Pharmaceutical compositions comprising cyclic compounds having selective KRAS inhibitory against hras and nras

Abstract

The present disclosure provides a pharmaceutical composition for treating or preventing, for example, a cell proliferative disease, the pharmaceutical composition comprising, as an active ingredient, a cyclic compound that selectively inhibits KRAS.

Description

Technical Field

[0001] In one aspect, the present invention relates to a pharmaceutical composition comprising a cyclic compound that selectively inhibits KRAS relative to HRAS and NRAS. In one aspect, the present invention relates to a pharmaceutical composition comprising a cyclic compound as an active ingredient for treating or preventing cell proliferative diseases (especially cancer). Background Art

[0002] RAS is a protein belonging to the small GTPase family, and KRAS, NRAS, and HRAS are known. RAS is in an active state or an inactive state depending on whether it binds to GTP or GDP. It is activated by an exchange reaction from GDP to GTP carried out by GEF (guanine nucleotide exchange factor) and inactivated by a hydrolysis reaction of GTP carried out by GAP (GTPase-activating protein) (NPL1). Activated RAS induces cell proliferation, survival, and differentiation by activating multiple downstream signals in the MAPK pathway, PI3K / Akt pathway, RAL pathway, etc., and constitutive activation of RAS plays an important role in the development and progression of cancer. In cancer, it is known that the RAS-RAF-MEK-ERK pathway is activated by activation of upstream signals of RAS, constitutive activation of RAS, and / or activating mutations of RAS (NPL 2). These activating mutations of RAS have been found in various cancer types. G12, G13, and Q61 are considered to be hotspots for RAS mutations, and G12 is frequently found mutated in KRAS, and Q61 is frequently found mutated in NRAS. It is also known that these mutations are associated with the prognosis of patients (NPL 3).

[0003] Meanwhile, when it comes to approaching intractable targets represented by inhibiting protein-protein interactions, medium-sized molecules (molecular weight of 500 to 2000 g / mol) may be superior to low molecular weight compounds. In addition, medium-sized molecules may be superior to antibodies because they can migrate into cells. Among medium-sized molecules with biological activity, peptide drugs are a very valuable molecular species, and more than 40 peptide drugs are commercially available (NPL 4). Representative examples of such peptide drugs include cyclosporin A and polymyxin B, which are peptides containing some non-natural amino acids. Non-natural amino acids refer to amino acids that are not naturally encoded on mRNA. Very interestingly, naturally occurring cyclosporin A and polymyxin B contain non-natural amino acids.

[0004] Since the discovery of the pharmaceutical uses of naturally occurring peptides, peptides with pharmacological activity and bioabsorbability have attracted attention, and those peptides with a molecular weight of about 500 to 2000 g / mol have been actively studied (NPL 5).

[0005] There are reports on conditions under which medium molecular weight peptides have increased membrane permeability and metabolic stability, which may contribute to improving their biokinetics (conditions required for drug-likeness) (PTL 1).

[0006] In addition, for conditions that may contribute to improving the biokinetics of medium molecular weight peptides, cyclic peptides have been shown to meet the conditions required for drug-likeness (PTL 2).

[0007] Peptides that bind to RAS have been discovered, and the binding sites between cyclic peptides and RAS have been studied by X-ray structural analysis (NPL 6, NPL 7, and NPL 8). In addition, cyclic peptides that significantly inhibit the binding between RAS and SOS have been discovered (PTL 3). Furthermore, competitive assays for binding to RAS have shown that some cyclic peptides inhibit the binding between a specific compound and RAS (PTL 4).

[0008] Citation List

[0009] Patent Document

[0010] [PTL 1]WO 2013 / 100132

[0011] [PTL 2]WO 2018 / 225864

[0012] [PTL 3]WO2012 / 122059

[0013] [PTL 4]WO 2017 / 181061

[0014] Non-Patent Document

[0015] [NPL 1]Nat.Rev.Drug Discov. November 2014; 13(11): 828-851.

[0016] [NPL 2]Nat.Rev.Dmg Discov. December 2014; 13(12): 928-942.

[0017] [NPL 3]Nat.Rev.Drug Discov. November 2016; 15(11): 771-785.

[0018] [NPL 4]Future Med.Chem. 2009, 1, 1289-1310.

[0019] [NPL 5]Current Topics in Medicinal Chemistry, 2013, Vol. 13, No. 7, 821-836.

[0020] [NPL 6]Biochem. Biophys. Res. Commun. 2017, 484, 605-611.

[0021] [NPL 7]Bioorg. Med. Chem. Lett. 2017, 27, 2757-2761.

[0022] [NPL 8]ACS Med. Chem. Lett. 2017, 8, 732-736.. Summary of the Invention

[0023] Technical Problem

[0024] The present invention relates to a pharmaceutical composition comprising a cyclic compound effective against cancers with RAS mutations, and unnatural amino acids and peptide compounds useful for the production of the cyclic compound.

[0025] PTL 1 and PTL 2 describe drug-like peptides, but do not describe peptides having antitumor effects against cancers including cancers with RAS mutations.

[0026] PTL 3 describes inhibition of the binding between RAS and SOS, and PTL 4 describes peptides that compete with compounds binding to RAS. However, none of these documents show any pharmacological effects, especially effects on tumor cells. These documents also do not describe drug-like peptides.

[0027] NPL 1 shows in detail the relationship between RAS and cancer. This document describes molecules that bind to RAS. Although their efficacy has been shown in preclinical studies, no compounds effective as drugs specifically against cancers with RAS mutations have been shown. Moreover, no drug-like cyclic peptides have been disclosed.

[0028] NPL 2 provides a detailed description of RAS and the RAF-MEK-ERK pathway downstream of RAS. Although this document proposes the possibility of treating cancers with RAS mutations with RAF, MEK, and ERK inhibitors, it does not show any compounds that directly inhibit RAS.

[0029] NPL 3 describes compounds that bind to the GTP / GDP binding site of RAS and inhibit the function of RAS and their mechanisms. This document describes in detail the interaction with the GTP / GDP binding site, but does not show pharmacological effects, especially pharmacological effects on tumor cells.

[0030] NPL 4 describes peptides used as drugs, but does not describe drug-like peptides or peptides useful for cancers with RAS mutations.

[0031] NPL 5 describes the molecular form and pharmacokinetics of cyclic peptides, but does not describe compounds useful for cancers with RAS mutations.

[0032] NPL 6 to 8 describe peptides that bind to RAS, but their effects on tumor cells are limited and, moreover, do not describe drug-like peptides.

[0033] Furthermore, to the best knowledge of the present inventors, there is no report on compounds having sufficient selective inhibitory effects on KRAS relative to HRAS and NRAS.

[0034] Solution to the Problem

[0035] As a result of dedicated research to find cyclic compounds having selective inhibitory effects on KRAS relative to HRAS and NRAS, the present inventors have found cyclic compounds and oligopeptide compounds that selectively interact with KRAS as compared with HRRAS and NRAS. Furthermore, the present inventors have found specific unnatural amino acids and specific oligopeptide compounds important for the production of the cyclic compounds, and a method for producing the cyclic compounds. Furthermore, the present inventors have found that the cyclic compounds have a pharmacological effect of inhibiting the growth of tumor cells having RAS mutations.

[0036] In one specific non-limiting embodiment, the present invention encompasses the following:

[0037] [1] A pharmaceutical composition comprising a cyclic compound represented by the following formula (1) or a salt thereof, or a solvate thereof:

[0038]

[0039] Wherein

[0040] L1 is a single bond, or is -CHM1-, -(CH2) n S(CH2) m -, -(CH2) n S(O)(CH2) m - or -(CH2) n S(O)2(CH2) m -, where n and m are each independently 1 or 2,

[0041] R1 is any one of the following (a1) to (a6):

[0042] (a1) R1 is hydrogen, C1-C7 alkyl, C2-C7 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy C1-C6 alkyl, C2-C6 alkenyloxy C1-C6 alkyl, C1-C6 alkylthio C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl C1-C6 alkyl, C3-C8 cycloalkoxy C1-C6 alkyl, C7-C 14 aralkyl or 5- to 10-membered heteroaryl C1-C6 alkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of: halogen, hydroxy, cyano, C1-C6 alkyl, aminocarbonyl (wherein the amino group is -NH2, mono-C1-C6 alkylamino, di-C1-C6 alkylamino or 4- to 8-membered cyclic amino), and C1-C6 alkylsulfonyl;

[0043] (a2) R1, together with P1, the carbon atom to which R1 is bonded, and the nitrogen atom to which P1 is bonded, forms a 4- to 7-membered saturated heterocycle;

[0044] (a3) R1, together with Q1 and the carbon atoms to which R1 and Q1 are bonded, forms a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocycle;

[0045] (a4) R1, together with M1, the carbon atom to which R1 is bonded, and the carbon atom to which M1 is bonded, forms a 3- to 8-membered alicyclic ring;

[0046] (a5) R1 and R5 together form a divalent group selected from the group consisting of: C1-C 10 alkylene, C2-C 10 alkenylene, C2-C 10 alkynylene, C3-C8 cycloalkylene, C6-C 10 arylene, -CO-NR A -, -NR A -CO-, and combinations of two or more of these, wherein one or more carbon atoms forming the divalent group are optionally substituted with one or more heteroatoms independently selected from the group consisting of N, O, and S, the divalent group is optionally substituted with one or more groups independently selected from the group consisting of halogen and C1-C6 alkyl, and RA is hydrogen or C1-C6 alkyl; or

[0047] (a6) R1 and R9 together form a divalent group selected from the group consisting of: C1-C 10 alkylene, C2-C 10 alkenylene, C2-C 10 alkynylene, C3-C8 cycloalkylene, C6-C 10 arylene, -CO-NR B -, -NR B-CO- and combinations of two or more of these moieties, wherein one or more carbon atoms forming said divalent group are optionally substituted with one or more heteroatoms independently selected from the group consisting of N, O, and S, said divalent group is optionally substituted with one or more groups independently selected from the group consisting of halogen and C1-C6 alkyl, and R B is hydrogen or C1-C6 alkyl;

[0048] Except when R1 and P1 form a 4- to 7-membered saturated heterocycle, P1 is hydrogen or C 1- C6 alkyl, wherein said C1-C6 alkyl is optionally substituted with one or more groups independently selected from the group consisting of: halogen, hydroxy, C1-C6 alkoxy, and aminocarbonyl (wherein said amino is -NH2, mono-C1-C6 alkylamino, di-C1-C6 alkylamino, or 4- to 8-membered cyclic amino),

[0049] Except when R1 and Q1 form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocycle, Q1 is hydrogen or C1-C6 alkyl, and

[0050] Except when R1 and M1 form a 3- to 8-membered alicyclic ring, M1 is hydrogen or C1-C6 alkyl,

[0051] R2 is any one of the following (b1) to (b4):

[0052] (b1) R2 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl C1-C6 alkyl, C3-C8 cycloalkoxy C1-C6 alkyl, or 4- to 7-membered heterocyclic group, each of which is optionally substituted with one or more groups independently selected from the group consisting of: halogen, hydroxy, cyano, and C1-C6 alkylsulfonyl;

[0053] (b2) R2, together with P2, the carbon atom to which R2 is bonded, and the nitrogen atom to which P2 is bonded, forms a 4- to 7-membered saturated heterocycle;

[0054] (b3) R2, together with Q2 and the carbon atoms to which R2 and Q2 are bonded, forms a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocycle; or

[0055] (b4) R2, together with R 11 forms a divalent group selected from the group consisting of: C1-C 10 alkylene, C2-C 10 alkenylene, C2-C 10 alkynylene, C3-C8 cycloalkylene, C6-C 10 arylene, -CO-NR C-, -NR C -CO-, -C3-C8 alkylene-NRc-, -C3-C8 alkenylene-NR C - and combinations of two or more of these terms, wherein one or more carbon atoms constituting the divalent group are optionally substituted with one or more heteroatoms independently selected from the group consisting of N, O and S, and the divalent group is optionally substituted with one or more groups independently selected from the group consisting of halogen and C1-C6 alkyl, and R C is hydrogen or C1-C6 alkyl;

[0056] Except when R2 and P2 form a 4- to 7-membered saturated heterocycle, P2 is hydrogen or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with one or more groups independently selected from the group consisting of: halogen, hydroxy, C1-C6 alkoxy and aminocarbonyl (wherein the amino group is -NH2, mono-C1-C6 alkylamino, di-C1-C6 alkylamino or 4- to 8-membered cyclic amino);

[0057] Except when R2 and Q2 form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocycle, Q2 is hydrogen or C1-C6 alkyl,

[0058] R3 is any one of the following (c1) to (c3):

[0059] (c1) R3 is hydrogen, C1-C6 alkyl, C1-C6 alkoxy C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl C1-C6 alkyl, C3-C8 cycloalkoxy C1-C6 alkyl or C7-C 14 arylalkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of: hydroxy and aminocarbonyl (wherein the amino group is -NH2, mono-C1-C6 alkylamino, di-C1-C6 alkylamino or 4- to 8-membered cyclic amino);

[0060] (c2) R3, together with P3, the carbon atom to which R3 is bonded, and the nitrogen atom to which P3 is bonded, forms a 4- to 7-membered saturated heterocycle, wherein the 4- to 7-membered saturated heterocycle is optionally substituted with one or more groups selected from the group consisting of C1-C6 alkyl and C1-C6 alkoxy; or

[0061] (c3) R3, together with Q3 and the carbon atom to which R3 and Q3 are bonded, forms a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocycle;

[0062] Except when R3 and P3 form a 4- to 7-membered saturated heterocycle, P3 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy C1-C6 alkyl, or C3-C8 cycloalkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, cyano, C1-C6 alkoxy, and C1-C6 aminoalkyl (wherein the amino is -NH2, mono-C1-C6 alkylamino, di-C1-C6 alkylamino, or 4- to 8-membered cyclic amino, and the 4- to 8-membered cyclic amino is optionally substituted with one or more halogen atoms),

[0063] Except when R3 and Q3 form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocycle, Q3 is hydrogen or C1-C6 alkyl,

[0064] R4 is any one of the following (d1) to (d4):

[0065] (d1) R4 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy C1-C6 alkyl, C2-C6 alkenoxy C1-C6 alkyl, or C1-C6 carboxyalkyl, each of which is optionally substituted with one or more hydroxy groups;

[0066] (d2) R4, together with P4, the carbon atom to which R4 is bonded, and the nitrogen atom to which P4 is bonded, forms a 4- to 7-membered saturated heterocycle, wherein the 4- to 7-membered saturated heterocycle is optionally substituted with one or more C1-C6 alkyl groups;

[0067] (d3) R4, together with Q4 and the carbon atoms to which R4 and Q4 are bonded, forms a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocycle; or

[0068] (d4) R4, together with P5, forms a divalent group selected from the group consisting of C1-C 10 alkylene, C2-C 10 alkenylene, C2-C 10 alkynylene, C3-C8 cycloalkylene, 3- to 7-membered heteroalkylene, C6-C 10 arylene, -CO-NR D -, -NR D -CO-, and combinations of two or more of these, wherein one or more carbon atoms constituting the divalent group are optionally substituted with one or more heteroatoms independently selected from the group consisting of N, O, and S, the divalent group is optionally substituted with one or more groups independently selected from the group consisting of halogen and C1-C6 alkyl, and R D is hydrogen or C1-C6 alkyl;

[0069] Except when R4 and P4 form a 4- to 7-membered saturated heterocycle, P4 is any one of the following (e1) to (e2):

[0070] (e1) P4 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, or C1-C6 alkoxy C1-C6 alkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of: halogen, hydroxy, C1-C6 alkoxy, and aminocarbonyl (wherein the amino group is -NH2, mono-C1-C6 alkylamino, di-C1-C6 alkylamino, or 4- to 8-membered cyclic amino); or

[0071] (e2) P4 together with P5 forms a divalent group selected from the group consisting of: C1-C 10 alkylene, C2-C 10 alkenylene, C2-C 10 alkynylene, C3-C8 cycloalkylene, C6-C 10 arylene, -CO-NR E -, -NR E -CO-, and combinations of two or more of these, wherein one or more carbon atoms forming the divalent group are optionally substituted with one or more heteroatoms independently selected from the group consisting of N, O, and S, the divalent group is optionally substituted with one or more groups independently selected from the group consisting of halogen and C1-C6 alkyl, and R E is hydrogen or C1-C6 alkyl;

[0072] Except when R4 and Q4 form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocycle, Q4 is hydrogen or C1-C6 alkyl,

[0073] Except when R1 and R5 form a divalent group, R5 is any one of the following (f1) to (f4):

[0074] (f1) R5 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkenyloxycarbonyl C1-C6 alkyl, C2-C6 alkynyl, C1-C6 alkoxy C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl C1-C6 alkyl, C3-C8 cycloalkoxy C1-C6 alkyl, C7-C 14 aralkyl, C6-C 10 aryloxy C1-C6 alkyl, C7-C 14an aralkyloxy C1-C6 alkyl or a 5- to 10-membered heteroaryl C1-C6 alkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of: halogen, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C1-C6 haloalkoxy, cyano, C1-C6 alkylsulfonyl, C2-C6 alkenyl, C3-C8 cycloalkyl and C1-C6 alkylcarbonyl; or

[0075] (f2) R5 and R8 together form a C4-C8 alkylene;

[0076] (f3) R5, together with P5, the carbon atom to which R5 is bonded, and the nitrogen atom to which P5 is bonded, forms a 4- to 7-membered saturated heterocycle; or

[0077] (f4) R5, together with Q5 and the carbon atom to which R5 and Q5 are bonded, forms a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocycle;

[0078] Except when R5 and P5 form a 4- to 7-membered saturated heterocycle, except when R4 and P5 form a divalent group, and except when P4 and P5 form a divalent group, P5 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy C1-C6 alkyl or C3-C8 cycloalkyl C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with one or more groups independently selected from the group consisting of: halogen, hydroxy, C1-C6 alkoxy, aminocarbonyl (wherein the amino group is -NH2, mono-C1-C6 alkylamino, di-C1-C6 alkylamino or a 4- to 8-membered cyclic amino group) and amino,

[0079] Except when R5 and Q5 form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocycle, Q5 is hydrogen or C1-C6 alkyl,

[0080] R6 is any one of the following (g1) to (g3):

[0081] (g1) R6 is hydrogen or C1-C6 alkyl;

[0082] (g2) R6, together with P6, the carbon atom to which R6 is bonded, and the nitrogen atom to which P6 is bonded, forms a 4- to 7-membered saturated heterocycle; or

[0083] (g3) R6, together with Q6 and the carbon atom to which R6 and Q6 are bonded, forms a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocycle;

[0084] Except when R6 and P6 form a 4- to 7-membered saturated heterocycle, P6 is C1-C6 alkyl or C3-C8 cycloalkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of: halogen, hydroxy, C1-C6 alkoxy, and aminocarbonyl (wherein the amino group is -NH2, mono-C1-C6 alkylamino, di-C1-C6 alkylamino, or 4- to 8-membered cyclic amino),

[0085] Except when R6 and Q6 form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocycle, Q6 is hydrogen or C1-C6 alkyl,

[0086] R7 is any one of the following (h1) to (h3):

[0087] (h1) R7 is C6-C 10 aryloxy C1-C6 alkyl, C7-C 14 arylalkyl, C7-C 14 arylalkoxy C1-C6 alkyl, or 5- to 10-membered heteroaryl C1-C6 alkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of: halogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkoxy, cyano, C1-C6 alkylsulfonyl, SF5, and C3-C8 cycloalkyl;

[0088] (h2) R7, together with P7, the carbon atom to which R7 is bonded, and the nitrogen atom to which P7 is bonded, forms a 4- to 7-membered saturated heterocycle; or

[0089] (h3) R7, together with Q7 and the carbon atom to which R7 and Q7 are bonded, forms a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocycle;

[0090] Except when R7 and P7 form a 4- to 7-membered saturated heterocycle, P7 is hydrogen or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with one or more groups independently selected from the group consisting of: halogen, hydroxy, C1-C6 alkoxy, and aminocarbonyl (wherein the amino group is -NH2, mono-C1-C6 alkylamino, di-C1-C6 alkylamino, or 4- to 8-membered cyclic amino),

[0091] Except when R7 and Q7 form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocycle, Q7 is hydrogen or C1-C6 alkyl,

[0092] Except when R5 and R8 form a C4-C8 alkylene, R8 is any one of the following (i1) to (i3):

[0093] (i1) R8 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy C1-C6 alkyl, C2-C6 alkenyloxycarbonyl C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl C1-C6 alkyl, C6-C 10 aryloxy C1-C6 alkyl, C7-C 14 aralkyl, C7-C 14 aralkoxy C1-C6 alkyl, 5- to 10-membered heteroaryl C1-C6 alkyl or 5- to 10-membered heteroaryloxy C1-C6 alkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, carboxy, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkoxy, cyano, aminocarbonyl (wherein the amino is -NH2, mono-C1-C6 alkylamino, di-C1-C6 alkylamino or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), 4- to 7-membered heterocycloalkyl, protected 4- to 7-membered heterocycloalkyl, 4- to 7-membered heterocyclic group and protected 4- to 7-membered heterocyclic group;

[0094] (i2) R8, together with P8, the carbon atom to which R8 is bonded, and the nitrogen atom to which P8 is bonded, forms a 4- to 7-membered saturated heterocycle, wherein the 4- to 7-membered saturated heterocycle is optionally fused to a saturated carbocyclic ring or an aromatic ring, and the 4- to 7-membered saturated heterocycle is optionally substituted with one or more halogen atoms, oxo, one or more C1-C6 alkyl groups, C1-C6 haloalkyl, C3-C8 spirocycloalkyl, C6-C 10 aryl, 5- to 10-membered heteroaryl, 4- to 8-membered cyclic amino (wherein the cyclic amino is optionally substituted with one or more halogen atoms) or OS8, and S8 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C3-C8 cycloalkyl C1-C6 alkyl, 4- to 7-membered heterocyclic group, C7-C 14 aralkyl (wherein the aralkyl is optionally substituted with one or more halogen atoms, C1-C6 alkyl, C1-C6 alkoxy or C1-C6 haloalkoxy), 5- to 10-membered heteroaryl C1-C6 alkyl or C3-C8 cycloalkyl; or

[0095] (i3) R8, together with Q8 and the carbon atoms to which R8 and Q8 are bonded, forms a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocycle;

[0096] Unless R8 and P8 form a 4- to 7-membered saturated heterocycle, P8 is hydrogen, C1-C6 alkyl, C1-C6 alkoxy C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy C2-C6 alkenyl, C3-C8 cycloalkyl, 4- to 7-membered heterocyclic group, 4- to 7-membered heterocyclic group C1-C6 alkyl, C6-C 10 aryl, C7-C 14 aralkyl, 5- to 10-membered heteroaryl or 5- to 10-membered heteroaryl C1-C6 alkyl, each of which is optionally substituted by one or more groups independently selected from the group consisting of: halogen, hydroxy, C1-C6 alkoxy and aminocarbonyl (wherein the amino group is -NH2, mono-C1-C6 alkylamino, di-C1-C6 alkylamino or 4- to 8-membered cyclic amino),

[0097] Unless R8 and Q8 form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocycle, Q8 is hydrogen or C1-C6 alkyl,

[0098] M9 is -N(P9)- or an oxygen atom;

[0099] Unless R1 and R9 form a divalent group, R9 is any one of the following (j1) to (j3):

[0100] (j1) R9 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy C1-C6 alkyl, C2-C6 alkenoxy C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl C1-C6 alkyl, C7-C 14 aralkyl or 5- to 10-membered heteroaryl C1-C6 alkoxy C1-C6 alkyl, each of which is optionally substituted by one or more groups independently selected from the group consisting of: halogen, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, aminocarbonyl (wherein the amino group is -NH2, mono-C1-C6 alkylamino, di-C1-C6 alkylamino or 4- to 8-membered cyclic amino) and C1-C6 alkylsulfonyl;

[0101] (j2) R9, together with P9, the carbon atom to which R9 is bonded and the nitrogen atom to which P9 is bonded, forms a 4- to 7-membered saturated heterocycle; or

[0102] (j3) R9, together with Q9 and the carbon atom to which R9 and Q9 are bonded, forms a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocycle, each of which is optionally substituted by one or more halogen atoms or one or more C1-C6 alkyl groups;

[0103] Except when R9 and P9 form a 4- to 7-membered saturated heterocycle, P9 is hydrogen or C1-C6 alkyl, wherein said C1-C6 alkyl is optionally substituted with one or more groups independently selected from the group consisting of: halogen, hydroxy, C1-C6 alkoxy, and aminocarbonyl (wherein said amino is -NH2, mono-C 1- C6 alkylamino, di-C1-C6 alkylamino, or 4- to 8-membered cyclic amino),

[0104] Except when R9 and Q9 form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocycle, Q9 is hydrogen or C1-C6 alkyl,

[0105] R 10 is any one of the following (k1) to (k3):

[0106] (k1) R 10 is C1-C6 alkyl, C2-C6 alkynyl, C1-C6 alkoxy C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl C1-C6 alkyl, C3-C8 cycloalkoxy C1-C6 alkyl, or C7-C 14 arylalkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of: halogen, hydroxy, and C1-C6 alkylsulfonyl;

[0107] (k2) R 10 together with the carbon atom to which P 10 , R 10 is bonded and the nitrogen atom to which P 10 is bonded forms a 4- to 7-membered saturated heterocycle; or

[0108] (k3) R 10 together with Q 10 and the carbon atoms to which R 10 and Q 10 are bonded forms a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocycle;

[0109] Except when R 10 and P 10 form a 4- to 7-membered saturated heterocycle, P 10 is hydrogen or C1-C6 alkyl, wherein said C1-C6 alkyl is optionally substituted with one or more groups independently selected from the group consisting of: halogen, hydroxy, C1-C6 alkoxy, and aminocarbonyl (wherein said amino is -NH2, mono-C 1- C6 alkylamino, di-C1-C6 alkylamino, or 4- to 8-membered cyclic amino),

[0110] Except when R 10 and Q 10Except when forming a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocycle, Q 10 is hydrogen or a C1-C6 alkyl group, and

[0111] L 11 is a single bond or is -CHM 11 -, -(CH2) n S(CH2) m -, -(CH2) n S(O)(CH2) m - or -(CH2) n S(O)2(CH2) m -, where n and m are each independently 1 or 2,

[0112] Except when R2 and R 11 form a divalent group, R 11 is any one of the following (l1) to (l5):

[0113] (l1) R 11 is hydrogen, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy C1-C6 alkyl group, a C7-C 14 arylalkyl group, an aminocarbonyl group (where the amino group is -NH2, a mono-C1-C6 alkylamino group, a di-C1-C6 alkylamino group, an N-C1-C6 alkyl-N-C2-C6 alkenylamino group or a 4- to 8-membered cyclic amino group) or a C3-C8 cycloalkyl group, each of which is optionally substituted by one or more groups independently selected from the group consisting of: halogen, oxo, hydroxy, a C1-C6 alkyl group, a C1-C6 alkoxy group, a 4- to 7-membered heterocyclic group, an aminocarbonyl group (where the amino group is -NH2, a mono-C1-C6 alkylamino group, a di-C1-C6 alkylamino group or a 4- to 8-membered cyclic amino group) and a C1-C6 alkylsulfonyl group;

[0114] (l2) R 11 is a peptide chain containing 1 to 4 amino acid residues;

[0115] (l3) R 11 together with the carbon atom to which P 11 , R 11 is bonded and the nitrogen atom to which P 11 is bonded forms a 4- to 7-membered saturated heterocycle;

[0116] (l4) R 11 together with Q 11 and R 11 and Q 11 forms a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocycle; or

[0117] (l5) R11 bonded to M 11 , R 11 The carbon atoms bonded to M and the carbon atoms bonded to M 11 together form a 3- to 8-membered alicyclic ring;

[0118] Except when R 11 and P 11 form a 4- to 7-membered saturated heterocyclic ring, P 11 is hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl C1-C6 alkyl or C7-C 14 arylalkyl, wherein the C1-C6 alkyl is optionally substituted by one or more groups independently selected from the group consisting of: halogen, hydroxy, C1-C6 alkoxy and aminocarbonyl (wherein the amino group is -NH2, mono-C1-C6 alkylamino, di-C1-C6 alkylamino or 4- to 8-membered cyclic amino),

[0119] Except when R 11 and Q 11 form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, Q 11 is hydrogen or C1-C6 alkyl, and

[0120] Except when R 11 and M 11 form a 3- to 8-membered alicyclic ring, M 11 is hydrogen, and

[0121] At least three of P1 to P 11 are not hydrogen.

[0122] [2A] The pharmaceutical composition according to [1] comprising a cyclic compound or a salt thereof, or a solvate thereof, wherein:

[0123] (a) R4 and P5 together form a divalent group, wherein the divalent group is *-C3-C8 alkylene-#, *-C3-C8 alkenylene-#, *-C1-C3 alkylene-C3-C8 cycloalkylene-C1-C3 alkylene-#, *-C 1- C3 alkylene-O-C3-C6 alkenylene-#, *-C1-C3 alkylene-CO-NR D -C1-C3 alkylene-#, *-C1-C3 alkylene-NR D -CO-C1-C3 alkylene-# or *-C1-C3 alkylene-3- to 7-membered heteroalkylene-C1-C3 alkylene-#, each of which is optionally substituted by one or more groups independently selected from the group consisting of halogen and C1-C6 alkyl, and RD is hydrogen or methyl,

[0124] * means the bonding point of the carbon atom bonded to R4, and

[0125] # denotes the bonding point of the nitrogen atom bonded to P5, or

[0126] (b) P4 and P5 together form a divalent group, where the divalent group is a C3-C8 alkylene or a C3-C8 alkenylene, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen and C1-C6 alkyl, or

[0127] (c) P5 is a C3-C6 alkyl, C 1- C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy C1-C6 alkyl, C3-C8 cycloalkyl C1-C6 alkyl or C1-C6 aminoalkyl.

[0128] [2B] The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof according to [1], wherein R4 and P5 together form a divalent group, where the divalent group is *-C4-C5 alkylene-# or *-C4-C5 alkenylene-#.

[0129] [2C] The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof according to [1], wherein R4 and P5 together form a divalent group, where the divalent group is *-C4-C5 alkenylene-#.

[0130] [3] The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof according to any one of [1] to [2C], wherein R4 and P5 together form a divalent group, and the partial structure *-CR4Q4-CO-NP5-* in the cyclic compound represented by formula (1) is represented by the following formula:

[0131]

[0132] wherein

[0133] Y 11 is hydrogen, C1-C6 alkyl or halogen,

[0134] Y 12 is hydrogen, C1-C6 alkyl or halogen,

[0135] Y 13 is hydrogen, C1-C6 alkyl or halogen, or

[0136] Y 13 together with Y 15 forms a C3-C8 alkylene or -O-,

[0137] Y 14 is hydrogen or C1-C6 alkyl,

[0138] Except when Y 13 and Y 15 forms a C3-C8 alkylene group or -O-, Y 15 is hydrogen, a C1-C6 alkyl group or a halogen,

[0139] Y 16 is hydrogen or a C1-C6 alkyl group,

[0140] Y 17 is hydrogen or a C1-C6 alkyl group,

[0141] Y 18 is hydrogen or a C1-C6 alkyl group,

[0142] R D is hydrogen or a C1-C6 alkyl group,

[0143] n is 0, 1 or 2,

[0144] m is 0, 1 or 2, and

[0145] * denotes the bonding point to an adjacent atom.

[0146] [4A] The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof according to [3], wherein the partial structure *-CR4Q4-CO-NP5-* is:

[0147]

[0148] [4B] The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof according to [3], wherein the partial structure *-CR4Q4-CO-NP5-* is:

[0149]

[0150] [5] The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof according to any one of [2A] to [2C], wherein P4 and P5 together form a divalent group, and the partial structure *-NP4-CR4Q4-CO-NP5-* in the cyclic compound represented by formula (1) is represented by the following formula:

[0151]

[0152] wherein

[0153] X1 is -CR4Q4-CO-,

[0154] Y 21 、Y 22 、Y 23 、Y 24 、Y 25 and Y 26Each independently is hydrogen or a C1-C6 alkyl group,

[0155] n is 0, 1 or 2,

[0156] m is 0, 1 or 2, and

[0157] * means a bonding point to an adjacent atom.

[0158] [6] The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof according to [5], wherein the partial structure *-NP4-CR4Q4-CO-NP5-* is:

[0159]

[0160] [7] The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof according to [2A], wherein P5 is n-propyl, isopropyl, n-butyl, isobutyl, isopentyl, neohexyl, 3-fluoropropyl, 3,3,3-trifluoropropyl, allyl, 2-methylallyl, propargyl, 3-butenyl, 2-methoxyethyl, 3-methoxypropyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl or cyclohexylmethyl.

[0161] [8] The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof according to any one of [1] to [7], wherein:

[0162] R1 and R5 together form a divalent group, wherein the divalent group is *-C1-C8 alkylene-C6-C 10 arylene-C1-C3 alkylene-#, *-C1-C8 alkylene-O-C6-C 10 arylene-C1-C3 alkylene-#, *-C2-C8 alkenylene-O-C6-C 10 arylene-C1-C3 alkylene-# or *-C2-C8 alkenylene-C6-C 10 arylene-C1-C3 alkylene-#, each of which is optionally substituted by one or more groups independently selected from the group consisting of halogen and C1-C6 alkyl,

[0163] * means a bonding point to the carbon atom to which R1 is bonded, and

[0164] # means a bonding point to the carbon atom to which R5 is bonded.

[0165] [9A]A pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof according to [8], except when R1 and R5 together form a divalent group, and the partial structure *-CR1Q1-L1-CO-NP2-CR2Q2-CO-NP3-CR3Q3-CO-NP4-CR4Q4-CO-NP5-CR5Q5-* in the cyclic compound represented by formula (1) is represented by the following formula:

[0166]

[0167] wherein

[0168] X2 is -L1-CO-NP2-CR2Q2-CO-NP3-CR3Q3-CO-NP4-CR4Q4-CO-NP5-,

[0169] Y 31 、Y 32 、Y 33 、Y 34 、Y 35 、Y 36 、Y 37 and Y 38 each independently represents hydrogen or a C1-C6 alkyl group,

[0170] n is 0, 1 or 2,

[0171] m is 0, 1, 2, 3 or 4; and

[0172] * means a bonding point to an adjacent atom.

[0173] [9B]A pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof according to [8], except when R1 and R5 together form a divalent group, and the partial structure *-CR1Q1-L1-CO-NP2-CR2Q2-CO-NP3-CR3Q3-CO-NP4-CR4Q4-CO-NP5-CR5Q5-* in the cyclic compound represented by formula (1) is represented by the following formula:

[0174]

[0175] wherein

[0176] X2 is -L1-CO-NP2-CR2Q2-CO-NP3-CR3Q3-CO-NP4-CR4Q4-CO-NP5-,

[0177] n is 1, 2, 3 or 4, and

[0178] * means a bonding point to an adjacent atom.

[0179] [9C]The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof according to any one of [1] to [8], wherein R4 and P5 together form a divalent group, and the partial structure *-CR4Q4-CO-NP5-* in the cyclic compound represented by formula (1) is:

[0180]

[0181] and

[0182] R1 and R5 together form a divalent group, and the partial structure *-CR1Q1-L 1- CO-NP2-CR2Q2-CO-NP3-CR3Q3-CO-NP4-CR4Q4-CO-NP5-CR5Q5-* is represented by the following formula:

[0183]

[0184] wherein

[0185] X2 is -L1-CO-NP2-CR2Q2-CO-NP3-CR3Q3-CO-NP4-CR4Q4-CO-NP5-,

[0186] n is 1, 2, 3 or 4, and

[0187] * means the bonding point with the adjacent atom.

[0188]

[10] The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof according to any one of [9A] to [9C], wherein the partial structure *-CR1Q1-L1-CO-NP2-CR2Q2-CO-NP3-CR3Q3-CO-NP4-CR4Q4-CO-NP5-CR5Q5-* is:

[0189]

[0190]

[11] The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof according to any one of [1] to [7], wherein:

[0191] R1 and R9 together form a divalent group, wherein the divalent group is *-C3-C8 alkylene-#, *-C3-C8 alkenylene-# or *-C1-C3 alkylene-O-C1-C8 alkylene-#, each of which is optionally substituted by one or more groups independently selected from the group consisting of halogen and C1-C6 alkyl,

[0192] * means the bonding point with the carbon atom to which R1 is bonded, and

[0193] # Refers to the bonding point of the carbon atom bonded to R9.

[0194]

[12] The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof according to

[11] , wherein R1 and R9 together form a divalent group, and the partial structure *-CR1Q1-NP1-CO-L in the cyclic compound represented by formula (1) 11 -CR 11 Q 11 -NP 11 -CO-CR 10 Q 10 -NP 10 -CO-CR9Q9-* is represented by the following formula:

[0195]

[0196] wherein

[0197] X3 is -NP 1- CO-L 11 -CR 11 Q 11 -NP 11 -CO-CR 10 Q 10 -NP 10 -CO-,

[0198] Y 41 、Y 42 、Y 43 、Y 44 、Y 45 and Y 46 are each independently hydrogen or C1-C6 alkyl,

[0199] n is an integer from 0 to 3,

[0200] m is an integer from 0 to 5, and

[0201] * Refers to the bonding point with an adjacent atom.

[0202]

[13] The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof according to

[12] , wherein the partial structure *-CR1Q1-NP1-CO-L 11 -CR 11x11 -NP 11 -CO-CR 10 Q 10 -NP 10 -CO-CR9Q9-* is:

[0203]

[0204]

[14] The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof according to any one of [1] to

[13] , wherein:

[0205] R2 and R 11 together form a divalent group, wherein the divalent group is *-C3-C8 alkylene-NR C -# or *-C3-C8 alkenylene-MR C -#, each of which is optionally substituted by one or more groups independently selected from the group consisting of halogen and C1-C6 alkyl, and R C is hydrogen or methyl,

[0206] * means the bonding point of the carbon atom bonded to R2, and

[0207] # means the bonding point of the carbon atom bonded to R 11 .

[0208]

[15] The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof according to

[14] , wherein R2 and R 11 together form a divalent group, and the partial structure *-CR2Q2-NP2-CO-L1-CR1Q1-NP1-CO-L 11 -CR 11 Q 11 -* in the cyclic compound represented by the formula (1) is represented by the following formula:

[0209]

[0210] wherein

[0211] X4 is -NP2-CO-L1-CR1Q1-NP1-CO-L 11 -,

[0212] Y 51 、Y 52 、Y 53 、Y 54 、Y 55 and Y 56 are each independently hydrogen or C1-C6 alkyl,

[0213] R C is hydrogen or C1-C6 alkyl,

[0214] n is an integer from 1 to 6, and

[0215] * means the bonding point to the adjacent atom.

[0216]

[16] The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof according to

[15] , wherein the partial structure *-CR2Q2-NP2-CO-L1-CR1Q1-NP1-CO-L 11 -CR 11 Q 11 -* is:

[0217]

[0218]

[17] The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof according to any one of [1] to

[16] , wherein L1 is a single bond, -CH2- or -CH2-S-CH2-.

[0219]

[18] The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof according to any one of [1] to

[17] , wherein R1 is: C1-C7 alkyl optionally substituted with di-C1-C6 alkylaminocarbonyl; C1-C6 haloalkyl; C1-C6 hydroxyalkyl; C2-C7 alkenyl; C2-C6 alkynyl; C1-C6 alkoxyC1-C6 alkyl optionally substituted with one or more halogen atoms; C2-C6 alkenoxyC1-C6 alkyl; C1-C6 alkylthioC1-C6 alkyl; C7-C optionally substituted with one or more halogen atoms, C1-C6 alkyl or cyano 14 arylalkyl; 5- to 10-membered heteroarylC1-C6 alkyl; C3-C8 cycloalkyl; C3-C8 cycloalkylC1-C6 alkyl; or C3-C8 cycloalkoxyC1-C6 alkyl.

[0220]

[19] The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof according to

[18] , wherein R1 is methyl, 2-methylpropyl, isopropyl, ethyl, n-propyl, n-butyl, n-hexyl, n-pentyl, n-heptyl, neopentyl, 3-(dimethylamino)-3-oxopropyl, cyclohexylmethyl, cyclopentylmethyl, cyclobutylmethyl, cyclopropylmethyl, 3,3-difluoropropyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl, 3,3-dichloropropyl, cyclopropoxymethyl, hydroxymethyl, n-propoxymethyl, methoxymethyl, 1-methoxyethyl, 2-methoxyethyl, ethoxymethyl, (2,2,2-trifluoroethoxy)methyl, allyloxymethyl, methylthiomethyl, allyl, hex-5-en-1-yl, pent-4-en-1-yl, but-3-en-1-yl, propargyl, cyclobutyl, benzyl, phenethyl, 2-cyanobenzyl, 3-cyanobenzyl, 4-cyanobenzyl, 4-chlorobenzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2-fluorobenzyl, 3-chlorobenzyl, 3,4-difluorobenzyl, 3,4-dichlorobenzyl, 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl, pyridin-3-ylmethyl, thiazol-4-ylmethyl, (thiophen-3-yl)methyl, (thiophen-2-yl)methyl, cyclopropyl, bicyclo[1.1.1]pentyl or hept-6-en-1-yl.

[0221]

[20] The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof according to any one of [1] to

[17] , wherein R1 and P1 together with the nitrogen atom to which P1 is bonded and the carbon atom to which R1 is bonded form a 4- to 7-membered saturated heterocycle.

[0222]

[21] The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof according to

[20] , wherein the 4- to 7-membered saturated heterocycle is an azepane ring.

[0223]

[22] The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof according to any one of [1] to

[19] , wherein P1 is hydrogen or C1-C6 alkyl.

[0224]

[23] The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof according to

[22] , wherein P1 is hydrogen, methyl or n-propyl.

[0225]

[24] The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof according to any one of [1] to

[23] , wherein Q1 is hydrogen or methyl.

[0226]

[25] The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof according to any one of [1] to

[24] , wherein R2 is C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C3-C8 cycloalkyl optionally substituted with one or more halogen atoms, C1-C6 alkoxy C1-C6 alkyl or a 4- to 7-membered heterocyclic group.

[0227]

[26] The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof according to

[25] , wherein R2 is ethyl, isopropyl, 1-methylpropyl, pentan-3-yl, 2,2,2-trifluoroethyl, hydroxymethyl, allyl, cyclopentyl, cyclobutyl, 3,3-difluorocyclobutyl, 1-methoxyethyl, 1-ethoxyethyl, 1-n-propoxyethyl, tetrahydropyran-4-yl, cyclopropyl, 2-methylpropyl or cyclohexyl.

[0228]

[27] The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof according to any one of [1] to

[26] , wherein P2 is hydrogen.

[0229]

[28] The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof according to any one of [1] to

[27] , wherein Q2 is hydrogen.

[0230]

[29] The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof according to any one of [1] to

[28] , wherein R3 is hydrogen, C1-C6 alkyl or C7-C 14 aralkyl.

[0231]

[30] The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof according to

[29] , wherein R3 is hydrogen, methyl, ethyl or benzyl.

[0232]

[31] The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof according to any one of [1] to

[28] , wherein R3 and P3 together with the nitrogen atom to which P3 is bonded and the carbon atom to which R3 is bonded form a 4- to 7-membered saturated heterocycle, and the 4- to 7-membered saturated heterocycle is optionally substituted with one or more C1-C6 alkyl groups or substituted with C1-C6 alkoxy.

[0233]

[32] The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof according to

[31] , wherein the 4- to 7-membered saturated heterocycle is a piperidine ring, a pyrrolidine ring, an azetidine ring, a morpholine ring or a thiomorpholine ring.

[0234]

[33] The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof according to any one of [1] to

[28] , wherein R3 and Q3 together with the carbon atoms to which they are bonded form a 3- to 8-membered alicyclic ring.

[0235]

[34] The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof according to

[33] , wherein the 3- to 8-membered alicyclic ring is a cyclopropane ring.

[0236]

[35] The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof according to any one of [1] to

[30] and

[33] to

[34] , wherein P3 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 cyanoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl or C1-C6 alkoxy C1-C6 alkyl.

[0237]

[36] The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof according to

[35] , wherein P3 is hydrogen, methyl, ethyl, n-propyl, cyanomethyl, 2-fluoroethyl, 2,2-difluoroethyl, allyl, propargyl, cyclopropyl or 2-methoxyethyl.

[0238]

[37] The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof according to any one of [1] to

[32] and

[35] to

[36] , wherein Q3 is hydrogen or methyl.

[0239]

[38] The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof according to any one of [1] to

[37] , wherein R4 is hydrogen, C1-C6 alkyl, C1-C6 hydroxyalkyl, C2-C6 alkenyl, C1-C6 alkoxy C1-C6 alkyl, C2-C6 alkenoxy C1-C6 alkyl or C1-C6 carboxyalkyl.

[0240]

[39] The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof according to

[38] , wherein R4 is hydrogen, methyl, ethyl, allyl, 2-methylallyl, but-3-en-1-yl, hydroxymethyl, n-propoxymethyl, allyloxymethyl or carboxymethyl.

[0241]

[40] The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof according to any one of [1] to

[37] , wherein R4 and P4 together with the nitrogen atom to which P4 is bonded and the carbon atom to which R4 is bonded form a 4- to 7-membered saturated heterocycle, and the 4- to 7-membered saturated heterocycle is optionally substituted by C1-C6 alkyl.

[0242]

[41] The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof according to

[40] , wherein the 4- to 7-membered saturated heterocycle is a piperidine ring, a pyrrolidine ring or an azetidine ring, and the 4- to 7-membered saturated heterocycle is optionally substituted with a methyl group.

[0243]

[42] The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof according to any one of [1] to

[39] , wherein P4 is C1-C6 alkyl or C1-C6 alkenyl.

[0244]

[43] The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof according to

[42] , wherein P4 is methyl, ethyl, n-propyl, n-butyl or 3-butenyl.

[0245]

[44] The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof according to any one of [1] to

[43] , wherein Q4 is hydrogen.

[0246]

[45] The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof according to any one of [1] to

[44] , wherein R5 is: C2-C6 alkynyl; C2-C6 alkenyloxycarbonyl C1-C6 alkyl; C3-C8 cycloalkyl; C3-C8 cycloalkyl C1-C6 alkyl optionally substituted with one or more halogen atoms; C7-C 14 arylalkyl, which is optionally substituted with one or more groups selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C2-C6 alkenyloxy, C2-C6 alkenyl, C3-C8 cycloalkyl and C1-C6 alkylcarbonyl; 5- to 10-membered heteroaryl C1-C6 alkyl; C3-C8 cycloalkyloxy C1-C6 alkyl; or C1-C6 alkoxy C1-C6 alkyl.

[0247]

[46] The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof according to

[45] , wherein R5 is benzyl, 4-fluorobenzyl, 4-chlorobenzyl, 4-fluoro-2-methylbenzyl, 4-fluoro-3-methylbenzyl, 2-chloro-4-fluorobenzyl, 3-chloro-4-fluorobenzyl, 2,4-difluorobenzyl, 3,4-difluorobenzyl, 4-fluoro-2-methoxybenzyl, 4-fluoro-3-methoxybenzyl, 4-bromobenzyl, 4-iodobenzyl, allyloxycarbonylmethyl, 4-methylbenzyl, 4-methoxybenzyl, 4-allyloxybenzyl, 4-(trifluoromethyl)benzyl, 4-(trifluoromethoxy)benzyl, propargyl, cyclopentyl, cyclohexylmethyl, 4,4-difluorocyclohexylmethyl, thiazol-2-ylmethyl, benzothiazol-6-ylmethyl, benzothiazol-5-ylmethyl, cyclobutoxymethyl, 3-methylbutoxymethyl, 4-vinylbenzyl, 4-chloro-2-fluorobenzyl, 4-(difluoromethyl)benzyl, 4-(trifluoromethyl)benzyl, 4-ethylbenzyl, 2-fluoro-4-methylbenzyl, 3-fluoro-4-methylbenzyl, 4-(1,1-difluoroethyl)benzyl, 4-cyclopropylbenzyl, 4-isopropylbenzyl, 4-methoxybenzyl, 4-acetylbenzyl or 1,1-difluoroinden-5-ylmethyl.

[0248]

[47] The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof according to any one of [1] to

[46] , wherein P5 is C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy C1-C6 alkyl, C3-C8 cycloalkyl C1-C6 alkyl or C1-C6 aminoalkyl.

[0249]

[48] The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof according to

[47] , wherein P5 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, isopentyl, neohexyl, 3-fluoropropyl, 3,3,3-trifluoropropyl, allyl, 2-methylallyl, propargyl, 3-butenyl, 2-methoxyethyl, 3-methoxypropyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl or 2-aminoethyl.

[0250]

[49] The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof according to any one of [1] to

[48] , wherein Q5 is hydrogen.

[0251]

[50] The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof according to any one of [1] to

[49] , wherein R6 is hydrogen or C1-C3 alkyl.

[0252]

[51] The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof according to

[50] , wherein R6 is hydrogen or methyl.

[0253]

[52] The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof according to any one of [1] to

[49] , wherein R6 and P6 together with the nitrogen atom to which P6 is bonded and the carbon atom to which R6 is bonded form a 4- to 7-membered saturated heterocycle.

[0254]

[53] The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof according to

[52] , wherein the 4- to 7-membered saturated heterocycle is a pyrrolidine ring.

[0255]

[54] The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof according to any one of [1] to

[51] , wherein P6 is a C1-C6 alkyl group.

[0256]

[55] The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof according to

[54] , wherein P6 is methyl, ethyl or n-propyl.

[0257]

[56] The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof according to any one of [1] to

[55] , wherein Q6 is hydrogen.

[0258]

[57] The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof according to any one of [1] to

[56] , wherein R7 is: C7-C 14 aralkyl, which is optionally substituted by one or more groups independently selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy and C3-C8 cycloalkyl; or 5- to 10-membered heteroaryl C1-C6 alkyl, which is optionally substituted by one or more groups independently selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy and C3-C8 cycloalkyl.

[0259]

[58] The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof according to

[57] , wherein R7 is: phenethyl, optionally substituted by one or more groups independently selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy and C3-C8 cycloalkyl; or 5- to 10-membered heteroaryl ethyl, which is optionally substituted by one or more groups independently selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy and C3-C8 cycloalkyl.

[0260]

[59] The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof according to

[58] , wherein R7 is 4-methylphenethyl, 2-fluoro-4-(trifluoromethyl)phenethyl, 3-fluoro-4-(trifluoromethyl)phenethyl, 3-fluoro-4-(difluoromethoxy)phenethyl, 3,5-difluoro-4-(trifluoromethyl)phenethyl, 3,4,5-trifluorophenethyl, 2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenethyl, 3-chloro-4-(trifluoromethyl)phenethyl, 4-chloro-3,5-difluorophenethyl, 3,4-dichlorophenethyl, 3,5-dichloro-4-(trifluoromethyl)phenethyl, 3,4,5-trichlorophenethyl, 3-methoxy-4-(trifluoromethyl)phenethyl, 3-methyl-4-(trifluoromethyl)phenethyl, benzothiazol-5-ylethyl, benzothiazol-6-ylethyl, 4-chloro-3,5-dimethylphenethyl, 4-(trifluoromethyl)phenethyl, 4-chlorophenethyl, 3-ethyl-4-trifluoromethylphenethyl, 3-methoxy-4-trifluoromethylphenethyl, 3-chloro-4-trifluoromethylphenethyl, 3,5-difluoro-4-trifluoromethylphenethyl, 4-chloro-3-fluoro-5-methoxyphenethyl, 4-ethyl-3-fluoro-5-methoxyphenethyl, 3,5-dimethyl-4-difluoromethylphenethyl, 3-methyl-5-fluoro-4-difluoromethylphenethyl, 3-methyl-5-chloro-4-difluoromethylphenethyl, 3-methoxy-5-fluoro-4-difluoromethylphenethyl, 2-(4-fluoro-2,3-dihydrobenzofuran-6-yl)ethyl, 3-cyclopropyl-4-trifluoromethylphenethyl, 2-(1,1-difluoroinden-6-yl)ethyl, 4-cyclopropyl-3-fluorophenethyl, 4-cyclopropyl-3-chlorophenethyl, 4-cyclopropyl-3-methylphenethyl, 4-ethyl-3-fluorophenethyl, 4-ethyl-3-chlorophenethyl, 3,5-difluoro-4-difluoromethylphenethyl, 4-chloro-3-trifluoromethylphenethyl, 4-chloro-3-methoxyphenethyl, 2-(7-fluoroinden-5-yl)ethyl, 3-methoxy-4-cyclopropylphenethyl, 3,5-dimethyl-4-cyclopropylphenethyl, 3,5-dichloro-4-difluoromethylphenethyl, 3-methoxy-4-difluoromethylphenethyl, 3-methoxy-4-ethylphenethyl, 2-(7-chlorobenzothiophen-5-yl)ethyl, 2-(2,3-dimethylbenzothiophen-5-yl)ethyl, 2-(2-fluoro-3-methylbenzothiophen-5-yl)ethyl, 2-(1,2,3-trimethylindol-5-yl)ethyl, 2-(7-chloro-1-methylindol-5-yl)ethyl, 2-(1,3-dimethylindol-6-yl)ethyl or 2-(1-methylindol-6-yl)ethyl.

[0261]

[60] The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof according to any one of [1] to

[59] , wherein P7 is hydrogen.

[0262]

[61] The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof according to any one of [1] to

[60] , wherein Q7 is hydrogen.

[0263]

[62] The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof according to any one of [1] to

[61] , wherein R8 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy C1-C6 alkyl or C3-C8 cycloalkyl C 1- C6 alkyl.

[0264]

[63] The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof according to

[62] , wherein R8 is hydrogen, methyl, n-butyl, 2,2-difluoroethyl, 3,3-difluoropropyl, cyclohexylmethyl, methoxymethyl, n-propoxymethyl, 3-methylbutoxymethyl or ethyl.

[0265]

[64] The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof according to any one of [1] to

[61] , wherein R8 and P8 together with the nitrogen atom to which P8 is bonded and the carbon atom to which R8 is bonded form a 4- to 7-membered saturated heterocycle, the 4- to 7-membered saturated heterocycle is optionally condensed with a 3- to 8-membered saturated carbocycle, and the 4- to 7-membered saturated heterocycle is optionally substituted with: one or more halogen atoms; one or more C1-C6 alkyl groups; C1-C6 haloalkyl; hydroxy; 4- to 7-membered heterocyclic oxy; oxo; C1-C6 alkoxy; C3-C8 cycloalkyl C1-C6 alkoxy; C1-C6 haloalkoxy; 4- to 8-membered cyclic amino optionally substituted with one or more halogen atoms; C3-C8 spiroalkyl; or C3-C8 cycloalkoxy.

[0266]

[65] The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof according to

[64] , wherein the 4- to 7-membered saturated heterocycle is a piperidine ring, a pyrrolidine ring, an azetidine ring, a morpholine ring, a thiomorpholine ring or an azepane ring.

[0267]

[66] The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof according to any one of [1] to

[63] , wherein P8 is hydrogen or C1-C6 alkyl.

[0268]

[67] The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof according to

[66] , wherein P8 is methyl, ethyl, n-propyl or n-butyl.

[0269]

[68] The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof according to any one of [1] to

[67] , wherein Q8 is hydrogen or methyl.

[0270]

[69] The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof according to any one of [1] to

[68] , wherein R9 is C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy C1-C6 alkyl, C1-C6 alkenyloxy C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl C1-C6 alkyl or C7 to C 14 arylalkyl.

[0271]

[70] The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof according to

[69] , wherein R9 is methyl, ethyl, n-propyl, isopropyl, 1-methylpropyl, 2-methylpropyl, allyl, cyclopropyl, cyclohexylmethyl, methoxymethyl, tert-butoxymethyl, allyloxymethyl or benzyl.

[0272]

[71] The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof according to any one of [1] to

[68] , wherein R9 and Q9 together with the carbon atom to which they are bonded form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, wherein the 3- to 8-membered alicyclic ring or 4- to 7-membered saturated heterocyclic ring is optionally substituted by one or more halogen atoms or one or more C1-C6 alkyl groups.

[0273]

[72] The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof according to

[71] , wherein the 3- to 8-membered alicyclic ring is a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, a cyclopentene ring, a cyclohexane ring.

[0274]

[73] The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof according to

[71] , wherein the 4- to 7-membered saturated heterocyclic ring is an oxetane ring or a tetrahydropyran ring.

[0275]

[74] The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof according to any one of [1] to

[73] , wherein P9 is hydrogen or C1-C6 alkyl.

[0276]

[75] The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof according to

[74] , wherein P9 is hydrogen or methyl.

[0277]

[76] The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof according to any one of [1] to

[70] and

[74] to

[75] , wherein Q9 is hydrogen or C1-C6 alkyl.

[0278]

[77] The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof according to

[76] , wherein Q9 is hydrogen or methyl.

[0279]

[78] The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof according to any one of [1] to

[77] , wherein R 10 is a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy C1-C6 alkyl group, a C3-C8 cycloalkyl group or a C3-C8 cycloalkyl C1-C6 alkyl group.

[0280]

[79] The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof according to

[78] , wherein R 10 is methyl, isopropyl, 1-methylpropyl, 2-methylpropyl, tert-butyl, pentan-3-yl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, n-propoxymethyl, cyclobutyl, cyclopentyl, cyclohexyl, 2,2-dimethylpropyl, cyclobutylmethyl or cyclopropylmethyl.

[0281]

[80] The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof according to any one of [1] to

[79] , wherein P 10 is hydrogen or a C1-C6 alkyl group.

[0282]

[81] The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof according to

[80] , wherein P 10 is hydrogen, methyl or ethyl.

[0283]

[82] The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof according to any one of [1] to

[81] , wherein Q 10 is hydrogen or a C1-C6 alkyl group.

[0284]

[83] The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof according to

[82] , wherein Q 10 is hydrogen or methyl.

[0285]

[84] The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof according to any one of [1] to

[83] , wherein L 11 is -CH2- or -CH2-S-CH2-.

[0286]

[85] The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof according to any one of [1] to

[84] , wherein R 11is: C1-C6 alkyl; di-C1-C6 alkylaminocarbonyl; N-C1-C6 alkyl-N-C2-C6 alkenylaminocarbonyl; N-C1-C6 alkyl-N-C1-C6 alkoxy-C1-C6 alkylaminocarbonyl; a cyclic aminocarbonyl optionally substituted with one or more C1-C6 alkyl groups or a 4- to 7-membered heterocyclic group; or C3-C8 cycloalkyl.

[0287]

[86] The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof, according to

[85] , wherein R 11 is methyl, dimethylaminocarbonyl, diethylaminocarbonyl, N-ethyl-N-methylaminocarbonyl, N-allyl-N-methylaminocarbonyl, N-propyl-N-methylaminocarbonyl, N-butenyl-N-methylaminocarbonyl, N-pentenyl-N-methylaminocarbonyl, N-hexenyl-N-methylaminocarbonyl, N-methoxyethyl-N-methylaminocarbonyl, azetidinylcarbonyl, pyrrolidinylcarbonyl, 3,3-dimethylpyrrolidinylcarbonyl, piperidinylcarbonyl, 4-methylpiperidinylcarbonyl, morpholinylcarbonyl, morpholino carbonyl, oxazolidin-3-ylcarbonyl, 1-(oxetane-3-yl)-piperazin-4-ylcarbonyl, 3-oxa-8-azabicyclo[3.2.1]octan-8-ylcarbonyl, cyclopropyl or 2-methylpropyl.

[0288]

[87] The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof, according to any one of [1] to

[84] , wherein R 11 and P 11 bonded to P 11 and the nitrogen atom to which R 11 is bonded together with the carbon atom to which R is bonded form a 4- to 7-membered saturated heterocycle.

[0289]

[88] The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof, according to

[87] , wherein the 4- to 7-membered saturated heterocycle is a pyrrolidine ring.

[0290]

[89] The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof, according to any one of [1] to

[86] , wherein P 11 is hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl-C1-C6 alkyl or C7-C 14 arylalkyl.

[0291]

[90] The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof, according to

[89] , wherein P 11 is hydrogen, methyl, ethyl, n-propyl, 2-cyclobutylethyl, 2-cyclopentylethyl or phenethyl.

[0292]

[91] The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof, according to any one of [1] to

[90] , wherein Q 11 is hydrogen.

[0293]

[92] The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof, according to any one of [1] to

[91] , wherein at least four of P1 to P 11 are not hydrogen.

[0294]

[93] The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof, according to any one of [1] to

[92] , wherein at least five of P1 to P 11 are not hydrogen.

[0295]

[94] The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof, according to any one of [1] to

[93] , wherein at least six of P1 to P 11 are not hydrogen.

[0296]

[95] The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof, according to [1], wherein the compound is selected from the compounds provided in Table 38.

[0297] [95A]A pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof, according to [1], wherein the compound is selected from the group consisting of the following items provided in Table 38: PP0824, PP0825, PP0978, PP0983, PP1086, PP1087, PP1089, PP1090, PP1091, PP1097, PP1103, PP1104, PP1105, PP1107, PP1108, PP1109, PP1110, PP1111, PP1112, PP1113, PP1114, PP1115, PP1116, PP1117, PP1118, PP1119, PP1120, PP1121, PP1122, PP1123, PP1124, PP1125, PP1126, PP1127, PP1128, PP1129, PP1130, PP1131, PP1132, PP1133, PP1134, PP1135, PP1136, PP1137, PP1140, PP1199, PP1242, PP1243, PP1244, PP1245, PP1246, PP1247, PP1248, PP1253, PP1266, PP1267, PP1268, PP1269, PP1271, PP1272, PP1273, PP1274, PP1275, PP1276, PP1278, PP1281, PP1295, PP1296, PP1297, PP1298, PP1299, PP1300, PP1301, PP1302, PP1303, PP1304, PP1305, PP1307, PP1308, PP1310, PP1316, PP1317, PP1318, PP1319, PP1320, PP1321, PP1324, PP1327, PP1331, PP1387, PP1388, PP1389, PP1392, PP1395, PP1396, PP1397, PP1398, PP1400, PP1406, PP1407, PP1411, PP1414, PP1423, PP1443, PP1447, PP1448, PP1449, PP1450, PP1451, PP1452, PP1453, PP1454, PP1455, PP1456, PP1457, PP1462, PP1463, PP1466, PP1467, PP1468, PP1472, PP1488, PP1497, PP1498, PP1499, PP1500, PP1501, PP1503, PP1505, PP1510, PP1511, PP1512, PP1513, PP1529,PP1531, PP1533, PP1534, PP1537, PP1538, PP1553, PP1574, PP1650, PP1827, PP1830, PP2093, PP2260, PP2316, PP2320, PP2328, PP2574, PP2576, PP2583, PP2687, PP2691, PP2957, PP3033, PP3034, PP3036, PP3037, PP3047, PP3093, PP3094, PP3095, PP3096, PP3097, PP3098, PP3099, PP3100, PP3101, PP3102, PP3103, PP3104, PP3105, PP3106, PP3110, PP3111, PP3112, PP3113, PP3114, PP3115, PP3116, PP3117, PP3118, PP3119, PP3120, PP3121, PP3158, PP3160, PP3167, PP3169, PP3171, PP3176, PP3178, PP3185, PP3187, PP3194, PP3198, PP3200, PP3207, PP3217, PP3226, PP3230, PP3231, PP3233, PP3234, PP3235, PP3236, PP3237, PP3238, PP3239, PP3240, PP3242, PP3243, PP3244, PP3245, PP3246, PP3247, PP3248, PP3249, PP3250, PP3252, PP3253, PP3254, PP3255, PP3256, PP3257, PP3276, PP3282, PP3283, PP3284, PP3285, PP3286, PP3287, PP3288, PP3289, PP3290, PP3292, PP3294, PP3299, PP3300, PP3302, PP3306, PP3308, PP3310, PP3314, PP3316, PP3318, PP3322, PP3324, PP3326, PP3327, PP3328, PP3329, PP3331, PP3352, PP3353, PP3356, PP3358, PP3364, PP3367, PP3368, PP3370, PP3373, PP3374, PP3376, PP3379, PP3382, PP3388, PP3394, PP3397, PP3404, PP3406, PP3408, PP3410, PP3414, PP3416, PP3418PP3419, PP3436, PP3438, PP3440, PP3442, PP3444, PP3447, PP3448, PP3452, PP3455, PP3456, PP3457, PP3475, PP3478, PP3481, PP3484, PP3496, PP3499, PP3500, PP3510, PP3511, PP3512, PP3513, PP3514, PP3515, PP3516, PP3517, PP3518, PP3519, PP3520, PP3521, PP3522, PP3523, PP3524, PP3525, PP3526, PP3527, PP3528, PP3529 and PP3530.

[0298] [95B] The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof according to [1], wherein the compound is selected from the group consisting of the following items provided in Table 38: PP1105, PP1693, PP2175, PP2320, PP2742, PP2750, PP2967, PP3194, PP3198, PP3234, PP3238, PP3255, PP3327, PP3356, PP3368, PP3374, PP3376, PP3388, PP3394, PP3414, PP3475, PP3478, PP3481, PP3484 and PP3510.

[0299] [95C] The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof according to [1], wherein the compound is selected from the group consisting of:

[0300] PP1105: (2S, 8S, 12R, 14S, 20S, 23S, 27S, 30S, 36S, 38Z)-20-cyclopentyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-27-isobutyl-N,N,4,19,22,26,32,35-octamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaooxo-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10,14 tetratetracont-38-ene-17,1′-cyclopentane]-23-carboxamide,

[0301] PP2320: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-Cyclopentyl-28-ethoxy-32-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,N,2,14,18,21,24,36-octamethyl-10-[(1S)-1-methylpropyl]-3,9,12,15,19,22,25,31,34,37,45-undecaooxo-13-propyl-38-[[4-(trifluoromethyl)phenyl]methyl]spiro[2,8,11,14,18,21,24,30,33,36,39-undecaazatetracyclo[37.5.1.0 4, 8 .0 26,30 tetratetracont-42-en-23,1'-cyclobutane]-17-carboxamide,

[0302] PP3478: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-Cyclopentyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-27-isobutyl-N,N,4,19,22,26,32,35-octamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaooxo-2-(p-tolylmethyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10,14 dotetracont-38-en-17,1'-cyclopentane]-23-carboxamide,

[0303] PP3475: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-Cyclopentyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-27-[(1R)-1-methoxyethyl]-N,N,4,19,22,26,32,35-octamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaooxo-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10 ,14 dotetracont-38-en-17,1'-cyclopentane]-23-carboxamide,

[0304] PP3484: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-27-isobutyl-N,N,4,16,19,22,26,32,35-nonamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaoxo-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10,14 tetratetracontacosa-38-ene-17,1′-cyclobutane]-23-carboxamide,

[0305] PP3481: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-27-[(1R)-1-methoxyethyl]-N,N,4,19,22,26,32,35-octamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaoxo-2-(p-tolylmethyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10,14 tetratetracontacosa-38-ene-17,1′-cyclopentane]-23-carboxamide,

[0306] PP3368: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-28-ethoxy-32-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,N,2,14,18,21,36-heptamethyl-10-[(1S)-1-methylpropyl]-3,9,12,15,19,22,25,31,34,37,45-undecaoxo-13-propyl-38-[[4-(trifluoromethyl)phenyl]methyl]spiro[24-oxa-2,8,11,14,18,21,30,33,36,39-decaazatetracyclo[37.5.1.0 4,8 .0 26,30 pentatetracontacosa-42-ene-23,1′-cyclobutane]-17-carboxamide,

[0307] PP3388: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-Cyclopentyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,N,4,19,22,26,32,35-octamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaooxo-27-propyl-2-[(p-tolylmethyl)spiro[16-oxa-1,4,7,10,19,22,26,29,32,35-decaazatricyclo[34.5.1.0 10,14 tetratetracont-38-ene-17,1'-cyclobutane]-23-carboxamide,

[0308] PP3374: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-Cyclopentyl-28-ethoxy-13-[(1R)-1-methoxyethyl]-32-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,N,2,14,18,21,36-heptamethyl-10-[(1S)-1-methylpropyl]-3,9,12,15,19,22,25,31,34,37,45-undecaooxo-38-[[4-(trifluoromethyl)phenyl]methyl]spiro[24-oxa-2,8,11,14,18,21,30,33,36,39-decaazatetracyclo[37.5.1.0 4,8 .0 26,30 pentatetracont-42-ene-23,1'-cyclobutane]-17-carboxamide,

[0309] PP3376: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-Cyclopentyl-12-ethoxy-27-[(1R)-1-methoxyethyl]-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,N,4,19,22,26,32,35-octamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaooxo-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[16-oxa-1,4,7,10,19,22,26,29,32,35-decaazatricyclo[34.5.1.0 10,14 tetratetracont-38-ene-17,1'-cyclobutane]-23-carboxamide,

[0310] PP3394: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-Cyclopentyl-12-ethoxy-27-[(1R)-1-methoxyethyl]-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,N,4,19,22,26,32,35-octamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaoxo-2-(p-tolylmethyl)spiro[16-oxa-1,4,7,10,19,22,26,29,32,35-decaazatricyclo[34.5.1.0 10,14 tetratetracont-38-ene-17,1′-cyclobutane]-23-carboxamide,

[0311] PP3194: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-Cyclopentyl-12-ethoxy-27-[(1R)-1-methoxyethyl]-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,N,3′,3′,4,19,22,26,32,35-decamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaoxo-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10,14 tetratetracont-38-ene-17,1′-cyclobutane]-23-carboxamide,

[0312] PP3198: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-8-[2-[3-Chloro-4-(trifluoromethyl)phenyl]ethyl]-20-cyclopentyl-12-ethoxy-27-[(1R)-1-methoxyethyl]-N,N,3′,3′,4,19,22,26,32,35-decamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaoxo-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10,14 tetratetracont-38-ene-17,1′-cyclobutane]-23-carboxamide,

[0313] PP3327: (6′S,9′S,13′S,16′S,22′S,29′S,35′S,40a′S,Z)-16′-((S)-sec-Butyl)-6′-cyclopentyl-35′-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-N,N,2′,5′,8′,12′,18′,21′,31′-nonamethyl-29′-(4-methylbenzyl)-1′,4′,7′,11′,14′,17′,20′,30′,33′,36′,41′-undecaooxo-13′-propyl-1′,2′,4′,5′,6′,7′,8′,9′,10′,11′,12′,13′,14′,15′,16′,17′,18′,19′,20′,21′,22′,23′,26′,27′,29′,30′,31′,32′,33′,34′,35′,36′,40′,40a′-tetratetracontahydro-38′H-dispiro[cyclobutane-1,3′-[22,28]methanopiperolino[1,2-j][1,4,7,10,13,16,19,23,26,29,32]undecaazacyclotetracontene-39′,1″-cyclopropane]-9′-carboxamide,

[0314] PP3234: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-8-[2-[3-Chloro-4-(trifluoromethyl)phenyl]ethyl]-20-cyclopentyl-12-ethoxy-N,N,4,16,19,22,26,32,35-nonamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaoxo-27-prop-2-ynyl-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10,14 tetracos-38-ene-17,1′-cyclobutane]-23-carboxamide,

[0315] PP3238: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-N,N,4,16,19,22,26,32,35-nonamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaoxo-27-prop-2-ynyl-2-(p-tolylmethyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.010,14 42-Carbon-38-ene-17,1′-cyclobutane]-23-carboxamide,

[0316] PP3255: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-Cyclopentyl-28-ethoxy-32-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,N,2,14,18,21,24,36-octamethyl-10-[(1S)-1-methylpropyl]-3,9,12,15,19,22,25,31,34,37,45-undecoxo-13-prop-2-ynyl-38-(p-tolylmethyl)spiro[2,8,11,14,18,21,24,30,33,36,39-undecaazatetracyclo[37.5.1.0 4,8 .0 26,30 45-Carbon-42-ene-23,1′-cyclobutane]-17-carboxamide,

[0317] PP3356: (6′S,9′S,13′S,16′S,22′S,29′S,35′S,40a′S,Z)-16′-((S)-sec-Butyl)-6′-cyclopentyl-35′-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-N,N,2′,5′,8′,12′,18′,21′,31′-nonamethyl-1′,4′,7′,11′,14′,17′,20′,30′,33′,36′,41′-undecoxo-13′-propyl-29′-(4-(trifluoromethyl)benzyl)-1′,2′,4′,5′,6′,7′,8′,9′,10′,11′,12′,13′,14′,15′,16′,17′,18′,19′,20′,21′,22′,23′,26′,27′,29′,30′,31′,32′,33′,34′,35′,36′,40′,40a′-tetratriaconta hydro-38′H-dispiro[cyclobutane-1,3′-[22,28]methanoptero[1,2-j][1,4,7,10,13,16,19,23,26,29,32]undecaazacyclotriacontene-39′,1″-cyclopropane]-9′-carboxamide,

[0318] PP1693: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-27-butyl-20-cyclopentyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-fluoro-N,N,3′,3′,4,19,22,26,32,35-decamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaoxo-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10,14 tetracosa-38-ene-17,1′-cyclobutane]-23-carboxamide,

[0319] PP3414: (6′S,9′S,13′S,16′S,22′S,29′S,35′S,40a′S,Z)-16′-((S)-sec-butyl)-35′-(3-chloro-4-(trifluoromethyl)phenethyl)-N,N,5′,8′,12′,18′,21′,31′-octamethyl-1′,4′,7′,11′,14′,17′,20′,30′,33′,36′,41′-undecaoxo-6′-(pentan-3-yl)-13′-propyl-29′-(4-(trifluoromethyl)benzyl)-1′,2′,4′,5′,6′,7′,8′,9′,10′,11′,12′,13′,14′,15′,16′,17′,18′,19′,20′,21′,22′,23′,26′,27′,29′,30′,31′,32′,33′,34′,35′,36′,40′,40a′-tetrahydro-38′H-dispiro[cyclobutane-1,3′-[22,28]methanopyrrolo[1,2-j][1,4,7,10,13,16,19,23,26,29,32]undecaazacyclooctatriene-39′,1″-cyclopropane]-9′-carboxamide,

[0320] PP2175: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-8-[2-(3,4-dichlorophenyl)ethyl]-12-ethoxy-20-(1-ethylpropyl)-N,N,3′,3′,4,19,22,26,32,35-decamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaooxo-27-propyl-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10,14 tetratetracontacosa-38-ene-17,1′-cyclobutane]-23-carboxamide,

[0321] PP2750: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-32-cyclopropyl-8-[2-(3,4-dichlorophenyl)ethyl]-20-(2,2-dimethylpropyl)-12-ethoxy-27-(methoxymethyl)-N,N,3′,3′,4,19,22,26,35-nonamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaooxo-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10,14 tetratetracontacosa-38-ene-17,1′-cyclobutane]-23-carboxamide,

[0322] PP2742: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-32-cyclopropyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-20-(2,2-dimethylpropyl)-12-ethoxy-N,N,3′,3′,4,19,22,26,35-nonamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaooxo-27-propyl-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10,14 tetratetracontacosa-38-ene-17,1′-cyclobutane]-23-carboxamide,

[0323] PP2967: (6′S,9′S,13′S,16′S,22′S,29′S,35′S,40a′S,Z)-16′-((S)-sec-Butyl)-35′-(3-chloro-4-(trifluoromethyl)phenethyl)-13′-(methoxymethyl)-N,N,3,3,5′,8′,12′,18′,21′,31′-decamethyl-29′-(4-methylbenzyl)-1′,4′,7′,11′,14′,17′,20′,30′,33′,36′,41′-undecaooxo-6′-(pentan-3-yl)-1′,2′,4′,5′,6′,7′,8′,9′,10′,11′,12′,13′,14′,15′,16′,17′,18′,19′,20′,21′,22′,23′,26′,27′,29′,30′,31′,32′,33′,34′,35′,36′,40′,40a′-tetratetracontahydro-38′H-dispiro[cyclobutane-1,3′-[22,28]methanopterop[1,2-j][1,4,7,10,13,16,19,23,26,29,32]undecaazacyclotetracontene-39′,1″-cyclopropane]-9′-carboxamide, and

[0324] PP3510: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38E)-20-cyclopentyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-38-fluoro-27-isobutyl-N,N,4,19,22,26,32,35-octamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaoxo-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10,14 tetracosa-38-ene-17,1′-cyclopentane]-23-carboxamide.

[0325] [95-1]A pharmaceutical composition comprising PP1105: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-27-isobutyl-N,N,4,19,22,26,32,35-octamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaooxo-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10,14 42-carbene-38-ene-17,1'-cyclopentane]-23-carboxamide or a salt thereof, or a solvate thereof.

[0326] [95-2]A pharmaceutical composition comprising PP2320: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-28-ethoxy-32-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,N,2,14,18,21,24,36-octamethyl-10-[(1S)-1-methylpropyl]-3,9,12,15,19,22,25,31,34,37,45-undecaooxo-13-propyl-38-[[4-(trifluoromethyl)phenyl]methyl]spiro[2,8,11,14,18,21,24,30,33,36,39-undecaazatetracyclo[37.5.1.0 4,8 .0 26,30 45-carbene-42-ene-23,1'-cyclobutane]-17-carboxamide or a salt thereof, or a solvate thereof.

[0327] [95-3]A pharmaceutical composition comprising PP3478: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-27-isobutyl-N,N,4,19,22,26,32,35-octamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaooxo-2-(p-tolylmethyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10,14 42-carbene-38-ene-17,1'-cyclopentane]-23-carboxamide or a salt thereof, or a solvate thereof.

[0328] [95-4]A pharmaceutical composition comprising PP3475: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-27-[(1R)-1-methoxyethyl]-N,N,4,19,22,26,32,35-octamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaoxo-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10 , 14 tetratetracont-38-ene-17,1′-cyclopentane]-23-carboxamide or a salt thereof, or a solvate thereof.

[0329] [95-5]A pharmaceutical composition comprising PP3484: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-27-isobutyl-N,N,4,16,19,22,26,32,35-nonamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaoxo-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10,14 tetratetracont-38-ene-17,1′-cyclobutane]-23-carboxamide or a salt thereof, or a solvate thereof.

[0330] [95-6]A pharmaceutical composition comprising PP3481: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-27-[(1R)-1-methoxyethyl]-N,N,4,19,22,26,32,35-octamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaoxo-2-(p-tolylmethyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10,1442-Carbon-38-ene-17,1′-cyclopentane]-23-carboxamide or its salt, or their solvate.

[0331] [95-7] A pharmaceutical composition comprising PP3368: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-28-ethoxy-32-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,N,2,14,18,21,36-heptamethyl-10-[(1S)-1-methylpropyl]-3,9,12,15,19,22,25,31,34,37,45-undecaooxo-13-propyl-38-[[4-(trifluoromethyl)phenyl]methyl]spiro[24-oxa-2,8,11,14,18,21,30,33,36,39-decaazatetracyclo[37.5.1.0 4,8 .0 26,30 45-Carbon-42-ene-23,1′-cyclobutane]-17-carboxamide or its salt, or their solvate.

[0332] [95-8] A pharmaceutical composition comprising PP3388: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,N,4,19,22,26,32,35-octamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaooxo-27-propyl-2-(p-tolylmethyl)spiro[16-oxa-1,4,7,10,19,22,26,29,32,35-decaazatricyclo[34.5.1.0 10,14 42-Carbon-38-ene-17,1′-cyclobutane]-23-carboxamide or its salt, or their solvate.

[0333] [95-9]A pharmaceutical composition comprising PP3374: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-28-ethoxy-13-[(1R)-1-methoxyethyl]-32-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,N,2,14,18,21,36-heptamethyl-10-[(1S)-1-methylpropyl]-3,9,12,15,19,22,25,31,34,37,45-undecaooxo-38-[[4-(trifluoromethyl)phenyl]methyl]spiro[24-oxa-2,8,11,14,18,21,30,33,36,39-decaazatetracyclo[37.5.1.0 4,8 .0 26,30 tetracosacont-42-en-23,1′-cyclobutane]-17-carboxamide or a salt thereof, or a solvate thereof.

[0334] [95-10]A pharmaceutical composition comprising PP3376: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-12-ethoxy-27-[(1R)-1-methoxyethyl]-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,N,4,19,22,26,32,35-octamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaooxo-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[16-oxa-1,4,7,10,19,22,26,29,32,35-decaazatricyclo[34.5.1.0 10,14 dotetracont-38-en-17,1′-cyclobutane]-23-carboxamide or a salt thereof, or a solvate thereof.

[0335] [95-11]A pharmaceutical composition comprising PP3394: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-12-ethoxy-27-[(1R)-1-methoxyethyl]-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,N,4,19,22,26,32,35-octamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaooxo-2-(p-tolylmethyl)spiro[16-oxa-1,4,7,10,19,22,26,29,32,35-decaazatricyclo[34.5.1.0 10,1442-Carbon-38-ene-17,1′-cyclobutane]-23-carboxamide or its salt, or their solvate.

[0336] [95-12] A pharmaceutical composition comprising PP3194: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-12-ethoxy-27-[(1R)-1-methoxyethyl]-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,N,3′,3′,4,19,22,26,32,35-decamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaooxo-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10,14 42-Carbon-38-ene-17,1′-cyclobutane]-23-carboxamide or its salt, or their solvate.

[0337] [95-13] A pharmaceutical composition comprising PP3198: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-8-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-20-cyclopentyl-12-ethoxy-27-[(1R)-1-methoxyethyl]-N,N,3′,3′,4,19,22,26,32,35-decamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaooxo-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10,14 42-Carbon-38-ene-17,1′-cyclobutane]-23-carboxamide or its salt, or their solvate.

[0338] [95-14]A pharmaceutical composition comprising PP3327: (6′S,9′S,13′S,16′S,22′S,29′S,35′S,40a′S,Z)-16′-((S)-sec-butyl)-6′-cyclopentyl-35′-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-N,N,2′,5′,8′,12′,18′,21′,31′-nonamethyl-29′-(4-methylbenzyl)-1′,4′,7′,11′,14′,17′,20′,30′,33′,36′,41′-undecaooxo-13′-propyl-1′,2′,4′,5′,6′,7′,8′,9′,10′,11′,12′,13′,14′,15′,16′,17′,18′,19′,20′,21′,22′,23′,26′,27′,29′,30′,31′,32′,33′,34′,35′,36′,40′,40a′-tetratetracontahydro-38′H-dispiro[cyclobutane-1,3′-[22,28]methanopyrrolo[1,2-j][1,4,7,10,13,16,19,23,26,29,32]undecaazacyclotetracontene-39′,1″-cyclopropane]-9′-carboxamide or a salt thereof, or a solvate thereof.

[0339] [95-15]A pharmaceutical composition comprising PP3234: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-8-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-20-cyclopentyl-12-ethoxy-N,N,4,16,19,22,26,32,35-nonamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaooxo-27-prop-2-ynyl-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10,14 tetracosa-38-ene-17,1′-cyclobutane]-23-carboxamide or a salt thereof, or a solvate thereof.

[0340] [95-16]A pharmaceutical composition comprising PP3238: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-N,N,4,16,19,22,26,32,35-nonamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaooxo-27-prop-2-ynyl-2-(p-tolylmethyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10,14 tetracosa-38-ene-17,1′-cyclobutane]-23-carboxamide or a salt thereof, or a solvate thereof.

[0341] [95-17]A pharmaceutical composition comprising PP3255: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-28-ethoxy-32-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,N,2,14,18,21,24,36-octamethyl-10-[(1S)-1-methylpropyl]-3,9,12,15,19,22,25,31,34,37,45-undecaooxo-13-prop-2-ynyl-38-(p-tolylmethyl)spiro[2,8,11,14,18,21,24,30,33,36,39-undecaazatetracyclo[37.5.1.0 4,8 .0 26,30 pentacosa-42-ene-23,1′-cyclobutane]-17-carboxamide or a salt thereof, or a solvate thereof.

[0342] [95-18]A pharmaceutical composition comprising PP3356: (6′S,9′S,13′S,16′S,22′S,29′S,35′S,40a′S,Z)-16′-((S)-sec-butyl)-6′-cyclopentyl-35′-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-N,N,2′,5′,8′,12′,18′,21′,31′-nonamethyl-1′,4′,7′,11′,14′,17′,20′,30′,33′,36′,41′-undecaooxo-13′-propyl-29′-(4-(trifluoromethyl)benzyl)-1′,2′,4′,5′,6′,7′,8′,9′,10′,11′,12′,13′,14′,15′,16′,17′,18′,19′,20′,21′,22′,23′,26′,27′,29′,30′,31′,32′,33′,34′,35′,36′,40′,40a′-tetratetrahydro-38′H-dispiro[cyclobutane-1,3′-[22,28]methanopyrrolo[1,2-j][1,4,7,10,13,16,19,23,26,29,32]undecaazacyclotetracont-39′,1″-cyclopropane]-9′-carboxamide or a salt thereof, or a solvate thereof.

[0343] [95-19]A pharmaceutical composition comprising PP1693: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-27-butyl-20-cyclopentyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-fluoro-N,N,3′,3′,4,19,22,26,32,35-decamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaoxo-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo 10,14 tetracosa-38-ene-17,1′-cyclobutane]-23-carboxamide or a salt thereof, or a solvate thereof.

[0344] [95-20]A pharmaceutical composition comprising PP3414: (6′S,9′S,13′S,16′S,22′S,29′S,35′S,40a′S,Z)-16′-((S)-sec-butyl)-35′-(3-chloro-4-(trifluoromethyl)phenethyl)-N,N,5′,8′,12′,18′,21′,31′-octamethyl-1′,4′,7′,11′,14′,17′,20′,30′,33′,36′,41′-undecaoxo-6′-(pentan-3-yl)-13′-propyl-29′-(4-(trifluoromethyl)benzyl)-1′,2′,4′,5′,6′,7′,8′,9′,10′,11′,12′,13′,14′,15′,16′,17′,18′,19′,20′,21′,22′,23′,26′,27′,29′,30′,31′,32′,33′,34′,35′,36′,40′,40a′-tetratetracontahydro-38′H-dispiro[cyclobutane-1,3′-[22,28]methanopyrrolo[1,2-j][1,4,7,10,13,16,19,23,26,29,32]undecazacyclotetratetracontene-39′,1″-cyclopropane]-9′-carboxamide or a salt thereof, or a solvate thereof.

[0345] [95-21]A pharmaceutical composition comprising PP2175: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-8-[2-(3,4-dichlorophenyl)ethyl]-12-ethoxy-20-(1-ethylpropyl)-N,N,3′,3′,4,19,22,26,32,35-decamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaoxo-27-propyl-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecazatricyclo[34.5.1.0 10,14 tetracosa-38-ene-17,1′-cyclobutane]-23-carboxamide or a salt thereof, or a solvate thereof.

[0346] [95-22]A pharmaceutical composition comprising PP2750: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-32-cyclopropyl-8-[2-(3,4-dichlorophenyl)ethyl]-20-(2,2-dimethylpropyl)-12-ethoxy-27-(methoxymethyl)-N,N,3′,3′,4,19,22,26,35-nonamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaoxo-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10,14 tetratetracont-38-ene-17,1′-cyclobutane]-23-carboxamide or a salt thereof, or a solvate thereof.

[0347] [95-23]A pharmaceutical composition comprising PP2742: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-32-cyclopropyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-20-(2,2-dimethylpropyl)-12-ethoxy-N,N,3′,3′,4,19,22,26,35-nonamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaoxo-27-propyl-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10,14 tetratetracont-38-ene-17,1′-cyclobutane]-23-carboxamide or a salt thereof, or a solvate thereof.

[0348] [95-24]A pharmaceutical composition comprising PP2967: (6′S,9′S,13′S,16′S,22′S,29′S,35′S,40a′S,Z)-16′-((S)-sec-butyl)-35′-(3-chloro-4-(trifluoromethyl)phenethyl)-13′-(methoxymethyl)-N,N,3,3,5′,8′,12′,18′,21′,31′-decamethyl-29′-(4-methylbenzyl)-1′,4′,7′,11′,14′,17′,20′,30′,33′,36′,41′-undecaooxo-6′-(pentan-3-yl)-1′,2′,4′,5′,6′,7′,8′,9′,10′,11′,12′,13′,14′,15′,16′,17′,18′,19′,20′,21′,22′,23′,26′,27′,29′,30′,31′,32′,33′,34′,35′,36′,40′,40a′-tetratetrahydro-38′H-dispiro[cyclobutane-1,3′-[22,28]methanopiperolino[1,2-j][1,4,7,10,13,16,19,23,26,29,32]undecaazacyclotetracontene-39′,1″-cyclopropane]-9′-carboxamide or a salt thereof, or a solvate thereof.

[0349] [95-25]A pharmaceutical composition comprising PP3510: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38E)-20-cyclopentyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-38-fluoro-27-isobutyl-N,N,4,19,22,26,32,35-octamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaoxo-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10,14 tetracosa-38-ene-17,1′-cyclopentane]-23-carboxamide or a salt thereof, or a solvate thereof.

[0350]

[96] The pharmaceutical composition according to any one of [1] to

[95] , wherein the cyclic compound or a salt thereof, or a solvate thereof has high selectivity for KRAS.

[0351]

[97] The pharmaceutical composition according to any one of [1] to

[96] , wherein the cyclic compound or a salt thereof, or a solvate thereof selectively inhibits KRAS.

[0352]

[98] The pharmaceutical composition according to any one of [1] to

[97] , wherein the divalent group formed by R4 and P5 together interacts with His95 of KRAS.

[0353]

[99] The pharmaceutical composition according to

[98] , wherein the divalent group formed by R4 and P5 together is represented by the following:

[0354]

[0355] and Y in the formula 13 and Y 15 interact with His95 of KRAS.

[0356]

[100] The cyclic compound or a salt thereof, or a solvate thereof according to any one of [1] to

[99] , which has a KRAS inhibitory activity that is 3 times or more the NRAS inhibitory activity and the HRAS inhibitory activity.

[0357]

[101] The cyclic compound or a salt thereof, or a solvate thereof according to

[100] , which has a KRAS inhibitory activity that is 5 times, 7 times, 10 times, 15 times or 20 times or more the NRAS inhibitory activity and the HRAS inhibitory activity.

[0358]

[102] The pharmaceutical composition according to any one of [1] to

[101] , which is used to selectively inhibit KRAS in a subject.

[0359]

[103] The pharmaceutical composition according to

[102] , wherein the KRAS inhibitory activity of the cyclic compound is 3 times or more the NRAS inhibitory activity and the HRAS inhibitory activity of the cyclic compound.

[0360]

[104] The pharmaceutical composition according to

[103] , wherein the KRAS inhibitory activity of the cyclic compound is 5 times, 7 times, 10 times, 15 times or 20 times or more the NRAS inhibitory activity and the HRAS inhibitory activity of the cyclic compound.

[0361]

[105] The pharmaceutical composition according to any one of [1] to

[104] , which is used to treat or prevent cancer in a subject.

[0362]

[106] The pharmaceutical composition according to any one of [1] to

[105] , which contains the cyclic compound or a salt thereof, or a solvate thereof as an active ingredient, and is used to treat or prevent cancer in a subject.

[107] The pharmaceutical composition according to

[105] or

[106] , wherein the cancer is solid cancer or blood cancer.

[0363] [107-1]The pharmaceutical composition according to

[105] or

[106] , wherein the cancer is selected from the group consisting of: lung cancer, esophageal cancer, gastric cancer, colorectal cancer, uterine cancer, ovarian cancer, pancreatic cancer, bladder cancer, thyroid cancer, skin cancer, leukemia, malignant lymphoma, and multiple myeloma.

[0364] [107-2]The pharmaceutical composition according to

[105] or

[106] , wherein the cancer is selected from the group consisting of: esophageal cancer, gastric cancer, colorectal cancer, uterine cancer, ovarian cancer, pancreatic cancer, bladder cancer, thyroid cancer, skin cancer, leukemia, malignant lymphoma, and multiple myeloma.

[0365] [107-3]The pharmaceutical composition according to any one of

[105] to [107-2], wherein the cancer is selected from the group consisting of: non-small cell lung cancer, small cell lung cancer, colon cancer, rectal cancer, uterine cancer, endometrial cancer, cervical cancer, pancreatic cancer, AML (acute myeloid leukemia), CML (chronic myeloid leukemia), ALL (acute lymphoblastic leukemia), CLL (chronic lymphocytic leukemia), Hodgkin lymphoma, and non-Hodgkin lymphoma.

[0366] [107-4]The pharmaceutical composition according to any one of

[105] to [107-2], wherein the cancer is selected from the group consisting of: colon cancer, rectal cancer, uterine cancer, endometrial cancer, cervical cancer, pancreatic cancer, AML (acute myeloid leukemia), CML (chronic myeloid leukemia), ALL (acute lymphoblastic leukemia), CLL (chronic lymphocytic leukemia), Hodgkin lymphoma, and non-Hodgkin lymphoma.

[0367] [107-5]The pharmaceutical composition according to any one of

[105] to [107-2], wherein the cancer is selected from the group consisting of: gastric cancer, colorectal cancer, ovarian cancer, pancreatic cancer, and bladder cancer.

[0368] [107-6]The pharmaceutical composition according to any one of

[105] to [107-5], wherein the cancer is associated with a defect in the RAS gene.

[0369] [107-7]The pharmaceutical composition according to [107-6], wherein the defect in the RAS gene is a mutation in the coding region of the RAS gene and / or an amplification of the copy number of the RAS gene.

[0370] [107-8]The pharmaceutical composition according to [107-7], wherein the RAS gene is one or more RAS genes selected from the group consisting of the KRAS gene, the NRAS gene, and the HRAS gene.

[0371] [107-9]The pharmaceutical composition according to [107-7], wherein the RAS gene is the KRAS gene.

[0372] [107-10]The pharmaceutical composition according to any one of

[105] to [107-9], wherein the cancer is associated with the production of a mutant RAS protein and / or an increase in the production of the RAS protein.

[0373] [107-11]The pharmaceutical composition according to [107-10], wherein the cancer is associated with the production of a mutant RAS protein.

[0374] [107-12]The pharmaceutical composition according to [107-11], wherein the mutant RAS protein is a mutant KRAS protein.

[0375] [107-13]The pharmaceutical composition according to any one of [107-10] to [107-12], wherein the mutant RAS protein has a mutation at at least one amino acid position selected from the group consisting of G12, G13, and Q61 in the amino acid sequences shown in SEQ ID No: 4, SEQ ID No: 5, or SEQ ID No: 6.

[0376] [107-14]The pharmaceutical composition according to any one of [107-10] to [107-13], wherein the mutant RAS protein is a mutant KRAS protein and includes at least one amino acid mutation selected from the group consisting of: G12A, G12C, G12D, G12S, G12V, G13D, Q61H, and Q61K as compared to the amino acid sequence shown in SEQ ID NO: 6.

[0377]

[108] The pharmaceutical composition according to any one of

[103] to

[107] , wherein the subject is a human.

[0378]

[109] The cyclic compound or a salt thereof, or a solvate thereof according to any one of [1] to

[101] , which is used for treating or preventing cancer in a subject.

[0379]

[110] The cyclic compound or a salt thereof, or a solvate thereof according to

[109] , wherein the cancer is at least one selected from the group consisting of: lung cancer, esophageal cancer, gastric cancer, colorectal cancer, uterine cancer, ovarian cancer, pancreatic cancer, bladder cancer, thyroid cancer, skin cancer, leukemia, malignant lymphoma, and multiple myeloma.

[0380] [110-1]The cyclic compound or a salt thereof, or a solvate thereof according to

[109] , wherein the cancer is at least one selected from the group consisting of: esophageal cancer, gastric cancer, colorectal cancer, uterine cancer, ovarian cancer, pancreatic cancer, bladder cancer, thyroid cancer, skin cancer, leukemia, malignant lymphoma, and multiple myeloma.

[0381] [110-2]The cyclic compound or a salt thereof, or a solvate thereof according to

[109] , wherein the cancer is at least one selected from the group consisting of: gastric cancer, colorectal cancer, ovarian cancer, pancreatic cancer, and bladder cancer.

[0382]

[111] The cyclic compound or a salt thereof, or a solvate thereof according to any one of [1] to

[101] , which is used for selectively inhibiting KRAS in a subject.

[0383]

[112] The cyclic compound or a salt thereof, or a solvate thereof according to any one of

[109] to

[111] , wherein the subject is a human.

[0384]

[113] Use of the cyclic compound or a salt thereof, or a solvate thereof according to any one of [1] to

[101] in the manufacture of a medicament for treating or preventing cancer in a subject.

[0385]

[114] The use according to

[113] , wherein the cancer is at least one selected from the group consisting of: lung cancer, esophageal cancer, gastric cancer, colorectal cancer, uterine cancer, ovarian cancer, pancreatic cancer, bladder cancer, thyroid cancer, skin cancer, leukemia, malignant lymphoma, and multiple myeloma.

[0386] [114-1]The use according to

[113] , wherein the cancer is at least one selected from the group consisting of: esophageal cancer, gastric cancer, colorectal cancer, uterine cancer, ovarian cancer, pancreatic cancer, bladder cancer, thyroid cancer, skin cancer, leukemia, malignant lymphoma, and multiple myeloma.

[0387] [114-2]The use according to

[113] , wherein the cancer is at least one selected from the group consisting of: gastric cancer, colorectal cancer, ovarian cancer, pancreatic cancer, and bladder cancer.

[0388]

[115] Use of the cyclic compound or a salt thereof, or a solvate thereof according to any one of [1] to

[101] in the manufacture of a medicament for selectively inhibiting KRAS in a subject.

[0389]

[116] The use according to any one of

[113] to

[115] , wherein the subject is a human.

[0390]

[117] A method for treating or preventing cancer in a subject, the method comprising administering to a subject in need thereof an effective amount of a cyclic compound or a salt thereof, or a solvate thereof, according to any one of [1] to

[101] .

[0391]

[118] The method according to

[117] , wherein the cancer is at least one selected from the group consisting of: lung cancer, esophageal cancer, gastric cancer, colorectal cancer, uterine cancer, ovarian cancer, pancreatic cancer, bladder cancer, thyroid cancer, skin cancer, leukemia, malignant lymphoma, and multiple myeloma.

[0392] [118-1]The method according to

[117] , wherein the cancer is at least one selected from the group consisting of: esophageal cancer, gastric cancer, colorectal cancer, uterine cancer, ovarian cancer, pancreatic cancer, bladder cancer, thyroid cancer, skin cancer, leukemia, malignant lymphoma, and multiple myeloma.

[0393] [118-2]The method according to

[117] , wherein the cancer is at least one selected from the group consisting of: gastric cancer, colorectal cancer, ovarian cancer, pancreatic cancer, and bladder cancer.

[0394]

[119] A method for selectively inhibiting KRAS in a subject, the method comprising administering to a subject in need thereof an effective amount of a cyclic compound or a salt thereof, or a solvate thereof, according to any one of [1] to

[101] .

[0395]

[120] The method according to any one of

[117] to

[119] , wherein the subject is a human.

[0396] In the above numbering scheme, unless otherwise specified, the numbers referred to by dependent items include the branch numbers of that number. For example, the [2] referred to by a dependent item includes its branch numbers, namely [2A], [2B], and [2C], and (for example) the

[95] referred to by a dependent item includes, in addition to

[95] , its branch numbers, namely [95-1] to [95-25]. The same applies to other numbers.

[0397] Effect of the Invention

[0398] The present disclosure may provide a pharmaceutical composition comprising a novel cyclic compound having selective KRAS inhibitory activity. Additionally, the present invention may provide a pharmaceutical composition comprising a cyclic compound as an active ingredient for treating or preventing cell proliferative diseases (especially cancer). BRIEF DESCRIPTION OF THE DRAWINGS

[0399] Figure 1Depicts the complete X-ray crystal structure of the complex of human wild-type KRAS protein and cyclic compound PP0463 as shown in Example 3. The human wild-type KRAS protein is shown in ribbon representation, the cyclic compound PP0463 is shown in stick representation, and guanosine diphosphate (GDP) is shown in ball-and-stick representation.

[0400] Figure 2 Depicts the characteristic interaction sites in the X-ray crystal structure of the complex of human wild-type KRAS protein and cyclic compound PP0463. The human wild-type KRAS protein is shown in ribbon and ball-and-stick representations, and the cyclic compound PP0463 is shown in stick representation. Dashed lines indicate interatomic distances.

[0401] Figure 3 Depicts the complete X-ray crystal structure of the complex of human wild-type KRAS protein and cyclic compound PP0316 as shown in Example 3. The human wild-type KRAS protein is shown in ribbon representation, the cyclic compound PP0316 is shown in stick representation, and GDP is shown in ball-and-stick representation.

[0402] Figure 4 Depicts the characteristic interaction sites in the X-ray crystal structure of the complex of human wild-type KRAS protein and cyclic compound PP0316. The human wild-type KRAS protein is shown in ribbon and ball-and-stick representations, and the cyclic compound PP0316 is shown in stick representation. Dashed lines indicate interatomic distances.

[0403] Figure 5 Depicts the complete X-ray crystal structure of the complex of human wild-type KRAS protein and cyclic compound PP0476 as shown in Example 3. The human wild-type KRAS protein is shown in ribbon representation, and the cyclic compound PP0476 is shown in stick representation, and GDP is shown in ball-and-stick representation.

[0404] Figure 6 Depicts the characteristic interaction sites in the X-ray crystal structure of the complex of human wild-type KRAS protein and cyclic compound PP0476. The human wild-type KRAS protein is shown in ribbon and ball-and-stick representations, and the cyclic compound PP0476 is shown in stick representation. Dashed lines indicate interatomic distances. Detailed Description

[0405] (Abbreviations)

[0406] The abbreviations used herein are as follows.

[0407] AA: Ammonium acetate

[0408] Boc: tert-Butyloxycarbonyl

[0409] CSA: (+)-10-Camphorsulfonic acid

[0410] CPME: Cyclopentyl methyl ether

[0411] DAST: (Diethylamino)sulfur trifluoride

[0412] DBU: 1,8-Diazabicyclo[5.4.0]-7-undecene

[0413] DCM: Dichloromethane

[0414] DCE: 1,2-Dichloroethane

[0415] DEAD: Diethyl azodicarboxylate

[0416] DEPBT: 3-(Diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one

[0417] DIAD: Diisopropyl azodicarboxylate

[0418] DIC: N,N′-Diisopropylcarbodiimide

[0419] DIPEA: N,N-Diisopropylethylamine

[0420] DHP: 3,4-Dihydro-2H-pyran

[0421] DMA: N,N-Dimethylacetamide

[0422] DMAP: N,N-Dimethyl-4-aminopyridine

[0423] DMF: N,N-Dimethylformamide

[0424] dtbbpy: 4,4′-Di-tert-butyl-2,2′-bipyridine

[0425] EDTA: Ethylenediaminetetraacetic acid

[0426] FA: Formic acid

[0427] Fmoc: 9-Fluorenylmethyloxycarbonyl

[0428] NMP: N-Methyl-2-pyrrolidone

[0429] TBME: tert-Butyl methyl ether

[0430] TES: Triethylsilane

[0431] TFA: Trifluoroacetic acid

[0432] TFE: 2,2,2-Trifluoroethanol

[0433] THF: Tetrahydrofuran

[0434] THP: Tetrahydropyranyl

[0435] TMSCl: Trimethylchlorosilane

[0436] HFIP: 1,1,1,3,3,3-Hexafluoroisopropanol

[0437] HOAt: 1-Hydroxy-7-azabenzotriazole

[0438] HOBt: 1-Hydroxybenzotriazole

[0439] HOOBt: 3,4-Dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine

[0440] IPAC: Isopropyl acetate

[0441] oxyma: Ethyl cyano(oximino)acetate

[0442] PPTS: Pyridinium p-toluenesulfonate

[0443] Pis: 2-Phenylisopropyl

[0444] WSCI·HCl, WSCDI: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride

[0445] TIPS: Triisopropylsilane

[0446] TfOH: Trifluoromethanesulfonic acid

[0447] HATU: O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate

[0448] DMSO: Dimethyl sulfoxide

[0449] Fmoc-Cl: 9H-Fluoren-9-ylmethyl chloroformate

[0450] Fmoc-OSu: N-Succinimidyl 9-fluorenylmethyl carbonate

[0451] Ns: o-Nitrobenzenesulfonyl

[0452] Trt: Triphenylmethyl

[0453] 9-BBN: 9-Borabicyclo[3.3.1]nonane

[0454] HMDS: 1,1,1,3,3,3-Hexamethyldisilazane

[0455] LDA: Lithium diisopropylamide

[0456] TMSOTf: Trimethylsilyl trifluoromethanesulfonate

[0457] PPA: Polyphosphoric acid

[0458] As used herein, when used in combination with a numerical value, the term "about" means a numerical range of -10% to +10% of that numerical value.

[0459] As used herein, the "-" indicating a range includes the values at both ends of the range. For example, "A - B" means a range of A or more and B or less.

[0460] As used herein, the unit of molecular weight is "g / mol" (hereinafter, the unit of molecular weight may be omitted).

[0461] The articles "a", "an", and "the" used in both the specification and the claims shall be construed to cover both the singular and the plural, unless otherwise stated herein or clearly contradicted by the context.

[0462] (Definition of functional groups, etc.)

[0463] As used herein, examples of the "halogen atom" include F, Cl, Br, and I.

[0464] As used herein, "alkyl" means a monovalent group derived by removing any one hydrogen atom from an aliphatic hydrocarbon, and has a hydrocarbon group or a subset of a hydrocarbon group structure that does not contain heteroatoms (atoms other than carbon and hydrogen atoms) or unsaturated carbon-carbon bonds in its backbone, but contains hydrogen and carbon atoms. Alkyl includes straight-chain and branched-chain alkyls. Specifically, alkyl has 1 to 20 carbon atoms (C1 - C 20 , hereinafter "C p -C q " means that the number of carbon atoms is from p to q), and is preferably C1 - C 10 alkyl, and more preferably C1 - C6 alkyl. Specific examples of alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl (2-methylpropyl), n-pentyl, sec-pentyl (1-methylbutyl), tert-pentyl (1,1-dimethylpropyl), neopentyl (2,2-dimethylpropyl), isopentyl (3-methylbutyl), 3-pentyl (1-ethylpropyl), 1,2-dimethylpropyl, 2-methylbutyl, n-hexyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1,1,2,2-tetramethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, and 2-ethylbutyl.

[0465] As used herein, "alkenyl" means having at least one double bond (two adjacent SP2 a monovalent group of (carbon atoms). Depending on the configuration of the double bond and substituents (if any), the geometric form of the double bond can be trans (E) or cis (Z) and cis or trans configurations. Alkenyl groups include straight-chain and branched-chain alkenyl groups. Alkenyl groups are preferably C2-C 10 alkenyl groups, and more preferably C2-C7 alkenyl groups or C2-C6 alkenyl groups, and specific examples include vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl (including cis and trans forms), 3-butenyl, pentenyl, 3-methyl-2-butenyl, hexenyl, and 6-heptenyl.

[0466] In this context, "alkynyl" means a monovalent group having at least one triple bond (two adjacent sp carbon atoms). Alkynyl groups include straight-chain and branched-chain alkynyl groups. Alkynyl groups are preferably C2-C 10 alkynyl groups, and more preferably C2-C6 alkynyl groups, and specific examples include ethynyl, 1-propynyl, propargyl, 3-butynyl, pentynyl, hexynyl, 3-phenyl-2-propynyl, 3-(2'-fluorophenyl)-2-propynyl, 2-hydroxy-2-propynyl, 3-(3-fluorophenyl)-2-propynyl, and 3-methyl-(5-phenyl)-4-pentynyl.

[0467] In this context, "cycloalkyl" means a saturated or partially saturated cyclic monovalent aliphatic hydrocarbon group and includes monocyclic, bicyclic, and spiro rings. Cycloalkyl groups are preferably C3-C8 cycloalkyl groups, and specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[1.1.1]heptyl, bicyclo[2.2.1]heptyl, and spiro[3.3]heptyl.

[0468] In this context, "aryl" means a monovalent aromatic hydrocarbon ring, and is preferably C6-C 10 aryl. Specific examples of aryl include phenyl and naphthyl (e.g., 1-naphthyl and 2-naphthyl). In this context, aryl includes bicyclic aryls in which the aromatic hydrocarbon ring is fused to another saturated or unsaturated ring, and for example includes aryls having a fused ring structure in which the aromatic hydrocarbon ring is a benzene ring and the saturated ring is a 5-membered, 6-membered, or 7-membered saturated hydrocarbon ring or saturated heterocycle. Specific examples include indanyl, 1,2,3,4-tetrahydronaphthyl, and 2,3-dihydrobenzofuran.

[0469] As used herein, "heterocyclic group" means a non-aromatic cyclic monovalent group containing 1 to 5 heteroatoms in addition to carbon atoms. The heterocyclic group may have double bonds and / or triple bonds within the ring, the carbon atoms within the ring may be oxidized to form carbonyl groups, and the heterocyclic group may be a monocyclic or fused ring. The number of atoms constituting the ring is preferably 3 to 10 (3- to 10-membered heterocyclic group) or 4 to 10 (4- to 10-membered heterocyclic group), and more preferably 3 to 7 (3- to 7-membered heterocyclic group) or 4 to 7 (4- to 7-membered heterocyclic group). Specific examples of the heterocyclic group include azetidinyl, oxiranyl, oxetanyl, azetidinyl, dihydrofuranyl, tetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, tetrahydropyridyl, tetrahydropyrimidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, pyrazolidinyl, imidolinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, 1,2-thiazinane, thiazolidinyl, azetidinyl, oxazolidinone, benzodioxolyl, benzoxazolyl, dioxolanyl, dioxanyl, tetrahydropyrrolo[1,2-c]imidazole, thietanyl, 3,6-diazabicyclo[3.1.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 3-oxa-8-azabicyclo[3.2.1]octanyl, sultam, and 2-oxaspiro[3.3]heptyl.

[0470] As used herein, "protected heterocyclic group" means a group in which one or more functional groups (such as amino groups) contained in the "heterocyclic group" defined above are protected by a protecting group, and is preferably a 4- to 7-membered protected heterocyclic group. Specific examples of the protecting group include Boc, Fmoc, Cbz, Troc, and Alloc, and specific examples of the protected heterocyclic group include Boc-protected azetidine.

[0471] As used herein, "heterocycloalkylidene" means a divalent group obtained by removing two hydrogen atoms from one carbon atom of the "heterocyclic group" defined above, wherein the free valence forms part of a double bond. The heterocycloalkylidene is preferably a 4- to 7-membered heterocycloalkylidene, and specific examples include tetrahydropyran-4-ylidene and azetidine-3-ylidene.

[0472] As used herein, "protected heterocycloalkylidene" means a group in which one or more functional groups (such as amino groups) contained in the "heterocycloalkylidene" defined above are protected by a protecting group, and is preferably a 4- to 7-membered protected heterocycloalkylidene. Specific examples of the protecting group include Boc, Fmoc, Cbz, Troc, and Alloc, and specific examples of the protected heterocycloalkylidene include Boc-protected azetidine-3-ylidene.

[0473] As used herein, "heteroaryl" means an aromatic cyclic monovalent group containing 1 to 5 heteroatoms in addition to carbon atoms. The ring can be a monocyclic ring, a fused ring formed with other rings, or can be partially saturated. The number of atoms constituting the ring is preferably 5 to 10 (5- to 10-membered heteroaryl), and more preferably 5 to 7 (5- to 7-membered heteroaryl). Specific examples of heteroaryl include furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, benzofuryl, benzothienyl, benzothiadiazolyl, benzothiazolyl, benzoxazolyl, benzoxadiazolyl, benzimidazolyl, indolyl, isoindolyl, indazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, benzodioxolyl, indazinyl, and imidazopyridyl.

[0474] As used herein, "alkoxy" means an oxy group bonded to the "alkyl" as defined above, and is preferably C1-C6 alkoxy. Specific examples of alkoxy include methoxy, ethoxy, 1-propoxy, 2-propoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, and 3-methylbutoxy.

[0475] As used herein, "alkylthio" means a thiol group bonded to the "alkyl" as defined above, and is preferably C1-C6 alkylthio. Specific examples of alkylthio include methylthio, ethylthio, 1-propylthio, 2-propylthio, n-butylthio, isobutylthio, sec-butylthio, and tert-butylthio.

[0476] As used herein, "alkenyloxy" means an oxy group bonded to the "alkenyl" as defined above, and is preferably C2-C6 alkenyloxy. Specific examples of alkenyloxy include vinyloxy, allyloxy, 1-propenyloxy, 2-propenyloxy, 1-butenyloxy, 2-butenyloxy (including cis and trans forms), 3-butenyloxy, pentyloxy, and hexyloxy.

[0477] As used herein, "cycloalkoxy" means an oxy group bonded to the "cycloalkyl" as defined above, and is preferably C3-C8 cycloalkoxy. Specific examples of cycloalkoxy include cyclopropoxy, cyclobutoxy, and cyclopentyloxy.

[0478] As used herein, "aryloxy" means an oxy group bonded to the "aryl" as defined above, and is preferably C6-C 10 aryloxy. Specific examples of aryloxy include phenoxy, 1-naphthyloxy, and 2-naphthyloxy.

[0479] As used herein, "amino" means -NH₂ in the narrow sense and -NRR' in the broad sense, where R and R' are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl or heteroaryl, or R and R' together with the nitrogen atom to which they are attached form a ring. The amino group is preferably -NH₂, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, 4- to 8-membered cyclic amino group, etc.

[0480] As used herein, "monoalkylamino" means a group corresponding to the "amino" defined above, where R is hydrogen and R' is the "alkyl" defined above, and is preferably mono-C₁-C₆ alkylamino. Specific examples of monoalkylamino include methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, sec-butylamino and tert-butylamino.

[0481] As used herein, "dialkylamino" means a group corresponding to the "amino" defined above, where R and R' are independently the "alkyl" defined above, and is preferably di-C₁-C₆ alkylamino. Specific examples of dialkylamino include dimethylamino and diethylamino.

[0482] As used herein, "cyclic amino" means a group corresponding to the "amino" defined above, where R and R' together with the nitrogen atom to which they are attached form a ring, and is preferably 4- to 8-membered cyclic amino. Specific examples of cyclic amino include 1-azetidinyl, 1-pyrrolidinyl, 1-piperidinyl, 1-piperazinyl, 4-morpholinyl, 3-oxazolidinyl, 1,1-dioxothiomorpholin-4-yl and 3-oxa-8-azabicyclo[3.2.1]octan-8-yl.

[0483] As used herein, "protected amino" means an amino group protected by any protecting group. Specific examples of protected amino include amino groups protected by protecting groups such as Boc, Fmoc, Cbz, Troc or Alloc.

[0484] As used herein, "alkylcarbonyl" means a carbonyl group bonded to the "alkyl" defined above, and is preferably C₁-C₆ alkylcarbonyl. Specific examples of alkylcarbonyl include acetyl, propionyl and butyryl. The number of carbon atoms listed in the above definition indicates the number of carbon atoms in the alkyl moiety. For example, "C₁-C₆" in "C₁-C₆ alkylcarbonyl" indicates that the alkyl moiety has 1 to 6 carbon atoms.

[0485] As used herein, "aminocarbonyl" means a carbonyl group bonded to the "amino" as defined above, and is preferably -CONH2, mono-C1-C6 alkylaminocarbonyl, di-C1-C6 alkylaminocarbonyl, and 4- to 8-membered cyclic aminocarbonyl. Specific examples of aminocarbonyl include -CONH2, dimethylaminocarbonyl, 1-azetidinylcarbonyl, 1-pyrrolidinylcarbonyl, 1-piperidinylcarbonyl, 1-piperazinylcarbonyl, 4-morpholinylcarbonyl, 3-oxazolidinylcarbonyl, 1,1-dioxothiomorpholin-4-ylcarbonyl, and 3-oxa-8-azabicyclo[3.2.1]oct-8-ylcarbonyl.

[0486] As used herein, "alkenyloxycarbonyl" means a carbonyl group bonded to the "alkenyloxy" as defined above, and is preferably C2-C6 alkenyloxycarbonyl. Specific examples of alkenyloxycarbonyl include vinyloxycarbonyl, allyloxycarbonyl, 1-propenyloxycarbonyl, 2-propenyloxycarbonyl, 1-butenyloxycarbonyl, 2-butenyloxycarbonyl (including cis and trans forms), 3-butenyloxycarbonyl, pentyenyloxycarbonyl, and hexyenyloxycarbonyl.

[0487] As used herein, "alkylsulfonyl" means a sulfonyl group bonded to the "alkyl" as defined above, and is preferably C1-C6 alkylsulfonyl. A specific example of alkylsulfonyl is methylsulfonyl.

[0488] As used herein, "hydroxyalkyl" means a group in which one or more hydrogens of the "alkyl" as defined above are replaced by a hydroxy group, and is preferably C1-C6 hydroxyalkyl. Specific examples of hydroxyalkyl include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl, and 5-hydroxypentyl.

[0489] As used herein, "haloalkyl" means a group in which one or more hydrogens of the "alkyl" as defined above are replaced by a halogen, and is preferably C1-C6 haloalkyl, and more preferably C1-C6 fluoroalkyl. Specific examples of haloalkyl include difluoromethyl, trifluoromethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3,3-difluoropropyl, 4,4-difluorobutyl, 5,5-difluoropentyl, and 1,1-difluoroethyl.

[0490] As used herein, "cyanoalkyl" means a group in which one or more hydrogens of the "alkyl" as defined above are replaced by a cyano group, and is preferably C1-C6 cyanoalkyl. Specific examples of cyanoalkyl include cyanomethyl and 2-cyanoethyl.

[0491] As used herein, "aminoalkyl" means a group in which one or more hydrogens of the above-defined "alkyl" are replaced by the above-defined "amino", and is preferably C1-C6 aminoalkyl. Specific examples of aminoalkyl include 1-pyridylmethyl, 2-(1-piperidyl)ethyl, 3-(1-piperidyl)propyl, 4-aminobutyl, and 2-aminoethyl.

[0492] As used herein, "carboxyalkyl" means a group in which one or more hydrogens of the above-defined "alkyl" are replaced by carboxy, and is preferably C1-C6 carboxyalkyl or C2-C6 carboxyalkyl. A specific example of carboxyalkyl is carboxymethyl. The number of carbon atoms listed in the above definition indicates the number of carbon atoms in the alkyl moiety. For example, "C1-C6 carboxyalkyl" means that the "C1-C6" indicates that the alkyl moiety has 1 to 6 carbon atoms.

[0493] As used herein, "alkenyloxycarbonylalkyl" means a group in which one or more hydrogens of the above-defined "alkyl" are replaced by the above-defined "alkenyloxycarbonyl", and is preferably C2-C6 alkenyloxycarbonyl C1-C6 alkyl, and more preferably C2-C6 alkenyloxycarbonyl C1-C2 alkyl. Specific examples of alkenyloxycarbonylalkyl include allyloxycarbonylmethyl and 2-(allyloxycarbonyl)ethyl.

[0494] As used herein, "alkoxyalkyl" means a group in which one or more hydrogens of the above-defined "alkyl" are replaced by the above-defined "alkoxy", and is preferably C1-C6 alkoxy C1-C6 alkyl, and more preferably C 1- C6 alkoxy C1-C2 alkyl. Specific examples of alkoxyalkyl include methoxymethyl, ethoxymethyl, 1-propoxymethyl, 2-propoxymethyl, n-butoxymethyl, isobutoxymethyl, sec-butoxymethyl, tert-butoxymethyl, pentyloxymethyl, 3-methylbutoxymethyl, 1-methoxyethyl, 2-methoxyethyl, 2-ethoxyethyl, 1-ethoxyethyl, and 1-n-propoxyethyl.

[0495] As used herein, "alkylthioalkyl" means a group in which one or more hydrogens of the above-defined "alkyl" are replaced by the above-defined "alkylthio", and is preferably C1-C6 alkylthio C1-C6 alkyl, and more preferably C1-C6 alkylthio C1-C2 alkyl. Specific examples of alkylthioalkyl include methylthiomethyl, ethylthiomethyl, 1-propylthiomethyl, 2-propylthiomethyl, n-butylthiomethyl, isobutylthiomethyl, sec-butylthiomethyl, and tert-butylthiomethyl.

[0496] As used herein, "alkenyloxyalkyl" means a group in which one or more hydrogens of the above-defined "alkyl" are replaced by the above-defined "alkenyloxy", and is preferably C2-C6 alkenyloxy C1-C6 alkyl, and more preferably C1-C6 alkenyloxy C1-C2 alkyl. Specific examples of alkenyloxyalkyl include vinyloxymethyl and allyloxymethyl.

[0497] As used herein, "cycloalkylalkyl" means a group in which one or more hydrogens of the above-defined "alkyl" are replaced by the above-defined "cycloalkyl", and is preferably C3-C8 cycloalkyl C1-C6 alkyl, and more preferably C3-C6 cycloalkyl C1-C2 alkyl. Specific examples of cycloalkylalkyl include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, and cyclohexylmethyl.

[0498] As used herein, "cycloalkyloxyalkyl" means a group in which one or more hydrogens of the above-defined "alkyl" are replaced by the above-defined "cycloalkyloxy", and is preferably C3-C8 cycloalkyloxy C1-C6 alkyl, and more preferably C3-C6 cycloalkyloxy C1-C2 alkyl. Specific examples of cycloalkyloxyalkyl include cyclopropoxymethyl and cyclobutoxymethyl.

[0499] As used herein, "heterocyclylalkyl" means a group in which one or more hydrogens of the above-defined "alkyl" are replaced by the above-defined "heterocyclyl", and is preferably 4- to 7-membered heterocyclyl C1-C6 alkyl, and more preferably 4- to 7-membered heterocyclyl C1-C2 alkyl. Specific examples of heterocyclylalkyl include 2-(tetrahydro-2H-pyran-4-yl)ethyl and 2-(azetidin-3-yl)ethyl.

[0500] As used herein, "alkylsulfonylalkyl" means a group in which one or more hydrogens of the above-defined "alkyl" are replaced by the above-defined "alkylsulfonyl", and is preferably C1-C6 alkylsulfonyl C1-C6 alkyl, and more preferably C1-C6 alkylsulfonyl C1-C2 alkyl. Specific examples of alkylsulfonylalkyl include methanesulfonylmethyl and 2-(methylsulfonyl)ethyl.

[0501] As used herein, "aminocarbonylalkyl" means a group in which one or more hydrogens of the above-defined "alkyl" are replaced by the above-defined "aminocarbonyl", and is preferably aminocarbonyl C1-C6 alkyl, and more preferably aminocarbonyl C1-C4 alkyl. Specific examples of aminocarbonylalkyl include methylaminocarbonylmethyl, dimethylaminocarbonylmethyl, tert-butylaminocarbonylmethyl, 1-azetidinylcarbonylmethyl, 1-pyrrolidinylcarbonylmethyl, 1-piperidinylcarbonylmethyl, 4-morpholinylcarbonylmethyl, 2-(methylaminocarbonyl)ethyl, 2-(dimethylaminocarbonyl)ethyl, 2-(1-azetidinylcarbonyl)ethyl, 2-(1-pyrrolidinylcarbonyl)ethyl, 2-(4-morpholinylcarbonyl)ethyl, 3-(dimethylaminocarbonyl)propyl, and 4-(dimethylaminocarbonyl)butyl.

[0502] As used herein, "aryloxyalkyl" means a group in which one or more hydrogens of the above-defined "alkyl" are replaced by the above-defined "aryloxy", and is preferably C6-C 10 aryloxy C1-C6 alkyl, and more preferably C6-C 10 aryloxy C1-C2 alkyl. Specific examples of aryloxyalkyl include phenoxymethyl and 2-phenoxyethyl.

[0503] As used herein, "aralkyl (arylalkyl)" means a group in which one or more hydrogen atoms of the above-defined "alkyl" are replaced by the above-defined "aryl", and is preferably C7-C 14 aralkyl, and more preferably C7-C 10 aralkyl. Specific examples of aralkyl include benzyl, phenethyl, and 3-phenylpropyl.

[0504] As used herein, "aralkyloxy" means an oxy group bonded to the above-defined "aralkyl", and is preferably C7-C 14 aralkyloxy, and more preferably C7-C 10 aralkyloxy. Specific examples of aralkyloxy include benzyloxy, phenethyloxy, and 3-phenylpropoxy.

[0505] As used herein, "aralkyloxyalkyl" means a group in which one or more hydrogens of the above-defined "alkyl" are replaced by the above-defined "aralkyloxy", and is preferably C7-C 14 aralkyloxy C1-C6 alkyl, and more preferably C7-C 14 aralkyloxy C1-C2 alkyl. Specific examples of aralkyloxyalkyl include benzyloxymethyl and 1-(benzyloxy)ethyl.

[0506] As used herein, "heteroarylalkyl" means a group in which one or more hydrogen atoms of "alkyl" as defined above are replaced by "heteroaryl" as defined above, and is preferably a 5- to 10-membered heteroaryl C1-C6 alkyl, and more preferably a 5- to 10-membered heteroaryl C1-C2 alkyl. Specific examples of heteroarylalkyl include 3-thienylmethyl, 4-thiazolylmethyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-(2-pyridyl)ethyl, 2-(3-pyridyl)ethyl, 2-(4-pyridyl)ethyl, 2-(6-quinolyl)ethyl, 2-(7-quinolyl)ethyl, 2-(6-indolyl)ethyl, 2-(5-indolyl)ethyl, and 2-(5-benzofuranyl)ethyl.

[0507] As used herein, "heteroarylalkoxy" means an oxy group bonded to "heteroarylalkyl" as defined above, and is preferably a 5- to 10-membered heteroaryl C1-C6 alkoxy, and more preferably a 5- to 10-membered heteroaryl C1-C2 alkoxy. Specific examples of heteroarylalkoxy include 3-thienylmethoxy and 3-pyridylmethoxy.

[0508] As used herein, "heteroarylalkoxyalkyl" means a group in which one or more hydrogens of "alkyl" as defined above are replaced by "heteroarylalkoxy" as defined above, and is preferably a 5- to 10-membered heteroaryl C1-C6 alkoxy C1-C6 alkyl, and more preferably a 5- to 10-membered heteroaryl C1-C2 alkoxy C1-C2 alkyl. Specific examples of heteroarylalkoxyalkyl include 3-pyridylmethoxymethyl.

[0509] As used herein, "heterocycloalkylalkyl" means a group in which one or more hydrogens of "alkyl" as defined above are replaced by "heterocycloalkyl" as defined above, and is preferably a 4- to 7-membered heterocycloalkyl C1-C6 alkyl, and more preferably a 4- to 7-membered heterocycloalkyl C1-C2 alkyl. Specific examples of heterocycloalkylalkyl include tetrahydro-4H-pyran-4-ylidene methyl and azetidin-3-ylidene methyl.

[0510] As used herein, "alkoxyalkenyl" means a group in which one or more hydrogens of "alkenyl" as defined above are replaced by "alkoxy" as defined above, and is preferably a C1-C6 alkoxy C2-C6 alkenyl. Specific examples of alkoxyalkenyl include (E)-4-methoxybut-2-en-1-yl.

[0511] As used herein, "aminocarbonylalkenyl" means a group in which one or more hydrogens of "alkenyl" as defined above are replaced by "aminocarbonyl" as defined above, and is preferably an aminocarbonyl C2-C6 alkenyl. Specific examples of aminocarbonylalkenyl include (E)-3-(dimethylaminocarbonyl)-prop-2-en-1-yl.

[0512] As used herein, "haloalkoxy" means a group in which one or more hydrogens of the above-defined "alkoxy" are replaced by halogen, and is preferably C1-C6 haloalkoxy. Specific examples of haloalkoxy include difluoromethoxy, trifluoromethoxy, 2,2-difluoroethoxy, and 2,2,2-trifluoroethoxy.

[0513] As used herein, "alkylene" means a divalent group derived by further removing any one hydrogen atom from the above "alkyl", and is preferably C4-C8 alkylene. Specific examples of alkylene include -CH2-, -(CH2)2-, -(CH2)3-, -CH(CH3)CH2-, -C(CH3)2-, -(CH2)4-, -CH(CH3)CH2CH2-, -C(CH3)2CH2-, -CH2CH(CH3)CH2-, -CH2C(CH3)2-, -CH2CH2CH(CH3)-, -(CH2)5-, -(CH2)6-, -(CH2)7-, and -(CH2)8-.

[0514] As used herein, "cycloalkylene" means a divalent group derived by further removing any one hydrogen atom from the above "cycloalkyl", and is preferably C3-C8 cycloalkylene. Specific examples of cycloalkylene include cyclopropane-1,2-diyl, cyclobutane-1,2-diyl, cyclopentane-1,2-diyl, and cyclohexane-1,2-diyl.

[0515] As used herein, "heterocyclylene" means a divalent group derived by removing any one hydrogen atom from the above "heterocyclic group", and is preferably a 3- to 7-membered heterocyclylene. Specific examples of heterocyclylene include oxolane-2,3-diyl, oxetane-2,3-diyl, tetrahydrofuran-2,5-diyl, and tetrahydropyran-2,6-diyl.

[0516] As used herein, "alkenylene" means a divalent group derived by further removing any one hydrogen atom from the above "alkenyl". Depending on the configuration of the double bond and substituents (if any), the geometric form of the double bond can be trans (E) or cis (Z) and cis or trans configurations. Alkenylene can be straight-chain or branched, and is preferably C2-C 10 alkenylene, and more preferably C2-C6 alkenylene.

[0517] As used herein, "alkynylene" means a divalent group derived by further removing any one hydrogen atom from the above "alkynyl". Alkynylene can be straight-chain or branched, and is preferably C2-C 10 alkynylene, and more preferably C2-C6 alkynylene.

[0518] As used herein, "arylene" means a divalent group derived by further removing any one hydrogen atom from the above-mentioned "aryl". The arylene may be monocyclic or fused-ring. The number of atoms constituting the ring is not particularly limited, and is preferably 6 to 10 (C6- 10 arylene). Specific examples of the arylene include 1,2-phenylene, 1,3-phenylene, 1,4-phenylene, 1,2-naphthylene, 1,3-naphthylene, and 1,4-naphthylene.

[0519] As used herein, "spiroalkyl" means a group formed by sharing one carbon atom constituting a cycloalkane ring with a carbon atom present in a bonding group. The spiroalkyl is preferably a C3-C8 spiroalkyl, and specific examples include spiropropyl, spirobutyl, spiropentyl, spirohexyl, spiroheptyl, and spirooctyl.

[0520] As used herein, "spiroheterocyclic group" means a group obtained by replacing one or more carbon atoms in the above-mentioned "spiroalkyl" with heteroatoms. The spiroheterocyclic group is preferably a 4- to 10-membered spiroheterocyclic group.

[0521] As used herein, "alicyclic ring" means a non-aromatic hydrocarbon ring. The alicyclic ring may have an unsaturated bond in the ring and may be a polycyclic ring having two or more rings. The carbon atoms constituting the ring may be oxidized to form a carbonyl group. The alicyclic ring is preferably a 3- to 8-membered alicyclic ring, and specific examples include cyclopropane ring, cyclobutane ring, cyclopentane ring, cyclohexane ring, cycloheptane ring, cyclooctane ring, and bicyclo[2.2.1]heptane ring.

[0522] As used herein, "saturated heterocycle" means a non-aromatic heterocycle containing 1 to 5 heteroatoms in addition to carbon atoms and having no double bond and / or triple bond in the ring. The saturated heterocycle may be monocyclic or may form a fused ring with another ring (e.g., an aromatic ring such as a benzene ring). The saturated heterocycle is preferably a 4- to 7-membered saturated heterocycle, and specific examples include azetidine ring, oxetane ring, tetrahydrofuran ring, tetrahydropyran ring, morpholine ring, thiomorpholine ring, pyrrolidine ring, 4-oxopyrrolidine ring, piperidine ring, 4-oxopiperidine ring, piperazine ring, pyrazolidine ring, imidazolidine ring, oxazolidine ring, isoxazolidine ring, thiazolidine ring, isothiazolidine ring, thiadiazolidine ring, oxazolidinone ring, dioxolane ring, dioxane ring, thiacyclobutane ring, octahydroindole ring, dihydroindole ring, and azepane ring.

[0523] As used herein, "peptide chain" means a peptide chain in which 1, 2, 3, 4, or more natural amino acids and / or unnatural amino acids are linked by amide bonds and / or ester bonds. The peptide chain is preferably a peptide chain containing 1 to 4 amino acid residues, and more preferably a peptide chain composed of 1 to 4 amino acid residues.

[0524] As used herein, "optionally substituted" means that the group may be substituted with any substituent.

[0525] As used herein, "optionally protected" means that the group can be protected with any protecting group.

[0526] As used herein, "one or more" means one or two or more. When used in the context of substituents of a group, the phrase means to cover numbers from one up to the maximum number of substituents allowed for the group. Specific examples of "one or more" include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 and / or greater numbers.

[0527] The wavy lines in the structural formulas herein can mean that any stereochemistry is allowed. For example, when an asymmetric center is provided with a wavy line, the stereochemistry of the asymmetric center can be in the S configuration or the R configuration. When a double bond is provided with a wavy line, the stereochemistry of the double bond can be in the E configuration or the Z configuration.

[0528] The compounds of the present disclosure can be their salts, and preferably their chemical or pharmaceutical salts. Additionally, the compounds or their salts of the present disclosure can be their solvates, and preferably their chemical or pharmaceutical solvates. Examples of salts of the compounds of the present disclosure include: hydrochloride; hydrobromide; hydroiodide; phosphate; phosphonate; sulfate; sulfonate, such as mesylate and tosylate; carboxylate, such as acetate, citrate, malate, tartrate, succinate and salicylate; alkali metal salts, such as sodium salt and potassium salt; alkaline earth metal salts, such as magnesium salt and calcium salt; and ammonium salts, such as ammonium salt, alkylammonium salt, dialkylammonium salt, trialkylammonium salt and tetraalkylammonium salt. These salts are prepared, for example, by contacting the compound with an acid or a base that can be used in the production of pharmaceuticals. In the present disclosure, a solvate of a compound refers to a molecular aggregate formed by the compound together with a solvent, and when the solvent is water, it is called a hydrate. The solvates of the compounds of the present disclosure are preferably hydrates, and specific examples of such hydrates include monohydrate to decahydrate, preferably monohydrate to pentahydrate, and more preferably monohydrate to trihydrate. The solvates of the compounds of the present disclosure include not only solvates formed by a single solvent (such as water, alcohol (e.g., methanol, ethanol, 1-propanol or 2-propanol) or dimethylformamide), but also solvates formed by multiple solvents.

[0529] As used herein, the term "amino acid" includes natural and unnatural amino acids. As used herein, the term "natural amino acid" refers to Gly, Ala, Ser, Thr, Val, Leu, Ile, Phe, Tyr, Trp, His, Glu, Asp, Gln, Asn, Cys, Met, Lys, Arg or Pro. Examples of unnatural amino acids include but are not particularly limited to β-amino acids, γ-amino acids, D-amino acids, N-substituted amino acids, α,α-disubstituted amino acids, amino acids with side chains different from those of natural amino acids, and hydroxycarboxylic acids. The amino acids herein can have any conformation. The selection of amino acid side chains is not particularly limited and can freely be selected from, for example, alkyl groups, alkenyl groups, alkynyl groups, aryl groups, heteroaryl groups, aralkyl groups, and cycloalkyl groups in addition to a hydrogen atom. One or two non-adjacent methylene groups in such groups are optionally substituted with an oxygen atom, a carbonyl group (-CO-), or a sulfonyl group (-SO2-). Each group can have a substituent, and there is no limitation on the substituent. For example, one or more substituents can freely and independently be selected from any substituents including a halogen atom, an O atom, an S atom, an N atom, a B atom, an Si atom, or a P atom. Examples include optionally substituted alkyl groups, alkenyl groups, alkynyl groups, aryl groups, heteroaryl groups, aralkyl groups, and cycloalkyl groups. In a non-limiting embodiment, the amino acids herein can be compounds having a carboxyl group and an amino group in the same molecule (even in such a case, proline, hydroxyproline, azetidine-2-carboxylic acid, etc., in which the nitrogen atom of the amino group binds to any atom of the side chain to form a ring, are also included in the amino acids).

[0530] The backbone amino group of the amino acid can be unsubstituted (NH2 group) or substituted (i.e., -NHR group, where R represents an alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, or cycloalkyl that can have a substituent, one or two non-adjacent methylene groups in such groups can be replaced by an oxygen atom, a carbonyl group (-CO-), or a sulfonyl group (-SO2-), and the carbon chain bonded to the N atom and the carbon atom at the α-position can form a ring, such as proline). The R substituent is selected in the same manner as the substituents in the above-described amino acid side chains. When the backbone amino group is substituted, R is included in the "amino acid side chain" as used herein. Such amino acids in which the backbone amino group is substituted are referred to herein as "N-substituted amino acids". As used herein, preferred examples of "N-substituted amino acids" include but are not limited to N-alkyl amino acids, N-C1-C6 alkyl amino acids, N-C1-C4 alkyl amino acids, and N-methyl amino acids.

[0531] As used herein, "amino acid" constituting a peptide compound includes all isotopes corresponding to each amino acid. An isotope of an "amino acid" refers to a case where at least one atom is replaced by an atom having the same atomic number (number of protons) and a different mass number (total number of protons and neutrons). Examples of isotopes contained in the "amino acid" constituting the peptide compounds of the present disclosure include hydrogen atom, carbon atom, nitrogen atom, oxygen atom, phosphorus atom, sulfur atom, fluorine atom, and chlorine atom, which respectively include 2 H and 3 H; 13 C and 14 C; 15 N; 17 O and 18 O; 31 P and 32 p; 35 S; 18 F; and 36 Cl.

[0532] As used herein, a substituent containing a halogen atom includes a halogen-substituted alkyl group, cycloalkyl group, alkenyl group, alkynyl group, aryl group, heteroaryl group, or aralkyl group. More specific examples include fluoroalkyl, difluoroalkyl, and trifluoroalkyl.

[0533] Substituents containing an O atom include groups such as hydroxy (-OH), oxy (-OR), carbonyl (-C(=O)-R), carboxy (-CO2H), oxycarbonyl (-C(=O)-OR), carbonyloxy (-O-C(=O)-R), thiocarbonyl (-C(=O)-SR), carbonylthio (-S-C(=O)-R), aminocarbonyl (-C(=O)-NHR), carbonylamino (-NH-C(=O)-R), oxycarbonylamino (-NH-C(=O)-OR), sulfonylamino (-NH-SO2-R), aminosulfonyl (-SO2-NHR), amidosulfonylamino (-NH-SO2-NHR), thiocarboxy (-C(=O)-SH), and carboxycarbonyl (-C(=O)-CO2H).

[0534] Examples of oxy (-OR) include alkoxy, cycloalkoxy, alkenyloxy, alkynyloxy, aryloxy, heteroaryloxy, and aralkyloxy. The alkoxy is preferably a C1-C4 alkoxy or a C1-C2 alkoxy, and particularly preferably methoxy or ethoxy.

[0535] Examples of carbonyl (-C(=O)-R) include formyl (-C(=O)-H), alkylcarbonyl, cycloalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, arylcarbonyl, heteroarylcarbonyl, and aralkylcarbonyl.

[0536] Examples of an oxycarbonyl (-C(=O)-OR) include an alkoxycarbonyl, a cycloalkoxycarbonyl, an alkenyloxycarbonyl, an alkynyloxycarbonyl, an aryloxycarbonyl, a heteroaryloxycarbonyl, and an aralkyloxycarbonyl.

[0537] Examples of a carbonyloxy (-O-C(=O)-R) include an alkylcarbonyloxy, a cycloalkylcarbonyloxy, an alkenylcarbonyloxy, an alkynylcarbonyloxy, an arylcarbonyloxy, a heteroarylcarbonyloxy, and an aralkylcarbonyloxy.

[0538] Examples of a thiocarbonyl (-C(=O)-SR) include an alkylthiocarbonyl, a cycloalkylthiocarbonyl, an alkenylthiocarbonyl, an alkynylthiocarbonyl, an arylthiocarbonyl, a heteroarylthiocarbonyl, and an aralkylthiocarbonyl.

[0539] Examples of a carbonylthio (-S-C(=O)-R) include an alkylcarbonylthio, a cycloalkylcarbonylthio, an alkenylcarbonylthio, an alkynylcarbonylthio, an arylcarbonylthio, a heteroarylcarbonylthio, and an aralkylcarbonylthio.

[0540] Examples of an aminocarbonyl (-C(=O)-NHR) include an alkylaminocarbonyl (such as a C1-C6 or C1-C4 alkylaminocarbonyl, and particularly an ethylaminocarbonyl and a methylaminocarbonyl), a cycloalkylaminocarbonyl, an alkenylaminocarbonyl, an alkynylaminocarbonyl, an arylaminocarbonyl, a heteroarylaminocarbonyl, and an aralkylaminocarbonyl. Additionally, examples further include compounds obtained by replacing the H atom bonded to the N atom in -C(=O)-NHR with an alkyl, a cycloalkyl, an alkenyl, an alkynyl, an aryl, a heteroaryl, or an aralkyl.

[0541] Examples of a carbonylamino (-NH-C(=O)-R) include an alkylcarbonylamino, a cycloalkylcarbonylamino, an alkenylcarbonylamino, an alkynylcarbonylamino, an arylcarbonylamino, a heteroarylcarbonylamino, and an aralkylcarbonylamino. Additionally, examples further include compounds obtained by replacing the H atom bonded to the N atom in -NH-C(=O)-R with an alkyl, a cycloalkyl, an alkenyl, an alkynyl, an aryl, a heteroaryl, or an aralkyl.

[0542] Examples of an oxycarbonylamino (-NH-C(=O)-OR) include an alkoxycarbonylamino, a cycloalkoxycarbonylamino, an alkenyloxycarbonylamino, an alkynyloxycarbonylamino, an aryloxycarbonylamino, a heteroaryloxycarbonylamino, and an aralkyloxycarbonylamino. Additionally, examples further include compounds obtained by replacing the H atom bonded to the N atom in -NH-C(=O)-OR with an alkyl, a cycloalkyl, an alkenyl, an alkynyl, an aryl, a heteroaryl, or an aralkyl.

[0543] Examples of sulfonylamino (-NH-SO2-R) include alkylsulfonylamino, cycloalkylsulfonylamino, alkenylsulfonylamino, alkynylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, and aralkylsulfonylamino. In addition, examples further include compounds obtained by replacing the H atom bonded to the N atom in -NH-SO2-R with alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or aralkyl.

[0544] Examples of aminosulfonyl (-SO2-NHR) include alkylaminosulfonyl, cycloalkylaminosulfonyl, alkenylaminosulfonyl, alkynylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl, and aralkylaminosulfonyl. In addition, examples further include compounds obtained by replacing the H atom bonded to the N atom in -SO2-NHR with alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or aralkyl.

[0545] Examples of sulfamoylamino (-NH-SO2-NHR) include alkylsulfamoylamino, cycloalkylsulfamoylamino, alkenylsulfamoylamino, alkynylsulfamoylamino, arylsulfamoylamino, heteroarylsulfamoylamino, and aralkylsulfamoylamino. In addition, the two H atoms bonded to the N atom in -NH-SO2-NHR can be independently replaced by substituents selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and aralkyl, and the two substituents can form a ring.

[0546] Substituents containing an S atom include groups such as thiol (-SH), thio (-S-R), sulfinyl (-S(=O)-R), sulfonyl (-SO2-R), and sulfo (-SO3H).

[0547] Examples of thio (-S-R) are selected from alkylthio, cycloalkylthio, alkenylthio, alkynylthio, arylthio, heteroarylthio, aralkylthio, and the like.

[0548] Examples of sulfonyl (-SO2-R) include alkylsulfonyl, cycloalkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, arylsulfonyl, heteroarylsulfonyl, and aralkylsulfonyl.

[0549] Substituents containing an N atom include groups such as azide (-N3, also referred to as "azido group"), cyano (-CN), primary amino group (-NH2), secondary amino group (-NH-R; also referred to as monosubstituted amino), tertiary amino group (-NR(R′); also referred to as disubstituted amino), amidino group (-C(═NH)-NH2), substituted amidino group (-C(═NR)-NR′R″), guanidino group (-NH-C(═NH)-NH2), substituted guanidino group (-NR-C(═NR′″)-NR′R″), aminocarbonylamino group (-NR-CO-NR′R″), pyridyl, piperidino, morpholino, and azetidinyl.

[0550] Examples of secondary amino groups (-NH-R; monosubstituted amino) include alkylamino, cycloalkylamino, alkenylamino, alkynylamino, arylamino, heteroarylamino, and aralkylamino.

[0551] Examples of tertiary amino groups (-NR(R′); disubstituted amino) include amino groups having any two substituents each independently selected from alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and aralkyl, such as alkyl(aralkyl)amino, and the two substituents may form a ring. Specific examples include dialkylamino, particularly C1-C6 dialkylamino, C1-C4 dialkylamino, dimethylamino, and diethylamino. As used herein, "C p -C q dialkylamino group" refers to an amino group substituted with two C p -C q alkyl groups, and the C p -C q alkyl groups may be the same or different.

[0552] Examples of substituted amidino groups (-C(═NR)-NR′R") include groups in which the three substituents R, R′, and R″ on the N atom are each independently selected from alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and aralkyl, such as alkyl(aralkyl)(aryl)amidino.

[0553] Examples of substituted guanidino groups (-NR-C(═NR′″)-NR′R″) include groups in which R, R′, R″, and R′″ are each independently selected from alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and aralkyl, and groups in which these substituents form a ring.

[0554] Examples of aminocarbonylamino groups (-NR-CO-NR′R") include groups in which R, R′, and R″ are each independently selected from a hydrogen atom, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and aralkyl, or groups in which these substituents form a ring.

[0555] In the present text, a "peptide residue" or "amino acid residue" that composes a peptide compound may be simply referred to as "peptide" or "amino acid", respectively.

[0556] In the present text, the meaning of the term "and / or" includes any combination obtained by appropriately combining "and" and "or". Specifically, for example, "A, B and / or C" includes the following seven variations:

[0557] (i) A, (ii) B, (iii) C, (iv) A and B, (v) A and C, (vi) B and C, (vii) A, B and C.

[0558] In one embodiment, the present disclosure relates to a cyclic compound represented by the following formula (1), or a salt thereof, or a solvate thereof.

[0559]

[0560] In the cyclic compound of formula (1), the ring is composed of 11 amino acid residues. In the present text, the amino acid residue having P1, Q1, R1 and L1 may be referred to as core 1, the amino acid residue having P2, Q2 and R2 may be referred to as core 2, the amino acid residue having P3, Q3 and R3 may be referred to as core 3, the amino acid residue having P4, Q4 and R4 may be referred to as core 4, the amino acid residue having P5, Q5 and R5 may be referred to as core 5, the amino acid residue having P6, Q6 and R6 may be referred to as core 6, the amino acid residue having P7, Q7 and R7 may be referred to as core 7, the amino acid residue having P8, Q8 and R8 may be referred to as core 8, the amino acid residue having M9, Q9 and R9 may be referred to as core 9, the amino acid residue having P 10 , Q 10 and R 10 may be referred to as core 10, and the amino acid residue having P 11 , Q 11 , R 11 and L 11 may be referred to as core 11.

[0561] In one embodiment, in formula (1), L1 is a single bond, or is -CHM1-, -(CH2) n S(CH2) m -, -(CH2) n S(O)(CH2) m - or -(CH2) n S(O)2(CH2) m -. Except when R1 and M1 form a 3- to 8-membered alicyclic ring, M1 is hydrogen. Here, n and m are each independently 1 or 2. L1 is preferably a single bond or -CH2- or -CH2-S-CH2-.

[0562] When L1 is -(CH2) n S(CH2) m -, specific examples of such a group include -CH2SCH2-, -CH2CH2SCH2-, -CH2SCH2CH2-, and -CH2CH2SCH2CH2-.

[0563] When L1 is -(CH2) n S(O)(CH2) m -, specific examples of such a group include -CH2S(O)CH2-, -CH2CH2S(O)CH2-, -CH2S(O)CH2CH2-, and -CH2CH2S(O)CH2CH2-.

[0564] When L1 is -(CH2) n S(O)2(CH2) m -, specific examples of such a group include -CH2S(O)2CH2-, -CH2CH2S(O)2CH2-, -CH2S(O)2CH2CH2-, and -CH2CH2S(O)2CH2CH2-.

[0565] In one embodiment, in formula (1), R1 is hydrogen, C1-C7 alkyl, C2-C7 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy C1-C6 alkyl, C2-C6 alkenyloxy C1-C6 alkyl, C1-C6 alkylthio C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl C1-C6 alkyl, C3-C8 cycloalkoxy C1-C6 alkyl, C7-C 14 arylalkyl or 5- to 10-membered heteroaryl C1-C6 alkyl, each of which may be substituted with one or more groups independently selected from the group consisting of: halogen, hydroxy, cyano, C1-C6 alkyl, aminocarbonyl (wherein the amino group is -NH2, mono-C1-C6 alkylamino, di-C1-C6 alkylamino or 4- to 8-membered cyclic amino), and C1-C6 alkylsulfonyl.

[0566] In this embodiment, R1 is preferably: C1-C7 alkyl optionally substituted with di-C1-C6 alkylaminocarbonyl; C1-C6 haloalkyl; C1-C6 hydroxyalkyl; C2-C7 alkenyl; C2-C6 alkynyl; C1-C6 alkoxy C1-C6 alkyl optionally substituted with one or more halogen atoms; C2-C6 alkenyloxy C1-C6 alkyl; C1-C6 alkylthio C1-C6 alkyl; C7-C 14 arylalkyl optionally substituted with one or more halogen atoms, C1-C6 alkyl or cyano; 5- to 10-membered heteroaryl C1-C6 alkyl; C3-C8 cycloalkyl; C3-C8 cycloalkyl C1-C6 alkyl; or C3-C8 cycloalkoxy C1-C6 alkyl.

[0567] In this embodiment, specific examples of R1 include methyl, 2-methylpropyl, isopropyl, ethyl, n-propyl, n-butyl, n-hexyl, n-pentyl, n-heptyl, neopentyl, 3-(dimethylamino)-3-oxopropyl, cyclohexylmethyl, cyclopentylmethyl, cyclobutylmethyl, cyclopropylmethyl, 3,3-difluoropropyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl, 3,3-dichloropropyl, cyclopropoxymethyl, hydroxymethyl, n-propoxymethyl, methoxymethyl, 2-methoxyethyl, ethoxymethyl, (2,2,2-trifluoroethoxy)methyl, allyloxymethyl, methylthiomethyl, allyl, hex-5-en-1-yl, pent-4-en-1-yl, but-3-en-1-yl, propargyl, cyclobutyl, benzyl, phenethyl, 2-cyanobenzyl, 3-cyanobenzyl, 4-cyanobenzyl, 4-chlorobenzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2-chlorobenzyl, 3-chlorobenzyl, 3,4-difluorobenzyl, 3,4-dichlorobenzyl, 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl, pyridin-3-ylmethyl, thiazol-4-ylmethyl, (thiophen-3-yl)methyl, (thiophen-2-yl)methyl, cyclopropyl, and hept-6-en-1-yl.

[0568] In one embodiment, R1, together with P1, the carbon atom to which R1 is bonded, and the nitrogen atom to which P1 is bonded, forms a 4- to 7-membered saturated heterocycle. In this case, the 4- to 7-membered saturated heterocycle is preferably an azetidine ring, a pyrrolidine ring, a piperidine ring, a piperazine ring, a morpholine ring, or a homopiperidine ring.

[0569] In one embodiment, R1, together with Q1 and the carbon atom to which R1 and Q1 are bonded, forms a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocycle. In this case, the 3- to 8-membered alicyclic ring is preferably a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, or a cyclohexane ring, and the 4- to 7-membered saturated heterocycle is preferably a tetrahydrofuran ring or a tetrahydropyran ring.

[0570] In one embodiment, R1, together with M1, the carbon atom to which R1 is bonded, and the carbon atom to which M1 is bonded, forms a 3- to 8-membered alicyclic ring. In this case, the 3- to 8-membered alicyclic ring is preferably a cyclopentane ring or a cyclohexane ring.

[0571] In one embodiment, R1 and R5 together form a divalent group selected from the group consisting of: C1-C 10 alkylene, C2-C 10 alkenylene, C2-C 10 alkynylene, C3-C8 cycloalkylene, C6-C 10 arylene, -CO-NR A -, -NR A-CO- and combinations of two or more of these groups. In this text, when combining three or more groups, like groups can be used two or more times. One or more carbon atoms constituting the divalent group may be substituted with one or more heteroatoms independently selected from the group consisting of N, O, and S. The divalent group may be substituted with one or more groups independently selected from the group consisting of halogen and C1-C6 alkyl. When the divalent group contains -CO-NR A - or -NR A -CO-, R A is hydrogen or C1-C6 alkyl, and preferably hydrogen or methyl.

[0572] The divalent group formed by R1 and R5 together is preferably *-C1-C8 alkylene-C6-C 10 arylene-C1-C3 alkylene-#, *-C1-C8 alkylene-O-C6-C 10 arylene-C1-C3 alkylene-#, *-C2-C8 alkenylene-O-C6-C 10 arylene-C1-C3 alkylene-# or *-C2-C8 alkenylene-C6-C 10 arylene-C1-C3 alkylene-#, each of which may be substituted with one or more groups independently selected from the group consisting of halogen and C1-C6 alkyl. * means the bonding point of the carbon atom bonded to R1, and # means the bonding point of the carbon atom bonded to R5.

[0573] In one embodiment, R1 and R5 together form a divalent group, and the partial structure *-CR1Q1-L1-CO-NP2-CR2Q2-CO-NP3-CR3Q3-CO-NP4-CR4Q4-CO-NP5-CR5Q5-* in the cyclic compound represented by formula (1) can be represented by the following formula:

[0574]

[0575] wherein

[0576] X2 is -L1-CO-NP2-CR2Q2-CO-NP3-CR3Q3-CO-NP4-CR4Q4-CO-NP5-,

[0577] Y 31 、Y 32 、Y 33 、Y 34 、Y 35 、Y 36 、Y 37 and Y 38 are each independently hydrogen or C1-C6 alkyl, and preferably hydrogen or methyl,

[0578] n is 0, 1 or 2,

[0579] m is 0, 1, 2, 3 or 4; and

[0580] * means a bonding point to an adjacent atom.

[0581] In one embodiment, R1 and R5 together form a divalent group, and the partial structure *-CR1Q1-L1-CO-NP2-CR2Q2-CO-NP3-CR3Q3-CO-NP4-CR4Q4-CO-NP5-CR5Q5-* in the cyclic compound represented by formula (1) is represented by the following formula:

[0582]

[0583] wherein

[0584] X2 is -L 1- CO-NP2-CR2Q2-CO-NP3-CR3Q3-CO-NP4-CR4Q4-CO-NP5-,

[0585] n is 1, 2, 3 or 4, and

[0586] * means a bonding point to an adjacent atom.

[0587] In one embodiment, R4 and P5 together form a divalent group, and the partial structure *-CR4Q4-CO-NP5-* in the cyclic compound represented by formula (1) is:

[0588]

[0589] and

[0590] R1 and R5 together form a divalent group, and the partial structure *-CR1Q1-L1-CO-NP2-CR2Q2-CO-NP3-CR3Q3-CO-NP4-CR4Q4-CO-NP5-CR5Q5-* in the cyclic compound represented by formula (1) is represented by the following formula:

[0591]

[0592] wherein

[0593] X2 is -L 1- CO-NP2-CR2Q2-CO-NP3-CR3Q3-CO-NP4-CR4Q4-CO-NP5-,

[0594] n is 1, 2, 3 or 4, and

[0595] * means a bonding point to an adjacent atom.

[0596] Partial structure *-CR1Q1-L 1- CO-NP2-CR2Q2-CO-NP3-CR3Q3-CO-NP4-CR4Q4-CO-NP5-CR5Q5-*, preferably:

[0597]

[0598]

[0599] In one embodiment, R1 and R9 together form a divalent group selected from the group consisting of: C 1- C 10 Alkylene, C2-C 10 Alkenylene, C2-C 10 Alkynylene, C3-C8 cycloalkylene, C6-C 10 Arylene, -CO-NR B -, -NR B -CO- and combinations of two or more of these terms. One or more carbon atoms constituting the divalent group may be substituted with one or more heteroatoms independently selected from the group consisting of N, O, and S. The divalent group may be substituted with one or more groups independently selected from the group consisting of halogen and C1-C6 alkyl. When the divalent group contains -CO-NR B - or -NR B -CO-, R B is hydrogen or C1-C6 alkyl, and preferably hydrogen or methyl.

[0600] The divalent group formed by R1 and R9 together is preferably *-C3-C8 alkylene-#, *-C3-C8 alkenylene-# or *-C1-C3 alkylene-O-C1-C8 alkylene-#, each of which may be substituted with one or more groups independently selected from the group consisting of halogen and C1-C6 alkyl. * means the bonding point of the carbon atom bonded to R1, and # means the bonding point of the carbon atom bonded to R9.

[0601] In one embodiment, the partial structure *-CR1Q1-NP 1- CO-L 11 -CR 11 Q 11 -NP 11- CO-CR 10 Q 10 -NP 10- CO-CR9Q9-* in the cyclic compound represented by formula (1) may be represented by the following formula:

[0602]

[0603] wherein

[0604] X3 is -NP 1- CO-L 11 -CR 11 Q 11 -NP 11 -CO-CR 10 Q 10 -NP 10 -CO-

[0605] Y 41 、Y 42 、Y 43 、Y 44 、Y 45 and Y 46 each independently is hydrogen or a C1-C6 alkyl group, and preferably is hydrogen or methyl,

[0606] n is an integer from 0 to 3,

[0607] m is an integer from 0 to 5, and

[0608] * means a bonding point to an adjacent atom.

[0609] The partial structure *-CR1Q1-NP 1- CO-L 11 -CR 11 Q 11 -NP 11 -CO-CR 10 Q 10 -NP 10 -CO-CR9Q9-* is preferably:

[0610]

[0611] In one embodiment, P1 is hydrogen or a C1-C6 alkyl group, wherein the C1-C6 alkyl group may be substituted by one or more groups independently selected from the group consisting of: halogen, hydroxyl, C1-C6 alkoxy, and aminocarbonyl (wherein the amino group is -NH2, mono-C1-C6 alkylamino, di-C1-C6 alkylamino, or 4- to 8-membered cyclic amino).

[0612] P1 is preferably hydrogen or a C1-C6 alkyl group, and more preferably is hydrogen, methyl, or n-propyl.

[0613] In one embodiment, Q1 is hydrogen or a C1-C6 alkyl group, and preferably is hydrogen or methyl.

[0614] In one embodiment, M1 is hydrogen or a C1-C6 alkyl group, and preferably is hydrogen or methyl.

[0615] Specific examples of the amino acid residues in Core 1 include Azp(2), D-MeLeu, EtLeu, Leu, MeAbu, MeAbu(4-F2), MeAbu(4-F3), MeAhxe(2), MeAib, MeAla, MeAla(2-Thie), MeAla(3-Pyr), MeAla(3-Thie), MeAla(4-Thz), MeAla(cBu), MeAla(cPent), MeAla(cPr), MeAla(tBu), MeAlgly, MeAnon(2), MeAOC(2), MeAocte(2), MeCha, MeCys(Me), MeGln(Me2), MeGly(cBu), MeHnl, MeHph, MeHse(Me), MeLeu, MeNle, MeNva, MeNva(5-Cl2), MeNva(5-F2), MePhe, MePhe(2-Cl), MePhe(2-CN), MePhe(2-F), MePhe(2-Me), MePhe(34-Cl2), MePhe(34-F2), MePhe(3-Cl), MePhe(3-CN), MePhe(3-F), MePhe(3-Me), MePhe(4-Cl), MePhe(4-CN), MePhe(4-F), MePhe(4-Me), MePRA, MeSer, MeSer(Al), MeSer(cPr), MeSer(Et), MeSer(Me), MeSer(nPr), MeSer(Tfe), MeVal, R-MeAMPA, MeGly(cPr), nPrLeu, and MeAnone(2), except when the side chain (R1) of Core 1 and the side chain (R5) of Core 5 or the side chain (R1) of Core 1 and the side chain (R9) of Core 9 together form a divalent group.

[0616] When the side chain (R1) of Core 1 and the side chain (R5) of Core 5 or the side chain (R1) of Core 1 and the side chain (R9) of Core 9 together form a divalent group, the group at the position of R1 corresponding to the amino acid residues listed above (or preferably MeAhpe(2), MeAlgly, MeAnon(2), MeAOC(2), MeAocte(2), MeHnl, MeSer(Al), or MeAnone(2)) can be linked to the group at the position corresponding to the side chain (R5) of Core 5 or the side chain (R9) of Core 9 using the method described in the following article section "General Production Method".

[0617] In one embodiment, in formula (1), R2 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl C1-C6 alkyl, C3-C8 cycloalkoxy C1-C6 alkyl or a 4- to 7-membered heterocyclic group, each of which may be substituted by one or more groups independently selected from the group consisting of halogen, hydroxy, cyano and C1-C6 alkylsulfonyl.

[0618] In this embodiment, R2 is preferably: C1-C6 alkyl; C2-C6 alkenyl; C1-C6 haloalkyl, C1-C6 hydroxyalkyl; C3-C8 cycloalkyl optionally substituted by one or more halogen atoms; C1-C6 alkoxy C1-C6 alkyl; a 4- to 7-membered heterocyclic group; or C3-C8 cycloalkyl.

[0619] Specific examples of R2 in this embodiment include ethyl, isopropyl, 1-methylpropyl, pentan-3-yl, 2,2,2-trifluoroethyl, hydroxymethyl, allyl, cyclopentyl, cyclobutyl, 3,3-difluorocyclobutyl, 1-methoxyethyl, 1-ethoxyethyl, 1-n-propoxyethyl, tetrahydropyran-4-yl, cyclopropyl, 2-methylpropyl and cyclohexyl.

[0620] In one embodiment, R2 together with P2, the carbon atom to which R2 is bonded, and the nitrogen atom to which P2 is bonded forms a 4- to 7-membered saturated heterocycle. In this case, the 4- to 7-membered saturated heterocycle is preferably an azetidine ring, pyrrolidine ring, piperidine ring, piperazine ring, morpholine ring.

[0621] In one embodiment, R2 together with Q2 and the carbon atoms to which R2 and Q2 are bonded forms a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocycle. In this case, the 3- to 8-membered alicyclic ring is preferably a cyclopropane ring, cyclobutane ring, cyclopentane ring or cyclohexane ring, and the 4- to 7-membered saturated heterocycle is preferably a tetrahydrofuran ring or a tetrahydropyran ring.

[0622] In one embodiment, R2 and R 11 together form a divalent group selected from the group consisting of C1-C 10 alkylene, C2-C 10 alkenylene, C2-C 10 alkynylene, C3-C8 cycloalkylene, C6-C 10 arylene, -CO-NR C -, -NR C -CO-, -C3-C8 alkylene-NR C -, -C3-C8 alkenylene-NRR C- and combinations of two or more of these items. One or more carbon atoms constituting the divalent group may be substituted with one or more heteroatoms independently selected from the group consisting of N, O, and S. The divalent group may be substituted with one or more groups independently selected from the group consisting of halogen and C1-C6 alkyl. When the divalent group contains -CO-NR C -, -NR C -CO-, -C3-C8 alkylene-NR C - or -C3-C8 alkenylene-NR C -, R C is hydrogen or C1-C6 alkyl, and preferably hydrogen or methyl.

[0623] R2 and R 11 together form a divalent group which is preferably *-C3-C8 alkylene-NR C -# or *-C3-C8 alkenylene-NR C -#, each of which may be substituted with one or more groups independently selected from the group consisting of halogen and C1-C6 alkyl. * means the bonding point of the carbon atom bonded to R2, and # means the bonding point of the carbon atom bonded to R 11 .

[0624] In one embodiment, the partial structure *-CR2Q2-NP2-CO-L 1- CR1Q1-NP l- CO-L 11 -CR 11 Q 11 -* in the cyclic compound represented by formula (1) may be represented by the following formula:

[0625]

[0626] wherein

[0627] X4 is -NP2-CO-L1-CR1Q1-NP1-CO-L 11 -,

[0628] Y 51 , Y 52 , Y 53 , Y 54 , Y 55 and Y 56 are each independently hydrogen or C1-C6 alkyl, and preferably hydrogen or methyl,

[0629] R C is hydrogen or C1-C6 alkyl, and preferably methyl,

[0630] n is an integer from 1 to 6, and

[0631] * refers to the bonding point with an adjacent atom.

[0632] Partial structure *-CR2Q2-NP2-CO-L1-CR1Q1-NP1-CO-L 11 -CR 11 Q 11 -* Preferably:

[0633]

[0634] In one embodiment, P2 is hydrogen or C1-C6 alkyl, where C 1- C6 alkyl may be substituted with one or more groups independently selected from the group consisting of: halogen, hydroxy, C1-C6 alkoxy, and aminocarbonyl (wherein the amino group is -NH2, mono-C1-C6 alkylamino, di-C1-C6 alkylamino, or 4- to 8-membered cyclic amino).

[0635] P2 is preferably hydrogen or C1-C6 alkyl, and more preferably hydrogen.

[0636] In one embodiment, Q2 is hydrogen or C1-C6 alkyl, and preferably hydrogen.

[0637] Except when the side chain (R2) of core 2 and the side chain (R 11 ) of core 11 together form a divalent group, specific examples of the amino acid residues in core 2 include Algly, Ile, Val, Gly(cBu), Gly(cBu-3-F2), aIle, Nva(3-Et), Gly(cPent), Abu(4-F3), Abu, Thr(Me), Thr(Et), Thr(nPr), Gly(4-THP), Gly(cPr), Leu, and Chg.

[0638] When the side chain (R2) of core 2 and the side chain (R 11 ) of core 11 together form a divalent group, the group at the position of R2 corresponding to the amino acid residue (or preferably Algly) listed above can be connected to the group at the position of the side chain (R 11 ) of core 11 using the method described in the following section "General Production Method" for example.

[0639] In one embodiment, in formula (1), R3 is hydrogen, C1-C6 alkyl, C1-C6 alkoxy C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl C1-C6 alkyl, C3-C8 cycloalkoxy C1-C6 alkyl, or C7-C 14An aralkyl group, each of which may be substituted by one or more groups independently selected from the group consisting of a hydroxyl group and an aminocarbonyl group (wherein the amino group is -NH2, mono-C1-C6 alkylamino, di-C1-C6 alkylamino or a 4- to 8-membered cyclic amino group).

[0640] In this embodiment, R3 is preferably hydrogen, a C1-C6 alkyl group or a C7-C 14 Aralkyl.

[0641] In this embodiment, specific examples of R3 include hydrogen, methyl, ethyl and benzyl.

[0642] In one embodiment, R3, together with P3, the carbon atom to which R3 is bonded, and the nitrogen atom to which P3 is bonded, forms a 4- to 7-membered saturated heterocyclic ring. The 4- to 7-membered saturated heterocyclic ring may be substituted by one or more groups selected from the group consisting of a C1-C6 alkyl group and a C1-C6 alkoxy group. The C1-C6 alkyl group is preferably methyl, and the C1-C6 alkoxy group is preferably methoxy or ethoxy. Specific examples of the 4- to 7-membered saturated heterocyclic ring include a piperidine ring, a pyrrolidine ring, an azetidine ring, a morpholine ring and a thiomorpholine ring. Specific examples of the alkyl-substituted 4- to 7-membered saturated heterocyclic ring include a 3-methylazetidine ring and a 3,3-dimethylazetidine ring. Specific examples of the alkoxy-substituted 4- to 7-membered saturated heterocyclic ring include a 3-ethoxypyrrolidine ring.

[0643] In one embodiment, R3, together with Q3 and the carbon atom to which R3 and Q3 are bonded, forms a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring. In this case, the 3- to 8-membered alicyclic ring is preferably a cyclopropane ring, a cyclobutane ring, a cyclopentane ring or a cyclohexane ring, and the 4- to 7-membered saturated heterocyclic ring is preferably a tetrahydrofuran ring or a tetrahydropyran ring.

[0644] In one embodiment, P3 is hydrogen, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy C1-C6 alkyl group or a C3-C8 cycloalkyl group, each of which may be substituted by one or more groups independently selected from the group consisting of a halogen, a hydroxyl group, a cyano group, a C1-C6 alkoxy group and a C1-C6 aminoalkyl group (wherein the amino group is -NH2, mono-C1-C6 alkylamino, di-C1-C6 alkylamino or a 4- to 8-membered cyclic amino group, and the 4- to 8-membered cyclic amino group may be substituted by one or more halogen atoms).

[0645] P3 is preferably hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 cyanoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl or C1-C6 alkoxy C1-C6 alkyl. Specific examples of P3 include hydrogen, methyl, ethyl, n-propyl, cyanomethyl, 2-fluoroethyl, 2,2-difluoroethyl, allyl, propargyl, cyclopropyl and 2-methoxyethyl.

[0646] In one embodiment, Q3 is hydrogen or C1-C6 alkyl, and is preferably hydrogen or methyl.

[0647] Specific examples of the amino acid residues in Core 3 include MeGly, Gly, Aze(2), Ala, D-Aze(2), (Me)Pro, Tmo(2), Mor(3), Pic(2), Hyp(Et), Pro, MeAla, nPrGly, EtGly, DfeGly, MfeGly, PraGly, AllylGly, MeAbu, Aze(2)(3S-Me), Aze(2)(3R-Me), Aze(2)(3-Me2), 1-ACPrC, NCMeGly, cPrGly, MePhe, EtAla, Pro(4S-Me), cisHyp(Me) and (MeOEt)Gly.

[0648] In one embodiment, in formula (1), R4 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy C1-C6 alkyl, C2-C6 alkenoxy C1-C6 alkyl or C1-C6 carboxyalkyl, each of which may be substituted with one or more hydroxyl groups.

[0649] In this embodiment, R4 is preferably hydrogen, C1-C6 alkyl, C1-C6 hydroxyalkyl, C2-C6 alkenyl, C1-C6 alkoxy C 1- C6 alkyl, C2-C6 alkenoxy C1-C6 alkyl or C1-C6 carboxyalkyl.

[0650] In this embodiment, specific examples of R4 include hydrogen, methyl, ethyl, allyl, 2-methylallyl, but-3-en-1-yl, hydroxymethyl, n-propoxymethyl, allyloxymethyl and carboxymethyl.

[0651] In one embodiment, in formula (1), R4, together with P4, the carbon atom to which R4 is bonded, and the nitrogen atom to which P4 is bonded, forms a 4- to 7-membered saturated heterocycle. The 4- to 7-membered saturated heterocycle may be substituted with one or more C1-C6 alkyl groups. The C1-C6 alkyl group is preferably methyl. Specific examples of the 4- to 7-membered saturated heterocycle include an azetidine ring, a pyrrolidine ring, a piperidine ring, a piperazine ring, and a morpholine ring. Specific examples of the alkyl-substituted 4- to 7-membered saturated heterocycle include a 3-methylazetidine ring.

[0652] In one embodiment, R4, together with Q4 and the carbon atoms to which R4 and Q4 are bonded, forms a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocycle. In this case, the 3- to 8-membered alicyclic ring is preferably a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, or a cyclohexane ring, and the 4- to 7-membered saturated heterocycle is preferably a tetrahydrofuran ring or a tetrahydropyran ring.

[0653] In one embodiment, R4 and P5 together form a divalent group selected from the group consisting of: C1-C 10 alkylene, C2-C 10 alkenylene, C2-C 10 alkynylene, C3-C8 cycloalkylene, 3- to 7-membered heteroalkylene, C6-C 10 arylene, -CO-NR D -, -NR D -CO-, and combinations of two or more of these. One or more carbon atoms constituting the divalent group may be substituted with one or more heteroatoms independently selected from the group consisting of N, O, and S. The divalent group may be substituted with one or more groups independently selected from the group consisting of halogen and C1-C6 alkyl. When the divalent group contains -CO-NR D - or -NR D -CO-, R D is hydrogen or C1-C6 alkyl, and is preferably hydrogen or methyl.

[0654] The divalent group formed by R4 and P5 together is preferably *-C3-C8 alkylene-#, *-C3-C8 alkenylene-#, *-C1-C3 alkylene-C3-C8 cycloalkylene-C1-C3 alkylene-#, *-C1-C3 alkylene-O-C3-C6 alkenylene-#, *-C1-C3 alkylene-CO-NR D -C1-C3 alkylene-#, *-C1-C3 alkylene-NR D-CO-C1-C3 alkylene-# or *-C1-C3 alkylene-3- to 7-membered heteroalkylene-C1-C3 alkylene-#, each of which may be substituted by one or more groups independently selected from the group consisting of halogen and C1-C6 alkyl. * means the bonding point of the carbon atom bonded to R4, and # means the bonding point of the nitrogen atom bonded to P5.

[0655] The divalent group formed by R4 and P5 is more preferably *-C4-C5 alkylene-# or *-C4-C5 alkenylene-#, and even more preferably *-C4-C5 alkenylene-#.

[0656] In one embodiment, the partial structure *-CR4Q4-CO-NP5-* in the cyclic compound represented by formula (1) may be represented by the following formula:

[0657]

[0658]

[0659] where

[0660] Y 11 is hydrogen, C1-C6 alkyl or halogen, and is preferably hydrogen, methyl or fluorine,

[0661] Y 12 is hydrogen, C1-C6 alkyl or halogen, and is preferably hydrogen, methyl or fluorine,

[0662] Y 13 is hydrogen, C1-C6 alkyl or halogen, and is preferably hydrogen, methyl or fluorine, or

[0663] Y 13 together with Y 15 forms C3-C8 alkylene or -O-, and is preferably methylene or -O-,

[0664] Y 14 is hydrogen or C1-C6 alkyl, and is preferably hydrogen,

[0665] except when Y 13 and Y 15 form C3-C8 alkylene or -O-, Y 15 is hydrogen, C1-C6 alkyl or halogen, and is preferably hydrogen, methyl or fluorine,

[0666] Y 16 is hydrogen or C1-C6 alkyl, and is preferably hydrogen or methyl,

[0667] Y 17 is hydrogen or C1-C6 alkyl, and is preferably hydrogen or methyl,

[0668] Y 18 is hydrogen or a C1-C6 alkyl group, and preferably is hydrogen or methyl,

[0669] R D is hydrogen or a C1-C6 alkyl group, and preferably is hydrogen or methyl,

[0670] n is 0, 1 or 2,

[0671] m is 0, 1 or 2, and

[0672] * denotes the bonding point to an adjacent atom.

[0673] The partial structure *-CR4Q4-CO-NP5-* is preferably:

[0674]

[0675]

[0676] In addition, the partial structure *-CR4Q4-CO-NP5-* is preferably:

[0677]

[0678] In one embodiment, P4 is hydrogen, a C1-C6 alkyl group, a C2-C6 alkenyl group or a C1-C6 alkoxy C1-C6 alkyl group, or P4 and P5 together form a divalent group.

[0679] When P4 is hydrogen, a C1-C6 alkyl group, a C2-C6 alkenyl group or a C1-C6 alkoxy C1-C6 alkyl group, each of them may be substituted by one or more groups independently selected from the group consisting of: halogen, hydroxy, C1-C6 alkoxy and aminocarbonyl (wherein the amino group is -NH2, mono-C1-C6 alkylamino, di-C1-C6 alkylamino or 4- to 8-membered cyclic amino). In this case, P4 is preferably a C1-C6 alkyl group or a C1-C6 alkenyl group. Specific examples of such P4 include methyl, ethyl, n-propyl, n-butyl and 3-butenyl.

[0680] When P4 and P5 together form a divalent group, the divalent group is selected from the group consisting of: C1-C 10 alkylene, C2-C 10 alkenylene, C2-C 10 alkynylene, C3-C8 cycloalkylene, C6-C 10 arylene, -CO-NR E -, -NR E-CO- and combinations of two or more of these moieties. One or more carbon atoms forming the divalent group may be substituted with one or more heteroatoms independently selected from the group consisting of N, O, and S, and the divalent group may be substituted with one or more groups independently selected from the group consisting of halogen and C1-C6 alkyl. When the divalent group contains -CO-NR E - or -NR E -CO-, R E is hydrogen or C1-C6 alkyl, and preferably hydrogen or methyl.

[0681] The divalent group formed by P4 and P5 together is preferably C3-C8 alkylene or C3-C8 alkenylene, each of which may be substituted with one or more groups independently selected from the group consisting of halogen and C1-C6 alkyl.

[0682] In one embodiment, the partial structure *-NP4-CR4Q4-CO-NP5-* in the cyclic compound represented by formula (1) may be represented by:

[0683]

[0684] wherein

[0685] Y 21 、Y 22 、Y 23 、Y 24 、Y 25 and Y 26 are each independently hydrogen or C1-C6 alkyl, and preferably hydrogen or methyl,

[0686] n is 0, 1, or 2,

[0687] m is 0, 1, or 2, and

[0688] * means the bonding point to an adjacent atom.

[0689] The partial structure *-NP4-CR4Q4-CO-NP5-* is preferably:

[0690]

[0691] In one embodiment, Q4 is hydrogen or C1-C6 alkyl, and preferably hydrogen.

[0692] Specific examples of the amino acid residues in Core 4 include Aze(2), Aze(2)(3S-Me), ButenylGly, D-MeSer(Al), EtGly, MeAhxe(2), MeAlgly, MeGly, MeMethagly, MeSer, MeSer(Al), nBuGly, nPrGly, Algly, and Asp, except when the side chain of Core 4 (R4) and the N-substituent of Core 5 (P5), or the N-substituent of Core 4 (P4) and the N-substituent of Core 5 (P5) together form a divalent group.

[0693] Except when the side chain of Core 4 (R4) and the N-substituent of Core 5 (P5), or the N-substituent of Core 4 (P4) and the N-substituent of Core 5 (P5) together form a divalent group, the group at the position of R4 or P4 corresponding to the amino acid residues listed above (or preferably ButenylGly, D-MeSer(Al), MeAhxe(2), MeAlgly, MeMethagly, MeSer(Al), Algly, or MeAsp) can be linked to the group at the position of the N-substituent of Core 5 (P5) using the methods described in the following article section "General Production Method", for example.

[0694] In one embodiment, in formula (1), R5 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkenyloxycarbonyl C1-C6 alkyl, C2-C6 alkynyl, C1-C6 alkoxy C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl C1-C6 alkyl, C3-C8 cycloalkoxy C1-C6 alkyl, C7-C 14 arylalkyl, C6-C 10 aryloxy C1-C6 alkyl, C7-C 14 arylalkoxy C1-C6 alkyl or 5- to 10-membered heteroaryl C1-C6 alkyl, each of which may be substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C1-C6 haloalkoxy, cyano, C1-C6 alkylsulfonyl, C2-C6 alkenyl, C3-C8 cycloalkyl, and C1-C6 alkylcarbonyl.

[0695] In this embodiment, R5 is preferably: C2-C6 alkynyl; C2-C6 alkenyloxycarbonyl C1-C6 alkyl; C3-C8 cycloalkyl; C3-C8 cycloalkyl C1-C6 alkyl optionally substituted with one or more halogen atoms; C7-C 14An arylalkyl group, which is optionally substituted with one or more groups selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C2-C6 alkenyloxy, C2-C6 alkenyl, C3-C8 cycloalkyl, and C1-C6 alkylcarbonyl; or a 5- to 10-membered heteroaryl C1-C6 alkyl; a C3-C8 cycloalkoxy C1-C6 alkyl; or a C1-C6 alkoxy C1-C6 alkyl.

[0696] In this embodiment, specific examples of R5 include benzyl, 4-fluorobenzyl, 4-chlorobenzyl, 4-fluoro-2-methylbenzyl, 4-fluoro-3-methylbenzyl, 2-chloro-4-fluorobenzyl, 3-chloro-4-fluorobenzyl, 2,4-difluorobenzyl, 3,4-difluorobenzyl, 4-fluoro-2-methoxybenzyl, 4-fluoro-3-methoxybenzyl, 4-bromobenzyl, 4-iodobenzyl, allyloxycarbonylmethyl, 4-methylbenzyl, 4-methoxybenzyl, 4-allyloxybenzyl, 4-(trifluoromethyl)benzyl, 4-(trifluoromethoxy)benzyl, propargyl, cyclopentyl, cyclohexylmethyl, 4,4-difluorocyclohexylmethyl, thiazol-2-ylmethyl, benzothiazol-6-ylmethyl, benzothiazol-5-ylmethyl, cyclobutoxymethyl, 3-methylbutoxymethyl, 4-vinylbenzyl, 4-chloro-2-fluorobenzyl, 4-(difluoromethyl)benzyl, 4-(trifluoromethyl)benzyl, 4-ethylbenzyl, 2-fluoro-4-methylbenzyl, 3-fluoro-4-methylbenzyl, 4-(1,1-difluoroethyl)benzyl, 4-cyclopropylbenzyl, 4-isopropylbenzyl, 4-methoxybenzyl, 4-acetylbenzyl, and 1,1-difluoroindan-5-ylmethyl.

[0697] In one embodiment, R5 and R8 together form a C4-C8 alkylene group. The C4-C8 alkylene group is preferably -(CH2)8-.

[0698] In one embodiment, in formula (1), R5, together with P5, the carbon atom to which R5 is bonded, and the nitrogen atom to which P5 is bonded, forms a 4- to 7-membered saturated heterocycle. In this case, the 4- to 7-membered saturated heterocycle is preferably an azetidine ring, a pyrrolidine ring, a piperidine ring, a piperazine ring, or a morpholine ring.

[0699] In one embodiment, in formula (1), R5 and R1 together form a divalent group. The details of this group are as described above.

[0700] In one embodiment, in formula (1), R5, together with Q5 and the carbon atom to which R5 and Q5 are bonded, forms a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocycle. In this case, the 3- to 8-membered alicyclic ring is preferably a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, or a cyclohexane ring, and the 4- to 7-membered saturated heterocycle is preferably a tetrahydrofuran ring or a tetrahydropyran ring.

[0701] In one embodiment, P5 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy C1-C6 alkyl or C3-C8 cycloalkyl C1-C6 alkyl, wherein the C1-C6 alkyl may be substituted with one or more groups independently selected from the group consisting of: halogen, hydroxy, C 1- C6 alkoxy, aminocarbonyl (wherein the amino group is -NH2, mono-C1-C6 alkylamino, di-C1-C6 alkylamino or 4- to 8-membered cyclic amino) and amino.

[0702] P5 is preferably C1-C6 alkyl, C3-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy C1-C6 alkyl, C3-C8 cycloalkyl C1-C6 alkyl or C1-C6 aminoalkyl. Specific examples of such P5 include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, isopentyl, neopentyl, 3-fluoropropyl, 3,3,3-trifluoropropyl, allyl, 2-methylallyl, propargyl, 3-butenyl, 2-methoxyethyl, 3-methoxypropyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl and 2-aminoethyl.

[0703] In one embodiment, in formula (1), P5 and R4 together form a divalent group. The details of this group are as described above.

[0704] In one embodiment, in formula (1), P5 and P4 together form a divalent group. The details of this group are as described above.

[0705] In one embodiment, Q5 is hydrogen or C1-C6 alkyl, and is preferably hydrogen.

[0706] Specific examples of the amino acid residues in Core 5 include AllylPhe, AllylPhe(4-CF3), AllylPhe(4-Cl), AllylPhe(4-F), AllylPhe(4-Me), AllylPhe(4-OCF3), AllylPhe(4-OMe), AllylPRA, ButenylAla(2-Thz), ButenylAla(5-Bzt), ButenylAla(6-Bzt), ButenylCha, ButenylCha(4-F2), ButenylPhe(24-F2), ButenylPhe(2-Cl-4-F), ButenylPhe(34-F2), ButenylPhe(3-Cl-4-F), ButenylPhe(4-Br), ButenylPhe(4-CF3), ButenylPhe(4-F), ButenylPhe(4-F-2-Me), ButenylPhe(4-F-2-OMe), ButenylPhe(4-F-3-Me), ButenylPhe(4-F-3-OMe), ButenylPhe(4-Me), cBuMePhe(4-CF3), cBuMePhe(4-Me), cHexMePhe(4-Me), cPentMePhe(4-CF3), cPentMePhe(4-Me), cPrMePhe(4-CF3), cPrMePhe(4-Me), EtGly(cPent), EtPhe, EtPhe(4-CF3), EtPhe(4-F), EtPhe(4-Me), iBuPhe(4-CF3), iBuPhe(4-Me), iPenPhe(4-CF3), iPenPhe(4-Me), iPrPhe(4-Me), MeOEtPhe(4-CF3), MeOEtPhe(4-Me), MeOnPrPhe(4-CF3), MeOnPrPhe(4-Me), MePhe, MePhe(4-CF3), MePhe(4-F), MePhe(4-Me), MethaPhe(4-CF3), MfpPhe(4-CF3), nBuPhe(4-CF3), nBuPhe(4-Me), neoHexPhe(4-CF3), neoHexPhe(4-Me), nPrCha(4-F2), nPrGly(cPent), nPrPhe, nPrPhe(4-CF3), except when the side chain of Core 5 (R5) and the side chain of Core 1 (R1), or the N-substituent of Core 5 (P5) and the side chain of Core 4 (R4) or the N-substituent of Core 4 (P4) together form a divalent group.nPrPhe(4-F), nPrPhe(4-Me), nPrPhe(4-OCF3), nPrTyr(Al), nPrTyr(Me), PraPhe(4-CF3), PraPhe(4-Me), TfpPhe(4-CF3), TfpPhe(4-Me), nPrSer(cBu), nPrSer(iPen), ButenylPhe(4-CH=CH2), ButenylPhe, ButenylPhe(4-Cl-2-F), ButenylPhe(4-CHF2), NH2EtPhe(4-CF3), ButenylPhe(4-Et), ButenylPhe(2-F-4-Me), ButenylPhe(3-F-4-Me), ButenylPhe(4-CF2Me), ButenylPhe(4-cPr), ButenylPhe(4-iPr), ButenylPhe(4-OMe), ButenylPhe(4-Ac), ButenylAla(5-Inda-1-F2) and AllylPhe(4-CF3).

[0707] Except when the side chain (R5) of core 5 and the side chain (R1) of core 1, or the N-substituent (P5) of core 5 and the side chain (R4) of core 4 or the N-substituent (P4) of core 4 together form a divalent group, the method described in the following section "General Production Method" can be used to connect the group at the position of R5 corresponding to the amino acid residues listed above (or preferably AllylPhe, AllylPhe(4-CF3), AllylPhe(4-Cl), AllylPhe(4-F), AllylPhe(4-Me), AllylPhe(4-OCF3), AllylPhe(4-OMe), ButenylAla(2-Thz), ButenylAla(5-Bzt), ButenylAla(6-Bzt), ButenylCha, ButenylCha(4-F2), ButenylPhe(24-F2), ButenylPhe(2-Cl-4-F), ButenylPhe(34-F2), ButenylPhe(3-Cl-4-F), ButenylPhe(4-Br), ButenylPhe(4-CF3), ButenylPhe(4-F), ButenylPhe(4-F-2-Me), ButenylPhe(4-F-2-OMe), ButenylPhe(4-F-3-Me), ButenylPhe(4-F-3-OMe), ButenylPhe(4-Me), MethaPhe(4-CF3), nPrTyr(Al), ButenylPhe(4-CH=CH2), ButenylPhe, ButenylPhe(4-Cl-2-F), ButenylPhe(4-CHF2), NH2EtPhe(4-CF3), ButenylPhe(4-Et), ButenylPhe(2-F-4-Me), ButenylPhe(3-F-4-Me), ButenylPhe(4-CF2Me), ButenylPhe(4-cPr), ButenylPhe(4-iPr), ButenylPhe(4-OMe), ButenylPhe(4-Ac), ButenylAla(5-Inda-1-F2) and AllylPhe(4-CF3)) to the group at the position of R1 corresponding to core 1, or the group at the position of P5 corresponding to these amino acid residues can be connected to the side chain (R4) of core 4 or the N-substituent (P4) of core 4.

[0708] In one embodiment, in formula (1), R6 is hydrogen or C1-C6 alkyl, and preferably hydrogen or C1-C3 alkyl. Specific examples of R6 include hydrogen and methyl.

[0709] In one embodiment, in formula (1), R6 together with P6, the carbon atom to which R6 is bonded, and the nitrogen atom to which P6 is bonded forms a 4- to 7-membered saturated heterocycle. In this case, the 4- to 7-membered saturated heterocycle is preferably an azetidine ring, a pyrrolidine ring, a piperidine ring, a piperazine ring, or a morpholine ring.

[0710] In one embodiment, in formula (1), R6 together with Q6 and the carbon atom to which R6 and Q6 are bonded forms a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocycle. In this case, the 3- to 8-membered alicyclic ring is preferably a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, or a cyclohexane ring, and the 4- to 7-membered saturated heterocycle is preferably a tetrahydrofuran ring or a tetrahydropyran ring.

[0711] In one embodiment, P6 is C1-C6 alkyl or C3-C8 cycloalkyl, each of which may be substituted by one or more groups independently selected from the group consisting of: halogen, hydroxy, C1-C6 alkoxy, and aminocarbonyl (wherein the amino group is -NH2, mono-C1-C6 alkylamino, di-C1-C6 alkylamino, or 4- to 8-membered cyclic amino).

[0712] P6 is preferably C1-C6 alkyl. Specific examples of such P6 include methyl, ethyl, and n-propyl.

[0713] In one embodiment, Q6 is hydrogen or C1-C6 alkyl, and preferably hydrogen.

[0714] Specific examples of the amino acid residues in core 6 include MeGly, D-Pro, D-MeAla, EtGly, and nPrGly.

[0715] In one embodiment, in formula (1), R7 is C6-C 10 aryloxy C1-C6 alkyl, C7-C 14 arylalkyl, C7-C 14 arylalkoxy C1-C6 alkyl, or 5- to 10-membered heteroaryl C1-C6 alkyl, each of which may be substituted by one or more groups independently selected from the group consisting of: halogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkoxy, cyano, C1-C6 alkylsulfonyl, SF5, and C3-C8 cycloalkyl.

[0716] In this embodiment, R7 is preferably: C7-C 14an arylalkyl group, optionally substituted by one or more groups independently selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, and C3-C8 cycloalkyl; or a 5- to 10-membered heteroaryl C1-C6 alkyl group, optionally substituted by one or more groups independently selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, and C3-C8 cycloalkyl.

[0717] In this embodiment, R7 is more preferably: phenethyl, optionally substituted by one or more groups independently selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, and C3-C8 cycloalkyl; or a 5- to 10-membered heteroaryl ethyl group, optionally substituted by one or more groups independently selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, and C3-C8 cycloalkyl.

[0718] In this embodiment, specific examples of R7 include 4-methylphenethyl, 2-fluoro-4-(trifluoromethyl)phenethyl, 3-fluoro-4-(trifluoromethyl)phenethyl, 3-fluoro-4-(difluoromethoxy)phenethyl, 3,5-difluoro-4-(trifluoromethyl)phenethyl, 3,4,5-trifluorophenethyl, 2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenethyl, 3-chloro-4-(trifluoromethyl)phenethyl, 4-chloro-3,5-difluorophenethyl, 3,4-dichlorophenethyl, 3,5-dichloro-4-(trifluoromethyl)phenethyl, 3,4,5-trichlorophenethyl, 3-methoxy-4-(trifluoromethyl)phenethyl, 3-methyl-4-(trifluoromethyl)phenethyl, benzothiazol-5-ylethyl, benzothiazol-6-ylethyl, 4-chloro-3,5-dimethylphenethyl, 4-(trifluoromethyl)phenethyl, 4-chlorophenethyl, 3-ethyl-4-trifluoromethylphenethyl, 4-chloro-3-fluoro-5-methoxyphenethyl, 4-ethyl-3-fluoro-5-methoxyphenethyl, 3,5-dimethyl-4-difluoromethylphenethyl, 3-methyl-5-fluoro-4-difluoromethylphenethyl, 3-methyl-5-chloro-4-difluoromethylphenethyl, 3-methoxy-5-fluoro-4-difluoromethylphenethyl, 2-(4-fluoro-2,3-dihydrobenzofuran-6-yl)ethyl, 3-cyclopropyl-4-trifluoromethylphenethyl, 2-(1,1-difluoroindan-6-yl)ethyl, 4-cyclopropyl-3-fluorophenethyl, 4-cyclopropyl-3-chlorophenethyl, 4-cyclopropyl-3-methylphenethyl, 4-ethyl-3-fluorophenethyl, 4-ethyl-3-chlorophenethyl, 3,5-difluoro-4-difluoromethylphenethyl, 4-chloro-3-trifluoromethylphenethyl, 4-chloro-3-methoxyphenethyl, 2-(7-fluoroindan-5-yl)ethyl, 3-methoxy-4-cyclopropylphenethyl, 3,5-dimethyl-4-cyclopropylphenethyl, 3,5-dichloro-4-difluoromethylphenethyl, 3-methoxy-4-difluoromethylphenethyl, 3-methoxy-4-ethylphenethyl, 2-(7-chlorobenzothiophen-5-yl)ethyl, 2-(2,3-dimethylbenzothiophen-5-yl)ethyl, 2-(2-fluoro-3-methylbenzothiophen-5-yl)ethyl, 2-(1,2,3-trimethylindol-5-yl)ethyl, 2-(7-chloro-1-methylindol-5-yl)ethyl, 2-(1,3-dimethylindol-6-yl)ethyl, and 2-(1-methylindol-6-yl)ethyl.

[0719] In one embodiment, in formula (1), R7, together with P7, the carbon atom to which R7 is attached, and the nitrogen atom to which P7 is attached, forms a 4- to 7-membered saturated heterocycle. In this case, the 4- to 7-membered saturated heterocycle is preferably an azetidine ring, a pyrrolidine ring, a piperidine ring, a piperazine ring, or a morpholine ring.

[0720] In one embodiment, in formula (1), R7, together with Q7 and the carbon atom to which R7 and Q7 are attached, forms a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring. In this case, the 3- to 8-membered alicyclic ring is preferably a cyclopropane ring, a cyclobutane ring, a cyclopentane ring or a cyclohexane ring, and the 4- to 7-membered saturated heterocyclic ring is preferably a tetrahydrofuran ring or a tetrahydropyran ring.

[0721] In one embodiment, P7 is hydrogen or a C1-C6 alkyl group, wherein the C1-C6 alkyl group is optionally substituted by one or more groups independently selected from the group consisting of: halogen, hydroxy, C1-C6 alkoxy and aminocarbonyl (wherein the amino group is -NH2, mono-C1-C6 alkylamino, di-C1-C6 alkylamino or a 4- to 8-membered cyclic amino group). P7 is preferably hydrogen.

[0722] In one embodiment, Q7 is hydrogen or a C1-C6 alkyl group, and is preferably hydrogen.

[0723] Specific examples of the amino acid residues in Core 7 include Hph(4-CF3-35-F2), Hph(34-C12), Hph(4-Cl-35-F2), Abu(5-Bzt), Hph(4-CF3-3-Cl), Hph(4-CF3-3-OMe), Hph(4-CF3-3-Me), Hph(4-CF3-35-C12), Hph(345-C13), Hph(3-F-4-OCHF2), Abu(6-Bzt), Hph(4-CF3-2356-F4), Hph(4-CF3-2-F), Hph(4-Me), Hph(4-CF3-3-F), Hph(345-F3), Hph(4-Cl-35-Me2), Hph(4-CF3), Hph(4-Cl), Hph(4-CF3-3-Et), Hph(4-Cl-3-F-5-OMe), Hph(4-Et-3-F-5-OMe), Hph(4-CHF2-35-Me2), Hph(4-CHF2-3-F-5-Me), Hph(4-CHF2-3-Cl-5-Me), Hph(4-CHF2-3-F-5-OMe), Abu(6-DHBzfr-4-F), Hph(4-CF3-3-cPr), Abu(5-Inda-1-F2), Hph(4-cPr-3-F), Hph(4-cPr-3-Cl), Hph(4-cPr-3-Me), Hph(4-Et-3-F), Hph(3-Cl-4-Et), Hph(4-CHF2-35-F2), Hph(4-Cl-3-CF3), Hph(4-Cl-3-OMe), Abu(6-Inda-4-F), Hph(4-cPr-3-OMe), Hph(4-cPr-35-Me2), Hph(4-CHF2-35-C12), Hph(4-CHF2-3-OMe), Hph(4-Et-3-OMe), Abu(5-Bzt-7-Cl), Abu(5-Bzt-23-Me2), Abu(5-Bzt-2-F-3-Me), Abu(123-Me3-6-Indo), Abu(1-Me-7-Cl-5-Indo), Abu(13-Me2-6-Indo), and Abu(1-Me-6-Indo).

[0724] In one embodiment, in formula (1), R8 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy C1-C6 alkyl, C2-C6 alkenyloxycarbonyl C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl C1-C6 alkyl, C6-C 10Aryloxy C1-C6 alkyl, C7-C 14 Aralkyl, C7-C 14 Aralkyloxy C1-C6 alkyl, 5- to 10-membered heteroaryl C1-C6 alkyl or 5- to 10-membered heteroaryl C1-C6 alkoxy C1-C6 alkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of: halogen, hydroxy, carboxy, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkoxy, cyano, aminocarbonyl (wherein the amino group is -NH2, mono-C1-C6 alkylamino, di-C1-C6 alkylamino or a 4- to 8-membered cyclic amino group, each of which is optionally substituted with halogen), 4- to 7-membered subheterocycloalkyl, protected 4- to 7-membered subheterocycloalkyl, 4- to 7-membered heterocyclic group and protected 4- to 7-membered heterocyclic group.

[0725] In this embodiment, R8 is preferably hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy C1-C6 alkyl or C3-C8 cycloalkyl C1-C6 alkyl.

[0726] Specific examples of R8 in this embodiment include hydrogen, methyl, n-butyl, 2,2-difluoroethyl, 3,3-difluoropropyl, cyclohexylmethyl, methoxymethyl, n-propoxymethyl, 3-methylbutoxymethyl and ethyl.

[0727] In one embodiment, in formula (1), R8 and R5 together can form a C4-C8 alkylene group. The C4-C8 alkylene group is preferably -(CH2)8-.

[0728] In one embodiment, in formula (1), R8, together with P8, the carbon atom to which R8 is attached, and the nitrogen atom to which P8 is attached, can form a 4- to 7-membered saturated heterocycle. The 4- to 7-membered saturated heterocycle can be condensed with a saturated carbocyclic ring or an aromatic ring. The 4- to 7-membered saturated heterocycle is optionally substituted with: one or more halogen atoms, oxo, one or more C1-C6 alkyl groups, C1-C6 haloalkyl, C3-C8 spirocycloalkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, 4- to 8-membered cyclic amino group (wherein the cyclic amino group is optionally substituted with one or more halogen atoms) or OS8. Here, S8 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C3-C8 cycloalkyl C1-C6 alkyl, 4- to 7-membered heterocyclic group, C7-C 14 Aralkyl (wherein the aralkyl is optionally substituted with one or more halogen atoms, C1-C6 alkyl, C1-C6 alkoxy or C1-C6 haloalkoxy), 5- to 10-membered heteroaryl C1-C6 alkyl or C3-C8 cycloalkyl.

[0729] When R8 and P8 form a 4- to 7-membered saturated heterocycle, the 4- to 7-membered saturated heterocycle is preferably an azetidine ring, a pyrrolidine ring, a piperidine ring, a piperazine ring, a morpholine ring, a thiomorpholine ring or a homopiperidine ring. These saturated heterocycles can be condensed with a 3- to 8-membered saturated carbocyclic ring (preferably a cyclopropane ring or a cyclohexane ring) or a 6- to 10-membered aromatic ring (preferably a benzene ring). When the 4- to 7-membered saturated heterocycle has one or more substituents, the 4- to 7-membered saturated heterocycle is preferably substituted with: one or more halogen atoms; one or more C1-C6 alkyl groups; C1-C6 haloalkyl; hydroxy; 4- to 7-membered heteroepoxy; oxo; C1-C6 alkoxy; C3-C8 cycloalkyl C1-C6 alkoxy; C1-C6 haloalkoxy; a 4- to 8-membered cyclic amino optionally substituted with one or more halogen atoms; C3-C8 spiroalkyl; or C3-C8 cycloalkoxy.

[0730] In one embodiment, in formula (1), R8 and Q8 together with the carbon atom to which they are attached can form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocycle. In this case, the 3- to 8-membered alicyclic ring is preferably a cyclopropane ring, a cyclobutane ring, a cyclopentane ring or a cyclohexane ring, and the 4- to 7-membered saturated heterocycle is preferably a tetrahydrofuran ring or a tetrahydropyran ring.

[0731] In one embodiment, P8 is hydrogen, C1-C6 alkyl, C1-C6 alkoxy C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy C2-C6 alkenyl, C3-C8 cycloalkyl, 4- to 7-membered heterocyclic group, 4- to 7-membered heterocyclic group C1-C6 alkyl, C6-C 10 aryl, C7-C 14 aralkyl, 5- to 10-membered heteroaryl or 5- to 10-membered heteroaryl C1-C6 alkyl, each of which may be substituted with one or more groups independently selected from the group consisting of: halogen, hydroxy, C1-C6 alkoxy and aminocarbonyl (wherein the amino is -NH2, mono-C1-C6 alkylamino, di-C1-C6 alkylamino or 4- to 8-membered cyclic amino).

[0732] P8 is preferably hydrogen or C1-C6 alkyl, and more preferably methyl, ethyl, n-propyl or n-butyl.

[0733] In one embodiment, Q8 is hydrogen or C1-C6 alkyl, and is preferably hydrogen or methyl.

[0734] Specific examples of the amino acid residues in core 8 include Hyp(Et), Pro(4-F2), Pro(4S-Me), Hyp(3)(Et(2-F2)), Pro(4R-CF3), Pro(4R-F), Pro, MeAbu(4-F2), MeNva(5-F2), Hyp(iBu), Hyp(nPr), MeNle, MeCha, MeSer(iPen), D-MeSer(nPr), MeAla, MeSer(Me), MeSer(nPr), EtGly, nBuGly, nPrGly, Ala, Aze(2), Mor(3), Tmo(2), Pic(2), Pro(4S-F), Hyp(Me), cisHyp(Me), cisHyp(3)(Me), cisHyp(3)(nPr), cisHyp(3)(Et), Hyp(3)(nPr), Hyp(3)(Et), Hyp(3)(Me), Hyp(3)(Me-cPent), Hyp(3)(Me-cPr), Hyp(3)(nBu), Hyp(3)(Tfp), Hyp(Me-cPent), Hyp(Me-cPr), Hyp(nBu), Hyp(Et(2-F2)), Hyp(Tfp)), cisHyp(3), Hyp(3), Hyp, cisHyp, Pro(3S4-C1), (Me)Pro, cisPro(4-pip-4-F2), Pro(4-pip-4-F2), EtAla, Pro(4-keto), Pro(4-Me2), MeGly, Pic(2)(4-F2), Pro(4-cPr), cisHyp(Et(2-F2)), cisHyp(Et), Hyp(THP), Nle, Gly, Pro(4R-Me), MeAbu, Pro(4R-Et), Pro(4R-nPr), Hyp(iPr), Hyp(cBu), Hyp(cPent) and Azp(2).

[0735] In one embodiment, in formula (1), M9 is -N(P9)- or an oxygen atom.

[0736] In one embodiment, in formula (1), R9 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy C1-C6 alkyl, C2-C6 alkenoxy C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl C1-C6 alkyl, C7-C 14An arylalkyl or 5- to 10-membered heteroaryl C1-C6 alkoxy C1-C6 alkyl, each of which may be substituted by one or more groups independently selected from the group consisting of: halogen, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, aminocarbonyl (wherein the amino group is -NH2, mono-C1-C6 alkylamino, di-C1-C6 alkylamino or a 4- to 8-membered cyclic amino group) and C1-C6 alkylsulfonyl.

[0737] In this embodiment, R9 is preferably C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy C 1- C6 alkyl, C1-C6 alkenyloxy C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl C1-C6 alkyl or C7-C 14 Arylalkyl.

[0738] In this embodiment, specific examples of R9 include methyl, ethyl, n-propyl, isopropyl, 1-methylpropyl, 2-methylpropyl, allyl, cyclopropyl, cyclohexylmethyl, methoxymethyl, tert-butoxymethyl, allyloxymethyl and benzyl.

[0739] In one embodiment, in formula (1), R9 together with P9, the carbon atom to which R9 is bonded, and the nitrogen atom to which P9 is bonded may form a 4- to 7-membered saturated heterocycle. In this case, the 4- to 7-membered saturated heterocycle is preferably an azetidine ring, pyrrolidine ring, piperidine ring, piperazine ring, morpholine ring.

[0740] In one embodiment, in formula (1), R9 together with Q9 and the carbon atom to which R9 and Q9 are bonded may form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocycle. The 3- to 8-membered alicyclic ring or the 4- to 7-membered saturated heterocycle may be substituted by one or more halogen atoms or one or more C1-C6 alkyl groups. In this case, the 3- to 8-membered alicyclic ring is preferably a cyclopropane ring, cyclobutane ring, cyclopentane ring, cyclopentene ring, cyclohexane ring, and the 4- to 7-membered saturated heterocycle is preferably an oxetane ring, tetrahydrofuran ring or tetrahydropyran ring.

[0741] In one embodiment, in formula (1), R9 and R1 together form a divalent group. The details of this group are as described above.

[0742] In one embodiment, P9 is hydrogen or a C1-C6 alkyl group, wherein the C1-C6 alkyl group is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C1-C6 alkoxy, and aminocarbonyl (wherein the amino group is -NH2, mono-C1-C6 alkylamino, di-C1-C6 alkylamino, or a 4- to 8-membered cyclic amino group). P9 is preferably hydrogen or a C1-C6 alkyl group, and more preferably hydrogen or methyl.

[0743] In one embodiment, Q9 is hydrogen or a C1-C6 alkyl group, and is preferably hydrogen or methyl.

[0744] Specific examples of the amino acid residues in core 9 include (Me)Abu, (Me)Cha, (Me)Gly(cPr), (Me)Ile, (Me)Leu, (Me)Nva, (Me)Phe, (Me)Ser(Al), (Me)Ser(Me), (Me)Ser(tBu), (Me)Val, 1-ACPrC, Aib, AoxeC, Athpc, cHex, cHex(4-F2), cLeu, cLeu(34-d), cVal, cVal(3-F2), cVal(3-Me2), D-(Me)Algly, D-Ala, D-Algly, MeAib, MecVal, MecLeu, Ala, MecVal(3-Me2), except when the side chain (R9) of core 9 and the side chain (R1) of core 1 together form a divalent group.

[0745] When the side chain (R9) of core 9 and the side chain (R1) of core 1 together form a divalent group, the group at the position of R9 corresponding to the amino acid residues listed above (or preferably D-(Me)Algly, (Me)Ser(Al), or D-Algly) can be linked to the group at the position of the side chain (R1) of core 1 using a method such as that described in the following "General Production Method" section.

[0746] In one embodiment, in formula (1), R 10 is a C1-C6 alkyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy C1-C6 alkyl group, a C3-C8 cycloalkyl group, a C3-C8 cycloalkyl C1-C6 alkyl group, a C3-C8 cycloalkoxy C1-C6 alkyl group, or a C7-C 14 arylalkyl group, each of which may be substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, and C1-C6 alkylsulfonyl.

[0747] In this embodiment, R 10Preferably a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy C1-C6 alkyl group, a C3-C8 cycloalkyl group or a C3-C8 cycloalkyl C1-C6 alkyl group.

[0748] R 10 Specific examples of which include methyl, isopropyl, 1-methylpropyl, 2-methylpropyl, tert-butyl, pentan-3-yl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, n-propoxymethyl, cyclobutyl, cyclopentyl, cyclohexyl, 2,2-dimethylpropyl, cyclobutylmethyl and cyclopropylmethyl.

[0749] In one embodiment, in formula (1), R 10 together with the carbon atom to which P 10 , R 10 is bonded and the nitrogen atom to which P 10 is bonded can form a 4- to 7-membered saturated heterocyclic ring. In this case, the 4- to 7-membered saturated heterocyclic ring is preferably an azetidine ring, a pyrrolidine ring, a piperidine ring, a piperazine ring, a morpholine ring.

[0750] In one embodiment, in formula (1), R 10 together with Q 10 and R 10 and the carbon atoms to which Q 10 is bonded can form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring. In this case, the 3- to 8-membered alicyclic ring is preferably a cyclopropane ring, a cyclobutane ring, a cyclopentane ring or a cyclohexane ring, and the 4- to 7-membered saturated heterocyclic ring is preferably a tetrahydrofuran ring or a tetrahydropyran ring.

[0751] In one embodiment, P 10 is hydrogen or a C1-C6 alkyl group, wherein the C1-C6 alkyl group may be substituted with one or more groups independently selected from the group consisting of: halogen, hydroxy, C1-C6 alkoxy and aminocarbonyl (wherein the amino group is -NH2, mono-C1-C6 alkylamino, di-C1-C6 alkylamino or a 4- to 8-membered cyclic amino group). P 10 is preferably hydrogen or a C1-C6 alkyl group, and more preferably hydrogen, methyl or ethyl.

[0752] In one embodiment, Q 10 is hydrogen or a C1-C6 alkyl group, and is preferably hydrogen or methyl.

[0753] Specific examples of the amino acid residues in core 10 include MeGly(cPent), MeNva(3-Et), MeLeu, MeVal, MeIle, MeChg, MeTle, MeAbu(4-F2), MeaIle, MeAbu(4-F3), MeGly(cBu), Gly(cPem), EtGly(cPent), Leu, MeAla(tBu), MeAla(cBu), and MeAla(cPr).

[0754] In one embodiment, in formula (1), L 11 is a single bond or is -CHM 11- -, -(CH2) n S(CH2) m -, -(CH2) n S(O)(CH2) m - or -(CH2) n S(O)2(CH2) m -, where n and m are each independently 1 or 2. Except when R 11 and M 11 form a 3- to 8-membered alicyclic ring, M 11 is hydrogen. L 11 is preferably -CH2- or -CH2-S-CH2-.

[0755] When L 11 is -(CH2) n S(CH2) m -, specific examples of this group include -CH2SCH2-, -CH2CH2SCH2-, -CH2SCH2CH2-, and -CH2CH2SCH2CH2-.

[0756] When L 11 is -(CH2) n S(O)(CH2) m -, specific examples of this group include -CH2S(O)CH2-, -CH2CH2S(O)CH2-, -CH2S(O)CH2CH2-, and -CH2CH2S(O)CH2CH2-.

[0757] When L 11 is -(CH2) n S(O)2(CH2) m -, specific examples of this group include -CH2S(O)2CH2-, -CH2CH2S(O)2CH2-, -CH2S(O)2CH2CH2-, and -CH2CH2S(O)2CH2CH2-.

[0758] In one embodiment, in formula (1), R 11 together with R2 forms a divalent group. Details of this group are as described above.

[0759] In one embodiment, in formula (1), R 11 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy C1-C6 alkyl, C7-C 14 arylalkyl, aminocarbonyl (wherein the amino group is -NH2, mono-C1-C6 alkylamino, di-C1-C6 alkylamino, N-C1-C6 alkyl-N-C2-C6 alkenylamino or a 4- to 8-membered cyclic amino group), or C3-C8 cycloalkyl, each of which may be substituted by one or more groups independently selected from the group consisting of: halogen, oxo, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, 4- to 7-membered heterocyclic group, aminocarbonyl (wherein the amino group is -NH2, mono-C1-C6 alkylamino, di-C1-C6 alkylamino or a 4- to 8-membered cyclic amino group), and C1-C6 alkylsulfonyl.

[0760] In this embodiment, R 11 is preferably: C1-C6 alkyl; di-C1-C6 alkylaminocarbonyl; N-C1-C6 alkyl-N-C2-C6 alkenylaminocarbonyl; N-C1-C6 alkyl-N-C1-C6 alkoxy C1-C6 alkylaminocarbonyl; cyclic aminocarbonyl optionally substituted by one or more C1-C6 alkyl groups or 4- to 7-membered heterocyclic groups; or C3-C8 cycloalkyl.

[0761] In this embodiment, R 11 specific examples include methyl, dimethylaminocarbonyl, diethylaminocarbonyl, N-ethyl-N-methylaminocarbonyl, N-allyl-N-methylaminocarbonyl, N-propyl-N-methylaminocarbonyl, N-butenyl-N-methylaminocarbonyl, N-pentenyl-N-methylaminocarbonyl, N-hexenyl-N-methylaminocarbonyl, N-methoxyethyl-N-methylaminocarbonyl, azetidinylcarbonyl, pyrrolidinylcarbonyl, 3,3-dimethylpyrrolidinylcarbonyl, piperidinylcarbonyl, 4-methylpiperidinylcarbonyl, morpholinylcarbonyl, morpholino carbonyl, oxazolidin-3-ylcarbonyl, 1-(oxetane-3-yl)-piperazin-4-ylcarbonyl, 3-oxa-8-azabicyclo[3.2.1]octan-8-ylcarbonyl, cyclopropyl, and 2-methylpropyl.

[0762] In one embodiment, in formula (1), R 11 is a peptide chain containing 1 to 4 amino acid residues. In this case, the 1 to 4 amino acid residues constituting the peptide chain may be natural amino acid residues or non-natural amino acid residues, and may be the same or different.

[0763] When L of core 11 11 is -(CH2) n S(CH2) m -, -(CH2) n S(O)(CH2) m or -(CH2) n S(O)2(CH2) m -, R 11 is preferably aminocarbonyl (wherein the amino group is -NH2, mono-C1-C6 alkylamino, di-C1-C6 alkylamino or 4- to 8-membered cyclic amino).

[0764] In one embodiment, in formula (1), R 11 together with the carbon atom to which P 11 , R 11 is bonded and the nitrogen atom to which P 11 is bonded can form a 4- to 7-membered saturated heterocyclic ring. In this case, the 4- to 7-membered saturated heterocyclic ring is preferably an azetidine ring, a pyrrolidine ring, a piperidine ring, a piperazine ring, or a morpholine ring.

[0765] In one embodiment, in formula (1), R 11 together with Q 11 and the carbon atoms to which R 11 and Q 11 are bonded can form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring. In this case, the 3- to 8-membered alicyclic ring is preferably a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, or a cyclohexane ring, and the 4- to 7-membered saturated heterocyclic ring is preferably a tetrahydrofuran ring or a tetrahydropyran ring.

[0766] In one embodiment, in formula (1), R 11 together with M 11 , the carbon atom to which R 11 is bonded and the carbon atom to which M 11 is bonded can form a 3- to 8-membered alicyclic ring. In this case, the 3- to 8-membered alicyclic ring is preferably a cyclopentane ring or a cyclohexane ring.

[0767] In one embodiment, in formula (1), M 11 is hydrogen.

[0768] In one embodiment, P 11 is hydrogen, C 1- C6 alkyl, C3-C8 cycloalkyl C1-C6 alkyl or C7-C 14 arylalkyl, wherein the C1-C6 alkyl can be substituted by one or more groups independently selected from the group consisting of: halogen, hydroxy, C1-C6 alkoxy, and aminocarbonyl (wherein the amino group is -NH2, mono-C1- C6 alkylamino, di-C1-C6 alkylamino, or 4- to 8-membered cyclic amino).

[0769] P 11 is preferably hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl C1-C6 alkyl, or C7-C 14 arylalkyl. Specific examples of such P 11 include hydrogen, methyl, ethyl, n-propyl, 2-cyclobutylethyl, 2-cyclopentylethyl, and phenethyl.

[0770] In one embodiment, Q 11 is hydrogen or C1-C6 alkyl, and is preferably hydrogen.

[0771] In one embodiment, R 11 is preferably -CONR 11A R 11B wherein R 11A and R 11B are each independently hydrogen or C1-C6 alkyl (preferably methyl), or R 11A and R 11B together with the nitrogen atom to which they are attached form a 4- to 8-membered saturated heterocycle. The 4- to 8-membered saturated heterocycle is optionally substituted with one or more groups independently selected from the group consisting of: one or more halogen atoms (preferably fluorine), one or more oxo groups, one or more C1-C6 alkyl groups (preferably C1-C4 alkyl), and 4- to 7-membered heterocyclic groups (preferably oxetan-3-yl).

[0772] Except when the side chain of core 11 (R 11) except when forming a divalent group together with the side chain (R2) of core 2, specific examples of the amino acid residues in core 11 include MeAsp-MeNAllyl, MeAsp-MeNButenyl, MeAsp-MeNPentenyl, MeAsp-MeNHexenyl, MeAsp-MeNEt, MeAsp-NMe2, MeAsp-mor, D-3-MeAbu, MeAsp-pyrro, MeAsp-aze, MeAsp-MeNnPr, MeAsp-MeNEtOMe, MeAsp-mor(35-bicyc), MeAsp-NEt2, MeAsp-pip, D-MeAsp-NMe2, MeAsp-mor(35-diMe), EtAsp-NMe2, D-3-Abu, D-Pro-(C#CH2), Asp-NMe2, MeAsp-mor(26-bicyc), cPentEtAsp-NMe2, cPentEtAsp-mor, EtAsp-mor, PhenethylAsp-mor, cBuEtAsp-mor, nPrAsp-mor, PhenethylAsp-NMe2, cBuEtAsp-NMe2, nPrAsp-NMe2, Asp-mor, MeAsp-pyrro(3-Me2), MeAsp-pip(4-Me), MeAsp-piz(oxe), MeAsp-oxz, MeGly(cPr) and nPrLeu.

[0773] When the side chain (R 11 ) of core 11 and the side chain (R2) of core 2 form a divalent group together, except for this case, the group at the position of R11 corresponding to the amino acid residues listed above (or preferably MeAsp-MeNAllyl, MeAsp-MeNgutenyl, MeAsp-MeNPentenyl or MeAsp-MeNHexenyl) can be linked to the group at the position corresponding to the side chain (R2) of core 2 by the method described in the following article section "General Production Method".

[0774] When L 11 is -(CH2) n S(CH2) m -, -(CH2) n S(O)(CH2) m or -(CH2) n S(O)2(CH2) m -, specific examples of the amino acid residues in core 11 include MeCys(AcOH)-NMe2.

[0775] In one embodiment, in formula (1), at least three, at least four, at least five, or at least six of P1 to P 11 are not hydrogen.

[0776] In one embodiment, in formula (1), at least three, at least four, at least five, or at least six of P1 to P 11 are preferably C1-C6 alkyl groups, where the C1-C6 alkyl groups are preferably methyl or ethyl.

[0777] In one embodiment, the present disclosure may be a compound having formula (1), wherein one of -CO-L1- and -CO-L 11 - is replaced by -(CH2) n C≡CCH2S(CH2) m -, -(CH2) n CH=CHCH2S(CH2) m -, or -(CH2) n+3 S(CH2) m -, where n is 1, 2, or 3, and m is 1 or 2. -S- may be oxidized to -S(O)- or -S(O)2-. Here, when -CO-L1- is replaced by -(CH2) n C≡CCH2S(CH2) m -, -(CH2) n CH=CHCH2S(CH2) m -, or -(CH2) n+3 S(CH2) m -, L 11 is a single bond, and when -CO-L 11 - is replaced by -(CH2) n C≡CCH2S(CH2) m -, -(CH2) n CH=CHCH2S(CH2) m -, or -(CH2) n+3 S(CH2) m -, L1 is a single bond. The groups in formula (1) other than L1 and L 11 are as described above.

[0778] In one embodiment, the present disclosure may be a compound represented by the following formula (1A), which further specifies the above formula (1).

[0779]

[0780] The definition of each group in formula (1A) is the same as the definition of each group in formula (1).

[0781] In one embodiment, the present disclosure may be a compound represented by the following formula (3), which further specifies the above formula (1).

[0782]

[0783] Each group in formula (3) has the same definition as each group in formula (1).

[0784] In one embodiment, the present disclosure may be a compound represented by the following formula (4), which further specifies the above formula (1).

[0785]

[0786] R1 to R in formula (4) 11 , P1 to P 11 , Q7 and Q9 are the same as R1 to R 11 , P1 to P 11 , Q7 and Q9 in the above formula (2), respectively, and n and m are each independently 1 or 2. In addition, -S- in formula (4) may be oxidized to -S(O)- or -S(O)2-.

[0787] In one embodiment, the present disclosure may be a compound represented by the following formula (5), which further specifies the above formula (1).

[0788]

[0789] R1 to R in formula (5) 11 , P1 to P 11 , Q7 and Q9 are the same as R1 to R 11 , P1 to P 11 , Q7 and Q9 in the above formula (2), respectively, and n and m are each independently 1 or 2. In addition, -S- in formula (5) may be oxidized to -S(O)- or -S(O)2-.

[0790] In one embodiment, the present disclosure may be the following formula (6), wherein -CO-L1- in the above formula (1) is replaced by -(CH2) n C≡CCH2S(CH2) m -, -(CH2) n CH=CHCH2S(CH2) m - or -(CH2) n+3 S(CH2) m -, and L 11 is a single bond.

[0791]

[0792] R1 to R in formula (6) 11 , P1 to P11 , Q7, and Q9 are respectively the same as R1 to R in the above formula (2) 11 , P1 to P 11 , Q7, and Q9,

[0793]

[0794] represents a single bond, a double bond or a triple bond, n is 1, 2 or 3, and m is 1 or 2. In addition, -S- in formula (6) can be oxidized to -S(O)- or -S(O)2-.

[0795] In one embodiment, the present disclosure can be the following formula (7), wherein -CO-L in the above formula (1) 11 - is replaced by -(CH2) n C≡CCH2S(CH2) m -, -(CH2) n CH=CHCH2S(CH2) m - or -(CH2) n+3 S(CH2) m -, and L1 is a single bond.

[0796]

[0797] R1 to R in formula (7) 11 , P1 to P 11 , Q7, and Q9 are respectively the same as R1 to R in formula (2) 11 , P1 to P 11 , Q7, and Q9,

[0798]

[0799] represents a single bond, a double bond or a triple bond, n is 1, 2 or 3, and m is 1 or 2. In addition, -S- in formula (7) can be oxidized to -S(O)- or -S(O)2-.

[0800] In one embodiment, the present disclosure can be a compound represented by the following formula (8).

[0801]

[0802] R2 to R in formula (8) 11 , P2 to P 11 , Q7, and Q9 are respectively the same as R2 to R in formula (1) mentioned above 11 , P2 to P 11 , Q7, and Q9, and n and m are each independently 1 or 2. Further, -S- in formula (8) can be oxidized to -S(O)- or -S(O)2-.

[0803] Specific examples of the cyclic compounds of the present disclosure include those provided in Table 38, and in particular, those listed below are preferred. The compound numbers listed below are consistent with the compound numbers given in Table 38.

[0804] PP1105: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-27-isobutyl-N,N,4,19,22,26,32,35-octamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaoxo-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10,14 tetratetracont-38-ene-17,1'-cyclopentane]-23-carboxamide,

[0805] PP2320: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-28-ethoxy-32-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,N,2,14,18,21,24,36-octamethyl-10-[(1S)-1-methylpropyl]-3,9,12,15,19,22,25,31,34,37,45-undecaoxo-13-propyl-38-[[4-(trifluoromethyl)phenyl]methyl]spiro[2,8,11,14,18,21,24,30,33,36,39-undecaazatetracyclo[37.5.1.0 4, 8 .0 26,30 pentatetracont-42-ene-23,1'-cyclobutane]-17-carboxamide,

[0806] PP3478: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-27-isobutyl-N,N,4,19,22,26,32,35-octamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaoxo-2-(p-tolylmethyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10,1442-Carbon-38-ene-17,1′-cyclopentane]-23-carboxamide,

[0807] PP3475: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-Cyclopentyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-27-[(1R)-1-methoxyethyl]-N,N,4,19,22,26,32,35-octamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaooxo-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10 ,14 42-Carbon-38-ene-17,1′-cyclopentane]-23-carboxamide,

[0808] PP3484: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-Cyclopentyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-27-isobutyl-N,N,4,16,19,22,26,32,35-nonamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaooxo-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10,14 42-Carbon-38-ene-17,1′-cyclobutane]-23-carboxamide,

[0809] PP3481: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-Cyclopentyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-27-[(1R)-1-methoxyethyl]-N,N,4,19,22,26,32,35-octamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaooxo-2-(p-tolylmethyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10,14 42-Carbon-38-ene-17,1′-cyclopentane]-23-carboxamide,

[0810] PP3368: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-Cyclopentyl-28-ethoxy-32-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,N,2,14,18,21,36-heptamethyl-10-[(1S)-1-methylpropyl]-3,9,12,15,19,22,25,31,34,37,45-undecaooxo-13-propyl-38-[[4-(trifluoromethyl)phenyl]methyl]spiro[24-oxa-2,8,11,14,18,21,30,33,36,39-decaazatetracyclo[37.5.1.0 4,8 .0 26,30 tetratetracont-42-ene-23,1'-cyclobutane]-17-carboxamide,

[0811] PP3388: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-Cyclopentyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,N,4,19,22,26,32,35-octamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaooxo-27-propyl-2-(p-tolylmethyl)spiro[16-oxa-1,4,7,10,19,22,26,29,32,35-decaazatricyclo[34.5.1.0 10,14 dotetracont-38-ene-17,1'-cyclobutane]-23-carboxamide,

[0812] PP3374: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-Cyclopentyl-28-ethoxy-13-[(1R)-1-methoxyethyl]-32-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,N,2,14,18,21,36-heptamethyl-10-[(1S)-1-methylpropyl]-3,9,12,15,19,22,25,31,34,37,45-undecaooxo-38-[[4-(trifluoromethyl)phenyl]methyl]spiro[24-oxa-2,8,11,14,18,21,30,33,36,39-decaazatetracyclo[37.5.1.0 4,8 .0 26,30 tetratetracont-42-ene-23,1'-cyclobutane]-17-carboxamide,

[0813] PP3376: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-12-ethoxy-27-[(1R)-1-methoxyethyl]-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,N,4,19,22,26,32,35-octamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaooxo-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[16-oxa-1,4,7,10,19,22,26,29,32,35-decaazatricyclo[34.5.1.0 10,14 tetratetracont-38-ene-17,1′-cyclobutane]-23-carboxamide,

[0814] PP3394: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-12-ethoxy-27-[(1R)-1-methoxyethyl]-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,N,4,19,22,26,32,35-octamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaooxo-2-(p-tolylmethyl)spiro[16-oxa-1,4,7,10,19,22,26,29,32,35-decaazatricyclo[34.5.1.0 10,14 tetratetracont-38-ene-17,1′-cyclobutane]-23-carboxamide,

[0815] PP3194: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-12-ethoxy-27-[(1R)-1-methoxyethyl]-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,N,3′,3′,4,19,22,26,32,35-decamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaooxo-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10,14 tetratetracont-38-ene-17,1′-cyclobutane]-23-carboxamide,

[0816] PP3198: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-8-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-20-cyclopentyl-12-ethoxy-27-[(1R)-1-methoxyethyl]-N,N,3′,3′,4,19,22,26,32,35-decamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaoxo-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10,14 tetracosa-38-ene-17,1′-cyclobutane]-23-carboxamide,

[0817] PP3327: (6′S,9′S,13′S,16'S,22′S,29′S,35′S,40a'S,Z)-16′-((S)-sec-butyl)-6′-cyclopentyl-35'-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-N,N,2′,5′,8′,12′,18′,21′,31′-nonamethyl-29'-(4-methylbenzyl)-1′,4′,7′,11′,14′,17′,20′,30′,33′,36′,41′-undecaoxo-13′-propyl-1′,2′,4′,5′,6′,7′,8′,9′,10′,11′,12′,13′,14′,15′,16′,17′,18′,19′,20′,21′,22′,23′,26′,27′,29′,30′,31′,32′,33′,34′,35′,36′,40′,40a'-tetratetra hydro-38'H-dispiro[cyclobutane-1,3′-[22,28]methanopyrrolo[1,2-j][1,4,7,10,13,16,19,23,26,29,32]undecaazacyclooctatriene-39′,1″-cyclopropane]-9′-carboxamide,

[0818] PP3234: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-8-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-20-cyclopentyl-12-ethoxy-N,N,4,16,19,22,26,32,35-nonamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaooxo-27-prop-2-ynyl-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10,14 tetratetracontacosa-38-ene-17,1'-cyclobutane]-23-carboxamide,

[0819] PP3238: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-N,N,4,16,19,22,26,32,35-nonamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaooxo-27-prop-2-ynyl-2-(p-tolylmethyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10,14 tetratetracontacosa-38-ene-17,1'-cyclobutane]-23-carboxamide,

[0820] PP3255: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-28-ethoxy-32-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,N,2,14,18,21,24,36-octamethyl-10-[(1S)-1-methylpropyl]-3,9,12,15,19,22,25,31,34,37,45-undecaooxo-13-prop-2-ynyl-38-(p-tolylmethyl)spiro[2,8,11,14,18,21,24,30,33,36,39-undecaazatetracyclo[37.5.1.0 4,8 .0 26,30 pentatetracontacosa-42-ene-23,1'-cyclobutane]-17-carboxamide,

[0821] PP3356: (6′S,9′S,13'S,16'S,22′S,29'S,35'S,40a'S,Z)-16′-((S)-sec-Butyl)-6′-cyclopentyl-35'-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-N,N,2′,5′,8′,12′,18′,21′,31′-nonamethyl-1′,4′,7′,11′,14′,17′,20′,30′,33′,36′,41′-undecaoXO-13′-propyl-29′-(4-(trifluoromethyl)benzyl)-1′,2′,4′,5′,6′,7′,8′,9′,10′,11′,12′,13′,14′,15′,16′,17′,18′,19′,20′,21′,22′,23′,26′,27′,29′,30′,31′,32′,33′,34′,35′,36′,40′,40a′-tetratetracontahydro-38'H-dispiro[cyclobutane-1,3′-[22,28]methanopiperolino[1,2-j][1,4,7,10,13,16,19,23,26,29,32]undecaazacyclotetracontene-39′,1″-cyclopropane]-9′-carboxamide,

[0822] PP1693: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-27-butyl-20-cyclopentyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-fluoro-N,N,3′,3′,4,19,22,26,32,35-dec amethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaoXO-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10,14 tetracos-38-ene-17,1′-cyclobutane]-23-carboxamide,

[0823] PP3414: (6′S,9′S,13'S,16'S,22′S,29'S,35'S,40a'S,Z)-16′-((S)-sec-Butyl)-35′-(3-chloro-4-(trifluoromethyl)phenethyl)-N,N,5′,8′,12′,18′,21′,31′-octamethyl-1′,4′,7′,11′,14′,17′,20′,30′,33′,36′,41′-undecaooxo-6′-(pentan-3-yl)-13′-propyl-29'-(4-(trifluoromethyl)benzyl)-1′,2′,4′,5′,6′,7′,8′,9′,10′,11′,12′,13′,14′,15′,16′,17′,18′,19′,20′,21′,22′,23′,26′,27',29',30′,31′,32′,33′,34′,35′,36′,40′,40a′-tetratetracontahydro-38'H-dispiro[cyclobutane-1,3′-[22,28]methanopiperolino[1,2-j][1,4,7,10,13,16,19,23,26,29,32]undecaazacyclotetracontene-39′,1″-cyclopropane]-9′-carboxamide,

[0824] PP2175: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-8-[2-(3,4-dichlorophenyl)ethyl]-12-ethoxy-20-(1-ethylpropyl)-N,N,3′,3′,4,19,22,26,32,35-decamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaooxo-27-propyl-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10,14 tetratetracont-38-ene-17,1′-cyclobutane]-23-carboxamide,

[0825] PP2750: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-32-cyclopropyl-8-[2-(3,4-dichlorophenyl)ethyl]-20-(2,2-dimethylpropyl)-12-ethoxy-27-(methoxymethyl)-N,N,3′,3′,4,19,22,26,35-nonamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaooxo-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10,14 tetratetracont-38-ene-17,1′-cyclobutane]-23-carboxamide,

[0826] PP2742: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-32-cyclopropyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-20-(2,2-dimethylpropyl)-12-ethoxy-N,N,3′,3′,4,19,22,26,35-nonamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaooxo-27-propyl-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10,14 tetratetracont-38-ene-17,1′-cyclobutane]-23-carboxamide,

[0827] PP2967: (6′S,9′S,13'S,16'S,22′S,29'S,35'S,40a′S,Z)-16′-((S)-sec-Butyl)-35′-(3-chloro-4-(trifluoromethyl)phenethyl)-13′-(methoxymethyl)-N,N,3,3,5′,8′,12′,18′,21′,31′-decamethyl-29'-(4-methylbenzyl)-1′,4′,7′,11′,14′,17′,20′,30′,33′,36′,41′-undecaooxo-6′-(pentan-3-yl)-1′,2′,4′,5′,6′,7′,8′,9′,10′,11′,12′,13′,14′,15′,16′,17′,18′,19′,20′,21′,22′,23′,26′,27′,29′,30′,31′,32′,33′,34′,35′,36′,40',40a'-tetratetracontahydro-38'H-dispiro[cyclobutane-1,3′-[22,28]methanopiperolino[1,2-j][1,4,7,10,13,16,19,23,26,29,32]undecaazacyclotetracontene-39′,1″-cyclopropane]-9′-carboxamide,

[0828] PP3510: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38E)-20-cyclopentyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-38-fluoro-27-isobutyl-N,N,4,19,22,26,32,35-octamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaooxo-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10,14 tetratetracont-38-ene-17,1′-cyclopentane]-23-carboxamide.

[0829] In one embodiment, the cyclic peptide compounds of the present disclosure have high selectivity for KRAS. In one embodiment, the cyclic compounds of the present disclosure selectively inhibit KRAS. Without wishing to be bound by a particular theory, the divalent group formed by R4 and P5 interacts with His95 of KRAS, and thereby high selectivity for KRAS can be achieved. Although three isotypes of the RAS protein are known, namely HRAS, KRAS, and NRAS, His95 is only present in KRAS. Thus, a compound that specifically interacts with His95 of KRAS can inhibit KRAS with high selectivity relative to NRAS and / or HRAS.

[0830] In the present disclosure, the sources of NRAS, HRAS, and KRAS are not particularly limited and may include those derived from various animals such as humans, mice, rats, rabbits, dogs, cats, cows, horses, pigs, goats, rhesus monkeys, cynomolgus monkeys, chimpanzees, and chickens, but HRAS, KRAS, and NRAS of human origin are preferred. The amino acid sequence of human - derived NRAS is shown in SEQ ID NO: 4, the amino acid sequence of human - derived HRAS is shown in SEQ ID NO: 5, and the amino acid sequence of human - derived KRAS is shown in SEQ ID NO: 6.

[0831] In one embodiment, when the divalent group formed by R4 and P5 together is represented by the following formula

[0832]

[0833] Y in this formula 13 and Y 15 can interact with His95 of KRAS.

[0834] In one embodiment, the cyclic compound of the present disclosure has a KRAS inhibitory activity that is 3 - fold or more than the NRAS inhibitory activity and / or the HRAS inhibitory activity. In one embodiment, the cyclic compound of the present disclosure has a KRAS binding activity that is 3 - fold or more than the NRAS binding activity and / or the HRAS binding activity.

[0835] In one embodiment, the cyclic compound of the present disclosure has a KRAS inhibitory activity that is 5 - fold, 7 - fold, 10 - fold, 15 - fold, or 20 - fold or more than the NRAS inhibitory activity and / or the HRAS inhibitory activity. In one embodiment, the cyclic compound of the present disclosure has a KRAS binding activity that is 5 - fold, 7 - fold, 10 - fold, 15 - fold, or 20 - fold or more than the NRAS binding activity and / or the HRAS binding activity.

[0836] In the present disclosure, the KRAS inhibitory activity relative to the NRAS inhibitory activity and / or the HRAS inhibitory activity can be determined by the ratio of the KRAS inhibitory activity of the cyclic compound of the present disclosure to the NRAS inhibitory activity and / or the HRAS inhibitory activity of the cyclic compound of the present disclosure. For example, when the ratio is defined as [IC 50 value of the cyclic compound of the present disclosure relative to NRAS and / or HRAS] divided by [IC 50When the value is such that a larger value of this ratio means that the KRAS inhibitory activity is higher than the NRAS inhibitory activity and / or the HRAS inhibitory activity, or in other words, the cyclic compound of the present disclosure has high KRAS-selective inhibitory activity. On the other hand, a smaller value of this ratio means that the KRAS inhibitory activity is lower than the NRAS inhibitory activity and / or the HRAS inhibitory activity, or in other words, the cyclic compound of the present disclosure has low KRAS-selective inhibitory activity.

[0837] In the present disclosure, the KRAS binding activity relative to the NRAS binding activity and / or the HRAS binding activity can be determined by the ratio of the KRAS binding activity of the cyclic compound of the present disclosure to the NRAS binding activity and / or the HRAS binding activity of the cyclic compound of the present disclosure. For example, when this ratio is defined as [KD value relative to NRAS and HRAS] divided by [KD relative to KRAS], a larger value means that the KRAS binding activity is higher than the NRAS binding activity and / or the HRAS binding activity, or in other words, the binding selectivity for KRAS is higher than that for NRAS and / or HRAS. On the other hand, a smaller value means that the KRAS binding activity is lower than the NRAS binding activity and / or the HRAS binding activity, or in other words, the binding selectivity for KRAS is lower than that for NRAS and / or HRAS.

[0838] In one embodiment, the present disclosure relates to an oligopeptide compound represented by the following formula (2) or a salt thereof, or a solvate thereof.

[0839]

[0840] The oligopeptide compound represented by formula (2) contains a partial structure in which three amino acid residues are connected. Herein, the amino acid residues having P 12 、Q 12 and R 12 may be referred to as the amino acid residues of core 12, the amino acid residues having P 13 、Q 13 and R 13 may be referred to as the amino acid residues of core 13, and the amino acid residues having P 14 、Q 14 and R 14 may be referred to as the amino acid residues of core 14.

[0841] In one embodiment, the oligopeptide compound of the present disclosure can be used to produce the cyclic compound represented by formula (1) using a solid-phase synthesis method. In this case, the N-terminus of the oligopeptide compound is preferably protected with a protecting group commonly used in solid-phase synthesis methods such as the Fmoc group.

[0842] In another embodiment, the oligopeptide compound of the present disclosure may be a compound having selective KRAS inhibitory activity.

[0843] In one embodiment, in formula (2), A1 is hydrogen, an amino protecting group, an amino acid residue, or a peptide residue.

[0844] When A1 is an amino protecting group, examples of such protecting groups include carbamate protecting groups, amide protecting groups, arylsulfonamide protecting groups, alkylamine protecting groups, and imide protecting groups. Specific examples of amino protecting groups include Fmoc, Boc, Cbz, Alloc, trifluoroacetyl, pentafluoropropionyl, phthaloyl, tosyl, 2-nitrobenzenesulfonyl, 4-nitrobenzenesulfonyl, and 2,4-dinitrobenzenesulfonyl. Among them, Fmoc is preferred.

[0845] When A1 is an amino acid residue, the amino acid residue may be any natural or unnatural amino acid residue.

[0846] When A1 is a peptide residue, the peptide residue is composed of any kind and number of natural and / or unnatural amino acid residues. The number of amino acid residues constituting the peptide residue is preferably 2 to 13, and more preferably 2 to 9.

[0847] In one embodiment, in formula (2), A2 is a hydroxyl group, an -O-carboxyl protecting group, an amino acid residue optionally loaded on a resin for solid-phase synthesis, a peptide residue optionally loaded on a resin for solid-phase synthesis, or a resin for solid-phase synthesis.

[0848] When A2 is an -O-carboxyl protecting group, examples of such protecting groups include alkyl ester protecting groups, benzyl ester protecting groups, and substituted alkyl ester protecting groups. Specific examples of carboxyl protecting groups include methyl, ethyl, tert-butyl, benzyl, trityl, cumyl, methoxytrityl, 2-(trimethylsilyl)ethyl, 2,2,2-trichloroethyl, and allyl.

[0849] When A2 is an amino acid residue, the amino acid residue may be any natural or unnatural amino acid residue.

[0850] When A2 is a peptide residue, the peptide residue is composed of any kind and number of natural and / or unnatural amino acid residues. The number of amino acid residues constituting the peptide residue is preferably 2 to 13, and more preferably 2 to 9.

[0851] When A2 is an amino acid residue or a peptide residue, the amino acid residue or peptide residue can be loaded onto a resin for solid-phase synthesis. When the peptide residue is loaded onto the resin for solid-phase synthesis, the peptide residue can be loaded onto the resin via the C-terminal amino acid residue or an amino acid residue at any other position in the peptide residue. Specific examples of the resin for solid-phase synthesis include CTC resin, Wang resin, and SASRIN resin. Among them, CTC resin is preferred.

[0852] In one embodiment, when A1 and A2 are amino acid residues and / or peptide residues, A1 and A2 can be linked. The peptide residue formed by the linking of A1 and A2 can contain any number and any kind of natural and / or unnatural amino acid residues. From the perspective of membrane permeability and metabolic stability, the peptide residue is preferably composed of 5 to 15 amino acid residues, and more preferably composed of 7 to 8 amino acid residues. When the cyclic compound of the present disclosure is composed of 11 amino acid residues, A1 is preferably composed of 3 amino acid residues, and A2 is preferably composed of 5 amino acid residues.

[0853] When A1 and A2 are amino acid residues and / or peptide residues, or when A1 and A2 are linked to form a peptide residue, specific examples of one or more amino acid residues constituting the peptide residue include Ala, Tyr, Phe, Gly, Pro, Ser, Val, Leu, Asp, Ile, Cha, Pra, Hph, Abu, Hyp, Nva, Nle, Aze, Mor, Tmo, Pic, Aib, Athpc, AoxeC, Algyl, Hex, PrC, Chg, Tle, their N-substituted derivatives (such as N-alkyl derivatives, preferably N-methyl derivatives), their side-chain variants, and their other derivatives. Specific examples of the side-chain variants of amino acid residues include those obtained by replacing a hydrogen atom in the side chain with a group selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, and cycloalkyl groups, and these groups can have any additional substituents containing a halogen atom, an O atom, an S atom, an N atom, a B atom, an Si atom, or a P atom.

[0854] In one embodiment, in formula (2), R 12 and P 13 together form a divalent group selected from the group consisting of: C1-C 10 alkylene, C2-C 10 alkenylene, C2-C 10 alkynylene, C3-C8 cycloalkylene, 3- to 7-membered heteroalkylene, C6-C 10 arylene, -CO-NR F -, -NR F-CO- and combinations of two or more of these moieties. One or more carbon atoms forming the divalent group may be substituted with one or more heteroatoms independently selected from the group consisting of N, O and S. The divalent group may be substituted with one or more groups independently selected from the group consisting of halogen and C1-C6 alkyl. When the divalent group contains -CO-NR F - or -NR F -CO-, R F is hydrogen or C 1- 6 alkyl, and preferably hydrogen or methyl.

[0855] R 12 and P 13 together form a divalent group of *-C3-C8 alkylene-#, *-C3-C8 alkenylene-#, *-C1-C3 alkylene-C3-C8 cycloalkylene-C1-C3 alkylene-#, *-C1-C3 alkylene-O-C3-C6 alkenylene-#, *-C1-C3 alkylene-CO-NR F -C1-C3 alkylene-#, *-C1-C3 alkylene-NR F -CO-C1-C3 alkylene-# or *-C1-C3 alkylene-3-to 7-membered heteroalkylene-C1-C3 alkylene-#, each of which may be substituted with one or more groups independently selected from the group consisting of halogen and C 1- 6 alkyl. * means the bonding point of the carbon atom bonded to R 12 , and # means the bonding point of the nitrogen atom bonded to P 13 . Further, the divalent group formed by R 12 and P 13 together is preferably *-C4-C5 alkylene-# or *-C4-C5 alkenylene-#, and more preferably *-C4-C5 alkenylene-#.

[0856] In one embodiment, the partial structure *-CR 12 Q 12 -CO-NP 13 -* in the oligopeptide compound represented by formula (2) may be represented by the following formula:

[0857]

[0858] where

[0859] Y 11 is hydrogen, C1-C6 alkyl or halogen, and preferably hydrogen, methyl or fluorine,

[0860] Y 12 is hydrogen, C 1- 6 alkyl or halogen, and preferably hydrogen, methyl or fluorine,

[0861] Y 13 is hydrogen, a C1-C6 alkyl group or a halogen, and preferably is hydrogen, methyl or fluorine, or

[0862] Y 13 together with Y 15 forms a C3-C8 alkylene group or -O-, and preferably is methylene or -O-,

[0863] Y 14 is hydrogen or C 1- C6 alkyl group, and preferably is hydrogen,

[0864] except when Y 13 and Y 15 form a C3-C8 alkylene group or -O-, Y 15 is hydrogen, a C1-C6 alkyl group or a halogen, and preferably is hydrogen, methyl or fluorine,

[0865] Y 16 is hydrogen or C 1- C6 alkyl group, and preferably is hydrogen or methyl,

[0866] Y 17 is hydrogen or a C1-C6 alkyl group, and preferably is hydrogen or methyl,

[0867] Y 18 is hydrogen or a C1-C6 alkyl group, and preferably is hydrogen or methyl,

[0868] R F is hydrogen or a C1-C6 alkyl group, and preferably is hydrogen or methyl,

[0869] n is 0, 1 or 2,

[0870] m is 0, 1 or 2, and

[0871] * indicates the bonding point to an adjacent atom.

[0872] The partial structure *-CR 12 Q 12 -CO-NP 13 -* is preferably:

[0873]

[0874] More preferably, it is desired that the partial structure *-CR 12 Q 12 -CO-NP 13 -* is a structure represented by the following formula:

[0875]

[0876] In one embodiment, in formula (2), P12 is a C1-C6 alkyl group, and preferably a methyl group.

[0877] In one embodiment, in formula (2), Q 12 is hydrogen or a C1-C6 alkyl group, and preferably hydrogen.

[0878] In one embodiment, in formula (2), R 13 is a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkenyloxycarbonyl C1-C6 alkyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy C1-C6 alkyl group, a C3-C8 cycloalkyl group, a C3-C8 cycloalkyl C1-C6 alkyl group, a C3-C8 cycloalkoxy C1-C6 alkyl group, a C7-C 14 arylalkyl group, a C6-C 10 aryloxy C1-C6 alkyl group, a C7-C 14 arylalkoxy C1-C6 alkyl group or a 5- to 10-membered heteroaryl C1-C6 alkyl group, each of which may be substituted by one or more groups independently selected from the group consisting of: halogen, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C1-C6 haloalkoxy, cyano, C1-C6 alkylsulfonyl, C2-C6 alkenyl, C3-C8 cycloalkyl and C1-C6 alkylcarbonyl.

[0879] In this embodiment, R 13 is preferably: a C2-C6 alkynyl group; a C2-C6 alkenyloxycarbonyl C1-C6 alkyl group; a C3-C8 cycloalkyl group; a C3-C8 cycloalkyl C1-C6 alkyl group optionally substituted by one or more halogen atoms; a C7-C 14 arylalkyl group, which is optionally substituted by one or more selected from halogen, C1-C6 alkyl, C 1- C6 alkoxy, C1-C6 haloalkyl, C 1- C6 haloalkoxy, C2-C6 alkenyloxy, C2-C6 alkenyl, C3-C8 cycloalkyl and C1-C6 alkylcarbonyl; a 5- to 10-membered heteroaryl C 1- C6 alkyl group; a C3-C8 cycloalkoxy C1-C6 alkyl group; or a C1-C6 alkoxy C1-C6 alkyl group.

[0880] In this embodiment, R 13Specific examples include 4-(trifluoromethyl)benzyl, 4-fluorobenzyl, 4-methylbenzyl, 4-fluoro-2-methylbenzyl, 4-bromobenzyl, 4-iodobenzyl, allyloxycarbonylmethyl, cyclohexylmethyl, 4,4-difluorocyclohexylmethyl, cyclobutoxymethyl, 3-methylbutoxymethyl, 4-vinylbenzyl, 4-chloro-2-fluorobenzyl, 4-(difluoromethyl)benzyl, 4-(trifluoromethyl)benzyl, 4-ethylbenzyl, 2-fluoro-4-methylbenzyl, 3-fluoro-4-methylbenzyl, 4-(1,1-difluoroethyl)benzyl, 4-cyclopropylbenzyl, 4-isopropylbenzyl, 4-methoxybenzyl, 4-acetylbenzyl, and 1,1-difluoroindan-5-ylmethyl.

[0881] In one embodiment, in formula (2), Q 13 is hydrogen or C 1- C6 alkyl, and preferably hydrogen.

[0882] In one embodiment, in formula (2), R 14 is hydrogen or C1-C6 alkyl, and preferably hydrogen.

[0883] In one embodiment, in formula (2), P 14 is C1-C6 alkyl, and preferably methyl.

[0884] In one embodiment, in formula (2), Q 14 is hydrogen or C1-C6 alkyl, and preferably hydrogen.

[0885] In one embodiment, the oligopeptide compound represented by formula (2) is preferably an oligopeptide compound having a structure represented by the following formula:

[0886]

[0887] wherein

[0888] A1 and A2 are the same as A1 and A2 in formula (2),

[0889] the dotted line is a single bond or a double bond,

[0890] Y 13 and Y 15 are independently hydrogen, methyl or halogen, or

[0891] Y 13 and Y 15 together form -CH2-,

[0892] R 13 is: C2-C4 alkenyloxycarbonyl C 1-C2 alkyl; C3-C8 cycloalkyl C1-C2 alkyl optionally substituted with one or more halogen atoms; or benzyl or phenethyl, optionally substituted with one or more groups selected from the group consisting of F, I, methyl, ethyl, and C1-C2 fluoroalkyl,

[0893] n is 0, 1, or 2; and

[0894] m is 0, 1, or 2.

[0895] Except when the side chain (R 12 ) of core 12 and the N-substituent (P 13 ) of core 13, or the N-substituent (P 12 ) of core 12 and the N-substituent (P 13 ) of core 13 together form a divalent group, specific examples of the amino acid residues in core 12 include MeAhxe(2), MeAlgly, and MeMethagly.

[0896] When the side chain (R12) of core 12 and the N-substituent (P 13 ) of core 13, or the N-substituent (P 12 ) of core 12 and the N-substituent (P 13 ) of core 13 together form a divalent group, except for this case, the groups at the positions corresponding to R 12 or P 12 of the amino acid residues listed above can be linked to the groups at the positions corresponding to the N-substituent (P 13 ) of core 13 using the methods described in the following article section "General Production Method".

[0897] Except when the N-substituent (P 13 ) of core 13 and the side chain (R 12 ) of core 12 or the N-substituent (P 12 ) of core 12 together form a divalent group, specific examples of the amino acid residues in core 13 include AllylPhe(4-CF3), ButenylAsp(OAl), ButenylCha, ButenylCha(4-F2), ButenylPhe(4-I), ButenylPhe(4-CF3), ButenylPhe(4-F), ButenylPhe(4-F-2-Me), ButenylPhe(4-Me), and MethaPhe(4-CF3).

[0898] When the N-substituent (P 13 ) of core 13 and the side chain (R 12 ) of core 12 or the N-substituent (P 12When forming a divalent group together, the group at the position corresponding to the amino acid residue listed above and the group at the position corresponding to the side chain (R 13 ) of Core 12 or the N-substituent (P 12 ) of Core 12 can be linked using the method described, for example, in the following section "General Production Method". 12

[0899] Specific examples of the amino acid residues of Core 14 include MeGly.

[0900] When the oligopeptide compound represented by formula (2) of the present disclosure is an Fmoc-protected tripeptide, the tripeptide is specifically a compound selected from the compounds (tp001) to (tp027) provided in Table 9.

[0901] tp001: N-((S)-2-((S)-3-((((9H-Fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-2-oxoazepan-1-yl)-3-(4-(trifluoromethyl)phenyl)propanoyl)-N-methylglycine,

[0902] tp002: N-((S)-2-((S)-3-((((9H-Fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-2-oxoazocan-1-yl)-3-(4-(trifluoromethyl)phenyl)propanoyl)-N-methylglycine,

[0903] tp003: N-((S)-2-((S)-3-((((9H-Fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-2-oxoazocan-1-yl)-3-(4-fluorophenyl)propanoyl)-N-methylglycine,

[0904] tp004: N-((S)-2-((S)-3-((((9H-Fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-2-oxoazocan-1-yl)-4-(allyloxy)-4-oxobutanoyl)-N-methylglycine,

[0905] tp005: N-((S)-2-((S)-3-((((9H-Fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-2-oxo-2,3,4,7-tetrahydro-1H-azepin-1-yl)-3-(4-(trifluoromethyl)phenyl)propanoyl)-N-methylglycine,

[0906] tp006: N-((S)-2-((S,Z)-3-((((9H-Fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-2-oxo-3,4,7,8-tetrahydroazacyclooctatetraen-1(2H)-yl)-3-(4-(trifluoromethyl)phenyl)propanoyl)-N-methylglycine,

[0907] tp007: N-((S)-2-((S,Z)-3-((((9H-Fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-2-oxo-3,4,7,8-tetrahydroazacyclooctatetraen-1(2H)-yl)-3-(p-tolyl)propanoyl)-N-methylglycine,

[0908] tp008: N-((S)-2-((S,Z)-3-((((9H-Fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-2-oxo-3,4,7,8-tetrahydroazacyclooctatetraen-1(2H)-yl)-3-(4-fluorophenyl)propanoyl)-N-methylglycine,

[0909] tp009: N-((S)-2-((S,Z)-3-((((9H-Fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-2-oxo-3,4,7,8-tetrahydroazacyclooctatetraen-1(2H)-yl)-3-(4-fluoro-2-methylphenyl)propanoyl)-N-methylglycine,

[0910] tp010: N-((S)-2-((S,Z)-3-((((9H-Fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-2-oxo-3,4,7,8-tetrahydroazacyclooctatetraen-1(2H)-yl)-3-cyclohexylpropanoyl)-N-methylglycine,

[0911] tp011: N-((S)-2-((S,Z)-3-((((9H-Fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-2-oxo-3,4,7,8-tetrahydroazacyclooctatetraen-1(2H)-yl)-3-(4,4-difluorocyclohexyl)propanoyl)-N-methylglycine,

[0912] tp012: N-((S)-2-((S,Z)-3-((((9H-Fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-2-oxo-3,4,7,8-tetrahydroazacyclooctatetraen-1(2H)-yl)-3-(4-iodophenyl)propanoyl)-N-methylglycine,

[0913] tp013: N-((S)-2-((S,Z)-3-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-2-oxo-3,4,5,8-tetrahydroazocine-1(2H)-yl)-3-(4-(trifluoromethyl)phenyl)propanoyl)-N-methylglycine,

[0914] tp014: N-((S)-2-((1R,5S,7R)-5-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-oxo-3-azabicyclo[5.1.0]octan-3-yl)-3-(4-(trifluoromethyl)phenyl)propanoyl)-N-methylglycine,

[0915] tp015: N-((S)-2-((S)-3-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-6-methyl-2-oxo-2,3,4,7-tetrahydro-1H-azepin-1-yl)-3-(4-(trifluoromethyl)phenyl)propanoyl)-N-methylglycine,

[0916] tp016: N-((S)-2-((3S,6R)-3-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-6-methyl-2-oxoazepan-1-yl)-3-(4-(trifluoromethyl)phenyl)propanoyl)-N-methylglycine,

[0917] tp017: N-((S)-2-((3S,5R,6R)-3-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-5,6-dimethyl-2-oxoazepan-1-yl)-3-(4-(trifluoromethyl)phenyl)propanoyl)-N-methylglycine,

[0918] tp018: N-((2S)-2-((3S,5S)-3-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-5,6-dimethyl-2-oxoazepan-1-yl)-3-(4-(trifluoromethyl)phenyl)propanoyl)-N-methylglycine,

[0919] tp019: N-((S)-2-((S)-3-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-5,6-dimethyl-2-oxo-2,3,4,7-tetrahydro-1H-aza -1-yl)-3-(4-(trifluoromethyl)phenyl)propanoyl)-N-methylglycine,

[0920] tp020: N-((S)-2-((3S,5S)-3-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-5-methyl-2-oxoazepan-1-yl)-3-(4-(trifluoromethyl)phenyl)propanoyl)-N-methylglycine,

[0921] tp021: N-((S)-2-((S)-3-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-5-methyl-2-oxo-2,3,4,7-tetrahydro-1H-azepin-1-yl)-3-(4-(trifluoromethyl)phenyl)propanoyl)-N-methylglycine,

[0922] tp022: N-((S)-2-((S,Z)-3-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-2-oxo-3,4,7,8-tetrahydroazacyclooctatetraen-1(2H)-yl)-3-(4-vinylphenyl)propanoyl)-N-methylglycine,

[0923] tp023: N-((S)-2-((S)-7-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-5,8-dioxo-1,4-diazacyclooctan-1-yl)-3-(4-(trifluoromethyl)phenyl)propanoyl)-N-methylglycine,

[0924] tp024: N-((S)-2-((S,Z)-3-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-2-oxo-3,4,7,8-tetrahydroazacyclooctatetraen-1(2H)-yl)-3-(4-bromophenyl)propanoyl)-N-methylglycine,

[0925] tp025: N-((S)-2-((S,Z)-3-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-2-oxo-3,4,7,8-tetrahydroazacyclooctatetraen-1(2H)-yl)-3-(4-(difluoromethyl)phenyl)propanoyl)-N-methylglycine,

[0926] tp026: N-((S)-2-((S,E)-3-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-5-fluoro-2-oxo-3,4,7,8-tetrahydroazacyclooctatetraen-1(2H)-yl)-3-(4-(trifluoromethyl)phenyl)propanoyl)-N-methylglycine, and

[0927] tp027: N-((S)-2-((S,E)-3-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-5-fluoro-2-oxo-3,4,7,8-tetrahydroazacyclooctatetraen-1(2H)-yl)-3-(p-tolyl)propanoyl)-N-methylglycine.

[0928] In one embodiment, the oligopeptide compound of the present disclosure has high selectivity for KRAS. In one embodiment, the oligopeptide compound of the present disclosure selectively inhibits KRAS. Without wishing to be bound by a particular theory, the divalent group formed by R 12 and P 13 interacts with His95 of KRAS, and thereby high selectivity for KRAS can be achieved. Although three isotypes of the RAS protein are known, namely HRAS, KRAS, and NRAS, His95 is only present in KRAS. Thus, a compound that specifically interacts with His95 of KRAS can inhibit KRAS with high selectivity relative to NRAS and HRAS.

[0929] In one embodiment, when the divalent group formed by R 12 and P 13 is represented by the following formula,

[0930]

[0931] Y 13 and Y 15 in this formula can interact with His95 of KRAS.

[0932] In the present disclosure, "interaction" means non-covalent interaction, such as electrostatic interaction (including ionic bond, hydrogen bond and dipole interaction), van der Waals interaction (including hydrophobic interaction), etc. For example, it means CH-π interaction, NH-π interaction, S-π interaction, cation-π interaction or halogen-π interaction. The interaction in the present disclosure can be mediated or not mediated by another molecule such as a water molecule, but preferably not mediated by another molecule such as a water molecule.

[0933] In the present disclosure, whether the 95th amino acid residue histidine (denoted as His95 or H95) in the human KRAS wild-type protein interacts with a cyclic compound or an oligopeptide compound can be determined by the interatomic distance between its non-hydrogen atoms (in the case of bonding via another molecule such as a water molecule, the interatomic distance between their non-hydrogen atoms does not consider such another molecule). When the interatomic distance is 5.1 angstroms or less, it can be determined that their non-hydrogen atoms interact with each other. In some embodiments, the interatomic distance between two interacting non-hydrogen atoms can be, for example or less, or less, or less, or less, or less, or less, or less, or less, or or less. Additionally, the interatomic distance can be or greater, or greater, or or greater.

[0934] In the present disclosure, the interatomic distance can be measured, for example, by analyzing the three-dimensional structure of a complex of a human KRAS wild-type protein and a cyclic compound or an oligopeptide compound of the present disclosure. Specifically, a crystal of a complex of a human KRAS wild-type protein and a cyclic compound or an oligopeptide compound of the present disclosure is prepared. X-ray diffraction measurement is performed on the crystal to obtain X-ray diffraction intensity data of a space group, a unit cell, etc. The obtained X-ray diffraction intensity data is applied to programs well-known to those skilled in the art for initial structure or refined structure determination, such as Coot (Emsley, P. et al., 2010), Phenix (Adams, P.D. et al., 2010), Phaser (J. Appl. Cryst. 40: 658-674 (2007)), Refmac5 (Acta Cryst. D67: 355-467 (2011)), and ARP / wARP (Cohen, S.X. et al., 2008), and thereby the three-dimensional structure of a complex of a human KRAS wild-type protein and a cyclic compound or an oligopeptide compound of the present disclosure can be determined.

[0935] Once the three-dimensional structure of the complex of the human KRAS wild-type protein and the cyclic compound or oligopeptide compound of the present disclosure is determined, the interatomic distances can be measured by methods well-known to those skilled in the art. For example, software programs (such as Discovery Studio 2020 Client, MOE (Molecular Operating Environment), or Maestro) that are used in molecular modeling or molecular simulation can be allowed to read the structural information of the complex of the cyclic compound or oligopeptide compound of the present disclosure with the human KRAS wild-type protein, and the functions incorporated in the software program (such as the distance monitor function in the case of Discovery Studio 2020 Client) can be used to measure the interatomic distances. Details of the conditions and criteria used by the software to determine the presence or absence of interactions can be viewed in the manuals, specifications, etc. attached to the software (for example, in the case of Discovery Studio 2020 Client, details of the conditions and criteria used to determine the presence or absence of interactions can be viewed by opening the web page of the manual from the help button, selecting "Receptor-Ligand Interaction Tool", then selecting "Theory - Receptor-Ligand Interaction", and further selecting "Nonbonded Interactions").

[0936] Crystals of the complex of the human KRAS wild-type protein and the cyclic compound or oligopeptide compound of the present disclosure can also be obtained by methods well-known to those skilled in the art. For example, a solution containing the cyclic compound or oligopeptide compound of the present disclosure is mixed with a solution containing the human KRAS wild-type protein to obtain a complex of the human KRAS wild-type protein and the cyclic compound or oligopeptide compound of the present disclosure. By subjecting the resulting complex to crystallization methods well-known to those skilled in the art (such as vapor diffusion methods, batch methods (batch method or microbatch method), dialysis method, or reverse diffusion method), crystals of the complex of the human KRAS wild-type protein and the cyclic compound or oligopeptide compound of the present disclosure can be prepared. Known vapor diffusion methods are the sitting drop method, the hanging drop method, and the sandwich drop method.

[0937] The human wild-type KRAS protein can also be obtained by methods known to those skilled in the art. For example, the human wild-type KRAS protein can be prepared by using recombinant polypeptide expression methods of cells, but this method is not limited thereto. In one embodiment, the nucleic acid encoding the human wild-type KRAS protein of the present disclosure is inserted into a suitable expression vector, the vector is introduced into a suitable cell, the transformed cell is cultured, and the expressed protein is isolated and purified. Such proteins can also be expressed as fusion proteins with another protein to facilitate purification. For example, methods for preparing fusion proteins with maltose-binding protein (vector pMAL series sold by New England BioLabs, USA) using Escherichia coli as a host, methods for preparing fusion proteins with glutathione-S-transferase (GST) (vector pGEX series sold by Amersham Pharmacia Biotech), methods for preparing proteins with a histidine tag added (pET series of Novagen), and methods for preparing proteins with a HAT tag added can be used. The host cell is not particularly limited as long as it is suitable for expressing recombinant proteins, and in addition to the above-mentioned Escherichia coli, yeast, various animal and plant cells, insect cells, etc. can also be used. Various methods known to those skilled in the art can be used to introduce the vector into the host cell. For example, for introduction into Escherichia coli, a calcium ion-mediated introduction method (Mandel, M., Higa, A. (1970) Journal of Molecular Biology, 53, 158-162 and Hanahan, D. (1983) Journal of Molecular Biology, 166, 557-580) can be used. The protein expressed in the host cell can be purified and recovered from the host cell or its cell culture or culture supernatant by methods known to those skilled in the art. When the protein is expressed as a fusion protein together with the above-mentioned maltose-binding protein, HAT tag, etc., affinity purification and gel filtration chromatography (size exclusion chromatography, SEC) purification can be easily performed. In affinity chromatography purification and SEC purification, AKTAxpress TM equipment (GE Healthcare), NGC TM chromatography system (Bio-Rad), BioLogic DuoFlow TM chromatography system (Bio-Rad), etc.

[0938] Interatomic energy can also be measured by methods well-known to those skilled in the art. For example, it is possible to easily calculate the interatomic energy by allowing a molecular simulation program well-known to those skilled in the art (such as the Discovery Studio 2020 client, MOE (Molecular Operating Environment), or Maestro) to read the three-dimensional structure of the substance to be measured and select the force field (such as Amber or CHARM) to be used for the calculation and the atoms for energy calculation according to the instructions of the program. For example, in the case of the Discovery Studio 2020 client, the interaction energy calculation function can be used to calculate the interatomic energy.

[0939] In one non-limiting embodiment, in the complex of the cyclic compound or oligopeptide compound of the present disclosure with the human KRAS wild-type protein, the cyclic compound or oligopeptide compound of the present disclosure interacts with His95 in the human KRAS wild-type protein.

[0940] Without wishing to be bound by a particular theory, it is believed that the formation of a complex of the cyclic compound or oligopeptide compound of the present disclosure with the human KRAS wild-type protein in this way is associated with a contribution to the high binding activity of the cyclic compound or oligopeptide compound of the present disclosure with the human KRAS wild-type protein, and furthermore, has binding selectivity with respect to HRAS and NRAS.

[0941] In one embodiment, the oligopeptide compound of the present disclosure has a KRAS inhibitory activity that is 3 times or more the NRAS inhibitory activity and the HRAS inhibitory activity. In one embodiment, the oligopeptide compound of the present disclosure has a KRAS binding activity that is 3 times or more the NRAS binding activity and / or the HRAS binding activity.

[0942] In one embodiment, the oligopeptide compound of the present disclosure has a KRAS inhibitory activity that is 5 times, 7 times, 10 times, 15 times, or 20 times or more the NRAS inhibitory activity and the HRAS inhibitory activity. In one embodiment, the oligopeptide compound of the present disclosure has a KRAS binding activity that is 5 times, 7 times, 10 times, 15 times, or 20 times or more the NRAS binding activity and / or the HRAS binding activity.

[0943] In one embodiment, the present disclosure relates to the use of the oligopeptide compound of the present disclosure for increasing the selectivity of KRAS. In one embodiment, the present disclosure relates to the use of the oligopeptide compound of the present disclosure for selectively inhibiting KRAS.

[0944] The present disclosure also relates to unnatural amino acids for use in producing the cyclic compounds of the present disclosure. In one embodiment, the unnatural amino acids of the present disclosure are N-protected unnatural amino acids for use in producing peptide compounds using solid-phase synthesis methods, and in another embodiment, the unnatural amino acids of the present disclosure are unnatural amino acids having a free amino group obtained by removing the protecting group from the N-protected unnatural amino acid. Examples of the protecting group of the N-protected unnatural amino acid include Fmoc group, Boc group, Cbz group, Alloc group, p-nitrobenzenesulfonyl group, dinitrophenylsulfonyl group, t-Bu group, trityl group, and cumyl group. Among them, Fmoc group, Boc group, Cbz group, and Alloc group are preferred, and Fmoc group is more preferred.

[0945] In one embodiment, examples of the N-protected unnatural amino acids having an Fmoc group as the protecting group in the present disclosure include the following amino acids or their salts, or their solvates listed in Table 4.

[0946] aa004: (2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]octanoic acid,

[0947] aa013: (2R)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-3-methylthiopropanoic acid,

[0948] aa019: (2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4,4-difluorobutanoic acid,

[0949] aa023: (2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-3-(3-thienyl)propanoic acid,

[0950] aa028: (2S)-3-(3,4-dichlorophenyl)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]propanoic acid,

[0951] aa043: (2S)-5,5-dichloro-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]pentanoic acid,

[0952] aa056: (2R)-3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-2-methylpropanoic acid,

[0953] aa098: (2S,3S)-1-(9H-fluoren-9-ylmethoxycarbonyl)-3-methylazetidine-2-carboxylic acid,

[0954] aa099: (2S,3R)-1-(9H-fluoren-9-ylmethoxycarbonyl)-3-methyl-azetidine-2-carboxylic acid,

[0955] aa100: (2S)-1-(9H-fluoren-9-ylmethoxycarbonyl)-3,3-dimethyl-azetidine-2-carboxylic acid,

[0956] aa111: (2R)-3-allyloxy-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]propanoic acid,

[0957] aa136: (2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(propyl)amino]-3-[4-(trifluoromethyl)phenyl]propanoic acid,

[0958] aa174: (2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(propyl)amino]-3-(p-tolyl)propanoic acid,

[0959] aa210: (2S)-2-cyclopentyl-2-[ethyl(9H-fluoren-9-ylmethoxycarbonyl)amino]acetic acid,

[0960] aa220: (2S)-4-(4-chloro-3,5-difluoro-phenyl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)butanoic acid,

[0961] aa229: (2S)-4-(benzothiophen-5-yl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)butanoic acid,

[0962] aa233: (2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-4-[3-methyl-4-(trifluoromethyl)phenyl]butanoic acid,

[0963] aa235: (2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-4-[3-methoxy-4-(trifluoromethyl)phenyl]butanoic acid,

[0964] aa239: (2S,4S)-1-(9H-fluoren-9-ylmethoxycarbonyl)-4-methyl-pyrrolidine-2-carboxylic acid,

[0965] aa244: (2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-5,5-difluoro-pentanoic acid,

[0966] aa246: (2S,4R)-1-(9H-fluoren-9-ylmethoxycarbonyl)-4-propoxy-pyrrolidine-2-carboxylic acid,

[0967] aa250: (2R)-2-[9H-Fluoren-9-ylmethoxycarbonyl(methyl)amino]-3-propoxy-propanoic acid,

[0968] aa264: (2S,3R)-1-(9H-Fluoren-9-ylmethoxycarbonyl)-3-(tetrahydro-2H-pyran-2-yloxy)pyrrolidine-2-carboxylic acid,

[0969] aa265: (2S,3S)-1-(9H-Fluoren-9-ylmethoxycarbonyl)-3-(tetrahydro-2H-pyran-2-yloxy)pyrrolidine-2-carboxylic acid,

[0970] aa268: (1S,2S,5R)-3-(9H-Fluoren-9-ylmethoxycarbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid,

[0971] aa279: (2S,4R)-1-(9H-Fluoren-9-ylmethoxycarbonyl)-4-(tetrahydro-2H-pyran-2-yloxy)pyrrolidine-2-carboxylic acid,

[0972] aa281: (2S,4R)-1-(9H-Fluoren-9-ylmethoxycarbonyl)-4-methoxypyrrolidine-2-carboxylic acid,

[0973] aa331: (2S)-3-Ethyl-2-[9H-Fluoren-9-ylmethoxycarbonyl(methyl)amino]pentanoic acid,

[0974] aa389: (2S)-2-[9H-Fluoren-9-ylmethoxycarbonyl(propyl)amino]-4-methylpentanoic acid,

[0975] aa391: (2S,3R)-2-(9H-Fluoren-9-ylmethoxycarbonylamino)-3-propoxybutanoic acid,

[0976] aa397: (2S)-2-[9H-Fluoren-9-ylmethoxycarbonyl(propyl)amino]-3-isopentyloxypropanoic acid,

[0977] aa398: (2S)-3-(Cyclobutoxy)-2-[9H-Fluoren-9-ylmethoxycarbonyl(propyl)amino]propanoic acid,

[0978] aa399: (2S)-4-(7-Chloro-1-methyl-1H-indol-5-yl)-2-(9H-Fluoren-9-ylmethoxycarbonylamino)butanoic acid,

[0979] aa400: (2S)-2-(9H-Fluoren-9-ylmethoxycarbonylamino)-4-(2-fluoro-3-methylbenzo[b]thiophen-5-yl)butanoic acid,

[0980] aa401: (2S)-4-(7-chlorobenzo[b]thiophen-5-yl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)butanoic acid,

[0981] aa402: (2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-4-(1-methyl-1H-indol-6-yl)butanoic acid,

[0982] aa403: (2S)-4-(1,3-dimethyl-1H-indol-6-yl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)butanoic acid,

[0983] aa404: (2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-4-(1,2,3-trimethyl-1H-indol-6-yl)butanoic acid,

[0984] aa405: (2S)-4-(2,3-dimethylbenzo[b]thiophen-5-yl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)butanoic acid,

[0985] aa406: (2S)-4-(3-chloro-4-ethylphenyl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)butanoic acid,

[0986] aa407: (2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-4-[4-(methoxymethyl)-3,5-dimethylphenyl]butanoic acid,

[0987] aa408: (2S)-4-(4-chloro-3-methoxyphenyl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)butanoic acid,

[0988] aa409: (2S)-4-[4-chloro-3-(trifluoromethyl)phenyl]-2-(9H-fluoren-9-ylmethoxycarbonylamino)butanoic acid,

[0989] aa410: (2S)-4-[4-(difluoromethyl)-3,5-difluorophenyl]-2-(9H-fluoren-9-ylmethoxycarbonylamino)butanoic acid,

[0990] aa411: (2S)-4-(4-chloro-3,5-dimethylphenyl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)butanoic acid,

[0991] aa414: (2S,4R)-4-(cyclopentyloxy)-1-(9H-fluoren-9-ylmethoxycarbonyl)pyrrolidine-2-carboxylic acid,

[0992] aa415: (2S,4R)-4-(cyclobutyloxy)-1-(9H-fluoren-9-ylmethoxycarbonyl)pyrrolidine-2-carboxylic acid,

[0993] aa423: (3S)-3-cyclobutyl-3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]propanoic acid,

[0994] aa424: (3R)-3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]pentanoic acid,

[0995] aa425: (3S)-3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-methyl-pentanoic acid,

[0996] aa426: (3S)-3-cyclohexyl-3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]propanoic acid,

[0997] aa443: (2S)-2-[but-3-en-1-yl(9H-fluoren-9-ylmethoxycarbonyl)amino]-3-(p-tolyl)propanoic acid,

[0998] aa511: (2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-4-[3-fluoro-5-methoxy-4-(trifluoromethyl)phenyl]butanoic acid, and

[0999] aa512: (2S)-4-[3-ethyl-4-(trifluoromethyl)phenyl]-2-(9H-fluoren-9-ylmethoxycarbonylamino)butanoic acid.

[1000] (General production method)

[1001] A general production method for the cyclic compounds or oligopeptide compounds of the present disclosure and the unnatural amino acids used in the production of these compounds will be described below. Herein, the cyclic compounds may sometimes be referred to as "cyclic peptide compounds". Herein, the "cyclic part" of the peptide compound means a cyclic part formed by connecting two or more amino acid residues.

[1002] Chemical Synthesis Method for Peptide Compounds

[1003] In the present text, examples of chemical synthesis methods for peptide compounds or cyclic compounds include liquid-phase synthesis methods, solid-phase synthesis methods using Fmoc synthesis, Boc synthesis, etc., and combinations thereof. In Fmoc synthesis, the basic unit is an amino acid with the main-chain amino group protected by an Fmoc group, and the side-chain functional groups are protected, as needed, with protecting groups that are not cleaved by piperidine or such bases (such as t-Bu group, THP group, or Trt group), and the amino acid with the main-chain carboxylic acid unprotected. The basic unit is not particularly limited as long as it has a combination of an Fmoc-protected amino group and a carboxyl group. For example, a dipeptide or a tripeptide can be the basic unit, and a cyclic structure can be formed between the nitrogen atom and / or substituents on the side chain contained in the dipeptide or tripeptide. The basic unit provided at the N-terminus can be a unit other than an Fmoc amino acid. Hydroxycarboxylic acids can be used as the basic unit, and in this case, the hydroxy group can be protected or can be unprotected. For example, it can be a Boc amino acid or a Tfa group or an Ns group, or a carboxylic acid analogue without an amino group. The side-chain carboxyl group of an amino acid having a main-chain carboxyl group or a side chain having a carboxyl group and in which the main-chain carboxyl group is protected with a suitable protecting group is loaded onto the solid phase by a chemical reaction with the functional group of the solid-phase carrier. Subsequently, the Fmoc group is deprotected by a base (such as piperidine or DBU), and a condensation reaction is carried out on the newly produced amino group and the amino acid or hydroxycarboxylic acid having a carboxyl group and protected as the basic unit added subsequently to produce a peptide bond. In the condensation reaction, various combinations (such as the combination of DIC and HOBt, the combination of DIC and HOAt, the combination of HATU and DIPEA, and the combination of HATU and HOAt) and DIPEA can be used as activators for the carboxyl group. The desired peptide sequence can be produced by repeating the Fmoc group deprotection and the subsequent peptide bond formation reaction. When a hydroxycarboxyl group is used as the basic unit, the hydroxy group can be unprotected, and a peptide bond is formed by a condensation reaction between the hydroxy group and the protected amino acid having a carboxyl group as the basic unit added subsequently. In this case, in the condensation reaction between the hydroxy group and the carboxyl group, various combinations such as the combination of DIC and DMAP, the combination of EDC and DMAP, the combination of DCC, HOBt, and DMAP can be used as activators for the carboxyl group. After obtaining the desired sequence, cleavage from the solid phase and deprotection of the protecting groups of the optionally introduced side-chain functional groups are carried out. In addition, conformational conversion and cyclization of the peptide can be carried out before cleavage from the solid phase. Cleavage from the solid phase and deprotection can be carried out under the same conditions, for example, in 90:10 TFA / H2O, or deprotection can be carried out under different conditions as needed. In some cases, a weak acid (such as 1% TFA) can be used to achieve cleavage from the solid phase, and a protecting group that can be deprotected with a Pd-containing catalyst, etc., can be used to utilize the orthogonality of the two chemical reactions. During or at the end of these steps, steps (such as cyclization) can also be carried out.For example, a side-chain carboxylic acid can be condensed with an N-terminal main-chain amino group, and a side-chain amino group can be condensed with a C-terminal main-chain carboxylic acid. Additionally, an alkene can be introduced at two or more sites of the side chain and / or nitrogen atom substituents and cyclized by a metathesis reaction. Furthermore, the double bond produced by cyclization can be reduced to a single bond. Additionally, the double bond produced by cyclization can be converted to a cyclopropane ring under conditions involving, for example, diiodomethane-diethylzinc. These steps such as cyclization, reduction, conversion to a cyclopropane ring, etc. can be carried out during the synthesis of basic units such as dipeptides or tripeptides. Meanwhile, reaction orthogonality is required between the carboxylic acid on the C-terminal side and the side-chain carboxylic acid to be cyclized, between the main-chain amino group or hydroxyl group on the N-terminal side and the side-chain amino group to be cyclized, or between the alkene of the side chain and / or the substituents of the nitrogen atom and the alkene to be cyclized. As described above, protecting groups are selected considering the orthogonality of protecting groups. Additionally, by placing a chloroacetyl group at the N-terminus, cyclization can also be carried out between the thiol groups of the cysteine residue side chains. The reaction product thus obtained can be purified by, for example, a reverse-phase column, a molecular sieve column, etc. Details of these procedures are described in, for example, the Solid-Phase Synthesis Handbook published by Merck on May 1, 2002. Commercially available resins for solid-phase synthesis are applicable, and examples include CTC resin, Wang resin, and SASRIN resin.

[1004] A general method for synthesizing an amino acid-loaded resin for use in peptide synthesis by a peptide synthesizer will be described below.

[1005] Fmoc amino acids can be loaded onto the resin by the methods described in WO2013 / 100132 or WO2018 / 225864. Specifically, for example, 2-chlorotrityl chloride resin and a solvent (e.g., dehydrated dichloromethane) are introduced into a reaction vessel equipped with a filter to swell the resin. Next, the solvent and the resin are separated, and then a mixture of the resin, the C-terminal free Fmoc amino acid dissolved in a solvent (e.g., dehydrated dichloromethane), a solvent (e.g., dehydrated methanol), and a base (e.g., diisopropylethylamine) is added to the reaction vessel and mixed to load the Fmoc amino acid onto the resin. After separating the resin and the reaction solution, the resin is mixed with a mixture of one or more solvents and a base (e.g., a mixture of dehydrated dichloromethane, dehydrated methanol, and diisopropylethylamine) to wash the resin. After washing the resin several times with a solvent (e.g., dichloromethane) as needed, the resin and the reaction solution are separated. By drying the resulting resin under reduced pressure overnight, an Fmoc amino acid-loaded resin can be obtained.

[1006]

[1007] (where n represents an integer from 1 to 11; P1 to P 11, Q1 to Q 11 and R1 to R 11 mean P1 to P as defined herein 11 , Q1 to Q 11 and R1 to R 11 ; L1 and L 11 mean L1 and L as described herein 11 ; L2 to L 10 are single bonds; and ○ (circle) means a resin part.)

[1008] The above structure shows that in Fmoc - amino acids, the 2 - chlorotrityl group on the resin is bonded to the carboxylic acid of the Fmoc amino acid via an ester bond.

[1009] In the production of the compounds described herein, when the defined groups undergo an undesired chemical transformation under the conditions of the method being carried out, the compound can be produced by, for example, protection and deprotection of functional groups. The choice of protecting groups and the introduction / removal procedures can be carried out according to the methods described, for example, in Greene's "Protective Groups in Organic Synthesis" (5th edition, John Wiley & Sons, 2014), which can be used appropriately according to the reaction conditions. Additionally, the order of reaction steps such as the introduction of substituents can be varied as needed. For example, protecting groups for amino groups are Fmoc, Boc, Cbz, or Alloc groups. These carbamate groups can be introduced by reacting the amino group with a carbamoylating agent in the presence of a basic catalyst. Examples of carbamoylating agents include Boc2O, BocOPh, FmocOSu, FmocCl, CbzCl, and AllocCl. Examples of basic catalysts include lithium carbonate, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate, cesium bicarbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, sodium phosphate, potassium phosphate, N - methylmorpholine, triethylamine, diisopropylethylamine, and N,N - dimethylaminopyridine. The carbamate groups as protecting groups for amino groups can be removed under basic conditions, acidic conditions, hydrogenolysis reaction conditions, etc.

[1010] ( Method for Synthesizing Cyclic Compounds by Cyclization of Peptide Compounds)

[1011] A method for converting a linear peptide compound into a cyclic peptide compound can be carried out by intramolecular bonding reactions according to methods described, for example, in Compositional Organic Transformations, A Guide to Function Group Preparations, 3rd Edition, R.C. Larock, or March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7th Edition, M.B. March. After the bonding reaction, further functional group transformation reactions can also be carried out. Examples of bonding reactions include C(O)-N bonds formed from carboxylic acids and amines; C-O-C bonds, C(O)-O bonds, and C(S)-O bonds using oxygen atoms; C(O)-S bonds, C(S)-S bonds, C-S-S-C bonds, C-S-C bonds, C-S(O)-C bonds, and C-S(O2)-C using sulfur atoms; and C-N-C bonds, C=N-C bonds, N-C(O)-N bonds, N-C(S)N bonds, and C(S)-N bonds using nitrogen atoms. In addition, examples include C-C bonding reactions catalyzed by transition metals, such as Suzuki reactions, Heck reactions, Sonogashira reactions, and metathesis reactions. Examples of functional group transformation reactions further carried out after the bonding reaction include oxidation reactions and reduction reactions. Specific examples are reactions for oxidizing sulfur atoms to convert them into sulfoxide groups or sulfone groups. Another example is a reduction reaction for reducing triple bonds or double bonds in carbon-carbon bonds to double bonds or single bonds. Although a closed-loop structure is formed through a peptide bond when two amino acids are bonded to the amino acid backbone, the covalent bond between the two amino acids can be formed through bonding between the side chains of the two amino acids, bonding between the side chain and the backbone, etc. The following black circles or black squares indicate amino acid residues, and the connected black circles or black squares represent a peptide chain connected by an amide bond. The number of amino acid residues constituting the peptide chain is not particularly limited, and the number of amino acid residues is not limited to the number of the following exemplified black circles or black squares.

[1012] ( General Preparation Method for Cyclic Compounds 1)

[1013]

[1014] The cyclic moiety of a cyclic compound having a linear moiety can be cyclized by activating the N-terminal amino group and the C-terminal side chain carboxyl group with an activating reagent (for example, in the case of aspartic acid or its derivatives, L = -CH2-, and in the case of glutamic acid or its derivatives, L = -CH2CH2-) or by converting it into an active ester and then condensing in the molecule to form a C(O)-N bond for cyclization.

[1015] ( General Preparation Method for Cyclic Compounds 2)

[1016]

[1017] The cyclic compound in which the straight-chain part is the C-terminus described in "General Preparation Method 1 for Cyclic Compounds" can be cyclized by activating the N-terminal amino group and the C-terminal side-chain carboxyl group with an activating reagent (e.g., in the case of aspartic acid or its derivatives, L = -CH2-, and in the case of glutamic acid or its derivatives, L = -CH2CH2-) or by converting it into an active ester and then condensing in the molecule to form a C(O)-N bond for cyclization.

[1018] ( General Preparation Method for Cyclic Compounds 3)

[1019] (Method of cyclization with a haloalkyl group and an SH group)

[1020]

[1021] The cyclic part of the cyclic compound having a straight-chain part can be cyclized by reacting the haloalkyl group of the amino acid residue in the molecule with the thiol group of the amino acid residue to form a C-S-C bond. The cyclic compound in which the straight-chain part is the C-terminus described in "General Preparation Method 1 for Cyclic Compounds" can also be cyclized similarly by reacting the haloalkyl group of the amino acid residue in the molecule with the thiol group of the amino acid residue to form a C-S-C bond. In addition, a C-S(O)-C or C-S(O2)-C bond can also be formed by oxidizing the sulfur atom and converting it into a sulfoxide or a sulfone.

[1022] (Method of cyclization with a vinyl group and an SH group)

[1023]

[1024]

[1025] (Method of cyclization with an ethynyl group and an SH group)

[1026]

[1027] ​The cyclic moiety of a cyclic compound having a linear moiety can be cyclized by reacting the ethynyl group of an amino acid residue in the molecule with the thiol group of an amino acid residue to form a C-S-C bond. The cyclic compound in which the linear moiety is the C-terminus as described in "General Preparation Method 1 for Cyclic Compounds" can also be cyclized similarly by reacting the ethynyl group of an amino acid residue in the molecule with the thiol group of an amino acid residue to form a C-S-C bond. In addition, a C-S(O)-C or C-S(O2)-C bond can also be formed by oxidizing the sulfur atom and converting it into a sulfoxide or a sulfone. The double bond site can also be reduced and converted into a single bond.

[1028] (Method of cyclization using vinyl and vinyl groups)

[1029]

[1030] The cyclic moiety of a cyclic compound having a linear moiety can be cyclized by reacting different vinyl groups of amino acid residues in the molecule with each other to form a C-C bond. The cyclic compound in which the linear moiety is the C-terminus as described in "General Preparation Method 1 for Cyclic Compounds" can also be cyclized similarly by reacting different vinyl groups of amino acid residues in the molecule with each other to form a C-C bond.

[1031] (Method of cyclization by forming a triazole ring using an azide group and an ethynyl group)

[1032]

[1033] The cyclic moiety of a cyclic compound having a linear moiety can be cyclized by reacting the azide group of an amino acid residue in the molecule with the ethynyl group of an amino acid residue to form a triazole ring. The cyclic compound in which the linear moiety is the C-terminus as described in "General Preparation Method 1 for Cyclic Compounds" can also be cyclized similarly by reacting the azide group of an amino acid residue in the molecule with the ethynyl group of an amino acid residue to form a triazole ring.

[1034] The general method for preparing peptide compounds by peptide modification is as follows. In the following scheme, P n represents a substituent on the nitrogen atom, R n and Q n each represent an amino acid side chain, the black circles represent amino acid residues, the connected black circles represent a peptide chain connected by an amide bond, and m represents the number of amino acid residues and can be any integer of 1 or greater.

[1035] (Method for preparing a peptide containing an N-alkyl amino acid)

[1036] Peptides containing N-alkyl amino acids can be synthesized using Fmoc-protected N-alkyl amino acids as starting materials according to the general peptide synthesis methods described in this example, or alternatively can be prepared by N-terminal nitrogen alkylation on the resin, as shown below. Specifically, a target peptide having an N-alkyl amino acid at the N-terminus can be prepared by reacting the nitrogen of the N-terminal Tfa amide (trifluoroacetamide) of the resin-loaded peptide with an alkyl halide under basic conditions, as described in reference to Organic Letters, 2008, 10, 4815-4818, etc., and then treating the peptide with a reducing agent. In addition, cyclic compounds can be prepared by extending the peptide, cleaving from the resin, cyclizing, deprotecting, and purifying according to the general peptide synthesis methods described in this example.

[1037]

[1038] The method described in Nature Protocols, 2012, 7, 432-444, shown below can also be used as another method for introducing P n onto the N-terminal nitrogen. Specifically, the N-terminal amine of the resin-loaded peptide can be converted to the Ns-substituted form, P n introduced by the Mitsunobu reaction, and then the Ns group deprotected to obtain the target peptide having P n at the N-terminus. In addition, cyclic compounds can be prepared by extending the peptide, cleaving from the resin, cyclizing, deprotecting, and purifying according to the general peptide synthesis methods described in this example.

[1039]

[1040] Peptides containing glycine with P n introduced onto the nitrogen atom can be synthesized using glycine with P n introduced onto the Fmoc-protected nitrogen atom as a starting material according to the general peptide synthesis methods described in this example, or alternatively can be prepared by a substitution reaction between an N-terminal halo-carbon and an amine, as shown below. Specifically, a target peptide having N-terminal glycine with P n introduced onto the nitrogen atom can be obtained by reacting the N-terminal amine with iodoacetic acid and then reacting it with any primary amine, as described in reference to Organic Letters, 2010, 12, 4928-4931, etc. In addition, cyclic compounds can be prepared by extending the peptide, cleaving from the resin, cyclizing, deprotecting, and purifying according to the general peptide synthesis methods described in this example.

[1041]

[1042] (Method for preparing peptides containing hydroxycarboxylic acid)

[1043] Peptides containing hydroxycarboxylic acids can be prepared using hydroxycarboxylic acids as starting materials by the condensation reaction of the N-terminal amino group on the resin with the hydroxycarboxylic acid and subsequent condensation reactions of the hydroxy group with protected amino acids as shown in the following methods. In addition, cyclic compounds can be prepared by extending the peptide, cleaving from the resin, cyclizing, deprotecting, and purifying according to the general peptide synthesis methods described in this example.

[1044]

[1045] (Method for preparing a peptide containing a hydroxycarboxylic acid)

[1046] Peptides containing hydroxycarboxylic acids can be prepared using hydroxycarboxylic acids with protected hydroxy groups as starting materials by the condensation reaction of the N-terminal amino group with the hydroxycarboxylic acid having a protected hydroxy group on the resin and subsequent deprotection reactions and condensation reactions of the newly generated hydroxy group with protected amino acids. In addition, cyclic compounds can be prepared by extending the peptide, cleaving from the resin, cyclizing, deprotecting, and purifying according to the general peptide synthesis methods described in this example.

[1047]

[1048] (Method for preparing a peptide containing an aryloxy or heteroaryloxy group in the side chain)

[1049] Peptides containing an aryloxy or heteroaryloxy group in the side chain can be prepared using Fmoc amino acids having the target aryloxy or heteroaryloxy group in the side chain as starting materials according to the general peptide synthesis methods described in this example, or alternatively, peptides having an alcohol in the side chain can be used as precursors and prepared by referring to Organic Letters, 2014, 16, 4944 - 4947, Tetrahedron Letters, 2003, 44, 3863 - 3865, etc., as follows. Specifically, peptides containing an aryloxy or heteroaryloxy group in the side chain can be prepared by reacting a peptide having an alcohol in the side chain with a triarylborinane-pyridine complex in the presence of copper(II) acetate.

[1050]

[1051] Peptides having an ether group on the side chain that does not include an aryloxy or heteroaryloxy group can be prepared using Fmoc amino acids having a target ether group on the side chain as starting materials according to the general peptide synthesis methods described in this example, or alternatively, peptides having an alcohol on the side chain can be used as precursors and prepared by referring to the methods described in Journal of Medicinal Chemistry, 2011, 54, 4815 - 4830 or Journal of Medicinal Chemistry, 2014, 57, 159 - 170, as follows. Specifically, peptides having a target ether group on the side chain can be prepared by reacting a peptide having an alcohol with an alkyl halide in the presence of silver(I) oxide, or by reacting a peptide having an alcohol with an alkyl halide using aqueous sodium hydroxide as a base in the presence of a phase transfer catalyst such as a tetraalkylammonium salt.

[1052]

[1053] (Method for preparing a peptide containing an aryl or heteroaryl group on the side chain)

[1054] Peptides having an aryl or heteroaryl group on the side chain can be prepared using Fmoc amino acids having a target aryl or heteroaryl group on the side chain as starting materials according to the general peptide synthesis methods described in this example, or alternatively, peptides having a carboxylic acid on the side chain can be used as precursors and prepared by referring to the methods described in J. Am. Chem. Soc., 2016, 138, 5016 - 5019, etc., as follows. Specifically, peptides having a target aryl or heteroaryl on the side chain can be prepared by activating a peptide having a carboxylic acid with N - hydroxyphthalimide and reacting it with any aryl halide or heteroaryl halide.

[1055]

[1056] Peptides having a substituent on the nitrogen atom within the molecule and / or having a carboxylic acid in the side chain and having a substituent on another nitrogen atom and / or having an aryl halide or heteroaryl halide in another side chain can be used to produce peptide compounds in which the peptide backbone is cross - linked. Specifically, the cross - linked compound can be produced by activating a peptide having a carboxylic acid with N - hydroxyphthalimide and cross - linking it by reacting with an aryl halide or heteroaryl halide within the molecule.

[1057]

[1058] Alternatively, peptides having an aryl or heteroaryl group on the side chain can also be synthesized by Suzuki coupling using peptides having boric acid on the side chain as precursors, as shown below. Specifically, a target peptide having an aromatic ring on the side chain can be prepared by using an Fmoc amino acid having boric acid on the side chain as a starting material to synthesize a precursor peptide and reacting it with any aryl halide in the presence of a palladium catalyst.

[1059]

[1060] Peptides having a substituent on a nitrogen atom within the molecule and / or having boric acid in the side chain and an aryl halide in a substituent of another nitrogen atom and / or in another side chain can be used to produce a peptide compound in which the peptide backbone is crosslinked. Specifically, the crosslinked compound can be produced by reacting a peptide having boric acid with an aryl halide within the molecule in the presence of a palladium catalyst and thereby crosslinking.

[1061]

[1062] Peptides having a substituent on a nitrogen atom within the molecule and / or having an alkene in the side chain and an aryl halide in a substituent of another nitrogen atom and / or in another side chain can be used to produce a peptide compound crosslinked with an arylene-containing alkylene. Specifically, the crosslinked compound can be produced by converting an alkene into a boron compound by hydroboration reaction on the alkene, which then reacts the boron compound with an aryl halide within the molecule in the presence of a palladium catalyst and thereby crosslinks.

[1063]

[1064] (Method for preparing a peptide containing an amide group on the side chain)

[1065] Peptides having an amide group on the side chain can be synthesized using an Fmoc amino acid having the target amide group on the side chain as a starting material, or alternatively can be synthesized by amidating a peptide having a carboxylic acid on the side chain as a precursor, as shown below. Specifically, a target peptide having an amide group on the side chain can be obtained by deprotecting a peptide having a protected carboxylic acid on the side chain to synthesize a precursor peptide having a carboxylic acid on the side chain and condensing it with any amine using a condensing agent (such as HATU).

[1066]

[1067] Peptide compounds in which the peptide backbone is crosslinked can be produced using peptides having substituents on the nitrogen atoms within the molecule and / or having a carboxylic acid in a side chain and having an amino group in the substituent of another nitrogen atom and / or in another side chain. Specifically, the crosslinked compound can be produced by deprotecting and synthesizing a precursor peptide having a carboxylic acid and an amino group and condensing them using a condensing agent (such as HATU) to effect crosslinking through an intramolecular amidation reaction.

[1068]

[1069] (Synthesis of peptides containing highly substituted structures that may contain double bonds in the side chains)

[1070] Peptides having highly substituted structures that may contain double bonds in the side chains can be synthesized using Fmoc amino acids having the target double bond in the side chain as starting materials, or alternatively can be prepared by functionalization of terminal alkenes. Specifically, peptides having a terminal alkene in the side chain can be synthesized according to the general peptide synthesis methods described in this example, and the side chain can be further transformed into a side chain having a highly substituted alkene by coupling with a substrate having either terminal alkene through olefin metathesis reaction. Additionally, the side chain can be transformed into the corresponding side chain by reducing the alkene through a hydrogenation reaction.

[1071]

[1072] Peptide compounds having a crosslinked peptide backbone can also be prepared using peptides having substituents on the nitrogen atoms and / or having multiple double bonds in the side chains. Specifically, the crosslinked compound can be prepared by synthesizing a peptide having alkenes at two sites in the substituent of the nitrogen atom and / or in the side chain according to the general peptide synthesis methods described in this example, and further crosslinking the two alkenes through olefin metathesis reaction with reference to Nature Protocols, 2011, 6, 761 - 771. Furthermore, the compound crosslinked with a saturated alkylene can be prepared by reducing the alkene through a hydrogenation reaction.

[1073]

[1074] Peptide compounds crosslinked with an arylene and a divalent group containing a double bond as crosslinked compounds can be produced using peptides containing an aryl group having an alkene-containing substituent in the substituent of the nitrogen atom and / or in the side chain. Specifically, the crosslinked compound can be produced by synthesizing a peptide having a substituent on the nitrogen atom within the molecule and / or containing an alkene in the side chain and having an aryl group containing an alkene in the substituent of another nitrogen atom and / or in another side chain according to the general peptide synthesis methods described in the example, and crosslinking the two alkenes through olefin metathesis reaction. Additionally, the compound crosslinked with an alkylene containing an arylene can be produced by reducing the alkene through a hydrogenation reaction.

[1075]

[1076] (Synthesis of Peptides Containing Triazole in the Side Chain)

[1077] Peptides having a triazole in the side chain can be prepared by a click reaction with an azide group. Specifically, a peptide compound having an azide group in the side chain can be synthesized by synthesizing a peptide having an azide group in the side chain according to the general peptide synthesis method described in this example, and preparing it by coupling the peptide with any acetylene in the presence of copper(I) iodide by referring to Bioorganic & Medicinal Chemistry Letters, 2009, 19, 4130 - 4133, etc.

[1078]

[1079] Peptide compounds in which the peptide backbone is crosslinked can be produced using a peptide having a substituent on a nitrogen atom within the molecule and / or having an azide group in the side chain and a substituent on another nitrogen atom and / or having an acetylene in another side chain. Specifically, the crosslinked compound can be produced by reacting a peptide having an azide group with an acetylene within the molecule in the presence of a palladium catalyst and thereby crosslinking.

[1080]

[1081] (Synthesis of Peptides Containing an Aryl Group Substituted with an Alkynyl Group in the Side Chain)

[1082] Peptides containing an aryl group substituted with an alkynyl group in the side chain can be synthesized by a Sonogashira coupling reaction with an aryl halide group. Specifically, conversion to a peptide compound having an aryl group substituted with an alkynyl group in the side chain can be carried out by synthesizing a peptide having an aryl iodide group in the side chain according to the general peptide synthesis method described in this example, and coupling the peptide with any acetylene in the presence of copper(I) iodide.

[1083]

[1084] Peptide compounds in which the peptide backbone is crosslinked can be produced using a peptide having a substituent on a nitrogen atom within the molecule and / or having an aryl halide in the side chain and a substituent on another nitrogen atom and / or having an acetylene in another side chain. Specifically, the crosslinked compound can be produced by coupling a peptide having an aryl iodide with an acetylene within the molecule in the presence of copper(I) iodide and thereby crosslinking.

[1085]

[1086] (General Method for Producing Oligopeptide Compounds)

[1087] A general method for producing an oligopeptide having a cyclic structure formed between a substituent of a nitrogen atom and a side chain is provided below. In the following scheme, PG1 and PG1′ represent protecting groups for the nitrogen atom, PG2 and PG2′ represent protecting groups for the oxygen atom, R n-1 , R n , R n+1 and Q n represent side chains of amino acids, P n-1 , P n and P n+1 represent substituents of the nitrogen atom, and Y1 and Y2 each represent hydrogen, a halogen, or an alkyl group. In the methods for producing amino acids provided below, groups other than the intended functional groups may undergo chemical reactions. In such ca...

Claims

1. A pharmaceutical composition comprising a cyclic compound represented by the following formula (1), a salt thereof, or a solvate thereof: Wherein: L1 is a single bond, or is -CHM1-, -(CH2) n S(CH2) m -, -(CH2) n S(O)(CH2) m - or -(CH2) n S(O)2(CH2) m -, where n and m are each independently 1 or 2, R1 is any one of the following (a1) to (a6): (a1)R1 is hydrogen, C1-C7 alkyl, C2-C7 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy C1-C6 alkyl, C2-C6 alkenyloxy C1-C6 alkyl, C1-C6 alkylthio C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl C1-C6 alkyl, C3-C8 cycloalkoxy C1-C6 alkyl, C7-C 14 arylalkyl or 5- to 10-membered heteroaryl C1-C6 alkyl, each of which is optionally substituted by one or more groups independently selected from the group consisting of halogen, hydroxy, cyano, C1-C6 alkyl, aminocarbonyl (wherein the amino is -NH2, mono-C1-C6 alkylamino, di-C1-C6 alkylamino or 4- to 8-membered cyclic amino), and C1-C6 alkylsulfonyl; (a2) R1, together with P1, the carbon atom to which R1 is bonded, and the nitrogen atom to which P1 is bonded, forms a 4- to 7-membered saturated heterocycle; (a3) R1, together with Q1 and the carbon atoms to which R1 and Q1 are bonded, forms a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocycle; (a4) R1, together with M1, the carbon atom to which R1 is bonded, and the carbon atom to which M1 is bonded, forms a 3- to 8-membered alicyclic ring; (a5)R1 and R5 together form a divalent group selected from the group consisting of: C1-C 10 alkylene, C2-C 10 alkenylene, C2-C 10 alkynylene, C3-C8 cycloalkylene, C6-C 10 arylene, -CO-NR A -, -NR A -CO- and combinations of two or more of these, wherein one or more carbon atoms forming the divalent group are optionally substituted with one or more heteroatoms independently selected from the group consisting of N, O, and S, the divalent group is optionally substituted with one or more groups independently selected from the group consisting of halogen and C1-C6 alkyl, and R A is hydrogen or C1-C6 alkyl; or (a6)R1 and R9 together form a divalent group selected from the group consisting of: C1-C 10 alkylene, C2-C 10 alkenylene, C2-C 10 alkynylene, C3-C8 cycloalkylene, C6-C 10 arylene, -CO-NR B -, -NR B -CO- and combinations of two or more of these, wherein one or more carbon atoms forming the divalent group are optionally substituted with one or more heteroatoms independently selected from the group consisting of N, O, and S, the divalent group is optionally substituted with one or more groups independently selected from the group consisting of halogen and C1-C6 alkyl, and R B is hydrogen or C1-C6 alkyl; Except when R1 and P1 form a 4- to 7-membered saturated heterocycle, P1 is hydrogen or a C1-C6 alkyl group, wherein the C1-C6 alkyl group is optionally substituted with one or more groups independently selected from the group consisting of: halogen, hydroxy, C1-C6 alkoxy, and aminocarbonyl (wherein the amino group is -NH2, mono-C1-C6 alkylamino, di-C1-C6 alkylamino, or a 4- to 8-membered cyclic amino group), Except when R1 and Q1 form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocycle, Q1 is hydrogen or a C1-C6 alkyl group, and Except when R1 and M1 form a 3- to 8-membered alicyclic ring, M1 is hydrogen or a C1-C6 alkyl group, R2 is any one of the following (b1) to (b4): (b1) R2 is a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy C1-C6 alkyl group, a C3-C8 cycloalkyl group, a C3-C8 cycloalkyl C1-C6 alkyl group, a C3-C8 cycloalkoxy C1-C6 alkyl group, or a 4- to 7-membered heterocyclic group, each of which is optionally substituted with one or more groups independently selected from the group consisting of: halogen, hydroxy, cyano, and C1-C6 alkylsulfonyl; (b2) R2, together with P2, the carbon atom to which R2 is bonded, and the nitrogen atom to which P2 is bonded, forms a 4- to 7-membered saturated heterocycle; (b3) R2, together with Q2 and the carbon atoms to which R2 and Q2 are bonded, forms a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocycle; or (b4)R2 and R 11 together form a divalent group selected from the group consisting of: C1-C 10 alkylene, C2-C 10 alkenylene, C2-C 10 alkynylene, C3-C8 cycloalkylene, C6-C 10 arylene, -CO-NR C -, -NR C -CO-, -C3-C8 alkylene-NR C -, -C3-C8 alkenylene-NR C - and combinations of two or more of these items, wherein one or more carbon atoms forming the divalent group are optionally substituted with one or more heteroatoms independently selected from the group consisting of N, O, and S, the divalent group is optionally substituted with one or more groups independently selected from the group consisting of halogen and C1-C6 alkyl, and R C is hydrogen or C1-C6 alkyl; Except when R2 and P2 form a 4- to 7-membered saturated heterocycle, P2 is hydrogen or a C1-C6 alkyl group, wherein the C1-C6 alkyl group is optionally substituted with one or more groups independently selected from the group consisting of: halogen, hydroxy, C1-C6 alkoxy, and aminocarbonyl (wherein the amino group is -NH2, mono-C1-C6 alkylamino, di-C1-C6 alkylamino, or a 4- to 8-membered cyclic amino group), Except when R2 and Q2 form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocycle, Q2 is hydrogen or a C1-C6 alkyl group, R3 is any one of the following (c1) to (c3): (c1)R3 is hydrogen, C1-C6 alkyl, C1-C6 alkoxy C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl C1-C6 alkyl, C3-C8 cycloalkoxy C1-C6 alkyl or C7-C 14 arylalkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of hydroxy and aminocarbonyl (wherein the amino group is -NH2, mono-C1-C6 alkylamino, di-C1-C6 alkylamino or 4- to 8-membered cyclic amino); (c2) R3, together with P3, the carbon atom to which R3 is bonded, and the nitrogen atom to which P3 is bonded, forms a 4- to 7-membered saturated heterocycle, wherein the 4- to 7-membered saturated heterocycle is optionally substituted with one or more groups selected from the group consisting of C1-C6 alkyl and C1-C6 alkoxy; or (c3)R3, together with Q3 and the carbon atom to which R3 and Q3 are bonded, forms a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring; Except when R3 and P3 form a 4- to 7-membered saturated heterocyclic ring, P3 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy C1-C6 alkyl or C3-C8 cycloalkyl, each of which is optionally substituted by one or more groups independently selected from the group consisting of: halogen, hydroxy, cyano, C1-C6 alkoxy and C1-C6 aminoalkyl (wherein the amino is -NH2, mono-C1-C6 alkylamino, di-C1-C6 alkylamino or 4- to 8-membered cyclic amino, and the 4- to 8-membered cyclic amino is optionally substituted by one or more halogen atoms), Except when R3 and Q3 form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, Q3 is hydrogen or C1-C6 alkyl, R4 is any one of the following (d1) to (d4): (d1)R4 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy C1-C6 alkyl, C2-C6 alkenoxy C1-C6 alkyl or C1-C6 carboxyalkyl, each of which is optionally substituted by one or more hydroxy groups; (d2)R4, together with P4, the carbon atom to which R4 is bonded and the nitrogen atom to which P4 is bonded, forms a 4- to 7-membered saturated heterocyclic ring, wherein the 4- to 7-membered saturated heterocyclic ring is optionally substituted by one or more C1-C6 alkyl groups; (d3)R4, together with Q4 and the carbon atom to which R4 and Q4 are bonded, forms a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring; or (d4)R4 and P5 together form a divalent group selected from the group consisting of: C1-C 10 alkylene, C2-C 10 alkenylene, C2-C 10 alkynylene, C3-C8 cycloalkylene, 3- to 7-membered heteroalkylene, C6-C 10 arylene, -CO-NR D -, -NR D -CO- and combinations of two or more of these items, wherein one or more carbon atoms forming the divalent group are optionally substituted with one or more heteroatoms independently selected from the group consisting of N, O, and S, the divalent group is optionally substituted with one or more groups independently selected from the group consisting of halogen and C1-C6 alkyl, and R D is hydrogen or C1-C6 alkyl; Except when R4 and P4 form a 4- to 7-membered saturated heterocyclic ring, P4 is any one of the following (e1) to (e2): (e1)P4 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl or C1-C6 alkoxy C1-C6 alkyl, each of which is optionally substituted by one or more groups independently selected from the group consisting of: halogen, hydroxy, C1-C6 alkoxy and aminocarbonyl (wherein the amino is -NH2, mono-C1-C6 alkylamino, di-C1-C6 alkylamino or 4- to 8-membered cyclic amino); or (e2) P4 and P5 together form a divalent group selected from the group consisting of: C1-C 10 alkylene, C2-C 10 alkenylene, C2-C 10 alkynylene, C3-C8 cycloalkylene, C6-C 10 arylene, -CO-NR E -, -NR E -CO- and combinations of two or more of these terms, wherein one or more carbon atoms constituting the divalent group are optionally substituted with one or more heteroatoms independently selected from the group consisting of N, O, and S, and the divalent group is optionally substituted with one or more groups independently selected from the group consisting of halogen and C1-C6 alkyl, and R E is hydrogen or C1-C6 alkyl; Except when R4 and Q4 form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, Q4 is hydrogen or C1-C6 alkyl, Except when R1 and R5 form a divalent group, R5 is any one of the following (f1) to (f4): (f1)R5 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkenyloxycarbonyl C1-C6 alkyl, C2-C6 alkynyl, C1-C6 alkoxy C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl C1-C6 alkyl, C3-C8 cycloalkoxy C1-C6 alkyl, C7-C 14 arylalkyl, C6-C 10 aryloxy C1-C6 alkyl, C7-C 14 arylalkoxy C1-C6 alkyl or 5- to 10-membered heteroaryl C1-C6 alkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of: halogen, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C1-C6 haloalkoxy, cyano and C1-C6 alkylsulfonyl, C2-C6 alkenyl, C3-C8 cycloalkyl and C1-C6 alkylcarbonyl; or (f2)R5, together with R8, forms a C4-C8 alkylene; (f3)R5, together with P5, the carbon atom to which R5 is bonded and the nitrogen atom to which P5 is bonded, forms a 4- to 7-membered saturated heterocyclic ring; or (f4)R5, together with Q5 and the carbon atom to which R5 and Q5 are bonded, forms a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring; Except when R5 and P5 form a 4- to 7-membered saturated heterocycle, except when R4 and P5 form a divalent group, and except when P4 and P5 form a divalent group, P5 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy C1-C6 alkyl or C3-C8 cycloalkyl C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with one or more groups independently selected from the group consisting of: halogen, hydroxy, C1-C6 alkoxy, aminocarbonyl (wherein the amino group is -NH2, mono-C1-C6 alkylamino, di-C1-C6 alkylamino or 4- to 8-membered cyclic amino) and amino, Except when R5 and Q5 form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocycle, Q5 is hydrogen or C1-C6 alkyl, R6 is any one of the following (g1) to (g3): (g1) R6 is hydrogen or C1-C6 alkyl; (g2) R6, together with P6, the carbon atom to which R6 is bonded, and the nitrogen atom to which P6 is bonded, forms a 4- to 7-membered saturated heterocycle; or (g3) R6, together with Q6 and the carbon atom to which R6 and Q6 are bonded, forms a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocycle; Except when R6 and P6 form a 4- to 7-membered saturated heterocycle, P6 is C1-C6 alkyl or C3-C8 cycloalkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of: halogen, hydroxy, C1-C6 alkoxy and aminocarbonyl (wherein the amino group is -NH2, mono-C1-C6 alkylamino, di-C1-C6 alkylamino or 4- to 8-membered cyclic amino), Except when R6 and Q6 form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocycle, Q6 is hydrogen or C1-C6 alkyl, R7 is any one of the following (h1) to (h3): (h1)R7 is C6-C 10 aryloxy C1-C6 alkyl, C7-C 14 arylalkyl, C7-C 14 aryloxyalkyl C1-C6 alkyl or 5- to 10-membered heteroaryl C1-C6 alkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of: halogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkoxy, cyano, C1-C6 alkylsulfonyl, SF5, and C3-C8 cycloalkyl; (h2) R7, together with P7, the carbon atom to which R7 is bonded, and the nitrogen atom to which P7 is bonded, forms a 4- to 7-membered saturated heterocycle; or (h3) R7, together with Q7 and the carbon atom to which R7 and Q7 are bonded, forms a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocycle; Except when R7 and P7 form a 4- to 7-membered saturated heterocycle, P7 is hydrogen or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with one or more groups independently selected from the group consisting of: halogen, hydroxy, C1-C6 alkoxy and aminocarbonyl (wherein the amino group is -NH2, mono-C1-C6 alkylamino, di-C1-C6 alkylamino or 4- to 8-membered cyclic amino), Except when R7 and Q7 form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocycle, Q7 is hydrogen or C1-C6 alkyl, Except when R5 and R8 form a C4-C8 alkylene, R8 is any one of the following (i1) to (i3): (i1) R8 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy C1-C6 alkyl, C2-C6 alkenyloxycarbonyl C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl C1-C6 alkyl, C6-C 10 aryloxy C1-C6 alkyl, C7-C 14 aralkyl, C7-C 14 aralkoxy C1-C6 alkyl, 5- to 10-membered heteroaryl C1-C6 alkyl or 5- to 10-membered heteroaryloxy C1-C6 alkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of: halogen, hydroxy, carboxy, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkoxy, cyano, aminocarbonyl (wherein the amino is -NH2, mono-C1-C6 alkylamino, di-C1-C6 alkylamino or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), 4- to 7-membered heterocycloalkyl, protected 4- to 7-membered heterocycloalkyl, 4- to 7-membered heterocyclic group and protected 4- to 7-membered heterocyclic group; (i2) R8, together with the carbon atom to which it is bonded, the carbon atom to which P8 is bonded, and the nitrogen atom to which P8 is bonded, forms a 4- to 7-membered saturated heterocycle, wherein the 4- to 7-membered saturated heterocycle is optionally condensed with a saturated carbocycle or an aromatic ring, and the 4- to 7-membered saturated heterocycle is optionally substituted with one or more halogen atoms, oxo, one or more C1-C6 alkyl groups, C1-C6 haloalkyl, C3-C8 spiroalkyl, C6-C 10 aryl, 5- to 10-membered heteroaryl, 4- to 8-membered cyclic amino (wherein the cyclic amino is optionally substituted with one or more halogen atoms) or OS8, and S8 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C3-C8 cycloalkylC1-C6 alkyl, 4- to 7-membered heterocyclic group, C7-C 14 aralkyl (wherein the aralkyl is optionally substituted with one or more halogen atoms, C1-C6 alkyl, C1-C6 alkoxy or C1-C6 haloalkoxy), 5- to 10-membered heteroarylC1-C6 alkyl or C3-C8 cycloalkyl; or (i3) R8, together with Q8 and the carbon atom to which R8 and Q8 are bonded, forms a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocycle; Except when R8 and P8 form a 4- to 7-membered saturated heterocycle, P8 is hydrogen, C1-C6 alkyl, C1-C6 alkoxy C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy C2-C6 alkenyl, C3-C8 cycloalkyl, 4- to 7-membered heterocyclic group, 4- to 7-membered heterocyclic group C1-C6 alkyl, C6-C 10 aryl, C7-C 14 aralkyl, 5- to 10-membered heteroaryl or 5- to 10-membered heteroaryl C1-C6 alkyl, each of which is optionally substituted by one or more groups independently selected from the group consisting of: halogen, hydroxy, C1-C6 alkoxy and aminocarbonyl (wherein the amino group is -NH2, mono-C1-C6 alkylamino, di-C1-C6 alkylamino or 4- to 8-membered cyclic amino), Q8 is hydrogen or C1-C6 alkyl, except when R8 and Q8 form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring. M9 is -N(P9)- or an oxygen atom; R9 is any one of the following (j1) to (j3), except when R1 and R9 form a divalent group: (j1)R9 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy C1-C6 alkyl, C2-C6 alkenoxy C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl C1-C6 alkyl, C7-C 14 arylalkyl or 5- to 10-membered heteroaryl C1-C6 alkoxy C1-C6 alkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of: halogen, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, aminocarbonyl (wherein the amino group is -NH2, mono-C1-C6 alkylamino, di-C1-C6 alkylamino or 4- to 8-membered cyclic amino) and C1-C6 alkylsulfonyl; (j2) R9, together with P9, the carbon atom to which R9 is bonded, and the nitrogen atom to which P9 is bonded, forms a 4- to 7-membered saturated heterocyclic ring; or (j3) R9, together with Q9 and the carbon atoms to which R9 and Q9 are bonded, forms a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, each of which is optionally substituted by one or more halogen atoms or one or more C1-C6 alkyl groups; P9 is hydrogen or C1-C6 alkyl, except when R9 and P9 form a 4- to 7-membered saturated heterocyclic ring, and the C1-C6 alkyl is optionally substituted by one or more groups independently selected from the group consisting of halogen, hydroxy, C1-C6 alkoxy, and aminocarbonyl (wherein the amino group is -NH2, mono-C1-C6 alkylamino, di-C1-C6 alkylamino, or 4- to 8-membered cyclic amino); Q9 is hydrogen or C1-C6 alkyl, except when R9 and Q9 form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring; R 10 any one of the following (k1) to (k3): (k1)R 10 is C1-C6 alkyl, C2-C6 alkynyl, C1-C6 alkoxy C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl C1-C6 alkyl, C3-C8 cycloalkoxy C1-C6 alkyl or C7-C 14 arylalkyl, each of which is optionally substituted by one or more groups independently selected from the group consisting of: halogen, hydroxy and C1-C6 alkylsulfonyl; (k2)R 10 together with the carbon atom bonded to P 10 , R 10 forms a 4- to 7-membered saturated heterocycle together with the nitrogen atom bonded to P; or 10 ​ (k3)R 10 Together with Q 10 and R 10 and Q 10 form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring together with the carbon atoms to which they are bonded; Except when R 10 and P 10 form a 4- to 7-membered saturated heterocycle, P 10 is hydrogen or a C1-C6 alkyl group, wherein the C1-C6 alkyl group is optionally substituted with one or more groups independently selected from the group consisting of: halogen, hydroxy, C1-C6 alkoxy, and aminocarbonyl (wherein the amino group is -NH2, mono-C1-C6 alkylamino, di-C1-C6 alkylamino, or 4- to 8-membered cyclic amino), Except when R 10 and Q 10 form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, Q 10 is hydrogen or a C1-C6 alkyl group, and L 11 is a single bond or -CHM 11 -, -(CH2) n S(CH2) m -, -(CH2) n S(O)(CH2) m - or -(CH2) n S(O)2(CH2) m -, where n and m are each independently 1 or 2, Except when R2 and R 11 form a divalent group, R 11 is any one of the following (l1) to (l5): (l1)R 11 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy C1-C6 alkyl, C7-C 14 arylalkyl, aminocarbonyl (wherein the amino group is -NH2, mono-C1-C6 alkylamino, di-C1-C6 alkylamino, N-C1-C6 alkyl-N-C2-C6 alkenylamino or 4- to 8-membered cyclic amino), or C3-C8 cycloalkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of: halogen, oxo, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, 4- to 7-membered heterocyclic group, aminocarbonyl (wherein the amino group is -NH2, mono-C1-C6 alkylamino, di-C1-C6 alkylamino or 4- to 8-membered cyclic amino), and C1-C6 alkylsulfonyl; (l2)R 11 is a peptide chain containing 1 to 4 amino acid residues; (l3)R 11 and P 11 , R 11 The carbon atom bonded to and the nitrogen atom bonded to P 11 together form a 4- to 7-membered saturated heterocycle; (l4)R 11 together with Q 11 and R 11 and Q 11 form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring together with the carbon atom to which they are bonded; or (l5)R 11 bonded to M 11 , R 11 and the carbon atom bonded to M 11 together form a 3- to 8-membered alicyclic ring; Except when R 11 and P 11 form a 4- to 7-membered saturated heterocycle, P 11 is hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl C1-C6 alkyl or C7-C 14 arylalkyl, wherein the C1-C6 alkyl is optionally substituted by one or more groups independently selected from the group consisting of: halogen, hydroxy, C1-C6 alkoxy and aminocarbonyl (wherein the amino group is -NH2, mono-C1-C6 alkylamino, di-C1-C6 alkylamino or 4- to 8-membered cyclic amino), Except when R 11 and Q 11 form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, Q 11 is hydrogen or a C1-C6 alkyl group, and Except when R 11 and M 11 form a 3- to 8-membered alicyclic ring, M 11 is hydrogen, and at least three of P1 to P 11 are not hydrogen.

2. The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof according to claim 1, wherein: (a) R4 and P5 together form a divalent group, wherein the divalent group is *-C3-C8 alkylene-#, *-C3-C8 alkenylene-#, *-C1-C3 alkylene-C3-C8 cycloalkylene-C1-C3 alkylene-#, *-C1-C3 alkylene-O-C3-C6 alkenylene-#, *-C1-C3 alkylene-CO-NR D -C1-C3 alkylene-# or *-C1-C3 alkylene-NR D -CO-C1-C3 alkylene-# or *-C1-C3 alkylene-3- to 7-membered heterocycloalkylene-C1-C3 alkylene-#, each of which is optionally substituted by one or more groups independently selected from the group consisting of halogen and C1-C6 alkyl, and R D is hydrogen or methyl, * represents the bonding point of the carbon atom bonded to R4, and # represents the bonding point of the nitrogen atom bonded to P5, or (b) P4 and P5 together form a divalent group, which is C3-C8 alkylene or C3-C8 alkenylene, each of which is optionally substituted by one or more groups independently selected from the group consisting of halogen and C1-C6 alkyl, or (c) P5 is C3-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyC1-C6 alkyl, C3-C8 cycloalkylC1-C6 alkyl, or C1-C6 aminoalkyl.

3. The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof according to claim 1 or 2, wherein R4 and P5 together form a divalent group, and the partial structure *-CR4Q4-CO-NP5-* in the cyclic compound represented by formula (1) is represented by the following formula: Wherein: Y 11 is hydrogen, a C1-C6 alkyl group or a halogen Y 12 is hydrogen, a C1-C6 alkyl group or a halogen, Y 13 is hydrogen, a C1-C6 alkyl group or a halogen, or Y 13 together with Y 15 forms a C3-C8 alkylene group or -O-, Y 14 is hydrogen or a C1-C6 alkyl group, Except when Y 13 and Y 15 form a C3-C8 alkylene or -O-, Y 15 is hydrogen, a C1-C6 alkyl or a halogen, Y 16 is hydrogen or a C1-C6 alkyl group, Y 17 is hydrogen or a C1-C6 alkyl group, Y 18 is hydrogen or a C1-C6 alkyl group, R D is hydrogen or a C1-C6 alkyl group, n is 0, 1, or 2, m is 0, 1, or 2, and * represents the bonding point with an adjacent atom.

4. The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof according to any one of claims 1 to 3, wherein: R1 and R5 together form a divalent group, wherein the divalent group is *-C1-C8 alkylene-C6-C 10 arylene-C1-C3 alkylene-#, *-C1-C8 alkylene-O-C6-C 10 arylene-C1-C3 alkylene-#, *-C2-C8 alkenylene-O-C6-C 10 arylene-C1-C3 alkylene-# or *-C2-C8 alkenylene-C6-C 10 arylene-C1-C3 alkylene-#, each of which is optionally substituted by one or more groups independently selected from the group consisting of halogen and C1-C6 alkyl, * represents the bonding point of the carbon atom bonded to R1, and # represents the bonding point of the carbon atom bonded to R5.

5. The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof according to any one of claims 1 to 3, wherein: R1 and R9 together form a divalent group, wherein the divalent group is *-C3-C8 alkylene-#, *-C3-C8 alkenylene-# or *-C1-C3 alkylene-O-C1-C8 alkylene-#, each of which is optionally substituted with one or more groups independently selected from the group consisting of: halogen, C1-C6 alkyl, C3-C8 spiroalkyl and 4- to 10-membered spiroheterocyclic group, * means the bonding point of the carbon atom bonded to R1, and # means the bonding point of the carbon atom bonded to R9.

6. The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof according to any one of claims 1 to 5, wherein: R2 and R 11 together form a divalent group, wherein the divalent group is *-C3-C8 alkylene-NR C -# or *-C3-C8 alkenylene-NR C -#, each of which is optionally substituted by one or more groups independently selected from the group consisting of halogen, C1-C6 alkyl, C3-C8 spiroalkyl, and 4- to 10-membered spiroheterocyclic group, and R C is hydrogen or methyl, * means the bonding point of the carbon atom bonded to R2, and # means the bonding point of the carbon atom bonded to R 11 ​ 7. The pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof according to any one of claims 2 to 6, wherein: L1 is a single bond, -CH2- or -CH2-S-CH2-; and / or Except when R1 and R5 together form a divalent group and except when R1 and R9 together form a divalent group, R1 is: C1-C7 alkyl optionally substituted with di-C1-C6 alkylaminocarbonyl; C1-C6 haloalkyl; C1-C6 hydroxyalkyl; C2-C7 alkenyl; C2-C6 alkynyl; C1-C6 alkoxyC1-C6 alkyl optionally substituted with one or more halogen atoms; C2-C6 alkenoxyC1-C6 alkyl; C1-C6 alkylthioC1-C6 alkyl; C7-C 14 arylalkyl; 5- to 10-membered heteroarylC1-C6 alkyl; C3-C8 cycloalkyl; C3-C8 cycloalkylC1-C6 alkyl; or C3-C8 cycloalkoxyC1-C6 alkyl; and / or R1 and P1 together with the nitrogen atom to which P1 is bonded and the carbon atom to which R1 is bonded form a 4- to 7-membered saturated heterocycle; and / or P1 is hydrogen or C1-C6 alkyl; and / or Q1 is hydrogen or methyl; and / or Except when R2 and R 11 together form a divalent group, R2 is: C1-C6 alkyl; C2-C6 alkenyl; C1-C6 haloalkyl; C1-C6 hydroxyalkyl; C3-C8 cycloalkyl optionally substituted with one or more halogen atoms; C1-C6 alkoxy C1-C6 alkyl; or a 4- to 7-membered heterocyclic group; and / or P2 is hydrogen; and / or Q2 is hydrogen, and / or R3 is hydrogen, C1-C6 alkyl or C7-C 14 arylalkyl; and / or R3 and P3 together with the nitrogen atom to which P3 is bonded and the carbon atom to which R3 is bonded form a 4- to 7-membered saturated heterocycle, and the 4- to 7-membered saturated heterocycle is optionally substituted with one or more C1-C6 alkyl groups or substituted with C1-C6 alkoxy; and / or R3 and Q3 together with the carbon atoms to which they are bonded form a 3- to 8-membered alicyclic ring; and / or P3 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 cyanoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl or C1-C6 alkoxy C1-C6 alkyl; and / or Q3 is hydrogen or methyl; and / or Except when R4 and P5 together form a divalent group, R4 is hydrogen, C1-C6 alkyl, C1-C6 hydroxyalkyl, C2-C6 alkenyl, C1-C6 alkoxy C1-C6 alkyl, C2-C6 alkenoxy C1-C6 alkyl or C1-C6 carboxyalkyl; and / or R4 and P4 together with the nitrogen atom to which P4 is bonded and the carbon atom to which R4 is bonded form a 4- to 7-membered saturated heterocycle, and the 4- to 7-membered saturated heterocycle is optionally substituted with C1-C6 alkyl; and / or Except when P4 and P5 together form a divalent group, P4 is C1-C6 alkyl or C1-C6 alkenyl; and / or Q4 is hydrogen; and / or Except when R5 and R1 together form a divalent group, R5 is: C2-C6 alkynyl; C2-C6 alkenyloxycarbonyl C1-C6 alkyl; C3-C8 cycloalkyl; C3-C8 cycloalkyl C1-C6 alkyl optionally substituted with one or more halogen atoms; C7-C 14 aralkyl, which is optionally substituted with one or more groups selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C2-C6 alkenyloxy, C2-C6 alkenyl, C3-C8 cycloalkyl and C1-C6 alkylcarbonyl; 5- to 10-membered heteroaryl C1-C6 alkyl; C3-C8 cycloalkyloxy C1-C6 alkyl; or C1-C6 alkoxy C1-C6 alkyl; and / or Q5 is hydrogen; and / or R6 is hydrogen or C1-C6 alkyl; and / or R6 and P6 together with the nitrogen atom to which P6 is bonded and the carbon atom to which R6 is bonded form a 4- to 7-membered saturated heterocycle; and / or P6 is C1-C6 alkyl; and / or Q6 is hydrogen; and / or R7 is: C7-C 14 aralkyl, optionally substituted by one or more groups independently selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, and C3-C8 cycloalkyl; or 5- to 10-membered heteroaryl C1-C6 alkyl, optionally substituted by one or more groups independently selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, and C3-C8 cycloalkyl; and / or P7 is hydrogen; and / or Q7 is hydrogen; and / or R8 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxyC1-C6 alkyl or C3-C8 cycloalkylC1-C6 alkyl; and / or R8 and P8 together with the nitrogen atom to which P8 is bonded and the carbon atom to which R8 is bonded form a 4- to 7-membered saturated heterocycle, the 4- to 7-membered saturated heterocycle is optionally condensed with a 3- to 8-membered saturated carbocycle, and the 4- to 7-membered saturated heterocycle is optionally substituted with: one or more halogen atoms; one or more C1-C6 alkyl groups; C1-C6 haloalkyl; hydroxy; 4- to 7-membered heterocyclic epoxy; oxo; C1-C6 alkoxy; C3-C8 cycloalkylC1-C6 alkoxy; C1-C6 haloalkoxy; 4- to 8-membered cyclic amino optionally substituted with one or more halogen atoms; C3-C8 spiroalkyl; or C3-C8 cycloalkoxy; and / or P8 is hydrogen or C1-C6 alkyl; and / or Q8 is hydrogen or methyl; and / or Except when R9 and R1 together form a divalent group, R9 is C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy C1-C6 alkyl, C1-C6 alkenyloxy C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl C1-C6 alkyl or C7 to C 14 arylalkyl; and / or R9 and Q9 together with the carbon atom to which they are bonded form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocycle, wherein the 3- to 8-membered alicyclic ring or 4- to 7-membered saturated heterocycle is optionally substituted with one or more halogen atoms or one or more C1-C6 alkyl groups; and / or P9 is hydrogen or C1-C6 alkyl; and / or Q9 is hydrogen or methyl; and / or R 10 is a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy C1-C6 alkyl group, a C3-C8 cycloalkyl group or a C3-C8 cycloalkyl C1-C6 alkyl group; and / or P 10 is hydrogen or a C1-C6 alkyl group; and / or Q 10 is hydrogen or methyl; and / or L 11 is -CH2- or -CH2-S-CH2-; and / or Except when R 11 and R2 together form a divalent group, R 11 is: C1-C6 alkyl; di-C1-C6 alkylaminocarbonyl; N-C1-C6 alkyl-N-C2-C6 alkenylaminocarbonyl; N-C1-C6 alkyl-N-C1-C6 alkoxy C1-C6 alkylaminocarbonyl; a cyclic aminocarbonyl optionally substituted by one or more C1-C6 alkyl groups or a 4- to 7-membered heterocyclic group; or C3-C8 cycloalkyl; and / or R 11 and P 11 with P 11 The nitrogen atom bonded to and R 11 Together with the carbon atom bonded to form a 4- to 7-membered saturated heterocycle; and / or P 11 is hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl C1-C6 alkyl or C7-C 14 arylalkyl; and / or Q 11 is hydrogen; and / or At least four, five, or six of P1 to P 11 are not hydrogen.

8. A pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof, according to any one of claims 1 to 7, for selectively inhibiting KRAS in a subject.

9. A pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof, according to any one of claims 1 to 7, wherein R 12 and P 13 The divalent group formed together interacts with His95 of KRAS.

10. A pharmaceutical composition comprising a cyclic compound or a salt thereof, or a solvate thereof, according to any one of claims 1 to 7, having a KRAS inhibitory activity that is 3 times or more the NRAS inhibitory activity and the HRAS inhibitory activity.

11. A pharmaceutical composition for treating or preventing a cell proliferative disease, the pharmaceutical composition comprising a cyclic compound selected from the group consisting of: PP1105: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-Cyclopentyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-27-isobutyl-N,N,4,19,22,26,32,35-octamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaooxo-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10,14 tetratetracont-38-ene-17,1'-cyclopentane]-23-carboxamide, PP2320: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-Cyclopentyl-28-ethoxy-32-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,N,2,14,18,21,24,36-octamethyl-10-[(1S)-1-methylpropyl]-3,9,12,15,19,22,25,31,34,37,45-undecaoxo-13-propyl-38-[[4-(trifluoromethyl)phenyl]methyl]spiro[2,8,11,14,18,21,24,30,33,36,39-undecaazatetracyclo[37.5.1.0 4，8 .0 26,30 tetratetracont-42-en-23,1′-cyclobutane]-17-carboxamide, PP3478: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-Cyclopentyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-27-isobutyl-N,N,4,19,22,26,32,35-octamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaoxo-2-(p-tolylmethyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10,14 tetratetracont-38-ene-17,1′-cyclopentane]-23-carboxamide, PP3475: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-Cyclopentyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-27-[(1R)-1-methoxyethyl]-N,N,4,19,22,26,32,35-octamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaoXO-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10,14 tetratetracont-38-ene-17,1′-cyclopentane]-23-carboxamide, PP3484: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-Cyclopentyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-27-isobutyl-N,N,4,16,19,22,26,32,35-nonamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaooxo-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10,14 tetratetracont-38-ene-17,1'-cyclobutane]-23-carboxamide, PP3481: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-Cyclopentyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-27-[(1R)-1-methoxyethyl]-N,N,4,19,22,26,32,35-octamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaoxo-2-(p-tolylmethyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10，14 tetratetracont-38-en-17,1′-cyclopentane]-23-carboxamide, PP3368: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-Cyclopentyl-28-ethoxy-32-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,N,2,14,18,21,36-heptamethyl-10-[(1S)-1-methylpropyl]-3,9,12,15,19,22,25,31,34,37,45-undecaoxo-13-propyl-38-[[4-(trifluoromethyl)phenyl]methyl]spiro[24-oxa-2,8,11,14,18,21,30,33,36,39-decaazatetracyclo[37.5.1.0 4，8 .0 26,30 tetracos-42-ene-23,1′-cyclobutane]-17-carboxamide, PP3388: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-Cyclopentyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,N,4,19,22,26,32,35-octamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaoXO-27-propyl-2-(p-tolylmethyl)spiro[16-oxa-1,4,7,10,19,22,26,29,32,35-decaazatricyclo[34.5.1.0 10,14 tetratetracont-38-ene-17,1'-cyclobutane]-23-carboxamide, PP3374: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-Cyclopentyl-28-ethoxy-13-[(1R)-1-methoxyethyl]-32-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,N,2,14,18,21,36-heptamethyl-10-[(1S)-1-methylpropyl]-3,9,12,15,19,22,25,31,34,37,45-undecaooxo-38-[[4-(trifluoromethyl)phenyl]methyl]spiro[24-oxa-2,8,11,14,18,21,30,33,36,39-decaazatetracyclo[37.5.1.0 4,8 .0 26,30 tetratetracont-42-ene-23,1′-cyclobutane]-17-carboxamide, PP3376: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-Cyclopentyl-12-ethoxy-27-[(1R)-1-methoxyethyl]-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,N,4,19,22,26,32,35-octamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaooxo-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[16-oxa-1,4,7,10,19,22,26,29,32,35-decaazatricyclo[34.5.1.0 10,14 tetratetracont-38-ene-17,1'-cyclobutane]-23-carboxamide, PP3394: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-Cyclopentyl-12-ethoxy-27-[(1R)-1-methoxyethyl]-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,N,4,19,22,26,32,35-octamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaoXO-2-(p-tolylmethyl)spiro[16-oxa-1,4,7,10,19,22,26,29,32,35-decaazatricyclo[34.5.1.0 10,14 tetratetracont-38-ene-17,1′-cyclobutane]-23-carboxamide, PP3194: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-Cyclopentyl-12-ethoxy-27-[(1R)-1-methoxyethyl]-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,N,3′,3′,4,19,22,26,32,35-decamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaoXO-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10,14 tetratetracont-38-ene-17,1′-cyclobutane]-23-carboxamide, PP3198: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-8-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-20-cyclopentyl-12-ethoxy-27-[(1R)-1-methoxyethyl]-N,N,3′,3′,4,19,22,26,32,35-decamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaoxo-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10 ,14 tetracosa-38-ene-17,1′-cyclobutane]-23-carboxamide, PP3327: (6′S, 9′S, 13′S, 16′S, 22′S, 29′S, 35′S, 40a′S, Z)-16′-((S)-sec-Butyl)-6′-cyclopentyl-35′-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-N,N,2′,5′,8′,12′,18′,21′,31′-nonamethyl-29′-(4-methylbenzyl)-1′,4′,7′,11′,14′,17′,20′,30′,33′,36′,41′-undecaooxo-13′-propyl-1′,2′,4′,5′,6′,7′,8′,9′,10′,11′,12′,13′,14′,15′,16′,17′,18′,19′,20′,21′,22′,23′,26′,27′,29′,30′,31′,32′,33′,34′,35′,36′,40′,40a′-tetratetracontahydro-38′H-dispiro[cyclobutane-1,3′-[22,28]methanoptero[1,2-j][1,4,7,10,13,16,19,23,26,29,32]undecaazacyclotetracontene-39′,1″-cyclopropane]-9′-carboxamide, PP3234: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-8-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-20-cyclopentyl-12-ethoxy-N,N,4,16,19,22,26,32,35-nonamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaoxo-27-prop-2-ynyl-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10,14 tetracosa-38-ene-17,1′-cyclobutane]-23-carboxamide, PP3238: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-Cyclopentyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-N,N,4,16,19,22,26,32,35-nonamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaoxo-27-prop-2-ynyl-2-(p-tolylmethyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10,14 tetratetracont-38-ene-17,1'-cyclobutane]-23-carboxamide, PP3255: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-Cyclopentyl-28-ethoxy-32-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,N,2,14,18,21,24,36-octamethyl-10-[(1S)-1-methylpropyl]-3,9,12,15,19,22,25,31,34,37,45-undecaooxo-13-prop-2-ynyl-38-(p-tolylmethyl)spiro[2,8,11,14,18,21,24,30,33,36,39-undecaazatetracyclo[37.5.1.0 4,8 .0 26,30 tetratetracont-42-ene-23,1′-cyclobutane]-17-carboxamide, PP3356: (6′S, 9′S, 13′S, 16′S, 22′S, 29′S, 35′S, 40a′S, Z)-16′-((S)-sec-Butyl)-6′-cyclopentyl-35′-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-N,N,2′,5′,8′,12′,18′,21′,31′-nonamethyl-1′,4′,7′,11′,14′,17′,20′,30′,33′,36′,41′-undecaooxo-13′-propyl-29′-(4-(trifluoromethyl)benzyl)-1′,2′,4′,5′,6′,7′,8′,9′,10′,11′,12′,13′,14′,15′,16′,17′,18′,19′,20′,21′,22′,23′,26′,27′,29′,30′,31′,32′,33′,34′,35′,36′,40′,40a′-tetratetracontahydro-38′H-dispiro[cyclobutane-1,3′-[22,28]methanoptero[1,2-j][1,4,7,10,13,16,19,23,26,29,32]undecaazacyclotetracontene-39′,1″-cyclopropane]-9′-carboxamide, PP1693: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-27-butyl-20-cyclopentyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-fluoro-N,N,3′,3′,4,19,22,26,32,35-decamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaoxo-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10,14 tetratetracont-38-ene-17,1′-cyclobutane]-23-carboxamide, PP3414: (6′S,9′S,13′S,16′S,22′S,29′S,35′S,40a′S,Z)-16′-((S)-sec-Butyl)-35′-(3-chloro-4-(trifluoromethyl)phenethyl)-N,N,5′,8′,12′,18′,21′,31′-octamethyl-1′,4′,7′,11′,14′,17′,20′,30′,33′,36′,41′-undecaooxo-6′-(pentan-3-yl)-13′-propyl-29′-(4-(trifluoromethyl)benzyl)-1′,2′,4′,5′,6′,7′,8′,9′,10′,11′,12′,13′,14′,15′,16′,17′,18′,19′,20′,21′,22′,23′,26′,27′,29′,30′,31′,32′,33′,34′,35′,36′,40′,40a′-tetratetracontahydro-38′H-dispiro[cyclobutane-1,3′-[22,28]methanopterop[1,2-j][1,4,7,10,13,16,19,23,26,29,32]undecaazacyclotetracontatriene-39′,1″-cyclopropane]-9′-carboxamide, PP2175: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-8-[2-(3,4-dichlorophenyl)ethyl]-12-ethoxy-20-(1-ethylpropyl)-N,N,3′,3′,4,19,22,26,32,35-decamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaoxo-27-propyl-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10,14 tetratetracont-38-ene-17,1′-cyclobutane]-23-carboxamide, PP2750: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-32-Cyclopropyl-8-[2-(3,4-dichlorophenyl)ethyl]-20-(2,2-dimethylpropyl)-12-ethoxy-27-(methoxymethyl)-N,N,3′,3′,4,19,22,26,35-nonamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaoxo-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10 ,14 tetratetracont-38-ene-17,1′-cyclobutane]-23-carboxamide, PP2742: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-32-Cyclopropyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-20-(2,2-dimethylpropyl)-12-ethoxy-N,N,3′,3′,4,19,22,26,35-nonamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaoxo-27-propyl-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10,14 tetracosa-38-ene-17,1′-cyclobutane]-23-carboxamide, PP2967: (6′S,9′S,13′S,16′S,22′S,29′S,35′S,40a′S,Z)-16′-((S)-sec-Butyl)-35′-(3-chloro-4-(trifluoromethyl)phenethyl)-13′-(methoxymethyl)-N,N,3,3,5′,8′,12′,18′,21′,31′-decamethyl-29′-(4-methylbenzyl)-1′,4′,7′,11′,14′,17′,20′,30′,33′,36′,41′-undecaooxo-6′-(pentan-3-yl)-1′,2′,4′,5′,6′,7′,8′,9′,10′,11′,12′,13′,14′,15′,16′,17′,18′,19′,20′,21′,22′,23′,26′,27′,29′,30′,31′,32′,33′,34′,35′,36′,40′,40a′-tetratetracontahydro-38′H-dispiro[cyclobutane-1,3′-[22,28]methanopterop[1,2-j][1,4,7,10,13,16,19,23,26,29,32]undecaazacyclotetracontatriene-39′,1″-cyclopropane]-9′-carboxamide, and PP3510: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38E)-20-Cyclopentyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-38-fluoro-27-isobutyl-N,N,4,19,22,26,32,35-octamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaoxo-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10,14 tetratetracont-38-ene-17,1′-cyclopentane]-23-carboxamide, a salt thereof, or a solvate thereof.

12. The pharmaceutical composition according to any one of claims 1 to 11, for treating or preventing cancer.

13. The pharmaceutical composition according to claim 12, wherein the cancer is solid cancer or blood cancer.

14. The pharmaceutical composition according to claim 12 or 13, wherein the cancer is selected from the group consisting of: lung cancer, esophageal cancer, gastric cancer, colorectal cancer, uterine cancer, ovarian cancer, pancreatic cancer, bladder cancer, thyroid cancer, skin cancer, leukemia, malignant lymphoma, and multiple myeloma.

15. The pharmaceutical composition according to any one of claims 12 to 14, wherein the cancer is selected from the group consisting of: non-small cell lung cancer, small cell lung cancer, colon cancer, rectal cancer, uterine cancer, endometrial cancer, cervical cancer, pancreatic cancer, AML (acute myeloid leukemia), CML (chronic myeloid leukemia), ALL (acute lymphoblastic leukemia), CLL (chronic lymphocytic leukemia), Hodgkin lymphoma, and non-Hodgkin lymphoma.

16. The pharmaceutical composition according to any one of claims 12 to 15, wherein the cancer is associated with a defect in the RAS gene.

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