Cyclic compound having selective KRAS inhibitory effect on hras and nras

JPWO2023214576A5Active Publication Date: 2026-01-15CHUGAI PHARMA CO LTD
View PDF 0 Cites 0 Cited by

Patent Information

Application Number
JP2024519229
Authority / Receiving Office
JP · JP
Patent Type
Applications
Current Assignee / Owner
Priority Date
2023-05-02
Filing Date
2023-05-02
Publication Date
2026-01-15
Estimated Expiration
2043-05-02
Patent Text Reader

Abstract

The present inventors found a cyclic compound that selectively inhibits KRAS. The present inventors also found that the cyclic compound interacts with a KRAS-specific amino acid residue.
Need to check novelty before this filing date? Find Prior Art

Description

Cyclic compounds with selective KRAS inhibitory activity over HRAS and NRAS

[0001] In one aspect, the present invention relates to a cyclic compound having a KRAS inhibitory activity that is selective for HRAS and NRAS.

[0002] RAS proteins belong to the small GTPase family, and include KRAS, NRAS, and HRAS. RAS proteins are activated or inactivated by their binding status to GDP or GTP. They are activated by the exchange of GDP for GTP by guanine nucleotide exchange factors (GEFs) and inactivated by the hydrolysis of GTP by GAPs (GTPase-activating proteins) (Non-Patent Document 1). Activated RAS induces cell proliferation, survival, and differentiation by activating various downstream signals, including the MAPK pathway, PI3K / Akt pathway, and RAL pathway. Constitutive activation of RAS plays an important role in the development and progression of cancer. It is known that activation of upstream RAS signals, constitutive activation of RAS, and / or activating mutations in RAS activate the RAS-RAF-MEK-ERK pathway in cancer (Non-Patent Document 2). These activating RAS mutations have been observed in numerous types of cancer. G12, G13, and Q61 are known as hotspots for RAS mutations, with frequent mutations at G12 in KRAS and Q61 in NRAS. These mutations are also known to be associated with poor patient prognosis (Non-Patent Document 3).

[0003] On the other hand, medium-molecular-weight compounds (molecular weight 500-2000 g / mol) may be superior to small-molecular-weight compounds in terms of access to tough targets, such as the inhibition of protein-protein interactions. Furthermore, medium-molecular-weight compounds may be superior to antibodies in terms of their ability to be transported into cells. Among physiologically active medium-molecular-weight compounds, peptide drugs are highly valuable molecular species, with over 40 types already on the market (Non-Patent Document 4). Representative examples of these peptide drugs include cyclosporin A and polymyxin B. These are peptides containing several unnatural amino acids. Unnatural amino acids are amino acids that are not naturally encoded by mRNA, and it is particularly interesting that naturally occurring cyclosporin A and polymyxin B contain unnatural amino acids.

[0004] Since it was discovered that naturally occurring peptides are useful as pharmaceuticals, attention has been focused on peptides that have pharmacological activity and can be absorbed by the body, and peptides with molecular weights of approximately 500 to 2000 g / mol have been actively studied (Non-Patent Document 5).

[0005] Conditions for improving membrane permeability and metabolic stability (conditions necessary for satisfying drug-likeness) that can contribute to improving the pharmacokinetics of medium-sized peptides have been reported (Patent Document 1).

[0006] Furthermore, conditions necessary for a medium-sized peptide to satisfy the drug-likeness of a cyclic peptide have been clarified as conditions that can contribute to the improvement of pharmacokinetics (Patent Document 2).

[0007] Peptides that bind to RAS have been identified, and the binding site between cyclic peptides and RAS has been analyzed by X-ray structural analysis (Non-Patent Documents 6, 7, and 8). Cyclic peptides that suggest inhibition of the binding between RAS and SOS have also been identified (Patent Document 3). Furthermore, a competitive assay of the binding of a specific compound to RAS has revealed a cyclic peptide that suggests inhibition of RAS binding (Patent Document 4).

[0008] International Publication No. WO 2013 / 100132 International Publication No. WO 2018 / 225864 International Publication No. WO 2012 / 122059 International Publication No. WO 2017 / 181061

[0009] Nat. Rev. Drug Discov. 2014 Nov;13(11):828-851.Nat. Rev. Drug Discov. 2014 Dec;13(12):928-942.Nat. Rev. Drug Discov. 2016 Nov;15(11):771-785.Future Med. Chem. 2009, 1, 1289-1310.Current Topics in Medicinal Chemistry, 2013, Vol. 13, No. 7, 821-836.Biochem. Biophys. Res. Commun. 2017, 484, 605-611.Bioorg. Med. Chem. Lett. 2017, 27, 2757-2761.ACS Med. Chem. Lett. 2017, 8, 732-736.

[0010] The present invention relates to cyclic compounds effective against RAS-mutated cancers and unnatural amino acids and peptide compounds useful for their production. Patent Documents 1 and 2 describe drug-like peptides, but do not describe peptides with antitumor effects against cancers, including RAS-mutated cancers. Patent Document 3 describes inhibition of the binding of RAS to SOS, and Patent Document 4 describes peptides that compete with compounds that bind to RAS, but these cited documents do not demonstrate pharmacological effects, particularly effects on tumor cells. Furthermore, these cited documents do not describe drug-like peptides.

[0011] Non-Patent Document 1 provides a detailed description of the relationship between RAS and cancer. While this document describes molecules that bind to RAS and have demonstrated efficacy in preclinical studies, it does not disclose any compounds specifically effective against RAS-mutated cancers, nor does it disclose any drug-like cyclic peptides. Non-Patent Document 2 provides a detailed description of RAS and the downstream RAF-MEK-ERK pathway. While this document suggests the possibility of treating RAS-mutated cancers with inhibitors of RAF, MEK, and ERK, it does not disclose any compounds that directly inhibit RAS. Non-Patent Document 3 describes compounds that bind to the GTP / GDP binding site of RAS and inhibit its function, and the mechanism behind this. While this document provides a detailed description of the interaction with the GTP / GDP binding site, it does not disclose any pharmacological effects, particularly on tumor cells. Non-Patent Document 4 describes peptides used as pharmaceuticals, but does not describe drug-like peptides or peptides useful for RAS-mutated cancers. Non-Patent Document 5 describes the molecular form of cyclic peptides and their pharmacokinetics, but does not describe compounds useful for RAS-mutated cancers. Non-Patent Documents 6 to 8 describe peptides that bind to RAS, but their effects on tumor cells are limited, and there is no description of drug-like peptides.

[0012] Furthermore, to the best of the present inventors' knowledge, there have been no reports of compounds that have sufficiently selective KRAS inhibitory activity against HRAS and NRAS.

[0013] The present inventors have conducted extensive research to find cyclic compounds that have selective KRAS inhibitory activity against HRAS and NRAS, and have found a cyclic compound that interacts selectively with KRAS compared to HRAS and NRAS. In addition, they have found that the pharmacological effect of this cyclic compound is the growth inhibitory activity against tumor cells harboring RAS mutations.

[0014] In one non-limiting specific embodiment, the present invention includes the following: [1] Formula (1): or a salt thereof, or a solvate thereof, wherein: １ is a single bond; R １ is C １ ~C ７ alkyl or R １ is R ５ and form a divalent group together, in this case, the partial structure in the cyclic compound represented by formula (1): *-CR １ Q １ -L １ -CO-NP ２ -CR ２ Q ２ -CO-NP ３ -CR ３ Q ３ -CO-NP ４ -CR ４ Q ４ -CO-NP ５ -CR ５ Q ５ -* is the following formula: wherein: X ２ Is, -L １ -CO-NP ２ -CR ２ Q ２ -CO-NP ３ -CR ３ Q ３ -CO-NP ４ -CR ４ Q ４ -CO-NP ５ - and is a single or double bond, teeth, means that when is a double bond, it may be in either E or Z stereochemistry, n is 0, 1 or 2, m is 0, 1, 2, 3 or 4, * denotes the point of attachment to the adjacent atom; P １ is C １ ~C ６ is alkyl; Q １ is hydrogen; R ２ is C １ ~C ６ alkyl; ２ is hydrogen; Q２ is hydrogen; R ３ is hydrogen or R ３ Is, P ３ , R ３ and a carbon atom to which P is bonded. ３ together with the nitrogen atom to which R is attached to form a 4- to 7-membered saturated heterocyclic ring; ３ and P ３ forms a 4- to 7-membered saturated heterocyclic ring, ３ is C １ ~C ６ Alkyl, or C ３ ~C ８ is cycloalkyl; Q ３ is hydrogen; R ４ Is, P ５ and form a divalent group together, and in this case, the partial structure *-CR in the cyclic compound represented by formula (1) ４ Q ４ -CO-NP ５ -* is the following formula: P ４ is C １ ~C ６ is alkyl; Q ４ is hydrogen, R ５ is R １ and R ５ forms a divalent group, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, and C ３ ~C ８ benzyl optionally substituted by one or more groups selected from the group consisting of cycloalkyl; ５ is hydrogen, R ６ is hydrogen; ６ is C １ ~C ６ is alkyl, and Q ６ is hydrogen, R ７ is a halogen, C １ ~C ６ Haloalkyl, and C １ ~C ６phenethyl optionally substituted by one or more groups independently selected from the group consisting of alkoxy; ７ is hydrogen, and Q ７ is hydrogen, R ８ Is, P ８ , R ８ and a carbon atom to which P is bonded. ８ together with the nitrogen atom to which it is attached to form a 4- to 7-membered saturated heterocyclic ring, and the 4- to 7-membered saturated heterocyclic ring is C １ ~C ６ optionally substituted by alkoxy; Q ８ is hydrogen, R ９ Is, Q ９ , and R ９ and Q ９ together with the carbon atom to which it is attached to form a 3- to 8-membered alicyclic ring, and the 3- to 8-membered alicyclic ring is １ ~C ６ optionally substituted by alkyl; ９ is hydrogen or C １ ~C ６ alkyl, R １０ is C １ ~C ６ Alkyl, or C ３ ~C ８ is cycloalkyl; １０ is C １ ~C ６ is alkyl, and Q １０ is hydrogen, and L １１ is -CH ２ - and R １１ Is Ji C １ ~C ６ alkylaminocarbonyl, or 4- to 8-membered cyclic aminocarbonyl; １１ is C １ ~C ６ is alkyl, and Q １１is hydrogen, and the cyclic compound represented by formula (1) 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-undecaoxo-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecazatricyclo[34.5.1.0] 10,14 ]dotetracont-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-undecazatricyclo[34.5.1.0] 10,14 ]dotetracont-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-undecazapentacyclo[24.15.11.2 43,46 .1 35,41 .09,13 ]pentapentaconta-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-undecazapentacyclo[24.15.11.2 43,46 .1 35,41 .0 9,13 ]pentapentaconta-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-undecazatricyclo[34.5.1.0] 10,14]dotetracont-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-undecazapentacyclo[24.15.11.2 43,46 .1 35,41 .0 9,13 ]pentapentaconta-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-undecazatricyclo[34.5.1.0] 10,14]dotetracont-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-undecazatetracyclo[37.5.1.0] 4,8 .0 26,30 ]pentatetracont-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-undecazatricyclo[34.5.1.0] 10,14 ]dotetracont-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-undecazapentacyclo[24.15.10.2 43,46 .1 35,41 .0 9,13]tetrapentaconta-37,43(53),44,46(52),47-pentaene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecane, 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-undecazapentacyclo[24.15.10.2 43,46 .1 35,41 .0 9,13 ]tetrapentaconta-37,43(53),44,46(52),47-pentaene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecane, 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-undecazapentacyclo[24.15.10.2 43,46 .1 35,41 .0 9,13]tetrapentaconta-37,43(53),44,46(52),47-pentaene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecane, 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-undecazatricyclo[34.5.1.0] 10,14 ]dotetracont-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-undecazatricyclo[34.5.1.0] 10,14 ]dotetracont-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-undecazapentacyclo[24.15.10.243,46 .1 35,41 .0 9,13 ]tetrapentaconta-37,43(53),44,46(52),47-pentaene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecane, 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 ]pentapentaconta-37,43(54),44,46(53)-tetraene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,55-undecane, 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]pentapentaconta-37,43(54),44,46(53)-tetraene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,55-undecane, 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 ]tetrapentaconta-37,43(53),44,46(52)-tetraene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecane, 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]tetrapentaconta-37,43(53),44,46(52)-tetraene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecane, 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 ]pentapentaconta-37,43(54),44,46(53),47-pentaene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,55-undecane, 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]tripentaconta-37,43(52),44,46(51)-tetraene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,53-undecane, 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 ]tripentaconta-37,43(52),44,46(51)-tetraene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,53-undecane, 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-undecazatricyclo[34.5.1.0] 10,14]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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-undecazatricyclo[34.5.1.0] 10,14 ]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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-undecazatricyclo[34.5.1.0] 10,14 ]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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-undecazatricyclo[34.5.1.010,14 ]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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-undecazatetracyclo[37.5.1.0] 4,8 .0 26,30 ]pentatetracont-42-ene-23,1'-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecane, 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]pentatetracont-42-ene-23,1'-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecane, 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-undecazatetracyclo[37.5.1.0] 4,8 .0 26,30 ]pentatetracont-42-ene-23,1'-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecane, 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-undecazatetracyclo[37.5.1.0] 4,8 .0 26,30]pentatetracont-42-ene-23,1'-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecane, 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-undecazatricyclo[34.5.1.0] 10,14 ]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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-undecazatricyclo[34.5.1.0] 10,14 ]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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-undecazatricyclo[34.5.1.0] 10,14]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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-undecazatricyclo[34.5.1.0] 10,14 ]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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-undecazatricyclo[34.5.1.0] 10,14 ]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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-undecazatricyclo[34.5.1.0] 10,14]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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-undecazatricyclo[34.5.1.0 10,14 ]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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-undecazatricyclo[34.5.1.0 10,14]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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-undecazatetracyclo[37.5.1.0] 4,8 .0 26,30 ]pentatetracont-42-ene-23,1'-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecane, 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-undecazatetracyclo[37.5.1.0] 4,8 .0 26,30]pentatetracont-42-ene-23,1'-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecane, 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-undecazatetracyclo[37.5.1.0] 4,8 .0 26,30 ]pentatetracont-42-ene-23,1'-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecane, 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-undecazatetracyclo[37.5.1.0] 4,8 .0 26,30]pentatetracont-42-ene-23,1'-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecane, 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-undecazatricyclo[34.5.1.0] 10,14 ]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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-undecazatricyclo[34.5.1.0] 10,14 ]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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-undecazatricyclo[34.5.1.0]10,14 ]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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-undecazatricyclo[34.5.1.0 10,14 ]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, (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-undecazapentacyclo[24.15.11.2 43,46 .1 35,41 .0 9,13]pentapentaconta-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-undecazapentacyclo[24.15.11.2 43,46 .1 35,41 .0 9,13 ]pentapentaconta-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]tetrapentaconta-37,43(53),44,46(52),47-pentaene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecane, (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 ]tetrapentaconta-37,43(53),44,46(52),47-pentaene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecane, (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]tetrapentaconta-37,43(53),44,46(52),47-pentaene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecane, (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 ]tetrapentaconta-37,43(53),44,46(52),47-pentaene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecane, 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 [2] A cyclic compound, a salt thereof, or a solvate thereof, selected from the group consisting of: [3] A cyclic compound, a salt thereof, or a solvate thereof, selected from the group consisting of: [4] A cyclic compound, a salt thereof, or a solvate thereof, selected from the group consisting of: [5] A cyclic compound, a salt thereof, or a solvate thereof, selected from the group consisting of: [6] A cyclic compound, a salt thereof, or a solvate thereof, selected from the group consisting of: [7] A cyclic compound, a salt thereof, or a solvate thereof, selected from the group consisting of: [8] A cyclic compound, a salt thereof, or a solvate thereof, selected from the group consisting of: [9] A cyclic compound, a salt thereof, or a solvate thereof, selected from the group consisting of:

[10] A cyclic compound, a salt thereof, or a solvate thereof, selected from the group consisting of:

[11] A cyclic compound, a salt thereof, or a solvate thereof, selected from the group consisting of: (In the formula, n, m, P １ , R ２ , R ３ , P ３ , P ４ , P ６ , R ７, R ８ , P ８ , R ９ , P ９ , Q ９ , R １０ , P １０ , R １１ , and P １１ is the same as [1]), and the cyclic compound represented by the formula (2) is represented by the formula: 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-undecazapentacyclo[24.15.11.2 43,46 .1 35,41 .0 9,13 ]pentapentaconta-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-undecazapentacyclo[24.15.11.2 43,46 .1 35,41 .0 9,13]pentapentaconta-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-undecazapentacyclo[24.15.11.2 43,46 .1 35,41 .0 9,13 ]pentapentaconta-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-undecazapentacyclo[24.15.10.2 43,46 .1 35,41 .0 9,13]tetrapentaconta-37,43(53),44,46(52),47-pentaene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecane, 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-undecazapentacyclo[24.15.10.2 43,46 .1 35,41 .0 9,13 ]tetrapentaconta-37,43(53),44,46(52),47-pentaene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecane, 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-undecazapentacyclo[24.15.10.2 43,46 .1 35,41 .0 9,13]tetrapentaconta-37,43(53),44,46(52),47-pentaene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecane, 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-undecazapentacyclo[24.15.10.2 43,46 .1 35,41 .0 9,13 ]tetrapentaconta-37,43(53),44,46(52),47-pentaene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecane, 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]pentapentaconta-37,43(54),44,46(53)-tetraene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,55-undecane, 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 ]pentapentaconta-37,43(54),44,46(53)-tetraene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,55-undecane, 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]tetrapentaconta-37,43(53),44,46(52)-tetraene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecane, 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 ]tetrapentaconta-37,43(53),44,46(52)-tetraene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecane, 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]pentapentaconta-37,43(54),44,46(53),47-pentaene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,55-undecane, 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 ]tripentaconta-37,43(52),44,46(51)-tetraene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,53-undecane, 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]tripentaconta-37,43(52),44,46(51)-tetraene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,53-undecane, (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-undecazapentacyclo[24.15.11.2 43,46 .1 35,41 .0 9,13 ]pentapentaconta-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-undecazapentacyclo[24.15.11.2 43,46 .1 35,41 .0 9,13]pentapentaconta-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 ]tetrapentaconta-37,43(53),44,46(52),47-pentaene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecane, (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]tetrapentaconta-37,43(53),44,46(52),47-pentaene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecane, (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 ]tetrapentaconta-37,43(53),44,46(52),47-pentaene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecane, (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]tetrapentaconta-37,43(53),44,46(52),47-pentaene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecane, 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 ]pentapentaconta-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. [3] The cyclic compound according to [1], wherein the compound represented by formula (1) is selected from the group consisting of: (In the formula, R １ is C １ ~C ７ alkyl; R ５ is C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, and C ３ ~C ８ benzyl optionally substituted by one or more groups selected from the group consisting of cycloalkyl; n, m, P １ , R ２ , R ３ , P ３ , P ４ , P ６ , R ７ , R ８ , P ８ , R ９ , P ９ , Q ９ , R １０ , P １０ , R １１ , and P １１is the same as [1]), and the cyclic compound represented by the formula (3) is (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-undecazatricyclo[34.5.1.0] 10,14 ]dotetracont-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-undecazatricyclo[34.5.1.0] 10,14 ]dotetracont-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-undecazatricyclo[34.5.1.0]10,14 ]dotetracont-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-undecazatricyclo[34.5.1.0] 10,14 ]dotetracont-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-undecazatetracyclo[37.5.1.0] 4,8 .0 26,30]pentatetracont-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-undecazatricyclo[34.5.1.0] 10,14 ]dotetracont-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-undecazatricyclo[34.5.1.0] 10,14 ]dotetracont-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-undecazatricyclo[34.5.1.0] 10,14]dotetracont-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-undecazatricyclo[34.5.1.0 10,14 ]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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-undecazatricyclo[34.5.1.0] 10,14 ]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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-undecazatricyclo[34.5.1.0] 10,14]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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-undecazatricyclo[34.5.1.0 10,14 ]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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-undecazatetracyclo[37.5.1.0] 4,8 .0 26,30]pentatetracont-42-ene-23,1'-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecane, 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 ]pentatetracont-42-ene-23,1'-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecane, 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-undecazatetracyclo[37.5.1.0] 4,8 .0 26,30]pentatetracont-42-ene-23,1'-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecane, 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-undecazatetracyclo[37.5.1.0] 4,8 .0 26,30 ]pentatetracont-42-ene-23,1'-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecane, 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-undecazatricyclo[34.5.1.0] 10,14 ]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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-undecazatricyclo[34.5.1.0]10,14 ]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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-undecazatricyclo[34.5.1.0] 10,14 ]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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-undecazatricyclo[34.5.1.0] 10,14]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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-undecazatricyclo[34.5.1.0] 10,14 ]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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-undecazatricyclo[34.5.1.0] 10,14]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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-undecazatricyclo[34.5.1.0 10,14 ]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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-undecazatricyclo[34.5.1.0 10,14]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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-undecazatetracyclo[37.5.1.0] 4,8 .0 26,30 ]pentatetracont-42-ene-23,1'-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecane, 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-undecazatetracyclo[37.5.1.0] 4,8 .0 26,30]pentatetracont-42-ene-23,1'-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecane, 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-undecazatetracyclo[37.5.1.0] 4,8 .0 26,30 ]pentatetracont-42-ene-23,1'-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecane, 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-undecazatetracyclo[37.5.1.0] 4,8 .0 26,30]pentatetracont-42-ene-23,1'-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecane, 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-undecazatricyclo[34.5.1.0] 10,14 ]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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-undecazatricyclo[34.5.1.0] 10,14 ]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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-undecazatricyclo[34.5.1.0]10,14 ]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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-undecazatricyclo[34.5.1.0 10,14 ]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecaone, or a salt or solvate thereof according to [1]. [4-1] 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-undecazatricyclo[34.5.1.0 10,14]dotetracont-38-ene-17,1'-cyclopentane]-23-carboxamide, or a salt thereof, or a solvate thereof. [4-2] 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-undecazatricyclo[34.5.1.0 10,14 ]dotetracont-38-ene-17,1'-cyclobutane]-23-carboxamide, or a salt thereof, or a solvate thereof. [4-3] 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-undecazapentacyclo[24.15.11.2 43,46 .1 35,41 .0 9,13]pentapentaconta-37,43(54),44,46(53),47-pentaene-16,1'-cyclobutane]-22-carboxamide, or a salt thereof, or a solvate thereof. [4-4] 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-undecazapentacyclo[24.15.11.2 43,46 .1 35,41 .0 9,13 ]pentapentaconta-37,43(54),44,46(53),47-pentaene-16,1'-cyclobutane]-22-carboxamide, or a salt thereof, or a solvate thereof. [4-5] 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-undecazatricyclo[34.5.1.0 10,14]dotetracont-38-ene-17,1'-cyclobutane]-23-carboxamide, or a salt thereof, or a solvate thereof. [4-6] 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-undecazapentacyclo[24.15.11.2 43,46 .1 35,41 .0 9,13 ]pentapentaconta-37,43(54),44,46(53)-tetraene-16,1'-cyclobutane]-22-carboxamide, or a salt thereof, or a solvate thereof. [4-7] 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-undecazatricyclo[34.5.1.0 10,14]dotetracont-38-ene-17,1'-cyclobutane]-23-carboxamide, or a salt thereof, or a solvate thereof. [4-8]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-undecazatetracyclo[37.5.1.0 4,8 .0 26,30 ]pentatetracont-42-ene-23,1'-cyclobutane]-17-carboxamide, or a salt thereof, or a solvate thereof. [4-9] 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-undecazatricyclo[34.5.1.0 10,14]dotetracont-38-ene-17,1'-cyclobutane]-23-carboxamide, or a salt thereof, or a solvate thereof. [4-10]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-undecazapentacyclo[24.15.10.2 43,46 .1 35,41 .0 9,13 ]tetrapentaconta-37,43(53),44,46(52),47-pentaene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecane, or a salt thereof, or a solvate thereof. [4-11]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-undecazapentacyclo[24.15.10.2 43,46 .1 35,41 .0 9,13]tetrapentaconta-37,43(53),44,46(52),47-pentaene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecane, or a salt thereof, or a solvate thereof. [4-12] 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-undecazapentacyclo[24.15.10.2 43,46 .1 35,41 .0 9,13 ]tetrapentaconta-37,43(53),44,46(52),47-pentaene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecane, or a salt thereof, or a solvate thereof. [4-13]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-undecazatricyclo[34.5.1.0 10,14]dotetracont-38-ene-17,1'-cyclobutane]-23-carboxamide, or a salt thereof, or a solvate thereof. [4-14]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-undecazatricyclo[34.5.1.0 10,14 ]dotetracont-38-ene-17,1'-cyclobutane]-23-carboxamide, or a salt thereof, or a solvate thereof. [4-15]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-undecazapentacyclo[24.15.10.2 43,46 .1 35,41 .0 9,13]tetrapentaconta-37,43(53),44,46(52),47-pentaene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecane, or a salt thereof, or a solvate thereof. [4-16]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 ]pentapentaconta-37,43(54),44,46(53)-tetraene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,55-undecane, or a salt thereof, or a solvate thereof. [4-17]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]pentapentaconta-37,43(54),44,46(53)-tetraene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,55-undecane, or a salt thereof, or a solvate thereof. [4-18]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 ]tetrapentaconta-37,43(53),44,46(52)-tetraene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecane, or a salt thereof, or a solvate thereof. [4-19]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]tetrapentaconta-37,43(53),44,46(52)-tetraene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecane, or a salt thereof, or a solvate thereof. [4-20]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 ]pentapentaconta-37,43(54),44,46(53),47-pentaene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,55-undecane, or a salt thereof, or a solvate thereof. [4-21]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]tripentaconta-37,43(52),44,46(51)-tetraene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,53-undecane, or a salt thereof, or a solvate thereof. [4-22]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 ]tripentaconta-37,43(52),44,46(51)-tetraene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,53-undecane, or a salt thereof, or a solvate thereof. [4-23]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-undecazatricyclo[34.5.1.0 10,14]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, or a salt thereof, or a solvate thereof. [4-24] 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-undecazatricyclo[34.5.1.0 10,14 ]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, or a salt thereof, or a solvate thereof. [4-25]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-undecazatricyclo[34.5.1.0 10,14]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, or a salt thereof, or a solvate thereof. [4-26]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-undecazatricyclo[34.5.1.0 10,14 ]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, or a salt thereof, or a solvate thereof. [4-27]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-undecazatetracyclo[37.5.1.0 4,8 .0 26,30]pentatetracont-42-ene-23,1'-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecane, or a salt thereof, or a solvate thereof. [4-28]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 ]pentatetracont-42-ene-23,1'-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecane, or a salt thereof, or a solvate thereof. [4-29]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-undecazatetracyclo[37.5.1.0 4,8 .0 26,30]pentatetracont-42-ene-23,1'-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecane, or a salt thereof, or a solvate thereof. [4-30]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-undecazatetracyclo[37.5.1.0 4,8 .0 26,30 ]pentatetracont-42-ene-23,1'-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecane, or a salt thereof, or a solvate thereof. [4-31]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-undecazatricyclo[34.5.1.0 10,14]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, or a salt thereof, or a solvate thereof. [4-32]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-undecazatricyclo[34.5.1.0 10,14 ]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, or a salt thereof, or a solvate thereof. [4-33]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-undecazatricyclo[34.5.1.0 10,14]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, or a salt thereof, or a solvate thereof. [4-34]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-undecazatricyclo[34.5.1.0 10,14 ]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, or a salt thereof, or a solvate thereof. [4-35]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-undecazatricyclo[34.5.1.0 10,14]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, or a salt thereof, or a solvate thereof. [4-36]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-undecazatricyclo[34.5.1.0 10,14 ]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, or a salt thereof, or a solvate thereof. [4-37]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-undecazatricyclo[34.5.1.0 10,14]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, or a salt thereof, or a solvate thereof. [4-38]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-undecazatricyclo[34.5.1.0 10,14 ]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, or a salt thereof, or a solvate thereof. [4-39]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-undecazatetracyclo[37.5.1.0 4,8 .0 26,30]pentatetracont-42-ene-23,1'-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecane, or a salt thereof, or a solvate thereof. [4-40]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-undecazatetracyclo[37.5.1.0 4,8 .0 26,30 ]pentatetracont-42-ene-23,1'-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecane, or a salt thereof, or a solvate thereof. [4-41]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-undecazatetracyclo[37.5.1.0 4,8 .0 26,30]pentatetracont-42-ene-23,1'-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecane, or a salt thereof, or a solvate thereof. [4-42]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-undecazatetracyclo[37.5.1.0 4,8 .0 26,30 ]pentatetracont-42-ene-23,1'-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecane, or a salt thereof, or a solvate thereof. [4-43]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-undecazatricyclo[34.5.1.0 10,14]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, or a salt thereof, or a solvate thereof. [4-44]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-undecazatricyclo[34.5.1.0 10,14 ]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, or a salt thereof, or a solvate thereof. [4-45]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-undecazatricyclo[34.5.1.0 10,14]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, or a salt thereof, or a solvate thereof. [4-46]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-undecazatricyclo[34.5.1.0 10,14 ]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, or a salt thereof, or a solvate thereof. [4-47] (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-undecazapentacyclo[24.15.11.2 43,46 .1 35,41 .0 9,13]pentapentaconta-37,43(54),44,46(53),47-pentaene-16,1'-cyclobutane]-22-carboxamide, or a salt thereof, or a solvate thereof. [4-48] (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-undecazapentacyclo[24.15.11.2 43,46 .1 35,41 .0 9,13 ]pentapentaconta-37,43(54),44,46(53),47-pentaene-16,1'-cyclobutane]-22-carboxamide, or a salt thereof, or a solvate thereof. [4-49] (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]tetrapentaconta-37,43(53),44,46(52),47-pentaene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecane, or a salt thereof or a solvate thereof. [4-50](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 ]tetrapentaconta-37,43(53),44,46(52),47-pentaene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecane, or a salt thereof or a solvate thereof. [4-51] (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]tetrapentaconta-37,43(53),44,46(52),47-pentaene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecane, or a salt thereof or a solvate thereof. [4-52] (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 ]tetrapentaconta-37,43(53),44,46(52),47-pentaene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecane, or a salt thereof or a solvate thereof. [4-53] (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]pentapentaconta-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. [5] The cyclic compound according to any one of [1] to [4-53], or a salt thereof. [6] The cyclic compound according to any one of [1] to [4-53], or a solvate thereof. [7] A solvate of the cyclic compound according to any one of [1] to [4-53], or a salt thereof. [8] The cyclic compound according to any one of [1] to [4-53]. [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.

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

[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.

[12] 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-undecazatricyclo[34.3.0.0] 12,15

[14] The cyclic compound according to any one of [1] to [4-53], or a salt thereof, or a solvate thereof, which has higher KRAS selectivity (KRAS selectivity over NRAS and / or KRAS selectivity over HRAS) than ]nonatriacontane-33,1'-cyclobutane-27-carboxamide.

[15] 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.

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

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

[16] The cyclic compound according to

[15] , or a salt thereof, or a solvate thereof, having a KRAS binding activity that is 5-fold, 7-fold, 10-fold, 15-fold, or 20-fold or more relative to the NRAS binding activity and the HRAS binding activity.

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

[18] The cyclic compound according to

[17] , or a salt thereof, or a solvate thereof, having a KRAS inhibitory activity that is 5-fold, 7-fold, 10-fold, 15-fold, or 20-fold or more relative to the NRAS inhibitory activity and the HRAS inhibitory activity.

[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.

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

[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.

[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.

[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.

[24] The pharmaceutical composition according to

[23] , wherein the cancer is lung cancer.

[25] The pharmaceutical composition according to any one of

[20] to

[24] , wherein the subject is a human.

[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.

[27] The cyclic compound according to

[26] , or a salt thereof, or a solvate thereof, for use in treating or preventing cancer in a subject.

[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.

[29] The cyclic compound according to any one of

[26] to

[28] , or a salt thereof, or a solvate thereof, wherein the subject is a human.

[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.

[31] The use according to

[30] , wherein the cancer is lung cancer.

[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.

[33] The use according to any one of

[30] to

[32] , wherein the subject is a human.

[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.

[35] The method according to

[34] , wherein the cancer is lung cancer.

[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.

[37] The method according to any one of

[34] to

[36] , wherein the subject is a human.

[0015] According to the present invention, it is possible to provide novel cyclic compounds having selective KRAS inhibitory activity.

[0016] (Abbreviations) The abbreviations used in the present invention are listed below. AA: Ammonium acetate Boc: tert-butoxycarbonyl CSA: (+)-10-Camphorsulfonic acid CPME: Cyclopentyl methyl ether DAST: (Diethylamino)sulfur trifluoride DBU: 1,8-diazabicyclo[5.4.0]-7-undecene DCM: Dichloromethane DCE: 1,2-dichloroethane DEAD: Diethyl azodicarboxylate DEPBT: 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one DIAD: Diisopropyl azodicarboxylate DIC: N,N'-Diisopropylcarbodiimide DIPEA: N,N-Diisopropylethylamine DHP: 3,4-Dihydro-2H-pyran DMA: N,N-Dimethylacetamide DMAP: N,N-Dimethyl-4-aminopyridine DMF: N,N-dimethylformamide dtbbpy: 4,4'-di-tert-butyl-2,2'-bipyridine EDTA: ethylenediaminetetraacetic acid FA: formic acid Fmoc: 9-fluorenylmethyloxycarbonyl NMP: N-methyl-2-pyrrolidone TBME: t-butyl methyl ether TES: triethylsilane TFA: trifluoroacetic acid TFE: 2,2,2-trifluoroethanol THF: tetrahydrofuran THP: tetrahydropyranyl TMSCl: chlorotrimethylsilane HFIP: 1,1,1,3,3,3-hexafluoroisopropyl alcohol HOAt: 1-hydroxy-7-azabenzotriazole HOBt: 1-hydroxybenzotriazole HOOBt: 3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine IPAC: isopropyl acetate, oxyma: ethyl cyano(hydroxyimino)acetate, PPTS: pyridinium p-toluenesulfonate, Pis: 2-phenylisopropyl, WSCI·HCl, WSCDI: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, TIPS: triisopropylsilane, TfOH: trifluoromethanesulfonic acid, HATU: O-(7-aza-1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate DMSO: dimethyl sulfoxide Fmoc-Cl: (9H-fluoren-9-yl)methyl carbonochloridate Fmoc-OSu: N-succinimidyl carbonate 9-fluorenylmethyl Ns: o-nitrobenzenesulfonyl Trt: triphenylmethyl 9-BBN: 9-borabicyclo[3.3.1]nonane HMDS: 1,1,1,3,3,3-hexamethyldisilazane LDA: lithium diisopropylamide TMSOTf: trimethylsilyl trifluoromethanesulfonate PPA: polyphosphoric acid,

[0017] As used herein, the term "about" when used in conjunction with a numerical value means a range of values ​​of plus and minus 10% of that numerical value.

[0018] In this specification, the term "to" indicating a range includes both ends of the range. For example, "A to B" means a range that is equal to or greater than A and equal to or less than B.

[0019] The unit of molecular weight in this specification is "g / mol" (hereinafter in this specification, the unit of molecular weight may be omitted).

[0020] The use of the articles "a," "an," and "the," both in this specification and in the claims, shall be construed to encompass both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

[0021] (Definition of Functional Groups, etc.) In this specification, examples of the "halogen atom" include F, Cl, Br and I.

[0022] As used herein, "alkyl" refers to a monovalent group derived from an aliphatic hydrocarbon by removing any one hydrogen atom, and does not contain heteroatoms (atoms other than carbon and hydrogen atoms) or unsaturated carbon-carbon bonds in the skeleton, but has a subset of hydrocarbyl or hydrocarbon group structures containing hydrogen and carbon atoms. Alkyl includes not only linear but also branched chain alkyls. Specific examples of alkyl include alkyls having 1 to 20 carbon atoms (C １ ~C ２０, hereinafter referred to as “C ｐ ~C ｑ " means that the number of carbon atoms is p to q), and preferably C １ ~C １０ Alkyl, more preferably C １ ~C ６ Specific examples of the alkyl include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, isobutyl (2-methylpropyl), n-pentyl, s-pentyl (1-methylbutyl), t-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.

[0023] As used herein, "alkenyl" refers to an alkyl group having at least one double bond (two adjacent SP ２ It is a monovalent group having 1 carbon atom. Depending on the configuration of the double bond and the substituents (if any), the geometry of the double bond can be in the Entgegen (E) or Zusammen (Z), cis or trans configuration. Alkenyl includes not only straight chains but also branched chains. C is preferred as alkenyl. ２ ~C １０ alkenyl, more preferably C ２ ~C ７ Alkenyl, C ２ ~C ６ Examples include alkenyl, specifically, for example, vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl (including cis and trans), 3-butenyl, pentenyl, 3-methyl-2-butenyl, hexenyl, and 6-heptenyl.

[0024] As used herein, "alkynyl" refers to a monovalent group having at least one triple bond (two adjacent SP carbon atoms). Alkynyl includes not only straight chain but also branched chain. C ２ ~C １０ Alkynyl, more preferably C ２ ~C ６ Specific examples include alkynyl, such as 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.

[0025] As used herein, the term "cycloalkyl" refers to a saturated or partially saturated cyclic monovalent aliphatic hydrocarbon group, including monocyclic, bicyclic, and spirocyclic rings. ３ ~C ８ Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, spiro[3.3]heptyl, and the like.

[0026] As used herein, "aryl" refers to a monovalent aromatic hydrocarbon ring, preferably C ６ ~C １０ Examples of aryl include phenyl and naphthyl (e.g., 1-naphthyl and 2-naphthyl). In this specification, aryl includes bicyclic aryl in which the aromatic hydrocarbon ring is fused with another saturated ring or unsaturated ring, and includes, for example, aryl having 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 saturated heterocycle. Specific examples include indanyl, 1,2,3,4-tetrahydronaphthyl, and 2,3-dihydrobenzofuran.

[0027] As used herein, "heterocyclyl" refers to a non-aromatic cyclic monovalent group containing 1 to 5 heteroatoms in addition to carbon atoms. The heterocyclyl may have a double and / or triple bond in the ring, and a carbon atom in the ring may be oxidized to form a carbonyl, and may be a monocyclic or fused 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), more preferably 3 to 7 (3- to 7-membered heterocyclyl) or 4 to 7 (4- to 7-membered heterocyclyl). Specific examples of heterocyclyl include azetidinyl, oxiranyl, oxetanyl, azetidinyl, dihydrofuryl, tetrahydrofuryl, dihydropyranyl, tetrahydropyranyl, tetrahydropyridyl, tetrahydropyrimidyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, and isothiazolidinyl. nyl, 1,2-thiazinane, thiadiazolidinyl, azetidinyl, oxazolidone, 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, 2-oxaspiro[3.3]heptyl, and the like.

[0028] As used herein, the term "protected heterocyclyl" refers to a group in which one or more functional groups included in the above-defined "heterocyclyl," such as an amino group, are protected with any protecting group, and preferably includes a protected 4- to 7-membered heterocyclyl. Specific examples of the protecting group include Boc, Fmoc, Cbz, Troc, and Alloc, and specific examples of the protected heterocyclyl include Boc-protected azetidine.

[0029] As used herein, "heterocycloalkylidene" refers to a divalent group resulting from the removal of two hydrogen atoms from one carbon atom of the above-defined "heterocyclyl," in which the free valence becomes part of a double bond. Preferred examples of heterocycloalkylidene include 4- to 7-membered heterocycloalkylidenes, and specific examples include tetrahydropyran-4-ylidene and azetidin-3-ylidene.

[0030] As used herein, the term "protected heterocycloalkylidene" refers to a group in which one or more functional groups included in the above-defined "heterocycloalkylidene," such as an amino group, are protected with any protecting group, and preferably includes a protected 4- to 7-membered heterocycloalkylidene. Specific examples of the protecting group include Boc, Fmoc, Cbz, Troc, and Alloc, and specific examples of the protected heterocycloalkylidene include Boc-protected azetidin-3-ylidene.

[0031] 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 monocyclic ring or a condensed ring with another ring, and may be partially saturated. The number of atoms constituting the ring is preferably 5 to 10 (5- to 10-membered heteroaryl), and more preferably 5 to 7 (5- to 7-membered heteroaryl). Specific examples of heteroaryl include furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, benzofuranyl, benzothienyl, benzothiadiazolyl, benzothiazolyl, benzoxazolyl, benzoxadiazolyl, benzimidazolyl, indolyl, isoindolyl, indazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, benzodioxolyl, indolizinyl, and imidazopyridyl.

[0032] As used herein, "alkoxy" refers to an oxy group to which the above-defined "alkyl" is bonded, and preferably C１ ~C ６ Specific examples of the alkoxy include methoxy, ethoxy, 1-propoxy, 2-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentyloxy, and 3-methylbutoxy.

[0033] As used herein, "alkylthio" refers to a thiol group having an "alkyl" bonded thereto, as defined above, and preferably C １ ~C ６ Specific examples of alkylthio include methylthio, ethylthio, 1-propylthio, 2-propylthio, n-butylthio, i-butylthio, s-butylthio, and t-butylthio.

[0034] As used herein, "alkenyloxy" refers to an oxy group having the above-defined "alkenyl" bonded thereto, and preferably C ２ ~C ６ Specific examples of alkenyloxy include vinyloxy, allyloxy, 1-propenyloxy, 2-propenyloxy, 1-butenyloxy, 2-butenyloxy (including cis and trans), 3-butenyloxy, pentenyloxy, and hexenyloxy.

[0035] As used herein, "cycloalkoxy" refers to an oxy group to which the above-defined "cycloalkyl" is bonded, and preferably C ３ ~C ８ Specific examples of cycloalkoxy include cyclopropoxy, cyclobutoxy, cyclopentyloxy, etc.

[0036] As used herein, "aryloxy" refers to an oxy group to which the above-defined "aryl" is bonded, and preferably C ６ ~C １０ Specific examples of the aryloxy include phenoxy, 1-naphthyloxy, and 2-naphthyloxy.

[0037] In the present specification, "amino" means, in a narrow sense, -NH ２ and broadly, -NRR', where 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. ２ , Mono C １ ~C ６ Alkylamino, DiC １ ~C ６ Examples thereof include alkylamino and 4- to 8-membered cyclic amino.

[0038] As used herein, the term "monoalkylamino" refers to a group in which R is hydrogen and R' is an "alkyl" as defined above, among the "amino" groups defined above, and preferably monoC １ ~C ６ Specific examples of monoalkylamino include methylamino, ethylamino, n-propylamino, i-propylamino, n-butylamino, s-butylamino, and t-butylamino.

[0039] As used herein, "dialkylamino" refers to a group in which R and R' are independently "alkyl" as defined above, among the "amino" groups defined above, and preferably diC １ ~C ６ Specific examples of dialkylamino include dimethylamino and diethylamino.

[0040] As used herein, "cyclic amino" refers to the above-defined "amino" in which R and R' form a ring together with the nitrogen atom to which they are attached, and preferably includes 4- to 8-membered cyclic amino. Specific examples of cyclic amino include 1-azetidyl, 1-pyrrolidyl, 1-piperidyl, 1-piperazyl, 4-morpholinyl, 3-oxazolidyl, 1,1-dioxidethiomorpholinyl-4-yl, 3-oxa-8-azabicyclo[3.2.1]octan-8-yl, and the like.

[0041] As used herein, the term "protected amino" refers to an amino group protected with any protecting group. Specific examples of the protected amino include amino protected with a protecting group such as Boc, Fmoc, Cbz, Troc, or Alloc.

[0042] As used herein, "alkylcarbonyl" refers to a carbonyl group having an "alkyl" as defined above bonded thereto, and preferably, １ ~C ６ Examples of alkylcarbonyl include acetyl, propionyl, and butyryl. The number of carbon atoms in the above definition indicates the number of carbon atoms in the alkyl moiety. For example, "C １ ~C ６ "C" in "Alkylcarbonyl" １ ~C ６ " indicates that the alkyl moiety has 1 to 6 carbon atoms.

[0043] As used herein, "aminocarbonyl" refers to a carbonyl group having the above-defined "amino" bonded thereto, and preferably -CONH ２ , Mono C １ ~C ６ Alkylaminocarbonyl, diC １ ~C ６ Examples of the aminocarbonyl include alkylaminocarbonyl and 4- to 8-membered cyclic aminocarbonyl. ２ , dimethylaminocarbonyl, 1-azetidinylcarbonyl, 1-pyrrolidinylcarbonyl, 1-piperidinylcarbonyl, 1-piperazinylcarbonyl, 4-morpholinylcarbonyl, 3-oxazolidinylcarbonyl, 1,1-dioxidethiomorpholinyl-4-ylcarbonyl, 3-oxa-8-azabicyclo[3.2.1]octan-8-ylcarbonyl, and the like.

[0044] As used herein, "alkenyloxycarbonyl" refers to a carbonyl group to which the above-defined "alkenyloxy" is bonded, and preferably C ２ ~C ６Specific examples of the alkenyloxycarbonyl include vinyloxycarbonyl, allyloxycarbonyl, 1-propenyloxycarbonyl, 2-propenyloxycarbonyl, 1-butenyloxycarbonyl, 2-butenyloxycarbonyl (including cis and trans), 3-butenyloxycarbonyl, pentenyloxycarbonyl, and hexenyloxycarbonyl.

[0045] As used herein, "alkylsulfonyl" refers to a sulfonyl group having an "alkyl" as defined above bonded thereto, and preferably C １ ~C ６ Specific examples of alkylsulfonyl include methylsulfonyl.

[0046] As used herein, "hydroxyalkyl" refers to a group in which one or more hydrogen atoms of the "alkyl" defined above have been replaced with a hydroxyl group, and C １ ~C ６ Hydroxyalkyl is preferred, and specific examples of hydroxyalkyl include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl, and 5-hydroxypentyl.

[0047] As used herein, "haloalkyl" refers to an "alkyl" defined above in which one or more hydrogen atoms are substituted with halogen atoms, and C １ ~C ６ Haloalkyl is preferred, C １ ~C ６ Fluoroalkyl is more preferred. Specific examples of haloalkyl include difluoromethyl, trifluoromethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3,3-difluoropropyl, 4,4-difluorobutyl, 5,5-difluoropentyl, and 1,1-difluoroethyl.

[0048] As used herein, "cyanoalkyl" refers to a group in which one or more hydrogen atoms of the "alkyl" defined above are substituted with cyano. １ ~C６ Cyanoalkyl is preferred, and specific examples of cyanoalkyl include cyanomethyl and 2-cyanoethyl.

[0049] As used herein, "aminoalkyl" refers to a group in which one or more hydrogen atoms of an "alkyl" defined above are substituted with an "amino" defined above, and １ ~C ６ Aminoalkyl is preferred, and specific examples of aminoalkyl include 1-pyridylmethyl, 2-(1-piperidyl)ethyl, 3-(1-piperidyl)propyl, 4-aminobutyl, and 2-aminoethyl.

[0050] As used herein, "carboxyalkyl" refers to a group in which one or more hydrogen atoms of the "alkyl" defined above are substituted with carboxy, and C １ ~C ６ Carboxyalkyl, C ２ ~C ６ Carboxyalkyl is preferred. Specific examples of carboxyalkyl include carboxymethyl. The number of carbon atoms in the above definition indicates the number of carbon atoms in the alkyl moiety. For example, "C １ ~C ６ "C" in "carboxyalkyl" １ ~C ６ " indicates that the alkyl moiety has 1 to 6 carbon atoms.

[0051] As used herein, "alkenyloxycarbonylalkyl" refers to a group in which one or more hydrogen atoms of an "alkyl" defined above are substituted with an "alkenyloxycarbonyl" defined above, and ２ ~C ６ Alkenyloxycarbonyl C １ ~C ６ Alkyl is preferred, C ２ ~C ６ Alkenyloxycarbonyl C １ ~C ２ Alkyl is more preferred. Specific examples of alkenyloxycarbonylalkyl include allyloxycarbonylmethyl and 2-(allyloxycarbonyl)ethyl.

[0052] As used herein, "alkoxyalkyl" refers to a group in which one or more hydrogen atoms of an "alkyl" defined above are substituted with an "alkoxy" defined above, and １ ~C ６ Alkoxy C １ ~C ６ Alkyl is preferred, C １ ~C ６ Alkoxy C １ ~C ２ Specific examples of alkoxyalkyl include methoxymethyl, ethoxymethyl, 1-propoxymethyl, 2-propoxymethyl, n-butoxymethyl, i-butoxymethyl, s-butoxymethyl, t-butoxymethyl, pentyloxymethyl, 3-methylbutoxymethyl, 1-methoxyethyl, 2-methoxyethyl, 2-ethoxyethyl, 1-ethoxyethyl, and 1-n-propyloxyethyl.

[0053] As used herein, "alkylthioalkyl" refers to a group in which one or more hydrogen atoms of an "alkyl" defined above are substituted with an "alkylthio" defined above, and C １ ~C ６ Alkylthio C １ ~C ６ Alkyl is preferred, C １ ~C ６ Alkylthio C １ ~C ２ Specific examples of alkylthioalkyl include methylthiomethyl, ethylthiomethyl, 1-propylthiomethyl, 2-propylthiomethyl, n-butylthiomethyl, i-butylthiomethyl, s-butylthiomethyl, and t-butylthiomethyl.

[0054] As used herein, "alkenyloxyalkyl" refers to a group in which one or more hydrogen atoms of an "alkyl" defined above are substituted with an "alkenyloxy" defined above, and C ２ ~C ６ Alkenyloxy C １ ~C ６ Alkyl is preferred, C １ ~C ６Alkenyloxy C １ ~C ２ Alkyl is more preferred. Specific examples of alkenyloxyalkyl include vinyloxymethyl and allyloxymethyl.

[0055] As used herein, "cycloalkylalkyl" refers to a group in which one or more hydrogen atoms of an "alkyl" defined above are substituted with a "cycloalkyl" defined above, and C ３ ~C ８ Cycloalkyl C １ ~C ６ Alkyl is preferred, C ３ ~C ６ Cycloalkyl C １ ~C ２ Alkyl is more preferred. Specific examples of cycloalkylalkyl include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, and cyclohexylmethyl.

[0056] As used herein, "cycloalkoxyalkyl" refers to a group in which one or more hydrogen atoms of an "alkyl" defined above are substituted with a "cycloalkoxy" defined above, and C ３ ~C ８ Cycloalkoxy C １ ~C ６ Alkyl is preferred, C ３ ~C ６ Cycloalkoxy C １ ~C ２ Alkyl is more preferred. Specific examples of cycloalkoxyalkyl include cyclopropoxymethyl and cyclobutoxymethyl.

[0057] As used herein, "heterocyclylalkyl" refers to a group in which one or more hydrogen atoms of an "alkyl" defined above are replaced by a "heterocyclyl" defined above, and includes 4- to 7-membered heterocyclyl C １ ~C ６ Alkyl is preferred, and 4- to 7-membered heterocyclyl C １ ~C ２Specific examples of heterocyclylalkyl include 2-(tetrahydro-2H-pyran-4-yl)ethyl and 2-(azetidin-3-yl)ethyl.

[0058] As used herein, "alkylsulfonylalkyl" refers to a group in which one or more hydrogen atoms of an "alkyl" defined above are substituted with an "alkylsulfonyl" defined above, and １ ~C ６ Alkylsulfonyl C １ ~C ６ Alkyl is preferred, C １ ~C ６ Alkylsulfonyl C １ ~C ２ Alkyl is more preferred. Specific examples of alkylsulfonylalkyl include methylsulfonylmethyl and 2-(methylsulfonyl)ethyl.

[0059] As used herein, "aminocarbonylalkyl" refers to a group in which one or more hydrogen atoms of an "alkyl" defined above are substituted with an "aminocarbonyl" defined above, and an aminocarbonyl C １ ~C ６ Alkyl is preferred, and aminocarbonyl C １ ~C ４ Specific examples of aminocarbonylalkyl include methylaminocarbonylmethyl, dimethylaminocarbonylmethyl, t-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.

[0060] As used herein, "aryloxyalkyl" refers to a group in which one or more hydrogen atoms of an "alkyl" defined above are substituted with an "aryloxy" defined above, and ６ ~C １０ Aryloxy C １ ~C ６ Alkyl is preferred, C ６ ~C １０ Aryloxy C １ ~C ２ Alkyl is more preferred. Specific examples of aryloxyalkyl include phenoxymethyl and 2-phenoxyethyl.

[0061] As used herein, "aralkyl (arylalkyl)" refers to a group in which at least one hydrogen atom of an "alkyl" defined above is substituted with an "aryl" defined above, and C ７ ~C １４ Aralkyl is preferred, C ７ ~C １０ Aralkyl is more preferred. Specific examples of aralkyl include benzyl, phenethyl, and 3-phenylpropyl.

[0062] As used herein, "aralkoxy" refers to an oxy group to which the above-defined "aralkyl" is bonded, and ７ ~C １４ Aralkoxy is preferred, C ７ ~C １０ Aralkoxy is more preferred. Specific examples of aralkoxy include benzyloxy, phenethyloxy, and 3-phenylpropoxy.

[0063] As used herein, "aralkoxyalkyl" refers to a group in which one or more hydrogen atoms of an "alkyl" defined above are substituted with an "aralkoxy" defined above, and C ７ ~C １４ Aralkoxy C １ ~C ６ Alkyl is preferred, C ７ ~C １４ Aralkoxy C １ ~C ２Alkyl is more preferred. Specific examples of aralkoxyalkyl include benzyloxymethyl and 1-(benzyloxy)ethyl.

[0064] As used herein, the term "heteroarylalkyl" refers to a group in which at least one hydrogen atom of an "alkyl" as defined above is substituted with a "heteroaryl" as defined above, and includes 5- to 10-membered heteroaryl C １ ~C ６ Alkyl is preferred, and 5- to 10-membered heteroaryl C １ ~C ２ 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.

[0065] As used herein, "heteroarylalkoxy" refers to an oxy group to which the above-defined "heteroarylalkyl" is bonded, and is a 5- to 10-membered heteroaryl C １ ~C ６ Alkoxy is preferred, and 5- to 10-membered heteroaryl C １ ~C ２ Alkoxy is more preferred. Specific examples of heteroarylalkoxy include 3-thienylmethoxy and 3-pyridylmethoxy.

[0066] As used herein, "heteroarylalkoxyalkyl" refers to a group in which one or more hydrogen atoms of an "alkyl" defined above are substituted with a "heteroarylalkoxy" defined above, and includes 5- to 10-membered heteroaryl C １ ~C ６ Alkoxy C １ ~C ６ Alkyl is preferred, and 5- to 10-membered heteroaryl C １ ~C ２ Alkoxy C １ ~C ２Alkyl is more preferred. Specific examples of heteroarylalkoxyalkyl include 3-pyridylmethoxymethyl.

[0067] As used herein, "heterocycloalkylidenealkyl" refers to a group in which one or more hydrogen atoms of the "alkyl" defined above are replaced by the "heterocycloalkylidene" defined above, and includes 4- to 7-membered heterocycloalkylidene C １ ~C ６ Alkyl is preferred, and 4- to 7-membered heterocycloalkylidene C １ ~C ２ Specific examples of heterocycloalkylidenealkyl include tetrahydro-4H-pyran-4-ylidenemethyl and azetidin-3-ylidenemethyl.

[0068] As used herein, "alkoxyalkenyl" refers to a group in which one or more hydrogen atoms of an "alkenyl" defined above are substituted with an "alkoxy" defined above, and １ ~C ６ Alkoxy C ２ ~C ６ Alkenyl is preferred. Specific examples of alkoxyalkenyl include (E)-4-methoxybut-2-en-1-yl.

[0069] As used herein, "aminocarbonylalkenyl" refers to a group in which one or more hydrogen atoms of the "alkenyl" defined above are substituted with the "aminocarbonyl" defined above, and ２ ~C ６ Alkenyl is preferred. Specific examples of aminocarbonylalkenyl include (E)-3-(dimethylaminocarbonylcarbonyl)-prop-2-en-1-yl.

[0070] As used herein, "haloalkoxy" refers to a group in which one or more hydrogen atoms of the "alkoxy" defined above are substituted with halogen atoms, and C １ ~C ６Haloalkoxy is preferred. Specific examples of haloalkoxy include difluoromethoxy, trifluoromethoxy, 2,2-difluoroethoxy, and 2,2,2-trifluoroethoxy.

[0071] As used herein, "alkylene" refers to a divalent group derived from the "alkyl" by further removing one optional hydrogen atom, and C ４ ~C ８ Alkylene is preferred. Specific examples of alkylene include —CH ２ -, -(CH ２ ) ２ -, -(CH ２ ) ３ -, -CH(CH ３ ) CH ２ -, -C(CH ３ ) ２ -, -(CH ２ ) ４ -, -CH(CH ３ ) CH ２ CH ２ -, -C(CH ３ ) ２ CH ２ -, -CH ２ CH (CH ３ ) CH ２ -, -CH ２ C(CH ３ ) ２ -, -CH ２ CH ２ CH (CH ３ ) -, -(CH ２ ) ５ -, -(CH ２ ) ６ -, -(CH ２ ) ７ -, -(CH ２ ) ８ - and others.

[0072] As used herein, "cycloalkylene" refers to a divalent group derived from the "cycloalkyl" by further removing one optional hydrogen atom, and C ３ ~C ８Cycloalkylene is preferred, and specific examples of cycloalkylene include cyclopropane-1,2-diyl, cyclobutane-1,2-diyl, cyclopentane-1,2-diyl, and cyclohexane-1,2-diyl.

[0073] As used herein, "heterocyclylene" refers to a divalent group derived from the "heterocyclyl" defined above by removing one optional hydrogen atom, and is preferably a 3- to 7-membered heterocyclylene. Specific examples of heterocyclylene include oxirane-2,3-diyl, oxetane-2,3-diyl, tetrahydrofuran-2,5-diyl, and tetrahydropyran-2,6-diyl.

[0074] As used herein, "alkenylene" refers to a divalent group derived from the above-mentioned "alkenyl" by further removing one optional hydrogen atom. Depending on the configuration of the double bond and substituents (if any), the geometry of the double bond can be entgegen (E) or zusammen (Z), cis or trans. Alkenylene includes linear and branched chains, and C ２ ~C １０ Alkenylene is preferred, C ２ ~C ６ Alkenylene is more preferred.

[0075] As used herein, "alkynylene" refers to a divalent group derived from the "alkynyl" by further removing one optional hydrogen atom. The alkynylene includes linear and branched ones, and C ２ ~C １０ Alkynylene is preferred, C ２ ~C ６ Alkynylene is more preferred.

[0076] As used herein, "arylene" refers to a divalent group derived from the above-mentioned "aryl" by further removing any one hydrogen atom. The arylene may be a single ring or a condensed ring. The number of atoms constituting the ring is not particularly limited, but is preferably 6 to 10 (C6-10 arylene). Specific examples of arylene include 1,2-phenylene, 1,3-phenylene, 1,4-phenylene, 1,2-naphthylene, 1,3-naphthylene, and 1,4-naphthylene.

[0077] As used herein, the term "spirocycloalkyl" refers to a group formed by sharing one carbon atom constituting a cycloalkane ring with a carbon atom in a group to which it is bonded. Preferred examples of spirocycloalkyl include C ３ ~C ８ Examples include spirocycloalkyl, specifically spirocyclopropyl, spirocyclobutyl, spirocyclopentyl, spirocyclohexyl, spirocycloheptyl, spirocyclooctyl, and the like.

[0078] As used herein, "spiroheterocyclyl" refers to a group in which one or more carbon atoms in the above-mentioned "spirocycloalkyl" are replaced by heteroatoms. Preferred heterospirocycloalkyls include 4- to 10-membered spiroheterocyclyls.

[0079] As used herein, "alicyclic ring" refers to a non-aromatic hydrocarbon ring. The alicyclic ring may have an unsaturated bond within the ring, or may be a polycyclic ring having two or more rings. Furthermore, the carbon atoms constituting the ring may be oxidized to form a carbonyl. Preferred examples of the alicyclic ring include 3- to 8-membered alicyclic rings, 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.

[0080] As used herein, the term "saturated heterocycle" refers to a non-aromatic heterocycle containing 1 to 5 heteroatoms in addition to carbon atoms and containing no double and / or triple bonds within the ring. The saturated heterocycle may be a monocycle or may form a condensed ring with another ring, for example, an aromatic ring such as a benzene ring. Preferred examples of the saturated heterocycle include 4- to 7-membered saturated heterocycles, such as an azetidine ring, an oxetane ring, a tetrahydrofuran ring, a tetrahydropyran ring, a morpholine ring, a thiomorpholine ring, a pyrrolidine ring, a 4-oxopyrrolidine ring, a piperidine ring, a 4-oxopiperidine ring, a piperazine ring, a pyrazolidine ring, an imidazolidine ring, an oxazolidine ring, an isoxazolidine ring, a thiazolidine ring, an isothiazolidine ring, a thiadiazolidine ring, an oxazolidone ring, a dioxolane ring, a dioxane ring, a thietane ring, an octahydroindole ring, an indoline ring, and an azepane ring.

[0081] As used herein, the term "peptide chain" refers to a peptide chain in which 1, 2, 3, 4, or more natural amino acids and / or unnatural amino acids are linked by amide bonds and / or ester bonds. The peptide chain is preferably a peptide chain containing 1 to 4 amino acid residues, and more preferably a peptide chain consisting of 1 to 4 amino acid residues.

[0082] As used herein, the term "optionally substituted" means that a group may be substituted with any substituent.

[0083] As used herein, the term "optionally protected" means that a group may be protected by any protecting group.

[0084] As used herein, "one or more" means one or more than one. When "one or more" is used in the context of substituents on a group, the term means a number from one to the maximum number of substituents permitted by that group. Specific examples of "one or more" include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and / or more.

[0085] The wavy lines in the structural formulae herein may mean that any stereochemistry is permitted. For example, if a wavy line is drawn at an asymmetric center, the stereochemistry of the asymmetric center may be either S-configuration or R-configuration. Also, if a wavy line is drawn at a double bond, the stereochemistry of the double bond may be either E-configuration or Z-configuration.

[0086] As used herein, "PPn 1 n 2 n 3 n 4 (where n 1 , n 2 , n 3 , and n 4 Each of the symbols "(a) and "b) independently represent an integer of 0 to 9" (e.g., PP1574, PP1640, etc.) represents a compound number.

[0087] The compound of the present invention can be a salt thereof, preferably a chemically or pharmaceutically acceptable salt thereof. The compound of the present invention or a salt thereof can also be a solvate thereof, preferably a chemically or pharmaceutically acceptable solvate thereof. Salts of the compound of the present invention include, for example, hydrochloride; hydrobromide; hydroiodide; phosphate; phosphonate; sulfate; sulfonate such as methanesulfonate and p-toluenesulfonate; carboxylate such as acetate, citrate, malate, tartrate, succinate, and salicylate; alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as magnesium salt and calcium salt; and ammonium salts such as ammonium salt, alkylammonium salt, dialkylammonium salt, trialkylammonium salt, and tetraalkylammonium salt. These salts can be produced, for example, by contacting the compound with an acid or base that can be used in the production of pharmaceuticals. In the present invention, a solvate of a compound refers to a compound that forms a molecular group together with a solvent, and when the solvent is water, it is called a hydrate. The solvate of the compound of the present invention is preferably a hydrate, and specific examples of such a hydrate include mono- to decahydrates, preferably mono- to pentahydrates, and more preferably mono- to trihydrates. The solvate of the compound of the present invention includes not only solvates with a single solvent such as water, alcohol (e.g., methanol, ethanol, 1-propanol, 2-propanol, etc.), and dimethylformamide, but also solvates with multiple solvents.

[0088] As used herein, "amino acid" includes natural amino acids and unnatural amino acids. As used herein, "natural amino acids" refers to Gly, Ala, Ser, Thr, Val, Leu, Ile, Phe, Tyr, Trp, His, Glu, Asp, Gln, Asn, Cys, Met, Lys, Arg, and Pro. Unnatural amino acids are not particularly limited, but examples include β-amino acids, γ-amino acids, D-amino acids, N-substituted amino acids, α,α-disubstituted amino acids, amino acids with side chains that are different from natural amino acids, and hydroxycarboxylic acids. As used herein, amino acids may have any configuration. The side chain of the amino acid is not particularly limited, and may be freely selected from, in addition to a hydrogen atom, for example, an alkyl group, an alkenyl group, an alkynyl group, an aryl group, a heteroaryl group, an aralkyl group, and a cycloalkyl group. In these groups, one or two non-adjacent methylene groups may be replaced by an oxygen atom, a carbonyl group (-CO-), or a sulfonyl group (-SO ２ -). Each of these may be substituted with a substituent, and the substituents are not limited, and may be independently selected from any substituents containing a halogen atom, an O atom, a S atom, a N atom, a B atom, a Si atom, or a P atom. That is, 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 carboxy 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).

[0089] The main chain amino group of the amino acid is unsubstituted (NH ２ group), and may be substituted (i.e., an —NHR group: R represents an alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, or cycloalkyl group which may have a substituent, and one or two non-adjacent methylene groups in these groups are replaced by an oxygen atom, a carbonyl group (—CO—), or a sulfonyl group (—SO ２-), or the carbon chain bonded to the N atom and the carbon atom at the α-position may form a ring, as in proline. The substituent of R is selected in the same manner as the substituent in the amino acid side chain described above. When the main chain amino group is substituted, R is included in the "amino acid side chain" in this specification. An amino acid in which such a main chain amino group is substituted is referred to as an "N-substituted amino acid" in this specification. As used herein, the "N-substituted amino acid" is preferably an N-alkyl amino acid, an N-C １ ~C ６ Alkylamino acid, N-C １ ~C ４ Examples include, but are not limited to, alkyl amino acids and N-methyl amino acids.

[0090] The "amino acids" constituting the peptide compounds herein include all corresponding isotopes. An isotope of an "amino acid" is one in which at least one atom has been replaced with an atom having the same atomic number (number of protons) but a different mass number (sum of the 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, each of which is ２ H. ３ H. １３ C. １４ C. １５ N. １７ O. １８ O. ３１ P. ３２ P. ３５ S. １８ F. ３６ Cl and the like are included.

[0091] In this specification, examples of the substituent containing a halogen atom include an alkyl group, a cycloalkyl group, an alkenyl group, an alkynyl group, an aryl group, a heteroaryl group, an aralkyl group, and the like, each of which has a halogen atom as a substituent, and more specific examples thereof include a fluoroalkyl, a difluoroalkyl, a trifluoroalkyl, and the like.

[0092] Substituents containing an O atom include hydroxy (-OH), oxy (-OR), carbonyl (-C(=O)-R), carboxy (-CO ２ H), oxycarbonyl (-C(=O)-OR), carbonyloxy (-O-C(=O)-R), thiocarbonyl (-C(=O)-SR), carbonylthio (-S-C(=O)-R), aminocarbonyl (-C(=O)-NHR), carbonylamino (-NH-C(=O)-R), oxycarbonylamino (-NH-C(=O)-OR), sulfonylamino (-NH-SO ２ -R), aminosulfonyl (-SO ２ -NHR), sulfamoylamino (-NH-SO ２ -NHR), thiocarboxy (-C(=O)-SH), carboxycarbonyl (-C(=O)-CO ２ H).

[0093] Examples of oxy (—OR) include alkoxy, cycloalkoxy, alkenyloxy, alkynyloxy, aryloxy, heteroaryloxy, aralkyloxy, etc. Alkoxy includes C １ ~C ４ Alkoxy, C １ ~C ２ Alkoxy is preferred, and methoxy or ethoxy is particularly preferred.

[0094] Examples of carbonyl (-C(=O)-R) include formyl (-C(=O)-H), alkylcarbonyl, cycloalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, arylcarbonyl, heteroarylcarbonyl, aralkylcarbonyl, and the like.

[0095] Examples of oxycarbonyl (-C(=O)-OR) include alkyloxycarbonyl, cycloalkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, aralkyloxycarbonyl, and the like.

[0096] Examples of carbonyloxy (—O—C(═O)—R) include alkylcarbonyloxy, cycloalkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, arylcarbonyloxy, heteroarylcarbonyloxy, and aralkylcarbonyloxy.

[0097] Examples of thiocarbonyl (-C(=O)-SR) include alkylthiocarbonyl, cycloalkylthiocarbonyl, alkenylthiocarbonyl, alkynylthiocarbonyl, arylthiocarbonyl, heteroarylthiocarbonyl, aralkylthiocarbonyl, and the like.

[0098] Examples of carbonylthio (-S-C(=O)-R) include alkylcarbonylthio, cycloalkylcarbonylthio, alkenylcarbonylthio, alkynylcarbonylthio, arylcarbonylthio, heteroarylcarbonylthio, aralkylcarbonylthio, and the like.

[0099] Examples of aminocarbonyl (—C(═O)—NHR) include alkylaminocarbonyl (e.g., C １ ~C ６ or C １ ~C ４ Examples include alkylaminocarbonyl, especially ethylaminocarbonyl and methylaminocarbonyl, cycloalkylaminocarbonyl, alkenylaminocarbonyl, alkynylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, aralkylaminocarbonyl, etc. In addition to these, examples include compounds in which the H atom bonded to the N atom in —C(═O)—NHR is further substituted with an alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or aralkyl.

[0100] Examples of carbonylamino (-NH-C(=O)-R) include alkylcarbonylamino, cycloalkylcarbonylamino, alkenylcarbonylamino, alkynylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, aralkylcarbonylamino, etc. In addition to these, compounds in which the H atom bonded to the N atom in -NH-C(=O)-R is further substituted with alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or aralkyl are also included.

[0101] Examples of oxycarbonylamino (-NH-C(=O)-OR) include alkoxycarbonylamino, cycloalkoxycarbonylamino, alkenyloxycarbonylamino, alkynyloxycarbonylamino, aryloxycarbonylamino, heteroaryloxycarbonylamino, aralkyloxycarbonylamino, etc. In addition to these, compounds in which the H atom bonded to the N atom in -NH-C(=O)-OR is further substituted with an alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or aralkyl are also included.

[0102] Sulfonylamino (-NH-SO ２ Examples of —R) include alkylsulfonylamino, cycloalkylsulfonylamino, alkenylsulfonylamino, alkynylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, aralkylsulfonylamino, etc. In addition to these, —NH—SO ２ Examples include compounds in which the H atom bonded to the N atom in —R is further substituted with alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or aralkyl.

[0103] Aminosulfonyl (-SO ２ Examples of —NHR) include alkylaminosulfonyl, cycloalkylaminosulfonyl, alkenylaminosulfonyl, alkynylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl, aralkylaminosulfonyl, and the like. ２Examples include compounds in which the H atom bonded to the N atom in —NHR is further substituted with alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or aralkyl.

[0104] Sulfamoylamino (-NH-SO ２ Examples of —NHR) include alkylsulfamoylamino, cycloalkylsulfamoylamino, alkenylsulfamoylamino, alkynylsulfamoylamino, arylsulfamoylamino, heteroarylsulfamoylamino, and aralkylsulfamoylamino. ２ The two H atoms bonded to the N atom in —NHR may be substituted with substituents independently selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and aralkyl, and these two substituents may form a ring.

[0105] Substituents containing an S atom include thiol (-SH), thio (-S-R), sulfinyl (-S(=O)-R), sulfonyl (-SO ２ -R), sulfo (-SO ３ H).

[0106] Examples of thio (-S-R) are selected from alkylthio, cycloalkylthio, alkenylthio, alkynylthio, arylthio, heteroarylthio, aralkylthio, and the like.

[0107] Sulfonyl (-SO ２ Examples of —R) include alkylsulfonyl, cycloalkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl, and the like.

[0108] As a substituent containing a nitrogen atom, azide (-N ３ , also called "azido group"), cyano (-CN), primary amino (-NH ２ ), secondary amino (-NH-R; also called monosubstituted amino), tertiary amino (-NR(R'); also called disubstituted amino), amidino (-C(=NH)-NH ２), substituted amidino (—C(═NR)—NR′R″), guanidino (—NH—C(═NH)—NH ２ ), substituted guanidino (—NR—C(═NR′″)—NR′R″), aminocarbonylamino (—NR—CO—NR′R″), pyridyl, piperidino, morpholino, azetidinyl, and the like.

[0109] Examples of secondary amino (-NH-R; monosubstituted amino) include alkylamino, cycloalkylamino, alkenylamino, alkynylamino, arylamino, heteroarylamino, and aralkylamino.

[0110] Examples of tertiary amino (—NR(R′); disubstituted amino) include an amino group having any two substituents independently selected from alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, etc., such as alkyl(aralkyl)amino, and these two substituents may form a ring. Specifically, dialkylamino, especially C １ -C ６ Dialkylamino, C １ -C ４ Examples include dialkylamino, dimethylamino, and diethylamino. ｐ -C ｑ "Dialkylamino group" means an amino group having C ｐ -C ｑ It means a group substituted with two alkyl groups, and both C ｐ -C ｑ The alkyl groups may be the same or different.

[0111] Examples of substituted amidino (-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.

[0112] Examples of substituted guanidino (-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, or groups in which these groups form a ring.

[0113] Examples of aminocarbonylamino (-NR-CO-NR'R") include groups in which R, R', and R" are each independently selected from a hydrogen atom, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and aralkyl, or groups in which these groups form a ring.

[0114] In this specification, the "peptide residues" and "amino acid residues" that constitute a peptide compound may be simply referred to as "peptides" and "amino acids," respectively.

[0115] In the present invention, the meaning of the term "and / or" includes any combination of "and" and "or" appropriately combined. Specifically, for example, "A, B, and / or C" includes the following seven variations: (i) A, (ii) B, (iii) C, (iv) A and B, (v) A and C, (vi) B and C, and (vii) A, B, and C.

[0116] 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: The cyclic compound of formula (1) has a ring structure composed of 11 amino acid residues. １ , Q １ , R １ , and L １ The amino acid residues having the following structure are designated as Core 1 and P ２ , Q ２ , and R ２ The amino acid residues having the following structure are designated as core 2 and P ３ , Q ３ , and R ３ The amino acid residues having the following structure are designated as core 3 and P ４ , Q ４ , and R ４The amino acid residues having the following structure are designated as core 4 and P ５ , Q ５ , and R ５ The amino acid residues having the following structure are core 5 and P ６ , Q ６ , and R ６ The amino acid residues having the following structure are core 6 and P ７ , Q ７ , and R ７ The amino acid residues having the following structure are core 7 and P ８ , Q ８ , and R ８ The amino acid residues having the following structure are core 8 and P ９ , Q ９ , and R ９ The amino acid residues having the following structure are core 9, P １０ , Q １０ , and R １０ The amino acid residues having the following structure are core 10 and P １１ , Q １１ , R １１ , and L １１ The amino acid residues having the following structure are sometimes referred to as core 11 amino acid residues.

[0117] In one embodiment, in formula (1), L １ is a single bond.

[0118] In one embodiment, in formula (1), R １ is C １ ~C ７ It is alkyl, preferably 2-methylpropyl or n-propyl.

[0119] In one embodiment, R １ is R ５ and form a divalent group together, in this case, the partial structure in the cyclic compound represented by formula (1): *-CR １ Q １ -L １ -CO-NP ２ -CR ２ Q ２ -CO-NP ３ -CR ３ Q ３ -CO-NP ４ -CR ４ Q ４ -CO-NP ５ -CR５ Q ５ -* is the following formula: In the formula: X ２ Is, -L １ -CO-NP ２ -CR ２ Q ２ -CO-NP ３ -CR ３ Q ３ -CO-NP ４ -CR ４ Q ４ -CO-NP ５ - and is a single bond or a double bond, n is 0, 1, or 2, m is 0, 1, 2, 3, or 4, and * represents a point of attachment to the adjacent atom. teeth, is a double bond, this means that it may be in either E or Z stereochemistry.

[0120] The formula may be: is preferred.

[0121] In one embodiment, P １ is C １ ~C ６ It is alkyl, preferably methyl.

[0122] In one embodiment, Q １ is hydrogen.

[0123] The side chain of Core 1 (R １ ) and the side chain of core 5 (R ５ ) together to form a divalent group, specific examples of the amino acid residue of Core 1 include MeLeu and MeNva. １ ) and the side chain of core 5 (R ５ ) together to form a divalent group, R of MeAhpe(2), MeAocte(2), MeAhxe(2) １ and the side chain (R ５ ) can be linked to a group at a position corresponding to the group 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30,

[0124] In one embodiment, in formula (1), R ２ is C １ ~C ６ It is alkyl, preferably 1-methylpropyl.

[0125] In one embodiment, P ２ is hydrogen.

[0126] In one embodiment, Q ２ is hydrogen.

[0127] A specific example of the amino acid residue of core 2 is Ile.

[0128] In one embodiment, in formula (1), R ３ is hydrogen.

[0129] In one embodiment, R ３ Is, P ３ , R ３ and a carbon atom to which P is bonded. ３ forms a 4- to 7-membered saturated heterocyclic ring together with the nitrogen atom to which it is bonded. A specific example of the 4- to 7-membered saturated heterocyclic ring is a pyrrolidine ring.

[0130] In one embodiment, P ３ is C １ ~C ６ Alkyl, or C ３ ~C ８ It is cycloalkyl, preferably methyl or cyclopropyl.

[0131] In one embodiment, Q ３ is hydrogen.

[0132] Specific examples of core 3 amino acid residues include MeGly, Pro, and cPrGly.

[0133] In one embodiment, R ４ Is, P ５ and form a divalent group together, and in this case, the partial structure *-CR in the cyclic compound represented by formula (1) ４ Q ４ -CO-NP ５ -* is the following formula: It is expressed as:

[0134] In one embodiment, P ４ is C １ ~C ６ It is alkyl, preferably methyl.

[0135] In one embodiment, Q ４ is hydrogen.

[0136] In addition, the side chain of Core 4 (R ４ ) and N-substituent of core 5 (P ５ ) together to form a divalent group, preferably R ４ and the N-substituent of core 5 (P ５ ) can be linked to a group at a position corresponding to the group 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30,

[0137] In one embodiment, in formula (1), R ５ is C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, and C ３ ~C ８ Benzyl optionally substituted by one or more groups independently selected from the group consisting of cycloalkyl, and preferably 4-cyclopropylbenzyl, 4-(trifluoromethyl)benzyl, 4-methylbenzyl, or 4-ethylbenzyl.

[0138] In one embodiment, in formula (1), R ５ is R １ and together form a divalent group, the details of which are as described above.

[0139] In one embodiment, P ５ is R ４ and together form a divalent group, the details of which are as described above.

[0140] In one embodiment, Q ５ is hydrogen.

[0141] The side chain of core 5 (R ５ ) and the side chain of Core 1 (R １ ) together form a divalent group, and the N-substituent (P５ ) and the side chain of core 4 (R ４ ) together to form a divalent group, for example, R in ButenylPhe(4-CH=CH2) ５ and P ５ and the side chain (R １ ) and the side chain of Core 4 (R ４ ) can be linked to the group at the position corresponding to the side chain (R ５ ) and the side chain of Core 1 (R １ ) does not form a divalent group, and the N-substituent (P ５ ) and the side chain of core 4 (R ４ ) forms a divalent group, for example, P of ButenylPhe(4-Et), ButenylPhe(4-cPr), or AllylPhe(4-CF3). ５ and the side chain (R ４ ) can be linked to a group at a position corresponding to the group 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30,

[0142] In one embodiment, in formula (1), R ６ is hydrogen.

[0143] In one embodiment, P ６ is C １ ~C ６ It is alkyl, preferably methyl.

[0144] In one embodiment, Q ６ is hydrogen.

[0145] A specific example of the amino acid residue in core 6 is MeGly.

[0146] In one embodiment, in formula (1), halogen, C １ ~C ６ Haloalkyl, and C １ ~C ６and phenethyl which may be substituted by one or more groups independently selected from the group consisting of alkoxy, and preferably 3,5-difluoro-4-(trifluoromethyl)phenethyl, 3,4-dichlorophenethyl, and 3-methoxy-4-(trifluoromethyl)phenethyl.

[0147] In one embodiment, P ７ is hydrogen.

[0148] In one embodiment, Q ７ is hydrogen.

[0149] Specific examples of core 7 amino acid residues include Hph(4-CF3-35-F2), Hph(34-Cl2), and Hph(4-CF3-3-OMe).

[0150] In one embodiment, in formula (1), R ８ Is, P ８ , R ８ and a carbon atom to which P is bonded. ８ can be combined with the nitrogen atom to which it is attached to form a 4- to 7-membered saturated heterocyclic ring. １ ~C ６ It may be substituted with alkoxy, preferably ethoxy, or n-propoxy. A specific example of the 4- to 7-membered saturated heterocyclic ring is a pyrrolidine ring.

[0151] In one embodiment, Q ８ is hydrogen.

[0152] Specific examples of amino acid residues in core 8 include Hyp(Et) and Hyp(nPr).

[0153] In one embodiment, in formula (1), R ９ Is, Q ９ , and R ９ and Q ９ together with the carbon atom to which it is attached to form a 3- to 8-membered alicyclic ring. The 3- to 8-membered alicyclic ring may be formed by one or more C １ ~C ６It may be substituted with an alkyl group, for example, two methyl groups. Specific examples of the 3- to 8-membered alicyclic ring include a cyclobutane ring and a cyclopentane ring.

[0154] In one embodiment, P ９ is hydrogen or C １ ~C ６ It is alkyl, preferably hydrogen or methyl.

[0155] Specific examples of core 9 amino acid residues include cLeu, cVal, cVal(3-Me2), and MecVal.

[0156] In one embodiment, in formula (1), R １０ is C １ ~C ６ Alkyl, or C ３ ~C ８ It is cycloalkyl, preferably pentan-3-yl or cyclopentyl.

[0157] In one embodiment, P １０ is C １ ~C ６ It is alkyl, preferably methyl.

[0158] In one embodiment, Q １０ is hydrogen.

[0159] Specific examples of amino acid residues in core 10 include MeGly(cPent) and MeNva(3-Et).

[0160] In one embodiment, in formula (1), L １１ Ha-CH ２ - is.

[0161] In one embodiment, in formula (1), R １１ Is Ji C １ ~C ６ It is alkylaminocarbonyl or 4- to 8-membered cyclic aminocarbonyl, and preferably dimethylaminocarbonyl, N-ethyl-N-methylaminocarbonyl, pyrrolidinylcarbonyl or piperidinylcarbonyl.

[0162] In one embodiment, P １１is C １ ~C ６ It is alkyl, preferably methyl.

[0163] In one embodiment, Q １１ is hydrogen.

[0164] In some embodiments, the compounds of the present invention are: 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-undecazatricyclo[34.5.1.0 10,14 ]dotetracont-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-undecazatricyclo[34.5.1.0] 10,14]dotetracont-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-undecazapentacyclo[24.15.11.2 43,46 .1 35,41 .0 9,13 ]pentapentaconta-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-undecazapentacyclo[24.15.11.2 43,46 .1 35,41 .0 9,13]pentapentaconta-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-undecazatricyclo[34.5.1.0] 10,14 ]dotetracont-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-undecazapentacyclo[24.15.11.2 43,46 .1 35,41 .0 9,13]pentapentaconta-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-undecazatricyclo[34.5.1.0] 10,14 ]dotetracont-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-undecazatetracyclo[37.5.1.0] 4,8 .0 26,30]pentatetracont-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-undecazatricyclo[34.5.1.0] 10,14 ]dotetracont-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-undecazapentacyclo[24.15.10.2 43,46 .1 35,41 .0 9,13 ]tetrapentaconta-37,43(53),44,46(52),47-pentaene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecane, 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-undecazapentacyclo[24.15.10.2 43,46 .135,41 .0 9,13 ]tetrapentaconta-37,43(53),44,46(52),47-pentaene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecane, 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-undecazapentacyclo[24.15.10.2 43,46 .1 35,41 .0 9,13 ]tetrapentaconta-37,43(53),44,46(52),47-pentaene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecane, 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-undecazatricyclo[34.5.1.0] 10,14]dotetracont-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-undecazatricyclo[34.5.1.0] 10,14 ]dotetracont-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-undecazapentacyclo[24.15.10.2 43,46 .1 35,41 .0 9,13 ]tetrapentaconta-37,43(53),44,46(52),47-pentaene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecane, 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 .09,13 ]pentapentaconta-37,43(54),44,46(53)-tetraene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,55-undecane, 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 ]pentapentaconta-37,43(54),44,46(53)-tetraene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,55-undecane, 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]tetrapentaconta-37,43(53),44,46(52)-tetraene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecane, 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 ]tetrapentaconta-37,43(53),44,46(52)-tetraene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecane, 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]pentapentaconta-37,43(54),44,46(53),47-pentaene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,55-undecane, 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 ]tripentaconta-37,43(52),44,46(51)-tetraene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,53-undecane, 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]tripentaconta-37,43(52),44,46(51)-tetraene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,53-undecane, 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-undecazatricyclo[34.5.1.0] 10,14 ]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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-undecazatricyclo[34.5.1.0] 10,14]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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-undecazatricyclo[34.5.1.0] 10,14 ]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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-undecazatricyclo[34.5.1.0 10,14]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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-undecazatetracyclo[37.5.1.0] 4,8 .0 26,30 ]pentatetracont-42-ene-23,1'-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecane, 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]pentatetracont-42-ene-23,1'-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecane, 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-undecazatetracyclo[37.5.1.0] 4,8 .0 26,30 ]pentatetracont-42-ene-23,1'-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecane, 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-undecazatetracyclo[37.5.1.0] 4,8 .0 26,30]pentatetracont-42-ene-23,1'-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecane, 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-undecazatricyclo[34.5.1.0] 10,14 ]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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-undecazatricyclo[34.5.1.0] 10,14 ]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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-undecazatricyclo[34.5.1.0] 10,14]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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-undecazatricyclo[34.5.1.0] 10,14 ]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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-undecazatricyclo[34.5.1.0] 10,14 ]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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-undecazatricyclo[34.5.1.0] 10,14]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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-undecazatricyclo[34.5.1.0 10,14 ]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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-undecazatricyclo[34.5.1.0 10,14]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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-undecazatetracyclo[37.5.1.0] 4,8 .0 26,30 ]pentatetracont-42-ene-23,1'-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecane, 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-undecazatetracyclo[37.5.1.0] 4,8 .0 26,30]pentatetracont-42-ene-23,1'-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecane, 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-undecazatetracyclo[37.5.1.0] 4,8 .0 26,30 ]pentatetracont-42-ene-23,1'-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecane, 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-undecazatetracyclo[37.5.1.0] 4,8 .0 26,30]pentatetracont-42-ene-23,1'-cyclobutane]-3,9,12,15,19,22,25,31,34,37,45-undecane, 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-undecazatricyclo[34.5.1.0] 10,14 ]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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-undecazatricyclo[34.5.1.0] 10,14 ]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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-undecazatricyclo[34.5.1.0]10,14 ]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, 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-undecazatricyclo[34.5.1.0 10,14 ]dotetracont-38-ene-17,1'-cyclobutane]-3,6,9,15,18,21,25,28,31,34,42-undecane, (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-undecazapentacyclo[24.15.11.2 43,46 .1 35,41 .0 9,13]pentapentaconta-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-undecazapentacyclo[24.15.11.2 43,46 .1 35,41 .0 9,13 ]pentapentaconta-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]tetrapentaconta-37,43(53),44,46(52),47-pentaene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecane, (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 ]tetrapentaconta-37,43(53),44,46(52),47-pentaene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecane, (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]tetrapentaconta-37,43(53),44,46(52),47-pentaene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecane, (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 ]tetrapentaconta-37,43(53),44,46(52),47-pentaene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecane, 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 ]pentapentaconta-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 or solvate thereof. These compounds may be included in the formula (1).

[0165] In some embodiments, the compounds of the present invention have the formula (2): Preferred are compounds represented by the formula n, m, P １ , R２ , R ３ , P ３ , P ４ , P ６ , R ７ , R ８ , P ８ , R ９ , P ９ , Q ９ , R １０ , P １０ , R １１ , and P １１ represents the same meaning as in formula (1). For example, the 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). (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-undecazapentacyclo[24.15.11.2 43,46 .1 35,41 .0 9,13 ]pentapentaconta-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-undecazapentacyclo[24.15.11.2 43,46 .135,41 .0 9,13 ]pentapentaconta-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 ]tetrapentaconta-37,43(53),44,46(52),47-pentaene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecane, (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]tetrapentaconta-37,43(53),44,46(52),47-pentaene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecane, (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 ]tetrapentaconta-37,43(53),44,46(52),47-pentaene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecane, (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]tetrapentaconta-37,43(53),44,46(52),47-pentaene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,54-undecane, 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 ]pentapentaconta-37,43(54),44,46(53),47-pentaene-16,1'-cyclobutane]-2,5,8,14,17,20,24,27,30,33,55-undecane

[0166] In some embodiments, the compounds of the present invention have the formula (3): In formula (3), a compound represented by R １ is C １ ~C ７ alkyl; R ５ is C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, and C ３ ~C ８ benzyl optionally substituted by one or more groups selected from the group consisting of cycloalkyl; n, m, P １ , R ２ , R ３ , P ３ , P ４ , P ６ , R ７ , R ８ , P ８ , R ９ , P ９ , Q ９ , R １０ , P １０ , R １１ , and P１１ represents the same meaning as in formula (1). For example, the compounds of 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).

[0167] In some embodiments, the cyclic compounds of the present invention have high selectivity for KRAS. In some embodiments, the cyclic compounds of the present invention selectively inhibit KRAS. Without being bound by any particular theory, R ４ and P ５ The divalent group formed by the interaction of these two with His95 of KRAS can achieve high selectivity for KRAS. RAS proteins are known to have three isotypes: HRAS, KRAS, and NRAS, but His95 is present only in KRAS. Therefore, a compound that specifically interacts with His95 of KRAS can inhibit KRAS with high selectivity for NRAS and / or HRAS.

[0168] 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, lemurs, 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 in SEQ ID NO: 2, and the amino acid sequence of human-derived KRAS in SEQ ID NO: 3.

[0169] In some embodiments, the cyclic compounds of the present invention have KRAS inhibitory activity that is at least three times greater than their NRAS and / or HRAS inhibitory activity, and in some embodiments, the cyclic compounds of the present invention have KRAS binding activity that is at least three times greater than their NRAS and / or HRAS binding activity.

[0170] In some embodiments, 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 NRAS and / or HRAS inhibitory activity. In some embodiments, 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 NRAS and / or HRAS binding activity.

[0171] In the present invention, the KRAS inhibitory activity relative to the NRAS inhibitory activity and / or HRAS inhibitory activity can be determined from the ratio of the NRAS inhibitory activity and / or HRAS inhibitory activity of the cyclic compound of the present invention to the KRAS inhibitory activity of the cyclic compound of the present invention. As an example, this ratio can be expressed as the IC of the cyclic compound of the present invention against NRAS and / or HRAS. ５０ value] is calculated by dividing the IC value of the cyclic compound of the present invention by the IC value of the KRAS ５０ When the ratio is defined as the value obtained by dividing the KRAS inhibitory activity by the NRAS inhibitory activity and / or HRAS inhibitory activity, a larger value means that the KRAS inhibitory activity relative to the NRAS inhibitory activity and / or HRAS inhibitory activity is large, i.e., the selective inhibitory activity of the cyclic compound of the present invention against KRAS is large; conversely, a smaller value means that the KRAS inhibitory activity relative to the NRAS inhibitory activity and / or HRAS inhibitory activity is small, i.e., the selective inhibitory activity of the cyclic compound of the present invention against KRAS is small.

[0172] In addition, in the present invention, the binding activity to KRAS relative to the binding activity to NRAS and / or the binding activity to HRAS can be calculated from the ratio of the binding activity to NRAS and / or the binding activity to HRAS of the cyclic compound of the present invention to the binding activity to KRAS of the cyclic compound of the present invention.As an example, when this ratio is defined as the value obtained by dividing [KD value for NRAS and HRAS] by [KD for KRAS], when this value is large, it means that the binding activity to KRAS relative to the binding activity to NRAS and / or the binding activity to HRAS is large, that is, the binding selectivity of KRAS relative to NRAS and / or HRAS is large; conversely, when this value is small, it means that the binding activity to KRAS relative to the binding activity to NRAS and / or the binding activity to HRAS is small, that is, the binding selectivity of KRAS relative to NRAS and / or HRAS is small.

[0173] In the present invention, "interaction" refers to a non-covalent interaction exemplified by electrostatic interactions (including ionic bonds, hydrogen bonds, and dipole interactions) and van der Waals interactions (including hydrophobic interactions). For example, it refers to a CH-π interaction, an NH-π interaction, an S-π interaction, a cation-π interaction, or a halogen-π interaction. The interaction in the present invention may be mediated by other molecules such as water molecules, or may not be mediated by other molecules such as water molecules, but is preferably an interaction not mediated by other molecules such as water molecules.

[0174] In the present invention, whether or not a cyclic compound interacts with histidine (referred to as His95 or H95), the 95th amino acid residue in the wild-type human KRAS protein, can be determined by the interatomic distance between the two non-hydrogen atoms (in the case of a bond via other molecules such as water molecules, the interatomic distance between the two non-hydrogen atoms is ignored). When the interatomic distance is 5.1 angstroms (Å) or less, it can be determined that the two non-hydrogen atoms interact. In some embodiments, the interatomic distance between the two interacting non-hydrogen atoms can be, for example, 5.1 Å or less, 4.8 Å or less, 4.5 Å or less, 4.3 Å or less, 4.2 Å or less, 4.1 Å or less, 4.0 Å or less, 3.9 Å or less, or 3.7 Å or less. It can also be 2.0 Å or more, 2.1 Å or more, or 2.5 Å or more.

[0175] In the present invention, interatomic distances can be measured, for example, by analyzing the three-dimensional structure of a complex between a wild-type human KRAS protein and a cyclic compound of the present invention. Specifically, crystals of the complex between a wild-type human KRAS protein and a cyclic compound of the present invention are prepared. X-ray diffraction of the crystals is performed to obtain X-ray diffraction intensity data such as the space group and unit cell. The obtained X-ray diffraction intensity data can be applied to a program for determining initial or refined structures 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), to determine the three-dimensional structure of the complex between human KRAS wild-type protein and the cyclic compound of the present invention.

[0176] Once the three-dimensional structure of the complex between the human KRAS wild-type protein and the cyclic compound of the present invention can be determined, it is possible to measure interatomic distances by methods well known to those skilled in the art. For example, structural information about the complex between the cyclic compound of the present invention and the human KRAS wild-type protein can be loaded into a software program used for molecular modeling or molecular simulation, such as Discovery studio 2020 Client, MOE (Molecular Operating Environment), or Maestro, and interatomic distances can be measured using a function built into the software program (e.g., the Distance Monitor function in the case of Discovery studio 2020 Client). In addition, details about the conditions and criteria used by the software to determine whether or not an interaction exists can be found in the instructions or specifications that came with the software (for example, in the case of Discovery studio 2020 Client, you can open the specifications web page from the help button, select "Receptor-Ligand Interactions tools," then select "Theory-Receptor-Ligand Interactions," and then select "Non-bond Interactions" to find details about the conditions and criteria used to determine whether or not an interaction exists).

[0177] Crystals of a complex between 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 between human KRAS wild-type protein and the cyclic compound of the present invention. Crystals of a complex between human KRAS wild-type protein and the cyclic compound of the present invention can be prepared by subjecting the resulting complex to crystallization methods well known to those skilled in the art, such as vapor diffusion, batch methods (bulk batch, microbatch), dialysis, and counterdiffusion. Known vapor diffusion methods include the sitting drop method, hanging drop method, and sandwich drop method.

[0178] Wild-type human KRAS protein can also be obtained by methods known to those skilled in the art. For example, wild-type human KRAS protein can be prepared using, but is not limited to, recombinant polypeptide expression methods using cells. In one embodiment, a nucleic acid encoding the wild-type human KRAS protein of the present invention is inserted into an appropriate expression vector, the vector is introduced into appropriate cells, the transformed cells are cultured, and the expressed protein is isolated and purified. Such proteins can also be expressed as fusion proteins with other proteins for purposes such as facilitating purification. For example, a method using Escherichia coli as a host to prepare a fusion protein with maltose-binding protein (vector pMAL series, available from New England BioLabs, USA), a method using glutathione S-transferase (GST) (vector pGEX series, available from Amersham Pharmacia Biotech), a method using a histidine tag (pET series, available from Novagen), or a method using a HAT tag can be used. Host cells are not particularly limited as long as they are suitable for expressing recombinant proteins. In addition to the aforementioned Escherichia coli, for example, yeast, various animal and plant cells, insect cells, etc. can be used. Various methods known to those skilled in the art can be used to introduce vectors into host cells. For example, introduction into Escherichia coli can be achieved using a calcium ion-based introduction method (Mandel, M., Higa, A. (1970) Journal of Molecular Biology, 53, 158-162; Hanahan, D. (1983) Journal of Molecular Biology, 166, 557-580). Proteins expressed in host cells can be purified and recovered from the host cells, their cell cultures, or culture supernatants by methods known to those skilled in the art. When proteins are expressed as fusion proteins with the aforementioned maltose-binding protein or HAT tag, for example, they can be easily purified by affinity purification or gel filtration chromatography (size exclusion chromatography, SEC).Affinity chromatography and SEC purification can be performed using an AKTAxpress™ instrument (GE Healthcare), an NGC™ chromatography system (Bio-Rad), or a BioLogic DuoFlow™ chromatography system (Bio-Rad), for example.

[0179] Interatomic energy can also be measured by methods well known to those skilled in the art. For example, the three-dimensional structure of the substance to be measured can be read into a molecular simulation program well known to those skilled in the art, such as Discovery Studio 2020 Client, MOE (Molecular Operating Environment), or Maestro, and calculations can be easily performed by selecting the force field (e.g., Amber, CHARM, etc.) to be used in the calculation and the atoms to be subjected to the energy calculation according to the instructions of the program. For example, in the case of Discovery Studio 2020 Client, interatomic energy can be calculated using the Calculate Interaction Energy function.

[0180] In a non-limiting embodiment, in a complex of the cyclic compound of the present invention and a wild-type human KRAS protein, the cyclic compound of the present invention interacts with His95 in the wild-type human KRAS protein.

[0181] Without being bound by any particular theory, it is believed that the formation of a complex between the cyclic compound of the present invention and the human KRAS wild-type protein in this manner is related to the contribution of the cyclic compound of the present invention to the high binding activity of the cyclic compound of the present invention to the human KRAS wild-type protein, as well as to the binding selectivity to HRAS and NRAS.

[0182] The present invention also relates to unnatural amino acids used in the production of cyclic compounds of the present invention. In one embodiment, the unnatural amino acids of the present invention are N-protected unnatural amino acids used in the production of peptide compounds using solid-phase synthesis. In another embodiment, the unnatural amino acids of the present invention are unnatural amino acids having a free amino group obtained by removing the protecting group from an N-protected unnatural amino acid. Examples of protecting groups for N-protected unnatural amino acids include Fmoc, Boc, Cbz, Alloc, nosyl, dinitronosyl, t-Bu, trityl, and cumyl groups. Of these, Fmoc, Boc, Cbz, and Alloc are preferred, with Fmoc being more preferred.

[0183] In one embodiment, N-protected unnatural amino acids having an Fmoc group as a protecting group in the present invention include, for example, the following amino acids listed in Table 4, or salts thereof, or solvates thereof. aa004: (2S)-2-[9H-Fluoren-9-ylmethoxycarbonyl(methyl)amino]octanoic acid, aa013: (2R)-2-[9H-Fluoren-9-ylmethoxycarbonyl(methyl)amino]-3-methylsulfanyl-propanoic acid, aa019: (2S)-2-[9H-Fluoren-9-ylmethoxycarbonyl(methyl)amino]-4,4-difluoro-butanoic acid, aa023: (2S)-2-[9H-Fluoren-9-ylmethoxycarbonyl(methyl)amino]-3-(3-thienyl)propanoic acid, aa028: (2S)-3-(3,4-dichlorophenyl)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]propanoic acid, aa043: (2S)-5,5-Dichloro-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]pentanoic acid, aa056: (2R)-3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-2-methyl-propanoic acid, aa098: (2S,3S)-1-(9H-fluoren-9-ylmethoxycarbonyl)-3-methyl-azetidine-2-carboxylic acid, aa099: (2S,3R)-1-(9H-fluoren-9-ylmethoxycarbonyl)-3-methyl-azetidine-2-carboxylic acid, aa100: (2S)-1-(9H-fluoren-9-ylmethoxycarbonyl)-3,3-Dimethyl-azetidine-2-carboxylic acid, aa111: (2R)-3-allyloxy-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]propanoic acid, aa136: (2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(propyl)amino]-3-[4-(trifluoromethyl)phenyl]propanoic acid, aa174: (2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(propyl)amino]-3-(p-tolyl)propanoic acid, aa210: (2S)-2-cyclopentyl-2-[ethyl(9H-fluoren-9-ylmethoxycarbonyl)amino]acetic acid, aa220: (2S)-4-(4-chloro-3,5-difluoro-phenyl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)butanoic acid, aa229: (2S)-4-(benzothiophen-5-yl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)butanoic acid, aa233: (2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-4-[3-methyl-4-(trifluoromethyl)phenyl]butanoic acid, aa235: (2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-4-[3-methoxy-4-(trifluoromethyl)phenyl]butanoic acid, aa239: (2S,4S)-1-(9H-fluoren-9-ylmethoxycarbonyl)-4-methyl-pyrrolidine-2-carboxylic acid, aa244: (2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-5,5-difluoro-pentanoic acid, aa246: (2S,4R)-1-(9H-Fluoren-9-ylmethoxycarbonyl)-4-propoxy-pyrrolidine-2-carboxylic acid, aa250: (2R)-2-[9H-Fluoren-9-ylmethoxycarbonyl(methyl)amino]-3-propoxy-propanoic acid, aa264: (2S,3R)-1-(9H-Fluoren-9-ylmethoxycarbonyl)-3-hydroxy-pyrrolidine-2-carboxylic acid, aa265: (2S,3S)-1-(9H-Fluoren-9-ylmethoxycarbonyl)-3-hydroxy-pyrrolidine-2-carboxylic acid, aa268: (1S,2S,5R)-3-(9H-Fluoren-9-ylmethoxycarbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid, aa279: (2S,4R)-1-(9H-Fluoren-9-ylmethoxycarbonyl)-4-tetrahydropyran-2-yloxy-pyrrolidine-2-carboxylic acid, aa281: (2S,4R)-1-(9H-Fluoren-9-ylmethoxycarbonyl)-4-methoxy-pyrrolidine-2-carboxylic acid, aa331: (2S)-3-ethyl-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]pentanoic acid. aa389: (2S)-2-[9H-Fluoren-9-ylmethoxycarbonyl(propyl)amino]-4-methyl-pentanoic acid, aa391: (2S,3R)-2-(9H-Fluoren-9-ylmethoxycarbonylamino)-3-propoxy-butanoic acid, aa397: (2S)-2-[9H-Fluoren-9-ylmethoxycarbonyl(propyl)amino]-3-isopentyloxy-propanoic acid, aa398: (2S)-3-(cyclobutoxy)-2-[9H-fluoren-9-ylmethoxycarbonyl(propyl)amino]propanoic acid, aa399: (2S)-4-(7-chloro-1-methyl-indol-5-yl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)butanoic acid, aa400: (2S)-2-(9H-Fluoren-9-ylmethoxycarbonylamino)-4-(2-fluoro-3-methyl-benzothiophen-5-yl)butanoic acid, aa401: (2S)-4-(7-chlorobenzothiophen-5-yl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)butanoic acid, aa402: (2S)-2-(9H-Fluoren-9-ylmethoxycarbonylamino)-4-(1-methylindol-6-yl)butanoic acid, aa403: (2S)-4-(1,3-dimethylindol-6-yl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)butanoic acid, aa404: (2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-4-(1,2,3-trimethylindol-6-yl)butanoic acid, aa405: (2S)-4-(2,3-Dimethylbenzothiophen-5-yl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)butanoic acid, aa406: (2S)-4-(3-chloro-4-ethyl-phenyl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)butanoic acid, aa407: (2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-4-[4-(methoxymethyl)-3,5-dimethyl-phenyl]butanoic acid, aa408: (2S)-4-(4-chloro-3-methoxy-phenyl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)butanoic acid, aa409: (2S)-4-[4-chloro-3-(trifluoromethyl)phenyl]-2-(9H-fluoren-9-ylmethoxycarbonylamino)butanoic acid, aa410: (2S)-4-[4-(difluoromethyl)-3,5-difluoro-phenyl]-2-(9H-fluoren-9-ylmethoxycarbonylamino)butanoic acid, aa411: (2S)-4-(4-chloro-3,5-dimethyl-phenyl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)butanoic acid, aa414: (2S,4R)-4-(cyclopentoxy)-1-(9H-fluoren-9-ylmethoxycarbonyl)pyrrolidine-2-carboxylic acid, aa415: (2S,4R)-4-(cyclobutoxy)-1-(9H-fluoren-9-ylmethoxycarbonyl)pyrrolidine-2-carboxylic acid, aa423: (3S)-3-cyclobutyl-3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]propanoic acid, aa424: (3R)-3-[9H-Fluoren-9-ylmethoxycarbonyl(methyl)amino]pentanoic acid, aa425: (3S)-3-[9H-Fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-methyl-pentanoic acid, aa426: (3S)-3-cyclohexyl-3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]propanoic acid, and aa443: (2S)-2-[but-3-enyl(9H-fluoren-9-ylmethoxycarbonyl)amino]-3-(p-tolyl)propanoic acid.

[0184] (General Production Method) General production methods for the cyclic compounds of the present invention, as well as the oligopeptide compounds and unnatural amino acids used to produce these compounds, are described below. Note that, in this specification, cyclic compounds are sometimes referred to as "cyclic peptide compounds." In this specification, the "cyclic portion" of a peptide compound refers to a cyclic portion formed by linking two or more amino acid residues.

[0185] Chemical Synthesis Methods for Peptide Compounds In the present specification, examples of chemical synthesis methods for peptide compounds or cyclic compounds include liquid-phase synthesis, solid-phase synthesis using Fmoc synthesis, Boc synthesis, or the like, and combinations thereof. In Fmoc synthesis, the base unit is an amino acid in which the main chain amino group is protected with an Fmoc group, and the side chain functional groups are protected as needed with a protecting group that is not cleaved by a base, such as a t-Bu group, a THP group, or a Trt group, or a piperidine, without protecting the main chain carboxylic acid. The base unit is not particularly limited as long as it has an Fmoc-protected amino group and a carboxyl group. For example, a dipeptide or tripeptide may be used as the base unit, and a cyclic structure may be formed between the substituent and / or side chain of the nitrogen atom contained in the dipeptide or tripeptide. The base unit to be positioned at the N-terminus may be other than an Fmoc amino acid. For example, it may be a Boc amino acid, a Tfa group, an Ns group, or a carboxylic acid analog without an amino group. The main chain carboxyl group or the side chain carboxyl group of an amino acid with a carboxyl group on the side chain protected by an appropriate protecting group is supported on the solid phase by chemical reaction with the functional group of the solid phase support. The Fmoc group is then deprotected with a base such as piperidine or DBU, and the newly generated amino group is condensed with the subsequently added carboxyl-containing amino acid of the base unit to form a peptide bond. Various combinations of carboxyl group activators are available for the condensation reaction, including DIC and HOBt, DIC and HOAt, and HATU and DIPEA. The desired peptide sequence can be generated by repeated Fmoc group removal and subsequent peptide bond formation. After obtaining the desired sequence, the peptide is cleaved from the solid phase and, if necessary, the introduced side chain functional group is deprotected. Alternatively, structural transformation or cyclization of the peptide can be performed before cleavage from the solid phase. Cleavage from the solid phase and deprotection are performed under the same conditions, for example, a 90:10 TFA / H ２The deprotection may be carried out using 0 or, if necessary, under separate conditions. Cleavage from the solid phase can be performed using a weak acid such as 1% TFA, or by using a protecting group that can be deprotected using a Pd-containing catalyst, etc., to take advantage of the orthogonality of the two chemical reactions. A step such as cyclization can be performed between or after these steps. For example, a side-chain carboxylic acid can be condensed with an amino group on the N-terminal main chain, or a side-chain amino group can be condensed with a carboxylic acid on the C-terminal main chain. Furthermore, olefins can be introduced into two or more positions on the side chain and / or nitrogen atom substituents, followed by cyclization by metathesis. Furthermore, the double bond formed by cyclization can be reduced to a single bond. The double bond formed by cyclization can also be converted to a cyclopropane ring using conditions such as diiodomethane-diethylzinc. These steps of cyclization, reduction, and conversion to a cyclopropane ring may also be performed during the synthesis of basic units such as dipeptides and tripeptides. Note that orthogonality is required between the C-terminal carboxylic acid and the side-chain carboxylic acid to be cyclized, between the N-terminal main-chain amino group or hydroxy group and the side-chain amino group to be cyclized, or between the olefin in the side-chain and / or nitrogen atom substituent and the olefin to be cyclized. As mentioned above, protecting groups are selected with consideration given to their orthogonality. Furthermore, by positioning a chloroacetyl group at the N-terminus, cyclization with the thiol group in the side chain of a cysteine ​​residue is also possible. The resulting reaction product can be purified using a reverse-phase column or a molecular sieve column. Details of these procedures are described, for example, in the Solid-Phase Synthesis Handbook published by Merck Ltd. on May 1, 2002. Commercially available resins for solid-phase synthesis can be used, such as CTC resin, Wang resin, or SASRIN resin.

[0186] The following describes a general method for synthesizing an amino acid-supported resin used in peptide synthesis using a peptide synthesizer.

[0187] The Fmoc amino acid can be supported on the resin according to the method described in WO 2013 / 100132 or WO 2018 / 225864. Specifically, for example, a 2-chlorotrityl chloride resin and a solvent (e.g., dehydrated dichloromethane) are placed in a reaction vessel equipped with a filter, and the resin is allowed to swell. The solvent and resin are then separated, and a mixture of the resin, a C-terminal free Fmoc amino acid dissolved in a solvent (e.g., dehydrated dichloromethane), a solvent (e.g., dehydrated methanol), and a base (e.g., diisopropylethylamine) is added to the reaction vessel and mixed, thereby supporting the Fmoc amino acid on the resin. After separating the resin from the reaction solution, the resin is mixed with a mixture of one or more solvents and a base (e.g., a mixture of dehydrated dichloromethane, dehydrated methanol, and diisopropylethylamine) and washed. The resin is washed with a solvent (e.g., dichloromethane) multiple times as necessary, and then the resin is separated from the reaction solution. The resulting resin is dried under reduced pressure overnight to obtain a resin carrying an Fmoc amino acid. (wherein n represents an integer of 1 to 11, and P １ ~P １１ , Q １ ~Q １１ , R １ ~R １１ is defined herein as P １ ~P １１ , Q １ ~Q １１ , R １ ~R １１ and L １ and L １１ is the L described herein １ and L １１ and L ２ ~L １０ indicates a single bond, and ○ indicates the resin site.) 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.

[0188] In the production of the compounds described herein, if a defined group undergoes an undesired chemical transformation under the conditions of the method, the compound can be produced by, for example, using means such as protection and deprotection of functional groups. Here, the selection and deprotection of protecting groups can be performed, for example, using the methods described in "Greene's, 'Protective Groups in Organic Synthesis' (5th Edition, John Wiley & Sons 2014)," which can be used appropriately depending on the reaction conditions. Furthermore, the order of reaction steps such as introducing substituents can be changed as necessary. For example, examples of protecting groups for amino groups include Fmoc, Boc, Cbz, and Alloc groups. These carbamate groups can be introduced by reacting an amino group with a carbamating agent in the presence of a base catalyst. Examples of the carbamating agent include Boc. ２ Examples of base 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, N,N-dimethylaminopyridine, etc. A carbamate group, which is a protecting group for an amino group, can be removed under basic conditions, acidic conditions, hydrogenolysis conditions, or the like.

[0189] (Method for synthesizing cyclic compounds by cyclization of peptide compounds) Linear peptide compounds can be converted into cyclic compounds by intramolecular bond formation reactions using methods such as those described in "Comprehensive Organic Transformations, A Guide to Functional Group Preparations, 3rd Edition, by R.C. Larock" or "March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7th Edition, by M.B. March." Functional group transformation reactions can also be performed after the bond formation reaction. Examples of bond formation reactions include the C(O)-N bond formed from a carboxylic acid and an amine, the COC bond using an oxygen atom, the C(O)-O bond, the C(S)-O bond, the C(O)-S bond using a sulfur atom, the C(S)-S bond, the C-S-C bond, the C-S-C bond, the C-S-C bond, the C-S-C bond, the C-S-C bond, the C-S-C bond, the C-S-C bond, the C-S-C bond, the C-S-C bond, the C-S-C bond, the C-N-C bond, the C-N-C bond, the C-N-C bond, the N-C-N bond, the N-C-N bond, and the C(S)-N bond using a nitrogen atom. Further examples include transition metal-catalyzed C-C bond formation reactions such as the Suzuki reaction, the Heck reaction, the Sonogashira reaction, and metathesis. Examples of functional group conversion reactions that can be performed after a bond formation reaction include oxidation and reduction reactions. Specifically, a reaction in which a sulfur atom is oxidized to form a sulfoxide group or a sulfone group is exemplified. Another example is a reduction reaction in which a triple bond or a double bond among carbon-carbon bonds is reduced to form a double bond or a single bond. When two amino acids are bonded to each other in the main chain of an amino acid, a closed ring structure is formed by a peptide bond. However, a covalent bond between the two amino acids may also be formed by bonding the side chains of the two amino acids together, or by bonding the side chains to the main chain. Below, black circles or black squares represent amino acid residues, and linked black circles or black squares represent peptide chains linked by amide bonds. There are no particular limitations on the number of amino acid residues that make up a peptide chain, and the number of amino acid residues is not limited to the number of black circles or black squares exemplified below.

[0190] (General method 1 for producing cyclic compounds) The cyclic portion of a cyclic compound with a linear portion consists of an amino group at the N-terminus and a carboxyl group at the C-terminus side chain (for example, in the case of aspartic acid and its derivatives, L = -CH ２ -, and in the case of glutamic acid and its derivatives, L = -CH ２ CH ２ -) can be activated with an activating agent or converted to an active ester, followed by intramolecular condensation to form a C(O)-N bond and cyclization.

[0191] (General method 2 for producing cyclic compounds)

[0192] In the cyclic compound in which the linear portion described in General Method 1 of Cyclic Compounds becomes C-Terminus, the amino group at the N-terminus and the carboxyl group at the side chain on the C-terminus side (for example, in the case of aspartic acid or its derivatives, L = -CH ２ -, and in the case of glutamic acid and its derivatives, L = -CH ２ CH ２ -) can be activated with an activating agent or converted to an active ester, followed by intramolecular condensation to form a C(O)-N bond and cyclization.

[0193] (General method 3 for producing cyclic compounds) (Method for cyclization with haloalkyl group and SH group) The cyclic portion of a cyclic compound with a linear portion can be cyclized by intramolecularly reacting the haloalkyl group of an amino acid residue with the thiol group of the amino acid residue to form a C-SC bond. Similarly, in the case of cyclic compounds in which the linear portion is C-Terminus, as described in General Cyclic Compound Preparation Method 1, the haloalkyl group of an amino acid residue can be cyclized intramolecularly with the thiol group of the amino acid residue to form a C-SC bond. Furthermore, the sulfur atom can be oxidized to sulfoxide or sulfone, forming a C-S(O)-C bond or a C-S(O2)-C bond.

[0194] (Method of cyclization with vinyl group and SH group) The cyclic portion of a cyclic compound with a linear portion can be cyclized by intramolecularly reacting the vinyl group of an amino acid residue with the thiol group of the amino acid residue to form a CSC bond. Similarly, the cyclic compound with a C-Terminated linear portion, as described in General Cyclic Compound Preparation Method 1, can be cyclized by intramolecularly reacting the vinyl group of an amino acid residue with the thiol group of the amino acid residue to form a CSC bond. Furthermore, the sulfur atom can be oxidized to a sulfoxide or sulfone to form a C-S(O)-C or C-S(O2)-C bond.

[0195] (Method of cyclization with ethynyl group and SH group) The cyclic portion of a cyclic compound with a linear portion can be cyclized by forming a C-SC bond through intramolecular reaction between the ethynyl group of an amino acid residue and the thiol group of an amino acid residue. Similarly, the cyclic compound with a C-Terminus linear portion, as described in General Cyclic Compound Preparation Method 1, can be cyclized by forming a C-SC bond through intramolecular reaction between the ethynyl group of an amino acid residue and the thiol group of an amino acid residue. Furthermore, the sulfur atom can be oxidized to a sulfoxide or sulfone, forming a C-S(O)-C bond or a C-S(O2)-C bond. The double bond can also be reduced to a single bond.

[0196] (Method of cyclization between vinyl groups) The cyclic portion of a cyclic compound with a linear portion can be cyclized by intramolecularly reacting vinyl groups of different amino acid residues to form a CC bond. Similarly, in the cyclic compound in which the linear portion is C-Terminus, as described in General Method 1 for Cyclic Compounds, the vinyl groups of different amino acid residues can be cyclized by intramolecularly reacting to form a CC bond.

[0197] (A method of forming a triazole ring between an azide group and an ethynyl group to cyclize the compound) The cyclic portion of a cyclic compound having a straight-chain portion can be cyclized by intramolecularly reacting an azide group of an amino acid residue with an ethynyl group of the amino acid residue to form a triazole ring. Similarly, the cyclic compound in which the straight-chain portion is C-Terminus described in General Production Method 1 for Cyclic Compounds can be cyclized by intramolecularly reacting an azide group of an amino acid residue with an ethynyl group of the amino acid residue to form a triazole ring.

[0198] A general method for producing a peptide compound by peptide modification is shown below. In the following scheme, ｎ represents a substituent of a nitrogen atom, and R ｎ and Q ｎ represents an amino acid side chain, a black circle represents an amino acid residue, linked black circles represent peptide chains linked by amide bonds, and m represents the number of amino acid residues and can be any integer value of 1 or more.

[0199] (Method for Producing Peptides Containing N-Alkylamino Acids) Peptides containing N-alkylamino acids can be synthesized using an Fmoc-protected N-alkylamino acid as a starting material according to the general peptide synthesis method described in this example, or by alkylating the N-terminal nitrogen on a resin as shown below. Specifically, the nitrogen of Tfa amide (trifluoroacetamide) at the N-terminus of a peptide supported on a resin is reacted with an alkyl halide under basic conditions, followed by treatment with a reducing agent, as described in Organic Letters, 2008, 10, 4815-4818, etc., to produce the desired peptide having an N-alkylamino acid at the N-terminus. Furthermore, cyclic compounds can be produced by peptide elongation, cleavage from the resin, cyclization, deprotection, and purification according to the general peptide synthesis method described in this example.

[0200] P at the N-terminal nitrogen ｎ As an alternative method for introducing P, the method described below in Nature Protocols, 2012, 7, 432-444 can also be used. Specifically, the N-terminal amine of the peptide supported on the resin is converted to an Ns-substituted product, and then P is introduced by Mitsunobu reaction.ｎ Then, the Ns group is deprotected to give the desired P ｎ Furthermore, a cyclic compound can be produced by carrying out peptide elongation, cleavage from the resin, cyclization, deprotection, and purification according to the general peptide synthesis method described in this example.

[0201] P on the nitrogen atom ｎ As a method for synthesizing a peptide containing glycine into which P is introduced, ｎ In addition to the synthesis method described in this example using glycine containing P as a starting material according to the general peptide synthesis method, it can also be produced by the substitution reaction of the N-terminal halocarbon with an amine as shown below. Specifically, the N-terminal amine is reacted with iodoacetic acid, and the resulting product is reacted with any primary amine, with reference to Organic Letters, 2010, 12, 4928-4931, etc., to produce a P on the target nitrogen atom. ｎ Furthermore, a cyclic compound can be produced by carrying out peptide elongation, cleavage from the resin, cyclization, deprotection, and purification according to the general peptide synthesis method described in this example.

[0202] (Method for Producing Peptides Having an Aryloxy or Heteroaryloxy Group in the Side Chain) Peptides having an aryloxy or heteroaryloxy group in the side chain can be produced by the general peptide synthesis method described in this example using an Fmoc amino acid having the desired aryloxy or heteroaryloxy group in the side chain as a starting material, or by using a peptide having an alcohol in the side chain as a precursor as shown below, with reference to Organic Letters, 2014, 16, 4944-4947 or Tetrahedron Letters, 2003, 44, 3863-3865, etc. Specifically, a peptide having an aryloxy or heteroaryloxy group in the side chain can be produced by reacting a peptide having an alcohol in the side chain with a triarylboroxane-pyridine complex in the presence of copper(II) acetate.

[0203] Peptides having an ether group other than an aryloxy group or heteroaryloxy group in the side chain can be produced by a method using an Fmoc amino acid having the desired ether group in the side chain as a starting material according to the general peptide synthesis method described in this example, or by using a peptide having an alcohol in the side chain as a precursor as shown below, with reference to the method described in Journal of Medicinal Chemistry, 2011, 54, 4815-4830 or the method described in Journal of Medicinal Chemistry, 2014, 57, 159-170. Specifically, a peptide having the desired ether group in the side chain can be produced by reacting an alcohol-containing peptide with an alkyl halide in the presence of silver(I) oxide, or by reacting an alcohol-containing peptide with an alkyl halide in the presence of a phase-transfer catalyst such as a tetraalkylammonium salt using aqueous sodium hydroxide as a base.

[0204] (Method for Producing Peptides Having an Aryl or Heteroaryl Group in the Side Chain) Peptides having an aryl or heteroaryl group in the side chain can be produced by a general peptide synthesis method described in the present Examples using an Fmoc amino acid having the desired aryl or heteroaryl group in the side chain as a starting material, or by reference to the method described in J. Am. Chem. Soc., 2016, 138, 5016-5019, using a peptide having a carboxylic acid in the side chain as a precursor, as shown below. Specifically, a peptide having a carboxylic acid in the side chain can be activated with N-hydroxyphthalimide and reacted with any aryl halide or heteroaryl halide to produce a peptide having a desired aryl or heteroaryl group in the side chain.

[0205] Furthermore, peptide compounds with crosslinked peptide backbones can be produced using peptides that have a carboxylic acid on a nitrogen atom substituent and / or a side chain and an aryl halide or heteroaryl halide on another nitrogen atom substituent and / or a side chain in the molecule. Specifically, a crosslinked compound can be produced by activating a peptide having a carboxylic acid with N-hydroxyphthalimide and crosslinking it by reaction with the aryl halide or heteroaryl halide in the molecule.

[0206] As an alternative method for producing peptides having an aryl or heteroaryl group in the side chain, they can also be synthesized by Suzuki coupling using a peptide having a boronic acid in the side chain as a precursor, as shown in the following method. Specifically, a precursor peptide is synthesized using an Fmoc amino acid having a boronic acid in the side chain as a starting material, and then reacted with any aryl halide in the presence of a palladium catalyst to produce the desired peptide having an aromatic ring in the side chain.

[0207] Furthermore, a peptide having a boronic acid on a nitrogen atom and / or a side chain and an aryl halide on another nitrogen atom and / or a side chain can be used to produce a peptide compound with a crosslinked peptide backbone. Specifically, a crosslinked compound can be produced by crosslinking a peptide having a boronic acid with an aryl halide in the molecule in the presence of a palladium catalyst.

[0208] Furthermore, peptide compounds having an olefin in the substituent and / or side chain of a nitrogen atom and an aryl halide in the substituent and / or side chain of another nitrogen atom in the molecule can be used to produce peptide compounds bridged with alkylenes, including arylenes. Specifically, a bridged compound can be produced by converting the olefin into a boron compound by hydroboration, and then reacting it with an aryl halide in the molecule in the presence of a palladium catalyst to form a crosslink.

[0209] (Method for Producing Peptides Having an Amide Group in the Side Chain) Peptides having an amide group in the side chain can be synthesized by amidation using a peptide having a carboxylic acid in the side chain as a precursor, as shown in the following method, in addition to a method using an Fmoc amino acid having the desired amide group in the side chain as a starting material. Specifically, a peptide having a protected carboxylic acid in the side chain is deprotected to synthesize a precursor peptide having a carboxylic acid in the side chain, and this precursor peptide can be condensed with any amine using HATU or the like as a condensing agent to obtain the desired peptide having an amide group in the side chain.

[0210] Furthermore, a peptide compound having a crosslinked peptide backbone can be produced using a peptide having a carboxylic acid at the substituent and / or side chain of a nitrogen atom and an amino group at the substituent and / or side chain of another nitrogen atom in the molecule. Specifically, a crosslinked compound can be produced by synthesizing a precursor peptide having a carboxylic acid and an amino group through deprotection, and then crosslinking the precursor peptide through an intramolecular amidation reaction by condensing the precursor peptide with a condensing agent such as HATU.

[0211] (Synthesis of Peptides Containing Highly Substituted Structures That May Contain Double Bonds in the Side Chain) Peptides having highly substituted structures that may contain double bonds in the side chain can be synthesized by using an Fmoc amino acid having a double bond in the desired side chain as a starting material, or by functionalizing a terminal olefin. Specifically, a peptide having a terminal olefin in the side chain can be synthesized according to the general peptide synthesis method described in this example, and then converted to a side chain having a highly substituted olefin by coupling with a substrate having any terminal olefin by an olefin metathesis reaction. The olefin can also be converted to the corresponding side chain by reducing it by a hydrogenation reaction.

[0212] Furthermore, peptide compounds with crosslinked peptide backbones can be produced using peptides with multiple double bonds in the nitrogen atom substituent and / or side chain. Specifically, a peptide with olefins at two positions in the nitrogen atom substituent and / or side chain can be synthesized according to the general peptide synthesis method described in this example, and the two olefins can be crosslinked by an olefin metathesis reaction with reference to Nature Protocols, 2011, 6, 761-771, to produce a crosslinked compound. Furthermore, a compound bridged with saturated alkylene can be produced by reducing the olefin by a hydrogenation reaction.

[0213] Furthermore, as the above-mentioned crosslinked compound, a peptide containing an aryl having an olefin-containing substituent in the nitrogen atom substituent and / or side chain can be used to produce a peptide compound crosslinked by an arylene and a divalent group containing a double bond. Specifically, a peptide having an olefin-containing aryl and an olefin in the nitrogen atom substituent and / or side chain can be synthesized according to the general peptide synthesis method described in this example, and two olefins can be crosslinked by an olefin metathesis reaction to produce a crosslinked compound. Furthermore, a compound crosslinked by an arylene-containing alkylene can be produced by reducing the olefin by a hydrogenation reaction.

[0214] (Synthesis of Peptides Having Triazole in the Side Chain) Peptides having triazole in the side chain can be produced by click reaction with an azide group. Specifically, a peptide having an azide group in the side chain is synthesized according to the general peptide synthesis method described in this example, and then coupled with any acetylene in the presence of copper(I) iodide, with reference to Bioorganic & Medicinal Chemistry Letters, 2009, 19, 4130-4133, etc., to produce a peptide compound having an azide group in the side chain.

[0215] Furthermore, a peptide having an azide group at a nitrogen atom substituent and / or a side chain and an acetylene at another nitrogen atom substituent and / or a side chain in the molecule can be used to produce a peptide compound with a crosslinked peptide backbone. Specifically, a crosslinked compound can be produced by crosslinking a peptide having an azide group with an acetylene in the molecule in the presence of a palladium catalyst.

[0216] (Synthesis of Peptide Having Aryl Group Substituted with Alkynyl Group in the Side Chain) A peptide having an aryl group substituted with an alkynyl group in the side chain can be synthesized by Sonogashira coupling reaction with an aryl halide group. Specifically, a peptide having an aryl iodide group in the side chain can be synthesized according to the general peptide synthesis method described in this example, and then converted into a peptide compound having an aryl group substituted with an alkynyl group in the side chain by coupling with any acetylene in the presence of copper(I) iodide.

[0217] Furthermore, a peptide having an aryl halide group at the nitrogen atom substituent and / or side chain and an acetylene at the nitrogen atom substituent and / or side chain in another nitrogen atom in the molecule can be used to produce a peptide compound with a crosslinked peptide backbone. Specifically, a peptide having an aryl iodide group can be crosslinked by coupling with the acetylene in the molecule in the presence of copper(I) iodide to produce a crosslinked compound.

[0218] (General Method for Producing Oligopeptide Compounds) A general method for producing an oligopeptide in which a cyclic structure is formed between a substituent on a nitrogen atom and a side chain is shown below. In the following scheme, PG １ and P.G. １ ' is a protecting group for the nitrogen atom, PG ２ and P.G. ２ ' is a protecting group for an oxygen atom, R ｎ－１ , R ｎ , R ｎ＋１ , Q ｎ is the side chain of an amino acid, P ｎ－１ , P ｎ , P ｎ＋１ is a substituent on a nitrogen atom, Y １ and Y ２ represents hydrogen, halogen, or alkyl, respectively. In the amino acid production methods described below, functional groups other than the intended one may undergo chemical reactions. In such cases, introducing protecting groups to the unintended functional groups allows only the desired reaction to proceed. Examples of such protecting group removal reactions include those described in Greene's "Protective Groups in Organic Synthesis" (5th ed., John Wiley & Sons 2014). For information on functional group transformation reactions in compounds, see Larock's Comprehensive Organic Transformations: A Guide to Functional Group Preparations (5th ed.) and Smith's March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure (8th ed.).

[0219] Oligopeptide compounds in which the nitrogen atom substituent of an amino acid and the side chain of another amino acid form a cyclic structure can be synthesized using the following method. An olefin-containing alkyl group can be introduced into a protected amino acid by treating it with an olefin-containing alkylating agent in the presence of a base. Subsequently, any amino acid with a protected C-terminus can be condensed to extend the C-terminus. The condensation reaction can be performed using various combinations of carboxyl group activators, such as DIC and HOBt, DIC and HOAt, or HATU and DIPEA. After deprotection of the nitrogen atom protecting group, the protected amino acid with an olefin in the side chain can be extended. The olefin in the molecule can then be cyclized by a metathesis reaction. Next, deprotection of the C-terminal protecting group produces a C-terminus-free oligopeptide compound in which a double bond is formed between the nitrogen atom substituent and the side chain.

[0220] Furthermore, an oligopeptide compound having a cyclic structure in which the double bond is converted to a single bond can be produced using an oligopeptide compound having a cyclic structure in which the double bond is converted to a single bond. Specifically, a C-terminal protected compound having a cyclic structure in which a double bond is converted to a single bond can be reduced by a hydrogenation reaction, and then the protecting group at the C-terminus can be deprotected to produce an oligopeptide compound having a free C-terminus in which an alkylene cyclic structure is formed between the nitrogen atom substituent and the side chain.

[0221] Furthermore, an oligopeptide compound having a cyclic structure containing a double bond can be used to produce an oligopeptide compound having a bridged structure in which the double bond has been converted to a cyclopropane ring. Specifically, the double bond of a C-terminal protected compound having a cyclic structure containing a double bond can be converted to a cyclopropane ring under conditions such as diiodomethane-diethylzinc. The protecting group at the C-terminus is then removed to produce an oligopeptide compound having a bridged structure in which the double bond has been converted to a cyclopropane ring.

[0222] Oligopeptide compounds in which a substituent on the nitrogen atom of an amino acid and the side chain of another amino acid form a cyclic structure can also be synthesized using the following method. An oxazolidinone compound with a cyclic protecting group can be obtained by reacting a protected amino acid with an aldehyde according to the method of Freidinger et al. (J. Org. Chem., 1983, 48(1), 77-81). Subsequently, an alkyl group having an olefin can be introduced onto the nitrogen atom by a ring-opening reaction using a silicon compound having an olefin according to the method of Nguyen et al. (Synthesis, 2009, 12, 1991). Subsequently, any amino acid with a protected C-terminus can be condensed to extend the C-terminus. Subsequently, the protecting group on the nitrogen atom is deprotected, and the protected amino acid having an olefin in the side chain can be extended. Subsequently, the olefin within the molecule can be cyclized by a metathesis reaction. The protecting group at the C-terminus is then deprotected to produce an oligopeptide compound with a free C-terminus that forms a cyclic structure containing a double bond between the substituent on the nitrogen atom and the side chain.

[0223] Oligopeptides containing an aryl group substituted with an alkenyl group (y = 0 to 2) in the side chain can be synthesized by Suzuki coupling reaction between an aryl halide 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 this example, and then converted into an oligopeptide compound having an aryl group substituted with an alkenyl group (y = 0 to 2) in the side chain by coupling with any boron compound having an alkenyl group in the presence of a palladium catalyst.

[0224] An oligopeptide compound in which a substituent on the nitrogen atom of an amino acid and the side chain of another amino acid form a cyclic structure via an amide bond can be synthesized using the following method. Specifically, a peptide with a protected C-terminus is synthesized according to the general synthesis method described in this example, the N-terminus is deprotected, and then an amino group having a protecting group can be introduced into the N-substituent by reductive amination with an aldehyde compound containing an amino group having a protecting group. Next, the peptide is condensed with a protected amino acid containing a carboxy group having a protecting group on the side chain, and the protecting groups of the carboxy group and amino group are removed, followed by intramolecular condensation and deprotection of the C-terminus, thereby converting the peptide into an oligopeptide compound in which a substituent on the nitrogen atom of an amino acid and the side chain of another amino acid form a cyclic structure via an amide bond.

[0225] (Method for Cyclizing Peptide Compounds on a Resin) Cyclic compounds and oligopeptide compounds having a cyclic structure can be cyclized by the method described in this example, or by a metathesis reaction on a resin as shown below. Specifically, a peptide supported on a resin is synthesized using the general peptide synthesis method described in this example, which has olefins at two positions in the nitrogen atom substituent and / or side chain, and the two olefins are cyclized by a metathesis reaction to produce a compound having a cyclic structure. Furthermore, cyclic compounds and oligopeptide compounds having a cyclic structure can be produced by carrying out peptide elongation, cleavage from the resin, cyclization, deprotection, and purification using the general peptide synthesis method described in this example.

[0226] (General Method for Producing Unnatural Amino Acids) A general method for producing unnatural amino acids with a free C-terminus in which the nitrogen atom of the amino acid is protected is shown below. １ and P.G. １ ' is a protecting group for the nitrogen atom, PG ２ and P.G. ２ ' is a protecting group for the oxygen atom, PG ３ and P.G. ４ is the protecting group of the amino acid side chain, R ｎ and Q ｎis the side chain of an amino acid, P ｎ is a substituent of a nitrogen atom, and P' is C １ -C ５ Alkyl, R, R', R'', and R''' each represent hydrogen or an amino group substituent. In the amino acid production methods described below, functional groups other than the intended one may undergo chemical reactions. In such cases, introducing a protecting group to the unintended functional group allows only the desired reaction to proceed. Examples of such protecting group removal reactions include the method described in Greene's "Protective Groups in Organic Synthesis" (5th ed., John Wiley & Sons 2014). For functional group transformation reactions in compounds, see Larock's Comprehensive Organic Transformations: A Guide to Functional Group Preparations (5th ed.) and Smith's March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure (8th ed.).

[0227] A protecting group (PG) is attached to the nitrogen atom of the amino acid. １ The following method can be used to produce an unnatural amino acid having a free N-terminus. A free N-terminus amino acid available from a commercial supplier can be subjected to a protecting group introduction reaction and, if necessary, a deprotection reaction according to standard methods to produce a desired unnatural amino acid having a free C-terminus.

[0228] A protecting group (PG) is attached to the nitrogen atom of the amino acid. １ The following method can be used to prepare an unnatural amino acid having a protecting group (PG′) at the N-terminus. １ The amino acid into which the C-terminus has been introduced can be subjected to a deprotection reaction and a protecting group introduction reaction by a standard method to produce the desired C-terminal free unnatural amino acid.

[0229] Substituents of nitrogen atoms of amino acids (P ｎThe following method can be used to produce an unnatural amino acid having an aminoalkyl group introduced at the nitrogen atom: A bromoacetate derivative available from a commercial supplier is reacted with an amino alcohol according to the method of King et al. (Tetrahedron Letters, 2002, 43(11), 1987-1990), and then a protecting group (PG) is introduced at the nitrogen atom. １ ) is introduced. Next, the hydroxyl group is oxidized according to the method of Dess et al. (J. Org. Chem., 1983, 48(22), 4155-4156), and then the aldehyde group is subjected to a reductive amination reaction according to the method of Borch et al. (J. Org. Chem. 1972, 37(10), 1673-1674) to introduce an amino group. The protecting group for the oxygen atom is then deprotected to produce the desired C-terminal free unnatural amino acid.

[0230] N-substituted amino acids are amino acids with a substituent (P ｎ The bromoacetate derivative, available from a commercial supplier, can be converted to an amine (P) in the presence of a base by the following scheme: ｎ NH ２ ) is reacted with a protecting group (PG １ The protecting group of the oxygen atom is then deprotected to produce the desired C-terminal free unnatural amino acid.

[0231] -CH to the nitrogen atom of the amino acid ２ An unnatural amino acid having a -P' group introduced therein can be produced by the following scheme. An oxazolidinone having a cyclic protecting group introduced therein can be obtained by reacting an aldehyde with an amino acid having a free C-terminus available from a commercial supplier according to the method of Freidinger et al. (J. Org. Chem., 1983, 48(1), 77-81). The desired unnatural amino acid having a free C-terminus can then be produced by a ring-opening reaction.

[0232] P on the nitrogen atom of amino acid ｎThe unnatural amino acid having the introduced group can be produced by the following scheme: A commercially available C-terminal free amino acid is treated with an alkylating agent (P ｎ -X) to form P ｎ Subsequently, a deprotection reaction and a protecting group introduction reaction are carried out by a standard method, whereby a C-terminal free unnatural amino acid can be produced.

[0233] An unnatural amino acid having an amide group introduced into the side chain of the amino acid can be produced by the following scheme. A commercially available protected amino acid (n = 1 or 2) is deprotected to obtain a carboxylic acid, and an amine (R"R"'NH) is then allowed to react with the resulting carboxylic acid to introduce an amide group into the side chain. The protecting group at the C-terminus is then deprotected to produce an unnatural amino acid with no C-terminus.

[0234] An amide group is introduced into the side chain of the amino acid, and a -CH ２ An unnatural amino acid having a -P' group introduced therein can be produced by the following scheme. A commercially available protected amino acid (n = 1 or 2) is reacted with an aldehyde according to the method of Freidinger et al. (J. Org. Chem., 1983, 48(1), 77-81) to obtain an oxazolidinone derivative having a cyclic protecting group introduced therein. Next, the protecting group of the side chain is removed, and then an amine (R"R"'NH) is reacted therewith to obtain an amide derivative. A ring-opening reaction is then carried out to produce the desired unnatural amino acid having a free C-terminus.

[0235] Unnatural amino acids having an amino group introduced into the side chain of the amino acid can be produced by the following scheme. An amide group can be introduced into the side chain by reacting an amine (R"R"'NH) with the carboxyl group of a commercially available protected amino acid (n = 1 or 2). Subsequently, a reduction reaction is carried out according to the method of Reeves et al. (Advanced Synthesis & Catalysis, 2013, 355(1), 47-52), followed by deprotection of the C-terminal protecting group, thereby producing an unnatural amino acid with a free C-terminus.

[0236] An amino group is introduced into the side chain of the amino acid, and -CH ２ An unnatural amino acid having a -P' group introduced therein can be produced by the following scheme. An amide group can be introduced into the side chain of an amino acid (n = 1 or 2) protected with a cyclic protecting group by reacting an amine (R"R"'NH) with the carboxyl group. Subsequently, a reduction reaction is carried out according to the method of Reeves et al. (Advanced Synthesis & Catalysis, 2013, 355(1), 47-52), followed by a ring-opening reaction, thereby producing the desired unnatural amino acid having a free C-terminus.

[0237] An unnatural amino acid having a fluoroalkyl group introduced into the side chain of the amino acid can be produced by the following scheme. The carboxyl group of a commercially available protected amino acid (n = 1 or 2) is converted to an aldehyde group by a standard method through reduction, and then a fluorine atom is introduced by a standard method, thereby converting the aldehyde group into a difluoromethyl group. The protecting group at the C-terminus is then deprotected to produce an unnatural amino acid with a free C-terminus.

[0238] A halogenated alkyl group is introduced into the side chain of the amino acid, and furthermore, a -CH ２An unnatural amino acid having a -P' group introduced therein can be produced according to the following scheme. The carboxyl group of an amino acid (n = 1 or 2) protected with a cyclic protecting group is converted to an aldehyde group by a standard method through reduction, and then a halogen atom is introduced by a standard method, thereby converting the aldehyde group into a dihalogenated methyl group. The cyclic protecting group at the C-terminus is then opened to produce an unnatural amino acid with a free C-terminus.

[0239] Alternatively, a halogenated alkyl group can be introduced into the side chain of an amino acid by the method shown below, and further, a -CH group can be introduced into the nitrogen atom of the amino acid. ２ It is possible to prepare a C-terminal free unnatural amino acid into which a -P' group has been introduced.

[0240] Unnatural amino acids having an aryl or heteroaryl group (these groups are referred to as "Ar" in the scheme) introduced into the side chain of the amino acid can be produced by the following scheme. The NHPI group can be introduced into the side chain by reacting N-hydroxyphthalimide (NHPI) with the carboxyl group of a protected amino acid (n = 1 or 2). According to the method of Huihui et al. (J. Am. Chem. Soc., 2016, 138(15), 5016-5019), an aryl or heteroaryl group can be introduced by reacting with an aryl halide or heteroaryl halide, thereby producing unnatural amino acids having an aralkyl or heteroaralkyl group in the side chain. The protecting group at the C-terminus is then removed to produce unnatural amino acids with a free C-terminus.

[0241] An aryl group or a heteroaryl group (these groups are referred to as "Ar" in the scheme) is introduced into the side chain of the amino acid, and further, a -CH ２Unnatural amino acids with an -P' group can be produced by the following scheme. An NHPI group can be introduced into the side chain by treating the carboxyl group of an amino acid (n = 1 or 2) protected with a cyclic protecting group with N-hydroxyphthalimide (NHPI). According to the method of Huihui et al. (J. Am. Chem. Soc., 2016, 138(15), 5016-5019), an aryl or heteroaryl group can be introduced by treating the amino acid with an aryl halide or heteroaryl halide, producing an unnatural amino acid protected with a cyclic protecting group having an aralkyl or heteroarylalkyl group in the side chain. A ring-opening reaction can then be performed to produce the desired unnatural amino acid with a free C-terminus.

[0242] Unnatural amino acids having an aryl or heteroaryl group (these groups are referred to as "Ar" in the scheme) introduced into the side chain of the amino acid can be produced by the following scheme. After introducing a protecting group into a commercially available protected amino acid (n = 0 or 1), an aryl or heteroaryl group is introduced by the action of an aryl halide or heteroaryl halide according to the method of He et al. (Org. Lett. 2014, 16(24), 6488-6491). This allows the production of unnatural amino acids having an aralkyl or heteroaralkyl group in the side chain. Subsequent deprotection and protecting group introduction reactions allow the production of the desired unnatural amino acid with a free C-terminus.

[0243]

[0244] An unnatural amino acid having a halogen atom introduced into the aralkyl group in the side chain of the amino acid can be produced by the following scheme: ａA boronate ester can be introduced into the aralkyl group, which may have a C-terminus, according to the method of Ishiyama et al. (J. Am. Chem. Soc. 2002, 124(3), 390-391). A halogen atom can be introduced into the introduced boryl group using an N-halogenated succinimide according to the method of Lindner et al. (Chem. Eur.J., 2016, 22, 13218-13235). The desired C-terminus-free unnatural amino acid can be produced by removing the protecting group from the resulting unnatural amino acid as needed.

[0245] A halogen atom is introduced into the aralkyl group of the amino acid side chain, and furthermore, -CH ２ An unnatural amino acid having a -P' group introduced therein can be produced by the following scheme: ａ A boronate ester can be introduced into the aryl group of an amino acid bearing an aralkyl group optionally containing a C-terminus, according to the method of Ishiyama et al. (J. Am. Chem. Soc. 2002, 124(3), 390-391). A halogen atom can be introduced into the introduced boryl group using an N-halogenated succinimide according to the method of Lindner et al. (Chem. Eur.J., 2016, 22, 13218-13235). The unnatural amino acid thus obtained can be deprotected as needed to produce the desired C-terminus-free unnatural amino acid.

[0246] An alkoxy group or an aralkoxy group (R ｂ A method for producing an unnatural amino acid having n=1 or 2 can be carried out according to the following scheme. After introducing a nosyl (Ns) group into a commercially available serine derivative (n=1 or 2) by a standard method, a cyclized product can be obtained according to the method of Mitsunobu et al. (Synthesis, 1981, 1,1-28). The cyclized product can be condensed with BF ３ ・OEt ２In the presence of a Lewis acid such as ｂ The resulting unnatural amino acid can be subjected to ring-opening with hydroxyl group (OH) to obtain a serine ether. The desired unnatural amino acid with a free C-terminus can be produced by removing the protecting group from the unnatural amino acid obtained as needed.

[0247] An alkoxy group or an aralkoxy group (R ｂ A method for producing an unnatural amino acid having n=1 or 2 can be carried out according to the following scheme: A commercially available cyclic compound (n=1 or 2) is treated with BF according to a standard method. ３ ・OEt ２ In the presence of a Lewis acid such as ｂ The resulting unnatural amino acid can be subjected to ring-opening with hydroxyl group (OH) to obtain a serine ether. The desired unnatural amino acid with a free C-terminus can be produced by removing the protecting group from the unnatural amino acid obtained as needed.

[0248] An alkoxy group or an aralkoxy group (R ｂ Unnatural amino acids having n=1 or 2 can be prepared by the following scheme: A commercially available serine derivative (n=1 or 2) is reacted with an alkylating agent (R ｂ -X) to obtain a serine ether. ｂ If R has a functional group that can be further converted, additional functional group conversion can be performed to obtain R ｂ can be converted to the desired functional group. Additional functional group conversions include, for example, reduction of multiple bonds. The unnatural amino acid obtained here can then be deprotected to produce the desired C-terminal-free unnatural amino acid.

[0249] An alkoxy group or an aralkoxy group (Rｂ and unnatural amino acids having a —CH group at the nitrogen atom of the amino acid. ２ An unnatural amino acid having a -P' group introduced therein can be produced according to the following scheme. A commercially available serine derivative or a serine derivative (n = 1 or 2) produced by the method described above is reacted with an aldehyde according to the method of Freidinger et al. (J. Org. Chem., 1983, 48(1), 77-81) to obtain an oxazolidinone derivative having a cyclic protecting group introduced therein. A ring-opening reaction is then carried out to produce the desired unnatural amino acid having a free C-terminus.

[0250] An unnatural amino acid having a protected hydroxy group on the side chain of the amino acid can be produced according to the following scheme: A commercially available serine derivative or a serine derivative (n = 1 or 2) produced by the method described above can be subjected to an appropriate deprotection reaction of the protecting group to produce the desired unnatural amino acid with a free C-terminus.

[0251] The amino acid side chain has a protective hydroxy group, and the nitrogen atom of the amino acid has -CH ２ An unnatural amino acid having a -P' group introduced therein can be produced by the following scheme. A commercially available serine derivative or a serine derivative (n = 1 or 2) produced by the method described above is reacted with an aldehyde according to the method of Freidinger et al. (J. Org. Chem., 1983, 48(1), 77-81) to obtain an oxazolidinone derivative having a cyclic protecting group introduced therein. Subsequently, a ring-opening reaction and a protecting group introduction reaction are carried out to produce the desired unnatural amino acid having a free C-terminus.

[0252] The hydroxyl group of the cyclic amino acid is provided with a substituent (R ｃ A cyclic unnatural amino acid having the desired —OR group introduced therein can be produced by the following scheme. A commercially available cyclic amino acid can be subjected to an appropriate functional group introduction reaction to produce the desired —OR group. ｃAs a conversion reaction of a functional group, according to the method of Williamson (Liebigs Ann. Chem. 1851, 77, 37-49), an alkylating agent (R ｃ By reacting R with R-X, an ether bond can be formed. ｃ If R has a functional group that can be further converted, additional functional group conversion can be performed to obtain R ｃ can be converted to the desired functional group. Then, a deprotection reaction can be carried out to produce the desired C-terminal free unnatural amino acid.

[0253] A protecting group (PG) is attached to the hydroxyl group of the cyclic amino acid. ３ A cyclic unnatural amino acid having a C-terminus free can be produced by the following scheme: A commercially available cyclic amino acid can be subjected to an appropriate deprotection reaction to remove a protecting group, thereby producing the desired C-terminus free unnatural amino acid.

[0254] An unnatural amino acid having a boronic acid introduced into its side chain can be produced by the following scheme. A commercially available glycine derivative can be reacted with an aldehyde according to the method of Lee et al. (Bioorg. Med. Chem. Lett., 2009, 19(17), 4887-5274) to obtain an unnatural amino acid having a boronic acid ester introduced therein. Subsequently, a suitable protecting group removal reaction can be carried out to produce the desired unnatural amino acid having a free C-terminus.

[0255] (Synthesis of Fmoc Unnatural Amino Acids Having a Carboxyl Group in the Side Chain 1) Fmoc unnatural amino acids having a carboxyl group in the side chain can be produced by the following scheme. ３ The main chain carboxyl group of the starting material (n=1 or 2) protected by can be converted to an amide group by condensing with an amine (R"R'"NH) in the presence of a condensing agent such as DIC. ３By carrying out the deprotection reaction of the above, it is possible to produce the desired Fmoc unnatural amino acid having a carboxyl group in the side chain.

[0256] (Synthesis of Fmoc unnatural amino acids with a carboxyl group in the side chain 2) An amino acid having a carboxyl group in the side chain and a -CH ２ An Fmoc unnatural amino acid having a -P' group introduced therein can be produced by the following scheme: ３ The main chain carboxyl group of the starting material (n=1 or 2) protected by PG can be converted to an amide group by condensation with an amine (R"R'"NH) in the presence of a condensing agent such as DIC. ３ By carrying out the deprotection reaction of the above, it is possible to produce the desired Fmoc unnatural amino acid having a carboxyl group in the side chain.

[0257] (Synthesis of Fmoc unnatural amino acids having vinyl halide in the side chain) Fmoc unnatural amino acids having vinyl halide in the side chain can be synthesized according to the method of Shendage et al. (Eur. J. Org. Chem., 2005, 719-727) using the following scheme: Boc-2-t-butyl-3-methylimidazolidin-4-one, available from a commercial supplier, is reacted with an alkylating agent having vinyl halide in the side chain in the presence of a base, and the desired Fmoc unnatural amino acid having vinyl halide in the side chain can be produced by the method described in the literature.

[0258] Unnatural amino acids (n = 1 or 2) containing a thioether group in the side chain can be produced by the following scheme: An amino acid with a protected side chain thiol group is subjected to amidation of the carboxylic acid, and after deprotection of the thiol group, the amino acid is reacted with a halogenated acetic acid with a protected carboxylic acid to form a thioether bond. The carboxylic acid in the side chain is then deprotected, thereby producing an amino acid having a thioether group in the side chain.

[0259] Peptides containing a thioether group in the peptide backbone can be produced by using as a starting material the above-mentioned amino acids having a thioether group in the side chain. Alternatively, they can also be produced by the method of Roberts et al. (Tetrahedron Letters, 1998, 39, 8357-8360), in which N-terminal bromoacetamide reacts with the side chain of cysteine, or by the method of Robey et al. (Journal of Peptide Research, 2000, 56, 115-120), in which N-terminal chloroacetamide reacts with the side chain of cysteine.

[0260] Furthermore, the compounds of the present invention, salts thereof, or solvates thereof include all stereoisomers of the target compounds obtained through the above-mentioned reaction steps (e.g., enantiomers, diastereomers (including cis and trans geometric isomers)), racemates of the isomers, and other mixtures thereof. For example, the compounds of the present invention may have one or more asymmetric centers, and the present invention includes racemic mixtures, diastereomeric mixtures, and enantiomers of such compounds.

[0261] When the compound according to the present invention is obtained as a free form, the compound can be converted into a salt which the compound may form, or a hydrate or solvate thereof, in a conventional manner.

[0262] Furthermore, when the compound according to the present invention is obtained as a salt, hydrate, or solvate of the compound, the compound can be converted into its free form by a conventional method.

[0263] <Pharmaceutical Compositions> The present invention provides pharmaceutical compositions containing the cyclic compound of the present invention. The pharmaceutical compositions of the present invention can be formulated by known methods by incorporating a pharmaceutically acceptable carrier in addition to the compound of the present invention, its salt, or a solvate thereof. For formulation, commonly used excipients, binders, lubricants, colorants, flavorings, and, if necessary, stabilizers, emulsifiers, absorption enhancers, surfactants, pH adjusters, preservatives, antioxidants, etc. can be used. The compositions are formulated by conventional methods by blending ingredients commonly used as raw materials for pharmaceutical formulations. For example, to produce an oral formulation, the compound of the present invention or a salt thereof and excipients, and, if necessary, binders, disintegrants, lubricants, colorants, flavorings, etc., are added, and then the composition is processed into powders, fine granules, granules, tablets, coated tablets, capsules, etc., by conventional methods.

[0264] Examples of these components 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 cetostearyl alcohol and behenyl alcohol; silicone resins; silicone oils; surfactants such as polyoxyethylene fatty acid esters, sorbitan fatty acid esters, glycerin 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, polyvinylpyrrolidone, and methylcellulose; lower alcohols such as ethanol and isopropanol; polyhydric alcohols such as glycerin, propylene glycol, dipropylene glycol, and sorbitol; sugars such as glucose and sucrose; inorganic powders such as silicic anhydride, aluminum magnesium silicate, and aluminum silicate; and purified water.

[0265] Examples of excipients include lactose, corn starch, sucrose, glucose, mannitol, sorbitol, crystalline cellulose, and silicon dioxide.

[0266] Examples of binders include polyvinyl alcohol, polyvinyl ether, methyl cellulose, ethyl cellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, polypropylene glycol-polyoxyethylene block polymer, and meglumine.

[0267] Examples of disintegrants include starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, sodium bicarbonate, calcium citrate, dextrin, pectin, and carboxymethylcellulose calcium.

[0268] Examples of lubricants include magnesium stearate, talc, polyethylene glycol, silica, and hydrogenated vegetable oil.

[0269] Coloring agents that are permitted to be added to pharmaceuticals are used, and flavoring agents include cocoa powder, peppermint, aromatic powder, peppermint oil, borneol, cinnamon powder, etc.

[0270] Of course, these tablets and granules may be coated with sugar or other suitable coatings as necessary. When producing liquid preparations such as syrups and injection preparations, the compound of the present invention or a pharmacologically acceptable salt thereof is formulated in a conventional manner by adding a pH adjuster, a solubilizer, an isotonicity agent, and, if necessary, a solubilizer, a stabilizer, etc.

[0271] For example, they can be administered parenterally in the form of a sterile solution or suspension in water or other pharmaceutically acceptable liquid for injection. For example, they can be formulated by appropriately combining them with pharmacologically acceptable carriers or vehicles, specifically, sterile water, physiological saline, vegetable oils, emulsifiers, suspending agents, surfactants, stabilizers, flavoring agents, excipients, vehicles, preservatives, binders, etc., and blending them in a unit dosage form required for generally accepted pharmaceutical practice. Specific examples of carriers include light anhydrous silicic acid, lactose, crystalline cellulose, mannitol, starch, carmellose calcium, carmellose sodium, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl acetal diethylaminoacetate, polyvinylpyrrolidone, gelatin, medium-chain fatty acid triglycerides, polyoxyethylene hydrogenated castor oil 60, sucrose, carboxymethylcellulose, cornstarch, inorganic salts, etc. The amount of active ingredient in these formulations is such that an appropriate dose within the indicated range can be obtained. Sterile compositions for injection can be formulated according to conventional pharmaceutical practice using a vehicle such as distilled water for injection.

[0272] Examples of aqueous solutions for injection include physiological saline, isotonic solutions containing glucose or other auxiliary drugs, such as D-sorbitol, D-mannose, D-mannitol, and sodium chloride, and these may be used in combination with an appropriate solubilizing agent, such as alcohol, specifically ethanol, polyalcohols such as propylene glycol and polyethylene glycol, or nonionic surfactants such as Polysorbate 80 (registered trademark) and HCO-50.

[0273] Examples of oily liquids include sesame oil and soybean oil, and they may be used in combination with solubilizing agents such as benzyl benzoate and benzyl alcohol. They may also contain buffers such as phosphate buffer and sodium acetate buffer, soothing agents such as procaine hydrochloride, stabilizers such as benzyl alcohol, phenol, and antioxidants. The prepared injection solution is usually filled into suitable ampoules.

[0274] The administration is preferably oral administration, but the administration method is not limited to oral administration. Specific examples of parenteral administration include injections, intranasal administrations, pulmonary administrations, transdermal administrations, etc. Examples of injections include intravenous injections, intramuscular injections, intraperitoneal injections, subcutaneous injections, etc., which can be used for systemic or local administration.

[0275] Furthermore, the administration method can be selected appropriately depending on the patient's age and symptoms. The dosage of a pharmaceutical composition containing a peptide compound produced by the method of the present invention can be selected, for example, from the range of 0.0001 mg to 1000 mg per kg of body weight per administration. Alternatively, the dosage can be selected, for example, from the range of 0.001 to 100,000 mg / body weight per patient, but is not necessarily limited to these values. The dosage and administration method vary depending on the patient's weight, age, symptoms, etc., but can be appropriately selected by those skilled in the art.

[0276] In certain embodiments, the cyclic compounds of the present invention, or salts thereof, or solvates thereof, or pharmaceutical compositions comprising the cyclic compounds of the present invention, or salts thereof, or solvates thereof, can bind to or selectively bind to KRAS in a subject and can be used to selectively inhibit KRAS.

[0277] In certain embodiments, the cyclic compounds of the present invention, or salts thereof, or solvates thereof, can bind to or selectively bind to KRAS in a subject and can be used in the manufacture of a medicament for selectively inhibiting KRAS.

[0278] In one aspect, the present invention relates to a method for binding or selectively binding a cyclic compound of the present invention to KRAS in a subject, or for selectively inhibiting KRAS in a subject, comprising administering to a subject in need thereof an effective amount of a cyclic compound of the present invention, or a salt thereof, or a solvate thereof.

[0279] Such a cyclic compound of the present invention, or a salt thereof, or a solvate thereof has high selectivity for KRAS in a subject. For example, a cyclic compound of the present invention may be 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-undecazatricyclo[3.0.0.0.0] 12,15 ]nonatriacontane-33,1'-cyclobutane]-27-carboxamide has higher KRAS selectivity (KRAS selectivity over NRAS and / or KRAS selectivity over HRAS).

[0280] In one embodiment, the pharmaceutical composition of the present invention has KRAS inhibitory activity that is three-fold or more greater than NRAS inhibitory activity and HRAS inhibitory activity.

[0281] In certain embodiments, the pharmaceutical composition of the present invention has KRAS inhibitory activity that is 5-fold, 7-fold, 10-fold, 15-fold, or 20-fold or more greater than NRAS inhibitory activity and HRAS inhibitory activity.

[0282] In certain embodiments, the cyclic compounds of the present invention, or salts thereof, or solvates thereof, or pharmaceutical compositions comprising the cyclic compounds of the present invention, or salts thereof, or solvates thereof, can be used to treat and / or prevent cancer in a subject.

[0283] In certain embodiments, the cyclic compounds of the present invention, or salts or solvates thereof, can be used in the manufacture of a medicament for treating and / or preventing cancer in a subject.

[0284] In certain aspects, the present invention relates to a method for treating and / or preventing cancer in a subject, comprising administering to a subject in need thereof an effective amount of a cyclic compound of the present invention, or a salt thereof, or a solvate thereof.

[0285] A specific example of cancer is lung cancer.

[0286] As used herein, the term "subject" includes mammals, preferably humans.

[0287] All prior art documents cited in this specification are hereby incorporated by reference.

[0288] The present invention will be further illustrated by the following examples and reference examples, but is not limited thereto. Unless otherwise specified, starting materials and reagents were obtained from commercial suppliers or synthesized using known methods. LC / MS analysis conditions are listed in Table 1.

[0289]

[0290] Example 1 Solid-Phase Synthesis of Peptide Compounds Peptide elongation was carried out using the following basic route (sometimes referred to as the basic peptide synthesis method) in accordance with the peptide synthesis method using the Fmoc method described in WO 2013 / 100132 or WO 2018 / 225864. Specifically, the five-step process involves: 1) a peptide elongation reaction using the Fmoc method from the N-terminus of an amino acid on a 2-chlorotrityl resin-supported carboxylic acid on the Asp side chain or a carboxylic acid on the peptide backbone; 2) a process for cleaving the peptide from the 2-chlorotrityl resin; 3) an amide cyclization by condensation of the carboxylic acid on the Asp side chain or the carboxylic acid on the peptide backbone, which is released from the 2-chlorotrityl resin during the cleavage process, with the amino group on the N-terminus (triangle unit) of the peptide chain; 4) deprotection of protecting groups on side chain functional groups contained in the peptide chain, as needed; and 5) purification of the compound by preparative HPLC. In this example, unless otherwise noted, peptide compounds were synthesized based on this basic route.

[0291] 1-1. Fmoc-amino acids used in peptide synthesis by a peptide synthesizer In the peptide synthesis described herein, the Fmoc-amino acids listed in Tables 2 to 4 were used for synthesis by a peptide synthesizer. The Fmoc-amino acids listed in Table 2 were synthesized according to the method described in WO2018 / 225851 or WO2018 / 225864. The Fmoc-amino acids listed in Table 3 were purchased from a commercial supplier. The Fmoc-amino acids listed in Table 4 were synthesized according to the scheme shown below.

[0292]

[0293]

[0294]

[0295] Synthesis of Fmoc-amino acid Synthesis of compound aa004

[0296] Compound aa004-a (3.00 g, 7.86 mmol) was dissolved in toluene (79 mL), and paraformaldehyde (708 mg, 23.6 mmol) and CSA (91 mg, 0.393 mmol) were added, followed by stirring at 90°C for 5 hours. After cooling to room temperature, paraformaldehyde (236 mg, 7.86 mmol) and CSA (46 mg, 0.197 mmol) were added, followed by stirring at 90°C for an additional 30 minutes. After cooling to room temperature, the mixture was filtered through Celite, and the residue was washed with ethyl acetate (50 mL). The filtrate was washed twice with saturated aqueous sodium bicarbonate solution (50 mL) and then with 50% brine (50 mL). This was dried over sodium sulfate and filtered, and the solvent was removed by distillation under reduced pressure to obtain compound aa004-b as a crude product. LCMS (ESI) m / z = 394 (M+H) + Retention time: 1.08 minutes (Analysis conditions SQDFA05)

[0297] The crude product of compound aa004-b (7.86 mmol) was dissolved in DCM (39 mL) and treated with boron trifluoride diethyl ether complex (BF ３ ・OEt ２ ) (2.96 mL, 23.6 mmol), TES (1.95 mL, 23.6 mmol), and water (0.142 mL, 7.86 mmol) were added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was washed with saturated ammonium chloride solution (40 mL), washed with 50% brine (40 mL), dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The resulting residue was dissolved in acetonitrile (40 mL) and washed twice with n-hexane (40 mL). The solvent was evaporated under reduced pressure to give compound aa004 (3.04 g, 98%). LCMS (ESI) m / z = 396 (M+H) + Retention time: 1.00 min (Analysis condition SQDFA05)

[0298] Synthesis of compound aa028

[0299] Using aa028-a as a starting material, aa028-b was obtained as a crude product (9.61 g, 94%) in the same manner as in the synthesis of compound aa004-b.

[0300] Using aa028-b as the starting material, aa028 (8.10 g, 84%) was obtained in the same manner as in the synthesis of compound aa004. LCMS (ESI) m / z = 470 (M + H) + Retention time: 0.99 min (Analysis condition SQDFA05).

[0301] Synthesis of compound aa018

[0302] Compound aa018-b (2.71 g, 87%) was obtained using compound aa018-a ((2S)-2-[9H-fluoren-9-ylmethoxycarbonylamino]pent-4-ynoic acid, Fmoc-PRA-OH) (3 g, 8.95 mmol) as the starting material in the same manner as in the synthesis of compound aa004-b. LCMS (ESI) m / z = 348 (M + H) + retention time: 0.87 minutes (analysis condition SQDFA05).

[0303] 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. LCMS (ESI) m / z = 350 (M + H) + Retention time: 0.79 minutes (Analysis condition SQDFA05).

[0304] Synthesis of compound aa049

[0305] Compound aa049-b (4.2 g, 82%) was obtained using compound aa049-a ((2S)-3-(2-chlorophenyl)-2-[9H-fluoren-9-ylmethoxycarbonylamino]propanoic acid, Fmoc-Phe(2-Cl)-OH) (5 g, 11.85 mmol) as the starting material in a manner similar to that for compound aa004-b. LCMS (ESI) m / z = 434 (M+H) + retention time: 1.01 min (analysis condition SQDFA05).

[0306] 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. LCMS (ESI) m / z = 436 (M + H) + Retention time: 0.94 minutes (Analysis condition SQDFA05).

[0307] Synthesis of compound aa199

[0308] Compound aa199-b was obtained as a crude product (206.8 g) using compound aa199-a ((2S)-2-[9H-fluoren-9-ylmethoxycarbonylamino]-3-[4-(trifluoromethyl)phenyl]propanoic acid, Fmoc-Phe(4-CF3)-OH) (200 g, 439 mmol) as starting materials in the same manner as in the synthesis of compound aa004-b. LCMS (ESI) m / z = 469 (M + H) + Retention time: 3.30 minutes (Analysis condition SMDmethod_03).

[0309] Using the obtained compound aa199-b (205 g), compound aa199 was obtained (195 g, 95% yield over two steps) in the same manner as in the synthesis of compound aa004. LCMS (ESI) m / z = 470 (M + H) + Retention time: 2.96 minutes (Analysis condition: SMDMethod_03).

[0310] Synthesis of compound aa013

[0311] Using aa013-a as the starting material, aa013-b was obtained as a crude product (5.29 g, 102%) in the same manner as in the synthesis of compound aa004-b. LCMS (ESI) m / z = 370 (M + H) + Retention time: 0.89 min (Analysis condition SQDFA05).

[0312] Compound aa013-b (5.29 g, 14.3 mmol) was dissolved in DCM (125 mL), and TES (22.9 mL, 143 mmol) and TFA (36.4 mL, 473 mmol) were added, followed by stirring at 38°C for 8 hours. The solvent was evaporated under reduced pressure, the mixture was dissolved in TBME (100 mL), and washed with 1 M aqueous dipotassium hydrogen phosphate (50 mL). The aqueous layer was extracted three times with TBME, and the organic layers were combined and the solvent was evaporated under reduced pressure. Acetonitrile / n-hexane = 1 / 2 (100 mL) was added, followed by extraction with 5% aqueous potassium bicarbonate (100 mL). The aqueous 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, and the solvent was evaporated under reduced pressure. Acetonitrile (100 mL) was added, and the mixture was washed with n-hexane (50 mL). The solvent was removed under reduced pressure to give compound aa013 (4.06 g, 76%). LCMS (ESI) m / z = 372 (M + H) + retention time: 0.83 minutes (analysis condition SQDFA05).

[0313] Synthesis of compound aa030

[0314] 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, washed with saturated aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate, and then filtered. The resulting solution was concentrated under reduced pressure to give compound aa030-b (859 mg) as a crude product. This was used in the next reaction without further purification.

[0315] Under a nitrogen atmosphere, TES (2.75 mL, 17.22 mmol) and TFA (3.98 mL, 51.7 mmol) were added to a solution of compound aa030-b (853 mg) in DCE (10 mL) at room temperature, and the mixture was stirred at 60°C for 5 hours. The reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure to obtain a crude product. t-Butyl methyl ether / n-hexane (1 / 1) was added to the crude product, and the mixture was extracted five times with saturated aqueous sodium bicarbonate. The pH of the resulting aqueous layer was adjusted to acidic using concentrated hydrochloric acid, and then the mixture was extracted three times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The solvent was evaporated under reduced pressure to obtain compound aa030 (811 mg, 99% yield over two steps). The resulting compound aa060 was used in peptide synthesis without further purification. LCMS (ESI) m / z = 427 (M+H) + retention time: 0.83 min (analysis condition SQDFA05).

[0316] Synthesis of compound aa029

[0317] Compound aa029-a ((2S)-3-(4-cyanophenyl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid, Fmoc-Phe(4-CN)-OH) (1 g, 2.425 mmol) was used as a starting material in the same manner as in the synthesis of compound aa030 to obtain compound aa029 as a crude product (1.14 g, 108% over two steps). The obtained compound aa029 was used in peptide synthesis without further purification. LCMS (ESI) m / z = 427 (M+H) + Retention time: 0.82 min (Analysis condition SQDFA05).

[0318] Synthesis of compound aa031

[0319] Compound aa031-b was obtained as a crude product using compound aa031-a ((2S)-3-(2-cyanophenyl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid, Fmoc-Phe(2-CN)-OH) (1 g, 2.425 mmol) as starting materials in the same manner as in the synthesis of compound aa030-b. The crude product obtained using the obtained compound aa031-b in the same manner as in 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 obtain compound aa031 (529 mg, 51% over two steps). LCMS (ESI) m / z = 427 (M + H) + retention time: 0.85 minutes (analysis condition SQDFA05).

[0320] Synthesis of compound aa050

[0321] Compound aa050-b was obtained as a crude product using compound aa050-a ((2S)-3-(3,4-difluorophenyl)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]propanoic acid, Fmoc-Phe(34-F2)-OH) (105 mg, 0.247 mmol) as starting materials in the same manner as in the synthesis of compound aa004-b. Compound aa050-b was further obtained in the same manner as in the synthesis of compound aa030 in the same manner as in the synthesis of compound aa030, using aa050-b (74.4 mg, 69% over two steps). LCMS (ESI) m / z = 438 (M+H) + Retention time: 0.88 minutes (Analysis condition SQDFA05).

[0322] Synthesis of compound aa019

[0323] 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. ３ ・OEt ２ ) (2.10 mL, 16.6 mmol) was added dropwise and stirred at room temperature for 1 hour. The solid was filtered off, and TES (5.51 mL, 34.6 mmol) and water (0.249 mL, 13.8 mmol) were added.３ ・OEt ２ (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. ３ ・OEt ２ (0.877 mL, 6.92 mmmol) was added and stirred at room temperature. The reaction solution was washed with saturated aqueous sodium chloride solution (25 mL) and then 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 three times with n-hexane (50 mL) to obtain compound aa019 (4.93 g, 95%). LCMS (ESI) m / z = 376 (M + H) + Retention time: 0.80 min (Analysis condition SQDFA05)

[0324] Synthesis of compound aa331

[0325] Using aa331-a as a starting material, aa331 (9.09 g, 86%) was obtained in the same manner as in the synthesis of compound aa019. LCMS (ESI) m / z = 382 (M + H) + Retention time: 0.94 min (Analysis condition SQDFA05).

[0326] Synthesis of compound aa020

[0327] Methyl (S)-N-tritylaziridine-2-carboxylate (aa020-a, CAS number 75154-68-6) (50 g, 146 mmol) was added to a mixed solution of chloroform (145 mL) and methanol (145 mL), and TFA (33 mL, 3 equivalents) was added dropwise at 0°C under a nitrogen atmosphere, followed by stirring for 7 hours. To this reaction solution was added DIPEA (127 mL, 5 equivalents) at 0°C, followed by dropwise addition of a solution of Fmoc-Cl (36 g, 139 mmol) in 1,4-dioxane (145 mL), 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 successively with water, aqueous ammonium chloride, aqueous sodium bicarbonate, and saturated brine. The resulting organic layer was dried over anhydrous sodium sulfate, and the solvent was then distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether, 0 / 100 to 10 / 90) to give compound aa020-b, (1-O-(9H-fluoren-9-ylmethyl) 2-O-methyl (2S)-aziridine-1,2-dicarboxylate) (40 g, 85%). LCMS (ESI) m / z = 324 (M+H) + retention time: 2.631 minutes (analysis condition SMDmethod_10).

[0328] Under a nitrogen atmosphere, compound aa020-b (1-O-(9H-fluoren-9-ylmethyl) 2-O-methyl (2S)-aziridine-1,2-dicarboxylate) (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 diethyl ether complex (BF) was added under ice cooling. ３ ・OEt ２ ) (0.291 mL, 2.319 mmol) was added. After reacting for 2 hours under ice-cooling, water and saturated aqueous sodium bicarbonate solution were added to the reaction solution to terminate the reaction. The aqueous layer was removed using a phase separator, and the organic layer was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 4 / 1) to obtain compound aa020-c (4.6 g, 78%). LCMS (ESI) m / z = 382 (M+H) + Retention time: 0.89 minutes (Analysis condition SQDFA05)

[0329] Calcium chloride (20.08 g, 181 mmol) was dissolved in water (50.2 mL), and lithium hydroxide monohydrate (2.024 g, 48.2 mmol) was added thereto and stirred at room temperature for 5 minutes to prepare aqueous solution A. Compound aa020-c (4.6 g, 12.06 mmol) was dissolved in isopropanol (201 mL) and THF (50.2 mL), and the previously prepared aqueous solution A was added and stirred at room temperature for 5 hours. After that, 1N hydrochloric acid (72 mL) was added to the reaction solution, and the isopropanol and THF were removed by concentration under reduced pressure. The resulting aqueous layer was diluted with water (50.2 mL) and extracted three times with ethyl acetate (total volume 100 mL). The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was 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%). LCMS (ESI) m / z = 368 (M+H) + retention time: 0.78 min (analysis condition SQDFA05).

[0330] A 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) in DCM (87 mL) was added with paraformaldehyde (1.815 g, 60.5 mmol), magnesium sulfate (2.36 g, 19.63 mmol), and boron trifluoride diethyl ether complex (BF) under a nitrogen atmosphere. ３ ・OEt ２ ) (1.184 mL, 9.42 mmol) was added and stirred at room temperature for 2 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the organic layer and aqueous layer were separated. The aqueous layer was extracted twice with DCM, and the combined organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was then evaporated under reduced pressure to give compound aa020-e as a crude product (3.1 g, quant.). LCMS (ESI) m / z = 380 (M + H) + Retention time: 0.93 minutes (Analysis condition SQDFA05)

[0331] A solution of the obtained compound aa020-e (2.98 g, 7.85 mmol) in DCM (26.2 mL) was added with triethylsilane (3.13 mL, 19.64 mmol), water (0.141 mL, 7.85 mmol), boron trifluoride diethyl ether complex (BF) under ice-cooling and nitrogen atmosphere. ３ ・OEt ２ ) (2.49 mL, 19.6 mmol) was added and stirred for 2 hours. A saturated aqueous solution of ammonium chloride was added to the reaction solution, and the organic layer was separated. The organic layer was washed with a saturated aqueous solution of ammonium chloride, then with saturated saline, and concentrated under reduced pressure to obtain a crude product. The obtained crude product was dissolved in acetonitrile and washed with n-hexane, and the acetonitrile layer was concentrated under reduced pressure to obtain compound aa020 (2.71 g, 90%). LCMS (ESI) m / z = 382 (M + H) + Retention time: 0.83 minutes (Analysis condition SQDFA05)

[0332] Synthesis of compound aa006

[0333] Compound aa006-b (10.5 g) was obtained as a crude product using compound aa006-a ((2S)-3-cyclopentyl-2-[9H-fluoren-9-ylmethoxycarbonylamino]propanoic acid, Fmoc-Ala(cPent)-OH) (10 g, 26.4 mmol) as the starting material in the same manner as in the synthesis of compound aa020-e. LCMS (ESI) m / z = 392 (M + H) + Retention time: 1.05 minutes (Analysis condition SQDFA05).

[0334] The resulting compound aa006-b (10.5 g) 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 obtain compound aa006 (10.11 g, 96% yield over two steps). LCMS (ESI) m / z = 394 (M + H) + retention time: 0.98 minutes (analysis condition SQDFA05).

[0335] Synthesis of compound aa010

[0336] Compound aa010-b was obtained as a crude product (3.63 g) using compound aa010-a ((2S)-3-cyclobutyl-2-[9H-fluoren-9-ylmethoxycarbonylamino]propanoic acid, Fmoc-Ala(cBu)-OH) (3.36 g, 9.19 mmol) as the starting material in the same manner as in the synthesis of compound aa020-e. LCMS (ESI) m / z = 378 (M + H) + retention time: 1.01 min (analysis condition SQDFA05).

[0337] The resulting compound aa010-b (3.63 g) 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-water / 0.1% formic acid-acetonitrile) to obtain compound aa010 (3.18 g, 91% yield over two steps). LCMS (ESI) m / z = 380 (M + H) + retention time: 0.94 minutes (analysis condition SQDFA05).

[0338] Synthesis of compound aa047

[0339] Using compound aa047-a ((2S)-2-[9H-fluoren-9-ylmethoxycarbonylamino]-3-(2-methylphenyl)propanoic acid, Fmoc-Phe(2-Me)-OH) (2 g, 4.98 mmol) as starting materials, a reaction solution obtained in the same manner as in the synthesis of compound aa020-e was added with saturated aqueous sodium bicarbonate solution, and the mixture was charged onto a silica gel column (2 v / w) and eluted with DCM to obtain compound aa047-b as a crude product (1.45 g). Compound aa047-b obtained was used in the same manner as in the synthesis of compound aa020 to obtain compound aa047 (1.21 g, 58% over two steps). LCMS (ESI) m / z = 416 (M + H) + retention time: 0.94 min (analysis condition SQDFA05).

[0340] Compound aa060 synthesis

[0341] Compound aa075-b was obtained as a crude product using compound aa060-a, (2S)-2-cyclobutyl-2-[9H-fluoren-9-ylmethoxycarbonylamino]acetic acid, and Fmoc-Gly(cBu)-OH (2.5 g, 7.11 mmol) as starting materials in a manner similar to that used for the synthesis of compound aa020-e. LCMS (ESI) m / z = 364 (M + H) + retention time: 0.97 minutes (analysis condition SQDFA05).

[0342] The entire amount of compound aa060-b obtained 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 obtain compound aa060 (2.32 g, 89% yield over two steps). LCMS (ESI) m / z = 366 (M + H) + retention time: 0.88 minutes (analysis condition SQDFA05).

[0343] Synthesis of compound aa021

[0344] 2-Nitrobenzenesulfonyl chloride (NsCl) (32.37 g, 146 mmol) and L-serine methyl ester hydrochloride (aa021-a, 25 g, 161 mmol, CAS number 5680-80-8) were dissolved in DCM (874 mL), and DIPEA (51 mL, 292 mmol) was added at 5°C. After stirring at room temperature for 1 hour, the mixture was washed twice with water (440 mL) and once with saturated brine / water (1 / 1, 440 mL), and then dried over magnesium sulfate. After filtering off the magnesium sulfate, the mixture was concentrated under reduced pressure to obtain compound aa021-b as a crude product (39.4 g, 89%). LCMS (ESI) m / z = 302.9 (M-H) - retention time: 0.729 min (analysis condition SMDmethod_06).

[0345] 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 cooling to -14°C, DEAD (55.0 mL, 121 mmol) was added over 10 minutes, and the mixture was stirred at -5°C for 50 minutes. n-Hexane (300 mL) was added, and the precipitate was removed by filtration. The filtrate was purified by silica gel column chromatography (n-hexane / DCM = 50:50 to 0:100) to obtain compound aa021-c (13.3 g, 62%). LCMS (ESI) m / z = 287 (M + H) + retention time: 0.872 minutes (analysis condition SMD method_06).

[0346] Compound aa021-c (10.7 g, 37.3 mmol) was dissolved in TFE (75 mL) and treated with boron trifluoride diethyl ether complex (BF ３ ・OEt ２ ) (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 (0.1% formic acid in acetonitrile / 0.1% formic acid in distilled water) to obtain compound aa021-d (12.3 g, 85%). LCMS (ESI) m / z = 387 (M+H) + retention time: 0.72 minutes (analysis condition SQDFA05).

[0347] 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. After stirring at room temperature for 90 minutes, formic acid (11.7 mL, 311 mmol) was added, and the mixture was diluted with water (30 mL). The mixture was then purified by reverse-phase column chromatography (0.1% formic acid in acetonitrile / 0.1% formic acid in distilled water) to obtain compound aa021-e (7.90 g, 68%). LCMS (ESI) m / z = 373 (M + H) + retention time: 0.63 minutes (analysis condition SQDFA05).

[0348] 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. This mixture was diluted with water (100 mL) and washed twice with TBME (200 mL). To the resulting aqueous solution, a solution of Fmoc-OSu (3.5 g) in 1,4-dioxane (150 mL) was added and the mixture was stirred for 25 minutes. A solution of Fmoc-OSu (700 mg) in 1,4-dioxane (10 mL) was then added and the mixture was stirred for 5 minutes. A solution of Fmoc-OSu (350 mg) in 1,4-dioxane (5 mL) was then added and the mixture was stirred for 5 minutes. A solution of Fmoc-OSu (350 mg) in 1,4-dioxane (5 mL) was further added and stirred for 5 minutes. After that, formic acid (3.9 mL) was added and the solvent was evaporated under reduced pressure. The resulting crude product was purified by reverse-phase column chromatography (0.1% formic acid in acetonitrile / 0.1% formic acid in distilled water) 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%). LCMS (ESI) m / z = 410 (M+H) + retention time: 2.35 minutes (analysis condition SQDFA05long).

[0349] Using compound aa021-f (2.00 g, 4.89 mmol) as a starting material, compound aa021-g was obtained as a crude product by the same method as in the synthesis of compound aa020-e. Compound aa021-g was then obtained by the same method as in the synthesis of compound aa020 (1.80 g, 87% yield over two steps). LCMS (ESI) m / z = 424 (M + H) + retention time: 0.84 min (analysis condition SQDFA05).

[0350] Synthesis of compound aa022

[0351] Under a nitrogen atmosphere, compound aa020-b (1 g, 3.09 mmol) was dissolved in toluene (6.2 mL), ethanol (0.542 mL, 9.28 mmol) was added, and then the mixture was cooled with ice and cooled with BF ３ ・OEt ２(0.059 mL, 0.464 mmol) was added dropwise over 5 minutes. The mixture was allowed to warm to room temperature and stirred for 2.5 hours. ３ The reaction was stopped by adding an aqueous solution, and the aqueous layer was removed using a phase separator. The organic layer was dried over anhydrous sodium sulfate, and the solvent was then evaporated under reduced pressure. Ethyl acetate / hexane (3 / 1, 24 mL) was added to the resulting residue, and the solvent was evaporated under reduced pressure. Hexane / TBME (85 / 15, 24 mL) was added to the resulting solid, and the mixture was stirred for 30 minutes. The solvent was then removed by filtration to obtain compound aa022-b (787 mg, 69%). LCMS (ESI) m / z = 370 (M+H) + Retention time: 0.86 minutes (Analysis condition SQDFA05)

[0352] Calcium chloride (2.25 g, 20.3 mmol) was dissolved in H ２ To this was added lithium hydroxide monohydrate (227 mg, 5.41 mmol), and the mixture was stirred at room temperature for 5 minutes to prepare aqueous solution A.

[0353] Compound aa022-b was dissolved in isopropanol (22.6 mL) and THF (57 mL), and the previously prepared aqueous solution A was added thereto, followed by stirring at room temperature for 7 hours. After that, 1N hydrochloric acid (8.1 mL) was added to the reaction solution, and then the isopropanol and THF were removed by concentration under reduced pressure. The resulting aqueous layer was ２ The organic layer was diluted with HCl and extracted three times with ethyl acetate. ２ The residue was triturated with ethyl acetate / n-hexane (1 / 5, 20 v / w) to give compound aa022-c (3.5 g, 79%). LCMS (ESI) m / z = 356 (M+H) + retention time: 0.78 min (analysis condition SQDFA05).

[0354] Using aa022-c as the starting material, aa022-d was obtained as a crude product (871 mg, 84%) in the same manner as in the synthesis of compound aa004-b. LCMS (ESI) m / z = 368 (M + H) + Retention time: 0.84 min (Analysis condition SQDFA05).

[0355] Using aa022-d as the starting material, aa022 (254 mg, 90%) was obtained in the same manner as in the synthesis of compound aa004. LCMS (ESI) m / z = 370 (M + H) + Retention time: 0.80 min (Analysis condition SQDFA05).

[0356] Synthesis of compound aa210

[0357] Compound aa210-a (5.00 g, 13.7 mmol) was dissolved in toluene (17 mL), 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, and toluene (17 mL), TFA (19.0 mL, 246 mmol), and TES (19.6 mL, 123 mmol) were added, followed by stirring at 50°C overnight. The solvent was evaporated under reduced pressure, and ethyl acetate was added. The mixture was washed with saturated aqueous sodium bicarbonate and then washed with saturated brine. The organic layer was dried over sodium sulfate and filtered, and the solvent was evaporated under reduced pressure. The residue was purified by reverse-phase chromatography (0.1% formic acid in acetonitrile / 0.1% formic acid in distilled water) to give aa210 (2.17 g, 40%). LCMS (ESI) m / z = 394 (M+H) + Retention time: 0.94 min (Analysis conditions SQDFA05)

[0358] Synthesis of compound aa201

[0359] 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 number 199006-54-7) was suspended in DCE (17.5 mL), and paraldehyde (5.61 mL, 42.0 mmol) and TFA (9.65 mL, 126 mmol) were added, followed by stirring at 60°C for 6 hours. The resulting reaction solution containing compound aa201-b was used directly in the next step. LCMS (ESI) m / z = 428 (M+H) + Retention time: 1.03 minutes (Analysis condition SQDFA05).

[0360] To the reaction solution of the obtained compound aa201-b, DCE (17.5 mL), TFA (19.3 mL, 252 mmol), and TES (20.1 mL, 126 mmol) were added, and the mixture was stirred at 60°C for 17 hours. After cooling to room temperature and concentrating under reduced pressure, the obtained residue was dissolved in ethyl acetate (40 mL). The organic layer was washed with saturated aqueous sodium bicarbonate (40 mL) and saturated brine (40 mL), dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The obtained residue was dissolved in acetonitrile (30 mL), washed twice with hexane (15 mL), and the solvent was evaporated under reduced pressure. The resulting residue was purified by reverse-phase column chromatography (0.1% formic acid in acetonitrile / 0.1% formic acid in distilled water) 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, 73% yield over two steps). LCMS (ESI) m / z = 430 (M+H) + retention time: 0.95 minutes (analysis condition SQDFA05).

[0361] Synthesis of compound aa164

[0362] Under 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 number 247113-86-6) was suspended in DCE (11.1 mL), and 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, followed by stirring at 60°C for 3 hours. Further, anhydrous magnesium sulfate (2.14 g, 17.7 mmol) was added, followed by stirring at 60°C for 1 hour. The resulting reaction solution containing compound aa164-b was used directly in the next reaction. LCMS (ESI) m / z=482 (M+H)+ Retention time: 1.04 minutes (Analysis conditions SQDFA05)

[0363] To the reaction solution containing the obtained compound aa164-b, DCE (11.1 mL), TFA (12.2 mL, 159 mmol), and triethylsilane (12.7 mL, 80 mmol) were added, and the mixture was stirred at 60°C for 10 hours. The mixture was cooled to room temperature, and the magnesium sulfate was removed by filtration. The mixture was then concentrated under reduced pressure. Since the desired reaction had not yet reached completion, the resulting residue was dissolved in DCE (22.2 mL), and TFA (18.3 mL, 239 mmol) and triethylsilane (12.7 mL, 80 mmol) were added. The mixture was then stirred at 60°C for 8 hours. After cooling to room temperature and concentration under reduced pressure, the resulting residue was dissolved in ethyl acetate (40 mL). The organic layer was washed with saturated aqueous sodium bicarbonate (40 mL) and saturated brine (40 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was dissolved in acetonitrile (30 mL), washed twice with hexane (15 mL), and the solvent was evaporated under reduced pressure. The resulting residue was purified by reverse-phase column chromatography (0.1% formic acid, water-acetonitrile) to give compound aa164 (1.90 g, 44% over two steps). LCMS (ESI) m / z = 484 (M+H) + retention time: 0.97 minutes (analysis condition SQDFA05).

[0364] Synthesis of compound aa136

[0365] Compound aa136-a (10.1 g, 22.1 mmol) was dissolved in toluene (28 mL), and propionaldehyde (14.3 mL, 199 mmol), TFA (15.3 mL, 199 mmol), and magnesium sulfate (7.99 g, 66.4 mmol) were added, followed by stirring at 60°C for 3 hours. The solid was removed by filtration through a silica gel pad, and the filtrate was washed twice with water (100 mL). Acetonitrile (20 mL) was added, and the mixture was washed with 1 M aqueous potassium hydrogen phosphate solution (30 mL), three times with 3.5% aqueous potassium bicarbonate solution (40 mL), and then with saturated brine (100 mL). The mixture was dried over anhydrous magnesium sulfate, filtered, and the solvent was removed by distillation 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. Cool to 0°C and add TiCl ４(4.88 mL, 44.3 mmol) was added and the mixture was stirred at room temperature for 15 minutes. Water (50 mL) was added dropwise, and the organic layer was washed with water (100 mL) and then with 1 M aqueous dipotassium hydrogen phosphate (50 mL). n-Hexane (90 mL) was added, and the mixture was extracted three times with a mixed solvent of acetonitrile (15 mL) and 1% aqueous potassium bicarbonate (30 mL). This was further extracted twice with a mixed solvent of acetonitrile (20 mL) and 1% aqueous potassium bicarbonate (30 mL). n-Hexane (90 mL) was added to the organic layer, and the mixture was extracted twice with a mixed solvent of acetonitrile (20 mL) and 1% aqueous potassium bicarbonate (30 mL). The aqueous layers were combined, and n-hexane (80 mL) was added. After phosphoric acid was added to adjust the pH to 3, the mixture was extracted three times with TBME (150 mL). The organic layer was washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, filtered, and the solvent was removed under reduced pressure to give compound aa136 (5.03 g, 46%). LCMS (ESI) m / z = 498 (M + H) + Retention time: 1.02 min (Analysis condition SQDFA05).

[0366] Synthesis of compound aa174

[0367] Using aa174-a as a starting material, aa174 (18.6 g, 84%) was obtained in the same manner as in the synthesis of compound aa136. LCMS (ESI) m / z = 460 (M + NH ４ ) + Retention time: 1.41 minutes (Analysis conditions SMD method_04)

[0368] Synthesis of compound aa264

[0369] 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. To this was added a 1,4-dioxane solution (14.5 mL) of Fmoc-OSu (2.44 g, 7.24 mmol). The resulting solid was crushed with a spatula and further pulverized by ultrasonic irradiation. 1,4-dioxane (15 mL) was added to this to dissolve the solid, and the mixture was stirred at room temperature for 40 minutes. The mixture was washed twice with n-hexane / CPME (3 / 1, 10 mL), and potassium hydrogen sulfate (3.70 g, 27.2 mmol) was added. The mixture was extracted three times with isopropyl acetate (30 mL), and the organic layer was washed with 50% brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to give compound aa264-b (2.39 g, 93%). LCMS (ESI) m / z = 355 (M + H) + retention time: 0.64 min (analysis condition SQDFA05).

[0370] Compound 264-b (2.39 g, 6.76 mmol) and PPTS (0.170 g, 0.676 mmol) were suspended in DCM (23 mL), DHP (1.39 mL, 15.2 mmol) was added, 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. This mixture was washed with water and saturated brine. The mixture was dried over anhydrous sodium sulfate and filtered, and the solvent was evaporated under reduced pressure. This mixture was dissolved in THF (25 mL), and 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, and the aqueous layer was removed. The aqueous layer was extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered, and the solvent was evaporated under reduced pressure. This was dissolved in DCM (30 mL), and n-hexane (30 mL) was added. DCM alone was distilled off under reduced pressure, and n-hexane was further distilled off under reduced pressure. n-Hexane was added to the resulting solid, and the mixture was subjected to ultrasonic irradiation. The n-hexane was removed by decantation, and then the mixture was dried under reduced pressure to obtain compound aa264 as a sodium salt. This was dissolved in isopropyl acetate (50 mL), and 0.05 M aqueous phosphoric acid solution (pH = 2, 90 mL) was added, followed by stirring at room temperature for 10 minutes, and the aqueous layer was removed. The aqueous layer was extracted with isopropyl acetate, and the organic layer was dried over anhydrous sodium sulfate and filtered, and the solvent was distilled off under reduced pressure. The resulting crude product was purified by reverse phase chromatography (0.1% formic acid in acetonitrile / 0.1% formic acid in distilled water) to obtain compound aa264 (2.33 g, 79%). LCMS (ESI) m / z = 456 (M + NH ３ ) + Retention time: 0.81 min (Analysis conditions SQDFA05)

[0371] Synthesis of compound aa265

[0372] Using aa265-a as a starting material, aa265 (1.38 g, 78%) was obtained in the same manner as in the synthesis of compound aa264. LCMS (ESI) m / z = 439 (M + H) + Retention time: 0.85 min (Analysis condition SQDFA05).

[0373] Synthesis of compound aa267

[0374] Using aa267-a as a starting material, aa267 (9.04 g, quant.) was obtained in the same manner as in the synthesis of compound aa264. LCMS (ESI) m / z = 460 (M + Na) + Retention time: 0.81 min (Analysis condition SQDFA05).

[0375] Synthesis of compound aa279

[0376] Using aa279-a as the starting material, aa279 (5.15 g, 83%) was obtained in the same manner as in the synthesis of compound aa264. LCMS (ESI) m / z = 460 (M + Na) + Retention time: 0.85 min (Analysis condition SQDFA05).

[0377] Synthesis of compound aa244

[0378] A mixture 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. After cooling to room temperature, the reaction solution was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain compound aa244-b as a crude product (52 g, 96%). This crude product was used in the next reaction without purification.

[0379] A solution of compound aa244-b (4 g, 13.64 mmol) in thionyl chloride (50 mL) was stirred at 85°C for 1 hour, and then the solvent was evaporated under reduced pressure. The residue was dissolved in THF (20 mL) and cooled to -78°C under a nitrogen atmosphere. A solution of lithium tri-tert-butoxyaluminum hydride (2.76 g, 10.87 mmol) in THF (20 mL) was added dropwise over 2.5 hours. After stirring at -78°C for 3 hours, water was added to the reaction solution, and the precipitate was removed by filtration. The filtrate was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to give compound aa244-c (2 g). １ H-NMR (400MHz, CDCl３ ) δ7.41-7.32 (m, 5H), 5.49 (br.s, 1H), 5.27-5.11 (m, 3H), 4.38-4.33 (m, 1H), 2.58-2.19 (m, 4H)

[0380] Under a nitrogen atmosphere, (diethylamino)sulfur trifluoride (DAST) (780 mg, 4.84 mmol) was added to a solution of compound aa244-c (450 mg, 1.62 mmol) in DCM (20 mL) at 0°C, and the mixture was stirred at room temperature for 16 hours. Water was added to the reaction mixture, which was then diluted with DCM and washed sequentially with aqueous sodium bicarbonate and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to give compound aa244-d (0.35 g, 72%). This was mixed with another lot synthesized in the same way and subjected to the next reaction. １ H-NMR (400MHz, CDCl ３ ) δ7.42-7.35 (m, 5H), 5.97-5.58 (m, 2H), 5.25-5.16 (m, 3H), 4.50-4.35 (m, 1H), 2.14-1.68 (m, 4H) １９ F-NMR (400MHz, CDCl ３ ) δ-116.562

[0381] Compound aa244-d (1 g, 3.34 mmol) and TES (12.63 g, 109 mmol) were dissolved in TFA / DCM (10 / 10 mL) and stirred at room temperature for 4 days, after which the solvent was evaporated under reduced pressure. The residue was diluted with aqueous sodium bicarbonate, washed with ether, and adjusted to pH 3 with 2N hydrochloric acid. Extraction was performed with DCM, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain compound aa244-e (0.6 g) as a crude product. This crude product was used in the next reaction without purification.

[0382] A mixture of compound aa244-e (0.6 g) and palladium-carbon (10%, 60 mg) in methanol (10 mL) was stirred for 16 hours under a hydrogen atmosphere of approximately 3 atm. The palladium-carbon was removed by filtration, and the solvent in the filtrate was distilled off under reduced pressure to obtain compound aa244-f (0.23 g) as a crude product. This crude product was mixed with another lot synthesized in the same way without purification, and the next reaction was carried out.

[0383] Fmoc-OSu (0.9 g, 1.5 equivalents) was added to a 1,4-dioxane / water (5 / 5 mL) mixture of compound aa244-f (0.3 g, 1.79 mmol) and potassium carbonate (745 mg, 5.4 mmol), and the mixture was stirred for 2 hours. The reaction mixture was diluted with water, washed with diethyl ether, and then adjusted to pH 3 with 2N hydrochloric acid. The mixture was extracted three times with ethyl acetate, and the combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by reverse-phase column chromatography (acetonitrile containing 0.05% TFA / distilled water containing 0.05% TFA) to yield compound aa244 (0.2 g, 29%). A separate lot synthesized in the same manner was also used for the peptide synthesis in this example. Retention time: 3.153 minutes (analysis condition: SMD method_19). １ H-NMR (300MHz, DMSO-d ６ ) δ12.94 (br.s, 1H), 7.92-7.88 (d, J=7.2Hz, 2H), 7.66-7.61 (m, 2H), 7.44-7.3 1 (m, 4H), 6.35-5.75 (m, 1H), 4.49-4.26 (m, 4H), 2.72 (s, 3H), 1.78-1.65 (m, 4H) １９ F-NMR (300MHz, DMSO-d ６ ) δ-115.730

[0384] Synthesis of compound aa043

[0385] Under a nitrogen atmosphere, aa244-c (18 g, 64.98 mmol) was dissolved in dichloromethane (50 mL), and a solution of phosphorus pentachloride (27 g, 130 mmol) in carbon tetrachloride (550 mL) was slowly added dropwise at 0°C. The reaction solution was stirred at room temperature for 16 hours, and then dichloromethane was added and diluted. The resulting solution was washed with water, and the aqueous phase was extracted twice with dichloromethane. The organic phases were then combined and washed with aqueous sodium bicarbonate. The resulting solution was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting crude product was purified by normal phase column chromatography (hexane-ethyl acetate) to obtain aa043-a (7.2 g, 33%).

[0386] aa043-a (7.2 g, 21.75 mmol) was dissolved in dichloromethane (150 mL), and triethylsilane (83.2 g, 718 mmol) and trifluoroacetic acid (24.8 g, 218 mmol) were added, followed by stirring at room temperature for 4 days. The reaction solution was concentrated under reduced pressure, and the resulting residue was dissolved in aqueous sodium bicarbonate, after which the aqueous phase was washed with diethyl ether. The resulting solution was then adjusted to pH 3 with 2N hydrochloric acid. The mixed solution was extracted twice with dichloromethane, and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate, after which the solvent was distilled off under reduced pressure. The resulting crude product aa043-b (5.5 g) was used directly in the next step.

[0387] A solution of 33% hydrogen bromide in acetic acid (10 mL) diluted with acetic acid (10 mL) was added to the crude product aa043-b (1.1 g), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water. The resulting solution was washed with diethyl ether, and the solvent was evaporated under reduced pressure to give crude product aa043-c (1.0 g). The crude product aa043-b was used directly in the next reaction. LCMS (ESI) m / z = 200 (M + H) + Retention time: 0.88 minutes (analysis conditions SMD method_12)

[0388] The crude product aa043-c (1.00 g) and potassium carbonate (1.48 g, 10.7 mmol) were dissolved in water (10 mL), and a 1,4-dioxane solution (10 mL) of Fmoc-OSu (1.8 g, 5.36 mmol) was added. After stirring at room temperature for 2 hours, the reaction solution was diluted with water. The resulting solution was washed with diethyl ether (30 mL), and 2N hydrochloric acid was added to adjust the pH to 3. The mixed solution was then extracted three times with ethyl acetate, and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure. The resulting concentrate was purified by reverse-phase column chromatography (water-acetonitrile) to give aa043 (0.5 g, 27%, 3 steps). LCMS (ESI) m / z = 422 (M+H) + , retention time: 2.3 minutes (analysis conditions: SMD method_13).

[0389] Synthesis of compound aa056

[0390] Under a nitrogen atmosphere, aa056-a (90 g, 443 mmol) and methyl iodide (314 g, 2.21 mol) were dissolved in tetrahydrofuran (3.15 L). The mixed solution was cooled to 0°C, and sodium hydride (60%, 77.56 g, 2.21 mol) was added with stirring. The reaction solution was stirred at 25°C for 3 hours and then added to ice water. The resulting solution was washed three times with t-butyl methyl ether / n-hexane (1 / 3). 1N hydrochloric acid was added to the aqueous phase to adjust the pH to 2-3, and the mixture was extracted three times with ethyl acetate. The resulting organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain aa056-b (94 g) as a crude product. The resulting crude product was used directly in the next reaction. LCMS (ESI) m / z=240 (M+Na)+ Retention time: 1.1 min (Analysis conditions SMD method_14)

[0391] The crude product of aa056-b (94 g) was dissolved in dichloromethane (600 mL). This solution was cooled to 0°C, and 4N HCl / 1,4-dioxane (660 mL) was added. The reaction solution was stirred at 25°C for 3 hours and concentrated under reduced pressure to give the crude product of aa056-c (90 g). LCMS (ESI) m / z = 118 (M + H) + Retention time: 0.25 minutes (analysis conditions SMD method_14).

[0392] The crude product of aa056-c (90 g) was dissolved in water (560 mL), and potassium carbonate was added to adjust the pH to 7. Subsequently, potassium carbonate (149 g, 1.08 mol), Fmoc-OSu (131 g, 389 mmol), and 1,4-dioxane (560 mL) were added to the reaction solution, and the mixture was stirred at 25°C for 3 hours. Thereafter, the reaction solution was washed with t-butyl methyl ether / n-hexane (1 / 3), and 1N hydrochloric acid was added to adjust the pH to 2-3. The solid was collected by filtration. The obtained solid was washed with water and dried under reduced pressure at 50°C for 16 hours to obtain aa056 (130 g, 86% (3 steps)). LCMS (ESI) m / z = 362 (M + Na) + Retention time: 2.0 minutes (Analysis condition SMD method_15)

[0393] Synthesis of compound aa246

[0394] Under a nitrogen atmosphere, aa246-a (30 g, 113 mmol) was dissolved in tetrahydrofuran (300 mL), and sodium hydride (oily, 60%, 5.97 g, 249 mmol) was added at 0°C. The reaction solution was stirred at room temperature for 4 hours, then cooled to 0°C, and 3-bromo-1-propene (15.73 g, 130 mmol) was added dropwise. The reaction solution was then stirred at room temperature for 2 hours, and ice water was added to quench the reaction. The resulting mixture was adjusted to pH 2 with concentrated hydrochloric acid and extracted twice with ethyl acetate. The organic phase was washed with saturated brine and then dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product of aa246-b (27.3 g). LCMS (ESI) m / z = 306 (M+H) + Retention time: 2.0 minutes (analysis conditions: SMD method_16).

[0395] The crude product of aa246-b (26 g) was dissolved in methanol (260 mL), and 2 M ammonia-methanol solution (63.9 mL) and 10% palladium on carbon (3.3 g) were added. The reaction solution was stirred under a hydrogen atmosphere at room temperature for 16 hours and then filtered. The obtained filtrate was concentrated under reduced pressure to give the crude product of aa246-c (14.2 g). LCMS (ESI) m / z = 174 (M + H) + Retention time: 0.84 minutes (analysis conditions SMD method_16).

[0396] The crude product of aa246-c (10 g) was dissolved in 1,4-dioxane (100 mL) and water (100 mL), and potassium carbonate (23.9 g, 172 mmol) was added. Fmoc-OSu (17.4 g, 51.7 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 16 hours and then filtered. The resulting filtrate was washed five times with t-butyl methyl ether / hexane (1 / 3), and the aqueous phase was adjusted to pH 2 with concentrated hydrochloric acid. The resulting solution was extracted twice with ethyl acetate. The organic phase was then washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give aa246 (15.3 g, 58%, 3 steps). LCMS (ESI) m / z = 396 (M+H) + , retention time: 2.0 min (analysis conditions: SMD method_11).

[0397] Synthesis of compound aa281

[0398] Under a nitrogen atmosphere, aa246-a (10 g, 43.2 mmol) was dissolved in tetrahydrofuran (150 mL) and cooled to -10°C, followed by the addition of sodium hydride (60%, 3.8 g, 95.1 mmol). The reaction solution was stirred at room temperature for 1 hour. Subsequently, methyl iodide (7.4 g, 51.9 mmol) was added dropwise at room temperature. The reaction solution was heated to 50°C and stirred at 50°C for 16 hours. A saturated aqueous solution of sodium bicarbonate was then added to the reaction solution. The aqueous phase was washed with diethyl ether (150 mL), and the pH was adjusted to 3 with the addition of 1N hydrochloric acid. The resulting mixture was extracted twice with ethyl acetate (200 mL). The organic phase was washed with saturated brine and a 5% aqueous solution of sodium thiosulfate, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain a crude product of aa281-a (11.1 g). LCMS (ESI) m / z=268 (M+Na)+ Retention time: 0.75 min (Analysis conditions SQDFA05)

[0399] The crude product of aa281-a (11.1 g) was dissolved in dichloromethane (110 mL), and 4N HCl / 1,4-dioxane (56.6 mL, 227 mL) was added. The reaction solution was stirred at room temperature for 2 hours, and then the solvent was evaporated under reduced pressure. The resulting residue was suspended in diet...

Claims

1. (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-undecazatetracyclo[37,38,39,42Z]] ]pentatetracont-42-ene-23,1'-cyclobutane]-17-carboxamide.

2. A pharmaceutical composition comprising the compound described in claim 1.

3. A pharmaceutical composition for selectively inhibiting KRAS in a subject, comprising the compound of claim 1.

4. A pharmaceutical composition for treating or preventing cancer in a subject, comprising an effective amount of a compound described in claim 1.

5. The pharmaceutical composition described in claim 4, wherein the cancer is lung cancer.

6. The pharmaceutical composition described in claim 4, wherein the subject is a human.

7. (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-undecazatetracyclo[37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,91,92,94,95,98,91,92,93,94,95,96,97 ... ]pentatetracont-42-ene-23,1'-cyclobutane]-17-carboxamide solvate.

8. The solvate described in claim 7, which is a hydrate.

9. A pharmaceutical composition comprising the solvate described in claim 7 or 8.

10. A pharmaceutical composition for selectively inhibiting KRAS in a subject, comprising the solvate of claim 7 or 8.

11. A pharmaceutical composition for treating or preventing cancer in a subject, comprising an effective amount of the solvate described in claim 7 or 8.

12. The pharmaceutical composition described in claim 11, wherein the cancer is lung cancer.

13. The pharmaceutical composition described in claim 11, wherein the subject is a human.

14. (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-undecazatetracyclo[37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,91,92,94,95,98,91,92,93,94,95,96,97 ...8,91 ]pentatetracont-42-ene-23,1'-cyclobutane]-17-carboxamide or a solvate thereof.

15. A pharmaceutical composition comprising the salt or solvate thereof described in claim 14.

16. A pharmaceutical composition for selectively inhibiting KRAS in a subject, comprising the salt or solvate thereof described in claim 14.

17. A pharmaceutical composition for treating or preventing cancer in a subject, comprising an effective amount of the salt or solvate thereof described in claim 14.

18. The pharmaceutical composition described in claim 17, wherein the cancer is lung cancer.

19. The pharmaceutical composition described in claim 17, wherein the subject is a human.