Cyclic compounds having selective inhibitory effect on KRAS relative to HRAS and NRAS

Abstract

The present inventor finds a cyclic compound that selectively inhibits KRAS. The inventors also found that the cyclic compounds interact with KRAS specific amino acid residues.

Description

Technical Field

[0001] In one aspect, the present invention relates to cyclic compounds. Background Art

[0002] RAS is a protein belonging to the small GTPase family, and KRAS, NRAS and HRAS are known. RAS is in an activated state or inactivated state depending on whether it is combined with GTP or GDP. It is activated by the exchange reaction from GDP to GTP carried out by GEF (guanine nucleotide exchange factor), and inactivated by the 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 MAPK pathway, PI3K / Akt pathway, RAL pathway, etc., and the 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 the activation of RAS upstream signals, the constitutive activation of RAS and / or the activating mutation of RAS (NPL 2). The activating mutations of these RAS have been found in multiple cancer types. G12, G13, and Q61 are considered hotspots for RAS mutations, with G12 frequently found in KRAS and Q61 frequently found in NRAS. These mutations are also known to be associated with patient prognosis (NPL 3).

[0003] At the same time, when it comes to approaching thorny targets represented by inhibition of 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 the medium-sized molecules with biological activity, peptide drugs are 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 unnatural amino acids. Unnatural amino acids refer to amino acids that are not naturally encoded on mRNA. It is very interesting that naturally occurring cyclosporin A and polymyxin B contain unnatural amino acids.

[0004] Since the discovery of pharmaceutical uses of naturally occurring peptides, peptides having pharmacological activity and bioabsorbability have attracted attention, and those having a molecular weight of approximately 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] Furthermore, with respect to conditions that may contribute to improved biokinetics of medium molecular weight peptides, cyclic peptides have been shown to satisfy 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, competition assays for binding to RAS have shown that some cyclic peptides inhibit the binding between specific compounds 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] WO 2012 / 122059

[0013] [PTL 4] WO 2017 / 181061

[0014] [Non-patent literature]

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

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

[0017] [NPL 3] NM. Rev. Drug Discov. 2016 Nov;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 Issues]

[0024] The present invention relates to cyclic compounds that are effective against RAS-mutated cancers and unnatural amino acid and peptide compounds that can be used for their production.

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

[0026] PTL 3 describes a peptide that inhibits the binding between RAS and SOS, and PTL 4 describes a peptide that competes with a compound that binds to RAS. However, none of these documents demonstrate any pharmacological effects, particularly against tumor cells. These documents also do not describe drug-like peptides.

[0027] NPL 1 details the relationship between RAS and cancer. The document describes molecules that bind to RAS. Although their efficacy has been demonstrated in preclinical studies, no compounds have been shown to be effective as drugs specifically targeting RAS-mutated cancers. Furthermore, 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 suggests the possibility of treating RAS-mutated cancers with RAF, MEK, and ERK inhibitors, it does not describe any compounds that directly inhibit RAS.

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

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

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

[0032] NPLs 6 to 8 describe peptides that bind to RAS, but their effects on tumor cells are limited and additionally no drug-like peptides are described.

[0033] Furthermore, to the best of the present inventors' knowledge, there are no reports on compounds that have sufficiently 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 that selectively inhibit KRAS relative to HRAS and NRAS, the present inventors discovered cyclic compounds that selectively interact with KRAS compared to HRAS and NRAS. Furthermore, the present inventors discovered that the cyclic compounds have a pharmacological effect of inhibiting the growth of tumor cells harboring RAS mutations.

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

[0037] [1] A cyclic compound represented by formula (1):

[0038]

[0039] in

[0040] L1 is a single bond;

[0041] R1 is a C1 to C7 alkyl group, or R1 and R5 are linked together to form a divalent group, wherein the partial structure of the cyclic compound represented by formula (1): *-CR1Q1-L1-CO-NP2-CR2Q2-CO-NP3-CR3Q3-CO-NP4-CR4Q4-CO-NP5-CR5Q5-* is represented by the following formula:

[0042]

[0043] in:

[0044] X2 is -L1-CO-NP2-CR2Q2-CO-NP3-CR3Q3-CO-NP4-CR4Q4-CO-NP5-,

[0045]

[0046] is a single bond or a double bond,

[0047]

[0048] E or Z configuration can be used if

[0049]

[0050] For double bonds,

[0051] n is 0, 1, or 2,

[0052] m is 0, 1, 2, 3 or 4,

[0053] * represents the connection point with the adjacent atom;

[0054] P1 is a C1 to C6 alkyl group;

[0055] Q1 is a hydrogen atom;

[0056] R2 is a C1 to C6 alkyl group;

[0057] P2 is a hydrogen atom;

[0058] Q2 is a hydrogen atom;

[0059] R3 is a hydrogen atom or R3, the carbon atom to which P3 and R3 are attached, and the nitrogen atom to which P3 is attached are connected together to form a 4- to 7-membered saturated heterocyclic ring;

[0060] P3 is a C1 to C6 alkyl group or a C3 to C8 cycloalkyl group, except when R3 and P3 form a 4- to 7-membered saturated heterocyclic ring;

[0061] Q3 is a hydrogen atom;

[0062] R4 and P5 are linked together to form a divalent group, wherein the partial structure *-CR4Q4-CO-NP5-* in the cyclic compound represented by formula (1) is represented by the following formula:

[0063]

[0064] P4 is a C1 to C6 alkyl group;

[0065] Q4 is a hydrogen atom,

[0066] R5 is benzyl optionally substituted with one or more groups selected from the group consisting of C1 to C6 alkyl, C1 to C6 haloalkyl, and C3 to C8 cycloalkyl, except when R1 and R5 form a divalent group;

[0067] Q5 is a hydrogen atom,

[0068] R6 is a hydrogen atom;

[0069] P6 is a C1 to C6 alkyl group,

[0070] Q6 is a hydrogen atom,

[0071] R7 is a phenethyl group optionally substituted with one or more groups selected from the group consisting of a halogen atom, a C1 to C6 haloalkyl group, and a C1 to C6 alkoxy group;

[0072] P7 is a hydrogen atom,

[0073] Q7 is a hydrogen atom,

[0074] R8, the carbon atom to which P8 and R8 are attached, and the nitrogen atom to which P8 is attached are joined together to form a 4- to 7-membered saturated heterocyclic ring, wherein the 4- to 7-membered saturated heterocyclic ring is optionally substituted with a C1 to C6 alkoxy group;

[0075] Q8 is a hydrogen atom,

[0076] R9 and Q9 and the carbon atom to which R9 and Q9 are attached are joined together to form a 3- to 8-membered alicyclic ring, wherein the 3- to 8-membered alicyclic ring is optionally substituted with one or more C1 to C6 alkyl groups;

[0077] P9 is a hydrogen atom or a C1 to C6 alkyl group,

[0078] R 10 is a C1 to C6 alkyl group or a C3 to C8 cycloalkyl group;

[0079] P 10 is a C1 to C6 alkyl group,

[0080] Q 10 is a hydrogen atom, and

[0081] L 11 is -CH2-,

[0082] R 11 is a di-C1 to C6 alkylaminocarbonyl group or a 4-membered to 8-membered cyclic aminocarbonyl group;

[0083] P 11 is a C1 to C6 alkyl group, and

[0084] Q 11 is a hydrogen atom,

[0085] or a salt thereof, or a solvate thereof, wherein

[0086] The cyclic compound represented by formula (1) is selected from the group consisting of:

[0087] PP1574: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-N-ethyl-27-isobutyl-N,4,19,22,26,32,35-heptamethyl-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 ]tetradec-38-ene-17,1′-cyclopentane]-23-carboxamide,

[0088] PP1650: (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,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 ]tetradec-38-ene-17,1′-cyclobutane]-23-carboxamide,

[0089] PP1827: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47E)-19-cyclopentyl-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-N-ethyl-N,3,18,21,25,31,34-heptamethyl-29-[(1S)-1-methylpropyl]-2,5,8,14,17,20,24,27,30,33,55-undecaoxo-spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24.15.11.2 43,46 .1 35,41 .0 9,13 ]pentacarbonyl-37,43(54),44,46(53),47-pentaene-16,1′-cyclobutane]-22-carboxamide,

[0090] PP1830: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47E)-19-cyclopentyl-11-ethoxy-N-ethyl-7-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,3,3′,3′,18,21,25,31,34-nonamethyl-29-[(1S)-1-methylpropyl]-2,5,8,14,17,20,24,27,30,33,55-undecaoxo-spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24.15.11.2 43,46 .1 35,41 .0 9,13 ]pentacarbonyl-37,43(54),44,46(53),47-pentaene-16,1′-cyclobutane]-22-carboxamide,

[0091] PP2093: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-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-(p-tolylmethyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10,14 ]tetradec-38-ene-17,1′-cyclobutane]-23-carboxamide,

[0092] PP2260: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z)-19-cyclopentyl-11-ethoxy-N-ethyl-7-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,3,3′,3′,18,21,25,31,34-nonamethyl-29-[(1S)-1-methylpropyl]-2,5,8,14,17,20,24,27,30,33,55-undecaoxo-spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24.15.11.2 43,46 .1 35,41 .0 9,13 ]pentadecane-37,43(54),44,46(53)-tetraene-16,1′-cyclobutane]-22-carboxamide,

[0093] PP2316: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,N,4,16,19,22,26,35-octamethyl-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 ]tetradec-38-ene-17,1′-cyclobutane]-23-carboxamide,

[0094] 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 ]pentadec-42-ene-23,1′-cyclobutane]-17-carboxamide,

[0095] PP2328: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,N,4,16,19,22,26,35-octamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaoxo-27-propyl-2-(p-tolylmethyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10,14 ]tetradec-38-ene-17,1′-cyclobutane]-23-carboxamide,

[0096] PP2574: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47E)-19-cyclopentyl-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-3,3′,3′,18,21,25,31,34-octamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24.15.10.2 43,46 .1 35,41 .0 9,13 ]pentacontan-37,43(53),44,46(52),47-pentacontan-16,1′-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecanone,

[0097] PP2576: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47E)-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-19-(1-ethylpropyl)-3,3′,3′,18,21,25,31,34-octamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24.15.10.2 43,46 .1 35,41 .0 9,13 ]pentacontan-37,43(53),44,46(52),47-pentacontan-16,1′-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecanone,

[0098] PP2583: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47E)-19-cyclopentyl-31-cyclopropyl-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-3,3′,3′,18,21,25,34-heptamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24.15.10.2 43,46 .1 35,41 .0 9,13]pentacontan-37,43(53),44,46(52),47-pentacontan-16,1′-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecanone,

[0099] PP2687: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-12-ethoxy-2-[(4-ethylphenyl)methyl]-27-isobutyl-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-spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10,14 ]tetradec-38-ene-17,1′-cyclobutane]-23-carboxamide,

[0100] PP2691: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-2-[(4-cyclopropylphenyl)methyl]-12-ethoxy-27-isobutyl-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-spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10,14 ]tetradec-38-ene-17,1′-cyclobutane]-23-carboxamide,

[0101] PP2957: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47E)-31-cyclopropyl-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-19-(1-ethylpropyl)-3,18,21,25,34-pentamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24.15.10.2] 43,46 .1 35,41 .0 9,13]pentacontan-37,43(53),44,46(52),47-pentacontan-16,1′-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecanone,

[0102] PP3033: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z)-19-cyclopentyl-11-ethoxy-7-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-3,18,21,25,31,34-hexamethyl-29-[(1S)-1-methylpropyl]-22-(piperidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24.15.11.2 43,46 .1 35,41 .0 9,13 ]pentacarbonyl-37,43(54),44,46(53)-tetraene-16,1′-cyclobutane]-2,5,8,14,17,20,24,27,30,33,55-undecanone,

[0103] PP3034: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z)-19-cyclopentyl-11-ethoxy-7-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-3,3′,3′,18,21,25,31,34-octamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24,15,11,25,31,34]- 43,46 .1 35,41 .0 9,13 ]pentacarbonyl-37,43(54),44,46(53)-tetraene-16,1′-cyclobutane]-2,5,8,14,17,20,24,27,30,33,55-undecanone,

[0104] PP3036: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z)-19-cyclopentyl-11-ethoxy-7-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-3,3′,3′,18,21,25,31,34-octamethyl-29-[(1S)-1-methylpropyl]-22-(piperidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24.15.10.2 43,46 .1 35,41 .09,13 ]54-tetradecanoic acid-37,43(53),44,46(52)-tetraene-16,1′-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecanone,

[0105] PP3037: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z)-19-cyclopentyl-11-ethoxy-7-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-3,3′,3′,18,21,25,31,34-octamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24.15.10.2 43,46 .1 35,41 .0 9,13 ]54-tetradecanoic acid-37,43(53),44,46(52)-tetraene-16,1′-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecanone,

[0106] PP3047: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47E)-7-[2-(3,4-dichlorophenyl)ethyl]-11-ethoxy-19-(1-ethylpropyl)-3,18,21,25,31,34-hexamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24.15.11.2 43,46 .1 35,41 .0 9,13 ]pentacarbonyl-37,43(54),44,46(53),47-pentaene-16,1′-cyclobutane]-2,5,8,14,17,20,24,27,30,33,55-undecanone,

[0107] PP3093: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z)-19-cyclopentyl-11-ethoxy-7-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-3,3′,3′,18,21,25,31,34-octamethyl-29-[(1S)-1-methylpropyl]-22-(piperidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24.15.9.2 43,46 .1 35,41.0 9,13 ]53 carbon-37,43 (52), 44,46 (51) -tetraene-16,1'-cyclobutane] -2,5,8,14,17,20,24,27,30,33,53-undecanone,

[0108] PP3094: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z)-19-cyclopentyl-7-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-3,3′,3′,18,21,25,31,34-octamethyl-29-[(1S)-1-methylpropyl]-11-propoxy-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24,15,9,2 43,46 .1 35,41 .0 9,13 ]53 carbon-37,43 (52),44,46 (51) -tetraene-16,1 '-cyclobutane] -2,5,8,14,17,20,24,27,30,33,53-undecanone,

[0109] PP3095: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-4,16,19,22,26,35-hexamethyl-30-[(1S)-1-methylpropyl]-23-(piperidine-1-carbonyl)-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 ]tetradec-38-ene-17,1′-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecanone,

[0110] PP3096: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-4,16,19,22,26,35-hexamethyl-30-[(1S)-1-methylpropyl]-23-(piperidine-1-carbonyl)-27-propyl-2-(p-tolylmethyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10,14]tetradec-38-ene-17,1′-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecanone,

[0111] PP3097: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-4,16,19,22,26,35-hexamethyl-30-[(1S)-1-methylpropyl]-27-propyl-23-(pyrrolidine-1-carbonyl)-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10,14 ]tetradec-38-ene-17,1′-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecanone,

[0112] PP3098: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-4,16,19,22,26,35-hexamethyl-30-[(1S)-1-methylpropyl]-27-propyl-2-(p-tolylmethyl)-23-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10,14 ]tetradec-38-ene-17,1′-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecanone,

[0113] PP3099: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-28-ethoxy-32-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-2,14,18,21,24,36-hexamethyl-10-[(1S)-1-methylpropyl]-17-(piperidine-1-carbonyl)-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]pentatetradec-42-ene-23,1′-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecanone,

[0114] PP3100: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-28-ethoxy-32-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-2,14,18,21,24,36-hexamethyl-10-[(1S)-1-methylpropyl]-17-(piperidine-1-carbonyl)-13-propyl-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 ]pentatetradec-42-ene-23,1′-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecanone,

[0115] PP3101: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-28-ethoxy-32-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-2,14,18,21,24,36-hexamethyl-10-[(1S)-1-methylpropyl]-13-propyl-17-(pyrrolidine-1-carbonyl)-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 ]pentacontan-42-ene-23,1′-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecanone,

[0116] PP3102: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-28-ethoxy-32-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-2,14,18,21,24,36-hexamethyl-10-[(1S)-1-methylpropyl]-13-propyl-38-(p-tolylmethyl)-17-(pyrrolidine-1-carbonyl)spiro[2,8,11,14,18,21,24,30,33,36,39-undecaazatetracyclo[37.5.1.0 4,8 .0 26,30]pentadec-42-ene-23,1′-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecanone,

[0117] PP3103: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-4,16,19,22,26,32,35-heptamethyl-30-[(1S)-1-methylpropyl]-23-(piperidine-1-carbonyl)-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 ]tetradec-38-ene-17,1′-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecanone,

[0118] PP3104: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-4,16,19,22,26,32,35-heptamethyl-30-[(1S)-1-methylpropyl]-23-(piperidine-1-carbonyl)-27-propyl-2-(p-tolylmethyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10,14 ]tetradec-38-ene-17,1′-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecanone,

[0119] PP3105: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-4,16,19,22,26,32,35-heptamethyl-30-[(1S)-1-methylpropyl]-27-propyl-23-(pyrrolidine-1-carbonyl)-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10,14 ]tetradec-38-ene-17,1′-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecanone,

[0120] PP3106: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-4,16,19,22,26,32,35-heptamethyl-30-[(1S)-1-methylpropyl]-27-propyl-2-(p-tolylmethyl)-23-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10,14 ]tetradec-38-ene-17,1′-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecanone,

[0121] PP3110: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-4,16,19,22,26,35-hexamethyl-30-[(1S)-1-methylpropyl]-23-(piperidine-1-carbonyl)-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 ]tetradec-38-ene-17,1′-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecanone,

[0122] PP3111: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-4,16,19,22,26,35-hexamethyl-30-[(1S)-1-methylpropyl]-23-(piperidine-1-carbonyl)-27-propyl-2-(p-tolylmethyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10,14 ]tetradec-38-ene-17,1′-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecanone,

[0123] PP3112: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-4,16,19,22,26,35-hexamethyl-30-[(1S)-1-methylpropyl]-27-propyl-23-(pyrrolidine-1-carbonyl)-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10,14 ]tetradec-38-ene-17,1′-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecanone,

[0124] PP3113: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-4,16,19,22,26,35-hexamethyl-30-[(1S)-1-methylpropyl]-27-propyl-2-(p-tolylmethyl)-23-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10,14 ]tetradec-38-ene-17,1′-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecanone,

[0125] PP3114: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-32-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-28-ethoxy-2,14,18,21,24,36-hexamethyl-10-[(1S)-1-methylpropyl]-17-(piperidine-1-carbonyl)-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 ]pentatetradec-42-ene-23,1′-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecanone,

[0126] PP3115: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-32-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-28-ethoxy-2,14,18,21,24,36-hexamethyl-10-[(1S)-1-methylpropyl]-17-(piperidine-1-carbonyl)-13-propyl-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 ]pentadec-42-ene-23,1′-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecanone,

[0127] PP3116: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-32-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-28-ethoxy-2,14,18,21,24,36-hexamethyl-10-[(1S)-1-methylpropyl]-13-propyl-17-(pyrrolidine-1-carbonyl)-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 ]pentatetradec-42-ene-23,1′-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecanone,

[0128] PP3117: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-32-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-28-ethoxy-2,14,18,21,24,36-hexamethyl-10-[(1S)-1-methylpropyl]-13-propyl-38-(p-tolylmethyl)-17-(pyrrolidine-1-carbonyl)spiro[2,8,11,14,18,21,24,30,33,36,39-undecaazatetracyclo[37.5.1.0 4,8 .0 26,30 ]pentacontan-42-ene-23,1′-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecanone,

[0129] PP3118: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-4,16,19,22,26,32,35-heptamethyl-30-[(1S)-1-methylpropyl]-23-(piperidine-1-carbonyl)-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 ]tetradec-38-ene-17,1′-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecanone,

[0130] PP3119: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-4,16,19,22,26,32,35-heptamethyl-30-[(1S)-1-methylpropyl]-23-(piperidine-1-carbonyl)-27-propyl-2-(p-tolylmethyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10,14 ]tetradec-38-ene-17,1′-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecanone,

[0131] PP3120: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-4,16,19,22,26,32,35-heptamethyl-30-[(1S)-1-methylpropyl]-27-propyl-23-(pyrrolidine-1-carbonyl)-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10,14 ]tetradec-38-ene-17,1′-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecanone,

[0132] PP3121: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-4,16,19,22,26,32,35-heptamethyl-30-[(1S)-1-methylpropyl]-27-propyl-2-(p-tolylmethyl)-23-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10,14 ]tetradec-38-ene-17,1′-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecanone,

[0133] (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47Z)-19-cyclopentyl-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-N-ethyl-N,3,18,21,25,31,34-heptamethyl-29-[(1S)-1-methylpropyl]-2,5,8,14,17,20,24,27,30,33,55-undecaoxo-spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24,15,11,25,31,34,41-undecaazapentacyclo] 43,46 .1 35,41 .0 9,13 ]pentacarbonyl-37,43(54),44,46(53),47-pentaene-16,1′-cyclobutane]-22-carboxamide,

[0134] (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47Z)-19-cyclopentyl-11-ethoxy-N-ethyl-7-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,3,3′,3′,18,21,25,31,34-nonamethyl-29-[(1S)-1-methylpropyl]-2,5,8,14,17,20,24,27,30,33,55-undecaoxo-spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24,15,11,2 43,46 .1 35,41 .0 9,13 ]pentacarbonyl-37,43(54),44,46(53),47-pentaene-16,1′-cyclobutane]-22-carboxamide,

[0135] (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47Z)-19-cyclopentyl-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-3,3′,3′,18,21,25,31,34-octamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24,15,10,25,31,34]- 43,46 .1 35,41 .0 9,13 ]pentacontan-37,43(53),44,46(52),47-pentacontan-16,1′-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecanone,

[0136] (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47Z)-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-19-(1-ethylpropyl)-3,3′,3′,18,21,25,31,34-octamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24,15,10,25]] 43,46 .1 35,41 .0 9,13 ]pentacontan-37,43(53),44,46(52),47-pentacontan-16,1′-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecanone,

[0137] (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47Z)-19-cyclopentyl-31-cyclopropyl-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-3,3′,3′,18,21,25,34-heptamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24,15,10,25,34]- 43,46 .1 35,41 .0 9，13 ]pentacontan-37,43(53),44,46(52),47-pentacontan-16,1′-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecanone,

[0138] (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47Z)-31-cyclopropyl-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-19-(1-ethylpropyl)-3,18,21,25,34-pentamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24,15,10,25,34]- 43,46 .1 35,41 .0 9,13 ]pentacontan-37,43(53),44,46(52),47-pentacontan-16,1′-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecanone, and

[0139] (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47Z)-7-[2-(3,4-dichlorophenyl)ethyl]-11-ethoxy-19-(1-ethylpropyl)-3,18,21,25,31,34-hexamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24,15,11,2 43,46 .1 35 ,41 .0 9,13 ]pentacarbonyl-37,43(54),44,46(53),47-pentaene-16,1′-cyclobutane]-2,5,8,14,17,20,24,27,30,33,55-undecanone.

[0140] [2] The cyclic compound according to [1], or a salt thereof, or a solvate thereof, wherein

[0141] The formula (1) is represented by the formula (2):

[0142]

[0143] in

[0144]

[0145] n, m, P1, R2, R3, P3, P4, P6, R7, R8, P8, R9, P9, Q9, R 10 、P 10 、R 11 and P11 Same as the definition in [1],

[0146] The cyclic compound represented by formula (2) is selected from the group consisting of:

[0147] PP1827: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47E)-19-cyclopentyl-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-N-ethyl-N,3,18,21,25,31,34-heptamethyl-29-[(1S)-1-methylpropyl]-2,5,8,14,17,20,24,27,30,33,55-undecaoxo-spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24.15.11.2 43,46 .1 35,41 .0 9,13 ]pentacarbonyl-37,43(54),44,46(53),47-pentaene-16,1′-cyclobutane]-22-carboxamide,

[0148] PP1830: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47E)-19-cyclopentyl-11-ethoxy-N-ethyl-7-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,3,3′,3′,18,21,25,31,34-nonamethyl-29-[(1S)-1-methylpropyl]-2,5,8,14,17,20,24,27,30,33,55-undecaoxo-spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24.15.11.2 43,46 .1 35,41 .0 9,13 ]pentacarbonyl-37,43(54),44,46(53),47-pentaene-16,1′-cyclobutane]-22-carboxamide,

[0149] PP2260: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z)-19-cyclopentyl-11-ethoxy-N-ethyl-7-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,3,3′,3′,18,21,25,31,34-nonamethyl-29-[(1S)-1-methylpropyl]-2,5,8,14,17,20,24,27,30,33,55-undecaoxo-spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24.15.11.2 43,46 .1 35,41 .0 9,13 ]pentadecane-37,43(54),44,46(53)-tetraene-16,1′-cyclobutane]-22-carboxamide,

[0150] PP2574: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47E)-19-cyclopentyl-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-3,3′,3′,18,21,25,31,34-octamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24.15.10.2 43,46 .1 35,41 .0 9，13 ]pentacontan-37,43(53),44,46(52),47-pentacontan-16,1′-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecanone,

[0151] PP2576: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47E)-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-19-(1-ethylpropyl)-3,3′,3′,18,21,25,31,34-octamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24.15.10.2 43,46 .1 35,41 .0 9,13]pentacontan-37,43(53),44,46(52),47-pentacontan-16,1′-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecanone,

[0152] PP2583: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47E)-19-cyclopentyl-31-cyclopropyl-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-3,3′,3′,18,21,25,34-heptamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24.15.10.2 43,46 .1 35,41 .0 9,13 ]pentacontan-37,43(53),44,46(52),47-pentacontan-16,1′-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecanone,

[0153] PP2957: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47E)-31-cyclopropyl-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-19-(1-ethylpropyl)-3,18,21,25,34-pentamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24.15.10.2 43,46 .1 35,41 .0 9,13 ]pentacontan-37,43(53),44,46(52),47-pentacontan-16,1′-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecanone,

[0154] PP3033: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z)-19-cyclopentyl-11-ethoxy-7-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-3,18,21,25,31,34-hexamethyl-29-[(1S)-1-methylpropyl]-22-(piperidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24.15.11.2 43,46.1 35,41 .0 9,13 ]pentacarbonyl-37,43(54),44,46(53)-tetraene-16,1′-cyclobutane]-2,5,8,14,17,20,24,27,30,33,55-undecanone,

[0155] PP3034: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z)-19-cyclopentyl-11-ethoxy-7-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-3,3′,3′,18,21,25,31,34-octamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24.15.11.2 43,46 .1 35,41 .0 9,13 ]pentacarbonyl-37,43(54),44,46(53)-tetraene-16,1′-cyclobutane]-2,5,8,14,17,20,24,27,30,33,55-undecanone,

[0156] PP3036: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z)-19-cyclopentyl-11-ethoxy-7-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-3,3′,3′,18,21,25,31,34-octamethyl-29-[(1S)-1-methylpropyl]-22-(piperidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24.15.10.2 43,46 .1 35,41 .0 9,13 ]54-tetradecanoic acid-37,43(53),44,46(52)-tetraene-16,1′-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecanone,

[0157] PP3037: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z)-19-cyclopentyl-11-ethoxy-7-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-3,3′,3′,18,21,25,31,34-octamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24.15.10.243,46 .1 35,41 .0 9,13 ]54-tetradecanoic acid-37,43(53),44,46(52)-tetraene-16,1′-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecanone,

[0158] PP3047: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47E)-7-[2-(3,4-dichlorophenyl)ethyl]-11-ethoxy-19-(1-ethylpropyl)-3,18,21,25,31,34-hexamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24.15.11.2 43,46 .1 35,41 .0 9,13 ]pentacarbonyl-37,43(54),44,46(53),47-pentaene-16,1′-cyclobutane]-2,5,8,14,17,20,24,27,30,33,55-undecanone,

[0159] PP3093: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z)-19-cyclopentyl-11-ethoxy-7-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-3,3′,3′,18,21,25,31,34-octamethyl-29-[(1S)-1-methylpropyl]-22-(piperidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24.15.9.2 43,46 .1 35,41 .0 9,13 ]53 carbon-37,43 (52),44,46 (51) -tetraene-16,1'-cyclobutane] -2,5,8,14,17,20,24,27,30,33,53-undecanone,

[0160] PP3094: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z)-19-cyclopentyl-7-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-3,3′,3′,18,21,25,31,34-octamethyl-29-[(1S)-1-methylpropyl]-11-propoxy-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24,15,9,2 43,46 .1 35,41 .0 9,13 ]53 carbon-37,43(52),44,46(51)-tetraene-16,1′-cyclobutane]-2,5,8,14,17,20,24,27,30,33,53-undecanone,

[0161] (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47Z)-19-cyclopentyl-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-N-ethyl-N,3,18,21,25,31,34-heptamethyl-29-[(1S)-1-methylpropyl]-2,5,8,14,17,20,24,27,30,33,55-undecaoxo-spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24,15,11,25] 43,46 .1 35,41 .0 9,13 ]pentacarbonyl-37,43(54),44,46(53),47-pentaene-16,1′-cyclobutane]-22-carboxamide,

[0162] (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47Z)-19-cyclopentyl-11-ethoxy-N-ethyl-7-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,3,3′,3′,18,21,25,31,34-nonamethyl-29-[(1S)-1-methylpropyl]-2,5,8,14,17,20,24,27,30,33,55-undecaoxo-spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24,15,11,2 43,46 .1 35,41 .0 9,13 ]pentacarbonyl-37,43(54),44,46(53),47-pentaene-16,1′-cyclobutane]-22-carboxamide,

[0163] (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47Z)-19-cyclopentyl-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-3,3′,3′,18,21,25,31,34-octamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24,15,10,25,31,34]- 43,46 .1 35,41 .0 9,13 ]pentacontan-37,43(53),44,46(52),47-pentacontan-16,1′-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecanone,

[0164] (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47Z)-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-19-(1-ethylpropyl)-3,3′,3′,18,21,25,31,34-octamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24,15,10,25]] 43,46 .1 35,41 .0 9,13 ]pentacontan-37,43(53),44,46(52),47-pentaene-16,1′-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecanone,

[0165] (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47Z)-19-cyclopentyl-31-cyclopropyl-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-3,3′,3′,18,21,25,34-heptamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24,15,10,25] 43,46 .1 35,41 .0 9，13]pentacontan-37,43(53),44,46(52),47-pentaene-16,1′-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecanone,

[0166] (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47Z)-31-cyclopropyl-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-19-(1-ethylpropyl)-3,18,21,25,34-pentamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24,15,10,25] 43,46 .1 35,41 .0 9,13 ]pentacontan-37,43(53),44,46(52),47-pentacontan-16,1′-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecanone, and

[0167] (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47Z)-7-[2-(3,4-dichlorophenyl)ethyl]-11-ethoxy-19-(1-ethylpropyl)-3,18,21,25,31,34-hexamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24,15,11,25,31,34-hexamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24,15,11,25,31,34-hexamethyl-29-[(1S)-1-methylpropyl] 43,46 .1 35 ,41 .0 9,13 ]pentacarbonyl-37,43(54),44,46(53),47-pentaene-16,1′-cyclobutane]-2,5,8,14,17,20,24,27,30,33,55-undecanone.

[0168] [3] The cyclic compound according to [1], or a salt thereof, or a solvate thereof, wherein

[0169] Formula (1) is represented by formula (3):

[0170]

[0171] in,

[0172] R1 is C1 to C7 alkyl;

[0173] R5 is benzyl optionally substituted with one or more groups selected from the group consisting of C1 to C6 alkyl, C1 to C6 haloalkyl, and C3 to C8 cycloalkyl;

[0174]

[0175] n, m, P1, R2, R3, P3, P4, P6, R7, R8, P8, R9, P9, Q9, R 10 、P 10 、R 11 and P 11 Same as the definition in [1], where

[0176] The cyclic compound represented by formula (3) is selected from the group consisting of:

[0177] PP1574: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-N-ethyl-27-isobutyl-N,4,19,22,26,32,35-heptamethyl-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 ]tetradec-38-ene-17,1′-cyclopentane]-23-carboxamide,

[0178] PP1650: (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,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 ]tetradec-38-ene-17,1′-cyclobutane]-23-carboxamide,

[0179] PP2093: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-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-(p-tolylmethyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10,14 ]tetradec-38-ene-17,1′-cyclobutane]-23-carboxamide,

[0180] PP2316: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,N,4,16,19,22,26,35-octamethyl-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 ]tetradec-38-ene-17,1′-cyclobutane]-23-carboxamide,

[0181] 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 ]pentadec-42-ene-23,1′-cyclobutane]-17-carboxamide,

[0182] PP2328: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,N,4,16,19,22,26,35-octamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaoxo-27-propyl-2-(p-tolylmethyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10,14 ]tetradec-38-ene-17,1′-cyclobutane]-23-carboxamide,

[0183] PP2687: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-12-ethoxy-2-[(4-ethylphenyl)methyl]-27-isobutyl-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-spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10,14 ]tetradec-38-ene-17,1′-cyclobutane]-23-carboxamide,

[0184] PP2691: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-2-[(4-cyclopropylphenyl)methyl]-12-ethoxy-27-isobutyl-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-spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10,14 ]tetradec-38-ene-17,1′-cyclobutane]-23-carboxamide,

[0185] PP3095: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-4,16,19,22,26,35-hexamethyl-30-[(1S)-1-methylpropyl]-23-(piperidine-1-carbonyl)-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 ]tetradec-38-ene-17,1′-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecanone,

[0186] PP3096: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-4,16,19,22,26,35-hexamethyl-30-[(1S)-1-methylpropyl]-23-(piperidine-1-carbonyl)-27-propyl-2-(p-tolylmethyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10,14 ]tetradec-38-ene-17,1′-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecanone,

[0187] PP3097: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-4,16,19,22,26,35-hexamethyl-30-[(1S)-1-methylpropyl]-27-propyl-23-(pyrrolidine-1-carbonyl)-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10,14 ]tetradec-38-ene-17,1′-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecanone,

[0188] PP3098: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-4,16,19,22,26,35-hexamethyl-30-[(1S)-1-methylpropyl]-27-propyl-2-(p-tolylmethyl)-23-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10,14 ]tetradec-38-ene-17,1′-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecanone,

[0189] PP3099: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-28-ethoxy-32-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-2,14,18,21,24,36-hexamethyl-10-[(1S)-1-methylpropyl]-17-(piperidine-1-carbonyl)-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 ]pentatetradec-42-ene-23,1′-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecanone,

[0190] PP3100: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-28-ethoxy-32-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-2,14,18,21,24,36-hexamethyl-10-[(1S)-1-methylpropyl]-17-(piperidine-1-carbonyl)-13-propyl-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 ]pentatetradec-42-ene-23,1′-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecanone,

[0191] PP3101: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-28-ethoxy-32-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-2,14,18,21,24,36-hexamethyl-10-[(1S)-1-methylpropyl]-13-propyl-17-(pyrrolidine-1-carbonyl)-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 ]pentatetradec-42-ene-23,1′-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecanone,

[0192] PP3102: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-28-ethoxy-32-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-2,14,18,21,24,36-hexamethyl-10-[(1S)-1-methylpropyl]-13-propyl-38-(p-tolylmethyl)-17-(pyrrolidine-1-carbonyl)spiro[2,8,11,14,18,21,24,30,33,36,39-undecaazatetracyclo[37.5.1.0 4,8 .0 26,30 ]pentatetradec-42-ene-23,1′-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecanone,

[0193] PP3103: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-4,16,19,22,26,32,35-heptamethyl-30-[(1S)-1-methylpropyl]-23-(piperidine-1-carbonyl)-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 ]tetradec-38-ene-17,1′-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecanone,

[0194] PP3104: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-4,16,19,22,26,32,35-heptamethyl-30-[(1S)-1-methylpropyl]-23-(piperidine-1-carbonyl)-27-propyl-2-(p-tolylmethyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10,14 ]tetradec-38-ene-17,1′-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecanone,

[0195] PP3105: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-4,16,19,22,26,32,35-heptamethyl-30-[(1S)-1-methylpropyl]-27-propyl-23-(pyrrolidine-1-carbonyl)-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10,14 ]tetradec-38-ene-17,1′-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecanone,

[0196] PP3106: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-4,16,19,22,26,32,35-heptamethyl-30-[(1S)-1-methylpropyl]-27-propyl-2-(p-tolylmethyl)-23-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10,14 ]tetradec-38-ene-17,1′-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecanone,

[0197] PP3110: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-4,16,19,22,26,35-hexamethyl-30-[(1S)-1-methylpropyl]-23-(piperidine-1-carbonyl)-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 ]tetradec-38-ene-17,1′-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecanone,

[0198] PP3111: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-4,16,19,22,26,35-hexamethyl-30-[(1S)-1-methylpropyl]-23-(piperidine-1-carbonyl)-27-propyl-2-(p-tolylmethyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10，14 ]tetradec-38-ene-17,1′-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecanone,

[0199] PP3112: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-4,16,19,22,26,35-hexamethyl-30-[(1S)-1-methylpropyl]-27-propyl-23-(pyrrolidine-1-carbonyl)-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10,14 ]tetradec-38-ene-17,1′-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecanone,

[0200] PP3113: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-4,16,19,22,26,35-hexamethyl-30-[(1S)-1-methylpropyl]-27-propyl-2-(p-tolylmethyl)-23-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10,14 ]tetradec-38-ene-17,1′-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecanone,

[0201] PP3114: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-32-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-28-ethoxy-2,14,18,21,24,36-hexamethyl-10-[(1S)-1-methylpropyl]-17-(piperidine-1-carbonyl)-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 ]pentadec-42-ene-23,1′-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecanone,

[0202] PP3115: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-32-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-28-ethoxy-2,14,18,21,24,36-hexamethyl-10-[(1S)-1-methylpropyl]-17-(piperidine-1-carbonyl)-13-propyl-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 ]pentatetradec-42-ene-23,1′-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecanone,

[0203] PP3116: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-32-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-28-ethoxy-2,14,18,21,24,36-hexamethyl-10-[(1S)-1-methylpropyl]-13-propyl-17-(pyrrolidine-1-carbonyl)-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 ]pentadec-42-ene-23,1′-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecanone,

[0204] PP3117: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-32-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-28-ethoxy-2,14,18,21,24,36-hexamethyl-10-[(1S)-1-methylpropyl]-13-propyl-38-(p-tolylmethyl)-17-(pyrrolidine-1-carbonyl)spiro[2,8,11,14,18,21,24,30,33,36,39-undecaazatetracyclo[37.5.1.0 4,8 .0 26,30 ]pentadec-42-ene-23,1′-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecanone,

[0205] PP3118: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-4,16,19,22,26,32,35-heptamethyl-30-[(1S)-1-methylpropyl]-23-(piperidine-1-carbonyl)-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 ]tetradec-38-ene-17,1′-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecanone,

[0206] PP3119: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-4,16,19,22,26,32,35-heptamethyl-30-[(1S)-1-methylpropyl]-23-(piperidine-1-carbonyl)-27-propyl-2-(p-tolylmethyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10,14 ]tetradec-38-ene-17,1′-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecanone,

[0207] PP3120: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-4,16,19,22,26,32,35-heptamethyl-30-[(1S)-1-methylpropyl]-27-propyl-23-(pyrrolidine-1-carbonyl)-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10,14 ]tetradodec-38-ene-17,1′-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecanone, and

[0208] PP3121: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-4,16,19,22,26,32,35-heptamethyl-30-[(1S)-1-methylpropyl]-27-propyl-2-(p-tolylmethyl)-23-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10,14 ]tetradodec-38-ene-17,1′-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecanone.

[0209] [4-1] A cyclic compound, which is PP1574: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-N-ethyl-27-isobutyl-N,4,19,22,26,32,35-heptamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecacyclo-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34,5.1.0] 10,14 ]tetradodec-38-ene-17,1′-cyclopentane]-23-carboxamide, or a salt thereof, or a solvate thereof.

[0210] [4-2] A cyclic compound, which is PP1650: (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,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 ]tetradodec-38-ene-17,1′-cyclobutane]-23-carboxamide, or a salt thereof, or a solvate thereof.

[0211] [4-3] A cyclic compound, which is PP1827: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47E)-19-cyclopentyl-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-N-ethyl-N,3,18,21,25,31,34-heptamethyl-29-[(1S)-1-methylpropyl]-2,5,8,14,17,20,24,27,30,33,55-undecaoxo-spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24,15,11,25,31,34-heptamethyl-29-[(1S)-1-methylpropyl]- 43,46 .1 35,41 .0 9,13]pentacarbonyl-37,43(54),44,46(53),47-pentaene-16,1′-cyclobutane]-22-carboxamide, or a salt thereof, or a solvate thereof.

[0212] [4-4] A cyclic compound, which is PP1830: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47E)-19-cyclopentyl-11-ethoxy-N-ethyl-7-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,3,3′,3′,18,21,25,31,34-nonamethyl-29-[(1S)-1-methylpropyl]-2,5,8,14,17,20,24,27,30,33,55-undecaoxo-spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[2,5,11,2 43, 46 .1 35,41 .0 9,13 ]pentacarbonyl-37,43(54),44,46(53),47-pentaene-16,1′-cyclobutane]-22-carboxamide, or a salt thereof, or a solvate thereof.

[0213] [4-5] A cyclic compound, which is PP2093: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-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-(p-tolylmethyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34,5.1.0 10,14 ]tetradodec-38-ene-17,1′-cyclobutane]-23-carboxamide, or a salt thereof, or a solvate thereof.

[0214] [4-6] A cyclic compound, which is PP2260: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z)-19-cyclopentyl-11-ethoxy-N-ethyl-7-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,3,3′,3′,18,21,25,31,34-nonamethyl-29-[(1S)-1-methylpropyl]-2,5,8,14,17,20,24,27,30,33,55-undecaoxo-spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24,15,11,25,31,34,41-undecaazapentacyclo[24,15,11,25,31,34,41-undecaazapentacyclo[24,15,11,25,31,34,41-undecaazapentacyclo[24,15,11,2 43,46 .1 35,41 .0 9 ,13 ]pentacarbonyl-37,43(54),44,46(53)-tetraene-16,1′-cyclobutane]-22-carboxamide, or a salt thereof, or a solvate thereof.

[0215] [4-7] A cyclic compound, which is PP2316: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,N,4,16,19,22,26,35-octamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecacyclo-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 ]tetradodec-38-ene-17,1′-cyclobutane]-23-carboxamide, or a salt thereof, or a solvate thereof.

[0216] [4-8] A cyclic compound, which is 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 .026,30 ]pentatetradec-42-ene-23,1′-cyclobutane]-17-carboxamide, or a salt thereof, or a solvate thereof.

[0217] [4-9] A cyclic compound, which is PP2328: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,N,4,16,19,22,26,35-octamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaoxo-27-propyl-2-(p-tolylmethyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[345.1.0 10,14 ]tetradodec-38-ene-17,1′-cyclobutane]-23-carboxamide, or a salt thereof, or a solvate thereof.

[0218] [4-10] A cyclic compound, which is PP2574: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47E)-19-cyclopentyl-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-3,3′,3′,18,21,25,31,34-octamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24,15,10,25,31,34,35,36,37,38,39,40-octamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24,15,10,25,31,34,35,36,38,39,40-octamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,35,36,39,40-octamethyl-29-[(1S)-1-methylpropyl] 43,46 .1 35,41 .0 9,13 ]pentacontan-37,43(53),44,46(52),47-pentaene-16,1′-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecanone, or a salt thereof, or a solvate thereof.

[0219] [4-11] A cyclic compound, which is PP2576: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47E)-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-19-(1-ethylpropyl)-3,3′,3′,18,21,25,31,34-octamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24,15,10,25,31,34] ... 43,46 .1 35,41 .0 9.13 ]pentacontan-37,43(53),44,46(52),47-pentaene-16,1′-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecanone, or a salt thereof, or a solvate thereof.

[0220] [4-12] A cyclic compound, which is PP2583: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47E)-19-cyclopentyl-31-cyclopropyl-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-3,3′,3′,18,21,25,34-heptamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24,15,10,25,34]- 43,46 .1 35,41 .0 9,13 ]pentacontan-37,43(53),44,46(52),47-pentaene-16,1′-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecanone, or a salt thereof, or a solvate thereof.

[0221] [4-13] A cyclic compound, which is PP2687: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-12-ethoxy-2-[(4-ethylphenyl)methyl]-27-isobutyl-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-spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[345.1.0 10,14 ]tetradodec-38-ene-17,1′-cyclobutane]-23-carboxamide, or a salt thereof, or a solvate thereof.

[0222] [4-14] A cyclic compound, which is PP2691: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-2-[(4-cyclopropylphenyl)methyl]-12-ethoxy-27-isobutyl-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-spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10,14 ]tetradodec-38-ene-17,1′-cyclobutane]-23-carboxamide, or a salt thereof, or a solvate thereof.

[0223] [4-15] A cyclic compound, which is PP2957: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47E)-31-cyclopropyl-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-19-(1-ethylpropyl)-3,18,21,25,34-pentamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24,15,10,25,34]-pentamethyl] ... 43,46 .1 35,41 .0 9,13]pentacontan-37,43(53),44,46(52),47-pentaene-16,1′-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecanone, or a salt thereof, or a solvate thereof.

[0224] [4-16] A cyclic compound, which is PP3033: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z)-19-cyclopentyl-11-ethoxy-7-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-3,18,21,25,31,34-hexamethyl-29-[(1S)-1-methylpropyl]-22-(piperidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24,15,1 ... 43,46 .1 35,41 .0 9,13 ]pentacarbonyl-37,43(54),44,46(53)-tetraene-16,1′-cyclobutane]-2,5,8,14,17,20,24,27,30,33,55-undecanone, or a salt thereof, or a solvate thereof.

[0225] [4-17] A cyclic compound, which is PP3034: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z)-19-cyclopentyl-11-ethoxy-7-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-3,3′,3′,18,21,25,31,34-octamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24,15,11,25,31,34,41-undecazapentacyclo[24,15,11,25,31,34,41-undecazapentacyclo[24,15,11,25,31,34,41-undecazapentacyclo[24,15,11,2 43,46 .1 35,41 .0 9，13 ]pentacarbonyl-37,43(54),44,46(53)-tetraene-16,1′-cyclobutane]-2,5,8,14,17,20,24,27,30,33,55-undecanone, or a salt thereof, or a solvate thereof.

[0226] [4-18] A cyclic compound, which is PP3036: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z)-19-cyclopentyl-11-ethoxy-7-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-3,3′,3′,18,21,25,31,34-octamethyl-29-[(1S)-1-methylpropyl]-22-(piperidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24,15,10,25,31,34,41-undecazapentacyclo[24,15,10,25,31,34,41-undecazapentacyclo[24,15,10,25,31,34,41-undecazapentacyclo[24,15,10,25,31,34,41-octamethyl-29-[(1S)-1-methylpropyl]-22-(piperidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24,15,10,2 43,46 .1 35,41 .0 9,13 ]Fifty-tetracarbon-37,43(53),44,46(52)-tetraene-16,1′-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecanone, or a salt thereof, or a solvate thereof.

[0227] [4-19] A cyclic compound, which is PP3037: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z)-19-cyclopentyl-11-ethoxy-7-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-3,3′,3′,18,21,25,31,34-octamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24,15,10,25,31,34,35]-1 ...35]-1-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,35]-1-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,35]-1-[(1S)-1-methylpropyl]-22-(py 43,46 .1 35，41 .0 9,13 ]Fifty-tetracarbon-37,43(53),44,46(52)-tetraene-16,1′-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecanone, or a salt thereof, or a solvate thereof.

[0228] [4-20] A cyclic compound, which is PP3047: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47E)-7-[2-(3,4-dichlorophenyl)ethyl]-11-ethoxy-19-(1-ethylpropyl)-3,18,21,25,31,34-hexamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24,15,1 ... 43,46 .1 35,41 .0 9,13]pentacarbonyl-37,43(54),44,46(53),47-pentaene-16,1′-cyclobutane]-2,5,8,14,17,20,24,27,30,33,55-undecanone, or a salt thereof, or a solvate thereof.

[0229] [4-21] A cyclic compound, which is PP3093: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z)-19-cyclopentyl-11-ethoxy-7-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-3,3′,3′,18,21,25,31,34-octamethyl-29-[(1S)-1-methylpropyl]-22-(piperidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24,15,9,25,31,34,41-undecazapentacyclo[24,15,9,25,31,34,41-undecazapentacyclo[24,15,9,25,31,34,41-octamethyl-29-[(1S)-1-methylpropyl]-22-(piperidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24,15,9,25,31,34,41-undecazapentacyclo[24,15,9,2 43,46 .1 35,41 .0 9,13 ]Fifty-three carbon-37,43(52),44,46(51)-tetraene-16,1′-cyclobutane]-2,5,8,14,17,20,24,27,30,33,53-undecanone, or a salt thereof, or a solvate thereof.

[0230] [4-22] A cyclic compound, which is PP3094: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z)-19-cyclopentyl-7-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-3,3′,3′,18,21,25,31,34-octamethyl-29-[(1S)-1-methylpropyl]-11-propoxy-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24,15,9,25,31,34,18,21 ... 43,46 .1 35,41 .0 9,13 ]Fifty-three carbon-37,43(52),44,46(51)-tetraene-16,1′-cyclobutane]-2,5,8,14,17,20,24,27,30,33,53-undecanone, or a salt thereof, or a solvate thereof.

[0231] [4-23] A cyclic compound, which is PP3095: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-4,16,19,22,26,35-hexamethyl-30-[(1S)-1-methylpropyl]-23-(piperidine-1-carbonyl)-27-propyl-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[345.1.0] 10,14 ]tetradodec-38-ene-17,1′-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecanone, or a salt thereof, or a solvate thereof.

[0232] [4-24] A cyclic compound, which is PP3096: (2S, 8S, 12R, 14S, 20S, 23S, 27S, 30S, 36S, 38Z)-20-cyclopentyl-32-cyclopropyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-4,16,19,22,26,35-hexamethyl-30-[(1S)-1-methylpropyl]-23-(piperidine-1-carbonyl)-27-propyl-2-(p-tolylmethyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[345.1.0] 10,14 ]tetradodec-38-ene-17,1′-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecanone, or a salt thereof, or a solvate thereof.

[0233] [4-25] A cyclic compound, which is PP3097: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-4,16,19,22,26,35-hexamethyl-30-[(1S)-1-methylpropyl]-27-propyl-23-(pyrrolidine-1-carbonyl)-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[345.1.0] 10 ,14]tetradodec-38-ene-17,1′-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecanone, or a salt thereof, or a solvate thereof.

[0234] [4-26] A cyclic compound, which is PP3098: (2S, 8S, 12R, 14S, 20S, 23S, 27S, 30S, 36S, 38Z)-20-cyclopentyl-32-cyclopropyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-4,16,19,22,26,35-hexamethyl-30-[(1S)-1-methylpropyl]-27-propyl-2-(p-tolylmethyl)-23-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[345.1.0] 10,14 ]tetradodec-38-ene-17,1′-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecanone, or a salt thereof, or a solvate thereof.

[0235] [4-27] A cyclic compound, which is PP3099: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-28-ethoxy-32-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-2,14,18,21,24,36-hexamethyl-10-[(1S)-1-methylpropyl]-17-(piperidine-1-carbonyl)-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 ]pentatetradec-42-ene-23,1′-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecanone, or a salt thereof, or a solvate thereof.

[0236] [4-28] A cyclic compound, which is PP3100: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-28-ethoxy-32-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-2,14,18,21,24,36-hexamethyl-10-[(1S)-1-methylpropyl]-17-(piperidine-1-carbonyl)-13-propyl-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 ]pentatetradec-42-ene-23,1′-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecanone, or a salt thereof, or a solvate thereof.

[0237] [4-29] A cyclic compound, which is PP3101: (1S, 4S, 10S, 13S, 17S, 20S, 26S, 28R, 32S, 38S, 42Z)-20-cyclopentyl-28-ethoxy-32-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-2,14,18,21,24,36-hexamethyl-10-[(1S)-1-methylpropyl]-13-propyl-17-(pyrrolidine-1-carbonyl)-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 ]pentatetradec-42-ene-23,1′-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecanone, or a salt thereof, or a solvate thereof.

[0238] [4-30] A cyclic compound, which is PP3102: (1S, 4S, 10S, 13S, 17S, 20S, 26S, 28R, 32S, 38S, 42Z)-20-cyclopentyl-28-ethoxy-32-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-2,14,18,21,24,36-hexamethyl-10-[(1S)-1-methylpropyl]-13-propyl-38-(p-tolylmethyl)-17-(pyrrolidine-1-carbonyl)spiro[2,8,11,14,18,21,24,30,33,36,39-undecaazatetracyclo[37.5.1.0 4,8 .0 26,30]pentatetradec-42-ene-23,1′-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecanone, or a salt thereof, or a solvate thereof.

[0239] [4-31] A cyclic compound, which is PP3103: (2S, 8S, 12R, 14S, 20S, 23S, 27S, 30S, 36S, 38Z)-20-cyclopentyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-4,16,19,22,26,32,35-heptamethyl-30-[(1S)-1-methylpropyl]-23-(piperidine-1-carbonyl)-27-propyl-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[345.1.0] 10,14 ]tetradodec-38-ene-17,1′-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecanone, or a salt thereof, or a solvate thereof.

[0240] [4-32] A cyclic compound, which is PP3104: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-4,16,19,22,26,32,35-heptamethyl-30-[(1S)-1-methylpropyl]-23-(piperidine-1-carbonyl)-27-propyl-2-(p-tolylmethyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[345.1.0] 10,14 ]tetradodec-38-ene-17,1′-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecanone, or a salt thereof, or a solvate thereof.

[0241] [4-33] A cyclic compound, which is PP3105: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-4,16,19,22,26,32,35-heptamethyl-30-[(1S)-1-methylpropyl]-27-propyl-23-(pyrrolidine-1-carbonyl)-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[345.1.0]10,14 ]tetradodec-38-ene-17,1′-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecanone, or a salt thereof, or a solvate thereof.

[0242] [4-34] A cyclic compound, which is PP3106: (2S, 8S, 12R, 14S, 20S, 23S, 27S, 30S, 36S, 38Z)-20-cyclopentyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-4,16,19,22,26,32,35-heptamethyl-30-[(1S)-1-methylpropyl]-27-propyl-2-(p-tolylmethyl)-23-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[345.1.0] 10,14 ]tetradodec-38-ene-17,1′-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecanone, or a salt thereof, or a solvate thereof.

[0243] [4-35] A cyclic compound, which is PP3110: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-4,16,19,22,26,35-hexamethyl-30-[(1S)-1-methylpropyl]-23-(piperidine-1-carbonyl)-27-propyl-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[345.1.0] 10,14 ]tetradodec-38-ene-17,1′-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecanone, or a salt thereof, or a solvate thereof.

[0244] [4-36] A cyclic compound, which is PP3111: (2S, 8S, 12R, 14S, 20S, 23S, 27S, 30S, 36S, 38Z)-20-cyclopentyl-32-cyclopropyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-4,16,19,22,26,35-hexamethyl-30-[(1S)-1-methylpropyl]-23-(piperidine-1-carbonyl)-27-propyl-2-(p-tolylmethyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[345.1.0] 10,14 ]tetradodec-38-ene-17,1′-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecanone, or a salt thereof, or a solvate thereof.

[0245] [4-37] A cyclic compound, which is PP3112: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-4,16,19,22,26,35-hexamethyl-30-[(1S)-1-methylpropyl]-27-propyl-23-(pyrrolidine-1-carbonyl)-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[345.1.0] 10 ,14 ]tetradodec-38-ene-17,1′-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecanone, or a salt thereof, or a solvate thereof.

[0246] [4-38] A cyclic compound, which is PP3113: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-4,16,19,22,26,35-hexamethyl-30-[(1S)-1-methylpropyl]-27-propyl-2-(p-tolylmethyl)-23-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[345.1.0] 10,14 ]tetradodec-38-ene-17,1′-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecanone, or a salt thereof, or a solvate thereof.

[0247] [4-39] A cyclic compound, which is PP3114: (1S, 4S, 10S, 13S, 17S, 20S, 26S, 28R, 32S, 38S, 42Z)-20-cyclopentyl-32-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-28-ethoxy-2,14,18,21,24,36-hexamethyl-10-[(1S)-1-methylpropyl]-17-(piperidine-1-carbonyl)-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 ]pentatetradec-42-ene-23,1′-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecanone, or a salt thereof, or a solvate thereof.

[0248] [4-40] A cyclic compound, which is PP3115: (1S, 4S, 10S, 13S, 17S, 20S, 26S, 28R, 32S, 38S, 42Z)-20-cyclopentyl-32-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-28-ethoxy-2,14,18,21,24,36-hexamethyl-10-[(1S)-1-methylpropyl]-17-(piperidine-1-carbonyl)-13-propyl-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 ]pentatetradec-42-ene-23,1′-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecanone, or a salt thereof, or a solvate thereof.

[0249] [4-41] A cyclic compound, which is PP3116: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-32-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-28-ethoxy-2,14,18,21,24,36-hexamethyl-10-[(1S)-1-methylpropyl]-13-propyl-17-(pyrrolidine-1-carbonyl)-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 ]pentatetradec-42-ene-23,1′-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecanone, or a salt thereof, or a solvate thereof.

[0250] [4-42] A cyclic compound, which is PP3117: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-32-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-28-ethoxy-2,14,18,21,24,36-hexamethyl-10-[(1S)-1-methylpropyl]-13-propyl-38-(p-tolylmethyl)-17-(pyrrolidine-1-carbonyl)spiro[2,8,11,14,18,21,24,30,33,36,39-undecaazatetracyclo[37.5.1.0] 4,8 .0 26,30 ]pentatetradec-42-ene-23,1′-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecanone, or a salt thereof, or a solvate thereof.

[0251] [4-43] A cyclic compound, which is PP3118: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-4,16,19,22,26,32,35-heptamethyl-30-[(1S)-1-methylpropyl]-23-(piperidine-1-carbonyl)-27-propyl-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[345.1.0] 10,14 ]tetradodec-38-ene-17,1′-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecanone, or a salt thereof, or a solvate thereof.

[0252] [4-44] A cyclic compound, which is PP3119: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-4,16,19,22,26,32,35-heptamethyl-30-[(1S)-1-methylpropyl]-23-(piperidine-1-carbonyl)-27-propyl-2-(p-tolylmethyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[345.1.0] 10,14 ]tetradodec-38-ene-17,1′-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecanone, or a salt thereof, or a solvate thereof.

[0253] [4-45] A cyclic compound, which is PP3120: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-4,16,19,22,26,32,35-heptamethyl-30-[(1S)-1-methylpropyl]-27-propyl-23-(pyrrolidine-1-carbonyl)-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[345.1.0] 10,14 ]tetradodec-38-ene-17,1′-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecanone, or a salt thereof, or a solvate thereof.

[0254] [4-46] A cyclic compound, which is PP3121: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-4,16,19,22,26,32,35-heptamethyl-30-[(1S)-1-methylpropyl]-27-propyl-2-(p-tolylmethyl)-23-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[345.1.0] 10,14 ]tetradodec-38-ene-17,1′-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecanone, or a salt thereof, or a solvate thereof.

[0255] [4-47] A cyclic compound, which is (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47Z)-19-cyclopentyl-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-N-ethyl-N,3,18,21,25,31,34-heptamethyl-29-[(1S)-1-methylpropyl]-2,5,8,14,17,20,24,27,30,33,55-undecaoxo-spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24,15,11,25,31,34-heptamethyl-29-[(1S)-1-methylpropyl]- 43,46 .1 35,41 .0 9,13 ]pentacarbonyl-37,43(54),44,46(53),47-pentaene-16,1′-cyclobutane]-22-carboxamide, or a salt thereof, or a solvate thereof.

[0256] [4-48] A cyclic compound, which is (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47Z)-19-cyclopentyl-11-ethoxy-N-ethyl-7-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,3,3′,3′,18,21,25,31,34-nonamethyl-29-[(1S)-1-methylpropyl]-2,5,8,14,17,20,24,27,30,33,55-undecaoxo-spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24,15,11,2 43,46 .1 35,41 .0 9,13 ]pentacarbonyl-37,43(54),44,46(53),47-pentaene-16,1′-cyclobutane]-22-carboxamide, or a salt thereof, or a solvate thereof.

[0257] [4-49] A cyclic compound, which is (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47Z)-19-cyclopentyl-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-3,3′,3′,18,21,25,31,34-octamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24,15,10,25,31,34,41-undecazapentacyclo] 43,46 .1 35,41 .0 9,13]pentacontan-37,43(53),44,46(52),47-pentaene-16,1′-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecanone, or a salt thereof, or a solvate thereof.

[0258] [4-50] A cyclic compound, which is (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47Z)-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-19-(1-ethylpropyl)-3,3′,3′,18,21,25,31,34-octamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24,15,10,25,31,34,35]-1-[1-methyl-2-pyrrolidine-1-carbonyl]spiro[3,6,9,15,18,21,25,28 ... 43,46 .1 35,41 .0 9,13 ]pentacontan-37,43(53),44,46(52),47-pentaene-16,1′-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecanone, or a salt thereof, or a solvate thereof.

[0259] [4-51] A cyclic compound, which is (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47Z)-19-cyclopentyl-31-cyclopropyl-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-3,3′,3′,18,21,25,34-heptamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24,15,10,25,34] 43,46 .1 35,41 .0 9,13 ]pentacontan-37,43(53),44,46(52),47-pentaene-16,1′-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecanone, or a salt thereof, or a solvate thereof.

[0260] [4-52] A cyclic compound, which is (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47Z)-31-cyclopropyl-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-19-(1-ethylpropyl)-3,18,21,25,34-pentamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24,15,10,25,34] ... 43,46 .1 35,41 .0 9,13 ]pentacontan-37,43(53),44,46(52),47-pentaene-16,1′-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecanone, or a salt thereof, or a solvate thereof.

[0261] [4-53] A cyclic compound, which is (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47Z)-7-[2-(3,4-dichlorophenyl)ethyl]-11-ethoxy-19-(1-ethylpropyl)-3,18,21,25,31,34-hexamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24,15,1 ... 43,46 .1 35，41 .0 9,13 ]pentacarbonyl-37,43(54),44,46(53),47-pentaene-16,1′-cyclobutane]-2,5,8,14,17,20,24,27,30,33,55-undecanone

[0262] [5] The cyclic compound according to any one of [1] to [4-53] or a salt thereof.

[0263] [6] The cyclic compound according to any one of [1] to [4-53] or a solvate thereof.

[0264] [7] A solvate of the cyclic compound according to any one of [1] to [4-53] or a salt thereof.

[0265] [8] The cyclic compound according to any one of [1] to [4-53].

[0266] [9] The cyclic compound according to any one of [1] to [4-53], or a salt thereof, or a solvate thereof, which binds to KRAS.

[0267]

[10] The cyclic compound according to any one of [1] to [4-53], or a salt thereof, or a solvate thereof, which inhibits KRAS.

[0268]

[11] The cyclic compound according to any one of [1] to [4-53], or a salt thereof, or a solvate thereof, which has high selectivity for KRAS.

[0269]

[12] The cyclic compound according to any one of [1] to [4-53] or a salt thereof, or a solvate thereof, having a PP higher than 1820: ((3S,9S,12S,17S,20S,23S,27S,30S,36S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]30-cyclopentyl-23-isobutyl-9-(isopentyloxymethyl)-N,N,7,17,18,24,28,31-octamethyl-20-[(1

[0015] S)-1-methylpropyl]-2,5,8,11,16,19,22,25,29,32,35-undecaoxo-10-propyl-spiro[1,4,7,10,15,18,21,24,28,31,34-undecaazatricyclo[34.3.0.012,15]nonatriacontane-33,1′-cyclobutane]-27-carboxamide) (KRAS selectivity for NRAS and / or KRAS selectivity for HRAS).

[0270]

[13] The cyclic compound according to any one of [1] to [4-53] or a salt thereof, or a solvate thereof, which selectively binds to KRAS.

[0271]

[14] The cyclic compound according to any one of [1] to [4-53], or a salt thereof, or a solvate thereof, which selectively inhibits KRAS.

[0272]

[15] The cyclic compound or salt thereof according to any one of [1] to [4-53], or a solvate thereof, which has a KRAS binding activity that is 3 times or more higher than the NRAS binding activity and HRAS binding activity.

[0273]

[16] The cyclic compound according to

[15] or a salt thereof, or a solvate thereof, which has a KRAS binding activity that is 5 times, 7 times, 10 times, 15 times, or 20 times or more higher than the NRAS binding activity and HRAS binding activity.

[0274]

[17] The cyclic compound according to any one of [1] to [4-53], or a salt thereof, or a solvate thereof, which has a KRAS inhibitory activity that is 3 times or more higher than the NRAS inhibitory activity and the HRAS inhibitory activity.

[0275]

[18] The cyclic compound according to

[17] or a salt thereof, or a solvate thereof, which has a KRAS inhibitory activity that is 5 times, 7 times, 10 times, 15 times, or 20 times or more greater than the NRAS inhibitory activity and HRAS inhibitory activity.

[0276]

[19] A pharmaceutical composition comprising the cyclic compound according to any one of [1] to [4-53] or a salt thereof, or a solvate thereof.

[0277]

[20] A pharmaceutical composition for selectively inhibiting KRAS in a subject, comprising the cyclic compound or a salt thereof according to any one of [1] to [4-53], or a solvate thereof.

[0278]

[21] The pharmaceutical composition according to

[20] , wherein the KRAS inhibitory activity of the compound is 3 times or more greater than the NRAS inhibitory activity and HRAS inhibitory activity of the compound.

[0279]

[22] The pharmaceutical composition according to

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

[0280]

[23] A pharmaceutical composition for treating or preventing cancer in a subject, comprising an effective amount of the cyclic compound according to any one of [1] to [4-53] or a salt thereof, or a solvate thereof.

[0281]

[24] The pharmaceutical composition according to

[23] , wherein the cancer is lung cancer.

[0282]

[25] The pharmaceutical composition according to any one of

[20] to

[24] , wherein the subject is a human.

[0283]

[26] The cyclic compound according to any one of [1] to [4-53] or a salt thereof, or a solvate thereof, for use in treating or preventing cancer in a subject.

[0284]

[27] The cyclic compound according to

[26] , or a salt thereof, or a solvate thereof, wherein the cancer is lung cancer.

[0285]

[28] The cyclic compound according to any one of [1] to [4-53] or a salt thereof, or a solvate thereof, for use in selectively inhibiting KRAS in a subject.

[0286]

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

[26] to

[28] , wherein the subject is a human.

[0287]

[30] Use of the cyclic compound according to any one of [1] to [4-53] or a salt thereof, or a solvate thereof, in the manufacture of a medicament for treating or preventing cancer in a subject.

[0288]

[31] The use according to

[30] , wherein the cancer is lung cancer.

[0289]

[32] Use of the cyclic compound according to any one of [1] to [4-53] or a salt thereof, or a solvate thereof, in the manufacture of a medicament for selectively inhibiting KRAS in a subject.

[0290]

[33] The use according to any one of

[30] to

[32] , wherein the subject is a human.

[0291]

[34] A method for treating or preventing cancer in a subject, comprising administering to a subject in need thereof an effective amount of the cyclic compound according to any one of [1] to [4-53] or a salt thereof, or a solvate thereof.

[0292]

[35] The method according to

[34] , wherein the cancer is lung cancer.

[0293]

[36] A method for selectively inhibiting KRAS in a subject, comprising administering to a subject in need thereof an effective amount of the cyclic compound according to any one of [1] to [4-53] or a salt thereof, or a solvate thereof.

[0294]

[37] The method according to any one of

[34] to

[36] , wherein the subject is a human.

[0295] [Effects of the Invention]

[0296] The present invention can provide novel cyclic compounds with selective KRAS inhibitory effects. DETAILED DESCRIPTION

[0297] (abbreviation)

[0298] The abbreviations used herein are as follows.

[0299] AA: Ammonium acetate

[0300] Boc: tert-Butoxycarbonyl

[0301] CSA: (+)-10-Camphorsulfonic acid

[0302] CPME: Cyclopentyl methyl ether

[0303] DAST: (diethylamino)sulfur trifluoride

[0304] DBU: 1,8-diazabicyclo[5.4.0]-7-undecene

[0305] DCM: dichloromethane

[0306] DCE: 1,2-dichloroethane

[0307] DEAD: diethyl azodicarboxylate

[0308] DEPBT: 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one

[0309] DIAD: diisopropyl azodicarboxylate

[0310] DIC: N, N'-diisopropylcarbodiimide

[0311] DIPEA: N,N-diisopropylethylamine

[0312] DHP: 3,4-dihydro-2H-pyran

[0313] DMA: N,N-dimethylacetamide

[0314] DMAP: N,N-dimethyl-4-aminopyridine

[0315] DMF: N,N-dimethylformamide

[0316] dtbbpy: 4,4′-di-tert-butyl-2,2′-bipyridine

[0317] EDTA: Ethylenediaminetetraacetic acid

[0318] FA: Formic acid

[0319] Fmoc: 9-fluorenylmethyloxycarbonyl

[0320] NMP: N-methyl-2-pyrrolidone

[0321] TBME: tert-butyl methyl ether

[0322] TES: triethylsilane

[0323] TFA: trifluoroacetic acid

[0324] TFE: 2,2,2-trifluoroethanol

[0325] THF: Tetrahydrofuran

[0326] THP: Tetrahydropyranyl

[0327] TMSCl: trimethylchlorosilane

[0328] HFIP: 1,1,1,3,3,3-hexafluoroisopropanol

[0329] HOAt: 1-hydroxy-7-azabenzotriazole

[0330] HOBt: 1-hydroxybenzotriazole

[0331] HOOBt: 3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine

[0332] IPAC: Isopropyl acetate

[0333] oxyma:cyano(oxime)ethyl acetate

[0334] PPTS: Pyridinium p-toluenesulfonate

[0335] Pis: 2-phenylisopropyl

[0336] WSCI·HCl, WSCDI: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride

[0337] TIPS: Triisopropylsilane

[0338] TfOH: trifluoromethanesulfonic acid

[0339] HATU: O-(7-aza-1H-benzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate

[0340] DMSO: dimethyl sulfoxide

[0341] Fmoc-Cl: (9H-fluoren-9-yl)methyl chloroformate

[0342] Fmoc-OSu: 9-fluorenylmethyl N-succinimidyl carbonate

[0343] Ns: o-nitrobenzenesulfonyl

[0344] Trt: trityl

[0345] 9-BBN: 9-Borabicyclo[3.3.1]nonane

[0346] HMDS: 1,1,1,3,3,3-hexamethyldisilazane

[0347] LDA: lithium diisopropylamide

[0348] TMSOTf: trimethylsilyl trifluoromethanesulfonate

[0349] PPA: polyphosphoric acid

[0350] Herein, the term "about," when used in conjunction with a numerical value, means a numerical range of +10% and -10% of the numerical value.

[0351] Herein, "-" indicating a range includes values ​​at both ends of the range. For example, "AB" means a range of A or more and B or less.

[0352] Herein, the unit of molecular weight is "g / mol" (hereinafter, the unit of molecular weight may be omitted).

[0353] The articles "a", "an" and "the" as used in both the specification and the claims are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. (Definition of functional groups, etc.)

[0354] Herein, examples of the "halogen atom" include F, Cl, Br and I.

[0355] As used herein, "alkyl" means a monovalent group derived from an aliphatic hydrocarbon by removing any one hydrogen atom and having a hydrocarbon group or a subset of hydrocarbon group structures that does not contain heteroatoms (referring to atoms other than carbon and hydrogen atoms) or unsaturated carbon-carbon bonds in its backbone, but contains hydrogen and carbon atoms. Alkyl groups include straight-chain and branched-chain alkyl groups. Specifically, an alkyl group has 1 to 20 carbon atoms (C1-C 20 , below “C p -C q " means that the number of carbon atoms is p to q), and 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.

[0356] As used herein, "alkenyl" means an alkenyl group having at least one double bond (two adjacent SP 2Depending on the configuration of the double bond and substituents (if present), the double bond geometry may be entgegen (E) or idiosyncratic (Z) and in cis or trans configuration. Alkenyl includes straight chain and branched alkenyl. Alkenyl is preferably C2-C 10 The group is an alkenyl group, and more preferably a C2-C7 alkenyl group or a C2-C6 alkenyl group, 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.

[0357] As used herein, "alkynyl" means a monovalent group having at least one triple bond (two adjacent SP carbon atoms). Alkynyl includes straight chain and branched chain alkynyl. Alkynyl is preferably C2-C 10 Alkynyl, and more preferably C2-C6 alkynyl, 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.

[0358] As used herein, "cycloalkyl" means a saturated or partially saturated cyclic monovalent aliphatic hydrocarbon group and includes monocyclic, bicyclic and spirocyclic rings. Cycloalkyl is preferably a C3-C8 cycloalkyl, and specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl and spiro[3.3]heptyl.

[0359] Herein, "aryl" means a monovalent aromatic hydrocarbon ring, and is preferably a C6-C 10 Aryl. Specific examples of aryl include phenyl and naphthyl (e.g., 1-naphthyl and 2-naphthyl). In this article, aryl includes a bicyclic aryl in which an aromatic hydrocarbon ring is fused to another saturated ring or unsaturated ring, and for example includes an aryl with a fused ring structure in which the aromatic hydrocarbon ring is a benzene ring and the saturated ring is a 5-, 6-, or 7-membered saturated hydrocarbon ring or a saturated heterocycle. Specific examples include indanyl, 1,2,3,4-tetrahydronaphthyl and 2,3-dihydrobenzofuran.

[0360] As used herein, "heterocyclyl" means a non-aromatic cyclic monovalent group containing 1 to 5 heteroatoms in addition to carbon atoms. The heterocyclyl may have double and / or triple bonds within the ring, the carbon atoms within the ring may be oxidized to form a carbonyl group, and the heterocyclyl may be a monocyclic or condensed ring. The number of atoms constituting the ring is preferably 3 to 10 (3- to 10-membered heterocyclyl) or 4 to 10 (4- to 10-membered heterocyclyl), and more preferably 3 to 7 (3- to 7-membered heterocyclyl) or 4 to 7 (4- to 7-membered heterocyclyl). Specific examples of heterocyclic groups include azetidinyl, oxirane, oxetanyl, azetidinyl, dihydrofuranyl, tetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydropyrimidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, 1,2-thiazinane, thiadiazole ... oxazolidinyl, azetidinyl, oxazolidinone, benzodioxanyl, 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.

[0361] Herein, the "protected heterocyclic group" means a group in which one or more functional groups (such as an amino group) 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.

[0362] As used herein, "heterocycloalkylene" means a divalent group obtained by removing two hydrogen atoms from one carbon atom of the "heterocyclyl" group defined above, wherein the free valences form part of a double bond. The heterocycloalkylene group is preferably a 4- to 7-membered heterocycloalkylene group, and specific examples include tetrahydropyran-4-ylidene and azetidin-3-ylidene.

[0363] Herein, the "protected heterocycloalkylene group" means a group in which one or more functional groups (such as an amino group) contained in the "heterocycloalkylene group" defined above are protected by a protecting group, and is preferably a 4- to 7-membered protected heterocycloalkylene group. Specific examples of the protecting group include Boc, Fmoc, Cbz, Troc, and Alloc, and specific examples of the protected heterocycloalkylene group include Boc-protected azetidin-3-ylidene.

[0364] As used herein, "heteroaryl" refers to an aromatic cyclic monovalent group containing 1 to 5 heteroatoms in addition to carbon atoms. The ring may be a single ring, a condensed ring with other rings, or 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 groups include furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, benzofuranyl, benzothienyl, benzothiadiazolyl, benzothiazolyl, benzoxazolyl, benzoxadiazolyl, benzimidazolyl, indolyl, isoindolyl, indazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, benzodioxolyl, indolizinyl, and imidazopyridinyl.

[0365] Herein, "alkoxy" means an oxy group bonded to the above-defined "alkyl" and is preferably a C1-C6 alkoxy group. Specific examples of the alkoxy group include methoxy, ethoxy, 1-propoxy, 2-propoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, and 3-methylbutoxy.

[0366] Herein, "alkylthio" means a thiol group bonded to the above-defined "alkyl" and is preferably a C1-C6 alkylthio group. Specific examples of alkylthio include methylthio, ethylthio, 1-propylthio, 2-propylthio, n-butylthio, isobutylthio, sec-butylthio and tert-butylthio.

[0367] Herein, "alkenyloxy" means an oxy group bonded to the above-defined "alkenyl" and is preferably a C2-C6 alkenyloxy group. Specific examples of alkenyloxy groups include vinyloxy, allyloxy, 1-propenyloxy, 2-propenyloxy, 1-butenyloxy, 2-butenyloxy (including cis and trans forms), 3-butenyloxy, pentenyloxy, and hexenyloxy.

[0368] Herein, "cycloalkoxy" means an oxy group bonded to the above-defined "cycloalkyl" and is preferably a C3-C8 cycloalkoxy group. Specific examples of the cycloalkoxy group include cyclopropyloxy, cyclobutyloxy, and cyclopentyloxy.

[0369] Herein, "aryloxy" means an oxy group bonded to the above-defined "aryl", and is preferably C6-C 10 Aryloxy groups. Specific examples of the aryloxy group include phenoxy, 1-naphthyloxy and 2-naphthyloxy groups.

[0370] As used herein, "amino" refers to -NH2 in a narrow sense and -NRR' in a broad sense, wherein R and R' are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, 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, and the like.

[0371] Herein, "monoalkylamino" means a group corresponding to the above-defined "amino" group, wherein R is hydrogen and R' is the above-defined "alkyl group", and is preferably a mono-C1-C6 alkylamino group. Specific examples of the monoalkylamino group include methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, sec-butylamino, and tert-butylamino.

[0372] Herein, "dialkylamino" means a group corresponding to the above-defined "amino" group, wherein R and R' are independently "alkyl" groups as defined above, and preferably di-C1-C6 alkylamino groups. Specific examples of dialkylamino groups include dimethylamino and diethylamino groups.

[0373] Herein, "cyclic amino group" means a group corresponding to the "amino group" defined above, wherein R and R' together with the nitrogen atom to which they are attached form a ring, and is preferably a 4- to 8-membered cyclic amino group. Specific examples of the cyclic amino group include 1-azetidinyl, 1-pyrrolidinyl, 1-piperidinyl, 1-piperazinyl, 4-morpholinyl, 3-oxazolidinyl, 1,1-dioxidothiomorpholinyl-4-yl and 3-oxa-8-azabicyclo[3.2.1]octan-8-yl.

[0374] Herein, "protected amino group" means an amino group protected by any protecting group. Specific examples of the protected amino group include amino groups protected by protecting groups such as Boc, Fmoc, Cbz, Troc or Alloc.

[0375] As used herein, "alkylcarbonyl" means a carbonyl group bonded to an "alkyl" group as defined above, and is preferably a C1-C6 alkylcarbonyl group. Specific examples of alkylcarbonyl groups include acetyl, propionyl, and butyryl. The number of carbon atoms listed in the above definition indicates the number of carbon atoms in the alkyl portion. For example, the "C1-C6" in "C1-C6 alkylcarbonyl" indicates that the alkyl portion has 1 to 6 carbon atoms.

[0376] Herein, "aminocarbonyl" means a carbonyl group bonded to the above-defined "amino" and is preferably -CONH2, a mono-C1-C6 alkylaminocarbonyl, a di-C1-C6 alkylaminocarbonyl, and a 4- to 8-membered cyclic aminocarbonyl group. Specific examples of the aminocarbonyl group include -CONH2, a dimethylaminocarbonyl, a 1-azetidinylcarbonyl, a 1-pyrrolidinylcarbonyl, a 1-piperidinylcarbonyl, a 1-piperazinylcarbonyl, a 4-morpholinylcarbonyl, a 3-oxazolidinylcarbonyl, a 1,1-dioxidothiomorpholinyl-4-ylcarbonyl, and a 3-oxa-8-azabicyclo[3.2.1]octan-8-ylcarbonyl group.

[0377] Herein, "alkenyloxycarbonyl" means a carbonyl group bonded to the above-defined "alkenyloxy" and is preferably a C2-C6 alkenyloxycarbonyl group. Specific examples of the alkenyloxycarbonyl group include vinyloxycarbonyl, allyloxycarbonyl, 1-propenyloxycarbonyl, 2-propenyloxycarbonyl, 1-butenyloxycarbonyl, 2-butenyloxycarbonyl (including cis and trans forms), 3-butenyloxycarbonyl, pentenyloxycarbonyl, and hexenyloxycarbonyl.

[0378] Herein, "alkylsulfonyl" means a sulfonyl group bonded to the above-defined "alkyl" and is preferably a C1-C6 alkylsulfonyl group. Specific examples of the alkylsulfonyl group include a methylsulfonyl group.

[0379] Herein, "hydroxyalkyl" means a group in which one or more hydrogen atoms of the above-defined "alkyl" are replaced by hydroxy groups, and is preferably a C1-C6 hydroxyalkyl group. Specific examples of hydroxyalkyl groups include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl, and 5-hydroxypentyl.

[0380] Herein, "haloalkyl" means a group in which one or more hydrogen atoms of the "alkyl" defined above are replaced by halogen, and is preferably a C1-C6 haloalkyl group, and more preferably a C1-C6 fluoroalkyl group. Specific examples of haloalkyl groups include difluoromethyl, trifluoromethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3,3-difluoropropyl, 4,4-difluorobutyl, 5,5-difluoropentyl, and 1,1-difluoroethyl.

[0381] Herein, "cyanoalkyl" means a group in which one or more hydrogens of the above-defined "alkyl" are replaced by a cyano group, and is preferably a C1-C6 cyanoalkyl. Specific examples of cyanoalkyl include cyanomethyl and 2-cyanoethyl.

[0382] Herein, "aminoalkyl" means a group in which one or more hydrogen atoms of the above-defined "alkyl" are replaced by the above-defined "amino" group, and is preferably a C1-C6 aminoalkyl group. Specific examples of aminoalkyl groups include 1-pyridylmethyl, 2-(1-piperidyl)ethyl, 3-(1-piperidyl)propyl, 4-aminobutyl, and 2-aminoethyl.

[0383] As used herein, "carboxyalkyl" means a group in which one or more hydrogen atoms of the "alkyl" group defined above are replaced by a carboxyl group, and is preferably a C1-C6 carboxyalkyl group or a C2-C6 carboxyalkyl group. Specific examples of carboxyalkyl groups include carboxymethyl. The number of carbon atoms listed in the above definition indicates the number of carbon atoms in the alkyl moiety. For example, the "C1-C6" in "C1-C6 carboxyalkyl" indicates that the alkyl moiety has 1 to 6 carbon atoms.

[0384] Herein, "alkenyloxycarbonylalkyl" means a group in which one or more hydrogen atoms of the above-defined "alkyl" are replaced by the above-defined "alkenyloxycarbonyl" group, and is preferably a C2-C6 alkenyloxycarbonylC1-C6 alkyl group, and more preferably a C2-C6 alkenyloxycarbonylC1-C2 alkyl group. Specific examples of the alkenyloxycarbonylalkyl group include allyloxycarbonylmethyl and 2-(allyloxycarbonyl)ethyl.

[0385] Herein, "alkoxyalkyl" means a group in which one or more hydrogen atoms of the above-defined "alkyl" are replaced by the above-defined "alkoxy" group, and is preferably a C1-C6 alkoxy C1-C6 alkyl group, and more preferably a C1-C6 alkoxy C1-C2 alkyl group. Specific examples of the alkoxyalkyl group 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.

[0386] Herein, "alkylthioalkyl" means a group in which one or more hydrogen atoms of the above-defined "alkyl" are replaced by the above-defined "alkylthio" group, and is preferably a C1-C6 alkylthioC1-C6 alkyl group, and more preferably a C1-C6 alkylthioC1-C2 alkyl group. Specific examples of the alkylthioalkyl group include methylthiomethyl, ethylthiomethyl, 1-propylthiomethyl, 2-propylthiomethyl, n-butylthiomethyl, isobutylthiomethyl, sec-butylthiomethyl, and tert-butylthiomethyl.

[0387] Herein, "alkenyloxyalkyl" means a group in which one or more hydrogen atoms of the above-defined "alkyl" are replaced by the above-defined "alkenyloxy" group, and is preferably a C2-C6 alkenyloxy C1-C6 alkyl group, and more preferably a C1-C6 alkenyloxy C1-C2 alkyl group. Specific examples of alkenyloxyalkyl groups include vinyloxymethyl and allyloxymethyl.

[0388] Herein, "cycloalkylalkyl" means a group in which one or more hydrogen atoms of the above-defined "alkyl" are replaced by the above-defined "cycloalkyl" group, and is preferably a C3-C8cycloalkylC1-C6alkyl group, and more preferably a C3-C6cycloalkylC1-C2alkyl group. Specific examples of the cycloalkylalkyl group include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, and cyclohexylmethyl.

[0389] Herein, "cycloalkoxyalkyl" means a group in which one or more hydrogen atoms of the above-defined "alkyl" are replaced by the above-defined "cycloalkoxy" group, and is preferably a C3-C8 cycloalkoxy C1-C6 alkyl group, and more preferably a C3-C6 cycloalkoxy C1-C2 alkyl group. Specific examples of the cycloalkoxyalkyl group include cyclopropyloxymethyl and cyclobutyloxymethyl.

[0390] Herein, "heterocyclylalkyl" means a group in which one or more hydrogen atoms of the above-defined "alkyl" are replaced by the above-defined "heterocyclyl" group, and is preferably a 4- to 7-membered heterocyclyl C1-C6 alkyl group, and more preferably a 4- to 7-membered heterocyclyl C1-C2 alkyl group. Specific examples of heterocyclylalkyl groups include 2-(tetrahydro-2H-pyran-4-yl)ethyl and 2-(azetidin-3-yl)ethyl.

[0391] Herein, "alkylsulfonylalkyl" means a group in which one or more hydrogen atoms of the above-defined "alkyl" are replaced by the above-defined "alkylsulfonyl" group, and is preferably a C1-C6 alkylsulfonylC1-C6 alkyl group, and more preferably a C1-C6 alkylsulfonylC1-C2 alkyl group. Specific examples of the alkylsulfonylalkyl group include methylsulfonylmethyl and 2-(methylsulfonyl)ethyl.

[0392] In this article, "aminocarbonylalkyl" means a group in which one or more hydrogens of the "alkyl" defined above are replaced by the "aminocarbonyl" defined above, and is preferably an aminocarbonyl C1-C6 alkyl, and more preferably an 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.

[0393] Herein, "aryloxyalkyl" means a group in which one or more hydrogen atoms of the above-defined "alkyl" are replaced by the above-defined "aryloxy" group, and is preferably a C6-C 10 Aryloxy C1-C6 alkyl, and more preferably C6-C 10 Aryloxy C1-C2 alkyl. Specific examples of the aryloxyalkyl group include phenoxymethyl and 2-phenoxyethyl.

[0394] 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 Arylalkyl, and more preferably C7-C 10 Aralkyl groups. Specific examples of the aralkyl group include benzyl, phenethyl and 3-phenylpropyl.

[0395] Herein, "aralkyloxy" means an oxy group bonded to the above-defined "aralkyl" and is preferably a C7-C 14 Aralkyloxy, and more preferably C7-C 10 Aralkyloxy. Specific examples of the aralkyloxy group include benzyloxy, phenethyloxy and 3-phenylpropoxy.

[0396] Herein, "aralkyloxyalkyl" means a group in which one or more hydrogen atoms of the above-defined "alkyl" are replaced by the above-defined "aralkyloxy" group, and is preferably a C7-C 14 Aralkyloxy C1-C6 alkyl, and more preferably C7-C 14 Aralkyloxy C1-C2 alkyl. Specific examples of the aralkyloxyalkyl group include benzyloxymethyl and 1-(benzyloxy)ethyl.

[0397] Herein, "heteroarylalkyl" means a group in which one or more hydrogen atoms of the "alkyl" defined above are replaced by the "heteroaryl" 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.

[0398] Herein, "heteroarylalkoxy" means an oxy group bonded to the above-defined "heteroarylalkyl" and is preferably a 5- to 10-membered heteroaryl C1-C6 alkoxy group, and more preferably a 5- to 10-membered heteroaryl C1-C2 alkoxy group. Specific examples of the heteroarylalkoxy group include 3-thienylmethoxy and 3-pyridylmethoxy.

[0399] Herein, "heteroarylalkoxyalkyl" means a group in which one or more hydrogen atoms of the above-defined "alkyl" group are replaced by the above-defined "heteroarylalkoxy" group, and is preferably a 5- to 10-membered heteroaryl C1-C6 alkoxy C1-C6 alkyl group, and more preferably a 5- to 10-membered heteroaryl C1-C2 alkoxy C1-C2 alkyl group. Specific examples of heteroarylalkoxyalkyl groups include 3-pyridylmethoxymethyl.

[0400] Herein, "heterocycloalkylenealkyl" means a group in which one or more hydrogen atoms of the above-defined "alkyl" are replaced by the above-defined "heterocycloalkylene" group, and is preferably a 4- to 7-membered heterocycloalkylene C1-C6 alkyl group, and more preferably a 4- to 7-membered heterocycloalkylene C1-C2 alkyl group. Specific examples of heterocycloalkylenealkyl include tetrahydro-4H-pyran-4-ylidenemethyl and azetidin-3-ylidenemethyl.

[0401] Herein, "alkoxyalkenyl" means a group in which one or more hydrogen atoms of the above-defined "alkenyl" are replaced by the above-defined "alkoxy" group, and is preferably a C1-C6 alkoxy C2-C6 alkenyl group. Specific examples of alkoxyalkenyl groups include (E)-4-methoxybut-2-en-1-yl.

[0402] Herein, "aminocarbonylalkenyl" means a group in which one or more hydrogen atoms of the above-defined "alkenyl" are replaced by the above-defined "aminocarbonyl" group, and is preferably an aminocarbonyl C2-C6 alkenyl group. Specific examples of aminocarbonylalkenyl groups include (E)-3-(dimethylaminocarbonylcarbonyl)-prop-2-en-1-yl.

[0403] Herein, "haloalkoxy" means a group in which one or more hydrogens of the "alkoxy" defined above are replaced by halogen, and is preferably a C1-C6 haloalkoxy group. Specific examples of haloalkoxy include difluoromethoxy, trifluoromethoxy, 2,2-difluoroethoxy and 2,2,2-trifluoroethoxy.

[0404] Herein, "alkylene" means a divalent group derived from the above-mentioned "alkyl" by further removing any hydrogen atom, and is preferably a C4-C8 alkylene group. 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-.

[0405] Herein, "cycloalkylene" means a divalent group derived by further removing any hydrogen atom from the above-mentioned "cycloalkyl", and is preferably a C3-C8 cycloalkylene. Specific examples of the cycloalkylene include cyclopropane-1,2-diyl, cyclobutane-1,2-diyl, cyclopentane-1,2-diyl and cyclohexane-1,2-diyl.

[0406] Herein, the "heterocyclylene group" means a divalent group derived by removing any hydrogen atom from the above-mentioned "heterocyclyl group", and is preferably a 3- to 7-membered heterocyclylene group. Specific examples of the heterocyclylene group include oxolane-2,3-diyl, oxetane-2,3-diyl, tetrahydrofuran-2,5-diyl, and tetrahydropyran-2,6-diyl.

[0407] As used herein, "alkenylene" means a divalent group derived from the above-mentioned "alkenyl" by further removing any hydrogen atom. Depending on the configuration of the double bond and substituents (if present), the double bond geometry may be heterolateral (E) or homolateral (Z) and in cis or trans configuration. Alkenylene may be straight or branched, and is preferably C2-C 10 Alkenylene, and more preferably C2-C6 alkenylene.

[0408] Herein, "alkynylene" means a divalent group derived by further removing any hydrogen atom from the above-mentioned "alkynyl". The alkynylene group may be linear or branched, and is preferably C2-C 10 It is more preferably a C2-C6 alkynylene group.

[0409] Herein, "arylene" means a divalent group derived by further removing any hydrogen atom from the above-mentioned "aryl". The arylene group may be a monocyclic ring or a condensed ring. The number of atoms constituting the ring is not particularly limited, and is preferably 6 to 10 (C 6-10 Specific examples of the arylene group include 1,2-phenylene, 1,3-phenylene, 1,4-phenylene, 1,2-naphthylene, 1,3-naphthylene, and 1,4-naphthylene.

[0410] In this article, "spirocycloalkyl" means a group formed by sharing one carbon atom constituting a cycloalkane ring with a carbon atom present in a bonding group. Spirocycloalkyl is preferably a C3-C8 spirocycloalkyl, and specific examples include spirocyclopropyl, spirocyclobutyl, spirocyclopentyl, spirocyclohexyl, spirocycloheptyl and spirocyclooctyl.

[0411] Herein, the "spiroheterocyclic group" means a group obtained by replacing one or more carbon atoms in the above-mentioned "spirocycloalkyl group" with a heteroatom. The spiroheterocyclic group is preferably a 4- to 10-membered spiroheterocyclic group.

[0412] As used herein, "alicyclic ring" means a non-aromatic hydrocarbon ring. The alicyclic ring may have an unsaturated bond within 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 a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, a cyclohexane ring, a cycloheptane ring, a cyclooctane ring, and a bicyclo[2.2.1]heptane ring.

[0413] In this article, " saturated heterocycle " means a non-aromatic heterocycle containing 1 to 5 heteroatoms and no double and / or triple bonds in the ring except carbon atoms. Saturated heterocycle can be a monocycle, or can form a condensed ring with another ring (for example, an aromatic ring, such as a benzene ring). 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, thietane ring, octahydroindole ring, dihydroindole ring and azepane ring.

[0414] In this article, "peptide chain" refers to a peptide chain in which 1, 2, 3, 4 or more natural amino acids and / or non-natural amino acids are linked by amide bonds and / or ester bonds. The peptide chain is preferably a peptide chain comprising 1 to 4 amino acid residues, and more preferably a peptide chain consisting of 1 to 4 amino acid residues.

[0415] As used herein, "optionally substituted" means that a group may be substituted with any substituent.

[0416] Herein, "optionally protected" means that the group may be protected with any protecting group.

[0417] As used herein, "one or more" means one or two or more. When "one or more" is used in the context of a substituent group, the phrase is intended to encompass numbers from one to the maximum number of substituents permitted for that group. Specific examples of "one or more" include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and / or more.

[0418] 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.

[0419] As used herein, "PPn 1 n 2 n 3 n 4 , where n 1 、n 2 、n 3 and n 4 The symbols represented by "each independently represents an integer from 0 to 9", such as PP1574 and PP1640, represent the number of the compound.

[0420] The compound of the present invention may be a salt thereof, and preferably a chemical or pharmaceutically acceptable salt thereof. In addition, the compound of the present invention or its salt may be a solvate thereof, and preferably a chemical or pharmaceutically acceptable solvate thereof. Examples of salts of the compounds of the present invention include hydrochlorides; hydrobromides; hydroiodides; phosphates; phosphonates; sulfates; sulfonates, such as methanesulfonates and p-toluenesulfonates; carboxylates, such as acetates, citrates, malates, tartrates, succinates and salicylates; alkali metal salts, such as sodium salts and potassium salts; alkali metal salts, such as magnesium salts and calcium salts; and ammonium salts, such as ammonium salts, alkylammonium salts, dialkylammonium salts, trialkylammonium salts and tetraalkylammonium salts. These salts are prepared, for example, by contacting the compound with an acid or base that can be used to produce a pharmaceutical. In the present invention, the solvate of a compound refers to a molecular group formed by the compound together with a solvent, and when the solvent is water, it is referred to as a hydrate. The solvate of the compounds of this invention is preferably a hydrate, and the specific examples of this type of hydrate include monohydrate to decahydrate, preferably monohydrate to pentahydrate, and more preferably monohydrate to trihydrate. The solvate of the compounds of this invention not only includes the solvate formed by a single solvent (such as water, alcohol (for example, methanol, ethanol, 1-propyl alcohol or 2-propyl alcohol) or dimethylformamide), but also includes the solvate formed by multiple solvents.

[0421] As used herein, the term "amino acid" includes natural and non-natural 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 non-natural 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, in addition to hydrogen atoms, can also be freely selected from, for example, alkyl groups, alkenyl groups, alkynyl groups, aryl groups, heteroaryl groups, aralkyl groups and cycloalkyl groups. One or two non-adjacent methylene groups in such groups are optionally substituted with oxygen atoms, carbonyl groups (-CO-) or sulfonyl groups (-SO2-). Each group may have a substituent, and there is no restriction on the substituent. For example, one or more substituents may be freely and independently selected from any substituent 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 acid herein may be a compound having a carboxyl group and an amino group in the same molecule (even in this case, imino acids such as proline and hydroxyproline are also included in the amino acid).

[0422] The main chain amino group of an amino acid may be unsubstituted (NH2 group) or substituted (i.e., -NHR group, wherein R represents an alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl or cycloalkyl group which may have a substituent, one or two non-adjacent methylene groups of such a group may be substituted 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 may form a ring, such as proline). The R substituent is selected in the same manner as the substituents in the amino acid side chains described above. When the main chain amino group is substituted, R is included in the "amino acid side chain" as used herein. Such amino acids in which the main chain 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.

[0423] As used herein, the "amino acids" constituting the peptide compounds include all isotopes corresponding to the respective amino acids. 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 (the total number of protons and neutrons). Examples of isotopes contained in the "amino acids" constituting the peptide compounds of the present invention include hydrogen atoms, carbon atoms, nitrogen atoms, oxygen atoms, phosphorus atoms, sulfur atoms, fluorine atoms, and chlorine atoms, 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.

[0424] As used herein, a substituent containing a halogen atom includes a halogen-substituted alkyl group, a cycloalkyl group, an alkenyl group, an alkynyl group, an aryl group, a heteroaryl group, or an aralkyl group. More specific examples include fluoroalkyl, difluoroalkyl, and trifluoroalkyl groups.

[0425] Substituents containing an O atom include groups such as hydroxy (—OH), oxy (—OR), carbonyl (—C(═O)—R), carboxyl (—CO2H), oxycarbonyl (—C(═O)—OR), carbonyloxy (—OC(═O)—R), thiocarbonyl (—C(═O)—SR), carbonylthio (—SC(═O)—R), aminocarbonyl (—C(═O)—NHR), carbonylamino (—NH—C(═O)—R), oxycarbonylamino (—NH—C(═O)—OR), sulfonylamino (—NH—SO2—R), aminosulfonyl (—SO2-NHR), sulfamoylamino (—NH—SO2-NHR), thiocarboxyl (—C(═O)—SH) and carboxycarbonyl (—C(═O)—CO2H).

[0426] Examples of the oxy group (-OR) include alkoxy, cycloalkoxy, alkenyloxy, alkynyloxy, aryloxy, heteroaryloxy, and aralkyloxy. The alkoxy group is preferably a C1-C4 alkoxy group or a C1-C2 alkoxy group, and particularly preferably a methoxy group or an ethoxy group.

[0427] Examples of the carbonyl group (—C(═O)—R) include a formyl group (—C(═O)—H), an alkylcarbonyl group, a cycloalkylcarbonyl group, an alkenylcarbonyl group, an alkynylcarbonyl group, an arylcarbonyl group, a heteroarylcarbonyl group, and an aralkylcarbonyl group.

[0428] Examples of the oxycarbonyl group (—C(═O)—OR) include an alkoxycarbonyl group, a cycloalkoxycarbonyl group, an alkenyloxycarbonyl group, an alkynyloxycarbonyl group, an aryloxycarbonyl group, a heteroaryloxycarbonyl group, and an aralkyloxycarbonyl group.

[0429] Examples of the carbonyloxy group (—OC(═O)—R) include an alkylcarbonyloxy group, a cycloalkylcarbonyloxy group, an alkenylcarbonyloxy group, an alkynylcarbonyloxy group, an arylcarbonyloxy group, a heteroarylcarbonyloxy group, and an aralkylcarbonyloxy group.

[0430] Examples of the thiocarbonyl group (—C(═O)—SR) include an alkylthiocarbonyl group, a cycloalkylthiocarbonyl group, an alkenylthiocarbonyl group, an alkynylthiocarbonyl group, an arylthiocarbonyl group, a heteroarylthiocarbonyl group, and an aralkylthiocarbonyl group.

[0431] Examples of the carbonylthio group (—SC(═O)—R) include an alkylcarbonylthio group, a cycloalkylcarbonylthio group, an alkenylcarbonylthio group, an alkynylcarbonylthio group, an arylcarbonylthio group, a heteroarylcarbonylthio group, and an aralkylcarbonylthio group.

[0432] Examples of the aminocarbonyl group (-C(=O)-NHR) include an alkylaminocarbonyl group (such as a C1-C6 or C1-C4 alkylaminocarbonyl group, and particularly an ethylaminocarbonyl group and a methylaminocarbonyl group), a cycloalkylaminocarbonyl group, an alkenylaminocarbonyl group, an alkynylaminocarbonyl group, an arylaminocarbonyl group, a heteroarylaminocarbonyl group, and an aralkylaminocarbonyl group. In addition, examples further include compounds obtained by replacing the H atom to which the N atom in -C(=O)-NHR is bonded with an alkyl group, a cycloalkyl group, an alkenyl group, an alkynyl group, an aryl group, a heteroaryl group, or an aralkyl group.

[0433] Examples of the carbonylamino group (-NH-C(=O)-R) include alkylcarbonylamino, cycloalkylcarbonylamino, alkenylcarbonylamino, alkynylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, and aralkylcarbonylamino. In addition, examples further include compounds obtained by replacing the H atom to which the N atom in -NH-C(=O)-R is bonded with an alkyl group, a cycloalkyl group, an alkenyl group, an alkynyl group, an aryl group, a heteroaryl group, or an aralkyl group.

[0434] Examples of the oxycarbonylamino group (-NH-C(=O)-OR) include alkoxycarbonylamino, cycloalkoxycarbonylamino, alkenyloxycarbonylamino, alkynyloxycarbonylamino, aryloxycarbonylamino, heteroaryloxycarbonylamino, and aralkyloxycarbonylamino. Examples further include compounds obtained by replacing the H atom to which the N atom in -NH-C(=O)-OR is bonded with an alkyl group, a cycloalkyl group, an alkenyl group, an alkynyl group, an aryl group, a heteroaryl group, or an aralkyl group.

[0435] 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 to which the N atom in -NH-SO2-R is bonded with an alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or aralkyl group.

[0436] Examples of aminosulfonyl groups (-SO2-NHR) include alkylaminosulfonyl groups, cycloalkylaminosulfonyl groups, alkenylaminosulfonyl groups, alkynylaminosulfonyl groups, arylaminosulfonyl groups, heteroarylaminosulfonyl groups, and aralkylaminosulfonyl groups. In addition, examples further include compounds obtained by replacing the H atom to which the N atom in -SO2-NHR is bonded with an alkyl group, a cycloalkyl group, an alkenyl group, an alkynyl group, an aryl group, a heteroaryl group, or an aralkyl group.

[0437] Examples of sulfamoylamino groups (-NH-SO2-NHR) include alkylsulfamoylamino groups, cycloalkylsulfamoylamino groups, alkenylsulfamoylamino groups, alkynylsulfamoylamino groups, arylsulfamoylamino groups, heteroarylsulfamoylamino groups, and aralkylsulfamoylamino groups. In addition, two H atoms bonded to the N atom in -NH-SO2-NHR may be replaced by a substituent independently selected from the group consisting of an alkyl group, a cycloalkyl group, an alkenyl group, an alkynyl group, an aryl group, a heteroaryl group, and an aralkyl group, and the two substituents may form a ring.

[0438] Substituents containing an S atom include groups such as thiol (-SH), sulfenyl (-SR), sulfinyl (-S(=O)-R), sulfonyl (-SO2-R), and sulfo (-SO3H).

[0439] Examples of the thio group (—SR) are selected from alkylthio, cycloalkylthio, alkenylthio, alkynylthio, arylthio, heteroarylthio, aralkylthio and the like.

[0440] Examples of the sulfonyl group (-SO2-R) include an alkylsulfonyl group, a cycloalkylsulfonyl group, an alkenylsulfonyl group, an alkynylsulfonyl group, an arylsulfonyl group, a heteroarylsulfonyl group and an aralkylsulfonyl group.

[0441] Substituents containing a N atom include groups such as azide (-N3, also known as an "azido group"), cyano (-CN), primary amino (-NH2), secondary amino (-NH-R; also known as a monosubstituted amino group), tertiary amino (-NR(R'); also known as a disubstituted amino group), amidino (-C(=NH)-NH2), substituted amidino (-C(=NR)-NR'R"), guanidino (-NH-C(=NH)-NH2), substituted guanidino (-NR-C(=NR"')-NR'R"), aminocarbonylamino (-NR-CO-NR'R"), pyridinyl, piperidino, morpholino, and azetidinyl.

[0442] Examples of the secondary amino group (—NH—R; monosubstituted amino group) include an alkylamino group, a cycloalkylamino group, an alkenylamino group, an alkynylamino group, an arylamino group, a heteroarylamino group, and an aralkylamino group.

[0443] Examples of tertiary amino groups (-NR(R'); disubstituted amino groups) include amino groups having any two substituents, each of which is independently selected from an alkyl group, a cycloalkyl group, an alkenyl group, an alkynyl group, an aryl group, a heteroaryl group, and an aralkyl group, such as an alkyl(aralkyl)amino group, and the two substituents may form a ring. Specific examples include dialkylamino groups, particularly C1-C6 dialkylamino groups, C1-C4 dialkylamino groups, dimethylamino groups, and diethylamino groups. As used herein, "C p -C q "Dialkylamino group" refers to a group consisting of two C p -C q an amino group substituted with an alkyl group, and C p -C q The alkyl groups can be the same or different.

[0444] 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.

[0445] Examples of substituted guanidinium 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 groups, and groups in which these substituents form a ring.

[0446] Examples of the aminocarbonylamino group (—NR—CO—NR′R″) include a group in which R, R′ and R″ are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, an alkenyl group, an alkynyl group, an aryl group, a heteroaryl group and an aralkyl group, or a group in which these substituents form a ring.

[0447] Herein, the "peptide residue" or "amino acid residue" constituting a peptide compound may be simply referred to as "peptide" or "amino acid," respectively.

[0448] In the present invention, 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 7 variations:

[0449] (i) A, (ii) B, (iii) C, (iv) A and B, (v) A and C, (vi) B and C, (vii) A, B and C.

[0450] In one embodiment, the present invention relates to a cyclic compound represented by the following formula (1) or a salt thereof, or a solvate thereof.

[0451]

[0452] In the cyclic compound of formula (1), the ring is composed of 11 amino acid residues. In this article, the amino acid residues having P1, Q1, R1 and L1 in the formula can be referred to as core 1, the amino acid residues having P2, Q2 and R2 can be referred to as core 2, the amino acid residues having P3, Q3 and R3 can be referred to as core 3, the amino acid residues having P4, Q4 and R4 can be referred to as core 4, the amino acid residues having P5, Q5 and R5 can be referred to as core 5, the amino acid residues having P6, Q6 and R6 can be referred to as core 6, the amino acid residues having P7, Q7 and R7 can be referred to as core 7, the amino acid residues having P8, Q8 and R8 can be referred to as core 8, the amino acid residues having P9, Q9 and R9 can be referred to as core 9, and the amino acid residues having P10, Q11 and R11 can be referred to as core 10. 10 , Q 10 and R 10 The amino acid residues of 11 , Q 11 、R 11 and L 11 The amino acid residues of can be referred to as core 11.

[0453] In one embodiment, in formula (1), L1 is a single bond.

[0454] In one embodiment, in formula (1), R1 is a C1 to C7 alkyl group, and is preferably a 2-methylpropyl group or an n-propyl group.

[0455] In one embodiment, R1 and R5 are linked together to form a divalent group, wherein the partial structure of the cyclic compound represented by formula (1): *-CR1Q1-L1-CO-NP2-CR2Q2-CO-NP3-CR3Q3-CO-NP4-CR4Q4-CO-NP5-CR5Q5-* is represented by the following formula:

[0456] ,

[0457] in:

[0458] X2 is -L1-CO-NP2-CR2Q2-CO-NP3-CR3Q3-CO-NP4-CR4Q4-CO-NP5-,

[0459]

[0460] is a single bond or a double bond,

[0461] n is 0, 1, or 2,

[0462] m is 0, 1, 2, 3 or 4,

[0463] * represents the connection point with the adjacent atom;

[0464] in

[0465]

[0466] E or Z configuration can be used if

[0467]

[0468] For double bonds.

[0469] The formula is preferably the following:

[0470]

[0471] In one embodiment, R1 is a C1 to C6 alkyl group, and preferably a methyl group.

[0472] In one embodiment, Q1 is a hydrogen atom.

[0473] The amino acid residue of core 1 is, for example, MeLeu or MeNva, except that the side chain of core 1 (R1) and the side chain of core 5 (R5) are linked together to form a divalent group.

[0474] If the side chain (R1) of core 1 and the side chain (R5) of core 5 are linked together to form a divalent group, the group at the position corresponding to R1 of MeAhpe (2), MeAocte (2) or MeAhxe (2) and the group at the position corresponding to the side chain (R5) of core 5 can be linked by using, for example, the method described in the "General Method" described later.

[0475] In one embodiment, in formula (1), R2 is a C1 to C6 alkyl group, and preferably a 1-methylpropyl group.

[0476] In one embodiment, P2 is a hydrogen atom.

[0477] In one embodiment, Q2 is a hydrogen atom.

[0478] The amino acid residue of core 2 is, for example, Ile.

[0479] In one embodiment, in formula (1), R3 is a hydrogen atom.

[0480] In one embodiment, R3, P3, and the carbon atom to which R3 is attached, as well as the nitrogen atom to which P3 is attached, are connected together to form a 4- to 7-membered saturated heterocyclic ring, such as a pyrrolidine ring.

[0481] In one embodiment, P3 is a C1 to C6 alkyl group or a C3 to C8 cycloalkyl group, and is preferably a methyl group or a cyclopropyl group.

[0482] In one embodiment, Q3 is a hydrogen atom.

[0483] The amino acid residue of core 3 is, for example, MeGly, Pro or cPrGly.

[0484] In one embodiment, R4 and P5 are linked together to form a divalent group, wherein the partial structure of the cyclic compound represented by formula (1): *-CR4Q4-CO-NP5-* is represented by the following formula:

[0485]

[0486] In one embodiment, R4 is a C1 to C6 alkyl group, and preferably a methyl group.

[0487] In one embodiment, Q4 is a hydrogen atom.

[0488] If the side chain (R4) of core 4 and the N substituent (P5) of core 5 are linked together to form a divalent group, preferably, the group at the position corresponding to R4 of MeAlgly and the group at the position corresponding to the N substituent (P5) of core 5 can be linked by using, for example, the method described in the "General Method" described later.

[0489] In one embodiment, in formula (1), R5 is a benzyl group optionally substituted with one or more groups independently selected from the group consisting of: C1 to C6 alkyl, C1 to C6 haloalkyl and C3 to C8 cycloalkyl, and preferably 4-cyclopropylbenzyl, 4-(trifluoromethyl)benzyl, 4-methylbenzyl or 4-ethylbenzyl.

[0490] In one embodiment, in formula (1), R5 and R1 are linked together to form a divalent group. The detailed information of the group is the same as defined above.

[0491] In one embodiment, P5 and R4 are linked together to form a divalent group. The detailed information of the group is the same as defined above.

[0492] In one embodiment, Q5 is a hydrogen atom.

[0493] If the side chain (R5) of core 5 and the side chain (R1) of core 1 are linked together to form a divalent group, and the N substituent (P5) of core 5 and the side chain (R4) of core 4 are linked together to form a divalent group, then more specifically, R5 of the butenyl group Phe (4-CH=CH2) and the group at the position corresponding to P5, and the side chain (R1) of core 1 and the group at the position corresponding to the side chain (R4) of core 4 can be linked separately by using, for example, the method described in the "General Method" described later.

[0494] In the case where the side chain (R5) of core 5 and the side chain (R1) of core 1 do not form a divalent group and the N substituent (P5) of core 5 and the side chain (R4) of core 4 form a divalent group, more specifically, the group at the position corresponding to P5 of butenyl Phe (4-Et), butenyl Phe (4-cPr) or allyl Phe (4-CF3) and the group at the position corresponding to the side chain (R4) of core 4 can be linked by using, for example, the method described in the "General Method" described later.

[0495] In one embodiment, in formula (1), R6 is a hydrogen atom.

[0496] In one embodiment, R6 is a C1 to C6 alkyl group, and preferably a methyl group.

[0497] In one embodiment, Q6 is a hydrogen atom.

[0498] The amino acid residue of core 6 is, for example, MeGly.

[0499] In one embodiment, in formula (1), the phenethyl group optionally substituted with one or more groups is preferably 3,5-difluoro-4-(trifluoromethyl)phenethyl, 3,4-difluorophenethyl or 3-methoxy-4-(trifluoromethyl)phenethyl, which groups are independently selected from the group consisting of halogen, C1 to C6 haloalkyl and C1 to C6 alkoxy.

[0500] In one embodiment, P7 is a hydrogen atom.

[0501] In one embodiment, Q7 is a hydrogen atom.

[0502] The amino acid residue of core 7 is, for example, Hph(4-CF3-35-F2), Hph(34-Cl2) or Hph(4-CF3-3-OMe).

[0503] In one embodiment, in formula (1), R8, P8, and the carbon atom to which R8 is attached, and the nitrogen atom to which P8 is attached, are linked together to form a 4- to 7-membered saturated heterocyclic ring. The 4- to 7-membered saturated heterocyclic ring is optionally substituted with a C1 to C6 alkoxy group, preferably an ethoxy group or an n-propoxy group. The 4- to 7-membered saturated heterocyclic ring is, for example, a pyrrolidine ring.

[0504] In one embodiment, Q8 is a hydrogen atom.

[0505] The amino acid residue of core 8 is, for example, Hyp(Et) or Hyp(nPr).

[0506] In one embodiment, in formula (1), R9 and Q9 and the carbon atom to which R9 and Q9 are attached are linked together to form a 3- to 8-membered alicyclic ring. The 3- to 8-membered alicyclic ring is optionally substituted with one or more C1 to C6 alkyl groups, such as two methyl groups. The 3- to 8-membered alicyclic ring is, for example, a cyclobutane ring or a cyclopentane ring.

[0507] In one embodiment, P9 is a hydrogen atom or a C1 to C6 alkyl group, and is preferably a hydrogen atom or a methyl group.

[0508] The amino acid residue of core 9 is, for example, cLeu, cVal, cVal(3-Me2) or MecVal.

[0509] In one embodiment, in formula (1), R 10 It is a C1 to C6 alkyl group or a C3 to C8 cycloalkyl group, and is preferably a pentan-3-yl group or a cyclopentyl group.

[0510] In one embodiment, R 10 is a C1 to C6 alkyl group, and preferably a methyl group.

[0511] In one embodiment, Q 10 A hydrogen atom.

[0512] The amino acid residue of core 10 is, for example, MeGly(cPent) or MeNva(3-Et).

[0513] In one embodiment, in formula (1), L 11 It is -CH2-.

[0514] In one embodiment, in formula (1), R 11It is a di-C1 to C6 alkylaminocarbonyl group or a 4- to 8-membered cyclic aminocarbonyl group, and is preferably a dimethylaminocarbonyl group, an N-ethyl-N-methylaminocarbonyl group, a pyrrolidinylcarbonyl group or a piperidinylcarbonyl group.

[0515] In one embodiment, P 11 is a C1 to C6 alkyl group, and preferably a methyl group.

[0516] In one embodiment, Q 11 A hydrogen atom.

[0517] In one embodiment, the compound of the present invention may be one or more compounds selected from the following:

[0518] PP1574: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-N-ethyl-27-isobutyl-N,4,19,22,26,32,35-heptamethyl-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 ]tetradec-38-ene-17,1′-cyclopentane]-23-carboxamide,

[0519] PP1650: (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,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 ]tetradec-38-ene-17,1′-cyclobutane]-23-carboxamide,

[0520] PP1827: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47E)-19-cyclopentyl-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-N-ethyl-N,3,18,21,25,31,34-heptamethyl-29-[(1S)-1-methylpropyl]-2,5,8,14,17,20,24,27,30,33,55-undecaoxo-spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24.15.11.2 43,46 .1 35,41 .0 9,13 ]pentacarbonyl-37,43(54),44,46(53),47-pentaene-16,1′-cyclobutane]-22-carboxamide,

[0521] PP1830: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47E)-19-cyclopentyl-11-ethoxy-N-ethyl-7-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,3,3′,3′,18,21,25,31,34-nonamethyl-29-[(1S)-1-methylpropyl]-2,5,8,14,17,20,24,27,30,33,55-undecaoxo-spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24.15.11.2 43,46 .1 35,41 .0 9,13 ]pentacarbonyl-37,43(54),44,46(53),47-pentaene-16,1′-cyclobutane]-22-carboxamide,

[0522] PP2093: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-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-(p-tolylmethyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10,14 ]tetradec-38-ene-17,1′-cyclobutane]-23-carboxamide,

[0523] PP2260: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z)-19-cyclopentyl-11-ethoxy-N-ethyl-7-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,3,3′,3′,18,21,25,31,34-nonamethyl-29-[(1S)-1-methylpropyl]-2,5,8,14,17,20,24,27,30,33,55-undecaoxo-spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24.15.11.2 43,46 .1 35,41 .0 9,13 ]pentadeca-37,43(54),44,46(53)-tetraene-16,1′-cyclobutane]-22-carboxamide,

[0524] PP2316: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,N,4,16,19,22,26,35-octamethyl-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 ]tetradec-38-ene-17,1′-cyclobutane]-23-carboxamide,

[0525] 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 ]pentadec-42-ene-23,1′-cyclobutane]-17-carboxamide,

[0526] PP2328: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,N,4,16,19,22,26,35-octamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaoxo-27-propyl-2-(p-tolylmethyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10,14 ]tetradec-38-ene-17,1′-cyclobutane]-23-carboxamide,

[0527] PP2574: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47E)-19-cyclopentyl-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-3,3′,3′,18,21,25,31,34-octamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24.15.10.2 43,46 .1 35,41 .0 9，13 ]pentacontan-37,43(53),44,46(52),47-pentacontan-16,1′-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecanone,

[0528] PP2576: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47E)-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-19-(1-ethylpropyl)-3,3′,3′,18,21,25,31,34-octamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24.15.10.2 43,46 .1 35,41 .0 9,13 ]pentacontan-37,43(53),44,46(52),47-pentacontan-16,1′-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecanone,

[0529] PP2583: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47E)-19-cyclopentyl-31-cyclopropyl-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-3,3′,3′,18,21,25,34-heptamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24.15.10.2 43,46 .1 35,41 .0 9,13 ]pentacontan-37,43(53),44,46(52),47-pentacontan-16,1′-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecanone,

[0530] PP2687: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-12-ethoxy-2-[(4-ethylphenyl)methyl]-27-isobutyl-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-spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10,14 ]tetradec-38-ene-17,1′-cyclobutane]-23-carboxamide,

[0531] PP2691: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-2-[(4-cyclopropylphenyl)methyl]-12-ethoxy-27-isobutyl-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-spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10,14 ]tetradec-38-ene-17,1′-cyclobutane]-23-carboxamide,

[0532] PP2957: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47E)-31-cyclopropyl-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-19-(1-ethylpropyl)-3,18,21,25,34-pentamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24.15.10.2] 43,46 .1 35,41 .0 9,13 ]pentacontan-37,43(53),44,46(52),47-pentacontan-16,1′-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecanone,

[0533] PP3033: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z)-19-cyclopentyl-11-ethoxy-7-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-3,18,21,25,31,34-hexamethyl-29-[(1S)-1-methylpropyl]-22-(piperidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24.15.11.2 43,46 .1 35,41 .0 9，13 ]pentacarbonyl-37,43(54),44,46(53)-tetraene-16,1′-cyclobutane]-2,5,8,14,17,20,24,27,30,33,55-undecanone,

[0534] PP3034: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z)-19-cyclopentyl-11-ethoxy-7-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-3,3′,3′,18,21,25,31,34-octamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24.15.11.2 43,46 .1 35,41 .0 9,13 ]pentacarbonyl-37,43(54),44,46(53)-tetraene-16,1′-cyclobutane]-2,5,8,14,17,20,24,27,30,33,55-undecanone,

[0535] PP3036: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z)-19-cyclopentyl-11-ethoxy-7-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-3,3′,3′,18,21,25,31,34-octamethyl-29-[(1S)-1-methylpropyl]-22-(piperidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24.15.10.2 43,46 .1 35，41 .0 9,13 ]54-tetradecanoic acid-37,43(53),44,46(52)-tetraene-16,1′-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecanone,

[0536] PP3037: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z)-19-cyclopentyl-11-ethoxy-7-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-3,3′,3′,18,21,25,31,34-octamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24.15.10.2 43,46 .1 35,41 .0 9,13 ]54-tetradecanoic acid-37,43(53),44,46(52)-tetraene-16,1′-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecanone,

[0537] PP3047: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47E)-7-[2-(3,4-dichlorophenyl)ethyl]-11-ethoxy-19-(1-ethylpropyl)-3,18,21,25,31,34-hexamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24.15.11.2 43,46 .1 35,41 .0 9,13 ]pentacarbonyl-37,43(54),44,46(53),47-pentaene-16,1′-cyclobutane]-2,5,8,14,17,20,24,27,30,33,55-undecanone,

[0538] PP3093: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z)-19-cyclopentyl-11-ethoxy-7-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-3,3′,3′,18,21,25,31,34-octamethyl-29-[(1S)-1-methylpropyl]-22-(piperidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24.15.9.2 43,46 .1 35,41 .0 9,13 ]53 carbon-37,43 (52),44,46 (51) -tetraene-16,1'-cyclobutane] -2,5,8,14,17,20,24,27,30,33,53-undecanone,

[0539] PP3094: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z)-19-cyclopentyl-7-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-3,3′,3′,18,21,25,31,34-octamethyl-29-[(1S)-1-methylpropyl]-11-propoxy-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24,15,9,25,31,34,35,37] 43,46 .1 35,41 .0 9,13 ]53 carbon-37,43 (52), 44,46 (51) -tetraene-16,1'-cyclobutane] -2,5,8,14,17,20,24,27,30,33,53-undecanone,

[0540] PP3095: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-4,16,19,22,26,35-hexamethyl-30-[(1S)-1-methylpropyl]-23-(piperidine-1-carbonyl)-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 ]tetradec-38-ene-17,1′-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecanone,

[0541] PP3096: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-4,16,19,22,26,35-hexamethyl-30-[(1S)-1-methylpropyl]-23-(piperidine-1-carbonyl)-27-propyl-2-(p-tolylmethyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10,14 ]tetradec-38-ene-17,1′-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecanone,

[0542] PP3097: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-4,16,19,22,26,35-hexamethyl-30-[(1S)-1-methylpropyl]-27-propyl-23-(pyrrolidine-1-carbonyl)-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10,14 ]tetradec-38-ene-17,1′-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecanone,

[0543] PP3098: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-4,16,19,22,26,35-hexamethyl-30-[(1S)-1-methylpropyl]-27-propyl-2-(p-tolylmethyl)-23-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10,14 ]tetradec-38-ene-17,1′-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecanone,

[0544] PP3099: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-28-ethoxy-32-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-2,14,18,21,24,36-hexamethyl-10-[(1S)-1-methylpropyl]-17-(piperidine-1-carbonyl)-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 ]pentatetradec-42-ene-23,1′-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecanone,

[0545] PP3100: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-28-ethoxy-32-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-2,14,18,21,24,36-hexamethyl-10-[(1S)-1-methylpropyl]-17-(piperidine-1-carbonyl)-13-propyl-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 ]pentatetradec-42-ene-23,1′-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecanone,

[0546] PP3101: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-28-ethoxy-32-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-2,14,18,21,24,36-hexamethyl-10-[(1S)-1-methylpropyl]-13-propyl-17-(pyrrolidine-1-carbonyl)-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 ]pentatetradec-42-ene-23,1′-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecanone,

[0547] PP3102: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-28-ethoxy-32-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-2,14,18,21,24,36-hexamethyl-10-[(1S)-1-methylpropyl]-13-propyl-38-(p-tolylmethyl)-17-(pyrrolidine-1-carbonyl)spiro[2,8,11,14,18,21,24,30,33,36,39-undecaazatetracyclo[37.5.1.0 4,8 .0 26,30 ]pentatetradec-42-ene-23,1′-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecanone,

[0548] PP3103: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-4,16,19,22,26,32,35-heptamethyl-30-[(1S)-1-methylpropyl]-23-(piperidine-1-carbonyl)-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 ]tetradec-38-ene-17,1′-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecanone,

[0549] PP3104: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-4,16,19,22,26,32,35-heptamethyl-30-[(1S)-1-methylpropyl]-23-(piperidine-1-carbonyl)-27-propyl-2-(p-tolylmethyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10,14 ]tetradec-38-ene-17,1′-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecanone,

[0550] PP3105: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-4,16,19,22,26,32,35-heptamethyl-30-[(1S)-1-methylpropyl]-27-propyl-23-(pyrrolidine-1-carbonyl)-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0] 10,14 ]tetradec-38-ene-17,1′-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecanone,

[0551] PP3106: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-4,16,19,22,26,32,35-heptamethyl-30-[(1S)-1-methylpropyl]-27-propyl-2-(p-tolylmethyl)-23-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10,14 ]tetradec-38-ene-17,1′-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecanone,

[0552] PP3110: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-4,16,19,22,26,35-hexamethyl-30-[(1S)-1-methylpropyl]-23-(piperidine-1-carbonyl)-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 ]tetradec-38-ene-17,1′-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecanone,

[0553] PP3111: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-4,16,19,22,26,35-hexamethyl-30-[(1S)-1-methylpropyl]-23-(piperidine-1-carbonyl)-27-propyl-2-(p-tolylmethyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10,14 ]tetradec-38-ene-17,1′-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecanone,

[0554] PP3112: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-4,16,19,22,26,35-hexamethyl-30-[(1S)-1-methylpropyl]-27-propyl-23-(pyrrolidine-1-carbonyl)-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10,14 ]tetradec-38-ene-17,1′-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecanone,

[0555] PP3113: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-4,16,19,22,26,35-hexamethyl-30-[(1S)-1-methylpropyl]-27-propyl-2-(p-tolylmethyl)-23-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10,14 ]tetradec-38-ene-17,1′-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecanone,

[0556] PP3114: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-32-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-28-ethoxy-2,14,18,21,24,36-hexamethyl-10-[(1S)-1-methylpropyl]-17-(piperidine-1-carbonyl)-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 ]pentatetradec-42-ene-23,1′-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecanone,

[0557] PP3115: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-32-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-28-ethoxy-2,14,18,21,24,36-hexamethyl-10-[(1S)-1-methylpropyl]-17-(piperidine-1-carbonyl)-13-propyl-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 ]pentatetradec-42-ene-23,1′-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecanone,

[0558] PP3116: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-32-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-28-ethoxy-2,14,18,21,24,36-hexamethyl-10-[(1S)-1-methylpropyl]-13-propyl-17-(pyrrolidine-1-carbonyl)-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 ]pentatetradec-42-ene-23,1′-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecanone,

[0559] PP3117: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-32-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-28-ethoxy-2,14,18,21,24,36-hexamethyl-10-[(1S)-1-methylpropyl]-13-propyl-38-(p-tolylmethyl)-17-(pyrrolidine-1-carbonyl)spiro[2,8,11,14,18,21,24,30,33,36,39-undecaazatetracyclo[37.5.1.0 4,8 .0 26,30 ]pentatetradec-42-ene-23,1′-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecanone,

[0560] PP3118: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-4,16,19,22,26,32,35-heptamethyl-30-[(1S)-1-methylpropyl]-23-(piperidine-1-carbonyl)-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 ]tetradec-38-ene-17,1′-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecanone,

[0561] PP3119: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-4,16,19,22,26,32,35-heptamethyl-30-[(1S)-1-methylpropyl]-23-(piperidine-1-carbonyl)-27-propyl-2-(p-tolylmethyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10,14 ]tetradec-38-ene-17,1′-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecanone,

[0562] PP3120: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-4,16,19,22,26,32,35-heptamethyl-30-[(1S)-1-methylpropyl]-27-propyl-23-(pyrrolidine-1-carbonyl)-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10,14 ]tetradec-38-ene-17,1′-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecanone,

[0563] PP3121: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-4,16,19,22,26,32,35-heptamethyl-30-[(1S)-1-methylpropyl]-27-propyl-2-(p-tolylmethyl)-23-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10,14 ]tetradec-38-ene-17,1′-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecanone,

[0564] (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47Z)-19-cyclopentyl-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-N-ethyl-N,3,18,21,25,31,34-heptamethyl-29-[(1S)-1-methylpropyl]-2,5,8,14,17,20,24,27,30,33,55-undecaoxo-spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24,15,11,25] 43,46 .1 35,41 .0 9,13 ]pentacarbonyl-37,43(54),44,46(53),47-pentaene-16,1′-cyclobutane]-22-carboxamide,

[0565] (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47Z)-19-cyclopentyl-11-ethoxy-N-ethyl-7-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,3,3′,3′,18,21,25,31,34-nonamethyl-29-[(1S)-1-methylpropyl]-2,5,8,14,17,20,24,27,30,33,55-undecaoxo-spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24,15,11,2 43,46 .1 35,41 .0 9,13 ]pentacarbonyl-37,43(54),44,46(53),47-pentaene-16,1′-cyclobutane]-22-carboxamide,

[0566] (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47Z)-19-cyclopentyl-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-3,3′,3′,18,21,25,31,34-octamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24,15,10,25]] 43,46 .1 35,41 .0 9，13 ]pentacontan-37,43(53),44,46(52),47-pentacontan-16,1′-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecanone,

[0567] (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47Z)-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-19-(1-ethylpropyl)-3,3′,3′,18,21,25,31,34-octamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24,15,10,25]] 43,46 .1 35,41 .0 9,13 ]pentacontan-37,43(53),44,46(52),47-pentacontan-16,1′-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecanone,

[0568] (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47Z)-19-cyclopentyl-31-cyclopropyl-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-3,3′,3′,18,21,25,34-heptamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24,15,10,25,34]- 43,46 .1 35,41 .0 9，13 ]pentacontan-37,43(53),44,46(52),47-pentacontan-16,1′-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecanone,

[0569] (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47Z)-31-cyclopropyl-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-19-(1-ethylpropyl)-3,18,21,25,34-pentamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24,15,10,25,34]- 43,46 .1 35,41 .0 9,13 ]pentacontan-37,43(53),44,46(52),47-pentacontan-16,1′-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecanone, and

[0570] (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47Z)-7-[2-(3,4-dichlorophenyl)ethyl]-11-ethoxy-19-(1-ethylpropyl)-3,18,21,25,31,34-hexamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24,15,11,2 43,46 .1 35 ,41 .0 9,13[]pentacarbonyl-37,43(54),44,46(53),47-pentaene-16,1′-cyclobutane]-2,5,8,14,17,20,24,27,30,33,55-undecanone or its salt, or its solvate. These compounds are included in the formula represented by formula (1).

[0571] In one embodiment, the compound of the present invention is preferably a compound represented by formula (2):

[0572]

[0573] in

[0574]

[0575] n, m, P1, R2, R3, P3, P4, P6, R7, R8, P8, R9, P9, Q9, R 10 、P 10 、R 11 and P 11 Same as the definition in formula (1).

[0576] For example, compounds PP1827, PP1830, PP2260, PP2574, PP2576, PP2583, PP2957, PP3033, PP3034, PP3036, PP3037, PP3047, PP3093, and PP3094, as well as the following compounds, may be included in formula (2).

[0577] (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47Z)-19-cyclopentyl-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-N-ethyl-N,3,18,21,25,31,34-heptamethyl-29-[(1S)-1-methylpropyl]-2,5,8,14,17,20,24,27,30,33,55-undecaoxo-spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24,15,11,25,31,34,41-undecaazapentacyclo] 43,46 .1 35,41 .0 9,13 ]pentacarbonyl-37,43(54),44,46(53),47-pentaene-16,1′-cyclobutane]-22-carboxamide,

[0578] (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47Z)-19-cyclopentyl-11-ethoxy-N-ethyl-7-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,3,3′,3′,18,21,25,31,34-nonamethyl-29-[(1S)-1-methylpropyl]-2,5,8,14,17,20,24,27,30,33,55-undecaoxo-spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24,15,11,2 43,46 .1 35,41 .0 9,13 ]pentacarbonyl-37,43(54),44,46(53),47-pentaene-16,1′-cyclobutane]-22-carboxamide,

[0579] (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47Z)-19-cyclopentyl-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-3,3′,3′,18,21,25,31,34-octamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24,15,10,25,31,34]- 43,46 .1 35,41 .0 9,13 ]pentacontan-37,43(53),44,46(52),47-pentacontan-16,1′-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecanone,

[0580] (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47Z)-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-19-(1-ethylpropyl)-3,3′,3′,18,21,25,31,34-octamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24,15,10,25]] 43,46 .1 35,41 .0 9,13 ]pentacontan-37,43(53),44,46(52),47-pentacontan-16,1′-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecanone,

[0581] (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47Z)-19-cyclopentyl-31-cyclopropyl-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-3,3′,3′,18,21,25,34-heptamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24,15,10,25,34]- 43,46 .1 35,41 .0 9,13 ]pentacontan-37,43(53),44,46(52),47-pentacontan-16,1′-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecanone,

[0582] (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47Z)-31-cyclopropyl-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-19-(1-ethylpropyl)-3,18,21,25,34-pentamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24,15,10,25] 43,46 .1 35,41 .0 9，13 ]pentacontan-37,43(53),44,46(52),47-pentacontan-16,1′-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecanone, and

[0583] (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47Z)-7-[2-(3,4-dichlorophenyl)ethyl]-11-ethoxy-19-(1-ethylpropyl)-3,18,21,25,31,34-hexamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24,15,11,25,31,34-hexamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24,15,11,25,31,34-hexamethyl-29-[(1S)-1-methylpropyl] 43,46 .1 35 ,41 .0 9，13]pentacarbonyl-37,43(54),44,46(53),47-pentaene-16,1′-cyclobutane]-2,5,8,14,17,20,24,27,30,33,55-undecanone.

[0584] In one embodiment, the compound of the present invention is preferably a compound represented by formula (3):

[0585]

[0586] In formula (3), R1 is a C1 to C7 alkyl group;

[0587] R5 is benzyl optionally substituted with one or more groups selected from the group consisting of:

[0588] C1 to C6 alkyl, C1 to C6 haloalkyl, and C3 to C8 cycloalkyl;

[0589]

[0590] n、m、P 1、 R2, R3, P3, P4, P6, R7, R8, P8, R9, P9, Q9, R 10 、P 10 、R 11 and P 11 Same as the definition in formula (1).

[0591] For example, compounds PP1574, PP1650, PP2093, PP2316, PP2320, PP2328, PP2687, PP2691, PP3095, PP3096, PP3097, PP3098, PP3099, PP3100, PP3101, PP3102, PP3103, PP3104, PP3105, PP3106, PP3110, PP3111, PP3112, PP3113, PP3114, PP3115, PP3116, PP3117, PP3118, PP3119, PP3120, and PP3121 can be included in formula (3).

[0592] In one embodiment, the cyclic compounds of the present invention have high selectivity for KRAS. In one embodiment, the cyclic compounds of the present invention selectively inhibit KRAS. Without wishing to be bound by a particular theory, the divalent group formed by R4 and P5 together interacts with His95 of KRAS, and thereby can achieve high selectivity for KRAS. Although three isoforms of RAS proteins are known to exist, namely HRAS, KRAS, and NRAS, His95 is only present in KRAS. Therefore, compounds that specifically interact with His95 of KRAS can inhibit KRAS with high selectivity relative to NRAS and / or HRAS.

[0593] In the present invention, the origin of NRAS, HRAS, and KRAS is 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 human-derived HRAS, KRAS, and NRAS are preferred. The amino acid sequence of human-derived NRAS is shown in SEQ ID NO: 1, the amino acid sequence of human-derived HRAS is shown in SEQ ID NO: 2, and the amino acid sequence of human-derived KRAS is shown in SEQ ID NO: 3.

[0594] In one embodiment, the cyclic compounds of the present invention have KRAS inhibitory activity that is 3 times or more greater than the NRAS inhibitory activity and / or HRAS inhibitory activity. In one embodiment, the cyclic compounds of the present invention have KRAS binding activity that is 3 times or more greater than the NRAS binding activity and / or HRAS binding activity.

[0595] In one embodiment, the cyclic compounds of the present invention have KRAS inhibitory activity that is 5-fold, 7-fold, 10-fold, 15-fold, or 20-fold or more greater than the NRAS inhibitory activity and / or HRAS inhibitory activity. In one embodiment, the cyclic compounds of the present invention have KRAS binding activity that is 5-fold, 7-fold, 10-fold, 15-fold, or 20-fold or more greater than the NRAS binding activity and / or HRAS binding activity.

[0596] In the present invention, 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 invention to the NRAS inhibitory activity and / or the HRAS inhibitory activity of the cyclic compound of the present invention. For example, when the ratio is defined as [IC of the cyclic compound of the present invention relative to NRAS and / or HRAS] 50 value] divided by [IC value of the cyclic compound of the present invention relative to KRAS 50[value], a larger value of the ratio means that the KRAS inhibitory activity is higher than the NRAS inhibitory activity and / or HRAS inhibitory activity, or in other words, the KRAS selective inhibitory activity of the cyclic compound of the present invention is high. On the other hand, a smaller value of the ratio means that the KRAS inhibitory activity is lower than the NRAS inhibitory activity and / or HRAS inhibitory activity, or in other words, the KRAS selective inhibitory activity of the cyclic compound of the present invention is low.

[0597] In the present invention, the KRAS binding activity relative to the NRAS binding activity and / or HRAS binding activity can be determined by the ratio of the KRAS binding activity of the cyclic compound of the present invention to the NRAS binding activity and / or HRAS binding activity of the cyclic compound of the present invention. For example, when the 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 HRAS binding activity, or in other words, the binding selectivity for KRAS is higher than 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 HRAS binding activity, or in other words, the binding selectivity for KRAS is lower than NRAS and / or HRAS.

[0598] In the present invention, "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 invention may or may not be mediated by another molecule such as water molecule, but is preferably not mediated by another molecule such as water molecule.

[0599] In the present invention, whether the 95th amino acid residue histidine (expressed as His95 or H95) in the human KRAS wild-type protein interacts with the cyclic compound can be determined by the interatomic distances of their non-hydrogen atoms (in the case of bonding via another molecule (such as a water molecule), the interatomic distances between their non-hydrogen atoms do not take such another molecule into account). When the interatomic distance is 5.1 angstroms, the interaction between the cyclic compound and the non-hydrogen atoms is determined. 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 smaller, or smaller, or smaller, or smaller, or smaller, or smaller, or smaller, or smaller, or or smaller. In addition, the interatomic distance can be or larger, or larger, or or larger.

[0600] In the present invention, 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 of the present invention. Specifically, a crystal of a complex of a human KRAS wild-type protein and a cyclic compound of the present invention is prepared. The crystal is subjected to X-ray diffraction measurement 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 for initial structure or fine structure determination well known to those skilled in the art, such as Coot (Emsley, P. et al., 2010), Phenix (Adams, PD et al., 2010), Phaser (J. Appl. Cryst. 40: 658-674 (2007)), Refmac5 (Acta Cryst. D67: 355-467 (2011)) and ARP / wARP (Cohen, SX et al., 2008), and thereby the three-dimensional structure of the complex of a human KRAS wild-type protein and a cyclic compound of the present invention can be determined.

[0601] Once the three-dimensional structure of the complex of the human KRAS wild-type protein and the cyclic compound of the present invention is determined, the interatomic distances can be measured by methods well known to those skilled in the art. For example, the structural information of the complex of the cyclic compound of the present invention and the human KRAS wild-type protein can be read by a software program (such as Discovery Studio 2020 Client, MOE (Molecular Operating Environment) or Maestro) that allows for use in molecular modeling or molecular simulation, and the interatomic distances can be measured using a function incorporated into the software program (such as the distance monitor function in the case of the Discovery Studio 2020 client). Detailed information on the conditions and criteria for the presence or absence of an interaction used by the software can be viewed in manuals, specifications, etc. attached to the software (for example, in the case of the Discovery Studio 2020 client, detailed information on the conditions and criteria for determining the presence or absence of an interaction can be viewed by opening the webpage of the instruction manual from the help button, selecting "Receptor-ligand interaction tool", then selecting "Theory-Receptor-ligand interaction", and further selecting "Non-bonded interaction").

[0602] Crystals of a complex of human KRAS wild-type protein and the cyclic compound of the present invention can also be obtained by methods well known to those skilled in the art. For example, a solution containing the cyclic compound of the present invention is mixed with a solution containing human KRAS wild-type protein to obtain a complex of human KRAS wild-type protein and the cyclic compound of the present invention. Crystals of a complex of human KRAS wild-type protein and the cyclic compound of the present invention can be prepared by subjecting the resulting complex to a crystallization method well known to those skilled in the art (such as vapor diffusion method, batch method (batch method or microbatch method), dialysis method or reverse diffusion method). Known vapor diffusion methods are sitting drop method, hanging drop method and sandwich drop method.

[0603] Human KRAS wild-type protein can also be obtained by methods known to those skilled in the art. For example, human KRAS wild-type protein can be prepared by a recombinant polypeptide expression method using a cell, but the method is not limited thereto. In one embodiment, the nucleic acid encoding the human KRAS wild-type protein of the present invention is inserted into a suitable expression vector, the vector is introduced into a suitable cell, the transformed cells are cultured, and the expressed protein is isolated and purified. Such proteins can also be expressed as a fusion protein with another protein to facilitate purification. For example, a method for preparing a fusion protein with maltose binding protein (a vector pMAL series sold by New England BioLabs, USA) using Escherichia coli as a host, a method for preparing a fusion protein with glutathione-S-transferase (GST) (a vector pGEX series sold by Amersham Pharmacia Biotech), a method for preparing a protein to which a histidine tag is added (Novagen's pET series), and a method for preparing a protein to which a HAT tag is added can be used. As long as the host cell is a cell suitable for expressing recombinant protein, there is no particular limitation, and in addition to the above-mentioned Escherichia coli (E. coli), for example, 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 introducing Escherichia coli, a method for introducing calcium ions (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 can be used. TM Equipment (GE Healthcare), NGC TM Chromatography system (Bio-Rad), BioLogic DuoFlow TM Chromatography system (Bio-Rad), etc.

[0604] Interatomic energy can also be measured by methods well known to those skilled in the art. For example, it is possible to easily calculate interatomic energy by allowing a molecular simulation program well known to those skilled in the art (such as Discovery Studio 2020 client, MOE (Molecular Operating Environment) or Maestro) to read the three-dimensional structure of the substance to be measured and selecting the force field to be used for calculation (such as Amber or CHARM) and the atoms to be calculated for energy calculation according to the instructions of the program. For example, in the case of the Discovery Studio 2020 client, the interatomic energy can be calculated using the calculation interaction energy function.

[0605] In one non-limiting example, in a complex of a cyclic compound of the present invention and a human KRAS wild-type protein, the cyclic compound of the present invention interacts with His95 in the human KRAS wild-type protein.

[0606] Without wishing to be bound by a particular theory, it is believed that the formation of a complex between the cyclic compounds of the present invention and the human KRAS wild-type protein in this manner is associated with a contribution to the high binding activity of the cyclic compounds to the human KRAS wild-type protein and, moreover, has binding selectivity relative to HRAS and NRAS.

[0607] The present invention also relates to non-natural amino acids for use in producing cyclic compounds of the present invention. In one embodiment, the non-natural amino acids of the present invention are N-protected non-natural amino acids for use in producing peptide compounds using solid phase synthesis methods, and in another embodiment, the non-natural amino acids of the present invention are non-natural amino acids having free amino groups obtained by removing protecting groups from N-protected non-natural amino acids. Examples of protecting groups for N-protected non-natural amino acids include Fmoc groups, Boc groups, Cbz groups, Alloc groups, p-nitrobenzenesulfonyl groups, dinitro-p-nitrobenzenesulfonyl groups, t-Bu groups, trityl groups, and cumyl groups. Among them, Fmoc groups, Boc groups, Cbz groups, and Alloc groups are preferred, and Fmoc groups are more preferred.

[0608] In one embodiment, examples of the N-protected non-natural amino acid having an Fmoc group as a protecting group in the present invention include the following amino acids listed in Table 4 or salts thereof, or solvates thereof.

[0609] aa004: (2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]octanoic acid,

[0610] aa013: (2R)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-3-methylsulfanyl-propionic acid,

[0611] aa019: (2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4,4-difluoro-butyric acid,

[0612] aa023: (2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-3-(3-thienyl)propanoic acid,

[0613] aa028: (2S)-3-(3,4-dichlorophenyl)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]propionic acid,

[0614] aa043: (2S)-5,5-dichloro-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]pentanoic acid,

[0615] aa056: (2R)-3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-2-methyl-propionic acid,

[0616] aa098: (2S,3S)-1-(9H-fluoren-9-ylmethoxycarbonyl)-3-methyl-azetidine-2-carboxylic acid,

[0617] aa099: (2S,3R)-1-(9H-fluoren-9-ylmethoxycarbonyl)-3-methyl-azetidine-2-carboxylic acid,

[0618] aa100: (2S)-1-(9H-fluoren-9-ylmethoxycarbonyl)-3,3-dimethyl-azetidine-2-carboxylic acid,

[0619] aa111: (2R)-3-allyloxy-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]propionic acid,

[0620] aa136: (2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(propyl)amino]-3-[4-(trifluoromethyl)phenyl]propanoic acid,

[0621] aa174: (2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(propyl)amino]-3-(p-tolyl)propanoic acid,

[0622] aa210: (2S)-2-cyclopentyl-2-[ethyl(9H-fluoren-9-ylmethoxycarbonyl)amino]acetic acid,

[0623] aa220: (2S)-4-(4-Chloro-3,5-difluoro-phenyl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)butanoic acid,

[0624] aa229: (2S)-4-(Benzothiophene-5-yl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)butanoic acid,

[0625] aa233: (2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-4-[3-methyl-4-(trifluoromethyl)phenyl]butanoic acid,

[0626] aa235: (2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-4-[3-methoxy-4-(trifluoromethyl)phenyl]butanoic acid,

[0627] aa239: (2S,4S)-1-(9H-fluoren-9-ylmethoxycarbonyl)-4-methyl-pyrrolidine-2-carboxylic acid,

[0628] aa244: (2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-5,5-difluoro-pentanoic acid,

[0629] aa246: (2S,4R)-1-(9H-fluoren-9-ylmethoxycarbonyl)-4-propoxy-pyrrolidine-2-carboxylic acid,

[0630] aa250: (2R)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-3-propoxy-propionic acid,

[0631] aa264: (2S,3R)-1-(9H-fluoren-9-ylmethoxycarbonyl)-3-tetrahydropyran-2-yloxy-pyrrolidine-2-carboxylic acid,

[0632] aa265: (2S,3S)-1-(9H-fluoren-9-ylmethoxycarbonyl)-3-tetrahydropyran-2-yloxy-pyrrolidine-2-carboxylic acid,

[0633] aa268: (1S,2S,5R)-3-(9H-fluoren-9-ylmethoxycarbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid,

[0634] aa279: (2S,4R)-1-(9H-fluoren-9-ylmethoxycarbonyl)-4-tetrahydropyran-2-yloxy-pyrrolidine-2-carboxylic acid,

[0635] aa281: (2S,4R)-1-(9H-fluoren-9-ylmethoxycarbonyl)-4-methoxy-pyrrolidine-2-carboxylic acid,

[0636] aa331: (2S)-3-Ethyl-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]pentanoic acid,

[0637] aa389: (2S)-2-[9H-Fluoren-9-ylmethoxycarbonyl(propyl)amino]-4-methyl-pentanoic acid,

[0638] aa391: (2S,3R)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-propoxy-butanoic acid,

[0639] aa397: (2S)-2-[9H-Fluoren-9-ylmethoxycarbonyl(propyl)amino]-3-isopentyloxy-propionic acid,

[0640] aa398: (2S)-3-(Cyclobutyloxy)-2-[9H-fluoren-9-ylmethoxycarbonyl(propyl)amino]propanoic acid,

[0641] aa399: (2S)-4-(7-Chloro-1-methyl-indol-5-yl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)butanoic acid,

[0642] aa400: (2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-4-(2-fluoro-3-methyl-benzothiophen-5-yl)butanoic acid,

[0643] aa401: (2S)-4-(7-chlorobenzothiophen-5-yl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)butanoic acid,

[0644] aa402: (2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-4-(1-methylindol-6-yl)butanoic acid,

[0645] aa403: (2S)-4-(1,3-dimethylindol-6-yl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)butanoic acid,

[0646] aa404: (2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-4-(1,2,3-trimethylindol-6-yl)butanoic acid,

[0647] aa405: (2S)-4-(2,3-dimethylbenzothiophen-5-yl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)butanoic acid,

[0648] aa406: (2S)-4-(3-Chloro-4-ethyl-phenyl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)butanoic acid,

[0649] aa407: (2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-4-[4-(methoxymethyl)-3,5-dimethylphenyl]butanoic acid,

[0650] aa408: (2S)-4-(4-Chloro-3-methoxy-phenyl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)butanoic acid,

[0651] aa409: (2S)-4-[4-chloro-3-(trifluoromethyl)phenyl]-2-(9H-fluoren-9-ylmethoxycarbonylamino)butanoic acid,

[0652] aa410: (2S)-4-[4-(Difluoromethyl)-3,5-difluoro-phenyl]-2-(9H-fluoren-9-ylmethoxycarbonylamino)butanoic acid,

[0653] aa411: (2S)-4-(4-chloro-3,5-dimethyl-phenyl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)butanoic acid,

[0654] aa414: (2S,4R)-4-(cyclopentyloxy)-1-(9H-fluoren-9-ylmethoxycarbonyl)pyrrolidine-2-carboxylic acid,

[0655] aa415: (2S,4R)-4-(cyclobutyloxy)-1-(9H-fluoren-9-ylmethoxycarbonyl)pyrrolidine-2-carboxylic acid,

[0656] aa423: (3S)-3-cyclobutyl-3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]propionic acid,

[0657] aa424: (3R)-3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]pentanoic acid,

[0658] aa425: (3S)-3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-methyl-pentanoic acid,

[0659] aa426: (3S)-3-cyclohexyl-3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]propionic acid, and

[0660] aa443: (2S)-2-[But-3-enyl(9H-fluoren-9-ylmethoxycarbonyl)amino]-3-(p-tolyl)propanoic acid.

[0661] (General production method)

[0662] The following describes a general method for producing the cyclic compounds of the present invention and the oligopeptide compounds and non-natural amino acids used in producing these compounds. Herein, the cyclic compounds may sometimes be referred to as "cyclic peptide compounds." Herein, the "cyclic portion" of the peptide compound means a cyclic portion formed by linking two or more amino acid residues.

[0663] Chemical synthesis methods for peptide compounds

[0664] In this article, the example of the chemical synthesis method for peptide compounds or cyclic compounds includes liquid phase synthesis method, solid phase synthesis method and combination thereof using Fmoc synthesis, Boc synthesis etc. In Fmoc synthesis, basic unit is the amino acid of main chain amino group with Fmoc group protection, and as needed with the protecting group (such as t-Bu group, THP group or Trt group) that is not cracked by piperidine or this type of alkali, and the unprotected amino acid of main chain carboxylic acid. Basic unit is just not particularly limited as long as it is the combination of amino group and carboxyl group with Fmoc protection. For example, dipeptide or tripeptide can be basic unit, and can form cyclic structure between the substituent on nitrogen atom and / or side chain contained in dipeptide or tripeptide. The basic unit arranged at N-terminal can be the unit other than Fmoc amino acid. For example, it can be Boc amino acid or Tfa group or Ns group, or do not have the carboxylic acid analogue of amino group. The main chain carboxyl group or the side chain carboxyl group of an amino acid having a carboxyl group and wherein the main chain carboxyl group is protected with a suitable protecting group is supported on the solid phase by chemical reaction with the functional group of the solid phase support. Subsequently, the Fmoc group is deprotected with a base (such as piperidine or DBU), and a condensation reaction is performed between the newly produced amino group and the subsequently added amino acid having a carboxyl group and protected by the basic unit to produce a peptide bond. In the condensation reaction, various combinations (such as DIC and HOBt, DIC and HOAt, and HATU and DIPEA) can serve as activators of the carboxyl group. The desired peptide sequence can be produced by repeating the Fmoc group deprotection and subsequent peptide bond formation reaction. After obtaining the desired sequence, cleavage from the solid phase and deprotection of the optionally introduced side chain functional group protecting group are performed. In addition, conformational transformation and cyclization of the peptide can be performed 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 desired. In some cases, weak acid (such as 1% TFA) can be used to realize cracking from solid phase, and the protecting group that can be used to deprotect with catalyst etc. containing Pd can be used to utilize the orthogonality of two chemical reactions.During these steps or at the end, step (such as cyclization) can also be carried out.For example, side chain carboxylic acid and N-terminal main chain amino group can be condensed, and side chain amino group and C-terminal main chain carboxylic acid can be condensed.In addition, olefin can be introduced into two or more sites of side chain and / or nitrogen atom substituent, and by metathesis reaction cyclization.In addition, the double bond produced by cyclization can be reduced to single bond.In addition, the double bond produced by cyclization can be converted into cyclopropane ring under the conditions involving diiodomethane-diethylzinc etc. These cyclizations, reductions, the steps of being converted into cyclopropane ring etc. can be carried out during the synthesis of basic unit (such as dipeptide or tripeptide).At the same time, 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 substituent of the nitrogen-atoms and the alkene to be cyclized, require reaction orthogonality. As mentioned above, the orthogonality of the blocking group is considered to select the blocking group. In addition, by placing a chloroacetyl group at the N-terminal, cyclization can also be carried out between the thiol groups of the cysteine ​​residue side chain. The reaction product thus obtained can be purified by reversed-phase columns, molecular sieve columns, etc. The details of these programs are described in, for example, the Solid-Phase Synthesis Handbook published by Merck on May 1, 2002. The commercially available resins for solid phase synthesis are applicable, and examples include CTC resins, Wang resins, and SASRIN resins.

[0665] A general method for synthesizing an amino acid-loaded resin for use in peptide synthesis by a peptide synthesizer will be described below.

[0666] Fmoc amino acid can be supported on resin by the method described in WO2013 / 100132 or WO2018 / 225864.Specifically, for example, 2-chlorotrityl chloride resin and solvent (for example, dehydrated dichloromethane) are introduced into the reaction vessel equipped with a filter so that the resin swells.Next, the solvent and resin are separated, and then the mixture of resin, the C-terminal free Fmoc amino acid dissolved in the solvent (for example, dehydrated dichloromethane), solvent (for example, dehydrated methanol) and alkali (for example, diisopropylethylamine) is added into the reaction vessel and mixed to support Fmoc amino acid on resin.After separating resin and reaction solution, resin is mixed with the mixture of one or more solvents and alkali (for example, dehydrated dichloromethane, dehydrated methanol and diisopropylethylamine) to wash resin.After repeatedly washing resin with solvent (for example, dichloromethane) as needed, separating resin and reaction solution.By drying the gained resin under reduced pressure overnight, the resin of Fmoc amino acid load can be obtained.

[0667]

[0668] (wherein n represents an integer from 1 to 11; P1 to P 11 , Q1 to Q 11 and R1 to R 11 means P1 to P2 as defined herein, respectively 11 , Q1 to Q 11 and R1 to R 11 ; L1 and L 11 means L1 and L as described herein, respectively 11 ; L2 to L 10 is a single bond; and o (circle) means the resin portion. )

[0669] The above structure shows that in the Fmoc-amino acid, the 2-chlorotrityl group on the resin is bonded to the carboxylic acid of the Fmoc amino acid via an ester bond.

[0670] In the production of compound described herein, when defined group experiences undesirable chemical transformation under the conditions of the method carried out, the compound can be produced by the protection and deprotection of functional group for example. The selection of blocking group and introduction / removal program can be carried out according to the method described in " Protective Groups in Organic Synthesis " (the 5th edition, John Wiley & Sons, 2014) of for example Greene, and this method can be suitably used according to reaction conditions. In addition, the order of the reactions steps such as the introduction of substituents can be changed as required. For example, the blocking group for amino group is Fmoc, Boc, Cbz or Alloc group. These carbamate groups can be introduced by making amino group react with carbamateizing agent in the presence of a basic catalyst. The example of carbamateizing agent comprises Boc O, 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 group as a protecting group for the amino group can be removed under alkaline conditions, acidic conditions, hydrogenolysis reaction conditions, etc.

[0671] (Method for synthesizing cyclic compounds by cyclization of peptide compounds)

[0672] The method for converting a linear peptide compound into a cyclic peptide compound can be carried out by performing a bond-forming reaction within the molecule according to the method described in, for example, 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 bond-forming reaction, further functional group conversion reactions can be carried out. Examples of bond-forming reactions include C(O)-N bonds formed by 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, CSSC bonds, CSC bonds, CS(O)-C bonds, and CS(O2)-C bonds using sulfur atoms; and C-N-C bonds, C=N-C bonds, NC(O)-N bonds, NC(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 reaction, Heck reaction, Sonogashira reaction, and metathesis reaction. Examples of functional group conversion reactions further performed after the bonding reaction include oxidation reactions and reduction reactions. A specific example is a reaction for oxidizing a sulfur atom to convert it into a sulfoxide group or a sulfone group. Another example is a reduction reaction for reducing a triple bond or double bond in a carbon-carbon bond to a double bond or a single bond. Although a closed ring structure is formed by 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 by bonding between the side chains of the two amino acids, bonding between the side chain and the backbone, etc. The black circles or black squares below indicate amino acid residues, and the connected black circles or black squares represent peptide chains connected by amide bonds. 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 black circles or black squares exemplified below.

[0673] (General Preparation Method 1 for Cyclic Compounds)

[0674]

[0675] The cyclic portion of a cyclic compound having a linear portion 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 converting it into an active ester and then condensing it in the molecule to form a C(O)-N bond.

[0676] (General Preparation Method 2 for Cyclic Compounds)

[0677]

[0678] The cyclic compound described in “General Preparation Method 1 for Cyclic Compounds” in which the straight-chain portion is the C-terminal 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 converting it into an active ester and then condensing it in the molecule to form a C(O)-N bond.

[0679] (General Preparation Method 3 for Cyclic Compounds)

[0680] (Method of cyclization using a haloalkyl group and an SH group)

[0681]

[0682] The cyclic portion of a cyclic compound having a linear portion can be cyclized by reacting a haloalkyl group of an amino acid residue in the molecule with a thiol group of the amino acid residue to form a C-S-C bond. The cyclic compound described in "General Preparation Method 1 for Cyclic Compounds" in which the linear portion is C-terminal can also be cyclized similarly by reacting a haloalkyl group of an amino acid residue in the molecule with a thiol group of the amino acid residue to form a C-S-C bond. In addition, a C-S-C (O) -C or C-S-C (O 2 ) -C bond can also be formed by oxidizing a sulfur atom and converting it into a sulfoxide or sulfone.

[0683] (Method of cyclization using vinyl group and SH group) The cyclic portion of a cyclic compound having a linear portion can be cyclized by reacting a vinyl group of an amino acid residue in the molecule with a thiol group of the amino acid residue to form a C-S-C bond. Cyclic compounds described in "General Preparation Method 1 for Cyclic Compounds" in which the linear portion is C-terminal can also be similarly cyclized by reacting a vinyl group of an amino acid residue in the molecule with a thiol group of the amino acid residue to form a C-S-C bond. In addition, a C-S-C (O) -C or C-S-C (O 2 ) -C bond can also be formed by oxidizing a sulfur atom and converting it into a sulfoxide or sulfone.

[0684] (Method of cyclization using ethynyl and SH groups)

[0685]

[0686] The cyclic portion of a cyclic compound having a straight chain portion 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 CSC bond. The cyclic compound described in "General Preparation Method 1 for Cyclic Compounds" wherein the straight chain portion is C-terminal can also be similarly 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 CSC bond. In addition, a C-S(O)-C or C-S(O2)-C bond can also be formed by oxidizing a sulfur atom and converting it into a sulfoxide or sulfone. Double bond sites can also be reduced and converted into single bonds.

[0687] (Method of cyclization using vinyl group and vinyl group)

[0688]

[0689] The cyclic portion of a cyclic compound having a linear portion can be cyclized by reacting different vinyl groups of amino acid residues in the molecule to form a C-C bond. The cyclic compound described in "General Preparation Method 1 for Cyclic Compounds" in which the linear portion is the C-terminus can also be cyclized similarly by reacting different vinyl groups of amino acid residues in the molecule to form a C-C bond.

[0690] (Method of cyclization by forming a triazole ring using an azide group and an ethynyl group)

[0691]

[0692] The cyclic portion of a cyclic compound having a linear portion can be cyclized by reacting an azide group of an amino acid residue in the molecule with an ethynyl group of an amino acid residue to form a triazole ring. The cyclic compound described in "General Preparation Method 1 for Cyclic Compounds" in which the linear portion is the C-terminus can also be cyclized similarly by reacting an azide group of an amino acid residue in the molecule with an ethynyl group of an amino acid residue to form a triazole ring.

[0693] The general method for preparing peptide compounds by peptide modification is as follows. In the following scheme, P n represents a substituent of a nitrogen atom, R n and Q n Each represents an amino acid side chain, black circles represent amino acid residues, connected black circles represent peptide chains connected by amide bonds, and m represents the number of amino acid residues and can be any integer of 1 or greater.

[0694] (Method for producing a peptide containing an N-alkyl amino acid)

[0695] The peptide that contains N-alkyl amino acid whose N-alkyl amino acid can use Fmoc protection as raw material, synthesizes according to the general peptide synthesis method of describing in this example, or can prepare by the N-terminal nitrogen alkylation on the resin, as shown below alternatively.Particularly, the target peptide with N-alkyl amino acid at N-terminal place can be by utilizing with reference to Organic Letters, 2008,10,4815-4818 etc. and the nitrogen of the N-terminal Tfa amides (trifluoroacetamide) of the peptide that makes resin load react under alkaline conditions with alkyl halide, and it is then prepared with reducing agent processing peptide.In addition, cyclic compound can be by extending peptide, cracking, cyclization, deprotection and purification from resin and prepare according to the general peptide synthesis method of describing in this example.

[0696]

[0697] The method described in Nature Protocols, 2012, 7, 432-444 shown below can also be used to convert P n Another method to introduce P into the N-terminal nitrogen. Specifically, the N-terminal amine of the resin-supported peptide can be converted into an Ns substituted form and introduced into P by Mitsunobu reaction. n , and then deprotecting the Ns group to obtain a P at the N-terminus n In addition, cyclic compounds can be prepared by extending the peptide, cleaving it from the resin, cyclizing it, deprotecting it, and purifying it according to the general peptide synthesis method described in this example.

[0698]

[0699] Contains P introduced onto nitrogen atoms n Peptides containing glycine can be treated with P-terminal peptides with Fmoc protection introduced onto the nitrogen atom. n Glycine is used as a starting material and synthesized according to the general peptide synthesis method described in this example, or alternatively, it can be prepared by a substitution reaction between an N-terminal halogenated carbon and an amine, as shown below. Specifically, a P having a P introduced to a nitrogen atom n The target peptide containing an N-terminal glycine can be obtained by reacting the N-terminal amine with iodoacetic acid and then reacting it with any primary amine, referring to Organic Letters, 2010, 12, 4928-4931, etc. In addition, a cyclic compound can be prepared by extending the peptide according to the general peptide synthesis method described in this example, cleaving it from the resin, cyclizing it, deprotecting it, and purifying it.

[0700]

[0701] (Method for preparing a peptide containing an aryloxy or heteroaryloxy group on the side chain)

[0702] Peptides containing an aryloxy or heteroaryloxy group on the side chain can be prepared using an Fmoc amino acid having a target aryloxy or heteroaryloxy group on the side chain as a raw material according to the general peptide synthesis method described in this example, or alternatively, peptides having an alcohol on the side chain can be used as precursors by referring to Organic Letters, 2014, 16, 4944-4947, Tetrahedron Letters, 2003, 44, 3863-3865, etc., as shown below. Specifically, peptides having an aryloxy or heteroaryloxy group on the side chain can be prepared by reacting a peptide having an alcohol on the side chain with a triarylborinane-pyridine complex in the presence of copper (II) acetate.

[0703]

[0704] Peptides having an ether group other than an aryloxy or heteroaryloxy group on the side chain can be prepared using an Fmoc amino acid having a target ether group on the side chain as a raw material according to the general peptide synthesis method described in this example, or alternatively, peptides having an alcohol on the side chain can be prepared as precursors by referring to the method described in Journal of Medicinal Chemistry, 2011, 54, 4815-4830 or Journal of Medicinal Chemistry, 2014, 57, 159-170, as shown below. 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 an aqueous sodium hydroxide solution as a base in the presence of a phase transfer catalyst such as a tetraalkylammonium salt.

[0705]

[0706] (Method for preparing a peptide containing an aryl or heteroaryl group on a side chain)

[0707] The peptide having an aryl or heteroaryl group on the side chain can be prepared using an Fmoc amino acid having a target aryl or heteroaryl group on the side chain as a raw material according to the general peptide synthesis method described in this example, or alternatively, a peptide having a carboxylic acid on the side chain can be prepared as a precursor by referring to the method described in J. Am. Chem. Soc., 2016, 138, 5016-5019, etc., as shown below. Specifically, the peptide having a target aryl or heteroaryl group on the side chain can be prepared by activating a peptide having a carboxylic acid on the side chain with N-hydroxyphthalimide and reacting it with any aryl halide or heteroaryl halide.

[0708]

[0709] Peptides having a carboxylic acid as a substituent of a nitrogen atom in the molecule and / or in a side chain and an aryl halide or heteroaryl halide as a substituent of another nitrogen atom and / or in another side chain can be used to produce peptide compounds in which the peptide backbone is cross-linked. Specifically, cross-linked compounds can be produced by activating a peptide having a carboxylic acid with N-hydroxyphthalimide and cross-linking it by reacting it with an aryl halide or heteroaryl halide in the molecule.

[0710]

[0711] Alternatively, peptides having an aryl or heteroaryl group on the side chain can also be synthesized by Suzuki coupling using a peptide having a boronic acid on the side chain as a precursor, as shown below. Specifically, the target peptide having an aromatic ring on the side chain can be prepared by synthesizing a precursor peptide using an Fmoc amino acid having a boronic acid on the side chain as a raw material and reacting it with any aryl halide in the presence of a palladium catalyst.

[0712]

[0713] A peptide having a boronic acid as a substituent of a nitrogen atom in the molecule and / or in a side chain and an aryl halide as 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 cross-linked. Specifically, the cross-linked compound can be produced by reacting a peptide having a boronic acid with an aryl halide in the molecule in the presence of a palladium catalyst, thereby cross-linking.

[0714]

[0715] A peptide compound cross-linked with an arylene-containing alkylene group can be produced using a peptide having an olefin as a substituent of a nitrogen atom in the molecule and / or in a side chain and an aryl halide as a substituent of another nitrogen atom and / or in another side chain. Specifically, the cross-linked compound can be produced by converting the olefin into a boron compound by a hydroboration reaction, which is then reacted with the intramolecular aryl halide in the presence of a palladium catalyst to produce a cross-linked peptide compound.

[0716]

[0717] (Method for preparing a peptide having an amide group on the side chain)

[0718] The peptide having an amide group on the side chain can be synthesized using an Fmoc amino acid having a target amide group on the side chain as a raw 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, the target peptide having an amide group on the side chain can be synthesized 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).

[0719]

[0720] Peptides having a carboxylic acid in a substituent of a nitrogen atom in the molecule and / or in a side chain and an amino group in a substituent of another nitrogen atom and / or in another side chain can be used to produce peptide compounds in which the peptide backbone is cross-linked. Specifically, cross-linked compounds can be produced by synthesizing precursor peptides having carboxylic acid and amino groups by deprotection, and condensing them using a condensing agent (such as HATU) to cross-link by an intramolecular amidation reaction.

[0721]

[0722] (Synthesis of peptides containing highly substituted structures that may contain double bonds in the side chains)

[0723] Peptides with highly substituted structures that may contain double bonds in their side chains can be synthesized using Fmoc amino acids with the desired double bonds in their side chains as starting materials, or alternatively, can be prepared by functionalization of terminal olefins. Specifically, peptides with terminal olefins in their side chains can be synthesized according to the general peptide synthesis method described in this example, and the side chains can be further converted into side chains with highly substituted olefins by coupling with substrates having any terminal olefins via an olefin metathesis reaction. In addition, side chains can be converted into corresponding side chains by reducing the olefins via a hydrogenation reaction.

[0724]

[0725] The peptide compound with cross-linked peptide backbone can also be prepared using peptides with multiple double bonds in the substituent of the nitrogen atom and / or in the side chain. Specifically, the cross-linked compound can be synthesized according to the general peptide synthesis method described in this example with a peptide having olefins at two sites of the substituent of the nitrogen atom and / or the side chain, and further prepared by cross-linking two olefins by olefin metathesis reaction with reference to Nature Protocols, 2011, 6, 761-771. In addition, the compound cross-linked with saturated alkylene groups can be prepared by reducing olefins by hydrogenation.

[0726]

[0727] Peptides containing an aryl group containing an olefin-containing substituent in a nitrogen atom and / or in a side chain can be used to produce peptide compounds cross-linked with an arylene group and a divalent group containing a double bond as a cross-linked compound. Specifically, the cross-linked compound can be produced by synthesizing a peptide containing an olefin in a substituent of a nitrogen atom in the molecule and / or in a side chain and an olefin in a substituent of another nitrogen atom and / or in another side chain according to the general peptide synthesis method described in the examples, and cross-linking the two olefins by an olefin metathesis reaction. In addition, compounds cross-linked with an alkylene group containing an arylene group can be produced by reducing the olefin by a hydrogenation reaction.

[0728]

[0729] (Synthesis of peptides containing triazole on the side chain)

[0730] Peptides having a triazole on the side chain can be prepared by a click reaction with an azido group. Specifically, a peptide compound having an azido group on the side chain can be prepared by synthesizing a peptide having an azido group on 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 with reference to Bioorganic & Medicinal Chemistry Letters, 2009, 19, 4130-4133, etc.

[0731]

[0732] Peptides having an azide group in a substituent of a nitrogen atom in the molecule and / or in a side chain and an acetylene in a substituent of another nitrogen atom and / or in another side chain can be used to produce peptide compounds in which the peptide backbone is cross-linked. Specifically, cross-linked compounds can be produced by reacting a peptide having an azide group with an acetylene in the molecule in the presence of a palladium catalyst, thereby cross-linking.

[0733]

[0734] (Synthesis of a peptide containing an aryl group substituted with an alkynyl group on the side chain)

[0735] A peptide containing an aryl group substituted with an alkynyl group on the side chain can be synthesized by a Sonogashira coupling reaction with an aryl halide group. Specifically, conversion into a peptide compound having an aryl group substituted with an alkynyl group on the side chain can be performed by synthesizing a peptide having an aryl iodide group on 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.

[0736]

[0737] Peptides having an aryl halide as a substituent of a nitrogen atom in the molecule and / or in a side chain and an acetylene as a substituent of another nitrogen atom and / or in another side chain can be used to produce peptide compounds in which the peptide backbone is cross-linked. Specifically, cross-linked compounds can be produced by coupling a peptide having an aryl iodide with an acetylene in the molecule in the presence of copper (I) iodide, thereby cross-linking.

[0738]

[0739] (General method for producing oligopeptide compounds)

[0740] A general method for producing oligopeptides having a cyclic structure formed between a nitrogen atom substituent and a side chain is provided below. In the following schemes, PG1 and PG1′ represent nitrogen atom protecting groups, PG2 and PG2′ represent oxygen atom protecting groups, and R n-1 、R n 、R n+1 and Q n represents the side chain of amino acid, P n-1 、P n and P n+1 Y represents the substituent of nitrogen-atoms, and Y and Y represent hydrogen, halogen or alkyl respectively. In the method for producing amino acids provided below, it is expected that the group outside the functional group can undergo chemical reaction. In such cases, introducing a blocking group to an unexpected functional group only enables the desired reaction to proceed. The reaction for connecting and detaching such blocking groups can be carried out by the method described in " Protective Groups in Organic Synthesis " (5th edition, John Wiley & Sons 2014) by Greene. For the conversion reaction of compound functional groups, reference can be made to Comprehensive Organic Transformations: A Guide to Functional Group Preparations (5th edition), Advanced Organic Chemistry: Reactions, Mechanisms, and Structure (8th edition) by Larock or March, Smith.

[0741] Oligopeptide compounds having a cyclic structure formed between the substituent of the nitrogen atom of an amino acid and the side chain of another amino acid can be synthesized using the following method. A protected amino acid can be reacted with an alkylating agent having an alkene in the presence of a base to introduce an alkyl group having an alkene. The C-terminus can then be extended with an amino acid by condensing with the amino acid protected at the C-terminus. The condensation reaction can be carried out using various combinations of carboxyl activators, such as a combination of DIC and HOBt, a combination of DIC and HOAt, and a combination of HATU and DIPEA. Subsequently, the protected nitrogen atom can be deprotected and then extended with a protected amino acid having an alkene in the side chain. The alkene in the molecule can then be cyclized by a metathesis reaction. The C-terminal protecting group can then be deprotected to produce an oligopeptide compound having a free C-terminus and a double bond-containing cyclic structure formed between the substituent of the nitrogen atom and the side chain.

[0742]

[0743] In addition, an oligopeptide compound having a cyclic structure containing a double bond can be used to produce an oligopeptide compound having a cyclic structure in which the double bond is converted into a single bond. Specifically, a C-terminal protected compound having a cyclic structure containing a double bond is reduced by a hydrogenation reaction, and then the C-terminal protecting group is deprotected, thereby producing an oligopeptide compound having a free C-terminal and a cyclic structure formed by an alkylene group between the substituent of the nitrogen atom and the side chain.

[0744]

[0745] In addition, an oligopeptide compound having a cyclic structure containing a double bond can be used to produce an oligopeptide compound having a cross-linked structure in which the double bond is converted into a cyclopropane ring. Specifically, a C-terminally protected compound having a cyclic structure containing a double bond can be subjected to conditions such as diiodomethane-diethylzinc to convert the double bond into a cyclopropane ring. Then, the C-terminal protecting group is deprotected, thereby producing an oligopeptide compound having a cross-linked structure in which the double bond is converted into a cyclopropane ring.

[0746]

[0747] An oligopeptide compound having a cyclic structure formed between the substituent of the nitrogen atom of an amino acid and the side chain of another amino acid can also be synthesized by the following method. According to the method of Freidinger et al. (J. Org. Chem., 1983, 48 (1), 77-81), an oxazolidinone compound having a cyclic protective group introduced can be obtained by allowing an aldehyde to act on a protected amino acid. Then, according to the method of Nguyen et al. (Synthesis, 2009, 12, 1991), an alkyl group having an alkene can be introduced into the nitrogen atom by performing a ring-opening reaction using a silicon compound having an alkene. The C-terminus can then be extended with an amino acid by condensing with a C-terminal protected amino acid. Subsequently, the protected nitrogen atom can be deprotected and then extended with a protected amino acid having an alkene in the side chain. The alkene in the molecule can then be cyclized by a metathesis reaction. The C-terminal protecting group is then deprotected, thereby producing an oligopeptide compound having a free C-terminus and a cyclic structure containing a double bond between the substituent of the nitrogen atom and the side chain.

[0748]

[0749] An oligopeptide containing an aryl group (y = 0 to 2) substituted with an alkenyl group in the side chain can be produced by a Suzuki coupling reaction between an aryl halide group and a boron compound having an alkenyl group. Specifically, a peptide having an aryl iodide group in the side chain can be synthesized according to the general oligopeptide synthesis method described in the examples, and then coupled with a boron compound having an alkenyl group in the presence of a palladium catalyst to convert it into an oligopeptide compound having an aryl group (y = 0 to 2) substituted with an alkenyl group in the side chain.

[0750]

[0751] The oligopeptide compound in which the substituent of the nitrogen atom of an amino acid forms a cyclic structure with the side chain of another amino acid through an amide bond can be synthesized using the following method. Specifically, the C-terminal protected peptide is synthesized according to the general synthesis method described in the example, and then deprotected at the N-terminus and subjected to a reductive amination reaction with an aldehyde compound containing an amino group with a protecting group to introduce an amino group with a protecting group in the N-substituent. It is then condensed with a protected amino acid containing a carboxyl group with a protecting group in the side chain. After removing the protecting groups of the carboxyl group and the amino group, the molecule is subjected to intramolecular condensation and deprotected at the C-terminus, thereby achieving conversion into an oligopeptide compound in which the substituent of the nitrogen atom of an amino acid forms a cyclic structure with the side chain of another amino acid through an amide bond.

[0752]

[0753] (Method for cyclizing a peptide compound on a resin)

[0754] In addition to being cyclized according to the method described in this example, cyclic compounds and oligopeptide compounds having a cyclic structure can also be cyclized by a metathesis reaction on a resin as shown in the following method. Specifically, as a resin-supported peptide, a peptide having olefins at two sites of the substituent and / or side chain of the nitrogen atom is synthesized according to the general peptide synthesis method described in this example, and then the two olefins can be cyclized by a metathesis reaction to produce a compound having a cyclic structure. In addition, the peptide can be extended, cleaved from the resin, cyclized, deprotected and purified according to the general peptide synthesis method described in this example to produce cyclic compounds and oligopeptide compounds having a cyclic structure.

[0755]

[0756] (General preparation method for unnatural amino acids)

[0757] The general method for preparing non-natural amino acids without C-terminal ends in which the nitrogen atoms of the amino acids are protected is as follows. In the following schemes, PG1 and PG1′ each represent a protecting group for a nitrogen atom, PG2 and PG2′ each represent a protecting group for an oxygen atom, PG3 and PG4 each represent a protecting group for an amino acid side chain, and Rn and Q n Each represents an amino acid side chain, P n represents a substituent of a nitrogen atom, P′ represents C 1- C5 alkyl, and R, R', R" and R'" each represent hydrogen or a substituent of an amino group. In the method for preparing amino acids as shown below, functional groups other than the target functional group may cause chemical reactions. In such cases, by introducing protecting groups onto non-target functional groups, only the desired reactions can be allowed to proceed. Examples of such protecting group introduction and removal reactions include the methods described in Greene's "Protective Groups in Organic Synthesis" (5th edition, John Wiley & Sons 2014). For transformation reactions of functional groups of compounds, reference can be made to Larock's "Comprehensive Organic Transformations: A Guide to Functional Group Preparations" (5th edition) or Smith's "March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure" (8th edition).

[0758] Non-natural amino acids having a protecting group (PG1) introduced onto the amino acid nitrogen atom can be prepared using the following method. The target non-natural amino acid without a C-terminus can be prepared by introducing a protecting group onto an amino acid without an N-terminus available from a commercial supplier and deprotecting it according to conventional methods as needed.

[0759]

[0760] The non-natural amino acid having a protecting group (PG1′) introduced onto the nitrogen atom of the amino acid can be prepared using the following method. The target non-natural amino acid without a C-terminus can be prepared according to a conventional method by deprotecting an amino acid having a protecting group (PG1) introduced onto the N-terminus available from a commercial supplier and introducing a protecting group.

[0761]

[0762] Having a substituent (P n ) can be prepared using the following method. According to the method of King et al. (Tetrahedron Letters, 2002, 43 (11), 1987-1990), a bromoacetate derivative available from a commercial supplier is reacted with an amino alcohol, and then a protecting group (PG1) is introduced onto the nitrogen atom. Next, the hydroxyl group is oxidized according to the method of Dess et al. (J. Org. Chem., 1983, 48 (22), 4155-4156), and the aldehyde group is reductively aminated to introduce the amino group according to the method of Borch et al. (J. Org. Chem. 1972, 37 (10), 1673-1674). Next, the target C-terminal-free non-natural amino acid can be prepared by deprotecting the protecting group of the oxygen atom.

[0763]

[0764] N-substituted amino acids can also be introduced into the amino acid nitrogen atom by the following substituents (P n ) is prepared according to the scheme of the invention. A bromoacetate derivative available from a commercial supplier is reacted with an amine (P n NH2) is reacted in the presence of a base, and then a protecting group (PG1) is introduced onto the nitrogen atom. Next, the target non-natural amino acid without a C-terminal end can be prepared by deprotecting the protecting group of the oxygen atom.

[0765]

[0766] Non-natural amino acids having a -CH2-P' group introduced onto the amino acid nitrogen atom can be prepared according to the following scheme. Oxazolidinone compounds having an introduced cyclic protecting group can be obtained by reacting an aldehyde with a C-terminus-free amino acid available from a commercial supplier according to the method of Freidinger et al. (J. Org. Chem., 1983, 48(1), 77-81). Next, the target C-terminus-free non-natural amino acid can be prepared by a ring-opening reaction.

[0767]

[0768] With P introduced into the nitrogen atom of the amino acid n The unnatural amino acids of the group can be prepared according to the following scheme. n The group can be obtained by alkylating the n -X) is introduced into a commercially available amino acid without a C-terminal end by acting thereon in the presence of a base. Then, the non-natural amino acid without a C-terminal end can be produced by performing a deprotection reaction and a protecting group introduction reaction by a conventional method.

[0769]

[0770] Non-natural amino acids having an amide group introduced into the amino acid side chain can be prepared according to the following scheme. The amide group can be introduced into the side chain by deprotecting a commercially available protected amino acid (n=1 or 2) and allowing an amine (R"R"'NH) to act on the resulting carboxylic acid. Next, non-natural amino acids without a C-terminus can be prepared by deprotecting the C-terminal protecting group.

[0771]

[0772] Non-natural amino acids having an amide group introduced into the side chain of an amino acid and a -CH2-P' group introduced into the nitrogen atom of the amino acid can be prepared according to the following scheme. Oxazolidinone compounds having an introduced cyclic protecting group can be obtained by allowing an aldehyde to act on a commercially available protected amino acid (n=1 or 2) according to the method of Freidinger et al. (J. Org. Chem., 1983, 48(1), 77-81). Next, an amide compound can be obtained by deprotecting the side chain protecting group and then allowing an amine (R"R"'NH) to act thereon. Next, the target non-natural amino acid without a C-terminus can be prepared by a ring-opening reaction.

[0773]

[0774] Non-natural amino acids with amino groups introduced into the amino acid side chains can be prepared according to the following scheme. Amide groups can be introduced into the side chains by allowing an amine (R″R″′NH) to act on the carboxyl group of a commercially available protected amino acid (n=1 or 2). Next, non-natural amino acids without a C-terminus can be prepared according to the method of Reeves et al. (Advanced Synthesis & Catalysis, 2013, 355(1), 47-52) by performing a reduction reaction and then deprotecting the protecting group at the C-terminus.

[0775]

[0776] Non-natural amino acids having an amino group introduced into the amino acid side chain and a -CH2-P' group introduced into the amino acid nitrogen atom can be prepared according to the following scheme. An amide group can be introduced into the side chain by allowing an amine (R"R"'NH) to act on the carboxyl group of an amino acid (n = 1 or 2) protected by a cyclic protecting group. Next, the target non-natural amino acid without a C-terminus can be prepared by performing a reduction reaction and then a ring-opening reaction according to the method of Reeves et al. (Advanced Synthesis & Catalysis, 2013, 355(1), 47-52).

[0777]

[0778] Non-natural amino acids with fluoroalkyl groups introduced into the amino acid side chains can be prepared according to the following scheme. The carboxyl group of a commercially available protected amino acid (n=1 or 2) can be reduced and converted into an aldehyde group according to conventional methods, and the aldehyde group can be converted into a difluoromethyl group by introducing a fluorine atom according to conventional methods. Next, non-natural amino acids without a C-terminal end can be prepared by deprotecting the C-terminal protecting group.

[0779]

[0780] Non-natural amino acids having a haloalkyl group introduced into the amino acid side chain and a -CH2-P' group introduced into the amino acid nitrogen atom can be prepared according to the following scheme. The carboxyl group of the amino acid (n = 1 or 2) protected by a cyclic protecting group can be reduced and converted into an aldehyde group according to conventional methods, and the aldehyde group can be converted into a dihalomethyl group by introducing a halogen atom according to conventional methods. Next, non-natural amino acids without a C-terminus can be prepared by ring opening of the C-terminal cyclic protecting group.

[0781]

[0782] A non-natural amino acid without a C-terminus having a haloalkyl group introduced into the amino acid side chain and a -CH2-P' group introduced into the amino acid nitrogen atom can also be prepared by the method shown below.

[0783]

[0784] Non-natural amino acids with aryl or heteroaryl groups (such groups are referred to as "Ar" in this scheme) introduced into the side chain of amino acids can be prepared according to the following scheme. N-hydroxyphthalimide (NHPI) groups can be introduced into the side chain by allowing NHPI to act on the carboxyl group of protected amino acids (n = 1 or 2). Non-natural amino acids with introduced aryl or heteroaryl groups and arylalkyl or heteroarylalkyl groups on the side chain can be prepared by reacting aryl halides or heteroaryl halides according to the method of Huihui et al. (J.Am.Chem.Soc., 2016, 138 (15), 5016-5019). Next, non-natural amino acids without a C-terminal end can be prepared by deprotecting the C-terminal protecting group.

[0785]

[0786] Non-natural amino acids having an aryl or heteroaryl group (such a group is referred to as "Ar" in this scheme) introduced into the side chain of an amino acid and having a -CH2-P' group introduced into the nitrogen atom of the amino acid can be prepared according to the following scheme. An N-hydroxyphthalimide (NHPI) group can be introduced into the side chain by allowing NHPI to act on the carboxyl group of an amino acid (n = 1 or 2) protected by a cyclic protecting group. Non-natural amino acids having an introduced aryl or heteroaryl group and having an arylalkyl or heteroarylalkyl group on the side chain and protected by a cyclic protecting group can be prepared by reacting an aryl halide or heteroaryl halide according to the method of Huihui et al. (J. Am. Chem. Soc., 2016, 138 (15), 5016-5019). Next, the target non-natural amino acid without a C-terminus can be prepared by a ring-opening reaction.

[0787]

[0788] The non-natural amino acid with an aryl or heteroaryl group (such a group is referred to as "Ar" in this scheme) introduced into the amino acid side chain can be prepared according to the following scheme. The non-natural amino acid with an introduced aryl or heteroaryl group and an aralkyl or heteroaralkyl group on the side chain can be prepared by introducing a protecting group into a commercially available protected amino group (n=0 or 1), and then reacting an aryl halide or heteroaryl halide according to the method of He et al. (Org. Lett. 2014, 16 (24), 6488-6491). Next, the target non-natural amino acid without a C-terminal end can be prepared by a deprotection reaction and a protecting group introduction reaction.

[0789]

[0790]

[0791] Non-natural amino acids having a halogen atom introduced into an arylalkyl group on an amino acid side chain can be prepared according to the following scheme. Boronic acid esters can be introduced into amino acids having a substituent (R) on an amino acid side chain according to the method of Ishiyama et al. (J. Am. Chem. Soc. 2002, 124(3), 390-391). a ) on the aralkyl group. Halogen atoms can be introduced into the introduced boronyl group using N-halosuccinimide according to the method of Lindner et al. (Chem. Eur. J., 2016, 22, 13218-13235). The target C-terminal-free non-natural amino acid can be prepared by appropriately introducing a protecting group into the obtained non-natural amino acid or removing the protecting group from the obtained non-natural amino acid as needed.

[0792]

[0793] Non-natural amino acids having a halogen atom introduced into an aralkyl group of an amino acid side chain and a -CH2-P' group introduced into a nitrogen atom of an amino acid can be prepared according to the following scheme. Boronic acid esters can be introduced into amino acids having a substituent (R) on their side chains according to the method of Ishiyama et al. (J. Am. Chem. Soc. 2002, 124(3), 390-391). a ) on the aryl group of an amino acid having an arylalkyl group. Halogen atoms can be introduced into the introduced boronyl group using N-halosuccinimide according to the method of Lindner et al. (Chem. Eur. J., 2016, 22, 13218-13235). The target C-terminal-free non-natural amino acid can be prepared by appropriately introducing a protecting group into the obtained non-natural amino acid or removing the protecting group from the obtained non-natural amino acid as needed.

[0794]

[0795] The amino acid side chain has an optionally substituted alkoxy or aralkyloxy group (R b Non-natural amino acids containing a 1,2-dimethylaminobenzenesulfonyl (Ns) group can be prepared according to the following scheme. Cyclized compounds can be obtained according to the method of Mitsunobu et al. (Synthesis, 1981, 1, 1-28) after introducing a p-nitrobenzenesulfonyl (Ns) group into a commercially available serine derivative (n=1 or 2) according to a conventional method. Serine ether compounds can be obtained by reacting the cyclized compound with a suitable alcohol (R b OH) by ring opening in the presence of a Lewis acid (such as BF3.OEt2). The target C-terminal-free non-natural amino acid can be prepared by appropriately introducing a protecting group into the obtained non-natural amino acid or removing the protecting group from the obtained non-natural amino acid as needed.

[0796]

[0797] The amino acid side chain has an optionally substituted alkoxy or aralkyloxy group (R b Non-natural amino acids with a (O) group can be prepared according to the following scheme. Serine ether compounds can be prepared by conventional methods by reacting commercially available cyclic compounds (n=1 or 2) with suitable alcohols (R b OH) is obtained by ring opening in the presence of a Lewis acid (such as BF3.OEt2). The target C-terminal-free non-natural amino acid can be prepared by appropriately introducing a protecting group into the obtained non-natural amino acid or removing the protecting group from the obtained non-natural amino acid as needed.

[0798]

[0799] The amino acid side chain has an optionally substituted alkoxy or aralkyloxy group (R b The non-natural amino acid containing a (O) group can be prepared according to the following scheme. Serine ether compounds can be obtained by allowing an alkylating agent (Rb-X) to act on a commercially available serine derivative (n=1 or 2) in the presence of a suitable base according to the method of Williamson et al. (Liebigs Anm. Chem. 1851, 77, 37-49). b When there is another convertible functional group, R b The target functional group can be converted to another functional group transformation. Examples of such other functional group transformations include multi-bond reduction reactions. Next, the target C-terminal-free non-natural amino acid can be prepared by deprotecting the obtained non-natural amino acid.

[0800]

[0801] The amino acid side chain has an optionally substituted alkoxy or aralkyloxy group (R b O) group and a non-natural amino acid having a -CH2-P' group introduced into the amino acid nitrogen atom can be prepared according to the following scheme. The oxazolidinone compound having an introduced cyclic protecting group can be obtained by allowing an aldehyde to act on a commercially available serine derivative or a serine derivative (n=1 or 2) prepared by the above method according to the method of Freidinger et al. (J. Org. Chem., 1983, 48(1), 77-81). Next, the target non-natural amino acid without a C-terminal end can be prepared by a ring-opening reaction.

[0802]

[0803] Non-natural amino acids having a protected hydroxyl group on the amino acid side chain can be prepared according to the following scheme. The target non-natural amino acid without a C-terminus can be prepared by appropriately introducing a protecting group into / appropriately removing the protecting group from a commercially available serine derivative or a serine derivative prepared by the above method (n=1 or 2).

[0804]

[0805] Non-natural amino acids having a protected hydroxyl group on the amino acid side chain and a -CH2-P' group introduced onto the amino acid nitrogen atom can be prepared according to the following scheme. Oxazolidinone compounds having an introduced cyclic protective group can be obtained by reacting an aldehyde with a commercially available serine derivative or a serine derivative (n=1 or 2) prepared by the above method according to the method of Freidinger et al. (J. Org. Chem., 1983, 48(1), 77-81). Next, the target non-natural amino acid without a C-terminus can be prepared by a ring-opening reaction and a protective group introduction reaction.

[0806]

[0807] Having a substituent (R c ) can be prepared according to the following scheme. The hydroxyl group of the commercially available cyclic amino acid can be converted into the target -OR by introducing a suitable functional group. c As a reaction for converting the functional group, the ether bond can be converted into an alkylating agent (R) by the method of Williamson et al. (Liebigs Ann. Chem. 1851, 77, 37-49). c -X) in the presence of a suitable base to produce.c When there is another convertible functional group, R c The target functional group can be converted to the target functional group by another functional group transformation. Next, the target non-natural amino acid without a C-terminus can be prepared by a deprotection reaction.

[0808]

[0809] Cyclic non-natural amino acids having a protecting group (PG3) introduced into the hydroxyl group of a cyclic amino acid can be prepared according to the following scheme. The target C-terminal-free non-natural amino acid can be prepared by appropriately introducing a protecting group into / appropriately removing a protecting group from a commercially available cyclic amino acid.

[0810]

[0811] Non-natural amino acids with boronic acid introduced into the amino acid side chain can be prepared according to the following scheme. Non-natural amino acids with introduced boronate esters can be obtained by reacting an aldehyde with a commercially available glycine derivative according to the method of Lee et al. (Bioorg. Med. Chem. Lett., 2009, 19(17), 4887-5274). Next, the target non-natural amino acid without a C-terminus can be prepared by appropriately introducing or removing a protecting group.

[0812]

[0813] (Synthesis of Fmoc non-natural amino acids having a carboxyl group on the side chain 1)

[0814] Fmoc non-natural amino acids having a carboxyl group on the side chain can be prepared according to the following scheme. The main chain carboxyl group of a starting material obtained from a commercial supplier and having a side chain carboxyl group (n=1 or 2) protected by PG3 can be converted into an amide group by condensing it with an amine (R"R"'NH) in the presence of a condensing agent such as DIC. Next, the target Fmoc non-natural amino acid having a carboxyl group on the side chain can be prepared by deprotecting PG3.

[0815]

[0816] (Synthesis of Fmoc non-natural amino acids having a carboxyl group on the side chain 2)

[0817] An Fmoc non-natural amino acid having a carboxyl group on the side chain and a -CH2-P' group introduced onto the amino acid nitrogen atom can be prepared according to the following scheme. The main chain carboxyl group of a starting material available from a commercial supplier and having a side chain carboxyl group (n = 1 or 2) protected by PG3 can be converted into an amide group by condensing it with an amine (R"R"'NH) in the presence of a condensing agent such as DIC. Next, the target Fmoc non-natural amino acid having a carboxyl group on the side chain can be prepared by deprotecting PG3.

[0818]

[0819] (Synthesis of Fmoc unnatural amino acids with vinyl halides on the side chains)

[0820] An Fmoc non-natural amino acid having a vinyl halide on the side chain can be synthesized by the following scheme according to the method of Shendage et al. (Eur. J. Org. Chem., 2005, 719-727). Boc-2-tert-butyl-3-methylimidazolidin-4-one available from a commercial supplier is reacted with an alkylating agent having a vinyl halide on the side chain in the presence of a base, and the desired Fmoc non-natural amino acid having a vinyl halide on the side chain can be produced by the method described in the literature.

[0821]

[0822] Non-natural amino acids (n=1 or 2) containing a thioether group on the side chain can be produced according to the following scheme. An amino acid having a protected side chain thiol group is subjected to carboxylic acid amidation, and after deprotection of the thiol group, a haloacetic acid with a protected carboxylic acid is reacted to form a thioether bond. Next, an amino acid having a thioether group on the side chain can be produced by deprotecting the side chain carboxylic acid.

[0823]

[0824] Peptides containing thioether groups on the peptide backbone can be produced by using the above-mentioned amino acids having thioether groups on the side chains as starting materials, but alternatively, they can also be produced by the method of Roberts et al., in which N-terminal bromoacetamide is reacted with the cysteine ​​side chain (Tetrahedron Letters, 1998, 39, 8357-8360), or by the method of Robey et al., in which N-terminal chloroacetamide is reacted with the cysteine ​​side chain (Journal of Peptide Research, 2000, 56, 115-120).

[0825] The compounds of the present invention and their salts and solvates thereof include all stereoisomers (such as enantiomers and diastereomers (including cis and trans geometric isomers)) of the target compounds obtained by the above-mentioned reaction steps, as well as racemates and other mixtures of such isomers. For example, the compounds of the present invention may have one or more asymmetric points, and the present invention encompasses racemic mixtures, diastereomeric mixtures and enantiomers of such compounds.

[0826] When the compounds according to the present invention are obtained in free form, they can be converted into salts which can be formed from such compounds, or hydrates or solvates thereof according to conventional methods.

[0827] When the compounds according to the present invention are obtained in the form of salts, hydrates or solvates of such compounds, they can be converted into the free forms of such compounds according to conventional methods.

[0828] <Pharmaceutical Composition>

[0829] The present invention provides a pharmaceutical composition containing the cyclic compound of the present invention.

[0830] The pharmaceutical composition of the present invention can be prepared by introducing a pharmaceutical carrier other than the compound of the present invention, its salt, or its solvate by conventional methods. Commonly used excipients, binders, lubricants, colorants, flavoring agents, and as needed stabilizers, emulsifiers, absorption promoters, surfactants, pH regulators, preservatives, antioxidants, etc. can be used for preparation, and they are blended with ingredients commonly used as raw materials for pharmaceutical preparations and prepared by conventional methods.

[0831] For example, oral preparations are prepared by adding the compound of the present invention or its salt and excipients and, if necessary, binders, disintegrants, lubricants, colorants, flavorings, etc., and then formulating them into powders, fine granules, granules, tablets, coated tablets, capsules, etc. by conventional methods.

[0832] Examples of these ingredients include animal and vegetable oils such as soybean oil, beef tallow and synthetic glycerides; hydrocarbons such as liquid paraffin, squalane and solid paraffin; ester oils such as octyldodecyl myristate and isopropyl myristate; higher alcohols such as cetearyl alcohol and behenyl alcohol; silicone resins; silicone oils; surfactants such as polyoxyethylene fatty acid esters, sorbitan fatty acid esters, glycerol fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene hydrogenated castor oil and polyoxyethylene-polyoxypropylene block copolymers; water-soluble polymers such as hydroxyethyl cellulose, polyacrylic acid, carboxyvinyl polymers, polyethylene glycol, polyvinyl pyrrolidone and methylcellulose; lower alcohols such as ethanol and isopropyl alcohol; polyols such as glycerol, propylene glycol, dipropylene glycol and sorbitol; sugars such as glucose and sucrose; inorganic powders such as silicic anhydride, magnesium aluminum silicate and aluminum silicate; and purified water.

[0833] Examples of excipients include lactose, corn starch, soft sugar, glucose, mannitol, sorbitol, microcrystalline cellulose and silicon dioxide.

[0834] Examples of the binder include polyvinyl alcohol, polyvinyl ether, methylcellulose, ethylcellulose, gum arabic, gum tragacanth, gelatin, shellac, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, polypropylene glycol-polyoxyethylene block polymers and meglumine.

[0835] Examples of disintegrants include starch, agar, gelatin powder, microcrystalline cellulose, calcium carbonate, sodium bicarbonate, calcium citrate, dextrin, pectin, and carboxymethylcellulose calcium.

[0836] Examples of lubricants include magnesium stearate, talc, polyethylene glycol, silicon dioxide and hydrogenated vegetable oils.

[0837] As coloring agents, those approved as drug additives are used, and as flavoring agents, cocoa powder, menthol, empasm, peppermint oil, borneol, cinnamon bark powder, etc. are used.

[0838] Obviously, these tablets and granules can be coated with sugar or other appropriate coatings as needed. When preparing liquid preparations (such as syrups and injectable preparations), they are prepared by adding pH regulators, solubilizers, tension regulators, etc. and, as needed, solubilizers, stabilizers, etc. to the compound of the present invention or its pharmacologically acceptable salt using conventional methods.

[0839] For example, pharmaceutical composition can be used parenterally in the form of an injectable sterile solution or a suspension with water or other medicinal liquids. For example, they are prepared by blending with a pharmacologically acceptable carrier or medium, specifically sterile water, saline, vegetable oil, emulsifier, suspending agent, surfactant, stabilizer, flavoring agent, excipient, vehicle, preservative or adhesive in a suitable combination and in a unit dosage form blended for the preparation generally approved. Specifically, carrier can include light anhydrous silicic acid, lactose, microcrystalline cellulose, mannitol, starch, carboxymethylcellulose calcium, sodium carboxymethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl acetal diethylamino acetate, polyvinyl pyrrolidone, gelatin, medium chain fatty acid triglyceride, polyoxyethylene hydrogenated castor oil 60, soft white sugar, carboxymethyl cellulose, corn starch and inorganic salt. In this type of preparation, the amount of active ingredient is designed to provide a suitable dose within a specified range.

[0840] Sterile compositions for injection can be formulated in a conventional manner using vehicles such as distilled water for injection.

[0841] Aqueous solutions for injection include, for example, isotonic solutions containing saline, glucose and other adjuvants (such as D-sorbitol, D-mannose, D-mannitol and sodium chloride), and can be used in combination with appropriate solubilizers (e.g., alcohol, specifically ethanol, polyols (e.g., propylene glycol or polyethylene glycol)) and nonionic surfactants (e.g., polysorbate 80 (registered trademark or HCO-50)).

[0842] Oily liquids include sesame oil and soybean oil, and can be used in combination with benzyl benzoate and benzyl alcohol as solubilizers. They can also be blended with buffers (such as phosphate buffer and sodium acetate buffer); analgesics (such as procaine hydrochloride); stabilizers (such as benzyl alcohol and phenol); and antioxidants. Prepared injections are usually packaged in suitable ampoules.

[0843] The administration method is preferably oral administration, but is not limited thereto. Specific examples of parenteral administration include injection, nasal administration, pulmonary administration, and transdermal administration. Examples of injection dosage forms include systemic or local administration by intravenous injection, intramuscular injection, intraperitoneal injection, subcutaneous injection, etc.

[0844] The method of administration can also be selected based on the patient's age and symptoms. The dosage of a pharmaceutical composition containing a peptide compound prepared by the method of the present invention can be selected, for example, within the range of 0.0001 mg to 1000 mg per kg of body weight per dose. Alternatively, the dosage can be selected, for example, within the range of 0.001 to 100,000 mg per patient's body weight; however, it is not necessarily limited to such values. The dosage and method of administration vary depending on the patient's weight, age, symptoms, etc., but can be appropriately selected by those skilled in the art.

[0845] In one embodiment, the cyclic compound of the present invention or its salt, or its solvate; or a pharmaceutical composition containing the cyclic compound of the present invention or its salt, or its solvate can bind to or selectively bind to KRAS in a subject and can be used to selectively inhibit KRAS.

[0846] In one embodiment, the cyclic compound of the present invention or its salt, or its solvate can bind to or selectively bind to KRAS in a subject and can be used to produce a drug that selectively inhibits KRAS.

[0847] In one embodiment, the present invention relates to a method for binding or selectively binding a cyclic compound of the present invention or a salt thereof, or a solvate thereof to KRAS in a subject, or a method for selectively inhibiting KRAS in a subject, comprising the step of administering an effective amount of a cyclic compound of the present invention or a salt thereof, or a solvate thereof to a subject in need thereof.

[0848] The cyclic compounds of the present invention or their salts, or their solvates as described above have high selectivity for KRAS in a subject. For example, the cyclic compounds of the present invention have a higher selectivity than PP1820: ((3S,9S,12S,17S,20S,23S,27S,30S,36S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]30-cyclopentyl-23-isobutyl-9-(isopentyloxymethyl)-N,N,7,17,18,24,28,31-octamethyl-20-[(1S)-1-methylpropyl]-2,5,8 , 11,16,19,22,25,29,32,35-undecaoxo-10-propyl-spiro[1,4,7,10,15,18,21,24,28,31,34-undecaazatricyclo[34.3.0.012,15]nonatriacontane-33,1′-cyclobutane]-27-carboxamide) with higher KRAS selectivity (KRAS selectivity for NRAS and / or KRAS selectivity for HRAS).

[0849] In one embodiment, the pharmaceutical composition of the present invention has a KRAS inhibitory activity that is 3 times or more greater than the NRAS inhibitory activity and HRAS inhibitory activity.

[0850] In one embodiment, the pharmaceutical composition of the present invention has a KRAS inhibitory activity that is 5-fold, 7-fold, 10-fold, 15-fold, or 20-fold or more greater than the NRAS inhibitory activity and HRAS inhibitory activity.

[0851] In one embodiment, the cyclic compound of the present invention, or its salt, or its solvate, or a pharmaceutical composition containing the cyclic compound of the present invention, or its salt, or its solvate, can be used to treat and / or prevent cancer in a subject.

[0852] In one embodiment, the cyclic compound of the present invention, or a salt thereof, or a solvate thereof can be used for the manufacture of a medicament for treating and / or preventing cancer in a subject.

[0853] In one embodiment, the present invention relates to a method for treating and / or preventing cancer in a subject, comprising the step of administering an effective amount of a cyclic compound of the present invention, or a salt thereof, or a solvate thereof to a subject in need thereof.

[0854] Specific examples of cancer include lung cancer.

[0855] As used herein, the term "subject" includes mammals, and preferably the mammal is a human.

[0856] All prior art documents cited in this specification are incorporated herein by reference.

[0857] [Example]

[0858] The scope of the present invention will now be further described by the following examples and reference examples, but the present invention is not limited thereto. When no production method is described, raw materials and reagents were obtained from commercial suppliers or synthesized using known methods. The analytical conditions for LC / MS are provided in Table 1.

[0859] [Table 1]

[0860]

[0861]

[0862]

[0863]

[0864]

[0865] Example 1 Solid Phase Synthesis of Peptide Compounds

[0866] According to the peptide synthesis method by the Fmoc method described in WO2013 / 100132 or WO2018 / 225864, peptide extension is carried out by the following basic route (also referred to as the basic peptide synthesis method). That is, it includes the following five steps:

[0867] 1) performing a peptide extension reaction from the N-terminus of an amino acid in which an Asp side chain carboxylic acid or a peptide backbone carboxylic acid is loaded on a 2-chlorotrityl resin by the Fmoc method,

[0868] 2) The process of cleaving peptides from 2-chlorotrityl resin,

[0869] 3) amide cyclization by condensation between the Asp side chain carboxylic acid or the peptide backbone carboxylic acid generated by the cleavage process removed from the 2-chlorotrityl resin and the amino group at the N-terminus of the peptide chain (triangular unit),

[0870] 4) optionally deprotecting the protecting groups of the side chain functional groups contained in the peptide chain, and

[0871] 5) Purification of the compound by preparative HPLC In this example, unless otherwise stated, peptide compounds were synthesized by this basic route.

[0872]

[0873] 1-1. Fmoc-amino acid for peptide synthesis using a peptide synthesizer

[0874] In the peptide syntheses described herein, the Fmoc-amino acids listed in Tables 2 to 4 were used for the synthesis performed by a peptide synthesizer.

[0875] The Fmoc-amino acids listed in Table 2 were synthesized according to the methods described in WO2018 / 225851 or WO2018 / 225864.

[0876] The Fmoc-amino acids listed in Table 3 were purchased from commercial suppliers.

[0877] The Fmoc-amino acids listed in Table 4 were synthesized according to the scheme shown below.

[0878] [Table 2]

[0879]

[0880] [Table 3]

[0881]

[0882]

[0883]

[0884]

[0885]

[0886]

[0887]

[0888]

[0889]

[0890]

[0891]

[0892] [Table 4]

[0893]

[0894]

[0895]

[0896]

[0897]

[0898]

[0899]

[0900] Synthesis of Fmoc-amino acids

[0901] Synthesis of compound aa004

[0902]

[0903] Compound aa004-a (3.00 g, 7.86 mmol) is dissolved in toluene (79 mL), paraformaldehyde (708 mg, 23.6 mmol) and CSA (91 mg, 0.393 mmol) are added, and the mixture is stirred at 90 ° C for 5 hours. After the mixture is cooled to room temperature, paraformaldehyde (236 mg, 7.86 mmol) and CSA (46 mg, 0.197 mmol) are added, and the mixture is further stirred at 90 ° C for 30 minutes. After cooling to room temperature, the mixture is filtered through diatomaceous earth, and the residue is washed with ethyl acetate (50 mL). The filtrate is washed twice with saturated sodium bicarbonate aqueous solution (50 mL) and washed with 50% brine (50 mL). It is dried over sodium sulfate and filtered out, and the solvent is distilled off under reduced pressure to obtain compound aa004-b as a crude product.

[0904] LCMS (ESI) m / z = 394 (M+H) +

[0905] Retention time: 1.08 minutes (analysis conditions SQDFA05)

[0906] The crude product t (7.86 mmol) of compound aa004-b was dissolved in DCM (39 mL), followed by the addition of boron trifluoride etherate (BF3·OEt2) (2.96 mL, 23.6 mmol), TES (1.95 mL, 23.6 mmol) and water (0.142 mL, 7.86 mmol), and the mixture was stirred at room temperature for 1 hour. The reaction solution was washed with saturated ammonium chloride solution (40 mL), washed with 50% brine (40 mL), then dried over sodium sulfate and filtered, and the solvent was distilled off under reduced pressure. The resulting residue was dissolved in acetonitrile (40 mL) and washed twice with n-hexane (40 mL). The solvent was distilled off under reduced pressure to obtain compound aa004 (3.04 g, 98%).

[0907] LCMS (ESI) m / z = 396 (M+H) +

[0908] Retention time: 1.00 min (analysis conditions SQDFA05)

[0909] Synthesis of compound aa028

[0910]

[0911] Using aa028-a as a starting material, aa028-b (9.61 g, 94%) was obtained as a crude product in the same manner as in the synthesis of compound aa004-b.

[0912] Using aa028-b as a starting material, aa028 (8.10 g, 84%) was obtained in the same manner as the synthesis of compound aa004.

[0913] LCMS (ESI) m / z = 470 (M+H) +

[0914] Retention time: 0.99 minutes (analysis conditions SQDFA05)

[0915] Synthesis of compound aa018

[0916]

[0917] Using compound aa018-a ((2S)-2-[9H-fluoren-9-ylmethoxycarbonylamino]pent-4-ynoic acid, Fmoc-PRA-OH) (3 g, 8.95 mmol) as a starting material, compound aa018-b (2.71 g, 87%) was obtained in the same manner as the synthesis of compound aa004-b.

[0918] LCMS (ESI) m / z = 348 (M+H)

[0919] Retention time: 0.87 minutes (analysis conditions SQDFA05)

[0920] Using the obtained compound aa018-b (989 mg, 2.85 mmol), compound aa018 (986 mg, 99%) was obtained in the same manner as in the synthesis of compound aa004.

[0921] LCMS (ESI) m / z = 350 (M+H) +

[0922] Retention time: 0.79 minutes (analysis conditions SQDFA05)

[0923] Synthesis of compound aa049

[0924]

[0925] Using compound aa049-a ((2S)-3-(2-chlorophenyl)-2-[9H-fluoren-9-ylmethoxycarbonylamino]propionic acid, Fmoc-Phe(2-Cl)-OH) (5 g, 11.85 mmol) as raw material, compound aa049-b (4.2 g, 82%) was obtained in the same manner as the synthesis of compound aa004-b.

[0926] LCMS (ESI) m / z = 434 (M+H) +

[0927] Retention time: 1.01 minutes (analysis conditions SQDFA05)

[0928] Using the obtained compound aa049-b (4.2 g), compound aa049 (3.32 g, 79%) was obtained in the same manner as in the synthesis of compound aa004.

[0929] LCMS (ESI) m / z = 436 (M+H) +

[0930] Retention time: 0.94 minutes (analysis conditions SQDFA05)

[0931] Synthesis of compound aa199

[0932]

[0933] Using compound aa199-a ((2S)-2-[9H-fluoren-9-ylmethoxycarbonylamino]-3-[4-(trifluoromethyl)phenyl]propionic acid, Fmoc-Phe(4-CF3)-OH) (200 g, 439 mmol) as raw material, compound aa199-b (206.8 g) was obtained in the same manner as the synthesis of compound aa004-b.

[0934] LCMS (ESI) m / z = 469 (M+H) +

[0935] Retention time: 3.30 minutes (Analysis conditions SMD method_03)

[0936] Using the obtained compound aa199-b (205 g), compound aa199 (195 g, 2 steps, 95%) was obtained in the same manner as in the synthesis of compound aa004.

[0937] LCMS (ESI) m / z = 470 (M+H) +

[0938] Retention time: 2.96 minutes (Analysis conditions SMD method_03)

[0939] Synthesis of compound aa013

[0940]

[0941] Using aa013-a as a starting material, aa013-b (5.29 g, 102%) was obtained as a crude product in the same manner as in the synthesis of compound aa004-b.

[0942] LCMS (ESI) m / z = 370 (M+H) +

[0943] Retention time: 0.89 minutes (analysis conditions SQDFA05)

[0944] Compound aa013-b (5.29 g, 14.3 mmol) was dissolved in DCM (125 mL), TES (22.9 mL, 143 mmol) and TFA (36.4 mL, 473 mmol) were added, and the mixture was stirred at 38 ° C for 8 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in TBME (100 mL) and washed with 1 M potassium dihydrogen phosphate aqueous solution (50 mL). The water layer was extracted 3 times with TBME, the organic layers were combined, and the solvent was distilled off under reduced pressure. Acetonitrile / normal hexane=1 / 2 (100 mL) was added, and the mixture was extracted with 5% potassium bicarbonate aqueous solution (100 mL). The water layer was acidified with 6 M hydrochloric acid and extracted twice with TBME (30 mL). The organic layer was dried over sodium sulfate and filtered off, and the solvent was distilled off under reduced pressure. Acetonitrile (100 mL) was added, the mixture was washed with n-hexane (50 mL), and the solvent was distilled off under reduced pressure to give compound aa013 (4.06 g, 76%).

[0945] LCMS (ESI) m / z = 372 (M+H)

[0946] Retention time: 0.83 minutes (analysis conditions SQDFA05)

[0947] Synthesis of compound aa030

[0948]

[0949] Under a nitrogen atmosphere, paraformaldehyde (172 mg, 5.74 mmol) and TFA (1.326 mL, 17.22 mmol) were added to a toluene solution (5.7 mL) of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-cyanophenyl)propanoic acid (aa030-a, Fmoc-Phe(3-CN)-OH) (789 mg, 1.913 mmol), and the mixture was stirred at room temperature for 5 hours and 30 minutes. The reaction solution was concentrated under reduced pressure, diluted with DCM, then washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, and filtered. The resulting solution was concentrated under reduced pressure to give compound aa030-b (859 mg) as a crude product. This compound was used in the next reaction without further purification.

[0950] In a nitrogen atmosphere, TES (2.75 mL, 17.22 mmol) and TFA (3.98 mL, 51.7 mmol) were added to a DCE (10 mL) solution of compound aa030-b (853 mg) at room temperature, and the mixture was stirred at 60° C. for 5 hours. The reaction solution was cooled to room temperature, the solvent was distilled off under reduced pressure, tert-butyl methyl ether / n-hexane (1 / 1) was added to the resulting crude product, and the mixture was extracted 5 times with a saturated aqueous sodium bicarbonate solution. The pH of the resulting aqueous layer was acidified with concentrated hydrochloric acid, and the mixture was then extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the solvent was then distilled off under reduced pressure to obtain compound aa030 (811 mg, 2 steps, 99%). The resulting compound aa060 was used for peptide synthesis without further purification.

[0951] LCMS (ESI) m / z = 427 (M+H) +

[0952] Retention time: 0.83 minutes (analysis conditions SQDFA05)

[0953] Synthesis of compound aa029

[0954]

[0955] Using compound aa029-a ((2S)-3-(4-cyanophenyl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)propionic acid, Fmoc-Phe(4-CN)-OH) (1 g, 2.425 mmol) as a starting material, compound aa029 (1.14 g, 2 steps, 108%) was obtained as a crude product in the same manner as for the synthesis of compound aa030. The obtained compound aa029 was used for peptide synthesis without further purification.

[0956] LCMS (ESI) m / z = 427 (M+H) +

[0957] Retention time: 0.82 minutes (analysis conditions SQDFA05)

[0958] Synthesis of compound aa031

[0959]

[0960] Using compound aa031-a ((2S)-3-(2-cyanophenyl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)propionic acid, Fmoc-Phe(2-CN)-OH) (1 g, 2.425 mmol) as a starting material, compound aa031-b was obtained as a crude product in the same manner as for the synthesis of compound aa030-b. Using the resulting compound aa031-b, the crude product obtained in the same manner as for the synthesis of compound aa030 was purified by reverse phase column chromatography (0.1% formic acid aqueous solution / 0.1% formic acid acetonitrile solution) to give compound aa031 (529 mg, 2 steps, 51%).

[0961] LCMS (ESI) m / z = 427 (M+H) +

[0962] Retention time: 0.85 minutes (analysis conditions SQDFA05)

[0963] Synthesis of compound aa050

[0964]

[0965] Using compound aa050-a ((2S)-3-(3,4-difluorophenyl)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]propionic acid, Fmoc-Phe(34-F2)-OH) (105 mg, 0.247 mmol) as a starting material, compound aa050-b was obtained as a crude product in the same manner as for the synthesis of compound aa004-b. In addition, using aa050-b, compound aa050 (74.4 mg, 2 steps, 69%) was obtained in the same manner as for the synthesis of compound aa030.

[0966] LCMS (ESI) m / z = 438 (M+H) +

[0967] Retention time: 0.88 minutes (analysis conditions SQDFA05)

[0968] Synthesis of compound aa019

[0969]

[0970] Compound aa019-a (5.00 g, 13.8 mmol) was suspended in DCM (46 mL), and paraformaldehyde (2.08 g, 69 mmol) and magnesium sulfate (4.16 g, 34.6 mmol) were added. Boron trifluoride etherate (BF3·OEt2) (2.10 mL, 16.6 mmol) was added dropwise, and the mixture was stirred at room temperature for 1 hour. The solid was filtered, and TES (5.51 mL, 34.6 mmol) and water (0.249 mL, 13.8 mmol) were added. BF3·OEt2 (2.63 mL, 20.8 mmol) was added dropwise at 0°C, and the mixture was stirred at room temperature for 1 hour. TES (1.10 mL, 6.92 mmol) was added, and the mixture was stirred at room temperature for 40 minutes. BF3·OEt2 (0.877 mL, 6.92 mmol) was added, and the mixture was stirred at room temperature. The reaction solution was washed with saturated sodium chloride aqueous solution (25 mL) and washed with saturated brine (50 mL). The organic layer was dried over sodium sulfate and filtered, and the solvent was distilled off under reduced pressure. The resulting solid was crushed and washed 3 times with n-hexane (50 mL) to give compound aa019 (4.93 g, 95%).

[0971] LCMS (ESI) m / z = 376 (M+H)

[0972] Retention time: 0.80 minutes (analysis conditions SQDFA05)

[0973] Synthesis of compound aa331

[0974]

[0975] Using aa331-a as a starting material, aa331 (9.09 g, 86%) was obtained in the same manner as the synthesis of compound aa019.

[0976] LCMS (ESI) m / z = 382 (M+H)

[0977] Retention time: 0.94 minutes (analysis conditions SQDFA05)

[0978] Synthesis of compound aa020

[0979]

[0980] Methyl (S)-N-tritylaziridine-2-carboxylate (aa020-a, CAS No. 75154-68-6) (50 g, 146 mmol) was added to a mixed solution of chloroform (145 mL) and methanol (145 mL). TFA (33 mL, 3 eq) was then added dropwise at 0°C under a nitrogen atmosphere, and the mixture was stirred for 7 hours. DIPEA (127 mL, 5 eq) was added to the reaction solution at 0°C, and a solution of fFmoc-Cl (36 g, 139 mmol) in 1,4-dioxane (145 mL) was further added dropwise, and the mixture was stirred at 0°C under a nitrogen atmosphere for 90 minutes. The reaction solution was concentrated under reduced pressure, diluted with ethyl acetate, and then washed sequentially with water, an aqueous ammonium chloride solution, an aqueous sodium bicarbonate solution, and saturated brine. After the obtained organic layer was dried over anhydrous sodium sulfate, the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (ethyl acetate / petroleum ether, 0 / 100 to 10 / 90) to obtain compound aa020-b ((2S)-aziridine-1,2-dicarboxylic acid 1-O-(9H-fluoren-9-ylmethyl) ester 2-O-methyl ester) (40 g, 85%).

[0981] LCMS (ESI) m / z = 324 (M+H)

[0982] Retention time: 2.631 minutes (Analysis conditions SMD method_10)

[0983] In a nitrogen atmosphere, compound aa020-b ((2S)-aziridine-1,2-dicarboxylic acid 1-O-(9H-fluoren-9-ylmethyl) ester 2-O-methyl ester) (5 g, 15.46 mmol) was dissolved in DCM (30.9 mL), cyclopropanol (1.665 mL, 26.3 mmol) was added, and then boron trifluoride etherate (BF3·OEt2) (0.291 mL, 2.319 mmol) was added while the mixture was ice-cooled. After the mixture was allowed to react for 2 hours while ice-cooling, water and a saturated aqueous sodium bicarbonate solution were added to the reaction solution to quench the reaction, the aqueous layer was removed by a phase separator, and the organic layer was then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 4 / 1) to give compound aa020-c (4.6 g, 78%).

[0984] LCMS (ESI) m / z = 382 (M+H)

[0985] Retention time: 0.89 minutes (analysis conditions SQDFA05)

[0986] Calcium chloride (20.08g, 181mmol) is dissolved in water (50.2mL), lithium hydroxide monohydrate (2.024g, 48.2mmol) is added thereto, and the mixture is stirred at room temperature for 5 minutes to prepare aqueous solution A. Compound aa020-c (4.6g, 12.06mmol) is dissolved in isopropyl alcohol (201mL) and THF (50.2mL), pre-prepared aqueous solution A is added, and the mixture is stirred at room temperature for 5 hours. Then, 1N hydrochloric acid (72mL) is added to the reaction solution, and isopropyl alcohol and THF are then removed by concentrating under reduced pressure. The gained aqueous layer is diluted with water (50.2mL) and extracted 3 times with ethyl acetate (total amount 100mL). The organic layer is washed with water and saturated brine, dried over anhydrous sodium sulfate, and filtered, and the filtrate is concentrated under reduced pressure. The resulting residue was washed with ethyl acetate / n-hexane (1 / 2, 20 v / w) to give aa020-d((2S)-3-cyclopropyloxy-2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid, Fmoc-Ser(cPr)-OH) (3.5 g, 79%).

[0987] LCMS (ESI) m / z = 368 (M+H)

[0988] Retention time: 0.78 minutes (analysis conditions SQDFA05)

[0989] Paraformaldehyde (1.815 g, 60.5 mmol), magnesium sulfate (2.36 g, 19.63 mmol), and boron trifluoride diethyl ether complex (BF3·OEt2) (1.184 mL, 9.42 mmol) were added to a DCM (87 mL) solution of compound aa020-d ((2S)-3-cyclopropyloxy-2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid, Fmoc-Ser(cPr)-OH) (2.89 g, 7.85 mmol) under a nitrogen atmosphere, and the mixture was stirred at room temperature for 2 hours. A saturated aqueous sodium bicarbonate solution was added to the reaction solution to separate the organic layer and the aqueous layer. The aqueous layer was extracted twice with DCM, the combined organic layers were washed with saturated brine and dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain compound aa020-e (3.1 g, quant.) as a crude product.

[0990] LCMS (ESI) m / z = 380 (M+H) +

[0991] Retention time: 0.93 minutes (analysis conditions SQDFA05)

[0992] Triethylsilane (3.13 mL, 19.64 mmol), water (0.141 mL, 7.85 mmol) and boron trifluoride ether complex (BF3·OEt2) (2.49 mL, 19.6 mmol) were added to a solution of compound aa020-e (2.98 g, 7.85 mmol) in DCM (26.2 mL) under ice-cold conditions and the mixture was stirred for 2 hours. Saturated aqueous ammonium chloride solution was added to the reaction solution to separate the organic layer. The organic layer was washed with saturated aqueous ammonium chloride solution, then with saturated brine, and concentrated under reduced pressure to obtain a crude product. The obtained crude product was dissolved in acetonitrile, washed with n-hexane, and the acetonitrile layer was concentrated under reduced pressure to obtain compound aa020 (2.71 g, 90%).

[0993] LCMS (ESI) m / z = 382 (M+H)

[0994] Retention time: 0.83 minutes (analysis conditions SQDFA05)

[0995] Synthesis of compound aa006

[0996]

[0997] Using compound aa006-a ((2S)-3-cyclopentyl-2-[9H-fluoren-9-ylmethoxycarbonylamino]propionic acid, Fmoc-Ala(cPent)-OH) (10 g, 26.4 mmol) as raw material, compound aa006-b (10.5 g) was obtained as a crude product in the same manner as the synthesis of compound aa020-e.

[0998] LCMS (ESI) m / z = 392 (M+H) +

[0999] Retention time: 1.05 minutes (analysis conditions SQDFA05)

[1000] The obtained compound aa006-b (10.5 g) was reacted in the same manner as in the synthesis of compound aa020, and the obtained crude product was then purified by reverse phase column chromatography (0.1% formic acid aqueous solution / 0.1% formic acid acetonitrile solution) to give compound aa006 (10.11 g, 2 steps, 96%).

[1001] LCMS (ESI) m / z = 394 (M+H) +

[1002] Retention time: 0.98 minutes (analysis conditions SQDFA05)

[1003] Synthesis of compound aa010

[1004]

[1005] Using compound aa010-a ((2S)-3-cyclobutyl-2-[9H-fluoren-9-ylmethoxycarbonylamino]propionic acid, Fmoc-Ala(cBu)-OH) (3.36 g, 9.19 mmol) as raw material, compound aa010-b (3.63 g) was obtained as a crude product in the same manner as the synthesis of compound aa020-e.

[1006] LCMS (ESI) m / z = 378 (M+H)

[1007] Retention time: 1.01 minutes (analysis conditions SQDFA05)

[1008] The obtained compound aa010-b (3.63 g) was reacted in the same manner as in the synthesis of compound aa020, and then the obtained crude product was purified by reverse phase column chromatography (0.1% formic acid-water / 0.1% formic acid-acetonitrile) to give compound aa010 (3.18 g, 2 steps, 91%).

[1009] LCMS (ESI) m / z = 380 (M+H) +

[1010] Retention time: 0.94 minutes (analysis conditions SQDFA05)

[1011] Synthesis of compound aa047

[1012]

[1013] Using compound aa047-a ((2S)-2-[9H-fluoren-9-ylmethoxycarbonylamino]-3-(2-methylphenyl)propionic acid, Fmoc-Phe(2-Me)-OH) (2 g, 4.98 mmol) as a starting material, a saturated aqueous sodium bicarbonate solution was added to the reaction solution obtained in the same manner as for the synthesis of compound aa020-e, and the mixture was loaded onto a silica gel column (2 v / w) and eluted with DCM to obtain compound aa047-b (1.45 g) as a crude product. Using the resulting compound aa047-b, compound aa047 (1.21 g, 2 steps, 58%) was obtained in the same manner as for the synthesis of compound aa020.

[1014] LCMS (ESI) m / z = 416 (M+H) +

[1015] Retention time: 0.94 minutes (analysis conditions SQDFA05)

[1016] Synthesis of compound aa060

[1017]

[1018] Using compound aa060-a ((2S)-2-cyclobutyl-2-[9H-fluoren-9-ylmethoxycarbonylamino]acetic acid, Fmoc-Gly(cBu)-OH) (2.5 g, 7.11 mmol) as a starting material, compound aa075-b was obtained as a crude product in the same manner as in the synthesis of compound aa020-e.

[1019] LCMS (ESI) m / z = 364 (M+H) +

[1020] Retention time: 0.97 minutes (analysis conditions SQDFA05)

[1021] The entire amount of compound aa060-b obtained as described above was reacted in the same manner as in the synthesis of compound aa020, and the resulting crude product was purified by reverse phase column chromatography (0.1% formic acid aqueous solution / 0.1% formic acid acetonitrile solution) to give compound aa060 (2.32 g, 2 steps, 89%).

[1022] LCMS (ESI) m / z = 366 (M+H) +

[1023] Retention time: 0.88 minutes (analysis conditions SQDFA05)

[1024] Synthesis of compound aa021

[1025]

[1026] 2-Nitrobenzenesulfonyl chloride (NsCl) (32.37 g, 146 mmol) and L-serine methyl ester hydrochloride (aa021-a, 25 g, 161 mmol, CAS No. 5680-80-8) were dissolved in DCM (874 mL), and DIPEA (51 mL, 292 mmol) was added at 5°C. The mixture was stirred at room temperature for 1 hour, then washed twice with water (440 mL), once with saturated brine / water (1 / 1, 440 mL), and then dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was then concentrated under reduced pressure to obtain compound aa021-b (39.4 g, 89%) as a crude product.

[1027] LCMS (ESI) m / z = 302.9 (MH)-

[1028] Retention time: 0.729 minutes (Analysis conditions SMD method_06)

[1029] Compound aa021-b (23 g, 75.6 mmol) was dissolved in DCM (598 mL) and triphenylphosphine (31.7 g, 121 mmol) was added at room temperature. After the mixture was cooled to -14°C, DEAD (55.0 mL, 121 mmol) was added over 10 minutes, and the mixture was then stirred at -5°C for 50 minutes. n-Hexane (300 mL) was added, and the precipitate was filtered off. The filtrate was purified by silica gel column chromatography (n-hexane / DCM = 50:50 to 0:100) to give compound aa021-c (13.3 g, 62%).

[1030] LCMS (ESI) m / z = 287 (M+H) +

[1031] Retention time: 0.872 minutes (Analytical conditions SMD method_06)

[1032] Compound aa021-c (10.7 g, 37.3 mmol) was dissolved in TFE (75 mL), boron trifluoride diethyl ether complex (BF3·OEt2) (0.469 mL, 3.73 mmol) was added, and the mixture was stirred at 70°C for 30 minutes. TFE was distilled off under reduced pressure, and the resulting crude product was purified by reverse phase column chromatography (acetonitrile containing 0.1% formic acid / distilled water containing 0.1% formic acid) to give compound aa021-d (12.3 g, 85%).

[1033] LCMS (ESI) m / z = 387 (M+H)

[1034] Retention time: 0.72 minutes (analysis conditions SQDFA05)

[1035] Compound aa021-d (12 g, 31.1 mmol) was dissolved in methanol (47 mL), and an aqueous solution (31 mL) of lithium hydroxide monohydrate (5.21 g, 124 mmol) was added. The mixture was stirred at room temperature for 90 minutes, and then formic acid (11.7 mL, 311 mmol) was added. The mixture was diluted with water (30 mL) and then purified by reverse phase column chromatography (acetonitrile containing 0.1% formic acid / distilled water containing 0.1% formic acid) to give compound aa021-e (7.90 g, 68%).

[1036] LCMS (ESI) m / z = 373 (M+H) +

[1037] Retention time: 0.63 minutes (analysis conditions SQDFA05)

[1038] Compound aa021-e (7.72 g, 20.7 mmol) was dissolved in acetonitrile (104 mL), potassium carbonate (7.17 g, 51.8 mmol) and dodecanethiol (7.44 mL, 31.1 mmol) were added, and the mixture was stirred at room temperature for 74 hours. It was diluted with water (100 mL) and washed twice with TBME (200 mL). A solution of Fmoc-OSu (3.5 g) in 1,4-dioxane (150 mL) was added to the resulting aqueous solution, and the mixture was stirred for 25 minutes. In addition, a solution of Fmoc-OSu (700 mg) in 1,4-dioxane (10 mL) was added, and the mixture was stirred for 5 minutes. In addition, a solution of Fmoc-OSu (350 mg) in 1,4-dioxane (5 mL) was added, and the mixture was stirred for 5 minutes. Separately, a solution of Fmoc-OSu (350 mg) in 1,4-dioxane (5 mL) was added, the mixture was stirred for 5 minutes, then formic acid (3.9 mL) was added, and the solvent was distilled off under reduced pressure. The resulting crude product was purified by reverse phase column chromatography (acetonitrile containing 0.1% formic acid / distilled water containing 0.1% formic acid) to give compound aa021-f ((2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-(2,2,2-trifluoroethoxy)propanoic acid, Fmoc-Ser(Tfe)-OH) (5.67 g, 67%).

[1039] LCMS (ESI) m / z = 410 (M+H) +

[1040] Retention time: 2.35 minutes (analysis conditions SQDFA05 long)

[1041] Using compound aa021-f (2.00 g, 4.89 mmol) as a starting material, compound aa021-g was obtained as a crude product in the same manner as compound aa020-e. Furthermore, compound aa021 (1.80 g, 2 steps, 87%) was obtained in the same manner as compound aa020.

[1042] LCMS (ESI) m / z = 424 (M+H) +

[1043] Retention time: 0.84 minutes (analysis conditions SQDFA05)

[1044] Synthesis of compound aa022

[1045]

[1046] In a nitrogen atmosphere, compound aa020-b (1 g, 3.09 mmol) was dissolved in toluene (6.2 mL), ethanol 1 (0.542 mL, 9.28 mmol) was added, and BF3·OEt2 (0.059 mL, 0.464 mmol) was then added dropwise over 5 minutes while ice cooling. The mixture was stirred for 2.5 hours while returning to room temperature. The reaction was quenched by adding a saturated NaHCO3 aqueous solution, and the aqueous layer was removed by a phase separator. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Ethyl acetate / hexane (3 / 1, 24 mL) was added to the resulting residue, and the solvent was distilled off under reduced pressure. Hexane / TBME (85 / 15, 24 mL) was added to the resulting solid, and the mixture was stirred for 30 minutes, and then the solvent was filtered off to obtain compound aa022-b (787 mg, 69%).

[1047] LCMS (ESI) m / z = 370 (M+H) +

[1048] Retention time: 0.86 minutes (analysis conditions SQDFA05)

[1049] Calcium chloride (2.25 g, 20.3 mmol) was dissolved in H 2 O (5.7 mL), lithium hydroxide monohydrate (227 mg, 5.41 mmol) was added thereto, and the mixture was stirred at room temperature for 5 minutes to prepare aqueous solution A.

[1050] Compound aa022-b was dissolved in isopropanol 1 (22.6 mL) and THF (57 mL), a pre-prepared aqueous solution A was added, and the mixture was stirred at room temperature for 7 hours. 1N hydrochloric acid (8.1 mL) was then added to the reaction solution, and isopropanol and THF were then removed by concentrating under reduced pressure. The resulting aqueous layer was diluted with H2O and extracted 3 times with ethyl acetate. The organic layer was washed with H2O and saturated brine, dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was ground with ethyl acetate / n-hexane (1 / 5, 20 v / w) to obtain compound aa022-c (3.5 g, 79%).

[1051] LCMS (ESI) m / z = 356 (M+H) +

[1052] Retention time: 0.78 minutes (analysis conditions SQDFA05)

[1053] Using aa022-c as a starting material, aa022-d (871 mg, 84%) was obtained as a crude product in the same manner as in the synthesis of compound aa004-b.

[1054] LCMS (ESI) m / z = 368 (M+H)

[1055] Retention time: 0.84 minutes (analysis conditions SQDFA05)

[1056] Using aa022-d as a starting material, aa022 (254 mg, 90%) was obtained in the same manner as the synthesis of compound aa004.

[1057] LCMS (ESI) m / z = 370 (M+H) +

[1058] Retention time: 0.80 minutes (analysis conditions SQDFA05)

[1059] Synthesis of compound aa210

[1060]

[1061] Compound aa210-a (5.00 g, 13.7 mmol) was dissolved in toluene (17 mL), and TFA (9.49 mL, 123 mmol) and paraldehyde (5.42 mL, 41.0 mmol) were added, and the mixture was stirred at 45 ° C for 24 hours. The mixture was cooled to 0 ° C, toluene (17 mL), TFA (19.0 mL, 246 mmol) and TES (19.6 mL, 123 mmol) were added, and the mixture was stirred at 50 ° C overnight. The solvent was distilled off under reduced pressure, ethyl acetate was added, and the mixture was washed with saturated sodium bicarbonate aqueous solution and washed with saturated brine. The organic layer was dried over sodium sulfate and filtered, and the solvent was distilled off under reduced pressure. Purification by reverse phase column chromatography (acetonitrile containing 0.1% formic acid / distilled water containing 0.1% formic acid) gave compound aa210 (2.17 g, 40%).

[1062] LCMS (ESI) m / z = 394 (M+H) +

[1063] Retention time: 0.94 minutes (analysis conditions SQDFA05)

[1064] Synthesis of compound aa201

[1065]

[1066] Under a nitrogen atmosphere, compound aa201-a ((2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-(4-methylphenyl)propanoic acid, Fmoc-Phe(4-Me)-OH) (5.62 g, 14.0 mmol, CAS No. 199006-54-7) was suspended in DCE (17.5 mL), and then paraldehyde (5.61 mL, 42.0 mmol) and TFA (9.65 mL, 126 mmol) were added, and the mixture was stirred at 60° C. for 6 hours. The resulting reaction solution containing compound aa201-b was used directly in the next step.

[1067] LCMS (ESI) m / z = 428 (M+H)

[1068] Retention time: 1.03 minutes (analysis conditions SQDFA05)

[1069] DCE (17.5 mL), TFA (19.3 mL, 252 mmol) and TES (20.1 mL, 126 mmol) are added to the reaction solution of obtained compound aa201-b, and the mixture is stirred at 60 ° C for 17 hours. After the mixture is cooled to room temperature and concentrated under reduced pressure, the obtained residue is dissolved in ethyl acetate (40 mL). The organic layer is washed with saturated sodium bicarbonate aqueous solution (40 mL) and saturated brine (40 mL), and dried over anhydrous sodium sulfate, and then the solvent is distilled off under reduced pressure. The obtained residue is dissolved in acetonitrile (30 mL), and washed twice with hexane (15 mL), and the solvent is distilled off under reduced pressure. The resulting residue was purified by reverse phase column chromatography (acetonitrile containing 0.1% formic acid / distilled water containing 0.1% formic acid) to give compound aa201 ((2S)-2-[ethyl(9H-fluoren-9-ylmethoxycarbonyl)amino]-3-(4-methylphenyl)propanoic acid, Fmoc-EtPhe(4-Me)-OH) (4.4 g, 2 steps, 73%).

[1070] LCMS (ESI) m / z = 430 (M+H) +

[1071] Retention time: 0.95 minutes (analysis conditions SQDFA05)

[1072] Synthesis of compound aa164

[1073]

[1074] In a nitrogen atmosphere, compound aa164-a ((2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-[4-(trifluoromethyl)phenyl]propanoic acid, Fmoc-Phe(4-CF3)-OH) (4.04 g, 8.87 mmol, CAS No. 247113-86-6) was suspended in DCE (11.1 mL), and then anhydrous magnesium sulfate (4.27 g, 35.4 mmol), paraldehyde (3.55 mL, 26.6 mmol) and TFA (6.11 mL, 80 mmol) were added, and the mixture was stirred at 60°C for 3 hours. In addition, anhydrous magnesium sulfate (2.14 g, 17.7 mmol) was added, and the mixture was stirred at 60°C for 1 hour. The resulting reaction solution containing compound aa164-b was used directly in the next reaction.

[1075] LCMS (ESI) m / z = 482 (M+H)

[1076] Retention time: 1.04 minutes (analysis conditions SQDFA05)

[1077] DCE (11.1mL), TFA (12.2mL, 159mmol) and triethylsilane (12.7mL, 80mmol) are added to the reaction solution containing compound aa164-b obtained, and the mixture is stirred at 60 ° C for 10 hours. The mixture is cooled to room temperature, magnesium sulfate is filtered out, and the mixture is concentrated under reduced pressure. Since the expected reaction is not complete, the resulting residue is dissolved in DCE (22.2mL), then TFA (18.3mL, 239mmol) and triethylsilane (12.7mL, 80mmol) are added, and the mixture is stirred at 60 ° C for 8 hours. After the mixture is cooled to room temperature and concentrated under reduced pressure, the resulting residue is dissolved in ethyl acetate (40mL). The organic layer is washed with saturated sodium bicarbonate aqueous solution (40mL) and saturated brine (40mL), and dried over anhydrous sodium sulfate, and then the solvent is distilled off under reduced pressure. The resulting residue was dissolved in acetonitrile (30 mL), washed twice with hexane (15 mL), and the solvent was distilled off under reduced pressure. The resulting residue was purified by reverse phase column chromatography (water / acetonitrile containing 0.1% formic acid) to give compound aa164 (1.90 g, 44% over 2 steps).

[1078] LCMS (ESI) m / z = 484 (M+H)

[1079] Retention time: 0.97 minutes (analysis conditions SQDFA05)

[1080] Synthesis of compound aa136

[1081]

[1082] Compound aa136-a (10.1 g, 22.1 mmol) was dissolved in toluene (28 mL), followed by the addition of propionaldehyde (14.3 mL, 199 mmol), TFA (15.3 mL, 199 mmol) and magnesium sulfate (7.99 g, 66.4 mmol), and the mixture was stirred at 60 ° C for 3 hours. The solid was filtered out with a silica gel pad, and the filtrate was washed twice with water (100 mL). Acetonitrile (20 mL) was added thereto, and the mixture was washed with 1 M potassium dihydrogen phosphate aqueous solution (30 mL), washed 3 times with 3.5% potassium bicarbonate aqueous solution (40 mL), and washed with saturated brine (100 mL). The mixture was dried over anhydrous magnesium sulfate and filtered, and the solvent was distilled off under reduced pressure to obtain compound aa136-b as a crude product. The crude product of compound aa136-b was dissolved in toluene (28 mL), and TES (7.07 mL, 44.3 mmol) was added. The mixture is cooled to 0 ℃, TiCl4 (4.88mL, 44.3mmol) is added, and the mixture is stirred at room temperature for 15 minutes. Water (50mL) is added dropwise, and the organic layer is washed with water (100mL), and washed with 1M dipotassium hydrogen phosphate aqueous solution (50mL). Normal hexane (90mL) is added, and the mixture is extracted 3 times with a mixed solvent of acetonitrile (15mL) and 1% potassium bicarbonate aqueous solution (30mL). In addition, the mixture is extracted twice with a mixed solvent of acetonitrile (20mL) and 1% potassium bicarbonate aqueous solution (30mL). Normal hexane (90mL) is added in the organic layer, and the mixture is extracted twice with a mixed solvent of acetonitrile (20mL) and 1% potassium bicarbonate aqueous solution (30mL). Combined aqueous layers, normal hexane (80mL) is added, phosphoric acid is added to regulate pH to 3, and then the mixture is extracted 3 times with TBME (150mL). The organic layer was washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, and filtered off, and the solvent was distilled off under reduced pressure to give compound aa136 (5.03 g, 46%).

[1083] LCMS (ESI) m / z = 498 (M+H)

[1084] Retention time: 1.02 minutes (analysis conditions SQDFA05)

[1085] Synthesis of compound aa174

[1086]

[1087] Using aa174-a as a starting material, aa174 (18.6 g, 84%) was obtained in the same manner as the synthesis of compound aa136.

[1088] LCMS (ESI) m / z = 460 (M + NH4) +

[1089] Retention time: 1.41 minutes (Analysis conditions SMD method_04)

[1090] Synthesis of compound aa264

[1091]

[1092] Compound aa264-a (H-cisHyp(3)-OH, 950 mg, 7.24 mmol) was dissolved in water (22 mL) and DIPEA (3.47 mL, 19.9 mmol) was added. A 1,4-dioxane solution (14.5 mL) of Fmoc-OSu (2.44 g, 7.24 mmol) was added. The resulting solid was crushed with a spatula and further pulverized by ultrasonic irradiation. 1,4-dioxane (15 mL) was added to dissolve the solid, and the solution was stirred at room temperature for 40 minutes. The mixture was washed twice with n-hexane / CPME (3 / 1, 10 mL), and potassium bisulfate (3.70 g, 27.2 mmol) was added. The mixture was extracted 3 times with isopropyl acetate (30 mL), the organic layer was washed with 50% brine (30 mL), dried over anhydrous sodium sulfate, filtered off, and the solvent was distilled off under reduced pressure to give compound aa264-b (2.39 g, 93%).

[1093] LCMS (ESI) m / z = 355 (M+H) +

[1094] Retention time: 0.64 minutes (analysis conditions SQDFA05)

[1095] Compound 264-b (2.39 g, 6.76 mmol) and PPTS (0.170 g, 0.676 mmol) were suspended in DCM (23 mL), followed by the addition of DHP (1.39 mL, 15.2 mmol), and the mixture was stirred at room temperature for 19 hours. PPTS (0.085 g, 0.338 mmol) and DHP (0.741 mL, 8.11 mmol) were added, and the mixture was stirred at room temperature for 3 hours. The mixture was washed with water and saturated brine. The mixture was dried over anhydrous sodium sulfate and filtered out, and the solvent was distilled off under reduced pressure. The mixture was dissolved in THF (25 mL), phosphate buffer (pH = 8.2, 25 mL) was added, and the mixture was stirred at 50 ° C for 11 hours. Ethyl acetate (25 mL) was added to remove the water layer, and the water layer was extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered out, and the solvent was distilled off under reduced pressure. It is dissolved in DCM (30mL), and n-hexane (30mL) is added. Only DCM is distilled out under reduced pressure, and n-hexane is further distilled out under reduced pressure. N-hexane is added in the gained solid, and it is irradiated with ultrasonic wave, and n-hexane is removed by decantation, and it is dried under reduced pressure to obtain compound aa264 as sodium salt. It is dissolved in isopropyl acetate (50mL), 0.05M phosphoric acid aqueous solution (pH=2, 90mL) is added, the mixture is stirred at room temperature for 10 minutes, and then the water layer is removed. The water layer is extracted with isopropyl acetate, the organic layer is dried over anhydrous sodium sulfate and filtered, and the solvent is distilled out under reduced pressure. The gained crude product is purified by reverse phase chromatography (acetonitrile containing 0.1% formic acid / distilled water containing 0.1% formic acid), to obtain compound aa264 (2.33g, 79%).

[1096] LCMS (ESI) m / z = 456 (M + NH3) +

[1097] Retention time: 0.81 minutes (analysis conditions SQDFA05)

[1098] Synthesis of compound aa265

[1099]

[1100] Using aa265-a as a starting material, aa265 (1.38 g, 78%) was obtained in the same manner as the synthesis of compound aa264.

[1101] LCMS (ESI) m / z = 439 (M+H) +

[1102] Retention time: 0.85 minutes (analysis conditions SQDFA05)

[1103] Synthesis of compound aa267

[1104]

[1105] Using aa267-a as a starting material, aa267 (9.04 g, quant) was obtained in the same manner as the synthesis of compound aa264.

[1106] LCMS (ESI) m / z = 460 (M + Na) +

[1107] Retention time: 0.81 minutes (analysis conditions SQDFA05)

[1108] Synthesis of compound aa279

[1109]

[1110] Using aa279-a as a starting material, aa279 (5.15 g, 83%) was obtained in the same manner as the synthesis of compound aa264.

[1111] LCMS (ESI) m / z = 460 (M + Na) +

[1112] Retention time: 0.85 minutes (analysis conditions SQDFA05)

[1113] Synthesis of compound aa244

[1114]

[1115] A mixed solution of compound aa244-a ((2S)-2-(phenylmethoxycarbonylamino)pentanedioic acid) (50 g, 177.8 mmol), paraformaldehyde (11.87 g), and p-toluenesulfonic acid (1.84 g, 10.69 mmol) in toluene (500 mL) was stirred at 120° C. for 16 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The so...

Claims

1. A cyclic compound represented by formula (1): in L1 is a single bond; R1 is a C1 to C7 alkyl group, or R1 and R5 are linked together to form a divalent group, wherein the partial structure of the cyclic compound represented by formula (1): *-CR1Q1-L1-CO-NP2-CR2Q2-CO-NP3-CR3Q3-CO-NP4-CR4Q4-CO-NP5-CR5Q5-* is represented by the following formula: in: X2 is -L1-CO-NP2-CR2Q2-CO-NP3-CR3Q3-CO-NP4-CR4Q4-CO-NP5-, is a single bond or a double bond, E or Z configuration can be used if For double bonds, n is 0, 1, or 2, m is 0, 1, 2, 3 or 4, * represents the connection point with the adjacent atom; P1 is a C1 to C6 alkyl group; Q1 is a hydrogen atom; R2 is C1 to C6 alkyl; P2 is a hydrogen atom; Q2 is a hydrogen atom; R3 is a hydrogen atom or R3 is connected to the carbon atom to which P3 and R3 are connected and the nitrogen atom to which P3 is connected to form a 4- to 7-membered saturated heterocyclic ring; P3 is C1 to C6 alkyl or C3 to C8 cycloalkyl, except when R3 and P3 form a 4- to 7-membered saturated heterocyclic ring; Q3 is a hydrogen atom; R4 and P5 are linked together to form a divalent group, wherein the partial structure *-CR4Q4-CO-NP5-* in the cyclic compound represented by formula (1) is represented by the following formula: P4 is a C1 to C6 alkyl group; Q4 is a hydrogen atom, R5 is benzyl optionally substituted with one or more groups selected from the group consisting of C1 to C6 alkyl, C1 to C6 haloalkyl, and C3 to C8 cycloalkyl, except when R1 and R5 form a divalent group; Q5 is a hydrogen atom, R6 is a hydrogen atom; P6 is a C1 to C6 alkyl group, Q6 is a hydrogen atom, R7 is a phenethyl group optionally substituted with one or more groups selected from the group consisting of a halogen atom, a C1 to C6 haloalkyl group, and a C1 to C6 alkoxy group; P7 is a hydrogen atom, Q7 is a hydrogen atom, R8 is joined together with the carbon atom to which P8 and R8 are attached and the nitrogen atom to which P8 is attached to form a 4- to 7-membered saturated heterocyclic ring, wherein the 4- to 7-membered saturated heterocyclic ring is optionally substituted with a C1 to C6 alkoxy group; Q8 is a hydrogen atom, R9 and Q9 and the carbon atom to which R9 and Q9 are attached are joined together to form a 3- to 8-membered alicyclic ring, wherein the 3- to 8-membered alicyclic ring is optionally substituted with one or more C1 to C6 alkyl groups; P9 is a hydrogen atom or a C1 to C6 alkyl group, R 10 is C1 to C6 alkyl or C3 to C8 cycloalkyl; P 10 is a C1 to C6 alkyl group, Q 10 for hydrogen atoms, and L 11 is -CH2-, R 11 is a di-C1 to C6 alkylaminocarbonyl group or a 4-membered to 8-membered cyclic aminocarbonyl group; P 11 is a C1 to C6 alkyl group, and Q 11 is a hydrogen atom, or a salt thereof, or a solvate thereof, wherein The cyclic compound represented by formula (1) is selected from the group consisting of: PP1574: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-N-ethyl-27-isobutyl-N,4,19,22,26,32,35-heptamethyl-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 ]tetradecene-38-ene-17,1′-cyclopentane]-23-carboxamide, PP1650: (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,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 ]tetradec-38-ene-17,1′-cyclobutane]-23-carboxamide, PP1827: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47E)-19-cyclopentyl-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-N-ethyl-N,3,18,21,25,31,34-heptamethyl-29-[(1S)-1-methylpropyl]-2,5,8,14,17,20,24,27,30,33,55-undecaoxo-spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24.15.11.2 43，46 .1 35，41 .0 9，13 ]pentacarbon-37,43(54),44,46(53),47-pentaene-16,1′-cyclobutane]-22-carboxamide, PP1830: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47E)-19-cyclopentyl-11-ethoxy-N-ethyl-7-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,3,3′,3′,18,21,25,31,34-nonamethyl-29-[(1S)-1-methylpropyl]-2,5,8,14,17,20,24,27,30,33,55-undecaoxo-spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24.15.11.2 43，46 .1 35，41 .0 9，13 ]pentacarbon-37,43(54),44,46(53),47-pentaene-16,1′-cyclobutane]-22-carboxamide, PP2093: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-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-(p-tolylmethyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10，14 ]tetradec-38-ene-17,1′-cyclobutane]-23-carboxamide, PP2260: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z)-19-cyclopentyl-11-ethoxy-N-ethyl-7-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,3,3′,3′,18,21,25,31,34-nonamethyl-29-[(1S)-1-methylpropyl]-2,5,8,14,17,20,24,27,30,33,55-undecaoxo-spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24.15.11.2 43，46 .1 35，41 .0 9，13 ]pentadeca-37,43(54),44,46(53)-tetraene-16,1′-cyclobutane]-22-carboxamide, PP2316: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,N,4,16,19,22,26,35-octamethyl-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 ]tetradec-38-ene-17,1′-cyclobutane]-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 ]pentadeca-42-ene-23,1′-cyclobutane]-17-carboxamide, PP2328: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,N,4,16,19,22,26,35-octamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaoxo-27-propyl-2-(p-tolylmethyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10，14 ]tetradec-38-ene-17,1′-cyclobutane]-23-carboxamide, PP2574: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47E)-19-cyclopentyl-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-3,3′,3′,18,21,25,31,34-octamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24.15.10.2 43，46 .1 35，41 .0 9，13 ]pentacontan-37,43(53),44,46(52),47-pentacontan-16,1′-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecanone, PP2576: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47E)-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-19-(1-ethylpropyl)-3,3′,3′,18,21,25,31,34-octamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24.15.10.2 43，46 .1 35，41 .0 9，13 ]pentacontan-37,43(53),44,46(52),47-pentacontan-16,1′-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecanone, PP2583: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47E)-19-cyclopentyl-31-cyclopropyl-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-3,3′,3′,18,21,25,34-heptamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24.15.10.2 43，46 .1 35，41 .0 9，13 ]pentacontan-37,43(53),44,46(52),47-pentacontan-16,1′-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecanone, PP2687: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-12-ethoxy-2-[(4-ethylphenyl)methyl]-27-isobutyl-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-spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10，14 ]tetradec-38-ene-17,1′-cyclobutane]-23-carboxamide, PP2691: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-2-[(4-cyclopropylphenyl)methyl]-12-ethoxy-27-isobutyl-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-spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10，14 ]tetradec-38-ene-17,1′-cyclobutane]-23-carboxamide, PP2957: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47E)-31-cyclopropyl-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-19-(1-ethylpropyl)-3,18,21,25,34-pentamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24.15.10.2 43，46 .1 35，41 .0 9，13 ]pentacontan-37,43(53),44,46(52),47-pentacontan-16,1′-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecanone, PP3033: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z)-19-cyclopentyl-11-ethoxy-7-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-3,18,21,25,31,34-hexamethyl-29-[(1S)-1-methylpropyl]-22-(piperidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.11.2 43，46 .1 35，41 .0 9，13 ]pentacarbon-37,43(54),44,46(53)-tetraene-16,1′-cyclobutane]-2,5,8,14,17,20,24,27,30,33,55-undecanone, PP3034: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z)-19-cyclopentyl-11-ethoxy-7-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-3,3′,3′,18,21,25,31,34-octamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.11.2 43，46 .1 35，41 .0 9，13 ]pentacarbon-37,43(54),44,46(53)-tetraene-16,1′-cyclobutane]-2,5,8,14,17,20,24,27,30,33,55-undecanone, PP3036: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z)-19-cyclopentyl-11-ethoxy-7-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-3,3′,3′,18,21,25,31,34-octamethyl-29-[(1S)-1-methylpropyl]-22-(piperidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.10.2 43，46 .1 35，41 .0 9，13 ] 54-tetra-37,43(53),44,46(52)-tetraene-16,1′-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecanone, PP3037: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z)-19-cyclopentyl-11-ethoxy-7-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-3,3′,3′,18,21,25,31,34-octamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.10.2 43，46 .1 35，41 .0 9，13 ] 54-tetra-37,43(53),44,46(52)-tetraene-16,1′-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecanone, PP3047: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47E)-7-[2-(3,4-dichlorophenyl)ethyl]-11-ethoxy-19-(1-ethylpropyl)-3,18,21,25,31,34-hexamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.11.2 43 ，46 .1 35，41 .0 9，13 ]pentacarbon-37,43(54),44,46(53),47-pentaene-16,1′-cyclobutane]-2,5,8,14,17,20,24,27,30,33,55-undecanone, PP3093: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z)-19-cyclopentyl-11-ethoxy-7-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-3,3′,3′,18,21,25,31,34-octamethyl-29-[(1S)-1-methylpropyl]-22-(piperidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.9.2 43，46 .1 35，41 .0 9，13 ]53 carbon-37,43(52),44,46(51)-tetraene-16,1′-cyclobutane]-2,5,8,14,17,20,24,27,30,33,53-undecanone, PP3094: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z)-19-cyclopentyl-7-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-3,3′,3′,18,21,25,31,34-octamethyl-29-[(1S)-1-methylpropyl]-11-propoxy-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.9.2 43，46 .1 35，41 .0 9，13 ]53 carbon-37,43(52),44,46(51)-tetraene-16,1′-cyclobutane]-2,5,8,14,17,20,24,27,30,33,53-undecanone, PP3095: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-4,16,19,22,26,35-hexamethyl-30-[(1S)-1-methylpropyl]-23-(piperidine-1-carbonyl)-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 ]tetradec-38-ene-17,1′-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecanone, PP3096: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-4,16,19,22,26,35-hexamethyl-30-[(1S)-1-methylpropyl]-23-(piperidine-1-carbonyl)-27-propyl-2-(p-tolylmethyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10，14 ]tetradec-38-ene-17,1′-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecanone, PP3097: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-4,16,19,22,26,35-hexamethyl-30-[(1S)-1-methylpropyl]-27-propyl-23-(pyrrolidine-1-carbonyl)-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10，14 ]tetradec-38-ene-17,1′-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecanone, PP3098: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-4,16,19,22,26,35-hexamethyl-30-[(1S)-1-methylpropyl]-27-propyl-2-(p-tolylmethyl)-23-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10，14 ]tetradec-38-ene-17,1′-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecanone, PP3099: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-28-ethoxy-32-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-2,14,18,21,24,36-hexamethyl-10-[(1S)-1-methylpropyl]-17-(piperidine-1-carbonyl)-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 ]pentadeca-42-ene-23,1′-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecanone, PP3100: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-28-ethoxy-32-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-2,14,18,21,24,36-hexamethyl-10-[(1S)-1-methylpropyl]-17-(piperidine-1-carbonyl)-13-propyl-38-(p-tolylmethyl)spiro[2,8,11,14,18,21,24,30,33,36,39-undecazatetracyclo[37.5.1.0 4，8 .0 26，30 ]pentadeca-42-ene-23,1′-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecanone, PP3101: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-28-ethoxy-32-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-2,14,18,21,24,36-hexamethyl-10-[(1S)-1-methylpropyl]-13-propyl-17-(pyrrolidine-1-carbonyl)-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 ]pentadeca-42-ene-23,1′-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecanone, PP3102: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-28-ethoxy-32-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-2,14,18,21,24,36-hexamethyl-10-[(1S)-1-methylpropyl]-13-propyl-38-(p-tolylmethyl)-17-(pyrrolidine-1-carbonyl)spiro[2,8,11,14,18,21,24,30,33,36,39-undecaazatetracyclo[37.5.1.0 4，8 .0 26，30 ]pentadeca-42-ene-23,1′-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecanone, PP3103: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-4,16,19,22,26,32,35-heptamethyl-30-[(1S)-1-methylpropyl]-23-(piperidine-1-carbonyl)-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 ]tetradec-38-ene-17,1′-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecanone, PP3104: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-4,16,19,22,26,32,35-heptamethyl-30-[(1S)-1-methylpropyl]-23-(piperidine-1-carbonyl)-27-propyl-2-(p-tolylmethyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10，14 ]tetradec-38-ene-17,1′-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecanone, PP3105: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-4,16,19,22,26,32,35-heptamethyl-30-[(1S)-1-methylpropyl]-27-propyl-23-(pyrrolidine-1-carbonyl)-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10，14 ]tetradec-38-ene-17,1′-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecanone, PP3106: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-4,16,19,22,26,32,35-heptamethyl-30-[(1S)-1-methylpropyl]-27-propyl-2-(p-tolylmethyl)-23-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10，14 ]tetradec-38-ene-17,1′-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecanone, PP3110: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-4,16,19,22,26,35-hexamethyl-30-[(1S)-1-methylpropyl]-23-(piperidine-1-carbonyl)-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 ]tetradec-38-ene-17,1′-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecanone, PP3111: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-4,16,19,22,26,35-hexamethyl-30-[(1S)-1-methylpropyl]-23-(piperidine-1-carbonyl)-27-propyl-2-(p-tolylmethyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10，14 ]tetradec-38-ene-17,1′-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecanone, PP3112: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-4,16,19,22,26,35-hexamethyl-30-[(1S)-1-methylpropyl]-27-propyl-23-(pyrrolidine-1-carbonyl)-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10，14 ]tetradec-38-ene-17,1′-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecanone, PP3113: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-4,16,19,22,26,35-hexamethyl-30-[(1S)-1-methylpropyl]-27-propyl-2-(p-tolylmethyl)-23-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10，14 ]tetradec-38-ene-17,1′-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecanone, PP3114: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-32-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-28-ethoxy-2,14,18,21,24,36-hexamethyl-10-[(1S)-1-methylpropyl]-17-(piperidine-1-carbonyl)-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 ]pentadeca-42-ene-23,1′-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecanone, PP3115: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-32-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-28-ethoxy-2,14,18,21,24,36-hexamethyl-10-[(1S)-1-methylpropyl]-17-(piperidine-1-carbonyl)-13-propyl-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 ]pentadeca-42-ene-23,1′-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecanone, PP3116: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-32-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-28-ethoxy-2,14,18,21,24,36-hexamethyl-10-[(1S)-1-methylpropyl]-13-propyl-17-(pyrrolidine-1-carbonyl)-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 ]pentadeca-42-ene-23,1′-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecanone, PP3117: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-32-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-28-ethoxy-2,14,18,21,24,36-hexamethyl-10-[(1S)-1-methylpropyl]-13-propyl-38-(p-tolylmethyl)-17-(pyrrolidine-1-carbonyl)spiro[2,8,11,14,18,21,24,30,33,36,39-undecaazatetracyclo[37.5.1.0 4，8 .0 26，30 ]pentadeca-42-ene-23,1′-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecanone, PP3118: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-4,16,19,22,26,32,35-heptamethyl-30-[(1S)-1-methylpropyl]-23-(piperidine-1-carbonyl)-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 ]tetradec-38-ene-17,1′-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecanone, PP3119: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-4,16,19,22,26,32,35-heptamethyl-30-[(1S)-1-methylpropyl]-23-(piperidine-1-carbonyl)-27-propyl-2-(p-tolylmethyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10，14 ]tetradec-38-ene-17,1′-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecanone, PP3120: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-4,16,19,22,26,32,35-heptamethyl-30-[(1S)-1-methylpropyl]-27-propyl-23-(pyrrolidine-1-carbonyl)-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10，14 ]tetradec-38-ene-17,1′-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecanone, PP3121: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-4,16,19,22,26,32,35-heptamethyl-30-[(1S)-1-methylpropyl]-27-propyl-2-(p-tolylmethyl)-23-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10，14 ]tetradec-38-ene-17,1′-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecanone, (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47Z)-19-cyclopentyl-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-N-ethyl-N,3,18,21,25,31,34-heptamethyl-29-[(1S)-1-methylpropyl]-2,5,8,14,17,20,24,27,30,33,55-undeca- oxo-spiro[3,6,9,15,18,21,25,28,31,34,41-undeca-pentacyclo[24,15,11,2 43，46 .1 35，41 .0 9，13 ]pentacarbon-37,43(54),44,46(53),47-pentaene-16,1′-cyclobutane]-22-carboxamide, (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47Z)-19-cyclopentyl-11-ethoxy-N-ethyl-7-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,3,3′,3′,18,21,25,31,34-nonamethyl-29-[(1S)-1-methylpropyl]-2,5,8,14,17,20,24,27,30,33,55-undecaoxo-spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24.15.11.2 43，46 .1 35，41 .0 9，13 ]pentacarbon-37,43(54),44,46(53),47-pentaene-16,1′-cyclobutane]-22-carboxamide, (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47Z)-19-cyclopentyl-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-3,3′,3′,18,21,25,31,34-octamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.10.2 43，46 .1 35，41 .0 9，13 ]pentacontan-37,43(53),44,46(52),47-pentacontan-16,1′-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecanone, (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47Z)-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-19-(1-ethylpropyl)-3,3′,3′,18,21,25,31,34-octamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.10.2 43，46 .1 35，41 .0 9.13 ]pentacontan-37,43(53),44,46(52),47-pentacontan-16,1′-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecanone, (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47Z)-19-cyclopentyl-31-cyclopropyl-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-3,3′,3′,18,21,25,34-heptamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.10.2 43，46 .1 35，41 .0 9，13 ]pentacontan-37,43(53),44,46(52),47-pentacontan-16,1′-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecanone, (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47Z)-31-cyclopropyl-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-19-(1-ethylpropyl)-3,18,21,25,34-pentamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.10.2 43，46 .1 35，41 .0 9，13 ]pentacontan-37,43(53),44,46(52),47-pentaene-16,1′-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecanone, and (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47Z)-7-[2-(3,4-dichlorophenyl)ethyl]-11-ethoxy-19-(1-ethylpropyl)-3,18,21,25,31,34-hexamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.11.2 43，46 .1 35， 41 .0 9，13 ]pentacarbon-37,43(54),44,46(53),47-pentaene-16,1′-cyclobutane]-2,5,8,14,17,20,24,27,30,33,55-undecanone.

2. The cyclic compound or its salt or solvate thereof according to claim 1, wherein the formula (1) is represented by the formula (2): in n, m, P1, R2, R3, P3, P4, P6, R7, R8, P8, R9, P9, Q9, R 10 , P 10 , R 11 and P 11 Same as defined in claim 1, The cyclic compound represented by formula (2) is selected from the group consisting of: PP1827: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47E)-19-cyclopentyl-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-N-ethyl-N,3,18,21,25,31,34-heptamethyl-29-[(1S)-1-methylpropyl]-2,5,8,14,17,20,24,27,30,33,55-undecaoxo-spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24.15.11.2 43，46 .1 35，41 .0 9，13 ]pentacarbon-37,43(54),44,46(53),47-pentaene-16,1′-cyclobutane]-22-carboxamide, PP1830: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47E)-19-cyclopentyl-11-ethoxy-N-ethyl-7-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,3,3′,3′,18,21,25,31,34-nonamethyl-29-[(1S)-1-methylpropyl]-2,5,8,14,17,20,24,27,30,33,55-undecaoxo-spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24.15.11.2 43，46 .1 35，41 .0 9，13 ]pentacarbon-37,43(54),44,46(53),47-pentaene-16,1′-cyclobutane]-22-carboxamide, PP2260: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z)-19-cyclopentyl-11-ethoxy-N-ethyl-7-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,3,3′,3′,18,21,25,31,34-nonamethyl-29-[(1S)-1-methylpropyl]-2,5,8,14,17,20,24,27,30,33,55-undecaoxo-spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24.15.11.2 43，46 .1 35，41 .0 9，13 ]pentadeca-37,43(54),44,46(53)-tetraene-16,1′-cyclobutane]-22-carboxamide, PP2574: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47E)-19-cyclopentyl-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-3,3′,3′,18,21,25,31,34-octamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24.15.10.2 43，46 .1 35，41 .0 9，13 ]pentacontan-37,43(53),44,46(52),47-pentacontan-16,1′-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecanone, PP2576: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47E)-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-19-(1-ethylpropyl)-3,3′,3′,18,21,25,31,34-octamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24.15.10.2 43，46 .1 35，41 .0 9，13 ]pentacontan-37,43(53),44,46(52),47-pentacontan-16,1′-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecanone, PP2583: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47E)-19-cyclopentyl-31-cyclopropyl-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-3,3′,3′,18,21,25,34-heptamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24.15.10.2 43，46 .1 35，41 .0 9，13 ]pentacontan-37,43(53),44,46(52),47-pentacontan-16,1′-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecanone, PP2957: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47E)-31-cyclopropyl-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-19-(1-ethylpropyl)-3,18,21,25,34-pentamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24.15.10.2 43，46 .1 35，41 .0 9，13 ]pentacontan-37,43(53),44,46(52),47-pentacontan-16,1′-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecanone, PP3033: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z)-19-cyclopentyl-11-ethoxy-7-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-3,18,21,25,31,34-hexamethyl-29-[(1S)-1-methylpropyl]-22-(piperidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.11.2 43，46 .1 35，41 .0 9，13 ]pentacarbon-37,43(54),44,46(53)-tetraene-16,1′-cyclobutane]-2,5,8,14,17,20,24,27,30,33,55-undecanone, PP3034: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z)-19-cyclopentyl-11-ethoxy-7-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-3,3′,3′,18,21,25,31,34-octamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.11.2 43，46 .1 35，41 .0 9，13 ]pentacarbon-37,43(54),44,46(53)-tetraene-16,1′-cyclobutane]-2,5,8,14,17,20,24,27,30,33,55-undecanone, PP3036: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z)-19-cyclopentyl-11-ethoxy-7-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-3,3′,3′,18,21,25,31,34-octamethyl-29-[(1S)-1-methylpropyl]-22-(piperidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.10.2 43，46 .1 35，41 .0 9，13 ] 54-tetra-37,43(53),44,46(52)-tetraene-16,1′-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecanone, PP3037: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z)-19-cyclopentyl-11-ethoxy-7-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-3,3′,3′,18,21,25,31,34-octamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.10.2 43，46 .1 35，41 .0 9，13 ] 54-tetra-37,43(53),44,46(52)-tetraene-16,1′-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecanone, PP3047: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47E)-7-[2-(3,4-dichlorophenyl)ethyl]-11-ethoxy-19-(1-ethylpropyl)-3,18,21,25,31,34-hexamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.11.2 43 ，46 .1 35，41 .0 9，13 ]pentacarbon-37,43(54),44,46(53),47-pentaene-16,1′-cyclobutane]-2,5,8,14,17,20,24,27,30,33,55-undecanone, PP3093: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z)-19-cyclopentyl-11-ethoxy-7-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-3,3′,3′,18,21,25,31,34-octamethyl-29-[(1S)-1-methylpropyl]-22-(piperidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.9.2 43，46 .1 35，41 .0 9，13 ]53 carbon-37,43(52),44,46(51)-tetraene-16,1′-cyclobutane]-2,5,8,14,17,20,24,27,30,33,53-undecanone, PP3094: (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z)-19-cyclopentyl-7-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-3,3′,3′,18,21,25,31,34-octamethyl-29-[(1S)-1-methylpropyl]-11-propoxy-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.9.2 43，46 .1 35，41 .0 9，13 ]53 carbon-37,43(52),44,46(51)-tetraene-16,1′-cyclobutane]-2,5,8,14,17,20,24,27,30,33,53-undecanone, (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47Z)-19-cyclopentyl-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-N-ethyl-N,3,18,21,25,31,34-heptamethyl-29-[(1S)-1-methylpropyl]-2,5,8,14,17,20,24,27,30,33,55-undeca- oxo-spiro[3,6,9,15,18,21,25,28,31,34,41-undeca-pentacyclo[24,15,11,2 43，46 .1 35，41 .0 9，13 ]pentacarbon-37,43(54),44,46(53),47-pentaene-16,1′-cyclobutane]-22-carboxamide, (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47Z)-19-cyclopentyl-11-ethoxy-N-ethyl-7-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,3,3′,3′,18,21,25,31,34-nonamethyl-29-[(1S)-1-methylpropyl]-2,5,8,14,17,20,24,27,30,33,55-undecaoxo-spiro[3,6,9,15,18,21,25,28,31,34,41-undecaazapentacyclo[24.15.11.2 43，46 .1 35，41 .0 9，13 ]pentacarbon-37,43(54),44,46(53),47-pentaene-16,1′-cyclobutane]-22-carboxamide, (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47Z)-19-cyclopentyl-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-3,3′,3′,18,21,25,31,34-octamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.10.2 43，46 .1 35，41 .0 9，13 ]pentacontan-37,43(53),44,46(52),47-pentacontan-16,1′-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecanone, (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47Z)-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-19-(1-ethylpropyl)-3,3′,3′,18,21,25,31,34-octamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.10.2 43，46 .1 35，41 .0 9，13 ]pentacontan-37,43(53),44,46(52),47-pentacontan-16,1′-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecanone, (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47Z)-19-cyclopentyl-31-cyclopropyl-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-3,3′,3′,18,21,25,34-heptamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.10.2 43，46 .1 35，41 .0 9，13 ]pentacontan-37,43(53),44,46(52),47-pentacontan-16,1′-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecanone, (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47Z)-31-cyclopropyl-7-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-11-ethoxy-19-(1-ethylpropyl)-3,18,21,25,34-pentamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.10.2 43，46 .1 35，41 .0 9，13 ]pentacontan-37,43(53),44,46(52),47-pentaene-16,1′-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecanone, and (1S,7S,11R,13S,19S,22S,26S,29S,35S,37Z,47Z)-7-[2-(3,4-dichlorophenyl)ethyl]-11-ethoxy-19-(1-ethylpropyl)-3,18,21,25,31,34-hexamethyl-29-[(1S)-1-methylpropyl]-22-(pyrrolidine-1-carbonyl)spiro[3,6,9,15,18,21,25,28,31,34,41-undecazapentacyclo[24.15.11.2 43，46 .1 35， 41 .0 9，13 ]pentacarbon-37,43(54),44,46(53),47-pentaene-16,1′-cyclobutane]-2,5,8,14,17,20,24,27,30,33,55-undecanone.

3. The cyclic compound or its salt or solvate thereof according to claim 1, wherein the formula (1) is represented by the formula (3): in, R1 is C1 to C7 alkyl; R5 is benzyl optionally substituted with one or more groups selected from the group consisting of C1 to C6 alkyl, C1 to C6 haloalkyl, and C3 to C8 cycloalkyl; n, m, P1, R2, R3, P3, P4, P6, R7, R8, P8, R9, P9, Q9, R 10 , P 10 , R 11 and P 11 Same as defined in claim 1, wherein The cyclic compound represented by formula (3) is selected from the group consisting of: PP1574: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-N-ethyl-27-isobutyl-N,4,19,22,26,32,35-heptamethyl-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 ]tetradecene-38-ene-17,1′-cyclopentane]-23-carboxamide, PP1650: (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,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 ]tetradec-38-ene-17,1′-cyclobutane]-23-carboxamide, PP2093: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-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-(p-tolylmethyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10，14 ]tetradec-38-ene-17,1′-cyclobutane]-23-carboxamide, PP2316: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,N,4,16,19,22,26,35-octamethyl-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 ]tetradec-38-ene-17,1′-cyclobutane]-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 ]pentadeca-42-ene-23,1′-cyclobutane]-17-carboxamide, PP2328: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,N,4,16,19,22,26,35-octamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaoxo-27-propyl-2-(p-tolylmethyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10，14 ]tetradec-38-ene-17,1′-cyclobutane]-23-carboxamide, PP2687: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-12-ethoxy-2-[(4-ethylphenyl)methyl]-27-isobutyl-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-spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10，14 ]tetradec-38-ene-17,1′-cyclobutane]-23-carboxamide, PP2691: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-2-[(4-cyclopropylphenyl)methyl]-12-ethoxy-27-isobutyl-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-spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10，14 ]tetradec-38-ene-17,1′-cyclobutane]-23-carboxamide, PP3095: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-4,16,19,22,26,35-hexamethyl-30-[(1S)-1-methylpropyl]-23-(piperidine-1-carbonyl)-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 ]tetradec-38-ene-17,1′-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecanone, PP3096: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-4,16,19,22,26,35-hexamethyl-30-[(1S)-1-methylpropyl]-23-(piperidine-1-carbonyl)-27-propyl-2-(p-tolylmethyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10，14 ]tetradec-38-ene-17,1′-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecanone, PP3097: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-4,16,19,22,26,35-hexamethyl-30-[(1S)-1-methylpropyl]-27-propyl-23-(pyrrolidine-1-carbonyl)-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10，14 ]tetradec-38-ene-17,1′-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecanone, PP3098: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-4,16,19,22,26,35-hexamethyl-30-[(1S)-1-methylpropyl]-27-propyl-2-(p-tolylmethyl)-23-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10，14 ]tetradec-38-ene-17,1′-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecanone, PP3099: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-28-ethoxy-32-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-2,14,18,21,24,36-hexamethyl-10-[(1S)-1-methylpropyl]-17-(piperidine-1-carbonyl)-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 ]pentadeca-42-ene-23,1′-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecanone, PP3100: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-28-ethoxy-32-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-2,14,18,21,24,36-hexamethyl-10-[(1S)-1-methylpropyl]-17-(piperidine-1-carbonyl)-13-propyl-38-(p-tolylmethyl)spiro[2,8,11,14,18,21,24,30,33,36,39-undecazatetracyclo[37.5.1.0 4，8 .0 26，30 ]pentadeca-42-ene-23,1′-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecanone, PP3101: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-28-ethoxy-32-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-2,14,18,21,24,36-hexamethyl-10-[(1S)-1-methylpropyl]-13-propyl-17-(pyrrolidine-1-carbonyl)-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 ]pentadeca-42-ene-23,1′-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecanone, PP3102: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-28-ethoxy-32-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-2,14,18,21,24,36-hexamethyl-10-[(1S)-1-methylpropyl]-13-propyl-38-(p-tolylmethyl)-17-(pyrrolidine-1-carbonyl)spiro[2,8,11,14,18,21,24,30,33,36,39-undecaazatetracyclo[37.5.1.0 4，8 .0 26，30 ]pentadeca-42-ene-23,1′-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecanone, PP3103: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-4,16,19,22,26,32,35-heptamethyl-30-[(1S)-1-methylpropyl]-23-(piperidine-1-carbonyl)-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 ]tetradec-38-ene-17,1′-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecanone, PP3104: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-4,16,19,22,26,32,35-heptamethyl-30-[(1S)-1-methylpropyl]-23-(piperidine-1-carbonyl)-27-propyl-2-(p-tolylmethyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10，14 ]tetradec-38-ene-17,1′-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecanone, PP3105: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-4,16,19,22,26,32,35-heptamethyl-30-[(1S)-1-methylpropyl]-27-propyl-23-(pyrrolidine-1-carbonyl)-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10，14 ]tetradec-38-ene-17,1′-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecanone, PP3106: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-12-ethoxy-8-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-4,16,19,22,26,32,35-heptamethyl-30-[(1S)-1-methylpropyl]-27-propyl-2-(p-tolylmethyl)-23-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10，14 ]tetradec-38-ene-17,1′-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecanone, PP3110: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-4,16,19,22,26,35-hexamethyl-30-[(1S)-1-methylpropyl]-23-(piperidine-1-carbonyl)-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 ]tetradec-38-ene-17,1′-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecanone, PP3111: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-4,16,19,22,26,35-hexamethyl-30-[(1S)-1-methylpropyl]-23-(piperidine-1-carbonyl)-27-propyl-2-(p-tolylmethyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10，14 ]tetradec-38-ene-17,1′-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecanone, PP3112: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-4,16,19,22,26,35-hexamethyl-30-[(1S)-1-methylpropyl]-27-propyl-23-(pyrrolidine-1-carbonyl)-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10，14 ]tetradec-38-ene-17,1′-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecanone, PP31]3: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-32-cyclopropyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-4,16,19,22,26,35-hexamethyl-30-[(1S)-1-methylpropyl]-27-propyl-2-(p-tolylmethyl)-23-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10，14 ]tetradec-38-ene-17,1′-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecanone, PP3114: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-32-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-28-ethoxy-2,14,18,21,24,36-hexamethyl-10-[(1S)-1-methylpropyl]-17-(piperidine-1-carbonyl)-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 ]pentadeca-42-ene-23,1′-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecanone, PP3115: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-32-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-28-ethoxy-2,14,18,21,24,36-hexamethyl-10-[(1S)-1-methylpropyl]-17-(piperidine-1-carbonyl)-13-propyl-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 ]pentadeca-42-ene-23,1′-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecanone, PP3116: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-32-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-28-ethoxy-2,14,18,21,24,36-hexamethyl-10-[(1S)-1-methylpropyl]-13-propyl-17-(pyrrolidine-1-carbonyl)-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 ]pentadeca-42-ene-23,1′-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecanone, PP3117: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-32-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-28-ethoxy-2,14,18,21,24,36-hexamethyl-10-[(1S)-1-methylpropyl]-13-propyl-38-(p-tolylmethyl)-17-(pyrrolidine-1-carbonyl)spiro[2,8,11,14,18,21,24,30,33,36,39-undecaazatetracyclo[37.5.1.0 4，8 .0 26，30 ]pentadeca-42-ene-23,1′-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecanone, PP3118: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-4,16,19,22,26,32,35-heptamethyl-30-[(1S)-1-methylpropyl]-23-(piperidine-1-carbonyl)-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 ]tetradec-38-ene-17,1′-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecanone, PP3119: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-4,16,19,22,26,32,35-heptamethyl-30-[(1S)-1-methylpropyl]-23-(piperidine-1-carbonyl)-27-propyl-2-(p-tolylmethyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10，14 ]tetradec-38-ene-17,1′-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecanone, PP3120: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-4,16,19,22,26,32,35-heptamethyl-30-[(1S)-1-methylpropyl]-27-propyl-23-(pyrrolidine-1-carbonyl)-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10，14 ]tetradec-38-ene-17,1′-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecanone, and PP3121: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-4,16,19,22,26,32,35-heptamethyl-30-[(1S)-1-methylpropyl]-27-propyl-2-(p-tolylmethyl)-23-(pyrrolidine-1-carbonyl)spiro[1,4,7,10,16,19,22,26,29,32,35-undecaazatricyclo[34.5.1.0 10，14 ]tetradodec-38-ene-17,1′-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecanone.

4. A cyclic compound or a salt thereof or a solvate thereof, wherein the compound is selected from the group consisting of PP1574, PP1650, PP1827, PP1830, PP2093, PP2260, PP2316, PP2320, PP2328, PP2574, PP2576, PP2583, PP2687, PP2691, PP2957, PP3033, PP3034, PP3036, PP3037, PP3047, 3114, PP3115, PP3116, PP3117, PP3118, PP3119, PP3120, and PP3121. The cyclic compound or a salt thereof according to claim 4. The cyclic compound according to claim 4 or a solvate thereof.

7. A solvate of the cyclic compound according to claim 4 or a salt thereof. The cyclic compound according to claim 4. 9 . The cyclic compound according to claim 1 , or a salt thereof, or a solvate thereof, which binds to KRAS. 10 . The cyclic compound according to claim 1 , or a salt thereof, or a solvate thereof, which inhibits KRAS. 11 . The cyclic compound according to any one of claims 1 to 8 , or a salt thereof, or a solvate thereof, which has a KRAS binding activity that is 3 times or more higher than the NRAS binding activity and the HRAS binding activity. 12 . The cyclic compound according to claim 1 , or a salt thereof, or a solvate thereof, which has a KRAS inhibitory activity that is 3 times or more greater than the NRAS inhibitory activity and the HRAS inhibitory activity. 13 . A pharmaceutical composition comprising the cyclic compound according to claim 1 , or a salt thereof, or a solvate thereof. 14 . A pharmaceutical composition for selectively inhibiting KRAS in a subject, the composition comprising the cyclic compound or a salt thereof or a solvate thereof according to any one of claims 1 to 8. 15 . A pharmaceutical composition for treating or preventing cancer in a subject, the composition comprising an effective amount of the cyclic compound according to any one of claims 1 to 8 or a salt thereof or a solvate thereof. The pharmaceutical composition according to claim 15 , wherein the cancer is lung cancer.

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