Interleukin-23 receptor peptide inhibitors

Abstract

This 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, psoriasis, and psoriatic arthritis. 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) 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. 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).

[0008] Notably, the peptides disclosed in Protagonist's 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.

[0009] 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.

[0010] 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.

[0011] 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.

[0012] Identifying stable and selective agonists that preferentially target the IL-23 pathway and can be used to treat intestinal inflammation remains challenging. In particular, we identified that the gastrointestinal stability and IL-23R potency 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).

[0013] 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.

[0014] 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]

[0015] [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]

[0016] [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 [Overview of the Initiative]

Problems to be Solved by the Invention

[0017] 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, including inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, psoriasis, and psoriatic arthritis. The compounds described herein exhibit improved properties compared to the compounds disclosed in International Publication No. 2023 / 099669 pamphlet.

[0018] The present invention addresses such a need by providing a novel peptide inhibitor that binds to IL-23R and inhibits IL-23-mediated signaling. The novel peptide inhibitor is stable in the gastrointestinal tract and thus suitable for oral administration.

Means for Solving the Problems

[0019] 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 1-4 alkyl optionally substituted with a pyridyl ring, Z is an amino acid sequence of formula I: X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14 (I) wherein, X1 is absent or selected from 3-(3-pyridyl)-Ala or 3-aminopropanoyl, X2 is an alanine residue substituted with a carbocyclic group or an aromatic or heteroaromatic group selected from the group consisting of 4-aminomethylphenylacetyl, phenyl, pyridyl, naphthyl, and quinolinyl, each of which may be substituted, 3-aminopropanoyl, 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 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 (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, X3 is any amino acid or ω-hydroxy-C 2-6 Selected from alkanates, X4 is 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, 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, 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 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, Cys, D-Cys, Beta-Cys, D-Beta-Cys, Homo-Cys, D-Homo-Cys, Beta-Homo-Cys, N-Me-Cys, and N-Me-Homo-Cys Selected from, 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 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, 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, 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 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, Cys, D-Cys, Beta-Cys, D-Beta-Cys, Homo-Cys, D-Homo-Cys, Beta-Homo-Cys, N-Me-Cys, and N-Me-Homo-Cys Selected from, 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 an optionally substituted carbocyclic or aromatic group selected from the group consisting of optionally substituted phenyl, pyridyl, naphthyl, and quinolinyl. X9 is selected from the group consisting of an optional tryptophan residue, an optional azatryptophan residue, an optional beta-homotryptophan 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, 2-Me-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), LAsp, 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 group, an optional Tyr residue, an optional His residue, a carbocyclic group or 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-CF3, 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, 2-Me-Ser, N-Me-Homo-Ser, Ser (OMe), 3-aminotetrahydrofuran-3-carbonyl, THP, 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, GABA, 2-(trimethyl-2-aminoethoxy)ethoxypropyl]propyl, and Lys, wherein 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 Lys is an imidazolyl, pyrimidyl, or pyridyl which may be substituted with F. Selected from the group consisting of, 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, wherein 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 is not present. X14 is either absent or selected from the group consisting of alanine residues substituted with a carbocyclic group or an aromatic or heteroaromatic group selected from the group consisting of Sar, optionally substituted His residues, 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, and optionally substituted phenyl, pyridyl, naphthyl, and quinolinyl, respectively. In the array, (i) The amino acid residue of X11 forms a lactam crosslink with the amino acid residue of X1, or if X1 is absent, with the amino acid residue of X2. (ii) X4 and X7 are amino acid residues that together form a lactam crosslink or a dithioether crosslink. compound, or a pharmaceutically acceptable salt or solvate thereof, The compound is [Table 1] JPEG2026518788000002.jpg251170 JPEG2026518788000003.jpg243170 JPEG2026518788000004.jpg241170 JPEG2026518788000005.jpg55170 and its pharmaceutically acceptable salts and solvates, In the table, * 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. (1c) represents a [2,11] lactam bridge, (2a) represents a [4,7] 1,3-dithio-propane-2-one bridge, and (2c) represents a [4,7] lactam bridge. The present invention provides compounds, or pharmaceutically acceptable salts or solvates thereof.

[0020] The above reference compound was disclosed in International Publication No. 2023 / 099669.

[0021] In a second aspect, 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. 1-4 It is alkyl, Z is given by equation I: X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14 (I) This is the amino acid sequence, and in the sequence, X1 is either absent or selected from 3-(3-pyridyl)-Ala or 3-aminopropanoyl. X2 is selected from the group consisting of 4-aminomethylphenylacetyl, 3-(3-pyridyl)-Ala, and 3-aminopropanoyl. X3 is selected from the group consisting of Ser, Ala, Phe, and N-Me-Ser. X4 is either Glu or Cys. X5 is a trumpet, X6 is selected from the group consisting of Gln, Q(Me), Q(2Me), Q(pyrrolidine), Ala, Phe, Lys(Ac), Dab(Ac), Cit, and Orn. X7 is either Dab or Cys. X8 is selected from the group consisting of Y(2-aminoethoxy), homo-Phe, 7-AzaTrp, beta-homo-Trp, and 7-F-Trp. X9 is selected from the group consisting of 2-Nal, 7-AzaTrp, beta-homo-Trp, and cyclopropyl-Ala. X10 is 2-Me-Leu or Aib, X11 is Glu, X12 is selected from the group consisting of Dab, iso-Dab, D-Arg, Gly-CF3, D-Gly-CF3, Nle, Gln, His, THP, Ser, D-Ser, 2-Me-Ser, Ser(OMe), and homo-Ser. X13 is selected from the group consisting of 3-(3-pyridyl)-Ala, D-3-(3-pyridyl)-Ala, 2-Me-3-(3-pyridyl)-Ala, N-Me-3-(3-pyridyl)-Ala, 3-(3,5-pyrimidyl)-Ala, His, D-His, and His(Me), or is not present. X14 is either absent or selected from the group consisting of Sar, D-His, beta-homo-Leu, and 3-(3-pyridyl)-Ala. In the array, (i) The Glu of X11 forms a lactam crosslink with the amino acid residue of X1, or if X1 is not present, the amino acid residue of X2. (ii) X4 and X7 are amino acid residues that together form a lactam crosslink or a dithioether crosslink. compound, Or provide a pharmaceutically acceptable salt or solvate thereof.

[0022] In some embodiments, the compound is [Table 2] Furthermore, rather than its pharmaceutically acceptable salts and solvates, In the table, * This indicates that the crosslinking in (1c), (2a), and (2c) uses the amine or carboxylic acid of the N-terminal or C-terminal peptide backbone, rather than the amine or carboxylic acid of the side chain. (1c) represents a [2,11] lactam bridge, (2a) represents a [4,7] 1,3-dithio-propane-2-one bridge, and (2c) represents a [4,7] lactam bridge.

[0023] Reference compounds Ref80, Ref81, Ref82, Ref120, Ref122, Ref125, Ref141, and Ref146 were disclosed in International Publication Brochure No. 2023 / 099669.

[0024] This invention does not relate to any compounds disclosed in International Publication No. 2023 / 099669.

[0025] In some embodiments, the compound is such that X1 is absent, X2 is 4-aminomethylphenylacetyl, X3 is Ser or N-Me-Ser, X6 is Gln or Q (pyrrolidine), X8 is Y (2-aminoethoxy), X9 is 2-Nal, X10 is 2-Me-Leu, X12 is Dab, D-Arg, or Ser, X13 is 3-(3-pyridyl)-Ala or absent, X14 is absent, and R 2 This is not the case where it is NH2.

[0026] In some embodiments, X1 is absent.

[0027] In some embodiments, X2 is 4-aminomethylphenylacetyl.

[0028] In some embodiments, X3 is Ser or Ala.

[0029] In some embodiments, X4 is Glu and X7 is Dab, and X4 and X7 together form a lactam crosslink.

[0030] In some embodiments, X6 is Gln.

[0031] In some embodiments, X8 is Y(2-aminoethoxy).

[0032] In some embodiments, X9 is 2-Nal.

[0033] In some embodiments, X10 is 2-Me-Leu.

[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, X14 is absent.

[0037] In some embodiments, R 2 NHR 3 And R 3 is hydrogen or C 1-4 It is alkyl. In some embodiments, R 2 is NH2. In some other embodiments, R 2 It is NHMe.

[0038] In some embodiments, both X4 and X7 are Cys, and together X4 and X7 form a dithioether crosslink, and the dithioether crosslink between X4 and X7 has the formula -SLYLS-, where, Each S is a sulfur atom and is part of the amino acid residues of X4 and X7. Each L is independently C 1-4 It is alkylene, Y either does not exist or is C (=O).

[0039] In some embodiments, L is independently C 1-2 It is an alkylene. In some embodiments, L is methylene. In some embodiments, Y is C (=O).

[0040] In some embodiments, the dithioether bridge between X4 and X7 is of the formula -SCH2C(=O)CH2S-, where each S is a sulfur atom and part of the amino acid residues of X4 and X7.

[0041] In some embodiments, X1 is absent, and X2 is 4-aminomethylphenylacetyl.

[0042] In some embodiments, X1 is absent, X2 is 4-aminomethylphenylacetyl, X8 is Y(2-aminoethoxy), X9 is 2-Nal, and X10 is 2-Me-Leu.

[0043] In some embodiments, X1 is absent, X2 is 4-aminomethylphenylacetyl, X3 is Ser or Ala, X8 is Y(2-aminoethoxy), X9 is 2-Nal, and X10 is 2-Me-Leu.

[0044] In some embodiments, X1 is absent, X2 is 4-aminomethylphenylacetyl, X3 is Ser or Ala, X6 is Gln, X8 is Y(2-aminoethoxy), X9 is 2-Nal, and X10 is 2-Me-Leu.

[0045] In some embodiments, X13 is 3-(3-pyridyl)-Ala, and X14 is absent.

[0046] In some embodiments, X13 is 3-(3-pyridyl)-Ala, X14 is absent, and R 2 It is NHMe.

[0047] In some embodiments, Z is an amino acid sequence selected from the group consisting of sequences listed in Table 1-1a.

[0048] In some embodiments, the compound is selected from the compounds listed in Table 1-1, or from pharmaceutically acceptable salts or solvates thereof.

[0049] 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.

[0050] 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 optionally the steps of forming an amide bond between amino acid residues at position X1, or, if X1 is absent, at positions X2 and X11, and optionally the steps of forming an amide bond between amino acid residues at positions X4 and X7 or forming two thioether bonds having a linker.

[0051] The present invention further provides the compound of the present invention, or a pharmaceutical composition containing the compound, for use in medical treatment methods.

[0052] 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.

[0053] 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.

[0054] 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.

[0055] Further aspects and embodiments of the present invention will become apparent from the following disclosure. [Modes for carrying out the invention]

[0056] 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.

[0057] 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.

[0058] 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.

[0059] The singular forms "a," "an," and "the" include the plural unless the context is clearly different.

[0060] The term "including" is used to mean "including but not limited to." "Including" and "including but not limited to" are used synonymously.

[0061] 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).

[0062] 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 2-6 Examples 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).

[0063] 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.

[0064] As used in the context of this invention, the terms “antagonist” and “inhibitor” typically refer to a substance that inhibits a receptor type in question by binding to (i.e., acting as a ligand for) that receptor type and blocking it.

[0065] 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.

[0066] 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.

[0067] 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.

[0068] 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.

[0069] 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.

[0070] 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)-.

[0071] 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 having amine and carboxylic acid functional groups. The carbonyl group of the carboxylic acid may be further functionalized, for example, by being converted to -CF3 in Gly-CF3 and D-Gly-CF3. This further functionalization may occur before, during, or after peptide coupling with other amino acid residues in the peptide chain.

[0072] 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-homo-Trp and beta-homo-Leu, the amine group and carboxylic acid group are separated by only one carbon atom, and the carbon atom attached to the amine group and the carbon atom attached to the carboxylic acid group are adjacent to each other.

[0073] Some of the amino acids described herein have side chains specific to each amino acid. Furthermore, these side chains may be further functionalized.

[0074] 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.

[0075] 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.

[0076] 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.

[0077] 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.

[0078] 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).

[0079] Examples of abbreviations for additional amino acid residues are listed in Table A. [Table 3] JPEG2026518788000008.jpg247170 JPEG2026518788000009.jpg233170 JPEG2026518788000010.jpg245170 JPEG2026518788000011.jpg245170 JPEG2026518788000012.jpg217170

[0080] 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-, and N-Me analogs (and combinations thereof) of the amino acid residues disclosed herein. In particular, Table A1 outlines the relevant analogs of the lysine amino acid, which can then be applied to derive the corresponding structures of all equivalent amino acid analogs disclosed herein. [Table 4]

[0081] Linear peptides are described from left to right, from the N-terminus to the C-terminus.

[0082] 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.

[0083] Unless otherwise specified, the peptide backbone (i.e., the amide bonds "-" between X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14 in 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, 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 in 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 and carboxylic acid residues that form the amide backbone of the peptide chain.

[0084] 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), the peptide backbone may instead be formed using the side chains of the amino acid residue.

[0085] For example, the following nomenclature in Table B is used to distinguish between the use of terminal and side-chain -NH2 and -COOH groups. [Table 5]

[0086] 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.

[0087] 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 6]

[0088] In the case of the NH-(4-(pyridin-3-yl)butanyl) group and the NH-(2-(pyridin-3-yl)ethyl) group, these are bonded to the carbonyl carbon of the carboxylic acid group of the C-terminal amino acid residue, such as Dab. An amide bond is formed by this bonding.

[0089] Lactam A lactam is a cyclic amide of the formula cyclo(R-NH-C(=O)-R), where each R may be any other suitable functional group bonded to the other R. Each R may be the same or different.

[0090] Thioether and dithioether A thioether is a functional group of the formula R-S-R, 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 R-S-L-Y-L-S-R where the linker is -L-Y-L-.

[0091] Head-to-tail cyclization The term "head-to-tail cyclization" means that the N-terminal amine (or its derivative) and the C-terminal carboxylic acid cyclize to form a cyclic peptide. Typically, an amide bond is formed by this cyclization.

[0092] 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.

[0093] C 1-4 alkyl group In the context of the compounds of the present invention, the group R 2 may exist as a C 1-4 alkyl group, including but not limited to, a C4 alkyl group such as butyl (n-Bu or -CH2CH2CH2CH3), or a C1 alkyl group such as methyl (Me or -CH3), a C2 alkyl group such as ethyl (-CH2CH3), a C3 alkyl group such as 1-propyl (-CH2CH2CH3) or 2-propyl (-CH(CH3)2). 1-3 Examples of the alkyl group include these.

[0094] C 1-3 alkyl group In the context of the compounds of the present invention, the group R 2 may exist as a C 1-3 alkyl group, including methyl (Me or -CH3, i.e., a C1 alkyl group), ethyl (-CH2CH3, i.e., a C2 alkyl group), 1-propyl (-CH2CH2CH3, i.e., a C3 alkyl group), and 2-propyl (-CH(CH3)2, i.e., a C3 alkyl group).

[0095] C 1-2 alkyl group In the context of the compounds of the present invention, the group R 2 may exist as a C 1-2 alkyl group, including methyl (Me or -CH3, i.e., a C1 alkyl group) and ethyl (-CH2CH3, i.e., a C2 alkyl group).

[0096] ω-hydroxy-C 2-6 alkanoic acid In this specification, the residue at the X3 position may be ω-hydroxy-C 2-6 alkanoic acid. This residue has the following structure:

Chemical formula

[0097] 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.

[0098] 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).

[0099] In one embodiment, alkylene is C 1-20It is an alkylene. In one embodiment, the alkylene is C 2-14 It is an alkylene. In one embodiment, the alkylene is C 3-9 It is an alkylene. In one embodiment, the alkylene is C 7-9 It is alkylene.

[0100] A straight-chain alkylene moiety having at least three carbon atoms and free valence at each end can also be designated as a multiple of methylene (for example, 1,4-butylene may also be called tetramethylene). In general, instead of using the suffix "ylene" for the alkylene moiety designated above, the suffix "diyl" can also be used (for example, 1,2-butylene may also be called butane-1,2-diyl). A "substituted alkylene" means that one or more hydrogen atoms of the alkylene group (for example, from one to the maximum number of hydrogen atoms bonded to the alkylene 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 substituent other than hydrogen (if 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 substituents selected from List A, for example, one, two, or three substituents, for example, one or two, for example, one substituent.

[0101] C 1-4 Alkylene group In the context of the compounds of the present invention, C may exist as the dithioether crosslinking group L. 1-4 The alkylene group is not limited to these, but also includes C1 alkylene groups such as methylene (-CH2-, i.e., a C1 alkylene group) and ethylene (-CH2CH2-, i.e., a C2 alkylene group). 1-2 An example is the alkylene group.

[0102] Alkylene oxy The term "alkylene oxy" means "alkylene-O-", where alkylene is defined and illustrated above. In one embodiment, alkylene oxy 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).

[0103] Carbocyclic and heterocyclic groups - cycloalkyl, heterocyclyl The terms "cycloalkyl" or "carbocyclic ring" preferably refer to a cyclic non-aromatic "alkyl" 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. A cycloalkyl 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 a 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 group 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 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 the partially or completely hydrogenated forms (dihydro, tetrahydro, or perhydro forms, etc.) of the heteroaryl groups mentioned below. 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.

[0105] Aromatic groups - aryl, heteroaryl The terms "aryl" or "aromatic ring" refer to monoradicals of aromatic cyclic hydrocarbons. Preferably, an 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).

[0106] 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.

[0107] 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.

[0108] 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', -X1 C(=X 1 )R’, and -X 1 C(=X 1 )X 1 selected from the group consisting of R’, where X 1 is independently selected from O, S, NH, and N(CH3), and each R’ is H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 5- or 6-membered cycloalkyl, 5- or 6-membered aryl, 5- or 6-membered heteroaryl, and 5- or 6-membered heterocyclyl, independently selected from the group consisting of, where each alkyl group, alkenyl group, alkynyl group, cycloalkyl group, aryl group, heteroaryl group, and heterocyclyl group is C 1-3 alkyl, 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 and 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 is independently methyl, ethyl, or propyl.

[0109] In some embodiments, the List A substituent is C 1-3 alkyl, phenyl, halogen, -CF3, -OH, -OCH3, -SCH3, -NH 2-z (CH3) z , -C(=O)OH, C(=O)OCH3, and -C(=O)CH3, where z is 0, 1, or 2, and C 1-3 alkyl is methyl, ethyl, propyl, or isopropyl.

[0110] In some embodiments, the List A substituent is selected from List A2 consisting of C(=O)CH3, methyl, ethyl, propyl, isopropyl, halogen (such as F, Cl, or Br, etc.), and -CF3.

[0111] Crosslinking portion The sequences disclosed herein include the crosslinking portions indicated within parentheses (e.g., (1a), (2a), etc.). These represent chemical crosslinks between specific residue pairs. Each pair of parentheses will occur twice as a pair within the sequence to indicate a single crosslinking portion. Most sequences have two crosslinking portions indicated by four sets of parentheses meaning two pairs of crosslinking portions.

[0112] The numbers within the parentheses indicate specific pairs of crosslinking portions (e.g., "1" indicates a crosslink between the amino acid residues at positions 2 and 11 and is also indicated by the bracket notation that defines the specific chemical crosslink). The letters indicate the type of chemical crosslink (e.g., "a" indicates a 1,3 - dithio - propane - 2 - one crosslink).

[0113] Specific chemical crosslinks are defined using brackets at the end of the table (e.g., [2,11], [4,7], etc.), showing the amino acid residues used for the crosslinking portion compared to the original starting peptide (the I3 peptide (isomer 3) described in Example 2 of WO 2023 / 099669 pamphlet). Therefore, these may not exactly match the actual amino acid numbers of the sequence numbers (e.g., in some parts of such sequences, the first amino acid residue is deleted compared to the original starting peptide).

[0114] The residue immediately preceding the parenthetical notation indicates that a specific residue is used in the cross-linking portion.

[0115] 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 a crosslink.

[0116] 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.

[0117] 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.

[0118] 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. 1-4 It is alkyl, Z is given by equation I: X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14 (I) This is the amino acid sequence, and in the sequence, X1 is either absent or selected from 3-(3-pyridyl)-Ala or 3-aminopropanoyl. X2 is an alanine residue substituted with a carbocyclic group or an aromatic or heteroaromatic group selected from the group consisting of 4-aminomethylphenylacetyl, phenyl, pyridyl, naphthyl, and quinolinyl, each of which may be substituted, 3-aminopropanoyl, 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 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 (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, X3 is any amino acid or ω-hydroxy-C 2-6 Selected from alkanates, X4 is 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, 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, 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 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, 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, Cys, D-Cys, Beta-Cys, D-Beta-Cys, Homo-Cys, D-Homo-Cys, Beta-Homo-Cys, N-Me-Cys, and N-Me-Homo-Cys Selected from, 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 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, 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, 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 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, 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, Cys, D-Cys, Beta-Cys, D-Beta-Cys, Homo-Cys, D-Homo-Cys, Beta-Homo-Cys, N-Me-Cys, and N-Me-Homo-Cys Selected from, 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 an optionally substituted carbocyclic or aromatic group selected from the group consisting of optionally substituted phenyl, pyridyl, naphthyl, and quinolinyl. X9 is selected from the group consisting of an optional tryptophan residue, an optional azatryptophan residue, an optional beta-homotryptophan 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, 2-Me-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 group, an optional Tyr residue, an optional His residue, a carbocyclic group or 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-CF3, 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, 2-Me-Ser, N-Me-Homo-Ser, Ser (OMe), 3-aminotetrahydrofuran-3-carbonyl, THP, 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, GABA, 2-(trimethyl-2-aminoethoxy)ethoxypropyl]propyl, and Lys, wherein 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 Lys is an imidazolyl, pyrimidyl, or pyridyl which may be substituted with F. Selected from the group consisting of, 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, wherein 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, X14 is either absent or selected from the group consisting of alanine residues substituted with a carbocyclic group or an aromatic or heteroaromatic group selected from the group consisting of Sar, optionally substituted His residues, 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, and optionally substituted phenyl, pyridyl, naphthyl, and quinolinyl, respectively. In the array, (i) The amino acid residue of X11 forms a lactam crosslink with the amino acid residue of X1, or if X1 is absent, with the amino acid residue of X2. (ii) X4 and X7 are amino acid residues that together form a lactam crosslink or a dithioether crosslink. compound, or a pharmaceutically acceptable salt or solvate thereof, The compound is [Table 7] JPEG2026518788000018.jpg250170 JPEG2026518788000019.jpg242170 JPEG2026518788000020.jpg251170 JPEG2026518788000021.jpg37170 and its pharmaceutically acceptable salts and solvates, In the table, * This indicates that the crosslinking in (1c), (2a), and (2c) uses the amine or carboxylic acid of the N-terminal or C-terminal peptide backbone, rather than the amine or carboxylic acid of the side chain. (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.

[0119] The above reference compound was disclosed in International Publication No. 2023 / 099669.

[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 3 C may be substituted with hydrogen or a pyridyl ring. 1-4 It is alkyl, Z is given by equation I: X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14 (I) This is the amino acid sequence, and in the sequence, X1 is either absent or selected from 3-(3-pyridyl)-Ala or 3-aminopropanoyl. X2 is selected from the group consisting of 4-aminomethylphenylacetyl, 3-(3-pyridyl)-Ala, and 3-aminopropanoyl. X3 is selected from the group consisting of Ser, Ala, Phe, and N-Me-Ser. X4 is either Glu or Cys. X5 is a trumpet, X6 is selected from the group consisting of Gln, Q(Me), Q(2Me), Q(pyrrolidine), Ala, Phe, Lys(Ac), Dab(Ac), Cit, and Orn. X7 is either Dab or Cys. X8 is selected from the group consisting of Y(2-aminoethoxy), homo-Phe, 7-AzaTrp, beta-homo-Trp, and 7-F-Trp. X9 is selected from the group consisting of 2-Nal, 7-AzaTrp, beta-homo-Trp, and cyclopropyl-Ala. X10 is 2-Me-Leu or Aib, X11 is Glu, X12 is selected from the group consisting of Dab, iso-Dab, D-Arg, Gly-CF3, D-Gly-CF3, Nle, Gln, His, THP, Ser, D-Ser, 2-Me-Ser, Ser(OMe), and homo-Ser. X13 is selected from the group consisting of 3-(3-pyridyl)-Ala, D-3-(3-pyridyl)-Ala, 2-Me-3-(3-pyridyl)-Ala, N-Me-3-(3-pyridyl)-Ala, 3-(3,5-pyrimidyl)-Ala, His, D-His, and His(Me), or is not present. X14 is either absent or selected from the group consisting of Sar, D-His, beta-homo-Leu, and 3-(3-pyridyl)-Ala. In the array, (i) The Glu of X11 forms a lactam crosslink with the amino acid residue of X1, or if X1 is not present, the amino acid residue of X2. (ii) X4 and X7 are amino acid residues that together form a lactam crosslink or a dithioether crosslink. compound, Or provide a pharmaceutically acceptable salt or solvate thereof.

[0121] In all embodiments, the compound of the present invention is [Table 8] Furthermore, rather than its pharmaceutically acceptable salts and solvates, In the table, * This indicates that the crosslinking in (1c), (2a), and (2c) uses the amine or carboxylic acid of the N-terminal or C-terminal peptide backbone, rather than the amine or carboxylic acid of the side chain. (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.

[0122] Reference compounds Ref80, Ref81, Ref82, Ref120, Ref122, Ref125, Ref141, and Ref146 were disclosed in International Publication Brochure No. 2023 / 099669.

[0123] This invention does not relate to any compounds disclosed in International Publication No. 2023 / 099669.

[0124] In some embodiments, the compound is such that X1 is absent, X2 is 4-aminomethylphenylacetyl, X3 is Ser or N-Me-Ser, X6 is Gln or Q (pyrrolidine), X8 is Y (2-aminoethoxy), X9 is 2-Nal, X10 is 2-Me-Leu, X12 is Dab, D-Arg, or Ser, X13 is 3-(3-pyridyl)-Ala or absent, X14 is absent, and R 2 This is not the case where it is NH2.

[0125] 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. 1-4 It is alkyl, Z is given by equation II: X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14 (II) This is the amino acid sequence, and in the sequence, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, X13, and X14 are as defined in formula I, In the array, (i) The Glu of X11 forms a lactam crosslink with the amino acid residue of X2, (ii) X4 and X7 are amino acid residues that together form a lactam crosslink or a dithioether crosslink. compound, Or provide a pharmaceutically acceptable salt or solvate thereof.

[0126] 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. 1-4 It is alkyl, Z is given by equation III: X1-[4-aminomethylphenylacetyl]-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14 (III) This is the amino acid sequence, and in the sequence, X1, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, X13, and X14 are as defined in formula I, In the array, (i) The Glu of X11 forms a lactam crosslink with the amino acid residue of X1, or, if X1 is absent, with the 4-aminomethyl-phenylacetyl residue of X2. (ii) X4 and X7 are amino acid residues that together form a lactam crosslink or a dithioether 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. 1-4 It is alkyl, Z is given by equation IV: X1-X2-[Ser]-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14 (IV) This is the amino acid sequence, and in the sequence, X1, X2, X4, X5, X6, X7, X8, X9, X10, X11, X12, X13, and X14 are as defined in formula I, In the array, (i) The Glu of X11 forms a lactam crosslink with the amino acid residue of X1, or if X1 is not present, the amino acid residue of X2. (ii) X4 and X7 are amino acid residues that together form a lactam crosslink or a dithioether crosslink. 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 And R 3 C may be substituted with hydrogen or a pyridyl ring.1-4 It is alkyl, Z is given by equation V: X1-X2-X3-[Glu]-X5-X6-[Dab]-X8-X9-X10-X11-X12-X13-X14 (V) This is the amino acid sequence, and in the sequence, X1, X2, X3, X5, X6, X8, X9, X10, X11, X12, X13, and X14 are as defined in formula I, In the array, (i) The Glu of X11 forms a lactam crosslink with the amino acid residue of X1, or if X1 is not present, the amino acid residue of X2. (ii) Glu of X4 and Dab of X7 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 3 And R 3 C may be substituted with hydrogen or a pyridyl ring. 1-4 It is alkyl, Z is given by equation VI: X1-X2-X3-X4-X5-[Gln]-X7-X8-X9-X10-X11-X12-X13-X14 (VI) This is the amino acid sequence, and in the sequence, X1, X2, X3, X4, X5, X7, X8, X9, X10, X11, X12, X13, and X14 are as defined in formula I, In the array, (i) The Glu of X11 forms a lactam crosslink with the amino acid residue of X1, or if X1 is not present, the amino acid residue of X2. (ii) X4 and X7 are amino acid residues that together form a lactam crosslink or a dithioether crosslink. 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 And R 3 C may be substituted with hydrogen or a pyridyl ring. 1-4 It is alkyl, Z is given by equation VII: X1-X2-X3-X4-X5-X6-X7-[Y(2-aminoethoxy)]-X9-X10-X11-X12-X13-X14 (VII) This is the amino acid sequence, and in the sequence, X1, X2, X3, X4, X5, X6, X7, X9, X10, X11, X12, X13, and X14 are as defined in formula I, In the array, (i) The Glu of X11 forms a lactam crosslink with the amino acid residue of X1, or if X1 is not present, the amino acid residue of X2. (ii) X4 and X7 are amino acid residues that together form a lactam crosslink or a dithioether 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. 1-4 It is alkyl, Z is given by equation VIII: X1-X2-X3-X4-X5-X6-X7-X8-[2-Nal]-X10-X11-X12-X13-X14 (VIII) This is the amino acid sequence, and in the sequence, X1, X2, X3, X4, X5, X6, X7, X8, X10, X11, X12, X13, and X14 are as defined in formula I, In the array, (i) The Glu of X11 forms a lactam crosslink with the amino acid residue of X1, or if X1 is not present, the amino acid residue of X2. (ii) X4 and X7 are amino acid residues that together form a lactam crosslink or a dithioether crosslink. 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 And R 3 C may be substituted with hydrogen or a pyridyl ring. 1-4 It is alkyl, Z is given by equation IX: X1-X2-X3-X4-X5-X6-X7-X8-X9-[2-Me-Leu]-X11-X12-X13-X14 (IX) This is the amino acid sequence, and in the sequence, X1, X2, X3, X4, X5, X6, X7, X8, X9, X11, X12, X13, and X14 are as defined in formula I, In the array, (i) The Glu of X11 forms a lactam crosslink with the amino acid residue of X1, or if X1 is not present, the amino acid residue of X2. (ii) X4 and X7 are amino acid residues that together form a lactam crosslink or a dithioether 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, R2 NHR 3 And R 3 C may be substituted with hydrogen or a pyridyl ring. 1-4 It is alkyl, Z is given by equation X: X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-[Dab]-X13-X14 (X) This is the amino acid sequence, and in the sequence, X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X13, and X14 are as defined in formula I, In the array, (i) The Glu of X11 forms a lactam crosslink with the amino acid residue of X1, or if X1 is not present, the amino acid residue of X2. (ii) X4 and X7 are amino acid residues that together form a lactam crosslink or a dithioether crosslink. 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 And R 3 C may be substituted with hydrogen or a pyridyl ring. 1-4 It is alkyl, Z is given by equation XI: X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-[3-(3-pyridyl)-Ala]-X14 (XI) This is the amino acid sequence, and in the sequence, X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, and X14 are as defined in formula I, In the array, (i) The Glu of X11 forms a lactam crosslink with the amino acid residue of X1, or if X1 is not present, the amino acid residue of X2. (ii) X4 and X7 are amino acid residues that together form a lactam crosslink or a dithioether 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. 1-4 It is alkyl, Z is given by equation XII: X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13 (XII) This is the amino acid sequence, and in the sequence, X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, and X13 are as defined in formula I, In the array, (i) The Glu of X11 forms a lactam crosslink with the amino acid residue of X1, or if X1 is not present, the amino acid residue of X2. (ii) X4 and X7 are amino acid residues that together form a lactam crosslink or a dithioether crosslink. 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 And R 3 C may be substituted with hydrogen or a pyridyl ring. 1-4 It is alkyl, Z is given by equation XIII: X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13 (XIII) This is the amino acid sequence, and in the sequence, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, and X13 are as defined in Equation I, In the array, (i) The Glu of X11 forms a lactam crosslink with the amino acid residue of X2, (ii) X4 and X7 are amino acid residues that together form a lactam crosslink or a dithioether 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. 1-4 It is alkyl, Z is given by equation XIV: [4-aminomethyl-phenylacetyl]-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14 (XIV) This is the amino acid sequence, and in the sequence, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, X13, and X14 are as defined in formula I, In the array, (i) The Glu of X11 forms a lactam crosslink with the 4-aminomethyl-phenylacetyl residue of X2, (ii) X4 and X7 are amino acid residues that together form a lactam crosslink or a dithioether crosslink. 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 And R 3 C may be substituted with hydrogen or a pyridyl ring. 1-4 It is alkyl, Z is given by equation XV: [4-aminomethyl-phenylacetyl]-X3-X4-X5-X6-X7-[Y(2-aminoethoxy)]-[2-Nal]-[2-Me-Leu]-X11-X12-X13-X14 (XV) This is the amino acid sequence, and in the sequence, X3, X4, X5, X6, X7, X11, X12, X13, and X14 are as defined in formula I, In the array, (i) The Glu of X11 forms a lactam crosslink with the 4-aminomethyl-phenylacetyl residue of X2, (ii) X4 and X7 are amino acid residues that together form a lactam crosslink or a dithioether 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. 1-4 It is alkyl, Z is given by equation XVI: [4-aminomethyl-phenylacetyl]-X3-X4-X5-X6-X7-[Y(2-aminoethoxy)]-[2-Nal]-[2-Me-Leu]-X11-X12-X13-X14 (XVI) This is the amino acid sequence, and in the sequence, X3 is selected from the group consisting of Ser and Ala. X4, X5, X6, X7, X11, X12, X13, and X14 are as defined in formula I, In the array, (i) The Glu of X11 forms a lactam crosslink with the 4-aminomethyl-phenylacetyl residue of X2, (ii) X4 and X7 are amino acid residues that together form a lactam crosslink or a dithioether crosslink. 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 And R 3 C may be substituted with hydrogen or a pyridyl ring. 1-4 It is alkyl, Z is given by equation XVII: [4-aminomethyl-phenylacetyl]-X3-X4-X5-[Gln]-X7-[Y(2-aminoethoxy)]-[2-Nal]-[2-Me-Leu]-X11-X12-X13-X14 (XVII) This is the amino acid sequence, and in the sequence, X3 is selected from the group consisting of Ser and Ala. X4, X5, X7, X11, X12, X13, and X14 are as defined in formula I, In the array, (i) The Glu of X11 forms a lactam crosslink with the 4-aminomethyl-phenylacetyl residue of X2, (ii) X4 and X7 are amino acid residues that together form a lactam crosslink or a dithioether crosslink. compound, Or provide a pharmaceutically acceptable salt or solvate thereof.

[0141] In some embodiments, the present invention is expressed by formula: ZR2 A compound of which, in the formula, R 2 NHR 3 And R 3 C may be substituted with hydrogen or a pyridyl ring. 1-4 It is alkyl, Z is given by equation XVIII: X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-[3-(3-pyridyl)-Ala] (XVIII) This is the amino acid sequence, and in the sequence, X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, and X12 are as defined in formula I, In the array, (i) The Glu of X11 forms a lactam crosslink with the amino acid residue of X1, or if X1 is not present, the amino acid residue of X2. (ii) X4 and X7 are amino acid residues that together form a lactam crosslink or a dithioether crosslink. compound, Or provide a pharmaceutically acceptable salt or solvate thereof.

[0142] 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 from formulas I to XVIII defined above. compound, Or provide a pharmaceutically acceptable salt or solvate thereof.

[0143] In some embodiments, the present invention is expressed by formula: Z-NHMe A compound of which, in the formula, Z is given by equation XVIII: X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-[3-(3-pyridyl)-Ala] (XVIII) This is the amino acid sequence, and in the sequence, X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, and X12 are as defined in formula I, In the array, (i) The Glu of X11 forms a lactam crosslink with the amino acid residue of X1, or if X1 is not present, the amino acid residue of X2. (ii) X4 and X7 are amino acid residues that together form a lactam crosslink or a dithioether crosslink. compound, Or provide a pharmaceutically acceptable salt or solvate thereof.

[0144] In some embodiments, the present invention provides compounds selected from the compounds in Table 1-1, or pharmaceutically acceptable salts or solvates thereof.

[0145] In some embodiments, the compound is [Table 9] JPEG2026518788000024.jpg236170 JPEG2026518788000025.jpg250170 JPEG2026518788000026.jpg244170 JPEG2026518788000027.jpg238170 JPEG2026518788000028.jpg245170 JPEG2026518788000029.jpg244170 JPEG2026518788000030.jpg250170 JPEG2026518788000031.jpg249170 JPEG2026518788000032.jpg237170 JPEG2026518788000033.jpg237170 JPEG2026518788000034.jpg238170 It is not JPEG2026518788000035.jpg91170.

[0146] Any internal shortening between X2 and X11, i.e., deletion of an amino acid residue, results in an inactive compound (see reference compounds Ref5, Ref6, and Ref7 in the examples of the brochure International Publication No. 2023 / 099669).

[0147] 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.

[0148] Furthermore, it will be understood that any of the following embodiments may be applicable to and combined with any of the formulas described herein.

[0149] R 2 R 2 NHR 3 Or C(=O)R 3 And R 3 C may be substituted with hydrogen or a pyridyl ring. 1-4 It is alkyl.

[0150] In some embodiments, R 2 NHR 3 And R 3 C may be substituted with hydrogen or a pyridyl ring. 1-4 It is alkyl.

[0151] In some embodiments, R 2 NHR 3 And R 3 C may be substituted with hydrogen or a pyrido-3-yl ring. 1-4 It is alkyl.

[0152] In some embodiments, R 2 NHR 3 And R 3 is hydrogen or C 1-4 It is alkyl. In some embodiments, R2 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).

[0153] In some embodiments, R 2 NHR 3 And R 3 C may be substituted with a pyridyl ring. 1-4 It is alkyl. In some embodiments, R 2 NHR 3 And R 3 is a C substituted with a pyridyl ring. 1-4 It is alkyl.

[0154] In some embodiments, R 2 NHR 3 And R 3 C may be substituted with a pyrido-3-yl ring. 1-4 It is alkyl. In some embodiments, R 2 NHR 3 And R 3 C is substituted with a pyrido-3-yl ring. 1-4 It is alkyl.

[0155] 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 R 3is 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]

[0156] 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 R 3 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]

[0157] Preferably, R 2 However, NHR 3 And R 3 C is substituted with a pyridyl ring 1-4 Alkyl, NHR 3For example, in embodiments where NH-(4-(pyridine-3-yl)butanyl) and NH-(2-(pyridine-3-yl)ethyl) are present, neither X13 nor X14 are present.

[0158] In some embodiments, R 2 These are NHMe, NH2, NHCH2CH2CH2CH2(pyrido-3-yl) [i.e., NH-(4-(pyridine-3-yl)butanyl)], or NHCH2CH2(pyrido-3-yl) [i.e., NH-(2-(pyridine-3-yl)ethyl)].

[0159] In some embodiments, R 2 is NHMe. In some embodiments, R 2 is NH2. In some embodiments, R 2 This is NHCH2CH2CH2CH2(pyrido-3-yl), that is, NH-(4-(pyridine-3-yl)butanyl). In some embodiments, R 2 This is NHCH2CH2 (pyrido-3-yl), or NH-(2-(pyridine-3-yl)ethyl).

[0160] Preferably, R 2 is NHMe or NH2. More preferably, R 2 It is NHMe.

[0161] In particular, R 2 The fact that it is NHMe is preferable because this modification improves SIF stability (see Example 2).

[0162] Z Z is expressed by the formula: X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14 This is the amino acid sequence, and in the sequence, X1 is either absent or selected from 3-(3-pyridyl)-Ala or 3-aminopropanoyl. X2 is an alanine residue substituted with a carbocyclic group or an aromatic or heteroaromatic group selected from the group consisting of 4-aminomethylphenylacetyl, phenyl, pyridyl, naphthyl, and quinolinyl, each of which may be substituted, 3-aminopropanoyl, 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 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 (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, X3 is any amino acid or ω-hydroxy-C 2-6 Selected from alkanates, X4 is 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, 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, 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 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, 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, Cys, D-Cys, Beta-Cys, D-Beta-Cys, Homo-Cys, D-Homo-Cys, Beta-Homo-Cys, N-Me-Cys, and N-Me-Homo-Cys Selected from, 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 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, 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, 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 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, 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, Cys, D-Cys, Beta-Cys, D-Beta-Cys, Homo-Cys, D-Homo-Cys, Beta-Homo-Cys, N-Me-Cys, and N-Me-Homo-Cys Selected from, 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 an optionally substituted carbocyclic or aromatic group selected from the group consisting of optionally substituted phenyl, pyridyl, naphthyl, and quinolinyl. X9 is selected from the group consisting of an optional tryptophan residue, an optional azatryptophan residue, an optional beta-homotryptophan 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, 2-Me-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 group, an optional Tyr residue, an optional His residue, a carbocyclic group or 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-CF3, 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, 2-Me-Ser, N-Me-Homo-Ser, Ser (OMe), 3-aminotetrahydrofuran-3-carbonyl, THP, 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, GABA, 2-(trimethyl-2-aminoethoxy)ethoxypropyl]propyl, and Lys, wherein 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 Lys is an imidazolyl, pyrimidyl, or pyridyl which may be substituted with F. Selected from the group consisting of, 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, 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 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 is not present. X14 is either absent or selected from the group consisting of alanine residues substituted with a carbocyclic group or an aromatic or heteroaromatic group selected from the group consisting of Sar, optionally substituted His residues, 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, and optionally substituted phenyl, pyridyl, naphthyl, and quinolinyl, respectively. In the array, (i) The amino acid residue of X11 forms a lactam crosslink with the amino acid residue of X1, or if X1 is absent, with the amino acid residue of X2. (ii) X4 and X7 are amino acid residues that together form a lactam crosslink or a dithioether crosslink. amino acid sequence, or a pharmaceutically acceptable salt or solvate thereof, The compound is [Table 10] JPEG2026518788000039.jpg250170 JPEG2026518788000040.jpg242170 JPEG2026518788000041.jpg251170 Not JPEG2026518788000042.jpg37170 and its pharmaceutically acceptable salts and solvates, In the table, * This indicates that the crosslinking in (1c), (2a), and (2c) uses the amine or carboxylic acid of the N-terminal or C-terminal peptide backbone, rather than the amine or carboxylic acid of the side chain. (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.

[0163] In some embodiments, Z is given by formula I: X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14 (I) This is the amino acid sequence, and in the sequence, X1 is either absent or selected from 3-(3-pyridyl)-Ala or 3-aminopropanoyl. X2 is selected from the group consisting of 4-aminomethylphenylacetyl, 3-(3-pyridyl)-Ala, and 3-aminopropanoyl. X3 is selected from the group consisting of Ser, Ala, Phe, and N-Me-Ser. X4 is either Glu or Cys. X5 is a trumpet, X6 is selected from the group consisting of Gln, Q(Me), Q(2Me), Q(pyrrolidine), Ala, Phe, Lys(Ac), Dab(Ac), Cit, and Orn. X7 is either Dab or Cys. X8 is selected from the group consisting of Y(2-aminoethoxy), homo-Phe, 7-AzaTrp, beta-homo-Trp, and 7-F-Trp. X9 is selected from the group consisting of 2-Nal, 7-AzaTrp, beta-homo-Trp, and cyclopropyl-Ala. X10 is 2-Me-Leu or Aib, X11 is Glu, X12 is selected from the group consisting of Dab, iso-Dab, D-Arg, Gly-CF3, D-Gly-CF3, Nle, Gln, His, THP, Ser, D-Ser, 2-Me-Ser, Ser(OMe), and homo-Ser. X13 is selected from the group consisting of 3-(3-pyridyl)-Ala, D-3-(3-pyridyl)-Ala, 2-Me-3-(3-pyridyl)-Ala, N-Me-3-(3-pyridyl)-Ala, 3-(3,5-pyrimidyl)-Ala, His, D-His, and His(Me), or is not present. X14 is either absent or selected from the group consisting of Sar, D-His, beta-homo-Leu, and 3-(3-pyridyl)-Ala. In the array, (i) The Glu of X11 forms a lactam crosslink with the amino acid residue of X1, or if X1 is not present, the amino acid residue of X2. (ii) X4 and X7 are amino acid residues that together form a lactam crosslink or a dithioether crosslink.

[0164] In some embodiments, Z is given by formula II: X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14 (II) A compound of which, in the formula, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, X13, and X14 are as defined in formula I, In the array, (i) The Glu of X11 forms a lactam crosslink with the amino acid residue of X2, (ii) X4 and X7 are amino acid residues that together form a lactam crosslink or a dithioether crosslink.

[0165] In some embodiments, Z is given by Equation III: X1-[4-aminomethylphenylacetyl]-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14 (III) This is the amino acid sequence, and in the sequence, X1, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, X13, and X14 are as defined in formula I, In the array, (i) The Glu of X11 forms a lactam crosslink with the amino acid residue of X1, or if X1 is absent, with the 4-aminomethyl-phenylacetyl residue of X2. (ii) X4 and X7 are amino acid residues that together form a lactam crosslink or a dithioether crosslink.

[0166] In some embodiments, Z is given by equation IV: X1-X2-[Ser]-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14 (IV) This is the amino acid sequence, and in the sequence, X1, X2, X4, X5, X6, X7, X8, X9, X10, X11, X12, X13, and X14 are as defined in formula I, In the array, (i) The Glu of X11 forms a lactam crosslink with the amino acid residue of X1, or if X1 is not present, the amino acid residue of X2. (ii) X4 and X7 are amino acid residues that together form a lactam crosslink or a dithioether crosslink.

[0167] In some embodiments, Z is given by equation V: X1-X2-X3-[Glu]-X5-X6-[Dab]-X8-X9-X10-X11-X12-X13-X14 (V) This is the amino acid sequence, and in the sequence, X1, X2, X3, X5, X6, X8, X9, X10, X11, X12, X13, and X14 are as defined in formula I, In the array, (i) The Glu of X11 forms a lactam crosslink with the amino acid residue of X1, or if X1 is not present, the amino acid residue of X2. (ii) Glu in X4 and Dab in X7 are amino acid residues that together form a lactam crosslink.

[0168] In some embodiments, Z is given by Equation VI: X1-X2-X3-X4-X5-[Gln]-X7-X8-X9-X10-X11-X12-X13-X14 (VI) This is the amino acid sequence, and in the sequence, X1, X2, X3, X4, X5, X7, X8, X9, X10, X11, X12, X13, and X14 are as defined in formula I, In the array, (i) The Glu of X11 forms a lactam crosslink with the amino acid residue of X1, or if X1 is not present, the amino acid residue of X2. (ii) X4 and X7 are amino acid residues that together form a lactam crosslink or a dithioether crosslink.

[0169] In some embodiments, Z is given by equation VII: X1-X2-X3-X4-X5-X6-X7-[Y(2-aminoethoxy)]-X9-X10-X11-X12-X13-X14 (VII) This is the amino acid sequence, and in the sequence, X1, X2, X3, X4, X5, X6, X7, X9, X10, X11, X12, X13, and X14 are as defined in formula I, In the array, (i) The Glu of X11 forms a lactam crosslink with the amino acid residue of X1, or if X1 is not present, the amino acid residue of X2. (ii) X4 and X7 are amino acid residues that together form a lactam crosslink or a dithioether crosslink.

[0170] In some embodiments, Z is given by formula VIII: X1-X2-X3-X4-X5-X6-X7-X8-[2-Nal]-X10-X11-X12-X13-X14 (VIII) This is the amino acid sequence, and in the sequence, X1, X2, X3, X4, X5, X6, X7, X8, X10, X11, X12, X13, and X14 are as defined in formula I, In the array, (i) The Glu of X11 forms a lactam crosslink with the amino acid residue of X1, or if X1 is not present, the amino acid residue of X2. (ii) X4 and X7 are amino acid residues that together form a lactam crosslink or a dithioether crosslink.

[0171] In some embodiments, Z is given by formula IX: X1-X2-X3-X4-X5-X6-X7-X8-X9-[2-Me-Leu]-X11-X12-X13-X14 (IX) This is the amino acid sequence, and in the sequence, X1, X2, X3, X4, X5, X6, X7, X8, X9, X11, X12, X13, and X14 are as defined in formula I, In the array, (i) The Glu of X11 forms a lactam crosslink with the amino acid residue of X1, or if X1 is not present, the amino acid residue of X2. (ii) X4 and X7 are amino acid residues that together form a lactam crosslink or a dithioether crosslink.

[0172] In some embodiments, Z is given by equation X: X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-[Dab]-X13-X14 (X) This is the amino acid sequence, and in the sequence, X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X13, and X14 are as defined in formula I, In the array, (i) The Glu of X11 forms a lactam crosslink with the amino acid residue of X1, or if X1 is not present, the amino acid residue of X2. (ii) X4 and X7 are amino acid residues that together form a lactam crosslink or a dithioether crosslink.

[0173] In some embodiments, Z is given by formula XI: X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-[3-(3-)pyridyl)-Ala]-X14 (XI) This is the amino acid sequence, and in the sequence, X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, and X14 are as defined in formula I, In the array, (i) The Glu of X11 forms a lactam crosslink with the amino acid residue of X1, or if X1 is not present, the amino acid residue of X2. (ii) X4 and X7 are amino acid residues that together form a lactam crosslink or a dithioether crosslink.

[0174] In some embodiments, Z is given by equation XII: X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13 (XII) This is the amino acid sequence, and in the sequence, X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, and X13 are as defined in formula I, In the array, (i) The Glu of X11 forms a lactam crosslink with the amino acid residue of X1, or if X1 is not present, the amino acid residue of X2. (ii) X4 and X7 are amino acid residues that together form a lactam crosslink or a dithioether crosslink.

[0175] In some embodiments, Z is given by formula XIII: X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13 (XIII) This is the amino acid sequence, and in the sequence, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, and X13 are as defined in formula I, In the array, (i) The Glu of X11 forms a lactam crosslink with the amino acid residue of X2, (ii) X4 and X7 are amino acid residues that together form a lactam crosslink or a dithioether crosslink.

[0176] In some embodiments, Z is given by equation XIV: [4-aminomethyl-phenylacetyl]-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14 (XIV) This is the amino acid sequence, and in the sequence, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, X13, and X14 are as defined in formula I, In the array, (i) The Glu of X11 forms a lactam crosslink with the 4-aminomethyl-phenylacetyl residue of X2, (ii) X4 and X7 are amino acid residues that together form a lactam crosslink or a dithioether crosslink.

[0177] In some embodiments, Z is given by equation XV: [4-aminomethyl-phenylacetyl]-X3-X4-X5-X6-X7-[Y(2-aminoethoxy)]-[2-Nal]-[2-Me-Leu]-X11-X12-X13-X14 (XV) This is the amino acid sequence, and in the sequence, X3, X4, X5, X6, X7, X11, X12, X13, and X14 are as defined in formula I, In the array, (i) The Glu of X11 forms a lactam crosslink with the 4-aminomethyl-phenylacetyl residue of X2, (ii) X4 and X7 are amino acid residues that together form a lactam crosslink or a dithioether crosslink.

[0178] In some embodiments, Z is given by equation XVI: [4-aminomethyl-phenylacetyl]-X3-X4-X5-X6-X7-[Y(2-aminoethoxy)]-[2-Nal]-[2-Me-Leu]-X11-X12-X13-X14 (XVI) This is the amino acid sequence, and in the sequence, X3 is selected from the group consisting of Ser and Ala. X4, X5, X6, X7, X11, X12, X13, and X14 are as defined in formula I, In the array, (i) The Glu of X11 forms a lactam crosslink with the 4-aminomethyl-phenylacetyl residue of X2, (ii) X4 and X7 are amino acid residues that together form a lactam crosslink or a dithioether crosslink.

[0179] In some embodiments, Z is given by equation XVII: [4-aminomethyl-phenylacetyl]-X3-X4-X5-[Gln]-X7-[Y(2-aminoethoxy)]-[2-Nal]-[2-Me-Leu]-X11-X12-X13-X14 (XVII) This is the amino acid sequence, and in the sequence, X3 is selected from the group consisting of Ser and Ala. X4, X5, X7, X11, X12, X13, and X14 are as defined in formula I, In the array, (i) The Glu of X11 forms a lactam crosslink with the 4-aminomethyl-phenylacetyl residue of X2, (ii) X4 and X7 are amino acid residues that together form a lactam crosslink or a dithioether crosslink.

[0180] In some embodiments, Z is given by formula XVIII: X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-[3-(3-pyridyl)-Ala] (XVIII) This is the amino acid sequence, and in the sequence, X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, and X12 are as defined in formula I, In the array, (i) The Glu of X11 forms a lactam crosslink with the amino acid residue of X1, or if X1 is not present, the amino acid residue of X2. (ii) X4 and X7 are amino acid residues that together form a lactam crosslink or a dithioether crosslink.

[0181] In some embodiments, Z is an amino acid sequence selected from the group consisting of sequences listed in Table 1-1a.

[0182] X1 X1 is either absent or selected from the group consisting of 3-(3-pyridyl)-Ala or 3-aminopropanoyl.

[0183] In some embodiments, X1 is absent. If X1 is absent, the amino acid residue of X2 forms a lactam crosslink with the Glu residue of X11.

[0184] In some embodiments, X1 is 3-(3-pyridyl)-Ala or 3-aminopropanoyl. In some embodiments, X1 is 3-(3-pyridyl)-Ala. In some embodiments, X1 is 3-aminopropanoyl.

[0185] If X1 is present, i.e., if X1 is 3-(3-pyridyl)-Ala or 3-aminopropanoyl, X1 may form a lactam crosslink with the Gly residue of X11. In some embodiments, if X1 is present, i.e., if X1 is 3-(3-pyridyl)-Ala or 3-aminopropanoyl, X1 forms a lactam crosslink with the Glu residue of X11.

[0186] Preferably, X1 does not exist.

[0187] X2 X2 is an alanine residue substituted with a carbocyclic group or an aromatic or heteroaromatic group selected from the group consisting of 4-aminomethylphenylacetyl, phenyl, pyridyl, naphthyl, and quinolinyl, each of which may be substituted, 3-aminopropanoyl, 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 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 (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.

[0188] In some embodiments, X2 is selected from the group consisting of 4-aminomethylphenylacetyl, 3-(3-pyridyl)-Ala, and 3-aminopropanoyl.

[0189] The amino acid residue of X2 may form a lactam crosslink with the Glu residue of X11. If X1 is not present, the amino acid residue of X2 will form a lactam crosslink with the Glu residue of X11.

[0190] In some embodiments, X2 is 4-aminomethylphenylacetyl. In some embodiments, X2 is 3-(3-pyridyl)-Ala. In some embodiments, X2 is 3-aminopropanoyl.

[0191] Preferably, X2 is 4-aminomethylphenylacetyl.

[0192] X3 X3 is any amino acid or ω-hydroxy-C 2-6 Selected from alkanic acids.

[0193] In some embodiments, X3 is selected from the group consisting of Ser, Ala, N-Me-Ala, Phe, and N-Me-Ser.

[0194] In some embodiments, X3 is selected from the group consisting of Ser, Ala, Phe, and N-Me-Ser.

[0195] In some embodiments, X3 is Ser or Ala.

[0196] In some embodiments, X3 is Ser. In some embodiments, X3 is Ala. In some embodiments, X3 is Phe. In some embodiments, X3 is N-Me-Ser.

[0197] Preferably, X3 is Ser.

[0198] X4 X4 is 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, 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, 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 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, 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, Cys, D-Cys, Beta-Cys, D-Beta-Cys, Homo-Cys, D-Homo-Cys, Beta-Homo-Cys, N-Me-Cys, and N-Me-Homo-Cys Selected from.

[0199] In some embodiments, X4 is Glu or Cys. The amino acid residue of X4 forms lactam crosslinks or dithioether crosslinks with the amino acid residue of X7.

[0200] In some embodiments, X4 is Glu. When X4 is Glu, the Glu of X4 forms a lactam crosslink with the amino acid residue of X7.

[0201] In some embodiments, X4 is Cys. When X4 is Cys, the Cys of X4 forms a dithioether crosslink with the amino acid residue of X7.

[0202] Preferably, X4 is Glu.

[0203] 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.

[0204] In some embodiments, X5 is a Trp or a 7-Me-Trp.

[0205] In some embodiments, X5 is a trp.

[0206] 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.

[0207] In some embodiments, X6 is selected from the group consisting of Gln, Q(Me), Q(2Me), Q(pyrrolidine), Ala, Phe, Lys(Ac), Dab(Ac), Cit, and Orn.

[0208] In some embodiments, X6 is Gln. In some embodiments, X6 is Q(Me). In some embodiments, X6 is Q(2Me). In some embodiments, X6 is Q(pyrrolidine). In some embodiments, X6 is Ala. In some embodiments, X6 is Phe. In some embodiments, X6 is Lys(Ac). In some embodiments, X6 is Dab(Ac). In some embodiments, X6 is Cit. In some embodiments, X6 is Orn.

[0209] Preferably, X6 is Gln.

[0210] X7 X7 is 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, 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, 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 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, 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, Cys, D-Cys, Beta-Cys, D-Beta-Cys, Homo-Cys, D-Homo-Cys, Beta-Homo-Cys, N-Me-Cys, N-Me-Homo-Cys Selected from.

[0211] In some embodiments, X7 is Dab or Cys. The amino acid residue of X7 forms a lactam crosslink or dithioether crosslink with the amino acid residue of X4.

[0212] In some embodiments, X7 is a Dab. When X7 is a Dab, the Dab of X7 forms a lactam crosslink with the amino acid residue of X4.

[0213] In some embodiments, X7 is Cys. When X7 is Cys, the Cys of X7 forms a dithioether crosslink with the amino acid residue of X4.

[0214] Preferably, X7 is Dab.

[0215] 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 substituted with optionally substituted carbocyclic or aromatic groups selected from the group consisting of optionally substituted phenyl, pyridyl, naphthyl, and quinolinyl.

[0216] In some embodiments, X8 is Y(2-aminoethoxy), homo-Phe, 7F(4-morpholine), 3-quinolinylalanine, Y(2-aminoethoxy)(N(Me)2, Y(n-pentylamine)(N +The following are selected from the group consisting of (Me)3), Y(2-trimethyl-PEG2), Y(2-aminoethoxy)(N(Me)2), 7-AzaTrp, beta-homo-Trp, and 7-F-Trp.

[0217] In some embodiments, X8 is selected from the group consisting of Y(2-aminoethoxy), homo-Phe, 7-AzaTrp, beta-homo-Trp, and 7-F-Trp.

[0218] In some embodiments, X8 is Y(2-aminoethoxy). In some embodiments, X8 is homo-Phe. In some embodiments, X8 is 7-AzaTrp. In some embodiments, X8 is beta-homo-Trp. In some embodiments, X8 is 7-F-Trp.

[0219] Preferably, X8 is Y(2-aminoethoxy).

[0220] X9 X9 is selected from the group consisting of an optional tryptophan residue, an optional azatryptophan residue, an optional beta-homotryptophan residue, an optional alanine residue, an optional phenylalanine residue, and an optional tyrosine residue.

[0221] In some embodiments, X9 is selected from the group consisting of 2-Nal, 7-AzaTrp, beta-homo-Trp, 3-quinolinylalanine, and cyclopropyl-Ala.

[0222] In some embodiments, X9 is selected from the group consisting of 2-Nal, 7-AzaTrp, beta-homo-Trp, and cyclopropyl-Ala.

[0223] In some embodiments, X9 is 2-Nal. In some embodiments, X9 is 7-AzaTrp. In some embodiments, X9 is beta-homo-Trp. In some embodiments, X9 is cyclopropyl-Ala.

[0224] Preferably, X9 is 2-Nal.

[0225] 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, 2-Me-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.

[0226] In some embodiments, X10 is selected from the group consisting of 2-Me-Leu and Aib.

[0227] In some embodiments, X10 is 2-Me-Leu. In some embodiments, X10 is Aib.

[0228] Preferably, X10 is 2-Me-Leu.

[0229] The inventors observed that the 10th position (X10) must contain an amino acid that addresses SIF stability (i.e., gastrointestinal stability). The amino acids 2-Me-Leu and Aib, particularly 2-Me-Leu, address SIF stability. For example, the inventors observed that when the amino acid residue at the 10th position (X10) is Gly, the SIF stability of the compound is significantly reduced.

[0230] 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.

[0231] In some embodiments, X11 is Glu.

[0232] The Glu residue of X11 forms a lactam crosslink with either the amino acid residue of X1 or, if X1 is absent, with the amino acid residue of X2. In some embodiments, the Glu residue of X11 forms a lactam crosslink with the amino acid residue of X1. In some embodiments, the Glu residue of X11 forms a lactam crosslink with the amino acid residue of X2.

[0233] If X1 is not present, the Glu residue of X11 forms a lactam crosslink with the amino acid residue of X2.

[0234] 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-CF3, 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, 2-Me-Ser, N-Me-Homo-Ser, Se r(OMe),3-aminotetrahydrofuran-3-carbonyl,THP,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, GABA, 2-(trimethyl-2-aminoethoxy)ethoxypropyl]propyl, and Lys, wherein 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 Lys is selected from the group consisting of imidazolyl, pyrimidyl, or pyridyl, which may be substituted with F.

[0235] In some embodiments, X12 is selected from the group consisting of Dab, iso-Dab, D-Arg, Gly-CF3, D-Gly-CF3, Nle, Gln, His, THP, Ser, D-Ser, 2-Me-Ser, Ser(OMe), and homo-Ser.

[0236] In some embodiments, X12 is selected from the group consisting of Dab, D-Arg, and Ser. In some embodiments, X12 is Dab or Ser. In some embodiments, X12 is Dab or D-Arg.

[0237] In some embodiments, X12 is Dab. In some embodiments, X12 is iso-Dab. In some embodiments, X12 is D-Arg. In some embodiments, X12 is Gly-CF3. In some embodiments, X12 is D-Gly-CF3. In some embodiments, X12 is Nle. In some embodiments, X12 is Gln. In some embodiments, X12 is His. In some embodiments, X12 is THP. In some embodiments, X12 is Ser. In some embodiments, X12 is D-Ser. In some embodiments, X12 is 2-Me-Ser. In some embodiments, X12 is Ser(OMe). In some embodiments, X12 is homo-Ser.

[0238] Preferably, X12 is Dab.

[0239] X13 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, wherein 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 either an imidazolyl, pyrimidyl, or pyridyl which may be substituted with F, or it is Dab, Orn, or Lys, or it does not exist.

[0240] In some embodiments, X13 is selected from the group consisting of 3-(3-pyridyl)-Ala, D-3-(3-pyridyl)-Ala, 2-Me-3-(3-pyridyl)-Ala, N-Me-3-(3-pyridyl)-Ala, 3-(3,5-pyrimidyl)-Ala, His, D-His, and His(Me), or is absent.

[0241] In some embodiments, X13 is either 3-(3-pyridyl)-Ala or absent. If X13 is absent, then X14 is also absent.

[0242] In some embodiments, X13 is 3-(3-pyridyl)-Ala. In some embodiments, X13 is D-3-(3-pyridyl)-Ala. In some embodiments, X13 is 2-Me-3-(3-pyridyl)-Ala. In some embodiments, X13 is N-Me-3-(3-pyridyl)-Ala. In some embodiments, X13 is 3-(3,5-pyrimidyl)-Ala. In some embodiments, X13 is His. In some embodiments, X13 is D-His. In some embodiments, X13 is His(Me). In some embodiments, X13 is absent.

[0243] Preferably, X13 is 3-(3-pyridyl)-Ala or is absent. More preferably, X13 is 3-(3-pyridyl)-Ala.

[0244] X14 X14 is either absent or selected from the group consisting of alanine residues substituted with a carbocyclic group or an aromatic or heteroaromatic group selected from the group consisting of Sar, optionally substituted His residues, 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, and optionally substituted phenyl, pyridyl, naphthyl, and quinolinyl.

[0245] In some embodiments, X14 is either absent or selected from the group consisting of Sar, D-His, beta-homo-Leu, and 3-(3-pyridyl)-Ala.

[0246] In some embodiments, X14 is absent. In such embodiments where X14 is absent, X13 may preferably be 3-(3-pyridyl)-Ala.

[0247] In some embodiments, X14 is Sar. In some embodiments, X14 is D-His. In some embodiments, X14 is beta-homo-Leu. In some embodiments, X14 is 3-(3-pyridyl)-Ala. If X14 is present, that is, if X14 is selected from the group consisting of Sar, D-His, beta-homo-Leu, and 3-(3-pyridyl)-Ala, then X13 may be 3-(3-pyridyl)-Ala or His.

[0248] Preferably, X14 does not exist.

[0249] 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 and / or carboxylic acid groups of the amino acid residues may be present in the side chains of the amino acid residues, such as Dab and Glu. 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, such as 4-aminomethylphenylacetyl, 3-(3-pyridyl)-Ala, and 3-aminopropanoyl, or the N-terminus or C-terminus of the peptide chain.

[0250] One amino acid residue contains an amine group, and the other amino acid residue contains a carboxylic acid group, forming a lactam (cyclic amide) between the amine group and the carboxylic acid group.

[0251] For simplicity, amino acid residues that form lactam crosslinks together will be considered by referring to residues that nominally exist before lactam formation.

[0252] The appropriate amino acid residues that work together to form lactam crosslinks can be selected from the following: • Amino acid residues containing amine groups such as 4-aminomethylphenylacetyl, 3-(3-pyridyl)-Ala, 3-aminopropanoyl, and Dab. • Amino acid residues containing carboxylic acid groups such as Glu.

[0253] 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.

[0254] First lactam bridge - X1 / X2 and X11 The first lactam crosslink is formed between a residue of X11 and an amino acid residue of X1, or X2 if X1 is absent. In some embodiments, the first lactam crosslink is formed between a residue of X11 and an amino acid residue of X1. In some embodiments, the first lactam crosslink is formed between a residue of X11 and an amino acid residue of X2. If X1 is absent, the first lactam crosslink is formed between a residue of X11 and an amino acid residue of X2. Preferably, the first lactam crosslink is formed between a residue of X11 and an amino acid residue of X2.

[0255] In some embodiments, the first lactam crosslink is formed between the Glu of X11 and the amino acid residue of X1, or X2 if X1 is absent. In some embodiments, the first lactam crosslink is formed between the Glu of X11 and the amino acid residue of X1. In some embodiments, the first lactam crosslink is formed between the Glu of X11 and the amino acid residue of X2. If X1 is absent, the first lactam crosslink is formed between the Glu of X11 and the amino acid residue of X2. Preferably, the first lactam crosslink is formed between the Glu of X11 and the amino acid residue of X2.

[0256] In embodiments in which the first lactam crosslink is formed between the Glu of X11 and the amino acid residue of X1, X1 is 3-(3-pyridyl)-Ala or 3-aminopropanoyl. That is, the following combinations of X1 and X11 form the lactam crosslink. X1 is 3-(3-pyridyl)-alanine, and X11 is Glu, and X1 is 3-aminopropanoyl and X11 is Glu.

[0257] In embodiments in which the first lactam crosslink is formed between the Glu of X11 and the amino acid residue of X2, X2 is 4-aminomethylphenylacetyl, 3-(3-pyridyl)-Ala, and 3-aminopropanoyl. That is, the following combinations of X2 and X11 form the lactam crosslink: X2 is 4-aminomethylphenylacetyl and X11 is Glu. X2 is 3-(3-pyridyl)-Ala and X11 is Glu, and X2 is 3-aminopropanoyl and X11 is Glu.

[0258] In such a combination, X1 does not exist.

[0259] Second lactam bridge - X4 and X7 A second lactam crosslink may be formed between the amino acid residues of X4 and X7. In such embodiments, X4 is Glu and X7 is Dab.

[0260] Preferably, the crosslinks between the amino acid residues of X4 and X7 are lactam crosslinks.

[0261] Dithioether crosslinking The dithioether crosslink is formed by two amino acid residues containing a sulfur moiety such as -SH. Preferably, the sulfur moiety of the amino acid residue is located in the side chain of the amino acid residue such as Cys.

[0262] For simplicity, amino acid residues that form dithioether crosslinks together will be considered by referring to residues that nominally exist before dithioether formation.

[0263] The appropriate amino acid residues that come together to form a dithioether crosslink may be Cys.

[0264] The inventors found that a linker is required between the thiol side chains of linked [4,7]cysteine ​​residues in the compound to maintain IL-23R inhibitory activity. Replacing the dithioether bridge with a disulfide bridge resulted in a loss of inhibitory activity (see Example 2 in International Publication No. 2023 / 099669).

[0265] Dithioether formula In some embodiments, the dithioether crosslink has the formula -SLYLS-, where, Each S is a sulfur atom and is part of one of the amino acid residues that form a dithioether crosslink. Each L is independent of C 1-4 It is alkylene, Y either does not exist or is C (=O).

[0266] L Each L is independent of C 1-4 It is alkylene.

[0267] In some embodiments, L is C 1-2 It is an alkylene. In some embodiments, L is a C1 alkylene (methylene or -CH2-). In some embodiments, L is a C2 alkylene (ethylene or -CH2CH2-).

[0268] Y Y either does not exist or is C (=O).

[0269] In some embodiments, Y does not exist. In some embodiments, Y is C (=O). Preferably, Y is C (=O).

[0270] Preferred dithioether crosslinking In some embodiments, the dithioether crosslink has the formula -SCH2C(=O)CH2S-, where each S is a sulfur atom and is part of one of the amino acid residues that form the dithioether crosslink.

[0271] Dithioether crosslinking - X4 and X7 A dithioether crosslink may be formed between the amino acid residues of X4 and X7. In such embodiments, X4 is Cys and X7 is Cys.

[0272] In embodiments in which a dithioether crosslink is formed between amino acid residues of X4 and X7, preferably the dithioether crosslink between X4 and X7 has the formula -SLYLS-, where, Each S is a sulfur atom and is part of the amino acid residues of X4 and X7. Each L is independent of C 1-4 It is alkylene, Y either does not exist or is C (=O).

[0273] In embodiments in which a dithioether crosslink is formed between the amino acid residues of X4 and X7, it is more preferable that the crosslink has the formula -SCH2C(=O)CH2S-, where each S is a sulfur atom and part of the amino acid residues of X4 and X7. That is, each L is -CH2- and Y is C(=O).

[0274] 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 (X1 / X2 in the case of a crosslink between X1 / X2 and X11, or X4 in the case of a crosslink between X4 and X7), i.e., the first atom bonded to the alpha carbon of the relevant residue in most amino acids, 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 X1 / X2 and X11, or X7 in the case of a crosslink between X4 and X7).

[0275] The contributions of amino acid residue crosslinks to their length and type are described below.

[0276] In some embodiments, the length of the bridge between X1 / X2 and X11 is at least 4 atomic lengths. In some embodiments, the length of the bridge between X1 / X2 and X11 is 10 atomic lengths or less. In some embodiments, the length of the bridge between X1 / X2 and X11 is 4 to 10 atomic lengths, for example, 4, 5, 6, 7, 8, 9, or 10 atomic lengths. In some embodiments, the length of the bridge between X1 / X2 and X11 is 4 to 9 atomic lengths, for example, 4, 5, 6, 7, 8, or 9 atomic lengths. In some embodiments, the length of the bridge between X1 / X2 and X11 is one of 4, 5, or 9 atomic lengths. In some embodiments, the length of the bridge between X1 / X2 and X11 is 4 atomic lengths. In some embodiments, the length of the bridge between X1 / X2 and X11 is one of 5 atomic lengths. In some embodiments, the length of the bridge between X1 / X2 and X11 is 9 atomic lengths.

[0277] In some embodiments, the length of the bridge between X4 and X7 is at least 4 atomic lengths. In some embodiments, the length of the bridge between X4 and X7 is 10 atomic lengths or less. In some embodiments, the length of the bridge between X4 and X7 is 4 to 10 atomic lengths, for example, 4, 5, 6, 7, 8, 9, or 10 atomic lengths. In some embodiments, the length of the bridge between X4 and X7 is 4 to 9 atomic lengths, for example, 4, 5, 6, 7, 8, or 9 atomic lengths. In some embodiments, the length of the bridge between X4 and X7 is 6 or 7 atomic lengths. In some embodiments, the length of the bridge between X4 and X7 is 6 atomic lengths. In some embodiments, the length of the bridge between X4 and X7 is 7 atomic lengths.

[0278] 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).

[0279] 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.

[0280] Amine-containing side chains: [Table 11]

[0281] Carboxylic acid-containing side chains: [Table 12]

[0282] Similarly, the contribution of the length of the N-terminal or C-terminal amino acid residue to the length of the lactam bridge 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., in most amino acids, the first atom bonded to the alpha carbon of the relevant residue) 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.

[0283] Therefore, the following amino acid residues are considered to have the following lengths.

[0284] N-terminus: [Table 13]

[0285] 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).

[0286] The following are examples of appropriate pairings of residues at the X1 / X2 and X11 positions, where the amide bond of the lactam crosslink is closer to the X11 position than the X1 / X2 position after formation. X2 is 4-aminomethylphenylacetyl, and X11 is Glu.

[0287] Alternatively, suitable pairings of residues at the X1 / X2 and X11 positions, where the amide bond in the lactam crosslink is closer to the X1 / X2 position than to the X11 position, include the following: X1 is 3-(3-pyridyl)-Ala, and X11 is Glu. X1 is 3-aminopropanoyl, and X11 is Glu. X2 is 3-(3-pyridyl)-Ala, and X11 is Glu. X2 is 3-aminopropanoyl, and X11 is Glu.

[0288] The position of the amide bond in the lactam crosslink between position 4 (X4) and position 7 (X7) may be equidistant from X4 and X7, for example, when X4 is Glu and X7 is Dab.

[0289] Preferably, the length of the lactam crosslink after amide bond formation (excluding any atoms in the peptide backbone) is 4, 5, 6, 7, 8, 9, or 10 atoms, for example, 4, 5, 6, or 9 atoms. In the case of lactam crosslinks between amino acid residues at positions X1 / X2 and X11, the length of the lactam crosslink after amide bond formation is 4, 5, or 9 atoms. In the case of lactam crosslinks between amino acid residues at positions X4 and X7, the length of the lactam crosslink after amide bond formation may be 6 atoms.

[0290] 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. Suitable pairings of residues at the X1 / X2 and X11 positions that result in a lactam crosslink of 4 atoms in length include 3-(3-pyridyl)-Ala and Glu.

[0291] In some embodiments, the length of the lactam crosslink after amide bond formation (excluding any atoms in the peptide backbone) is 5 atoms. Suitable pairings of residues at positions X1 / X2 and X11 that result in a lactam crosslink of 5 atoms in length include 3-aminopropanoyl and Glu.

[0292] In some embodiments, the length of the lactam crosslink after amide bond formation (excluding any atoms in the peptide backbone) is 6 atoms. Suitable pairings of residues at positions X4 and X7 that result in a lactam crosslink with a length of 6 atoms include Glu and Dab.

[0293] 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.

[0294] Preferably, the length of the lactam crosslink after the formation of the amide bond (excluding any atoms in the peptide backbone) is 8 atoms.

[0295] 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 the X1 / X2 and X11 positions that result in a lactam crosslink with a length of 9 atoms include 4-aminomethylphenylacetyl and Glu.

[0296] 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.

[0297] Dithioether crosslinking The contribution of the side chain to the length of the dithioether crosslink is counted as the number of atoms in the straight chain from the first atom of the side chain (an atom of the peptide backbone, i.e., in the case of most amino acids, bonded to the alpha carbon of the relevant residue) to the atom participating in the dithioether bond of the crosslink (i.e., the sulfur atom) up to that atom.

[0298] Therefore, typical sulfur-containing side chains are considered to have the following side chain lengths. It will be understood that the crosslinking lengths of any amino acid residue disclosed herein can be deciphered using the following. [Table 14]

[0299] Preferably, X4 is Cys and X7 is Cys.

[0300] Next, the lengths of the side chains of X4 and X7 are added to the contribution of the linker between the sulfur moieties of the amino acid residues at positions X4 and X7 to determine the length of the bridge. In embodiments where the dithioether bridge has the formula -SLYLS-, the contribution of the linker is counted as the number of atoms in -LYL-, since the sulfur atoms have already been counted in the length of the side chains.

[0301] Preferably, the length of the dithioether crosslink after its formation (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, 8, or 9 atoms, for example, 7 or 8 atoms.

[0302] In some embodiments, the length of the dithioether bridge is 5 atomic lengths. In some embodiments, the length of the dithioether bridge is 6 atomic lengths.

[0303] In some embodiments, the length of the dithioether crosslink is 7 atoms long, such as in the case of the crosslinked -SCH2C(=O)CH2S-.

[0304] In some embodiments, the length of the dithioether bridge is 8 atomic lengths. In some embodiments, the length of the dithioether bridge is 9 atomic lengths. In some embodiments, the length of the dithioether bridge is 10 atomic lengths.

[0305] Preferably, the dithioether bridge has a length of 7 atoms.

[0306] 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 synthetic examples therein. This method typically further includes the step of forming an amide bond between the amino acid residue at position 1 (X1), or, if the amino acid residue at position 1 is absent, the amino acid residue at position 2 (X2), and the amino acid residue at position 11 (X11); and optionally further includes the step of forming an amide bond or two thioether bonds with a linker between the amino acid residues at positions 4 (X4) and 7 (X7), 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.

[0307] 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 residue at position 1, or, if the amino acid residue at position 1 is absent, the amino acid residue at position 2, and the amino acid residue at position 11, and optionally forming an amide bond between the amino acid residues at positions 4 and 7, or forming two thioether bonds having a linker.

[0308] The order of steps in the synthesis of a compound does not necessarily have to be the order mentioned above.

[0309] For example, the order of crosslink formation (lactam crosslink / amide bond, dithioether crosslink / two thioether bonds) may be in any order. In some embodiments, a crosslink is first formed between the amino acid residue at position 1, or the amino acid residue at position 2 if the amino acid residue at position 1 is absent, and the amino acid residue at position 11, followed by the crosslink between the amino acid residues at positions 4 and 7. In other embodiments, a crosslink is first formed between the amino acid residues at positions 4 and 7, followed by the crosslink between the amino acid residue at position 1, or the amino acid residue at position 2 if the amino acid residue at position 1 is absent, and the amino acid residue at position 11.

[0310] 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.

[0311] The comparative activity is as described below in IC 50 It can be measured by any appropriate means, such as determining the value.

[0312] 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.

[0313] 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.

[0314] 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.

[0315] K d The 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 dA 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.

[0316] 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.

[0317] 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 50 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 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.

[0318] 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).

[0319] 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).

[0320] 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).

[0321] 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).

[0322] 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).

[0323] 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).

[0324] 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).

[0325] 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).

[0326] 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).

[0327] 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).

[0328] 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 Values ​​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.

[0329] 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).

[0330] 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).

[0331] 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).

[0332] 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).

[0333] 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).

[0334] 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).

[0335] 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).

[0336] 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).

[0337] 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).

[0338] 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).

[0339] Such assays can be carried out under the conditions described in Examples 3-1 and 3-2 below.

[0340] 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%, 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.

[0341] 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.

[0342] 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.

[0343] 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.

[0344] 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.

[0345] therapy use The compounds of the present invention, and pharmaceutical compositions containing such compounds, are useful in methods for preventing or treating various conditions.

[0346] 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.

[0347] 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.

[0348] In some embodiments, the condition can be selected from inflammatory bowel disease (IBD), such as Crohn's disease or ulcerative colitis, and psoriasis.

[0349] In some embodiments, the condition can be selected from inflammatory bowel disease (IBD) and psoriasis.

[0350] 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.

[0351] 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.

[0352] The compounds described herein may be administered by any common or standard mode of administration in the art, such as orally, intravenously, intramuscularly, subcutaneously, sublingually, intranasally, intradermally, via suppository route, or by implantation. In the preferred embodiments of the present invention described herein, administration is by oral administration. [Examples]

[0353] 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.

[0354] Amino acids and specific R 2The 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: Efficacy Percentage pSTAT3 phosphorylation signaling transcription factor 3 BRET Bioluminescence Resonance Energy Transfer TAMRA 5'-Tetramethylrhodamine-5-Carboxamide

[0355] 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]

[0356] Compound synthesis The following compounds listed in Table 1-1 below were synthesized. [Table 15] JPEG2026518788000048.jpg255170 JPEG2026518788000049.jpg251170 JPEG2026518788000050.jpg251170 JPEG2026518788000051.jpg221170 JPEG2026518788000052.jpg251170 JPEG2026518788000053.jpg251170 JPEG2026518788000054.jpg217170 JPEG2026518788000055.jpg252170 JPEG2026518788000056.jpg139170

[0357] 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, [4,7] is a cross-link between amino acid residues 4 and 7, and [1,11] is a cross-link between amino acid residues 1 and 11. * This indicates that the crosslinks in (1c), (2a), (2c), and (4c) use the amine or carboxylic acid in the N-terminal or C-terminal peptide backbone, rather than the amine or carboxylic acid in the side chain. (1c) represents a [2,11] lactam bridge, (2a) represents a [4,7] 1,3-dithio-propane-2-one bridge, (2c) represents a [4,7] lactam bridge, and (4c) represents a [1,11] lactam bridge.

[0358] The compound numbers in Table 1-1 correspond to the same numbers as the sequence numbers shown in Table 1-1a below. [Table 16] JPEG2026518788000058.jpg242170 JPEG2026518788000059.jpg241170 JPEG2026518788000060.jpg241170 JPEG2026518788000061.jpg84170In the table, * This indicates that the crosslinks in (1c), (2a), (2c), and (4c) use the amine or carboxylic acid in the N-terminal or C-terminal peptide backbone, rather than the amine or carboxylic acid in the side chain. (1c) represents a [2,11] lactam bridge, (2a) represents a [4,7] 1,3-dithio-propane-2-one bridge, (2c) represents a [4,7] lactam bridge, and (4c) represents a [1,11] lactam bridge.

[0359] For comparison, four compounds containing two 1,3-dithio-propan-2-one bridges, as described by Kong et al., 2020 (Nature Biomedical Engineering, 2020, 4, 560-571), were synthesized (Table 1-2). [Table 17]

[0360] (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.

[0361] 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 18]

[0362] (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.

[0363] Other synthesized reference compounds are listed in Table 1-4. These reference compounds were disclosed in International Publication No. 2023 / 099669. [Table 19] JPEG2026518788000065.jpg250170 JPEG2026518788000066.jpg51170

[0364] (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.

[0365] Unless otherwise specified, the reagents and solvents used below are commercially available in standard laboratory or analytical grades and were used without further purification.

[0366] 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.

[0367] TentaGel® was used as the polymer support base resin. The synthesizer was filled with resin that had been swollen with DMF before use.

[0368] Without making any changes to the basic procedure, naturally occurring amino acids and other suitable building blocks were used.

[0369] 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.

[0370] 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.

[0371] 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.

[0372] 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.

[0373] 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.

[0374] 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.

[0375] 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.

[0376] 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.

[0377] Dithioether formation: A method for forming a dithioether from the reaction of two unprotected cysteines with a linker can be carried out as previously described in Kong et al., 2020 (Nature Biomedical Engineering, 2020, 4, 560-571), or by the modified method described below.

[0378] The crude intermediate peptide was dissolved in a 3:7 mixture of water / acetonitrile (1 mg / mL). DODT (2 equivalents) was added, and the mixture was stirred at room temperature for 10 minutes. The pH was adjusted to pH 8 by adding 0.2 M ammonium carbonate. Linker (2 equivalents) was added directly to the solution, and the mixture was allowed to shake overnight at room temperature. The solution was filtered through a 0.45 μm filter and loaded directly onto a preparative HPLC column for final purification.

[0379] Examples of linkers used in synthetic compounds include the following: • 1,3-Dibromopropan-2-one, CAS number 816-39-7.

[0380] Gly-CF3 and D-Gly-CF3: The diamino acids "Fmoc-Gly-CF3-3Pal-OH" and "Fmoc-D-Gly-CF3-3Pal-OH" were synthesized using the same synthetic procedure as "Fmoc-Gly-CF3-Phe-OH" (i.e., compound 4c shown in Table 1 after hydrolysis step (i) of scheme 1b), as described in Solid-Phase Synthesis of Gly-Ψ[CH(CF3)NH]-Peptides, Sgorbati et al., J. Org. Chem, 2021, 86, 9225-9232. These diamino acids were used, for example, in the synthesis of compounds 16 and 17.

[0381] 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 or replaced. For example, peptides with standard lysine in their sequence were synthesized using the unit Fmoc-Lys(Boc)-OH, where Fmoc is the N-terminal amine protecting group and Boc is the side-chain protecting group. Conversely, peptides containing iso-Lys 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.

[0382] The side-chain protecting group "Boc" may be replaced with the "Alloc" protecting group when performing side-chain on-resin modification.

[0383] 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).

[0384] 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.

[0385] Those skilled in the art will understand that the compounds of the present invention can be produced using standard peptide synthesis methods. [Examples]

[0386] 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.

[0387] The inventors identified Ref122 as a preferred compound from International Publication No. 2023 / 099669 (Compound 122 in International Publication No. 2023 / 099669). [Table 20]

[0388] Ref122 was powerful (K i hIL-23R has a molecular weight of 0.00541 nM, compared to an IC with a molecular weight of 0.0066 nM. 50 (hIL-23R) and 0.028nM IC 50 (equivalent to pSTAT3 - see Examples 3-1 and 3-2, Tables 3-1 and 3-2 below). However, Ref122 was not stable under SIF assay (only 25% of intact Ref122 remained after 4 hours in the SIF assay - see Example 3-3, Table 3-3 below), which suggests that its stability in the gastrointestinal tract is not sufficient.

[0389] The inventors identified the major metabolites formed after incubation of Ref122 in an SIF assay. These included peptides that lacked the C-terminal 3Pal(3-(3-pyridyl)-Ala) amino acid.

[0390] Therefore, based on this insight and using Ref122 as a peptide starting point, we attempted four different methods to improve SIF by addressing the C-terminus. (i) Changing the C-terminal amino acid to a D-isomer amino acid, (ii) Methylating the C-terminal amino acid, (iii) Adding a non-natural amino acid to the C-terminus, (iv) Derivatization of the C-terminus.

[0391] (i) Change the C-terminal amino acid to a D-isomer amino acid. The inventors modified the C-terminal 3-Pal of Ref122 to D-3-Pal and D-His. The D-His and D-3-Pal modifications moderately improved SIF stability, with intact peptides remaining at 41% and 56% after 4 hours, respectively (Table 2-1). However, both modifications slightly reduced the potency of the compound. [Table 21] JPEG2026518788000069.jpg7170

[0392] (ii) Methylation of the C-terminal amino acid Furthermore, to prevent cleavage, the inventors methylated the C-terminal 3-Pal of Ref122. They methylated the 2-position of 3-Pal (2-Me-3-Pal), methylated the amine group of 3-Pal (N-Me-3-Pal), and methylated the C-terminal amide (C=NHMe).

[0393] All three modifications significantly improved SIF stability, with over 80% of the intact peptide remaining after 4 hours (Table 2-2). 2-Me-3-Pal and N-Me-3-Pal slightly reduced the compound's potency. However, methylation of the C-terminal amide preserved potency. Therefore, C-terminal methylation improved SIF stability while maintaining the compound's potency. [Table 22]

[0394] (iii) Adding a non-natural amino acid to the C-terminus The inventors also tested whether the 3-Pal cleavage of Ref122 could be prevented by adding an additional non-natural amino acid residue to the C-terminus. They tested the addition of sarcosine (Sar), D-histidine ({d}H), and beta-homo-Leu at position 14.

[0395] The addition of D-histidine did not increase the stability of SIF, but the modification preserved the compound's potency (Table 2-3).

[0396] However, the addition of Sar and beta-homo-Leu significantly improved SIF stability, with the amount of intact peptide remaining after 4 hours exceeding 102% (Table 2-3). The addition of beta-homo-Leu slightly reduced the potency of the compound, while the addition of Sar maintained the potency. [Table 23]

[0397] (iv) Derivatization of the C-terminus Finally, the inventors also tested whether the removal of 3-Pal and the derivatization of the C-terminal group would prevent the decomposition of Ref122. The C-terminus was derivatized using an alkyl group substituted with a pyridyl group.

[0398] Both C-terminal derivatives tested significantly improved SIF stability and prevented degradation of the intact peptide after 4 hours (Table 2-4). The C-terminal derivatives slightly reduced the potency of the compounds; compound 7, containing the shorter derivative "NH-(2-(pyridine-3-yl)ethyl)", was more potent than compound 6, which had the longer derivative "NH-(4-(pyridine-3-yl)butanyl)". [Table 24]

[0399] In conclusion, the inventors have found four methods for improving the SIF stability of the compounds disclosed herein. These modifications, used individually or in combination, can improve the SIF stability of the compounds and, in many cases, also maintain or improve the efficacy of the compounds against IL-23R.

[0400] In particular, the inventors identified compound 8 of (ii), compound 9 of (iii), and compound 7 of (iv) as particularly potent and SIF-stable compounds. [Examples]

[0401] 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.

[0402] 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.

[0403] 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.

[0404] 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.

[0405] 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.

[0406] 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.

[0407] K of Compounds in International Publication No. 2023 / 099669 i Value and corresponding IC 50 value [Table 25] [Table 26] JPEG2026518788000075.jpg255170 JPEG2026518788000076.jpg103170 [Example 3-2]

[0408] 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.

[0409] 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.

[0410] 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. 6The 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. 80 Only 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).

[0411] 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. 50Compound 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 the following characteristics are desirable. Typically, compounds capable of completely inhibiting the IL23-induced response are desirable. Due to experimental error in specific assays, typically, a value equal to or greater than 95% is considered capable of completely inhibiting IL23R-induced signaling. [Table 27] JPEG2026518788000078.jpg251170 JPEG2026518788000079.jpg37170 [Examples 3-3 and 3-4]

[0412] 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).

[0413] 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.

[0414] 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]

[0415] 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] [Examples 3-5]

[0416] 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.

[0417] The assay procedure was as follows:

[0418] 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).

[0419] 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).

[0420] 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.

[0421] 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.

[0422] 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].

[0423] 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).

[0424] 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.

[0425] Compound potency (IC 50The data for ) and maximum inhibition (%) are shown in Table 3-5.

[0426] 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]

[0427] (References) Cheng and Prusoff, Biochem. Pharmacol., 1973, 22(23), 3099-3108. Kong et al., Nature Biomedical Engineering, 2020, 4, 560-571. Sgorbati et al., J. Org. Chem, 2021, 86, 9225-9232. 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

[0428] Clause 1. Formula: ZR2 A compound of which, in the formula, R 2 NHR 3 And R 3 C may be substituted with hydrogen or a pyridyl ring. 1-4 It is alkyl, Z is given by equation I: X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14 (I) This is the amino acid sequence, and in the sequence, X1 is either absent or selected from 3-(3-pyridyl)-Ala or 3-aminopropanoyl. X2 is selected from the group consisting of 4-aminomethylphenylacetyl, 3-(3-pyridyl)-Ala, and 3-aminopropanoyl. X3 is selected from the group consisting of Ser, Ala, Phe, and N-Me-Ser. X4 is either Glu or Cys. X5 is a trumpet, X6 is selected from the group consisting of Gln, Q(Me), Q(2Me), Q(pyrrolidine), Ala, Phe, Lys(Ac), Dab(Ac), Cit, and Orn. X7 is either Dab or Cys. X8 is selected from the group consisting of Y(2-aminoethoxy), homo-Phe, 7-AzaTrp, beta-homo-Trp, and 7-F-Trp. X9 is selected from the group consisting of 2-Nal, 7-AzaTrp, beta-homo-Trp, and cyclopropyl-Ala. X10 is 2-Me-Leu or Aib, X11 is Glu, X12 is selected from the group consisting of Dab, iso-Dab, D-Arg, Gly-CF3, D-Gly-CF3, Nle, Gln, His, THP, Ser, D-Ser, 2-Me-Ser, Ser(OMe), and homo-Ser. X13 is selected from the group consisting of 3-(3-pyridyl)-Ala, D-3-(3-pyridyl)-Ala, 2-Me-3-(3-pyridyl)-Ala, N-Me-3-(3-pyridyl)-Ala, 3-(3,5-pyrimidyl)-Ala, His, D-His, and His(Me), or is not present. X14 is either absent or selected from the group consisting of Sar, D-His, beta-homo-Leu, and 3-(3-pyridyl)-Ala. In the array, (i) The Glu of X11 forms a lactam crosslink with the amino acid residue of X1, or if X1 is not present, the amino acid residue of X2. (ii) X4 and X7 are amino acid residues that together form a lactam crosslink or a dithioether crosslink. compound, or a pharmaceutically acceptable salt or solvate thereof, The compound is [Table 31] Furthermore, rather than its pharmaceutically acceptable salts and solvates, In the table, * This indicates that the crosslinking in (1c), (2a), and (2c) uses the amine or carboxylic acid of the N-terminal or C-terminal peptide backbone, rather than the amine or carboxylic acid of the side chain. (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. compound, or a pharmaceutically acceptable salt or solvate thereof.

[0429] 2. X1 is absent, X2 is 4-aminomethylphenylacetyl, X3 is Ser or N-Me-Ser, X6 is Gln or Q (pyrrolidine), X8 is Y (2-aminoethoxy), X9 is 2-Nal, X10 is 2-Me-Leu, X12 is Dab, D-Arg, or Ser, X13 is 3-(3-pyridyl)-Ala or absent, X14 is absent, and R 2 The compounds described in Clause 1, not those in which NH2 is present.

[0430] 3. A compound as described in Clause 1 or 2, in which X1 is not present.

[0431] 4. A compound according to any one of the clauses 1 to 3, wherein X2 is 4-aminomethylphenylacetyl.

[0432] 5. A compound according to any one of clauses 1 to 4, wherein X3 is Ser or Ala.

[0433] 6. The compound described in Clause 5, wherein X3 is Ser.

[0434] 7. A compound according to any one of clauses 1 to 6, wherein X4 is Glu, X7 is Dab, and X4 and X7 together form a lactam crosslink.

[0435] 8. A compound described in any one of clauses 1 to 7, wherein X6 is Gln.

[0436] 9. A compound according to any one of clauses 1 to 8, wherein X8 is Y(2-aminoethoxy).

[0437] 10. A compound according to any one of clauses 1 to 9, wherein X9 is 2-Nal.

[0438] 11. A compound according to any one of the clauses 1 to 10, wherein X10 is 2-Me-Leu.

[0439] 12. A compound described in any one of clauses 1 to 11, wherein X12 is Dab.

[0440] 13. The compound described in any one of clauses 1 to 12, wherein X13 is 3-(3-pyridyl)-Ala or is not present.

[0441] 14. The compound according to Clause 13, wherein X13 is 3-(3-pyridyl)-Ala.

[0442] 15. A compound described in any one of clauses 1 to 14, for which X14 does not exist.

[0443] 16. R 2 However, NHR 3 And R 3 However, hydrogen or C 1-4 A compound that is alkyl, as described in any one of clauses 1 to 15.

[0444] 17. R 2 A compound as described in Clause 16, wherein the compound is NH2.

[0445] 18. R 2 A compound as described in Clause 16, wherein the compound is NHMe.

[0446] 19. Both X4 and X7 are Cys, and together X4 and X7 form a dithioether crosslink, and the dithioether crosslink between X4 and X7 has the formula -SLYLS-, where, Each S is a sulfur atom and is part of the amino acid residues of X4 and X7. Each L independently, C 1-4 It is alkylene, Y either does not exist or is C (=O). A compound as described in any one of the clauses 1-6 or 8-18.

[0447] 20. Each L independently C 1-2 A compound that is alkylene, as described in Clause 19.

[0448] 21. The compound according to Clause 20, wherein each L is methylene.

[0449] 22. A compound described in any one of clauses 19 to 21, wherein Y is C (=O).

[0450] 23. The compound according to any one of clauses 19 to 22, wherein the dithioether bridge between X4 and X7 is of the formula -SCH2C(=O)CH2S-, where each S is a sulfur atom and is part of the amino acid residues of X4 and X7.

[0451] 24. A compound according to any one of clauses 1 to 23, wherein X1 is absent and X2 is 4-aminomethylphenylacetyl.

[0452] 25. A compound according to any one of clauses 1 to 24, wherein X1 is absent, X2 is 4-aminomethyl-phenylacetyl, X8 is Y(2-aminoethoxy), X9 is 2-Nal, and X10 is 2-Me-Leu.

[0453] 26. A compound according to any one of clauses 1 to 25, wherein X1 is absent, X2 is 4-aminomethylphenylacetyl, X3 is Ser or Ala, X8 is Y(2-aminoethoxy), X9 is 2-Nal, and X10 is 2-Me-Leu.

[0454] 27. A compound according to any one of clauses 1 to 26, wherein X1 is absent, X2 is 4-aminomethylphenylacetyl, X3 is Ser or Ala, X6 is Gln, X8 is Y(2-aminoethoxy), X9 is 2-Nal, and X10 is 2-Me-Leu.

[0455] 28. The compound described in any one of clauses 1 to 27, wherein X13 is 3-(3-pyridyl)-Ala and X14 is absent.

[0456] 29. X13 is 3-(3-pyridyl)-Ala, X14 is absent, and R2 A compound as described in any one of clauses 1 to 28, wherein the compound is NHMe.

[0457] 30. 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.

[0458] 31. A compound specified in Clause 1, selected from the compounds in Table 1-1, or a pharmaceutically acceptable salt or solvate thereof.

[0459] 32. A pharmaceutical composition comprising a compound described in any one of clauses 1 to 31 in combination with a pharmaceutically acceptable carrier, excipient, or medium.

[0460] 33. A method for synthesizing a compound described in any one of Clauses 1 to 31, comprising the steps of synthesizing an analog by solid-phase or liquid-phase peptide synthesis, optionally isolating and / or purifying the final product, and optionally further comprising forming an amide bond between amino acid residues at position X1 or, if X1 is absent, at positions X2 and X11, and optionally further comprising forming an amide bond between amino acid residues at positions X4 and X7 or forming two thioether bonds having a linker.

[0461] 34. A compound described in any one of Clauses 1 to 31, or a pharmaceutical composition described in Clause 32, for use in a method of medical treatment.

[0462] 35. A compound described in any one of Clauses 1 to 31 or a pharmaceutical composition described in Clause 32 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.

[0463] 36. Compounds or pharmaceutical compositions for use as described in Clause 35, for use in methods for preventing or treating inflammatory bowel disease (IBD) and / or psoriasis.

[0464] 37. Use of a compound described in any one of Clauses 1 to 31 or a pharmaceutical composition described in Clause 32 in the manufacture of a pharmaceutical for the prevention or treatment of inflammatory bowel disease (IBD), such as Crohn's disease or ulcerative colitis, psoriasis, psoriatic arthritis, and combinations thereof.

[0465] 38. Use of the compound or pharmaceutical composition described in Clause 37, where 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.

[0466] 39. 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 the step of administering to a subject an effective amount of a compound described in any one of Clauses 1 to 31 or a pharmaceutical composition described in Clause 32.

[0467] 40. Methods for the prevention or treatment of inflammatory bowel disease (IBD) and / or psoriasis as described in Clause 39.

[0468] 41. A pharmaceutical composition as described in Clause 32, 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. １－４ It is alkyl, Z is given by equation I: X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14 (I) This is the amino acid sequence, and in the sequence, X1 is either absent or selected from 3-(3-pyridyl)-Ala or 3-aminopropanoyl. X2 is an alanine residue substituted with a carbocyclic group or an aromatic or heteroaromatic group selected from the group consisting of 4-aminomethylphenylacetyl, phenyl, pyridyl, naphthyl, and quinolinyl, each of which may be substituted, 3-aminopropanoyl, 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, 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 (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, X3 is any amino acid or ω-hydroxy-C ２－６ Selected from alkanates, X4 is 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, 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, 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, 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, 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, Cys, D-Cys, Beta-Cys, D-Beta-Cys, Homo-Cys, D-Homo-Cys, Beta-Homo-Cys, N-Me-Cys, and N-Me-Homo-Cys Selected from, 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 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, 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, 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, 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, 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, Cys, D-Cys, Beta-Cys, D-Beta-Cys, Homo-Cys, D-Homo-Cys, Beta-Homo-Cys, N-Me-Cys, and N-Me-Homo-Cys Selected from, 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 an optionally substituted carbocyclic or aromatic group selected from the group consisting of optionally substituted phenyl, pyridyl, naphthyl, and quinolinyl. X9 is selected from the group consisting of an optional tryptophan residue, an optional azatryptophan residue, an optional beta-homotryptophan 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, 2-Me-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 a carbon cyclic group, aromatic group or heteroaromatic group selected from the group consisting of a Phe group which may be substituted, a Tyr residue which may be substituted, a His residue which may be substituted, 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)-imidazolidine-2-carbonyl, 3-aminopropanoyl, Gly-CF3, D-Gly-CF3, 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, 2-Me-Ser, N-Me-homo-Ser, Ser(OMe), 3-aminotetrahydrofuran-3-carbonyl, THP, 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, GABA, 2-(trimethyl-2-aminoethoxy)ethoxy]propyl, and Lys, wherein the side chain -NH of the Lys ２ is -C(=O)(CH ２ ) ｎ R Ｋ It is substituted with, where n is 0 to 2, and R Ｋ Lys is an imidazolyl, pyrimidyl, or pyridyl which may be substituted with F. Selected from the group consisting of, 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 a 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 an imidazolyl, pyrimidyl, or pyridyl which may be substituted with F, selected from the group consisting of Dab, Orn, or Lys, or is not present. X14 is absent, or selected from the group consisting of alanine residues substituted with a carbocyclic group or an aromatic or heteroaromatic group selected from the group consisting of Saar, an optionally substituted His residue, 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, and optionally substituted phenyl, pyridyl, naphthyl, and quinolinyl, respectively. In the array, (i) The amino acid residue of X11 forms a lactam crosslink with the amino acid residue of X1, or if X1 is not present, the amino acid residue of X2. (ii) X4 and X7 are amino acid residues that together form a lactam crosslink or a dithioether crosslink. compound, or a pharmaceutically acceptable salt or solvate thereof, The aforementioned compound, Table 1 Furthermore, rather than its pharmaceutically acceptable salts and solvates, In the table, ＊ This indicates that the crosslinking of (1c), (2a), and (2c) uses the amine or carboxylic acid of the N-terminal or C-terminal peptide backbone, rather than the amine or carboxylic acid of the side chain. (1c) represents a [2,11] lactam crosslink, (2a) represents a [4,7] 1,3-dithio-propan-2-one crosslink, and (2c) represents a [4,7] lactam crosslink. A compound, or a pharmaceutically acceptable salt or solvate thereof.

2. The compound according to claim 1, wherein X2 is selected from the group consisting of 4-aminomethylphenylacetyl, 3-(3-pyridyl)-Ala, and 3-aminopropanoyl.

3. The compound according to claim 1 or 2, wherein X3 is selected from the group consisting of Ser, Ala, N-Me-Ala, Phe, and N-Me-Ser.

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

5. The compound according to any one of claims 1 to 4, wherein X5 is trp or 7-Me-Trp.

6. The compound according to any one of claims 1 to 5, wherein X6 is selected from the group consisting of Gln, Q(Me), Q(2Me), Q(pyrrolidine), Ala, Phe, Lys(Ac), Lys(NMePEG3), Dab(Ac), Cit, and Orn.

7. The compound according to any one of claims 1 to 6, wherein X7 is selected from Dab or Cys.

8. X8 is Y(2-aminoethoxy), homo-Phe, F(4-morpholine), 3-quinolinylalanine, Y(2-aminoethoxy)(N(Me)2, Y(npentylamine)(N ＋ A compound according to any one of claims 1 to 7, selected from the group consisting of (Me)3), Y(2-trimethyl-PEG2), Y(2-aminoethoxy)(N(Me)2), 7-AzaTrp, beta-homo-Trp, and 7-F-Trp.

9. The compound according to any one of claims 1 to 8, wherein X9 is selected from the group consisting of 2-Na, 7-AzaTrp, beta-homo-Trp, 3-quinolinylalanine, and cyclopropyl-Ala.

10. The compound according to any one of claims 1 to 9, wherein X10 is 2-Me-Leu or Aib.

11. The compound according to any one of claims 1 to 10, wherein X11 is Glu.

12. The compound according to any one of claims 1 to 11, wherein X12 is selected from the group consisting of Dab, iso-Dab, D-Arg, Gly-CF3, D-Gly-CF3, Nle, Gln, His, THP, Ser, D-Ser, 2-Me-Ser, Ser(OMe), and homo-Ser.

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, 2-Me-3-(3-pyridyl)-Ala, N-Me-3-(3-pyridyl)-Ala, 3-(3,5-pyrimidyl)-Ala, His, D-His, and His(Me), or is absent.

14. The compound according to any one of claims 1 to 13, wherein X14 is absent or selected from the group consisting of Sar, D-His, beta-homo-Leu, and 3-(3-pyridyl)-Ala.

15. X1 is absent, X2 is 4-aminomethylphenylacetyl, X3 is Ser or N-Me-Ser, X6 is Gln or Q (pyrrolidine), X8 is Y (2-aminoethoxy), X9 is 2-Na, X10 is 2-Me-Leu, X12 is Dab, D-Arg, or Ser, X13 is 3-(3-pyridyl)-Ala or absent, X14 is absent, and R ２ NH ２ The compound according to any one of claims 1 to 14, which is not the case in the aforementioned case.

16. X1 does not exist, Optionally, X2 is 4-aminomethylphenylacetyl. Optionally, X3 is either Ser or Ala, and optionally, X3 is Ser. Optionally, X6 is Gln. The compound according to any one of claims 1 to 15.

17. X8 is Y(2-aminoethoxy), Optionally, X9 is 2-Nal. Optionally, X10 is 2-Me-Leu, Optionally, X12 is Dab. The compound according to any one of claims 1 to 16.

18. X13 is either 3-(3-pyridyl)-Ala or is absent, and optionally X13 is 3-(3-pyridyl)-Ala, Optional selection, X14 does not exist. The compound according to any one of claims 1 to 17.

19. R ２ However, NHR ３ And R ３ is hydrogen or C １－４ It is an alkyl group, and R is optionally selected. ２ NH ２ The compound according to any one of claims 1 to 18, or NHMe.

20. The compound according to any one of claims 1 to 19, wherein X4 is Glu, X7 is Dab, and X4 and X7 together form a lactam crosslink.

21. Both X4 and X7 are Cys, and together X4 and X7 form a dithioether crosslink, and the dithioether crosslink between X4 and X7 has the formula -S-L-Y-L-S-, where, Each S is a sulfur atom and is part of the amino acid residues of X4 and X7. Each L independently, C １－４ It is alkylene, Y either does not exist or is C (=O), Optionally, each L independently becomes C １－２ It is an alkylene, and each L is optionally methylene. By choice, Y is C (=O), Optionally, the dithioether crosslink between X4 and X7 is of formula -SCH ２ C(=O)CH ２ It is S-, and each S is a sulfur atom and part of the amino acid residues of X4 and X7. The compound according to any one of claims 1 to 19.

22. Either X1 is absent and X2 is 4-aminomethylphenylacetyl, or Either X1 is absent, X2 is 4-aminomethylphenylacetyl, X8 is Y(2-aminoethoxy), X9 is 2-Na, and X10 is 2-Me-Leu, or Either X1 is absent, X2 is 4-aminomethylphenylacetyl, X3 is Ser or Al, X8 is Y(2-aminoethoxy), X9 is 2-Na, and X10 is 2-Me-Leu, or Either X1 is absent, X2 is 4-aminomethylphenylacetyl, X3 is Ser or Al, X6 is Gln, X8 is Y(2-aminoethoxy), X9 is 2-Na, and X10 is 2-Me-Leu, or X13 is 3-(3-pyridyl)-Ala and X14 is absent, or X13 is 3-(3-pyridyl)-Ala, X14 is absent, and R ２ That is NHMe. The compound according to any one of claims 1 to 21.

23. Z is Table 2 An amino acid sequence selected from the group consisting of, ＊ This indicates that the crosslinks in (1c), (2a), (2c), and (4c) use the amine or carboxylic acid of the N-terminal or C-terminal peptide backbone, rather than the amine or carboxylic acid of the side chain. (1c) represents a [2,11] lactam bridge, (2a) represents a [4,7] 1,3-dithio-propan-2-one bridge, (2c) represents a [4,7] lactam bridge, and (4c) represents a [1,11] lactam bridge. The compound according to claim 1. 【Request Item 24】 【Table 3】 A compound selected from, or a pharmaceutically acceptable salt or solvate thereof, In the table, ＊ This indicates that the crosslinks in (1c), (2a), (2c), and (4c) use the amine or carboxylic acid of the N-terminal or C-terminal peptide backbone, rather than the amine or carboxylic acid of the side chain. (1c) represents a [2,11] lactam bridge, (2a) represents a [4,7] 1,3-dithio-propan-2-one bridge, (2c) represents a [4,7] lactam bridge, and (4c) represents a [1,11] lactam bridge. The compound according to claim 1.

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

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

27. A method for synthesizing a compound according to any one of claims 1 to 24, comprising the steps of synthesizing an analog by solid-phase or liquid-phase peptide synthesis, optionally isolating and / or purifying the final product, and optionally further comprising forming an amide bond between amino acid residues at position X1, or, if position X1 is absent, at positions X2 and X11, and optionally further comprising forming an amide bond between amino acid residues at positions X4 and X7 or forming two thioether bonds having a linker.

28. A compound according to any one of claims 1 to 24, or a pharmaceutical composition according to claim 25 or 26, for use in a method of medical treatment.

29. A compound according to any one of claims 1 to 24 or a pharmaceutical composition according to claim 25 or 26 for use in methods for preventing or treating inflammatory bowel disease (IBD), psoriasis, psoriatic arthritis, and combinations thereof.

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

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