Interleukin-23 receptor peptide inhibitors

Abstract

The present invention relates to compounds that are peptide inhibitors of the interleukin-23 receptor (IL-23R), and to their use in the treatment or prevention of various diseases, conditions, or disorders, including inflammatory bowel diseases such as Crohn's disease or ulcerative colitis, psoriatic arthritis, and psoriasis. These compounds exhibit good physical and chemical stability in the gastrointestinal tract.

Description

[Technical Field]

[0001] The present invention relates to interleukin-23 receptor (IL-23R, interleukin-23) peptide inhibitors and their medical use in the treatment and / or prevention of various diseases, conditions, or disorders, including inflammatory bowel disease (IBD), such as Crohn's disease or ulcerative colitis, psoriasis, psoriatic arthritis, and other conditions and disorders described herein. [Background technology]

[0002] Interleukin-23 (IL-23) is a heterodimer cytokine composed of a unique p19 subunit and the p40 subunit of interleukin-12 (IL-12). IL-12 is a cytokine involved in the development of interferon-gamma (IFN-γ) producing T helper 1 (Th1) cells. Although both IL-23 and IL-12 contain the p40 subunit, they have different phenotypic characteristics. Animals lacking IL-12 are susceptible to inflammatory autoimmune diseases, while IL-23-deficient animals are resistant. This is because CD4 cells in the central nervous system (CNS) of IL-23-deficient animals produce interleukin-6 (IL-6), interleukin-17 (IL-17), and tumor necrosis factor (TNF). + This is thought to be because the number of T cells is reduced. Furthermore, IL-12 mainly affects naive CD4 + While IL-23 acts on T cells, IL-23 acts on memory CD4 + It preferentially acts on T cells.

[0003] The receptor that binds to IL-23 is the interleukin-23 receptor (IL-23R). IL-23R is a heterodimer receptor composed of the IL-12Rβ1 subunit and the IL-23R subunit. When IL-23 binds to IL-23R, the JAK-STAT signaling pathway is activated, thereby activating the Janus kinase (JAK) molecules JAK2 and tyrosine kinase 2 (TYK2), as well as the signal transducer and activator of transcription protein (STAT) STAT1, STAT3, STAT4, and STAT5. STAT4 activation is substantially weaker compared to IL-12 activation, and different DNA-binding STAT complexes are formed in response to IL-23. IL-23R constitutively associates with JAK2 and ligand-dependently associates with STAT3.

[0004] IL-23R is expressed on various adaptive and innate immune cells, including T helper 17 (Th17) cells, gamma-delta (γδ) T cells, natural killer (NK) cells, dendritic cells, macrophages, and innate lymphoid cells. These cells are found in large quantities in the gut. In particular, elevated levels of IL-23R gene expression and protein levels have been found on the intestinal mucosal surface in patients with inflammatory bowel disease (IBD). IL-23 is associated with pathogenic CD4 cells that produce IL-6, IL-17, and TNF. + It is thought that this effect is mediated by promoting the development of T cell populations.

[0005] IL-23 production is abundant in the gut and is thought to play a crucial role in regulating the balance between tolerance and immunity through its effects on Th1 and Th17-related cytokines via both T cell-dependent and T cell-independent pathways in intestinal inflammation. Furthermore, IL-23 is thought to suppress regulatory T cell responses and promote inflammation in the gut. Additionally, IL-23R polymorphisms have been associated with susceptibility to inflammatory bowel disease (IBD), further establishing the critical role of the IL-23 pathway in gut homeostasis.

[0006] Therefore, IL-23 is thought to play a crucial role in the pathogenesis of autoimmune inflammation and related diseases and disorders, such as multiple sclerosis, asthma, rheumatoid arthritis, psoriasis, psoriatic arthritis, and inflammatory bowel disease (IBD), including ulcerative colitis and Crohn's disease. Studies in acute and chronic mouse models of IBD have revealed the major roles of IL-23R and downstream effector cytokines in disease pathogenesis.

[0007] The anti-IL-23 antibody risankizumab (ABBV-006) is approved for the treatment of inflammatory diseases, including psoriasis, psoriatic arthritis, and Crohn's disease, and is also being studied for the treatment of ulcerative colitis.

[0008] Protagonist Therapeutics, Inc.'s IL-23 antagonist peptide PTG-200 is in Phase II clinical trials for Crohn's disease. In addition, Protagonist, in collaboration with Janssen Biotech, Inc., is clinically testing two second-generation IL-23 antagonist peptides for psoriasis: JNJ-77242113 (or JNJ-2113, formerly known as PN-235) and PN-232. Protagonist has filed several patent applications in the field of IL-23R inhibitors: International Publication Brochure 2016 / 011208, International Publication Brochure 2017 / 011820, International Publication Brochure 2018 / 022937, International Publication Brochure 2018 / 136646, International Publication Brochure 2020 / 014646, International Publication Brochure 2021 / 007433, International Publication Brochure 2021 / 146441, International Publication Brochure 2021 / 146458, International Publication Brochure 2023 / 288017, International Publication Brochure 2023 / 288019, International Publication Brochure 2023 / 288028, and International Publication Brochure 2024 / 015958. Furthermore, Protagonist has disclosed another peptide, compound C, as an IL-23R inhibitor in its International Publication No. 2016 / 011208, International Publication No. 2017 / 011820, and in Sayago et al., 2018 (ACS Med. Chem. Lett., 2018, 9, 912-916).

[0009] Notably, the peptides disclosed in the above-mentioned Protagonist patent applications, International Publication Nos. 2016 / 011208, 2017 / 011820, 2018 / 022937, 2018 / 136646, 2020 / 014646, 2021 / 007433, 2021 / 146441, 2021 / 146458, 2023 / 288028, and 2024 / 015958, contain only a single crosslinking moiety. None of these applications disclose the use of two crosslinking moieties to stabilize IL-23R peptide inhibitors.

[0010] Kong et al., 2020 (Nature Biomedical Engineering, 2020, 4, 560-571) disclose the development of an orally administered peptide for the treatment of protease resistance. The authors generated a peptide as an inhibitor of coagulation factor XIa, and another peptide as an IL-23R gastrointestinal protease resistance peptide antagonist. The peptide generated as an IL-23R antagonist contained two dithioether crosslinks (specifically, a 1,3-dithio-propan-2-one crosslink) between two pairs of cysteine ​​residues in the peptide chain. Based on IL-23R inhibition, the authors identified peptide I5 as the most promising candidate for further development as an oral therapeutic agent for inflammatory diseases such as Crohn's disease.

[0011] International Publication No. 2023 / 288017 discloses bicyclic (and some tricyclic) peptide inhibitors of IL-23R. The peptides are up to 15 amino acid residues long, and all of them have at least two bonds that crosslink certain amino acid residues. International Publication No. 2023 / 288019 discloses lipid-added peptide inhibitors of IL-23R. The peptides are up to 15 amino acid residues long, and any of them have one or two bonds that crosslink certain amino acid residues. Of the peptides with two crosslinks, one is either a disulfide bond or a dithioether bond, and the other is an amide bond. Both applications propose the use of inhibitors for the treatment of autoimmune inflammation and related diseases and disorders, including IBD, Crohn's disease, ulcerative colitis, psoriasis, and psoriatic arthritis.

[0012] However, none of the peptide crosslinks disclosed in Kong et al., 2020 (Nature Biomedical Engineering, 2020, 4, 560-571), International Publication No. 2023 / 288017, and International Publication No. 2023 / 288019 are the same as those of the present invention in terms of position, type of binding, and / or the number of amino acid residues between crosslinking amino acids.

[0013] Identifying stable and selective agonists that preferentially target the IL-23 pathway and can be used to treat intestinal inflammation, including Crohn's disease, ulcerative colitis, and related diseases, remains challenging. In particular, we identified that the gastrointestinal stability and IL-23R efficacy of the peptide disclosed in Kong et al., 2020 (Nature Biomedical Engineering, 2020, 4, 560-571) may have room for further improvement to become orally administered IL-23R peptide blockers. In particular, peptide I5 from Kong et al., 2020 (Nature Biomedical Engineering, 2020, 4, 560-571), the most promising candidate, exhibited lower stability in simulated intestinal fluid (SIF) assays and lower efficacy against IL-23R compared to Protagonist's compound CSayago et al., 2018 (ACS Med. Chem. Lett., 2018, 9, 912-916).

[0014] Therefore, there remains a need for novel therapeutic agents targeting the IL-23 pathway that can be used to treat and prevent IL-23-related diseases, including those associated with autoimmune inflammation in the intestinal tract. Furthermore, compounds and methods that specifically target IL-23R from the luminal side of the intestine may provide therapeutic benefits to IBD patients suffering from localized inflammation of the intestinal tissue.

[0015] The inventors have also filed International Publication No. 2023 / 099669 relating to peptide inhibitors of IL-23R. The present invention relates to further peptide inhibitors that have improved gastrointestinal stability and / or more potently inhibit IL-23R than the peptides disclosed in International Publication No. 2023 / 099669. [Prior art documents] [Patent Documents]

[0016] [Patent Document 1] International Publication No. 2016 / 011208 Brochure [Patent Document 2] International Publication No. 2017 / 011820 Brochure [Patent Document 3] International Publication No. 2018 / 022937 Brochure [Patent Document 4] International Publication No. 2018 / 136646 Brochure [Patent Document 5] International Publication No. 2020 / 014646 Brochure [Patent Document 6] International Publication No. 2021 / 007433 brochure [Patent Document 7] International Publication No. 2021 / 146441 brochure [Patent Document 8] International Publication No. 2021 / 146458 brochure [Patent Document 9] International Publication No. 2023 / 288017 brochure [Patent Document 10] International Publication No. 2023 / 288019 brochure [Patent Document 11] International Publication No. 2023 / 288028 brochure [Patent Document 12] International Publication No. 2024 / 015958 Brochure [Patent Document 13] International Publication No. 2023 / 099669 Brochure [Non-patent literature]

[0017] [Non-Patent Document 1] Sayago et al., ACS Med. Chem. Lett., 2018, 9, 912-916 [Non-Patent Document 2] Kong et al., Nature Biomedical Engineering, 2020, 4, 560-571

Summary of the Invention

Problems to be Solved by the Invention

[0018] The present invention relates to a compound that is a peptide inhibitor of interleukin-23 receptor (IL-23R). Such compounds exhibit a favorable combination of properties such as very potent inhibition of IL-23R and / or high stability in the gastrointestinal tract. Furthermore, the compounds described herein may be useful for the treatment of various diseases, conditions, and disorders related to IL-23R, such as inflammatory bowel disease, Crohn's disease, ulcerative colitis, and psoriasis. Also, the compounds described herein can exhibit improved properties as compared to the compounds disclosed in International Publication No. WO2023 / 099669 pamphlet.

[0019] The present invention addresses such a need by providing a novel peptide inhibitor that binds to IL-23R and inhibits IL-23-mediated signal transduction. The novel peptide inhibitor is stable in the gastrointestinal tract and is thus suitable for oral administration.

Means for Solving the Problems

[0020] In a first aspect, the present invention provides a compound of the formula: Z-R 2 wherein, R 2 is NHR 3 or C(=O)R 3 where R 3 is hydrogen, or C 1-6 alkyl optionally substituted with a pyridyl ring, NHR 3 or C(=O)R 3 or is absent, Z is of formula I: X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13 (I) and in the sequence, X2 is Lys, D-lys, iso-Lys, D-iso-Lys, beta-Lys, D-beta-Lys, homo-Lys, D-homo-Lys, beta-homo-Lys, N-Me-Lys, N-Me-homo-Lys, (N3)-Lys, D-(N3)-Lys, (N3)-beta-Lys, (N3)-D-beta-Lys, (N3)-homo-Lys, (N3)-D-homo-Lys, (N3)-beta-homo-Lys, Dpr, D-Dpr, iso-Dpr, D-iso-Dpr, beta-Dpr, D-beta-Dpr, homo-Dpr, D-homo-Dpr, beta-homo-Dpr, N-Me-Dpr, N-Me-homo-Dpr, (N3)-Dpr, D-(N3)-Dpr, (N3)-beta-Dpr, (N3)-D-beta-Dpr, (N3)-homo-Dpr, (N3)-D-homo-Dpr, (N3)-beta-homo-Dpr, Dab, D-Dab, iso-Dab, D-iso-Dab, beta-Dab, D-beta-Dab, homo-Dab, D-homo-Dab, beta-homo-Dab, N-Me-Dab, N-Me-homo-Dab, (N3)-Dab, D-(N3)-Dab, (N3)-beta-Dab, (N3)-D-beta-Dab, (N3)-homo-Dab, (N3)-D-homo-Dab, (N3)-beta-homo-Dab, Orn, D-Orn, Iso-Orn, D-Iso-Orn, Beta-Orn, D-Beta-Orn, Homo-Orn, D-Homo-Orn, Beta-Homo-Orn, N-Me-Orn, N-Me-Homo-Orn, (N3)-Orn, D-(N3)-Orn, (N3)-Beta-Orn, (N3)-D-Beta-Orn, (N3)-Homo-Orn, (N3)-D-Homo-Orn, (N3)-Beta-Homo-Orn, Lys (Gly), Asp, D-Asp, Iso-Asp, D-Iso-Asp, Beta-Asp, D-Beta-Asp, Homo-Asp, D-Homo-Asp, Beta-Homo-Asp, N-Me-Asp, N-Me-Homo-Asp, (N3)-Asp, D-(N3)-Asp, (N3)-Beta-Asp, (N3)-D-Beta-Asp, (N3)-Homo-Asp, (N3)-D-Homo-Asp, (N3)-Beta-Homo-Asp, Glu, D-Glu, Iso-Glu, D-Iso-Glu, Beta-Glu, D-Beta-Glu, Homo-Glu, D-Homo-Glu, Beta-Homo-Glu, N-Me-Glu, N-Me-Homo-Glu, (N3)-Glu, D-(N3)-Glu, (N3)-Beta-Glu, (N3)-D-Beta-Glu, (N3)-Homo-Glu, (N3)-D-Homo-Glu, (N3)-Beta-Homo-Glu, 2-amino-6-carboxyhexanoyl and 3-aminopropanoyl Selected from the group consisting of, X3 is any amino acid, ω-hydroxy-C 2-6 Selected from alkanates, or absent, X4 is Val, D-Val, Beta-Val, D-Beta-Val, Homo-Val, D-Homo-Val, Beta-Homo-Val, N-mer-Val, N-mer-Homo-Val, 2-mer-Val, Ala, D-Ala, Beta-Ala, D-Beta-Ala, Homo-Ala, D-Homo-Ala, Beta-Homo-Ala, N-Me-Ala, N-Me-Homo-Ala, Gly, Beta-Gly, Homo-Gly, Beta-Homo-Gly, N-Me-Gly, N-Me-Homo-Gly Leu, D-Leu, Beta-Leu, D-Beta-Leu, Homo-Leu, D-Homo-Leu, Beta-Homo-Leu, N-Me-Leu, N-Me-Homo-Leu, 2-Me-Leu, Ile, D-Ile, Beta-Ile, D-Beta-Ile, Homo-Ile, D-Homo-Ile, Beta-Homo-Ile, N-Me-Ile, N-Me-Homo-Ile, or absent. X5 is selected from the group consisting of a tryptophan residue that may be substituted, azatryptophan residue that may be substituted, and a beta-homotryptophan residue that may be substituted. X6 may be a substituted Gln residue, a substituted Lys residue, a substituted Arg residue, a substituted Dab residue, a substituted Orn residue, a substituted Phe residue, Ala, D-Ala, Beta-Ala, D-Beta-Ala, Homo-Ala, D-Homo-Ala, Beta-Homo-Ala, N-Me-Ala, N-Me-Homo-Ala, Cit, D-Cit, Beta-Cit, D-Beta-Cit, Homo-Cit, D-Homo-Cit, Beta-Homo-Cit, N-Me-Cit, N-Me-Homo-Cit, Glu, D-Glu, Iso-Glu, D-Iso-Glu, Beta-Glu, D-Beta-G Selected from the group consisting of lu, homo-Glu, D-homo-Glu, beta-homo-Glu, N-Me-Glu, N-Me-homo-Glu, Tyr, D-Tyr, beta-Tyr, D-beta-Tyr, homo-Tyr, D-homo-Tyr, beta-homo-Tyr, N-Me-Tyr, N-Me-homo-Tyr, Val, D-Val, beta-Val, D-beta-Val, homo-Val, D-homo-Val, beta-homo-Val, N-Me-Val, N-Me-homo-Val, or His, D-His, beta-His, D-beta-His, homo-His, D-homo-His, beta-homo-His, N-Me-His, and N-Me-homo-His, X7 is Asp, D-Asp, iso-Asp, D-iso-Asp, beta-Asp, D-beta-Asp, homo-Asp, D-homo-Asp, beta-homo-Asp, N-Me-Asp, N-Me-homo-Asp, Glu, D-Glu, Iso-Glu, D-Iso-Glu, Beta-Glu, D-Beta-Glu, Homo-Glu, D-Homo-Glu, Beta-Homo-Glu, N-Me-Glu, N-Me-Homo-Glu, Dab, D-Dab, iso-Dab, D-iso-Dab, beta-Dab, D-beta-Dab, homo-Dab, D-homo-Dab, beta-homo-Dab, N-Me-Dab, N-Me-homo-Dab, Orn, D-Orn, Iso-Orn, D-Iso-Orn, Beta-Orn, D-Beta-Orn, Homo-Orn, D-Homo-Orn, Beta-Homo-Orn, N-Me-Orn, N-Me-Homo-Orn, Lys, D-Lys, iso-Lys, beta-Lys, D-iso-Lys, D-beta-Lys, homo-Lys, D-homo-Lys, beta-homo-Lys, N-Me-Lys, N-Me-homo-Lys Pra, D-Pra, Beta-Pra, D-Beta-Pra, Homo-Pra, D-Homo-Pra, Beta-Homo-Pra, N-Me-Pra, N-Me-Homo-Pra, Selected from the group consisting of Hpg, D-Hpg, beta-Hpg, D-beta-Hpg, homo-Hpg, D-homo-Hpg, beta-homo-Hpg, N-Me-Hpg, and N-Me-homo-Hpg, X8 is selected from the group consisting of an optionally substituted tryptophan residue, an optionally substituted azatryptophan residue, an optionally substituted beta-homotryptophan residue, an optionally substituted tyrosine residue, an optionally substituted phenylalanine residue, an optionally substituted homophenylalanine residue, and an alanine residue substituted with a carbocyclic group or an aromatic or heteroaromatic group selected from the group consisting of phenyl, pyridyl, naphthyl, and quinolinyl, each of which may be substituted. X9 is selected from the group consisting of an optional tryptophan residue, an optional azatryptophan residue, an optional alanine residue, an optional phenylalanine residue, and an optional tyrosine residue. The X10 is Val, D-Val, Beta-Val, D-Beta-Val, Homo-Val, D-Homo-Val, Beta-Homo-Val, N-mer-Val, N-mer-Homo-Val, 2-mer-Val, Gly, Beta-Gly, Homo-Gly, Beta-Homo-Gly, N-Me-Gly, N-Me-Homo-Gly Dab, D-Dab, iso-Dab, D-iso-Dab, beta-Dab, D-beta-Dab, homo-Dab, D-homo-Dab, beta-homo-Dab, N-Me-Dab, N-Me-homo-Dab, Lys, D-lys, iso-lys, D-iso-lys, beta-lys, D-beta-lys, homo-lys, D-homo-lys, beta-homo-lys, N-Me-lys, N-Me-homo-lys Aib, D-Aib, Beta-Aib, D-Beta-Aib, Homo-Aib, D-Homo-Aib, Beta-Homo-Aib, N-Me-Aib, N-Me-Homo-Aib, Ala, D-Ala, Beta-Ala, D-Beta-Ala, Homo-Ala, D-Homo-Ala, Beta-Homo-Ala, N-Me-Ala, N-Me-Homo-Ala, Leu, D-Leu, Beta-Leu, D-Beta-Leu, Homo-Leu, D-Homo-Leu, Beta-Homo-Leu, N-Me-Leu, N-Me-Homo-Leu, 2-Me-Leu, Ile, D-Ile, Beta-Ile, D-Beta-Ile, Homo-Ile, D-Homo-Ile, Beta-Homo-Ile, N-Me-Ile, N-Me-Homo-Ile, Furthermore, carbocyclic or heterocyclic rings having amino substituents and carbonyl substituents. Selected from the group consisting of, X11 is Dpr, D-Dpr, iso-Dpr, D-iso-Dpr, beta-Dpr, D-beta-Dpr, homo-Dpr, D-homo-Dpr, beta-homo-Dpr, N-Me-Dpr, N-Me-homo-Dpr, Dab, D-Dab, iso-Dab, D-iso-Dab, beta-Dab, D-beta-Dab, homo-Dab, D-homo-Dab, beta-homo-Dab, N-Me-Dab, N-Me-homo-Dab, Orn, D-Orn, Iso-Orn, D-Iso-Orn, Beta-Orn, D-Beta-Orn, Homo-Orn, D-Homo-Orn, Beta-Homo-Orn, N-Me-Orn, N-Me-Homo-Orn, Lys, D-lys, iso-Lys, D-iso-Lys, beta-Lys, D-beta-Lys, homo-Lys, D-homo-Lys, beta-homo-Lys, N-Me-Lys, N-Me-homo-Lys, Lys(Me), Lys (Gly), Asp, D-Asp, iso-Asp, D-iso-Asp, beta-Asp, D-beta-Asp, homo-Asp, D-homo-Asp, beta-homo-Asp, N-Me-Asp, N-Me-homo-Asp, Glu, D-Glu, Iso-Glu, D-Iso-Glu, Beta-Glu, D-Beta-Glu, Homo-Glu, D-Homo-Glu, Beta-Homo-Glu, N-Me-Glu, N-Me-Homo-Glu, and 2-amino-6-carboxyhexanoyl Selected from the group consisting of, X12 is an alanine residue substituted with an optional Phe residue, an optional Tyr residue, an optional His residue, a carbocyclic group or aromatic or heteroaromatic group selected from the group consisting of phenyl, pyridyl, naphthyl, and quinolinyl, each of which is substituted, Dab, D-Dab, iso-Dab, D-iso-Dab, beta-Dab, D-beta-Dab, homo-Dab, D-homo-Dab, beta-homo-Dab, N-Me-Dab, N-Me-homo-Dab, Gly, beta-Gly, homo-Gly, beta-homo-Gly, N-Me-Gly, N-Me-homo-Gly, Pro, 5-aminopentanoyl, 4-aminopiperidine-4-carbonyl, (R,S)-imidazolidined-2-carbonyl, 3-aminopropanoyl, Gly-CF3, D-Gly-CF 3, Nle, Gln, D-Gln, Iso-Gln, D-Iso-Gln, Beta-Gln, D-Beta-Gln, Homo-Gln, D-Homo-Gln, Beta-Homo-Gln, N-Me-Gln, N-Me-Homo-Gln, THP, Ser, D-Ser, Beta-Ser, D-Beta-Ser, Homo-Ser, D-Homo-Ser, Beta-Homo-Ser, N-Me-Ser, N-Me-Homo-Ser, Se r(OMe),3-aminotetrahydrofuran-3-carbonyl,Arg,D-Arg,Beta-Arg,D-beta-Arg,Homo-Arg,D-homo-Arg,Beta-homo-Arg,N-Me-Arg,N-Me-homo-Arg,Thr,D-Thr,Beta-Thr,D-beta-Thr,Homo-Thr,D-homo-Thr,Beta-homo-Thr,N-Me-Thr,N-Me-homo-Thr Glu, D-Glu, Iso-Glu, D-Iso-Glu, Beta-Glu, D-Beta-Glu, Homo-Glu, D-Homo-Glu, Beta-Homo-Glu, N-Me-Glu, N-Me-Homo-Glu, Asn, D-Asn, Beta-Asn, D-Beta-Asn, Homo-Asn, D-Homo-Asn, Beta-Homo-Asn, N-Me-Asn, N-Me-Homo-Asn, 4-Aminobutanoyl, 2-(trimethyl-2-aminoethoxy)ethoxypropyl]propyl, and Lys, where the side chain -NH2 of Lys is -C(=O)(CH2) n R Kis replaced, n is from 0 to 2, and R K is optionally substituted with F, is selected from the group consisting of imidazolyl, pyrimidyl, or pyridyl, and consists of Lys, or X12 is absent, X13 is an optionally substituted His residue, an optionally substituted Phe residue, a carbocyclic group or an aromatic group or a heteroaromatic group selected from the group consisting of phenyl, pyridyl, naphthyl, and quinolinyl which may each be optionally substituted, or an alanine residue substituted with the same, Asn, D-Asn, beta-Asn, D-beta-Asn, homo-Asn, D-homo-Asn, beta-homo-Asn, N-Me-Asn, N-Me-homo-Asn, Gly, beta-Gly, homo-Gly, beta-homo-Gly, N-Me-Gly, N-Me-homo-Gly, and Dab, Orn, or Lys, wherein the side-chain -NH2 is -C(=O)(CH2) n R K is replaced, n is from 0 to 2, and R K is optionally substituted with F, is selected from the group consisting of Dab, Orn, or Lys, and consists of imidazolyl, pyrimidyl, or pyridyl, or is absent, In the sequence, (i) X2 and X11 are amino acid residues that together form a lactam bridge, (ii) X2 and X7 are amino acid residues that together form a lactam bridge or a bridge containing a triazole ring, (iii) Optionally, when X13 is present, X10 and X13 are amino acid residues that together form a lactam bridge, compound, or a pharmaceutically acceptable salt or solvate thereof is provided.

[0021] In a second aspect, the present invention relates to a compound of the formula: Z-R 2 wherein, in the formula, R 2 is NHR 3 or C(=O)R 3And R 3 C may be substituted with hydrogen or a pyridyl ring. 1-6 Alkyl, NHR 3 Or C(=O)R 3 is or does not exist, Z is given by equation I: X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13 (I) This is the amino acid sequence, and in the sequence, X2 is selected from the group consisting of Lys, D-Lys, iso-Lys, beta-Lys, D-beta-Lys, homo-Lys, D-homo-Lys, beta-homo-Lys, N-Me-Lys, Dab, D-Dab, iso-Dab, Glu, iso-Glu, D-iso-Glu, Orn, D-Orn, Dpr, Lys(Gly), (N3)-Lys, and D-(N3)-Lys. X3 is selected from the group consisting of Thr, Ile, 3-aminopropanoyl, 4-aminobutanoyl, beta-homo-Ile, beta-homo-Thr, Gly, N-Me-3-aminopropanoyl, and Ser, or is absent. X4 is either Val or does not exist. X5 is selected from the group consisting of Trp, 1-Me-Trp, and beta-homo-Trp. X6 is Gln, X7 is selected from the group consisting of Glu, D-Glu, Homo-Glu, Asp, Pra, and Hpg. X8 is selected from the group consisting of Y(2-aminoethoxy), Y(Me), Y(nPr), Y(Bn), Trp, D-Phe, 2-Me-Phe, F(4-Me), F(4-Bu), 3-(2-pyridyl)-Ala, 3-(3-pyridyl)-Ala, 3-(4-pyridyl)-Ala, and cyclopropyl-Ala. X9 is 2-Nal or cyclopropyl-Ala, X10 is selected from the group consisting of 2-Me-Leu, 2-Me-Val, Dab, Gly, Lys, and Aib. X11 is selected from the group consisting of Glu, homo-Glu, beta-homo-Glu, Dab, iso-Dab, Lys, Lys(Me), Orn, and 2-amino-6-carboxyhexanoyl. X12 consists of Dab, His, D-His, His(1-Me), 3-(2-pyridyl)-Ala, 3-(3-pyridyl)-Ala, 3-(4-pyridyl)-Ala, 3-(3-quinolinyl)-Ala, Gly, Pro, 5-aminopentanoyl, 4-aminopiperidine-4-carbonyl, (R,S)-imidazolidined-2-carbonyl, and Lys, where the side chain -NH2 of Lys is -C(=O)(CH2). n R K It is substituted with, where n is 0 to 2, and R K is selected from the group consisting of Lys, which may be imidazolyl, pyrimidyl, or pyridyl substituted with F, or X12 does not exist. X13 is selected from the group consisting of 3-(3-pyridyl)-Ala, D-3-(3-pyridyl)-Ala, and 3-(3,5-pyrimidyl)-Ala, or is absent. In the array, (i) X2 and X11 are amino acid residues that together form a lactam crosslink, (ii) X2 and X7 are amino acid residues that together form a lactam crosslink or a crosslink containing a triazole ring, (iii) Optionally, if X13 is present, X10 and X13 are amino acid residues that together form a lactam crosslink. compound, Or provide a pharmaceutically acceptable salt or solvate thereof.

[0022] In some embodiments, the compound is given by formula: ZR 2 And in the formula, R 2 NHR 3 And R 3 C may be substituted with hydrogen or a pyridyl ring. 1-6 Alkyl, NHR 3is or does not exist, Z is given by equation Ia: X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13 (Ia) This is the amino acid sequence, and in the sequence, X2 is selected from the group consisting of Lys, D-Lys, iso-Lys, beta-Lys, D-beta-Lys, homo-Lys, D-homo-Lys, beta-homo-Lys, N-Me-Lys, Dab, D-Dab, Glu, iso-Glu, Orn, D-Orn, Lys(Gly), (N3)-Lys, and D-(N3)-Lys. X3 is selected from the group consisting of Thr, Trp, Ile, 3-aminopropanoyl, 4-aminobutanoyl, beta-homo-Ile, beta-homo-Thr, Gly, and N-Me-3-aminopropanoyl, and 3-hydroxypropanoic acid, or is absent. X4 is either Val or does not exist. X5 is either a trp or a 1-Me-Trp. X6 is Gln, Gln(Me), Dab(Ac-N-Me), Dab(Ac), or Gln(2Me). X7 is selected from the group consisting of Glu, homo-Glu, Asp, Pra, and Hpg. X8 is Y(2-aminoethoxy), Y(Me), Y(Bn), Y(2-aminoethoxy)(N(Me)2), Y(npentylamine)(N + Selected from the group consisting of (Me)3), Y(2-trimethyl-PEG2), F(4-Me), F(4-Bu), cyclopropyl-Ala, F(4-morpholine), F(4-THP), Y(CH3-2-F), F(4-F), F(4-piperazine), F(4-imidazole), Y(CH3-3-F), F(4-piperidine), 5-AzaTrp, Y(Ac-2-aminoethoxy), 7-AzaTrp, 6-AzaTrp, and F(4-CONH2), X9 is 2-Nal, X10 is selected from the group consisting of 2-Me-Leu, 2-Me-Val, D-Ala, Dab, Gly, and Aib. X11 is selected from the group consisting of Glu, homo-Glu, Lys, Lys(Me), Orn, and 2-amino-6-carboxyhexanoyl. X12 is selected from the group consisting of Dab, His, S(OCH3), D-His, His(1-Me), 3-(3-quinolinyl)-Ala, and 4-aminopiperidine-4-carbonyl. X13 is either 3-(3-pyridyl)-Ala, 3-(3,5-pyrimidyl)-Ala, or absent. In the array, (i) X2 and X11 are amino acid residues that together form a lactam crosslink, (ii) X2 and X7 are amino acid residues that together form a lactam crosslink or a crosslink containing a triazole ring, (iii) Optionally, if X13 is present, X10 and X13 are amino acid residues that together form a lactam crosslink. Is it a formula? or a pharmaceutically acceptable salt or solvate thereof.

[0023] In some embodiments, the compound is given by formula: ZR 2 And in the formula, R 2 NHR 3 And R 3 C may be substituted with hydrogen or a pyridyl ring. 1-6 Alkyl, NHR 3 is or does not exist, Z is given by equation Ia: X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13 (Ia) This is the amino acid sequence, and in the sequence, X2 is selected from the group consisting of Lys, D-Lys, iso-Lys, beta-Lys, D-beta-Lys, homo-Lys, D-homo-Lys, beta-homo-Lys, N-Me-Lys, Dab, D-Dab, Glu, iso-Glu, Orn, D-Orn, Lys(Gly), (N3)-Lys, and D-(N3)-Lys. X3 is selected from the group consisting of Thr, Ile, 3-aminopropanoyl, 4-aminobutanoyl, beta-homo-Ile, beta-homo-Thr, Gly, and N-Me-3-aminopropanoyl, or is absent. X4 is either Val or does not exist. X5 is either a trp or a 1-Me-Trp. X6 is Gln, X7 is selected from the group consisting of Glu, homo-Glu, Asp, Pra, and Hpg. X8 is selected from the group consisting of Y(2-aminoethoxy), Y(Me), Y(Bn), F(4-Me), F(4-Bu), and cyclopropyl-Ala. X9 is 2-Nal, X10 is selected from the group consisting of 2-Me-Leu, 2-Me-Val, Dab, Gly, and Aib. X11 is selected from the group consisting of Glu, homo-Glu, Lys, Lys(Me), Orn, and 2-amino-6-carboxyhexanoyl. X12 is selected from the group consisting of Dab, His, D-His, His(1-Me), 3-(3-quinolinyl)-Ala, and 4-aminopiperidine-4-carbonyl. X13 is either 3-(3-pyridyl)-Ala, 3-(3,5-pyrimidyl)-Ala, or absent. In the array, (i) X2 and X11 are amino acid residues that together form a lactam crosslink, (ii) X2 and X7 are amino acid residues that together form a lactam crosslink or a crosslink containing a triazole ring, (iii) Optionally, if X13 is present, X10 and X13 are amino acid residues that together form a lactam crosslink. Is it a formula? or a pharmaceutically acceptable salt or solvate thereof.

[0024] In some embodiments, the side chains of amino acid residues of X2 are used for the lactam crosslink between X2 and X11, and the N-terminus of the amino acid residues of X2 is used for the crosslink between X2 and X7.

[0025] In some embodiments, X2 is Lys.

[0026] In some embodiments, X3 is selected from the group consisting of Thr, Ile, and 3-aminopropanoyl, or is absent.

[0027] In some embodiments, X4 is absent.

[0028] In some embodiments, X5 is a trp.

[0029] In some embodiments, X7 is Glu.

[0030] In some embodiments, X8 is Y(2-aminoethoxy), Y(Me), or F(4-Me).

[0031] In some embodiments, X9 is 2-Nal.

[0032] In some embodiments, X10 is 2-Me-Leu or 2-Me-Val.

[0033] In some embodiments, X11 is Glu.

[0034] In some embodiments, X12 is Dab.

[0035] In some embodiments, X13 is 3-(3-pyridyl)-Ala or is absent. In some embodiments, X13 is 3-(3-pyridyl)-Ala.

[0036] In some embodiments, R 2 NHR 3 And R 3 is hydrogen or C 1-6 It is alkyl. In some embodiments, R 2 is NH2. In some embodiments, R 2 It is NHMe.

[0037] In some embodiments, X2 is Lys, X5 is Trp, X9 is 2-Nal, and X10 is 2-Me-Leu.

[0038] In some embodiments, X2 is Lys, X5 is Trp, X9 is 2-Nal, X10 is 2-Me-Leu, and R 2 It is either NH2 or NHMe.

[0039] In some embodiments, X2 is Lys, X5 is Trp, X9 is 2-Nal, X10 is 2-Me-Leu, X13 is 3-(3-pyridyl)-Ala, or is absent, R 2 It is either NH2 or NHMe.

[0040] In some embodiments, X2 is Lys, X5 is Trp, X7 is Glu, X9 is 2-Nal, X10 is 2-Me-Leu, X13 is 3-(3-pyridyl)-Ala, or is absent, R 2 It is either NH2 or NHMe.

[0041] In some embodiments, Z is an amino acid sequence selected from the group consisting of sequences listed in Table 1-1a.

[0042] In some embodiments, the compound is selected from the compounds listed in Table 1-1, or from pharmaceutically acceptable salts or solvates thereof.

[0043] The present invention further provides compositions comprising the compounds described above. The compositions may be pharmaceutical compositions and may include pharmaceutically acceptable carriers, excipients, or media.

[0044] The present invention further provides a method for synthesizing the compounds described above. This method may further include the steps of synthesizing a peptide by a solid-phase or liquid-phase method, and optionally the steps of isolating and / or purifying the final product, and further the steps of forming an amide bond between the amino acid residues at positions X2 and X11, and further the steps of forming an amide bond or triazole between the amino acid residues at positions X2 and X7, and further the steps of forming an amide bond between the amino acid residues at positions X10 and X13.

[0045] The present invention further provides the compound of the present invention, or a pharmaceutical composition containing the compound, for use in medical treatment methods.

[0046] Furthermore, the present invention provides compounds of the present invention, or pharmaceutical compositions containing such compounds, for use in methods for preventing or treating inflammatory bowel diseases (IBD), such as Crohn's disease or ulcerative colitis, psoriasis, psoriatic arthritis, and combinations thereof. In some embodiments, the condition is inflammatory bowel disease (IBD) and / or psoriasis.

[0047] Furthermore, the present invention provides the use of the compounds of the present invention or pharmaceutical compositions containing said compounds in the manufacture of pharmaceuticals for the prevention or treatment of inflammatory bowel diseases (IBD), such as Crohn's disease or ulcerative colitis, psoriasis, psoriatic arthritis, and combinations thereof. In some embodiments, the condition is inflammatory bowel disease (IBD) and / or psoriasis.

[0048] Furthermore, the present invention provides a method for preventing or treating inflammatory bowel disease (IBD), such as Crohn's disease or ulcerative colitis, psoriasis, psoriatic arthritis, and combinations thereof, comprising administering a therapeutically effective amount of the compound of the present invention or a pharmaceutical composition containing the compound to a subject. In some embodiments, the condition is inflammatory bowel disease (IBD) and / or psoriasis.

[0049] Further aspects and embodiments of the present invention will become apparent from the following disclosure. [Modes for carrying out the invention]

[0050] definition Unless otherwise defined herein, scientific and technical terms used herein have the meanings generally understood by those skilled in the art. In general, the nomenclature used herein in relation to the techniques of chemistry, molecular biology, cell and cancer biology, immunology, microbiology, pharmacology, and protein and nucleic acid chemistry described herein is well known and commonly used in the art.

[0051] All publications, patents, and published patent applications referenced in this application are incorporated herein by reference. In the event of any conflict, this specification, including its specific definitions, shall prevail.

[0052] Throughout this specification, the word “comprise,” or variations such as “comprises” or “comprising,” will be understood to mean that a specified integer or component, or a specified group of integers or components, is included, but not that any other integer or component, or a group of integers or components, is excluded.

[0053] The singular forms "a," "an," and "the" include the plural unless the context is clearly different.

[0054] The term "including" is used to mean "including but not limited to." "Including" and "including but not limited to" are used synonymously.

[0055] The terms “patient,” “subject,” and “individual” can be used synonymously and refer to either humans or non-human animals. Subjects are typically mammals, including humans, non-human primates (including apes, Old World monkeys, and New World monkeys), domestic animals (e.g., cattle, pigs), companion animals (e.g., dogs, cats), and rodents (e.g., mice and rats).

[0056] As used herein, the term “pharmaceutically acceptable salt” is intended to indicate a salt that is not harmful to the patient or subject to which the salt in question is administered. For example, a salt selected from acid addition salts and basic salts may be appropriate. Examples of acid addition salts include chloride salts, citrates, and acetates. Examples of basic salts include those in which the cation is an alkali metal cation such as sodium or potassium ions, an alkaline earth metal cation such as calcium or magnesium ions, and N(R) 1 )(R 2 )(R 3 )(R 4 ) + It is an ion of type R 1 , R 2 , R 3 , and R 4 These are, independently, typically hydrogen, and may be substituted C. 1-6 Alkyl or optionally substituted C 2-6 Salts selected from substituted ammonium ions such as ions that specify alkenyls are included. Related C 1-6 Examples of alkyl groups include methyl, ethyl, 1-propyl, and 2-propyl groups. Related C 2-6Examples of alkenyl groups include ethenyl, 1-propenyl, and 2-propenyl. Other examples of pharmaceutically acceptable salts can be found in "Remington's Pharmaceutical Sciences", 17. th edition, Alfonso R. Gennaro (Ed.), Mark Publishing Company, Easton, PA, USA, 1985 (and more recent editions), and "Encyclopaedia of Pharmaceutical Technology", 3 rd This information is described in James Swarbrick (Ed.), Informa Healthcare USA (Inc.), NY, USA, 2007, and in J. Pharm. Sci. 66: 2 (1977).

[0057] In the context of this invention, the term “solvate” refers to a stoichiometrically defined complex formed between a solute (in this case, the peptide or a pharmaceutically acceptable salt thereof according to the present invention) and a solvent. The solvent in this case may be, for example, water, ethanol, or, but not limited to these, another pharmaceutically acceptable—typically small-molecule—organic species such as acetic acid or lactic acid. When the solvent in question is water, such a solvate is usually called a hydrate.

[0058] As used in the context of this invention, the terms “antagonist” and “inhibitor” typically refer to substances that inhibit a receptor type in question by binding to (i.e., acting as a ligand for) that receptor type and blocking it.

[0059] Each embodiment of the present invention described herein may be used alone or in combination with one or more other embodiments of the present invention.

[0060] Where used herein in the context of the therapeutic methods or other therapeutic interventions described above according to the present invention, the terms “therapeutic effective dose” or “effective dose” mean an amount sufficient to cure, improve, alleviate or partially prevent the clinical symptoms of a particular disease, disorder, or condition that is the target of the treatment or other therapeutic intervention, as measured, for example, by an established clinical endpoint or other biomarker (established or experimental). The therapeutic-related dose may be determined empirically by those skilled in the art based on the indication being treated or prevented and the target to whom the therapeutic-related dose is administered. For example, a person skilled in the art would know that one or more of the clinically relevant biological activity indicators described herein include, for example, myeloperoxidase (MPO), interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-22 (IL-22), interleukin-17A (IL-17A), interleukin-17F (IL-17F), lipocalin 2 (LCN2), matrix metallopeptidase 9 (MMP9), S100 calcium-binding protein A8 (S100A8), microRNA-223-3p (miR223-3p), and claudin 8 (CLDN8). 8) and phosphorylated signal transducer and activator of transcription 3 (pSTAT3) protein, polynucleotides encoding any of these proteins, and polynucleotides containing a region complementary to microRNA-223-3p, or any of the polynucleotides encoding any of these proteins as described in International Publication No. 2018 / 089693, can be measured. Those skilled in the art can determine clinically relevant amounts by measurement in vitro or in vivo.

[0061] The amount sufficient to achieve one or all of these effects is defined as the therapeutically effective dose. Optimal efficacy can be achieved by adjusting the dosage and method of administration. The effective dose for a given purpose will depend, among other factors, on the severity of the disease, disorder, or condition to which the particular treatment or other therapeutic intervention is being pursued, the subject's weight and overall condition, diet, concomitant medications, and other factors well known to those skilled in the art. Determining the most suitable dosage size and administration regimen for administering the peptide or its pharmaceutically acceptable salt or solvate according to the present invention to humans can be guided by the results obtained by the present invention and confirmed in a well-designed clinical trial. Effective dosages and treatment protocols can be determined conventionally by starting with a low dose in experimental animals, then increasing the dosage while monitoring the effect, and similarly systematically changing the administration regimen. When determining the optimal dosage for a given subject, clinicians can consider numerous factors; such considerations are well known to those skilled in the art.

[0062] In this context, the term “treatment” and its grammatical variations (e.g., “treated,” “treating,” “to treat”) refer to a method for obtaining a beneficial or desired clinical outcome. For the purposes of this invention, beneficial or desired clinical outcomes include, but are not limited to, symptom relief, reduction of disease severity, stabilization of the disease state (i.e., no worsening), delay or slowing of disease progression, improvement or recovery of the disease state, and remission (whether partial or complete), whether detectable or undetectable. “Treatment” may also mean extending survival compared to the survival expected without treatment. Therefore, the subject requiring treatment (e.g., a human) may already be suffering from the disease or disorder in question. The term “treatment” includes inhibiting or reducing the increase in the severity of a pathological condition or symptom (e.g., inflammation) compared to the absence of treatment, but does not necessarily imply the complete cessation of the associated disease, disorder, or condition.

[0063] When used in this context, the term “prevention” and its grammatical variations (e.g., “prevented,” “preventing,” “preventing”) refer to methods for interfering with or preventing the onset of a condition, disease, or disorder, or for altering a pathology. Thus, “prevention” can refer to preventive or protective measures. For the purposes of the present invention, beneficial or desired clinical outcomes include, but are not limited to, preventing or slowing the symptoms, progression, or onset of a disease, whether detectable or undetectable. Thus, the subject requiring “prevention” (e.g., a human) may not yet be suffering from the disease or disorder in question. Therefore, the term “prevention” includes inhibiting or slowing the onset of a disease compared to having no treatment, and does not necessarily imply permanent prevention of the disease, disorder, or condition in question.

[0064] Amino acid nomenclature The term "amino acid" refers to an organic compound that, in its isolated state, contains an amino group or amine group (-NH2 or -NHR) and a carboxylic acid group (-COOH). As is well known to those skilled in the art, the amine group and carboxylic acid group of an amino acid residue react together to form a peptide having an amide bond, also called a peptide bond, of the formula -NH-C(=O)- or -NR-C(=O)-.

[0065] Therefore, the term "amino acid" is not limited to natural and unnatural alpha and beta amino acids, but also includes residues such as 3-aminopropanoyl and 4-aminobutanoyl (when they form part of a peptide). This term also includes cyclic structures such as carbocyclic and heterocyclic structures that have amine and carboxylic acid functional groups. The amine group of an amino acid may be further functionalized with an azide group (-N3), for example, (N3)-Lys or D-(N3)-Lys.

[0066] Some amino acids described herein have both an amine group and a carboxylic acid group bonded to the same carbon atom and are called alpha (α) amino acids. Some amino acids described herein have the amine group and carboxylic acid group separated by only 1, 2, 3, 4, 5, or 6 carbon atoms. For example, in beta-Lys and D-beta-Lys, the amine group and carboxylic acid group are separated by only one carbon atom, and the carbon atom connected to the amine group and the carbon atom connected to the carboxylic acid group are adjacent to each other.

[0067] Some of the amino acids described herein have side chains specific to each amino acid. Furthermore, these side chains may be further functionalized.

[0068] Throughout this specification, naturally occurring amino acids are referred to by conventional three-letter or one-letter abbreviations (e.g., Ala or A for alanine, Arginine, etc.) unless they are referred to by their formal names. For certain less common or naturally occurring amino acids (i.e., amino acids other than the 20 amino acids encoded by the standard mammalian genetic code), unless they are referred to by their formal names (e.g., ornithine, etc.), commonly used three-letter or four-letter codes, including 2-Nal(3-(2-naphthyl)-alanine), are used for those residues.

[0069] Unless otherwise indicated, both the L and D isomers of the amino acid in question are referred to. In one embodiment, unless otherwise specified, the amino acid referred to herein is in the L isomer form. In one embodiment, unless otherwise specified, the amino acid referred to herein is in the D isomer form. In a preferred embodiment, unless otherwise specified, the amino acid referred to herein is in the L isomer form.

[0070] Unless otherwise specified, both homomorphic and non-homomorphic forms of the amino acid in question are referred to. As is evident from Table A below, the prefix "homo" in the names of amino acids indicates that a methylene group is attached to the α-carbon of the amino acid. In one embodiment, unless otherwise specified, the amino acids referred to herein are non-homomorphic. In one embodiment, unless otherwise specified, the amino acids referred to herein are homomorphic. In a preferred embodiment, unless otherwise specified, the amino acids referred to herein are non-homomorphic.

[0071] Unless otherwise specified, both the alpha and beta forms of the amino acid in question are referred to. As is evident from Table A below, the prefix "beta" in the amino acid name indicates that the carbon skeleton is elongated by the insertion of one carbon atom immediately following the acidic group of the amino acid skeleton. In one embodiment, unless otherwise specified, the amino acid referred to herein is the alpha form. In one embodiment, unless otherwise specified, the amino acid referred to herein is the beta form. In a preferred embodiment, unless otherwise specified, the amino acid referred to herein is the alpha form.

[0072] An amino acid residue is the amino acid portion within a peptide chain. A non-natural amino acid residue can be identified as a defined non-natural amino acid fragment of a peptide chain (for example, the non-natural amino acid 3-aminopropanoic acid can be identified as the non-natural amino acid residue 3-aminopropanoyl in a peptide chain).

[0073] Examples of abbreviations for additional amino acid residues are listed in Table A. [Table 1] JPEG2026518789000002.jpg251170 JPEG2026518789000003.jpg250170 JPEG2026518789000004.jpg243170 JPEG2026518789000005.jpg252170 JPEG2026518789000006.jpg235170 JPEG2026518789000007.jpg242170 JPEG2026518789000008.jpg237170 JPEG2026518789000009.jpg238170 JPEG2026518789000010.jpg244170 JPEG2026518789000011.jpg222170 JPEG2026518789000012.jpg252170 JPEG2026518789000013.jpg202170

[0074] Using Table A above and Table A1 below, those skilled in the art will be able to derive the structures of all D, beta, homo, homo-beta, N-Me, and N3 analogs (and combinations thereof) of the amino acid residues disclosed herein. In particular, Table A1 outlines the relevant analogs of the lysine amino acid, and by applying them thereafter, the corresponding structures of all equivalent amino acid analogs disclosed herein can be derived. [Table 2] JPEG2026518789000015.jpg239170 JPEG2026518789000016.jpg37170

[0075] Linear peptides are described from left to right, from the N-terminus to the C-terminus.

[0076] Non-natural (or naturally occurring) amino acids and non-natural (or naturally occurring) amino acid residues are amino acids and amino acid residues that are not naturally present in a peptide chain. Non-natural amino acids may be formed as secondary metabolites of bacteria, fungi, plants, or marine organisms, or they can be chemically synthesized.

[0077] Unless otherwise specified, the peptide backbone (i.e., the amide bonds "-" between X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13 of the peptide chain) is formed by amino acid residues joined by amide bonds via terminal -NH2 and -COOH groups. That is, the "terminal -NH2 group" is either an alpha-amine group in the case of alpha-amino acids, or a beta-amine group in the case of beta-amino acids such as bLys, {d}bLys, and beta-hLys, and the "terminal -COOH group" is an alpha-carboxylic acid group in the case of alpha-amino acids. Therefore, a person skilled in the art will understand that the amino acids of the peptide chain (i.e., the amino acids specified for at least X3, X4, X5, X6, X7, X8, X9, X10, X11, and X12) are in the form of -NH-XC(=O)-, where X represents the amino acid structure between the amine residue and the carboxylic acid residue that forms the amide backbone of the peptide chain.

[0078] If an amino acid residue contains two or more amine groups (-NH2, e.g., Lys and Dab) or carboxylic acid groups (-COOH, e.g., Glu and D-Glu), the peptide backbone may instead be formed using the side chains of the amino acid residue.

[0079] For example, the following nomenclature is used to distinguish between the use of terminal and side-chain -NH2 and -COOH groups. [Table 3] JPEG2026518789000018.jpg186170

[0080] It will be understood that by using Table B above in conjunction with Tables A and A1, the structures of all corresponding isoanalogs disclosed herein can be derived.

[0081] The C-terminus of a peptide can be derivatized with a pyridyl-substituted alkyl group to improve gastrointestinal stability (see Example 2). The following C-terminal derivatives are disclosed in Table C. [Table 4]

[0082] In the case of the NH-(2-(pyridine-3-yl)ethyl) group, NH-(4-(pyridine-3-yl)butanyl) group, NH-(6-(pyridine-3-yl)hexanyl) group, and NH-(3-(pyridine-3-yl)propyl) group, these are bonded to the carbonyl carbon of the carboxylic acid group of the C-terminal amino acid residue, such as Glu, beta-homo-Glu, and Dab. This bond forms an amide bond.

[0083] In the case of the 3-pyridylpropionyl group and the 6-(3-pyridyl)hexanoyl group, they are bonded to the amine group of the C-terminal amino acid residue, such as iso-Dab. This bond forms an amide bond.

[0084] Lactam Lactams are cyclic amides of the formula cyclo(R-NH-C(=O)-R), where each R may be any other suitable functional group bonded to another R. Each R may be the same or different.

[0085] Thioether and dithioether A thioether is a functional group of the formula RSR, where R may be any other suitable functional group. A dithioether is a functional group containing two thioether groups linked together by a linker, such as RSLYLSR, where the linker is -LYL-.

[0086] Head-to-tail cyclization The term "head-to-tail cyclization" refers to the cyclization of an N-terminal amine (or its derivative) and a C-terminal carboxylic acid to form a cyclic peptide. Typically, this cyclization results in the formation of an amide bond.

[0087] Alkyl The term "alkyl" refers to a monoradical of a saturated linear or branched hydrocarbon. Preferably, an alkyl group contains 1 to 40 carbon atoms, i.e., 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, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 carbon atoms, for example 1 to 30, for example 1 to 20, for example 1 to 12, for example 1 to 10, for example 1 to 8, for example 1 to 6, or 1 to 4 carbon atoms. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl (also called 2-propyl or 1-methylethyl), butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl, neo-pentyl, 1,2-dimethylpropyl, isoamyl, n-hexyl, isohexyl, sec-hexyl, n-heptyl, isoheptyl, n-octyl, 2-ethylhexyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-undecyl, n-dodecyl, n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n-heptadecyl, n-octadecyl, n-nonadecyl, n-icosyl, n-triacontyl, and n-tetracontyl. "Substituted alkyl" means that one or more hydrogen atoms of an alkyl group (for example, from one to the maximum number of hydrogen atoms bonded to the alkyl group, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, e.g., 1 to 5, 1 to 4, 1 to 3, or 1 or 2) are replaced by a non-hydrogen substituent (if more than one hydrogen atom is replaced, the substituents may be the same or different). In one embodiment, the alkyl is substituted with one or more substituents selected from List A, e.g., 1, 2, or 3, e.g., 1 or 2, e.g., 1 substituent. Examples of substituted alkyls include chloromethyl, dichloromethyl, fluoromethyl, and difluoromethyl.

[0088] C 1-6 alkyl group In the context of the compound of the present invention, group R 2 C may exist as 1-6 The alkyl group is not limited to these, but may include C6 alkyl groups such as hexanyl (-CH2CH2CH2CH2CH2CH3), C5 alkyl groups such as pentanyl (-CH2CH2CH2CH2CH3), or C 1-4 Alkyl groups are examples.

[0089] C 1-4 alkyl group In the context of the compound of the present invention, group R 2 C may exist as 1-4 The alkyl groups are not limited to these, but include C4 alkyl groups such as butyl (n-Bu or -CH2CH2CH2CH3), or C alkyl groups such as methyl (Me or -CH3, i.e., C1 alkyl group), ethyl (-CH2CH3, i.e., C2 alkyl group), 1-propyl (-CH2CH2CH3, i.e., C3 alkyl group), or 2-propyl (-CH(CH3)2, i.e., C3 alkyl group). 1-3 Alkyl groups are examples.

[0090] C 1-3 alkyl group In the context of the compound of the present invention, group R 2 C may exist as 1-3 Examples of alkyl groups include methyl (Me or -CH3, i.e., C1 alkyl group), ethyl (-CH2CH3, i.e., C2 alkyl group), 1-propyl (-CH2CH2CH3, i.e., C3 alkyl group), and 2-propyl (-CH(CH3)2, i.e., C3 alkyl group).

[0091] C 1-2 alkyl group In the context of the compound of the present invention, group R 2 C may exist as 1-2 Examples of alkyl groups include methyl (Me or -CH3, i.e., C1 alkyl group) and ethyl (-CH2CH3, i.e., C2 alkyl group).

[0092] ω-hydroxy-C 2-6 Alkanic acid In this specification, the residue at position X3 is ω-hydroxy-C 2-6 It may also be an alkanate. This residue has the following structure: [ka] It can be expressed as follows, where n is 1, 2, 3, 4, or 5.

[0093] In some embodiments, n is selected from 1, 2, or 3, and therefore ω-hydroxy-C 2-6 Alkanes are ω-hydroxy-C 2-4 It is an alkanic acid. In some embodiments, n is 2, and therefore ω-hydroxy-C 2-6 Alkanes are ω-hydroxy-C3 alkanes such as 3-hydroxypropanoic acid.

[0094] Alkilen The term "alkylene" refers to a diradical of a saturated linear or branched hydrocarbon. Preferably, the alkylene group contains 1 to 40 carbon atoms, i.e., 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, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 carbon atoms, for example 1 to 30, for example 1 to 20, for example 1 to 12, for example 1 to 10, for example 1 to 8, for example 1 to 6, or 1 to 4 carbon atoms. Examples of alkylene groups include methylene, ethylene (i.e., 1,1-ethylene, 1,2-ethylene), propylene (i.e., 1,1-propylene, 1,2-propylene (-CH(CH3)CH2-), 2,2-propylene (-C(CH3)2-), and 1,3-propylene), and butylene isomers (e.g., 1,1-butylene, 1,2-butylene, 2,2-butylene) ,1,3-butylene, 2,3-butylene (cis or trans, or mixtures thereof), 1,4-butylene, 1,1-isobutylene, 1,2-isobutylene, and 1,3-isobutylene), pentylene isomers (e.g., 1,1-pentylene, 1,2-pentylene, 1,3-pentylene, 1,4-pentylene, 1,5-pentylene, 1,1-isopentylene) 1,1-sec-pentyl, 1,1-neo-pentyl), hexylene isomers (e.g., 1,1-hexylene, 1,2-hexylene, 1,3-hexylene, 1,4-hexylene, 1,5-hexylene, 1,6-hexylene, and 1,1-isohexylene), heptylene isomers (e.g., 1,1-heptylene, 1,2-heptylene, 1,3-heptylene, 1,4-heptylene), Examples include butylene, 1,5-heptylene, 1,6-heptylene, 1,7-heptylene, and 1,1-isoheptylene, and octylene isomers (e.g., 1,1-octylene, 1,2-octylene, 1,3-octylene, 1,4-octylene, 1,5-octylene, 1,6-octylene, 1,7-octylene, 1,8-octylene, and 1,1-isooctylene).

[0095] In one embodiment, alkylene is C 1-20is an alkylene. In one embodiment, the alkylene is C 2-14 is an alkylene. In one embodiment, the alkylene is C 3-9 is an alkylene. In one embodiment, the alkylene is C 7-9 is an alkylene.

[0096] The straight-chain alkylene moiety having at least 3 carbon atoms and free valences at each end can also be specified as a multiple of methylene (for example, 1,4-butylene may sometimes be referred to as tetramethylene). Generally, instead of using the suffix "ylene" for the alkylene moiety specified above, the suffix "diyl" can also be used (for example, 1,2-butylene may sometimes be referred to as butane-1,2-diyl). "Substituted alkylene" means that one or more (for example, from 1 to the maximum number of hydrogen atoms bonded to the alkylene group, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, for example, 1 to 5, 1 to 4, 1 to 3, or 1 or 2) hydrogen atoms of the alkylene group are replaced with substituents other than hydrogen (when more than one hydrogen atom is replaced, the substituents may be the same or different). In one embodiment, the alkylene is substituted with one or more, for example, 1, 2, or 3, for example, 1 or 2, for example, 1 substituent selected from List A.

[0097] C 1-4 alkylene group may be present as the group L of the dithioether bridge in the context of the compounds of the present invention and C 1-4 Examples of the alkylene group include, but are not limited to, C such as methylene (-CH2-, that is, C1 alkylene group) and ethylene (-CH2CH2-, that is, C2 alkylene group). 1-2 alkylene groups are mentioned.

[0098] alkyleneoxy The term "alkyleneoxy" means "alkylene - O -", and the alkylene is defined and exemplified above. In one embodiment, the alkyleneoxy is (C 2-3) means alkylene oxy. In one embodiment, alkylene oxy means (C2) alkylene oxy (ethylene oxy). In one embodiment, alkylene oxy means (C3) alkylene oxy (propylene oxy).

[0099] Carbocyclic and heterocyclic groups - cycloalkyl, cycloalkylene, cycloalkenyl, cycloalkenylene, heterocyclyl The terms "cycloalkyl" and "cycloalkenyl" preferably refer to cyclic non-aromatic forms of "alkyl" and "alkenyl" having 3 to 40 carbon atoms, for example 3 to 30, for example 3 to 20, for example 3 to 14 carbon atoms, for example 3 to 12, or 3 to 10 carbon atoms, i.e., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 carbon atoms (for example 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms), more preferably 3 to 7 carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, and adamantyl. Examples of cycloalkenyl groups include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, and cyclodecenyl. A cycloalkyl or cycloalkenyl group may consist of one ring (monocyclic), two rings (bicyclic), or more than two rings (polycyclic). "Substituting cycloalkyl" means that one or more hydrogen atoms of the cycloalkyl group (for example, from one to the maximum number of hydrogen atoms bonded to the cycloalkyl group, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, e.g., 1 to 5, 1 to 4, or 1 to 3, or 1 or 2) are replaced by a non-hydrogen substituent (if more than one hydrogen atom is replaced, the substituents may be the same or different). In one embodiment, the cycloalkyl or cycloalkenyl is substituted with one or more substituents selected from List A, e.g., one, two, or three, e.g., one or two, e.g., one substituent.

[0100] The terms "cycloalkylene" and "cycloalkenylene" preferably represent cyclic non-aromatic forms of "alkylene" and "alkenylene" having 3 to 40, such as 3 to 30, such as 3 to 20, such as 3 to 14, for example 3 to 12, or 3 to 10 carbon atoms, that is, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 carbon atoms (for example, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms), more preferably 3 to 10 carbon atoms, such as 5 to 10 carbon atoms. In one embodiment, the cycloalkylene is (C 5-10 ) cycloalkylene. In one embodiment, the cycloalkylene is (C 3-10 ) cycloalkylene. In one embodiment, the cycloalkenylene is (C 3-10 ) cycloalkenylene. In one embodiment, the cycloalkenylene is (C 5-10 ) cycloalkenylene. Exemplary cycloalkylene groups include cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, cyclooctylene, cyclononylene, and cyclodecylene. Exemplary cycloalkenylene groups include cyclopentenenylene and cyclohexenylene. In one embodiment, the cycloalkylene or cycloalkenylene is substituted with one or more, such as one, two, or three, for example one or two, for example one substituent selected from List A.

[0101] The terms “heterocyclyl” or “heterocyclic ring” mean a cycloalkyl group as defined above, wherein one, two, three, or four carbon atoms of the cycloalkyl group are replaced by heteroatoms of oxygen, nitrogen, silicon, selenium, phosphorus, or sulfur, preferably O, S, or N. A heterocyclyl group has one or two rings, preferably containing 3 to 10 ring atoms, for example, 3, 4, 5, 6, or 7. Preferably, in each ring of the heterocyclyl group, the maximum number of O atoms is 1, the maximum number of S atoms is 1, and the maximum total number of O and S atoms is 2. The term “heterocyclyl” also means to include partially or completely hydrogenated forms (dihydro, tetrahydro, or perhydro forms, etc.) of the heteroaryl groups mentioned above. Examples of heterocyclyl groups include morpholinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl (also called piperidyl), piperazinyl, dihydrofuranyl and tetrahydrofuranyl, dihydrothienyl and tetrahydrothienyl, dihydropyranyl and tetrahydropyranyl, urotropinyl, lactones, lactams, cyclic imides, and cyclic anhydrides. A "substituted heterocyclyl" means that one or more hydrogen atoms of a heterocyclyl group (for example, from one to the maximum number of hydrogen atoms bonded to the heterocyclyl group, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, e.g., 1 to 5, 1 to 4, or 1 to 3, or 1 or 2) are replaced by a non-hydrogen substituent (if more than one hydrogen atom is replaced, the substituents may be the same or different). In one embodiment, the heterocyclyl is substituted with one or more substituents selected from List A, for example, one, two, or three substituents, for example, one or two, for example, one substituent.

[0102] Aromatic groups - aryl, heteroaryl, arylene, heteroarylene The term "aryl" refers to a monoradical of an aromatic cyclic hydrocarbon. Preferably, the aryl group contains 3 to 14 carbon atoms (e.g., 5, 6, 7, 8, 9, or 10, e.g., 5, 6, or 10) that can be arranged in one ring (e.g., phenyl) or two or more fused rings (e.g., naphthyl). Exemplary aryl groups include cyclopropenilium, cyclopentadienyl, phenyl, indenyl, naphthyl, azlenyl, fluorenyl, anthryl, and phenanthryl. Preferably, "aryl" refers to a monocyclic ring containing 6 carbon atoms or an aromatic bicyclic ring system containing 10 carbon atoms. Preferred examples are phenyl and naphthyl. The term "aryl" does not include fullerenes. "Substitutive aryl" means that one or more hydrogen atoms of an aryl group (for example, from one to the maximum number of hydrogen atoms bonded to the aryl group, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, e.g., 1 to 5, 1 to 4, or 1 to 3, or 1 or 2) are replaced by a non-hydrogen substituent (if more than one hydrogen atom is replaced, the substituents may be the same or different). In one embodiment, the aryl is substituted with one or more substituents selected from List A, e.g., 1, 2, or 3, e.g., 1 or 2, e.g., 1 substituent. Examples of substituted aryls include biphenyl, 2-fluorophenyl, 2-chloro-6-methylphenyl, anilinyl, 4-hydroxyphenyl, and methoxyphenyl (i.e., 2-, 3-, or 4-methoxyphenyl).

[0103] The terms “heteroaryl” or “heteroaromatic ring” refer to the aryl group as defined above, in which one or more carbon atoms of the aryl group are replaced by heteroatoms of O, S, or N. Preferably, a heteroaryl refers to a five-membered or six-membered aromatic monocyclic ring in which one, two, or three carbon atoms are replaced by the same or different heteroatoms of O, N, or S. Alternatively, it refers to an aromatic bicyclic or tricyclic ring system in which one, two, three, four, or five carbon atoms are replaced by the same or different heteroatoms of O, N, or S. Preferably, in each ring of the heteroaryl group, the maximum number of O atoms is 1, the maximum number of S atoms is 1, and the maximum total number of O and S atoms is 2. Exemplary heteroaryl groups include furanyl, thienyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, triazinyl, benzofuranyl, indolyl, isoindolyl, benzothienyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, and benzotri Examples include zolyl, quinolinil, isoquinolinil, benzodiadinil, quinoxalinil, quinazolinil, benzotriazinil, pyridadinil, phenoxadinil, thiazolopyridinil, pyrrolothiazolyl, phenothiazinil, isobenzofuranil, clomenil, xanthenil, pyrrolidinil, indazolyl, purinil, quinolidinil, phthalazinil, naphthyridinil, sinnolinil, pteridinil, carbazolyl, phenanthridine, acridinil, perimidinil, phenanthrolinil, and phenadinil. Examples of five- or six-membered heteroaryl groups include furanyl, thienyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrrolyl, imidazolyl (e.g., 2-imidazolyl), pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl (e.g., 4-pyridyl), pyrimidinyl, pyrazinyl, triazinyl, and pyridazinyl."Substituting heteroaryl" means that one or more hydrogen atoms of a heteroaryl group (for example, from one to the maximum number of hydrogen atoms bonded to the heteroaryl group, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, e.g., 1 to 5, 1 to 4, or 1 to 3, or 1 or 2) are replaced by a non-hydrogen substituent (if more than one hydrogen atom is replaced, the substituents may be the same or different). In one embodiment, the heteroaryl is substituted with one or more substituents selected from List A, e.g., 1, 2, or 3, e.g., 1 or 2, e.g., 1 substituent.

[0104] The term "arylene" refers to a diradical of an aromatic cyclic hydrocarbon. Preferably, the aryl group contains 3 to 14 carbon atoms (e.g., 5, 6, 7, 8, 9, or 10, e.g., 5, 6, or 10) that can be arranged in one ring (e.g., phenyl) or two or more fused rings (e.g., naphthyl). Preferably, "arylene" is C 5-14 It is arylene. More preferably, "arylene" is C 6-14 It is an arylene. More preferably, "arylene" refers to a monocyclic ring containing six carbon atoms, or an aromatic bicyclic ring system containing ten carbon atoms. 6-10 The material is an arylene. Preferably, "arylene" refers to a monocyclic ring containing six carbon atoms or an aromatic bicyclic ring system containing ten carbon atoms. Preferred examples are phenylene (which may be 1,2-phenylene, 1,3-phenylene, or 1,4-phenylene) and naphthylene (which may be 1,2-naphthylene, 1,3-naphthylene, 1,4-naphthylene, 1,5-naphthylene, 1,6-naphthylene, 1,7-naphthylene, or 1,8-naphthylene).

[0105] Optional substituents Many of the amino acid residues described herein may be optionally substituted. In some embodiments, the substituents are selected from the group defined in List A below. In some embodiments, the substituents are selected from the group defined in List A1 below. In some embodiments, the substituents are selected from the group defined in List A2 below.

[0106] The substituents in "List A" are C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkynyl, 6-14 member (e.g., 6-10 member), aryl, 3-14 member (e.g., 5 or 6 member), heteroaryl, 3-14 member (e.g., 3-7 member), cycloalkyl, 3-14 member (e.g., 3-7 member), heterocyclyl, halogen, -CN, azide, -NO2, -OR', -N(R')2, -S(O) 0-2 R', -S(O) 1-2 OR', -OS(O) 1-2 R', -OS(O) 1-2 OR', -S(O) 1-2 N(R')2, -OS(O) 1-2 N(R')2, -N(R')S(O) 1-2 R', -N(R')S(O) 1-2 OR', -C(=X 1 )R', -C(=X 1 )X 1 R', -X 1 C(=X 1 )R', and -X 1 C(=X 1 )X 1 Selected from the group consisting of R', in the formula, X 1 R' is independently selected from O, S, NH, and N(CH3), and each R' is H, C 1-4 Alkyl, C 2-4 Alkenil, C 2-4 Independently selected from the group consisting of alkynyl, 5-membered or 6-membered cycloalkyl, 5-membered or 6-membered aryl, 5-membered or 6-membered heteroaryl, and 5-membered or 6-membered heterocyclyl, wherein each of the alkyl group, alkenyl group, alkynyl group, cycloalkyl group, aryl group, heteroaryl group, and heterocyclyl group is C 1-3Alkyl, halogen, -CF3, -CN, azide, -NO2, -OH, -O(C 1-3 Alkyl), -S(C 1-3 Alkyl), -NH2, -NH(C 1-3 Alkyl), -N(C 1-3 Alkyl)2,-N + (C 1-3 Alkyl)3,-NHS(O)2(C 1-3 Alkyl), -S(O)2NH 2-z (C 1-3 Alkyl) z -C(=O)OH, -C(=O)O(C 1-3 Alkyl), -C(=O)NH 2-z (C 1-3 Alkyl) z , -NHC(=O)(C 1-3 Alkyl), -NHC(=NH)NH z-2 (C 1-3 Alkyl) z , and -N(C 1-3 Alkyl)C(=NH)NH 2-z (C 1-3 Alkyl) z It may be substituted with one, two, or three substituents independently selected from the group consisting of, where each z is independently 0, 1, or 2, and each C 1-3 Alkyl compounds are independently methyl, ethyl, or propyl.

[0107] In some embodiments, the substituent in List A is C 1-3 Alkyl, phenyl, halogen, -CF3, -OH, -OCH3, -SCH3, -NH 2-z (CH3) z Selected from list A1 consisting of -C(=O)OH, C(=O)OCH3, and -C(=O)CH3, where z is 0, 1, or 2, C 1-3 Alkyl compounds are methyl, ethyl, propyl, or isopropyl.

[0108] In some embodiments, the substituents in List A are selected from List A2, which consists of C(=O)CH3, methyl, ethyl, propyl, isopropyl, halogens (such as F, Cl, or Br), and -CF3.

[0109] bridging part The sequences disclosed herein include crosslinking segments indicated in parentheses (e.g., (1a), (2a), etc.). These represent chemical crosslinks between specific pairs of residues. Each pair of parentheses will appear twice in the sequence to indicate a single crosslinking segment. Most sequences have two crosslinking segments indicated by four sets of parentheses, each representing a pair of crosslinking segments.

[0110] Numbers in parentheses indicate specific crosslinking subpairs (for example, "1" indicates a crosslink between amino acid residues at positions 2 and 11, also indicated by square brackets that define specific chemical crosslinks). Letters indicate the type of chemical crosslink (for example, "a" indicates a 1,3-dithio-propan-2-one crosslink, and "c" indicates a lactam crosslink).

[0111] Specific chemical crosslinks are indicated using square brackets at the end of the table (e.g., [2,11], [2,7], [10,13], etc.), and the amino acid residues used in the crosslinking portion are shown in comparison to the original start peptide (I3 peptide (isomer 3) described in Example 2 of International Publication No. 2023 / 099669). Therefore, these may not exactly match the actual amino acid numbers of the sequence numbers (for example, in some of these sequences, the first amino acid residue is deleted compared to the original start peptide).

[0112] The residue immediately preceding the parenthetical notation indicates that a specific residue is used in the cross-linking portion.

[0113] The parenthetical notation immediately followed by † The notation indicates that an alpha-amine (-NH2) group (or a beta-amine group in the case of bLys, {d}bLys, and beta-hLys, or in the case of (N3)-K and {d}(N3)-K, the alpha-amine is converted to an azide group) is used in the formation of the crosslink.

[0114] The parenthetical notation immediately followed by ‡The notation indicates that an alpha-carboxylic acid (-COOH) group is used in the formation of the crosslink.

[0115] Both alpha-amine (-NH2) groups (or beta-amine groups in the case of bLys, {d}bLys, and beta-hLys) and alpha-carboxylic acid (-COOH) groups have conventionally been used to form the peptide skeleton (see, for example, Table B).

[0116] The parenthetical notation immediately followed by * The notation " indicates that the terminal -NH2 (at the beginning of the sequence, i.e., the N-terminus) or -COOH (at the end of the sequence, i.e., the C-terminus) is used to form the crosslink. The crosslinked portion is triazole, * When the notation " is used at the N-terminus, the terminal -NH2 is converted to the azide (-N3) of the N-terminal amino acid residue.

[0117] SMILES string Below the structure described by the amino acid sequence of each compound disclosed herein, a Simplified Molecular-Input Line-Entry System (SMILES) string is provided. SMILES strings are a line notation for describing the structure of a chemical species using short American Standard Code for Information Interchange (ASCII) strings. SMILES strings can be imported into most molecular editors (e.g., ChemDraw®, BIOVIA Draw) and converted back into a two-dimensional or three-dimensional diagram of the chemical structure. In the event of any discrepancy between the structure of the amino acid sequence and the structure provided by the SMILES string, the SMILES string takes precedence.

[0118] compound The present invention provides compounds that are peptide inhibitors of IL-23R. These compounds exhibit a combination of desirable properties, such as very potent inhibition of IL-23R and / or high stability in the gastrointestinal tract (see Example 3). Furthermore, the compounds described herein may be useful in the treatment of various diseases, conditions, and disorders related to IL-23R, such as inflammatory bowel diseases such as Crohn's disease or ulcerative colitis, psoriasis, and psoriatic arthritis. The compounds described herein exhibit improved properties (such as potent inhibition and / or higher gastrointestinal stability) compared to the compounds disclosed in International Publication No. 2023 / 099669.

[0119] This invention is based on the formula: ZR 2 A compound of which, in the formula, R 2 NHR 3 Or C(=O)R 3 And R 3 C may be substituted with hydrogen or a pyridyl ring. 1-6 Alkyl, NHR 3 Or C(=O)R 3 is or does not exist, Z is given by equation I: X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13 (I) This is the amino acid sequence, and in the sequence, X2 is Lys, D-lys, iso-Lys, D-iso-Lys, beta-Lys, D-beta-Lys, homo-Lys, D-homo-Lys, beta-homo-Lys, N-Me-Lys, N-Me-homo-Lys, (N3)-Lys, D-(N3)-Lys, (N3)-beta-Lys, (N3)-D-beta-Lys, (N3)-homo-Lys, (N3)-D-homo-Lys, (N3)-beta-homo-Lys, Dpr, D-Dpr, iso-Dpr, D-iso-Dpr, beta-Dpr, D-beta-Dpr, homo-Dpr, D-homo-Dpr, beta-homo-Dpr, N-Me-Dpr, N-Me-homo-Dpr, (N3)-Dpr, D-(N3)-Dpr, (N3)-beta-Dpr, (N3)-D-beta-Dpr, (N3)-homo-Dpr, (N3)-D-homo-Dpr, (N3)-beta-homo-Dpr, Dab, D-Dab, iso-Dab, D-iso-Dab, beta-Dab, D-beta-Dab, homo-Dab, D-homo-Dab, beta-homo-Dab, N-Me-Dab, N-Me-homo-Dab, (N3)-Dab, D-(N3)-Dab, (N3)-beta-Dab, (N3)-D-beta-Dab, (N3)-homo-Dab, (N3)-D-homo-Dab, (N3)-beta-homo-Dab, Orn, D-Orn, Iso-Orn, D-Iso-Orn, Beta-Orn, D-Beta-Orn, Homo-Orn, D-Homo-Orn, Beta-Homo-Orn, N-Me-Orn, N-Me-Homo-Orn, (N3)-Orn, D-(N3)-Orn, (N3)-Beta-Orn, (N3)-D-Beta-Orn, (N3)-Homo-Orn, (N3)-D-Homo-Orn, (N3)-Beta-Homo-Orn, Lys (Gly), Asp, D-Asp, Iso-Asp, D-Iso-Asp, Beta-Asp, D-Beta-Asp, Homo-Asp, D-Homo-Asp, Beta-Homo-Asp, N-Me-Asp, N-Me-Homo-Asp, (N3)-Asp, D-(N3)-Asp, (N3)-Beta-Asp, (N3)-D-Beta-Asp, (N3)-Homo-Asp, (N3)-D-Homo-Asp, (N3)-Beta-Homo-Asp, Glu, D-Glu, Iso-Glu, D-Iso-Glu, Beta-Glu, D-Beta-Glu, Homo-Glu, D-Homo-Glu, Beta-Homo-Glu, N-Me-Glu, N-Me-Homo-Glu, (N3)-Glu, D-(N3)-Glu, (N3)-Beta-Glu, (N3)-D-Beta-Glu, (N3)-Homo-Glu, (N3)-D-Homo-Glu, (N3)-Beta-Homo-Glu, Selected from the group consisting of 2-amino-6-carboxyhexanoyl and 3-aminopropanoyl, X3 is any amino acid, ω-hydroxy-C 2-6 Selected from alkanates, or absent, X4 is Val D-Val, Beta-Val, D-Beta-Val, Homo-Val, D-Homo-Val, Beta-Homo-Val, N-mer-Val, N-mer-Homo-Val, 2-mer-Val, Ala, D-Ala, Beta-Ala, D-Beta-Ala, Homo-Ala, D-Homo-Ala, Beta-Homo-Ala, N-Me-Ala, N-Me-Homo-Ala, Gly, Beta-Gly, Homo-Gly, Beta-Homo-Gly, N-Me-Gly, N-Me-Homo-Gly Leu, D-Leu, Beta-Leu, D-Beta-Leu, Homo-Leu, D-Homo-Leu, Beta-Homo-Leu, N-Me-Leu, N-Me-Homo-Leu, 2-Me-Leu, Ile, D-Ile, Beta-Ile, D-Beta-Ile, Homo-Ile, D-Homo-Ile, Beta-Homo-Ile, N-Me-Ile, N-Me-Homo-Ile, or absent. X5 is selected from the group consisting of a tryptophan residue that may be substituted, azatryptophan residue that may be substituted, and a beta-homotryptophan residue that may be substituted. X6 may be a substituted Gln residue, a substituted Lys residue, a substituted Arg residue, a substituted Dab residue, a substituted Orn residue, a substituted Phe residue, Ala, D-Ala, Beta-Ala, D-Beta-Ala, Homo-Ala, D-Homo-Ala, Beta-Homo-Ala, N-Me-Ala, N-Me-Homo-Ala, Cit, D-Cit, Beta-Cit, D-Beta-Cit, Homo-Cit, D-Homo-Cit, Beta-Homo-Cit, N-Me-Cit, N-Me-Homo-Cit, Glu, D-Glu, Iso-Glu, D-Iso-Glu, Beta-Glu, D-Beta-G Selected from the group consisting of lu, homo-Glu, D-homo-Glu, beta-homo-Glu, N-Me-Glu, N-Me-homo-Glu, Tyr, D-Tyr, beta-Tyr, D-beta-Tyr, homo-Tyr, D-homo-Tyr, beta-homo-Tyr, N-Me-Tyr, N-Me-homo-Tyr, Val, D-Val, beta-Val, D-beta-Val, homo-Val, D-homo-Val, beta-homo-Val, N-Me-Val, N-Me-homo-Val, or His, D-His, beta-His, D-beta-His, homo-His, D-homo-His, beta-homo-His, N-Me-His, and N-Me-homo-His, X7 is Asp, D-Asp, iso-Asp, D-iso-Asp, beta-Asp, D-beta-Asp, homo-Asp, D-homo-Asp, beta-homo-Asp, N-Me-Asp, N-Me-homo-Asp, Glu, D-Glu, Iso-Glu, D-Iso-Glu, Beta-Glu, D-Beta-Glu, Homo-Glu, D-Homo-Glu, Beta-Homo-Glu, N-Me-Glu, N-Me-Homo-Glu, Dab, D-Dab, iso-Dab, D-iso-Dab, beta-Dab, D-beta-Dab, homo-Dab, D-homo-Dab, beta-homo-Dab, N-Me-Dab, N-Me-homo-Dab, Orn, D-Orn, Iso-Orn, D-Iso-Orn, Beta-Orn, D-Beta-Orn, Homo-Orn, D-Homo-Orn, Beta-Homo-Orn, N-Me-Orn, N-Me-Homo-Orn, Lys, D-Lys, iso-Lys, beta-Lys, D-iso-Lys, D-beta-Lys, homo-Lys, D-homo-Lys, beta-homo-Lys, N-Me-Lys, N-Me-homo-Lys Pra, D-Pra, Beta-Pra, D-Beta-Pra, Homo-Pra, D-Homo-Pra, Beta-Homo-Pra, N-Me-Pra, N-Me-Homo-Pra, Selected from the group consisting of Hpg, D-Hpg, beta-Hpg, D-beta-Hpg, homo-Hpg, D-homo-Hpg, beta-homo-Hpg, N-Me-Hpg, and N-Me-homo-Hpg, X8 is selected from the group consisting of an optionally substituted tryptophan residue, an optionally substituted azatryptophan residue, an optionally substituted beta-homotryptophan residue, an optionally substituted tyrosine residue, an optionally substituted phenylalanine residue, an optionally substituted homophenylalanine residue, and an alanine residue substituted with a carbocyclic group or an aromatic or heteroaromatic group selected from the group consisting of phenyl, pyridyl, naphthyl, and quinolinyl, each of which may be substituted. X9 is selected from the group consisting of an optional tryptophan residue, an optional azatryptophan residue, an optional alanine residue, an optional phenylalanine residue, and an optional tyrosine residue. The X10 is Val, D-Val, Beta-Val, D-Beta-Val, Homo-Val, D-Homo-Val, Beta-Homo-Val, N-mer-Val, N-mer-Homo-Val, 2-mer-Val, Gly, Beta-Gly, Homo-Gly, Beta-Homo-Gly, N-Me-Gly, N-Me-Homo-Gly Dab, D-Dab, iso-Dab, D-iso-Dab, beta-Dab, D-beta-Dab, homo-Dab, D-homo-Dab, beta-homo-Dab, N-Me-Dab, N-Me-homo-Dab, Lys, D-lys, iso-lys, D-iso-lys, beta-lys, D-beta-lys, homo-lys, D-homo-lys, beta-homo-lys, N-Me-lys, N-Me-homo-lys Aib, D-Aib, Beta-Aib, D-Beta-Aib, Homo-Aib, D-Homo-Aib, Beta-Homo-Aib, N-Me-Aib, N-Me-Homo-Aib, Ala, D-Ala, Beta-Ala, D-Beta-Ala, Homo-Ala, D-Homo-Ala, Beta-Homo-Ala, N-Me-Ala, N-Me-Homo-Ala, Leu, D-Leu, Beta-Leu, D-Beta-Leu, Homo-Leu, D-Homo-Leu, Beta-Homo-Leu, N-Me-Leu, N-Me-Homo-Leu, 2-Me-Leu, Ile, D-Ile, Beta-Ile, D-Beta-Ile, Homo-Ile, D-Homo-Ile, Beta-Homo-Ile, N-Me-Ile, N-Me-Homo-Ile, Furthermore, carbocyclic or heterocyclic rings having amino substituents and carbonyl substituents. Selected from the group consisting of, X11 is Dpr, D-Dpr, iso-Dpr, D-iso-Dpr, beta-Dpr, D-beta-Dpr, homo-Dpr, D-homo-Dpr, beta-homo-Dpr, N-Me-Dpr, N-Me-homo-Dpr, Dab, D-Dab, iso-Dab, D-iso-Dab, beta-Dab, D-beta-Dab, homo-Dab, D-homo-Dab, beta-homo-Dab, N-Me-Dab, N-Me-homo-Dab, Orn, D-Orn, Iso-Orn, D-Iso-Orn, Beta-Orn, D-Beta-Orn, Homo-Orn, D-Homo-Orn, Beta-Homo-Orn, N-Me-Orn, N-Me-Homo-Orn, Lys, D-lys, iso-Lys, D-iso-Lys, beta-Lys, D-beta-Lys, homo-Lys, D-homo-Lys, beta-homo-Lys, N-Me-Lys, N-Me-homo-Lys, Lys(Me), Lys (Gly), Asp, D-Asp, iso-Asp, D-iso-Asp, beta-Asp, D-beta-Asp, homo-Asp, D-homo-Asp, beta-homo-Asp, N-Me-Asp, N-Me-homo-Asp, Glu, D-Glu, Iso-Glu, D-Iso-Glu, Beta-Glu, D-Beta-Glu, Homo-Glu, D-Homo-Glu, Beta-Homo-Glu, N-Me-Glu, N-Me-Homo-Glu, and 2-amino-6-carboxyhexanoyl Selected from the group consisting of, X12 is an alanine residue substituted with an optional Phe residue, an optional Tyr residue, an optional His residue, a carbocyclic group or an aromatic or heteroaromatic group selected from the group consisting of optional phenyl, pyridyl, naphthyl, and quinolinyl, Dab, D-Dab, iso-Dab, D-iso-Dab, beta-Dab, D-beta-Dab, homo-Dab, D-homo-Dab, beta-homo-Dab, N-Me-Dab, N-Me-homo-Dab, Gly, beta-Gly, homo-Gly, beta-homo-Gly, N-Me-Gly, N-Me-homo-Gly, Pro, 5-aminopentanoyl, 4-aminopiperidine-4-carbonyl, (R,S)-imidazolidined-2-carbonyl, 3-aminopropanoyl, Gly-CF3, D-Gly-C F3, Nle, Gln, D-Gln, Iso-Gln, D-Iso-Gln, Beta-Gln, D-Beta-Gln, Homo-Gln, D-Homo-Gln, Beta-Homo-Gln, N-Me-Gln, N-Me-Homo-Gln, THP, Ser, D-Ser, Beta-Ser, D-Beta-Ser, Homo-Ser, D-Homo-Ser, Beta-Homo-Ser, N-Me-Ser, N-Me-Homo-Ser, Se r(OMe),3-aminotetrahydrofuran-3-carbonyl,Arg,D-Arg,Beta-Arg,D-beta-Arg,Homo-Arg,D-homo-Arg,Beta-homo-Arg,N-Me-Arg,N-Me-homo-Arg,Thr,D-Thr,Beta-Thr,D-beta-Thr,Homo-Thr,D-homo-Thr,Beta-homo-Thr,N-Me-Thr,N-Me-homo-Thr Glu, D-Glu, Iso-Glu, D-Iso-Glu, Beta-Glu, D-Beta-Glu, Homo-Glu, D-Homo-Glu, Beta-Homo-Glu, N-Me-Glu, N-Me-Homo-Glu, Asn, D-Asn, Beta-Asn, D-Beta-Asn, Homo-Asn, D-Homo-Asn, Beta-Homo-Asn, N-Me-Asn, N-Me-Homo-Asn, 4-Aminobutanoyl, 2-(trimethyl-2-aminoethoxy)ethoxypropyl]propyl, and Lys, where the side chain -NH2 of Lys is -C(=O)(CH2) n R KIt is substituted with, where n is 0 to 2, and R K is selected from the group consisting of Lys, which is imidazolyl, pyrimidyl, or pyridyl, which may be substituted with F, or X12 is absent. X13 is an optional His residue, an optional Phe residue, an alanine residue substituted with a carbocyclic group or an aromatic or heteroaromatic group selected from the group consisting of optional phenyl, pyridyl, naphthyl, and quinolinyl, each of which may be substituted, Asn, D-Asn, beta-Asn, D-beta-Asn, homo-Asn, D-homo-Asn, beta-homo-Asn, N-Me-Asn, N-Me-homo-Asn, Gly, beta-Gly, homo-Gly, beta-homo-Gly, N-Me-Gly, N-Me-homo-Gly Furthermore, Dab, Orn, or Lys, where the side chain -NH2 is C(=O)(CH2) n R K It is substituted with, and in the formula n is 0 to 2, R K is selected from the group consisting of Dab, Orn, or Lys, which may be imidazolyl, pyrimidyl, or pyridyl substituted with F. or does not exist, In the array, (i) X2 and X11 are amino acid residues that together form a lactam crosslink, (ii) X2 and X7 are amino acid residues that together form a lactam crosslink or a crosslink containing a triazole ring, (iii) Optionally, if X13 is present, X10 and X13 are amino acid residues that together form a lactam crosslink. compound, Or provide a pharmaceutically acceptable salt or solvate thereof.

[0120] In some embodiments, the present invention is expressed by formula: ZR 2 A compound of which, in the formula, R 2 NHR 3 And R 3C may be substituted with hydrogen or a pyridyl ring. 1-6 Alkyl, NHR 3 is or does not exist, Z is given by equation Ia: X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13 (Ia) This is the amino acid sequence, and in the sequence, X2 is selected from the group consisting of Lys, D-Lys, iso-Lys, beta-Lys, D-beta-Lys, homo-Lys, D-homo-Lys, beta-homo-Lys, N-Me-Lys, Dab, D-Dab, Glu, iso-Glu, Orn, D-Orn, Lys(Gly), (N3)-Lys, and D-(N3)-Lys. X3 is selected from the group consisting of Thr, Trp, Ile, 3-aminopropanoyl, 4-aminobutanoyl, beta-homo-Ile, beta-homo-Thr, Gly, and N-Me-3-aminopropanoyl, and 3-hydroxypropanoic acid, or is absent. X4 is either Val or does not exist. X5 is either a trp or a 1-Me-Trp. X6 is Gln, Gln(Me), Dab(Ac-N-Me), Dab(Ac), or Gln(2Me). X7 is selected from the group consisting of Glu, homo-Glu, Asp, Pra, and Hpg. X8 is selected from the group consisting of Y(2-aminoethoxy), Y(Me), Y(Bn), F(4-Me), F(4-Bu), cyclopropyl-Ala, F(4-morpholine), F(4-THP), Y(CH3-2-F), F(4-F), F(4-piperazine), F(4-imidazole), Y(CH3-3-F), F(4-piperidine), 5-AzaTrp, Y(Ac-2-aminoethoxy), 7-AzaTrp, 6-AzaTrp, and F(4-CONH2). X9 is 2-Nal, X10 is selected from the group consisting of 2-Me-Leu, 2-Me-Val, D-Ala, Dab, Gly, and Aib. X11 is selected from the group consisting of Glu, homo-Glu, Lys, Lys(Me), Orn, and 2-amino-6-carboxyhexanoyl. X12 is selected from the group consisting of Dab, His, S(OCH3), D-His, His(1-Me), 3-(3-quinolinyl)-Ala, and 4-aminopiperidine-4-carbonyl. X13 is either 3-(3-pyridyl)-Ala, 3-(3,5-pyrimidyl)-Ala, or absent. In the array, (i) X2 and X11 are amino acid residues that together form a lactam crosslink, (ii) X2 and X7 are amino acid residues that together form a lactam crosslink or a crosslink containing a triazole ring, (iii) Optionally, if X13 is present, X10 and X13 are amino acid residues that together form a lactam crosslink. compound, Or provide a pharmaceutically acceptable salt or solvate thereof.

[0121] In some embodiments, the present invention is expressed by formula: ZR 2 A compound of which, in the formula, R 2 NHR 3 Or C(=O)R 3 And R 3 C may be substituted with hydrogen or a pyridyl ring. 1-6 Alkyl, NHR 3 Or C(=O)R 3 is or does not exist, Z is given by equation I: X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13 (I) This is the amino acid sequence, and in the sequence, X2 is selected from the group consisting of Lys, D-Lys, iso-Lys, beta-Lys, D-beta-Lys, homo-Lys, D-homo-Lys, beta-homo-Lys, N-Me-Lys, Dab, D-Dab, iso-Dab, Glu, iso-Glu, D-iso-Glu, Orn, D-Orn, Dpr, Lys(Gly), (N3)-Lys, and D-(N3)-Lys. X3 is selected from the group consisting of Thr, Ile, 3-aminopropanoyl, 4-aminobutanoyl, beta-homo-Ile, beta-homo-Thr, Gly, N-Me-3-aminopropanoyl, and Ser, or is absent. X4 is either Val or does not exist. X5 is selected from the group consisting of Trp, 1-Me-Trp, and beta-homo-Trp. X6 is Gln, X7 is selected from the group consisting of Glu, D-Glu, Homo-Glu, Asp, Pra, and Hpg. X8 is selected from the group consisting of Y(2-aminoethoxy), Y(Me), Y(nPr), Y(Bn), Trp, D-Phe, 2-Me-Phe, F(4-Me), F(4-Bu), 3-(2-pyridyl)-Ala, 3-(3-pyridyl)-Ala, 3-(4-pyridyl)-Ala, and cyclopropyl-Ala. X9 is 2-Nal or cyclopropyl-Ala, X10 is selected from the group consisting of 2-Me-Leu, 2-Me-Val, Dab, Gly, Lys, and Aib. X11 is selected from the group consisting of Glu, homo-Glu, beta-homo-Glu, Dab, iso-Dab, Lys, Lys(Me), Orn, and 2-amino-6-carboxyhexanoyl. X12 consists of Dab, His, D-His, His(1-Me), 3-(2-pyridyl)-Ala, 3-(3-pyridyl)-Ala, 3-(4-pyridyl)-Ala, 3-(3-quinolinyl)-Ala, Gly, Pro, 5-aminopentanoyl, 4-aminopiperidine-4-carbonyl, (R,S)-imidazolidined-2-carbonyl, and Lys, where the side chain -NH2 of Lys is -C(=O)(CH2). n R K It is substituted with, where n is 0 to 2, and R K is selected from the group consisting of Lys, which may be imidazolyl, pyrimidyl, or pyridyl substituted with F, or X12 does not exist. X13 is selected from the group consisting of 3-(3-pyridyl)-Ala, D-3-(3-pyridyl)-Ala, and 3-(3,5-pyrimidyl)-Ala, or is absent. In the array, (i) X2 and X11 are amino acid residues that together form a lactam crosslink, (ii) X2 and X7 are amino acid residues that together form a lactam crosslink or a crosslink containing a triazole ring, (iii) Optionally, if X13 is present, X10 and X13 are amino acid residues that together form a lactam crosslink. compound, Or provide a pharmaceutically acceptable salt or solvate thereof.

[0122] Furthermore, the present invention relates to formula: ZR 2 A compound of which, in the formula, R 2 NHR 3 And R 3 C may be substituted with hydrogen or a pyridyl ring. 1-6 Alkyl, NHR 3 is or does not exist, Z is given by equation Ia: X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13 (Ia) This is the amino acid sequence, and in the sequence, X2 is selected from the group consisting of Lys, D-Lys, iso-Lys, beta-Lys, D-beta-Lys, homo-Lys, D-homo-Lys, beta-homo-Lys, N-Me-Lys, Dab, D-Dab, Glu, iso-Glu, Orn, D-Orn, Lys(Gly), (N3)-Lys, and D-(N3)-Lys. X3 is selected from the group consisting of Thr, Ile, 3-aminopropanoyl, 4-aminobutanoyl, beta-homo-Ile, beta-homo-Thr, Gly, and N-Me-3-aminopropanoyl, or is absent. X4 is either Val or does not exist. X5 is either a trp or a 1-Me-Trp. X6 is Gln, X7 is selected from the group consisting of Glu, homo-Glu, Asp, Pra, and Hpg. X8 is selected from the group consisting of Y(2-aminoethoxy), Y(Me), Y(Bn), F(4-Me), F(4-Bu), and cyclopropyl-Ala. X9 is 2-Nal, X10 is selected from the group consisting of 2-Me-Leu, 2-Me-Val, Dab, Gly, and Aib. X11 is selected from the group consisting of Glu, homo-Glu, Lys, Lys(Me), Orn, and 2-amino-6-carboxyhexanoyl. X12 is selected from the group consisting of Dab, His, D-His, His(1-Me), 3-(3-quinolinyl)-Ala, and 4-aminopiperidine-4-carbonyl. X13 is either 3-(3-pyridyl)-Ala, 3-(3,5-pyrimidyl)-Ala, or absent. In the array, (i) X2 and X11 are amino acid residues that together form a lactam crosslink, (ii) X2 and X7 are amino acid residues that together form a lactam crosslink or a crosslink containing a triazole ring, (iii) Optionally, if X13 is present, X10 and X13 are amino acid residues that together form a lactam crosslink. compound, Or provide a pharmaceutically acceptable salt or solvate thereof.

[0123] Furthermore, the present invention relates to formula: ZR 2 A compound of which, in the formula, R 2 NHR 3 Or C(=O)R 3 And R 3 C may be substituted with hydrogen or a pyridyl ring. 1-6 Alkyl, NHR 3 Or C(=O)R 3 is or does not exist, Z is given by equation II: X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13 (II) This is the amino acid sequence, and in the sequence, X2 is selected from the group consisting of Lys, D-Lys, iso-Lys, beta-Lys, D-beta-Lys, homo-Lys, D-homo-Lys, beta-homo-Lys, N-Me-Lys, Dab, D-Dab, iso-Dab, Glu, iso-Glu, D-iso-Glu, Orn, D-Orn, Dpr, Lys(Gly), (N3)-Lys, and D-(N3)-Lys. X3 is selected from the group consisting of Thr, Ile, 3-aminopropanoyl, 4-aminobutanoyl, beta-homo-Ile, beta-homo-Thr, Gly, N-Me-3-aminopropanoyl, and Ser, or is absent. X4 is either Val or does not exist. X5 is selected from the group consisting of Trp, 1-Me-Trp, and beta-homo-Trp. X6 is Gln, X7 is selected from the group consisting of Glu, D-Glu, Homo-Glu, Asp, Pra, and Hpg. X8 is selected from the group consisting of Y(2-aminoethoxy), Y(Me), Y(nPr), Y(Bn), Trp, D-Phe, 2-Me-Phe, F(4-Me), F(4-Bu), 3-(2-pyridyl)-Ala, 3-(3-pyridyl)-Ala, 3-(4-pyridyl)-Ala, and cyclopropyl-Ala. X9 is 2-Nal or cyclopropyl-Ala, X10 is selected from the group consisting of 2-Me-Leu, 2-Me-Val, Dab, Gly, Lys, and Aib. X11 is selected from the group consisting of Glu, homo-Glu, beta-homo-Glu, Dab, iso-Dab, Lys, Lys(Me), Orn, and 2-amino-6-carboxyhexanoyl. X12 consists of Dab, His, D-His, His(1-Me), 3-(2-pyridyl)-Ala, 3-(3-pyridyl)-Ala, 3-(4-pyridyl)-Ala, 3-(3-quinolinyl)-Ala, Gly, Pro, 5-aminopentanoyl, 4-aminopiperidine-4-carbonyl, (R,S)-imidazolidined-2-carbonyl, and Lys, where the side chain -NH2 of Lys is -C(=O)(CH2). n R K It is substituted with, where n is 0 to 2, and R K is selected from the group consisting of Lys, which may be imidazolyl, pyrimidyl, or pyridyl substituted with F, or X12 does not exist. X13 is selected from the group consisting of 3-(3-pyridyl)-Ala, D-3-(3-pyridyl)-Ala, and 3-(3,5-pyrimidyl)-Ala, or is absent. In the array, (i) X2 and X11 are amino acid residues that together form a lactam crosslink, (ii) X2 and X7 are amino acid residues that together form a lactam crosslink or a crosslink containing a triazole ring. compound, Or provide a pharmaceutically acceptable salt or solvate thereof.

[0124] Furthermore, in some embodiments, the present invention is based on the formula: ZR 2 A compound of which, in the formula, R 2 NHR 3 And R 3 C may be substituted with hydrogen or a pyridyl ring. 1-6 Alkyl, NHR 3 is or does not exist, Z is given by equation IIa: X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13 (IIa) This is the amino acid sequence, and in the sequence, X2 is selected from the group consisting of Lys, D-Lys, iso-Lys, beta-Lys, D-beta-Lys, homo-Lys, D-homo-Lys, beta-homo-Lys, N-Me-Lys, Dab, D-Dab, Glu, iso-Glu, Orn, D-Orn, Lys(Gly), (N3)-Lys, and D-(N3)-Lys. X3 is selected from the group consisting of Thr, Ile, 3-aminopropanoyl, 4-aminobutanoyl, beta-homo-Ile, beta-homo-Thr, Gly, and N-Me-3-aminopropanoyl, or is absent. X4 is either Val or does not exist. X5 is either a trp or a 1-Me-Trp. X6 is Gln, X7 is selected from the group consisting of Glu, homo-Glu, Asp, Pra, and Hpg. X8 is selected from the group consisting of Y(2-aminoethoxy), Y(Me), Y(Bn), F(4-Me), F(4-Bu), and cyclopropyl-Ala. X9 is 2-Nal, X10 is selected from the group consisting of 2-Me-Leu, 2-Me-Val, Dab, Gly, and Aib. X11 is selected from the group consisting of Glu, homo-Glu, Lys, Lys(Me), Orn, and 2-amino-6-carboxyhexanoyl. X12 is selected from the group consisting of Dab, His, D-His, His(1-Me), 3-(3-quinolinyl)-Ala, and 4-aminopiperidine-4-carbonyl. X13 is either 3-(3-pyridyl)-Ala, 3-(3,5-pyrimidyl)-Ala, or absent. In the array, (i) X2 and X11 are amino acid residues that together form a lactam crosslink, (ii) X2 and X7 are amino acid residues that together form a lactam crosslink or a crosslink containing a triazole ring. compound, Or provide a pharmaceutically acceptable salt or solvate thereof.

[0125] In some embodiments, the present invention provides a compound of the above formula, wherein Z is one amino acid sequence of formulas I, Ia, II, and IIa, the lactam crosslink between X2 and X11 uses the side chain of the amino acid residue of X2, and the crosslink between X2 and X7 uses the N-terminus of the amino acid residue of X2. In such embodiments, X2 is selected from the group consisting of Lys, D-Lys, beta-Lys, D-beta-Lys, homo-Lys, D-homo-Lys, beta-homo-Lys, N-Me-Lys, Dab, D-Dab, Glu, Orn, D-Orn, Lys(Gly), (N3)-Lys, and D-(N3)-Lys.

[0126] In some embodiments, the present invention is expressed by formula: ZR 2 A compound of which, in the formula, R 2 NHR 3 Or C(=O)R 3 And R 3 C may be substituted with hydrogen or a pyridyl ring. 1-6 Alkyl, NHR 3 Or C(=O)R 3 is or does not exist, Z is given by equation III: [Lys]-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13 (III) This is the amino acid sequence, and in the sequence, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, and X13 are defined by any one of the above formulas I, Ia, II, and IIa, In the array, (i) Lys of X2 forms a lactam crosslink with the amino acid residue of X11, (ii) Lys of X2 forms a lactam crosslink with the amino acid residue of X7, (iii) Optionally, if X13 is present, X10 and X13 are amino acid residues that together form a lactam crosslink. compound, Or provide a pharmaceutically acceptable salt or solvate thereof.

[0127] In some embodiments, the present invention is expressed by formula: ZR 2 A compound of which, in the formula, R 2 NHR 3 And R 3 C may be substituted with hydrogen or a pyridyl ring. 1-6 Alkyl, NHR 3 is or does not exist, Z is given by equation IIIa: [Lys]-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13 (IIIa) This is the amino acid sequence, and in the sequence, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, and X13 are defined by any one of the above formulas I, Ia, II, and IIa, In the array, (i) Lys of X2 forms a lactam crosslink with the amino acid residue of X11, (ii) Lys of X2 forms a lactam crosslink with the amino acid residue of X7. compound, Or provide a pharmaceutically acceptable salt or solvate thereof.

[0128] In some embodiments, the present invention is expressed by formula: ZR 2 A compound of which, in the formula, R 2 NHR 3 Or C(=O)R 3 And R 3 C may be substituted with hydrogen or a pyridyl ring. 1-6 Alkyl, NHR 3 Or C(=O)R 3 is or does not exist, Z is given by equation IV: X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13 (IV) This is the amino acid sequence, and in the sequence, X3 is selected from the group consisting of Thr, Ile, and 3-aminopropanoyl, or is absent. X2, X4, X5, X6, X7, X8, X9, X10, X11, X12, and X13 are defined by any one of the above formulas I, Ia, II, and IIa, In the array, (i) X2 and X11 are amino acid residues that together form a lactam crosslink, (ii) X2 and X7 are amino acid residues that together form a lactam crosslink or a crosslink containing a triazole ring, (iii) Optionally, if X13 is present, X10 and X13 are amino acid residues that together form a lactam crosslink. compound, Or provide a pharmaceutically acceptable salt or solvate thereof.

[0129] In some embodiments, the present invention is expressed by formula: ZR 2 A compound of which, in the formula, R 2 NHR 3And R 3 C may be substituted with hydrogen or a pyridyl ring. 1-6 Alkyl, NHR 3 is or does not exist, Z is given by equation IVa: X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13 (IVa) This is the amino acid sequence, and in the sequence, X3 is selected from the group consisting of Thr, Ile, and 3-aminopropanoyl, or is absent. X2, X4, X5, X6, X7, X8, X9, X10, X11, X12, and X13 are defined by any one of the above formulas I, Ia, II, and IIa, In the array, (i) X2 and X11 are amino acid residues that together form a lactam crosslink, (ii) X2 and X7 are amino acid residues that together form a lactam crosslink or a crosslink containing a triazole ring. compound, Or provide a pharmaceutically acceptable salt or solvate thereof.

[0130] In some embodiments, the present invention is expressed by formula: ZR 2 A compound of which, in the formula, R 2 NHR 3 Or C(=O)R 3 And R 3 C may be substituted with hydrogen or a pyridyl ring. 1-6 Alkyl, NHR 3 Or C(=O)R 3 is or does not exist, Z is given by equation V: X2-X3-X5-X6-X7-X8-X9-X10-X11-X12-X13 (V) This is the amino acid sequence, and in the sequence, X2, X3, X5, X6, X7, X8, X9, X10, X11, X12, and X13 are defined by any one of the above formulas I, Ia, II, and IIa, In the array, (i) X2 and X11 are amino acid residues that together form a lactam crosslink, (ii) X2 and X7 are amino acid residues that together form a lactam crosslink or a crosslink containing a triazole ring, (iii) Optionally, if X13 is present, X10 and X13 are amino acid residues that together form a lactam crosslink. compound, Or provide a pharmaceutically acceptable salt or solvate thereof.

[0131] In some embodiments, the present invention is expressed by formula: ZR 2 A compound of which, in the formula, R 2 NHR 3 And R 3 C may be substituted with hydrogen or a pyridyl ring. 1-6 Alkyl, NHR 3 is or does not exist, Z is given by equation Va: X2-X3-X5-X6-X7-X8-X9-X10-X11-X12-X13 (Va) This is the amino acid sequence, and in the sequence, X2, X3, X5, X6, X7, X8, X9, X10, X11, X12, and X13 are defined by any one of the above formulas I, Ia, II, and IIa, In the array, (i) X2 and X11 are amino acid residues that together form a lactam crosslink, (ii) X2 and X7 are amino acid residues that together form a lactam crosslink or a crosslink containing a triazole ring. compound, Or provide a pharmaceutically acceptable salt or solvate thereof.

[0132] In some embodiments, the present invention is expressed by formula: ZR 2 A compound of which, in the formula, R 2 NHR 3 Or C(=O)R 3 And R 3 C may be substituted with hydrogen or a pyridyl ring. 1-6 Alkyl, NHR 3 Or C(=O)R 3 is or does not exist, Z is given by equation VI: X2-X3-X4-[Trp]-X6-X7-X8-X9-X10-X11-X12-X13 (VI) This is the amino acid sequence, and in the sequence, X2, X3, X4, X6, X7, X8, X9, X10, X11, X12, and X13 are defined by any one of the above formulas I, Ia, II, and IIa, In the array, (i) X2 and X11 are amino acid residues that together form a lactam crosslink, (ii) X2 and X7 are amino acid residues that together form a lactam crosslink or a crosslink containing a triazole ring, (iii) Optionally, if X13 is present, X10 and X13 are amino acid residues that together form a lactam crosslink. compound, Or provide a pharmaceutically acceptable salt or solvate thereof.

[0133] In some embodiments, the present invention is expressed by formula: ZR 2 A compound of which, in the formula, R 2 NHR 3 And R 3 C may be substituted with hydrogen or a pyridyl ring. 1-6 Alkyl, NHR 3 is or does not exist, Z is given by equation VIa: X2-X3-X4-[Trp]-X6-X7-X8-X9-X10-X11-X12-X13 (VIa) This is the amino acid sequence, and in the sequence, X2, X3, X4, X6, X7, X8, X9, X10, X11, X12, and X13 are defined by any one of the above formulas I, Ia, II, and IIa, In the array, (i) X2 and X11 are amino acid residues that together form a lactam crosslink, (ii) X2 and X7 are amino acid residues that together form a lactam crosslink or a crosslink containing a triazole ring. compound, Or provide a pharmaceutically acceptable salt or solvate thereof.

[0134] In some embodiments, the present invention is expressed by formula: ZR 2 A compound of which, in the formula, R 2 NHR 3 Or C(=O)R 3 And R 3 C may be substituted with hydrogen or a pyridyl ring. 1-6 Alkyl, NHR 3 Or C(=O)R 3 is or does not exist, Z is given by equation VII: X2-X3-X4-X5-X6-[Glu]-X8-X9-X10-X11-X12-X13 (VII) This is the amino acid sequence, and in the sequence, X2, X3, X4, X5, X6, X8, X9, X10, X11, X12, and X13 are defined by any one of the above formulas I, Ia, II, and IIa, In the array, (i) X2 and X11 are amino acid residues that together form a lactam crosslink, (ii) The Glu of X7 forms a lactam crosslink with the amino acid residue of X2, (iii) Optionally, if X13 is present, X10 and X13 are amino acid residues that together form a lactam crosslink. compound, Or provide a pharmaceutically acceptable salt or solvate thereof.

[0135] In some embodiments, the present invention is expressed by formula: ZR 2 A compound of which, in the formula, R 2 NHR 3 And R 3 C may be substituted with hydrogen or a pyridyl ring. 1-6 Alkyl, NHR 3 is or does not exist, Z is given by equation VIIa: X2-X3-X4-X5-X6-[Glu]-X8-X9-X10-X11-X12-X13 (VIIa) This is the amino acid sequence, and in the sequence, X2, X3, X4, X5, X6, X8, X9, X10, X11, X12, and X13 are defined by any one of the above formulas I, Ia, II, and IIa, In the array, (i) X2 and X11 are amino acid residues that together form a lactam crosslink, (ii) The Glu of X7 forms a lactam crosslink with the amino acid residue of X2. compound, Or provide a pharmaceutically acceptable salt or solvate thereof.

[0136] In some embodiments, the present invention is expressed by formula: ZR 2 A compound of which, in the formula, R 2 NHR 3 Or C(=O)R 3 And R 3 C may be substituted with hydrogen or a pyridyl ring. 1-6 Alkyl, NHR 3Or C(=O)R 3 is or does not exist, Z is given by equation VIII: X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13 (VIII) This is the amino acid sequence, and in the sequence, X8 is Y(2-aminoethoxy), Y(Me), or F(4-Me), X2, X3, X4, X5, X6, X7, X9, X10, X11, X12, and X13 are defined by any one of the above formulas I, Ia, II, and IIa, In the array, (i) X2 and X11 are amino acid residues that together form a lactam crosslink, (ii) X2 and X7 are amino acid residues that together form a lactam crosslink or a crosslink containing a triazole ring, (iii) Optionally, if X13 is present, X10 and X13 are amino acid residues that together form a lactam crosslink. compound, Or provide a pharmaceutically acceptable salt or solvate thereof.

[0137] In some embodiments, the present invention is expressed by formula: ZR 2 A compound of which, in the formula, R 2 NHR 3 And R 3 C may be substituted with hydrogen or a pyridyl ring. 1-6 Alkyl, NHR 3 is or does not exist, Z is given by equation VIIIa: X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13 (VIIIa) This is the amino acid sequence, and in the sequence, X8 is Y(2-aminoethoxy), Y(Me), or F(4-Me), X2, X3, X4, X5, X6, X7, X9, X10, X11, X12, and X13 are defined by any one of the above formulas I, Ia, II, and IIa, In the array, (i) X2 and X11 are amino acid residues that together form a lactam crosslink, (ii) X2 and X7 are amino acid residues that together form a lactam crosslink or a crosslink containing a triazole ring. compound, Or provide a pharmaceutically acceptable salt or solvate thereof.

[0138] In some embodiments, the present invention is expressed by formula: ZR 2 A compound of which, in the formula, R 2 NHR 3 Or C(=O)R 3 And R 3 C may be substituted with hydrogen or a pyridyl ring. 1-6 Alkyl, NHR 3 Or C(=O)R 3 is or does not exist, Z is given by equation IX: X2-X3-X4-X5-X6-X7-[Y(2-aminoethoxy)]-X9-X10-X11-X12-X13 (IX) This is the amino acid sequence, and in the sequence, X2, X3, X4, X5, X6, X7, X9, X10, X11, X12, and X13 are defined by any one of the above formulas I, Ia, II, and IIa, In the array, (i) X2 and X11 are amino acid residues that together form a lactam crosslink, (ii) X2 and X7 are amino acid residues that together form a lactam crosslink or a crosslink containing a triazole ring, (iii) Optionally, if X13 is present, X10 and X13 are amino acid residues that together form a lactam crosslink. compound, Or provide a pharmaceutically acceptable salt or solvate thereof.

[0139] In some embodiments, the present invention is expressed by formula: ZR 2 A compound of which, in the formula, R 2 NHR 3 And R 3 C may be substituted with hydrogen or a pyridyl ring. 1-6 Alkyl, NHR 3 is or does not exist, Z is given by equation IX: X2-X3-X4-X5-X6-X7-[Y(2-aminoethoxy)]-X9-X10-X11-X12-X13 (IX) This is the amino acid sequence, and in the sequence, X2, X3, X4, X5, X6, X7, X9, X10, X11, X12, and X13 are defined by any one of the above formulas I, Ia, II, and IIa, In the array, (i) X2 and X11 are amino acid residues that together form a lactam crosslink, (ii) X2 and X7 are amino acid residues that together form a lactam crosslink or a crosslink containing a triazole ring. compound, Or provide a pharmaceutically acceptable salt or solvate thereof.

[0140] In some embodiments, the present invention is expressed by formula: ZR 2 A compound of which, in the formula, R 2 NHR 3 Or C(=O)R 3 And R 3 C may be substituted with hydrogen or a pyridyl ring. 1-6 Alkyl, NHR 3 Or C(=O)R 3 is or does not exist, Z is given by equation X: X2-X3-X4-X5-X6-X7-X8-[2-Nal]-X10-X11-X12-X13 (X) This is the amino acid sequence, and in the sequence, X2, X3, X4, X5, X6, X7, X8, X10, X11, X12, and X13 are defined by any one of the above formulas I, Ia, II, and IIa, In the array, (i) X2 and X11 are amino acid residues that together form a lactam crosslink, (ii) X2 and X7 are amino acid residues that together form a lactam crosslink or a crosslink containing a triazole ring, (iii) Optionally, if X13 is present, X10 and X13 are amino acid residues that together form a lactam crosslink. compound, Or provide a pharmaceutically acceptable salt or solvate thereof.

[0141] In some embodiments, the present invention is expressed by formula: ZR 2 A compound of which, in the formula, R 2 NHR 3 And R 3 C may be substituted with hydrogen or a pyridyl ring. 1-6 Alkyl, NHR 3 is or does not exist, Z is given by equation Xa: X2-X3-X4-X5-X6-X7-X8-[2-Nal]-X10-X11-X12-X13 (Xa) This is the amino acid sequence, and in the sequence, X2, X3, X4, X5, X6, X7, X8, X10, X11, X12, and X13 are defined by any one of the above formulas I, Ia, II, and IIa, In the array, (i) X2 and X11 are amino acid residues that together form a lactam crosslink, (ii) X2 and X7 are amino acid residues that together form a lactam crosslink or a crosslink containing a triazole ring. compound, Or provide a pharmaceutically acceptable salt or solvate thereof.

[0142] In some embodiments, the present invention is expressed by formula: ZR 2 A compound of which, in the formula, R 2 NHR 3 Or C(=O)R 3 And R 3 C may be substituted with hydrogen or a pyridyl ring. 1-6 Alkyl, NHR 3 Or C(=O)R 3 is or does not exist, Z is given by equation XI: X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13 (XI) This is the amino acid sequence, and in the sequence, X10 is 2-Me-Leu or 2-Me-Val, X2, X3, X4, X5, X6, X7, X8, X9, X11, X12, and X13 are defined by any one of the above formulas I, Ia, II, and IIa, In the array, (i) X2 and X11 are amino acid residues that together form a lactam crosslink, (ii) X2 and X7 are amino acid residues that together form a lactam crosslink or a crosslink containing a triazole ring. compound, Or provide a pharmaceutically acceptable salt or solvate thereof.

[0143] In some embodiments, the present invention is expressed by formula: ZR 2 A compound of which, in the formula, R 2 NHR 3 And R3 C may be substituted with hydrogen or a pyridyl ring. 1-6 Alkyl, NHR 3 is or does not exist, Z is the amino acid sequence of formula XI as defined above. compound, Or provide a pharmaceutically acceptable salt or solvate thereof.

[0144] In some embodiments, the present invention is expressed by formula: ZR 2 A compound of which, in the formula, R 2 NHR 3 Or C(=O)R 3 And R 3 C may be substituted with hydrogen or a pyridyl ring. 1-6 Alkyl, NHR 3 Or C(=O)R 3 is or does not exist, Z is given by equation XII: X2-X3-X4-X5-X6-X7-X8-X9-[2-Me-Leu]-X11-X12-X13 (XII) This is the amino acid sequence, and in the sequence, X2, X3, X4, X5, X6, X7, X8, X9, X11, X12, and X13 are defined by any one of the above formulas I, Ia, II, and IIa, In the array, (i) X2 and X11 are amino acid residues that together form a lactam crosslink, (ii) X2 and X7 are amino acid residues that together form a lactam crosslink or a crosslink containing a triazole ring. compound, Or provide a pharmaceutically acceptable salt or solvate thereof.

[0145] In some embodiments, the present invention is expressed by formula: ZR 2 A compound of which, in the formula, R2 NHR 3 And R 3 C may be substituted with hydrogen or a pyridyl ring. 1-6 Alkyl, NHR 3 is or does not exist, Z is the amino acid sequence of formula XII as defined above. compound, Or provide a pharmaceutically acceptable salt or solvate thereof.

[0146] In some embodiments, the present invention is expressed by formula: ZR 2 A compound of which, in the formula, R 2 NHR 3 Or C(=O)R 3 And R 3 C may be substituted with hydrogen or a pyridyl ring. 1-6 Alkyl, NHR 3 Or C(=O)R 3 is or does not exist, Z is given by equation XIII: X2-X3-X4-X5-X6-X7-X8-X9-X10-[Glu]-X12-X13 (XIII) This is the amino acid sequence, and in the sequence, X2, X3, X4, X5, X6, X7, X8, X9, X10, X12, and X13 are defined by any one of the above formulas I, Ia, II, and IIa, In the array, (i) The Glu of X11 forms a lactam crosslink with the amino acid residue of X2, (ii) X2 and X7 are amino acid residues that together form a lactam crosslink or a crosslink containing a triazole ring, (iii) Optionally, if X13 is present, X10 and X13 are amino acid residues that together form a lactam crosslink. compound, Or provide a pharmaceutically acceptable salt or solvate thereof.

[0147] In some embodiments, the present invention is expressed by formula: ZR 2 A compound of which, in the formula, R 2 NHR 3 And R 3 C may be substituted with hydrogen or a pyridyl ring. 1-6 Alkyl, NHR 3 is or does not exist, Z is given by equation XIIIa: X2-X3-X4-X5-X6-X7-X8-X9-X10-[Glu]-X12-X13 (XIIIa) This is the amino acid sequence, and in the sequence, X2, X3, X4, X5, X6, X7, X8, X9, X10, X12, and X13 are defined by any one of the above formulas I, Ia, II, and IIa, In the array, (i) The Glu of X11 forms a lactam crosslink with the amino acid residue of X2, (ii) X2 and X7 are amino acid residues that together form a lactam crosslink or a crosslink containing a triazole ring. compound, Or provide a pharmaceutically acceptable salt or solvate thereof.

[0148] In some embodiments, the present invention is expressed by formula: ZR 2 A compound of which, in the formula, R 2 NHR 3 Or C(=O)R 3 And R 3 C may be substituted with hydrogen or a pyridyl ring. 1-6 Alkyl, NHR 3 Or C(=O)R 3 is or does not exist, Z is given by equation XIV: X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-[Dab]-X13 (XIV) This is the amino acid sequence, and in the sequence, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, and X13 are defined by any one of the above formulas I, Ia, II, and IIa, In the array, (i) X2 and X11 are amino acid residues that together form a lactam crosslink, (ii) X2 and X7 are amino acid residues that together form a lactam crosslink or a crosslink containing a triazole ring, (iii) Optionally, if X13 is present, X10 and X13 are amino acid residues that together form a lactam crosslink. compound, Or provide a pharmaceutically acceptable salt or solvate thereof.

[0149] In some embodiments, the present invention is expressed by formula: ZR 2 A compound of which, in the formula, R 2 NHR 3 And R 3 C may be substituted with hydrogen or a pyridyl ring. 1-6 Alkyl, NHR 3 is or does not exist, Z is given by equation XIVa: X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-[Dab]-X13 (XIVa) This is the amino acid sequence, and in the sequence, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, and X13 are defined by any one of the above formulas I, Ia, II, and IIa, In the array, (i) X2 and X11 are amino acid residues that together form a lactam crosslink, (ii) X2 and X7 are amino acid residues that together form a lactam crosslink or a crosslink containing a triazole ring. compound, Or provide a pharmaceutically acceptable salt or solvate thereof.

[0150] In some embodiments, the present invention is expressed by formula: ZR 2 A compound of which, in the formula, R 2 NHR 3 Or C(=O)R 3 And R 3 C may be substituted with hydrogen or a pyridyl ring. 1-6 Alkyl, NHR 3 Or C(=O)R 3 is or does not exist, Z is given by equation XV: X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13 (XV) This is the amino acid sequence, and in the sequence, X13 is either 3-(3-pyridyl)-Ala or absent. X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, and X12 are defined by any one of the above formulas I, Ia, II, and IIa, In the array, (i) X2 and X11 are amino acid residues that together form a lactam crosslink, (ii) X2 and X7 are amino acid residues that together form a lactam crosslink or a crosslink containing a triazole ring, (iii) Optionally, if X13 is present, X10 and X13 are amino acid residues that together form a lactam crosslink. compound, Or provide a pharmaceutically acceptable salt or solvate thereof.

[0151] In some embodiments, the present invention is expressed by formula: ZR 2 A compound of which, in the formula, R 2 NHR 3 And R 3C may be substituted with hydrogen or a pyridyl ring. 1-6 Alkyl, NHR 3 is or does not exist, Z is given by equation XVa: X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13 (XVa) This is the amino acid sequence, and in the sequence, X13 is either 3-(3-pyridyl)-Ala or absent. X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, and X12 are defined by any one of the above formulas I, Ia, II, and IIa, In the array, (i) X2 and X11 are amino acid residues that together form a lactam crosslink, (ii) X2 and X7 are amino acid residues that together form a lactam crosslink or a crosslink containing a triazole ring. compound, Or provide a pharmaceutically acceptable salt or solvate thereof.

[0152] In some embodiments, the present invention is expressed by formula: ZR 2 A compound of which, in the formula, R 2 NHR 3 Or C(=O)R 3 And R 3 C may be substituted with hydrogen or a pyridyl ring. 1-6 Alkyl, NHR 3 Or C(=O)R 3 is or does not exist, Z is given by equation XVI: X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-[3-(3-pyridyl)-Ala] (XVI) This is the amino acid sequence, and in the sequence, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, and X12 are defined by any one of the above formulas I, Ia, II, and IIa, In the array, (i) X2 and X11 are amino acid residues that together form a lactam crosslink, (ii) X2 and X7 are amino acid residues that together form a lactam crosslink or a crosslink containing a triazole ring, (iii) Optionally, 3-(3-pyridyl)-Ala of X13 forms a lactam crosslink with the amino acid residue of X10. compound, Or provide a pharmaceutically acceptable salt or solvate thereof.

[0153] In some embodiments, the present invention is expressed by formula: ZR 2 A compound of which, in the formula, R 2 NHR 3 And R 3 C may be substituted with hydrogen or a pyridyl ring. 1-6 Alkyl, NHR 3 is or does not exist, Z is given by equation XVIa: X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-[3-(3-pyridyl)-Ala] (XVIa) A compound of which, in the formula, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, and X12 are defined by any one of the above formulas I, Ia, II, and IIa, In the array, (i) X2 and X11 are amino acid residues that together form a lactam crosslink, (ii) X2 and X7 are amino acid residues that together form a lactam crosslink or a crosslink containing a triazole ring. compound, Or provide a pharmaceutically acceptable salt or solvate thereof.

[0154] In some embodiments, the present invention is expressed by formula: ZR 2 A compound of which, in the formula, R 2 NHR 3 Or C(=O)R 3 And R 3 C may be substituted with hydrogen or a pyridyl ring. 1-6 Alkyl, NHR 3 Or C(=O)R 3 is or does not exist, Z is given by equation XVII: [Lys]-X3-X4-[Trp]-X6-X7-X8-[2-Nal]-[2-Me-Leu]-X11-X12-X13 (XVII) This is the amino acid sequence, and in the sequence, X3, X4, X6, X7, X8, X11, X12, and X13 are defined by any one of the above formulas I, Ia, II, and IIa, In the array, (i) Lys of X2 forms a lactam crosslink with the amino acid residue of X11, (ii) Lys of X2 forms a lactam crosslink with the amino acid residue of X7. compound, Or provide a pharmaceutically acceptable salt or solvate thereof.

[0155] In some embodiments, the present invention is expressed by formula: ZR 2 A compound of which, in the formula, R 2 NHR 3 And R 3 C may be substituted with hydrogen or a pyridyl ring. 1-6 Alkyl, NHR 3 is or does not exist, Z is given by equation XVIIa: [Lys]-X3-X4-[Trp]-X6-X7-X8-[2-Nal]-[2-Me-Leu]-X11-X12-X13 (XVIIa) This is the amino acid sequence, and in the sequence, X3, X4, X6, X7, X8, X11, X12, and X13 are defined by any one of the above formulas I, Ia, II, and IIa, In the array, (i) Lys of X2 forms a lactam crosslink with the amino acid residue of X11, (ii) Lys of X2 forms a lactam crosslink with the amino acid residue of X7. compound, Or provide a pharmaceutically acceptable salt or solvate thereof.

[0156] In some embodiments, the present invention is expressed by formula: Z-NH2 or Z-NHMe A compound of which, in the formula, Z is one of the amino acid sequences of formulas I, Ia, II, IIa, III, IIIa, IV, IVa, V, Va, VI, Via, VII, VIIa, VIII, VIIIa, IX, IXa, X, Xa, XI, XII, XIII, XIIIa, XIV, XIVa, XV, XVa, XVI, XVIa, XVII, and XVIIa as defined above. compound, Or provide a pharmaceutically acceptable salt or solvate thereof.

[0157] In some embodiments, the present invention is expressed by formula: Z-NH2 or Z-NHMe A compound of which, in the formula, Z is given by equation XVIII: [Lys]-X3-X4-[Trp]-X6-X7-X8-[2-Nal]-[2-Me-Leu]-X11-X12-X13 (XVIII) This is the amino acid sequence, and in the sequence, X13 is either 3-(3-pyridyl)-Ala or absent. X3, X4, X6, X7, X8, X11, and X12 are defined by any one of the above formulas I, Ia, II, and IIa, In the array, (i) Lys of X2 forms a lactam crosslink with the amino acid residue of X11, (ii) Lys of X2 forms a lactam crosslink with the amino acid residue of X7. compound, Or provide a pharmaceutically acceptable salt or solvate thereof.

[0158] In some embodiments, the present invention is expressed by formula: Z-NH2 or Z-NHMe A compound of which, in the formula, Z is given by equation XIX: [Lys]-X3-X4-[Trp]-X6-[Glu]-X8-[2-Nal]-[2-Me-Leu]-X11-X12-X13 (XIX) This is the amino acid sequence, and in the sequence, X13 is either 3-(3-pyridyl)-Ala or absent. X3, X4, X6, X8, X11, and X12 are defined by any one of the above formulas I, Ia, II, and IIa, In the array, (i) Lys of X2 forms a lactam crosslink with the amino acid residue of X11, (ii) Lys of X2 and Glu of X7 combine to form lactam crosslinks. compound, Or provide a pharmaceutically acceptable salt or solvate thereof.

[0159] In some embodiments, the present invention provides compounds selected from the compounds in Table 1-1, or pharmaceutically acceptable salts or solvates thereof.

[0160] In previously disclosed compounds that are inhibitors of IL-23R, such as those disclosed in International Publication No. 2023 / 099669, any internal shortening, which is the deletion of an amino acid residue between X2 and X11, resulted in an inactive compound (see reference compounds Ref5, Ref6, and Ref7 in Example 2 of International Publication No. 2023 / 099669). However, we have now observed that certain deletions between X2 and X11 of the compounds of this disclosure, for example at X3 and / or X4, are acceptable and can even improve the potency and / or gastrointestinal stability and / or bioavailability of the compounds disclosed herein (see Example 2 below).

[0161] It will be understood that the present invention encompasses salts and solvates of such compounds. Suitable salts and solvates of peptides are known in the art.

[0162] Furthermore, it will be understood that any of the following embodiments may be applicable to and combined with any of the formulas described herein.

[0163] R 2 R 2 NHR 3 Or C(=O)R 3 And R 3 C may be substituted with hydrogen or a pyridyl ring. 1-6 Alkyl, NHR 3 Or C(=O)R 3 It is either true or not true.

[0164] In some embodiments, R 2 It does not exist. In some such embodiments, X13 is present and forms a lactam crosslink with the amino acid residue of X10.

[0165] In some embodiments, R 2 NHR 3 And R 3 is hydrogen or C 1-6 It is alkyl. In some embodiments, R2 NHR 3 And R 3 is hydrogen or C 1-5 It is alkyl. In some embodiments, R 2 NHR 3 And R 3 is hydrogen or C 1-4 It is alkyl. In some embodiments, R 2 NHR 3 And R 3 is hydrogen or C 1-3 It is alkyl. In some embodiments, R 2 NHR 3 And R 3 is hydrogen or C 1-2 It is alkyl. In some embodiments, R 2 NHR 3 And R 3 This is hydrogen or a C1 alkyl group (methyl or Me).

[0166] In some embodiments, R 2 NHR 3 And R 3 C may be substituted with a pyridyl ring. 1-6 It is alkyl. In some such embodiments, R 2 The group is bonded to the carbonyl carbon of the carboxylic acid group of the C-terminal amino acid residue. The C-terminal amino acid may be Glu, beta-homo-Glu, or Dab.

[0167] In some embodiments, R 2 NHR 3 And R 3 C may be substituted with a pyridyl ring. 1-6 It is alkyl. In some embodiments, R 2 NHR 3 And R 3 C may be substituted with a pyrido-3-yl ring. 1-6 It is alkyl.

[0168] In some embodiments, R 2 NHR 3 And R3 is a C substituted with a pyridyl ring. 1-6 It is alkyl. In some embodiments, R 2 NHR 3 And R 3 C is substituted with a pyrido-3-yl ring. 1-6 It is alkyl.

[0169] In some embodiments, R 2 NHR 3 And R 3 is a C6 alkyl group substituted with a pyridyl ring. In some embodiments, R 2 NHR 3 And R 3 is a C6 alkyl group substituted with a pyrido-3-yl ring. In some embodiments, R 2 NHR 3 And R 3 R is a hexanyl (i.e., -CH2CH2CH2CH2CH2CH3) substituted with a pyrido-3-yl ring. In some embodiments, R 2 NHR 3 And R 3 This is -CH2CH2CH2CH2CH2CH2(pyrido-3-yl). That is, NHCH2CH2CH2CH2CH2CH2(pyrido-3-yl) or NH-(6-(pyridine-3-yl)hexanyl). The NH-(6-(pyridine-3-yl)hexanyl) group has the following structure. [ka]

[0170] In some embodiments, R 2 NHR 3 And R 3 is a C4 alkyl group substituted with a pyridyl ring. In some embodiments, R 2 NHR 3 And R 3 is a C4 alkyl group substituted with a pyrido-3-yl ring. In some embodiments, R 2 NHR 3 And R3 is n-Bu substituted with a pyrido-3-yl ring. In some embodiments, R 2 NHR 3 And R 3 This is -CH2CH2CH2CH2(pyrido-3-yl). That is, NHCH2CH2CH2CH2(pyrido-3-yl) or NH-(4-(pyridine-3-yl)butanyl). The NH-(4-(pyridine-3-yl)butanyl) group has the following structure. [ka]

[0171] In some embodiments, R 2 NHR 3 And R 3 is a C3 alkyl group substituted with a pyridyl ring. In some embodiments, R 2 NHR 3 And R 3 is a C3 alkyl substituted with a pyrido-3-yl ring. In some embodiments, R 2 NHR 3 And R 3 is an n-Pr substituted with a pyrido-3-yl ring. In some embodiments, R 2 NHR 3 And R 3 It is -CH2CH2CH2(pyrido-3-yl). That is, it is NHCH2CH2CH2(pyrido-3-yl) or NH-(3-(pyridine-3-yl)propyl). The NH-(3-(pyridine-3-yl)propyl) group has the following structure. [ka]

[0172] In some embodiments, R 2 NHR 3 And R 3 is a C2 alkyl group substituted with a pyridyl ring. In some embodiments, R 2 NHR 3 And R3 is a C2 alkyl substituted with a pyrido-3-yl ring. In some embodiments, R 2 NHR 3 And R 3 is ethyl (Et) substituted with a pyrido-3-yl ring. In some embodiments, R 2 NHR 3 And R 3 It is -CH2CH2(pyrido-3-yl). That is, it is NHCH2CH2(pyrido-3-yl) or NH-(2-(pyridine-3-yl)ethyl). The NH-(2-(pyridine-3-yl)ethyl) group has the following structure. [ka]

[0173] In some embodiments, R 2 C(=O)R 3 And R 3 C may be substituted with a pyridyl ring. 1-6 It is alkyl. In some embodiments, R 2 C(=O)R 3 And R 3 C may be substituted with a pyrido-3-yl ring. 1-6 It is alkyl. In some such embodiments, R 2 The group is bonded to the amine group of the C-terminal amino acid residue. The C-terminal amino acid may be iso-Dab.

[0174] In some embodiments, R 2 C(=O)R 3 And R 3 C may be substituted with a pyridyl ring. 1-6 It is alkyl. In some embodiments, R 2 C(=O)R 3 And R 3 C may be substituted with a pyrido-3-yl ring. 1-6 It is alkyl.

[0175] In some embodiments, R 2C(=O)R 3 And R 3 is a C substituted with a pyridyl ring. 1-6 It is alkyl. In some embodiments, R 2 C(=O)R 3 And R 3 C is substituted with a pyrido-3-yl ring. 1-6 It is alkyl.

[0176] In some embodiments, R 2 C(=O)R 3 And R 3 is a C5 alkyl group substituted with a pyridyl ring. In some embodiments, R 2 C(=O)R 3 And R 3 is a C5 alkyl group substituted with a pyrido-3-yl ring. In some embodiments, R 2 C(=O)R 3 And R 3 is a pentanyl substituted with a pyrido-3-yl ring. In some embodiments, R 2 C(=O)R 3 And R 3 This is -CH2CH2CH2CH2CH2(pyrido-3-yl). That is, C(=O)CH2CH2CH2CH2CH2(pyrido-3-yl) or 6-(3-pyridyl)hexanoyl. The 6-(3-pyridyl)hexanoyl group has the following structure. [ka]

[0177] In some embodiments, R 2 C(=O)R 3 And R 3 is a C2 alkyl group substituted with a pyridyl ring. In some embodiments, R 2 C(=O)R 3 And R 3 is a C2 alkyl substituted with a pyrido-3-yl ring. In some embodiments, R 2 C(=O)R 3And R 3 is ethyl (Et) substituted with a pyrido-3-yl ring. In some embodiments, R 2 C(=O)R 3 And R 3 It is -CH2CH2 (pyrido-3-yl). That is, C(=O)CH2CH2 (pyrido-3-yl) or 3-pyridylpropionyl. The 3-pyridylpropionyl group has the following structure. [ka]

[0178] In some embodiments, R 2 These are NHMe, NH2, NH-(6-(pyridin-3-yl)hexanyl) [i.e., NHCH2CH2CH2CH2CH2CH2(pyrido-3-yl)], NHCH2CH2CH2CH2(pyrido-3-yl) [i.e., NH-(4-(pyridin-3-yl)butanyl)], NH-(3-(pyridin-3-yl)propyl) [i.e., NHCH2CH2CH2(pyrido-3-yl)], NHCH2CH2(pyrido-3-yl) [i.e., NH-(2-(pyridin-3-yl)ethyl)], C(=O)CH2CH2CH2CH2CH2(pyrido-3-yl) [i.e., 6-(3-pyridyl)hexanoyl], or C(=O)CH2CH2(pyrido-3-yl) [i.e., 3-pyridylpropionyl].

[0179] In some embodiments, R 2 It does not exist. In some embodiments, R 2 is NHMe. In some embodiments, R 2 is NH2. In some embodiments, R 2 This is NHCH2CH2CH2CH2CH2CH2(pyrido-3-yl), that is, NH-(6-(pyridine-3-yl)hexanyl). In some embodiments, R 2 This is NHCH2CH2CH2CH2(pyrido-3-yl), that is, NH-(4-(pyridine-3-yl)butanyl). In some embodiments, R 2This is NHCH2CH2CH2(pyrido-3-yl), that is, NH-(3-(pyridine-3-yl)propyl). In some embodiments, R 2 This is NHCH2CH2(pyrido-3-yl), that is, NH-(2-(pyridine-3-yl)ethyl). In some embodiments, R 2 This is C(=O)CH2CH2CH2CH2CH2(pyrido-3-yl), that is, 6-(3-pyridyl)hexanoyl. In some embodiments, R 2 This is C(=O)CH2CH2 (pyrido-3-yl), or 3-pyridylpropionyl.

[0180] Preferably, R 2 is NHMe or NH2. More preferably, R 2 It is NHMe.

[0181] Z Z is given by equation I: X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13 (I) This is the amino acid sequence, and in the sequence, X2 is Lys, D-lys, iso-Lys, D-iso-Lys, beta-Lys, D-beta-Lys, homo-Lys, D-homo-Lys, beta-homo-Lys, N-Me-Lys, N-Me-homo-Lys, (N3)-Lys, D-(N3)-Lys, (N3)-beta-Lys, (N3)-D-beta-Lys, (N3)-homo-Lys, (N3)-D-homo-Lys, (N3)-beta-homo-Lys, Dpr, D-Dpr, iso-Dpr, D-iso-Dpr, beta-Dpr, D-beta-Dpr, homo-Dpr, D-homo-Dpr, beta-homo-Dpr, N-Me-Dpr, N-Me-homo-Dpr, (N3)-Dpr, D-(N3)-Dpr, (N3)-beta-Dpr, (N3)-D-beta-Dpr, (N3)-homo-Dpr, (N3)-D-homo-Dpr, (N3)-beta-homo-Dpr, Dab, D-Dab, iso-Dab, D-iso-Dab, beta-Dab, D-beta-Dab, homo-Dab, D-homo-Dab, beta-homo-Dab, N-Me-Dab, N-Me-homo-Dab, (N3)-Dab, D-(N3)-Dab, (N3)-beta-Dab, (N3)-D-beta-Dab, (N3)-homo-Dab, (N3)-D-homo-Dab, (N3)-beta-homo-Dab, Orn, D-Orn, Iso-Orn, D-Iso-Orn, Beta-Orn, D-Beta-Orn, Homo-Orn, D-Homo-Orn, Beta-Homo-Orn, N-Me-Orn, N-Me-Homo-Orn, (N3)-Orn, D-(N3)-Orn, (N3)-Beta-Orn, (N3)-D-Beta-Orn, (N3)-Homo-Orn, (N3)-D-Homo-Orn, (N3)-Beta-Homo-Orn, Lys (Gly), Asp, D-Asp, Iso-Asp, D-Iso-Asp, Beta-Asp, D-Beta-Asp, Homo-Asp, D-Homo-Asp, Beta-Homo-Asp, N-Me-Asp, N-Me-Homo-Asp, (N3)-Asp, D-(N3)-Asp, (N3)-Beta-Asp, (N3)-D-Beta-Asp, (N3)-Homo-Asp, (N3)-D-Homo-Asp, (N3)-Beta-Homo-Asp, Glu, D-Glu, Iso-Glu, D-Iso-Glu, Beta-Glu, D-Beta-Glu, Homo-Glu, D-Homo-Glu, Beta-Homo-Glu, N-Me-Glu, N-Me-Homo-Glu, (N3)-Glu, D-(N3)-Glu, (N3)-Beta-Glu, (N3)-D-Beta-Glu, (N3)-Homo-Glu, (N3)-D-Homo-Glu, (N3)-Beta-Homo-Glu, Selected from the group consisting of 2-amino-6-carboxyhexanoyl and 3-aminopropanoyl, X3 is any amino acid, ω-hydroxy-C 2-6 Selected from alkanates, or absent, X4 is Val D-Val, Beta-Val, D-Beta-Val, Homo-Val, D-Homo-Val, Beta-Homo-Val, N-mer-Val, N-mer-Homo-Val, 2-mer-Val, Ala, D-Ala, Beta-Ala, D-Beta-Ala, Homo-Ala, D-Homo-Ala, Beta-Homo-Ala, N-Me-Ala, N-Me-Homo-Ala, Gly, Beta-Gly, Homo-Gly, Beta-Homo-Gly, N-Me-Gly, N-Me-Homo-Gly Leu, D-Leu, Beta-Leu, D-Beta-Leu, Homo-Leu, D-Homo-Leu, Beta-Homo-Leu, N-Me-Leu, N-Me-Homo-Leu, 2-Me-Leu, Selected from the group consisting of Ile, D-Ile, β-Ile, D-β-Ile, homo-Ile, D-homo-Ile, β-homo-Ile, N-Me-Ile, N-Me-homo-Ile, or not present. X5 is selected from the group consisting of a tryptophan residue that may be substituted, azatryptophan residue that may be substituted, and a beta-homotryptophan residue that may be substituted. X6 may be a substituted Gln residue, a substituted Lys residue, a substituted Arg residue, a substituted Dab residue, a substituted Orn residue, a substituted Phe residue, Ala, D-Ala, Beta-Ala, D-Beta-Ala, Homo-Ala, D-Homo-Ala, Beta-Homo-Ala, N-Me-Ala, N-Me-Homo-Ala, Cit, D-Cit, Beta-Cit, D-Beta-Cit, Homo-Cit, D-Homo-Cit, Beta-Homo-Cit, N-Me-Cit, N-Me-Homo-Cit, Glu, D-Glu, Iso-Glu, D-Iso-Glu, Beta-Glu, D-Beta-G Selected from the group consisting of lu, homo-Glu, D-homo-Glu, beta-homo-Glu, N-Me-Glu, N-Me-homo-Glu, Tyr, D-Tyr, beta-Tyr, D-beta-Tyr, homo-Tyr, D-homo-Tyr, beta-homo-Tyr, N-Me-Tyr, N-Me-homo-Tyr, Val, D-Val, beta-Val, D-beta-Val, homo-Val, D-homo-Val, beta-homo-Val, N-Me-Val, N-Me-homo-Val, or His, D-His, beta-His, D-beta-His, homo-His, D-homo-His, beta-homo-His, N-Me-His, and N-Me-homo-His, X7 is Asp, D-Asp, iso-Asp, D-iso-Asp, beta-Asp, D-beta-Asp, homo-Asp, D-homo-Asp, beta-homo-Asp, N-Me-Asp, N-Me-homo-Asp, Glu, D-Glu, Iso-Glu, D-Iso-Glu, Beta-Glu, D-Beta-Glu, Homo-Glu, D-Homo-Glu, Beta-Homo-Glu, N-Me-Glu, N-Me-Homo-Glu, Dab, D-Dab, iso-Dab, D-iso-Dab, beta-Dab, D-beta-Dab, homo-Dab, D-homo-Dab, beta-homo-Dab, N-Me-Dab, N-Me-homo-Dab, Orn, D-Orn, Iso-Orn, D-Iso-Orn, Beta-Orn, D-Beta-Orn, Homo-Orn, D-Homo-Orn, Beta-Homo-Orn, N-Me-Orn, N-Me-Homo-Orn, Lys, D-Lys, iso-Lys, beta-Lys, D-iso-Lys, D-beta-Lys, homo-Lys, D-homo-Lys, beta-homo-Lys, N-Me-Lys, N-Me-homo-Lys Pra, D-Pra, Beta-Pra, D-Beta-Pra, Homo-Pra, D-Homo-Pra, Beta-Homo-Pra, N-Me-Pra, N-Me-Homo-Pra, Selected from the group consisting of Hpg, D-Hpg, beta-Hpg, D-beta-Hpg, homo-Hpg, D-homo-Hpg, beta-homo-Hpg, N-Me-Hpg, and N-Me-homo-Hpg, X8 is selected from the group consisting of an optionally substituted tryptophan residue, an optionally substituted azatryptophan residue, an optionally substituted beta-homotryptophan residue, an optionally substituted tyrosine residue, an optionally substituted phenylalanine residue, an optionally substituted homophenylalanine residue, and an alanine residue substituted with a carbocyclic group or an aromatic or heteroaromatic group selected from the group consisting of phenyl, pyridyl, naphthyl, and quinolinyl, each of which may be substituted. X9 is selected from the group consisting of an optional tryptophan residue, an optional azatryptophan residue, an optional alanine residue, an optional phenylalanine residue, and an optional tyrosine residue. The X10 is Val, D-Val, Beta-Val, D-Beta-Val, Homo-Val, D-Homo-Val, Beta-Homo-Val, N-mer-Val, N-mer-Homo-Val, 2-mer-Val, Gly, Beta-Gly, Homo-Gly, Beta-Homo-Gly, N-Me-Gly, N-Me-Homo-Gly Dab, D-Dab, iso-Dab, D-iso-Dab, beta-Dab, D-beta-Dab, homo-Dab, D-homo-Dab, beta-homo-Dab, N-Me-Dab, N-Me-homo-Dab, Lys, D-lys, iso-lys, D-iso-lys, beta-lys, D-beta-lys, homo-lys, D-homo-lys, beta-homo-lys, N-Me-lys, N-Me-homo-lys Aib, D-Aib, Beta-Aib, D-Beta-Aib, Homo-Aib, D-Homo-Aib, Beta-Homo-Aib, N-Me-Aib, N-Me-Homo-Aib, Ala, D-Ala, Beta-Ala, D-Beta-Ala, Homo-Ala, D-Homo-Ala, Beta-Homo-Ala, N-Me-Ala, N-Me-Homo-Ala, Leu, D-Leu, Beta-Leu, D-Beta-Leu, Homo-Leu, D-Homo-Leu, Beta-Homo-Leu, N-Me-Leu, N-Me-Homo-Leu, 2-Me-Leu, Ile, D-Ile, Beta-Ile, D-Beta-Ile, Homo-Ile, D-Homo-Ile, Beta-Homo-Ile, N-Me-Ile, N-Me-Homo-Ile, Furthermore, carbocyclic or heterocyclic rings having amino substituents and carbonyl substituents. Selected from the group consisting of, X11 is Dpr, D-Dpr, iso-Dpr, D-iso-Dpr, beta-Dpr, D-beta-Dpr, homo-Dpr, D-homo-Dpr, beta-homo-Dpr, N-Me-Dpr, N-Me-homo-Dpr, Dab, D-Dab, iso-Dab, D-iso-Dab, beta-Dab, D-beta-Dab, homo-Dab, D-homo-Dab, beta-homo-Dab, N-Me-Dab, N-Me-homo-Dab, Orn, D-Orn, Iso-Orn, D-Iso-Orn, Beta-Orn, D-Beta-Orn, Homo-Orn, D-Homo-Orn, Beta-Homo-Orn, N-Me-Orn, N-Me-Homo-Orn, Lys, D-lys, iso-Lys, D-iso-Lys, beta-Lys, D-beta-Lys, homo-Lys, D-homo-Lys, beta-homo-Lys, N-Me-Lys, N-Me-homo-Lys, Lys(Me), Lys (Gly), Asp, D-Asp, iso-Asp, D-iso-Asp, beta-Asp, D-beta-Asp, homo-Asp, D-homo-Asp, beta-homo-Asp, N-Me-Asp, N-Me-homo-Asp, Glu, D-Glu, Iso-Glu, D-Iso-Glu, Beta-Glu, D-Beta-Glu, Homo-Glu, D-Homo-Glu, Beta-Homo-Glu, N-Me-Glu, N-Me-Homo-Glu, and 2-amino-6-carboxyhexanoyl Selected from the group consisting of, X12 is an alanine residue substituted with an optional Phe residue, an optional Tyr residue, an optional His residue, a carbocyclic group or an aromatic or heteroaromatic group selected from the group consisting of optional phenyl, pyridyl, naphthyl, and quinolinyl, Dab, D-Dab, iso-Dab, D-iso-Dab, beta-Dab, D-beta-Dab, homo-Dab, D-homo-Dab, beta-homo-Dab, N-Me-Dab, N-Me-homo-Dab, Gly, beta-Gly, homo-Gly, beta-homo-Gly, N-Me-Gly, N-Me-homo-Gly, Pro, 5-aminopentanoyl, 4-aminopiperidine-4-carbonyl, (R,S)-imidazolidined-2-carbonyl, 3-aminopropanoyl, Gly-CF3, D-Gly-C F3, Nle, Gln, D-Gln, Iso-Gln, D-Iso-Gln, Beta-Gln, D-Beta-Gln, Homo-Gln, D-Homo-Gln, Beta-Homo-Gln, N-Me-Gln, N-Me-Homo-Gln, THP, Ser, D-Ser, Beta-Ser, D-Beta-Ser, Homo-Ser, D-Homo-Ser, Beta-Homo-Ser, N-Me-Ser, N-Me-Homo-Ser, Se r(OMe),3-aminotetrahydrofuran-3-carbonyl,Arg,D-Arg,Beta-Arg,D-beta-Arg,Homo-Arg,D-homo-Arg,Beta-homo-Arg,N-Me-Arg,N-Me-homo-Arg,Thr,D-Thr,Beta-Thr,D-beta-Thr,Homo-Thr,D-homo-Thr,Beta-homo-Thr,N-Me-Thr,N-Me-homo-Thr Glu, D-Glu, Iso-Glu, D-Iso-Glu, Beta-Glu, D-Beta-Glu, Homo-Glu, D-Homo-Glu, Beta-Homo-Glu, N-Me-Glu, N-Me-Homo-Glu, Asn, D-Asn, Beta-Asn, D-Beta-Asn, Homo-Asn, D-Homo-Asn, Beta-Homo-Asn, N-Me-Asn, N-Me-Homo-Asn, 4-Aminobutanoyl, 2-(trimethyl-2-aminoethoxy)ethoxypropyl]propyl, and Lys, where the side chain -NH2 of Lys is -C(=O)(CH2) n R KIt is substituted with, where n is 0 to 2, and R K is selected from the group consisting of Lys, which is imidazolyl, pyrimidyl, or pyridyl, which may be substituted with F, or X12 is absent. X13 is an optional His residue, an optional Phe residue, an alanine residue substituted with a carbocyclic group or an aromatic or heteroaromatic group selected from the group consisting of optional phenyl, pyridyl, naphthyl, and quinolinyl, each of which may be substituted, Asn, D-Asn, beta-Asn, D-beta-Asn, homo-Asn, D-homo-Asn, beta-homo-Asn, N-Me-Asn, N-Me-homo-Asn, Gly, beta-Gly, homo-Gly, beta-homo-Gly, N-Me-Gly, N-Me-homo-Gly and Dab, Orn, or Lys, where the side chain -NH2 is C(=O)(CH2) n R K It is substituted with, where n is 0 to 2, and R K is selected from the group consisting of Dab, Orn, or Lys, which may be imidazolyl, pyrimidyl, or pyridyl substituted with F. or does not exist, In the array, (i) X2 and X11 are amino acid residues that together form a lactam crosslink, (ii) X2 and X7 are amino acid residues that together form a lactam crosslink or a crosslink containing a triazole ring, (iii) Optionally, if X13 is present, X10 and X13 are amino acid residues that together form a lactam crosslink. amino acid sequence, or a pharmaceutically acceptable salt or solvate thereof.

[0182] In some embodiments, Z is given by formula I: X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13 (I) This is the amino acid sequence, and in the sequence, X2 is selected from the group consisting of Lys, D-Lys, iso-Lys, beta-Lys, D-beta-Lys, homo-Lys, D-homo-Lys, beta-homo-Lys, N-Me-Lys, Dab, D-Dab, iso-Dab, Glu, iso-Glu, D-iso-Glu, Orn, D-Orn, Dpr, Lys(Gly), (N3)-Lys, and D-(N3)-Lys. X3 is selected from the group consisting of Thr, Ile, 3-aminopropanoyl, 4-aminobutanoyl, beta-homo-Ile, beta-homo-Thr, Gly, N-Me-3-aminopropanoyl, and Ser, or is absent. X4 is either Val or does not exist. X5 is selected from the group consisting of Trp, 1-Me-Trp, and beta-homo-Trp. X6 is Gln, X7 is selected from the group consisting of Glu, D-Glu, Homo-Glu, Asp, Pra, and Hpg. X8 is selected from the group consisting of Y(2-aminoethoxy), Y(Me), Y(nPr), Y(Bn), Trp, D-Phe, 2-Me-Phe, F(4-Me), F(4-Bu), 3-(2-pyridyl)-Ala, 3-(3-pyridyl)-Ala, 3-(4-pyridyl)-Ala, and cyclopropyl-Ala. X9 is 2-Nal or cyclopropyl-Ala, X10 is selected from the group consisting of 2-Me-Leu, 2-Me-Val, Dab, Gly, Lys, and Aib. X11 is selected from the group consisting of Glu, homo-Glu, beta-homo-Glu, Dab, iso-Dab, Lys, Lys(Me), Orn, and 2-amino-6-carboxyhexanoyl. X12 consists of Dab, His, D-His, His(1-Me), 3-(2-pyridyl)-Ala, 3-(3-pyridyl)-Ala, 3-(4-pyridyl)-Ala, 3-(3-quinolinyl)-Ala, Gly, Pro, 5-aminopentanoyl, 4-aminopiperidine-4-carbonyl, (R,S)-imidazolidined-2-carbonyl, and Lys, where the side chain -NH2 of Lys is -C(=O)(CH2). n R K It is substituted with, where n is 0 to 2, and R K is selected from the group consisting of Lys, which may be imidazolyl, pyrimidyl, or pyridyl substituted with F, or X12 does not exist. X13 is selected from the group consisting of 3-(3-pyridyl)-Ala, D-3-(3-pyridyl)-Ala, and 3-(3,5-pyrimidyl)-Ala, or is absent. In the array, (i) X2 and X11 are amino acid residues that together form a lactam crosslink, (ii) X2 and X7 are amino acid residues that together form a lactam crosslink or a crosslink containing a triazole ring, (iii) Optionally, if X13 is present, X10 and X13 are amino acid residues that together form a lactam crosslink.

[0183] In some embodiments, Z is given by formula Ia: X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13 (Ia) This is the amino acid sequence, and in the sequence, X2 is selected from the group consisting of Lys, D-Lys, iso-Lys, beta-Lys, D-beta-Lys, homo-Lys, D-homo-Lys, beta-homo-Lys, N-Me-Lys, Dab, D-Dab, Glu, iso-Glu, Orn, D-Orn, Lys(Gly), (N3)-Lys, and D-(N3)-Lys. X3 is selected from the group consisting of Thr, Ile, 3-aminopropanoyl, 4-aminobutanoyl, beta-homo-Ile, beta-homo-Thr, Gly, and N-Me-3-aminopropanoyl, or is absent. X4 is either Val or does not exist. X5 is either a trp or a 1-Me-Trp. X6 is Gln, X7 is selected from the group consisting of Glu, homo-Glu, Asp, Pra, and Hpg. X8 is selected from the group consisting of Y(2-aminoethoxy), Y(Me), Y(Bn), F(4-Me), F(4-Bu), and cyclopropyl-Ala. X9 is 2-Nal, X10 is selected from the group consisting of 2-Me-Leu, 2-Me-Val, Dab, Gly, and Aib. X11 is selected from the group consisting of Glu, homo-Glu, Lys, Lys(Me), Orn, and 2-amino-6-carboxyhexanoyl. X12 is selected from the group consisting of Dab, His, D-His, His(1-Me), 3-(3-quinolinyl)-Ala, and 4-aminopiperidine-4-carbonyl. X13 is either 3-(3-pyridyl)-Ala, 3-(3,5-pyrimidyl)-Ala, or absent. In the array, (i) X2 and X11 are amino acid residues that together form a lactam crosslink, (ii) X2 and X7 are amino acid residues that together form a lactam crosslink or a crosslink containing a triazole ring, (iii) Optionally, if X13 is present, X10 and X13 are amino acid residues that together form a lactam crosslink.

[0184] In some embodiments, Z is given by formula II: X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13 (II) This is the amino acid sequence, and in the sequence, X2 is selected from the group consisting of Lys, D-Lys, iso-Lys, beta-Lys, D-beta-Lys, homo-Lys, D-homo-Lys, beta-homo-Lys, N-Me-Lys, Dab, D-Dab, iso-Dab, Glu, iso-Glu, D-iso-Glu, Orn, D-Orn, Dpr, Lys(Gly), (N3)-Lys, and D-(N3)-Lys. X3 is selected from the group consisting of Thr, Ile, 3-aminopropanoyl, 4-aminobutanoyl, beta-homo-Ile, beta-homo-Thr, Gly, N-Me-3-aminopropanoyl, and Ser, or is absent. X4 is either Val or does not exist. X5 is selected from the group consisting of Trp, 1-Me-Trp, and beta-homo-Trp. X6 is Gln, X7 is selected from the group consisting of Glu, D-Glu, Homo-Glu, Asp, Pra, and Hpg. X8 is selected from the group consisting of Y(2-aminoethoxy), Y(Me), Y(nPr), Y(Bn), Trp, D-Phe, 2-Me-Phe, F(4-Me), F(4-Bu), 3-(2-pyridyl)-Ala, 3-(3-pyridyl)-Ala, 3-(4-pyridyl)-Ala, and cyclopropyl-Ala. X9 is 2-Nal or cyclopropyl-Ala, X10 is selected from the group consisting of 2-Me-Leu, 2-Me-Val, Dab, Gly, Lys, and Aib. X11 is selected from the group consisting of Glu, homo-Glu, beta-homo-Glu, Dab, iso-Dab, Lys, Lys(Me), Orn, and 2-amino-6-carboxyhexanoyl. X12 consists of Dab, His, D-His, His(1-Me), 3-(2-pyridyl)-Ala, 3-(3-pyridyl)-Ala, 3-(4-pyridyl)-Ala, 3-(3-quinolinyl)-Ala, Gly, Pro, 5-aminopentanoyl, 4-aminopiperidine-4-carbonyl, (R,S)-imidazolidined-2-carbonyl, and Lys, where the side chain -NH2 of Lys is -C(=O)(CH2). n R K It is substituted with, where n is 0 to 2, and R K is selected from the group consisting of Lys, which may be imidazolyl, pyrimidyl, or pyridyl substituted with F, or X12 does not exist. X13 is selected from the group consisting of 3-(3-pyridyl)-Ala, D-3-(3-pyridyl)-Ala, and 3-(3,5-pyrimidyl)-Ala, or is absent. In the array, (i) X2 and X11 are amino acid residues that together form a lactam crosslink, (ii) X2 and X7 are amino acid residues that together form a lactam crosslink or a crosslink containing a triazole ring.

[0185] In some embodiments, Z is given by formula IIa: X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13 (IIa) This is the amino acid sequence, and in the sequence, X2 is selected from the group consisting of Lys, D-Lys, iso-Lys, beta-Lys, D-beta-Lys, homo-Lys, D-homo-Lys, beta-homo-Lys, N-Me-Lys, Dab, D-Dab, Glu, iso-Glu, Orn, D-Orn, Lys(Gly), (N3)-Lys, and D-(N3)-Lys. X3 is selected from the group consisting of Thr, Ile, 3-aminopropanoyl, 4-aminobutanoyl, beta-homo-Ile, beta-homo-Thr, Gly, and N-Me-3-aminopropanoyl, or is absent. X4 is either Val or does not exist. X5 is either a trp or a 1-Me-Trp. X6 is Gln, X7 is selected from the group consisting of Glu, homo-Glu, Asp, Pra, and Hpg. X8 is selected from the group consisting of Y(2-aminoethoxy), Y(Me), Y(Bn), F(4-Me), F(4-Bu), and cyclopropyl-Ala. X9 is 2-Nal, X10 is selected from the group consisting of 2-Me-Leu, 2-Me-Val, Dab, Gly, and Aib. X11 is selected from the group consisting of Glu, homo-Glu, Lys, Lys(Me), Orn, and 2-amino-6-carboxyhexanoyl. X12 is selected from the group consisting of Dab, His, D-His, His(1-Me), 3-(3-quinolinyl)-Ala, and 4-aminopiperidine-4-carbonyl. X13 is either 3-(3-pyridyl)-Ala, 3-(3,5-pyrimidyl)-Ala, or absent. In the array, (i) X2 and X11 are amino acid residues that together form a lactam crosslink, (ii) X2 and X7 are amino acid residues that together form a lactam crosslink or a crosslink containing a triazole ring.

[0186] In some embodiments, Z is given by Equation III: [Lys]-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13 (III) This is the amino acid sequence, and in the sequence, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, and X13 are defined by any one of the above formulas I, Ia, II, and IIa, In the array, (i) Lys of X2 forms a lactam crosslink with the amino acid residue of X11, (ii) Lys of X2 forms a lactam crosslink with the amino acid residue of X7, (iii) Optionally, if X13 is present, X10 and X13 are amino acid residues that together form a lactam crosslink.

[0187] In some embodiments, Z is given by formula IIIa: [Lys]-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13 (IIIa) This is the amino acid sequence, and in the sequence, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, and X13 are defined by any one of the above formulas I, Ia, II, and IIa, In the array, (i) Lys of X2 forms a lactam crosslink with the amino acid residue of X11, (ii) Lys of X2 forms a lactam crosslink with the amino acid residue of X7.

[0188] In some embodiments, Z is given by equation IV: X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13 (IV) This is the amino acid sequence, and in the sequence, X3 is selected from the group consisting of Thr, Ile, and 3-aminopropanoyl, or is absent. X2, X4, X5, X6, X7, X8, X9, X10, X11, X12, and X13 are defined by any one of the above formulas I, Ia, II, and IIa, In the array, (i) X2 and X11 are amino acid residues that together form a lactam crosslink, (ii) X2 and X7 are amino acid residues that together form a lactam crosslink or a crosslink containing a triazole ring, (iii) Optionally, if X13 is present, X10 and X13 are amino acid residues that together form a lactam crosslink.

[0189] In some embodiments, Z is given by formula IVa: X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13 (IVa) This is the amino acid sequence, and in the sequence, X3 is selected from the group consisting of Thr, Ile, and 3-aminopropanoyl, or is absent. X2, X4, X5, X6, X7, X8, X9, X10, X11, X12, and X13 are defined by any one of the above formulas I, Ia, II, and IIa, In the array, (i) X2 and X11 are amino acid residues that together form a lactam crosslink, (ii) X2 and X7 are amino acid residues that together form a lactam crosslink or a crosslink containing a triazole ring.

[0190] In some embodiments, Z is given by equation V: X2-X3-X5-X6-X7-X8-X9-X10-X11-X12-X13 (V) This is the amino acid sequence, and in the sequence, X2, X3, X5, X6, X7, X8, X9, X10, X11, X12, and X13 are defined by any one of the above formulas I, Ia, II, and IIa, In the array, (i) X2 and X11 are amino acid residues that together form a lactam crosslink, (ii) X2 and X7 are amino acid residues that together form a lactam crosslink or a crosslink containing a triazole ring, (iii) Optionally, if X13 is present, X10 and X13 are amino acid residues that together form a lactam crosslink.

[0191] In some embodiments, Z is given by formula Va: X2-X3-X5-X6-X7-X8-X9-X10-X11-X12-X13 (Va) This is the amino acid sequence, and in the sequence, X2, X3, X5, X6, X7, X8, X9, X10, X11, X12, and X13 are defined by any one of the above formulas I, Ia, II, and IIa, In the array, (i) X2 and X11 are amino acid residues that together form a lactam crosslink, (ii) X2 and X7 are amino acid residues that together form a lactam crosslink or a crosslink containing a triazole ring.

[0192] In some embodiments, Z is given by Equation VI: X2-X3-X4-[Trp]-X6-X7-X8-X9-X10-X11-X12-X13 (VI) This is the amino acid sequence, and in the sequence, X2, X3, X4, X6, X7, X8, X9, X10, X11, X12, and X13 are defined by any one of the above formulas I, Ia, II, and IIa, In the array, (i) X2 and X11 are amino acid residues that together form a lactam crosslink, (ii) X2 and X7 are amino acid residues that together form a lactam crosslink or a crosslink containing a triazole ring, (iii) Optionally, if X13 is present, X10 and X13 are amino acid residues that together form a lactam crosslink.

[0193] In some embodiments, Z is given by equation VIa: X2-X3-X4-[Trp]-X6-X7-X8-X9-X10-X11-X12-X13 (VIa) This is the amino acid sequence, and in the sequence, X2, X3, X4, X6, X7, X8, X9, X10, X11, X12, and X13 are defined by any one of the above formulas I, Ia, II, and IIa, In the array, (i) X2 and X11 are amino acid residues that together form a lactam crosslink, (ii) X2 and X7 are amino acid residues that together form a lactam crosslink or a crosslink containing a triazole ring.

[0194] In some embodiments, Z is given by equation VII: X2-X3-X4-X5-X6-[Glu]-X8-X9-X10-X11-X12-X13 (VII) This is the amino acid sequence, and in the sequence, X2, X3, X4, X5, X6, X8, X9, X10, X11, X12, and X13 are defined by any one of the above formulas I, Ia, II, and IIa, In the array, (i) X2 and X11 are amino acid residues that together form a lactam crosslink, (ii) The Glu of X7 forms a lactam crosslink with the amino acid residue of X2, (iii) Optionally, if X13 is present, X10 and X13 are amino acid residues that together form a lactam crosslink.

[0195] In some embodiments, Z is given by formula VIIa: X2-X3-X4-X5-X6-[Glu]-X8-X9-X10-X11-X12-X13 (VIIa) This is the amino acid sequence, and in the sequence, X2, X3, X4, X5, X6, X8, X9, X10, X11, X12, and X13 are defined by any one of the above formulas I, Ia, II, and IIa, In the array, (i) X2 and X11 are amino acid residues that together form a lactam crosslink, (ii) The Glu in X7 forms a lactam crosslink with the amino acid residue of X2.

[0196] In some embodiments, Z is given by formula VIII: X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13 (VIII) This is the amino acid sequence, and in the sequence, X8 is Y(2-aminoethoxy), Y(Me), or F(4-Me), X2, X3, X4, X5, X6, X7, X9, X10, X11, X12, and X13 are defined by any one of the above formulas I, Ia, II, and IIa, In the array, (i) X2 and X11 are amino acid residues that together form a lactam crosslink, (ii) X2 and X7 are amino acid residues that together form a lactam crosslink or a crosslink containing a triazole ring, (iii) Optionally, if X13 is present, X10 and X13 are amino acid residues that together form a lactam crosslink.

[0197] In some embodiments, Z is given by formula VIIIa: X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13 (VIIIa) This is the amino acid sequence, and in the sequence, X8 is Y(2-aminoethoxy), Y(Me), or F(4-Me), X2, X3, X4, X5, X6, X7, X9, X10, X11, X12, and X13 are defined by any one of the above formulas I, Ia, II, and IIa, In the array, (i) X2 and X11 are amino acid residues that together form a lactam crosslink, (ii) X2 and X7 are amino acid residues that together form a lactam crosslink or a crosslink containing a triazole ring.

[0198] In some embodiments, Z is given by formula IX: X2-X3-X4-X5-X6-X7-[Y(2-aminoethoxy)]-X9-X10-X11-X12-X13 (IX) This is the amino acid sequence, and in the sequence, X2, X3, X4, X5, X6, X7, X9, X10, X11, X12, and X13 are defined by any one of the above formulas I, Ia, II, and IIa, In the array, (i) X2 and X11 are amino acid residues that together form a lactam crosslink, (ii) X2 and X7 are amino acid residues that together form a lactam crosslink or a crosslink containing a triazole ring, (iii) Optionally, if X13 is present, X10 and X13 are amino acid residues that together form a lactam crosslink.

[0199] In some embodiments, Z is given by formula IX: X2-X3-X4-X5-X6-X7-[Y(2-aminoethoxy)]-X9-X10-X11-X12-X13 (IX) This is the amino acid sequence, and in the sequence, X2, X3, X4, X5, X6, X7, X9, X10, X11, X12, and X13 are defined by any one of the above formulas I, Ia, II, and IIa, In the array, (i) X2 and X11 are amino acid residues that together form a lactam crosslink, (ii) X2 and X7 are amino acid residues that together form a lactam crosslink or a crosslink containing a triazole ring.

[0200] In some embodiments, Z is given by equation X: X2-X3-X4-X5-X6-X7-X8-[2-Nal]-X10-X11-X12-X13 (X) This is the amino acid sequence, and in the sequence, X2, X3, X4, X5, X6, X7, X8, X10, X11, X12, and X13 are defined by any one of the above formulas I, Ia, II, and IIa, In the array, (i) X2 and X11 are amino acid residues that together form a lactam crosslink, (ii) X2 and X7 are amino acid residues that together form a lactam crosslink or a crosslink containing a triazole ring, (iii) Optionally, if X13 is present, X10 and X13 are amino acid residues that together form a lactam crosslink.

[0201] In some embodiments, Z is given by equation Xa: X2-X3-X4-X5-X6-X7-X8-[2-Nal]-X10-X11-X12-X13 (Xa) This is the amino acid sequence, and in the sequence, X2, X3, X4, X5, X6, X7, X8, X10, X11, X12, and X13 are defined by any one of the above formulas I, Ia, II, and IIa, In the array, (i) X2 and X11 are amino acid residues that together form a lactam crosslink, (ii) X2 and X7 are amino acid residues that together form a lactam crosslink or a crosslink containing a triazole ring.

[0202] In some embodiments, Z is given by formula XI: X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13 (XI) This is the amino acid sequence, and in the sequence, X10 is 2-Me-Leu or 2-Me-Val, X2, X3, X4, X5, X6, X7, X8, X9, X11, X12, and X13 are defined by any one of the above formulas I, Ia, II, and IIa, In the array, (i) X2 and X11 are amino acid residues that together form a lactam crosslink, (ii) X2 and X7 are amino acid residues that together form a lactam crosslink or a crosslink containing a triazole ring.

[0203] In some embodiments, Z is given by equation XII: X2-X3-X4-X5-X6-X7-X8-X9-[2-Me-Leu]-X11-X12-X13 (XII) This is the amino acid sequence, and in the sequence, X2, X3, X4, X5, X6, X7, X8, X9, X11, X12, and X13 are defined by any one of the above formulas I, Ia, II, and IIa, In the array, (i) X2 and X11 are amino acid residues that together form a lactam crosslink, (ii) X2 and X7 are amino acid residues that together form a lactam crosslink or a crosslink containing a triazole ring.

[0204] In some embodiments, Z is given by formula XIII: X2-X3-X4-X5-X6-X7-X8-X9-X10-[Glu]-X12-X13 (XIII) This is the amino acid sequence, and in the sequence, X2, X3, X4, X5, X6, X7, X8, X9, X10, X12, and X13 are defined by any one of the above formulas I, Ia, II, and IIa, In the array, (i) The Glu of X11 forms a lactam crosslink with the amino acid residue of X2, (ii) X2 and X7 are amino acid residues that together form a lactam crosslink or a crosslink containing a triazole ring, (iii) Optionally, if X13 is present, X10 and X13 are amino acid residues that together form a lactam crosslink.

[0205] In some embodiments, Z is given by formula XIIIa: X2-X3-X4-X5-X6-X7-X8-X9-X10-[Glu]-X12-X13 (XIIIa) This is the amino acid sequence, and in the sequence, X2, X3, X4, X5, X6, X7, X8, X9, X10, X12, and X13 are defined by any one of the above formulas I, Ia, II, and IIa, In the array, (i) The Glu of X11 forms a lactam crosslink with the amino acid residue of X2, (ii) X2 and X7 are amino acid residues that together form a lactam crosslink or a crosslink containing a triazole ring.

[0206] In some embodiments, Z is given by equation XIV: X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-[Dab]-X13 (XIV) This is the amino acid sequence, and in the sequence, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, and X13 are defined by any one of the above formulas I, Ia, II, and IIa, In the array, (i) X2 and X11 are amino acid residues that together form a lactam crosslink, (ii) X2 and X7 are amino acid residues that together form a lactam crosslink or a crosslink containing a triazole ring, (iii) Optionally, if X13 is present, X10 and X13 are amino acid residues that together form a lactam crosslink.

[0207] In some embodiments, Z is given by formula XIVa: X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-[Dab]-X13 (XIVa) This is the amino acid sequence, and in the sequence, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, and X13 are defined by any one of the above formulas I, Ia, II, and IIa, In the array, (i) X2 and X11 are amino acid residues that together form a lactam crosslink, (ii) X2 and X7 are amino acid residues that together form a lactam crosslink or a crosslink containing a triazole ring.

[0208] In some embodiments, Z is given by equation XV: X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13 (XV) This is the amino acid sequence, and in the sequence, X13 is either 3-(3-pyridyl)-Ala or absent. X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, and X12 are defined by any one of the above formulas I, Ia, II, and IIa, In the array, (i) X2 and X11 are amino acid residues that together form a lactam crosslink, (ii) X2 and X7 are amino acid residues that together form a lactam crosslink or a crosslink containing a triazole ring, (iii) Optionally, if X13 is present, X10 and X13 are amino acid residues that together form a lactam crosslink.

[0209] In some embodiments, Z is given by equation XVa: X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13 (XVa) This is the amino acid sequence, and in the sequence, X13 is either 3-(3-pyridyl)-Ala or absent. X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, and X12 are defined by any one of the above formulas I, Ia, II, and IIa, In the array, (i) X2 and X11 are amino acid residues that together form a lactam crosslink, (ii) X2 and X7 are amino acid residues that together form a lactam crosslink or a crosslink containing a triazole ring.

[0210] In some embodiments, Z is given by equation XVI: X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-[3-(3-pyridyl)-Ala] (XVI) This is the amino acid sequence, and in the sequence, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, and X12 are defined by any one of the above formulas I, Ia, II, and IIa, In the array, (i) X2 and X11 are amino acid residues that together form a lactam crosslink, (ii) X2 and X7 are amino acid residues that together form a lactam crosslink or a crosslink containing a triazole ring, (iii) Optionally, 3-(3-pyridyl)-Ala of X13 forms a lactam crosslink with the amino acid residue of X10.

[0211] In some embodiments, Z is given by equation XVIa: X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-[3-(3-pyridyl)-Ala] (XVIa) This is the amino acid sequence, and in the sequence, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, and X12 are defined by any one of the above formulas I, Ia, II, and IIa, In the array, (i) X2 and X11 are amino acid residues that together form a lactam crosslink, (ii) X2 and X7 are amino acid residues that together form a lactam crosslink or a crosslink containing a triazole ring.

[0212] In some embodiments, Z is given by equation XVII: [Lys]-X3-X4-[Trp]-X6-X7-X8-[2-Nal]-[2-Me-Leu]-X11-X12-X13 (XVII) This is the amino acid sequence, and in the sequence, X3, X4, X6, X7, X8, X11, X12, and X13 are defined by any one of the above formulas I, Ia, II, and IIa, In the array, (i) Lys of X2 forms a lactam crosslink with the amino acid residue of X11, (ii) Lys of X2 forms a lactam crosslink with the amino acid residue of X7.

[0213] In some embodiments, Z is given by formula XVIIa: [Lys]-X3-X4-[Trp]-X6-X7-X8-[2-Nal]-[2-Me-Leu]-X11-X12-X13 (XVIIa) This is the amino acid sequence, and in the sequence, X3, X4, X6, X7, X8, X11, X12, and X13 are defined by any one of the above formulas I, Ia, II, and IIa, In the array, (i) Lys of X2 forms a lactam crosslink with the amino acid residue of X11, (ii) Lys of X2 forms a lactam crosslink with the amino acid residue of X7.

[0214] In some embodiments, Z is given by formula XVIII: [Lys]-X3-X4-[Trp]-X6-X7-X8-[2-Nal]-[2-Me-Leu]-X11-X12-X13 (XVIII) This is the amino acid sequence, and in the sequence, X13 is either 3-(3-pyridyl)-Ala or absent. X3, X4, X6, X7, X8, X11, and X12 are defined by any one of the above formulas I, Ia, II, and IIa, In the array, (i) Lys of X2 forms a lactam crosslink with the amino acid residue of X11, (ii) Lys of X2 forms a lactam crosslink with the amino acid residue of X7.

[0215] In some embodiments, Z is given by formula XIX: [Lys]-X3-X4-[Trp]-X6-[Glu]-X8-[2-Nal]-[2-Me-Leu]-X11-X12-X13 (XIX) This is the amino acid sequence, and in the sequence, X13 is either 3-(3-pyridyl)-Ala or absent. X3, X4, X6, X8, X11, and X12 are defined by any one of the above formulas I, Ia, II, and IIa, In the array, (i) Lys of X2 forms a lactam crosslink with the amino acid residue of X11, (ii) The Lys of X2 and the Glu of X7 combine to form a lactam crosslink.

[0216] In some embodiments, Z is an amino acid sequence selected from the group consisting of sequences listed in Table 1-1a.

[0217] X2 X2 is Lys, D-lys, iso-Lys, D-iso-Lys, beta-Lys, D-beta-Lys, homo-Lys, D-homo-Lys, beta-homo-Lys, N-Me-Lys, N-Me-homo-Lys, (N3)-Lys, D-(N3)-Lys, (N3)-beta-Lys, (N3)-D-beta-Lys, (N3)-homo-Lys, (N3)-D-homo-Lys, (N3)-beta-homo-Lys, Dpr, D-Dpr, iso-Dpr, D-iso-Dpr, beta-Dpr, D-beta-Dpr, homo-Dpr, D-homo-Dpr, beta-homo-Dpr, N-Me-Dpr, N-Me-homo-Dpr, (N3)-Dpr, D-(N3)-Dpr, (N3)-beta-Dpr, (N3)-D-beta-Dpr, (N3)-homo-Dpr, (N3)-D-homo-Dpr, (N3)-beta-homo-Dpr, Dab, D-Dab, iso-Dab, D-iso-Dab, beta-Dab, D-beta-Dab, homo-Dab, D-homo-Dab, beta-homo-Dab, N-Me-Dab, N-Me-homo-Dab, (N3)-Dab, D-(N3)-Dab, (N3)-beta-Dab, (N3)-D-beta-Dab, (N3)-homo-Dab, (N3)-D-homo-Dab, (N3)-beta-homo-Dab, Orn, D-Orn, Iso-Orn, D-Iso-Orn, Beta-Orn, D-Beta-Orn, Homo-Orn, D-Homo-Orn, Beta-Homo-Orn, N-Me-Orn, N-Me-Homo-Orn, (N3)-Orn, D-(N3)-Orn, (N3)-Beta-Orn, (N3)-D-Beta-Orn, (N3)-Homo-Orn, (N3)-D-Homo-Orn, (N3)-Beta-Homo-Orn, Lys (Gly), Asp, D-Asp, Iso-Asp, D-Iso-Asp, Beta-Asp, D-Beta-Asp, Homo-Asp, D-Homo-Asp, Beta-Homo-Asp, N-Me-Asp, N-Me-Homo-Asp, (N3)-Asp, D-(N3)-Asp, (N3)-Beta-Asp, (N3)-D-Beta-Asp, (N3)-Homo-Asp, (N3)-D-Homo-Asp, (N3)-Beta-Homo-Asp, Selected from the group consisting of Glu, D-Glu, iso-Glu, D-iso-Glu, beta-Glu, D-beta-Glu, homo-Glu, D-homo-Glu, beta-homo-Glu, N-Me-Glu, N-Me-homo-Glu, (N3)-Glu, D-(N3)-Glu, (N3)-beta-Glu, (N3)-D-beta-Glu, (N3)-homo-Glu, (N3)-D-homo-Glu, (N3)-beta-homo-Glu, and 2-amino-6-carboxyhexanoyl and 3-aminopropanoyl.

[0218] In some embodiments, X2 is selected from the group consisting of Dab, D-Dab, iso-Dab, Lys, iso-Lys, D-beta-Lys, N-Me-Lys, homo-Lys, D-Lys, D-homo-Lys, beta-Lys, beta-homo-Lys, Lys(Gly), (N3)-Lys, D-(N3)-Lys, D-iso-Glu, iso-Glu, Glu, Orn, D-Orn, Dpr, and Lys(Gly).

[0219] In some embodiments, X2 is selected from the group consisting of Lys, D-Lys, iso-Lys, beta-Lys, D-beta-Lys, homo-Lys, D-homo-Lys, beta-homo-Lys, N-Me-Lys, Dab, D-Dab, iso-Dab, Glu, iso-Glu, D-iso-Glu, Orn, D-Orn, Dpr, Lys(Gly), (N3)-Lys, and D-(N3)-Lys.

[0220] The amino acid residue of X2 forms a (first) lactam crosslink with the amino acid residue of X11, and a (second) lactam crosslink or a crosslink containing a triazole ring with the amino acid residue of X7.

[0221] Preferably, the side chain of the amino acid residue of X2 is used for the lactam crosslink between X2 and X11, and the N-terminus of the amino acid residue of X2 is used for the crosslink between X2 and X7.

[0222] In some embodiments, where the amino acid residue of X2 forms a (first) lactam crosslink with the amino acid residue of X11 and a (second) lactam crosslink with the amino acid residue of X7, X2 is selected from the group consisting of Lys, D-Lys, iso-Lys, beta-Lys, D-beta-Lys, homo-Lys, D-homo-Lys, beta-homo-Lys, N-Me-Lys, Dab, D-Dab, iso-Dab, Glu, iso-Glu, D-iso-Glu, Orn, D-Orn, Dpr, and Lys(Gly).

[0223] In some embodiments, where the amino acid residue of X2 forms a (first) lactam crosslink with the amino acid residue of X11 and a (second) crosslink containing a triazole ring with the amino acid residue of X7, X2 is (N3)-Lys or D-(N3)-Lys.

[0224] In some embodiments, X2 is selected from the group consisting of Lys, D-Lys, iso-Lys, beta-Lys, D-beta-Lys, homo-Lys, D-homo-Lys, beta-homo-Lys, N-Me-Lys, Dab, D-Dab, Glu, iso-Glu, Orn, D-Orn, Lys(Gly), (N3)-Lys, and D-(N3)-Lys.

[0225] In some embodiments, X2 is selected from the group consisting of Lys, D-Lys, iso-Lys, D-beta-Lys, homo-Lys, beta-homo-Lys, N-Me-Lys, Dab, D-Dab, iso-Dab, Glu, iso-Glu, D-iso-Glu, Orn, and D-Orn.

[0226] In some embodiments, X2 is selected from the group consisting of Lys, D-Lys, iso-Lys, D-beta-Lys, homo-Lys, N-Me-Lys, Dab, D-Dab, Glu, and D-Orn.

[0227] In some embodiments, X2 is Lys. In some embodiments, X2 is D-Lys. In some embodiments, X2 is iso-Lys. In some embodiments, X2 is beta-Lys. In some embodiments, X2 is D-beta-Lys. In some embodiments, X2 is homo-Lys. In some embodiments, X2 is D-homo-Lys. In some embodiments, X2 is beta-homo-Lys. In some embodiments, X2 is N-Me-Lys. In some embodiments, X2 is Dab. In some embodiments, X2 is D-Dab. In some embodiments, X2 is iso-Dab. In some embodiments, X2 is Glu. In some embodiments, X2 is iso-Glu. In some embodiments, X2 is D-iso-Glu. In some embodiments, X2 is Orn. ​​In some embodiments, X2 is D-Orn. In some embodiments, X2 is Dpr. In some embodiments, X2 is Lys(Gly). In some embodiments, X2 is (N3)-Lys. In some embodiments, X2 is D-(N3)-Lys.

[0228] Preferably, X2 is Lys.

[0229] X3 X3 is any amino acid, ω-hydroxy-C 2-6 Selected from alkanates, or absent.

[0230] In some embodiments, X3 is selected from the group consisting of Thr, Ile, 3-aminopropanoyl, 4-aminobutanoyl, beta-homo-Ile, beta-homo-Thr, beta-homo-Trp, Gly, N-Me-3-aminopropanoyl, Ser, Trp, Phe, N-Me-Ser, N-Me-Ala, and 3-hydroxypropanoic acid, or is absent.

[0231] In some embodiments, X3 is selected from the group consisting of Thr, Ile, 3-aminopropanoyl, 4-aminobutanoyl, beta-homo-Ile, beta-homo-Thr, Gly, N-Me-3-aminopropanoyl, and Ser, or is absent.

[0232] X3 may not be present in the compounds disclosed herein, and in such cases, there is no loss of activity (see Example 2 below). Internal shortening, which is the deletion of an amino acid residue between X2 and X11 (X3, etc.) in other IL-23R peptide inhibitors, has been previously reported to result in inactive compounds (see Reference Compounds Ref5, Ref6, and Ref7 in the Examples of Brochure International Publication No. 2023 / 099669).

[0233] In some embodiments, X3 is selected from the group consisting of Thr, Ile, 3-aminopropanoyl, 4-aminobutanoyl, beta-homo-Ile, beta-homo-Thr, Gly, and N-Me-3-aminopropanoyl, or is absent.

[0234] In some embodiments, X3 is selected from the group consisting of Thr, Ile, 3-aminopropanoyl, and Gly, or is absent.

[0235] In some embodiments, X3 is selected from the group consisting of Thr, Ile, 3-aminopropanoyl, Gly, and Ser, or is absent.

[0236] In some embodiments, X3 is selected from the group consisting of Thr, Ile, 3-aminopropanoyl, and Gly, or is absent.

[0237] In some embodiments, X3 is selected from the group consisting of Thr, Ile, and 3-aminopropanoyl, or is absent.

[0238] In some embodiments, X3 is Thr, Ile, or absent.

[0239] In some embodiments, X3 is Thr. In some embodiments, X3 is Ile. In some embodiments, X3 is 3-aminopropanoyl. In some embodiments, X3 is 4-aminobutanoyl. In some embodiments, X3 is beta-homo-Ile. In some embodiments, X3 is beta-homo-Thr. In some embodiments, X3 is Gly. In some embodiments, X3 is N-Me-3-aminopropanoyl. In some embodiments, X3 is Ser. In some embodiments, X3 is absent.

[0240] Preferably, X3 is selected from the group consisting of Thr, Ile, and 3-aminopropanoyl, or is absent. More preferably, X3 is Thr, Ile, or is absent.

[0241] X4 X4 is Val, D-Val, Beta-Val, D-Beta-Val, Homo-Val, D-Homo-Val, Beta-Homo-Val, N-mer-Val, N-mer-Homo-Val, 2-mer-Val, Ala, D-Ala, Beta-Ala, D-Beta-Ala, Homo-Ala, D-Homo-Ala, Beta-Homo-Ala, N-Me-Ala, N-Me-Homo-Ala, Gly, Beta-Gly, Homo-Gly, Beta-Homo-Gly, N-Me-Gly, N-Me-Homo-Gly Leu, D-Leu, Beta-Leu, D-Beta-Leu, Homo-Leu, D-Homo-Leu, Beta-Homo-Leu, N-Me-Leu, N-Me-Homo-Leu, 2-Me-Leu, It is selected from the group consisting of Ile, D-Ile, beta-Ile, D-beta-Ile, homo-Ile, D-homo-Ile, beta-homo-Ile, N-Me-Ile, and N-Me-homo-Ile, or it does not exist.

[0242] In some embodiments, X4 is either Val or does not exist.

[0243] In some embodiments, X4 is Val. In some embodiments, X4 does not exist.

[0244] X4 may be omitted from the compounds disclosed herein, and in such cases, there is no loss of activity (see Example 2 below). Internal shortening, which is the deletion of an amino acid residue between X2 and X11 (X4, etc.) in other IL-23R peptide inhibitors, has been previously reported to result in inactive compounds (see Reference Compounds Ref5, Ref6, and Ref7 in the Examples section of International Publication No. 2023 / 099669).

[0245] Preferably, X4 does not exist.

[0246] X5 X5 is selected from the group consisting of a tryptophan residue that may be substituted, azatryptophan residue that may be substituted, and a beta-homotryptophan residue that may be substituted.

[0247] In some embodiments, X5 is selected from the group consisting of Trp, 1-Me-Trp, 7-Aza-Trp, 7-Me-Trp, and beta-homo-Trp.

[0248] In some embodiments, X5 is selected from the group consisting of Trp, 1-Me-Trp, and beta-homo-Trp.

[0249] In some embodiments, X5 is a Trp or a 1-Me-Trp.

[0250] In some embodiments, X5 is a Trp. In some embodiments, X5 is a 1-Me-Trp. In some embodiments, X5 is a beta-homo-Trp.

[0251] Preferably, X5 is a trump.

[0252] X6 X6 may be a substituted Gln residue, a substituted Lys residue, a substituted Arg residue, a substituted Dab residue, a substituted Orn residue, a substituted Phe residue, Ala, D-Ala, Beta-Ala, D-Beta-Ala, Homo-Ala, D-Homo-Ala, Beta-Homo-Ala, N-Me-Ala, N-Me-Homo-Ala, Cit, D-Cit, Beta-Cit, D-Beta-Cit, Homo-Cit, D-Homo-Cit, Beta-Homo-Cit, N-Me-Cit, N-Me-Homo-Cit, Glu, D-Glu, Iso-Glu, D-Iso-Glu, Beta-Glu, D-Beta-G Selected from the group consisting of lu, homo-Glu, D-homo-Glu, beta-homo-Glu, N-Me-Glu, N-Me-homo-Glu, Tyr, D-Tyr, beta-Tyr, D-beta-Tyr, homo-Tyr, D-homo-Tyr, beta-homo-Tyr, N-Me-Tyr, N-Me-homo-Tyr, Val, D-Val, beta-Val, D-beta-Val, homo-Val, D-homo-Val, beta-homo-Val, N-Me-Val, N-Me-homo-Val, or His, D-His, beta-His, D-beta-His, homo-His, D-homo-His, beta-homo-His, N-Me-His, and N-Me-homo-His.

[0253] In some embodiments, X6 is selected from the group consisting of Dab(Ac), Dab(Ac-N-Me), Gln, Gln(2Me), K(NMePEG3), and Gln(Me).

[0254] In some embodiments, X6 is Gln.

[0255] X7 X7 is Asp, D-Asp, iso-Asp, D-iso-Asp, beta-Asp, D-beta-Asp, homo-Asp, D-homo-Asp, beta-homo-Asp, N-Me-Asp, N-Me-homo-Asp, Glu, D-Glu, Iso-Glu, D-Iso-Glu, Beta-Glu, D-Beta-Glu, Homo-Glu, D-Homo-Glu, Beta-Homo-Glu, N-Me-Glu, N-Me-Homo-Glu, Dab, D-Dab, iso-Dab, D-iso-Dab, beta-Dab, D-beta-Dab, homo-Dab, D-homo-Dab, beta-homo-Dab, N-Me-Dab, N-Me-homo-Dab, Orn, D-Orn, Iso-Orn, D-Iso-Orn, Beta-Orn, D-Beta-Orn, Homo-Orn, D-Homo-Orn, Beta-Homo-Orn, N-Me-Orn, N-Me-Homo-Orn, Lys, D-Lys, iso-Lys, beta-Lys, D-iso-Lys, D-beta-Lys, homo-Lys, D-homo-Lys, beta-homo-Lys, N-Me-Lys, N-Me-homo-Lys Pra, D-Pra, Beta-Pra, D-Beta-Pra, Homo-Pra, D-Homo-Pra, Beta-Homo-Pra, N-Me-Pra, N-Me-Homo-Pra, Hpg, D-Hpg, Beta-Hpg, D-Beta-Hpg, Homo-Hpg, D-Homo-Hpg, Beta-Homo-Hpg, N-Me-Hpg, and N-Me-Homo-Hpg It is selected from the group consisting of the following.

[0256] In some embodiments, X7 is selected from the group consisting of Asp, D-Glu, Glu, Pra, Hpg, and homo-Glu.

[0257] In some embodiments, X7 is selected from the group consisting of Glu, homo-Glu, Asp, Pra, and Hpg. The amino acid residues of X7 form a lactam crosslink or a crosslink containing a triazole ring with the amino acid residues of X2.

[0258] In some embodiments, where the amino acid residue of X7 forms a lactam crosslink with the amino acid residue of X2, X7 is selected from the group consisting of Glu, homo-Glu, and Asp.

[0259] In embodiments where the amino acid residue of X7 forms a crosslink containing a triazole ring with the amino acid residue of X2, X7 is Pra or Hpg.

[0260] In some embodiments, X7 is Glu or Asp.

[0261] In some embodiments, X7 is Glu. In some embodiments, X7 is homo-Glu. In some embodiments, X7 is Asp. In some embodiments, X7 is Pra. In some embodiments, X7 is Hpg.

[0262] Preferably, X7 is Glu. The inventors reason that, from a synthetic standpoint, having X7 as Glu is more advantageous than having X7 as Asp because Asp in amide crosslinks is potentially more isomerized than Glu.

[0263] X8 X8 is selected from the group consisting of optionally substituted tryptophan residues, optionally substituted azatryptophan residues, optionally substituted beta-homotryptophan residues, optionally substituted tyrosine residues, optionally substituted phenylalanine residues, optionally substituted homophenylalanine residues, and alanine residues each substituted with an optionally substituted carbocyclic group or an aromatic or heteroaromatic group selected from the group consisting of phenyl, pyridyl, naphthyl, and quinolinyl.

[0264] In some embodiments, X8 is Y(2-aminoethoxy), Y(2-aminoethoxy)(N(Me)2), Y(n-pentylamine)(N + (Me)3), Y(2-trimethyl-PEG2), homo-Phe, 7-AzaTrp, beta-homo-Trp, 7-F-Trp, F(4-morpholine), 3-quinolinylalanine, Y(Me), Y(nPr), Y(Bn), Trp, D-Phe, 2-Me-Phe, F(4-Me), F(4-Bu), 3-(2-pyridyl)-Ala, 3-(3-pyridyl) The group is selected from -Ala, 3-(4-pyridyl)-Ala, cyclopropyl-Ala, F(4-THP), Y(CH3-2-F), F(4-F), F(4-piperazine), F(4-imidazole), F(piperidine), Y(CH3-3-F), 5-AzaTrp, Y(Ac-2-aminoethoxy), 6-AzaTrp, and F(4-CONH2).

[0265] In some embodiments, X8 is selected from the group consisting of Y(2-aminoethoxy), Y(Me), Y(nPr), Y(Bn), Trp, D-Phe, 2-Me-Phe, F(4-Me), F(4-Bu), 3-(2-pyridyl)-Ala, 3-(3-pyridyl)-Ala, 3-(4-pyridyl)-Ala, and cyclopropyl-Ala.

[0266] In some embodiments, X8 is selected from the group consisting of Y(2-aminoethoxy), Y(Me), Y(Bn), F(4-Me), F(4-Bu), and cyclopropyl-Ala.

[0267] In some embodiments, X8 is selected from the group consisting of Y(2-aminoethoxy), Y(Me), F(4-Me), and cyclopropyl-Ala.

[0268] In some embodiments, X8 is selected from the group consisting of Y(2-aminoethoxy), Y(Me), and F(4-Me).

[0269] In some embodiments, X8 is Y(2-aminoethoxy) or Y(Me).

[0270] In some embodiments, X8 is Y(2-aminoethoxy). In some embodiments, X8 is Y(Me). In some embodiments, X8 is Y(nPr). In some embodiments, X8 is Y(Bn). In some embodiments, X8 is Trp. In some embodiments, X8 is D-Phe. In some embodiments, X8 is 2-Me-Phe. In some embodiments, X8 is F(4-Me). In some embodiments, X8 is F(4-Bu). In some embodiments, X8 is 3-(2-pyridyl)-Ala. In some embodiments, X8 is 3-(3-pyridyl)-Ala. In some embodiments, X8 is 3-(4-pyridyl)-Ala. In some embodiments, X8 is cyclopropyl-Ala.

[0271] Preferably, X8 is Y(2-aminoethoxy), Y(Me), or F(4-Me). More preferably, X8 is Y(2-aminoethoxy) or Y(Me). Even more preferably, X8 is Y(2-aminoethoxy).

[0272] X9 X9 is selected from the group consisting of an optionally substituted tryptophan residue, an optionally substituted azatryptophan residue, an optionally substituted alanine residue, an optionally substituted phenylalanine residue, and an optionally substituted tyrosine residue. In some embodiments, X9 is 2-Nal or cyclopropyl-Ala.

[0273] In some embodiments, X9 is 2-Nal. In some embodiments, X9 is cyclopropyl-Ala.

[0274] Preferably, X9 is 2-Nal.

[0275] X10 The X10 is Val, D-Val, Beta-Val, D-Beta-Val, Homo-Val, D-Homo-Val, Beta-Homo-Val, N-mer-Val, N-mer-Homo-Val, 2-mer-Val, Gly, Beta-Gly, Homo-Gly, Beta-Homo-Gly, N-Me-Gly, N-Me-Homo-Gly Dab, D-Dab, iso-Dab, D-iso-Dab, beta-Dab, D-beta-Dab, homo-Dab, D-homo-Dab, beta-homo-Dab, N-Me-Dab, N-Me-homo-Dab, Lys, D-lys, iso-lys, D-iso-lys, beta-lys, D-beta-lys, homo-lys, D-homo-lys, beta-homo-lys, N-Me-lys, N-Me-homo-lys Aib, D-Aib, Beta-Aib, D-Beta-Aib, Homo-Aib, D-Homo-Aib, Beta-Homo-Aib, N-Me-Aib, N-Me-Homo-Aib, Ala, D-Ala, Beta-Ala, D-Beta-Ala, Homo-Ala, D-Homo-Ala, Beta-Homo-Ala, N-Me-Ala, N-Me-Homo-Ala, Leu, D-Leu, Beta-Leu, D-Beta-Leu, Homo-Leu, D-Homo-Leu, Beta-Homo-Leu, N-Me-Leu, N-Me-Homo-Leu, 2-Me-Leu, Ile, D-Ile, Beta-Ile, D-Beta-Ile, Homo-Ile, D-Homo-Ile, Beta-Homo-Ile, N-Me-Ile, N-Me-Homo-Ile, Furthermore, carbocyclic or heterocyclic rings having amino substituents and carbonyl substituents. It is selected from the group consisting of the following.

[0276] In some embodiments, X10 is selected from the group consisting of Dab, 2-Me-Leu, 2-Me-Val, Aib, D-Ala, Gly, and Lys.

[0277] In some embodiments, X10 is selected from the group consisting of 2-Me-Leu, 2-Me-Val, Dab, Gly, Lys, and Aib. If X13 is present, the amino acid residues of X10 may form lactam crosslinks with the amino acid residues of X13.

[0278] In some embodiments where X13 is present and an amino acid residue of X10 forms a lactam crosslink with an amino acid residue of X13, X10 is selected from the group consisting of Dab and Lys. In some embodiments where X13 is present and an amino acid residue of X10 forms a lactam crosslink with an amino acid residue of X13, X10 is Dab.

[0279] In some embodiments, X10 is selected from the group consisting of 2-Me-Leu, 2-Me-Val, Dab, Gly, and Aib.

[0280] In some embodiments, X10 is selected from the group consisting of 2-Me-Leu, 2-Me-Val, and Gly.

[0281] In some embodiments, X10 is 2-Me-Leu. In some embodiments, X10 is 2-Me-Val. In some embodiments, X10 is Dab. In some embodiments, X10 is Gly. In some embodiments, X10 is Lys. In some embodiments, X10 is Aib.

[0282] Preferably, X10 is 2-Me-Leu or 2-Me-Val. More preferably, X10 is 2-Me-Leu.

[0283] X11 X11 is Dpr, D-Dpr, iso-Dpr, D-iso-Dpr, beta-Dpr, D-beta-Dpr, homo-Dpr, D-homo-Dpr, beta-homo-Dpr, N-Me-Dpr, N-Me-homo-Dpr, Dab, D-Dab, iso-Dab, D-iso-Dab, beta-Dab, D-beta-Dab, homo-Dab, D-homo-Dab, beta-homo-Dab, N-Me-Dab, N-Me-homo-Dab, Orn, D-Orn, Iso-Orn, D-Iso-Orn, Beta-Orn, D-Beta-Orn, Homo-Orn, D-Homo-Orn, Beta-Homo-Orn, N-Me-Orn, N-Me-Homo-Orn, Lys, D-lys, iso-Lys, D-iso-Lys, beta-Lys, D-beta-Lys, homo-Lys, D-homo-Lys, beta-homo-Lys, N-Me-Lys, N-Me-homo-Lys, Lys(Me), Lys (Gly), Asp, D-Asp, iso-Asp, D-iso-Asp, beta-Asp, D-beta-Asp, homo-Asp, D-homo-Asp, beta-homo-Asp, N-Me-Asp, N-Me-homo-Asp, Glu, D-Glu, Iso-Glu, D-Iso-Glu, Beta-Glu, D-Beta-Glu, Homo-Glu, D-Homo-Glu, Beta-Homo-Glu, N-Me-Glu, N-Me-Homo-Glu, and 2-amino-6-carboxyhexanoyl It is selected from the group consisting of the following.

[0284] In some embodiments, X11 is selected from the group consisting of Glu, homo-Glu, beta-homo-Glu, Dab, iso-Dab, Lys, Lys(Me), Orn, and 2-amino-6-carboxyhexanoyl. The amino acid residues of X11 form lactam crosslinks with the amino acid residues of X2.

[0285] In some embodiments, X11 is selected from the group consisting of Glu, homo-Glu, Lys, Lys(Me), Orn, and 2-amino-6-carboxyhexanoyl.

[0286] In some embodiments, X11 is selected from the group consisting of Glu, homo-Glu, Lys, and 2-amino-6-carboxyhexanoyl.

[0287] In some embodiments, X11 is Glu or 2-amino-6-carboxyhexanoyl.

[0288] In some embodiments, X11 is Glu. In some embodiments, X11 is homo-Glu. In some embodiments, X11 is beta-homo-Glu. In some embodiments, X11 is Dab. In some embodiments, X11 is iso-Dab. In some embodiments, X11 is Lys. In some embodiments, X11 is Lys(Me). In some embodiments, X11 is Orn. ​​In some embodiments, X11 is 2-amino-6-carboxyhexanoyl.

[0289] Preferably, X11 is Glu.

[0290] X12 X12 is an alanine residue substituted with an optional Phe residue, an optional Tyr residue, an optional His residue, a carbocyclic group or an aromatic or heteroaromatic group selected from the group consisting of optional phenyl, pyridyl, naphthyl, and quinolinyl, Dab, D-Dab, iso-Dab, D-iso-Dab, beta-Dab, D-beta-Dab, homo-Dab, D-homo-Dab, beta-homo-Dab, N-Me-Dab, N-Me-homo-Dab, Gly, beta-Gly, homo-Gly, beta-homo-Gly, N-Me-Gly, N-Me-homo-Gly, Pro, 5-aminopentanoyl, 4-aminopiperidine-4-carbonyl, (R,S)-imidazolidined-2-carbonyl, 3-aminopropanoyl, Gly-CF3, D-Gly-C F3, Nle, Gln, D-Gln, Iso-Gln, D-Iso-Gln, Beta-Gln, D-Beta-Gln, Homo-Gln, D-Homo-Gln, Beta-Homo-Gln, N-Me-Gln, N-Me-Homo-Gln, THP, Ser, D-Ser, Beta-Ser, D-Beta-Ser, Homo-Ser, D-Homo-Ser, Beta-Homo-Ser, N-Me-Ser, N-Me-Homo-Ser, Se r(OMe),3-aminotetrahydrofuran-3-carbonyl,Arg,D-Arg,Beta-Arg,D-beta-Arg,Homo-Arg,D-homo-Arg,Beta-homo-Arg,N-Me-Arg,N-Me-homo-Arg,Thr,D-Thr,Beta-Thr,D-beta-Thr,Homo-Thr,D-homo-Thr,Beta-homo-Thr,N-Me-Thr,N-Me-homo-Thr Glu, D-Glu, Iso-Glu, D-Iso-Glu, Beta-Glu, D-Beta-Glu, Homo-Glu, D-Homo-Glu, Beta-Homo-Glu, N-Me-Glu, N-Me-Homo-Glu, Asn, D-Asn, Beta-Asn, D-Beta-Asn, Homo-Asn, D-Homo-Asn, Beta-Homo-Asn, N-Me-Asn, N-Me-Homo-Asn, 4-Aminobutanoyl, 2-(trimethyl-2-aminoethoxy)ethoxypropyl]propyl, and Lys, where the side chain -NH2 of Lys is -C(=O)(CH2) n R KIt is substituted with, where n is 0 to 2, and R K X12 is selected from the group consisting of Lys, which is imidazolyl, pyrimidyl, or pyridyl, which may be substituted with F, or X12 does not exist.

[0291] In some embodiments, X12 is Dab, His, D-His, His(1-Me), 3-(2-pyridyl)-Ala, 3-(3-pyridyl)-Ala, 3-(4-pyridyl)-Ala, 3-(3-quinolinyl)-Ala, Gly, Pro, Ser(OCH3), 5-aminopentanoyl, 4-aminopiperidine-4-carbonyl, (R,S)-imidazolidin-2-carbonyl, and Lys, where the side chain -NH2 of Lys is -C(=O)(CH2) n R K It is substituted with, where n is 0 to 2, and R K X12 is selected from the group consisting of Lys, which is imidazolyl, pyrimidyl, or pyridyl, which may be substituted with F, or X12 does not exist.

[0292] In some embodiments, X12 is Dab, His, D-His, His(1-Me), 3-(2-pyridyl)-Ala, 3-(3-pyridyl)-Ala, 3-(4-pyridyl)-Ala, 3-(3-quinolinyl)-Ala, Gly, Pro, 5-aminopentanoyl, 4-aminopiperidine-4-carbonyl, (R,S)-imidazolidin-2-carbonyl, and Lys, where the side chain -NH2 of Lys is -C(=O)(CH2) n R K It is substituted with, where n is 0 to 2, and R K X12 is selected from the group consisting of Lys, which is imidazolyl, pyrimidyl, or pyridyl, which may be substituted with F, or X12 does not exist.

[0293] X12 is Lysine, and the side chain -NH2 of Lysine is -C(=O)(CH2). n R K It is substituted with, where n is 0 to 2, and R KIn embodiments where Lys is an imidazolyl, pyrimidyl, or pyridyl which may be substituted with F, X12 may be selected from the group consisting of K(piconilate), K(2-pyridylacetyl), K(2-pyridylpropionyl), K(nicotinate), K(3-pyridylacetyl), K(3-pyridylpropionyl), K(isonicotinyl), K(4-pyridylacetyl), K(4-pyridylpropionyl), K(3,5-pyrimidine), K(4-pyridyl-3-fluoroacetyl), K(imidazoleacetyl), and K(imidazolepropanoyl).

[0294] In other words, K (piconilate) is when n is 0, and R K This is the case for pyrido-2-yl. K(2-pyridylacetyl) is n = 1, R K This is the case for pyrido-2-yl. K(2-pyridylpropionyl) is when n is 2 and R K This is the case for pyrido-2-yl. K (nicotinate) is when n is 0 and R K This is the case for pyrido-3-yl. K(3-pyridylacetyl) is n = 1, R K This is the case for pyrido-3-yl. K(3-pyridylpropionyl) is n = 2, R K This is the case for pyrido-3-yl. K (isonicotinyl) is when n is 0 and R K This is the case for pyrido-4-yl. K(4-pyridylacetyl) is n = 1, R K This is the case for pyrido-4-yl. K(4-pyridylpropionyl) is n = 2, R K This is the case for pyrido-4-yl. K(3,5-pyrimidine) is when n is 0 and R K This is the case for 3,5-pyrimidinyl. K(4-pyridyl-3-fluoroacetyl) has n = 1 and R K This is the case where the 2nd position is substituted with F, and R K This is the case for 1H-imidazole-2-yl. K (imidazolepropanoyl) is n = 2, R KThis is the case for 1H-imidazole-2-yl.

[0295] In some embodiments, X12 is selected from the group consisting of Dab, His, D-His, His(1-Me), 3-(3-quinolinyl)-Ala, and 4-aminopiperidine-4-carbonyl.

[0296] In some embodiments, X12 is selected from the group consisting of Dab, His, and Gly, or it is not present.

[0297] In some embodiments, X12 is selected from the group consisting of Dab, or it does not exist.

[0298] In some embodiments, X12 is Dab. In some embodiments, X12 is His. In some embodiments, X12 is D-His. In some embodiments, X12 is His(1-Me). In some embodiments, X12 is 3-(2-pyridyl)-Ala. In some embodiments, X12 is 3-(3-pyridyl)-Ala. In some embodiments, X12 is 3-(4-pyridyl)-Ala. In some embodiments, X12 is 3-(3-quinolinyl)-Ala. In some embodiments, X12 is Gly. In some embodiments, X12 is Pro. In some embodiments, X12 is 5-aminopentanoyl. In some embodiments, X12 is 4-aminopiperidine-4-carbonyl. In some embodiments, X12 is (R,S)-imidazolidined-2-carbonyl. In some embodiments, X12 is K(piconilate). In some embodiments, X12 is K(2-pyridylacetyl). In some embodiments, X12 is K(2-pyridylpropionyl). In some embodiments, X12 is K(nicotinate). In some embodiments, X12 is K(3-pyridylacetyl). In some embodiments, X12 is K(3-pyridylpropionyl). In some embodiments, X12 is K(isonicotinyl). In some embodiments, X12 is K(4-pyridylacetyl). In some embodiments, X12 is K(4-pyridylpropionyl). In some embodiments, X12 is K(3,5-pyrimidine). In some embodiments, X12 is K(4-pyridyl-3-fluoroacetyl). In some embodiments, X12 is K(imidazoleacetyl). In some embodiments, X12 is K (imidazolepropanoyl). In some embodiments, X12 is absent.

[0299] Preferably, X12 is Dab.

[0300] X13 X13 is an optional His residue, an optional Phe residue, an alanine residue substituted with a carbocyclic group or an aromatic or heteroaromatic group selected from the group consisting of optional phenyl, pyridyl, naphthyl, and quinolinyl, each of which may be substituted, Asn, D-Asn, beta-Asn, D-beta-Asn, homo-Asn, D-homo-Asn, beta-homo-Asn, N-Me-Asn, N-Me-homo-Asn, Gly, beta-Gly, homo-Gly, beta-homo-Gly, N-Me-Gly, N-Me-homo-Gly and Dab, Orn, or Lys, where the side chain -NH2 is C(=O)(CH2) n R K It is substituted with, where n is 0 to 2, and R K X13 is selected from the group consisting of Dab, Orn, or Lys, and is an imidazolyl, pyrimidyl, or pyridyl which may be substituted with F, or it is absent. In some embodiments, X13 is selected from the group consisting of 3-(3-pyridyl)-Ala, D-3-(3-pyridyl)-Ala, and 3-(3,5-pyridyl)-Ala, or it is absent. If X13 is present, the amino acid residue of X13 may form a lactam crosslink with the amino acid residue of X10.

[0301] In embodiments where X13 is present and the amino acid residue of X13 forms a lactam crosslink with the amino acid residue of X10, X13 may be 3-(3-pyridyl)-Ala.

[0302] In some embodiments, X13 is selected from the group consisting of 3-(3-pyridyl)-Ala and D-3-(3-pyridyl)-Ala, or is absent.

[0303] In some embodiments, X13 is 3-(3-pyridyl)-Ala, 3-(3,5-pyrimidyl), or absent.

[0304] In some embodiments, X13 is 3-(3-pyridyl)-Ala or is absent.

[0305] In some embodiments, X13 is 3-(3-pyridyl)-Ala. In some embodiments, X13 is D-3-(3-pyridyl)-Ala. In some embodiments, X13 is 3-(3,5-pyrimidyl)-Ala. In some embodiments, X13 is absent.

[0306] Preferably, X13 is 3-(3-pyridyl)-Ala or is absent. More preferably, X13 is 3-(3-pyridyl)-Ala.

[0307] Lactam Bridge Lactam crosslinks are formed by one amino acid residue containing an amine group and another amino acid residue containing a carboxylic acid group. The amine group and / or carboxylic acid group of the amino acid residue may be present in the side chain of the amino acid residue, such as Lys, D-Lys, iso-Lys, beta-Lys, D-beta-Lys, homo-Lys, D-homo-Lys, beta-homo-Lys, N-Me-Lys, Lys(Me), Lys(Gly), Dab, D-Dab, iso-Dab, Orn, D-Orn, Dpr, Glu, D-Glu, iso-Glu, D-iso-Glu, homo-Glu, beta-homo-Glu, and Asp. Alternatively, the amine and / or carboxylic acid groups of the amino acid residues may be the amine or carboxylic acid of the peptide backbone of any amino acid, or the N-terminus or C-terminus of a peptide chain, such as Lys, D-Lys, iso-Lys, beta-Lys, D-beta-Lys, homo-Lys, D-homo-Lys, beta-homo-Lys, N-Me-Lys, Dab, D-Dab, iso-Dab, Orn, D-Orn, Dpr, Lys(Gly), Glu, iso-Glu, D-iso-Glu, 3-(3-pyridyl)-Ala, and 2-amino-6-carboxyhexanoyl.

[0308] For simplicity, amino acid residues that form lactam crosslinks together will be considered by referring to residues that nominally exist before lactam formation.

[0309] The appropriate amino acid residues that work together to form lactam crosslinks can be selected from the following: • Amino acid residues containing amine groups: Lys, D-Lys, iso-Lys, beta-Lys, D-beta-Lys, homo-Lys, D-homo-Lys, beta-homo-Lys, N-Me-Lys, Lys(Me), Lys(Gly), Dab, D-Dab, iso-Dab, Orn, D-Orn, Dpr, 3-(3-pyridyl)-Ala, (N3)-Lys, and D-(N3)-Lys. • Amino acid residues containing carboxylic acid groups: Glu, D-Glu, iso-Glu, D-iso-Glu, homo-Glu, beta-homo-Glu, Asp, 2-amino-6-carboxyhexanoyl, and iso-Dab.

[0310] The inventors have found that replacing dithioether crosslinks with lactam crosslinks can result in an increase in the potency of the IL-23R peptide inhibitor previously described in Example 2 of International Publication No. 2023 / 099669.

[0311] First lactam bridge - X2 and X11 The first lactam crosslink is formed between the amino acid residues of X2 and X11.

[0312] One of the residues at positions X2 and X11 is an amino acid residue containing an amine group, and the other is an amino acid residue containing a carboxylic acid group, with a lactam (cyclic amide) formed between the amine group and the carboxylic acid group.

[0313] In some embodiments, the amino acid residue containing an amine group is located at X2, and the amino acid residue containing a carboxylic acid group is located at X11. In some such embodiments, X2 is Lys, D-lys, iso-Lys, D-iso-Lys, beta-Lys, D-beta-Lys, homo-Lys, D-homo-Lys, beta-homo-Lys, N-Me-Lys, N-Me-homo-Lys, (N3)-Lys, D-(N3)-Lys, (N3)-beta-Lys, (N3)-D-beta-Lys, (N3)-homo-Lys, (N3)-D-homo-Lys, (N3)-beta-homo-L ys, Dpr, D-Dpr, iso-Dpr, D-iso-Dpr, beta-Dpr, D-beta-Dpr, homo-Dpr, D-homo-Dpr, beta-homo-Dpr, N-Me-Dpr, N-Me-homo-Dpr, (N3)-Dpr, D-(N3)-Dpr, (N3)-beta-Dpr, (N3)-D-beta-Dpr, (N3)-homo-Dpr, (N3)-D-homo-Dpr, (N3)-beta-homo-Dpr , Dab, D-Dab, Beta-Dab, D-Beta-Dab, Homo-Dab, D-Homo-Dab, Beta-Homo-Dab, N-Me-Dab, N-Me-Homo-Dab, (N3)-Dab, D-(N3)-Dab, (N3)-Beta-Dab, (N3)-D-Beta-Dab, (N3)-Homo-Dab, (N3)-D-Homo-Dab, (N3)-Beta-Homo-Dab, Orn, D-Orn, Iso-Orn Selected from D-iso-Orn, beta-Orn, D-beta-Orn, homo-Orn, D-homo-Orn, beta-homo-Orn, N-Me-Orn, N-Me-homo-Orn, (N3)-Orn, D-(N3)-Orn, (N3)-beta-Orn, (N3)-D-beta-Orn, (N3)-homo-Orn, (N3)-D-homo-Orn, (N3)-beta-homo-Orn, and Lys(Gly).

[0314] In some such embodiments, X2 is selected from the group consisting of Dab, D-Dab, Lys, iso-Lys, D-beta-Lys, N-Me-Lys, homo-Lys, D-Lys, D-homo-Lys, beta-Lys, beta-homo-Lys, Lys(Gly), (N3)-Lys, D-(N3)-Lys, Orn, D-Orn, Dpr, and Lys(Gly).

[0315] In some such embodiments, X2 is selected from Lys, D-Lys, iso-Lys, beta-Lys, D-beta-Lys, homo-Lys, D-homo-Lys, beta-homo-Lys, N-Me-Lys, Dab, D-Dab, iso-Dab, Orn, D-Orn, Dpr, Lys(Gly), (N3)-Lys, and D-(N3)-Lys.

[0316] In some such embodiments, X11 is selected from Asp, D-Asp, iso-Asp, D-iso-Asp, beta-Asp, D-beta-Asp, homo-Asp, D-homo-Asp, beta-homo-Asp, N-Me-Asp, N-Me-homo-Asp, Glu, D-Glu, iso-Glu, D-iso-Glu, beta-Glu, D-beta-Glu, homo-Glu, D-homo-Glu, beta-homo-Glu, N-Me-Glu, N-Me-homo-Glu, 2-amino-6-carboxyhexanoyl, and iso-dab.

[0317] In some such embodiments, X11 is selected from the group consisting of Glu, homo-Glu, beta-homo-Glu, 2-amino-6-carboxyhexanoyl, and iso-Dab.

[0318] In other words, in an embodiment in which an amino acid residue containing an amine group is present in X2 and an amino acid residue containing a carboxylic acid group is present in X11, the appropriate combinations of X2 and X11 are as follows. X2 is D-Lys, and X11 is Glu. X2 is Lys, and X11 is Glu. X2 is homo-Lys, and X11 is Glu. X2 is D-homo-Lys, and X11 is Glu. X2 is D-Orn, and X11 is homo-Glu. X2 is D-Dab, and X11 is 2-amino-6-carboxyhexanoyl. X2 is D-Orn, and X11 is Glu. X2 is D-Dab, and X11 is Glu. X2 is beta-Lys, and X11 is Glu. X2 is D-beta-Lys, and X11 is Glu. X2 is Lys, and X11 is iso-Dab. X2 is Dab, and X11 is Glu. X2 is Lys (Gly), and X11 is Glu. X2 is Lys, and X11 is beta-homo-Glu. X2 is Ne-Me-Lys, and X11 is Glu. X2 is Orn, and X11 is Glu. X2 is Dpr, and X11 is Glu. X2 is beta-homo-Lys, and X11 is Glu. X2 is iso-Lys, and X11 is Glu. X2 is iso-Dab, and X11 is Glu. X2 is (N3)-Lys, and X11 is Glu. X2 is D-(N3)-Lys, and X11 is Glu.

[0319] In some embodiments, the amino acid residue containing an amine group is present in X11, and the amino acid residue containing a carboxylic acid group is present in X2. X2 is Asp, D-Asp, iso-Asp, D-iso-Asp, beta-Asp, D-beta-Asp, homo-Asp, D-homo-Asp, beta-homo-Asp, N-Me-Asp, N-Me-homo-Asp, (N3)-Asp, D-(N3)-Asp, (N3)-beta-Asp, (N3)-D-beta-Asp, (N3)-homo-Asp, (N3)-D-homo-Asp, (N3)-beta-homo-Asp, Glu, D-Glu, iso-Glu, D- Selected from iso-Glu, beta-Glu, D-beta-Glu, homo-Glu, D-homo-Glu, beta-homo-Glu, N-Me-Glu, N-Me-homo-Glu, (N3)-Glu, D-(N3)-Glu, (N3)-beta-Glu, (N3)-D-beta-Glu, (N3)-homo-Glu, (N3)-D-homo-Glu, (N3)-beta-homo-Glu, and 2-amino-6-carboxyhexanoyl and 3-aminopropanoyl.

[0320] In some such embodiments, X2 is selected from Glu, iso-Glu, and D-iso-Glu.

[0321] In some such embodiments, X11 is Dpr, D-Dpr, iso-Dpr, D-iso-Dpr, beta-Dpr, D-beta-Dpr, homo-Dpr, D-homo-Dpr, beta-homo-Dpr, N-Me-Dpr, and N-Me-homo-Dpr, Dab, D-Dab, iso-Dab, D-iso-Dab, beta-Dab, D-beta-Dab, homo-Dab, D-homo-Dab, beta-homo-Dab, N-Me-Dab, N-Me-homo- The following are selected: Dab, Orn, D-Orn, Iso-Orn, D-Iso-Orn, Beta-Orn, D-Beta-Orn, Homo-Orn, D-Homo-Orn, Beta-Homo-Orn, N-Me-Orn, N-Me-Homo-Orn, Lys, D-lys, Iso-Lys, D-Iso-Lys, Beta-Lys, D-Beta-Lys, Homo-Lys, D-Homo-Lys, Beta-Homo-Lys, N-Me-Lys, N-Me-Homo-Lys, and Lys(Me).

[0322] In some such embodiments, X11 is selected from the group consisting of Dab, Lys, Lys(Me), and Orn.

[0323] In other words, in an embodiment in which an amino acid residue containing an amine group is present in X2 and an amino acid residue containing a carboxylic acid group is present in X11, the appropriate combinations of X2 and X11 are as follows. X2 is Glu, and X11 is Orn. X2 is Glu, and X11 is Lys(Me). X2 is Glu, and X11 is Lys. X2 is iso-Glu, and X11 is Lys. X2 is iso-Glu, and X11 is Dab. X2 is D-iso-Glu, and X11 is Lys. X2 is D-iso-Glu, and X11 is Dab.

[0324] Second lactam bridge - X2 and X7 A second lactam crosslink may be formed between the amino acid residues of X2 and X7.

[0325] Preferably, the crosslinks between the amino acid residues of X2 and X7 are lactam crosslinks.

[0326] One of the residues at positions X2 and X7 is an amino acid residue containing an amine group, and the other is an amino acid residue containing a carboxylic acid group, forming a lactam (cyclic amide) between the amine group and the carboxylic acid group.

[0327] In some embodiments, the amino acid residue containing an amine group is located at X2, and the amino acid residue containing a carboxylic acid group is located at X7. In some such embodiments, X2 is Lys, D-lys, iso-Lys, D-iso-Lys, beta-Lys, D-beta-Lys, homo-Lys, D-homo-Lys, beta-homo-Lys, N-Me-Lys, N-Me-homo-Lys, (N3)-Lys, D-(N3)-Lys, (N3)-beta-Lys, (N3)-D-beta-Lys, (N3)-homo-Lys, (N3)-D-homo-Lys, (N3)-beta-homo-L ys, Dpr, D-Dpr, iso-Dpr, D-iso-Dpr, beta-Dpr, D-beta-Dpr, homo-Dpr, D-homo-Dpr, beta-homo-Dpr, N-Me-Dpr, N-Me-homo-Dpr, (N3)-Dpr, D-(N3)-Dpr, (N3)-beta-Dpr, (N3)-D-beta-Dpr, (N3)-homo-Dpr, (N3)-D-homo-Dpr, (N3)-beta-homo-Dpr , Dab, D-Dab, Beta-Dab, D-Beta-Dab, Homo-Dab, D-Homo-Dab, Beta-Homo-Dab, N-Me-Dab, N-Me-Homo-Dab, (N3)-Dab, D-(N3)-Dab, (N3)-Beta-Dab, (N3)-D-Beta-Dab, (N3)-Homo-Dab, (N3)-D-Homo-Dab, (N3)-Beta-Homo-Dab, Orn, D-Orn, Iso-Orn Selected from D-iso-Orn, beta-Orn, D-beta-Orn, homo-Orn, D-homo-Orn, beta-homo-Orn, N-Me-Orn, N-Me-homo-Orn, (N3)-Orn, D-(N3)-Orn, (N3)-beta-Orn, (N3)-D-beta-Orn, (N3)-homo-Orn, (N3)-D-homo-Orn, (N3)-beta-homo-Orn, and Lys(Gly).

[0328] In some such embodiments, X2 is selected from the group consisting of Dab, D-Dab, Lys, iso-Lys, D-beta-Lys, N-Me-Lys, homo-Lys, D-Lys, D-homo-Lys, beta-Lys, beta-homo-Lys, Lys(Gly), (N3)-Lys, D-(N3)-Lys, Orn, D-Orn, Dpr, and Lys(Gly). In some such embodiments, X2 is selected from the group consisting of Lys, D-Lys, iso-Lys, beta-Lys, D-beta-Lys, homo-Lys, D-homo-Lys, beta-homo-Lys, N-Me-Lys, Dab, D-Dab, iso-Dab, Orn, D-Orn, Dpr, Lys(Gly), iso-Glu, and D-iso-Glu.

[0329] In some such embodiments, X7 is selected from the group consisting of Asp, D-Asp, iso-Asp, D-iso-Asp, beta-Asp, D-beta-Asp, homo-Asp, D-homo-Asp, beta-homo-Asp, N-Me-Asp, N-Me-homo-Asp, Glu, D-Glu, iso-Glu, D-iso-Glu, beta-Glu, D-beta-Glu, homo-Glu, D-homo-Glu, beta-homo-Glu, N-Me-Glu, and N-Me-homo-Glu.

[0330] In some such embodiments, X7 is selected from the group consisting of Glu, D-Glu, Homo-Glu, and Asp.

[0331] In other words, in an embodiment in which an amino acid residue containing an amine group is present in X2 and an amino acid residue containing a carboxylic acid group is present in X7, the appropriate combinations of X2 and X7 are as follows. X2 is D-Lys, and X7 is Glu. X2 is Lys, and X7 is Glu. X2 is D-Lys, and X7 is Asp. X2 is homo-Lys, and X7 is Glu. X2 is D-homo-Lys, and X7 is Glu. X2 is D-Orn, and X7 is Glu. X2 is D-Dab, and X7 is Glu. X2 is D-Orn, and X7 is Asp. X2 is D-Dab, and X7 is Asp. X2 is beta-Lys, and X7 is Glu. X2 is D-beta-Lys, and X7 is Asp. X2 is D-beta-Lys, and X7 is Glu. X2 is Lys, and X7 is D-Glu. X2 is Dab, and X7 is Glu. X2 is Lys, and X7 is homo-Glu. X2 is Glu, and X7 is Glu. X2 is Lys (Gly), and X7 is Glu. X2 is Ne-Me-Lys, and X7 is Glu. X2 is Orn, and X7 is Glu. X2 is Dpr, and X7 is Glu. X2 is beta-homo-Lys, and X7 is Glu. X2 is iso-Lys and X7 is Glu. X2 is iso-Dab and X7 is Glu. X2 is iso-Glu, and X7 is Glu. X2 is D-iso-Glu, and X7 is Glu.

[0332] Alternatively, amino acid residues containing an amine group are located at X7, and amino acid residues containing a carboxylic acid group are located at X2.

[0333] Preferably, an amino acid residue containing an amine group is located at X2, and an amino acid residue containing a carboxylic acid group is located at X7.

[0334] Optional third lactam bridge - X10 and X13 If X13 is present, an optional third lactam crosslink may be formed between the amino acid residues of X10 and X13.

[0335] In some such embodiments, one of the residues at positions X10 and X13 is an amino acid residue containing an amine group, and the other is an amino acid residue containing a carboxylic acid group, with a lactam (cyclic amide) formed between the amine group and the carboxylic acid group.

[0336] In some embodiments, amino acid residues containing an amine group are present in X13, and amino acid residues containing a carboxylic acid group are present in X10. In some such embodiments, In some such embodiments, X10 is selected from Dab, D-Dab, iso-Dab, D-iso-Dab, beta-Dab, D-beta-Dab, homo-Dab, D-homo-Dab, beta-homo-Dab, N-Me-Dab, N-Me-homo-Dab, Lys, D-lys, iso-Lys, D-iso-Lys, beta-Lys, D-beta-Lys, homo-Lys, D-homo-Lys, beta-homo-Lys, N-Me-Lys, and N-Me-homo-Lys.

[0337] In some such embodiments, X10 is Dab or Lys.

[0338] In some such embodiments, D13 is an alanine residue substituted with a carbocyclic group or an aromatic or heteroaromatic group selected from the group consisting of phenyl, pyridyl, naphthyl, and quinolinyl, each of which may be substituted, as well as Dab, Orn, or Lys, where the side chain -NH2 is -C(=O)(CH2) n R K It is substituted with, where n is 0 to 2, and R K is imidazolyl, pyrimidyl, or pyridyl, which may be substituted with F.

[0339] In some such embodiments, X13 is 3-(3-pyridyl)-Ala.

[0340] In other words, in an embodiment in which an amino acid residue containing an amine group is present in X13 and an amino acid residue containing a carboxylic acid group is present in X10, the appropriate combinations of X13 and X10 are as follows. X10 is Dab, and X13 is 3-(3-pyridyl)-Ala. X10 is Lys, and X13 is 3-(3-pyridyl)-Ala.

[0341] Alternatively, amino acid residues containing an amine group are located at X10, and amino acid residues containing a carboxylic acid group are located at X13.

[0342] Preferably, amino acid residues containing an amine group are located in X13, and amino acid residues containing a carboxylic acid group are located in X10.

[0343] Crosslinking containing a triazole ring The crosslinking, which includes a triazole ring, is formed by one amino acid residue containing an azide (-N3) group and another amino acid residue containing an alkyne group. In some embodiments, the azide and / or alkyne groups of the amino acid residues are located on the side chains of the amino acid residues.

[0344] The appropriate amino acid residues that combine to form a crosslink containing a triazole ring can be selected from the following: • Amino acid residues containing an azide group: (N3)-Lys and D-(N3)-Lys. • Amino acid residues containing alkyne groups: Pra and Hpg

[0345] The compounds of the present invention may include crosslinks (instead of lactam crosslinks) containing a triazole ring formed between the amino acid residues at positions X2 and X7.

[0346] One of the residues at positions X2 and X7 is an amino acid residue containing an azide group (-N3), and the other is an amino acid residue containing an alkyne group, forming a triazole (1,2,3-triazole, etc.) between the azide group and the alkyne group. The reaction for triazole ring formation is a hysgen azide-alkyne 1,3-dipolar cycloaddition reaction. Typically, in this reaction, a 1,4-disubstituted 1,2,3-triazole ring (in contrast to a 1,5-disubstituted 1,2,3-triazole ring) is formed as the main isomer. The 1,5-disubstituted 1,2,3-triazole ring can usually be isolated as a subisomer.

[0347] The azide group and / or alkyne group may be present in the side chain of the amino acid residue. The alkyne is preferably a terminal alkyne (-C≡CH). Suitable amino acid residues whose side chains can contribute to the formation of a triazole ring (such as a 1,2,3-triazole ring) include Pra and Hpg (which have side chains containing an alkyne group).

[0348] Alternatively, the azide and / or alkyne groups of the amino acid residues may be at the N-terminus or C-terminus of the peptide chain. For example, the azide group may be derived from the amine group of the peptide backbone of any amino acid, such as (N3)-Lys and D-(N3)-Lys, or it may be at the N-terminus of the peptide chain.

[0349] In some embodiments, the amino acid residue containing an azide group is located at X2, and the amino acid residue containing an alkyne group is located at X7. In some such embodiments, X2 is (N3)-Lys, D-(N3)-Lys, (N3)-Beta-Lys, (N3)-D-Beta-Lys, (N3)-Homo-Lys, (N3)-D-Homo-Lys, (N3)-Beta-Homo-Lys, (N3)-Dpr, D-(N3)-Dpr, (N3)-Beta-Dpr, (N3)-D-Beta-Dpr, (N3)-Homo-Dpr, (N3)-D-Homo-Dpr, (N3)-Beta-Homo-Dpr, (N3)-Dab, D-(N3)-Dab, (N3)-Beta-Dab, (N3)-D-Beta-Dab, (N3)-Homo-Dab, (N3)-D-Homo-Dab, (N3)-Beta-Homo-Dab, (N3)-D-Homo-Dab 3) Selected from (N3)-Orn, D-(N3)-Orn, (N3)-Beta-Orn, (N3)-D-Beta-Orn, (N3)-Homo-Orn, (N3)-D-Homo-Orn, (N3)-Beta-Homo-Orn, (N3)-Asp, D-(N3)-Asp, (N3)-Beta-Asp, (N3)-D-Beta-Asp, (N3)-Homo-Asp, (N3)-D-Homo-Asp, (N3)-Beta-Homo-Asp, (N3)-Glu, D-(N3)-Glu, (N3)-Beta-Glu, (N3)-D-Beta-Glu, (N3)-Homo-Glu, (N3)-D-Homo-Glu, and (N3)-Beta-Homo-Glu.

[0350] In some such embodiments, X2 is (N3)-Lys and D-(N3)-Lys.

[0351] In some such embodiments, X7 are Pra and Hpg.

[0352] In other words, in an embodiment in which an amino acid residue containing an azide group is present in X2 and an amino acid residue containing an alkyne group is present in X7, the appropriate combinations of X2 and X7 are as follows. X2 is (N3)-Lys, and X7 is Pra. X2 is D-(N3)-Lys, and X7 is Hpg.

[0353] Alternatively, amino acid residues containing an azide group are located at X7, and amino acid residues containing an alkyne group are located at X2.

[0354] Preferably, an amino acid residue containing an azide group is located at X2, and an amino acid residue containing an alkyne group is located at X7.

[0355] Crosslink length The length of a crosslink is counted as the number of atoms in the linear chain from the first atom bonded to the alpha carbon of the amino acid adjacent to the carboxylic acid portion of the first residue (X2 in the case of a crosslink between X2 and X11, X2 in the case of a crosslink between X2 and X7, or X10 in the case of a crosslink between X10 and X13), that is, in most cases, the alpha carbon of the relevant residue, to the first atom bonded to the carboxylic acid portion of the amino acid adjacent to the carbon of the second residue (X11 in the case of a crosslink between X2 and X11, X7 in the case of a crosslink between X2 and X7, or X13 in the case of a crosslink between X10 and X13).

[0356] The contributions of amino acid residue crosslinks to their length and type are described below.

[0357] In some embodiments, the length of the bridge between X2 and X11 is at least 3 atomic lengths. In some embodiments, the length of the bridge between X2 and X11 is 11 atomic lengths or less. In some embodiments, the length of the bridge between X2 and X11 is 3 to 11 atomic lengths, for example, 3, 4, 5, 6, 7, 8, 9, 10, or 11 atomic lengths. In some embodiments, the length of the bridge between X2 and X11 is 4 to 11 atomic lengths, for example, 4, 5, 6, 7, 8, 9, 10, or 11 atomic lengths, for example, 4, 5, 6, 7, 8, 9, or 11 atomic lengths. In some embodiments, the length of the bridge between X2 and X11 is 4 atomic lengths. In some embodiments, the length of the bridge between X2 and X11 is 5 atomic lengths. In some embodiments, the length of the bridge between X2 and X11 is 6 atomic lengths. In some embodiments, the length of the bridge between X2 and X11 is 7 atomic lengths. In some embodiments, the length of the bridge between X2 and X11 is 8 atomic lengths. In some embodiments, the length of the bridge between X2 and X11 is 9 atomic lengths. In some embodiments, the length of the bridge between X2 and X11 is 11 atomic lengths.

[0358] In some embodiments, the length of the bridge between X2 and X7 is at least 3 atomic lengths. In some embodiments, the length of the bridge between X2 and X7 is 11 atomic lengths or less. In some embodiments, the length of the bridge between X2 and X7 is 3 to 11 atomic lengths, for example, 3, 4, 5, 6, 7, 8, 9, 10, or 11 atomic lengths. In some embodiments, the length of the bridge between X2 and X7 is 3 to 6 atomic lengths, for example, 3, 4, 5, or 6 atomic lengths, for example, 3, 4, or 6 atomic lengths. In some embodiments, the length of the bridge between X2 and X7 is 3 atomic lengths. In some embodiments, the length of the bridge between X2 and X7 is 4 atomic lengths. In some embodiments, the length of the bridge between X2 and X7 is 6 atomic lengths.

[0359] In some embodiments, the length of the bridge between X10 and X13 is at least 3 atomic lengths. In some embodiments, the length of the bridge between X10 and X13 is 11 atomic lengths or less. In some embodiments, the length of the bridge between X10 and X13 is 3 to 11 atomic lengths, for example, 3, 4, 5, 6, 7, 8, 9, 10, or 11 atomic lengths. In some embodiments, the length of the bridge between X10 and X13 is 4 to 6 atomic lengths, for example, 4, 5, or 6 atomic lengths, for example, 4 or 6 atomic lengths. In some embodiments, the length of the bridge between X10 and X13 is 4 atomic lengths. In some embodiments, the length of the bridge between X10 and X13 is 6 atomic lengths.

[0360] Lactam Bridge The contribution of the side chain to the length of the lactam bridge is counted as the number of atoms in the straight chain from the first atom of the side chain (bonded to an atom in the peptide backbone, i.e., the alpha carbon of the relevant residue in most amino acids) to the atom participating in the amide bond of the lactam bridge (i.e., the carbon atom of the carboxylic acid functional group or the nitrogen atom of the amine group).

[0361] Therefore, typical acid-containing and amine-containing side chains are considered to have the following side chain lengths. It will be understood that the following can be used to decipher the crosslinking length of any amino acid residue disclosed herein.

[0362] Amine-containing side chains: [Table 5] JPEG2026518789000028.jpg137170

[0363] Carboxylic acid-containing side chains: [Table 6]

[0364] Similarly, the contribution of the lactam bridge length to the amide bond of the peptide backbone by the use of amine or carboxylic acid groups (i.e., alpha-amine groups (or beta-amine groups in the case of bLys, {d}bLys, and beta-hLys, or alpha-amines converted to azide groups in the case of (N3)-K and {d}(N3)-K), or alpha-carboxylic acid groups) of amino acid residues conventionally used in the amide bond of the peptide backbone is counted as the number of atoms in the straight chain from the first atom bonded to the atom (carbon) adjacent to the carboxylic acid portion of the amino acid residue (i.e., the first atom bonded to the alpha carbon of the relevant residue in most amino acids) to the atom participating in the amide bond of the lactam bridge (i.e., the carbon atom of the carboxylic acid functional group or the nitrogen atom of the amine group) up to that atom.

[0365] Therefore, the following amino acid residues are considered to have the following lengths. The use of conventionally used alpha-amine groups (or beta-amine groups in the case of bLys, {d}bLys, and beta-hLys, or alpha-amines converted to azide groups in the case of (N3)-K and {d}(N3)-K) in the lactam crosslinked peptide skeleton. [Table 7] JPEG2026518789000031.jpg190170

[0366] The use of alpha-carboxylic acid groups, which are conventionally used in the peptide backbone of lactam crosslinks. [Table 8]

[0367] The position of the amide bond in a lactam crosslink may affect the potency of the compound. The inventors observed that the closer the amide bond is to position 11 (X11), the more active the compound is, and the closer it is to position 2 (X2), the less active the compound is (see Example 2 and Table 2-3b in International Publication No. 2023 / 099669).

[0368] The following are examples of appropriate pairings of residues at positions X2 and X11, where the amide bond of the lactam crosslink is closer to position X11 than position X2 after formation. X2 is D-Lys, and X11 is Glu. X2 is Lys, and X11 is Glu. X2 is homo-Lys, and X11 is Glu. X2 is D-homo-Lys, and X11 is Glu. X2 is D-Orn, and X11 is homo-Glu. X2 is D-Orn, and X11 is Glu. X2 is beta-Lys, and X11 is Glu. X2 is D-beta-Lys, and X11 is Glu. X2 is Lys, and X11 is iso-Dab. X2 is Lys (Gly), and X11 is Glu. X2 is Lys, and X11 is beta-homo-Glu. X2 is Ne-Me-Lys, and X11 is Glu. X2 is Orn, and X11 is Glu. X2 is beta-homo-Lys, and X11 is Glu. X2 is (N3)-Lys, and X11 is Glu. X2 is D-(N3)-Lys, and X11 is Glu. X2 is Glu, and X11 is Orn. X2 is Glu, and X11 is Lys(Me). X2 is Glu, and X11 is Lys.

[0369] Alternatively, suitable pairings of residues at positions X2 and X11, where the amide bond in the lactam crosslink is closer to position X2 than to position X11, include the following: X2 is D-Dab, and X11 is 2-amino-6-carboxyhexanoyl. X2 is Dpr, and X11 is Glu. X2 is iso-Lys † Therefore, X11 is Glu. X2 iso-Dab † Therefore, X11 is Glu. X2 is iso-Glu ‡ Therefore, X11 is Lys. X2 is iso-Glu ‡ Therefore, X11 is Dab. X2 is D-iso-Glu ‡ Therefore, X11 is Lys. X2 is D-iso-Glu ‡ Therefore, X11 is Dab.

[0370] in this case, † This indicates that the alpha-amine group (or beta-amine group in the case of bLys, {d}bLys, and beta-hLys) conventionally used in the peptide backbone is used for crosslinking. ‡ This indicates that the alpha-carboxylic acid group, which is conventionally used in peptide backbones, is used for crosslinking.

[0371] Alternatively, suitable pairings of residues at positions X2 and X11, where the amide bond in the lactam crosslink is located midway between positions X2 and X11 (i.e., at an equal or equidistant distance), include the following: X2 is D-Dab, and X11 is Glu. X2 is Dab, and X11 is Glu.

[0372] The position of the amide bond in the lactam crosslink between position 2 (X2) and position 7 (X7) may be closer to position X7 than to position X2. Appropriate pairings of residues at positions X2 and X7, such that the position of the amide bond in the lactam crosslink is closer to position X7 than to position X2 after formation, include the following: X2 is iso-Lys and X7 is Glu. X2 is iso-Dab and X7 is Glu.

[0373] Alternatively, suitable pairings of residues at positions X2 and X7, where the amide bond in the lactam crosslink is closer to position X2 than to position X7, include the following: X2 is D-Lys † Therefore, X7 is Glu. X2 is Lys † Therefore, X7 is Glu. X2 is D-Lys † Therefore, X7 is Asp. X2 is homo-Lys † Therefore, X7 is Glu. X2 is D-homo-Lys † Therefore, X7 is Glu. X2 is D-Orn † Therefore, X7 is Glu. X2 is a D-Dab † Therefore, X7 is Glu. X2 is D-Orn † Therefore, X7 is Asp. X2 is D-Dab † Therefore, X7 is Asp. X2 is beta-lys † Therefore, X7 is Glu. X2 is D-beta-Lys † Therefore, X7 is Asp. X2 is D-beta-Lys, and X7 is Glu. X2 is Lys † Therefore, X7 is D-Glu. X2 is Dab † Therefore, X7 is Glu. X2 is Lys † Therefore, X7 is homo-Glu. X2 is Glu ‡ Therefore, X7 is Glu. X2 is Lys(Gly) † Therefore, X7 is Glu. X2 is Ne-Me-Lys † Therefore, X7 is Glu. X2 is Orn † Therefore, X7 is Glu. X2 is Dpr † Therefore, X7 is Glu. X2 is beta-homo-Lys † Therefore, X7 is Glu. X2 is iso-Glu ‡ Therefore, X7 is Glu. X2 is D-iso-Glu ‡ Therefore, X7 is Glu.

[0374] in this case, † This indicates that the alpha-amine group (or beta-amine group in the case of bLys, {d}bLys, and beta-hLys) conventionally used in the peptide backbone is used for crosslinking. ‡ This indicates that the alpha-carboxylic acid group, which is conventionally used in peptide backbones, is used for crosslinking.

[0375] The position of the amide bond in an optional lactam crosslink between position 10 (X10) and position 13 (X13) may be closer to position X13 than to position X10. Appropriate pairings of residues at positions X10 and X13 that result in the amide bond being closer to position X13 than to position X10 after formation include the following: X10 is Dab, and X13 is 3-(3-pyridyl)-Ala. X10 is Lys, and X13 is 3-(3-pyridyl)-Ala.

[0376] Alternatively, appropriate pairing of residues at positions X10 and X13, such that the position of the amide bond in the optional lactam crosslink is closer to position X10 than to position X13. Preferably, the position of the amide bond in the optional lactam crosslink between positions 10 (X10) and 13 (X13) is closer to position X13 than to position X10.

[0377] Preferably, the length of the lactam crosslink after the formation of the amide bond (excluding any atoms in the peptide backbone) is 5, 6, 7, 8, 9, or 10 atoms, for example 6, 7, 8, or 9 atoms, for example 7 or 8 atoms.

[0378] In some embodiments, the length of the lactam crosslink after the formation of the amide bond (excluding any atoms in the peptide backbone) is 3 atoms. A suitable pairing of residues at positions X2 and X7, where the lactam crosslink has a length of 3 atoms, is when X2 is D-Lys † And X7 is Asp, and X2 is D-Orn † X7 is Asp, and X2 is D-Dab. † And X7 is Asp, and X2 is D-beta-Lys † One example is X7, which is ASP.

[0379] In some embodiments, the length of the lactam crosslink after the formation of the amide bond (excluding any atoms in the peptide backbone) is 4 atoms. A suitable pairing of the residues at positions X2 and X11, where the lactam crosslink has a length of 4 atoms, is when X2 is iso-Lys †In this case, X11 is Glu and X2 is iso-Dab. † In this case, X11 is Glu, and X2 is iso-Glu. ‡ The result is that X11 is Dab, and X2 is D-iso-Glu ‡ Examples include those where X11 is Dab. A suitable pairing of the residues at positions X2 and X7, where the lactam crosslink has a length of 4 atoms, is when X2 is D-Lys † And X7 is Glu, and X2 is Lys † And X7 is Glu, and X2 is homo-Lys † And X7 is Glu, and X2 is D-homo-Lys † And X7 is Glu, and X2 is D-Orn † And X7 is Glu, and X2 is D-Dab. † And X7 is Glu, and X2 is beta-Lys † And X7 is Glu, and X2 is D-beta-Lys † And X7 is Glu, and X2 is Lys † In this case, X7 is D-Glu, and X2 is Dab. † And X7 is Glu, and X2 is Lys † In this case, X7 is homo-Glu, and X2 is Glu ‡ And X7 is Glu, and X2 is Lys (Gly). † And X7 is Glu, and X2 is Ne-Me-Lys † And X7 is Glu, and X2 is Orn † And X7 is Glu, and X2 is Dpr † And X7 is Glu, and X2 is beta-homo-Lys † In this case, X7 is Glu, and X2 is iso-Glu. ‡ The result is that X7 is Glu, and X2 is D-iso-Glu ‡ Examples include those where X7 is Glu. A suitable pairing of the residues at positions X10 and X13, where the lactam crosslink has a length of 4 atoms, is where X10 is Dab and X13 is 3-(3-pyridyl)-Ala.

[0380] In some embodiments, the length of the lactam crosslink after the formation of the amide bond (excluding any atoms in the peptide backbone) is 5 atoms. A suitable pairing of residues at positions X2 and X11 for a lactam crosslink to be 5 atoms long is when X2 is Dpr and X11 is Glu.

[0381] In some embodiments, the length of the lactam crosslink after the formation of the amide bond (excluding any atoms in the peptide backbone) is 6 atoms. A suitable pairing of the residues at positions X2 and X11, where the lactam crosslink has a length of 6 atoms, is that X2 is iso-Glu † And X11 is Lys, and X2 is D-iso-Glu ‡ Examples include those where X11 is Lys, where X2 is D-Dab and X11 is Glu, and where X2 is Dab and X11 is Glu. A suitable pairing of the residues at positions X2 and X7, where the lactam crosslink has a length of 6 atoms, is where X2 is iso-Dab and X7 is Glu. A suitable pairing of the residues at positions X10 and X13, where the lactam crosslink has a length of 6 atoms, is where X10 is Lys and X13 is 3-(3-pyridyl)-Ala.

[0382] In some embodiments, the length of the lactam crosslink after the formation of the amide bond (excluding any atoms in the peptide backbone) is 7 atoms. Suitable pairings of residues at positions X2 and X11 that result in a lactam crosslink of length 7 atoms include X2 being D-Orn and X11 being homo-Glu, X2 being D-Orn and X11 being Glu, X2 being beta-Lys and X11 being Glu, X2 being D-beta-Lys and X11 being Glu, X2 being Orn and X11 being Glu, X2 being Glu and X11 being Orn, and X2 being Glu and X11 being Lys(Me).

[0383] Preferably, the length of the lactam crosslink after the formation of the amide bond (excluding any atoms in the peptide backbone) is 8 atoms. Appropriate pairings of the residues at positions X2 and X11, where the lactam crosslink has a length of 8 atoms, include those where X2 is D-Lys and X11 is Glu, X2 is Lys and X11 is Glu, X2 is Lys and X11 is iso-Dab, X2 is Lys and X11 is beta-homo-Glu, X2 is Ne-Me-Lys and X11 is Glu, X2 is beta-homo-Lys and X11 is Glu, X2 is (N3)-Lys and X11 is Glu, X2 is D-(N3)-Lys and X11 is Glu, X2 is Glu and X11 is Lys, and X2 is D-Dab and X11 is 2-amino-6-carboxyhexanoyl. A suitable pairing of the residues at positions X2 and X7, where the lactam crosslink has a length of 8 atoms, is when X2 is iso-Lys and X7 is Glu.

[0384] In some embodiments, the length of the lactam crosslink after the formation of the amide bond (excluding any atoms in the peptide backbone) is 9 atoms. Suitable pairings of residues at positions X2 and X11 that result in a lactam crosslink of length 9 atoms include X2 being homo-Lys and X11 being Glu, and X2 being D-homo-Lys and X11 being Glu.

[0385] In some embodiments, the length of the lactam crosslink after the formation of the amide bond (excluding any atoms in the peptide backbone) is 10 atoms.

[0386] In some embodiments, the length of the lactam crosslink after the formation of the amide bond (excluding any atoms in the peptide backbone) is 11 atoms. A suitable pairing of residues at positions X2 and X11 that results in a lactam crosslink of 11 atoms is when X2 is Lys (Gly) and X11 is Glu.

[0387] in this case, †This indicates that the alpha-amine group (or beta-amine group in the case of bLys, {d}bLys, and beta-hLys) conventionally used in the peptide backbone is used for crosslinking. ‡ This indicates that the alpha-carboxylic acid group, which is conventionally used in peptide backbones, is used for crosslinking.

[0388] Crosslinking containing a triazole ring The contribution of the side chain to the length of the crossbridge containing the triazole ring is from the first atom of the side chain (bonded to the atom of the peptide backbone, i.e., the alpha carbon of the relevant residue in the case of most amino acids) to the atom participating in the formation of the triazole ring (i.e., the first nitrogen atom of the azide group bonded to the side chain in both 1,4-disubstituted 1,2,3-triazole and 1,5-disubstituted 1,2,3-triazole) (i.e., - N =N + =N - ), or in the case of 1,4-disubstituted 1,2,3-triazoles, two carbon atoms of the alkyne group, or in the case of 1,5-disubstituted triazoles, one carbon atom of the alkyne group (i.e., - C It is counted as the number of atoms in the straight chain up to the atom containing ≡CH)).

[0389] Therefore, typical alkyne-containing side chains are considered to have the following side chain lengths. It will be understood that the following can be used to decipher the crosslinking length of any amino acid residue disclosed herein.

[0390] Alkyne-containing side chain (in the case of 1,4-disubstituted 1,2,3-triazole): [Table 9]

[0391] Similarly, the contribution of the azide or alkyne converted from the amine or carboxylic acid of an amino acid residue to the length of the crossbridge containing the triazole ring is from the first atom bonded to the atom (carbon) adjacent to the carboxylic acid portion of the amino acid residue (i.e., the first atom bonded to the alpha carbon of the relevant residue in most amino acids) to the atom participating in the formation of the triazole ring (i.e., the first nitrogen atom of the azide group bonded to the side chain in both 1,4-disubstituted 1,2,3-triazole and 1,5-disubstituted 1,2,3-triazole (i.e., - N =N + =N - ), or in the case of 1,4-disubstituted 1,2,3-triazoles, two carbon atoms of the alkyne group, or in the case of 1,5-disubstituted triazoles, one carbon atom of the alkyne group (i.e., - C It is counted as the number of atoms in the straight chain up to the atom containing the ≡CH)).

[0392] Therefore, the following amino acid residues are considered to have the following lengths. It will be understood that the crosslinking lengths of any amino acid residue disclosed herein can be deciphered using the following.

[0393] The use of azides converted from conventionally used alpha-amine groups in the triazole crosslinked peptide backbone. [Table 10]

[0394] The position of triazole in the crosslinking can affect the potency of the compound.

[0395] In some embodiments, the position of the triazole in a crosslinking containing a triazole ring is closer to the X7 position than to the X2 position after formation (i.e., the number of atoms in the straight chain from the first atom bonded to the atom (carbon) adjacent to the carboxylic acid portion of the amino acid residue (i.e., the first atom bonded to the alpha carbon of the related residue in most amino acids) to the triazole ring).

[0396] Alternatively, in some embodiments, the position of the triazole in the crosslink containing the triazole ring is closer to the X2 position than to the X7 position after formation (i.e., the number of atoms in the linear chain from the first atom bonded to the atom (carbon) adjacent to the carboxylic acid portion of the amino acid residue (i.e., the first atom bonded to the alpha carbon of the relevant residue in most amino acids) to the triazole ring). Suitable pairings of the residues at the X2 and X7 positions, where the position of the triazole in the crosslink containing the triazole ring is closer to the X2 position than to the X7 position after formation, include X2 being (N3)-Lys and X7 being Pra, and X2 being D-(N3)-Lys and X7 being Hpg. Preferably, the length of the crosslink containing the triazole ring after triazole formation (excluding any atoms in the peptide backbone) is 3, 4, 5, 6, 7, 8, 9, 10, or 11 atoms, e.g., 4, 5, 6, or 7 atoms, e.g., 4, 5, or 6 atoms, e.g., 4 or 5 atoms.

[0397] In some embodiments, the length of the crosslink containing the triazole ring provided by the two side chains after triazole formation (excluding any atoms in the peptide backbone) is 4 atoms. A suitable pairing of residues at positions X2 and X7 for a crosslink containing the triazole ring to have a length of 4 atoms is when X2 is (N3)-Lys and X7 is Pra.

[0398] In some embodiments, the length of the crosslink containing the triazole ring, provided by the two side chains after triazole formation (excluding any atoms in the peptide backbone), is 5 atoms. A suitable pairing of residues at positions X2 and X7, where the crosslink containing the triazole ring has a length of 5 atoms, is such that X2 is D-(N3)-Lys and X7 is Hpg.

[0399] Compound Synthesis The present invention further provides a method for synthesizing the compounds of the present invention. The compounds (sometimes called peptides) can be adequately prepared by standard synthetic methods. Thus, peptides can be synthesized, for example, by a standard solid-phase or liquid-phase method, comprising the steps of synthesizing the peptide stepwise or in fragment assembly, and optionally isolating and purifying the final peptide product. In this context, see International Publication No. 98 / 11125, or in particular Fields, GB et al., "Principles and Practice of Solid-Phase Peptide Synthesis"; Synthetic Peptides, Gregory A. Grant (ed.), Oxford University Press (2 nd See edition, 2002) and the synthesis examples therein. This method typically further comprises the step of forming an amide bond between the amino acid residues at positions 2 (X2) and 11 (X11), and optionally further comprising the step of forming an amide bond or triazole between the amino acid residues at positions 2 (X2) and 7 (X7), and optionally further comprising the step of forming an amide bond between the amino acid residues at positions X10 and X13, for example as described below. In the case of solid-phase synthesis, cyclization can be carried out in situ on the solid phase (e.g., resin), that is, before removing the peptide from the solid phase.

[0400] The synthesis of some exemplary compounds of the present invention is provided in Example 1. Generally, a method for synthesizing the compounds comprises the steps of synthesizing the compound by solid-phase or liquid-phase peptide synthesis, optionally isolating and / or purifying the final product, optionally forming an amide bond between the amino acid residues at positions 2 and 11, optionally forming an amide bond between the amino acid residues at positions 4 and 7 or forming a triazole, and optionally forming an amide bond between the amino acid residues at positions 10 and 13.

[0401] The order of steps in the synthesis of a compound does not necessarily have to be the order mentioned above.

[0402] For example, the order of crosslink formation (lactam crosslinks / amide bonds; triazole crosslinks) may be any order. In some embodiments, a crosslink is formed first between the amino acid residues at positions 2 and 11, then a crosslink is formed secondly between the amino acid residues at positions 2 and 7, and then an optional crosslink is formed thirdly between the amino acid residues at positions 10 and 13. In other embodiments, a crosslink is formed first between the amino acid residues at positions 2 and 7, then a crosslink is formed secondly between the amino acid residues at positions 2 and 11, and then an optional crosslink is formed thirdly between the amino acid residues at positions 10 and 13.

[0403] In other embodiments, a crosslink is first formed between the amino acid residues at positions 2 and 11, then an optional crosslink is secondly formed between the amino acid residues at positions 10 and 13, and then a crosslink is thirdly formed between the amino acid residues at positions 2 and 7. In other embodiments, an optional crosslink is first formed between the amino acid residues at positions 10 and 13, then a crosslink is secondly formed between the amino acid residues at positions 2 and 11, and then a crosslink is thirdly formed between the amino acid residues at positions 2 and 7.

[0404] In other embodiments, a crosslink is first formed between the amino acid residues at positions 2 and 7, then an optional crosslink is secondly formed between the amino acid residues at positions 10 and 13, and then a crosslink is thirdly formed between the amino acid residues at positions 2 and 11.

[0405] Effectiveness of the compound The compounds of the present invention are interleukin-23 receptor (IL-23R) inhibitors, that is, they can bind to one or more receptors or receptor complexes that are considered to be physiological receptors for interleukin-23 (IL-23) and block signal transduction.

[0406] The comparative activity is as described below in IC 50 It can be measured by any appropriate means, such as determining the value.

[0407] The compounds of the present invention are described in International Publication No. 2016 / 011208, International Publication No. 2018 / 022937, International Publication No. 2018 / 136646, International Publication No. 2020 / 014646, International Publication No. 2021 / 146441, International Publication No. 2021 / 146458, International Publication No. 2023 / 288017, International Publication No. 2023 / 288019, International Publication No. 2023 / 288028, and Kong et al., 2020 (Nature Biomedical Engineering, 2020, 4, Compared to other peptide IL-23R inhibitors, such as the analogs described in International Publication No. 2023 / 099669 and International Publication No. 2024 / 015958 (560-571), the compounds of the present invention can exhibit significantly advantageous properties. Compared to any of these analogs, the compounds of the present invention can exhibit improved efficacy, for example, in the form of enhanced in vitro efficacy against IL-23R.

[0408] In addition or alternatively, the compounds of the present invention can exhibit improved gastrointestinal (GI) stability compared to any of the IL-23R peptide inhibitors described in the art.

[0409] Those skilled in the art will be familiar with appropriate assay methods. Examples are provided below. For example, the assay can use human IL-23R (see example below). It should be understood that even if the precursor protein sequence is referenced, the assay can use mature proteins lacking the signal sequence.

[0410] K dThe value can be used as a numerical measure of binding affinity to a given receptor. d The value, also called the equilibrium dissociation constant, is a measure of how tightly a compound binds to its receptor in a particular assay. d The fact that K is small means d A higher value indicates that the compound binds more tightly to the receptor with higher affinity compared to other compounds. Therefore, for example, in a particular assay, the K of another compound inhibitor of IL-23R d K lower than the [IL-23R] value d Compounds with an [IL-23R] value can be considered to have a stronger binding affinity (or bind more tightly) to IL-23R than other IL-23R inhibitors.

[0411] K of compounds against receptors d If there is no experimental method to directly determine the IC of a compound, 50 By determining the IC, the binding affinity of the compound can be estimated. 50 This is determined by the ability of the compound to compete with the labeled compound for the receptor. In such a competitive assay, the IC20 concentration is set such that half of the labeled compound is dissociated from the receptor by the unlabeled compound. 50 It is called a value. IC 50 The value is the affinity of the compound to the receptor (i.e., its K d It is proportional to the value and depends on factors such as the concentration of the labeled compound used, the affinity of the labeled compound to the receptor, and the assay incubation time, and is therefore assay system dependent.

[0412] In the binding assay method, IC 50 The value can be used as a numerical formula to measure how tightly a compound binds to a receptor in a particular assay. 50 The fact that it is small means that IC 50A higher value indicates that the compound binds more tightly to the receptor with higher affinity compared to other compounds. Therefore, for example, in a particular assay, the IC of another compound inhibitor of IL-23R 50 ICs with a value lower than [IL-23R] 50 Compounds with an [IL-23R] value can be considered to have a stronger binding affinity (or bind more tightly) to IL-23R than other IL-23R inhibitors.

[0413] In some embodiments of the compounds of the present invention, IC for IL-23R 50 This is below 1000 nM (for example, 0.0001 to 1000 nM).

[0414] In some embodiments of the compounds of the present invention, IC for IL-23R 50 This is below 500 nM (for example, 0.0001 to 500 nM).

[0415] In some embodiments of the compounds of the present invention, IC for IL-23R 50 This is below 100 nM (for example, 0.0001 to 100 nM).

[0416] In some embodiments of the compounds of the present invention, IC for IL-23R 50 This is below 50 nM (for example, 0.0001 to 50 nM).

[0417] In some embodiments of the compounds of the present invention, IC for IL-23R 50 This is below 30 nM (for example, 0.0001 to 30 nM).

[0418] In some embodiments of the compounds of the present invention, IC for IL-23R 50 This is below 20 nM (for example, 0.0001 to 20 nM).

[0419] In some embodiments of the compounds of the present invention, IC for IL-23R 50 This is below 10 nM (for example, 0.0001 to 10 nM).

[0420] In some embodiments of the compounds of the present invention, IC for IL-23R 50 This is below 5 nM (for example, 0.0001 to 5 nM).

[0421] In some embodiments of the compounds of the present invention, IC for IL-23R 50 This is less than 1 nM (for example, 0.0001 to 1 nM).

[0422] In some embodiments of the compounds of the present invention, IC for IL-23R 50 This is below 0.5 nM (for example, 0.0001 to 0.5 nM).

[0423] In functional assays, the ability of compounds to inhibit IL-23-mediated signaling is measured in cell-based assays, and IC is used as a numerical measure of inhibitory efficacy. 50 The value can be used. 50 The value is a measure of the concentration of a compound required to achieve half of its maximum activity in a particular assay. Therefore, for example, in a particular assay, a lower IC50 than that of another compound inhibitor of IL-23R would indicate a lower IC50 than that of another compound inhibitor of IL-23R. 50 Compounds with an [IL-23R] value can be considered to have half the inhibitory efficacy of other IL-23R peptide inhibitors, possibly by better blocking IL-23-mediated signaling.

[0424] In some embodiments of the compounds of the present invention, IC is used for IL-23-mediated signaling. 50 This is below 1000 nM (for example, 0.0001 to 1000 nM).

[0425] In some embodiments of the compounds of the present invention, IC is used for IL-23-mediated signaling. 50 This is below 500 nM (for example, 0.0001 to 500 nM).

[0426] In some embodiments of the compounds of the present invention, IC is used for IL-23-mediated signaling.50 This is below 100 nM (for example, 0.0001 to 100 nM).

[0427] In some embodiments of the compounds of the present invention, IC is used for IL-23-mediated signaling. 50 This is below 50 nM (for example, 0.0001 to 50 nM).

[0428] In some embodiments of the compounds of the present invention, IC is used for IL-23-mediated signaling. 50 This is below 30 nM (for example, 0.0001 to 30 nM).

[0429] In some embodiments of the compounds of the present invention, IC is used for IL-23-mediated signaling. 50 This is below 20 nM (for example, 0.0001 to 20 nM).

[0430] In some embodiments of the compounds of the present invention, IC is used for IL-23-mediated signaling. 50 This is below 10 nM (for example, 0.0001 to 10 nM).

[0431] In some embodiments of the compounds of the present invention, IC is used for IL-23-mediated signaling. 50 This is below 5 nM (for example, 0.0001 to 5 nM).

[0432] In some embodiments of the compounds of the present invention, IC is used for IL-23-mediated signaling. 50 This is less than 1 nM (for example, 0.0001 to 1 nM).

[0433] In some embodiments of the compounds of the present invention, IC is used for IL-23-mediated signaling. 50 This is below 0.5 nM (for example, 0.0001 to 0.5 nM).

[0434] In some embodiments of the compounds of the present invention, IC is used for IL-23-mediated signaling. 50 This is below 0.5 nM (for example, 0.0001 to 0.5 nM).

[0435] Such assays can be carried out under the conditions described in Examples 3-1 and 3-2 below.

[0436] In addition, or alternatively, the compounds of the present invention can exhibit gastrointestinal (GI) stability, i.e., resistance to degradation in the gastrointestinal tract. This can be measured using simulated intestinal fluid (SIF) assays and / or simulated gastric fluid (SGF) assays. For example, after incubation for 1 or 4 hours under the conditions described in Examples 3-3 and 3-4, the compounds of the present invention can retain at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, or at least 85%, at least 90%, at least 95%, or at least 99% of the residual compound or peptide. Preferably, the compounds retain at least 70% (or more) of the compound after incubation for 1 or 4 hours under SIF and / or SGF assays.

[0437] Pharmaceutical composition The present invention also extends to compositions such as pharmaceutical compositions containing the compounds of the present invention. As with all aspects of the present invention, it should be understood that references to the compounds of the present invention include references to pharmaceutically acceptable salts and solvates.

[0438] The compounds of the present invention are suitable for administration with or without storage and can typically be formulated as a pharmaceutical composition containing a therapeutically effective amount of at least one peptide of the present invention, together with a pharmaceutically acceptable carrier, excipient, or medium.

[0439] The pharmaceutical composition can be used by any common or standard mode of administration in the art, such as orally, intravenously, intramuscularly, subcutaneously, sublingually, intranasally, intradermally, via suppository route, or implanted. In preferred embodiments of the present invention described herein, the pharmaceutical composition is a composition for oral administration.

[0440] The term "pharmaceutically acceptable carrier" includes any standard pharmaceutical carrier. Pharmaceutically acceptable carriers for therapeutic use are well known in the pharmaceutical industry, e.g., "Remington's Pharmaceutical Sciences", 17 th This edition is described in Alfonso R. Gennaro (Ed.), Mark Publishing Company, Easton, PA, USA, 1985.

[0441] therapy use The compounds of the present invention, and pharmaceutical compositions containing such compounds, are useful in methods for preventing or treating various conditions.

[0442] A method of prevention or treatment includes the step of administering a therapeutically effective amount of the compound of the present invention or a pharmaceutical composition containing the compound to a target.

[0443] In some embodiments, the condition can be selected from inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease, celiac disease (non-tropical sprue), intestinal diseases associated with seronegative arthritis, microscopic colitis, collagenous colitis, eosinophilic gastroenteritis, colitis associated with radiotherapy or chemotherapy, colitis associated with innate immune disorders such as leukocyte adhesion deficiency I, chronic granulomatous diseases, glycogen storage disease type 1b, Hermanskie-Padlak syndrome, Chediak-Higashi syndrome, and Wiscott-Aldrich syndrome, cystitis occurring after colectomy and ileoanal anastomosis, gastrointestinal cancer, pancreatitis, insulin-dependent diabetes mellitus, mastitis, cholecystitis, cholangitis, pericholangitis, chronic bronchitis, chronic sinusitis, asthma, psoriasis, psoriatic arthritis, ankylosing spondylitis, and graft-versus-host disease. In a preferred embodiment, the symptoms can be selected from inflammatory bowel disease (IBD) such as Crohn's disease or ulcerative colitis, psoriatic arthritis, and psoriasis.

[0444] In some embodiments, the condition can be selected from inflammatory bowel disease (IBD), such as Crohn's disease or ulcerative colitis, and psoriasis.

[0445] In some embodiments, the condition can be selected from inflammatory bowel disease (IBD) and psoriasis.

[0446] The subject or patient may be an animal subject or a patient. The subject or patient may be a human subject or a patient. Preferably, the subject is a human subject or a patient.

[0447] Dosage Typical dosages of the compound used in the context of the present invention may range from about 0.0001 to about 100 mg / kg body weight per day, for example, from about 0.0005 to about 50 mg / kg body weight per day, for example, from about 0.001 to about 10 mg / kg body weight per day, for example, from about 0.01 to about 1 mg / kg body weight per day, and may be administered in one or more doses, for example, one to three doses. The exact dosage used will depend, in particular, on the nature and severity of the disease or disorder to be treated, the sex, age, weight, and general condition of the person to be treated, any other possible comorbidities or disorders being treated or planned, and other factors that a physician in the art would know.

[0448] The compounds described herein may be administered by any mode of administration common or standard in the art, such as orally, intravenously, intramuscularly, subcutaneously, sublingually, intranasally, intradermally, via suppository route, or by implantation. In preferred embodiments of the present invention described herein, administration is by oral administration. [Examples]

[0449] The following examples illustrate certain embodiments of the present invention. Unless otherwise described in detail, the following examples were performed using standard techniques that are well known and commonplace to those skilled in the art. It should be understood that these examples are for illustrative purposes only and do not imply any definitive explanation of the conditions or scope of the present invention. Therefore, these examples should not be construed as limiting the scope of the present invention in any way.

[0450] Amino acids and specific R 2 The abbreviations used in the base can be found in Tables A-C. Other abbreviations used in the examples include the following: t BuOH tert-butanol DODT 2,2'-(ethylenedioxy)diethanethiol Pd(PPh3)4Tetrakis(triphenylphosphine)Palladium(0)) PhSiH3 Phenylsilane PyBOP (benzotriazole-1-yloxytripyrrolidinophosphonium hexafluorophosphate) equiv. equivalent amount rt room temperature aq. Water-based IL-23R Interleukin-23 receptor hIL-23R Human Interleukin-23 Receptor GI gastrointestinal SIF simulated intestinal fluid SGF simulated gastric fluid Nluc NanoBRET Luciferase Assay SD standard deviation %Eff (Efficiency Percentage) pSTAT3 phosphorylation signaling transcription factor 3 BRET Bioluminescence Resonance Energy Transfer TAMRA 5'-Tetramethylrhodamine-5-Carboxamide

[0451] The following examples are provided to illustrate certain embodiments of the present invention and are not intended to limit the scope of the invention. [Examples]

[0452] Compound Synthesis The following compounds listed in Table 1-1 below were synthesized. [Table 11] JPEG2026518789000036.jpg251170 JPEG2026518789000037.jpg251170 JPEG2026518789000038.jpg249170 JPEG2026518789000039.jpg246170 JPEG2026518789000040.jpg245170 JPEG2026518789000041.jpg251170 JPEG2026518789000042.jpg230170 JPEG2026518789000043.jpg245170 JPEG2026518789000044.jpg251170 JPEG2026518789000045.jpg251170 JPEG2026518789000046.jpg251170 JPEG2026518789000047.jpg238170 JPEG2026518789000048.jpg238170 JPEG2026518789000049.jpg234170 JPEG2026518789000050.jpg226170 JPEG2026518789000051.jpg230170 JPEG2026518789000052.jpg243170 JPEG2026518789000053.jpg238170 JPEG2026518789000054.jpg226170 JPEG2026518789000055.jpg243170 JPEG2026518789000056.jpg226170 JPEG2026518789000057.jpg91170

[0453] A cross-linked amino acid residue is the amino acid residue immediately preceding the parentheses below. Square brackets indicate a cross-linked amino acid residue. For example, [2,11] is a cross-link between amino acid residues 2 and 11. Similarly, [2,7] is a cross-link between amino acid residues 2 and 7, and [10,13] is a cross-link between amino acid residues 10 and 13.

[0454] †This indicates that the crosslinks in (1c), (6c), (6g), and (7c) use an alpha-amine group of an amino acid (or a beta-amine group in the case of bLys, {d}bLys, and beta-hLys, or an alpha-amine converted to an azide group in the case of (N3)-K and {d}(N3)-K) for crosslinking.

[0455] ‡ This indicates that the crosslinks in (1c), (6c), (6g), and (7c) use the alpha-carboxylic acid group of an amino acid for crosslinking.

[0456] (1c) represents a [2,11] lactam crosslink, (6c) represents a [2,7] lactam crosslink, (6g) represents a [2,7] 1,4-disubstituted 1,2,3-triazole crosslink, and (7c) represents a [10,13] lactam crosslink.

[0457] The compound numbers in Table 1-1 correspond to the same numbers as the sequence numbers shown in Table 1-1a below. [Table 12] JPEG2026518789000059.jpg240170 JPEG2026518789000060.jpg240170 JPEG2026518789000061.jpg240170 JPEG2026518789000062.jpg240170 JPEG2026518789000063.jpg240170 JPEG2026518789000064.jpg240170 JPEG2026518789000065.jpg250170 JPEG2026518789000066.jpg251170 JPEG2026518789000067.jpg251170 JPEG2026518789000068.jpg230170In the table, †This indicates that the crosslinks in (1c), (6c), (6g), and (7c) use an alpha-amine group of an amino acid (or a beta-amine group in the case of bLys, {d}bLys, and beta-hLys, or an alpha-amine converted to an azide group in the case of (N3)-K and {d}(N3)-K) for crosslinking. ‡ This indicates that the crosslinks in (1c), (6c), (6g), and (7c) use the alpha-carboxylic acid group of an amino acid for crosslinking. (1c) represents a [2,11] lactam crosslink, (6c) represents a [2,7] lactam crosslink, (6g) represents a [2,7] 1,4-disubstituted 1,2,3-triazole crosslink, and (7c) represents a [10,13] lactam crosslink.

[0458] For comparison, we synthesized three compounds from Kong et al., 2020 (Nature Biomedical Engineering, 2020, 4, 560-571) that have two 1,3-dithio-propan-2-one bridges (Table 1-2). [Table 13]

[0459] (1a) represents a [2,11]1,3-dithio-propan-2-one bridge, (2a) represents a [4,7]1,3-dithio-propan-2-one bridge, (4a) represents a [1,11]1,3-dithio-propan-2-one bridge, and (5a) represents a [4,9]1,3-dithio-propan-2-one bridge.

[0460] In addition, two compounds from Protagonist's patent applications (compound C from International Publication No. 2016 / 011208, International Publication No. 2017 / 011820, and Sayago et al., 2018 (ACS Med. Chem. Lett., 2018, 9, 912-916), and peptide 993 from International Publication No. 2018 / 089693), which have a cross-linked cystathionine amino acid residue at [2,7], were synthesized (Table 1-3). [Table 14]

[0461] (16i) represents a [2,7] thioether crosslink. The combination of Abu at position X2, Cys at position X7, and the [2,7] thioether crosslink forms a cystathionine as the crosslinking amino acid residue.

[0462] Other synthesized reference compounds are listed in Table 1-4. These reference compounds were disclosed in International Publication No. 2023 / 099669. [Table 15] JPEG2026518789000072.jpg248170 JPEG2026518789000073.jpg51170

[0463] (1c) represents a [2,11]lactam crosslink, (2a) represents a [4,7]1,3-dithio-propane-2-one crosslink, and (2c) represents a [4,7]lactam crosslink. * This indicates that the crosslinking in (1c), (2a), and (2c) uses the N-terminal or C-terminal peptide backbone amine or carboxylic acid, rather than the side chain amine or carboxylic acid.

[0464] Unless otherwise specified, the reagents and solvents used below are commercially available in standard laboratory or analytical grades and were used without further purification.

[0465] Equipment and synthesis strategies The peptides were synthesized in batch mode using a peptide synthesizer such as the CEM Liberty Blue peptide synthesizer, following a solid-phase peptide synthesis procedure that uses 9-fluorenylmethyloxycarbonyl (Fmoc) as the N-α-amino protecting group and an appropriate general protecting group as the side-chain functional group.

[0466] TentaGel® was used as the polymer support base resin. The synthesizer was filled with resin that had been swollen with DMF before use.

[0467] Without making any changes to the basic procedure, naturally occurring amino acids and other suitable building blocks were used.

[0468] Optical isomers of specific amino acids (including those not found in nature) were used in the synthesis of the compound. Definitions can be found in Tables A and B. Specific R 2 The definition of the base is listed in Table C.

[0469] Coupling in the CEM Liberty Blue peptide synthesizer A solution of Fmoc-protected amino acids (4 equivalents) was added to the resin along with a coupling reagent solution (4 equivalents) and a base solution (8 equivalents). The mixture was coupled either by heating it to 50°C in a microwave unit for 10 minutes or by coupling it for 60 minutes without heating. The mixture was aerated with nitrogen during coupling.

[0470] In cases of difficult coupling (e.g., coupling of a residue immediately following an N-methylated amino acid residue, or coupling of other sterically hindered amino acid residues known to those skilled in the art), the coupling was repeated one or more times.

[0471] Deprotection The Fmoc group was deprotected using piperidine in DMF or another suitable solvent. The deprotection solution was added to the reaction vessel, and the mixture was heated for 5 minutes to reach a temperature of approximately 50°C. After draining the reaction vessel, the resin was washed with DMF or another suitable solvent.

[0472] Lactam formation: The following procedure for coupling Glu and Lys is representative of all lactam formations in which the amino acid side chain containing a carboxyl functional group is protected with Oall and the amino acid side chain containing an amino group is protected with Alloc. After assembling the full-length peptide sequence, deprotection of Glu (Oall) and Lys (Alloc) was performed using Pd(PPh3)4 (0.05 equivalents) and PhSiH3 (10 equivalents) in DCM. Subsequently, lactam crosslinks were formed between the carboxylic acid side chain of Glu and the amine side chain of Lys using PyBOP (2 equivalents) and DIPEA (3.0 equivalents) in DMF. Both steps were performed while the peptide was still bound to the resin.

[0473] Peptides having lactams from the side chain to the N-terminal amine were prepared similarly. After assembling the full-length peptide sequence, the Fmoc protecting group of the N-terminal amine remained intact. Glu(Oall) was deprotected with Pd(PPh3)4 as described, followed by Fmoc deprotection (see the "Cleavage" section). Lactam crosslinking was similarly formed with PyBOP.

[0474] Cutting: The dried peptide resin was treated with TFA and a suitable scavenger for approximately 2 hours. The volume of the filtrate was reduced, and diethyl ether was added to precipitate the crude peptide. The crude peptide precipitate was washed several times with diethyl ether and finally dried.

[0475] HPLC purification of crude peptides: Crude peptides were purified by preparative reverse-phase HPLC at a flow rate of 20–40 ml / min using a conventional HPLC instrument such as a Gilson GX-281 with a 331 / 332 pump combination for two-component gradient applications, equipped with a column such as a 5 × 25 cm Gemini NX 5u C18 110A column and a fraction collector. The HPLC was performed using an appropriate gradient of buffer A (0.1% formic acid aqueous solution) or A (0.1% TFA aqueous solution) and buffer B (0.1% formic acid, 90% MeCN aqueous solution) or B (0.1% TFA, 90% MeCN aqueous solution). The fractions were analyzed by analytical HPLC and MS, and the selected fractions were pooled and lyophilized. The final product was characterized by HPLC and MS.

[0476] Iso-amino acids: Peptides containing isoamino acids were synthesized using standard Fmoc SPPS with amino acid units in which the N-terminal and side-chain protecting groups were swapped. For example, a peptide containing standard lysine was synthesized using the unit Fmoc-Lys(Boc)-OH, where Fmoc is the protecting group for the N-terminal amine and Boc is the protecting group for the side chain. Conversely, peptides containing iso-Lys, for example, are synthesized using the Boc-Lys(Fmoc)-OH unit, rather than Fmoc-Lys(Boc)-OH. The coupling conditions for attaching the unit to the peptide, and the subsequent deprotection conditions for removing the Fmoc group, are the same as those described for standard Fmoc SPPS synthesis.

[0477] The side-chain protecting group "Boc" may be replaced with the "Alloc" protecting group when performing side-chain on-resin modification.

[0478] Triazole formation: Crude intermediate peptide, H2O / t The mixture was dissolved in BuOH 2:1 (1 mg / mL). 4.4 equivalents of CuSO45H2O and 4.4 equivalents of L-ascorbic acid (CAS 50-81-7) were added to the mixture. The mixture was protected from light and stirred for 24 hours.

[0479] The solution was loaded directly onto a preparative HPLC column for final purification.

[0480] Analytical HPLC: Final accuracy was determined using an analytical HPLC (Agilent 1100 / 1200 series) equipped with an autosampler, degasser, 20 μl flow cell, and Chromeleon software. HPLC was performed at 40°C at a flow rate of 1.2 ml / min using analytical columns such as a Kinetex 2.6 μm XB-C18 100A 100 × 4.6 mm column. Compounds were detected and quantified at 215 nm. Buffers used were Buffer A (0.1% TFA aqueous solution) and Buffer B (0.1% TFA, 90% MeCN aqueous solution).

[0481] Mass spectrometry: Final MS analysis was performed using a conventional mass spectrometer equipped with an electrospray detector with lock mass calibration and MassLynx software, e.g., a Waters Xevo G2 ToF. As specified in the chromatogram, it was operated in positive mode using direct injection and cone voltages of 15V (1TOF), 30V (2TOF), or 45V (3TOF). The accuracy was 5 ppm, and the typical resolution was 15,000–20,000.

[0482] Those skilled in the art will understand that the compounds of the present invention can be produced using standard peptide synthesis methods. [Examples]

[0483] Structure-Activity Relationship (SAR) of Compounds The SARs for peptides I1 (isomer 3), I3 (isomer 3), I4 (isomer 3), and I5 (isomer 3) in Kong et al., 2020 (Nature Biomedical Engineering, 2020, 4, 560-571) and the compounds disclosed in International Publication No. 2023 / 099669 are described in Example 2 of International Publication No. 2023 / 099669, which is incorporated by reference.

[0484] As part of further research into IL-23R inhibitors, the inventors identified from the NMR structure of Ref18 (compound 18 in International Publication No. 2023 / 099669) that the side chain at position 7 (Cys residue) and the N-terminal amino acid residue (Lys at position 2) were in close proximity. The sequence of Ref18 is as follows: [Table 16]

[0485] Because of this proximity, the inventors hypothesized that the [4,7] bridge could be replaced with a bridge between the side chain of the amino acid at position 7 and the N-terminal amine. This new [2,7,11] scaffold, as shown in compound 2, contained two bridges, one at [2,11] (side chain to side chain) and the other at [2,7] (side chain to tail, i.e., side chain to N-terminus). [Table 17]

[0486] The experimental data, as shown in Table 2-1 below, demonstrates that changing the crosslinking from [2,11][4,7] (Ref120 and Ref155) to [2,7,11], combined with crosslinking optimization (compound 1 and compound 2), maintains the efficacy of IL-23R inhibition. [Table 18]

[0487] The inventors observed that the cross-linking length between the side chain at position 7 and the N-terminus at position 2 is optimal for glutamic acid than for aspartic acid at position 7 (Table 2-2, comparing compounds 1 and 3, and compounds 6 and 8). [Table 19]

[0488] The inventors have found that, as shown in Table 2-3, changing the C-terminus from "NH2" to "NHMe" maintains efficacy and improves SIF stability. [Table 20]

[0489] Furthermore, the inventors observed that SIF stability must be addressed at position 10 by using certain amino acid residues such as 2-Me-Leu. Substitution of position 10 with glycine resulted in a complete loss of SIF stability, and therefore the resulting compound exhibited poor gastrointestinal stability (Table 2-4). [Table 21]

[0490] Furthermore, SIF stability must be addressed at position 12 by using certain amino acid residues such as Dab. The amino acid residue at position 12 affects both potency and SIF stability. Therefore, only certain substitutions at position 12 enabled both good SIF stability and potency (Table 2-5). [Table 22]

[0491] However, unlike previously disclosed IL-23R inhibitors, this novel [2,7,11] scaffold allowed the inventors to delete amino acid residues between positions 2 and 11 of a particular optimized [2,7,11] peptide without completely losing efficacy. The inventors had previously observed that such deletions in other scaffolds resulted in a complete loss of IL-23R inhibitory efficacy (see, for example, compounds Ref5 (deletion at position 3), Ref6 (deletion at position 6), and Ref7 (deletion at position 10) in Example 3 of International Publication No. 2023 / 099669).

[0492] In International Publication No. 2023 / 099669, we found that deletion of the amino acid residue at position 4, which had been previously used for [4,7] crosslinking of IL-23R inhibitors, preserved the inhibitory efficacy of IL-23R in the case of certain optimized [2,7,11] peptides (Table 2-6). [Table 23]

[0493] The deletion at position 4 is acceptable only if specific substitutions are present at other positions in the peptide, and only if so. Table 2-7 below illustrates the effects of substitutions, particularly at positions 2 and 3, in combination with the shortening at position 4. Introducing a 3-aminopropanoyl amino acid residue at position 3 (compound 45) improves potency compared to compound 36 (which has a Thr residue at position 3). Introducing glycine at position 3 maintains potency, but only if it is also accompanied by a beta-homo-Lys substitution at position 2 (compound 99). Substitutions at position 3 affect SIF stability. When glycine is present at position 3, SIF stability is lower than that of peptides with 3-aminopropanoyl. [Table 24] [Examples]

[0494] Biological assays [Example 3-1] Binding assay for estimating the binding affinity of compounds to human IL-23R The compound's binding affinity to IL-23R was estimated by its ability to dissociate a fluorophore-labeled reference compound from human IL-23R. The assay principle relies on bioluminescence resonance energy transfer (BRET) between the fluorophore-labeled reference compound bound to the IL-23R portion of a fusion protein consisting of IL-23R fused to the nanoluc luciferase enzyme (Nanoluc). Nanoluc is located at the N-terminus, close to the ligand binding domain. When the fluorophore of the fluorophore-labeled compound and Nanoluc in the fusion protein are in close proximity, bioluminescent energy generated from the conversion of the Nanoluc substrate is transferred to the fluorophore, resulting in an increase in BRET. If an unlabeled compound is present, it dissociates the fluorophore-labeled peptide from its binding site, resulting in a decrease in BRET. The concentration at which half of the fluorophore-labeled peptide is dissociated by the unlabeled compound depends on the compound's affinity to IL-23R, and the IC50 is calculated based on the IC50. 50 This is called concentration.

[0495] The fusion protein was generated by subcloning a small linker sequence in a mammalian expression plasmid and an in-frame sequence encoding a mature human IL-23R (main acceptance number UniProtKB-Q5VWK5, amino acids 22-629), as well as a secretory signal and Nanoluc protein (N1371, Promega). This plasmid also contained a gene conferring resistance to the antibiotic hygromycin. Cell lines stably expressing the Nluc-IL23R fusion protein were generated by transfecting HEK293 cells with the expression plasmid and selected with hygromycin for 3 weeks in a growth medium consisting of 10% volume / volume FBS, 1% volume / volume P / S, 1 mM sodium pyruvate, 1 × NEAA, and 0.3 mg / mL hygromycin in DMEM containing Glutamax-I. The remaining cells were grown and considered as a pool clone of the stably expressing Nluc-IL23R fusion protein.

[0496] Cells expressing the Nluc-IL23R fusion protein were expanded and grown in growth medium, and the cell pellets in 18 T175 flasks were homogenized to prepare the membrane (at 4°C in subsequent steps). The cell pellets were dissolved in 10 mM Tris, 7.5 mM EDTA, and a protease inhibitor (Complete, Roche), and homogenized using a 15 mL glass dynasium for 50 strokes. The homogenate was centrifuged at 1500 rpm for 10 minutes, and the supernatant was transferred to an SV-34 tube. The crude membrane was pelletized by centrifuging at 40000 g for 20 minutes at 4°C. The supernatant was then removed, and the pellet was resuspended in 5 mL buffer containing 50 mM HEPES pH 7.4, 5 mM EGTA, and 5 mM MgCl2, and homogenized. Aliquots of the resuspended and homogenized membranes containing the Nluc-IL23R fusion protein were stored at -80°C until use.

[0497] Compounds to be tested for binding to IL-23R were sequentially diluted with assay buffer (50 mM HEPES pH 7.4, 5 mM EGTA, 5 mM MgCl2, 0.005% Tween-20, and 0.05% casein). These diluted compounds were then added to the wells of a white 384-well plate (Corning 3572) in a volume of 6.25 μL, along with a 12.5 μL diluted membrane containing Nluc-IL23R fusion protein (0.42 μg / well) and 6.25 μL of a fluorescently labeled peptide, all prepared in the same assay buffer, to achieve a final concentration of 3.1 nM. The plate was sealed with a light-impermeable plate seal and incubated at room temperature for 2 hours at 400 rpm in an orbital shaker. To determine the BRET ratio, the plate seal was removed, and 25 μL of 1:500 diluted Nanoluc substrate (Promega N1572) was added to each well. The mixture was incubated in an orbital shaker at 400 rpm for 1-2 minutes. The plate was then read using an Envision plate reader equipped with a luminescence mirror module (barcode 404) with filters corresponding to Nanoluc substrate emission (M470 filter; 470 nm, bandwidth 24 nm) and TAMRA fluorescence (M595p filter; 595 nm, bandwidth 60 nm). The BRET ratio was calculated as fluorescence from TAMRA / nanoluc bioluminescence.

[0498] In the data analysis, the BRET ratio was normalized against the BRET signal of the 3.1 nM TAMRA-labeled peptide alone (without the addition of the unlabeled compound) and the BRET signal under complete dissociation (by adding a very high concentration of the unlabeled peptide). Compound potency (IC) 50 The IC of each compound was estimated by computer-aided curve fitting using a 4-parameter logistic (4PL) nonlinear model. 50 The maximum value was determined by computer-aided curve fitting using a 4-parameter logistic (4PL) nonlinear model. Compound potency (IC 50 The data for ) and maximum dissociation (dissociation %) are shown in Table 3-1. Typically, low IC 50Compounds possessing the following characteristics are desirable. Typically, compounds with a high degree of TAMRA-labeled peptide dissociation are desirable. Due to experimental errors in specific assays, typically, a value equal to or greater than 90% was considered capable of completely dissociating the TAMRA-labeled peptide.

[0499] In the previous application, International Publication No. 2023 / 099669, the data was K i It was provided as a calculated value. In this application, the inventors have provided data to IC 50 Provided as a value. The Cheng-Prussov formula is K i and IC 50 The relationship with K i =IC 50 / (1+[L L ] / K dL ) is written as, and in the formula [L L ] is the concentration of the labeled compound used, and K dL K is the equilibrium dissociation constant of the labeled compound (Cheng and Prusoff, Biochem. Pharmacol., 1973, 22(23), 3099-3108). To enable comparison between numerical values, the inventors have used K for a number of compounds in International Publication No. 2023 / 099669. i and IC 50 We made that decision.

[0500] K of Compounds in International Publication No. 2023 / 099669 i Value and IC 50 value [Table 25] [Table 26] JPEG2026518789000085.jpg252170 JPEG2026518789000086.jpg252170 JPEG2026518789000087.jpg229170JPEG2026518789000088.jpg8170[Example 3-2]

[0501] Inhibition of IL-23-mediated STAT3 signaling by compounds The ability of compounds to inhibit IL-23-mediated signaling was determined in human-derived DB cell lines (CRL-2289) (hereinafter referred to as DB cells) that endogenously express human IL-23R and human IL-12R β1 subunits. Upon binding to IL-23, IL-23R forms a heterodimeric signaling complex with IL-12R β1, thereby promoting phosphorylation of STAT3 via the JAK2 / STAT3 pathway and forming phosphorylated STAT3. In this assay, the functional antagonistism of compounds against IL-23-mediated phosphorylated STAT3 formation in DB cells was quantified using a reagent capable of measuring the phosphorylation state of Tyr705 of STAT3, in the form of a phosphorylated STAT3 (Tyr705) MSD (Meso Scale Discovery) kit.

[0502] This assay was used to quantify the functional antagonism of compounds and rank the inhibitor compounds according to their potency. For the compounds tested in this assay, the IC2016 IC2016 was obtained from the concentration response curves of the compounds in the presence of a constant concentration of human IL-23. 50 Furthermore, to calculate the maximum inhibitory response, the response was normalized relative to a control value.

[0503] The assay procedure was as follows: DB cells were maintained in growth medium consisting of RPMI-1640 [Invitrogen 61870-010] supplemented with 10% volume / volume fetal bovine serum (FBS) [(heat inactivated), Invitrogen 10270-106] and 1% volume / volume penicillin-streptomycin (Pen-Strep) solution [Invitrogen 15140]. On the day of the assay, the cells were resuspended in assay buffer consisting of RPMI-1640 [Invitrogen 61870-010] supplemented with 0.1% weight / volume BSA [Sigma-Aldrich A9430] and 7.5 × 10⁶ cells. 6 The cells / mL density was adjusted. Compounds to be tested for inhibition of hIL-23-mediated signaling were sequentially diluted to 3× final concentration in assay buffer. Also, 3× hIL-23 EC 80 A 1.7 nM hIL-23 solution was prepared in assay buffer. To initiate the assay, 20 μL of DB cell suspension (equivalent to 150,000 cells / well) was added to a well of a 96-well V-bottom polypropylene plate [Corning 3363], followed by the addition of 3 × 20 μL of diluted test compound to another well. After pre-incubating the DB cells with the inhibitor in a cell incubator (37°C, 5% CO2) for 15 minutes, the prepared 3 × hIL-23 EC was used. 80 20 μL of the solution was added to each well and incubated in a cell incubator (37°C, 5% CO2) for 90 minutes. Some wells were treated with buffer only or EC. 80Only IL-23 equivalent to the target was added to obtain the data necessary for normalization. To complete the assay, the plate was centrifuged at 1000G for 5 minutes to pellet the cells, the supernatant was removed using an 8-channel manual pipette, and then 50 μL / well of Complete Lysis Buffer from the MSD STAT3 kit (catalog no. K150SVD, Mesoscale) was added to the cell pellet. To completely lyse the cells and allow them to release phosphorylated STAT3 for detection, the plate was sealed with aluminum foil, shaken at room temperature for 10 minutes (500 rpm), and then allowed to stand at -80°C for at least 15 minutes. Detection of phosphorylated STAT3 levels in the cell lysates of individual wells was determined using the MSD STAT3 kit (catalog no. K150SVD, Mesoscale) and read with a Meso QuickPlex SQ 120 plate reader (Mesoscale).

[0504] In the data analysis, raw data counts from the Meso QuickPlex SQ 120 plate reader were used for EC of hIL-23 alone (without added compounds). 80 The compound potency (IC) was normalized for the response due to buffer levels. 50 Compound potency (IC) and maximum inhibitory response (inhibition%) were estimated by computer-aided curve fitting using a 4-parameter logistic (4PL) nonlinear model. 50 The data for IC and the maximum inhibitory response (dissociation %) are shown in Table 3-2. 50 The lower the value, the stronger the compound. Typically, a low IC value indicates a stronger compound. 50 Compounds possessing this property are desirable. Typically, compounds capable of completely inhibiting the IL23-induced response are desirable. Due to experimental error, a value equal to or greater than 95% is considered capable of completely inhibiting IL23R-induced signaling. [Table 27] JPEG2026518789000090.jpg250170 JPEG2026518789000091.jpg37170 [Examples 3-3 and 3-4]

[0505] Determination of peptide stability in simulated gastric juice (SGF) and simulated intestinal juice (SIF). SGF and SIF were prepared according to the United States Pharmacopeia (Test Solutions, United States Pharmacopeia 35, NF 30, 2012). SGF was prepared by dissolving sodium chloride (0.2 g) in 50 mL of water. The pH of the solution was adjusted to 1.2 by adding 0.7 mL of 10 M HCl, and the volume was then increased to 100 mL with water. Immediately before incubation, 64 mg of porcine pepsin (P7125, Sigma Aldrich) was gently dissolved in 20 mL of preheated (37°C) solution (3.2 g / L). SIF was prepared by dissolving monopotassium phosphate (0.68 g) in 50 mL of water and adjusting the pH to 6.8 with 1 M NaOH. The volume was then increased to 100 mL with water. Immediately before incubation, 200 mg of porcine pancreatin (P1625, Sigma Aldrich) was gently dissolved in 20 mL of preheated (37°C) solution (10 g / L).

[0506] To initiate incubation, 20 μL of peptide stock solution in 50% volume / vol isopropanol was placed at the bottom of the well plate, and 580 μL of matrix solution was added to achieve a final substrate concentration of 10 μM. Incubation was carried out at 37°C with gentle shaking. At 0, 1, and 4 hours, 70 μL aliquots were taken and quenched in 210 μL of ice-cold precipitant solution (95% volume / vol acetonitrile with 0.1% volume / vol formic acid). After the final time point, the sampling plate was mixed on a shaking table for 10 minutes and centrifuged at 2200 g for 10 minutes. The resulting 70 μL supernatant was diluted with 150 μL of water, mixed, centrifuged, and analyzed by liquid chromatography-high-resolution mass spectrometry. After the 4-hour sample, a zero sample was reinjected to confirm that no instrument sensitivity deviation occurred during the run. The residual percentage at each time point was calculated relative to time point zero based on the absolute peak area.

[0507] The in vitro SIF results (expressed as the percentage of peptide remaining after a specified period) are summarized in Table 3-3 below. Compounds with SIF stability above 70% (after 4 hours) are considered to have very high SIF stability. Compounds with SIF stability between 30% and 70% (including 30% and 70%) (after 4 hours) are considered to have moderate SIF stability. Compounds with SIF stability below 30% (after 4 hours) are considered to be SIF unstable. SIF stability values ​​above 100% are due to analytical uncertainty and indicate that the compound has not degraded. Preferred compounds are those with minimal or no degradation, i.e., high (at least 70%) SIF stability, preferably close to 100% SIF stability. [Table 28] JPEG2026518789000093.jpg252170 JPEG2026518789000094.jpg56170

[0508] The in vitro SGF results (expressed as the percentage of peptides remaining after a specified period) are summarized in Tables 3-4 below. Compounds with SGF stability above 70% (after 4 hours) are considered to have very high SGF stability. Compounds with SGF stability between 30% and 70% (including 30% and 70%) (after 4 hours) are considered to have moderate SGF stability. Compounds with SGF stability below 30% (after 4 hours) are considered to be SGF unstable. SGF stability values ​​above 100% are due to analytical uncertainty and indicate that the compound has not degraded. Preferred compounds are those with minimal or no degradation, i.e., high (at least 70%) SGF stability, preferably close to 100% SGF stability. [Table 29] JPEG2026518789000096.jpg187170 [Example 3-5]

[0509] Functional inhibition of IL-23-mediated IFN-γ secretion by IL-23R inhibitor compounds The ability of IL-23-R inhibitor compounds to inhibit IL-23-mediated IFN-γ secretion was evaluated using an in vitro human whole blood assay. This assay can be used to quantify the functional antagonistism of IL-23R inhibitors and to rank inhibitor potencies based on concentration-response curves (CRCs) generated in the presence of constant IL-23, IL-2, and IL-18 concentrations. 50 Furthermore, the maximum inhibitory response can be calculated from this curve.

[0510] The assay procedure was as follows:

[0511] On the day of the experiment, human blood was obtained from a voluntary donor at Blodbanken Hvidovre Hospital in Denmark and collected in a BD sodium heparin vacutainer tube (catalog number 367876, Avantor).

[0512] The buffer used consisted of RPMI-1640 [Catalog No. 61870-010, Thermo Fisher Scientific] supplemented with 1% volume / volume penicillin-streptomycin (Pen-Strep) solution [Catalog No. 15140, Thermo Fisher Scientific], 1 mM sodium pyruvate [Catalog No. 11360-039, Thermo Fisher Scientific], 25 mM HEPES buffer [Catalog No. 15630-056, Thermo Fisher Scientific], and 0.05% volume / volume casein [Catalog No. C4765, Sigma-Aldrich] (hereinafter referred to as the assay buffer).

[0513] On the day of the assay, the compounds to be tested for inhibition of hIL-23-mediated signaling were sequentially diluted to 4× final concentrations in assay buffer. In addition, an hIL-23 stimulating solution equivalent to 4× hIL-23 EC80 (1.6 ng / ml) [catalog number 11349-IL; R&D Systems] was prepared in assay buffer along with 4× hIL-2 [catalog number BT-002; R&D Systems] (40 ng / ml) and 4× hIL-18 [catalog number 9124-IL; R&D Systems] (80 ng / ml). To start the assay, 25 μL of the prepared 4× diluted test compounds were added to the wells of a 96-well plate [catalog number 167425; Thermo Scientific], followed by the addition of 50 μL of human whole blood to each well. Blood and inhibitors were pre-incubated in a cell incubator (37°C, 5% CO2) for 15 minutes. Then, 25 μL of the prepared 4× stimulation solution was added to each well, and the cells were incubated in a humidity chamber of the cell incubator (37°C, 5% CO2) for 16–24 hours.

[0514] To complete the assay, 100 μL of PBS pH 7.4 [catalog no. 10010-015; Thermo Fisher Scientific] was added to each well, and the plate was centrifuged at 350 × G for 10 minutes to pelletize the blood. The supernatant was removed and added to a 96-well V-bottom polypropylene plate [Corning 3363] using an 8-channel manual pipette.

[0515] The sample was further diluted 30× with diluent 57 buffer from the MSD U-PLEX human IFN-γ assay [catalog number K151TTK-2; Mesoscale Discovery].

[0516] IFN-γ levels in the supernatant of each well were determined using the MSD U-PLEX Human IFN-γ Assay Kit (catalog number K151TTK-2; Mesoscale Discovery) and read using a Meso QuickPlex SQ 120 plate reader (Mesoscale Discovery).

[0517] In the data analysis, raw data counts from the Meso QuickPlex SQ 120 plate reader were converted to IFN-γ concentrations using the standard curve provided with the kit. Compound potency (IC) 50 The IC50 values ​​of the test compounds were estimated by computer-aided curve fitting using a 4-parameter logistic (4PL) nonlinear model. The IC50 values ​​of the test compounds are the concentrations that achieve 50% of the maximum inhibition of the hIL-23 agonist-induced response (under specific conditions, - here in the presence of hIL-2 and hIL-18 as shown above). Maximum inhibition is expressed as a percentage, where 0% is the activity level induced by the reference agonist alone (hIL23R together with IL-2 and IL-18 as shown above), and 100% is the baseline activity level of the unstimulated receptor in the absence of the reference agonist.

[0518] Compound efficacy of the five individual compounds of the present invention (IC 50 The data for ) and maximum inhibition (%) are shown in Table 3-5 below.

[0519] Typically, low IC 50 Compounds possessing the following properties are desirable. Typically, compounds capable of completely inhibiting the IL23-induced response are preferred. [Table 30]

[0520] (References) Cheng and Prusoff, Biochem. Pharmacol., 1973, 22(23), 3099-3108. Kong et al., Nature Biomedical Engineering, 2020, 4, 560-571. WO 2023 / 099669 Sayago et al., ACS Med. Chem. Lett., 2018, 9, 912-916. WO 2016 / 011208 WO 2017 / 011820 WO 2018 / 022937 WO 2018 / 089693 WO 2018 / 136646 WO 2020 / 014646 WO 2021 / 007433 WO 2021 / 146441 WO 2021 / 146458 WO 2023 / 288017 WO 2023 / 288019 WO 2023 / 288028 US 2013 / 0029907

[0521] Clause 1. Formula: ZR 2 A compound of which, in the formula, R 2 NHR 3 Or C(=O)R 3 And R 3 C may be substituted with hydrogen or a pyridyl ring. 1-6 Alkyl, NHR 3 Or C(=O)R 3 is or does not exist, Z is given by equation I: X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13 (I) This is the amino acid sequence, and in the sequence, X2 is selected from the group consisting of Lys, D-Lys, iso-Lys, beta-Lys, D-beta-Lys, homo-Lys, D-homo-Lys, beta-homo-Lys, N-Me-Lys, Dab, D-Dab, iso-Dab, Glu, iso-Glu, D-iso-Glu, Orn, D-Orn, Dpr, Lys(Gly), (N3)-Lys, and D-(N3)-Lys. X3 is selected from the group consisting of Thr, Ile, 3-aminopropanoyl, 4-aminobutanoyl, beta-homo-Ile, beta-homo-Thr, Gly, N-Me-3-aminopropanoyl, and Ser, or is absent. X4 is either Val or does not exist. X5 is selected from the group consisting of Trp, 1-Me-Trp, and beta-homo-Trp. X6 is Gln, X7 is selected from the group consisting of Glu, D-Glu, Homo-Glu, Asp, Pra, and Hpg. X8 is selected from the group consisting of Y(2-aminoethoxy), Y(Me), Y(nPr), Y(Bn), Trp, D-Phe, 2-Me-Phe, F(4-Me), F(4-Bu), 3-(2-pyridyl)-Ala, 3-(3-pyridyl)-Ala, 3-(4-pyridyl)-Ala, and cyclopropyl-Ala. X9 is 2-Nal or cyclopropyl-Ala, X10 is selected from the group consisting of 2-Me-Leu, 2-Me-Val, Dab, Gly, Lys, and Aib. X11 is selected from the group consisting of Glu, homo-Glu, beta-homo-Glu, Dab, iso-Dab, Lys, Lys(Me), Orn, and 2-amino-6-carboxyhexanoyl. X12 is Dab, His, D-His, His(1-Me), 3-(2-pyridyl)-Ala, 3-(3-pyridyl)-Ala, 3-(4-pyridyl)-Ala, 3-(3-quinolinyl)-Ala, Gly, Pro, 5-aminopentanoyl, 4-aminopiperidine-4-carbonyl, (R,S)-imidazolidined-2-carbonyl, and Lys, wherein the side chain -NH2 of Lys is -C(=O)(CH2) n R K It is substituted with, where n is 0 to 2, and R K is selected from the group consisting of Lys, which may be imidazolyl, pyrimidyl, or pyridyl substituted with F, or X12 does not exist. X13 is selected from the group consisting of 3-(3-pyridyl)-Ala, D-3-(3-pyridyl)-Ala, and 3-(3,5-pyrimidyl)-Ala, or is absent. In the array, (i) X2 and X11 are amino acid residues that together form a lactam crosslink, (ii) X2 and X7 are amino acid residues that together form a lactam crosslink or a crosslink containing a triazole ring, (iii) Optionally, if X13 is present, X10 and X13 are amino acid residues that together form a lactam crosslink. compound, or a pharmaceutically acceptable salt or solvate thereof.

[0522] 2. ZR 2 And in the formula, R 2 However, NHR 3 And R 3 However, C may be substituted with hydrogen or a pyridyl ring. 1-6 Alkyl, NHR 3 is or does not exist, Z is given by equation Ia: X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13 (Ia) This is the amino acid sequence, and in the sequence, X2 is selected from the group consisting of Lys, D-Lys, iso-Lys, beta-Lys, D-beta-Lys, homo-Lys, D-homo-Lys, beta-homo-Lys, N-Me-Lys, Dab, D-Dab, Glu, iso-Glu, Orn, D-Orn, Lys(Gly), (N3)-Lys, and D-(N3)-Lys. X3 is selected from the group consisting of Thr, Ile, 3-aminopropanoyl, 4-aminobutanoyl, beta-homo-Ile, beta-homo-Thr, Gly, and N-Me-3-aminopropanoyl, or is absent. X4 is either Val or does not exist. X5 is either a trp or a 1-Me-Trp. X6 is Gln, X7 was selected from the group consisting of Glu, Homo-Glu, Asp, Pra, and Hpg. X8 is selected from the group consisting of Y(2-aminoethoxy), Y(Me), Y(Bn), F(4-Me), F(4-Bu), and cyclopropyl-Ala. X9 is 2-Nal, X10 is selected from the group consisting of 2-Me-Leu, 2-Me-Val, Dab, Gly, and Aib. X11 is selected from the group consisting of Glu, homo-Glu, Lys, Lys(Me), Orn, and 2-amino-6-carboxyhexanoyl. X12 is selected from the group consisting of Dab, His, D-His, His(1-Me), 3-(3-quinolinyl)-Ala, and 4-aminopiperidine-4-carbonyl. X13 is either 3-(3-pyridyl)-Ala, 3-(3,5-pyrimidyl)-Ala, or absent. In the array, (i) X2 and X11 are amino acid residues that together form a lactam crosslink, (ii) X2 and X7 are amino acid residues that together form a lactam crosslink or a crosslink containing a triazole ring, (iii) Optionally, if X13 is present, X10 and X13 are amino acid residues that together form a lactam crosslink. Compounds as described in Clause 1, or a pharmaceutically acceptable salt or solvate thereof.

[0523] 3. The compound according to Clause 1 or 2, wherein the lactam crosslink between X2 and X11 uses the side chain of the amino acid residue of X2, and the crosslink between X2 and X7 uses the N-terminus of the amino acid residue of X2.

[0524] 4. A compound described in any one of clauses 1 to 3, wherein X2 is Lys.

[0525] 5. The compound according to any one of clauses 1 to 4, wherein X3 is selected from the group consisting of Thr, Ile, and 3-aminopropanoyl, or is absent.

[0526] 6. A compound described in any one of clauses 1-5, for which X4 does not exist.

[0527] 7. A compound described in any one of clauses 1 to 6, wherein X5 is Trp.

[0528] 8. A compound described in any one of clauses 1 to 7, wherein X7 is Glu.

[0529] 9. A compound according to any one of clauses 1 to 8, wherein X8 is Y(2-aminoethoxy), Y(Me), or F(4-Me).

[0530] 10. The compound according to Clause 8, wherein X8 is Y(2-aminoethoxy).

[0531] 11. A compound according to any one of clauses 1 to 10, wherein X9 is 2-Nal.

[0532] 12. The compound according to any one of the clauses 1 to 11, wherein X10 is 2-Me-Leu or 2-Me-Val.

[0533] 13. The compound according to Clause 11, wherein X10 is 2-Me-Leu.

[0534] 14. A compound according to any one of clauses 1 to 13, wherein X11 is Glu.

[0535] 15. A compound described in any one of clauses 1 to 14, wherein X12 is Dab.

[0536] 16. The compound described in any one of clauses 1 to 15, wherein X13 is 3-(3-pyridyl)-Ala or is not present.

[0537] 17. The compound according to Clause 16, wherein X13 is 3-(3-pyridyl)-Ala.

[0538] 18. R 2 However, NHR 3 And in the formula R 3 is hydrogen or C 1-6 A compound that is alkyl, as described in any one of clauses 1 to 17.

[0539] 19. R 2 A compound as described in Clause 18, wherein the compound is NH2.

[0540] 20. R 2 A compound as described in Clause 18, wherein the compound is NHMe.

[0541] 21. A compound according to any one of clauses 1 to 20, wherein X2 is Lys, X5 is Trp, X9 is 2-Nal, and X10 is 2-Me-Leu.

[0542] 22. X2 is Lys, X5 is Trp, X9 is 2-Nal, X10 is 2-Me-Leu, and R 2 A compound according to any one of clauses 1 to 21, wherein is NH2 or NHMe.

[0543] 23. X2 is Lys, X5 is Trp, X9 is 2-Nal, X10 is 2-Me-Leu, X13 is 3-(3-pyridyl)-Ala or is absent, and R 2 A compound according to any one of clauses 1 to 22, wherein is NH2 or NHMe.

[0544] 24. X2 is Lys, X5 is Trp, X7 is Glu, X9 is 2-Nal, X10 is 2-Me-Leu, X13 is 3-(3-pyridyl)-Ala or is absent, and R 2 A compound according to any one of clauses 1 to 23, wherein is NH2 or NHMe.

[0545] 25. The compound described in Clause 1, wherein Z is an amino acid sequence selected from the group consisting of sequences listed in Table 1-1a.

[0546] 26. A compound specified in Clause 1, selected from the compounds in Table 1-1, or a pharmaceutically acceptable salt or solvate thereof.

[0547] 27. A pharmaceutical composition comprising a compound described in any one of clauses 1 to 26 in combination with a pharmaceutically acceptable carrier, excipient, or medium.

[0548] 28. A method for synthesizing a compound described in any one of Clauses 1 to 26, comprising the steps of synthesizing an analog by solid-phase or liquid-phase peptide synthesis, optionally isolating and / or purifying the final product, and further optionally forming an amide bond between the amino acid residues at positions X2 and X11, and further optionally forming an amide bond between the amino acid residues at positions X2 and X7 or forming a triazole, and further optionally forming an amide bond between the amino acid residues at positions X10 and X13.

[0549] 29. A compound described in any one of Clauses 1 to 26, or a pharmaceutical composition described in Clause 27, for use in a method of medical treatment.

[0550] 30. A compound according to any one of Clauses 1 to 26, or a pharmaceutical composition according to Clause 27, for use in a method for preventing or treating inflammatory bowel disease (IBD), Crohn's disease, ulcerative colitis, and psoriasis.

[0551] 31. Compounds or pharmaceutical compositions for use as described in Clause 30, for use in methods for preventing or treating inflammatory bowel disease (IBD) and / or psoriasis.

[0552] 32. Use of any one of the compounds described in Clauses 1 to 26 or the pharmaceutical composition described in Clause 27 in the manufacture of a pharmaceutical for the prevention or treatment of inflammatory bowel disease (IBD), such as Crohn's disease or ulcerative colitis, psoriatic arthritis, and psoriasis.

[0553] 33. Use of the compound or pharmaceutical composition described in Clause 32, wherein the use of the compound or pharmaceutical composition is in the manufacture of a medicament for the prevention or treatment of inflammatory bowel disease (IBD) and / or psoriasis.

[0554] 34. A method for preventing or treating inflammatory bowel disease (IBD), such as Crohn's disease or ulcerative colitis, psoriatic arthritis, and psoriasis, comprising the step of administering to a subject a therapeutically effective amount of a compound described in any one of Clauses 1 to 26 or a pharmaceutical composition described in Clause 27.

[0555] 35. Methods for the prevention or treatment of inflammatory bowel disease (IBD) and / or psoriasis as described in Clause 34.

[0556] 36. A pharmaceutical composition as described in Clause 27, for oral administration.

Claims

1. formula: Z-R ２ A compound of which, in the formula, R ２ NHR ３ Or C(=O)R ３ And R ３ C may be substituted with hydrogen or a pyridyl ring. １－６ The above NHR is alkyl ３ Or C(=O)R ３ is or does not exist, Z is given by equation I: X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13 (I) This is the amino acid sequence, and in the sequence, X2 is, Lys, D-Lys, iso-Lys, D-iso-Lys, beta-Lys, D-beta-Lys, homo-Lys, D-homo-Lys, beta-homo-Lys, N-Me-Lys, N-Me-homo-Lys, (N ３ )-Lys, D-(N ３ )-Lys, (N ３ )-beta-Lys, (N ３ )-D-beta-Lys, (N ３ )-homo-Lys, (N ３ )-D-homo-Lys, (N ３ )-beta-homo-Lys, Dpr, D-Dpr, iso-Dpr, D-iso-Dpr, beta-Dpr, D-beta-Dpr, homo-Dpr, D-homo-Dpr, beta-homo-Dpr, N-Me-Dpr, N-Me-homo-Dpr, (N ３ )-Dpr, D-(N ３ )-Dpr, (N ３ )-Beta-Dpr, (N ３ )-D-beta-Dpr, (N ３ )-homo-Dpr, (N ３ )-D-homo-Dpr, (N ３ )-Beta-Homo-Dpr, Dab, D-Dab, Iso-Dab, D-Iso-Dab, Beta-Dab, D-Beta-Dab, Homo-Dab, D-Homo-Dab, Beta-Homo-Dab, N-Me-Dab, N-Me-Homo-Dab, (N ３ )-Dab, D-(N ３ )-Dab, (N ３ )-Beta-Dab, (N ３ )-D-beta-Dab, (N ３ )-Homo-Dab, (N ３ )-D-homo-Dab, (N ３ )-Beta-Homo-Dab, Orn, D-Orn, Iso-Orn, D-Iso-Orn, Beta-Orn, D-Beta-Orn, Homo-Orn, D-Homo-Orn, Beta-Homo-Orn, N-Me-Orn, N-Me-Homo-Orn, (N ３ )-Orn, D-(N ３ )-Orn, (N ３ )-Beta-Orn, (N ３ )-D-Beta-Orn, (N ３ )-Homo-Orn, (N ３ )-D-homo-Orn, (N ３ )-Beta-Homo-Orn, Lys (Gly), Asp, D-Asp, Iso-Asp, D-Iso-Asp, Beta-Asp, D-Beta-Asp, Homo-Asp, D-Homo-Asp, Beta-Homo-Asp, N-Me-Asp, N-Me-Homo-Asp, (N ３ )-Asp, D-(N ３ )-Asp, (N ３ )-Beta-Asp, (N ３ )-D-beta-Asp, (N ３ )-homo-Asp, (N ３ )-D-homo-Asp, (N ３ )-Beta-Homo-Asp, Glu, D-Glu, Iso-Glu, D-Iso-Glu, Beta-Glu, D-Beta-Glu, Homo-Glu, D-Homo-Glu, Beta-Homo-Glu, N-Me-Glu, N-Me-Homo-Glu, (N ３ )-Glu, D-(N ３ )-Glu, (N ３ )-Beta-Glu, (N ３ )-D-beta-Glu, (N ３ )-Homo-Glu, (N ３ )-D-homo-Glu, (N ３ )-Beta-Homo-Glu, 2-amino-6-carboxyhexanoyl and 3-aminopropanoyl Selected from the group consisting of, X3 is any amino acid, ω-hydroxy-C ２－６ Selected from alkanates, or absent, X4 is Val, D-Val, Beta-Val, D-Beta-Val, Homo-Val, D-Homo-Val, Beta-Homo-Val, N-Me-Val, N-Me-Homo-Val, 2-Me-Val, Ala, D-Ala, Beta-Ala, D-Beta-Ala, Homo-Ala, D-Homo-Ala, Beta-Homo-Ala, N-Me-Ala, N-Me-Homo-Ala, Gly, Beta-Gly, Homo-Gly, Beta-Homo-Gly, N-Me-Gly, N-Me-Homo-Gly, Leu, D-Leu, Beta-Leu, D-Beta-Leu, Homo-Leu, D-Homo-Leu, Beta-Homo-Leu, N-Me-Leu, N-Me-Homo-Leu, 2-Me-Leu, Ile, D-Ile, Beta-Ile, D-Beta-Ile, Homo-Ile, D-Homo-Ile, Beta-Homo-Ile, N-Me-Ile, and N-Me-Homo-Ile Selected from the group consisting of, or if none exist, X5 is selected from the group consisting of a tryptophan residue that may be substituted, azatryptophan residue that may be substituted, and a beta-homotryptophan residue that may be substituted. X6 may be a substituted Gln residue, a substituted Lys residue, a substituted Arg residue, a substituted Dab residue, a substituted Orn residue, a substituted Phe residue, Ala, D-Ala, Beta-Ala, D-Beta-Ala, Homo-Ala, D-Homo-Ala, Beta-Homo-Ala, N-Me-Ala, N-Me-Homo-Ala, Cit, D-Cit, Beta-Cit, D-Beta-Cit, Homo-Cit, D-Homo-Cit, Beta-Homo-Cit, N-Me-Cit, N-Me-Homo-Cit, Glu, D-Glu, Iso-Glu, D-Iso-Glu, Beta-Glu, D-Beta-G Selected from the group consisting of lu, homo-Glu, D-homo-Glu, beta-homo-Glu, N-Me-Glu, N-Me-homo-Glu, Tyr, D-Tyr, beta-Tyr, D-beta-Tyr, homo-Tyr, D-homo-Tyr, beta-homo-Tyr, N-Me-Tyr, N-Me-homo-Tyr, Val, D-Val, beta-Val, D-beta-Val, homo-Val, D-homo-Val, beta-homo-Val, N-Me-Val, N-Me-homo-Val, or His, D-His, beta-His, D-beta-His, homo-His, D-homo-His, beta-homo-His, N-Me-His, and N-Me-homo-His, X7 is Asp, D-Asp, iso-Asp, D-iso-Asp, beta-Asp, D-beta-Asp, homo-Asp, D-homo-Asp, beta-homo-Asp, N-Me-Asp, N-Me-homo-Asp, Glu, D-Glu, Iso-Glu, D-Iso-Glu, Beta-Glu, D-Beta-Glu, Homo-Glu, D-Homo-Glu, Beta-Homo-Glu, N-Me-Glu, N-Me-Homo-Glu, Dab, D-Dab, iso-Dab, D-iso-Dab, beta-Dab, D-beta-Dab, homo-Dab, D-homo-Dab, beta-homo-Dab, N-Me-Dab, N-Me-homo-Dab, Orn, D-Orn, Iso-Orn, D-Iso-Orn, Beta-Orn, D-Beta-Orn, Homo-Orn, D-Homo-Orn, Beta-Homo-Orn, N-Me-Orn, N-Me-Homo-Orn, Lys, D-Lys, iso-Lys, beta-Lys, D-iso-Lys, D-beta-Lys, homo-Lys, D-homo-Lys, beta-homo-Lys, N-Me-Lys, N-Me-homo-Lys, Pra, D-Pra, Beta-Pra, D-Beta-Pra, Homo-Pra, D-Homo-Pra, Beta-Homo-Pra, N-Me-Pra, N-Me-Homo-Pra, Hpg, D-Hpg, Beta-Hpg, D-Beta-Hpg, Homo-Hpg, D-Homo-Hpg, Beta-Homo-Hpg, N-Me-Hpg, and N-Me-Homo-Hpg Selected from the group consisting of, X8 is selected from the group consisting of an optionally substituted tryptophan residue, an optionally substituted azatryptophan residue, an optionally substituted beta-homotryptophan residue, an optionally substituted tyrosine residue, an optionally substituted phenylalanine residue, an optionally substituted homophenylalanine residue, and an alanine residue substituted with a carbocyclic group or an aromatic or heteroaromatic group selected from the group consisting of phenyl, pyridyl, naphthyl, and quinolinyl, each of which may be substituted. X9 is selected from the group consisting of an optional tryptophan residue, an optional azatryptophan residue, an optional alanine residue, an optional phenylalanine residue, and an optional tyrosine residue. X10 is, Val, D-Val, Beta-Val, D-Beta-Val, Homo-Val, D-Homo-Val, Beta-Homo-Val, N-Me-Val, N-Me-Homo-Val, 2-Me-Val, Gly, Beta-Gly, Homo-Gly, Beta-Homo-Gly, N-Me-Gly, N-Me-Homo-Gly, Dab, D-Dab, iso-Dab, D-iso-Dab, beta-Dab, D-beta-Dab, homo-Dab, D-homo-Dab, beta-homo-Dab, N-Me-Dab, N-Me-homo-Dab, Lys, D-lys, iso-lys, D-iso-lys, beta-lys, D-beta-lys, homo-lys, D-homo-lys, beta-homo-lys, N-me-lys, N-me-homo-lys, Aib, D-Aib, Beta-Aib, D-Beta-Aib, Homo-Aib, D-Homo-Aib, Beta-Homo-Aib, N-Me-Aib, N-Me-Homo-Aib, Ala, D-Ala, Beta-Ala, D-Beta-Ala, Homo-Ala, D-Homo-Ala, Beta-Homo-Ala, N-Me-Ala, N-Me-Homo-Ala, Leu, D-Leu, Beta-Leu, D-Beta-Leu, Homo-Leu, D-Homo-Leu, Beta-Homo-Leu, N-Me-Leu, N-Me-Homo-Leu, 2-Me-Leu, Ile, D-Ile, Beta-Ile, D-Beta-Ile, Homo-Ile, D-Homo-Ile, Beta-Homo-Ile, N-Me-Ile, N-Me-Homo-Ile Furthermore, carbocyclic or heterocyclic rings having amino substituents and carbonyl substituents. Selected from the group consisting of, X11 is, Dpr, D-Dpr, iso-Dpr, D-iso-Dpr, beta-Dpr, D-beta-Dpr, homo-Dpr, D-homo-Dpr, beta-homo-Dpr, N-Me-Dpr, N-Me-homo-Dpr, Dab, D-Dab, iso-Dab, D-iso-Dab, beta-Dab, D-beta-Dab, homo-Dab, D-homo-Dab, beta-homo-Dab, N-Me-Dab, N-Me-homo-Dab, Orn, D-Orn, Iso-Orn, D-Iso-Orn, Beta-Orn, D-Beta-Orn, Homo-Orn, D-Homo-Orn, Beta-Homo-Orn, N-Me-Orn, N-Me-Homo-Orn, Lys, D-lys, iso-lys, D-iso-lys, beta-lys, D-beta-lys, homo-lys, D-homo-lys, beta-homo-lys, N-me-lys, N-me-homo-lys, Lys(Me), Lys (Gly), Asp, D-Asp, iso-Asp, D-iso-Asp, beta-Asp, D-beta-Asp, homo-Asp, D-homo-Asp, beta-homo-Asp, N-Me-Asp, N-Me-homo-Asp, Glu, D-Glu, iso-Glu, D-iso-Glu, beta-Glu, D-beta-Glu, homo-Glu, D-homo-Glu, beta-homo-Glu, N-Me-Glu, N-Me-homo-Glu, and 2-amino-6-carboxyhexanoyl Selected from the group consisting of, X12 may be a Phe residue, a Tyr residue, a His residue, an alanine residue substituted with a carbocyclic group or an aromatic or heteroaromatic group selected from the group consisting of phenyl, pyridyl, naphthyl, and quinolinyl, each of which may be substituted, Dab, D-Dab, iso-Dab, D-iso-Dab, beta-Dab, D-beta-Dab, homo -Dab, D-homo-Dab, Beta-homo-Dab, N-Me-Dab, N-Me-homo-Dab, Gly, Beta-Gly, Homo-Gly, Beta-homo-Gly, N-Me-Gly, N-Me-homo-Gly, Pro, 5-aminopentanoyl, 4-aminopiperidine-4-carbonyl, (R,S)-imidazolidined-2-carbonyl, 3-aminopropanoyl, Gly-CF3, D-Gly-C F3, Nle, Gln, D-Gln, iso-Gln, D-iso-Gln, Beta-Gln, D-beta-Gln, Homo-Gln, D-homo-Gln, Beta-homo-Gln, N-Me-Gln, N-Me-homo-Gln, THP, Ser, D-Ser, Beta-Ser, D-beta-Ser, Homo-Ser, D-homo-Ser, Beta-homo-Ser, N-Me-Ser, N-Me-homo-Ser, S er(OMe), 3-aminotetrahydrofuran-3-carbonyl, Arg, D-Arg, Beta-Arg, D-beta-Arg, Homo-Arg, D-homo-Arg, Beta-homo-Arg, N-Me-Arg, N-Me-homo-Arg, Thr, D-Thr, Beta-Thr, D-beta-Thr, Homo-Thr, D-homo-Thr, Beta-homo-Thr, N-Me-Thr, N-Me-homo-Thr Glu, D-Glu, Iso-Glu, D-Iso-Glu, Beta-Glu, D-Beta-Glu, Homo-Glu, D-Homo-Glu, Beta-Homo-Glu, N-Me-Glu, N-Me-Homo-Glu, Asn, D-Asn, Beta-Asn, D-Beta-Asn, Homo-Asn, D-Homo-Asn, Beta-Homo-Asn, N-Me-Asn, N-Me-Homo-Asn, 4-Aminobutanoyl, 2-(trimethyl-2-aminoethoxy)ethoxy]propyl, and Lys, wherein the side chain of Lys is -NH ２ is -C(=O)(CH ２ ) ｎ R Ｋ It is substituted with, where n is 0 to 2, and R Ｋ is selected from the group consisting of Lys, which may be imidazolyl, pyrimidyl, or pyridyl substituted with F, or X12 is absent. X13 is an optionally substituted His residue, an optionally substituted Phe residue, an alanine residue substituted with a carbocyclic group or an aromatic or heteroaromatic group selected from the group consisting of optionally substituted phenyl, pyridyl, naphthyl, and quinolinyl, Asn, D-Asn, Beta-Asn, D-Beta-Asn, Homo-Asn, D-Homo-Asn, Beta-Homo-Asn, N-Me-Asn, N-Me-Homo-Asn, Gly, Beta-Gly, Homo-Gly, Beta-Homo-Gly, N-Me-Gly, N-Me-Homo-Gly and Dab, Orn, or Lys, with side chain -NH ２ is C(=O)(CH ２ ) ｎ R Ｋ It is substituted with, where n is 0 to 2, and R Ｋ is selected from the group consisting of Dab, Orn, or Lys, which may be imidazolyl, pyrimidyl, or pyridyl substituted with F. or does not exist, In the array, (i) X2 and X11 are amino acid residues that together form a lactam crosslink, (ii) X2 and X7 are amino acid residues that together form a lactam crosslink or a crosslink containing a triazole ring, (iii) Optionally, if X13 is present, X10 and X13 are amino acid residues that together form a lactam crosslink. The aforementioned compound, or a pharmaceutically acceptable salt or solvate thereof.

2. X2 is Dab, D-Dab, Iso-Dab, Lys, Iso-Lys, D-Beta-Lys, N-Me-Lys, Homo-Lys, D-Lys, D-Homo-Lys, Beta-Lys, Beta-Homo-Lys, Lys(Gly), (N ３ )-Lys, D-(N ３ The compound according to claim 1, selected from the group consisting of )-Lys, D-iso-Glu, iso-Glu, Glu, Orn, D-Orn, Dpr, and Lys(Gly).

3. The compound according to claim 1 or 2, wherein X3 is selected from the group consisting of Thr, Ile, 3-aminopropanoyl, 4-aminobutanoyl, beta-homo-Ile, beta-homo-Thr, beta-homo-Trp, Gly, N-Me-3-aminopropanoyl, Ser, Trp, Phe, N-Me-Ser, N-Me-Ala, and 3-hydroxypropanoic acid, or is absent.

4. The compound according to any one of claims 1 to 3, wherein X4 is absent or is Val.

5. The compound according to any one of claims 1 to 4, wherein X5 is selected from the group consisting of Trp, 1-Me-Trp, 7-Aza-Trp, 7-Me-Trp, and beta-homo-Trp.

6. The compound according to any one of claims 1 to 5, wherein X6 is selected from the group consisting of Dab(Ac), Dab(Ac-N-Me), Gln, Gln(2Me), K(NMePEG3), and Gln(Me).

7. The compound according to any one of claims 1 to 6, wherein X7 is selected from the group consisting of Asp, D-Glu, Glu, Pra, Hpg, and Homo-Glu.

8. X8 is Y(2-aminoethoxy), Y(2-aminoethoxy)(N(Me)2), Y(npentylamine)(N ＋ (Me)3), Y(2-trimethyl-PEG2), homo-Phe, 7-AzaTrp, beta-homo-Trp, 7-F-Trp, F(4-morpholine), 3-quinolinylalanine, Y(Me), Y(nPr), Y(Bn), Trp, D-Phe, 2-Me-Phe, F(4-Me), F(4-Bu), 3-(2-pyridyl)-Ala, 3-(3-pyridyl)-Ala, 3-(4-pyridyl A compound according to any one of claims 1 to 7, selected from the group consisting of Lysyl)-Ala, Cyclopropyl-Ala, F(4-THP), Y(CH3-2-F), F(4-F), F(4-piperazine), F(4-imidazole), F(4-piperidine), Y(CH3-3-F), 5-AzaTrp, Y(Ac-2-aminoethoxy), 6-AzaTrp, and F(4-CONH2).

9. The compound according to any one of claims 1 to 8, wherein X9 is selected from the group consisting of 2Na and cyclopropyl-Ala.

10. The compound according to any one of claims 1 to 9, wherein X10 is selected from the group consisting of Dab, 2-Me-Leu, 2-Me-Val, Aib, D-Ala, Gly, and Lys.

11. The compound according to any one of claims 1 to 10, wherein X11 is selected from the group consisting of Dab, 2-amino-6-carboxyhexanoyl, beta-homo-Glu, Glu, homo-Glu, iso-Dab, Lys, Orn, and Lys(Me).

12. X12 is Dab, His, D-His, His(1-Me), 3-(2-pyridyl)-Ala, 3-(3-pyridyl)-Ala, 3-(4-pyridyl)-Ala, 3-(3-quinolinyl)-Ala, Gly, Pro, Ser(OCH3), 5-aminopentanoyl, 4-aminopiperidine-4-carbonyl, (R,S)-imidazolidin-2-carbonyl, and Lys, wherein the side chain of Lys is -NH ２ ga -C(=O)(CH ２ ) ｎ R Ｋ It is substituted with, and n is between 0 and 2, R Ｋ The compound according to any one of claims 1 to 11, wherein the compound is selected from the group consisting of Lys, which is imidazolyl, pyrimidyl, or pyridyl, which may be substituted with F, or X12 is absent.

13. The compound according to any one of claims 1 to 12, wherein X13 is selected from the group consisting of 3-(3-pyridyl)-Ala, D-3-(3-pyridyl)-Ala, and 3-(3,5-pyrimidyl)-Ala, or is absent.

14. Z-R ２ And in the formula, R ２ However, NHR ３ And R ３ However, C may be substituted with hydrogen or a pyridyl ring. １－６ The above NHR is alkyl ３ is or does not exist, Z is given by equation Ia: X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13 (Ia) This is the amino acid sequence, and in the sequence, X2 is Lys, D-Lys, iso-Lys, beta-Lys, D-beta-Lys, homo-Lys, D-homo-Lys, beta-homo-Lys, N-Me-Lys, Dab, D-Dab, Glu, iso-Glu, Orn, D-Orn, Lys(Gly), (N ３ )-Lys, and D-(N ３ Selected from the group consisting of )-Lys, X3 is selected from the group consisting of Thr, Trp, Ile, 3-aminopropanoyl, 4-aminobutanoyl, beta-homo-Ile, beta-homo-Thr, Gly, and N-Me-3-aminopropanoyl, 3-hydroxypropanoic acid, or is not present. X4 is either Val or does not exist. X5 is Trp or 1-Me-Trp, X6 is Gln, Gln(Me), Dab(Ac-N-Me), Dab(Ac), or Gln(2Me), X7 is selected from the group consisting of Glu, Homo-Glu, Asp, Pra, and Hpg. X8 is Y(2-aminoethoxy), Y(Me), Y(Bn), Y(2-aminoethoxy)(N(Me)2), Y(npentylamine)(N ＋ Selected from the group consisting of (Me)3), Y(2-trimethyl-PEG2), F(4-Me), F(4-Bu), cyclopropyl-Ala, F(4-morpholine), F(4-THP), Y(CH3-2-F), F(4-F), F(4-piperazine), F(4-imidazole), Y(CH3-3-F), F(4-piperidine), 5-AzaTrp, Y(Ac-2-aminoethoxy), 7-AzaTrp, 6-AzaTrp, and F(4-CONH2), X9 is 2-Nal, X10 is selected from the group consisting of 2-Me-Leu, 2-Me-Val, D-Ala, Dab, Gly, and Aib. X11 is selected from the group consisting of Glu, homo-Glu, Lys, Lys(Me), Orn, and 2-amino-6-carboxyhexanoyl. X12 is selected from the group consisting of Dab, His, S(OCH3), D-His, His(1-Me), 3-(3-quinolinyl)-Ala, and 4-aminopiperidine-4-carbonyl. X13 is either 3-(3-pyridyl)-Ala, 3-(3,5-pyrimidyl)-Ala, or absent. In the array, (i) X2 and X11 are amino acid residues that together form a lactam crosslink, (ii) X2 and X7 are amino acid residues that together form a lactam crosslink or a crosslink containing a triazole ring, (iii) Optionally, if X13 is present, X10 and X13 are amino acid residues that together form a lactam crosslink. A compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt or solvate thereof.

15. The compound according to any one of claims 1 to 14, wherein the side chain of the amino acid residue of X2 is used for the lactam crosslink between X2 and X11, and the N-terminus of the amino acid residue of X2 is used for the crosslink between X2 and X7.

16. X2 is Lys, Optionally, X3 may be selected from the group consisting of Thr, Ile, and 3-aminopropanoyl, or it may not exist. If X4 is not available as an optional choice, The compound according to any one of claims 1 to 15.

17. X5 is Trp, Optionally, X7 is Glu. Optionally, X8 is Y(2-aminoethoxy), Y(Me), or F(4-Me), and optionally, X8 is Y(2-aminoethoxy). The compound according to any one of claims 1 to 16.

18. X9 is 2-Na, Optionally, X10 is 2-Me-Leu or 2-Me-Val, and optionally, X10 is 2-Me-Leu, Optionally, X11 is Glu. The compound according to any one of claims 1 to 17.

19. X12 is Dab, Optionally, X13 is either 3-(3-pyridyl)-Ala or absent, and optionally, X13 is 3-(3-pyridyl)-Ala. The compound according to any one of claims 1 to 18.

20. R ２ However, NHR ３ And in the formula R ３ is hydrogen or C １－６ It is alkyl, and R is optional. ２ NH ２ The compound according to any one of claims 1 to 19, or NHMe.

21. X2 is Lys, X5 is Trp, X9 is 2-Nal, and X10 is 2-Me-Leu, or X2 is Lys, X5 is Trp, X9 is 2-Nal, X10 is 2-Me-Leu, and R ２ NH ２ Or it is NHMe, or X2 is Lys, X5 is Trp, X9 is 2-Nal, X10 is 2-Me-Leu, X13 is 3-(3-pyridyl)-Ala or is absent, and R ２ NH ２ Or it is NHMe, or X2 is Lys, X5 is Trp, X7 is Glu, X9 is 2-Nal, X10 is 2-Me-Leu, X13 is 3-(3-pyridyl)-Ala or does not exist, and R ２ is NH ２ or NHMe, The compound according to any one of claims 1 to 20.

22. Z is Table 31 An amino acid sequence selected from the group consisting of the following: In the array, † The crosslinking of (1c), (6c), (6g), and (7c) is the alpha-amine group of the amino acid (or the beta-amine group in the case of bLys, {d}bLys, and beta-hLys, or (N ３ )-K and {d}(N ３ )-K indicates that an alpha-amine converted to an azide group is used for the crosslinking. ‡ This indicates that the crosslinks in (1c), (6c), (6g), and (7c) use the alpha-carboxylic acid group of an amino acid for the crosslinking. (1c) represents a [2,11] lactam crosslink, (6c) represents a [2,7] lactam crosslink, (6g) represents a [2,7] 1,4-disubstituted 1,2,3-triazole crosslink, and (7c) represents a [10,13] lactam crosslink. The compound according to claim 1. 【Request Item 23】 【Table 32】 Selected from, In the array, † indicates that the crosslinks of (1c), (6c), (6g), and (7c) use the alpha - amine group of the amino acid (or, in the case of bLys, {d}bLys, and beta - hLys, the beta - amine group, or the alpha - amine ３ converted to an azide group in the case of (N ３ ) - K and {d}(N ) - K) for said crosslink, ‡ This indicates that the crosslinks in (1c), (6c), (6g), and (7c) use the alpha-carboxylic acid group of an amino acid for the crosslinking. (1c) represents a [2,11] lactam crosslink, (6c) represents a [2,7] lactam crosslink, (6g) represents a [2,7] 1,4-disubstituted 1,2,3-triazole crosslink, and (7c) represents a [10,13] lactam crosslink. The compound described in claim 1, or a pharmaceutically acceptable salt or solvate thereof.

24. A pharmaceutical composition comprising a compound according to any one of claims 1 to 23 in combination with a pharmaceutically acceptable carrier, excipient, or medium.

25. The pharmaceutical composition according to claim 24, for oral administration.

26. A method for synthesizing a compound according to any one of claims 1 to 23, comprising the steps of synthesizing an analog by solid-phase or liquid-phase peptide synthesis, optionally isolating and / or purifying the final product, further comprising optionally forming an amide bond between amino acid residues at positions X2 and X11, optionally forming an amide bond between amino acid residues at positions X2 and X7 or forming a triazole, and optionally forming an amide bond between amino acid residues at positions X10 and X13.

27. A compound according to any one of claims 1 to 23 or a pharmaceutical composition according to claim 24 or 25 for use in a method of medical treatment.

28. A compound according to any one of claims 1 to 23 or a pharmaceutical composition according to claim 24 or 25 for use in a method for preventing or treating a disease or condition selected from inflammatory bowel disease (IBD), psoriasis, psoriatic arthritis, and combinations thereof.

29. A compound or pharmaceutical composition for use according to claim 28, wherein IBD is selected from Crohn's disease or ulcerative colitis.

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