another more preferably, AA ¹ is β-(d)-Asp or γ-(d)-Glu,

where even more preferably, AA ¹ is β-(d)-Asp, and

in another more preferably, AA ¹ is Asp.

Preferably, AA ² is a group represented by formula [II-1] or formula [II-2]:

[II-1], [II-2]

a group represented by the formula [IV-7], [IV-8], [IV-9], [IV-11] or [IV-12]:

[IV-7], [IV-8], [IV-9], [IV-11], [IV-12]

Ala,

the group represented by formula [IV-27]:

[IV-27]

or

Pro,

wherein, preferably, R ^AA2 is hydroxy or amino,

more preferably, AA ² is a group represented by formula [II-1]:

[II-1]

or a group represented by formula [IV-7], [IV-8], [IV-9], [IV-11] or [IV-12]:

[IV-7], [IV-8], [IV-9], [IV-11], [IV-12]

where preferably R ^AA2 is amino,

even more preferably, AA ² is

group represented by formula [IV-7] or [IV-9]:

[IV-7], [IV-9]

or a group represented by formula [II-1]:

[II-1]

where preferably R ^AA2 is amino,

particularly preferably, AA ² is

group represented by formula [II-1]:

[II-1]

where preferably R ^AA2 is amino, and

in another particularly preferred, AA ² is

group represented by formula [IV-7] or [IV-9]:

[IV-7], [IV-9].

Preferably, AA ³ is a Val, Leu, Ile, group represented by the formula [IV-2]:

[IV-2]

Phe, a group represented by the formula [IV-3], [IV-4], or [IV-5]:

[IV-3], [IV-4], [IV-5]

or Trp,

more preferably, AA ³ is Val, Leu, Ile, Phe or Trp,

even more preferably, AA ³ is Val, Leu or Ile,

particularly preferably, AA ³ is Val,

in another particularly preferred, AA ³ is Leu, and

in another particularly preferred, AA ³ is Ile.

Preferably, AA ⁴ is a single bond, Pro, Gly, homoSer, Met, Glu, (N-Me)Ala, (N-Me)Val, (N-Me)Leu, (N-Me)Ile, (N-Me)Phe, (N-Me)Tyr, (N-Me)Ser, (N-Me)Met, (N-Me)Asp, (N-Me)Glu, (d)-Pro, (d)-Ala, (d)-Phe, (d)-Tyr, (d)-Ser, (d)-Thr or (d)-(N-Me)Glu,

more preferably, AA ⁴ is (N-Me)Ala, (N-Me)Val, (N-Me)Leu, (N-Me)Ile, (N-Me)Phe, (N-Me)Tyr, (N-Me)Ser, (N-Me)Met, (N-Me)Asp, (N-Me)Glu, (d)-Pro, (d)-Ala, (d)-Phe, (d)-Tyr, (d)-Ser, (d)-Thr or (d)-(N-Me)Glu,

even more preferably, AA ⁴ is (N-Me)Glu or (N-Me)Asp,

wherein particularly preferably AA ⁴ is (N-Me)Glu, and

even more preferably, AA ⁴ is (N-Me)Ile, (N-Me)Val or (N-Me)Leu,

wherein AA ⁴ is particularly preferably (N-Me)Ile.

Preferably, AA ⁵ is β-Ala, GABA, Ape, Acp, Pro, (d)-Pro, β-homoPro, single bond, Arg, (d)-Arg,

the group represented by [IV-7], [IV-9] or [IV-13]:

[IV-7], [IV-9], [IV-13]

Lys, (d)-Lys,

Ala, a group represented by the formula [IV-1]:

[IV-1]

group represented by formula [IV-27], [IV-28] or [IV-29]:

[IV-27], [IV-28], [IV-29]

Phe, His, Thr, or

group represented by any of the formulas [III-6] - [III-13]:

[III-6], [III-7], [III-8], [III-9], [III-10], [III-11], [III-12], [III-13]

more preferably, AA ⁵ is β-Ala, GABA, Ape, Acp, Pro, (d)-Pro, β-homoPro, single bond, Arg, (d)-Arg,

a group represented by the formula [IV-7], [IV-9] or [IV-13]:

[IV-7], [IV-9], [IV-13]

Lys or (d)-Lys,

even more preferably, AA ⁵ is β-Ala, GABA, Ape, Acp, Pro, (d)-Pro or β-homoPro, and

particularly preferably, AA ⁵ is β-Ala, GABA, Ape, Acp or β-homoPro.

Preferably, W ¹ is -L ¹ - or -L ¹ '-L ¹ "-,

where L ¹ represents a single bond,

L ¹ ' is selected from the group consisting of β-Ala, GABA, Ape, Acp,

group represented by any of the formulas [III-6] - [III-13]:

[III-6], [III-7], [III-8], [III-9], [III-10], [III-11], [III-12], [III-13]

and a group represented by any of the formulas [IV-23] and [IV-24]:

[IV-23], [IV-24];

and L ¹ " is a single bond, Asn, (d)-Ser, (d)-Thr, Lys, Arg or Glu,

more preferably, W ¹ is -L ¹ - or -L ¹ '-L ¹ "-,

where L ¹ represents a single bond,

L ¹ ' is β-Ala, GABA, Ape, Acp, or

group represented by any of the formulas [III-6] - [III-13]:

[III-6], [III-7], [III-8], [III-9], [III-10], [III-11], [III-12], [III-13]

and L ¹ " is Asn, (d)-Ser, (d)-Thr or Glu,

where even more preferably W ¹ is -L ¹ - or -L ¹ '-L ¹ "-,

where L ¹ represents a single bond,

L ¹ ' is β-Ala, GABA, Ape, or Acp, and

L ¹ " is Asn, (d)-Ser, (d)-Thr or Glu,

where particularly preferably W ¹ is -L ¹ -,

where L ¹ represents a single bond, and

in another more preferably, W ¹ is -L ¹ '-L ¹ "-,

where L ¹ ' represents a group represented by the formula [IV-23] or [IV-24]:

[IV-23], [IV-24];

and L ¹ " represents a single bond.

Preferably, L ² is a single bond.

Preferably, L ^N1 is of formula -C(=O)- or formula -S(=O) ₂ -,

more preferably, L ^N1 is the formula -C(=O)-, and

in another more preferably, L ^N1 represents the formula -S(=O) ₂ -.

Preferably, L ^N2 is a single bond of formula -O- or formula -C(=O)-NH-,

more preferably, L ^N2 is the formula -O- or the formula -C(=O)-NH-,

even more preferably, L ^N2 is of formula -O-, and

even more preferably, L ^N2 is of the formula -C(=O)-NH-.

Preferably, ring A is a benzene ring or a pyridine ring,

more preferably, ring A is a benzene ring,

preferably, R ^A1 and R ^A2 each independently represent a hydrogen atom or a halogen atom, and

more preferably, R ^A1 and R ^A2 each represent a hydrogen atom.

Preferably, ring B is phenyl or pyridyl,

more preferably, ring B is phenyl,

preferably, R ^B1 , R ^B2 and R ^B3 each independently represent a hydrogen atom, carbamoyl, a halogen atom, C _1-6 alkyl, halogen C _1-6 alkyl, C _1-6 alkoxy or halogen C _1-6 alkoxy, and

more preferably, R ^B1 , R ^B2 and R ^B3 each independently represent a hydrogen atom, carbamoyl, a halogen atom, C _1-6 alkoxy or halogen C _1-6 alkoxy.

Preferably, W ^C is a single bond or a linker consisting of one or more amino acids, where

one to three amino acids forming the linker are not limited, but are preferably the same or different and each is selected from the group consisting of: Gly, Pro, Arg, (d)-Arg, Lys, (d)-Lys, β-Ala, GABA and Ape, where

if Lys or (d)-Lys is included in the group represented by W ^C ,

then the amino on the side chain of Lys or (d)-Lys is optionally substituted:

C _2-16 alkylcarbonyl substituted at the end by carboxy,

Lys, wherein the amino on the side chain of Lys is optionally substituted with a C _2-16 alkylcarbonyl substituted at the end of a carboxy, or

(d)-Lys, wherein the amino on the side chain of (d)-Lys is optionally substituted with a C _2-16 alkylcarbonyl substituted at the carboxy end,

more preferably, W ^C represents a single bond, Pro, Arg, (d)-Arg, Lys, (d)-Lys or (d)-Lys-(d)-Lys,

even more preferably, W ^C represents a single bond, Arg, (d)-Arg, Lys or (d)-Lys,

particularly preferably, W ^C represents a single bond, and

in another particularly preferred embodiment, W ^C is (d)-Lys.

Preferably, R ^C is:

formula -OH, formula -NH ₂ ,

C _1-6 alkylamino, wherein the C _1-6 alkyl of the C _1-6 alkylamino is optionally substituted with one group selected from the group consisting of hydroxy, amino, and four- to seven-membered saturated heterocyclyl containing one nitrogen atom, or

a four- to seven-membered saturated heterocyclyl containing one nitrogen atom and optionally another containing one heteroatom, wherein the four- to seven-membered saturated heterocyclyl containing one nitrogen atom and optionally another containing one heteroatom is optionally substituted with one group selected from the group consisting of hydroxy and C _1-6 alkyl, wherein the C _1-6 alkyl is optionally substituted with one carbamoyl; and two carbon atoms in the four- to seven-membered saturated heterocyclyl containing one nitrogen atom and optionally another containing one heteroatom are optionally crosslinked with a C _1-4 alkanediyl,

more preferably, R ^C is the formula -OH or the formula -NH ₂ , and

even more preferably, R ^C is of the formula -NH ₂ .

Another preferred embodiment of the compounds of the present invention is a substituted polypeptide represented by formula [I'], or a pharmaceutically acceptable salt thereof, wherein

AA ¹ is β-Asp, γ-Glu or γ-(d)-Glu,

AA ² is a group represented by formula [II-1] or formula [II-2]:

[II-1], [II-2]

where R ^AA2 is hydroxy or amino,

AA ³ is Val, Leu, Ile, Phe or Trp,

AA ⁴ is a single bond, Pro, (N-Me)Ala, (N-Me)Val, (N-Me)Leu, (N-Me)Ile, (N-Me)Phe, (N-Me)Tyr, (N-Me)Ser, (N-Me)Asp, or (N-Me)Glu,

AA ⁵ is a single bond, Pro, (d)-Pro, β-homoPro, Arg, (d)-Arg, Lys, (d)-Lys, β-Ala, GABA, Ape or Acp,

W ¹ represents L ¹ and L ¹ represents a single bond,

L ² is a single bond,

L ^N1 is the formula -S(=O) ₂ -,

L ^N2 represents a single bond, formula -O- or formula -C(=O)-NH-,

ring A is a benzene ring,

R ^A1 and R ^A2 each represent a hydrogen atom,

ring B is phenyl,

R ^B1 , R ^B2 and R ^B3 each independently represent a hydrogen atom, carbamoyl, a halogen atom or C _1-6 alkoxy,

W ^C represents a single bond, Pro, Arg, (d)-Arg, Lys, (d)-Lys, or (d)-Lys-(d)-Lys, and

R ^C represents the formula -NH ₂ .

Another preferred embodiment of the present invention is a substituted polypeptide represented by formula [I'], or a pharmaceutically acceptable salt thereof, wherein

AA ¹ is β-Asp, γ-Glu or γ-(d)-Glu,

where even more preferably, AA ¹ is γ-(d)-Glu,

AA ² is a group represented by the formula [II-1]:

[II-1]

where R ^AA2 is amino,

AA ³ represents Val, Leu or Ile,

where even more preferably, AA ³ is Val,

even more preferably, AA ³ is Leu, and

even more preferably, AA ³ is Ile,

AA ⁴ is (N-Me)Val, (N-Me)Leu, (N-Me)Ile, (N-Me)Asp or (N-Me)Glu,

where even more preferably, AA ⁴ is (N-Me)Val, (N-Me)Leu or (N-Me)Ile,

wherein particularly preferably AA ⁴ is (N-Me)Ile,

even more preferably, AA ⁴ is (N-Me)Asp or (N-Me)Glu,

wherein AA ⁴ is particularly preferably (N-Me)Glu,

AA ⁵ is Pro, (d)-Pro, β-homoPro, β-Ala, GABA, Ape or Acp,

where even more preferably, AA ⁵ is Pro, (d)-Pro or β-homoPro,

where particularly preferably AA ⁵ is β-homoPro,

even more preferably, AA ⁵ is β-Ala, GABA, Ape or Acp,

where particularly preferably AA ⁵ is β-Ala, GABA or Ape,

W ¹ is L ¹ ,

L ¹ is a single bond,

L ² is a single bond,

L ^N1 is the formula -S(=O) ₂ -,

L ^N2 represents a single bond, formula -O- or formula -C(=O)-NH-,

where even more preferably, L ^N1 is of the formula -C(=O)-, and

even more preferably, L ^N1 is of the formula -S(=O) ₂ -,

ring A is a benzene ring,

R ^A1 and R ^A2 each represent a hydrogen atom,

ring B is phenyl,

R ^B1 , R ^B2 and R ^B3 each independently represent a hydrogen atom, carbamoyl, a halogen atom or C _1-6 alkoxy,

W ^C represents a single bond or (d)-Lys,

where even more preferably, W ^C represents a single bond, and

even more preferably, W ^C is (d)-Lys, and

R ^C represents the formula -NH ₂ .

Another preferred embodiment of the compounds of the present invention is a substituted polypeptide or a pharmaceutically acceptable salt thereof, wherein

W ¹ is -L ¹ '-L ¹ »-,

L ² is a single bond, and

the polypeptide is represented by the formula [I'-A]:

[I'-A],

wherein preferably, embodiments AA ² , AA ³ , AA ⁴ , AA ⁵ , L ¹ ', L ¹ ", L ^N1 , L ^N2 , R ^B1 , R ^B2 , R ^B3 , W ^C and R ^C are as described above.

In a more preferred embodiment of the polypeptide represented by formula [I'-A] or a pharmaceutically acceptable salt thereof,

AA ² is a group represented by the formula [II-1]:

[II-1]

or a group represented by formula [IV-7], [IV-8], [IV-9], [IV-11] or [IV-12]:

[IV-7], [IV-8], [IV-9], [IV-11], [IV-12]

where R ^AA2 is amino,

AA ³ is Val, Leu, Ile, Phe or Trp,

AA ⁴ is (N-Me)Val, (N-Me)Leu, (N-Me)Ile, (N-Me)Asp or (N-Me)Glu,

AA ⁵ is β-Ala, GABA, Ape, Acp, Pro, (d)-Pro or β-homoPro,

L ¹ ' represents β-Ala, GABA, Ape, Acp or a group represented by the formula [IV-23] or [IV-24]:

[IV-23], [IV-24];

L ¹ " represents a single bond, Asn, (d)-Ser, (d)-Thr or Glu,

L ^N1 is the formula -C(=O)- or the formula -S(=O) ₂ -,

L ^N2 is the formula -O- or the formula -C(=O)-NH-,

R ^B1 , R ^B2 and R ^B3 each independently represent a hydrogen atom, carbamoyl, a halogen atom, C _1-6 alkoxy or halogen C _1-6 alkoxy,

W ^C represents a single bond, Arg, (d)-Arg, Lys, or (d)-Lys, and

R ^C represents the formula -OH or the formula -NH ₂ .

In an even more preferred embodiment of the polypeptide represented by formula [I'-A] or a pharmaceutically acceptable salt thereof,

AA ² is a group represented by the formula [IV-7] or [IV-9]:

[IV-7], [IV-9]

AA ³ represents Val, Leu or Ile,

AA ⁴ is (N-Me)Ile or (N-Me)Glu,

AA ⁵ is β-Ala, GABA, Ape, Acp or β-homoPro,

L ¹ ' represents GABA or Ape,

L ¹ " is Asn, Glu, (d)-Ser or (d)-Thr,

L ^N1 is the formula -C(=O)- or the formula -S(=O) ₂ -,

L ^N2 is the formula -O- or the formula -C(=O)-NH-,

R ^B1 represents carbamoyl or fluorine atom,

R ^B2 represents a hydrogen atom,

R ^B3 represents a hydrogen atom,

W ^C is a single bond, and

R ^C represents the formula -NH ₂ .

A particularly preferred mode of the present embodiment is as follows.

In a polypeptide represented by formula [I'-A] or a pharmaceutically acceptable salt thereof,

AA ² is a group represented by the formula [IV-7] or [IV-9]:

[IV-7], [IV-9]

AA ³ represents Val,

AA ³ could be Leu,

AA ³ may be Ile,

AA ⁴ is (N-Me)Ile,

AA ⁴ may be (N-Me)Glu,

AA ⁵ is β-Ala, GABA, Ape or Acp,

AA ⁵ may be β-homoPro,

L ¹ ' represents GABA or Ape,

L ¹ " is Asn, Glu, (d)-Ser or (d)-Thr,

the combination of L ¹ ' and L ¹ " is preferably GABA-Asn, Ape-Asn, Ape-Glu, Ape-(d)-Ser or Ape-(d)-Thr,

L ^N1 represents the formula -C(=O)-,

L ^N1 can be the formula -S(=O) ₂ -,

L ^N2 is the formula -O- and L ^N2 can be the formula -C(=O)-NH-,

R ^B1 represents carbamoyl or fluorine atom,

R ^B2 represents a hydrogen atom,

R ^B3 represents a hydrogen atom,

W ^C is a single bond, and

R ^C represents the formula -NH ₂ .

In another particularly preferred mode of the present embodiment,

the substituted polypeptide represented by formula [I'-A] is any of the following:

Another preferred embodiment of the compounds of the present invention is a substituted polypeptide or a pharmaceutically acceptable salt thereof,

where W ¹ represents -L ¹ -, where L ¹ represents a single bond,

L ² is a single bond, and

the substituted polypeptide is represented by the formula [I'-B]:

[I'-B],

where preferably, embodiments AA ¹ , AA ² , AA ³ , AA ⁴ , AA ⁵ , L ^N1 , L ^N2 , R ^B1 , R ^B2 , R ^B3 , W ^C and R ^C are as described above.

In a more preferred embodiment of the polypeptide represented by formula [I'-B] or a pharmaceutically acceptable salt thereof,

AA ¹ is β-Asp, β-(d)-Asp, γ-Glu or γ-(d)-Glu,

AA ² is a group represented by the formula [II-1]:

[II-1]

or a group represented by formula [IV-7], [IV-8], [IV-9], [IV-11] or [IV-12]:

[IV-7], [IV-8], [IV-9], [IV-11], [IV-12]

where R ^AA2 is amino,

AA ³ is Val, Leu, Ile, Phe or Trp,

AA ⁴ is (N-Me)Val, (N-Me)Leu, (N-Me)Ile, (N-Me)Asp or (N-Me)Glu,

AA ⁵ is β-Ala, GABA, Ape, Acp or β-homoPro,

L ^N1 is the formula -C(=O)- or the formula -S(=O) ₂ -,

L ^N2 represents a single bond, formula -O- or formula -C(=O)-NH-,

R ^B1 , R ^B2 and R ^B3 each independently represent a hydrogen atom, carbamoyl, a halogen atom, C _1-6 alkoxy or halogen C _1-6 alkoxy,

W ^C represents a single bond, Arg, (d)-Arg, Lys, or (d)-Lys, and

R ^C represents the formula -OH or the formula -NH ₂ .

In an even more preferred embodiment of the polypeptide represented by formula [I'-B] or a pharmaceutically acceptable salt thereof,

AA ¹ is β-(d)-Asp or γ-(d)-Glu,

AA ² is a group represented by the formula [II-1]:

[II-1]

or a group represented by formula [IV-7] or [IV-9]:

[IV-7], [IV-9]

where R ^AA2 is amino,

AA ³ represents Val, Leu or Ile,

AA ⁴ is (N-Me)Ile or (N-Me)Glu,

AA ⁵ is β-Ala, GABA, Ape, Acp or β-homoPro,

L ^N1 is the formula -C(=O)- or the formula -S(=O) ₂ -,

L ^N2 is the formula -O- or the formula -C(=O)-NH-,

R ^B1 represents carbamoyl, chlorine atom, bromine atom, methoxy or trifluoromethoxy,

R ^B2 represents a hydrogen atom,

R ^B3 represents a hydrogen atom,

W ^C represents a single bond or (d)-Lys, and

R ^C represents the formula -NH ₂ .

A particularly preferred mode of the present embodiment is as follows.

In a polypeptide represented by formula [I'-B] or a pharmaceutically acceptable salt thereof,

AA ¹ is β-(d)-Asp,

AA ¹ may be γ-(d)-Glu,

AA ² is a group represented by the formula [II-1]:

[II-1]

where R ^AA2 is amino,

AA ² may be a group represented by the formula [IV-7] or [IV-9]:

[IV-7], [IV-9]

AA ³ represents Val,

AA ³ could be Leu,

AA ³ may be Ile,

AA ⁴ is (N-Me)Ile,

AA ⁴ may be (N-Me)Glu,

AA ⁵ is β-Ala, GABA, Ape or Acp,

AA ⁵ may be β-homoPro,

L ^N1 is the formula -C(=O)-,

L ^N1 can be the formula -S(=O) ₂ -,

L ^N2 is the formula -O-,

L ^N2 can be of the formula -C(=O)-NH-,

R ^B1 represents carbamoyl, chlorine atom, bromine atom, methoxy or trifluoromethoxy,

R ^B2 represents a hydrogen atom,

R ^B3 represents a hydrogen atom,

W ^C is a single bond,

W ^C can be (d)-Lys, and

R ^C represents the formula -NH ₂ .

In another particularly preferred mode of the present embodiment,

the substituted polypeptide represented by formula [I'-B] is any of the following:

Another preferred embodiment of the compounds of the present invention is a substituted polypeptide or a pharmaceutically acceptable salt thereof,

where L ² is a single bond and

the substituted polypeptide is represented by the formula [I'-C]:

[I'-C],

Where

preferably, the variants AA ¹ , AA ² , AA ³ , AA ⁴ , AA ⁵ , W ¹ , L ^N1 , L ^N2 , R ^B1 , R ^B2 , R ^B3 , W ^C and R ^C are as described above.

In a more preferred embodiment of the polypeptide represented by formula [I'-C] or a pharmaceutically acceptable salt thereof,

AA ¹ is Asp, β-(d)-Asp or γ-(d)-Glu,

AA ² is a group represented by the formula [IV-7] or [IV-9]:

[IV-7], [IV-9]

or a group represented by formula [II-1]:

[II-1]

where R ^AA2 is amino,

AA ³ represents Val, Leu or Ile,

AA ⁴ is (N-Me)Ile or (N-Me)Glu,

AA ⁵ is Ape or β-homoPro,

W ¹ represents -L ¹ - or -L ¹ '-L ¹ »-,

where L ¹ represents a single bond,

L ¹ ' is GABA or Ape, and

L ¹ " is Asn, (d)-Ser, (d)-Thr or Glu,

L ^N1 is the formula -C(=O)- or the formula -S(=O) ₂ -,

L ^N2 is the formula -O- or the formula -C(=O)-NH-,

R ^B1 , R ^B2 and R ^B3 each independently represent a hydrogen atom, carbamoyl, a halogen atom, C _1-6 alkoxy or halogen C _1-6 alkoxy,

W ^C represents a single bond or (d)-Lys, and

R ^C represents the formula -NH ₂ .

In an even more preferred embodiment of the polypeptide represented by formula [I'-C] or a pharmaceutically acceptable salt thereof,

AA ¹ is Asp,

AA ¹ may be β-(d)-Asp,

AA ¹ may be γ-(d)-Glu,

AA ² is a group represented by the formula [IV-7] or [IV-9]:

[IV-7], [IV-9]

AA ² can be a group represented by the formula [II-1']:

[II-1']

where R ^AA2 is amino,

AA ³ represents Val,

AA ³ could be Leu,

AA ³ may be Ile,

AA ⁴ is (N-Me)Ile,

AA ⁴ may be (N-Me)Glu,

AA ⁵ represents Ape,

AA ⁵ may be β-homoPro,

W ¹ represents -L ¹ - or -L ¹ '-L ¹ "-,

L ¹ is a single bond,

the combination of L ¹ ' and L ¹ " (-L ¹ '-L ¹ "-) represents GABA-Asn, Ape-Asn, Ape-Glu, Ape-(d)-Ser or Ape-(d)-Thr,

L ^N1 is the formula -C(=O)-,

L ^N1 can be the formula -S(=O) ₂ -,

L ^N2 is the formula -O-,

L ^N2 can be of the formula -C(=O)-NH-,

R ^B1 represents carbamoyl, chlorine atom, bromine atom, methoxy or trifluoromethoxy,

R ^B2 represents a hydrogen atom,

R ^B3 represents a hydrogen atom,

W ^C is a single bond,

W ^C can be (d)-Lys, and

R ^C represents the formula -NH ₂ .

In a particularly preferred mode of the present invention,

the substituted polypeptide represented by formula [I'-C] is any of the following:

,

,

In another particularly preferred mode of the present embodiment,

the substituted polypeptide represented by the formula [I'-C] is as follows:

.

In another particularly preferred mode of the present embodiment,

the substituted polypeptide represented by the formula [I'-C] is as follows:

.

In another particularly preferred mode of the present embodiment,

the substituted polypeptide represented by the formula [I'-C] is as follows:

.

In another particularly preferred mode of the present embodiment,

the substituted polypeptide represented by the formula [I'-C] is as follows:

.

In another particularly preferred mode of the present embodiment,

the substituted polypeptide represented by the formula [I'-C] is as follows:

.

In another particularly preferred mode of the present embodiment,

the substituted polypeptide represented by the formula [I’-C] is as follows:

.

In another particularly preferred mode of the present embodiment,

the substituted polypeptide represented by the formula [I’-C] is as follows:

.

In another particularly preferred mode of the present embodiment,

the substituted polypeptide represented by the formula [I’-C] is as follows:

.

In another particularly preferred mode of the present embodiment,

the substituted polypeptide represented by the formula [I’-C] is as follows:

.

In another particularly preferred mode of the present embodiment,

the substituted polypeptide represented by the formula [I’-C] is as follows:

.

In another particularly preferred mode of the present embodiment,

the substituted polypeptide represented by the formula [I’-C] is as follows:

.

In another particularly preferred mode of the present embodiment,

the substituted polypeptide represented by the formula [I’-C] is as follows:

.

In another particularly preferred mode of the present embodiment,

the substituted polypeptide represented by the formula [I’-C] is as follows:

.

In another particularly preferred mode of the present embodiment,

the substituted polypeptide represented by the formula [I’-C] is as follows:

.

In another particularly preferred mode of the present embodiment,

the substituted polypeptide represented by the formula [I’-C] is as follows:

.

Another preferred embodiment of the compounds of the present invention is a substituted polypeptide represented by formula [1], or a pharmaceutically acceptable salt thereof, wherein

AA ¹ is β-Asp, γ-Glu or γ-(d)-Glu,

AA ² is a group represented by formula [II-1] or formula [II-2]:

[II-1], [II-2]

where R ^AA2 is hydroxy or amino,

AA ³ is Val, Leu, Ile, Phe or Trp,

AA ⁴ is a single bond, Pro, (N-Me)Ala, (N-Me)Val, (N-Me)Leu, (N-Me)Ile, (N-Me)Phe, (N-Me)Tyr, (N-Me)Ser, (N-Me)Asp, or (N-Me)Glu,

AA ⁵ is a single bond, Pro, (d)-Pro, β-homoPro, Arg, (d)-Arg, Lys, (d)-Lys, β-Ala, GABA, Ape or Acp,

L ¹ is a single bond,

L ² is a single bond,

L ^N1 is the formula -S(=O) ₂ -,

L ^N2 represents a single bond, formula -O- or formula -C(=O)-NH-,

R ^A represents a hydrogen atom,

R ^B represents a hydrogen atom, carbamoyl, halogen atom or C _1-6 alkoxy,

L ^C represents a single bond, Pro, Arg, (d)-Arg, Lys, (d)-Lys, or (d)-Lys-(d)-Lys, and

R ^C represents the formula -NH ₂ .

Each of the compounds of the present invention is a compound having a polypeptide backbone consisting of three to seven amino acids and further having a substituted benzoyl or substituted phenylsulfonyl, and may be in the form of a pharmaceutically acceptable salt thereof.

Examples of the pharmaceutically acceptable salt include: inorganic acid salts such as hydrochlorides, hydrobromides, hydroiodides, phosphates, sulfates and nitrates; acid addition salts such as sulfonates including methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates and trifluoromethanesulfonates and organic acid salts including oxalates, tartrates, citrates, maleates, succinates, acetates, trifluoroacetates, benzoates, mandalates, ascorbates, lactates, gluconates and malates; amino acid salts such as glycinates, lysinates, arginates, ornithinates, glutamates and aspartates; inorganic salts such as lithium salts, sodium salts, potassium salts, calcium salts and magnesium salts; and salts with an organic base such as ammonium salts, triethylamine salts, diisopropylamine salts and cyclohexylamine salts. The salts include hydrated salts.

Each of the compounds of the present invention may have an asymmetric center, and in this case, various optical isomers exist for it. Thus, each of the compounds of the present invention may exist as an individual optically active substance in any of the (R)-form and the (S)-form, or as a racemate or a mixture (RS). For a compound having two or more asymmetric centers, diastereomers additionally exist due to their optical isomerism. The scope of the compounds of the present invention also includes mixtures containing all forms in any ratio. For example, diastereomers can be separated by a method well known to those skilled in the art, such as a fractional crystallization method, and optically active substances can be obtained by an organic chemistry method well known to those skilled in the art for this purpose. In addition, geometric isomers such as a cis form and a trans form may exist for each of the compounds of the present invention. Moreover, each of the compounds of the present invention exhibits tautomerism, and various tautomers thereof exist. The scope of the compounds of the present invention also includes these isomers and mixtures containing them, in any ratio.

In addition, if any of the compounds of the present invention or a salt thereof forms a hydrate or a solvate, the hydrate or solvate is also included within the scope of the compounds of the present invention or their salts.

"Matrix metalloprotease 2 (MMP2)" is one of the zinc-active site endopeptidases.

As described above, MMP2 degrades extracellular matrix including collagen and gelatin, and thus participates in cell infiltration and migration, metastasis, etc., thus participating in pathological conditions of cancer, organ fibrosis, and so on.

Therefore, cancer and organ fibrosis and symptoms related to cancer and organ fibrosis can be prevented or treated by inhibiting MMP2.

The compounds of the present invention have an effect of inhibiting MMP2. Accordingly, the compounds of the present invention can be used as an MMP2 inhibitor or an active ingredient of a drug for preventing or treating cancer or organ fibrosis.

In addition, the compounds of the present invention can be used as an active ingredient of a medicine for the prevention or treatment of symptoms associated with cancer and organ fibrosis.

Examples of "cancers" include breast cancer, pancreatic cancer, bladder cancer, colorectal cancer, ovarian cancer, prostate cancer, brain tumors, stomach cancer, hepatocellular carcinoma, head and neck cancer, melanoma, uterine cancer, esophageal cancer, renal cell carcinoma, lung cancer, and glioma. Examples of "cancer-related symptoms" include pain due to tumor cell proliferation or tumor growth, weight loss, and paraneoplastic syndrome.

Examples of "organ fibrosis" include chronic kidney disease, interstitial pneumonia, and idiopathic pulmonary fibrosis. Examples of "symptoms related to organ fibrosis" include proteinuria, renal dysfunction, etc. in chronic kidney disease, and dyspnea on exertion, dry cough, etc. in interstitial pneumonia and idiopathic pulmonary fibrosis.

The MMP2 inhibiting action of any of the compounds of the present invention can be evaluated by a known procedure such as the method described below in the Experimental Examples herein.

For the pharmaceutical preparations according to the present invention, a compound having an MMP2 inhibiting effect, which is any of the compounds of the present invention contained in the pharmaceutical preparations, or a pharmaceutically acceptable salt thereof, may be administered alone or together with a pharmaceutically acceptable additive.

As the agent, a general excipient or diluent and, if necessary, a binder, a disintegrating agent, a lubricating agent, a coating agent, a sugar coating agent, a pH adjuster and a solubilizer or an aqueous or non-aqueous solvent which is generally used as an additive can be used. Specific examples of additives may include water, lactose, dextrose, fructose, sucrose, sorbitol, mannitol, polyethylene glycol, propylene glycol, starch, corn starch, acacia, gelatin, arginate, calcium silicate, calcium phosphate, cellulose, aqueous syrup, methylcellulose, polyvinylpyrrolidone, alkyl para-hydroxybenzoate, talc, stearic acid, magnesium stearate, agar, pectin, acacia, glycerin, sesame oil, olive oil, soybean oil, cocoa butter, ethylene glycol, low viscosity hydroxypropyl cellulose (HPC-L), microcrystalline cellulose, carboxymethyl cellulose (CMC), sodium carboxymethyl cellulose (CMC-Na) and other common additives.

The pharmaceutical preparation of the present invention may be in any form of solid compositions, liquid compositions and other compositions, and the optimal form is selected as needed.

The pharmaceutical preparation of the present invention can be prepared, for example, into a tablet, pill, capsule, granule, powder agent, powder, solution, emulsion, suspension or injection by a conventional preparation technology by adding the above-mentioned additive to any of the compounds of the present invention.

The pharmaceutical preparation of the present invention can be formulated by forming a clathrate compound with any of the compounds of the present invention and α-, β- or γ-cyclodextrin or methylated cyclodextrin.

With respect to the compounds that can be used in combination with any of the compounds of the present invention, the pharmaceutical preparations of the present invention can be prepared as a single formulation (combination drug) or two or more formulations (concomitant drugs) obtained by separate formulation.

If these compounds are formulated separately into two or more formulations, the individual formulations may be administered simultaneously or separately at specified intervals. In the latter case, either formulation may be administered first. The two or more formulations may be administered in different numbers of doses per day. The two or more formulations may be administered by different routes.

If these compounds are formulated separately into two or more formulations, they may be administered simultaneously or separately at very short intervals, and how to use them in combination should be indicated by means of a document such as an accompanying document or an advertising brochure for a commercially available pharmaceutical product.

It is also necessary to separately formulate these active ingredients in the form of a set consisting of two compositions.

The form of administration when any of the compounds of the present invention is used as an MMP2 inhibitor or the like is not limited, and any of the compounds of the present invention can be directly administered orally or parenterally. Alternatively, an agent containing any of the compounds of the present invention as an active ingredient can be administered orally or parenterally.

Also, in a case where any of the compounds of the present invention is used as an agent for preventing or treating cancer or organ fibrosis or symptoms associated with cancer or organ fibrosis, any of the compounds of the present invention can be directly administered orally or parenterally. Alternatively, an agent containing any of the compounds of the present invention as an active ingredient can be administered orally or parenterally.

For parenteral administration, intravenous administration, subcutaneous administration or transdermal administration are preferred.

Examples of the dosage form for parenteral administration include an injection, a drip infusion, a drug implant, a transdermal drug, a transmucosal drug, and a patch, and the dosage form may be a microsphere formulation.

The dose of any of the compounds of the present invention varies depending on subjects, administration routes, target diseases, symptoms, etc., and it is generally desirable to orally or parenterally administer to an adult patient a single dose of 0.1 mg to 1000 mg, preferably 1 mg to 200 mg, once to three times a day or once every 2 to 3 days.

Examples of the preparation of the compositions of the compounds of the present invention will be shown below.

Example of receiving 1

A granule containing the following components is obtained.

Components: compound represented by the general formula [I'], lactose and corn starch, HPC-L.

The compound represented by the general formula [I'] and lactose are sieved. Corn starch is sieved. They are mixed using a mixer. An aqueous solution of HPC-L is added to the mixed powder and the resulting mixture is kneaded, granulated (extrusion granulation) and then dried. The resulting dry granule is sieved through a vibrating sieve to obtain a granule.

Example of receiving 2

A powder for encapsulation is obtained containing the following components.

Components: compound represented by the general formula [I'], lactose and corn starch, magnesium stearate.

The compound, the compound represented by the general formula [I'], and lactose are sifted. Corn starch is sifted. They are mixed together with magnesium stearate using a mixer to obtain a powder. The resulting powder can be encapsulated.

Example of getting 3

An encapsulation granule is obtained containing the following components.

Components: compound represented by the general formula [I'], lactose and corn starch, HPC-L.

The compound represented by the general formula [I'] and lactose are sieved. Corn starch is sieved. They are mixed using a mixer. An aqueous solution of HPC-L is added to the mixed powder, the resulting mixture is kneaded, granulated and then dried. The resulting dry granules are sieved through a vibrating sieve to adjust the particle size and granules are obtained. The resulting granules can be encapsulated.

Example of getting 4

Tablets containing the following components are obtained.

Components: compound represented by the general formula [I'], lactose, microcrystalline cellulose, magnesium stearate and CMC-Na.

The compound represented by the general formula [I'], lactose, microcrystalline cellulose and CMC-Na are sieved and mixed together. Magnesium stearate is added to the mixed powder to obtain a mixed powder for the formulation. This mixed powder is subjected to direct compression to obtain a tablet.

Example of getting 5

An injection containing the following components is received.

Ingredients: compound represented by general formula [I'], purified egg yolk lecithin, oleic acid, purified soybean oil, glycerin and water for injection.

The compound represented by the general formula [I'], purified egg yolk lecithin and oleic acid are added to purified soybean oil to dissolve therein, then water for injection mixed with glycerin is added, and the resulting mixture is emulsified with an emulsifier. Water for injection is also added thereto, and the resulting mixture is poured into aliquots into ampoules, which are sealed and sterilized to obtain injections.

The methods for producing the compound [I'] according to the present invention will be described in detail below, but the production is not limited to the exemplified production methods. The solvent used for the production may be any solvent that does not inhibit individual reactions, and does not limit the following description.

When preparing compound [I'], the order of the preparation steps can be changed accordingly.

When prepared, each parent compound can be used in the form of its salt, and examples of such salts include the “pharmaceutically acceptable salt” provided above.

Compound [I'] can be obtained by solid-phase synthesis, liquid-phase synthesis or a combination of both. Examples of the preparation by solid-phase synthesis will be shown in the following preparation methods.

Compound [I'] can be prepared by the methods shown in any of Schemes 1-9, or any combination thereof.

The side chain of each amino acid forming the polypeptide group of the compound [I'] may have a functional group, and the functional group may be protected by a protecting group. Examples of the protecting group include tBu for carboxy, Trt for carbamoyl, tBu for hydroxy, tBu for phenolic hydroxide, tBu for thiol (sulfanyl), Boc for amino, Trt for imidazolyl, Boc for indolyl, and Pbf for guanidino. Each of these protecting groups can be deprotected by treatment with an acid.

Each of the amino acids can be used for production even if the functional group in the side chain is not protected.

Method A: A method for producing compound [1-f], a compound in which the amino acid of the N-terminal amino acid of the polypeptide group is sulfonylated and the carboxy of the C-terminal amino acid is amidated (-CONH ₂ )

Compound [1-f] can be obtained, for example, by solid-phase synthesis, the essence of which is described below (Scheme 1).

Scheme 1

Where

R ^A1 , R ^A2 , R ^B1 , R ^B2 , R ^B3 , L ^N2 , ring A and ring B have the same definitions as described above,

HZ ^x -OH is an amino acid,

x is an integer from 1 to m,

m is an integer between 2 and 15,

where Z ^x corresponds to AA ^x , L ² , W ¹ or W ^c in the compound represented by formula [I'] and may represent a single bond, and

PG ^x is a liposoluble protecting group that protects amino acids (HZ ^x -OH).

(1) [Stage 1-1]

The resin having an Fmoc protected amino (compound [1-a]) is subjected to Fmoc removal using a base.

(2) [Stage 1-2]

The resin obtained in (1) is reacted with an amino acid whose amino is substituted with a liposoluble protecting group (PG ^x ) (compound [1-b]) to effect an amidation reaction between the free amino in the resin and the carboxy in compound [1-b].

(3) [Stage 1-3]

The liposoluble protecting group of the amino N-terminal amino acid of the polypeptide group in the compound obtained in (2) is deprotected.

(4)

By repeating steps (2) and (3) two or more times, a compound [1-c] can be obtained in which the carboxy of the C-terminal amino acid of the polypeptide group is bound to the resin and the amino of the N-terminal amino acid is free.

(5) [Stage 1-4]

Compound [1-e] can be obtained by reacting compound [1-c] obtained in (4) with compound [1-d] to sulfonylate free amino in compound [1-c].

(6) [Stage 1-5]

Compound [1-f], one of the compounds of the present invention, can be obtained by using an acid on the compound [1-e] obtained in (5) to cleave the bond with the resin. Examples of the acid usable in the present step may include TFA.

At the same time, if a protected functional group is present in the side chain of an amino acid forming a polypeptide group, the protecting group of the functional group may be simultaneously deprotected.

The compound [1-f] obtained by the described method can be isolated/purified by known separation/purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization and chromatography.

In the method described in Scheme 1, the resin [1-a], the compound [1-b] and the compound [1-d] used as the starting compounds can be obtained by producing by a known method, or by purchasing commercially available products thereof.

Method B: a method for producing compound [2-c], a compound in which the amino acid of the N-terminal amino acid of the polypeptide group is acylated and the carboxy of the C-terminal amino acid is amidated (-CONH ₂ )

Compound [2-c] can be obtained, for example, by solid-phase synthesis, the essence of which is described below (Scheme 2), using compound [1-c] as a starting material.

Scheme 2

Where

R ^A1 , R ^A2 , R ^B1 , R ^B2 , R ^B3 , L ^N2 , ring A, ring B, HZ ^x -OH, x, m and Z ^x have the same definitions as described above, and

Y ¹ represents hydroxy or chlorine atom.

(1) [Stage 2-1]

Compound [2-b] can be obtained by allowing compound [2-a] to react with compound [1-c] for amidation reaction.

(2) [Stage 2-2]

Compound [2-c], one of the compounds of the present invention, can be obtained by using an acid on the compound [2-b] obtained in (1) to cleave the bond with the resin. Examples of acids usable in the present step may include TFA.

At the same time, if a protected functional group is present on the side chain of an amino acid forming a polypeptide group, the protecting group of the functional group may be simultaneously deprotected.

The compound [2-c] obtained by the described method can be isolated/purified by known separation/purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization and chromatography.

In the method described in Scheme 2, the compound [2-a] used as a starting material can be obtained by a known method or by purchasing a commercially available product thereof. The compound [1-c] can be obtained by the method described in Scheme 1.

Method C-1: A method for producing compound [3-h], a compound in which the amino group of the N-terminal amino acid of the polypeptide portion is sulfonylated or acylated, and the carboxy group of the C-terminal amino acid is secondarily or tertiarily amidated.

Compound [3-h] can be obtained, for example, by solid-phase synthesis, the essence of which is described below (Scheme 3).

Examples of the resin (resin [3-a]) used in the present production method may include chlorotrityl chloride resin and Wang resin.

Scheme 3

Where

R ^A1 , R ^A2 , R ^B1 , R ^B2 , R ^B3 , L ^N1 , L ^N2 , ring A, ring B, HZ ^x -OH, x, m, Z ^x , PG ^x and Y ¹ have the same definitions as described above,

R ^r represents hydroxy or chlorine atom,

R ^c' and R ^c" are the same or different and each represents a hydrogen atom or C _1-6 alkyl, wherein C _1-6 alkyl is optionally substituted with one group selected from the group consisting of hydroxy, amino and C _1-6 alkoxy,

R ^c' and R ^c" can be taken together with the adjacent nitrogen atom to form a four- to seven-membered saturated heterocycle containing a nitrogen atom, where

a four- to seven-membered saturated heterocycle containing a nitrogen atom formed by R ^c' and R ^c" taken together with the adjacent nitrogen atom, optionally substituted with one group selected from the group consisting of hydroxy, amino, C _1-6 alkyl and C _1-6 alkoxy, and

two carbon atoms in a four- to seven-membered saturated heterocycle containing a nitrogen atom formed by R ^c' and R ^c" taken together with the adjacent nitrogen atom, optionally cross-linked with a C _1-4 alkanediyl.

(1) [Stage 3-1]

Compound [3-c] can be prepared by reacting the resin (compound [3-a]) with an amino acid whose amino acid is substituted with a liposoluble protecting group (PG ¹ ) (compound [3-b]).

(2) [Stage 3-2]

The liposoluble protecting group (PG ¹ ) in compound [3-c] obtained in (1) is deprotected.

(3) [Stage 3-3]

The compound obtained in (2) is reacted with an amino acid whose amino is substituted with a liposoluble protecting group (PG ^x ) (compound [1-b]) to undergo an amidation reaction between the free amino in the compound obtained in (1) and the carboxy in compound [1-b].

(4) [Stage 3-4]

The liposoluble protecting group of the amino N-terminal amino acid of the polypeptide group in the compound obtained in (3) is deprotected.

(5)

By repeating steps (3) and (4) two or more times, a compound [3-d] can be obtained in which the carboxy of the C-terminal amino acid of the polypeptide group is bonded to the resin and the amino of the N-terminal amino acid is free.

(6) [Stage 3-5]

Compound [3-e] can be obtained by reacting compound [3-d] obtained in (5) with compound [1-d] or compound [2-a] to sulfonate or acylate free amino in compound [3-d].

(7) [Stage 3-6]

The compound [3-f] in which the carboxyl of the C-terminal amino acid of the polypeptide group is free can be obtained by using an acid on the compound [3-e] obtained in (6) to cleave the bond with the resin. Examples of the acid used in the present step may include TFA.

At the same time, if a protected functional group is present on the side chain of an amino acid forming a polypeptide group, the protecting group of the functional group may be simultaneously deprotected.

(8) [Stage 3-7]

Compound [3-h], one of the compounds of the present invention, can be obtained by allowing compound [3-g] to act on compound [3-f] obtained in (7) for amidation reaction.

The compound [3-h] obtained by the described method can be isolated/purified by known separation/purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization and chromatography.

In the method described in Scheme 3, compound [3-a], compound [3-b], compound [1-b], compound [1-d], compound [2-a] and [3-g] used as starting compounds can be obtained by a known method or by purchasing commercially available products thereof.

Method C-2: A method for producing compound [4-e], a compound in which the amino of the N-terminal amino acid of the polypeptide group is sulfonylated or acylated, and the carboxy of the C-terminal amino acid is secondary or tertiary amidated

Alternatively, compound [4-e] can be obtained, for example, by solid-phase synthesis, the essence of which is described below (Scheme 4).

In Scheme 4, as an example, a method for obtaining a compound is presented, where the functional group is present in the side chain of the m-th amino acid, counted from the C-terminal amino acid of the polypeptide group in the compound [4-e].

Examples of the resin used in the present production method may include, as in Scheme 3, chlorotrityl chloride resin and Wang resin.

Scheme 4

Where

R ^A1 , R ^A2 , R ^B1 , R ^B2 , R ^B3 , L ^N1 , L ^N2 , ring A, ring B, HZ ^x -OH, x, m, Z ^x , R ^c' and R ^c» have the same definitions as described above,

m' is an integer between 1 and 15, provided that the relation "m'≤m" is satisfied,

L ^sc is C _1-4 alkanediyl,

FG ^sc is the above functional group present on the side chain of the m-th amino acid, counting from the C-terminal amino acid of the polypeptide group,

wherein examples of the functional group may include the formula -O- (formula -OH), the formula -S- (formula -SH), the formula -NH- (formula -NH ₂ ), the formula -C(=O)O- (formula -C(=O)OH), the formula -C(=O)NH- (formula -C(=O)NH ₂ ) and the formula -NHC(=NH)NH- (-NHC(=NH)NH ₂ ), and

PG ^sc is a protecting group for a functional group,

wherein examples of the functional group may include, as described above, tBu, Trt, Boc and Pbf.

(1) [Stage 4-1]

Compound [4-b], in which the carboxyl of the C-terminal amino acid of the polypeptide group is free, can be obtained by using an acid on compound [4-a] to cleave the bond with the resin.

Meanwhile, the removal of the protective group (PG ^sc ) present on the side chain of the m-th amino acid counted from the C-terminal amino acid can be prevented by using a weak acid as the acid. Examples of the weak acid may include HFIP, acetic acid, and dilute TFA.

(2) [Stage 4-2]

Compound [4-d] can be obtained by allowing compound “4-c” to act on compound [4-b] obtained in (1) to undergo amidation reaction between free carboxy in compound [4-b] and amino in compound [4-c].

(3) [Stage 4-3]

Compound [4-e], one of the compounds of the present invention, can be produced by using an acid to remove the above-mentioned protective group (PG ^sc ) present on the side chain of the m-th amino acid counted from the C-terminal amino acid. Examples of the acid used in the present step may include TFA.

The compound [4-e] obtained by the described method can be isolated/purified by known separation/purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization and chromatography.

In the method described in Scheme 4, the compound [4-c] used as the starting compound can be obtained by a known method or by purchasing a commercially available product thereof. The compound [4-a] can be obtained by the method described in Scheme 3.

Method D: A method for producing a compound [5-f] in which a functional group is present on the side chain of an amino acid forming a polypeptide group, the functional group is substituted by a polypeptide linker, and the amino acid of the N-terminal amino acid of the polypeptide linker is replaced with “C _1-20 alkylcarbonyl substituted with carboxy”

Compound [5-f] can be obtained by solid-phase synthesis, the essence of which is described below (Scheme 5).

In this document, the polypeptide linker consists of one to five amino acids.

In Scheme 5, as an example, a method for producing a compound is shown, wherein a functional group is present on the side chain of the m-th amino acid, counting from the C-terminal amino acid of the polypeptide group in the compound [5-f], the functional group is substituted by a polypeptide linker, and the amino of the N-terminal amino acid of the polypeptide linker is substituted by “C _1-20 alkylcarbonyl substituted with carboxy”.

Scheme 5

Where

R ^A1 , R ^A2 , R ^B1 , R ^B2 , R ^B3 , L ^N1 , L ^N2 , ring A, ring B, HZ ^x -OH, x, m, m', Z ^x and L ^sc have the same definitions as described above,

PG ^s' is a protecting group for the above functional group (FG ^sc' ) present on the side chain of an amino acid, where examples of the protecting group include Dde, ivDde, Alloc and Mtt for amino,

HZ ^{sc y} -OH is an amino acid that forms a polypeptide linker attached to a functional group (FG ^sc' ),

y is an integer between 1 and p,

p is an integer between 0 and 5,

PG ^{sc y} is a liposoluble protecting group that protects amino acids (HZ ^{sc y} -OH),

FG ^sc' is a functional group present on the side chain of an amino acid; examples of the functional group may include the formula -NH- (formula -NH ₂ ) and the formula -COO- (formula -COOH); Scheme 5 shows the case where FG ^sc' is the formula -NH- (formula -NH ₂ ), and

n is an integer between 1 and 20.

(1) [Stage 5-1]

The protecting group (PG ^S' ) for the functional group present on the side chain of the m-th amino acid, counting from the C-terminal amino acid of the polypeptide group in compound [5-a] is subjected to selective deprotection.

(2) [Stage 5-2]

The compound obtained in (1) is reacted with an amino acid whose amino is substituted with a liposoluble protecting group (PG ^{sc y} ) (compound [5-b]) to undergo an amidation reaction between the free functional group (FG ^sc' ) in the compound obtained in (1) and the carboxy in compound [5-b].

(3) [Stage 5-3]

The liposoluble protecting group (PG ^{sc y} ) is deprotected.

(4)

By repeating steps (2) and (3) one or more times, a compound [5-c] can be obtained in which the carboxy of the C-terminal amino acid of the polypeptide group is bonded to the resin, the functional group present on the side chain of the m-th amino acid, counting from the C-terminal amino acid, is substituted by the polypeptide linker, the amino of the N-terminal amino acid of the polypeptide linker is free.

(5) [Stage 5-4]

Compound [5-e] can be obtained by reacting compound [5-c] obtained in (4) with compound [5-d], which is an alkane dicarboxylic acid, to react amidation of free amino in compound [5-c] with one carboxy in compound [5-d].

(6) [Stage 5-5]

Compound [5-f], one of the compounds of the present invention, can be obtained by using an acid on the compound [5-e] obtained in (5) to cleave a bond with a resin. Examples of the acid used in the present step may include TFA.

At the same time, if a protected functional group is present on the side chain of an amino acid forming a polypeptide group, the protecting group of the functional group may be simultaneously deprotected.

The compound [5-f] obtained by the described method can be isolated/purified by known separation/purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization and chromatography.

In the method described in Scheme 5, compound [5-b] and compound [5-d] used as starting compounds can be obtained by a known method or by purchasing commercially available products thereof. Compound [5-a] can be obtained by the method described in Scheme 1 or Scheme 2 or, or a method similar to any of them.

Method E: A method for producing a compound [6-c] in which a functional group is present on the side chain of each of two amino acids of the amino acids forming a polypeptide group, and the functional groups are substituted with the same polypeptide linker (-Z ^{sc 1} -Z ^{sc 2} -…-Z ^{sc y'} -) to form a ring.

Compound [6-c] can be obtained, for example, by solid-phase synthesis, the essence of which is described below (Scheme 6).

In this document, the polypeptide linker consists of one to five amino acids.

In Scheme 6, as an example, a method for obtaining a compound is presented, where the functional group is present on the side chain of the m-th and m"-th amino acid, counting from the C-terminal amino acid of the polypeptide group, and the functional groups are substituted with the same polypeptide linker to form a ring.

Scheme 6

Where

R ^A1 , R ^A2 , R ^B1 , R ^B2 , R ^B3 , L ^N1 , L ^N2 , ring A, ring B, HZ ^x -OH, x, m, m', Z ^x and L ^sc have the same definitions as described above,

m" is an integer from 2 to 15, provided that the relation "m'<m"≤m" is satisfied,

the polypeptide linker (-Z ^{sc 1} -Z ^{sc 2} -…-Z ^{sc y'} -) in compound [6-c] corresponds to L ³ in the compound represented by formula [I'], where L ³ is Gly, β-Ala or GABA,

y' is an integer between 1 and p',

p' is an integer between 1 and 4,

L ^sc' and L ^sc" each represent C _1-4 alkanediyl,

FG ^sc' and FG ^sc" each represent a functional group present on the side chain of an amino acid, wherein the functional group is of formula -O- (formula -OH), formula -S- (formula -SH), formula -NH- (formula -NH ₂ ), formula -C(=O)O- (formula -C(=O)OH) or formula -C(=O)NH- (formula -C(=O)NH ₂ ), and

PG ^sc' and PG ^sc" each represent a protecting group for a functional group present on the side chain of an amino acid, where the functional group is, for example, Dde, ivDde, Alloc, or allyl.

(1) [Stage 6-1]

The protecting group (PG ^sc' ) for the functional group present on the side chain of the m-th amino acid, counted from the C-terminal amino acid of the polypeptide group in compound [6-a] is subjected to selective deprotection.

(2) [Stage 6-2]

The compound obtained in (1) is reacted with an amino acid whose amino is substituted with a liposoluble protecting group (PG ^{sc y'} ) (compound [6-d]) to undergo an amidation reaction between the free functional group (FG ^sc' ) in the compound obtained in (1) and the carboxy in compound [6-d] whose amino is protected with a liposoluble protecting group.

(3) [Stage 6-3]

The liposoluble protecting group is deprotected.

(4)

By repeating steps (2) and (3) once or several times, a compound [6-b] can be obtained in which a functional group present on the side chain of the m-th amino acid counted from the C-terminal amino acid of the polypeptide group is substituted by a polypeptide linker, the amino acid of the N-terminal amino acid of the polypeptide linker is free, and a functional group (FG ^sc" ) present on the side chain of the m"th amino acid counted from the C-terminal amino acid is protected by a protecting group (PG ^sc" ).

(5) [Stage 6-4]

The protecting group (PG ^sc" ) present on the side chain of the m" amino acid, counted from the C-terminal amino acid of the polypeptide group in compound [6-b], is subjected to selective deprotection.

(6) [Stage 6-5]

"Free functional group (FG ^sc" )" and "free amino in Z ^scp' " in the compound obtained in (5) react to undergo intramolecular cyclization reaction.

(7) [Stage 6-6]

Compound [6-c], one of the compounds of the present invention, can be obtained by using an acid on the compound obtained in (6) to cleave a bond with a resin. Examples of the acid used in the present step may include TFA.

At the same time, if a protected functional group is present on the side chain of an amino acid forming a polypeptide group, the protecting group of the functional group may be simultaneously deprotected.

The compound [6-c] obtained by the described method can be isolated/purified by known separation/purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization and chromatography.

In the method described in Scheme 6, the compound [6-d] used as a starting compound can be obtained by a known method or by purchasing a commercially available product thereof. The compound [6-a] can be obtained by the method described in Scheme 1 or Scheme 2 or a method similar to any of these.

Method F: A method for preparing compound [7-f] which has a substituent, “alkylaminocarbonyl substituted with a functional group,” on ring B

Compound [7-f] can be obtained, for example, by solid-phase synthesis, the essence of which is described below (Scheme 7).

Scheme 7

Where

R ^A1 , R ^A2 , R ^B1 , R ^B2 , L ^N1 , L ^N2 , ring A, ring B, HZ ^x -OH, x, m, Z ^x and Y ¹ have the same definitions as described above,

L ^R is C _1-4 alkanediyl,

FG ^R represents a functional group attached to "alkyl (L ^R )""alkylaminocarbonyl (L ^R -NHC(=O)-)", the substituent present on the B ring, and examples thereof may include the formula -O- (formula -OH), the formula -S- (formula -SH), the formula -NH- (formula -NH ₂ ), the formula -C(=O)O- (formula -C(=O)OH) and the formula -C(=O)NH- (formula -C(=O)NH ₂ ),

PG ^R is a protecting group for a functional group (FG ^R ), where examples of the protecting group include tBu for carboxy, Trt for carbamoyl, tBu for hydroxy, tBu for thiol (sulfanyl), and Boc for amino, and each of these protecting groups can be deprotected by treatment with acid.

(1) [Stage 7-1]

Compound [7-c], which has carboxy on ring B, can be obtained by reacting compound [1-c] with compound [7-a] or compound [7-b] to sulfonate or acylate the free amino N-terminal amino acid of the polypeptide group in compound [1-c].

(2) [Stage 7-2]

Compound [7-e] can be obtained by reacting compound [7-c] with compound [7-d] to undergo an amidation reaction between carboxy in compound [7-c] and amino in compound [7-d].

(3) [Stage 7-3]

The compound [7-f], one of the compounds of the present invention, can be obtained by using an acid on the compound [7-e] obtained in (2) to cleave the bond with the resin and simultaneously remove the protecting group (PG ^R ) of the functional group of the "alkylaminocarbonyl substituted with a functional group (FG ^R )" present on the ring B. Examples of the acid used in the present step may include TFA. Meanwhile, if the protected functional group is present on the side chain of the amino acid forming the polypeptide group, the protecting group of the functional group can be simultaneously deprotected.

The compound [7-f] obtained by the described method can be isolated/purified by known separation/purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization and chromatography.

In the method described in Scheme 7, compound [7-a], compound [7-b], and compound [7-d] used as starting compounds can be obtained by a known method or by purchasing commercially available products thereof. Compound [1-c] can be obtained by the method described in Scheme 1 or a similar method.

Method G: A method for preparing compound [8-f] in which ring A is directly substituted with ring B

Compound [8-f] can be obtained, for example, by solid-phase synthesis, the essence of which is described below (Scheme 8).

Scheme 8

Where

R ^A1 , R ^A2 , R ^B1 , R ^B2 , R ^B3 , L ^N1 , ring A, ring B, HZ ^x -OH, x, m, Z ^x and Y ¹ have the same definitions as described above,

LG ^A represents a leaving group, wherein examples of the leaving group may include a chlorine atom, a bromine atom, an iodine atom and a halogen C _1-6 alkylsulfonyloxy, and

M ^B is a boronic acid, a boronic acid ester, an alkyltin, an alkylsilane, or an alkoxysilane.

(1) [Stage 8-1]

Compound [8-c] can be obtained by reacting compound [1-c] with compound [8-a] or compound [8-b] to sulfonate or acylate the free amino N-terminal amino acid of the polypeptide group in compound [1-c].

(2) [Stage 8-2]

The compound [8-e] in which the ring A is directly substituted with the ring B can be obtained by coupling the compound [8-c] with the compound [8-d] in the presence of a metal catalyst and a base. Examples of the metal catalyst may include tetrakis(triphenylphosphine)palladium, palladium acetate and tris(dibenzylideneacetone)dipalladium. Examples of the base may include metal carbonates such as cesium carbonate, potassium carbonate and sodium carbonate and potassium phosphate, cesium fluoride and tetrabutylammonium fluoride.

(3) [Stage 8-3]

Compound [8-f], one of the compounds of the present invention, can be obtained by using an acid on the compound [8-e] obtained in (2) to cleave a bond with a resin. Examples of the acid used in the present step may include TFA.

At the same time, if a protected functional group is present on the side chain of an amino acid forming a polypeptide group, the protecting group of the functional group may be simultaneously deprotected.

The compound [8-f] obtained by the described method can be isolated/purified by known separation/purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization and chromatography.

In the method described in Scheme 8, compound [8-a], compound [8-b], and compound [8-d] used as starting compounds can be obtained by a known method or by purchasing commercially available products thereof. Compound [1-c] can be obtained by the method described in Scheme 1 or a similar method.

Method H: A method for preparing compound [9-f] which has an “arylcarbonylamino (ring formula B-C(=O)NH-)” substituent on ring A

Compound [9-f] can be obtained, for example, by solid-phase synthesis, the essence of which is described below (Scheme 9).

Scheme 9

Where

R ^A1 , R ^A2 , R ^B1 , R ^B2 , R ^B3 , L ^N1 , ring A, ring B, HZ ^x -OH, x, m, Z ^x and Y ¹ have the same definitions as described above,

Y ² represents hydroxy or chlorine atom, and

PG ^A is a liposoluble protecting group that protects the amino present on the A ring,

wherein examples of the liposoluble group may include Fmoc.

(1) [Stage 9-1]

As in Step 8-1 of Scheme 8, compound [9-c] can be obtained by reacting compound [1-c] with compound [9-a] or compound [9-b] to sulfonate or acylate the free amino N-terminal amino acid of the polypeptide group in compound [1-c].

(2) [Stage 9-2]

The liposoluble protecting group (PG ^A ) in compound [9-c] obtained in (1) is deprotected.

(3) [Stage 9-3]

Compound [9-e] can be obtained by reacting the compound obtained in (2) with compound [9-d] to undergo an amidation (acylation) reaction between free amino in the compound obtained in (2) and carboxy in compound [9-d].

(4) [Stage 9-4]

Compound [9-f], one of the compounds of the present invention, can be obtained by using an acid on the compound [9-e] obtained in (3) to cleave a bond with a resin. Examples of the acid used in the present step may include TFA.

At the same time, if a protected functional group is present on the side chain of an amino acid forming a polypeptide group, the protecting group of the functional group may be simultaneously deprotected.

The compound [9-f] obtained by the described method can be isolated/purified by known separation/purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization and chromatography.

In the method described in Scheme 9, compound [9-a], compound [9-b], and compound [9-d] used as starting compounds can be obtained by a known method or by purchasing commercially available products thereof. Compound [1-c] can be obtained by the method described in Scheme 1 or a similar method.

All kinds of amino acids can be used as amino acids in the methods shown in Schemes 1-9 for producing compound [I'] of the present invention, and examples of amino acids include natural proteogenic L-amino acids: Gly, Ala, Val, Leu, Ile, Pro, Phe, His, Trp, Tyr, Ser, Thr, Met, Cys, Asp, Glu, Asn, Gln, Lys and Arg.

In addition, amino acids of non-natural origin, including natural non-proteogenic amino acids and the D-forms of natural proteogenic L-amino acids described above, can be used in the present production methods.

In this document, examples of non-naturally occurring amino acids used in the present production methods include the following:

- (d)-Pro, (d)-Ser, (d)-Thr, (d)-Asp, (d)-Glu, (d)-Arg, (d)-Lys

- β-homoPro

- β-Ala, GABA, Ape, Acp

- (N-Me)Ala, (N-Me)Val, (N-Me)Leu, (N-Me)Ile, (N-Me)Phe, (N-Me)Tyr, (N-Me)Ser, (N-Me)Asp, (N-Me)Glu

- a group represented by formula [II-1] or formula [II-2]:

[II-1], [II-2]

where R ^AA2 is hydroxy or amino; and

- amino acids listed in Table 1 and Table 2

Examples of the fat-soluble protecting groups may include carbonate protecting groups, amide protecting groups and alkyl protecting groups such as 9-fluorenylmethoxycarbonyl (Fmoc), tert-butyloxycarbonyl (Boc), benzyl (Bn), allyl (Allyl), allyloxycarbonyl (Alloc) and acetyl (Ac). The introduction of a fat-soluble protecting group into an amino acid, such as the introduction of Fmoc, can be achieved by adding 9-fluorenylmethyl-N-succinidyl carbonate and sodium hydrogen carbonate to the reaction. It is recommended to carry out the reaction at a temperature of 0 to 50°C, preferably at room temperature, for about 1 to 5 hours.

Commercially available amino acids protected with a lipid-soluble protecting group can be used. Examples include Fmoc-Ser-OH, Fmoc-Asn-OH, Fmoc-Val-OH, Fmoc-Leu-OH, Fmoc-Ile-OH, Fmoc-Ala-OH, Fmoc-Tyr-OH, Fmoc-Gly-OH, Fmoc-Lys-OH, Fmoc-Arg-OH, Fmoc-His-OH, Fmoc-Asp-OH, Fmoc-Glu-OH, Fmoc-Gln-OH, Fmoc-Thr-OH, Fmoc-Cys-OH, Fmoc-Met-OH, Fmoc-Phe-OH, Fmoc-Trp-OH, and Fmoc-Pro-OH.

Examples of amino acids protected with a lipid-soluble protecting group and having a protecting group introduced into the side chain may include Fmoc-Arg(Pbf)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Cys(tBu)-OH, Fmoc-Glu(OtBu)-OH, Fmoc-Gln(Trt)-OH, Fmoc-His(Trt)-OH, Fmoc-Lys(Boc)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Trp(Boc)-OH, and Fmoc-Tyr(tBu)-OH.

The resin may be any resin commonly used for solid-phase synthesis, and, for example, 2-chlorotrityl chloride resin which is functionalized with a chlorine atom, Wang resin, HMPA-PEGA resin, and amino-PEGA resin which is functionalized with amino are applicable.

Solid-phase synthesis using an amide synthesis resin is recommended as a method for producing an amide formed at the C-terminus of a peptide. For example, Rink-Amide-AM resin, SAL-PEG resin, SAL-MBHA resin or Rink-Amide-PEGA resin can be used. The amide formed at the C-terminus of a peptide can be obtained by cleaving the peptide from the resin.

For coupling an amino acid whose amino is substituted with a fat-soluble protective group to a resin, for example, in the case where a resin containing hydroxy or a resin functionalized with a chlorine atom is used, coupling can be carried out through coupling a carboxy amino acid to the resin to form an ester bond.

In the case of using an amino-functionalized resin, the coupling can be achieved by the carboxyl group of the amino acid forming an amide bond with the resin.

In case of using 2-chlorotrityl chloride resin, esterification can be carried out using substances such as diisopropylethylamine (DIPEA), triethylamine, pyridine and 2,4,6-collidine.

In the case of using a resin containing hydroxy, a known dehydrating/condensing agent such as 1-(mesitylene-2-sulfonyl)-3-nitro-1,2,4,-triazole (MSNT), dicyclohexylcarbodiimide (DCK), and diisopropylcarbodiimide (DIC) can be used as an esterification catalyst. Regarding the use ratio of the amino acid and the dehydrating/condensing agent, the amount of the latter is usually 1 to 10 equivalents and preferably 2 to 5 equivalents per equivalent of the former.

For example, the esterification reaction is usually carried out in such a manner that a resin is placed in a solid phase column, the resin is washed with a solvent, and then an amino acid solution is added thereto. Examples of the washing solvent may include chloroform, dimethylformamide (DMF), 2-propanol, and dichloromethane. Examples of the solvent for dissolving amino acids in the present document include chloroform, dimethyl sulfoxide (DMSO), DMF, and dichloromethane. The esterification reaction is recommended to be carried out at a temperature of 0 to 50°C, preferably at room temperature for about 10 minutes to 30 hours, preferably for about 15 minutes to 24 hours.

At the same time, it is also preferable to acetylate the unreacted hydroxy on the solid phase using acetic anhydride or the like for capping.

The removal of the fat-soluble protective group can be carried out, for example, by treatment with a base. Examples of the base may include piperidine and morpholine. In this case, it is preferable to carry out the removal in the presence of a solvent. Examples of the solvent may include DMF, DMSO and methanol.

It is preferable to carry out the amidation reaction between the released amino and carboxy of any amino acid, the amino of which is substituted with a fat-soluble protecting group, in the presence of an activator and a solvent.

Examples of activators may include dicyclohexylcarbodiimide (DCK), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (WSC/HCl), diphenylphosphoryl azide (DPPA), carbonyldiimidazole (CDI), diethyl cyanophosphonate (DEPC), benzotriazol-1-yloxy-trispyrrolidinophosphonium. (DIPCI), benzotriazol-1-yloxy-trispyrrolidinophosphonium hexafluorophosphate (PyBOP), 1-hydroxybenzotriazole (HOBt), hydroxysuccinimide (HOSu), dimethylaminopyridine (DMAP), 1-hydroxy-7-azabenzotriazole (HOAt), hydroxyphthalimide (HOPht), pentafluorophenol (Pfp-OH), 2-(1H-benzotriazol-1-yl)-1,1,3,3,-tetramethyluronium hexafluorophosphate (HBTU), 1-[bis(dimethylamino)methylene]-5-chloro-1H-benzotriazole hexafluorophosphate 3-oxide (HCTU), O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphonate (HATU), tetrafluoroborate O-benzotriazol-1-yl-1,1,3,3-tetramethyluronium (TBTU), 3,4-dihydro-3-hydrodi-4-oxa-1,2,3-benzotriazine (Dhbt), N-[1-(cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino(morpholino)]uronium hexafluorophosphate (COMU), and ethyl cyano(hydroxyimino)acetate (Oxyma).

It is necessary to set the amount of the activator used to be from 1 to 20 equivalents, preferably from 1 to 10 equivalents, more preferably from 1 to 5 equivalents with respect to any amino acid whose amino group is protected by a protective group having fat solubility.

Examples of solvents may include DMF, DMSO, and dichloromethane. It is recommended to carry out the reaction at a temperature of 0 to 50°C, preferably at room temperature, for about 10 minutes to 30 hours, preferably about 15 minutes to 2 hours.

The cleavage of the peptide chain from the resin can be carried out by treatment with an acid. Examples of acids may include trifluoroacetic acid (TFA) and hydrogen fluoride (HF). It is recommended to carry out the reaction of separation from the resin at a temperature of 0 to 50°C, preferably at room temperature, for about 10 minutes to 10 hours, preferably for about 30 minutes to 4 hours.

The present invention is described in more detail with reference to the following examples, reference examples and experimental examples, however, they do not limit the present invention, and any modifications can be made without departing from the scope of the present invention.

The abbreviations in this specification are shown below.

APCI: Atmospheric Pressure Chemical Ionization

Arg (Pbf): N ^ω -2,2,4,6,7-pentamethyldihydrobenzofuransulfonylarginine

Bu: butyl

BuOH: butanol

Dde: 1-(4,4-dimethyl-2,6-dioxocyclohexylidene)-3-ethyl

DMSO-d ₆ : hexadeuterated dimethyl sulfoxide

Evaporative Light Scattering Detector (ELSD)

ESI: electrospray ionization

HPLC: High Performance Liquid Chromatography

ivDde: 1-(4,4-dimethyl-2,6-dioxocyclohexylidene)-3-methylbutyl

LCMS: liquid chromatography/mass spectrometry

NMP: 1-methyl-2-pyrrolidone

Trt: trityl

UV: ultraviolet rays

In this document, "room temperature" refers to a temperature between 20 and 30°C unless otherwise specified.

"Ice cooling" refers to temperatures between 0 and 5°C unless otherwise stated.

In this document, Biotage (registered trademark) SNAP Ultra manufactured by Biotage AB, or REVELERIS (registered trademark) Silica 40 µm manufactured by BUCHI Labortechnik AG are used as "silica gel cartridge" in purification by column chromatography.

In purification by reversed-phase column chromatography (hereinafter sometimes referred to as preparative LCMS), suitable conditions are selected from the two conditions shown below and the purification is carried out.

Separation apparatus: Agilent 1260 Infinity and Agilent 6130 (ionization method: electron spray ionization: ESI) or Agilent 385-ELSD when using an ESRD sensor, each from Agilent Technologies, are used.

Solvent: solution A; water with 0.1% formic acid, solution B; acetonitrile with 0.1% formic acid.

Flow rate: 50 ml/min

Use one of the following columns.

Waters XBridge Prep C18, 5 µm, 30x50 mm

Waters XSelect CSH C18, 5 µm, 30×50 mm

(Separation Conditions A)

0.0-0.5 min (solution A/solution B=90/10)

0.5-7.5 min (solution A/solution B=90/10-20/80)

7.5-7.95 min (solution A/solution B=20/80)

7.95-8.0 min (solution A/solution B=20/80-5/95)

8.0-9.0 min (solution A/solution B=5/95)

(Separation Conditions B)

0.0-0.5 min (solution A/solution B=95/5)

0.5-7.5 min (solution A/solution B=95/5-50/50)

7.5-7.95 min (solution A/solution B=50/50)

7.95-8.0 min (solution A/solution B=50/50-5/95)

8.0-9.0 min (solution A/solution B=5/95)

The measurement results shown in this document are determined using the following instruments.

Microwave reactor: Initiator (Biotage AB)

NMR spectrum: [1H-NMR] 600 MHz: JNM-ECA600 (JEOL Ltd.), 400 MHz: AVANCE III HD 400 (Bruker)

The high performance liquid chromatography (LCMS) mass spectrum and retention time (RT) in this specification are determined under the conditions shown below.

Measuring apparatus: LCMS-2010EV, Shimadzu Corporation

Column: Shimadzu XR-ODS, 2.2 µm, 2.0×30 mm

Ionization method: ESI/APCI dual source

Solvent: solution A; water with 0.1% formic acid, solution B; acetonitrile with 0.1% formic acid.

Flow rate: 0.6 ml/min, detection method: UV 210 nm, 254 nm

(Assay Conditions A)

0.0-1.0 min (solution A/solution B=90/10-60/40)

1.0-2.0 min (solution A/solution B=60/40-1/99)

2.0-2.6 min (solution A/solution B=1/99)

(Assay Conditions B)

0.0-0.5 min (solution A/solution B=90/10)

0.5-1.5 min (solution A/solution B=90/10-70/30)

1.5-2.5 min (solution A/solution B=70/30-1/99)

2.5-5.0 min (solution A/solution B=1/99)

The names of the compounds in the Preparation Examples, Reference Examples, and Examples are given in accordance with “ACD/Name 2019,1,2 (ACD Labs 2019,1,2, Advanced Chemistry Development Inc.)”.

Reference Example 1. 4-(4-Carbamoylbenzamide)benzenesulfonyl chloride

To a solution of 4-carbamoylbenzoic acid (150 g) in DMF (180 ml), WSC monohydrochloride (209 g), HOBt monohydrate (167 g) and DIPEA (380 ml) were added. After stirring at room temperature for 5 minutes, aniline (99 ml) was added and the product was stirred at room temperature for 72 hours. Water was added to the reaction solution and the solid precipitate was collected by filtration to give N-phenyl terephthalamide (147 g) as a yellow amorphous substance.

Chlorosulfonic acid (407 ml) was added to the obtained N-phenyl terephthalamide, and the product was stirred at 60°C for 1 hour with heating. The reaction mixture was cooled on ice and then added to ice water. The solid precipitate was collected by filtration, washed with water, and then dried to give the title compound (198 g) as a light yellow solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.54 (br s, 1 H), 7.62 (d, J=8.2 Hz, 2 H), 7.79 (d, J=8.2 Hz, 2 H), 7.96-8.09 (m, 4 H), 8.14 (br s, 1 H), 10.46 (s, 1 H)

Reference Example 2. 4-(4-(Trifluoromethoxy)benzamide)benzenesulfonyl chloride

By the procedure of Reference Example 1, the title compound was obtained as a yellow solid from the appropriate starting material.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.52 (d, J=8.3 Hz, 2 H), 7.58 (d, J=8.3 Hz, 2 H), 7.72 (d, J=8.3 Hz, 2 H), 8.08 (d, J=8.3 Hz, 2 H), 10.42 (s, 1 H)

Reference Example 3. 4-(4-(Methylcarbamoyl)benzamide)benzenesulfonyl chloride

By the procedure of Reference Example 1, the title compound was obtained as a grey solid from the appropriate starting material.

¹ H NMR (600 MHz, DMSO-d ₆ ) δ ppm 2.81 (d, J=4.1 Hz, 3 H), 7.57-7.61 (m, 2 H), 7.72-7.78 (m, 2 H), 7.96 (d, J=8.7 Hz, 2 H), 8.03 (d, J=8.7 Hz, 2 H), 8.62 (q, J=4.1, 1 H), 10.42 (s, 1 H)

Reference Example 4. 4-(4-(Dimethylcarbamoyl)benzamide)benzenesulfonyl chloride

By the procedure of Reference Example 1, the title compound was obtained as a brown solid from the appropriate starting material.

¹ H NMR (600 MHz, DMSO-d ₆ ) δ ppm 2.91 (s, 3 H), 3.01 (s, 3 H), 7.54 (d, J=8.3 Hz, 2 H), 7.58 (d, J=8.3 Hz, 2 H), 7.74 (d, J=8.3 Hz, 2 H), 8.01 (d, J=8.3 Hz, 2 H), 10.41 (s, 1 H)

Reference Example 5. 4-(4-(Trifluoromethyl)benzamide)benzenesulfonyl chloride

By the procedure of Reference Example 1, the title compound was obtained as a white solid from the appropriate starting material.

¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.81 (d, J=8.2 Hz, 2 H), 7.93 (d, J=8.1 Hz, 2 H), 8.01 (d, J=8.2 Hz, 2 H), 8.08 (d, J=8.1 Hz, 3 H)

Reference Example 6. 4-(4-Cyanobenzamide)benzenesulfonyl chloride

By the procedure of Reference Example 1, the title compound was obtained as a light brown solid from the appropriate starting material.

¹ H NMR (600 MHz, DMSO-d ₆ ) δ ppm 7.58 (d, J=8.3 Hz, 2 H), 7.74 (d, J=8.3 Hz, 2 H), 7.99 (d, J=8.3 Hz, 2 H), 8.01 (d, J=8.3 Hz, 2 H), 10.42 (s, 1 H)

Reference Example 7. 4-(4-(1,1,2,2-Tetrafluoroethoxy)benzamide)benzenesulfonyl chloride

By the procedure of Reference Example 1, the title compound was obtained as a yellow solid from the appropriate starting material.

¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 5.95 (tt, J=53.2 Hz, 2.8 Hz, 1 H), 7.37 (d, J=8.6 Hz, 2 H), 7.92 (d, J=7.2 Hz, 2 H), 7.94 (d, J=7.2 Hz, 2 H), 8.05 (d, J=8.6 Hz, 2 H), 8.12 (s, 1 H)

Reference Example 8. 4-(2-Fluorobenzamide)benzenesulfonyl chloride

By the procedure of Reference Example 1, the title compound was obtained as a white solid from the appropriate starting material.

¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.20-7.27 (m, 1 H), 7.37 (dd, J=7.6 Hz, 7.6 Hz, 1 H), 7.56-7.63 (m, 1 H), 7.95 (d, J=9.1 Hz, 2 H), 8.06 (d, J=9.1 Hz, 2 H), 8.20 (td, J=8.0 Hz, 1.8 Hz, 1 H), 8.75 (d, J=16.9 Hz, 1 H)

Reference example 9. 2-Fluoro-4-phenoxybenzoic acid

To a solution of 2,4-difluorobenzaldehyde (250 mg) and phenol (199 mg) in DMF (10 ml), potassium carbonate (535 mg) was added, and the product was stirred at 120°C for 4 hours with heating. After cooling to room temperature, the reaction solution was diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 2-fluoro-4-phenoxybenzaldehyde.

In tetrahydrofuran (5 ml) and water (5 ml), the obtained 2-fluoro-4-phenoxybenzaldehyde was dissolved, sodium dihydrogen phosphate (844 mg), 2-methyl-2-butene (1.49 ml) and sodium chlorite (636 mg) were added thereto, and the product was stirred at room temperature for 3 hours. Chloroform was added to the reaction solution, which was washed with water. The organic layer was passed through a phase separator and concentrated under reduced pressure to obtain the title compound (182 mg) as a white solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 6.75-6.92 (m, 2 H), 7.17 (d, J=7.5 Hz, 2 H), 7.24-7.33 (m, 1 H), 7.43-7.55 (m, 2 H), 7.83-7.97 (m, 1 H), 13.0 (br s, 1 H)

Reference Example 10. 4-(4-Carbamoyl-2-fluorophenoxy)benzoic acid

By the procedure of Reference Example 9, the title compound was obtained as a white solid from the appropriate starting material.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.12 (d, J=8.4 Hz, 1 H), 7.19 (d, J=8.4 Hz, 2 H), 7.40 (t, J=8.3 Hz, 1 H), 7.53 (br s, 1 H), 7.82 (t, J=8.3 Hz, 1 H), 7.90-8.00 (m, 2 H), 8.07 (br s, 1 H), 9.95 (s, 1 H)

Reference example 11. 3-Fluoro-4-(2-fluorophenoxy)benzoic acid

By the procedure of Reference Example 9, the title compound was obtained as a white solid from the appropriate starting material.

¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 6.89 (t, J=8.1 Hz, 1 H), 7.10-7.25 (m, 4H), 7.80 (d, J=8.4 Hz, 1 H), 7.89 (d, J=11.3 Hz, 1 H)

Reference Example 12. 5-((4-(4-Carbamoylphenoxy)phenyl)sulfonamide)pentanoic acid

(1)

To a solution of benzyl 5-aminopentanoate tosylate (1.48 g) in chloroform (20 ml), triethylamine (2.3 ml) and 4-fluorobenzenesulfonyl chloride (800 mg) were added under ice-cooling, and the product was stirred under ice-cooling for 1 hour. After completion of the reaction, saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and extraction was performed with chloroform. The organic layer was passed through a phase separator and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, hexane:ethyl acetate=80:20-50:50) to obtain benzyl 5-((4-fluorophenyl)sulfonamide)pentanoate (1.24 g) as a colorless oily substance.

¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.46-1.56 (m, 2 H), 1.58-1.68 (m, 2 H), 2.33 (t, J=7.0 Hz, 2 H), 2.96 (q, J=6.5 Hz, 2 H), 4.40-4.47 (m, 1 H), 5.09 (s, 2 H), 7.18 (t, J=8.2 Hz, 2 H), 7.31-7.39 (m, 5 H), 7.86 (dd, J=7.6 Hz, 5.3 Hz, 2 H)

(2)

To a solution of benzyl 5-((4-fluorophenyl)sulfonamide)pentanoate (500 mg) obtained in (1) in DMF (13 ml), 4-hydroxybenzonitrile (179 mg) and potassium carbonate (567 mg) were added, and the product was stirred under microwave irradiation at 180°C for 1 hour. After cooling the reaction solution, ethyl acetate and water were added to the reaction mixture for liquid separation. After washing the aqueous layer with ethyl acetate, the pH was adjusted to 1 with 1 M aqueous hydrochloric acid, and extraction was performed with a mixed solvent of ethyl acetate/toluene. The organic layer was washed with water, then dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 5-((4-(4-cyanophenoxy)phenyl)sulfonamide)pentanoic acid (285 mg) as a white solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.32-1.49 (m, 4 H), 2.10-2.17 (m, 2 H), 2.69-2.78 (m, 2 H), 7.23-7.31 (m, 2 H), 7.43 (t, J=8.7 Hz, 2 H), 7.59-7.66 (m, 1 H), 7.81-7.87 (m, 3 H), 7.91 (d, J=8.3 Hz, 1 H)

(3)

To a solution of 5-((4-(4-cyanophenoxy)phenyl)sulfonamide)pentanoic acid (100 mg) obtained in (2) in DMSO (2 ml), potassium carbonate (81 mg) and 30% hydrogen peroxide solution (0.15 ml) were added, and the product was stirred at room temperature for 2 hours. After completion of the reaction, an aqueous solution of sodium thiosulfate and 1 M aqueous hydrochloric acid were added, and extraction was performed with ethyl acetate. The organic layer was washed with water, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound (89 mg) as a white solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.32-1.50 (m, 4 H), 2.10-2.18 (m, 2 H), 2.69-2.78 (m, 2 H), 7.16 (d, J=8.2 Hz, 1 H), 7.19 (d, J=8.6 Hz, 1 H), 7.34 (br s, 1 H), 7.43 (t, J=8.6 Hz, 2 H), 7.52-7.58 (m, 1 H), 7.59-7.66 (m, 1 H), 7.86- 7.79 (m, 3 H), 7.96 (d, J=7.7 Hz, 1 H), 12.0 (br s, 1 H)

Example 1. Synthesis of compound No. 1: (N-[4-(4-carbamoylbenzamido)benzene-1-sulfonyl]-D-γ-glutamyl-(4S)-4-amino-L-prolyl-L-leucyl-N-(5-amino-5-oxopentyl)-N ² -methyl-L-α-glutamine)

(1)

Fmoc-Rink Amide AM resin (0.10 mmol) was treated with a solution of piperidine in DMF (concentration: 40%, 1.6 mL) for 3 min and then treated with a solution of piperidine in DMF (concentration: 20%, 1.6 mL) for 12 min to deprotect Fmoc on the resin. Then, a solution of Fmoc-Ape-OH (0.40 mmol) in DMF (0.8 mL), a solution of COMU (0.40 mmol) and Oxyma (0.40 mmol) in DMF (0.8 mL), and a solution of DIPEA (0.80 mmol) in NMP (0.4 mL) were added and the mixture was shaken at room temperature for 40 min to introduce the remainder of Ape. In the same manner, Fmoc deprotection and condensation were repeated: specifically, Fmoc-(N-Me)Glu(OtBu)-OH, Fmoc-Leu-OH, Fmoc-(2S,4S)-(4-NHBoc)Pro-OH and Fmoc-(d)-Glu-OtBu were condensed successively, wherein deprotection was performed for the N-terminal Fmoc formed in the resin after each condensation by treating with piperidine/DMF in the above manner, and H-γ-(d)-Glu(OtBu)-(2S,4S)-(4-NHBoc)Pro-Leu-(N-Me)Glu(OtBu)-Ape-Rink Amide AM resin was synthesized.

(2)

To the resin obtained in (1) was added a solution of 4-(4-carbamoylbenzamide)benzenesulfonyl chloride (0.30 mmol) obtained in Reference Example 1 and DIPEA (0.60 mmol) in DMF (3 ml), and the mixture was shaken at room temperature for 1 hour. After completion of the reaction, the resulting resin was washed with DMF (3 ml × three times) and chloroform (3 ml × three times).

(3)

To the resin obtained in (2) was added TFA:water:triisopropylsilane (92.5:2.5:5, 4 ml), the mixture was shaken at room temperature for 1.5 hours, and the resin was removed by filtration. The operation in which cooled diethyl ether was added to the filtrate, the resulting white powder was precipitated by centrifugation, and diethyl ether was removed by decantation was repeated three times to obtain the crude peptide product. The resulting crude product was purified by preparative LCMS (separation conditions B). The eluate was fractionated using test tubes, and the eluted fractions containing the desired product were collected and lyophilized to give the title compound (46 mg) as a white powder.

Example 2. Synthesis of compound No. 106: (N ² -[4-(4-phenoxybenzamido)butanoyl]-L-asparaginyl-N-[(2S)-4-amino-1-({(2S)-1-[{(2S,3S)-1-[(2S)-2-(2-amino-2-oxoethyl)pyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl}(methyl)amino]-4-methyl-1-oxopentan-2-yl}amino)-1-oxobutan-2-yl]-L-α-asparagine)

(1)

Fmoc-NH-SAL-PEG resin (0.12 mmol) was treated with a solution of piperidine in DMF (concentration: 40%, 1.9 mL) for 3 min and then treated with a solution of piperidine in DMF (concentration: 20%, 1.9 mL) for 12 min to deprotect Fmoc on the resin. Then, a solution of Fmoc-β-homoPro-OH (0.48 mmol) in DMF (1.0 mL), a solution of COMU (0.48 mmol) and Oxyma (0.48 mmol) in DMF (1.0 mL), and a solution of DIPEA (0.96 mmol) in NMP (0.48 mL) were added, and the mixture was shaken at room temperature for 40 min to introduce the remainder of β-homoPro. According to the same procedure, Fmoc deprotection and condensation were repeated: specifically, Fmoc-(N-Me)Ile-OH, Fmoc-Leu-OH, Fmoc-Dab(Boc)-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Asn(Trt)-OH, Fmoc-GABA-OH and 4-phenoxybenzoic acid were sequentially condensed, and Ph-O-Ph-CO-GABA-Asn(Trt)-Asp(OtBu)-Dab(Boc)-Leu-(N-Me)Ile-β-homoPro-NH-SAL-PEG resin was synthesized. After completion of the reaction, the obtained resin was washed with DMF (3 ml × three times) and chloroform (3 ml × three times).

(2)

To the resin obtained in (1) was added TFA:water:triisopropylsilane:dithiothreitol (90:2.5:5:2.5, 4 ml), the mixture was shaken at room temperature for 2 hours, and the resin was removed by filtration. The operation in which cooled diethyl ether was added to the filtrate, the resulting white powder was precipitated by centrifugation, and diethyl ether was removed by decantation was repeated three times to obtain a crude peptide product. The resulting crude product was purified by preparative LCMS (separation conditions A). The eluate was fractionated using test tubes, and the eluted fractions containing the desired product were collected and lyophilized to give the title compound (14 mg) as a white powder.

Example 3. Synthesis of Compound No. 177: (N ² -(4-{4-[4-(methylcarbamoyl)phenoxy]benzamido}butanoyl)-L-asparaginyl-L-α-aspartyl-L-alanyl-L-leucyl-L-methionyl-L-prolinamide)

(1)

Fmoc-NH-SAL-PEG resin (0.10 mmol) was treated with a solution of piperidine in DMF (concentration: 40%, 1.6 mL) for 3 min and then treated with a solution of piperidine in DMF (concentration: 20%, 1.6 mL) for 12 min to deprotect Fmoc on the resin. Then, a solution of Fmoc-Pro-OH (0.40 mmol) in DMF (0.8 mL), a solution of COMU (0.40 mmol) and Oxyma (0.40 mmol) in DMF (0.8 mL), and a solution of DIPEA (0.80 mmol) in NMP (0.4 mL) were added and the mixture was shaken at room temperature for 40 min to introduce the remainder of Pro. In the same manner, Fmoc deprotection and condensation are repeated: specifically, Fmoc-Met-OH, Fmoc-Leu-OH, Fmoc-Ala-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Asn(Trt)-OH and Fmoc-GABA-OH are condensed successively, wherein deprotection is performed for the N-terminal Fmoc formed in the resin after each condensation by treating with piperidine/DMF in the above manner, and H-GABA-Asn(Trt)-Asp(OtBu)-Ala-Leu-Met-Pro-NH-SAL-PEG resin is synthesized.

(2)

To the resin obtained in (1), a solution of 4,4'-oxybisbenzoic acid (0.75 mmol), HATU (0.15 mmol) and DIPEA (2.0 mmol) in DMF (3 ml) was added, and the mixture was shaken at room temperature for 2 h. After completion of the reaction, the resulting resin was washed with DMF (3 ml x three times).

(3)

To the resin obtained in (2) were added a solution of HATU (0.30 mmol), DIPEA (0.60 mmol) and a solution of methylamine in methanol (concentration: 9.8 mol/L, 0.30 mmol) in DMF (3 ml), and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, the resulting resin was washed with DMF (3 ml x three times) and chloroform (3 ml x three times).

(4)

To the resin obtained in (3) was added TFA:water:triisopropylsilane:dithiothreitol (90:2.5:5:2.5, 4 ml), the mixture was shaken at room temperature for 2 hours, and the resin was removed by filtration. The operation in which cooled diethyl ether was added to the filtrate, the resulting white powder was precipitated by centrifugation, and diethyl ether was removed by decantation was repeated three times to obtain the crude peptide product. The resulting crude product was purified by preparative LCMS (separation conditions A). The eluate was fractionated using test tubes, and the eluted fractions containing the desired product were collected and lyophilized to give the title compound (30 mg) as a white powder.

Example 4. Synthesis of Compound No. 587: (N-{5-[(4-methylphenyl)ethynyl]thiophene-2-sulfonyl}-β-alanyl-L-asparaginyl-L-α-aspartyl-L-alanyl-L-leucyl-N-methyl-L-methionyl-L-prolinamide)

(1)

Fmoc-NH-SAL-PEG resin (0.10 mmol) was treated with a solution of piperidine in DMF (concentration: 40%, 1.6 mL) for 3 min, and then treated with a solution of piperidine in DMF (concentration: 20%, 1.6 mL) for 12 min to deprotect Fmoc on the resin. Then, a solution of Fmoc-Pro-OH (0.40 mmol) in DMF (0.8 mL), a solution of COMU (0.40 mmol) and Oxyma (0.40 mmol) in DMF (0.8 mL), and a solution of DIPEA (0.80 mmol) in NMP (0.4 mL) were added, and the mixture was shaken at room temperature for 40 min to introduce the remainder of Pro. In the same manner, Fmoc deprotection and condensation were repeated: specifically, Fmoc-(N-Me)Met-OH, Fmoc-Leu-OH, Fmoc-Ala-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Asn(Trt)-OH and Fmoc-β-Ala-OH were condensed successively, wherein deprotection was performed for the N-terminal Fmoc formed in the resin after each condensation by treating with piperidine/DMF in the above manner, and H-β-Ala-Asn(Trt)-Asp(OtBu)-Ala-Leu-(N-Me)Met-Pro-NH-SAL-PEG resin was synthesized.

(2)

To the resin obtained in (1) was added a solution of 5-bromothiophene-2-sulfonyl chloride (0.20 mmol) and DIPEA (0.40 mmol) in DMF (3 ml), and the mixture was shaken at room temperature for 2 hours. After completion of the reaction, the resulting resin was washed with DMF (3 ml x three times) and chloroform (3 ml x three times).

(3)

To the resin obtained in (2) was added TFA:water:triisopropylsilane:dithiothreitol (90:2.5:5:2.5, 4 ml), the mixture was shaken at room temperature for 2 hours, and the resin was removed by filtration. The operation in which cooled diethyl ether was added to the filtrate, the resulting white powder was precipitated by centrifugation, and diethyl ether was removed by decantation was repeated three times to obtain the crude peptide product. The resulting crude product was purified by preparative LCMS (separation conditions B). The eluate was fractionated using test tubes, and the eluted fractions containing the desired product were collected and lyophilized to give 5-Br-thiophene-2-SO ₂ -β-Ala-Asn-Asp-Ala-Leu-(N-Me)Met-Pro-NH ₂ (27 mg) as a white powder.

(4)

The compound obtained in (3) was dissolved in DMF (0.5 ml), 4-ethynyltoluene (0.30 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.01 mmol), triethylamine (0.18 mmol) and copper iodide (0.01 mmol) were added thereto, and the mixture was stirred under nitrogen atmosphere at 50°C for 5 hours with heating. After cooling to room temperature, the reaction solution was diluted with DMSO, filtered and purified by preparative LCMS (separation conditions A). The eluate was fractionated using test tubes, and the eluted fractions containing the target product were collected and lyophilized to give the title compound (4 mg) as a white powder.

Example 5. Synthesis of compound No. 608: (N-[(2S)-4-amino-1-({(2S)-1-[{(2S,3S)-1-[(2S)-2-(2-amino-2-oxoethyl)pyrrolidine- 1-il]-3-m ethyl-1-oxopentan-2-yl}(methyl)amino]-4-methyl-1-oxopentan-2-yl}amino)-1-oxobutan-2-yl]-N ² -[4-(1-phenyl-1H-1,2,3-triazol-4-yl)benzene-1-sulfonyl]-D-glutamine)

(1)

Fmoc-Rink Amide AM resin (0.10 mmol) was treated with a solution of piperidine in DMF (concentration: 40%, 1.6 mL) for 3 min and then treated with a solution of piperidine in DMF (concentration: 20%, 1.6 mL) for 12 min to deprotect Fmoc on the resin. Then, a solution of Fmoc-β-homoPro-OH (0.40 mmol) in DMF (0.8 mL), a solution of COMU (0.40 mmol) and Oxyma (0.40 mmol) in DMF (0.8 mL), and a solution of DIPEA (0.80 mmol) in NMP (0.4 mL) were added, and the mixture was shaken at room temperature for 40 min to introduce the remaining β-homoPro. In the same manner, Fmoc deprotection and condensation were repeated: specifically, Fmoc-(N-Me)Ile-OH, Fmoc-Leu-OH, Fmoc-Dab(Boc)-OH and Fmoc-(d)-Glu-OtBu were condensed successively, wherein deprotection was performed for the N-terminal Fmoc formed in the resin after each condensation by treating with piperidine/DMF in the manner mentioned above, and H-γ-(d)-Glu(OtBu)-Dab(Boc)-Leu-(N-Me)Ile-β-homoPro-Rink Amide AM resin was synthesized.

(2)

To the resin obtained in (1) was added a solution of 4-bromobenzenesulfonyl chloride (0.30 mmol) and DIPEA (0.60 mmol) in DMF (2 ml), and the mixture was shaken at room temperature for 2 hours. After completion of the reaction, the resulting resin was washed with DMF (2 ml x three times).

(3)

To the resin obtained in (2) was added a solution of trimethylsilylacetylene (0.30 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.03 mmol) and copper iodide (0.03 mmol) in DMF (2 ml), and the mixture was stirred under microwave irradiation at 80°C for 30 minutes with heating. After completion of the reaction, the resulting resin was washed with DMF (2 ml x three times) and chloroform (2 ml x three times).

To the obtained resin, a solution of tetrabutylammonium fluoride in tetrahydrofuran (concentration: 0.33 mol/L, 0.50 mmol) was added, and the mixture was shaken at room temperature for 1 hour. After completion of the reaction, the obtained resin was washed with DMF (2 ml x three times) and chloroform (2 ml x three times).

(4)

To the resin obtained in (3) was added a solution of azidobenzene (0.20 mmol), copper(II) sulfate pentahydrate (0.40 mmol) and ascorbic acid (0.40 mmol) in water (2 ml) and tBuOH (1 ml), and the mixture was stirred under microwave irradiation at 60°C for 1 hour with heating. After completion of the reaction, the resulting resin was washed with DMF (2 ml x three times) and chloroform (2 ml x three times).

(5)

To the resin obtained in (4) was added TFA:water:triisopropylsilane (92.5:2.5:5, 4 ml), the mixture was shaken at room temperature for 2 hours, and the resin was removed by filtration. The operation in which cooled diethyl ether was added to the filtrate, the resulting white powder was precipitated by centrifugation, and diethyl ether was removed by decantation was repeated three times to obtain the crude peptide product. The resulting crude product was purified by preparative LCMS (separation conditions A). The eluate was fractionated using test tubes, and the eluted fractions containing the desired product were collected and lyophilized to give the title compound (12 mg) as a white powder.

Example 6. Synthesis of compound No. 634: (N ² -(4'-acetyl[1,1'-biphenyl]-4-sulfonyl)-N-[(2S)-1-({(2S)-1-[{(2S,3S)-1-[(2S )-2-(2-amino-2-oxoethyl)pyrrolidine- 1-yl]-3-methyl-1-oxopentan-2-yl}(methyl)amino]-4-methyl-1-oxopentan-2-yl}amino)-1-oxopropan-2-yl]-D-asparagine )

(1)

Fmoc-NH-SAL-PEG resin (0.10 mmol) was treated with a solution of piperidine in DMF (concentration: 40%, 1.6 mL) for 3 min and then treated with a solution of piperidine in DMF (concentration: 20%, 1.6 mL) for 12 min to deprotect Fmoc on the resin. Then, a solution of Fmoc-β-homoPro-OH (0.40 mmol) in DMF (0.8 mL), a solution of COMU (0.40 mmol) and Oxyma (0.40 mmol) in DMF (0.8 mL), and a solution of DIPEA (0.80 mmol) in NMP (0.4 mL) were added and the mixture was shaken at room temperature for 40 min to introduce the remainder of β-homoPro. In the same manner, Fmoc deprotection and condensation were repeated: specifically, Fmoc-(N-Me)Ile-OH, Fmoc-Leu-OH, Fmoc-Ala-OH and Fmoc-(d)-Asp-OtBu were condensed successively, deprotection was performed for the N-terminal Fmoc formed in the resin after each condensation by treating with piperidine/DMF in the above manner, and H-β-(d)-Asp(OtBu)-Ala-Leu-(N-Me)Ile-β-homoPro-NH-SAL-PEG was synthesized with the resin.

(2)

To the resin obtained in (1) was added a solution of 4-iodobenzenesulfonyl chloride (0.30 mmol) and DIPEA (0.60 mmol) in DMF (2 ml), and the mixture was shaken at room temperature for 2 hours. After completion of the reaction, the resulting resin was washed with DMF (2 ml x three times) and chloroform (2 ml x three times).

(3)

To the resin obtained in (2) was added a solution of 4-acetylphenylboronic acid (0.40 mmol), tetrakis(triphenylphosphine)palladium(0) (0.03 mmol) and potassium phosphate (0.50 mmol) in 1,4-dioxane (1.5 ml) and water (1.5 ml), and the mixture was stirred under microwave irradiation at 100°C for 30 minutes with heating. After completion of the reaction, the resulting resin was washed with DMF (2 ml x three times) and chloroform (2 ml x three times).

(4)

To the resin obtained in (3) was added TFA:water:triisopropylsilane (92.5:2.5:5, 4 ml), the mixture was shaken at room temperature for 2 hours, and the resin was removed by filtration. The operation in which cooled diethyl ether was added to the filtrate, the resulting white powder was precipitated by centrifugation, and diethyl ether was removed by decantation was repeated three times to obtain the crude peptide product. The resulting crude product was purified by preparative LCMS (separation conditions A). The eluate was fractionated using test tubes, and the eluted fractions containing the desired product were collected and lyophilized to give the title compound (8 mg) as a white powder.

Example 7. Synthesis of compound No. 692: (N-[(2S)-3-amino-1-({(2S)-1-[{(2S,3S)-1-[(2S)-2-(2-amino-2-oxoethyl)pyrrolidin- 1-yl]-3-me til-1-oxopentan-2-yl}(methyl)amino]-4-methyl-1-oxopentan-2-yl}amino)-1-oxopropan-2-yl]-N ^2- [4-(4-methoxybenzamido)benzene-1-sulfonyl]-D-asparagine)

(1)

Fmoc-Rink Amide AM resin (0.10 mmol) was treated with a solution of piperidine in DMF (concentration: 40%, 1.6 mL) for 3 min and then treated with a solution of piperidine in DMF (concentration: 20%, 1.6 mL) for 12 min to deprotect Fmoc on the resin. Then, a solution of Fmoc-β-homoPro-OH (0.40 mmol) in DMF (0.8 mL), a solution of COMU (0.40 mmol) and Oxyma (0.40 mmol) in DMF (0.8 mL), and a solution of DIPEA (0.80 mmol) in NMP (0.4 mL) were added, and the mixture was shaken at room temperature for 40 min to introduce the remaining β-homoPro. In the same manner, Fmoc deprotection and condensation were repeated: specifically, Fmoc-(N-Me)Ile-OH, Fmoc-Leu-OH, Fmoc-Dap(Boc)-OH, and Fmoc-(d)-Asp-OtBu were condensed successively, deprotection was performed for the N-terminal Fmoc formed in the resin after each condensation by treating with piperidine/DMF in the same manner as above, and H-γ-(d)-Asp(OtBu)-Dap(Boc)-Leu-(N-Me)Ile-β-homoPro-Rink Amide AM resin was synthesized.

(2)

To the resin obtained in (1) was added a solution of (9H-fluoren-9-yl)methyl (4-(chlorosulfonyl)phenyl)carbamate (0.30 mmol) and DIPEA (0.60 mmol) in 1,4-dioxane (3 ml), and the mixture was shaken at room temperature for 1 hour. After completion of the reaction, the resulting resin was washed with DMF (3 ml × three times). Then, a solution of piperidine in DMF (concentration: 20%, 3 ml) and Oxyma (0.01 mmol) were added, and the product was shaken at room temperature for 10 minutes.

(3)

To the resin obtained in (2) was added a solution of 4-methoxybenzoyl chloride (0.30 mmol) and DIPEA (0.60 mmol) in 1,4-dioxane (2 ml), and the mixture was shaken at room temperature for 3 hours. After completion of the reaction, the resulting resin was washed with chloroform (3 ml x three times).

(4)

To the resin obtained in (3) was added TFA:water:triisopropylsilane:dithiothreitol (90:2.5:5:2.5, 4 ml), the mixture was shaken at room temperature for 2 hours, and the resin was removed by filtration. The operation in which cooled diethyl ether was added to the filtrate, the resulting white powder was precipitated by centrifugation, and diethyl ether was removed by decantation was repeated three times to obtain the crude peptide product. The resulting crude product was purified by preparative LCMS (separation conditions A). The eluate was fractionated using test tubes, and the eluted fractions containing the desired product were collected and lyophilized to give the title compound (12 mg) as a white powder.

Example 8. Synthesis of Compound No. 892: ([(2S,5S,8S,20S)-8-[{(2S,3S)-1-[(2S)-2-(2-amino-2-oxoethyl)pyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl}(methyl)carbamoyl]-5-methyl-3,6,14,17,21-pentaoxo-20-{4-[(4-phenoxybenzene-1-sulfonyl)amino]butanamido}-1,4,7,13,16-pentaazacyclogencosan-2-yl]acetic acid)

(1)

Fmoc-NH-SAL-PEG resin (0.12 mmol) was treated with a solution of piperidine in DMF (concentration: 40%, 1.9 mL) for 3 min and then treated with a solution of piperidine in DMF (concentration: 20%, 1.9 mL) for 12 min to deprotect Fmoc on the resin. Then, a solution of Fmoc-β-homoPro-OH (0.48 mmol) in DMF (1.0 mL), a solution of COMU (0.48 mmol) and Oxyma (0.48 mmol) in DMF (1.0 mL), and a solution of DIPEA (0.96 mmol) in NMP (0.48 mL) were added and the mixture was shaken at room temperature for 40 min to introduce the remainder of β-homoPro. In the same manner, Fmoc deprotection and condensation were repeated: specifically, Fmoc-(N-Me)Ile-OH, Fmoc-Lys(Dde)-OH, Fmoc-Ala-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Glu(OAllyl)-OH and Fmoc-GABA-OH were condensed successively, deprotection was performed for the N-terminal Fmoc formed in the resin after each condensation by treating with piperidine/DMF in the above manner, and H-GABA-Glu(OAllyl)-Asp(OtBu)-Ala-Lys(Dde)-(N-Me)Ile-β-homoPro-SAL-PEG resin was synthesized.

(2)

To the resin obtained in (1) was added a solution of 4-phenoxybenzenesulfonyl chloride (0.36 mmol) and DIPEA (0.72 mmol) in DMF (3 ml), and the mixture was shaken at room temperature for 1.5 hours. After completion of the reaction, the resulting resin was washed with DMF (3 ml x three times).

(3)

To the resin prepared in (2) were added a solution of hydrazine monohydrate in DMF (concentration: 5%, 3 ml) and allyl alcohol (3.1 mmol), and the mixture was shaken at room temperature for 30 min to deprotect Dde from the Lys side chain. Then, a solution of Fmoc-Gly-OH (0.48 mmol), COMU (0.48 mmol), Oxyma (0.48 mmol), and DIPEA (0.96 mmol) in DMF (3 ml) was added, and the mixture was shaken at room temperature for 30 min to introduce the Gly residue. After completion of the reaction, the resulting resin was washed with DMF (3 ml x three times) and chloroform (3 ml x three times).

(4)

To the resin obtained in (3), a solution of tetrakis(triphenylphosphine)palladium(0) (0.12 mmol) and phenylsilane (0.60 mmol) in chloroform (4 ml) was added, and the mixture was shaken at room temperature for 1.5 hours to deprotect Allyl from the Glu side chain. Then, a solution of piperidine in DMF (concentration: 20%, 3 ml) was added, and the mixture was shaken at room temperature for 30 minutes to deprotect Fmoc. After completion of the reaction, the resulting residue was washed with DMF (3 ml x five times).

(5)

To the resin obtained in (4) was added a solution of PyBOP (0.36 mmol) and DIPEA (0.12 mmol) in DMF (4 ml), and the mixture was shaken at room temperature for 2 h. After completion of the reaction, the resulting residue was washed with DMF (3 ml x three times) and chloroform (3 ml x three times).

(6)

To the resin obtained in (5) was added TFA:water:triisopropylsilane:dithiothreitol (90:2.5:5:2.5, 4 ml), the mixture was shaken at room temperature for 2 hours, and the resin was removed by filtration. The operation in which cooled diethyl ether was added to the filtrate, the resulting white powder was precipitated by centrifugation, and diethyl ether was removed by decantation was repeated three times to obtain the crude peptide product. The resulting crude product was purified by preparative LCMS (separation conditions A). The eluate was fractionated using test tubes, and the eluted fractions containing the desired product were collected and lyophilized to give the title compound (10 mg) as a white powder.

Example 9. Synthesis of compound No. 903: ((2S,5S,32R)-2-{[(2S)-1-({(2S)-1-[{(2S,3S)-1-[(2S)-2-(2-amino-2-oxoethyl)pyrrolidine-1-and l]-3-methyl-1-oxopentan-2-yl}(methyl)amino]-4-methyl-1-oxopentan-2-yl}amino)-1-oxopropane -2-yl]carbamoyl}-4,11,20,29,34-pentaoxo-5-{4-[(4-phenoxybenzene-1-sulfonyl)amino]butanamido}-13,16,22,25-tetraoxa-3,10,19,28,33-pentaazaoctatetracontane-1,32,48-tricarboxylic acid)

(1)

Fmoc-Rink Amide AM resin (0.12 mmol) was treated with a solution of piperidine in DMF (concentration: 40%, 1.9 mL) for 3 min and then treated with a solution of piperidine in DMF (concentration: 20%, 1.9 mL) for 12 min to deprotect Fmoc on the resin. Then, a solution of Fmoc-β-homoPro-OH (0.48 mmol) in DMF (1.0 mL), a solution of COMU (0.48 mmol) and Oxyma (0.48 mmol) in DMF (1.0 mL), and a solution of DIPEA (0.96 mmol) in NMP (0.48 mL) were added, and the mixture was shaken at room temperature for 40 min to introduce the remaining β-homoPro. In the same manner, Fmoc deprotection and condensation were repeated: specifically, Fmoc-(N-Me)Ile-OH, Fmoc-Leu-OH, Fmoc-Ala-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Lys(Dde)-OH and Fmoc-GABA-OH were condensed successively, wherein deprotection was performed for the N-terminal Fmoc formed in the resin after each condensation by treating with piperidine/DMF in the manner mentioned above, and H-GABA-Lys(Dde)-Asp(OtBu)-Ala-Leu-(N-Me)Ile-β-homoPro-Rink Amide AM resin was synthesized.

(2)

To the resin obtained in (1) was added a solution of 4-phenoxybenzenesulfonyl chloride (0.36 mmol) and DIPEA (0.72 mmol) in DMF (3 ml), and the mixture was shaken at room temperature for 2 hours. After completion of the reaction, the resulting resin was washed with DMF (3 ml x three times).

(3)

To the resin obtained in (2), DMF solution of hydrazine monohydrate (concentration: 5%, 3 ml) was added, and the mixture was shaken at room temperature for 30 minutes. This operation was repeated four times to deprotect Dde from the Lys side chain. For the obtained resin, condensation and deFmoc were carried out repeatedly: specifically, Fmoc-Adox-OH, Fmoc-Adox-OH, and Fmoc-Glu-OtBu were condensed successively to extend the Lys side chain with the peptide. Deprotection was carried out for the N-terminal Fmoc from the Lys side chain by treating with piperidine/DMF.

(4)

To the resin obtained in (3), hexadecanedioxide (0.96 mmol), COMU (0.18 mmol), Oxyma (0.18 mmol) and DIPEA (0.96 mmol) in DMF (3 ml) were added, and the mixture was shaken at room temperature for 1 hour. After completion of the reaction, the resulting resin was washed with DMF (3 ml x four times) and chloroform (3 ml x three times).

(5)

To the resin obtained in (4) was added TFA:water:triisopropylsilane:dithiothreitol (90:2.5:5:2.5, 4 ml), the mixture was shaken at room temperature for 2 hours, and the resin was removed by filtration. The operation in which cooled diethyl ether was added to the filtrate, the resulting white powder was precipitated by centrifugation, and diethyl ether was removed by decantation was repeated three times to obtain a crude peptide product. The resulting crude product was purified by preparative LCMS (separation conditions A). The eluate was fractionated using test tubes, and the eluted fractions containing the desired product were collected and lyophilized to give the title compound (29 mg) as a white powder.

The structures of the compounds represented by the formula [I'-1], which were synthesized in Example 1 or by the method as in Example 1, are shown in the following table.

[I'-1]

[Table 5]

The structure of the compound represented by the formula [I'-2], which is synthesized by the method as in Example 1, is shown in the following table.

[I'-2]

[Table 6]

The structure of the compound represented by the formula [I'-3], which is synthesized by the method as in Example 1, is shown in the following table.

[I'-3]

[Table 7]

The structure of the compound represented by the formula [I'-4], which is synthesized by the method as in Example 1, is shown in the following table.

[I'-4]

[Table 8]

The structure of the compound represented by the formula [I'-5], which is synthesized by the method as in Example 1, is shown in the following table.

[I'-5]

[Table 9]

The structure of the compound represented by the formula [I'-6], which is synthesized by the method as in Example 1, is shown in the following table.

[I'-6]

[Table 10]

The structures of the compounds represented by the formula [I'-7], which are synthesized by the method as in Example 1, are shown in the following table.

[I'-7]

[Table 11]

The structures of the compounds represented by the formula [I'-8], which were synthesized by the method as in Example 1, are shown in the following table.

[I'-8]

[Table 12]

The structures of the compounds represented by the formula [I'-9], which were synthesized in Example 2 or by the method as in Example 2, are shown in the following table.

[I'-9]

[Table 13]

The structures of the compounds represented by the formula [I'-10], which were synthesized by the method as in Example 9, are shown in the following table.

[I'-10]

[Table 14]

The structures of the compounds represented by the formula [I'-9], which were synthesized in Example 2 or by the method as in Example 2, are shown in the following table.

[I'-9]

[Table 15]

The structures of the compounds represented by the formula [I'-9], which were synthesized in Example 3 or by the method as in Example 3, are shown in the following table.

[I'-9]

[Table 16]

The structure of the compound represented by the formula [I'-11], which is synthesized by the method as in Example 2, is shown in the following table.

[I'-11]

[Table 17]

The structures of the compounds represented by the formula [I'-12], which were synthesized by the method as in Example 2, are shown in the following table.

[I'-12]

[Table 18]

The structures of the compounds represented by the formula [I'-13], which were synthesized by the method as in Example 2, are shown in the following table.

[I'-13]

[Table 19]

The structures of the compounds represented by the formula [I'-14], which were synthesized by the method as in Example 2, are shown in the following table.

[I'-14]

[Table 20]

The structures of the compounds represented by the formula [I'-15], which were synthesized by the method as in Example 2, are shown in the following table.

[I'-15]

[Table 21]

The structures of the compounds represented by the formula [I'-14], which were synthesized by the method as in Example 2, are shown in the following table.

[I'-14]

[Table 22]

The structures of the compounds represented by the formula [I'-16], which were synthesized in Example 4 or by the method as in Example 4, are shown in the following table.

[I'-16]

[Table 23]

The structure of the compound represented by the formula [I'-17], which is synthesized by the method as in Example 2, is shown in the following table.

[I'-17]

[Table 24]

The structure of the compound represented by the formula [I'-18], which is synthesized by the method as in Example 2, is shown in the following table.

[I'-18]

[Table 25]

The structure of the compound represented by the formula [I'-19], which is synthesized by the method as in Example 2, is shown in the following table.

[I'-19]

[Table 26]

The structure of the compound represented by the formula [I'-20], which is synthesized by the method as in Example 1, is shown in the following table.

[I'-20]

[Table 27]

The structures of the compounds represented by the formula [I'-21], which were synthesized by the method as in Example 1, are shown in the following table.

[I'-21]

[Table 28]

The structure of the compound represented by the formula [I'-22], which is synthesized by the method as in Example 2, is shown in the following table.

[I'-22]

[Table 29]

The structure of the compound represented by the formula [I'-23] synthesized by the method as in Example 2 is shown in the following table.

[I'-23]

[Table 30]

The structure of the compound represented by the formula [I'-24], which is synthesized by the method as in Example 2, is shown in the following table.

[I'-24]

[Table 31]

The structure of the compound represented by the formula [I'-25], which is synthesized by the method as in Example 2, is shown in the following table.

[I'-25]

[Table 32]

The structures of the compounds represented by the formula [I'-26], which were synthesized by the method as in Example 2, are shown in the following table.

[I'-26]

[Table 33]

The structures of the compounds represented by the formula [I'-27], which were synthesized by the method as in Example 1, are shown in the following table.

[I'-27]

[Table 34]

The structure of the compound represented by the formula [I'-28], which is synthesized by the method as in Example 1, is shown in the following table.

[I'-28]

[Table 35]

The structure of the compound represented by the formula [I'-29], which is synthesized by the method as in Example 1, is shown in the following table.

[I'-29]

[Table 36]

The structure of the compound represented by the formula [I'-30], which was synthesized by the method as in Example 5, is shown in the following table.

[I'-30]

[Table 37]

The structure of the compound represented by the formula [I'-31], which is synthesized by the method as in Example 5, is shown in the following table.

[I'-31]

[Table 38]

The structures of the compounds represented by the formula [I'-32], which were synthesized by the method as in Example 1, are shown in the following table.

[Table 39]

The structures of the compounds represented by the formula [I'-32], which were synthesized in Example 6 or by the method as in Example 6, are shown in the following table.

[I'-32]

[Table 40]

The structure of the compound represented by the formula [I'-33], which is synthesized by the method as in Example 1, is shown in the following table.

[Table 41]

The structures of the compounds represented by the formula [I'-34], which were synthesized by the method as in Example 1, are shown in the following table.

[Table 42]

The structures of the compounds represented by the formula [I'-34], which were synthesized in Example 7 or by the method as in Example 7, are shown in the following table.

[Table 43]

The structures of the compounds represented by the formula [I'-35], which were synthesized by the method as in Example 1, are shown in the following table.

[I'-35]

[Table 44]

The structures of the compounds represented by the formula [I'-36], which were synthesized by the method as in Example 1, are shown in the following table.

[I'-36]

[Table 45]

The structures of the compounds represented by the formula [I'-37], which were synthesized in Example 8 or by the method as in Example 8, are shown in the following table.

[I'-37]

[Table 46]

The structures of the compounds represented by the formula [I'-38], which were synthesized in Example 9 or by the method as in Example 9, are shown in the following table.

[I'-38]

[Table 47]

The structures of the compounds represented by the formula [I'-39], which were synthesized by the method as in Example 9, are shown in the following table.

[I'-39]

[Table 48]

The structures of the compounds represented by the formula [I'-40], which are synthesized by the method as in Example 9, are shown in the following table:

[I'-40]

Where

structure represented by formula [VII-2]:

-AA ^WC1 -AA ^WC2 -AA ^WC3 -AA ^WC4 -AA ^WC5 - [VII-2]

corresponds to W ^C , which is a "linker consisting of one to three amino acids" in the compound represented by formula [I'],

Where

AA ^WC1 , AA ^WC2 , AA ^WC4 and AA ^WC5 are the same or different and each is selected from the group consisting of a single bond and (d)-Lys,

AA ^WC3 is Lys or (d)-Lys, and

AA ^WCS represents a single bond or (d)-Lys.

[Table 49]

The high performance liquid chromatography (LCMS) mass spectra, retention times (RT) and analytical conditions for the compounds of the present invention are shown in the following table.

[Table 50]

Connection No. LCMS analysis MS
(found) MS
(calculated) Holding time of the VU (min) Analysis conditions 1 916.7 [M+H] ⁺ 916.4 [M+H] ⁺ 0.97 A 2 902.5 [M+H] ⁺ 902.4 [M+H] ⁺ 0.98 A 3 902.5 [M+H] ⁺ 902.4 [M+H] ⁺ 0.99 A 4 916.4 [M+H] ⁺ 916.4 [M+H] ⁺ 0.94 A 5 902.4 [M+H] ⁺ 902.4 [M+H] ⁺ 0.81 A 6 916.4 [M+H] ⁺ 916.4 [M+H] ⁺ 0.90 A 7 950.4 [M+H] ⁺ 950.4 [M+H] ⁺ 0.99 A 8 989.4 [M+H] ⁺ 989.4 [M+H] ⁺ 1.01 A 9 900.6 [M+H] ⁺ 900.4 [M+H] ⁺ 1.08 A 10 886.4 [M+H] ⁺ 886.4 [M+H] ⁺ 1.02 A 11 900.5 [M+H] ⁺ 900.4 [M+H] ⁺ 1.10 A 12 858.4 [M+H] ⁺ 858.4 [M+H] ⁺ 0.98 A 13 934.4 [M+H] ⁺ 934.4 [M+H] ⁺ 1.20 A 14 950.5 [M+H] ⁺ 950.4 [M+H] ⁺ 1.02 A 15 874.4 [M+H] ⁺ 874.4 [M+H] ⁺ 0.88 A 16 870.4 [M+H] ⁺ 870.4 [M+H] ⁺ 0.96 A 17 914.5 [M+H] ⁺ 914.4 [M+H] ⁺ 0.99 A 18 900.4 [M+H] ⁺ 900.3 [M+H] ⁺ 0.95 A 19 900.3 [M+H] ⁺ 900.3 [M+H] ⁺ 0.92 A 20 928.6 [M+H] ⁺ 928.4 [M+H] ⁺ 1.01 A 21 914.4 [M+H] ⁺ 914.4 [M+H] ⁺ 0.94 A 22 888.3 [M+H] ⁺ 888.3 [M+H] ⁺ 0.87 A 23 902.4 [M+H] ⁺ 902.4 [M+H] ⁺ 0.89 A 24 930.4 [M+H] ⁺ 930.4 [M+H] ⁺ 0.99 A 25 914.4 [M+H] ⁺ 914.4 [M+H] ⁺ 0.91 A 26 945.5 [M+H] ⁺ 945.4 [M+H] ⁺ 0.69 A 27 945.4 [M+H] ⁺ 945.4 [M+H] ⁺ 0.69 A 28 973.4 [M+H] ⁺ 973.4 [M+H] ⁺ 0.70 A 29 973.4 [M+H] ⁺ 973.4 [M+H] ⁺ 0.71 A 30 817.3 [M+H] ⁺ 817.3 [M+H] ⁺ 0.89 A 31 674.1 [M+H] ⁺ 674.3 [M+H] ⁺ 0.85 A 32 1013.5 [M+H] ⁺ 1013.4 [M+H] ⁺ 1.00 A 33 1042.7 [MH] ^- 1042.5 [MH] ^- 0.74 A 34 1042.6 [MH] ^- 1042.5 [MH] ^- 0.74 A 35 1070.7 [MH] ^- 1070,5 [MH] ^- 0.75 A 36 1070,5 [MH] ^- 1070,5 [MH] ^- 0.76 A 37 587.0 [M+2H] ²⁺ 586.8 [M+2H] ²⁺ 0.64 A 38 898.7 [M+H] ⁺ 898.4 [M+H] ⁺ 1.07 A 39 912.6 [M+H] ⁺ 912.4 [M+H] ⁺ 1.06 A 40 830.3 [M+H] ⁺ 830.4 [M+H] ⁺ 1.28 A 41 860.4 [M+H] ⁺ 860.4 [M+H] ⁺ 1.27 A 42 864.4 [M+H] ⁺ 864.3 [M+H] ⁺ 1.38 A 43 848.4 [M+H] ⁺ 848.4 [M+H] ⁺ 1.30 A 44 846.4 [M+H] ⁺ 846.4 [M+H] ⁺ 1.28 A 45 877.5 [M+H] ⁺ 877.4 [M+H] ⁺ 1.46 A 46 877.5 [M+H] ⁺ 877.4 [M+H] ⁺ 1.47 A 47 875.5 [MH] ^- 875.4 [MH] ^- 1.48 A 48 888.5 [MH] ^- 888.3 [MH] ^- 1.74 A 49 876.5 [MH] ^- 876.3 [MH] ^- 1.71 A 50 905.6 [M+H] ⁺ 905.3 [M+H] ⁺ 1.36 A 51 889.5 [M+H] ⁺ 889.4 [M+H] ⁺ 1.44 A 52 893.5 [M+H] ⁺ 893.3 [M+H] ⁺ 1.32 A 53 907.5 [M+H] ⁺ 907.3 [M+H] ⁺ 1.29 A 54 903.6 [M+H] ⁺ 903.4 [M+H] ⁺ 1.40 A 55 903.6 [M+H] ⁺ 903.4 [M+H] ⁺ 1.40 A 56 976.4 [M+H] ⁺ 976.4 [M+H] ⁺ 1.66 A 57 956.6 [MH] ^- 956.4 [MH] ^- 1.63 A 58 970.7 [MH] ^- 970.4 [MH] ^- 1.65 A 59 970.6 [MH] ^- 970.4 [MH] ^- 1.64 A 60 985.0 [MH] ^- 984.5 [MH] ^- 1.72 A 61 1001.6 [M+H] ⁺ 1001,5 [M+H] ⁺ 1.37 A 62 1015.6 [M+H] ⁺ 1015.5 [M+H] ⁺ 1.35 A 63 1029.6 [M+H] ⁺ 1029.5 [M+H] ⁺ 1.35 A 64 988.6 [M+H] ⁺ 988.4 [M+H] ⁺ 1.59 A 65 984.6 [MH] ^- 984.5 [MH] ^- 1.66 A 66 1000,6 [MH] ^- 1000.4 [MH] ^- 1.58 A 67 1001.6 [M+H] ⁺ 1001,5 [M+H] ⁺ 1.33 A 68 1031.6 [M+H] ⁺ 1031.4 [M+H] ⁺ 1.29 A 69 1017.5 [M+H] ⁺ 1017.4 [M+H] ⁺ 1.29 A 70 1027.7 [MH] ^- 1027.5 [MH] ^- 1.40 A 71 1015.6 [M+H] ⁺ 1015.5 [M+H] ⁺ 1.37 A 72 1045.6 [M+H] ⁺ 1045.5 [M+H] ⁺ 1.31 A 73 1031.5 [M+H] ⁺ 1031.4 [M+H] ⁺ 1.30 A 74 973.6 [M+H] ⁺ 973.4 [M+H] ⁺ 1.31 A 75 1002.6 [M+H] ⁺ 1002.4 [M+H] ⁺ 1.60 A 76 1032.7 [M+H] ⁺ 1032.4 [M+H] ⁺ 1.35 A 77 1078.7 [M+H] ⁺ 1078.4 [M+H] ⁺ 1.39 A 78 1047.7 [M+H] ⁺ 1047.5 [M+H] ⁺ 1.44 A 79 1063.6 [M+H] ⁺ 1063.4 [M+H] ⁺ 1.37 A 80 1088.8 [M+H] ⁺ 1088.5 [M+H] ⁺ 1.06 A 81 1102.7 [M+H] ⁺ 1102.5 [M+H] ⁺ 1.06 A 82 1025.6 [M+H] ⁺ 1025.5 [M+H] ⁺ 1.03 A 83 1037.7 [MH] ^- 1037.5 [MH] ^- 1.02 A 84 1032.8 [M+H] ⁺ 1032.5 [M+H] ⁺ 1.37 A 85 1016.7 [M+H] ⁺ 1016.5 [M+H] ⁺ 1.45 A 86 1050.7 [M+H] ⁺ 1050.5 [M+H] ⁺ 1.42 A 87 1034.7 [M+H] ⁺ 1034.5 [M+H] ⁺ 1.48 A 88 1103.8 [MH] ^- 1103.5 [MH] ^- 1.20 A 89 1089.8 [M+H] ⁺ 1089.5 [M+H] ⁺ 1.25 A 90 1188.1 [MH] ^- 1187.6 [MH] ^- 1.16 A 91 1216.0 [MH] ^- 1215.6 [MH] ^- 1.19 A 92 905.7 [MH] ^- 905.5 [MH] ^- 1.72 A 93 923.6 [MH] ^- 923.5 [MH] ^- 1.73 A 94 948.7 [MH] ^- 948.5 [MH] ^- 1.62 A 95 966.6 [MH] ^- 966.5 [MH] ^- 1.65 A 96 893.7 [MH] ^- 893.5 [MH] ^- 1.80 A 97 911.7 [MH] ^- 911,5 [MH] ^- 1.82 A 98 938.7 [M+H] ⁺ 938.5 [M+H] ⁺ 1.71 A 99 956.7 [M+H] ⁺ 956.5 [M+H] ⁺ 1.74 A 100 919.7 [MH] ^- 919.5 [MH] ^- 1.73 A 101 937.7 [MH] ^- 937.5 [MH] ^- 1.75 A 102 933.7 [MH] ^- 933.5 [MH] ^- 1.81 A 103 962.6 [MH] ^- 962.5 [MH] ^- 1.63 A 104 980.7 [MH] ^- 980.5 [MH] ^- 1.66 A 105 976.7 [MH] ^- 976.5 [MH] ^- 1.71 A 106 979.7 [M+H] ⁺ 979.5 [M+H] ⁺ 1.33 A 107 965.7 [M+H] ⁺ 965.5 [M+H] ⁺ 1.28 A 108 995.6 [M+H] ⁺ 995.5 [M+H] ⁺ 1.25 A 109 981.6 [M+H] ⁺ 981.5 [M+H] ⁺ 1.23 A 110 993.7 [M+H] ⁺ 993.5 [M+H] ⁺ 1.34 A 111 979.6 [M+H] ⁺ 979.5 [M+H] ⁺ 1.31 A 112 1009.6 [M+H] ⁺ 1009.5 [M+H] ⁺ 1.26 A 113 995.6 [M+H] ⁺ 995.5 [M+H] ⁺ 1.25 A 114 934.7 [MH] ^- 934.5 [MH] ^- 1.60 A 115 891.6 [MH] ^- 891.5 [MH] ^- 1.66 A 116 903.6 [MH] ^- 903.5 [MH] ^- 1.68 A 117 917.6 [MH] ^- 917.5 [MH] ^- 1.74 A 118 931.7 [MH] ^- 931.5 [MH] ^- 1.76 A 119 933.7 [MH] ^- 933.5 [MH] ^- 1.80 A 120 947.7 [MH] ^- 947.5 [MH] ^- 1.85 A 121 947.7 [MH] ^- 947.5 [MH] ^- 1.85 A 122 965.6 [MH] ^- 965.5 [MH] ^- 1.79 A 123 948.7 [MH] ^- 948.5 [MH] ^- 1.33 A 124 981.7 [MH] ^- 981.5 [MH] ^- 1.87 A 125 949.6 [MH] ^- 949.5 [MH] ^- 1.65 A 126 963.7 [MH] ^- 963.5 [MH] ^- 1.67 A 127 962.6 [MH] ^- 962.5 [MH] ^- 1.35 A 128 948.7 [MH] ^- 948.5 [MH] ^- 1.60 A 129 997.7 [MH] ^- 997.5 [MH] ^- 1.74 A 130 1020.6 [MH] ^- 1020,5 [MH] ^- 1.85 A 131 935.7 [MH] ^- 935.5 [MH] ^- 1.41 A 132 932.8 [MH] ^- 932.5 [MH] ^- 1.40 A 133 946.7 [MH] ^- 946.5 [MH] ^- 1.39 A 134 996.6 [M+H] ⁺ 996.5 [M+H] ⁺ 1.50 A 135 962.7 [MH] ^- 962.5 [MH] ^- 1.49 A 136 978.7 [M+H] ⁺ 978.6 [M+H] ⁺ 1.54 A 137 997.7 [M+H] ⁺ 997.5 [M+H] ⁺ 1.32 A 138 1011.8 [M+H] ⁺ 1011.5 [M+H] ⁺ 1.35 A 139 1013.6 [M+H] ⁺ 1013.5 [M+H] ⁺ 1.29 A 140 1027.7 [M+H] ⁺ 1027.5 [M+H] ⁺ 1.28 A 141 999.6 [M+H] ⁺ 999.5 [M+H] ⁺ 1.28 A 142 1013.6 [M+H] ⁺ 1013.5 [M+H] ⁺ 1.28 A 143 980.8 [M+H] ⁺ 980.5 [M+H] ⁺ 1.38 A 144 1010.7 [M+H] ⁺ 1010.5 [M+H] ⁺ 1.27 A 145 995.7 [M+H] ⁺ 995.5 [M+H] ⁺ 1.07 A 146 964.7 [M+H] ⁺ 964.5 [M+H] ⁺ 1.46 A 147 994.7 [M+H] ⁺ 994.5 [M+H] ⁺ 1.34 A 148 977.9 [MH] ^- 977.6 [MH] ^- 1.10 A 149 1013.7 [M+H] ⁺ 1013.5 [M+H] ⁺ 1.26 A 150 998.7 [M+H] ⁺ 998.5 [M+H] ⁺ 1.42 A 151 1028.6 [M+H] ⁺ 1028.5 [M+H] ⁺ 1.30 A 152 1013.6 [M+H] ⁺ 1013.5 [M+H] ⁺ 1.09 A 153 997.7 [M+H] ⁺ 997.5 [M+H] ⁺ 1.35 A 154 993.7 [M+H] ⁺ 993.5 [M+H] ⁺ 1.37 A 155 996.7 [M+H] ⁺ 996.5 [M+H] ⁺ 1.30 A 156 980.7 [M+H] ⁺ 980.5 [M+H] ⁺ 1.39 A 157 854.4 [M-2H] ^2- 854.5 [M-2H] ^2- 1.44 A 158 870.7 [M+2H] ²⁺ 870.5 [M+2H] ²⁺ 1.56 A 159 1675.3 [MH] ^- 1675.0 [MH] ^- 1.01 A 160 853.4 [M+2H] ²⁺ 853.0 [M+2H] ²⁺ 1.10 A 161 1012.6 [MH] ^- 1012,5 [MH] ^- 1.36 A 162 1025.7 [MH] ^- 1025.5 [MH] ^- 1.28 A 163 1026.0 [MH] ^- 1025.5 [MH] ^- 1.31 A 164 1041.8 [M+H] ⁺ 1041.5 [M+H] ⁺ 1.28 A 165 1025.8 [M+H] ⁺ 1025.5 [M+H] ⁺ 1.35 A 166 1039.7 [M+H] ⁺ 1039.5 [M+H] ⁺ 1.33 A 167 1055.7 [M+H] ⁺ 1055.5 [M+H] ⁺ 1.25 A 168 1087.7 [M+H] ⁺ 1087.5 [M+H] ⁺ 1.10 A 169 1060.6 [M+H] ⁺ 1060.5 [M+H] ⁺ 1.10 A 170 1059.6 [MH] ^- 1059.5 [MH] ^- 1.94 B 171 1062.6 [M+H] ⁺ 1062.5 [M+H] ⁺ 1.98 B 172 1020.6 [M+H] ⁺ 1020.5 [M+H] ⁺ 1.97 B 173 996.8 [M+H] ⁺ 996.5 [M+H] ⁺ 1.30 A 174 980.8 [M+H] ⁺ 980.5 [M+H] ⁺ 1.38 A 175 1152.0 [MH] ^- 1151.6 [MH] ^- 1.11 A 176 1180.0 [MH] ^- 1179.6 [MH] ^- 1.14 A 177 995.7 [MH] ^- 995.4 [MH] ^- 1.30 A 178 1055.4 [M+H] ⁺ 1055.4 [M+H] ⁺ 1.29 A 179 548.7 [M+2H] ²⁺ 548.3 [M+2H] ²⁺ 0.82 A 180 555.7 [M+2H] ²⁺ 555.3 [M+2H] ²⁺ 0.84 A 181 1121.8 [MH] ^- 1121.6 [MH] ^- 0.86 A 182 1110.7 [M+H] ⁺ 1110.5 [M+H] ⁺ 1.03 A 183 1124.7 [M+H] ⁺ 1124.5 [M+H] ⁺ 1.04 A 184 1079.0 [MH] ^- 1078.6 [MH] ^- 0.91 A 185 1063.4 [MH] ^- 1062.6 [MH] ^- 1.00 A 186 1093.0 [MH] ^- 1092.6 [MH] ^- 0.97 A 187 1077.0 [MH] ^- 1076.6 [MH] ^- 1.01 A 188 1106.9 [MH] ^- 1106.6 [MH] ^- 0.94 A 189 1090.9 [MH] ^- 1090.6 [MH] ^- 1.00 A 190 1121.1 [MH] ^- 1120.6 [MH] ^- 0.97 A 191 1105.0 [MH] ^- 1104.6 [MH] ^- 1.02 A 192 1093.1 [MH] ^- 1092.6 [MH] ^- 0.99 A 193 1077.0 [MH] ^- 1076.6 [MH] ^- 1.03 A 194 1106.9 [MH] ^- 1106.6 [MH] ^- 1.01 A 195 1091.0 [MH] ^- 1090.6 [MH] ^- 1.05 A 196 1121.0 [MH] ^- 1120.6 [MH] ^- 1.00 A 197 1105.0 [MH] ^- 1104.6 [MH] ^- 1.04 A 198 1118.9 [MH] ^- 1118.6 [MH] ^- 1.06 A 199 1164.8 [MH] ^- 1164.6 [MH] ^- 1.05 A 200 1151.7 [M+H] ⁺ 1151.6 [M+H] ⁺ 1.17 A 201 1150.7 [M+H] ⁺ 1150.6 [M+H] ⁺ 1,12 A 202 958.5 [M+H] ⁺ 958.4 [M+H] ⁺ 1.62 A 203 1059.7 [M+H] ⁺ 1059.5 [M+H] ⁺ 1.36 A 204 1073.7 [M+H] ⁺ 1073.5 [M+H] ⁺ 1.34 A 205 1016.7 [M+H] ⁺ 1016.5 [M+H] ⁺ 1.40 A 206 1084.7 [M+H] ⁺ 1084.5 [M+H] ⁺ 1.07 A 207 1098.7 [M+H] ⁺ 1098.5 [M+H] ⁺ 1.07 A 208 1041.7 [M+H] ⁺ 1041.5 [M+H] ⁺ 1,12 A 209 1070.6 [M+H] ⁺ 1070.5 [M+H] ⁺ 1.04 A 210 1038.7 [M+H] ⁺ 1038.5 [M+H] ⁺ 1.49 B 211 1023.7 [M+H] ⁺ 1023.5 [M+H] ⁺ 1.62 B 212 1053.7 [M+H] ⁺ 1053.5 [M+H] ⁺ 1.52 B 213 1038.7 [M+H] ⁺ 1038.5 [M+H] ⁺ 1.33 B 214 1022.7 [M+H] ⁺ 1022.5 [M+H] ⁺ 1.57 B 215 1007.7 [M+H] ⁺ 1007.6 [M+H] ⁺ 1.70 B 216 1037.6 [M+H] ⁺ 1037.5 [M+H] ⁺ 1.59 B 217 1020.6 [MH] ^- 1020.6 [MH] ^- 1.44 B 218 1036.7 [M+H] ⁺ 1036.5 [M+H] ⁺ 1.08 A 219 1052.7 [M+H] ⁺ 1052.5 [M+H] ⁺ 1.03 A 220 1066.6 [M+H] ⁺ 1066.5 [M+H] ⁺ 1.03 A 221 1024.7 [M+H] ⁺ 1024.5 [M+H] ⁺ 0.98 A 222 1052.7 [M+H] ⁺ 1052.5 [M+H] ⁺ 1.02 A 223 1067.7 [M+H] ⁺ 1067.5 [M+H] ⁺ 1.04 A 224 1010.6 [M+H] ⁺ 1010.5 [M+H] ⁺ 1.00 A 225 1024.5 [M+H] ⁺ 1024.5 [M+H] ⁺ 1.01 A 226 1038.6 [M+H] ⁺ 1038.5 [M+H] ⁺ 1.03 A 227 1039.6 [M+H] ⁺ 1039.5 [M+H] ⁺ 1.03 A 228 1053.6 [M+H] ⁺ 1053.5 [M+H] ⁺ 1.04 A 229 1008.7 [M+H] ⁺ 1008.5 [M+H] ⁺ 1.05 A 230 1036.7 [M+H] ⁺ 1036.5 [M+H] ⁺ 1.09 A 231 1023.7 [M+H] ⁺ 1023.5 [M+H] ⁺ 1.07 A 232 1051.7 [M+H] ⁺ 1051.5 [M+H] ⁺ 1.10 A 233 1066.6 [M+H] ⁺ 1066.5 [M+H] ⁺ 1.02 A 234 1050.6 [M+H] ⁺ 1050.6 [M+H] ⁺ 1.07 A 235 1039.7 [M+H] ⁺ 1039.5 [M+H] ⁺ 1.04 A 236 1023.7 [M+H] ⁺ 1023.5 [M+H] ⁺ 1,12 A 237 1053.7 [M+H] ⁺ 1053.5 [M+H] ⁺ 1.04 A 238 1039.7 [M+H] ⁺ 1039.5 [M+H] ⁺ 1.04 A 239 1023.7 [M+H] ⁺ 1023.5 [M+H] ⁺ 1.11 A 240 1025.6 [M+H] ⁺ 1025.5 [M+H] ⁺ 1.04 A 241 1024.6 [M+H] ⁺ 1024.5 [M+H] ⁺ 1.02 A 242 1053.6 [M+H] ⁺ 1053.5 [M+H] ⁺ 1.04 A 243 1052.6 [M+H] ⁺ 1052.5 [M+H] ⁺ 1.00 A 244 1036.7 [MH] ⁺ 1036.5 [MH] ⁺ 1.05 A 245 1065.8 [M+H] ⁺ 1065.6 [M+H] ⁺ 0.95 A 246 1079.8 [M+H] ⁺ 1079.6 [M+H] ⁺ 0.95 A 247 533.6 [M+2H] ²⁺ 533.3 [M+2H] ²⁺ 0.90 A 248 1050.7 [M+H] ⁺ 1050.6 [M+H] ⁺ 1.06 A 249 1064.7 [M+H] ⁺ 1064.6 [M+H] ⁺ 1.07 A 250 1038.7 [M+H] ⁺ 1038.5 [M+H] ⁺ 0.99 A 251 1022.7 [M+H] ⁺ 1022.5 [M+H] ⁺ 1.05 A 252 1024.7 [M+H] ⁺ 1024.5 [M+H] ⁺ 1.00 A 253 1052.6 [M+H] ⁺ 1052.5 [M+H] ⁺ 1.00 A 254 1064.8 [M+H] ⁺ 1064.6 [M+H] ⁺ 1.16 A 255 1104.8 [M+H] ⁺ 1104.6 [M+H] ⁺ 1.31 A 256 1066.7 [M+H] ⁺ 1066.5 [M+H] ⁺ 1.04 A 257 1080.7 [M+H] ⁺ 1080.5 [M+H] ⁺ 1.04 A 258 1081.7 [M+H] ⁺ 1081.5 [M+H] ⁺ 1.07 A 259 1053.6 [M+H] ⁺ 1053.5 [M+H] ⁺ 1.07 A 260 1067.7 [M+H] ⁺ 1067.5 [M+H] ⁺ 1.06 A 261 1051.6 [M+H] ⁺ 1051.5 [M+H] ⁺ 1.13 A 262 1082.7 [M+H] ⁺ 1082.5 [M+H] ⁺ 1.09 A 263 1098.6 [M+H] ⁺ 1098.5 [M+H] ⁺ 1.03 A 264 1097.7 [M+H] ⁺ 1097.5 [M+H] ⁺ 1.11 A 265 1113.6 [M+H] ⁺ 1113.5 [M+H] ⁺ 1.05 A 266 1096.6 [M+H] ⁺ 1096.6 [M+H] ⁺ 1.07 A 267 1112.7 [M+H] ⁺ 1112.5 [M+H] ⁺ 1.03 A 268 1066.7 [M+H] ⁺ 1066.5 [M+H] ⁺ 1.03 A 269 1092.7 [M+H] ⁺ 1092.5 [M+H] ⁺ 1.06 A 270 1106.7 [M+H] ⁺ 1106.6 [M+H] ⁺ 1.11 A 271 1136.7 [M+H] ⁺ 1136.6 [M+H] ⁺ 1.03 A 272 1096.6 [M+H] ⁺ 1096.5 [M+H] ⁺ 1.01 A 273 1076.7 [M+H] ⁺ 1076.6 [M+H] ⁺ 1.16 A 274 1092.6 [M+H] ⁺ 1092.6 [M+H] ⁺ 1.07 A 275 1090.7 [M+H] ⁺ 1090.6 [M+H] ⁺ 1.22 A 276 1120.7 [M+H] ⁺ 1120.6 [M+H] ⁺ 1.10 A 277 1080.6 [M+H] ⁺ 1080.6 [M+H] ⁺ 1.07 A 278 1103.7 [M+H] ⁺ 1103.5 [M+H] ⁺ 1.09 A 279 1036.8 [M+H] ⁺ 1036.5 [M+H] ⁺ 1.06 A 280 1052.7 [M+H] ⁺ 1052.5 [M+H] ⁺ 1.02 A 281 1050.7 [M+H] ⁺ 1050.6 [M+H] ⁺ 1.08 A 282 1066.7 [M+H] ⁺ 1066.5 [M+H] ⁺ 1.03 A 283 1036.8 [M+H] ⁺ 1036.5 [M+H] ⁺ 1.06 A 284 1052.6 [M+H] ⁺ 1052.5 [M+H] ⁺ 1.00 A 285 1025.7 [M+H] ⁺ 1025.5 [M+H] ⁺ 1.02 A 286 1007.7 [MH] ^- 1007,5 [MH] ^- 1.04 A 287 1085.7 [M+H] ⁺ 1085.5 [M+H] ⁺ 1.22 A 288 1085.7 [M+H] ⁺ 1085.5 [M+H] ⁺ 1.21 A 289 1101.7 [M+H] ⁺ 1101,5 [M+H] ⁺ 1.11 A 290 1101,5 [M+H] ⁺ 1101,5 [M+H] ⁺ 1.11 A 291 527.6 [M+2H] ²⁺ 527.3 [M+2H] ²⁺ 0.83 A 292 534.5 [M+2H] ²⁺ 534.3 [M+2H] ²⁺ 0.80 A 293 505.9 [M+2H] ²⁺ 505.8 [M+2H] ²⁺ 0.86 A 294 506.0 [M+2H] ²⁺ 505.8 [M+2H] ²⁺ 0.86 A 295 993.5 [MH] ^- 993.5 [MH] ^- 1.03 A 296 520.0 [M+2H] ²⁺ 519.8 [M+2H] ²⁺ 0.85 A 297 513.1 [M+2H] ²⁺ 512.8 [M+2H] ²⁺ 0.87 A 298 1036.8 [MH] ^- 1036.5 [MH] ^- 0.86 A 299 1051.8 [MH] ^- 1051.5 [MH] ^- 0.76 A 300 991.7 [M+H] ⁺ 991.5 [M+H] ⁺ 1.11 A 301 1007.6 [M+H] ⁺ 1007.5 [M+H] ⁺ 1.04 A 302 1005.6 [M+H] ⁺ 1005.5 [M+H] ⁺ 1,12 A 303 1021.6 [M+H] ⁺ 1021.5 [M+H] ⁺ 1.06 A 304 1051.7 [M+H] ⁺ 1051.5 [M+H] ⁺ 1.11 A 305 534.5 [M+2H] ²⁺ 534.2 [M+2H] ²⁺ 1.05 A 306 1037.7 [MH] ^- 1037.5 [MH] ^- 0.78 A 307 1037.7 [MH] ^- 1037.5 [MH] ^- 0.75 A 308 1081.8 [M+H] ⁺ 1081.5 [M+H] ⁺ 1.07 A 309 1035.8 [M+H] ⁺ 1035.6 [M+H] ⁺ 1.31 A 310 1048.9 [MH] ^- 1048.6 [MH] ^- 0.98 A 311 1066.8 [M+H] ⁺ 1066.6 [M+H] ⁺ 0.88 A 312 1062.8 [MH] ^- 1062.6 [MH] ^- 1.00 A 313 1078.9 [MH] ^- 1078.6 [MH] ^- 0.91 A 314 1038.7 [M+H] ⁺ 1038.5 [M+H] ⁺ 1.06 A 315 1011.7 [M+H] ⁺ 1011.5 [M+H] ⁺ 1.07 A 316 1071.7 [M+H] ⁺ 1071.5 [M+H] ⁺ 1.18 A 317 1044.7 [M+H] ⁺ 1044.5 [M+H] ⁺ 1.18 A 318 1065.7 [M+H] ⁺ 1065.6 [M+H] ⁺ 1.11 A 319 1039.8 [M+H] ⁺ 1039.5 [M+H] ⁺ 1.04 A 320 1039.7 [M+H] ⁺ 1039.5 [M+H] ⁺ 1.03 A 321 1035.7 [M+H] ⁺ 1035.5 [M+H] ⁺ 1.09 A 322 1124.7 [M+H] ⁺ 1124.5 [M+H] ⁺ 1.22 A 323 1049.8 [M+H] ⁺ 1049.6 [M+H] ⁺ 1.32 A 324 1064.8 [M+H] ⁺ 1065.6 [M+H] ⁺ 1.24 A 325 1067.8 [M+H] ⁺ 1067.6 [M+H] ⁺ 1.26 A 326 1082.7 [M+H] ⁺ 1083.5 [M+H] ⁺ 1.17 A 327 1124.7 [M+H] ⁺ 1124.5 [M+H] ⁺ 1.21 A 328 538.6 [M+2H] ²⁺ 538.3 [M+2H] ²⁺ 0.85 A 329 1073.8 [MH] ^- 1073.5 [MH] ^- 0.85 A 330 1041.7 [M+H] ⁺ 1041.5 [M+H] ⁺ 1.08 A 331 1041.7 [M+H] ⁺ 1041.5 [M+H] ⁺ 1.07 A 332 1092.7 [MH] ^- 1092.6 [MH] ^- 0.86 A 333 1092.9 [MH] ^- 1092.6 [MH] ^- 0.86 A 334 534.6 [M+2H] ²⁺ 534.3 [M+2H] ²⁺ 1.03 A 335 1027.7 [M+H] ⁺ 1027.5 [M+H] ⁺ 1.00 A 336 1092.8 [M+H] ⁺ 1092.6 [M+H] ⁺ 1.09 A 337 1108.7 [M+H] ⁺ 1108.6 [M+H] ⁺ 1.05 A 338 1079.8 [M+H] ⁺ 1079.6 [M+H] ⁺ 1.06 A 339 1079.8 [M+H] ⁺ 1079.6 [M+H] ⁺ 1.05 A 340 1095.7 [M+H] ⁺ 1095.5 [M+H] ⁺ 1.01 A 341 1095.7 [M+H] ⁺ 1095.5 [M+H] ⁺ 1.01 A 342 1053.7 [M+H] ⁺ 1053.5 [M+H] ⁺ 1.04 A 343 1053.6 [M+H] ⁺ 1053.5 [M+H] ⁺ 1.04 A 344 1048.9 [MH] ^- 1048.6 [MH] ^- 0.92 A 345 1053.7 [M+H] ⁺ 1053.5 [M+H] ⁺ 1.20 A 346 1069.7 [M+H] ⁺ 1069.5 [M+H] ⁺ 1.14 A 347 1009.8 [M+H] ⁺ 1009.5 [M+H] ⁺ 1.06 A 348 1023.8 [M+H] ⁺ 1023.5 [M+H] ⁺ 1.08 A 349 984.6 [M+H] ⁺ 984.5 [M+H] ⁺ 1.04 A 350 1422.4 [MH] ^- 1421.8 [MH] ^- 0.60 A 351 470.1 [M+3H] ³⁺ 469.9 [M+3H] ³⁺ 0.67 A 352 1025.7 [M+H] ⁺ 1025.5 [M+H] ⁺ 1.02 A 353 1009.7 [M+H] ⁺ 1009.5 [M+H] ⁺ 1.07 A 354 1053.7 [M+H] ⁺ 1053.5 [M+H] ⁺ 1.06 A 355 1037.7 [M+H] ⁺ 1037.6 [M+H] ⁺ 1.13 A 356 1076.8 [MH] ^- 1076.6 [MH] ^- 0.99 A 357 1064.7 [M+H] ⁺ 1064.6 [M+H] ⁺ 1.09 A 358 1080.7 [M+H] ⁺ 1080.5 [M+H] ⁺ 1.04 A 359 1070.6 [M+H] ⁺ 1070.5 [M+H] ⁺ 1.07 A 360 1086.6 [M+H] ⁺ 1086.5 [M+H] ⁺ 1.04 A 361 1038.9 [MH] ^- 1038.5 [MH] ^- 0.80 A 362 1052.7 [MH] ^- 1052.5 [MH] ^- 0.83 A 363 1079.8 [MH] ^- 1079.6 [MH] ^- 0.71 A 364 513.1 [M+2H] ²⁺ 512.8 [M+2H] ²⁺ 0.91 A 365 520.1 [M+2H] ²⁺ 519.8 [M+2H] ²⁺ 0.98 A 366 1064.0 [MH] ^- 1063.6 [MH] ^- 0.78 A 367 1107.0 [MH] ^- 1106.6 [MH] ^- 0.94 A 368 1091.1 [MH] ^- 1090.6 [MH] ^- 1.00 A 369 1064.9 [MH] ^- 1064.5 [MH] ^- 0.86 A 370 1049.1 [MH] ^- 1048.6 [MH] ^- 0.99 A 371 1009.9 [M+H] ⁺ 1009.5 [M+H] ⁺ 0.66 A 372 1021.8 [MH] ^- 1021.5 [MH] ^- 0.66 A 373 1035.9 [MH] ^- 1035.6 [MH] ^- 0.62 A 374 1092.0 [MH] ^- 1091.6 [MH] ^- 0.73 A 375 1035.9 [MH] ^- 1035.5 [MH] ^- 0.68 A 376 1049.9 [MH] ^- 1049.6 [MH] ^- 0.68 A 377 1065.8 [M+H] ⁺ 1065.6 [M+H] ⁺ 0.67 A 378 1093.8 [M+H] ⁺ 1093.6 [M+H] ⁺ 0.73 A 379 925.5 [M+H] ⁺ 925.5 [M+H] ⁺ 1.13 A 380 955.5 [M+H] ⁺ 955.5 [M+H] ⁺ 1.00 A 381 939.6 [M+H] ⁺ 939.5 [M+H] ⁺ 1.13 A 382 812.5 [M+H] ⁺ 812.4 [M+H] ⁺ 0.97 A 383 1032.7 [M+H] ⁺ 1032.6 [M+H] ⁺ 1.09 A 384 1192.9 [MH] ^- 1192.6 [MH] ^- 0.86 A 385 1176.9 [MH] ^- 1176.6 [MH] ^- 0.89 A 386 1221.0 [MH] ^- 1220.6 [MH] ^- 0.85 A 387 1204.9 [MH] ^- 1204.6 [MH] ^- 0.93 A 388 1220.9 [MH] ^- 1220.6 [MH] ^- 0.72 A 389 1205.0 [MH] ^- 1204.7 [MH] ^- 0.80 A 390 1249.0 [MH] ^- 1248.6 [MH] ^- 0.74 A 391 1232.9 [MH] ^- 1232.7 [MH] ^- 0.81 A 392 1036.7 [M+H] ⁺ 1036.5 [M+H] ⁺ 1.05 A 393 1052.7 [M+H] ⁺ 1052.5 [M+H] ⁺ 1.01 A 394 1037.7 [M+H] ⁺ 1037.5 [M+H] ⁺ 1.07 A 395 1053.6 [M+H] ⁺ 1053.5 [M+H] ⁺ 1.04 A 396 1062.9 [MH] ^- 1062.6 [MH] ^- 0.93 A 397 1078.9 [MH] ^- 1078.5 [MH] ^- 0.85 A 398 1009.7 [M+H] ⁺ 1009.5 [M+H] ⁺ 1.06 A 399 1025.7 [M+H] ⁺ 1025.5 [M+H] ⁺ 1.02 A 400 1206.8 [MH] ^- 1206.6 [MH] ^- 0.83 A 401 1191.0 [MH] ^- 1190.6 [MH] ^- 0.90 A 402 1178.9 [MH] ^- 1178.6 [MH] ^- 0.82 A 403 1163.0 [MH] ^- 1162.6 [MH] ^- 0.86 A 404 1179.0 [MH] ^- 1178.6 [MH] ^- 0.83 A 405 1163.1 [MH] ^- 1162.6 [MH] ^- 0.86 A 406 1206.9 [MH] ^- 1206.6 [MH] ^- 0.84 A 407 1191.0 [MH] ^- 1190.6 [MH] ^- 0.88 A 408 1110.0 [MH] ^- 1109.5 [MH] ^- 0.79 A 409 1093.9 [MH] ^- 1093.6 [MH] ^- 0.99 A 410 1081.9 [MH] ^- 1081.5 [MH] ^- 0.78 A 411 1065.7 [MH] ^- 1065.6 [MH] ^- 0.98 A 412 1026.7 [M+H] ⁺ 1026.5 [M+H] ⁺ 0.97 A 413 1010.7 [M+H] ⁺ 1010.5 [M+H] ⁺ 1.09 A 414 1040.7 [M+H] ⁺ 1040.5 [M+H] ⁺ 0.99 A 415 1024.8 [M+H] ⁺ 1024.5 [M+H] ⁺ 1.10 A 416 1054.7 [M+H] ⁺ 1054.5 [M+H] ⁺ 1.01 A 417 1092.7 [M+H] ⁺ 1092.5 [M+H] ⁺ 0.81 A 418 1093.9 [MH] ^- 1093.6 [MH] ^- 0.97 A 419 1109.9 [MH] ^- 1109.5 [MH] ^- 0.81 A 420 1065.8 [MH] ^- 1065.6 [MH] ^- 0.95 A 421 1081.8 [MH] ^- 1081.5 [MH] ^- 0.78 A 422 1039.8 [MH] ^- 1039.5 [MH] ^- 0.79 A 423 1053.7 [MH] ^- 1053.5 [MH] ^- 0.78 A 424 1051.9 [MH] ^- 1051.6 [MH] ^- 0.97 A 425 1067.8 [MH] ^- 1067.5 [MH] ^- 0.77 A 426 1066.7 [M+H] ⁺ 1066.5 [M+H] ⁺ 1.07 A 427 1038.8 [M+H] ⁺ 1038.6 [M+H] ⁺ 1.11 A 428 1049.8 [MH] ^- 1049.5 [MH] ^- 0.85 A 429 1377.2 [MH] ^- 1376.7 [MH] ^- 0.75 A 430 1361.0 [MH] ^- 1360.7 [MH] ^- 0.80 A 431 680.9 [M-2H] ^2- 680.8 [M-2H] ^2- 0.72 A 432 1347.1 [MH] ^- 1346.7 [MH] ^- 0.75 A 433 1376.8 [MH] ^- 1376.7 [MH] ^- 0.74 A 434 1361.2 [MH] ^- 1360.7 [MH] ^- 0.80 A 435 1363.0 [MH] ^- 1362.7 [MH] ^- 0.73 A 436 1347.1 [MH] ^- 1346.7 [MH] ^- 0.77 A 437 1025.8 [M+H] ⁺ 1025.5 [M+H] ⁺ 0.96 A 438 1023.8 [MH] ^- 1023.5 [MH] ^- 0.96 A 439 1038.1 [MH] ^- 1037.5 [MH] ^- 0.95 A 440 1321.1 [MH] ^- 1320.7 [MH] ^- 0.72 A 441 1305.1 [MH] ^- 1304.7 [MH] ^- 0.76 A 442 1307.1 [MH] ^- 1306.7 [MH] ^- 0.71 A 443 1291.1 [MH] ^- 1290.7 [MH] ^- 0.73 A 444 1321.1 [MH] ^- 1320.7 [MH] ^- 0.70 A 445 1305.1 [MH] ^- 1304.7 [MH] ^- 0.75 A 446 1307.0 [MH] ^- 1306.7 [MH] ^- 0.70 A 447 1291.2 [MH] ^- 1290.7 [MH] ^- 0.73 A 448 1037.9 [MH] ^- 1037.5 [MH] ^- 0.97 A 449 1053.8 [M+H] ⁺ 1053.6 [M+H] ⁺ 0.97 A 450 1051.9 [MH] ^- 1051.6 [MH] ^- 0.98 A 451 1065.8 [MH] ^- 1065.6 [MH] ^- 0.99 A 452 1065.9 [MH] ^- 1065.6 [MH] ^- 0.97 A 453 1050.8 [M+H] ⁺ 1050.6 [M+H] ⁺ 1.08 A 454 1020.8 [MH] ^- 1020,5 [MH] ^- 1.04 A 455 1020.9 [MH] ^- 1020,5 [MH] ^- 1.08 A 456 1022.9 [MH] ^- 1022.5 [MH] ^- 1.05 A 457 1179.0 [MH] ^- 1178.6 [MH] ^- 1.00 A 458 1179.0 [MH] ^- 1178.6 [MH] ^- 0.98 A 459 1150.9 [MH] ^- 1150.6 [MH] ^- 0.98 A 460 1151.0 [MH] ^- 1150.6 [MH] ^- 0.98 A 461 1335.1 [MH] ^- 1334.7 [MH] ^- 0.85 A 462 669.1 [M+2H] ²⁺ 668.9 [M+2H] ²⁺ 0.86 A 463 1279.3 [MH] ^- 1278.7 [MH] ^- 0.82 A 464 1194.9 [MH] ^- 1194.6 [MH] ^- 0.82 A 465 1195.0 [MH] ^- 1194.6 [MH] ^- 0.83 A 466 1167.1 [MH] ^- 1166.6 [MH] ^- 0.80 A 467 1166.9 [MH] ^- 1166.6 [MH] ^- 0.79 A 468 1351.2 [MH] ^- 1350.7 [MH] ^- 0.71 A 469 1351.1 [MH] ^- 1350.7 [MH] ^- 0.70 A 470 1295.1 [MH] ^- 1294.7 [MH] ^- 0.69 A 471 1295.0 [MH] ^- 1294.7 [MH] ^- 0.68 A 472 1193.0 [MH] ^- 1192.7 [MH] ^- 0.99 A 473 1193.0 [MH] ^- 1192.7 [MH] ^- 0.99 A 474 1165.1 [MH] ^- 1164.6 [MH] ^- 0.99 A 475 1165.0 [MH] ^- 1164.6 [MH] ^- 0.99 A 476 1349.2 [MH] ^- 1348.8 [MH] ^- 0.87 A 477 1349.5 [MH] ^- 1348.8 [MH] ^- 0.86 A 478 1293.1 [MH] ^- 1292.7 [MH] ^- 0.84 A 479 648.0 [M+2H] ²⁺ 647.9 [M+2H] ²⁺ 0.83 A 480 1052.9 [M+H] ⁺ 1052.6 [M+H] ⁺ 1.13 A 481 1052.9 [MH] ^- 1052.5 [MH] ^- 1.01 A 482 1037.0 [MH] ^- 1036.6 [MH] ^- 1.07 A 483 1205.2 [MH] ^- 1204.7 [MH] ^- 0.94 A 484 1177.2 [MH] ^- 1176.6 [MH] ^- 0.91 A 485 1022.9 [MH] ^- 1022.5 [MH] ^- 1.08 A 486 1037.0 [MH] ^- 1036.6 [MH] ^- 1.15 A 487 1164.9 [MH] ^- 1164.7 [MH] ^- 0.91 A 488 1193.0 [MH] ^- 1192.7 [MH] ^- 0.96 A 489 1178.9 [MH] ^- 1178.6 [MH] ^- 0.97 A 490 1165.1 [MH] ^- 1164.6 [MH] ^- 1.01 A 491 1193.1 [MH] ^- 1192.7 [MH] ^- 1.01 A 492 980.9 [MH] ^- 980.5 [MH] ^- 1.00 A 493 1080.1 [MH] ^- 1079.6 [MH] ^- 0.99 A 494 1008.9 [MH] ^- 1008.6 [MH] ^- 0.98 A 495 1023.0 [MH] ^- 1022.6 [MH] ^- 0.99 A 496 1063.9 [MH] ^- 1063.6 [MH] ^- 0.92 A 497 1051.9 [MH] ^- 1051.6 [MH] ^- 0.98 A 498 1006.9 [MH] ^- 1006.5 [MH] ^- 0.94 A 499 994.8 [MH] ^- 994.5 [MH] ^- 0.99 A 500 1105.7 [MH] ^- 1105.6 [MH] ^- 0.96 A 501 1093.8 [MH] ^- 1093.6 [MH] ^- 1.00 A 502 1021.9 [MH] ^- 1021.6 [MH] ^- 0.77 A 503 1009.9 [MH] ^- 1009.6 [MH] ^- 0.81 A 504 992.9 [MH] ^- 992.5 [MH] ^- 0.91 A 505 980.8 [MH] ^- 980.5 [MH] ^- 0.98 A 506 1050.0 [MH] ^- 1049.5 [MH] ^- 0.86 A 507 1037.9 [MH] ^- 1037.5 [MH] ^- 0.87 A 508 993.9 [MH] ^- 994.5 [MH] ^- 1.04 A 509 1191.0 [MH] ^- 1190.6 [MH] ^- 0.88 A 510 1163.0 [MH] ^- 1162.6 [MH] ^- 0.87 A 511 994.8 [MH] ^- 994.5 [MH] ^- 1.04 A 512 1008.8 [MH] ^- 1008,5 [MH] ^- 1.05 A 513 1052.0 [MH] ^- 1051.6 [MH] ^- 0.92 A 514 1179.0 [MH] ^- 1178.6 [MH] ^- 0.94 A 515 1150.9 [MH] ^- 1150.6 [MH] ^- 0.92 A 516 1007.7 [MH] ^- 1007,5 [MH] ^- 0.76 A 517 995.7 [MH] ^- 995.5 [MH] ^- 0.77 A 518 1221.9 [MH] ^- 1221.7 [MH] ^- 0.84 A 519 1193.9 [MH] ^- 1193.7 [MH] ^- 0.83 A 520 1109.0 [MH] ^- 1108.6 [MH] ^- 0.93 A 521 1123.0 [MH] ^- 1122.6 [MH] ^- 0.93 A 522 937.8 [MH] ^- 937.5 [MH] ^- 1.00 A 523 937.8 [MH] ^- 937.5 [MH] ^- 1.01 A 524 1067.1 [MH] ^- 1066.6 [MH] ^- 0.72 A 525 1067.0 [MH] ^- 1066.6 [MH] ^- 0.72 A 526 1080.8 [MH] ^- 1080.6 [MH] ^- 0.77 A 527 1080.5 [MH] ^- 1080.6 [MH] ^- 0.77 A 528 1108.9 [MH] ^- 1108.6 [MH] ^- 0.68 A 529 1009.9 [MH] ^- 1009.5 [MH] ^- 0.88 A 530 1009.9 [MH] ^- 1009.5 [MH] ^- 0.89 A 531 1023.8 [MH] ^- 1023.5 [MH] ^- 0.88 A 532 1023.9 [MH] ^- 1023.5 [MH] ^- 0.88 A 533 1037.9 [MH] ^- 1037.5 [MH] ^- 0.89 A 534 1051.9 [MH] ^- 1051.6 [MH] ^- 0.89 A 535 514.3 [M+2H] ²⁺ 513.8 [M+2H] ²⁺ 0.73 A 536 514.2 [M+2H] ²⁺ 513.8 [M+2H] ²⁺ 0.69 A 537 521.2 [M+2H] ²⁺ 520.8 [M+2H] ²⁺ 0.69 A 538 1053.0 [MH] ^- 1052.6 [MH] ^- 0.72 A 539 1052.9 [MH] ^- 1052.6 [MH] ^- 0.70 A 540 1095.0 [MH] ^- 1094.6 [MH] ^- 0.88 A 541 1108.9 [MH] ^- 1108.6 [MH] ^- 0.88 A 542 1038.0 [MH] ^- 1037.5 [MH] ^- 0.87 A 543 1094.0 [MH] ^- 1093.6 [MH] ^- 0.82 A 544 1094.0 [MH] ^- 1093.6 [MH] ^- 0.82 A 545 1080.0 [MH] ^- 1079.6 [MH] ^- 0.76 A 546 1079.8 [MH] ^- 1079.6 [MH] ^- 0.78 A 547 1038.8 [MH] ^- 1038.6 [MH] ^- 0.99 A 548 1038.9 [MH] ^- 1038.6 [MH] ^- 1.00 A 549 1024.9 [MH] ^- 1024.6 [MH] ^- 0.93 A 550 1024.9 [MH] ^- 1024.6 [MH] ^- 0.98 A 551 1109.0 [MH] ^- 1108.6 [MH] ^- 0.71 A 552 1095.0 [MH] ^- 1094.6 [MH] ^- 0.64 A 553 1095.0 [MH] ^- 1094.6 [MH] ^- 0.66 A 554 1053.7 [MH] ^- 1053.6 [MH] ^- 0.80 A 555 1053.8 [MH] ^- 1053.6 [MH] ^- 0.80 A 556 1039.8 [MH] ^- 1039.6 [MH] ^- 0.74 A 557 1039.8 [MH] ^- 1039.6 [MH] ^- 0.74 A 558 1094.9 [MH] ^- 1094.6 [MH] ^- 0.99 A 559 1109.9 [MH] ^- 1109.6 [MH] ^- 0.78 A 560 1095.8 [MH] ^- 1095.6 [MH] ^- 0.72 A 561 1039.0 [MH] ^- 1038.5 [MH] ^- 0.77 A 562 1038.8 [MH] ^- 1038.5 [MH] ^- 0.76 A 563 1053.0 [MH] ^- 1052.6 [MH] ^- 0.76 A 564 1052.9 [MH] ^- 1052.6 [MH] ^- 0.75 A 565 1066.9 [MH] ^- 1066.6 [MH] ^- 0.75 A 566 1067.0 [MH] ^- 1066.6 [MH] ^- 0.75 A 567 1051.9 [MH] ^- 1051.6 [MH] ^- 0.99 A 568 1051.9 [MH] ^- 1051.6 [MH] ^- 0.99 A 569 1051.9 [MH] ^- 1051.6 [MH] ^- 0.99 A 570 1051.9 [MH] ^- 1051.6 [MH] ^- 0.99 A 571 1081.9 [MH] ^- 1081.5 [MH] ^- 0.82 A 572 1081.9 [MH] ^- 1081.5 [MH] ^- 0.80 A 573 1023.9 [MH] ^- 1023.5 [MH] ^- 0.82 A 574 1023.9 [MH] ^- 1023.5 [MH] ^- 0.82 A 575 1065.9 [MH] ^- 1065.6 [MH] ^- 1.02 A 576 1065.8 [MH] ^- 1065.6 [MH] ^- 0.99 A 577 1066.9 [MH] ^- 1066.6 [MH] ^- 1.05 A 578 1021.8 [MH] ^- 1021.5 [MH] ^- 1.10 A 579 1031.9 [MH] ^- 1031.5 [MH] ^- 1.30 A 580 1019.8 [MH] ^- 1019.6 [MH] ^- 1.14 A 581 1031.8 [MH] ^- 1031.6 [MH] ^- 1,12 A 582 1047.8 [MH] ^- 1047.6 [MH] ^- 1.17 A 583 1059.8 [MH] ^- 1059.6 [MH] ^- 1.14 A 584 990.8 [MH] ^- 990.5 [MH] ^- 1.32 A 585 992.7 [MH] ^- 992.5 [MH] ^- 1.38 A 586 1004.7 [MH] ^- 1004.5 [MH] ^- 1.35 A 587 1002.7 [MH] ^- 1002.4 [MH] ^- 1.81 A 588 1016.7 [MH] ^- 1016.4 [MH] ^- 1.83 A 589 970.7 [MH] ^- 970.4 [MH] ^- 1.79 A 590 939.5 [MH] ^- 939.4 [MH] ^- 1.08 A 591 941.6 [M+H] ⁺ 941.4 [M+H] ⁺ 0.89 A 592 939.4 [MH] ^- 939.4 [MH] ^- 1.49 A 593 801.3 [M+H] ⁺ 801.2 [M+H] ⁺ 1.89 B 594 774.5 [MH] ^- 774.4 [MH] ^- 1.53 A 595 835.3 [M+H] ⁺ 835.4 [M+H] ⁺ 1.04 A 596 989.6 [M+H] ⁺ 989.5 [M+H] ⁺ 1.34 A 597 974.5 [MH] ^- 974.4 [MH] ^- 1.65 A 598 974.5 [MH] ^- 974.4 [MH] ^- 1.63 A 599 958.6 [M+H] ⁺ 958.4 [M+H] ⁺ 1.64 A 600 991.7 [M+H] ⁺ 991.5 [M+H] ⁺ 1.22 A 601 1007.7 [M+H] ⁺ 1007.5 [M+H] ⁺ 1.15 A 602 844.6 [MH] ^- 844.3 [MH] ^- 0.98 A 603 858.5 [MH] ^- 858.4 [MH] ^- 0.97 A 604 828.4 [MH] ^- 828.4 [MH] ^- 1.06 A 605 842.5 [MH] ^- 842.5 [MH] ^- 1.04 A 606 872.7 [MH] ^- 872.4 [MH] ^- 1.07 A 607 872.5 [MH] ^- 872.4 [MH] ^- 0.87 A 608 881.6 [M+H] ⁺ 881.4 [M+H] ⁺ 1.38 A 609 928.6 [M+H] ⁺ 928.4 [M+H] ⁺ 1.07 A 610 826.4 [M+H] ⁺ 826.3 [M+H] ⁺ 1.39 A 611 830.8 [MH] ^- 830.3 [MH] ^- 1.37 A 612 846.5 [M+H] ⁺ 846.4 [M+H] ⁺ 1.34 A 613 816.5 [M+H] ⁺ 816.4 [M+H] ⁺ 1.45 A 614 830.5 [M+H] ⁺ 830.4 [M+H] ⁺ 1.42 A 615 870.4 [M+H] ⁺ 870.4 [M+H] ⁺ 1.63 A 616 884.4 [M+H] ⁺ 884.4 [M+H] ⁺ 1.61 A 617 846.4 [M+H] ⁺ 846.4 [M+H] ⁺ 1.48 A 618 860.4 [M+H] ⁺ 860.4 [M+H] ⁺ 1.45 A 619 858.5 [M+H] ⁺ 858.4 [M+H] ⁺ 1.51 A 620 826.5 [MH] ^- 826.4 [MH] ^- 1.35 A 621 810.5 [MH] ^- 810.4 [MH] ^- 1.44 A 622 856.5 [MH] ^- 856.4 [MH] ^- 1.36 A 623 840.6 [MH] ^- 840.4 [MH] ^- 1.43 A 624 844.5 [MH] ^- 844.3 [MH] ^- 1.40 A 625 828.5 [MH] ^- 828.4 [MH] ^- 1.47 A 626 860.5 [MH] ^- 860.3 [MH] ^- 1.49 A 627 844.6 [MH] ^- 844.3 [MH] ^- 1.55 A 628 868.6 [MH] ^- 868.4 [MH] ^- 1.28 A 629 852.6 [MH] ^- 852.4 [MH] ^- 1.36 A 630 870.5 [MH] ^- 870.4 [MH] ^- 1.33 A 631 854.6 [MH] ^- 854.4 [MH] ^- 1.40 A 632 858.5 [MH] ^- 858.4 [MH] ^- 1.29 A 633 759.3 [MH] ^- 759.3 [MH] ^- 1.28 A 634 811.6 [MH] ^- 811.4 [MH] ^- 1.67 A 635 812.6 [MH] ^- 812.4 [MH] ^- 1.38 A 636 826.5 [MH] ^- 826.4 [MH] ^- 1.50 A 637 832.6 [M+H] ⁺ 832.3 [M+H] ⁺ 1.14 A 638 862.5 [M+H] ⁺ 862.4 [M+H] ⁺ 1.16 A 639 846.6 [M+H] ⁺ 846.4 [M+H] ⁺ 1,12 A 640 876.6 [M+H] ⁺ 876.4 [M+H] ⁺ 1.15 A 641 816.5 [M+H] ⁺ 816.4 [M+H] ⁺ 1.22 A 642 830.5 [M+H] ⁺ 830.4 [M+H] ⁺ 1.20 A 643 889.6 [MH] ^- 889.4 [MH] ^- 1.10 A 644 845.5 [M+H] ⁺ 845.3 [M+H] ⁺ 1.22 A 645 827.6 [MH] ^- 827.4 [MH] ^- 1.32 A 646 859.5 [M+H] ⁺ 859.4 [M+H] ⁺ 1.21 A 647 843.5 [M+H] ⁺ 843.4 [M+H] ⁺ 1.29 A 648 845.5 [M+H] ⁺ 845.3 [M+H] ⁺ 1.71 B 649 843.5 [M+H] ⁺ 843.4 [M+H] ⁺ 1.79 B 650 859.5 [M+H] ⁺ 859.4 [M+H] ⁺ 1.70 B 651 843.5 [M+H] ⁺ 843.4 [M+H] ⁺ 1.80 B 652 873.6 [M+H] ⁺ 873.4 [M+H] ⁺ 1.71 B 653 857.6 [M+H] ⁺ 857.4 [M+H] ⁺ 1.79 B 654 863.5 [M+H] ⁺ 863.3 [M+H] ⁺ 1.27 A 655 847.6 [M+H] ⁺ 847.4 [M+H] ⁺ 1.35 A 656 877.6 [M+H] ⁺ 877.3 [M+H] ⁺ 1.25 A 657 861.6 [M+H] ⁺ 861.4 [M+H] ⁺ 1.33 A 658 859.5 [M+H] ⁺ 859.4 [M+H] ⁺ 1.32 A 659 843.6 [M+H] ⁺ 843.4 [M+H] ⁺ 1.44 A 660 873.6 [M+H] ⁺ 873.4 [M+H] ⁺ 1.30 A 661 857.6 [M+H] ⁺ 857.4 [M+H] ⁺ 1.39 A 662 913.5 [M+H] ⁺ 913.3 [M+H] ⁺ 1.48 A 663 897.5 [M+H] ⁺ 897.4 [M+H] ⁺ 1.54 A 664 927.6 [M+H] ⁺ 927.3 [M+H] ⁺ 1.45 A 665 911.6 [M+H] ⁺ 911.4 [M+H] ⁺ 1.51 A 666 921.5 [MH] ^- 921.4 [MH] ^- 1.42 A 667 937.3 [M+H] ⁺ 937.3 [M+H] ⁺ 1.36 A 668 870.5 [M+H] ⁺ 870.3 [M+H] ⁺ 1.23 A 669 884.6 [M+H] ⁺ 884.4 [M+H] ⁺ 1.21 A 670 1071.7 [M+H] ⁺ 1071.5 [M+H] ⁺ 1.28 A 671 907.3 [M+H]+ 907.3 [M+H]+ 1.48 A 672 852.5 [MH] ^- 852.4 [MH] ^- 1.32 A 673 921.3 [M+H] ⁺ 921.3 [M+H] ⁺ 1.44 A 674 886.5 [M+H] ⁺ 886.4 [M+H] ⁺ 1.13 A 675 900.6 [M+H] ⁺ 900.4 [M+H] ⁺ 1.18 A 676 900.6 [M+H] ⁺ 900.4 [M+H] ⁺ 1,12 A 677 912.6 [MH] ^- 912.4 [MH] ^- 1.17 A 678 902.5 [M+H] ⁺ 902.4 [M+H] ⁺ 1.06 A 679 916.5 [M+H] ⁺ 916.4 [M+H] ⁺ 1.11 A 680 914.6 [MH] ^- 914.4 [MH] ^- 1.05 A 681 930.5 [M+H] ⁺ 930.4 [M+H] ⁺ 1.10 A 682 848.4 [M+H] ⁺ 848.4 [M+H] ⁺ 1.44 A 683 834.4 [M+H] ⁺ 834.4 [M+H] ⁺ 1.39 A 684 871.6 [MH] ^- 871.4 [MH] ^- 1.10 A 685 889.6 [MH] ^- 889.4 [MH] ^- 1.15 A 686 885.6 [MH] ^- 885.4 [MH] ^- 1.19 A 687 955.6 [MH] ^- 955.4 [MH] ^- 1.36 A 688 939.7 [MH] ^- 939.4 [MH] ^- 1.34 A 689 987.6 [MH] ^- 987.4 [MH] ^- 1.38 A 690 898.4 [M+H] ⁺ 898.4 [M+H] ⁺ 1.10 A 691 875.4 [M+H] ⁺ 875.4 [M+H] ⁺ 1.26 A 692 859.5 [M+H] ⁺ 859.4 [M+H] ⁺ 1.35 A 693 889.4 [M+H] ⁺ 889.4 [M+H] ⁺ 1.24 A 694 873.4 [M+H] ⁺ 873.4 [M+H] ⁺ 1.33 A 695 887.6 [M+H] ⁺ 887.4 [M+H] ⁺ 1.31 A 696 915.6 [M+H] ⁺ 915.5 [M+H] ⁺ 1.51 A 697 903.5 [M+H] ⁺ 903.4 [M+H] ⁺ 1.23 A 698 901.6 [M+H] ⁺ 901.4 [M+H] ⁺ 1.37 A 699 915.6 [M+H] ⁺ 915.5 [M+H] ⁺ 1.46 A 700 913.6 [M+H] ⁺ 913.4 [M+H] ⁺ 1.43 A 701 941.5 [M+H] ⁺ 941.4 [M+H] ⁺ 1.51 A 702 917.6 [M+H] ⁺ 917.4 [M+H] ⁺ 1.31 A 703 929.6 [M+H] ⁺ 929.4 [M+H] ⁺ 1.36 A 704 957.5 [M+H] ⁺ 957.4 [M+H] ⁺ 1.45 A 705 879.5 [M+H] ⁺ 879.3 [M+H] ⁺ 1.39 A 706 863.5 [M+H] ⁺ 863.3 [M+H] ⁺ 1.47 A 707 893.5 [M+H] ⁺ 893.3 [M+H] ⁺ 1.37 A 708 877.5 [M+H] ⁺ 877.4 [M+H] ⁺ 1.45 A 709 768.4 [M+H] ⁺ 768.2 [M+H] ⁺ 1.37 A 710 752.4 [M+H] ⁺ 752.3 [M+H] ⁺ 1.53 A 711 782.4 [M+H] ⁺ 782.3 [M+H] ⁺ 1.35 A 712 766.4 [M+H] ⁺ 766.3 [M+H] ⁺ 1.52 A 713 751.2 [MH] ^- 751.2 [MH] ^- 1.64 A 714 864.5 [M+H] ⁺ 864.3 [M+H] ⁺ 1.65 A 715 846.3 [MH] ^- 846.3 [MH] ^- 1.75 A 716 893.5 [M+H] ⁺ 893.3 [M+H] ⁺ 1.34 A 717 877.5 [M+H] ⁺ 877.4 [M+H] ⁺ 1.43 A 718 891.5 [M+H] ⁺ 891.4 [M+H] ⁺ 1.43 A 719 907.5 [M+H] ⁺ 907.3 [M+H] ⁺ 1.34 A 720 1003.8 [MH] ^- 1003.5 [MH] ^- 1.15 A 721 1031.7 [MH] ^- 1031.5 [MH] ^- 1.17 A 722 918.7 [MH] ^- 918.4 [MH] ^- 1.16 A 723 1017.8 [MH] ^- 1017,5 [MH] ^- 1.15 A 724 1045.8 [MH] ^- 1045.5 [MH] ^- 1.17 A 725 932.7 [MH] ^- 932.4 [MH] ^- 1.15 A 726 891.6 [M+H] ⁺ 891.4 [M+H] ⁺ 1.40 A 727 851.5 [M+H] ⁺ 851.3 [M+H] ⁺ 1.46 A 728 881.5 [M+H] ⁺ 881.4 [M+H] ⁺ 1.47 A 729 927.5 [M+H] ⁺ 927.4 [M+H] ⁺ 1.58 A 730 906.6 [MH] ^- 906.4 [MH] ^- 1.21 A 731 851.5 [M+H] ⁺ 851.3 [M+H] ⁺ 1.45 A 732 865.5 [M+H] ⁺ 865.4 [M+H] ⁺ 1.47 A 733 879.5 [M+H] ⁺ 879.4 [M+H] ⁺ 1.47 A 734 893.6 [M+H] ⁺ 893.4 [M+H] ⁺ 1.48 A 735 1104.7 [M+H] ⁺ 1104.5 [M+H] ⁺ 1.61 A 736 1132.8 [M+H] ⁺ 1132.5 [M+H] ⁺ 1.68 A 737 1159.0 [MH] ^- 1158.6 [MH] ^- 1.77 A 738 864.5 [MH] ^- 864.4 [MH] ^- 1.27 A 739 864.5 [MH] ^- 864.4 [MH] ^- 1.23 A 740 878.7 [MH] ^- 878.4 [MH] ^- 1.22 A 741 878.6 [MH] ^- 878.4 [MH] ^- 1.21 A 742 892.6 [MH] ^- 892.4 [MH] ^- 1.20 A 743 906.6 [MH] ^- 906.4 [MH] ^- 1.20 A 744 906.6 [MH] ^- 906.4 [MH] ^- 1.18 A 745 922.6 [MH] ^- 922.4 [MH] ^- 1.10 A 746 849.6 [MH] ^- 849.4 [MH] ^- 1.23 A 747 892.6 [MH] ^- 892.4 [MH] ^- 1.20 A 748 906.6 [MH] ^- 906.4 [MH] ^- 1.22 A 749 920.7 [MH] ^- 920.4 [MH] ^- 1.20 A 750 934.9 [MH] ^- 934.4 [MH] ^- 1.23 A 751 906.6 [MH] ^- 906.4 [MH] ^- 1.22 A 752 920.6 [MH] ^- 920.4 [MH] ^- 1.22 A 753 934.7 [MH] ^- 934.4 [MH] ^- 1.22 A 754 948.6 [MH] ^- 948.4 [MH] ^- 1.24 A 755 920.6 [MH] ^- 920.4 [MH] ^- 1.21 A 756 934.7 [MH] ^- 934.4 [MH] ^- 1.23 A 757 948.7 [MH] ^- 948.6 [MH] ^- 1.23 A 758 962.7 [MH] ^- 962.7 [MH] ^- 1.24 A 759 899.6 [M+H] ⁺ 899.4 [M+H] ⁺ 1.55 A 760 960.7 [MH] ^- 960.6 [MH] ^- 1.22 A 761 949.5 [M+H] ⁺ 949.4 [M+H] ⁺ 1.53 A 762 990.8 [MH] ^- 990.5 [MH] ^- 1.23 A 763 975.6 [M+H] ⁺ 975.4 [M+H] ⁺ 1.54 A 764 972.7 [MH] ^- 972.6 [MH] ^- 1.23 A 765 853.5 [M+H] ⁺ 853.3 [M+H] ⁺ 1.26 A 766 991.7 [MH] ^- 991.8 [MH] ^- 1.22 A 767 1019.8 [MH] ^- 1019.6 [MH] ^- 1.23 A 768 1147.9 [MH] ^- 1147.9 [MH] ^- 1.09 A 769 1175.9 [MH] ^- 1175.7 [MH] ^- 1.11 A 770 1147.9 [MH] ^- 1147.9 [MH] ^- 1.08 A 771 1119.7 [MH] ^- 1119.7 [MH] ^- 1.09 A 772 1003.7 [MH] ^- 1003.5 [MH] ^- 1.22 A 773 1164.0 [MH] ^- 1163.7 [MH] ^- 1.00 A 774 595.5 [M-2H] ^2- 595.3 [M-2H] ^2- 1.01 A 775 1163.9 [MH] ^- 1163.7 [MH] ^- 1.00 A 776 1136.0 [MH] ^- 1135.6 [MH] ^- 0.98 A 777 864.5 [MH] ^- 864.6 [MH] ^- 1.25 A 778 878.5 [MH] ^- 878.6 [MH] ^- 1.23 A 779 878.5 [MH] ^- 878.6 [MH] ^- 1.23 A 780 892.7 [MH] ^- 892.5 [MH] ^- 1.23 A 781 892.5 [MH] ^- 892.5 [MH] ^- 1.23 A 782 977.8 [MH] ^- 977.4 [MH] ^- 1.19 A 783 991.8 [MH] ^- 991.4 [MH] ^- 1.27 A 784 1007.8 [MH] ^- 1007.4 [MH] ^- 1.11 A 785 992.8 [MH] ^- 992.4 [MH] ^- 1.28 A 786 905.5 [M+H] ⁺ 905.3 [M+H] ⁺ 1.30 A 787 893.5 [M+H] ⁺ 893.3 [M+H] ⁺ 1.26 A 788 921.5 [M+H] ⁺ 921.4 [M+H] ⁺ 1.32 A 789 905.5 [M+H] ⁺ 905.3 [M+H] ⁺ 1.31 A 790 891.4 [M+H] ⁺ 891.3 [M+H] ⁺ 1.31 A 791 864.4 [M+H] ⁺ 864.4 [M+H] ⁺ 1.51 A 792 888.6 [M+H] ⁺ 888.5 [M+H] ⁺ 1.03 A 793 902.6 [M+H] ⁺ 902.4 [M+H] ⁺ 1.02 A 794 870.5 [MH] ^- 870.6 [MH] ^- 1.10 A 795 886.5 [M+H] ⁺ 886.6 [M+H] ⁺ 1.08 A 796 888.6 [M+H] ⁺ 888.4 [M+H] ⁺ 1.13 A 797 902.7 [M+H] ⁺ 902.7 [M+H] ⁺ 1.15 A 798 904.6 [M+H] ⁺ 904.7 [M+H] ⁺ 1.00 A 799 918.6 [M+H] ⁺ 918.5 [M+H] ⁺ 1.02 A 800 903.7 [MH] ^- 903.5 [MH] ^- 0.77 A 801 884.6 [MH] ^- 884.6 [MH] ^- 1.05 A 802 927.5 [MH] ^- 927.5 [MH] ^- 1.02 A 803 1000.8 [MH] ^- 1000,5 [MH] ^- 1.00 A 804 1028.7 [MH] ^- 1028.8 [MH] ^- 1.00 A 805 1156.9 [MH] ^- 1156.8 [MH] ^- 0.89 A 806 1184.9 [MH] ^- 1184.6 [MH] ^- 0.91 A 807 1129.0 [MH] ^- 1128.7 [MH] ^- 0.87 A 808 1043.0 [MH] ^- 1042.5 [MH] ^- 1.00 A 809 1171.0 [MH] ^- 1170.7 [MH] ^- 0.85 A 810 1171.0 [MH] ^- 1170.7 [MH] ^- 0.84 A 811 1142.8 [MH] ^- 1142.6 [MH] ^- 0.83 A 812 1014.8 [MH] ^- 1014.7 [MH] ^- 0.99 A 813 1199.0 [MH] ^- 1198.6 [MH] ^- 0.86 A 814 873.5 [MH] ^- 873.4 [MH] ^- 1.01 A 815 901.6 [MH] ^- 901.4 [MH] ^- 1.00 A 816 901.7 [MH] ^- 901.4 [MH] ^- 0.99 A 817 915.8 [MH] ^- 915.7 [MH] ^- 0.99 A 818 915.6 [MH] ^- 915.7 [MH] ^- 0.99 A 819 900.6 [M+H] ⁺ 900.4 [M+H] ⁺ 1.08 A 820 1026.8 [MH] ^- 1026.7 [MH] ^- 0.90 A 821 1054.7 [MH] ^- 1054.5 [MH] ^- 0.92 A 822 1183.0 [MH] ^- 1182.7 [MH] ^- 0.75 A 823 1211.0 [MH] ^- 1210.6 [MH] ^- 0.76 A 824 1183.1 [MH] ^- 1182.7 [MH] ^- 0.75 A 825 1155.0 [MH] ^- 1154.6 [MH] ^- 0.73 A 826 874.6 [M+H] ⁺ 874.6 [M+H] ⁺ 1.07 A 827 886.6 [M+H] ⁺ 886.6 [M+H] ⁺ 1.04 A 828 1072.0 [MH] ^- 1071.8 [MH] ^- 0.99 A 829 1099.9 [MH] ^- 1099.5 [MH] ^- 1.00 A 830 1256.0 [MH] ^- 1255.6 [MH] ^- 0.86 A 831 1228.1 [MH] ^- 1227.6 [MH] ^- 0.82 A 832 1085.8 [MH] ^- 1085.6 [MH] ^- 0.99 A 833 1242.1 [MH] ^- 1241.7 [MH] ^- 0.83 A 834 1270.1 [MH] ^- 1269.8 [MH] ^- 0.85 A 835 1242.1 [MH] ^- 1241.7 [MH] ^- 0.83 A 836 1228.0 [MH] ^- 1227.9 [MH] ^- 0.86 A 837 1199.8 [MH] ^- 1199.6 [MH] ^- 0.85 A 838 884.5 [MH] ^- 884.6 [MH] ^- 1.09 A 839 872.5 [M+H] ⁺ 872.6 [M+H] ⁺ 1.06 A 840 844.5 [MH] ^- 844.5 [MH] ^- 1.13 A 841 858.5 [MH] ^- 858.6 [MH] ^- 1.13 A 842 872.8 [MH] ^- 872.6 [MH] ^- 1.14 A 843 886.7 [MH] ^- 886.4 [MH] ^- 1.16 A 844 859.6 [MH] ^- 859.6 [MH] ^- 1.00 A 845 870.5 [MH] ^- 870.6 [MH] ^- 1.06 A 846 872.5 [M+H] ⁺ 872.6 [M+H] ⁺ 1.09 A 847 872.5 [M+H] ⁺ 872.6 [M+H] ⁺ 1.06 A 848 900.5 [M+H] ⁺ 900.4 [M+H] ⁺ 1.17 A 849 900.6 [M+H] ⁺ 900.4 [M+H] ⁺ 1.20 A 850 914.6 [M+H] ⁺ 914.7 [M+H] ⁺ 1.10 A 851 886.5 [M+H] ⁺ 886.4 [M+H] ⁺ 1,12 A 852 886.7 [MH] ^- 886.4 [MH] ^- 1.11 A 853 886.7 [MH] ^- 886.4 [MH] ^- 1.13 A 854 887.7 [MH] ^- 887.4 [MH] ^- 1.18 A 855 891.6 [M+H] ⁺ 891.4 [M+H] ⁺ 1.45 A 856 887.6 [MH] ^- 887.4 [MH] ^- 1.44 A 857 901.4 [M+H] ⁺ 901.4 [M+H] ⁺ 1.24 A 858 915.5 [MH] ^- 915.4 [MH] ^- 1.02 A 859 816.3 [MH] ^- 816.3 [MH] ^- 0.96 A 860 771.3 [MH] ^- 771.3 [MH] ^- 0.90 A 861 743.2 [MH] ^- 743.3 [MH] ^- 0.82 A 862 757.2 [MH] ^- 757.3 [MH] ^- 0.86 A 863 785.4 [MH] ^- 785.3 [MH] ^- 0.94 A 864 800.4 [MH] ^- 800.3 [MH] ^- 0.64 A 865 803.3 [M+H] ⁺ 803.3 [M+H] ⁺ 0.93 A 866 817.4 [M+H] ⁺ 817.3 [M+H] ⁺ 0.91 A 867 817.4 [M+H] ⁺ 817.3 [M+H] ⁺ 0.86 A 868 775.3 [M+H] ⁺ 775.3 [M+H] ⁺ 0.84 A 869 851.4 [M+H] ⁺ 851.3 [M+H] ⁺ 1.01 A 870 835.3 [M+H] ⁺ 835.3 [M+H] ⁺ 1.22 A 871 759.3 [M+H] ⁺ 759.3 [M+H] ⁺ 0.96 A 872 799.4 [MH] ^- 799.4 [MH] ^- 1.08 A 873 787.4 [M+H] ⁺ 787.3 [M+H] ⁺ 1.03 A 874 801.4 [M+H] ⁺ 801.4 [M+H] ⁺ 1,12 A 875 803.3 [M+H] ⁺ 803.3 [M+H] ⁺ 0.89 A 876 816.4 [M+H] ⁺ 816.4 [M+H] ⁺ 0.68 A 877 729.3 [MH] ^- 729.3 [MH] ^- 0.85 A 878 828.3 [MH] ^- 828.3 [MH] ^- 0.64 A 879 769.5 [MH] ^- 769.3 [MH] ^- 1.01 A 880 759.5 [MH] ^- 759.3 [MH] ^- 0.81 A 881 835.3 [MH] ^- 835.3 [MH] ^- 1.00 A 882 819.3 [MH] ^- 819.3 [MH] ^- 1.20 A 883 743.3 [MH] ^- 743.3 [MH] ^- 0.94 A 884 773.3 [MH] ^- 773.3 [MH] ^- 0.89 A 885 844.4 [M+H] ⁺ 844.4 [M+H] ⁺ 0.72 A 886 803.3 [M+H] ⁺ 803.3 [M+H] ⁺ 0.78 A 887 867.4 [M+H] ⁺ 867.3 [M+H] ⁺ 0.77 A 888 914.7 [MH] ^- 914.4 [MH] ^- 0.92 A 889 900.6 [MH] ^- 900.4 [MH] ^- 0.83 A 890 1015.5 [M+H] ⁺ 1015.4 [M+H] ⁺ 0.96 A 891 1054.7 [MH] ^- 1054.5 [MH] ^- 1.67 A 892 1053.7 [MH] ^- 1053.5 [MH] ^- 1.62 A 893 1105.8 [M+Na] ⁺ 1105.5 [M+Na] ⁺ 1.60 A 894 1098.6 [M+H] ⁺ 1098.5 [M+H] ⁺ 1.26 A 895 1100.6 [M+H] ⁺ 1100.5 [M+H] ⁺ 1.19 A 896 987.6 [M+H] ⁺ 987.5 [M+H] ⁺ 1.29 A 897 1073.6 [M+Na] ⁺ 1073.5 [M+Na] ⁺ 1.59 A 898 1080.8 [M+H] ⁺ 1080.5 [M+H] ⁺ 1.23 A 899 1082.7 [M+H] ⁺ 1082.5 [M+H] ⁺ 1.17 A 900 1546.2 [MH] ^- 1545.8 [MH] ^- 1.64 A 901 1598.2 [M+Na] ⁺ 1597.8 [M+Na] ⁺ 1.67 A 902 785.1 [M+2H] ²⁺ 785.0 [M+2H] ²⁺ 1.17 A 903 1686.5 [MH] ^- 1685.9 [MH] ^- 1.95 A 904 1714.3 [MH] ^- 1713.9 [MH] ^- 2.06 A 905 1651.7 [MH] ^- 1651.0 [MH] ^- 1.40 A 906 1733.4 [M+H] ⁺ 1732.9 [M+H] ⁺ 1.67 A 907 1696.5 [MH] ^- 1696.0 [MH] ^- 1.21 A 908 841.6 [M+2H] ²⁺ 841.5 [M+2H] ²⁺ 1.25 A 909 1696.4 [MH] ^- 1696.0 [MH] ^- 1.22 A 910 1733.2 [M+H] ⁺ 1732.9 [M+H] ⁺ 1.67 A 911 1695.9 [MH] ^- 1696.0 [MH] ^- 1.23 A 912 1662.8 [MH] ^- 1662.1 [MH] ^- 1.23 A 913 1664.4 [MH] ^- 1664.0 [MH] ^- 1.20 A 914 1724.6 [M+H] ⁺ 1724.0 [M+H] ⁺ 2.05 B 915 1726.5 [M+H] ⁺ 1725.9 [M+H] ⁺ 1.54 A 916 1687.6 [MH] ^- 1687.1 [MH] ^- 1.10 A 917 1689.6 [MH] ^- 1689.0 [MH] ^- 1.06 A 918 1754.5 [M+H] ⁺ 1753.9 [M+H] ⁺ 2.05 B 919 1736.6 [MH] ^- 1736.0 [MH] ^- 2.07 B 920 1717.6 [MH] ^- 1717.0 [MH] ^- 1.60 B 921 1701.2 [MH] ^- 1701.1 [MH] ^- 1.63 B 922 1723.9 [MH] ^- 1723.9 [MH] ^- 1.95 B 923 1710.6 [M+H] ⁺ 1710.0 [M+H] ⁺ 1.97 B 924 1689.5 [MH] ^- 1689.0 [MH] ^- 1.53 B 925 1673.0 [MH] ^- 1673.0 [MH] ^- 1.57 B 926 1445.0 [MH] ^- 1444.9 [MH] ^- 1.94 B 927 1573.7 [MH] ^- 1573.0 [MH] ^- 1.77 B 928 1829.7 [MH] ^- 1829.2 [MH] ^- 1.56 B 929 1957.9 [MH] ^- 1957.3 [MH] ^- 1.52 B 930 1433.4 [MH] ^- 1432.8 [MH] ^- 1.77 B 931 1561.4 [MH] ^- 1560.9 [MH] ^- 1.63 B 932 1817.3 [MH] ^- 1817.1 [MH] ^- 1.49 B 933 1945.8 [MH] ^- 1945.2 [MH] ^- 1.39 B 934 1689.7 [MH] ^- 1689.0 [MH] ^- 1.52 B 935 1773.7 [MH] ^- 1773.0 [MH] ^- 1.55 B 936 886.3 [M-2H] ^2- 886.0 [M-2H] ^2- 1.60 B 937 1597.3 [M+H] ⁺ 1596.9 [M+H] ⁺ 1.97 B 938 1452.3 [M+H] ⁺ 1451.8 [M+H] ⁺ 1.98 B 939 1434.3 [MH] ^- 1433.8 [MH] ^- 1.97 B 940 1726.5 [M+H] ⁺ 1725.9 [M+H] ⁺ 1.98 B 941 1307.0 [M+H] ⁺ 1306.7 [M+H] ⁺ 2.01 B 942 1417.5 [MH] ^- 1416.9 [MH] ^- 1.32 A 943 1545.6 [MH] ^- 1545.0 [MH] ^- 1.16 A 944 1461.0 [MH] ^- 1460.9 [MH] ^- 1.39 A 945 1589.7 [MH] ^- 1588.9 [MH] ^- 1.21 A 946 1661.6 [MH] ^- 1661.0 [MH] ^- 0.97 A 947 1645.8 [MH] ^- 1645.0 [MH] ^- 1.00 A 948 1461.3 [MH] ^- 1460.8 [MH] ^- 1.29 A 949 1617.2 [MH] ^- 1616.9 [MH] ^- 1.14 A 950 1675.4 [MH] ^- 1675.0 [MH] ^- 1.03 A 951 1291.0 [M+H] ⁺ 1290.8 [M+H] ⁺ 1.55 A 952 1335.1 [M+H] ⁺ 1334.8 [M+H] ⁺ 1.61 A 953 1319.1 [M+H] ⁺ 1318.8 [M+H] ⁺ 1.64 A 954 1745.5 [MH] ^- 1745.1 [MH] ^- 1.20 A 955 1729.8 [MH] ^- 1729.1 [MH] ^- 1.23 A 956 839.2 [M+2H] ²⁺ 838.5 [M+2H] ²⁺ 1.18 A 957 1702.8 [MH] ^- 1702.0 [MH] ^- 1.30 A 958 1718.3 [MH] ^- 1718.0 [MH] ^- 1.26 A 959 1674.3 [MH] ^- 1674.0 [MH] ^- 1.16 A 960 1702.4 [MH] ^- 1702.0 [MH] ^- 1.25 A 961 1690.2 [MH] ^- 1690.0 [MH] ^- 1.15 A 962 1719.3 [MH] ^- 1719.0 [MH] ^- 1.28 A 963 1675.2 [MH] ^- 1675.0 [MH] ^- 1.21 A 964 1703.4 [MH] ^- 1703.0 [MH] ^- 1.34 A 965 1691.1 [MH] ^- 1691.0 [MH] ^- 1.20 A 966 1719.4 [MH] ^- 1719.0 [MH] ^- 1.32 A 967 1418.0 [MH] ^- 1417.8 [MH] ^- 1.54 A 968 1448.0 [M+H] ⁺ 1447.8 [M+H] ⁺ 1.63 A 969 1420.0 [M+H] ⁺ 1419.8 [M+H] ⁺ 1.53 A 970 1446.1 [MH] ^- 1445.8 [MH] ^- 1.63 A 971 1546.3 [MH] ^- 1545.9 [MH] ^- 1.30 A 972 1573.9 [MH] ^- 1573.9 [MH] ^- 1.41 A

The inhibitory effect of the compounds of the present invention on MMP2 was determined by the method described in Test Examples 1-1 and 1-2 shown below.

Experimental Example 1-1: Evaluation test for the inhibitory effect of the compounds of the present invention on human MMP2 (Method 1)

The activity of the compounds on human MMP2 inhibition was determined by an enzymatic assay using MOCAc-Pro-Leu-Gly-Leu-A2pr(Dnp)-Ala-Arg-NH ₂ as a substrate. In a reaction solution [50 mmol/L Tris-HCl (pH 7.5), 150 mmol/L NaCl, 10 mmol/L CaCl ₂ , 0.05% Brij L23], 100 μg/mL recombinant human MMP2 enzyme and 1 mmol/L 4-aminophenylmercuric acetate were mixed and reacted at 37°C for 60 minutes. Human MMP2 activated during the reaction was poured into a 96-well microplate to achieve a final concentration of 0.7 or 7 ng/mL. In addition, the compounds of the present invention, which had been diluted to various concentrations, were added and left to stand at room temperature for 15 minutes. Then, MOCAc-Pro-Leu-Gly-Leu-A2pr(Dnp)-Ala-Arg- _NH2 was added to reach a final concentration of 5 or 16 μmol/L, and the enzymatic reaction was initiated. After reacting at room temperature for 2 hours, the fluorescence intensity (Ex 320 nm/Em 400 nm) was measured using a microplate reader. The enzyme inhibition rate (%) was calculated using the measured fluorescence values according to the following formula, and 50% inhibitory concentrations (IC ₅₀ values) of the compounds of the invention were calculated.

Degree of enzyme inhibition (%) = [1-(A-B)/(C-B)] * 100

A: Fluorescence value with the addition of the compound

B: Fluorescence value without adding compound and enzyme.

C: Fluorescence value without adding compound

Experimental Example 1-2: Evaluation Test for Inhibitory Effect of Compounds of the Present Invention on Human MMP2 (Method 2)

The activity of the compounds on human MMP2 inhibition was determined by an enzymatic assay using MOCAc-Pro-Leu-Gly-Leu-A2pr(Dnp)-Ala-Arg-NH ₂ as a substrate. In a reaction solution [50 mmol/L Tris-HCl (pH 7.5), 150 mmol/L NaCl, 10 mmol/L CaCl ₂ , 0.05% Brij L23], 12.5 μg/mL recombinant human MMP2 enzyme and 1 mmol/L 4-aminophenylmercuric acetate were mixed and reacted at 37°C for 60 minutes. Human MMP2 activated by the reaction was poured into a 384-well microplate to achieve a final concentration of 7 or 2.8 ng/mL. Then, the compounds of the present invention, which have been diluted to various concentrations, are added and left to stand at a temperature for 10 minutes, then MOCAc-Pro-Leu-Gly-Leu-A2pr(Dnp)-Ala-Arg- _NH2 is added to reach a final concentration of 16 or 5 μmol/L, and the enzymatic reaction is initiated. After reacting at room temperature for 1-2 hours, the fluorescence intensity (Ex 320 nm/Em 405 nm) is measured using a microplate reader. The enzyme inhibition rates (%) are calculated using the measured fluorescence values according to the following formula, and 50% inhibitory concentrations (IC ₅₀ values) of the compounds of the invention are calculated.

Degree of enzyme inhibition (%) = [1-(A-B)/(C-B)] * 100

A: Fluorescence value with the addition of the compound

B: Fluorescence value without adding compound and enzyme.

C: Fluorescence value without adding compound

The results of the inhibitory effect of the compounds of the present invention on the activity of the human MMP2 enzyme are shown in the following tables.

[Table 51-1]

Connection No. Human MMP2, IC ₅₀ (nmol/L) Experimental example No. Connection No. Human MMP2, IC ₅₀ (nmol/L) Experimental example No. 1 0.22 1-1 29 0,140 1-2 2 2.04 1-2 30 0.107 1-2 3 0.25 1-1 31 0.199 1-2 4 0.128 1-2 32 0.0996 1-2 5 0.608 1-2 33 0.144 1-2 6 0.198 1-2 34 0,130 1-2 7 0.898 1-2 35 0.147 1-2 8 3.15 1-2 36 0.152 1-2 9 0.29 1-1 37 0.178 1-2 10 0.107 1-2 38 0.27 1-1 11 0.109 1-2 39 0.27 1-1 12 0.109 1-2 40 0.451 1-2 13 0.0784 1-2 41 0.0719 1-2 14 0.0897 1-2 42 0.113 1-2 15 0.108 1-2 43 0.594 1-2 16 0.119 1-2 44 4.75 1-2 17 0.199 1-2 45 0.32 1-1 18 0.135 1-2 46 0.31 1-1 19 0.148 1-2 47 4.1 1-1 20 0.20 1-1 48 0,0740 1-2 21 0.101 1-2 49 0.113 1-2 22 0.109 1-2 50 0.089 1-1 23 0.0923 1-2 51 0.21 1-1 24 0.105 1-2 52 0.12 1-1 25 0.178 1-2 53 0,0702 1-2 26 0.151 1-2 54 0.095 1-1 27 0.152 1-2 55 0.13 1-1 28 0.136 1-2

[Table 51-2]

Connection No. Human MMP2, IC ₅₀ (nmol/L) Experimental example No. Connection No. Human MMP2, IC ₅₀ (nmol/L) Experimental example No. 56 0.083 1-1 86 0.40 1-1 57 0.078 1-1 87 0.84 1-1 58 0.097 1-1 88 0.97 1-1 59 0.046 1-1 89 0.58 1-1 60 0.97 1-1 90 1.4 1-1 61 0.13 1-1 91 1.5 1-1 62 0,090 1-1 92 0.31 1-1 63 0.61 1-1 93 0.34 1-1 64 0,060 1-1 94 0.088 1-1 65 0.083 1-1 95 0.13 1-1 66 0.047 1-1 96 0.74 1-1 67 0.11 1-1 97 0.84 1-1 68 0.068 1-1 98 0.27 1-1 69 0.19 1-1 99 0.33 1-1 70 0.34 1-1 100 1,2 1-1 71 0.89 1-1 101 1,2 1-1 72 0.52 1-1 102 0.55 1-1 73 1.9 1-1 103 0.67 1-1 74 8.1 1-1 104 0.51 1-1 75 0.097 1-1 105 0.30 1-1 76 0.055 1-1 106 0.16 1-1 77 0.25 1-1 107 0.32 1-1 78 0.037 1-1 108 0.19 1-1 79 0.091 1-1 109 0.70 1-1 80 0.22 1-1 110 0.37 1-1 81 0.48 1-1 111 0.96 1-1 82 0.83 1-1 112 0.55 1-1 83 0.37 1-1 113 2,2 1-1 84 0.17 1-1 114 0.072 1-1 85 0.49 1-1 115 0.42 1-1

[Table 51-3]

Connection No. Human MMP2, IC ₅₀ (nmol/L) Experimental example No. Connection No. Human MMP2, IC ₅₀ (nmol/L) Experimental example No. 116 0.055 1-1 146 1.7 1-1 117 0.55 1-1 147 0.14 1-1 118 0.40 1-1 148 0.48 1-1 119 0.17 1-1 149 0.11 1-1 120 0.21 1-1 150 3.3 1-1 121 0.19 1-1 151 0.33 1-1 122 0.16 1-1 152 0.85 1-1 123 1.11 1-1 153 0.066 1-1 124 0.31 1-1 154 0.44 1-1 125 0.47 1-1 155 0.19 1-1 126 0.29 1-1 156 0.088 1-1 127 0.24 1-1 157 1.24 1-1 128 0.15 1-1 158 1.38 1-1 129 0.46 1-1 159 0.37 1-1 130 0.36 1-1 160 0.68 1-1 131 0.36 1-1 161 0.33 1-1 132 0.43 1-1 162 0.60 1-1 133 0.88 1-1 163 0.12 1-1 134 2.0 1-1 164 0.37 1-1 135 9.3 1-1 165 0.23 1-1 136 4.7 1-1 166 0.39 1-1 137 0.60 1-1 167 0.58 1-1 138 0.26 1-1 168 1,2 1-1 139 1,1 1-1 169 2.5 1-1 140 0.43 1-1 170 0.072 1-1 141 1.0 1-1 171 0.068 1-1 142 2.1 1-1 172 0.13 1-1 143 2.6 1-1 173 0.19 1-1 144 0.26 1-1 174 0.55 1-1 145 0.72 1-1 175 2.0 1-1

[Table 51-4]

Connection No. Human MMP2, IC ₅₀ (nmol/L) Experimental example No. Connection No. Human MMP2, IC ₅₀ (nmol/L) Experimental example No. 176 1.9 1-1 206 0.101 1-1 177 0.21 1-1 207 0.49 1-1 178 3.6 1-1 208 0.61 1-1 179 3.5 1-1 209 0.094 1-1 180 2.6 1-1 210 0.17 1-1 181 3.1 1-1 211 2.9 1-1 182 0.49 1-1 212 0.62 1-1 183 7.0 1-1 213 1.9 1-1 184 0.61 1-1 214 0.096 1-1 185 1.0 1-1 215 2.6 1-1 186 2.0 1-1 216 0.21 1-1 187 2.8 1-1 217 0.72 1-1 188 0.81 1-1 218 0.32 1-1 189 0.86 1-1 219 0.47 1-1 190 1.8 1-1 220 0.12 1-1 191 2.7 1-1 221 0.53 1-1 192 1.9 1-1 222 0.051 1-1 193 1.7 1-1 223 0.20 1-1 194 3.7 1-1 224 1,1 1-1 195 2.7 1-1 225 0.33 1-1 196 1.7 1-1 226 0.12 1-1 197 2.6 1-1 227 0.49 1-1 198 5.1 1-1 228 0.19 1-1 199 1.4 1-1 229 0.39 1-1 200 7.4 1-1 230 0.103 1-1 201 1.4 1-1 231 1,1 1-1 202 0.097 1-1 232 0.18 1-1 203 0.13 1-1 233 0.17 1-1 204 0.42 1-1 234 0.14 1-1 205 0.80 1-1 235 0.22 1-1

[Table 51-5]

Connection No. Human MMP2, IC ₅₀ (nmol/L) Experimental example No. Connection No. Human MMP2, IC ₅₀ (nmol/L) Experimental example No. 236 0.10 1-1 266 1.5 1-1 237 0.53 1-1 267 1.6 1-1 238 0.11 1-1 268 0.16 1-1 239 0.108 1-1 269 0.15 1-1 240 0.44 1-1 270 0.12 1-1 241 0.32 1-1 271 0.084 1-1 242 6.3 1-1 272 0.13 1-1 243 0.33 1-1 273 0,071 1-1 244 0.27 1-1 274 0.12 1-1 245 0.16 1-1 275 0.096 1-1 246 0.64 1-1 276 0.103 1-1 247 1.9 1-1 277 0.12 1-1 248 6.0 1-1 278 0.71 1-1 249 8.9 1-1 279 0.084 1-1 250 0.093 1-1 280 0.15 1-1 251 0.18 1-1 281 0.047 1-1 252 0.31 1-1 282 0.059 1-1 253 3.5 1-1 283 0.046 1-1 254 0.18 1-1 284 0.064 1-1 255 0.072 1-1 285 0.091 1-1 256 0.13 1-1 286 1.15 1-1 257 0.68 1-1 287 0.35 1-1 258 0.94 1-1 288 1.9 1-1 259 0.083 1-1 289 0.29 1-1 260 0.15 1-1 290 1.3 1-1 261 0.13 1-1 291 0.11 1-1 262 0.14 1-1 292 0.14 1-1 263 0.17 1-1 293 2.8 1-1 264 0.97 1-1 294 2.1 1-1 265 2.0 1-1 295 2.8 1-1

[Table 51-6]

Connection No. Human MMP2, IC ₅₀ (nmol/L) Experimental example No. Connection No. Human MMP2, IC ₅₀ (nmol/L) Experimental example No. 296 0.96 1-1 326 1.9 1-1 297 0.35 1-1 327 0.92 1-1 298 3.4 1-1 328 0.43 1-1 299 0.62 1-1 329 2.5 1-1 300 0.86 1-1 330 0.22 1-1 301 2.0 1-1 331 0.22 1-1 302 0.29 1-1 332 0.14 1-1 303 0.21 1-1 333 0.84 1-1 304 1.05 1-1 334 0.63 1-1 305 1.9 1-1 335 0.56 1-1 306 2,2 1-1 336 0.13 1-1 307 3.7 1-1 337 0.17 1-1 308 0.48 1-1 338 0.13 1-1 309 1.4 1-1 339 0.62 1-1 310 3.2 1-1 340 0.16 1-1 311 4.5 1-1 341 0.77 1-1 312 0.29 1-1 342 3.9 1-1 313 0.57 1-1 343 7.0 1-1 314 0.11 1-1 344 0.13 1-1 315 0.54 1-1 345 0.10 1-1 316 1.06 1-1 346 0.11 1-1 317 2,3 1-1 347 0.059 1-1 318 0.15 1-1 348 0.083 1-1 319 0.75 1-1 349 1.4 1-1 320 0.061 1-1 350 0.21 1-1 321 5.8 1-1 351 0.34 1-1 322 0.27 1-1 352 0.26 1-1 323 0.17 1-1 353 0.28 1-1 324 7.8 1-1 354 0.076 1-1 325 0.17 1-1 355 0.12 1-1

[Table 51-7]

Connection No. Human MMP2, IC ₅₀ (nmol/L) Experimental example No. Connection No. Human MMP2, IC ₅₀ (nmol/L) Experimental example No. 356 0.19 1-1 386 0.12 1-1 357 0.10 1-1 387 0.12 1-1 358 0.14 1-1 388 0.20 1-1 359 5.1 1-1 389 0.39 1-1 360 2.5 1-1 390 0.36 1-1 361 0.20 1-1 391 0.37 1-1 362 0.27 1-1 392 0.15 1-1 363 0.24 1-1 393 0.28 1-1 364 0.25 1-1 394 0.17 1-1 365 0.49 1-1 395 0.48 1-1 366 0.33 1-1 396 0.40 1-1 367 0.17 1-1 397 0.61 1-1 368 0.28 1-1 398 0.12 1-1 369 0.76 1-1 399 0.13 1-1 370 1,2 1-1 400 0.43 1-1 371 2.1 1-1 401 0.43 1-1 372 6.5 1-1 402 0.31 1-1 373 4.7 1-1 403 0.20 1-1 374 1.9 1-1 404 0.42 1-1 375 2.4 1-1 405 0.15 1-1 376 3.4 1-1 406 0.45 1-1 377 2.8 1-1 407 0.15 1-1 378 2.6 1-1 408 2.0 1-1 379 0.20 1-1 409 1.8 1-1 380 0.75 1-1 410 1,1 1-1 381 0.23 1-1 411 0.59 1-1 382 5.3 1-1 412 0.30 1-1 383 6.3 1-1 413 0.13 1-1 384 0.13 1-1 414 0.27 1-1 385 0.17 1-1 415 0.082 1-1

[Table 51-8]

Connection No. Human MMP2, IC ₅₀ (nmol/L) Experimental example No. Connection No. Human MMP2, IC ₅₀ (nmol/L) Experimental example No. 416 0.29 1-1 446 0.46 1-1 417 1.5 1-1 447 0.50 1-1 418 2.1 1-1 448 0.19 1-1 419 1.8 1-1 449 0.17 1-1 420 1.5 1-1 450 0.24 1-1 421 2.6 1-1 451 0.16 1-1 422 1.8 1-1 452 0.14 1-1 423 1.9 1-1 453 30 1-1 424 0.44 1-1 454 0.19 1-1 425 0.62 1-1 455 0.46 1-1 426 0.27 1-1 456 0.61 1-1 427 0.073 1-1 457 0.24 1-1 428 1.0 1-1 458 0.27 1-1 429 0.15 1-1 459 0.25 1-1 430 0,071 1-1 460 0.29 1-1 431 0.69 1-1 461 0.29 1-1 432 0.38 1-1 462 0.33 1-1 433 0.19 1-1 463 0.76 1-1 434 0.23 1-1 464 0.79 1-1 435 0.45 1-1 465 0.82 1-1 436 0.30 1-1 466 1,1 1-1 437 0.21 1-1 467 0.85 1-1 438 0.26 1-1 468 0.52 1-1 439 0.16 1-1 469 0.85 1-1 440 0.28 1-1 470 0.81 1-1 441 0.29 1-1 471 1.6 1-1 442 0.67 1-1 472 0.21 1-1 443 0.32 1-1 473 0.18 1-1 444 0.17 1-1 474 0.30 1-1 445 0.24 1-1 475 0.19 1-1

[Table 51-9]

Connection No. Human MMP2, IC ₅₀ (nmol/L) Experimental example No. Connection No. Human MMP2, IC ₅₀ (nmol/L) Experimental example No. 476 0.20 1-1 506 0.15 1-1 477 0.46 1-1 507 0.16 1-1 478 0.53 1-1 508 0.30 1-1 479 0.66 1-1 509 0.28 1-1 480 0.45 1-1 510 0.40 1-1 481 2.4 1-1 511 0.20 1-1 482 0.90 1-1 512 0.15 1-1 483 0.22 1-1 513 0.18 1-1 484 0.26 1-1 514 0.22 1-1 485 0.096 1-1 515 0.29 1-1 486 0.39 1-1 516 1.3 1-1 487 1.4 1-1 517 1.3 1-1 488 1.8 1-1 518 1.4 1-1 489 0.27 1-1 519 1.6 1-1 490 0.86 1-1 520 0.32 1-1 491 0.81 1-1 521 0.41 1-1 492 0.68 1-1 522 3.1 1-1 493 0.55 1-1 523 1.9 1-1 494 0.37 1-1 524 0.12 1-1 495 0.44 1-1 525 0.15 1-1 496 0.23 1-1 526 0.21 1-1 497 0.24 1-1 527 0.32 1-1 498 0.32 1-1 528 0.23 1-1 499 0.31 1-1 529 0.49 1-1 500 0.25 1-1 530 0.42 1-1 501 0.32 1-1 531 0.35 1-1 502 0.30 1-1 532 0.31 1-1 503 0.45 1-1 533 0.34 1-1 504 0.34 1-1 534 0.29 1-1 505 0.38 1-1 535 0.31 1-1

[Table 51-10]

Connection No. Human MMP2, IC ₅₀ (nmol/L) Experimental example No. Connection No. Human MMP2, IC ₅₀ (nmol/L) Experimental example No. 536 0.35 1-1 566 0.59 1-1 537 0.28 1-1 567 0.54 1-1 538 0.22 1-1 568 0.92 1-1 539 0.23 1-1 569 0.93 1-1 540 0.29 1-1 570 1.0 1-1 541 0.35 1-1 571 1.7 1-1 542 0.45 1-1 572 1.8 1-1 543 1.3 1-1 573 4.3 1-1 544 1.3 1-1 574 4.8 1-1 545 1.0 1-1 575 2.0 1-1 546 0.98 1-1 576 2.8 1-1 547 0.59 1-1 577 0.34 1-1 548 0.67 1-1 578 0.36 1-1 549 0.52 1-1 579 0.249 1-2 550 0.52 1-1 580 0.436 1-2 551 0.92 1-1 581 0.412 1-2 552 0.62 1-1 582 0.254 1-2 553 1,1 1-1 583 0.217 1-2 554 0.89 1-1 584 1.82 1-2 555 0.87 1-1 585 1.20 1-2 556 0.55 1-1 586 1.03 1-2 557 0.44 1-1 587 0.19 1-1 558 0.66 1-1 588 0.12 1-1 559 0.42 1-1 589 0.12 1-1 560 0.42 1-1 590 3.2 1-1 561 0.74 1-1 591 0.98 1-1 562 0.58 1-1 592 0.38 1-1 563 0.49 1-1 593 2.6 1-1 564 0.44 1-1 594 1.8 1-1 565 0.42 1-1 595 3.83 1-2

[Table 51-11]

Connection No. Human MMP2, IC ₅₀ (nmol/L) Experimental example No. Connection No. Human MMP2, IC ₅₀ (nmol/L) Experimental example No. 596 1.3 1-1 626 0.18 1-1 597 0.27 1-1 627 <0.05 1-2 598 4.1 1-1 628 0.0914 1-2 599 0.39 1-1 629 0.0655 1-2 600 0.98 1-1 630 0.11 1-1 601 1.03 1-1 631 <0.05 1-2 602 0.59 1-1 632 0.0682 1-2 603 1.6 1-1 633 0.135 1-2 604 0.94 1-1 634 0.13 1-1 605 0.80 1-1 635 0.83 1-1 606 0.355 1-2 636 0.94 1-1 607 2.68 1-2 637 0.48 1-1 608 0.34 1-1 638 0.14 1-1 609 0.24 1-1 639 1.0 1-1 610 0.70 1-1 640 0.38 1-1 611 0.15 1-1 641 0.57 1-1 612 0.31 1-1 642 1.6 1-1 613 0.12 1-1 643 0.320 1-2 614 0.35 1-1 644 0.26 1-1 615 0.18 1-1 645 0.41 1-1 616 0.36 1-1 646 0.29 1-1 617 0.087 1-1 647 0.35 1-1 618 0.17 1-1 648 5.9 1-1 619 0.30 1-1 649 0.70 1-1 620 0.132 1-2 650 1.6 1-1 621 0,0867 1-2 651 2.0 1-1 622 <0.05 1-2 652 1,1 1-1 623 <0.05 1-2 653 0.74 1-1 624 0.159 1-2 654 0.21 1-1 625 0.103 1-2 655 0.27 1-1

[Table 51-12]

Connection No. Human MMP2, IC ₅₀ (nmol/L) Experimental example No. Connection No. Human MMP2, IC ₅₀ (nmol/L) Experimental example No. 656 0.72 1-1 686 0,0488 1-2 657 0.56 1-1 687 0.0577 1-2 658 0.055 1-1 688 0.0513 1-2 659 0.065 1-1 689 0.0319 1-2 660 0.12 1-1 690 0.0974 1-2 661 0.11 1-1 691 0.065 1-1 662 0.093 1-1 692 0.068 1-1 663 0.13 1-1 693 0,079 1-1 664 0.19 1-1 694 0.094 1-1 665 0.17 1-1 695 0.53 1-1 666 0.035 1-1 696 0.22 1-1 667 0,079 1-1 697 0.28 1-1 668 0.25 1-1 698 0.31 1-1 669 0.37 1-1 699 0.27 1-1 670 5.3 1-1 700 0.41 1-1 671 0.069 1-1 701 0.27 1-1 672 0.23 1-1 702 0.25 1-1 673 0.061 1-1 703 0.33 1-1 674 0.22 1-1 704 0.42 1-1 675 3.7 1-1 705 0.066 1-1 676 0.49 1-1 706 0,080 1-1 677 6.3 1-1 707 0.14 1-1 678 0.20 1-1 708 0.16 1-1 679 1.5 1-1 709 0.41 1-1 680 0.33 1-1 710 0.29 1-1 681 4.1 1-1 711 1.0 1-1 682 1.68 1-2 712 0.27 1-1 683 1.86 1-2 713 0.11 1-1 684 0.126 1-2 714 0.065 1-1 685 0.134 1-2 715 0.069 1-1

[Table 51-13]

Connection No. Human MMP2, IC ₅₀ (nmol/L) Experimental example No. Connection No. Human MMP2, IC ₅₀ (nmol/L) Experimental example No. 716 0.48 1-1 746 1.0 1-1 717 0.80 1-1 747 0.88 1-1 718 0.43 1-1 748 0.96 1-1 719 0.55 1-1 749 1,1 1-1 720 0.72 1-1 750 0.78 1-1 721 0.43 1-1 751 1.4 1-1 722 0.66 1-1 752 1.6 1-1 723 0.41 1-1 753 1.7 1-1 724 0.45 1-1 754 2,3 1-1 725 0.51 1-1 755 1.9 1-1 726 2.4 1-1 756 1.3 1-1 727 0.39 1-1 757 1.4 1-1 728 1.9 1-1 758 0.86 1-1 729 1.4 1-1 759 2.1 1-1 730 2.9 1-1 760 1.4 1-1 731 0.20 1-1 761 1.5 1-1 732 0.16 1-1 762 1,1 1-1 733 0.11 1-1 763 0.78 1-1 734 0.10 1-1 764 1.7 1-1 735 0.65 1-1 765 1.7 1-1 736 1,2 1-1 766 0.27 1-1 737 4.5 1-1 767 0.29 1-1 738 1,2 1-1 768 0.35 1-1 739 1.0 1-1 769 0.34 1-1 740 1.4 1-1 770 0.31 1-1 741 0.61 1-1 771 0.44 1-1 742 0.57 1-1 772 0.81 1-1 743 0.78 1-1 773 5.4 1-1 744 1.0 1-1 774 5.1 1-1 745 1.7 1-1 775 4.4 1-1

[Table 51-14]

Connection No. Human MMP2, IC ₅₀ (nmol/L) Experimental example No. Connection No. Human MMP2, IC ₅₀ (nmol/L) Experimental example No. 776 5.2 1-1 806 0.28 1-1 777 1.0 1-1 807 1.0 1-1 778 1,1 1-1 808 0.55 1-1 779 1.3 1-1 809 1.9 1-1 780 0.97 1-1 810 0.99 1-1 781 1.8 1-1 811 0.82 1-1 782 0.41 1-1 812 1.3 1-1 783 2.1 1-1 813 1.6 1-1 784 2.1 1-1 814 1.5 1-1 785 0.51 1-1 815 0.98 1-1 786 0,0830 1-2 816 1.3 1-1 787 0,0670 1-2 817 0.93 1-1 788 0.0645 1-2 818 1,1 1-1 789 0.0553 1-2 819 0.42 1-1 790 0,0605 1-2 820 0.70 1-1 791 0.584 1-2 821 1,2 1-1 792 0.11 1-1 822 1,1 1-1 793 0.23 1-1 823 0.95 1-1 794 0.15 1-1 824 1.0 1-1 795 0.19 1-1 825 1,1 1-1 796 0.22 1-1 826 0.32 1-1 797 0.30 1-1 827 0.58 1-1 798 0.59 1-1 828 1.4 1-1 799 0.72 1-1 829 1.5 1-1 800 1.6 1-1 830 1.7 1-1 801 1.3 1-1 831 1,1 1-1 802 1.4 1-1 832 1,1 1-1 803 0.46 1-1 833 1.4 1-1 804 0.32 1-1 834 1,2 1-1 805 0.46 1-1 835 1,2 1-1

[Table 51-15]

Connection No. Human MMP2, IC ₅₀ (nmol/L) Experimental example No. Connection No. Human MMP2, IC ₅₀ (nmol/L) Experimental example No. 836 1,2 1-1 866 0.137 1-2 837 1.0 1-1 867 0.213 1-2 838 0.61 1-1 868 0.143 1-2 839 0.62 1-1 869 0.106 1-2 840 0.80 1-1 870 0.124 1-2 841 0.74 1-1 871 0,140 1-2 842 0.82 1-1 872 0.123 1-2 843 1,1 1-1 873 0.135 1-2 844 1.4 1-1 874 0.133 1-2 845 1.3 1-1 875 0.191 1-2 846 2,3 1-1 876 0.158 1-2 847 2.1 1-1 877 0.136 1-2 848 1,1 1-1 878 0.124 1-2 849 1.3 1-1 879 0.133 1-2 850 0.92 1-1 880 0.146 1-2 851 0.66 1-1 881 0.106 1-2 852 0.64 1-1 882 0.0996 1-2 853 0.57 1-1 883 0.143 1-2 854 0.89 1-1 884 0.153 1-2 855 0.67 1-1 885 0.128 1-2 856 0.19 1-1 886 1.09 1-2 857 0.307 1-2 887 1.34 1-2 858 0.17 1-1 888 0.153 1-2 859 0.25 1-1 889 0,170 1-2 860 0.108 1-2 890 0.158 1-2 861 0.124 1-2 891 1.6 1-1 862 0.114 1-2 892 1.7 1-1 863 0.118 1-2 893 1.15 1-1 864 0.107 1-2 894 1,1 1-1 865 0,150 1-2 895 1.3 1-1

[Table 51-16]

Connection No. Human MMP2, IC ₅₀ (nmol/L) Experimental example No. Connection No. Human MMP2, IC ₅₀ (nmol/L) Experimental example No. 896 1,2 1-1 926 0,090 1-1 897 0.87 1-1 927 0,090 1-1 898 6.4 1-1 928 0.081 1-1 899 4.2 1-1 929 0.12 1-1 900 0.055 1-1 930 0.074 1-1 901 0.054 1-1 931 0.081 1-1 902 0.049 1-1 932 0,077 1-1 903 0.127 1-1 933 0.084 1-1 904 0.20 1-1 934 0.086 1-1 905 0.092 1-1 935 0,079 1-1 906 0.19 1-1 936 0.11 1-1 907 0,080 1-1 937 0.13 1-1 908 0.049 1-1 938 0.21 1-1 909 0.13 1-1 939 0.20 1-1 910 2.5 1-1 940 0.26 1-1 911 3.1 1-1 941 0.22 1-1 912 0,111 1-1 942 0,080 1-1 913 0.38 1-1 943 0.081 1-1 914 0.23 1-1 944 0.15 1-1 915 1.19 1-1 945 0.11 1-1 916 0.19 1-1 946 0.093 1-1 917 0.61 1-1 947 0.082 1-1 918 0.31 1-1 948 0.12 1-1 919 0.18 1-1 949 0.12 1-1 920 0.18 1-1 950 0.19 1-1 921 0.085 1-1 951 0.088 1-1 922 0.27 1-1 952 0.29 1-1 923 0.13 1-1 953 0.21 1-1 924 0.096 1-1 954 0.11 1-1 925 0.16 1-1 955 0.17 1-1

[Table 51-17]

Connection No. Human MMP2, IC ₅₀ (nmol/L) Experimental example No. Connection No. Human MMP2, IC ₅₀ (nmol/L) Experimental example No. 956 0.18 1-1 965 0.50 1-1 957 0.12 1-1 966 0.37 1-1 958 0.35 1-1 967 0.18 1-1 959 0.23 1-1 968 0.23 1-1 960 0.28 1-1 969 0.14 1-1 961 0.28 1-1 970 0.25 1-1 962 0.38 1-1 971 0.16 1-1 963 0.26 1-1 972 0.36 1-1 964 0.27 1-1

The inhibitory effect of the compounds of the invention on different types of MMP can be determined by the methods described in Experimental Examples 2-9.

Experimental Example 2: Evaluation test of the inhibitory effect of the compounds of the present invention on human MMP1

The activity of the compounds on human MMP1 inhibition was determined by an enzymatic assay using MOCAc-Lys-Pro-Leu-Gly-Leu-A2pr(Dnp)-Ala-Arg-NH ₂ as a substrate. In a reaction solution [50 mmol/L Tris-HCl (pH 7.5), 150 mmol/L NaCl, 10 mmol/L CaCl ₂ , 0.05% Brij L23], 50 μg/mL recombinant human MMP1 enzyme and 1 mmol/L 4-aminophenylmercuric acetate were mixed and reacted at 37°C for 120 minutes. Human MMP1 activated during the reaction was poured into a 96-well microplate to achieve a final concentration of 8 ng/mL. In addition, the compounds of the present invention, which had been diluted to various concentrations, were added and left to stand at room temperature for 15 minutes. Then, MOCAc-Lys-Pro-Leu-Gly-Leu-A2pr(Dnp)-Ala-Arg- _NH2 was added to reach a final concentration of 11 μmol/L, and the enzymatic reaction was initiated. After reacting at room temperature for 1 hour, the fluorescence intensity (Ex 320 nm/Em 400 nm) was measured using a microplate reader. The enzyme inhibition rate (%) was calculated using the measured fluorescence values according to the following formula, and 50% inhibitory concentrations (IC ₅₀ values) of the compounds of the invention were calculated.

Degree of enzyme inhibition (%) = [1-(A-B)/(C-B)] * 100

A: Fluorescence value with the addition of the compound

B: Fluorescence value without adding compound and enzyme.

C: Fluorescence value without adding compound

Experimental Example 3: Evaluation test of the inhibitory effect of the compounds of the present invention on human MMP3

The activity of the compounds on human MMP3 inhibition was determined by an enzymatic assay using MOCAc-Arg-Pro-Lys-Pro-Val-Glu-Nva-Trp-Arg-Lys(Dnp)-NH ₂ as a substrate. In a reaction solution [50 mmol/L Tris-HCl (pH 7.5), 150 mmol/L NaCl, 10 mmol/L CaCl ₂ , 0.05% Brij L23], 3 μg/mL recombinant human MMP3 enzyme and 5 mg/mL chymotrypsin were mixed. After reaction at 37°C for 30 min, 2 mmol/L PMSF was added to stop the reaction. The human MMP3 activated during the reaction was poured into a 96-well microplate to achieve a final concentration of 52 ng/mL. In addition, the compounds of the present invention, which had been diluted to various concentrations, were added and left to stand at room temperature for 15 minutes. Then, MOCAc-Arg-Pro-Lys-Pro-Val-Glu-Nva-Trp-Arg-Lys(Dnp) _-NH2 was added to reach a final concentration of 26 μmol/L, and the enzymatic reaction was initiated. After reacting at room temperature for 1 hour, the fluorescence intensity (Ex 320 nm/Em 400 nm) was measured using a microplate reader. The enzyme inhibition rate (%) was calculated using the measured fluorescence values according to the following formula, and 50% inhibitory concentrations (IC ₅₀ values) of the compounds of the invention were calculated.

Degree of enzyme inhibition (%) = [1-(A-B)/(C-B)] * 100

A: Fluorescence value with the addition of the compound

B: Fluorescence value without adding compound and enzyme.

C: Fluorescence value without adding compound

Experimental Example 4: Evaluation test of the inhibitory effect of the compounds of the present invention on human MMP7

The activity of the compounds on human MMP7 inhibition was determined by an enzymatic assay using MOCAc-Pro-Leu-Gly-Leu-A2pr(Dnp)-Ala-Arg-NH ₂ as a substrate. In a reaction solution [50 mmol/L Tris-HCl (pH 7.5), 150 mmol/L NaCl, 10 mmol/L CaCl ₂ , 0.05% Brij L23], 50 μg/mL recombinant human MMP7 enzyme and 1 mmol/L 4-aminophenylmercuric acetate were mixed and reacted at 37°C for 60 minutes. Human MMP7 activated during the reaction was poured into a 96-well microplate to achieve a final concentration of 18 ng/mL. In addition, the compounds of the present invention, which had been diluted to various concentrations, were added and left to stand at room temperature for 15 minutes. Then, MOCAc-Pro-Leu-Gly-Leu-A2pr(Dnp)-Ala-Arg- _NH2 was added to reach a final concentration of 22 μmol/L, and the enzymatic reaction was initiated. After reacting at room temperature for 1 hour, the fluorescence intensity (Ex 320 nm/Em 400 nm) was measured using a microplate reader. The enzyme inhibition rate (%) was calculated using the measured fluorescence values according to the following formula, and 50% inhibitory concentrations (IC ₅₀ values) of the compounds of the invention were calculated.

Degree of enzyme inhibition (%) = [1-(A-B)/(C-B)] * 100

A: Fluorescence value with the addition of the compound

B: Fluorescence value without adding compound and enzyme.

C: Fluorescence value without adding compound

Experimental Example 5: Evaluation test of the inhibitory effect of the compounds of the present invention on human MMP8

The activity of the compounds on human MMP8 inhibition was determined by an enzymatic assay using MOCAc-Pro-Leu-Gly-Leu-A2pr(Dnp)-Ala-Arg-NH ₂ as a substrate. In a reaction solution [50 mmol/L Tris-HCl (pH 7.5), 150 mmol/L NaCl, 10 mmol/L CaCl ₂ , 0.05% Brij L23], 100 μg/mL recombinant human MMP8 enzyme and 1 mmol/L 4-aminophenylmercuric acetate were mixed and reacted at 37°C for 60 minutes. Human MMP8 activated during the reaction was poured into a 96-well microplate to achieve a final concentration of 149 ng/mL. In addition, the compounds of the present invention, which had been diluted to various concentrations, were added and left to stand at room temperature for 15 minutes. Then, MOCAc-Pro-Leu-Gly-Leu-A2pr(Dnp)-Ala-Arg- _NH2 was added to reach a final concentration of 25 μmol/L, and the enzymatic reaction was initiated. After reacting at room temperature for 1 hour, the fluorescence intensity (Ex 320 nm/Em 400 nm) was measured using a microplate reader. The enzyme inhibition rate (%) was calculated using the measured fluorescence values according to the following formula, and 50% inhibitory concentrations (IC ₅₀ values) of the compounds of the invention were calculated.

Degree of enzyme inhibition (%) = [1-(A-B)/(C-B)] * 100

A: Fluorescence value with the addition of the compound

B: Fluorescence value without adding compound and enzyme.

C: Fluorescence value without adding compound

Experimental Example 6: Evaluation test of the inhibitory effect of the compounds of the present invention on human MMP9

The activity of the compounds on human MMP9 inhibition was determined by an enzymatic assay using MOCAc-Pro-Leu-Gly-Leu-A2pr(Dnp)-Ala-Arg-NH ₂ as a substrate. In a reaction solution [50 mmol/L Tris-HCl (pH 7.5), 150 mmol/L NaCl, 10 mmol/L CaCl ₂ , 0.05% Brij L23], 50 μg/mL recombinant human MMP9 enzyme and 1 mmol/L 4-aminophenylmercuric acetate were mixed and reacted at 37°C for 24 h. Human MMP9 activated during the reaction was poured into a 96-well microplate to achieve a final concentration of 58 ng/mL. In addition, the compounds of the present invention, which had been diluted to various concentrations, were added and left to stand at room temperature for 15 minutes. Then, MOCAc-Pro-Leu-Gly-Leu-A2pr(Dnp)-Ala-Arg- _NH2 was added to reach a final concentration of 3 μmol/L, and the enzymatic reaction was initiated. After reacting at room temperature for 1 hour, the fluorescence intensity (Ex 320 nm/Em 400 nm) was measured using a microplate reader. The enzyme inhibition rate (%) was calculated using the measured fluorescence values according to the following formula, and 50% inhibitory concentrations (IC ₅₀ values) of the compounds of the invention were calculated.

Degree of enzyme inhibition (%) = [1-(A-B)/(C-B)] * 100

A: Fluorescence value with the addition of the compound

B: Fluorescence value without adding compound and enzyme.

C: Fluorescence value without adding compound

Experimental Example 7: Evaluation test of the inhibitory effect of the compounds of the present invention on human MMP12

The activity of the compounds on human MMP12 inhibition was determined by an enzymatic assay using MOCAc-Pro-Leu-Gly-Leu-A2pr(Dnp)-Ala-Arg-NH ₂ as a substrate. In a reaction solution [50 mmol/L Tris-HCl (pH 7.5), 150 mmol/L NaCl, 10 mmol/L CaCl ₂ , 0.05% Brij L23], 50 μg/mL recombinant human MMP12 enzyme and 1 mmol/L 4-aminophenylmercuric acetate were mixed and reacted at 37°C for 4 or 24 h. Human MMP12 activated during the reaction was poured into a 96-well microplate to achieve a final concentration of 17 or 5.2 ng/mL. In addition, the compounds of the present invention, which had been diluted to various concentrations, were added and left to stand at room temperature for 15 minutes. Then, MOCAc-Pro-Leu-Gly-Leu-A2pr(Dnp)-Ala-Arg- _NH2 was added to reach a final concentration of 5 or 14 μmol/L, and the enzymatic reaction was initiated. After reacting at room temperature for 1 hour, the fluorescence intensity (Ex 320 nm/Em 400 nm) was measured using a microplate reader. The enzyme inhibition rate (%) was calculated using the measured fluorescence values according to the following formula, and 50% inhibitory concentrations (IC ₅₀ values) of the compounds of the invention were calculated.

Degree of enzyme inhibition (%) = [1-(A-B)/(C-B)] * 100

A: Fluorescence value with the addition of the compound

B: Fluorescence value without adding compound and enzyme.

C: Fluorescence value without adding compound

The results of the inhibitory effect of the compound of the invention on the enzymatic activity of human MMP12 are shown in the following table.

[Table 52]

Connection No. Human MMP12, IC ₅₀ (nmol/L) 1 253 3 502 9 160 20 254 52 190 149 4478 223 1367 230 1270 320 1897 347 2769 666 80 691 101 701 169 766 756 796 411

Experimental Example 8: Evaluation test of the inhibitory effect of the compounds of the present invention on human MMP13

The activity of the compounds on human MMP13 inhibition was determined by an enzymatic assay using MOCAc-Pro-Leu-Gly-Leu-A2pr(Dnp)-Ala-Arg-NH ₂ as a substrate. In a reaction solution [50 mmol/L Tris-HCl (pH 7.5), 150 mmol/L NaCl, 10 mmol/L CaCl ₂ , 0.05% Brij L23], 50 μg/mL recombinant human MMP13 enzyme and 1 mmol/L 4-aminophenylmercuric acetate were mixed and reacted at 37°C for 2 hours. Human MMP13 activated during the reaction was poured into a 96-well microplate to achieve a final concentration of 5 ng/mL. In addition, the compounds of the present invention, which had been diluted to various concentrations, were added and left to stand at room temperature for 15 minutes. Then, MOCAc-Pro-Leu-Gly-Leu-A2pr(Dnp)-Ala-Arg- _NH2 was added to reach a final concentration of 6 μmol/L, and the enzymatic reaction was initiated. After reacting at room temperature for 1 hour, the fluorescence intensity (Ex 320 nm/Em 400 nm) was measured using a microplate reader. The enzyme inhibition rate (%) was calculated using the measured fluorescence values according to the following formula, and 50% inhibitory concentrations (IC ₅₀ values) of the compounds of the invention were calculated.

Degree of enzyme inhibition (%) = [1-(A-B)/(C-B)] * 100

A: Fluorescence value with the addition of the compound

B: Fluorescence value without adding compound and enzyme.

C: Fluorescence value without adding compound

The results of the inhibitory effect of the compound of the invention on the enzymatic activity of human MMP13 are shown in the following table.

[Table 53]

Connection No. Human MMP13, IC ₅₀ (nmol/L) 1 240 3 732 9 250 20 224 52 679 149 1293 223 174 230 114 320 94 347 162 666 81 691 142 701 116 766 699 796 685

Experimental Example 9: Evaluation test of the inhibitory effect of the compounds of the present invention on human MMP14

The activity of the compounds on human MMP14 inhibition was determined by an enzymatic assay using MOCAc-Lys-Pro-Leu-Gly-Leu-A2pr(Dnp)-Ala-Arg- _NH2 as a substrate. In a reaction solution [50 mmol/L Tris-HCl (pH 7.5), 200 mmol/L NaCl, 5 mmol/L _CaCl2 , 20 μmol/L _ZnSO4 , 0.05% Brij L23], 100 μg/mL recombinant human MMP14 enzyme and 5 mg/mL trypsin were mixed. After reaction at room temperature for 25 min, trypsin inhibitor was added to reach 25 μg/mL, thereby stopping the reaction. Human MMP14 activated by the reaction was poured into a 96-well microplate to make the final concentration 6 ng/mL. In addition, the compounds of the present invention, which had been diluted to various concentrations, were added and left to stand at room temperature for 15 minutes. Then, MOCAc-Lys-Pro-Leu-Gly-Leu-A2pr(Dnp)-Ala-Arg- _NH2 was added to make the final concentration 5 μmol/L, and the enzymatic reaction was initiated. After reacting at room temperature for 1 hour, the fluorescence intensity (Ex 320 nm/Em 400 nm) was measured using a microplate reader. The enzyme inhibition rate (%) was calculated using the measured fluorescence values according to the following formula, and 50% inhibitory concentrations (IC ₅₀ values) of the compounds of the invention were calculated.

Degree of enzyme inhibition (%) = [1-(A-B)/(C-B)] * 100

A: Fluorescence value with the addition of the compound

B: Fluorescence value without adding compound and enzyme.

C: Fluorescence value without adding compound/

INDUSTRIAL APPLICABILITY

The compounds of the present invention have an excellent MMP2 inhibition effect, and the present invention can provide a pharmaceutical product effective for the prevention or treatment of cancer and organ fibrosis and symptoms associated with cancer and organ fibrosis, and is expected to reduce the burden on patients, thereby contributing to the development of the pharmaceutical industry.

--->

SEQUENCE LIST

<110> TAISHO PHARMACEUTICAL CO., LTD.

<120> POLYPEPTIDE WITH MMP-2 INHIBITING EFFECT

<130> FA0061-20155

<150> JP 2019-203338

<151> 2019-11-08

<160> 47

<170> PatentIn version 3.5

<210> 1

<211> 6

<212> PROTEIN

<213> Artificial sequence

<220>

<223> peptide chain [I'-1]: Compound No. 1-39

<220>

<221> OTHER_SIGN

<222> (1)..(1)

<223> gamma-(d)-Glu, beta-Asp, beta-(d)-Asp, or gamma-Glu

<220>

<221> OTHER_SIGN

<222> (2)..(2)

<223> (2S,4S)-(4-amino)Pro

<220>

<221> OTHER_SIGN

<222> (3)..(3)

<223> Leu, Val, Ile, Phe or Trp

<220>

<221> OTHER_SIGN

<222> (4)..(4)

<223> (N-Me)Glu, (N-Me)Ile, (N-Me)Val, (N-Me)Leu, (N-Me)Phe, (N-Me)Tyr,

(N-Me)Ser, Pro, (N-Me)Asp or single bond

<220>

<221> OTHER_SIGN

<222> (5)..(5)

<223> Ape, beta-homoPro, Pro, (d)-Pro, beta-Ala, GABA, Acp, Lys,

(d)-Lys, Arg, (d)-Arg or single bond

<220>

<221> OTHER_SIGN

<222> (6)..(6)

<223> single bond, Pro, Lys, (d)-Lys, Arg, (d)-Arg (d)-Lys-(d)-Lys

<400> 1

Xaa Xaa Xaa Xaa Xaa Xaa

1 5

<210> 2

<211> 6

<212> PROTEIN

<213> Artificial sequence

<220>

<223> peptide chain [I'-2]: Compound No. 40

<220>

<221> OTHER_SIGN

<222> (1)..(1)

<223> gamma-(d)-Glu

<220>

<221> OTHER_SIGN

<222> (2)..(2)

<223> (2S,4S)-(4-amino)Pro

<220>

<221> OTHER_SIGN

<222> (3)..(3)

<223> Leu

<220>

<221> OTHER_SIGN

<222> (4)..(4)

<223>(N-Me)Glu

<220>

<221> OTHER_SIGN

<222> (5)..(5)

<223> Ape

<220>

<221> OTHER_SIGN

<222> (6)..(6)

<223> single bond

<400> 2

Xaa Xaa Xaa Xaa Xaa Xaa

1 5

<210> 3

<211> 6

<212> PROTEIN

<213> Artificial sequence

<220>

<223> peptide chain [I'-3]: Compound No. 41

<220>

<221> OTHER_SIGN

<222> (1)..(1)

<223> gamma-(d)-Glu

<220>

<221> OTHER_SIGN

<222> (2)..(2)

<223> (2S,4S)-(4-amino)Pro

<220>

<221> OTHER_SIGN

<222> (3)..(3)

<223> Leu

<220>

<221> OTHER_SIGN

<222> (4)..(4)

<223>(N-Me)Glu

<220>

<221> OTHER_SIGN

<222> (5)..(5)

<223> Ape

<220>

<221> OTHER_SIGN

<222> (6)..(6)

<223> single bond

<400> 3

Xaa Xaa Xaa Xaa Xaa Xaa

1 5

<210> 4

<211> 6

<212> PROTEIN

<213> Artificial sequence

<220>

<223> peptide chain [I'-4]: Compound No. 42

<220>

<221> OTHER_SIGN

<222> (1)..(1)

<223> gamma-(d)-Glu

<220>

<221> OTHER_SIGN

<222> (2)..(2)

<223> (2S,4S)-(4-amino)Pro

<220>

<221> OTHER_SIGN

<222> (3)..(3)

<223> Leu

<220>

<221> OTHER_SIGN

<222> (4)..(4)

<223>(N-Me)Glu

<220>

<221> OTHER_SIGN

<222> (5)..(5)

<223> Ape

<220>

<221> OTHER_SIGN

<222> (6)..(6)

<223> single bond

<400> 4

Xaa Xaa Xaa Xaa Xaa Xaa

1 5

<210> 5

<211> 6

<212> PROTEIN

<213> Artificial sequence

<220>

<223> peptide chain [I'-5]: Compound No. 43

<220>

<221> OTHER_SIGN

<222> (1)..(1)

<223> gamma-(d)-Glu

<220>

<221> OTHER_SIGN

<222> (2)..(2)

<223> (2S,4S)-(4-amino)Pro

<220>

<221> OTHER_SIGN

<222> (3)..(3)

<223> Leu

<220>

<221> OTHER_SIGN

<222> (4)..(4)

<223>(N-Me)Glu

<220>

<221> OTHER_SIGN

<222> (5)..(5)

<223> Ape

<220>

<221> OTHER_SIGN

<222> (6)..(6)

<223> single bond

<400> 5

Xaa Xaa Xaa Xaa Xaa Xaa

1 5

<210> 6

<211> 6

<212> PROTEIN

<213> Artificial sequence

<220>

<223> peptide chain [I'-6]: Compound No. 44

<220>

<221> OTHER_SIGN

<222> (1)..(1)

<223> gamma-(d)-Glu

<220>

<221> OTHER_SIGN

<222> (2)..(2)

<223> (2S,4S)-(4-amino)Pro

<220>

<221> OTHER_SIGN

<222> (3)..(3)

<223> Leu

<220>

<221> OTHER_SIGN

<222> (4)..(4)

<223>(N-Me)Glu

<220>

<221> OTHER_SIGN

<222> (5)..(5)

<223> Ape

<220>

<221> OTHER_SIGN

<222> (6)..(6)

<223> single bond

<400> 6

Xaa Xaa Xaa Xaa Xaa Xaa

1 5

<210> 7

<211> 6

<212> PROTEIN

<213> Artificial sequence

<220>

<223> peptide chain [I'-7]: Compound No. 45-55

<220>

<221> OTHER_SIGN

<222> (1)..(1)

<223> beta-(d)-Asp, gamma-(d)-Glu, or gamma-Glu

<220>

<221> OTHER_SIGN

<222> (2)..(2)

<223> (2S,4S)-(4-amino)Pro, (S)-piperazine, (2S,4R)-(4-amino)Pro,

(2S,4S)-(4-hydroxy)Pro or (2S,4R)-(4-hydroxy)Pro

<220>

<221> OTHER_SIGN

<222> (3)..(3)

<223> Leu

<220>

<221> OTHER_SIGN

<222> (4)..(4)

<223> (N-Me)Ile or (N-Me)Glu

<220>

<221> OTHER_SIGN

<222> (5)..(5)

<223> Ape or beta-homoPro

<220>

<221> OTHER_SIGN

<222> (6)..(6)

<223> single bond

<400> 7

Xaa Xaa Xaa Xaa Xaa Xaa

1 5

<210> 8

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<223> peptide chain [I'-8]: Compound No. 56-91

<220>

<221> OTHER_SIGN

<222> (1)..(1)

<223> GABA, (N-Me)GABA or Ape

<220>

<221> OTHER_SIGN

<222> (2)..(2)

<223> Asn, (N-Me)Asn, Glu, Gln, (d)-Ser, homoSer, (d)-Thr or Arg

<220>

<221> OTHER_SIGN

<222> (3)..(3)

<223> Asp

<220>

<221> OTHER_SIGN

<222> (4)..(4)

<223> Ala, Dap, Dab or Orn

<220>

<221> OTHER_SIGN

<222> (5)..(5)

<223> Leu or Dab

<220>

<221> OTHER_SIGN

<222> (6)..(6)

<223> Met, (N-Me)Val, (N-Me)Ile, Glu, (N-Me)Glu or homoGlu

<220>

<221> OTHER_SIGN

<222> (7)..(7)

<223> beta-homoPro or Pro

<220>

<221> OTHER_SIGN

<222> (8)..(8)

<223> single bond, (d)-Lys or (d)-Arg

<220>

<221> OTHER_SIGN

<222> (9)..(9)

<223> -NH2 or -OH

<400> 8

Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa

1 5

<210> 9

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<223> peptide chain [I'-9]: Compound No. 92-156

<220>

<221> OTHER_SIGN

<222> (1)..(1)

<223> GABA or (N-Me)GABA

<220>

<221> OTHER_SIGN

<222> (2)..(2)

<223> (N-Me)Ala, (N-Me)Asn, Asn, (d)-Asn, (N-Me)Gly, Aze(2), Pro,

homoPro, (N-Me)Val, (N-Me)Leu, (N-Me)Ile, (N-Me)Met, (d)-Lys,

(N-Me)Phe, (N-Me)Asp, (N-Me)Glu, (N-Me)Lys, Gln, (N-Me)Tyr,

(N-Me)Trp, (N-Me)Thr, Val, Glu or Orn

<220>

<221> OTHER_SIGN

<222> (3)..(3)

<223> Asp

<220>

<221> OTHER_SIGN

<222> (4)..(4)

<223> Ala, Dab, Dap or Dap(Me)

<220>

<221> OTHER_SIGN

<222> (5)..(5)

<223> Leu

<220>

<221> OTHER_SIGN

<222> (6)..(6)

<223> (N-Me)Ile, (N-Me)Glu or (N-Me)Asp

<220>

<221> OTHER_SIGN

<222> (7)..(7)

<223> Aib, Pro or beta-homoPro

<220>

<221> OTHER_SIGN

<222> (8)..(8)

<223> single bond

<220>

<221> OTHER_SIGN

<222> (9)..(9)

<223> -NH2

<400> 9

Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa

1 5

<210> 10

<211> 11

<212> PROTEIN

<213> Artificial sequence

<220>

<223> peptide chain [I'-10]: Compound No. 157-160

<220>

<221> OTHER_SIGN

<222> (1)..(1)

<223> gamma-Glu or (d)-Lys

<220>

<221> OTHER_SIGN

<222> (2)..(2)

<223> Adox or (d)-Lys

<220>

<221> OTHER_SIGN

<222> (3)..(3)

<223> Adox or (d)-Lys

<220>

<221> OTHER_SIGN

<222> (4)..(4)

<223> single bond

<220>

<221> OTHER_SIGN

<222> (5)..(5)

<223> single bond

<220>

<221> OTHER_SIGN

<222> (6)..(6)

<223> Lys

<220>

<221> OTHER_SIGN

<222> (7)..(7)

<223> Asp

<220>

<221> OTHER_SIGN

<222> (8)..(8)

<223> Dab

<220>

<221> OTHER_SIGN

<222> (9)..(9)

<223> Leu

<220>

<221> OTHER_SIGN

<222> (10)..(10)

<223>(N-Me)Glu

<220>

<221> OTHER_SIGN

<222> (11)..(11)

<223> beta-homoPro

<400> 10

Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa

1 5 10

<210> 11

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<223> peptide chain [I'-9]: Compound No. 161-176

<220>

<221> OTHER_SIGN

<222> (1)..(1)

<223> GABA, Ape or Adox

<220>

<221> OTHER_SIGN

<222> (2)..(2)

<223> Asn, Gln, (d)-Ser, Glu or (d)-Thr

<220>

<221> OTHER_SIGN

<222> (3)..(3)

<223> Asp

<220>

<221> OTHER_SIGN

<222> (4)..(4)

<223> Dab

<220>

<221> OTHER_SIGN

<222> (5)..(5)

<223> Leu

<220>

<221> OTHER_SIGN

<222> (6)..(6)

<223> (N-Me)Glu or (N-Me)Ile

<220>

<221> OTHER_SIGN

<222> (7)..(7)

<223> Beta-homoPro

<220>

<221> OTHER_SIGN

<222> (8)..(8)

<223> single bond, (d)-Lys or (d)-Arg

<220>

<221> OTHER_SIGN

<222> (9)..(9)

<223> -NH2 or -OH (compound #161 only)

<400> 11

Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa

1 5

<210> 12

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<223> peptide chain [I'-9]: Compound No. 177-201

<220>

<221> OTHER_SIGN

<222> (1)..(1)

<223> GABA, Ape or Acp

<220>

<221> OTHER_SIGN

<222> (2)..(2)

<223> Asn, Lys, Arg or Glu

<220>

<221> OTHER_SIGN

<222> (3)..(3)

<223> Asp

<220>

<221> OTHER_SIGN

<222> (4)..(4)

<223> Ala or Dab

<220>

<221> OTHER_SIGN

<222> (5)..(5)

<223> Leu

<220>

<221> OTHER_SIGN

<222> (6)..(6)

<223> Met, (N-Me)Glu or (N-Me)Ile

<220>

<221> OTHER_SIGN

<222> (7)..(7)

<223> Pro or beta-homoPro

<220>

<221> OTHER_SIGN

<222> (8)..(8)

<223> single bond

<220>

<221> OTHER_SIGN

<222> (9)..(9)

<223> -NH2

<400> 12

Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa

1 5

<210> 13

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<223> peptide chain [I'-11]: Compound No. 202

<220>

<221> OTHER_SIGN

<222> (1)..(1)

<223>GABA

<220>

<221> OTHER_SIGN

<222> (2)..(2)

<223> Asn

<220>

<221> OTHER_SIGN

<222> (3)..(3)

<223> Asp

<220>

<221> OTHER_SIGN

<222> (4)..(4)

<223> Ala

<220>

<221> OTHER_SIGN

<222> (5)..(5)

<223> Leu

<220>

<221> OTHER_SIGN

<222> (6)..(6)

<223> Met

<220>

<221> OTHER_SIGN

<222> (7)..(7)

<223> Pro

<220>

<221> OTHER_SIGN

<222> (8)..(8)

<223> single bond

<220>

<221> OTHER_SIGN

<222> (9)..(9)

<223> -NH2

<400> 13

Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa

1 5

<210> 14

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<223> peptide chain [I'-12]: Compound No. 203-205

<220>

<221> OTHER_SIGN

<222> (1)..(1)

<223> Acp

<220>

<221> OTHER_SIGN

<222> (2)..(2)

<223> Asn, Gln or Ala

<220>

<221> OTHER_SIGN

<222> (3)..(3)

<223> Asp

<220>

<221> OTHER_SIGN

<222> (4)..(4)

<223> Dab

<220>

<221> OTHER_SIGN

<222> (5)..(5)

<223> Leu

<220>

<221> OTHER_SIGN

<222> (6)..(6)

<223>(N-Me)Glu

<220>

<221> OTHER_SIGN

<222> (7)..(7)

<223> beta-homoPro

<220>

<221> OTHER_SIGN

<222> (8)..(8)

<223> single bond

<220>

<221> OTHER_SIGN

<222> (9)..(9)

<223> -NH2

<400> 14

Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa

1 5

<210> 15

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<223> peptide chain [I'-13]: Compound No. 206-209

<220>

<221> OTHER_SIGN

<222> (1)..(1)

<223> Acp or Ape

<220>

<221> OTHER_SIGN

<222> (2)..(2)

<223> Asn, Gln or Ala

<220>

<221> OTHER_SIGN

<222> (3)..(3)

<223> Asp

<220>

<221> OTHER_SIGN

<222> (4)..(4)

<223> Dab

<220>

<221> OTHER_SIGN

<222> (5)..(5)

<223> Leu

<220>

<221> OTHER_SIGN

<222> (6)..(6)

<223>(N-Me)Glu

<220>

<221> OTHER_SIGN

<222> (7)..(7)

<223> beta-homoPro

<220>

<221> OTHER_SIGN

<222> (8)..(8)

<223> single bond

<220>

<221> OTHER_SIGN

<222> (9)..(9)

<223> -NH2

<400> 15

Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa

1 5

<210> 16

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<223> peptide chain [I'-14]: Compound No. 210-315

<220>

<221> OTHER_SIGN

<222> (1)..(1)

<223> GABA, beta-Ala, Ape, epsilon-Lys, epsilon-(d)-Lys, Acp, Adox,

gamma-Dab, delta-(d)-Orn, gamma-(d)-Dab, beta-Dap, beta-(d)-Dap

or -NH-(CH2)2-O-CH2-CO-

<220>

<221> OTHER_SIGN

<222> (2)..(2)

<223> Asn, Val, Glu, Orn, (N-Me)Asn, Gln, (d)-Asn, (d)-Gln, (d)-Ser,

(d)-Ala, Phe, (d)-Phe, Tyr, (d)-Tyr, beta-Dap, beta-(d)-Dap,

beta-Ala, Dab, Dap, (d)-Dab, Aze(2), (N-Me)Glu, (N-Me)Ile or

(N-Me)Lys

<220>

<221> OTHER_SIGN

<222> (3)..(3)

<223> Asp

<220>

<221> OTHER_SIGN

<222> (4)..(4)

<223> Dab, Dap, Dap(Me), Dab(Me) or Dab(Me)2

<220>

<221> OTHER_SIGN

<222> (5)..(5)

<223> Leu

<220>

<221> OTHER_SIGN

<222> (6)..(6)

<223> (N-Me)Glu, (N-Me)Ile, (N-Me)Asp or (N-Me)Asn

<220>

<221> OTHER_SIGN

<222> (7)..(7)

<223> beta-homoPro

<220>

<221> OTHER_SIGN

<222> (8)..(8)

<223> single bond

<220>

<221> OTHER_SIGN

<222> (9)..(9)

<223> NH2, OH, NHEt, piperidin-1-yl, NHMe, azetidin-1-yl,

pyrrolidin-1-yl, (4-OH)piperidin-1-yl, NH-(CH2)2-OH or

(3-OH)azetidin-1-yl

<400> 16

Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa

1 5

<210> 17

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<223> peptide chain [I'-15]: Compound No. 316-317

<220>

<221> OTHER_SIGN

<222> (1)..(1)

<223> Ape

<220>

<221> OTHER_SIGN

<222> (2)..(2)

<223> Asn or (d)-Ser

<220>

<221> OTHER_SIGN

<222> (3)..(3)

<223> Asp

<220>

<221> OTHER_SIGN

<222> (4)..(4)

<223> Dab

<220>

<221> OTHER_SIGN

<222> (5)..(5)

<223> Leu

<220>

<221> OTHER_SIGN

<222> (6)..(6)

<223> (N-Me)Ile

<220>

<221> OTHER_SIGN

<222> (7)..(7)

<223> beta-homoPro

<220>

<221> OTHER_SIGN

<222> (8)..(8)

<223> single bond

<220>

<221> OTHER_SIGN

<222> (9)..(9)

<223> -NH2

<400> 17

Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa

1 5

<210> 18

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<223> peptide chain [I'-14]: Compound No. 318-586

<220>

<221> OTHER_SIGN

<222> (1)..(1)

<223> Ape, -NH-(CH2)2-O-CH2-CO-, Adox, GABA, Acp, delta-Orn,

epsilon-(d)-Lys or epsilon-Lys

<220>

<221> OTHER_SIGN

<222> (2)..(2)

<223> (N-Me)Glu, Thr, (d)-Thr, (d)-Pro, Trp, (N-Me)Leu, (N-Me)Met,

(d)-Trp, His, (d)-His, Cys, (d)-Cys, Arg, (d)-Arg, (d)-Glu,

(d)-Ser, Lys(Ac), Cit, (d)-Cit, beta-Asp, beta-(d)-Asp, Lys, Met,

single bond, (N-Me)Gln, Asn, (N-Me)Arg, (d)-Lys, Gln, Glu, Ala,

<220>

<221> OTHER_SIGN

<222> (2)..(2)

<223> Dap, Dab or Gly

<220>

<221> OTHER_SIGN

<222> (3)..(3)

<223> Asp, aspartimide or beta-Asp

<220>

<221> OTHER_SIGN

<222> (4)..(4)

<223> Dab, Dap or Aze(2)

<220>

<221> OTHER_SIGN

<222> (5)..(5)

<223> Leu, Phe or Ile

<220>

<221> OTHER_SIGN

<222> (6)..(6)

<223> (N-Me)Ile, (N-Me)Glu, Dap, Dab, Orn, (N-Me)Arg, (N-Me)Lys,

single bond, (N-Me)Val, (N-Me)Ala or (N-Me)Leu

<220>

<221> OTHER_SIGN

<222> (7)..(7)

<223> beta-homoPro, single bond, Pro, Arg, Lys, beta-Ala, GABA, Ape,

His, (d)-Arg, (d)-Lys, Dap, Dab, Orn, homoPro,

(2S,4R)-(4-amino)Pro, beta-Dap, beta-(d)-Dap, gamma-Dab,

delta-Orn, delta-(d)-Orn, epsilon-Lys, epsilon-(d)-Lys, Aze(2),

<220>

<221> OTHER_SIGN

<222> (7)..(7)

<223> (d)-Aze(2), (N-Me)beta-Ala, Acp or gamma-(d)-Dab

<220>

<221> OTHER_SIGN

<222> (8)..(8)

<223> single bond, (d)-Lys-(d)-Lys-(d)-Lys, (d)-Lys, (d)-Arg, Lys, Arg,

Arg-Arg, (d)-Arg-(d)-Arg, Lys-Lys, (d)-Lys-(d)-Lys, beta-Ala or

GABA

<220>

<221> OTHER_SIGN

<222> (9)..(9)

<223> -NH2, -OH, -NH-(CH2)2-NH2, -NH-(CH2)4-NH2 or -NH-(CH2)5-NH2

<400> 18

Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa

1 5

<210> 19

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<223> peptide chain [I'-16]: Compound No. 587-589

<220>

<221> OTHER_SIGN

<222> (1)..(1)

<223> beta-Ala or GABA

<220>

<221> OTHER_SIGN

<222> (2)..(2)

<223> Asn

<220>

<221> OTHER_SIGN

<222> (3)..(3)

<223> Asp

<220>

<221> OTHER_SIGN

<222> (4)..(4)

<223> Ala

<220>

<221> OTHER_SIGN

<222> (5)..(5)

<223> Leu

<220>

<221> OTHER_SIGN

<222> (6)..(6)

<223> (N-Me)Met or (N-Me)Val

<220>

<221> OTHER_SIGN

<222> (7)..(7)

<223> Pro

<220>

<221> OTHER_SIGN

<222> (8)..(8)

<223> single bond

<220>

<221> OTHER_SIGN

<222> (9)..(9)

<223> -NH2

<400> 19

Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa

1 5

<210> 20

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<223> peptide chain [I'-17]: Compound No. 590

<220>

<221> OTHER_SIGN

<222> (1)..(1)

<223> Ape

<220>

<221> OTHER_SIGN

<222> (2)..(2)

<223> Asn

<220>

<221> OTHER_SIGN

<222> (3)..(3)

<223> Asp

<220>

<221> OTHER_SIGN

<222> (4)..(4)

<223> Ala

<220>

<221> OTHER_SIGN

<222> (5)..(5)

<223> Leu

<220>

<221> OTHER_SIGN

<222> (6)..(6)

<223> Met

<220>

<221> OTHER_SIGN

<222> (7)..(7)

<223> Pro

<220>

<221> OTHER_SIGN

<222> (8)..(8)

<223> single bond

<220>

<221> OTHER_SIGN

<222> (9)..(9)

<223> -NH2

<400> 20

Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa

1 5

<210> 21

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<223> peptide chain [I'-18]: Compound No. 591

<220>

<221> OTHER_SIGN

<222> (1)..(1)

<223>GABA

<220>

<221> OTHER_SIGN

<222> (2)..(2)

<223> Asn

<220>

<221> OTHER_SIGN

<222> (3)..(3)

<223> Asp

<220>

<221> OTHER_SIGN

<222> (4)..(4)

<223> Ala

<220>

<221> OTHER_SIGN

<222> (5)..(5)

<223> Leu

<220>

<221> OTHER_SIGN

<222> (6)..(6)

<223> Met

<220>

<221> OTHER_SIGN

<222> (7)..(7)

<223> Pro

<220>

<221> OTHER_SIGN

<222> (8)..(8)

<223> single bond

<220>

<221> OTHER_SIGN

<222> (9)..(9)

<223> -NH2

<400> 21

Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa

1 5

<210> 22

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<223> peptide chain [I'-19]: Compound No. 592

<220>

<221> OTHER_SIGN

<222> (1)..(1)

<223> Ape

<220>

<221> OTHER_SIGN

<222> (2)..(2)

<223> Asn

<220>

<221> OTHER_SIGN

<222> (3)..(3)

<223> Asp

<220>

<221> OTHER_SIGN

<222> (4)..(4)

<223> Ala

<220>

<221> OTHER_SIGN

<222> (5)..(5)

<223> Leu

<220>

<221> OTHER_SIGN

<222> (6)..(6)

<223> Met

<220>

<221> OTHER_SIGN

<222> (7)..(7)

<223> Pro

<220>

<221> OTHER_SIGN

<222> (8)..(8)

<223> single bond

<220>

<221> OTHER_SIGN

<222> (9)..(9)

<223> -NH2

<400> 22

Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa

1 5

<210> 23

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<223> peptide chain [I'-20]: Compound No. 593

<220>

<221> OTHER_SIGN

<222> (1)..(1)

<223> single bond

<220>

<221> OTHER_SIGN

<222> (2)..(2)

<223> single bond

<220>

<221> OTHER_SIGN

<222> (3)..(3)

<223> beta-(d)-Asp

<220>

<221> OTHER_SIGN

<222> (4)..(4)

<223> Ala

<220>

<221> OTHER_SIGN

<222> (5)..(5)

<223> Leu

<220>

<221> OTHER_SIGN

<222> (6)..(6)

<223>(N-Me)Glu

<220>

<221> OTHER_SIGN

<222> (7)..(7)

<223> beta-homoPro

<220>

<221> OTHER_SIGN

<222> (8)..(8)

<223> single bond

<220>

<221> OTHER_SIGN

<222> (9)..(9)

<223> -NH2

<400> 23

Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa

1 5

<210> 24

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<223> peptide chain [I'-21]: Compound No. 594-595

<220>

<221> OTHER_SIGN

<222> (1)..(1)

<223> single bond

<220>

<221> OTHER_SIGN

<222> (2)..(2)

<223> single bond

<220>

<221> OTHER_SIGN

<222> (3)..(3)

<223> beta-(d)-Asp or gamma-(d)-Glu

<220>

<221> OTHER_SIGN

<222> (4)..(4)

<223> Ala or (2S,4S)-(4-amino)Pro

<220>

<221> OTHER_SIGN

<222> (5)..(5)

<223> Leu

<220>

<221> OTHER_SIGN

<222> (6)..(6)

<223> (N-Me)Ile or (N-Me)Glu

<220>

<221> OTHER_SIGN

<222> (7)..(7)

<223> beta-homoPro or Ape

<220>

<221> OTHER_SIGN

<222> (8)..(8)

<223> single bond

<220>

<221> OTHER_SIGN

<222> (9)..(9)

<223> -NH2

<400> 24

Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa

1 5

<210> 25

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<223> peptide chain [I'-22]: Compound No. 596

<220>

<221> OTHER_SIGN

<222> (1)..(1)

<223>GABA

<220>

<221> OTHER_SIGN

<222> (2)..(2)

<223> Asn

<220>

<221> OTHER_SIGN

<222> (3)..(3)

<223> Asp

<220>

<221> OTHER_SIGN

<222> (4)..(4)

<223> Dab

<220>

<221> OTHER_SIGN

<222> (5)..(5)

<223> Leu

<220>

<221> OTHER_SIGN

<222> (6)..(6)

<223> (N-Me)Ile

<220>

<221> OTHER_SIGN

<222> (7)..(7)

<223> Pro

<220>

<221> OTHER_SIGN

<222> (8)..(8)

<223> single bond

<220>

<221> OTHER_SIGN

<222> (9)..(9)

<223> -NH2

<400> 25

Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa

1 5

<210> 26

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<223> peptide chain [I'-23]: Compound No. 597

<220>

<221> OTHER_SIGN

<222> (1)..(1)

<223>GABA

<220>

<221> OTHER_SIGN

<222> (2)..(2)

<223> Asn

<220>

<221> OTHER_SIGN

<222> (3)..(3)

<223> Asp

<220>

<221> OTHER_SIGN

<222> (4)..(4)

<223> Ala

<220>

<221> OTHER_SIGN

<222> (5)..(5)

<223> Leu

<220>

<221> OTHER_SIGN

<222> (6)..(6)

<223> Met

<220>

<221> OTHER_SIGN

<222> (7)..(7)

<223> Pro

<220>

<221> OTHER_SIGN

<222> (8)..(8)

<223> single bond

<220>

<221> OTHER_SIGN

<222> (9)..(9)

<223> -NH2

<400> 26

Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa

1 5

<210> 27

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<223> peptide chain [I'-24]: Compound No. 598

<220>

<221> OTHER_SIGN

<222> (1)..(1)

<223>GABA

<220>

<221> OTHER_SIGN

<222> (2)..(2)

<223> Asn

<220>

<221> OTHER_SIGN

<222> (3)..(3)

<223> Asp

<220>

<221> OTHER_SIGN

<222> (4)..(4)

<223> Ala

<220>

<221> OTHER_SIGN

<222> (5)..(5)

<223> Leu

<220>

<221> OTHER_SIGN

<222> (6)..(6)

<223> Met

<220>

<221> OTHER_SIGN

<222> (7)..(7)

<223> Pro

<220>

<221> OTHER_SIGN

<222> (8)..(8)

<223> single bond

<220>

<221> OTHER_SIGN

<222> (9)..(9)

<223> -NH2

<400> 27

Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa

1 5

<210> 28

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<223> peptide chain [I'-25]: Compound No. 599

<220>

<221> OTHER_SIGN

<222> (1)..(1)

<223>GABA

<220>

<221> OTHER_SIGN

<222> (2)..(2)

<223> Asn

<220>

<221> OTHER_SIGN

<222> (3)..(3)

<223> Asp

<220>

<221> OTHER_SIGN

<222> (4)..(4)

<223> Ala

<220>

<221> OTHER_SIGN

<222> (5)..(5)

<223> Leu

<220>

<221> OTHER_SIGN

<222> (6)..(6)

<223> Met

<220>

<221> OTHER_SIGN

<222> (7)..(7)

<223> Pro

<220>

<221> OTHER_SIGN

<222> (8)..(8)

<223> single bond

<220>

<221> OTHER_SIGN

<222> (9)..(9)

<223> -NH2

<400> 28

Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa

1 5

<210> 29

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<223> peptide chain [I'-26]: Compound No. 600-601

<220>

<221> OTHER_SIGN

<222> (1)..(1)

<223>GABA

<220>

<221> OTHER_SIGN

<222> (2)..(2)

<223> Asn

<220>

<221> OTHER_SIGN

<222> (3)..(3)

<223> Asp

<220>

<221> OTHER_SIGN

<222> (4)..(4)

<223> Dab

<220>

<221> OTHER_SIGN

<222> (5)..(5)

<223> Leu

<220>

<221> OTHER_SIGN

<222> (6)..(6)

<223> (N-Me)Ile or (N-Me)Glu

<220>

<221> OTHER_SIGN

<222> (7)..(7)

<223> beta-homoPro

<220>

<221> OTHER_SIGN

<222> (8)..(8)

<223> single bond

<220>

<221> OTHER_SIGN

<222> (9)..(9)

<223> -NH2

<400> 29

Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa

1 5

<210> 30

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<223> peptide chain [I'-27]: Compound No. 602-605

<220>

<221> OTHER_SIGN

<222> (1)..(1)

<223> single bond

<220>

<221> OTHER_SIGN

<222> (2)..(2)

<223> single bond

<220>

<221> OTHER_SIGN

<222> (3)..(3)

<223> beta-(d)-Asp

<220>

<221> OTHER_SIGN

<222> (4)..(4)

<223> Dap or Dab

<220>

<221> OTHER_SIGN

<222> (5)..(5)

<223> Leu

<220>

<221> OTHER_SIGN

<222> (6)..(6)

<223> (N-Me)Glu or (N-Me)Ile

<220>

<221> OTHER_SIGN

<222> (7)..(7)

<223> beta-homoPro

<220>

<221> OTHER_SIGN

<222> (8)..(8)

<223> single bond

<220>

<221> OTHER_SIGN

<222> (9)..(9)

<223> -NH2

<400> 30

Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa

1 5

<210> 31

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<223> peptide chain [I'-28]: Compound No. 606

<220>

<221> OTHER_SIGN

<222> (1)..(1)

<223> single bond

<220>

<221> OTHER_SIGN

<222> (2)..(2)

<223> single bond

<220>

<221> OTHER_SIGN

<222> (3)..(3)

<223> gamma-(d)-Glu

<220>

<221> OTHER_SIGN

<222> (4)..(4)

<223> (2S,4S)-(4-amino)Pro

<220>

<221> OTHER_SIGN

<222> (5)..(5)

<223> Leu

<220>

<221> OTHER_SIGN

<222> (6)..(6)

<223>(N-Me)Glu

<220>

<221> OTHER_SIGN

<222> (7)..(7)

<223> Ape

<220>

<221> OTHER_SIGN

<222> (8)..(8)

<223> single bond

<220>

<221> OTHER_SIGN

<222> (9)..(9)

<223> -OH

<400> 31

Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa

1 5

<210> 32

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<223> peptide chain [I'-29]: Compound No. 607

<220>

<221> OTHER_SIGN

<222> (1)..(1)

<223> single bond

<220>

<221> OTHER_SIGN

<222> (2)..(2)

<223> single bond

<220>

<221> OTHER_SIGN

<222> (3)..(3)

<223> gamma-(d)-Glu

<220>

<221> OTHER_SIGN

<222> (4)..(4)

<223> (2S,4S)-(4-amino)Pro

<220>

<221> OTHER_SIGN

<222> (5)..(5)

<223> Leu

<220>

<221> OTHER_SIGN

<222> (6)..(6)

<223>(N-Me)Glu

<220>

<221> OTHER_SIGN

<222> (7)..(7)

<223> Ape

<220>

<221> OTHER_SIGN

<222> (8)..(8)

<223> single bond

<220>

<221> OTHER_SIGN

<222> (9)..(9)

<223> -OH

<400> 32

Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa

1 5

<210> 33

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<223> peptide chain [I'-30]: Compound No. 608

<220>

<221> OTHER_SIGN

<222> (1)..(1)

<223> single bond

<220>

<221> OTHER_SIGN

<222> (2)..(2)

<223> single bond

<220>

<221> OTHER_SIGN

<222> (3)..(3)

<223> gamma-(d)-Glu

<220>

<221> OTHER_SIGN

<222> (4)..(4)

<223> Dab

<220>

<221> OTHER_SIGN

<222> (5)..(5)

<223> Leu

<220>

<221> OTHER_SIGN

<222> (6)..(6)

<223> (N-Me)Ile

<220>

<221> OTHER_SIGN

<222> (7)..(7)

<223> beta-homoPro

<220>

<221> OTHER_SIGN

<222> (8)..(8)

<223> single bond

<220>

<221> OTHER_SIGN

<222> (9)..(9)

<223> -NH2

<400> 33

Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa

1 5

<210> 34

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<223> peptide chain [I'-31]: Compound No. 609

<220>

<221> OTHER_SIGN

<222> (1)..(1)

<223> single bond

<220>

<221> OTHER_SIGN

<222> (2)..(2)

<223> single bond

<220>

<221> OTHER_SIGN

<222> (3)..(3)

<223> gamma-(d)-Glu

<220>

<221> OTHER_SIGN

<222> (4)..(4)

<223> Dab

<220>

<221> OTHER_SIGN

<222> (5)..(5)

<223> Leu

<220>

<221> OTHER_SIGN

<222> (6)..(6)

<223>(N-Me)Glu

<220>

<221> OTHER_SIGN

<222> (7)..(7)

<223> Ape

<220>

<221> OTHER_SIGN

<222> (8)..(8)

<223> single bond

<220>

<221> OTHER_SIGN

<222> (9)..(9)

<223> -NH2

<400> 34

Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa

1 5

<210> 35

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<223> peptide chain [I'-32]: Compound No. 610-633

<220>

<221> OTHER_SIGN

<222> (1)..(1)

<223> single bond

<220>

<221> OTHER_SIGN

<222> (2)..(2)

<223> single bond

<220>

<221> OTHER_SIGN

<222> (3)..(3)

<223> beta-(d)-Asp or gamma-(d)-Glu

<220>

<221> OTHER_SIGN

<222> (4)..(4)

<223> Ala, Dap, Dab, Orn or (2S,4S)-(4-amino)Pro

<220>

<221> OTHER_SIGN

<222> (5)..(5)

<223> Ala(2-Pyr) or Leu

<220>

<221> OTHER_SIGN

<222> (6)..(6)

<223> Met, (N-Me)Ile or (N-Me)Glu

<220>

<221> OTHER_SIGN

<222> (7)..(7)

<223> Pro, beta-homoPro, Ape or single bond

<220>

<221> OTHER_SIGN

<222> (8)..(8)

<223> single bond

<220>

<221> OTHER_SIGN

<222> (9)..(9)

<223> -NH2

<400> 35

Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa

1 5

<210> 36

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<223> peptide chain [I'-32]: Compound No. 634-642

<220>

<221> OTHER_SIGN

<222> (1)..(1)

<223> single bond

<220>

<221> OTHER_SIGN

<222> (2)..(2)

<223> single bond

<220>

<221> OTHER_SIGN

<222> (3)..(3)

<223> beta-(d)-Asp

<220>

<221> OTHER_SIGN

<222> (4)..(4)

<223> Ala, Dap or Dab

<220>

<221> OTHER_SIGN

<222> (5)..(5)

<223> Leu

<220>

<221> OTHER_SIGN

<222> (6)..(6)

<223> (N-Me)Glu or (N-Me)Ile

<220>

<221> OTHER_SIGN

<222> (7)..(7)

<223> beta-homoPro

<220>

<221> OTHER_SIGN

<222> (8)..(8)

<223> single bond

<220>

<221> OTHER_SIGN

<222> (9)..(9)

<223> -NH2

<400> 36

Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa

1 5

<210> 37

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<223> peptide chain [I'-33]: Compound No. 643

<220>

<221> OTHER_SIGN

<222> (1)..(1)

<223> single bond

<220>

<221> OTHER_SIGN

<222> (2)..(2)

<223> single bond

<220>

<221> OTHER_SIGN

<222> (3)..(3)

<223> gamma-(d)-Glu

<220>

<221> OTHER_SIGN

<222> (4)..(4)

<223> (2S,4S)-(4-amino)Pro

<220>

<221> OTHER_SIGN

<222> (5)..(5)

<223> Leu

<220>

<221> OTHER_SIGN

<222> (6)..(6)

<223>(N-Me)Glu

<220>

<221> OTHER_SIGN

<222> (7)..(7)

<223> Ape

<220>

<221> OTHER_SIGN

<222> (8)..(8)

<223> single bond

<220>

<221> OTHER_SIGN

<222> (9)..(9)

<223> -OH

<400> 37

Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa

1 5

<210> 38

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<223> peptide chain [I'-34]: Compound No. 644-690

<220>

<221> OTHER_SIGN

<222> (1)..(1)

<223> single bond or Ape

<220>

<221> OTHER_SIGN

<222> (2)..(2)

<223> single bond or Glu

<220>

<221> OTHER_SIGN

<222> (3)..(3)

<223> beta-(d)-Asp, beta-Asp, gamma-Glu, gamma-(d)-Glu or Asp

<220>

<221> OTHER_SIGN

<222> (4)..(4)

<223> Dap, Dab or (2S,4S)-(4-amino)Pro

<220>

<221> OTHER_SIGN

<222> (5)..(5)

<223> Leu

<220>

<221> OTHER_SIGN

<222> (6)..(6)

<223> (N-Me)Glu, (N-Me)Ile or (N-Me)Val

<220>

<221> OTHER_SIGN

<222> (7)..(7)

<223> beta-homoPro or Ape

<220>

<221> OTHER_SIGN

<222> (8)..(8)

<223> single bond

<220>

<221> OTHER_SIGN

<222> (9)..(9)

<223> -NH2 or -OH

<400> 38

Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa

1 5

<210> 39

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<223> peptide chain [I'-34]: Compound No. 691-704

<220>

<221> OTHER_SIGN

<222> (1)..(1)

<223> single bond

<220>

<221> OTHER_SIGN

<222> (2)..(2)

<223> single bond

<220>

<221> OTHER_SIGN

<222> (3)..(3)

<223> beta-(d)-Asp or gamma-(d)-Glu

<220>

<221> OTHER_SIGN

<222> (4)..(4)

<223> Dap or Dab

<220>

<221> OTHER_SIGN

<222> (5)..(5)

<223> Leu

<220>

<221> OTHER_SIGN

<222> (6)..(6)

<223> (N-Me)Glu or (N-Me)Ile

<220>

<221> OTHER_SIGN

<222> (7)..(7)

<223> beta-homoPro

<220>

<221> OTHER_SIGN

<222> (8)..(8)

<223> single bond

<220>

<221> OTHER_SIGN

<222> (9)..(9)

<223> -NH2

<400> 39

Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa

1 5

<210> 40

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<223> peptide chain [I'-35]: Compound No. 705-791

<220>

<221> OTHER_SIGN

<222> (1)..(1)

<223> single bond

<220>

<221> OTHER_SIGN

<222> (2)..(2)

<223> single bond

<220>

<221> OTHER_SIGN

<222> (3)..(3)

<223> beta-(d)-Asp, gamma-(d)-Glu, or gamma-Glu

<220>

<221> OTHER_SIGN

<222> (4)..(4)

<223> Dap, Dab, Ala, (S)-piperazine or (2S,4S)-(4-amino)Pro

<220>

<221> OTHER_SIGN

<222> (5)..(5)

<223> Leu or Nle

<220>

<221> OTHER_SIGN

<222> (6)..(6)

<223> (N-Me)Glu, (N-Me)Ile, Lys(CO-(CH2)10-CO2H), Lys(CO-(CH2)12-CO2H),

Lys(CO-(CH2)14-CO2H), homoSer, (N-Me)Val, (N-Me)Leu or (N-Me)Asp

<220>

<221> OTHER_SIGN

<222> (7)..(7)

<223> beta-homoPro, single bond, Ala, Thr, Phe, Lys, beta-Ala, GABA,

Ape, Acp, beta-Dap, beta-(d)-Dap, gamma-Dab, gamma-(d)-Dab,

delta-Orn, epsilon-Lys, epsilon-(d)-Lys, (4)Abz, Pro or

delta-(d)-Orn

<220>

<221> OTHER_SIGN

<222> (8)..(8)

<223> single bond, (d)-Lys, (d)-Arg, (d)-Arg-(d)-Lys,

(d)-Arg-(d)-Arg, (d)-Lys-(d)-Arg or (d)-Lys-(d)-Lys

<220>

<221> OTHER_SIGN

<222> (9)..(9)

<223> NH2, NH-(CH2)2-NH2, NH-(CH2)3-NH2, NH-(CH2)4-NH2, NH-(CH2)5-NH2,

(4-Me)piperazin-1-yl, morpholin-4-yl, [VI-8], [VI-16], [VI-18] or

OH

<400> 40

Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa

1 5

<210> 41

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<223> peptide chain [I'-36]: Compound No. 792-890

<220>

<221> OTHER_SIGN

<222> (1)..(1)

<223> single bond

<220>

<221> OTHER_SIGN

<222> (2)..(2)

<223> single bond

<220>

<221> OTHER_SIGN

<222> (3)..(3)

<223> beta-(d)-Asp, gamma-(d)-Glu, or gamma-Glu

<220>

<221> OTHER_SIGN

<222> (4)..(4)

<223> Dap, Dab, (S)-piperazine, Pro or (2S,4S)-(4-amino)Pro

<220>

<221> OTHER_SIGN

<222> (5)..(5)

<223> Leu, Ala(cPropyl), Ala(4-Thz), Ile, Val or Tyr

<220>

<221> OTHER_SIGN

<222> (6)..(6)

<223> (N-Me)Glu, (N-Me)Ile, (N-Me)Val, (N-Me)Leu, single bond,

(N-Me)Ser, (N-Me)Tyr, (N-Me)Phe, (N-Me)Ala, (N-Me)Asp, (N-Me)Lys,

Gly, (d)-Arg, (d)-Pro, (d)-Ser, (d)-Tyr, (d)-Phe, (d)-Ala,

(d)-Thr, (N-Me)Arg, (d)-(N-Me)Glu or Glu

<220>

<221> OTHER_SIGN

<222> (7)..(7)

<223> beta-homoPro, Ape, Acp, gamma-Dab, beta-(d)-Dap, delta-Orn,

delta-(d)-Orn, epsilon-Lys, epsilon-(d)-Lys, Pro, beta-Ala, GABA,

beta-Dap, Aze(2), (d)-Aze(2), Aze(3), cis-NH(3)cPen,

single bond or (d)-Lys

<220>

<221> OTHER_SIGN

<222> (8)..(8)

<223> single bond, (d)-Lys, (d)-Arg, (d)-Arg-(d)-Lys,

(d)-Arg-(d)-Arg, (d)-Lys-(d)-Lys, (d)-Lys-(d)-Arg, Gly-(d)-Lys,

Gly-(d)-Arg, Gly-(d)-Arg-(d)-Arg, Gly-(d)-Lys-(d)-Arg,

beta-Ala-(d)-Lys, beta-Ala-(d)-Arg-(d)-Lys,

beta-Ala-(d)-Arg-(d)-Arg,

<220>

<221> OTHER_SIGN

<222> (8)..(8)

<223> beta-Ala-(d)-Lys-(d)-Arg, Gly-(d)-Arg-(d)-Lys,

Gly-(d)-Lys-(d)-Lys or Ape

<220>

<221> OTHER_SIGN

<222> (9)..(9)

<223> NH2, [VI-14] or OH

<400> 41

Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa

1 5

<210> 42

<211> 8

<212> PROTEIN

<213> Artificial sequence

<220>

<223> peptide chain [I'-37]: Compound No. 891-899

<220>

<221> OTHER_SIGN

<222> (1)..(1)

<223>GABA

<220>

<221> OTHER_SIGN

<222> (2)..(2)

<223> cross-linked to Lys at position 5 via Gly, GABA or

beta-Ala

<220>

<221> OTHER_SIGN

<222> (4)..(4)

<223> Ala or Dab

<220>

<221> OTHER_SIGN

<222> (6)..(6)

<223> (N-Me)Ile or (N-Me)Asp

<220>

<221> OTHER_SIGN

<222> (7)..(7)

<223> beta-homoPro or single bond

<220>

<221> OTHER_SIGN

<222> (8)..(8)

<223> -OH or -NH2

<400> 42

Xaa Glu Asp Xaa Lys Xaa Xaa Xaa

1 5

<210> 43

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<223> peptide chain [I'-38]: Compound No. 900-911

<220>

<221> OTHER_SIGN

<222> (1)..(1)

<223> gamma-Glu, Lys or (d)-Lys

<220>

<221> OTHER_SIGN

<222> (2)..(2)

<223> Adox, Lys, or (d)-Lys

<220>

<221> OTHER_SIGN

<222> (3)..(3)

<223> Adox, Lys, or (d)-Lys

<220>

<221> OTHER_SIGN

<222> (4)..(4)

<223> Lys or (d)-Lys

<220>

<221>MOD_RES

<222> (4)..(4)

<223>GABA

<220>

<221> OTHER_SIGN

<222> (5)..(5)

<223> Asp

<220>

<221> OTHER_SIGN

<222> (6)..(6)

<223> Ala or Dab

<220>

<221> OTHER_SIGN

<222> (7)..(7)

<223> Leu

<220>

<221> OTHER_SIGN

<222> (8)..(8)

<223> (N-Me)Ile or (N-Me)Glu

<220>

<221> OTHER_SIGN

<222> (9)..(9)

<223> beta-homoPro

<400> 43

Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa

1 5

<210> 44

<211> 11

<212> PROTEIN

<213> Artificial sequence

<220>

<223> peptide chain [I'-39]: Compound No. 912-955

<220>

<221> OTHER_SIGN

<222> (1)..(1)

<223> (d)-Lys, gamma-Glu, Lys, Arg, (d)-Arg, Adox or single bond

<220>

<221> OTHER_SIGN

<222> (2)..(2)

<223> (d)-Lys, Adox, single bond, Lys, Arg or (d)-Arg

<220>

<221> OTHER_SIGN

<222> (3)..(3)

<223> (d)-Lys, Adox, single bond, Lys, Arg, (d)-Arg or gamma-Glu

<220>

<221> OTHER_SIGN

<222> (4)..(4)

<223> Single bond or (d)-Lys

<220>

<221> OTHER_SIGN

<222> (5)..(5)

<223> Single bond or (d)-Lys

<220>

<221>MOD_RES

<222> (6)..(6)

<223> GABA or Ape

<220>

<221> OTHER_SIGN

<222> (7)..(7)

<223> Asp

<220>

<221> OTHER_SIGN

<222> (8)..(8)

<223> Dab

<220>

<221> OTHER_SIGN

<222> (9)..(9)

<223> Leu

<220>

<221> OTHER_SIGN

<222> (10)..(10)

<223> (N-Me)Ile, (N-Me)Asp or (N-Me)Glu

<220>

<221> OTHER_SIGN

<222> (11)..(11)

<223> beta-homoPro

<400> 44

Xaa Xaa Xaa Xaa Xaa Lys Xaa Xaa Xaa Xaa Xaa

1 5 10

<210> 45

<211> 12

<212> PROTEIN

<213> Artificial sequence

<220>

<223> peptide chain [I'-40]: Compound No. 956-972

<220>

<221> OTHER_SIGN

<222> (1)..(1)

<223> Ape

<220>

<221> OTHER_SIGN

<222> (4)..(4)

<223> Dab

<220>

<221> OTHER_SIGN

<222> (6)..(6)

<223> (N-Me)Ile or (N-Me)Glu

<220>

<221> OTHER_SIGN

<222> (7)..(7)

<223> beta-homoPro

<220>

<221> OTHER_SIGN

<222> (8)..(8)

<223> (d)-Lys or single bond

<220>

<221> OTHER_SIGN

<222> (9)..(9)

<223> (d)-Lys or single bond

<220>

<221> OTHER_SIGN

<222> (10)..(10)

<223> Lys or (d)-Lys

<220>

<221>MOD_RES

<222> (10)..(10)

<223> (d)-Lys or single bond

<220>

<221> OTHER_SIGN

<222> (11)..(11)

<223> (d)-Lys or single bond

<220>

<221> OTHER_SIGN

<222> (12)..(12)

<223> (d)-Lys or single bond

<400> 45

Xaa Glu Asp Xaa Leu Xaa Xaa Xaa Xaa Xaa Xaa Xaa

1 5 10

<210> 46

<211> 10

<212> PROTEIN

<213> Artificial sequence

<220>

<223> the peptide chain [I'] specified in paragraph 1

<220>

<221> OTHER_SIGN

<222> (1)..(1)

<223> L(N1):-C(=O)- or -S(=O)2-

<220>

<221> OTHER_SIGN

<222> (2)..(2)

<223> W(1):L1 or L1'-L1''; L1 is a single bond, and

L1' is a single bond, beta-Ala, GABA,

(N-Me)GABA, Ape, Acp, [III-6], [III-7], [III-8], [III-9],

[III-10], [III-11], [III-12], [III-13], [IV-23] or [IV-24]

<220>

<221> OTHER_SIGN

<222> (2)..(2)

<223> W(1):L1 or L1'-L1''; L1'' represents a single bond,

Gly, (N-Me)Gly, Ala, (N-Me)Ala, (d)-Ala, Val, (N-Me)Val,

(N-Me)Leu, (N-Me)Ile, [IV-27], Pro, (d)-Pro, homoPro, Phe,

(N-Me)Phe, (d)-Phe, His, (d)-His, Trp, (N-Me)Trp, (d)-Trp, Tyr,

(N-Me)Tyr, (d)-Tyr,

<220>

<221> OTHER_SIGN

<222> (2)..(2)

<223> W(1):L1 or L1'-L1''; L1'' is Thr, (N-Me)Thr,

(d)-Thr, Cys, (d)-Cys, Met, (N-Me)Met, (N-Me)Asp, Glu, (N-Me)Glu,

(d)-Glu, Asn, (N-Me)Asn, (d)-Asn, Gln, (N-Me)Gln, (d)-Gln, Arg,

(N-Me)Arg, (d)-Arg, Cit, (d)-Cit, [IV-7], [IV-9], [IV-10],

[IV-13], Lys,

<220>

<221> OTHER_SIGN

<222> (2)..(2)

<223> W(1):L1 or L1'-L1''; L1'' is (N-Me)Lys, (d)-Lys,

[IV-14], beta-Ala、beta-Asp、beta-(d)-Asp, [III-6], [III-7],

(d)-Ser or homoSer

<220>

<221> OTHER_SIGN

<222> (3)..(3)

<223> AA1: Asp, beta-Asp, beta-(d)-Asp, gamma-Glu, or gamma-(d)-Glu

<220>

<221> OTHER_SIGN

<222> (4)..(4)

<223> L2: Single Link

<220>

<221> OTHER_SIGN

<222> (5)..(5)

<223> AA2: Ala, [IV-7], [IV-8], [IV-9], [IV-11], [IV-12], [IV-13],

[IV-27], Pro, [II-1] or [II-2]

<220>

<221> OTHER_SIGN

<222> (6)..(6)

<223>AA3: Val, Leu, Ile, [IV-2], Phe, Trp, Tyr, Lys, [IV-3], [IV-4],

[IV-5] or [IV-9]

<220>

<221> OTHER_SIGN

<222> (7)..(7)

<223> AA4: Single bond, Gly, (d)-Ala, (N-Me)Ala, (N-Me)Val,

(N-Me)Leu, (N-Me)Ile, Pro, (d)-Pro, (N-Me)Phe, (d)-Phe, (N-Me)Tyr,

(d)-Tyr, (N-Me)Ser, (d)-Ser, homoSer, (d)-Thr, Met, (N-Me)Met,

(N-Me)Asp, Glu, (N-Me)Glu, (d)-(N-Me)Glu, homoGlu, (N-Me)Asn,

<220>

<221> OTHER_SIGN

<222> (7)..(7)

<223> AA4: ... (N-Me)Arg, (d)-Arg, [IV-7], [IV-9], [IV-13], Lys or

(N-Me)Lys

<220>

<221> OTHER_SIGN

<222> (8)..(8)

<223> AA5: Single bond, Ala, [IV-1], [IV-27], [IV-28], [IV-29], Pro,

(d)-Pro, beta-homoPro, homoPro, [II-1'], Phe, His, Thr, Arg,

(d)-Arg, [IV-7], [IV-9], [IV-13], Lys, (d)-Lys, beta-Ala,

(N-Me)-beta-Ala, GABA, Ape, Acp, [III-6], [III-7], [III-8],

<220>

<221> OTHER_SIGN

<222> (8)..(8)

<223> AA5: ...[III-9], [III-10], [III-11], [III-12], [III-13], [IV-25]

or[IV-26]

<220>

<221> OTHER_SIGN

<222> (9)..(9)

<223> Wc: single bond or linker consisting of 1 to 3 amino acids,

where 1 - 3 amino acids may be the same or different, and

selected from the group consisting of Gly, Pro,

Arg, (d)-Arg, Lys, (d)-Lys, beta-Ala, GABA and Ape

<220>

<221> OTHER_SIGN

<222> (10)..(10)

<223> Rc: -OH, -NH2, C1-6 alkylamino or 4-7 member saturated

heterocyclyl containing one nitrogen and optionally one

heteroatom.

<400> 46

Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa

1 5 10

<210> 47

<211> 10

<212> PROTEIN

<213> Artificial sequence

<220>

<223> the peptide chain [I] specified in paragraph 8

<220>

<221> OTHER_SIGN

<222> (1)..(1)

<223> L(N1):-C(=O)- or -S(=O)2-

<220>

<221> OTHER_SIGN

<222> (2)..(2)

<223> L1: Single Link

<220>

<221> OTHER_SIGN

<222> (3)..(3)

<223> AA1: beta-Asp, gamma-Glu or gamma-(d)-Glu

<220>

<221> OTHER_SIGN

<222> (4)..(4)

<223> L2: Single Link

<220>

<221> OTHER_SIGN

<222> (5)..(5)

<223>AA2: [II-1] or [II-2]

<220>

<221> OTHER_SIGN

<222> (6)..(6)

<223>AA3: Val, Leu, Ile, Phe or Trp

<220>

<221> OTHER_SIGN

<222> (7)..(7)

<223> AA4: Single bond, Pro, (N-Me)Ala, (N-Me)Val, (N-Me)Leu,

(N-Me)Ile, (N-Me)Phe, (N-Me)Tyr, (N-Me)Ser, (N-Me)Asp or

(N-Me)Glu

<220>

<221> OTHER_SIGN

<222> (8)..(8)

<223> AA5: Single bond, Pro, (d)-Pro, beta-homoPro, Arg, (d)-Arg,

Lys, (d)-Lys, beta-Ala, GABA, Ape or Acp

<220>

<221> OTHER_SIGN

<222> (9)..(9)

<223> Lc: single bond, Pro, Arg, (d)-Arg, Lys, (d)-Lys or (d)

-Lys-(d) -Lys

<220>

<221> OTHER_SIGN

<222> (10)..(10)

<223> Rc: -OH or -NH2

<400> 47

Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa

1 5 10

<---

Claims (35)

1. A substituted polypeptide represented by the formula [I'-B]: or a pharmaceutically acceptable salt thereof, Where AA ¹ is β-(d)-Asp or γ-(d)-Glu; AA ² is a group represented by the formula [II-1]: or a group represented by formula [IV-7] or [IV-9]: where R ^AA2 is amino, AA ³ represents Val, Leu or Ile, AA ⁴ is (N-Me)Ile or (N-Me)Glu, AA ⁵ is β-Ala, GABA, Ape, Acp or β-homoPro, L ^N1 is the formula -C(=O)- or the formula -S(=O) ₂ -, L ^N2 is the formula -O- or the formula -C(=O)-NH-, R ^B1 represents carbamoyl, chlorine atom, bromine atom, methoxy or trifluoromethoxy, R ^B2 represents a hydrogen atom, R ^B3 represents a hydrogen atom, represents a hydrogen atom, W ^C represents a single bond or (d)-Lys, and R ^C represents the formula -NH ₂ . 2. A substituted polypeptide or a pharmaceutically acceptable salt thereof according to claim 1, wherein the substituted polypeptide is selected from the compounds shown in the following: , , , , , , , , , 3. A pharmaceutical preparation having MMP2 inhibitory activity, containing a substituted polypeptide or a pharmaceutically acceptable salt thereof according to claim 1 or 2 as an active ingredient. 4. An MMP2 inhibitor comprising a substituted polypeptide or a pharmaceutically acceptable salt thereof according to claim 1 or 2 as an active ingredient. 5. A medicinal product having MMP2 inhibitory activity for the prevention or treatment of cancer or organ fibrosis, or a symptom associated with cancer or organ fibrosis, containing a substituted polypeptide or a pharmaceutically acceptable salt thereof according to claim 1 or 2 as an active ingredient.