Peptide inhibitors of interleukin-23 receptor

Abstract

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

Description

Technical Field

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

[0002] Interleukin-23 (IL-23) is a heterodimeric 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 T helper 1 (Th1) cells that produce interferon-gamma (IFN-γ). Although both IL-23 and IL-12 contain p40 subunits, they have different phenotypic characteristics. Animals lacking IL-12 are susceptible to inflammatory autoimmune diseases, while animals lacking IL-23 are resistant. This is thought to be because the central nervous system (CNS) of animals lacking IL-23 produces interleukin-6 (IL-6), interleukin-17 (IL-17), and CD4+ of tumor necrosis factor (TNF). + A decrease in the number of T cells. Furthermore, compared to the primary action of naïve CD4 cells... + Compared to IL-12 in T cells, IL-23 preferentially acts on memory CD4 cells. + T cells.

[0003] The receptor that binds to IL-23 is the interleukin-23 receptor (IL-23R). IL-23R is a heterodimeric receptor composed of the IL-12Rβ1 and IL-23R subunits. The binding of IL-23 to IL-23R activates the JAK-STAT signaling pathway: activating the Janus kinase (JAK) molecules JAK2 and tyrosine kinase 2 (TYK2), as well as the signal transducer and activator of transcription (STAT) proteins STAT1, STAT3, STAT4, and STAT5. In response to IL-23, STAT4 activation is significantly weaker than in response to IL-12, and a distinct DNA-binding STAT complex is formed. IL-23R constitutively associates with JAK2 and with STAT3 in a ligand-dependent manner.

[0004] IL-23R is expressed on a variety of adaptive and innate immune cells, including T-helper 17 (Th17) cells, γ-δ (γδ) T cells, natural killer (NK) cells, dendritic cells, macrophages, and innate lymphocytes. These cells are abundant in the intestine. In particular, elevated gene expression and protein levels of IL-23R have been found on the intestinal mucosal surface in patients with inflammatory bowel disease (IBD). It is believed that IL-23R promotes the production of pathogenic CD4+ IL-6, IL-17, and TNF. + This function is mediated by the development of T cell populations.

[0005] IL-23 is abundant in the gut, where it is believed to play a crucial role in regulating the balance between tolerance and immunity through both T-cell-dependent and T-cell-independent pathways of intestinal inflammation, influencing Th1 and Th17-related cytokines. IL-23 is also thought to suppress regulatory T-cell responses in the gut, thus favoring inflammation. Furthermore, IL-23R polymorphisms have been associated with susceptibility to inflammatory bowel disease (IBD), further confirming the critical role of the IL-23 pathway in intestinal homeostasis.

[0006] Therefore, IL-23 is considered 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), such as 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) has been approved for the treatment of inflammatory diseases, including psoriasis, psoriatic arthritis, and Crohn's disease, and is also being investigated for the treatment of ulcerative colitis.

[0008] Protagonist Therapeutics, Inc.'s IL-23 antagonist peptide PTG-200 is currently in a Phase II clinical trial for Crohn's disease. Protagonist, in collaboration with Janssen Biotech, Inc., also has two second-generation IL-23 antagonist peptides in clinical trials: JNJ-77242113 (or JNJ-2113; formerly PN-235) for psoriasis; and PN-232. Protagonist has filed several patent applications in the field of IL-23R inhibitors: WO 2016 / 011208, WO 2017 / 011820, WO 2018 / 022937, WO 2018 / 136646, WO 2020 / 014646, WO 2021 / 007433, WO 2021 / 146441, WO 2021 / 146458, WO 2023 / 288017, WO 2023 / 288019, WO 2023 / 288028 and WO 2024 / 015958. Protagonist also disclosed another peptide, compound C, as an IL-23R inhibitor in WO 2016 / 011208, WO 2017 / 011820 and Sayago et al., 2018.

[0009] It is noteworthy that the peptides disclosed in the aforementioned Protagonist patent applications WO 2016 / 011208, WO 2017 / 011820, WO 2018 / 022937, WO 2018 / 136646, WO 2020 / 014646, WO 2021 / 007433, WO 2021 / 146441, WO 2021 / 146458, WO 2023 / 288028, and WO 2024 / 015958 contain only a single bridging portion. None of these applications disclose the use of two bridging portions to stabilize peptide inhibitors of IL-23R.

[0010] Kong et al., 2020, disclosed the development of a proteolytically resistant therapeutic peptide for oral administration. The authors derived a peptide as an inhibitor of coagulation factor Xia and other peptides as antagonists of gastrointestinal protease resistance to IL-23R. The peptide derived as an IL-23R antagonist contains two disulfide bridges (specifically, a 1,3-dithio-propane-2-one bridge) 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 treatment for inflammatory disorders such as Crohn's disease.

[0011] WO 2023 / 288017 discloses bicyclic (and some tricyclic) peptide inhibitors of IL-23R. These peptides are up to 15 amino acid residues long, and all of them have (at least) two bonds bridging some amino acid residues. WO 2023 / 288019 discloses esterified peptide inhibitors of IL-23R. These peptides are up to 15 amino acid residues long and have one or two bonds bridging some amino acid residues. In peptides with two bridges, one is a disulfide bond or a disulfide ether bond and the other is an amide bond. Both applications propose the use of inhibitors to treat autoimmune inflammatory diseases and related disorders, including IBD, Crohn's disease, ulcerative colitis, psoriasis, and psoriatic arthritis.

[0012] However, none of the peptides disclosed in Kong et al., 2020, WO 2023 / 288017 and WO 2023 / 288019 have the same bridges as those in this invention—neither in position, bond type and / or in the number of amino acid residues between the bridging amino acids.

[0013] Challenges remain in identifying stable and selective drugs that preferentially target the IL-23 pathway for the treatment of intestinal inflammation, such as intestinal diseases including Crohn's disease, ulcerative colitis, and related conditions. In particular, for orally administered IL-23R peptide blockers, the inventors have determined that the gastrointestinal stability and IL-23R potency of the peptides disclosed in Kong et al., 2020, can still be further improved. Specifically, compared to Protagonist's compound C (Sayago et al., 2018), Kong et al., 2020's most promising candidate peptide I5 exhibited lower stability and lower IL-23R potency in simulated intestinal fluid (SIF) assays.

[0014] Therefore, there remains a need for novel therapies targeting the IL-23 pathway, which could be used to treat and prevent IL-23-related diseases, including those associated with autoimmune inflammation in the gut. Furthermore, compounds and methods for specifically targeting IL-23R from the intestinal lumen could provide therapeutic benefits to IBD patients with localized inflammation in the intestinal tissue.

[0015] The inventors have also filed WO 2023 / 099669 regarding peptide inhibitors involving IL-23R. This invention relates to additional peptide inhibitors that have improved stability in the gastrointestinal tract and / or more effective inhibition of IL-23R compared to the peptides disclosed in WO 2023 / 099669. Summary of the Invention

[0016] This invention relates to compounds that are peptide inhibitors of the interleukin-23 receptor (IL-23R). These compounds exhibit a favorable combination of properties, such as potent inhibition of IL-23R and / or high stability in the gastrointestinal tract. Furthermore, the compounds described herein can be used to treat a variety of diseases, conditions, and disorders involving IL-23R, such as inflammatory bowel disease, Crohn's disease, ulcerative colitis, and psoriasis. The compounds described herein also exhibit improved properties compared to those disclosed in WO2023 / 099669.

[0017] This invention addresses these needs by providing novel peptide inhibitors that bind to IL-23R to inhibit IL-23-mediated signaling. Due to their stability in the gastrointestinal tract, these novel peptide inhibitors are also suitable for oral administration.

[0018] In a first aspect, the present invention provides compounds of the following formula, or pharmaceutically acceptable salts or solvates thereof:

[0019] ZR 2

[0020] in

[0021] R 2 It is NHR 3 Or C(=O)R 3 , where R 3 It is a C that is hydrogen or optionally substituted with a pyridine ring. 1-6 Alkyl groups, or those that are not present; and

[0022] Z is the amino acid sequence of formula I:

[0023]

[0024] in

[0025] X2 is selected from:

[0026] Lys, D-lys, iso-Lys, D-iso-Lys, β-Lys, D-β-Lys, homo-Lys, D-homo-Lys, β-homo-Lys, N-Me-Lys, N-Me-homo-Lys, (N3)-Lys, D-(N3)-Lys, (N3)-β-Lys, (N3)-D-β-Lys, (N3)-high-Lys, (N3)-D-high-Lys, (N3)-β-high-Lys,

[0027] Dpr, D-Dpr, iso-Dpr, D-iso-Dpr, β-Dpr, D-β-Dpr, high-Dpr, D-high-Dpr, β-high-Dpr, N-Me-Dpr, N-Me-high-Dpr, (N3)-Dpr, D-(N3)-Dpr, (N3)-β-Dpr, (N3)-D-β-Dpr, (N3)-high-Dpr, (N3)-D-high-Dpr, (N3)-β-high-Dpr,

[0028] Dab, D-Dab, iso-Dab, D-iso-Dab, β-Dab, D-β-Dab, homo-Dab, D-homo-Dab, β-homo-Dab, N-Me-Dab, N-Me-homo-Dab, (N3)-Dab, D-(N3)-Dab, (N3)-β-Dab, (N3)-D-β-Dab, (N3)-high-Dab, (N3)-D-high-Dab, (N3)-β-high-Dab,

[0029] Orn, D-Orn, Different-Orn, D-Different-Orn, β-Orn, D-β-Orn, High-Orn, D-High-Orn, β-High-Orn, N-Me-Orn, N-Me-High-Orn, (N3)-Orn, D-(N3)-Orn, (N3)-β-Orn, (N3)-D-β-Orn, (N3)-High-Orn, (N3)-D-High-Orn, (N3)-β-High-Orn

[0030] Lys(Gly),

[0031] Asp, D-Asp, iso-Asp, D-iso-Asp, β-Asp, D-β-Asp, homo-Asp, D-homo-Asp, β-homo-Asp, N-Me-Asp, N-Me-homo-Asp, (N3)-Asp, D-(N3)-Asp, (N3)-β-Asp, (N3)-D-β-Asp, (N3)-high-Asp, (N3)-D-high-Asp, (N3)-β-high-Asp,

[0032] Glu, D-Glu, iso-Glu, D-iso-Glu, β-Glu, D-β-Glu, homo-Glu, D-homo-Glu, β-homo-Glu, N-Me-Glu, N-Me-homo-Glu, (N3)-Glu, D-(N3)-Glu, (N3)-β-Glu, (N3)-D-β-Glu, (N3)-ho-Glu, (N3)-D-ho-Glu, (N3)-β-ho-Glu,

[0033] 2-Amino-6-carboxyhexanoyl and 3-aminopropionyl;

[0034] X3 is selected from any amino acid, ω-hydroxy-C 2-6 Alkyl acids may not exist;

[0035] X4 is Val, D-Val, β-Val, D-β-Val, Homo-Val, D-homo-Val, β-homo-Val, N-Me-Val, N-Me-homo-Val, 2-Me-Val,

[0036] Ala, D-Ala, β-Ala, D-β-Ala, Homo-Ala, D-homo-Ala, β-homo-Ala, N-Me-Ala, N-Me-homo-Ala,

[0037] Gly, β-Gly, homo-Gly, β-homo-Gly, N-Me-Gly, N-Me-homo-Gly,

[0038] Leu, D-Leu, β-Leu, D-β-Leu, high-Leu, D-high-Leu, β-high-Leu, N-Me-Leu, N-Me-high-Leu, 2-Me-Leu,

[0039] Ile, D-Ile, β-Ile, D-β-Ile, high-Ile, D-high-Ile, β-high-Ile, N-Me-Ile, N-Me-high-Ile or do not exist;

[0040] X5 is selected from optionally substituted tryptophan residues, optionally substituted azatryptophan residues, and optionally substituted β-homotraphan residues;

[0041] X6 is selected from optionally substituted Gln residues, optionally substituted Lys residues, optionally substituted Arg residues, optionally substituted Dab residues, optionally substituted Orn residues, optionally substituted Phe residues, Ala, D-Ala, β-Ala, D-β-Ala, high-Ala, D-high-Ala, β-high-Ala, N-Me-Ala, N-Me-high-Ala, Cit, D-Cit, β-Cit, D-β-Cit, high-Cit, D-high-Cit, β-high-Cit, N-Me-Cit, N-Me-high-Cit, Glu, D-Glu, iso-Glu, D-iso-Glu, β-Glu, D-β-G lu, Homo-Glu, D-homo-Glu, β-homo-Glu, N-Me-Glu, N-Me-ho-Glu, Tyr, D-Tyr, β-Tyr, D-β-Tyr, Homo-Tyr, D-homo-Tyr, β-homo-Tyr, N-Me-Tyr, N-Me-homo-Tyr, Val, D-Val, β-Val, D-β-Val, Homo-Val, D-homo-Val, β-homo-Val, N-Me-Val, N-Me-homo-Val or His, D-His, β-His, D-β-His, homo-His, D-homo-His, β-homo-His, N-Me-His, and N-Me-homo-His;

[0042] X7 is selected from Asp, D-Asp, hetero-Asp, D-heterogeneous-Asp, β-Asp, D-β-Asp, high-Asp, D-high-Asp, β-high-Asp, N-Me-Asp, N-Me-high-Asp.

[0043] Glu, D-Glu, iso-Glu, D-iso-Glu, β-Glu, D-β-Glu, homo-Glu, D-homo-Glu, β-homo-Glu, N-Me-Glu, N-Me-homo-Glu,

[0044] Dab, D-Dab, iso-Dab, D-iso-Dab, β-Dab, D-β-Dab, homo-Dab, D-homo-Dab, β-homo-Dab, N-Me-Dab, N-Me-homo-Dab,

[0045] Orn, D-Orn, Different-Orn, D-Different-Orn, β-Orn, D-β-Orn, High-Orn, D-High-Orn, β-High-Orn, N-Me-Orn, N-Me-High-Orn

[0046] Lys, D-Lys, iso-Lys, β-Lys, D-iso-Lys, D-β-Lys, homo-Lys, D-homo-Lys, β-homo-Lys, N-Me-Lys, N-Me-homo-Lys,

[0047] Pra, D-Pra, β-Pra, D-β-Pra, high-Pra, D-high-Pra, β-high-Pra, N-Me-Pra, N-Me-high-Pra,

[0048] Hpg, D-Hpg, β-Hpg, D-β-Hpg, high-Hpg, D-high-Hpg, β-high-Hpg, N-Me-Hpg, and N-Me-high-Hpg;

[0049] X8 is selected from optionally substituted tryptophan residues, optionally substituted azatryptophan residues, optionally substituted β-homotrapetin residues, optionally substituted tyrosine residues, optionally substituted phenylalanine residues, optionally substituted homophenylalanine residues, and alanine residues substituted with a carbocyclic group or an aromatic or heteroaromatic group, wherein the aromatic or heteroaromatic group is selected from phenyl, pyridyl, naphthyl, and quinolinyl, each optionally substituted.

[0050] X9 is selected from optionally substituted tryptophan residues, optionally substituted azatryptophan residues, optionally substituted alanine residues, optionally substituted phenylalanine residues, and optionally substituted tyrosine residues.

[0051] X10 is selected from,

[0052] Val, D-Val, β-Val, D-β-Val, Homo-Val, D-homo-Val, β-homo-Val, N-Me-Val, N-Me-homo-Val, 2-Me-Val,

[0053] Gly, β-Gly, homo-Gly, β-homo-Gly, N-Me-Gly, N-Me-homo-Gly,

[0054] Dab, D-Dab, iso-Dab, D-iso-Dab, β-Dab, D-β-Dab, homo-Dab, D-homo-Dab, β-homo-Dab, N-Me-Dab, N-Me-homo-Dab,

[0055] Lys, D-lys, iso-Lys, D-iso-Lys, β-Lys, D-β-Lys, homo-Lys, D-homo-Lys, β-homo-Lys, N-Me-Lys, N-Me-homo-Lys,

[0056] Aib, D-Aib, β-Aib, D-β-Aib, Homo-Aib, D-homo-Aib, β-homo-Aib, N-Me-Aib, N-Me-ho-Aib,

[0057] Ala, D-Ala, β-Ala, D-β-Ala, Homo-Ala, D-homo-Ala, β-homo-Ala, N-Me-Ala, N-Me-homo-Ala,

[0058] Leu, D-Leu, β-Leu, D-β-Leu, high-Leu, D-high-Leu, β-high-Leu, N-Me-Leu, N-Me-high-Leu, 2-Me-Leu,

[0059] Ile, D-Ile, β-Ile, D-β-Ile, high-Ile, D-high-Ile, β-high-Ile, N-Me-Ile, N-Me-high-Ile,

[0060] And carbocyclic or heterocyclic rings with amino and carbonyl substituents;

[0061] X11 is selected from:

[0062] Dpr, D-Dpr, iso-Dpr, D-iso-Dpr, β-Dpr, D-β-Dpr, high-Dpr, D-high-Dpr, β-high-Dpr, N-Me-Dpr, N-Me-high-Dpr,

[0063] Dab, D-Dab, iso-Dab, D-iso-Dab, β-Dab, D-β-Dab, homo-Dab, D-homo-Dab, β-homo-Dab, N-Me-Dab, N-Me-homo-Dab,

[0064] Orn, D-Orn, Different-Orn, D-Different-Orn, β-Orn, D-β-Orn, High-Orn, D-High-Orn, β-High-Orn, N-Me-Orn, N-Me-High-Orn

[0065] Lys, D-lys, iso-Lys, D-iso-Lys, β-Lys, D-β-Lys, homo-Lys, D-homo-Lys, β-homo-Lys, N-Me-Lys, N-Me-homo-Lys, Lys(Me),

[0066] Lys(Gly),

[0067] Asp, D-Asp, hetero-Asp, D-heterogeneous-Asp, β-Asp, D-β-Asp, high-Asp, D-high-Asp, β-high-Asp, N-Me-Asp, N-Me-high-Asp

[0068] Glu, D-Glu, iso-Glu, D-iso-Glu, β-Glu, D-β-Glu, homo-Glu, D-homo-Glu, β-homo-Glu, N-Me-Glu, N-Me-homo-Glu, and

[0069] 2-Amino-6-carboxyhexanoyl;

[0070] X12 is selected from: optionally substituted Phe residues; optionally substituted Tyr residues; optionally substituted His residues; alanine residues substituted with a carbocyclic group or an aromatic or heteroaromatic group selected from phenyl, pyridyl, naphthyl, and quinolinyl, each optionally substituted; Dab, D-Dab, iso-Dab, D-iso-Dab, β-Dab, D-β-Dab, high-Dab, D-high-Dab, β-high-Dab, N-Me-Dab, N-Me-high-Dab, Gly, β-Gly, high-Gly, β-high-Gly, N-Me-Gly, N-Me-high-Gly, Pro, 5-aminopentanoyl, 4-aminopiperidin-4-carbonyl, (R,S)-imidazolidine-2-carbonyl, 3-aminopropionyl, Gly-CF3, D-Gly-CF3, Nle, Gln, D -Gln, iso-Gln, D-iso-Gln, β-Gln, D-β-Gln, homo-Gln, D-homo-Gln, β-homo-Gln, N-Me-Gln, N-Me-homo-Gln ,THP,Ser,D-Ser,β-Ser,D-β-Ser,high-Ser,D-high-Ser,β-high-Ser,N-Me-Ser,N-Me-high-Ser,Ser( OMe), 3-aminotetrahydrofuran-3-carbonyl, Arg, D-Arg, β-Arg, D-β-Arg, high-Arg, D-high-Arg, β-high-Arg, N-Me-Arg, N-Me-high-Arg, Thr, D-Thr, β-Thr, D-β-Thr, high-Thr, D-high-Thr, β-high-Thr, N-Me-Thr, N-Me-high-Thr Glu, D-Glu, iso-Glu, D-iso-Glu, β-Glu, D-β-Glu, high-Glu, D-high-Glu, β-high-Glu, N-Me-Glu, N-Me-high-Glu, Asn, D-Asn, β-Asn, D-β-Asn, high-Asn, D-high-Asn, β-high-Asn, N-Me-Asn, N-Me-high-Asn, 4-aminobutyryl, 2-(trimethyl-2-aminoethoxy)ethoxy]propyl and Lys, wherein the side chain -NH2 of Lys is replaced by -C(=O)(CH2). n R K Replace, where n is 0 to 2 and R K It is either an imidazole, pyrimidin, or pyridinyl group optionally substituted with F, or X12 is not present; and

[0071] X13 is selected from: optionally substituted His residues; optionally substituted Phe residues; alanine residues substituted with a carbocyclic group or an aromatic or heteroaromatic group, wherein the aromatic or heteroaromatic group is selected from phenyl, pyridyl, naphthyl, and quinolinyl, each optionally substituted; Asn, D-Asn, β-Asn, D-β-Asn, high-Asn, D-high-Asn, β-high-Asn, N-Me-Asn, N-Me-high-Asn, Gly, β-Gly, high-Gly, β-high-Gly, N-Me-Gly, N-Me-high-Gly,

[0072] And Dab, Orn, or Lys, where the side chain -NH2 is replaced by -C(=O)(CH2). n R K Replace, where n is 0 to 2 and R K It is an imidazole, pyrimidin, or pyridinyl group optionally substituted with F.

[0073] Or it may not exist;

[0074] in

[0075] (i) X2 and X11 are amino acid residues that together form a lactam bridge;

[0076] (ii) X2 and X7 are amino acid residues that together form a lactam bridge or a bridge containing a triazole ring; and

[0077] (iii) Optionally, when X13 is present, X10 and X13 are amino acid residues that together form a lactam bridge.

[0078] In a second aspect, the present invention provides compounds of the following formula, or pharmaceutically acceptable salts or solvates thereof:

[0079] ZR 2

[0080] in

[0081] R 2 It is NHR 3 Or C(=O)R 3 , where R 3 It is a C that is hydrogen or optionally substituted with a pyridine ring. 1-6 Alkyl groups, or those that are not present; and

[0082] Z is the amino acid sequence of formula I:

[0083]

[0084] in

[0085] X2 is selected from Lys, D-Lys, iso-Lys, β-Lys, D-β-Lys, high-Lys, D-high-Lys, β-high-Lys, N-Me-Lys, Dab, D-Dab, iso-Dab, Glu, iso-Glu, D-iso-Glu, Orn, D-Orn, Dpr, Lys(Gly), (N3)-Lys, and D-(N3)-Lys;

[0086] X3 is selected from Thr, Ile, 3-aminopropionyl, 4-aminobutyryl, β-high-Ile, β-high-Thr, Gly, N-Me-3-aminopropionyl, and Ser, or may not exist;

[0087] X4 is Val or does not exist;

[0088] X5 is selected from Trp, 1-Me-Trp, and β-high-Trp;

[0089] X6 is Gln;

[0090] X7 is selected from Glu, D-Glu, High-Glu, Asp, Pra and Hpg;

[0091] X8 is selected from Y(2-aminoethoxy), Y(Me), Y(nPr), Y(Bn), Trp, D-Phe, 2-Me-Phe, F(4-Me), F(4-Bu), 3-(2-pyridyl)-Ala, 3-(3-pyridyl)-Ala, 3-(4-pyridyl)-Ala and cyclopropyl-Ala;

[0092] X9 is 2-Nal or cyclopropyl-Ala;

[0093] X10 is selected from 2-Me-Leu, 2-Me-Val, Dab, Gly, Lys and Aib;

[0094] X11 is selected from Glu, high-Glu, β-high-Glu, Dab, iso-Dab, Lys, Lys(Me), Orn and 2-amino-6-carboxyhexanoyl;

[0095] X12 is selected from Dab, His, D-His, His(1-Me), 3-(2-pyridyl)-Ala, 3-(3-pyridyl)-Ala, 3-(4-pyridyl)-Ala, 3-(3-quinolinyl)-Ala, Gly, Pro, 5-aminopentanoyl, 4-aminopiperidine-4-carbonyl, (R,S)-imidazolidine-2-carbonyl, and Lys, wherein the side chain -NH2 of Lys is replaced by -C(=O)(CH2). n R K Replace, where n is 0 to 2 and R KIt is either an imidazole, pyrimidin, or pyridinyl group optionally substituted with F, or X12 is not present; and

[0096] X13 is selected from 3-(3-pyridinyl)-Ala, D-3-(3-pyridinyl)-Ala and 3-(3,5-pyrimidinyl)-Ala, or is not present;

[0097] in

[0098] (i) X2 and X11 are amino acid residues that together form a lactam bridge;

[0099] (ii) X2 and X7 are amino acid residues that together form a lactam bridge or a bridge containing a triazole ring; and

[0100] (iii) Optionally, when X13 is present, X10 and X13 are amino acid residues that together form a lactam bridge.

[0101] In some embodiments, the compound is a compound of the following formula, or a pharmaceutically acceptable salt or solvate thereof:

[0102] ZR 2

[0103] in

[0104] R 2 It is NHR 3 , where R 3 It is a C that is hydrogen or optionally substituted with a pyridine ring. 1-6 Alkyl groups, or those that are not present; and

[0105] Z is the amino acid sequence of formula Ia:

[0106]

[0107] in

[0108] X2 is selected from Lys, D-Lys, iso-Lys, β-Lys, D-β-Lys, high-Lys, D-high-Lys, β-high-Lys, N-Me-Lys, Dab, D-Dab, Glu, iso-Glu, Orn, D-Orn, Lys(Gly), (N3)-Lys, and D-(N3)-Lys;

[0109] X3 is selected from Thr, Trp, Ile, 3-aminopropionyl, 4-aminobutyryl, β-high-Ile, β-high-Thr, Gly, and N-Me-3-aminopropionyl, 3-hydroxypropionic acid, or is not present;

[0110] X4 is Val or does not exist;

[0111] X5 is either Trp or 1-Me-Trp;

[0112] X6 is Gln, Gln(Me), Dab(Ac-N-Me), Dab(Ac) or Gln(2Me);

[0113] X7 is selected from Glu, High-Glu, Asp, Pra, and Hpg;

[0114] X8 is selected from Y(2-aminoethoxy), Y(Me), Y(Bn), Y(2-aminoethoxy)(N(Me)2), Y(n-pentylamine)(N+(Me)3), Y(2-trimethyl-PEG2), F(4-Me), F(4-Bu), cyclopropyl-Ala, F(4-morpholine), F(4-THP), Y(CH3-2-F), F(4-F), F(4-piperazine), F(4-imidazolium), Y(CH3-3-F), F(4-piperidine), 5-AzaTrp, Y(Ac-2-aminoethoxy), 7-AzaTrp, 6-AzaTrp, F(4-CONH2);

[0115] X9 is 2-Nal;

[0116] X10 is selected from 2-Me-Leu, 2-Me-Val, D-Ala, Dab, Gly, and Aib;

[0117] X11 is selected from Glu, high-Glu, Lys, Lys(Me), Orn and 2-amino-6-carboxyhexanoyl;

[0118] X12 is selected from Dab, His, S(OCH3), D-His, His(1-Me), 3-(3-quinolinyl)-Ala, and 4-aminopiperidine-4-carbonyl; and

[0119] X13 is 3-(3-pyridyl)-Ala, 3-(3,5-pyrimidinyl)-Ala, or it does not exist;

[0120] in

[0121] (i) X2 and X11 are amino acid residues that together form a lactam bridge;

[0122] (ii) X2 and X7 are amino acid residues that together form a lactam bridge or a bridge containing a triazole ring; and

[0123] (iii) Optionally, when X13 is present, X10 and X13 are amino acid residues that together form a lactam bridge.

[0124] In some embodiments, the compound is a compound of the following formula, or a pharmaceutically acceptable salt or solvate thereof:

[0125] ZR 2

[0126] in

[0127] R 2 It is NHR 3 , where R 3 It is a C that is hydrogen or optionally substituted with a pyridine ring. 1-6 Alkyl groups, or those that are not present; and

[0128] Z is the amino acid sequence of formula Ia:

[0129]

[0130] in

[0131] X2 is selected from Lys, D-Lys, iso-Lys, β-Lys, D-β-Lys, high-Lys, D-high-Lys, β-high-Lys, N-Me-Lys, Dab, D-Dab, Glu, iso-Glu, Orn, D-Orn, Lys(Gly), (N3)-Lys, and D-(N3)-Lys;

[0132] X3 is selected from Thr, Ile, 3-aminopropionyl, 4-aminobutyryl, β-high-Ile, β-high-Thr, Gly, and N-Me-3-aminopropionyl, or is not present;

[0133] X4 is Val or does not exist;

[0134] X5 is either Trp or 1-Me-Trp;

[0135] X6 is Gln;

[0136] X7 is selected from Glu, High-Glu, Asp, Pra, and Hpg;

[0137] X8 is selected from Y(2-aminoethoxy), Y(Me), Y(Bn), F(4-Me), F(4-Bu) and cyclopropyl-Ala;

[0138] X9 is 2-Nal;

[0139] X10 is selected from 2-Me-Leu, 2-Me-Val, Dab, Gly, and Aib;

[0140] X11 is selected from Glu, high-Glu, Lys, Lys(Me), Orn and 2-amino-6-carboxyhexanoyl;

[0141] X12 is selected from Dab, His, D-His, His(1-Me), 3-(3-quinolinyl)-Ala, and 4-aminopiperidine-4-carbonyl; and

[0142] X13 is 3-(3-pyridyl)-Ala, 3-(3,5-pyrimidinyl)-Ala, or it does not exist;

[0143] in

[0144] (i) X2 and X11 are amino acid residues that together form a lactam bridge;

[0145] (ii) X2 and X7 are amino acid residues that together form a lactam bridge or a bridge containing a triazole ring; and

[0146] (iii) Optionally, when X13 is present, X10 and X13 are amino acid residues that together form a lactam bridge.

[0147] In some embodiments, the lactam bridge between X2 and X11 uses the side chain of the amino acid residue at X2, and the bridge between X2 and X7 uses the N-terminus of the amino acid residue at X2.

[0148] In some implementations, X2 is Lys.

[0149] In some implementations, X3 is selected from Thr, Ile, and 3-aminopropionyl, or is not present.

[0150] In some implementations, X4 is not present.

[0151] In some implementations, X5 is Trp.

[0152] In some implementations, X7 is Glu.

[0153] In some embodiments, X8 is Y (2-aminoethoxy), Y (Me), or F (4-Me). In some embodiments, X8 is Y (2-aminoethoxy).

[0154] In some implementations, X9 is 2-Nal.

[0155] In some implementations, X10 is 2-Me-Leu or 2-Me-Val. In some implementations, X10 is 2-Me-Leu.

[0156] In some implementations, X11 is Glu.

[0157] In some implementations, X12 is Dab.

[0158] In some embodiments, X13 is 3-(3-pyridyl)-Ala or is absent. In some embodiments, X13 is 3-(3-pyridyl)-Ala.

[0159] In some implementation schemes, R 2 It is NHR 3 , where R 3 Is it hydrogen or C? 1-6 Alkyl group. In some embodiments, R 2 It is NH2. In some implementations, R 2 It is NHMe.

[0160] In some implementations, X2 is Lys; X5 is Trp; X9 is 2-Nal; and X10 is 2-Me-Leu.

[0161] In some implementations, X2 is Lys; X5 is Trp; X9 is 2-Nal; X10 is 2-Me-Leu; and R 2 It is NH2 or NHMe.

[0162] In some implementations, X2 is Lys; X5 is Trp; X9 is 2-Nal; X10 is 2-Me-Leu; X13 is 3-(3-pyridyl)-Ala or is absent, and R 2 It is NH2 or NHMe.

[0163] In some implementations, X2 is Lys; X5 is Trp; X7 is Glu; X9 is 2-Nal; X10 is 2-Me-Leu; X13 is 3-(3-pyridyl)-Ala or is absent, and R 2 It is NH2 or NHMe.

[0164] In some implementations, Z is an amino acid sequence selected from the sequences listed in Table 1-1a.

[0165] In some embodiments, the compound is selected from the compounds in Table 1-1, or their pharmaceutically acceptable salts or solvates.

[0166] The present invention also provides compositions comprising the compounds described above. The compositions may be pharmaceutical compositions and may contain pharmaceutically acceptable carriers, excipients, or loading agents.

[0167] The present invention also provides a method for synthesizing the compounds as described above. The method may include the steps of synthesizing peptides by solid-phase or liquid-phase methods, and optionally the steps of separating and / or purifying the final product, and optionally the steps of forming amide bonds between amino acid residues at positions X2 and X11, and optionally the steps of forming amide bonds or forming triazoles between amino acid residues at positions X2 and X7, and optionally the steps of forming amide bonds between amino acid residues at positions X10 and X13.

[0168] The present invention also provides compounds of the present invention or pharmaceutical compositions comprising said compounds in a method of medical treatment.

[0169] The present invention also provides compounds of the present invention or pharmaceutical compositions comprising said compounds for the prevention or treatment of inflammatory bowel disease (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.

[0170] The present invention also provides the use of the compounds of the present invention or pharmaceutical compositions comprising said compounds in the manufacture of medicaments for the prevention or treatment of inflammatory bowel disease (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.

[0171] The present invention also provides methods for preventing or treating inflammatory bowel disease (IBD), such as Crohn's disease or ulcerative colitis, psoriasis, psoriatic arthritis, and combinations thereof; said methods comprising administering to a subject a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition comprising said compound. In some embodiments, the condition is inflammatory bowel disease (IBD) and / or psoriasis.

[0172] Other aspects and embodiments of the invention will become apparent from the following disclosure. Detailed Implementation

[0173] definition

[0174] Unless otherwise defined herein, the scientific and technical terms used herein shall have the meanings commonly understood by one of ordinary skill in the art. Generally, the nomenclature used herein in relation to the chemistry, molecular biology, cell and cancer biology, immunology, microbiology, pharmacology, and protein and nucleic acid chemistry discussed herein is well-known and commonly used in the art.

[0175] All publications, patents, and published patent applications mentioned in this application are specifically incorporated herein by reference. In case of conflict, this specification (including its specific definitions) shall prevail.

[0176] Throughout this specification, the word "comprise" or its variations such as "comprises" or "comprising" shall be understood to mean that the whole or component or group of the said whole or component is included, but does not exclude any other whole or component or group of the whole or component.

[0177] Unless the context clearly indicates otherwise, a noun without a quantifier indicates one or more species.

[0178] The term "including / contains" is used to mean "including / contains but not limited to". "Including / contains" and "including / contains but not limited to" are used interchangeably.

[0179] The terms “patient,” “object,” and “individual” are used interchangeably and can refer to humans or non-human animals. Objects are typically mammals, including humans, non-human primates (including apes, Old World monkeys, and New World monkeys), livestock (e.g., cattle, pigs), companion animals (e.g., dogs, cats), and rodents (e.g., mice and rats).

[0180] The term "medicinal salt" as used herein is intended to mean a salt that is harmless to the patient or subject to which the salt is administered. It may suitably be a salt selected, for example, from acid addition salts and basic salts. Examples of acid addition salts include chloride salts, citrates, and acetates. Examples of basic salts include salts in which the cation is selected from: alkali metal cations, such as sodium or potassium ions; alkaline earth metal cations, such as calcium or magnesium ions; and substituted ammonium ions, such as N(R) ions. 1 (R) 2 (R) 3 (R) 4 ) + Type Ions, of which R 1 R 2 R 3 and R 4 Typically, C represents hydrogen independently, with optional substitutions. 1-6 Alkyl or optionally substituted C 2-6 Alkenyl. Related C 1-6 Examples of alkyl groups include methyl, ethyl, 1-propyl, and 2-propyl. Possibly related C 2-6Examples of alkenyl groups include vinyl, 1-propenyl, and 2-propenyl. Other examples of pharmaceutically usable salts are described in: “Remington's Pharmaceutical Sciences”, 17th edition, Alfonso R. Gennaro (ed.), Mark Publishing Company, Easton, PA, USA, 1985 (and more recent editions), “Encyclopaedia of Pharmaceutical Technology”, 3rd edition, James Swarbrick (ed.), Informa Healthcare USA (Inc.), NY, USA, 2007, and J. Pharm. Sci. 66: 2 (1977).

[0181] In the context of this invention, the term "solvate" refers to a stoichiometric complex formed between a solute (hereinafter referring to the peptide or its pharmaceutically acceptable salt according to the invention) and a solvent. In this case, the solvent may be, for example, water, ethanol, or other pharmaceutically acceptable, typically small-molecule organic substances, such as, but not limited to, acetic acid or lactic acid. When the solvent involved is water, such sovates are generally referred to as hydrates.

[0182] As used in the context of this invention, the terms "antagonist" and "inhibitor" refer to substances that inhibit the type of receptor involved, typically by binding to the receptor (i.e., acting as a ligand) and blocking the receptor.

[0183] Each embodiment of the invention described herein may be used alone or in combination with one or more other embodiments of the invention.

[0184] In the context of the aforementioned treatments or other therapeutic interventions, the term "therapeuticly effective amount" or "effective amount" as used herein refers to an amount sufficient to cure, improve, alleviate, or partially prevent the clinical manifestations of a particular disease, disorder, or condition that is the target of the treatment or other therapeutic intervention, for example, as measured by established clinical endpoints or other biomarkers (established or experimental). Those skilled in the art can empirically determine the treatment-related amount based on the indication for ongoing treatment or prevention and the subject being treated with the treatment-related amount. For example, a technician may measure one or more of the clinically relevant bioactivity markers described herein, such as 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), claudin 8 (CLDN8), and phosphorylated signal transducer and activator 3. The protein of transcription (pSTAT3), polynucleotides encoding any of the above proteins, and polynucleotides containing regions complementary to microRNA-223-3p or any polynucleotide encoding any of the above proteins, as described in WO 2018 / 089693. Clinically relevant quantities can be determined by in vitro or in vivo measurements.

[0185] The amount sufficient to achieve any or all of these effects is defined as the therapeutically effective amount. The dosage and method of administration can be customized to achieve optimal efficacy. The effective amount for a given purpose will depend in particular on: the severity of the disease, disorder, or condition targeted by the specific treatment or other therapeutic intervention; the weight and general condition of the subject involved; diet; possible concurrent medications; and other factors known to those skilled in the art. The determination of the appropriate dose and dosing regimen most suitable for administration to humans of the peptides or their pharmaceutically acceptable salts or solvates according to the invention can be guided by the results obtained from the invention and can be confirmed in a suitably designed clinical trial. Effective doses and treatment regimens can be determined by conventional means, starting with a low dose in laboratory animals and subsequently increasing the dose while monitoring effects, and also systematically changing the dosing regimen. When determining the optimal dose for a given subject, clinicians may consider several factors. Such considerations are known to those skilled in the art.

[0186] As used in this context, the term "treatment" and its grammatical variations (e.g., "treated", "treating", "treat") refer to a method for achieving a beneficial or desired clinical outcome. For the purposes of this invention, beneficial or desired clinical outcomes include, but are not limited to, relief of symptoms, reduction of disease severity, stabilization of the disease state (i.e., non-deterioration), delay or slowing of disease progression, improvement or mitigation of the disease state, and remission (whether partial or complete), whether detectable or undetectable. "Treatment" may also mean extended survival relative to the expected survival time without treatment. Therefore, the object requiring treatment (e.g., a person) may be an object already suffering from the disease or disorder involved. The term "treatment" includes suppressing or reducing the severity of a pathological state or symptom (e.g., inflammation) relative to the absence of treatment, and does not necessarily imply the complete cessation of the associated disease, disorder, or condition.

[0187] As used in the context of this invention, the term "prevention" and its grammatical variations (e.g., "prevented," "preventing," "prevent") refer to methods for preventing or inhibiting the occurrence of a symptom, disease, or disorder, or for altering its pathological condition. Therefore, "prevention" can refer to preventative or proactive measures. For the purposes of this invention, advantageous or desired clinical outcomes include, but are not limited to, preventing or mitigating the symptoms, progression, or occurrence of a disease, whether detectable or undetectable. Therefore, the object requiring "prevention" (e.g., a person) can be an object that does not yet suffer from the disease or disorder involved. Thus, the term "prevention" includes suppressing or mitigating the onset of a disease relative to the absence of treatment, and does not necessarily imply permanent prevention of the associated disease, disorder, or symptom.

[0188] Amino acid nomenclature

[0189] The term "amino acid" is an organic compound that, when alone, contains an amino or amine group (-NH2 or -NHR) and a carboxylic acid group (-COOH). As is known to those skilled in the art, the amine and carboxylic acid groups of an amino acid residue react with each other to form a peptide having an amide bond, also known as a peptide bond, which is of the formula –NH-C(=O)- or –NR-C(=O)-.

[0190] Therefore, the term "amino acid" is not limited to including natural or non-natural α and β amino acids, but also includes (when forming a peptide) residues such as 3-aminopropionyl and 4-aminobutyryl. The term also includes cyclic structures having amine and carboxylic acid functional groups, such as carbocyclic and heterocyclic structures. The amino group of an amino acid can be further functionalized, for example, as an azide group (-N3), such as in (N3)-Lys or D-(N3)-Lys.

[0191] Some amino acids described herein have an amine and a carboxylic acid group attached to the same carbon atom; these are called α (alpha) amino acids. Some amino acids described herein have an amine and a carboxylic acid group separated by 1, 2, 3, 4, 5, or 6 carbon atoms. For example, β-Lys and D-β-Lys have an amine and a carboxylic acid group separated by one carbon atom, such that the carbon atom attached to the amine group and the carbon atom attached to the carboxylic acid group are adjacent to each other.

[0192] Some of the amino acids described in this article have side chains unique to each amino acid. These side chains can also be further functionalized.

[0193] Throughout this specification, naturally occurring amino acids are referred to by their full names (e.g., alanine, arginine, etc.) or by their usual three-letter or one-letter abbreviations (e.g., Ala or A for alanine, Arg or R for arginine, etc.). In the case of certain less common or non-naturally occurring amino acids (i.e., amino acids other than the 20 amino acids encoded by the standard mammalian genetic code), in addition to being referred to by their full names (e.g., ornithine, etc.), their residues are indicated by the commonly used three- or four-character code, including 2-Nal(3-(2-naphthyl)-alanine).

[0194] Unless otherwise stated, references are made to both the L and D isomers of the amino acid in question. In one embodiment, unless otherwise stated, the amino acid referred to herein is its L isomer. In another embodiment, unless otherwise stated, the amino acid referred to herein is its D isomer. In a preferred embodiment, unless otherwise stated, the amino acid referred to herein is its L isomer.

[0195] Unless otherwise stated, references are made to both the homo and non-homo forms of the amino acids involved. As is evident in Table A below, the prefix "homo" in amino acid names indicates the addition of a methylene group to the α-carbon of the amino acid. In one embodiment, unless otherwise stated, the amino acid referred to herein is its non-homo form. In one embodiment, unless otherwise stated, the amino acid referred to herein is its homo form. In a preferred embodiment, unless otherwise stated, the amino acid referred to herein is its non-homo form.

[0196] Unless otherwise stated, references are made to both the α and β forms of the amino acid in question. As is evident in Table A below, the prefix "β (beta)" in amino acid names indicates that the carbon skeleton has been extended by inserting a carbon atom immediately after the acid group of the amino acid skeleton. In one embodiment, unless otherwise stated, the amino acid referred to herein is its α form. In another embodiment, unless otherwise stated, the amino acid referred to herein is its β form. In a preferred embodiment, unless otherwise stated, the amino acid referred to herein is its α form.

[0197] Amino acid residues are the amino acid portions of a peptide chain. Non-natural amino acid residues can be identified as segments of non-natural amino acids defined in the peptide chain (e.g., the non-natural amino acid 3-aminopropionic acid can be identified as the non-natural amino acid residue 3-aminopropionyl in the peptide chain).

[0198] Other exemplary abbreviations for amino acid residues are described in Table A.

[0199] Table A

[0200] amino acid residues structure D-Lys or {d}K is also known as: D-lysine or (2R)-2,6-diaminohexanoic acid. β-Lys or bLys is also known as: L-β-lysine or (3S)-3,6-diaminohexanoic acid D-β-Lys or {d}bLys is also known as: D-β-lysine or (3R)-3,6-diaminohexanoic acid. High-Lys or hLys is also known as: L-high-lysine or (2S)-2-amino-7-aminoheptanoic acid D-high-Lys or {d}hLys is also known as: D-high-lysine or (2R)-2-amino-7-aminoheptanoic acid. β-Hylo-Lys or β-hLys is also known as: L-beta-hylolysine, L-β-hylolysine, or (3S)-3,7-diaminoheptanoic acid. N-Me-Lys is also known as: N2-methyl-L-lysine or (2S)-6-amino-2-(methylamino)hexanoic acid. Dab (also known as iso-Dab – see Table B) is also called: (2S)-2,4-diaminobutyric acid D-Dab is also known as {d}Dab or D-2,4-diaminobutyric acid or (2R)-2,4-diaminobutyric acid. D-Glu (also known as D-iso-Glu – see Table B) is also called: D-glutamic acid Orn is also known as L-ornithine or (2S)-2,5-diaminovaleric acid. D-Orn is also known as D-ornithine or (2R)-2,5-diaminovaleric acid. Dpr is also known as: 3-amino-L-alanine or (2S)-2,3-diaminopropionic acid. Citrulline 2-amino-5-(carbamoylamino)valerate, also known as: Citrulline 2-amino-5-(carbamoylamino)valerate Lys(Gly) or K(G) is also known as: (2S)-2-amino-6-[(2-aminoacetyl)amino]hexanoic acid <![CDATA[(N3)-Lys or (N3)-K is also known as: (2S)-6-amino-2-azido-hexanoic acid]]> <![CDATA[D-(N3)-Lys or {d}(N3)-K is also known as: (2R)-6-amino-2-azido-hexanoic acid]]> 3-Aminopropionic acid 4-Aminobutyric acid is also known as GABA or γ-aminobutyric acid. β-homo-Ile or β-hIle is also known as: L-beta-homo-leucine, L-β-homo-leucine, or (3R,4S)-3-amino-4-methyl-hexanoic acid β-Homo-Thr or β-hThr is also known as: L-beta-homothreonine, L-β-homothreonine, or (3R,4R)-3-amino-4-hydroxy-valerate. N-Me-3-aminopropionic acid 1-Me-Trp is also known as 1-methyl-L-tryptophan or (2S)-2-amino-3-(1-methylindol-3-yl)propionic acid. β-Hyper-Trp or β-hTrp is also known as: L-beta-hypertryptophan, L-β-hypertryptophan, or (3S)-3-amino-4-(1H-indol-3-yl)butyric acid. High-Glu or hGlu is also known as: L-high glutamic acid or (2S)-2-aminohexanoic acid. Pra is also known as: L-propyloglucylic acid or (2S)-2-aminopentan-4-alkynic acid. Hpg is also known as: L-homopropylglycine or (2S)-2-aminohexano-5-ynyl acid. Y(2-aminoethoxy) is also known as: (2S)-2-amino-3-[4-(2-aminoethoxy)phenyl]propionic acid Y(Me) is also known as: 4-methoxy-L-phenylalanine or (2S)-2-amino-3-(4-methoxyphenyl)propionic acid. Y(nPr) is also known as (2S)-2-amino-3-(4-propoxyphenyl)propionic acid. Y(Bn) is also known as: (2S)-2-amino-3-(4-benzyloxyphenyl)propionic acid D-Phe or {d}F is also known as: D-phenylalanine or (2R)-2-amino-3-phenyl-propionic acid. 2-Me-Phe is also known as alpha-methyl-L-phenylalanine, α-methyl-L-phenylalanine, or (2S)-2-amino-2-methyl-3-phenylpropionic acid. F(4-Me) is also known as 4-methyl-L-phenylalanine or (2S)-2-amino-3-(p-tolyl)propionic acid. F(4-Bu) is also known as butyl-L-phenylalanine, 4-butyl-L-phenylalanine, or (2S)-2-amino-3-(4-butylphenyl)propionic acid. 3-(2-pyridyl)-Ala is also known as 3-(2-pyridyl)-L-alanine or (2S)-2-amino-3-(pyridin-2-yl)propionic acid. 3-(3-pyridyl)-Ala is also known as: 3-(3-pyridyl)-L-alanine, 3-Pal, or (2S)-2-amino-3-(pyridin-3-yl)propionic acid. 3-(4-pyridyl)-Ala is also known as 3-(4-pyridyl)-L-alanine or (2S)-2-amino-3-(pyridin-4-yl)propionic acid. Cyclopropyl-Ala is also known as cyclopropyl-L-alanine or (2S)-2-amino-3-cyclopropyl-propionic acid. 2-Nal is also known as: 3-(2-naphthyl)-L-alanine or (2S)-2-amino-3-(2-naphthyl)propionic acid 2-Me-Leu is also known as 2-methyl-L-leucine, alpha-methylleucine, α-methylleucine, or (2S)-2-amino-2,4-dimethylvaleric acid. 2-Me-Val is also known as 2-methyl-L-valine, alpha-methylvaline, α-methylvaline, or (2S)-2-amino-2,3-dimethylbutyric acid. Aib is also known as 2-aminoisobutyric acid, α-methylalanine, 2-methylalanine, or 2-amino-2-methyl-propionic acid. β-Hydroxyglutamate or β-hGlu is also known as L-beta-hydroxyglutamate, L-β-hydroxyglutamate, or (3S)-3-aminohexanoic acid. Lys(Me) or K(Me) is also known as: N6-methyl-L-lysine or (2S)-2-amino-6-(methylamino)hexanoic acid. 2-Amino-6-carboxyhexanoic acid D-His or {d}H is also known as: D-histidine or (2R)-2-amino-3-(1H-imidazol-4-yl)propionic acid. His(1-Me) or H(1-Me) or His(Me) or H(Me) are also known as: 1-methyl-L-histidine or (2S)-2-amino-3-(1-methylimidazol-4-yl)propionic acid 3-(3-quinolinyl)-Ala is also known as 3-(3-quinolinyl)-L-alanine or (2S)-2-amino-3-(3-quinolinyl)propionic acid. 5-Aminovaleric acid 4-Aminopiperidine-4-carboxylic acid (R,S)-Imidazolidine-2-carboxylic acid K (piconilate) is also known as (2S)-2-amino-6-(pyridine-2-carbonylamino)hexanoic acid. K(2-pyridylacetyl) is also known as: (2S)-2-amino-6-[[2-(2-pyridyl)acetyl]amino]hexanoic acid K(2-pyridylpropionyl) is also known as: (2S)-2-amino-6-[3-(2-pyridyl)propionylamino]hexanoic acid K (nicotinic acid) is also known as: (2S)-2-amino-6-(pyridine-3-carbonylamino)hexanoic acid K(3-pyridylacetyl) is also known as: (2S)-2-amino-6-[[2-(3-pyridyl)acetyl]amino]hexanoic acid K(3-pyridylpropionyl) is also known as: (2S)-2-amino-6-[3-(3-pyridyl)propionylamino]hexanoic acid K (isonicotinyl) is also known as: (2S)-2-amino-6-(pyridine-4-carbonylamino)hexanoic acid K(4-pyridylacetyl) is also known as: (2S)-2-amino-6-[[2-(4-pyridyl)acetyl]amino]hexanoic acid K(4-pyridylpropionyl) is also known as: (2S)-2-amino-6-[3-(4-pyridyl)propionylamino]hexanoic acid K(3,5-pyrimidine) is also known as: (2S)-2-amino-6-(pyrimidine-5-carbonylamino)hexanoic acid. K(4-pyridyl-3-fluoroacetyl) is also known as: (2S)-2-amino-6-[[2-(2-fluoro-4-pyridyl)acetyl]amino]hexanoic acid K (imidazolium acetyl) is also known as: (2S)-2-amino-6-[[2-(2H-imidazol-2-yl)acetyl]amino]hexanoic acid K (imidazolium propionyl) is also known as: (2S)-2-amino-6-[3-(2H-imidazol-2-yl)propionylamino]hexanoic acid D-3-(3-pyridyl)-Ala or {d}3-(3-pyridyl)-Ala is also known as: 3-(3-pyridyl)-D-alanine, D-3-Pal, or (2R)-2-amino-3-(pyridin-3-yl)propionic acid. 3-(3,5-pyrimidinyl)-Ala is also known as: (2S)-2-amino-3-pyrimidin-5-yl-propionic acid Q(Me) is also known as: N5-L-methylglutamine or (2S)-2-amino-5-(methylamino)-5-oxovaleric acid. F(4-morpholine) is also known as: 4-morpholine-L-phenylalanine or (2S)-2-amino-3-(4-morpholine-4-ylphenyl)propionic acid. Dab(Ac-N-Me) Dab(Ac) D-Ala or {d}A is also known as: (R)-2-aminopropionic acid F(4-THP) is also known as 4-tetrahydropyran-L-phenylalanine(2S)-2-amino-3-(4-tetrahydropyranyl-4-ylphenyl)propionic acid. S(Me) is also known as: O-methyl-L-serine Y(CH3-2-F) is also known as: 4-methoxy-2-fluoro-L-phenylalanine or (2S)-2-amino-3-(4-methoxy-2-fluorophenyl)propionic acid. F(4-F) is also known as 4-fluoro-L-phenylalanine or (2S)-2-amino-3-(4-fluorophenyl)propionic acid. F(4-piperazine) is also known as: 4-piperazine-L-phenylalanine or (2S)-2-amino-3-(4-piperazine-4-ylphenyl)propionic acid. F(4-imidazolium) is also known as: 4-imidazolium-L-phenylalanine or (2S)-2-amino-3-(4-imidazolylphenyl)propionic acid. Y(CH3-3-F) is also known as: 4-methoxy-3-fluoro-L-phenylalanine or (2S)-2-amino-3-(4-methoxy-3-fluorophenyl)propionic acid. F(4-piperidine) is also known as: 4-piperidine-L-phenylalanine or (2S)-2-amino-3-(4-piperidine-4-ylphenyl)propionic acid. 5-AzaTrp is also known as: 5-aza-L-tryptophan (S)-2-amino-3-(1H-pyrrolo[3,2-c]pyridin-3-yl)propionic acid Y(Ac-2-aminoethoxy) 7-AzaTrp is also known as: 7-aza-L-tryptophan (S)-2-amino-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)-propionic acid 6-AzaTrp is also known as 6-aza-L-tryptophan. 3-Hydroxypropionic acid F(4-CONH2) D-Trp or {d}W is also known as: D-tryptophan(R)-2-amino-3-(3-indole)propionic acid, D-α-amino-3-indolepropionic acid Q(2Me) is also known as: N,N,dimethyl-L-glutamine ((2S)-2-amino-5-(dimethylamino)-5-oxopentanoic acid) Y(2-aminoethoxy)(N(Me)2) <![CDATA[Y(n-pentylamine)(N + (Me)3)]]> Y(2-trimethyl-PEG2)(S)-2-(2-(2-(4-(2-amino-2-carboxyethyl)phenoxy)ethoxy)ethoxy)-N,N,N-trimethylethyl-1-ammonium

[0201] Using Table A above and Table A1 below, those skilled in the art can obtain the structures of any D, β, high, high-β, N-Me, and N3 analogs (and combinations thereof) of the amino acid residues disclosed herein. In particular, Table A1 outlines relevant analogs of the lysine amino acid, which can then be applied to obtain the corresponding structures of any equivalent amino acid analogs disclosed herein.

[0202] Table A1

[0203] amino acid residues structure Lysine is also known as L-lysine or (2S)-2,6-diaminohexanoic acid (L-lysine). D-Lys or {d}K is also known as: D-lysine or (2R)-2,6-diaminohexanoic acid. β-Lys or bLys is also known as: L-β-lysine or (3S)-3,6-diaminohexanoic acid D-β-Lys or {d}bLys is also known as: D-β-lysine or (3R)-3,6-diaminohexanoic acid. High-Lys or hLys is also known as: L-high-lysine or (2S)-2-amino-7-amino-heptanoic acid D-high-Lys or {d}hLys is also known as: D-high-lysine or (2R)-2-amino-7-amino-heptanoic acid. β-Hylo-Lys or β-hLys is also known as: L-beta-hylolysine, L-β-hylolysine, or (3S)-3,7-diaminoheptanoic acid. N-Me-Lys is also known as: N2-methyl-L-lysine or (2S)-6-amino-2-(methylamino)hexanoic acid. N-Me-high-Lys, also known as: N2-methyl-L-high-lysine <![CDATA[(N3)-Lys or (N3)-K is also known as: (2S)-6-amino-2-azido-hexanoic acid]]> <![CDATA[D-(N3)-Lys or {d}(N3)-K is also known as: (2R)-6-amino-2-azido-hexanoic acid]]>

[0204] Linear peptides are written from left to right, from the N-terminus to the C-terminus.

[0205] Non-natural (or non-naturally occurring) amino acids and amino acid residues are amino acids and amino acid residues that are not naturally present in peptide chains. Non-natural amino acids can be formed as secondary metabolites in bacteria, fungi, plants, or marine organisms, or they can be chemically synthesized.

[0206] Unless otherwise specified, the peptide backbone (i.e., the amide bonds "-" between X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13 in the peptide chain) is formed by amino acid residues linked by amide bonds through their terminal -NH2 and -COOH groups. Specifically, the "terminal -NH2 group" is the α-amine group of an α-amino acid or the β-amine group of a β-amino acid (e.g., bLys, {d}bLys, and β-hLys); and the "terminal -COOH group" is the α-carboxylic acid group of an α-amino acid. It will thus be understood by those skilled in the art that the amino acids in the peptide chain (i.e., at least those specified by X3, X4, X5, X6, X7, X8, X9, X10, X11, and X12) will be in the form –NH-XC(=O)-, where X represents the amino acid structure between the amine and carboxylic acid residues forming the amide backbone of the peptide chain.

[0207] When an amino acid residue contains two or more amine groups (-NH2, such as Lys and Dab) or carboxylic acid groups (-COOH, such as Glu and D-Glu), the peptide backbone may alternatively be formed using the side chains of the amino acid residue.

[0208] For example, the following nomenclature is used to distinguish the use of -NH2 and -COOH groups at the terminal and side chains:

[0209] Table B

[0210] amino acid residues residues in the peptide chain Heteroresidues in peptide chains <![CDATA[Lys / Iso-Lys Side chain: -CH2CH2CH2CH2NH2]]> Light Different-Lys <![CDATA[Dab / iso-Dab Side chain: -CH2CH2NH2]]> Ghost hetero-Dab <![CDATA[Glu / Iso-Glu Side chain: -CH2CH2COOH]]> Glu Iso-Glu <![CDATA[D-Glu / D-iso-Glu Side chain: -CH2CH2COOH]]> D-Glu D-iso-Glu

[0211] It should be understood that Table B above, in combination with Tables A and A1, can be used to obtain the structure of any corresponding hetero-analogs disclosed herein.

[0212] The C-terminus of the peptide can be derived into a pyridyl-substituted alkyl group to improve gastrointestinal stability (see Example 2). The following C-terminal derivatives are disclosed in Table C:

[0213] Table C

[0214] <![CDATA[C-terminal derivative (R 2 group)]]> structure 3-Pyridylpropionyl 6-(3-pyridyl)hexanoyl NH-(2-(pyridin-3-yl)ethyl) NH-(4-(pyridin-3-yl)butyl) NH-(6-(pyridin-3-yl)hexyl) NH-(3-(pyridin-3-yl)propyl)

[0215] For NH-(2-(pyridin-3-yl)ethyl), NH-(4-(pyridin-3-yl)butyl), NH-(6-(pyridin-3-yl)hexyl), and NH-(3-(pyridin-3-yl)propyl) groups, these groups are linked to the carbonyl carbon of the carboxylic acid group of the C-terminal amino acid residue, as in Glu, β-homo-Glu, and Dab. The linkage forms an amide bond.

[0216] For 3-pyridylpropionyl and 6-(3-pyridyl)hexanoyl groups, these groups are linked to the amino group of a C-terminal amino acid residue, such as iso-Dab. The linkage forms an amide bond.

[0217] lactam

[0218] A lactam is a cyclic amide of the formula (R-NH-C(=O)-R), wherein each R can be any other suitable functional group attached to another R. Each R can be the same or different.

[0219] Sulfides and disulfides

[0220] Thioethers are functional groups of the formula RSR, where R can be any other suitable functional group. Dithioethers are functional groups containing two thioether groups linked together by a linker, such as RSLYLSR, where the linker is -LYL-.

[0221] Head-to-tail circularization

[0222] The term "head-to-tail cyclization" refers to the cyclization of an N-terminal amine (or a derivative thereof) and a C-terminal carboxylic acid to form a cyclic peptide. Typically, this cyclization forms an amide bond.

[0223] alkyl

[0224] The term "alkyl" refers to a monovalent group of a saturated straight-chain or branched hydrocarbon. Preferably, the 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 carbon atoms, for example, 1 to 12 carbon atoms, for example, 1 to 10 carbon atoms, for example, 1 to 8 carbon atoms, for example, 1 to 6 or 1 to 4 carbon atoms. Exemplary alkyl groups include methyl, ethyl, propyl, isopropyl (also known as 2-propyl or 1-methylethyl), butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl, neopentyl, 1,2-dimethylpropyl, isopentyl, 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-pentadecanyl, n-hexadecyl, n-heptadecyl, n-octadecyl, n-nonadecanyl, n-eicosyl, n-tridecyl, n-tetradecyl, etc. "Substituted alkyl" means that one or more hydrogen atoms of an alkyl group (e.g., 1 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, or 1 to 3, or 1 or 2) are replaced by substituents other than hydrogen atoms (when more than one hydrogen atom is replaced, the substituents can be the same or different). In one embodiment, the alkyl group is replaced by 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 alkyl groups include chloromethyl, dichloromethyl, fluoromethyl, and difluoromethyl.

[0225] C 1-6 alkyl

[0226] In the context of the compounds of this invention, R can be used as a functional group. 2 Existing C 1-6 Alkyl groups include, but are not limited to, C6 alkyl groups such as hexyl (-CH2CH2CH2CH2CH2CH3), C5 alkyl groups such as pentyl (-CH2CH2CH2CH2CH3), or C... 1-4 alkyl.

[0227] C 1-4 alkyl

[0228] In the context of the compounds of this invention, R can be used as a functional group. 2 Existing C 1-4 Alkyl groups include, but are not limited to, C4 alkyl groups such as butyl (n-Bu or -CH2CH2CH2CH3) or C 1-3Alkyl groups, such as methyl (Me or -CH3, i.e., C1 alkyl), ethyl (-CH2CH3, i.e., C2 alkyl), 1-propyl (-CH2CH2CH3, i.e., C3 alkyl) or 2-propyl (-CH(CH3)2, i.e., C3 alkyl).

[0229] C 1-3 alkyl

[0230] In the context of the compounds of this invention, R can be used as a functional group. 2 Existing C 1-3 Alkyl groups include methyl (Me or -CH3, i.e., C1 alkyl), ethyl (-CH2CH3, i.e., C2 alkyl), 1-propyl (-CH2CH2CH3, i.e., C3 alkyl) and 2-propyl (-CH(CH3)2, i.e., C3 alkyl).

[0231] C 1-2 alkyl

[0232] In the context of the compounds of this invention, R can be used as a functional group. 2 Existing C 1-2 Alkyl groups include methyl (Me or -CH3, i.e., C1 alkyl) and ethyl (-CH2CH3, i.e., C2 alkyl).

[0233] ω-hydroxy-C 2-6 Alkane

[0234] The residue at the X3 position in this article can be ω-hydroxy-C. 2-6 Alkic acid. This residue can be represented by the following structure:

[0235]

[0236] Where n is 1, 2, 3, 4 or 5.

[0237] In some embodiments, n is selected from 1, 2, or 3, such that ω-hydroxy-C 2-6 Alkanoic acids are ω-hydroxy-C 2-4 Alkyl acids. In some embodiments, n is 2, such that ω-hydroxy-C 2-6 Alkanoic acids are ω-hydroxy-C3 alkanoic acids, such as 3-hydroxypropionic acid.

[0238] Alkylene

[0239] The term "alkylene" refers to a divalent group of a saturated straight-chain or branched hydrocarbon. Preferably, the alkylene comprises 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, 1 to 20, 1 to 12, 1 to 10, 1 to 8, 1 to 6, or 1 to 4 carbon atoms. Exemplary alkylenes 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), 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), and pentylene isomers (e.g., 1,1-pentylene, 1,2-pentylene, 1,3-pentylene, 1,4-pentylene, 1,5-pentylene, 1,1- Isopentyl, 1,1-sec-pentyl, 1,1-neopentyl), hexane isomers (e.g., 1,1-hexane, 1,2-hexane, 1,3-hexane, 1,4-hexane, 1,5-hexane, 1,6-hexane and 1,1-isohexane), heptamethrin isomers (e.g., 1,1-heptamethrin, 1,2-heptamethrin, 1,3-heptamethrin, 1,4-hexane, 1,5-hexane, 1,6-hexane and 1,1-isohexane), and heptamethrin isomers (e.g., 1,1-heptamethrin, 1,2-heptamethrin, 1,3-heptamethrin, 1,4-hexane, 1,5-hexane, 1,6 ,4-heptenyl, 1,5-heptenyl, 1,6-heptenyl, 1,7-heptenyl and 1,1-isoheptenyl), octyl isomers (e.g. 1,1-octyl, 1,2-octyl, 1,3-octyl, 1,4-octyl, 1,5-octyl, 1,6-octyl, 1,7-octyl, 1,8-octyl and 1,1-isooctyl), etc.

[0240] In one embodiment, the alkylene group is C 1-20 Alkylene. In one embodiment, the alkylene is C10. 2-14 Alkylene. In one embodiment, the alkylene is C10. 3-9 Alkylene. In one embodiment, the alkylene is C10. 7-9 Alkylene.

[0241] A straight-chain alkylene moiety having at least 3 carbon atoms and a free valence at each end may also be referred to as multiple methylene groups (e.g., 1,4-butylene may also be referred to as tetramethylene). Typically, as an alternative to the term "ylene" used with the aforementioned alkylene moiety, the term "diyl" may also be used (e.g., 1,2-butylene may also be referred to as but-1,2-diyl). "Substituted alkylene" means that one or more hydrogen atoms of the alkylene moiety (e.g., from 1 to a maximum number of hydrogen atoms bonded to the alkylene moiety, 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 substituents other than hydrogen (when more than one hydrogen atom is replaced, the substituents may be the same or different). In one embodiment, the alkylene moiety is replaced by one or more substituents selected from List A, e.g., 1, 2, or 3, e.g., 1 or 2, e.g., 1 substituent).

[0242] C 1-4 Alkylene

[0243] In the context of the compounds of this invention, the C group that can function as a disulfide bridge exists. 1-4 Alkylenes include, but are not limited to, C 1-2 Alkylenes, such as methylene (-CH2-, i.e., C1 alkylene) and ethylene (-CH2CH2-, i.e., C2 alkylene).

[0244] alkylene oxides

[0245] The term "alkyleneoxy" means "alkylene-O-(alkylene-O-)", where the alkylene group is as defined and exemplified above. In one embodiment, alkyleneoxy means (C 2-3 ) Alkylene oxide. In one embodiment, alkylene oxide means (C2) alkylene oxide (ethylene oxide). In one embodiment, alkylene oxide means (C3) alkylene oxide (propylene oxide).

[0246] Carbocyclic and heterocyclic groups—cycloalkyl, cycloalkylene, cycloalkenyl, cycloalkenyl, heterocyclic groups

[0247] The terms "cycloalkyl" and "cycloalkenyl" refer to the cyclic non-aromatic forms of "alkyl" and "alkenyl" that preferably have 3 to 40, 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 (e.g., 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms), more preferably 3 to 7 carbon atoms. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, and adamantyl. Exemplary cycloalkenyl groups include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, and cyclodecenyl. The cycloalkyl or cycloalkenyl group may consist of one ring (monocyclic), two rings (bicyclic), or more than two rings (polycyclic). "Substituted cycloalkyl" means that one or more hydrogen atoms of the cycloalkyl group (e.g., from one to a 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, 1 to 3, or 1 or 2) are replaced by substituents other than hydrogen (when more than one hydrogen atom is replaced, the substituents may be the same or different). In one embodiment, the cycloalkyl or cycloalkenyl group is substituted by one or more substituents selected from List A, e.g., 1, 2, or 3, e.g., 1 or 2, e.g., 1 substituent).

[0248] The terms "cycloalkylene" and "cycloalkenyl" refer to the cyclic non-aromatic form of "alkylene" and "alkenyl," which preferably have 3 to 40, 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 (e.g., 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms), more preferably 3 to 10 carbon atoms, for example 5 to 10 carbon atoms. In one embodiment, the cycloalkylene is (C 5-10 ) Cycloalkylene. In one embodiment, the cycloalkylene is (C 3-10 ) Cycloalkylene. In one embodiment, the cycloalkylene group is (C 3-10 ) Cycloalkenyl. In one embodiment, the cycloalkenyl group is (C 5-10 Cycloalkenyl groups. Exemplary cycloalkylene groups include: cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, cyclooctylene, cyclononylene, and cyclodecylene. Exemplary cycloalkenyl groups include cyclopentenylene and cyclohexenylene. In one embodiment, the cycloalkylene or cycloalkenyl group is selected from one or more of List A, such as 1, 2, or 3, such as 1 or 2, such as 1 substituent substitution.

[0249] The term "heterocyclic group" or "heterocycle" means a cycloalkyl group as defined above, wherein 1, 2, 3, or 4 carbon atoms in the cycloalkyl group are replaced by heteroatoms of oxygen, nitrogen, silicon, selenium, phosphorus, or sulfur, preferably O, S, or N. The heterocyclic group preferably has 1 to 2 rings, each ring containing 3 to 10 ring atoms, for example 3, 4, 5, 6, or 7 ring atoms. Preferably, in each ring of the heterocyclic 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 "heterocyclic group" is also intended to cover the partially or fully hydrogenated forms (e.g., dihydro, tetrahydro, or all-hydrogen forms) of the aforementioned heteroaryl groups. Exemplary heterocyclic groups include morpholino, pyrrolyl, imidazoalkyl, pyrazolyl, piperidinyl (also known as piperidyl), piperazinyl, dihydrofuranyl and tetrahydrofuranyl, dihydrothiophene and tetrahydrothiophene, dihydropyranyl and tetrahydropyranyl, hexamethylenetetramine, lactone, lactam, cyclic imide, and cyclic anhydride. "Substituted heterocyclic group" means that one or more hydrogen atoms of the heterocyclic group (e.g., from 1 to the maximum number of hydrogen atoms bonded to the heterocyclic 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 substituents other than hydrogen (when more than one hydrogen atom is replaced, the substituents can be the same or different). In one embodiment, the heterocyclic group is selected from one or more of the list A, such as 1, 2 or 3, such as 1 or 2, such as 1 substituent.

[0250] Aromatic groups—aryl, heteroaryl, arylene, heteroaryl

[0251] The term "aryl" refers to a monovalent group in an aromatic cyclic hydrocarbon. Preferably, the aryl group contains 3 to 14 (e.g., 5, 6, 7, 8, 9, or 10, e.g., 5, 6, or 10) carbon atoms, which may be arranged in a single ring (e.g., phenyl) or two or more fused rings (e.g., naphthyl). Exemplary aryl groups include cyclopropenyl groups. (cyclopropenylium), cyclopentadienyl, phenyl, indene, naphthyl, azulel, fluorenyl, anthracene, and phenanthryl. Preferably, "aryl" refers to a monocyclic aromatic ring containing 6 carbon atoms or an aromatic bicyclic system containing 10 carbon atoms. Preferred examples are phenyl and naphthyl. Aryl does not cover fullerenes. "Substituted aryl" means that one or more hydrogen atoms of the aryl group (e.g., from 1 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 substituents other than hydrogen (when more than one hydrogen atom is replaced, the substituents can be the same or different). In one embodiment, the aryl group is substituted by 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 aryl groups include biphenyl, 2-fluorophenyl, 2-chloro-6-methylphenyl, aniline, 4-hydroxyphenyl, and methoxyphenyl (i.e., 2-methoxyphenyl, 3-methoxyphenyl, or 4-methoxyphenyl).

[0252] The term "heteroaryl" or "heteroary ring" refers to an aryl group as defined above, wherein one or more carbon atoms of the aryl group are replaced by O, S, or N heteroatoms. Preferably, a heteroaryl refers to a five- or six-membered aromatic monocyclic ring, wherein one, two, or three carbon atoms are replaced by the same or different O, N, or S heteroatoms. Alternatively, it refers to an aromatic bicyclic or tricyclic system, wherein one, two, three, four, or five carbon atoms are replaced by the same or different O, N, or S heteroatoms. Preferably, the maximum number of O atoms in each ring of the heteroaryl is one, the maximum number of S atoms is one, and the maximum total number of O and S atoms is two. Exemplary heteroaryl groups include furanyl, thiophene, etc. azole group, iso azole group, Diazolyl, pyrrolyl, imidazoleyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, triazinyl, benzofuranyl, indoleyl, isoindoleyl, benzothiophenyl, 1H-indazoleyl, benzimidazoleyl, benzo[…] Azolyl, indoxazinyl, benzo[a]iso Azolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, benzodiazinyl, quinoxalinyl, quinazolinyl, benzotriazinyl, pyridazinyl, phen Zinyl, thiazopyridyl, pyrrolothiazolyl, phenothiazinyl, isobenzofuranyl, chromenyl, xanthyl, pyrrolizinyl, indazyl, indazole, purine, quinazinyl, phthalazinyl, naphthidyl, cinnamyl, pteridinyl, carbazole, phenanthridine, acridineyl, perimidinyl, phenanthridineyl, and phenothiazinyl. Exemplary 5- or 6-membered heteroaryl groups include furanyl, thiopheneyl, azole group, iso azole group, Diazolyl, pyrroloyl, imidazolyl (e.g., 2-imidazolyl), pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl (e.g., 4-pyridinyl), pyrimidinyl, pyrazinyl, triazinyl, and pyridazinyl. "Substituted heteroaryl" means that one or more hydrogen atoms of the heteroaryl group (e.g., from 1 to a 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 substituents other than hydrogen (when more than one hydrogen atom is replaced, the substituents can be the same or different). In one embodiment, the heteroaryl group is substituted by one or more substituents selected from List A, e.g., 1, 2, or 3, e.g., 1 or 2, e.g., 1 substituent.

[0253] The term "arylene" refers to a divalent group in an aromatic cyclic hydrocarbon. Preferably, the aryl group contains 3 to 14 (e.g., 5, 6, 7, 8, 9, or 10, e.g., 5, 6, or 10) carbon atoms, which may be arranged in a single ring (e.g., phenyl) or two or more fused rings (e.g., naphthyl). Preferably, "arylene" is C 5-14 Aromatic. More preferably, "aromatic" is C 6-14 Aromatic. Even more preferably, "aromatic" is C 6-10 Aromaticyl refers to a monocyclic aromatic ring containing 6 carbon atoms or an aromatic bicyclic aromatic ring containing 10 carbon atoms. Preferably, "aromaticyl" refers to a monocyclic aromatic ring containing 6 carbon atoms or an aromatic bicyclic aromatic ring containing 10 carbon atoms. Preferred examples are phenylene (which may be 1,2-phenylene, 1,3-phenylene, or 1,4-phenylene) and naphthylene (which may be 1,2-naphthylene, 1,3-naphthylene, 1,4-naphthylene, 1,5-naphthylene, 1,6-naphthylene, 1,7-naphthylene, or 1,8-naphthylene).

[0254] Optional substituents

[0255] The amino acid residues described herein may optionally be 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.

[0256] "List A" replaces the base selection: C 1-6 Alkyl, C 2-6 alkenyl, C 2-6Alkynyl, 6 to 14 nucleotides (e.g., 6 to 10 nucleotides) aryl, 3 to 14 nucleotides (e.g., 5 or 6 nucleotides) heteroaryl, 3 to 14 nucleotides (e.g., 3 to 7 nucleotides) cycloalkyl, 3 to 14 nucleotides (e.g., 3 to 7 nucleotides) heterocyclic, 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- 2OR'、-S(O) 1-2 N(R')2、-OS(O) 1-2 N(R')2、-N(R')S(O) 1-2 R'、-N(R')S(O) 1-2 OR'、-C(=X 1 )R'、-C(=X 1 )X 1 R'、-X 1 C(=X 1 )R' and -X 1 C(=X 1 )X 1 R', where X 1 Each R' is independently selected from O, S, NH, and N (CH3); and each R' is independently selected from H and C. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 The group comprises an alkynyl group, a 5- or 6-membered cycloalkyl group, a 5- or 6-membered aryl group, a 5- or 6-membered heteroaryl group, and a 5- or 6-membered heterocyclic group, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclic groups is optionally substituted by one, two, or three substituents, said substituents being independently selected from C10. 1-3 Alkyl, halogen, -CF3, -CN, azide, -NO2, -OH, -O(C) 1-3 alkyl), -S(C 1-3 Alkyl groups, -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 group), -S(O)2NH 2-z (C 1-3 alkyl) z -C(=O)OH, -C(=O)O(C 1-3 Alkyl group), -C(=O)NH 2-z (C 1-3 alkyl) z -NHC(=O)(C 1-3 Alkyl group), -NHC(=NH)NHz-2 (C 1-3 alkyl) z and -N(C 1-3 alkyl)C(=NH)NH 2-z (C 1-3 alkyl) z Each z is independently 0, 1, or 2 and each C 1-3 The alkyl group is independently methyl, ethyl, or propyl.

[0257] In some implementations, the substituents in list A are selected from list A1, which consists of the following: C 1-3 Alkyl, phenyl, halogen, -CF3, -OH, -OCH3, -SCH3, -NH2- z (CH3) z -C(=O)OH, C(=O)OCH3, and -C(=O)CH3, where z is 0, 1, or 2 and C 1-3 The alkyl group is methyl, ethyl, propyl, or isopropyl.

[0258] In some embodiments, the substituents in list A are selected from list A2 and consist of: C(=O)CH3, methyl, ethyl, propyl, isopropyl, halogen (e.g., F, Cl or Br) and -CF3.

[0259] Bridging section

[0260] The sequences disclosed herein contain bridging portions (e.g., (1a), (2a), etc.) indicated in parentheses. These represent chemical bridges between specific residue pairs. Each set of parentheses will appear twice in the sequence as a pair to indicate a single bridging portion. Most sequences have two bridging portions, indicated by four sets of parentheses, signifying two pairs of bridging portions.

[0261] The numbers in parentheses indicate specific bridging pairs (e.g., "1" indicates a bridge between amino acid residues at positions 2 and 11, which is also indicated by square bracket symbols that define specific chemical bridges). The letters indicate the type of chemical bridge (e.g., "a" indicates a 1,3-dithio-propane-2-one bridge, while "c" indicates a lactam bridge).

[0262] Specific chemical bridges are defined at the end of the table using square brackets (e.g., [2,11], [2,7], [10,13], etc.) to indicate the amino acid residues used in the bridging portion compared to the original starting peptide (e.g., the I3 peptide (isomer 3) described in Example 2 of WO2023 / 099669). Therefore, these amino acid residues may not be specifically aligned (line-up) with the actual amino acid number of SEQ ID NO: (e.g., in some of these sequences, the first amino acid residue has been missing compared to the original starting peptide).

[0263] The residues directly before the parentheses indicate the specific residues used in the bridging section.

[0264] Directly after the parentheses " † The symbol indicates that the α-amine (-NH2) group (or the β-amine group for bLys, {d}bLys and β-hLys or the α-amine that has been converted to an azide group for (N3)-K and {d}(N3)-K) is used to form a bridge.

[0265] Directly after the parentheses " ‡ The symbol indicates that the α-carboxylic acid (-COOH) group is used to form a bridge.

[0266] Both the α-amine (-NH2) group (or the β-amine group for bLys, {d}bLys and β-hLys) and the α-carboxylic acid (-COOH) group are conventionally used to form the peptide backbone (see, for example, Table B).

[0267] Directly after the parentheses " The symbol "-NH2 (if at the beginning of the sequence, i.e., N-terminus) or -COOH (if at the end of the sequence, i.e., C-terminus)" indicates the terminal component used to form a bridge. This is especially relevant when the bridging portion is a triazole. When the symbol is used at the N-terminus, the terminal -NH2 has been converted into an azide (-N3) of the N-terminal amino acid residue.

[0268] SMILES string

[0269] Below the structure described by the amino acid sequence of each compound disclosed herein is a Simplified Molecular-Input Line-Entry System (SMILES) string. SMILES strings are linear notations used to describe the structure of chemical substances using short American Standard Code for Information Interchange (ASCII) strings. SMILES strings can be imported into most molecular editors (such as ChemDraw® and BIOVIA Draw) for conversion back into two-dimensional or three-dimensional diagrams of chemical structures. When there is a discrepancy between the structure provided by the amino acid sequence and the structure provided by the SMILES string, the SMILES string prevails.

[0270] compound

[0271] This invention provides compounds as peptide inhibitors of IL-23R. These compounds exhibit a favorable combination of properties, such as highly potent inhibition of IL-23R and / or high stability in the gastrointestinal tract (see Example 3). Furthermore, the compounds described herein can be used to treat a variety of diseases, conditions, and disorders involving IL-23R, such as inflammatory bowel diseases (e.g., Crohn's disease or ulcerative colitis), psoriasis, and psoriatic arthritis. Compared to the compounds disclosed in WO2023 / 099669, the compounds described herein exhibit improved properties (e.g., more potent inhibition and / or greater gastrointestinal stability).

[0272] This invention provides compounds of the following formula, or pharmaceutically acceptable salts or solvates thereof:

[0273] ZR 2

[0274] in

[0275] R 2 It is NHR 3 Or C(=O)R 3 , where R 3 It is a C that is hydrogen or optionally substituted with a pyridine ring. 1-6 Alkyl groups, or those that are not present; and

[0276] Z is the amino acid sequence of formula I:

[0277]

[0278] in

[0279] X2 is selected from

[0280] Lys, D-lys, iso-Lys, D-iso-Lys, β-Lys, D-β-Lys, homo-Lys, D-homo-Lys, β-homo-Lys, N-Me-Lys, N-Me-homo-Lys, (N3)-Lys, D-(N3)-Lys, (N3)-β-Lys, (N3)-D-β-Lys, (N3)-high-Lys, (N3)-D-high-Lys, (N3)-β-high-Lys,

[0281] Dpr, D-Dpr, iso-Dpr, D-iso-Dpr, β-Dpr, D-β-Dpr, high-Dpr, D-high-Dpr, β-high-Dpr, N-Me-Dpr, N-Me-high-Dpr, (N3)-Dpr, D-(N3)-Dpr, (N3)-β-Dpr, (N3)-D-β-Dpr, (N3)-high-Dpr, (N3)-D-high-Dpr, (N3)-β-high-Dpr,

[0282] Dab, D-Dab, iso-Dab, D-iso-Dab, β-Dab, D-β-Dab, homo-Dab, D-homo-Dab, β-homo-Dab, N-Me-Dab, N-Me-homo-Dab, (N3)-Dab, D-(N3)-Dab, (N3)-β-Dab, (N3)-D-β-Dab, (N3)-high-Dab, (N3)-D-high-Dab, (N3)-β-high-Dab,

[0283] Orn, D-Orn, Different-Orn, D-Different-Orn, β-Orn, D-β-Orn, High-Orn, D-High-Orn, β-High-Orn, N-Me-Orn, N-Me-High-Orn, (N3)-Orn, D-(N3)-Orn, (N3)-β-Orn, (N3)-D-β-Orn, (N3)-High-Orn, (N3)-D-High-Orn, (N3)-β-High-Orn

[0284] Lys(Gly),

[0285] Asp, D-Asp, iso-Asp, D-iso-Asp, β-Asp, D-β-Asp, homo-Asp, D-homo-Asp, β-homo-Asp, N-Me-Asp, N-Me-homo-Asp, (N3)-Asp, D-(N3)-Asp, (N3)-β-Asp, (N3)-D-β-Asp, (N3)-high-Asp, (N3)-D-high-Asp, (N3)-β-high-Asp,

[0286] Glu, D-Glu, iso-Glu, D-iso-Glu, β-Glu, D-β-Glu, homo-Glu, D-homo-Glu, β-homo-Glu, N-Me-Glu, N-Me-homo-Glu, (N3)-Glu, D-(N3)-Glu, (N3)-β-Glu, (N3)-D-β-Glu, (N3)-ho-Glu, (N3)-D-ho-Glu, (N3)-β-ho-Glu,

[0287] 2-Amino-6-carboxyhexanoyl and 3-aminopropionyl;

[0288] X3 is selected from any amino acid, ω-hydroxy-C 2-6 Alkyl acids may not exist;

[0289] X4 is Val D-Val, β-Val, D-β-Val, Homo-Val, D-homo-Val, β-homo-Val, N-Me-Val, N-Me-homo-Val, 2-Me-Val,

[0290] Ala, D-Ala, β-Ala, D-β-Ala, Homo-Ala, D-homo-Ala, β-homo-Ala, N-Me-Ala, N-Me-homo-Ala,

[0291] Gly, β-Gly, homo-Gly, β-homo-Gly, N-Me-Gly, N-Me-homo-Gly,

[0292] Leu, D-Leu, β-Leu, D-β-Leu, high-Leu, D-high-Leu, β-high-Leu, N-Me-Leu, N-Me-high-Leu, 2-Me-Leu,

[0293] Ile, D-Ile, β-Ile, D-β-Ile, high-Ile, D-high-Ile, β-high-Ile, N-Me-Ile, N-Me-high-Ile or do not exist;

[0294] X5 is selected from optionally substituted tryptophan residues, optionally substituted azatryptophan residues, and optionally substituted β-homotraphan residues;

[0295] X6 is selected from optionally substituted Gln residues, optionally substituted Lys residues, optionally substituted Arg residues, optionally substituted Dab residues, optionally substituted Orn residues, optionally substituted Phe residues, Ala, D-Ala, β-Ala, D-β-Ala, high-Ala, D-high-Ala, β-high-Ala, N-Me-Ala, N-Me-high-Ala, Cit, D-Cit, β-Cit, D-β-Cit, high-Cit, D-high-Cit, β-high-Cit, N-Me-Cit, N-Me-high-Cit, Glu, D-Glu, iso-Glu, D-iso-Glu, β-Glu, D-β-G lu, Homo-Glu, D-homo-Glu, β-homo-Glu, N-Me-Glu, N-Me-ho-Glu, Tyr, D-Tyr, β-Tyr, D-β-Tyr, Homo-Tyr, D-homo-Tyr, β-homo-Tyr, N-Me-Tyr, N-Me-homo-Tyr, Val, D-Val, β-Val, D-β-Val, Homo-Val, D-homo-Val, β-homo-Val, N-Me-Val, N-Me-homo-Val or His, D-His, β-His, D-β-His, homo-His, D-homo-His, β-homo-His, N-Me-His, and N-Me-homo-His;

[0296] X7 is selected from Asp, D-Asp, hetero-Asp, D-heterogeneous-Asp, β-Asp, D-β-Asp, high-Asp, D-high-Asp, β-high-Asp, N-Me-Asp, N-Me-high-Asp.

[0297] Glu, D-Glu, iso-Glu, D-iso-Glu, β-Glu, D-β-Glu, homo-Glu, D-homo-Glu, β-homo-Glu, N-Me-Glu, N-Me-homo-Glu,

[0298] Dab, D-Dab, iso-Dab, D-iso-Dab, β-Dab, D-β-Dab, homo-Dab, D-homo-Dab, β-homo-Dab, N-Me-Dab, N-Me-homo-Dab,

[0299] Orn, D-Orn, Different-Orn, D-Different-Orn, β-Orn, D-β-Orn, High-Orn, D-High-Orn, β-High-Orn, N-Me-Orn, N-Me-High-Orn

[0300] Lys, D-Lys, iso-Lys, β-Lys, D-iso-Lys, D-β-Lys, homo-Lys, D-homo-Lys, β-homo-Lys, N-Me-Lys, N-Me-homo-Lys,

[0301] Pra, D-Pra, β-Pra, D-β-Pra, high-Pra, D-high-Pra, β-high-Pra, N-Me-Pra, N-Me-high-Pra,

[0302] Hpg, D-Hpg, β-Hpg, D-β-Hpg, high-Hpg, D-high-Hpg, β-high-Hpg, N-Me-Hpg, and N-Me-high-Hpg;

[0303] X8 is selected from optionally substituted tryptophan residues, optionally substituted azatryptophan residues, optionally substituted β-homotrapetin residues, optionally substituted tyrosine residues, optionally substituted phenylalanine residues, optionally substituted homophenylalanine residues, and alanine residues substituted with a carbocyclic group or an aromatic or heteroaromatic group, wherein the aromatic or heteroaromatic group is selected from phenyl, pyridyl, naphthyl, and quinolinyl, each optionally substituted.

[0304] X9 is selected from optionally substituted tryptophan residues, optionally substituted azatryptophan residues, optionally substituted alanine residues, optionally substituted phenylalanine residues, and optionally substituted tyrosine residues.

[0305] X10 is selected from,

[0306] Val, D-Val, β-Val, D-β-Val, Homo-Val, D-homo-Val, β-homo-Val, N-Me-Val, N-Me-homo-Val, 2-Me-Val,

[0307] Gly, β-Gly, homo-Gly, β-homo-Gly, N-Me-Gly, N-Me-homo-Gly,

[0308] Dab, D-Dab, iso-Dab, D-iso-Dab, β-Dab, D-β-Dab, homo-Dab, D-homo-Dab, β-homo-Dab, N-Me-Dab, N-Me-homo-Dab,

[0309] Lys, D-lys, iso-Lys, D-iso-Lys, β-Lys, D-β-Lys, homo-Lys, D-homo-Lys, β-homo-Lys, N-Me-Lys, N-Me-homo-Lys,

[0310] Aib, D-Aib, β-Aib, D-β-Aib, Homo-Aib, D-homo-Aib, β-homo-Aib, N-Me-Aib, N-Me-ho-Aib,

[0311] Ala, D-Ala, β-Ala, D-β-Ala, Homo-Ala, D-homo-Ala, β-homo-Ala, N-Me-Ala, N-Me-homo-Ala,

[0312] Leu, D-Leu, β-Leu, D-β-Leu, high-Leu, D-high-Leu, β-high-Leu, N-Me-Leu, N-Me-high-Leu, 2-Me-Leu,

[0313] Ile, D-Ile, β-Ile, D-β-Ile, high-Ile, D-high-Ile, β-high-Ile, N-Me-Ile, N-Me-high-Ile,

[0314] And carbocyclic or heterocyclic rings with amino and carbonyl substituents;

[0315] X11 is selected from:

[0316] Dpr, D-Dpr, iso-Dpr, D-iso-Dpr, β-Dpr, D-β-Dpr, high-Dpr, D-high-Dpr, β-high-Dpr, N-Me-Dpr, N-Me-high-Dpr,

[0317] Dab, D-Dab, iso-Dab, D-iso-Dab, β-Dab, D-β-Dab, homo-Dab, D-homo-Dab, β-homo-Dab, N-Me-Dab, N-Me-homo-Dab,

[0318] Orn, D-Orn, Different-Orn, D-Different-Orn, β-Orn, D-β-Orn, High-Orn, D-High-Orn, β-High-Orn, N-Me-Orn, N-Me-High-Orn

[0319] Lys, D-lys, iso-Lys, D-iso-Lys, β-Lys, D-β-Lys, homo-Lys, D-homo-Lys, β-homo-Lys, N-Me-Lys, N-Me-homo-Lys, Lys(Me),

[0320] Lys(Gly),

[0321] Asp, D-Asp, hetero-Asp, D-heterogeneous-Asp, β-Asp, D-β-Asp, high-Asp, D-high-Asp, β-high-Asp, N-Me-Asp, N-Me-high-Asp

[0322] Glu, D-Glu, iso-Glu, D-iso-Glu, β-Glu, D-β-Glu, homo-Glu, D-homo-Glu, β-homo-Glu, N-Me-Glu, N-Me-homo-Glu, and

[0323] 2-Amino-6-carboxyhexanoyl;

[0324] X12 is selected from: optionally substituted Phe residues; optionally substituted Tyr residues; optionally substituted His residues; alanine residues substituted with a carbocyclic group or an aromatic or heteroaromatic group selected from phenyl, pyridyl, naphthyl, and quinolinyl, each optionally substituted; Dab, D-Dab, iso-Dab, D-iso-Dab, β-Dab, D-β-Dab, high-Dab, D-high-Dab, β-high-Dab, N-Me-Dab, N-Me-high-Dab, Gly, β-Gly, high-Gly, β-high-Gly, N-Me-Gly, N-Me-high-Gly, Pro, 5-aminopentanoyl, 4-aminopiperidin-4-carbonyl, (R,S)-imidazolidine-2-carbonyl, 3-aminopropionyl, Gly-CF3, D-Gly-CF3, Nle, Gln, D -Gln, iso-Gln, D-iso-Gln, β-Gln, D-β-Gln, homo-Gln, D-homo-Gln, β-homo-Gln, N-Me-Gln, N-Me-homo-Gln ,THP,Ser,D-Ser,β-Ser,D-β-Ser,high-Ser,D-high-Ser,β-high-Ser,N-Me-Ser,N-Me-high-Ser,Ser( OMe), 3-aminotetrahydrofuran-3-carbonyl, Arg, D-Arg, β-Arg, D-β-Arg, high-Arg, D-high-Arg, β-high-Arg, N-Me-Arg, N-Me-high-Arg, Thr, D-Thr, β-Thr, D-β-Thr, high-Thr, D-high-Thr, β-high-Thr, N-Me-Thr, N-Me-high-Thr Glu, D-Glu, iso-Glu, D-iso-Glu, β-Glu, D-β-Glu, high-Glu, D-high-Glu, β-high-Glu, N-Me-Glu, N-Me-high-Glu, Asn, D-Asn, β-Asn, D-β-Asn, high-Asn, D-high-Asn, β-high-Asn, N-Me-Asn, N-Me-high-Asn, 4-aminobutyryl, 2-(trimethyl-2-aminoethoxy)ethoxy]propyl and Lys, wherein the side chain -NH2 of Lys is replaced by -C(=O)(CH2). n R K Replace, where n is 0 to 2 and R K It is either an imidazole, pyrimidin, or pyridinyl group optionally substituted with F, or X12 is not present; and

[0325] X13 is selected from: optionally substituted His residues; optionally substituted Phe residues; alanine residues substituted with a carbocyclic group or an aromatic or heteroaromatic group, wherein the aromatic or heteroaromatic group is selected from phenyl, pyridyl, naphthyl, and quinolinyl, each optionally substituted; Asn, D-Asn, β-Asn, D-β-Asn, high-Asn, D-high-Asn, β-high-Asn, N-Me-Asn, N-Me-high-Asn, Gly, β-Gly, high-Gly, β-high-Gly, N-Me-Gly, N-Me-high-Gly,

[0326] And Dab, Orn, or Lys, where the side chain -NH2 is replaced by -C(=O)(CH2). n R K Replace, where n is 0 to 2 and R K It is an imidazole, pyrimidin, or pyridinyl group optionally substituted with F.

[0327] Or it may not exist;

[0328] in

[0329] (i) X2 and X11 are amino acid residues that together form a lactam bridge;

[0330] (ii) X2 and X7 are amino acid residues that together form a lactam bridge or a bridge containing a triazole ring; and

[0331] (iii) Optionally, when X13 is present, X10 and X13 are amino acid residues that together form a lactam bridge.

[0332] In some embodiments, the present invention provides compounds of the following formula, or pharmaceutically acceptable salts or solvates thereof:

[0333] ZR 2

[0334] in

[0335] R 2 It is NHR 3 , where R 3 It is a C that is hydrogen or optionally substituted with a pyridine ring. 1-6 Alkyl groups, or those that are not present; and

[0336] Z is the amino acid sequence of formula Ia:

[0337]

[0338] in

[0339] X2 is selected from Lys, D-Lys, iso-Lys, β-Lys, D-β-Lys, high-Lys, D-high-Lys, β-high-Lys, N-Me-Lys, Dab, D-Dab, Glu, iso-Glu, Orn, D-Orn, Lys(Gly), (N3)-Lys, and D-(N3)-Lys;

[0340] X3 is selected from Thr, Trp, Ile, 3-aminopropionyl, 4-aminobutyryl, β-high-Ile, β-high-Thr, Gly, and N-Me-3-aminopropionyl, 3-hydroxypropionic acid, or is not present;

[0341] X4 is Val or does not exist;

[0342] X5 is either Trp or 1-Me-Trp;

[0343] X6 is Gln, Gln(Me), Dab(Ac-N-Me), Dab(Ac) or Gln(2Me);

[0344] X7 is selected from Glu, High-Glu, Asp, Pra, and Hpg;

[0345] X8 is selected from Y(2-aminoethoxy), Y(Me), Y(Bn), F(4-Me), F(4-Bu), cyclopropyl-Ala, F(4-morpholine), F(4-THP), Y(CH3-2-F), F(4-F), F(4-piperazine), F(4-imidazolium), Y(CH3-3-F), F(4-piperidine), 5-AzaTrp, Y(Ac-2-aminoethoxy), 7-AzaTrp, 6-AzaTrp, and F(4-CONH2).

[0346] X9 is 2-Nal;

[0347] X10 is selected from 2-Me-Leu, 2-Me-Val, D-Ala, Dab, Gly, and Aib;

[0348] X11 is selected from Glu, high-Glu, Lys, Lys(Me), Orn and 2-amino-6-carboxyhexanoyl;

[0349] X12 is selected from Dab, His, S(OCH3), D-His, His(1-Me), 3-(3-quinolinyl)-Ala, and 4-aminopiperidine-4-carbonyl; and

[0350] X13 is 3-(3-pyridyl)-Ala, 3-(3,5-pyrimidinyl)-Ala, or it does not exist;

[0351] in

[0352] (i) X2 and X11 are amino acid residues that together form a lactam bridge;

[0353] (ii) X2 and X7 are amino acid residues that together form a lactam bridge or a bridge containing a triazole ring; and

[0354] (iii) Optionally, when X13 is present, X10 and X13 are amino acid residues that together form a lactam bridge.

[0355] In some embodiments, the present invention provides compounds of the following formula, or pharmaceutically acceptable salts or solvates thereof:

[0356] ZR 2

[0357] in

[0358] R 2 It is NHR 3 Or C(=O)R 3 , where R 3 It is a C that is hydrogen or optionally substituted with a pyridine ring. 1-6 Alkyl groups, or those that are not present; and

[0359] Z is the amino acid sequence of formula I:

[0360]

[0361] in

[0362] X2 is selected from Lys, D-Lys, iso-Lys, β-Lys, D-β-Lys, high-Lys, D-high-Lys, β-high-Lys, N-Me-Lys, Dab, D-Dab, iso-Dab, Glu, iso-Glu, D-iso-Glu, Orn, D-Orn, Dpr, Lys(Gly), (N3)-Lys, and D-(N3)-Lys;

[0363] X3 is selected from Thr, Ile, 3-aminopropionyl, 4-aminobutyryl, β-high-Ile, β-high-Thr, Gly, N-Me-3-aminopropionyl, and Ser, or may not exist;

[0364] X4 is Val or does not exist;

[0365] X5 is selected from Trp, 1-Me-Trp, and β-high-Trp;

[0366] X6 is Gln;

[0367] X7 is selected from Glu, D-Glu, High-Glu, Asp, Pra and Hpg;

[0368] X8 is selected from Y(2-aminoethoxy), Y(Me), Y(nPr), Y(Bn), Trp, D-Phe, 2-Me-Phe, F(4-Me), F(4-Bu), 3-(2-pyridyl)-Ala, 3-(3-pyridyl)-Ala, 3-(4-pyridyl)-Ala and cyclopropyl-Ala;

[0369] X9 is 2-Nal or cyclopropyl-Ala;

[0370] X10 is selected from 2-Me-Leu, 2-Me-Val, Dab, Gly, Lys and Aib;

[0371] X11 is selected from Glu, high-Glu, β-high-Glu, Dab, iso-Dab, Lys, Lys(Me), Orn and 2-amino-6-carboxyhexanoyl;

[0372] X12 is selected from Dab, His, D-His, His(1-Me), 3-(2-pyridyl)-Ala, 3-(3-pyridyl)-Ala, 3-(4-pyridyl)-Ala, 3-(3-quinolinyl)-Ala, Gly, Pro, 5-aminopentanoyl, 4-aminopiperidine-4-carbonyl, (R,S)-imidazolidine-2-carbonyl, and Lys, wherein the side chain -NH2 of Lys is replaced by -C(=O)(CH2). n R K Replace, where n is 0 to 2 and R K It is either an imidazole, pyrimidin, or pyridinyl group optionally substituted with F, or X12 is not present; and

[0373] X13 is selected from 3-(3-pyridinyl)-Ala, D-3-(3-pyridinyl)-Ala and 3-(3,5-pyrimidinyl)-Ala, or is not present;

[0374] in

[0375] (i) X2 and X11 are amino acid residues that together form a lactam bridge;

[0376] (ii) X2 and X7 are amino acid residues that together form a lactam bridge or a bridge containing a triazole ring; and

[0377] (iii) Optionally, when X13 is present, X10 and X13 are amino acid residues that together form a lactam bridge.

[0378] This invention also provides compounds of the following formula, or pharmaceutically acceptable salts or solvates thereof:

[0379] ZR 2

[0380] in

[0381] R 2 It is NHR 3 , where R 3 It is a C that is hydrogen or optionally substituted with a pyridine ring. 1-6 Alkyl groups, or those that are not present; and

[0382] Z is the amino acid sequence of formula Ia:

[0383]

[0384] in

[0385] X2 is selected from Lys, D-Lys, iso-Lys, β-Lys, D-β-Lys, high-Lys, D-high-Lys, β-high-Lys, N-Me-Lys, Dab, D-Dab, Glu, iso-Glu, Orn, D-Orn, Lys(Gly), (N3)-Lys, and D-(N3)-Lys;

[0386] X3 is selected from Thr, Ile, 3-aminopropionyl, 4-aminobutyryl, β-high-Ile, β-high-Thr, Gly, and N-Me-3-aminopropionyl, or is not present;

[0387] X4 is Val or does not exist;

[0388] X5 is either Trp or 1-Me-Trp;

[0389] X6 is Gln;

[0390] X7 is selected from Glu, High-Glu, Asp, Pra, and Hpg;

[0391] X8 is selected from Y(2-aminoethoxy), Y(Me), Y(Bn), F(4-Me), F(4-Bu) and cyclopropyl-Ala;

[0392] X9 is 2-Nal;

[0393] X10 is selected from 2-Me-Leu, 2-Me-Val, Dab, Gly, and Aib;

[0394] X11 is selected from Glu, high-Glu, Lys, Lys(Me), Orn and 2-amino-6-carboxyhexanoyl;

[0395] X12 is selected from Dab, His, D-His, His(1-Me), 3-(3-quinolinyl)-Ala, and 4-aminopiperidine-4-carbonyl; and

[0396] X13 is 3-(3-pyridyl)-Ala, 3-(3,5-pyrimidinyl)-Ala, or it does not exist;

[0397] in

[0398] (i) X2 and X11 are amino acid residues that together form a lactam bridge;

[0399] (ii) X2 and X7 are amino acid residues that together form a lactam bridge or a bridge containing a triazole ring; and

[0400] (iii) Optionally, when X13 is present, X10 and X13 are amino acid residues that together form a lactam bridge.

[0401] This invention also provides compounds of the following formula, or pharmaceutically acceptable salts or solvates thereof:

[0402] ZR 2

[0403] in

[0404] R 2 It is NHR 3 Or C(=O)R 3 , where R 3 It is a C that is hydrogen or optionally substituted with a pyridine ring. 1-6 Alkyl groups, or those that are not present; and

[0405] Z is the amino acid sequence of formula II:

[0406]

[0407] in

[0408] X2 is selected from Lys, D-lys, iso-Lys, β-Lys, D-β-Lys, high-Lys, D-high-Lys, β-high-Lys, N-Me-Lys, Dab, D-Dab, iso-Dab, Glu, iso-Glu, D-iso-Glu, Orn, D-Orn, Dpr, Lys(Gly), (N3)-Lys, and D-(N3)-Lys;

[0409] X3 is selected from Thr, Ile, 3-aminopropionyl, 4-aminobutyryl, β-high-Ile, β-high-Thr, Gly, N-Me-3-aminopropionyl, and Ser, or may not exist;

[0410] X4 is Val or does not exist;

[0411] X5 is selected from Trp, 1-Me-Trp, and β-high-Trp;

[0412] X6 is Gln;

[0413] X7 is selected from Glu, D-Glu, High-Glu, Asp, Pra and Hpg;

[0414] X8 is selected from Y(2-aminoethoxy), Y(Me), Y(nPr), Y(Bn), Trp, D-Phe, 2-Me-Phe, F(4-Me), F(4-Bu), 3-(2-pyridyl)-Ala, 3-(3-pyridyl)-Ala, 3-(4-pyridyl)-Ala and cyclopropyl-Ala;

[0415] X9 is 2-Nal or cyclopropyl-Ala;

[0416] X10 is selected from 2-Me-Leu, 2-Me-Val, Dab, Gly, Lys and Aib;

[0417] X11 is selected from Glu, high-Glu, β-high-Glu, Dab, iso-Dab, Lys, Lys(Me), Orn and 2-amino-6-carboxyhexanoyl;

[0418] X12 is selected from Dab, His, D-His, His(1-Me), 3-(2-pyridyl)-Ala, 3-(3-pyridyl)-Ala, 3-(4-pyridyl)-Ala, 3-(3-quinolinyl)-Ala, Gly, Pro, 5-aminopentanoyl, 4-aminopiperidine-4-carbonyl, (R,S)-imidazolidine-2-carbonyl, and Lys, wherein the side chain -NH2 of Lys is replaced by -C(=O)(CH2). n R K Replace, where n is 0 to 2 and R K It is either an imidazole, pyrimidin, or pyridinyl group optionally substituted with F, or X12 is not present; and

[0419] X13 is selected from 3-(3-pyridinyl)-Ala, D-3-(3-pyridinyl)-Ala and 3-(3,5-pyrimidinyl)-Ala, or is not present;

[0420] in

[0421] (i) X2 and X11 are amino acid residues that together form a lactam bridge; and

[0422] (ii) X2 and X7 are amino acid residues that together form a lactam bridge or a bridge containing a triazole ring.

[0423] In some embodiments, the present invention also provides compounds of the following formula, or pharmaceutically acceptable salts or solvates thereof:

[0424] ZR 2

[0425] in

[0426] R 2 It is NHR 3 , where R 3 It is a C that is hydrogen or optionally substituted with a pyridine ring. 1-6 Alkyl groups, or those that are not present; and

[0427] Z is the amino acid sequence of formula IIa:

[0428]

[0429] in

[0430] X2 is selected from Lys, D-Lys, iso-Lys, β-Lys, D-β-Lys, high-Lys, D-high-Lys, β-high-Lys, N-Me-Lys, Dab, D-Dab, Glu, iso-Glu, Orn, D-Orn, Lys(Gly), (N3)-Lys, and D-(N3)-Lys;

[0431] X3 is selected from Thr, Ile, 3-aminopropionyl, 4-aminobutyryl, β-high-Ile, β-high-Thr, Gly, and N-Me-3-aminopropionyl, or is not present;

[0432] X4 is Val or does not exist;

[0433] X5 is either Trp or 1-Me-Trp;

[0434] X6 is Gln;

[0435] X7 is selected from Glu, High-Glu, Asp, Pra, and Hpg;

[0436] X8 is selected from Y(2-aminoethoxy), Y(Me), Y(Bn), F(4-Me), F(4-Bu) and cyclopropyl-Ala;

[0437] X9 is 2-Nal;

[0438] X10 is selected from 2-Me-Leu, 2-Me-Val, Dab, Gly, and Aib;

[0439] X11 is selected from Glu, high-Glu, Lys, Lys(Me), Orn and 2-amino-6-carboxyhexanoyl;

[0440] X12 is selected from Dab, His, D-His, His(1-Me), 3-(3-quinolinyl)-Ala, and 4-aminopiperidine-4-carbonyl; and

[0441] X13 is 3-(3-pyridyl)-Ala, 3-(3,5-pyrimidinyl)-Ala, or it does not exist;

[0442] in

[0443] (i) X2 and X11 are amino acid residues that together form a lactam bridge; and

[0444] (ii) X2 and X7 are amino acid residues that together form a lactam bridge or a bridge containing a triazole ring.

[0445] In some embodiments, the present invention provides compounds of the above formula, wherein Z is the amino acid sequence of any of the above formulas I, Ia, II, and IIa, wherein the lactam bridge between X2 and X11 uses the side chain of the amino acid residue at X2, and the bridge between X2 and X7 uses the N-terminus of the amino acid residue at X2. In some such embodiments, X2 is selected from Lys, D-Lys, β-Lys, D-β-Lys, high-Lys, D-high-Lys, β-high-Lys, N-Me-Lys, Dab, D-Dab, Glu, Orn, D-Orn, Lys(Gly), (N3)-Lys, and D-(N3)-Lys.

[0446] In some embodiments, the present invention provides compounds of the following formula, or pharmaceutically acceptable salts or solvates thereof:

[0447] ZR 2

[0448] in

[0449] R 2 It is NHR 3 Or C(=O)R 3 , where R 3 It is a C that is hydrogen or optionally substituted with a pyridine ring. 1-6 Alkyl groups, or those that are not present; and

[0450] Z is the amino acid sequence of formula III:

[0451]

[0452] in

[0453] X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, and X13 are defined as in any of Equations I, Ia, II, and IIa above; and

[0454] in

[0455] (i) The Lys residue at X2 forms a lactam bridge with the amino acid residue at X11;

[0456] (ii) The Lys residue at X2 forms a lactam bridge with the amino acid residue at X7; and

[0457] (iii) Optionally, when X13 is present, X10 and X13 are amino acid residues that together form a lactam bridge.

[0458] In some embodiments, the present invention provides compounds of the following formula, or pharmaceutically acceptable salts or solvates thereof:

[0459] ZR 2

[0460] in

[0461] R 2 It is NHR 3 , where R 3 It is a C that is hydrogen or optionally substituted with a pyridine ring. 1-6 Alkyl groups, or those that are not present; and

[0462] Z is the amino acid sequence of formula IIIa:

[0463]

[0464] in

[0465] X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, and X13 are defined as in any of Equations I, Ia, II, and IIa above; and

[0466] in

[0467] (i) The Lys residue at X2 forms a lactam bridge with the amino acid residue at X11; and

[0468] (ii) Lys at X2 forms a lactam bridge with the amino acid residue at X7.

[0469] In some embodiments, the present invention provides compounds of the following formula, or pharmaceutically acceptable salts or solvates thereof:

[0470] ZR 2

[0471] in

[0472] R 2 It is NHR 3 Or C(=O)R 3 , where R 3 It is a C that is hydrogen or optionally substituted with a pyridine ring. 1-6 Alkyl groups, or those that are not present; and

[0473] Z is the amino acid sequence of formula IV:

[0474]

[0475] in

[0476] X3 is selected from Thr, Ile, and 3-aminopropionyl, or it may not exist;

[0477] X2, X4, X5, X6, X7, X8, X9, X10, X11, X12, and X13 are defined as in any of Equations I, Ia, II, and IIa above; and

[0478] in

[0479] (i) X2 and X11 are amino acid residues that together form a lactam bridge;

[0480] (ii) X2 and X7 are amino acid residues that together form a lactam bridge or a bridge containing a triazole ring; and

[0481] (iii) Optionally, when X13 is present, X10 and X13 are amino acid residues that together form a lactam bridge.

[0482] In some embodiments, the present invention provides compounds of the following formula, or pharmaceutically acceptable salts or solvates thereof:

[0483] ZR 2

[0484] in

[0485] R 2 It is NHR 3 , where R 3 It is a C that is hydrogen or optionally substituted with a pyridine ring. 1-6 Alkyl groups, or those that are not present; and

[0486] Z is the amino acid sequence of formula IVa:

[0487]

[0488] in

[0489] X3 is selected from Thr, Ile, and 3-aminopropionyl, or it may not exist;

[0490] X2, X4, X5, X6, X7, X8, X9, X10, X11, X12, and X13 are defined as in any of Equations I, Ia, II, and IIa above; and

[0491] in

[0492] (i) X2 and X11 are amino acid residues that together form a lactam bridge; and

[0493] (ii) X2 and X7 are amino acid residues that together form a lactam bridge or a bridge containing a triazole ring.

[0494] In some embodiments, the present invention provides compounds of the following formula, or pharmaceutically acceptable salts or solvates thereof:

[0495] ZR 2

[0496] in

[0497] R 2 It is NHR 3 Or C(=O)R 3 , where R 3 It is a C that is hydrogen or optionally substituted with a pyridine ring. 1-6 Alkyl groups, or those that are not present; and

[0498] Z is the amino acid sequence of formula V:

[0499]

[0500] in

[0501] X2, X3, X5, X6, X7, X8, X9, X10, X11, X12, and X13 are defined as in any of Equations I, Ia, II, and IIa above; and

[0502] in

[0503] (i) X2 and X11 are amino acid residues that together form a lactam bridge;

[0504] (ii) X2 and X7 are amino acid residues that together form a lactam bridge or a bridge containing a triazole ring; and

[0505] (iii) Optionally, when X13 is present, X10 and X13 are amino acid residues that together form a lactam bridge.

[0506] In some embodiments, the present invention provides compounds of the following formula, or pharmaceutically acceptable salts or solvates thereof:

[0507] ZR 2

[0508] in

[0509] R 2 It is NHR 3 , where R 3 It is a C that is hydrogen or optionally substituted with a pyridine ring. 1-6 Alkyl groups, or those that are not present; and

[0510] Z is the amino acid sequence of formula Va:

[0511]

[0512] in

[0513] X2, X3, X5, X6, X7, X8, X9, X10, X11, X12, and X13 are defined as in any of Equations I, Ia, II, and IIa above; and

[0514] in

[0515] (i) X2 and X11 are amino acid residues that together form a lactam bridge; and

[0516] (ii) X2 and X7 are amino acid residues that together form a lactam bridge or a bridge containing a triazole ring.

[0517] In some embodiments, the present invention provides compounds of the following formula, or pharmaceutically acceptable salts or solvates thereof:

[0518] ZR 2

[0519] in

[0520] R 2 It is NHR 3 Or C(=O)R 3 , where R 3 It is a C that is hydrogen or optionally substituted with a pyridine ring. 1-6 Alkyl groups, or those that are not present; and

[0521] Z is the amino acid sequence of formula VI:

[0522]

[0523] in

[0524] X2, X3, X4, X6, X7, X8, X9, X10, X11, X12, and X13 are defined as in any of Equations I, Ia, II, and IIa above; and

[0525] in

[0526] (i) X2 and X11 are amino acid residues that together form a lactam bridge;

[0527] (ii) X2 and X7 are amino acid residues that together form a lactam bridge or a bridge containing a triazole ring; and

[0528] (iii) Optionally, when X13 is present, X10 and X13 are amino acid residues that together form a lactam bridge.

[0529] In some embodiments, the present invention provides compounds of the following formula, or pharmaceutically acceptable salts or solvates thereof:

[0530] ZR 2

[0531] in

[0532] R 2 It is NHR 3 , where R 3 It is a C that is hydrogen or optionally substituted with a pyridine ring. 1-6 Alkyl groups, or those that are not present; and

[0533] Z is the amino acid sequence of formula VIa:

[0534]

[0535] in

[0536] X2, X3, X4, X6, X7, X8, X9, X10, X11, X12, and X13 are defined as in any of Equations I, Ia, II, and IIa above; and

[0537] in

[0538] (i) X2 and X11 are amino acid residues that together form a lactam bridge; and

[0539] (ii) X2 and X7 are amino acid residues that together form a lactam bridge or a bridge containing a triazole ring.

[0540] In some embodiments, the present invention provides compounds of the following formula, or pharmaceutically acceptable salts or solvates thereof:

[0541] ZR 2

[0542] in

[0543] R 2 It is NHR 3 Or C(=O)R 3 , where R 3 It is a C that is hydrogen or optionally substituted with a pyridine ring. 1-6 Alkyl groups, or those that are not present; and

[0544] Z is the amino acid sequence of formula VII:

[0545]

[0546] in

[0547] X2, X3, X4, X5, X6, X8, X9, X10, X11, X12, and X13 are defined as in any of Equations I, Ia, II, and IIa above; and

[0548] in

[0549] (i) X2 and X11 are amino acid residues that together form a lactam bridge;

[0550] (ii) The Glu residue at X7 forms a lactam bridge with the amino acid residue at X2; and

[0551] (iii) Optionally, when X13 is present, X10 and X13 are amino acid residues that together form a lactam bridge.

[0552] In some embodiments, the present invention provides compounds of the following formula, or pharmaceutically acceptable salts or solvates thereof:

[0553] ZR 2

[0554] in

[0555] R 2 It is NHR 3 , where R 3 It is a C that is hydrogen or optionally substituted with a pyridine ring. 1-6 Alkyl groups, or those that are not present; and

[0556] Z is the amino acid sequence of formula VIIa:

[0557]

[0558] in

[0559] X2, X3, X4, X5, X6, X8, X9, X10, X11, X12, and X13 are defined as in any of Equations I, Ia, II, and IIa above; and

[0560] in

[0561] (i) X2 and X11 are amino acid residues that together form a lactam bridge; and

[0562] (ii) Glu at X7 forms a lactam bridge with the amino acid residue at X2.

[0563] In some embodiments, the present invention provides compounds of the following formula, or pharmaceutically acceptable salts or solvates thereof:

[0564] ZR 2

[0565] in

[0566] R2 It is NHR 3 Or C(=O)R 3 , where R 3 It is a C that is hydrogen or optionally substituted with a pyridine ring. 1-6 Alkyl groups, or those that are not present; and

[0567] Z is the amino acid sequence of formula VIII:

[0568]

[0569] in

[0570] X8 is Y (2-aminoethoxy), Y (Me), or F (4-Me);

[0571] X2, X3, X4, X5, X6, X7, X9, X10, X11, X12, and X13 are defined as in any of Equations I, Ia, II, and IIa above; and

[0572] in

[0573] (i) X2 and X11 are amino acid residues that together form a lactam bridge;

[0574] (ii) X2 and X7 are amino acid residues that together form a lactam bridge or a bridge containing a triazole ring; and

[0575] (iii) Optionally, when X13 is present, X10 and X13 are amino acid residues that together form a lactam bridge.

[0576] In some embodiments, the present invention provides compounds of the following formula, or pharmaceutically acceptable salts or solvates thereof:

[0577] ZR 2

[0578] in

[0579] R 2 It is NHR 3 , where R 3 It is a C that is hydrogen or optionally substituted with a pyridine ring. 1-6 Alkyl groups, or those that are not present; and

[0580] Z is the amino acid sequence of formula VIIIa:

[0581]

[0582] in

[0583] X8 is Y (2-aminoethoxy), Y (Me), or F (4-Me);

[0584] X2, X3, X4, X5, X6, X7, X9, X10, X11, X12, and X13 are defined as in any of Equations I, Ia, II, and IIa above; and

[0585] in

[0586] (i) X2 and X11 are amino acid residues that together form a lactam bridge; and

[0587] (ii) X2 and X7 are amino acid residues that together form a lactam bridge or a bridge containing a triazole ring.

[0588] In some embodiments, the present invention provides compounds of the following formula, or pharmaceutically acceptable salts or solvates thereof:

[0589] ZR 2

[0590] in

[0591] R 2 It is NHR 3 Or C(=O)R 3 , where R 3 It is a C that is hydrogen or optionally substituted with a pyridine ring. 1-6 Alkyl groups, or those that are not present; and

[0592] Z is the amino acid sequence of formula IX:

[0593]

[0594] in

[0595] X2, X3, X4, X5, X6, X7, X9, X10, X11, X12, and X13 are defined as in any of Equations I, Ia, II, and IIa above; and

[0596] in

[0597] (i) X2 and X11 are amino acid residues that together form a lactam bridge;

[0598] (ii) X2 and X7 are amino acid residues that together form a lactam bridge or a bridge containing a triazole ring; and

[0599] (iii) Optionally, when X13 is present, X10 and X13 are amino acid residues that together form a lactam bridge.

[0600] In some embodiments, the present invention provides compounds of the following formula, or pharmaceutically acceptable salts or solvates thereof:

[0601] ZR 2

[0602] in

[0603] R 2 It is NHR 3 , where R 3 It is a C that is hydrogen or optionally substituted with a pyridine ring. 1-6 Alkyl groups, or those that are not present; and

[0604] Z is the amino acid sequence of formula IX:

[0605]

[0606] in

[0607] X2, X3, X4, X5, X6, X7, X9, X10, X11, X12, and X13 are defined as in any of Equations I, Ia, II, and IIa above; and

[0608] in

[0609] (i) X2 and X11 are amino acid residues that together form a lactam bridge; and

[0610] (ii) X2 and X7 are amino acid residues that together form a lactam bridge or a bridge containing a triazole ring.

[0611] In some embodiments, the present invention provides compounds of the following formula, or pharmaceutically acceptable salts or solvates thereof:

[0612] ZR 2

[0613] in

[0614] R 2 It is NHR 3 Or C(=O)R 3 , where R 3 It is a C that is hydrogen or optionally substituted with a pyridine ring. 1-6 Alkyl groups, or those that are not present; and

[0615] Z is the amino acid sequence of formula X:

[0616]

[0617] in

[0618] X2, X3, X4, X5, X6, X7, X8, X10, X11, X12, and X13 are defined as in any of Equations I, Ia, II, and IIa above; and

[0619] in

[0620] (i) X2 and X11 are amino acid residues that together form a lactam bridge;

[0621] (ii) X2 and X7 are amino acid residues that together form a lactam bridge or a bridge containing a triazole ring; and

[0622] (iii) Optionally, when X13 is present, X10 and X13 are amino acid residues that together form a lactam bridge.

[0623] In some embodiments, the present invention provides compounds of the following formula, or pharmaceutically acceptable salts or solvates thereof:

[0624] ZR 2

[0625] in

[0626] R 2 It is NHR 3 , where R 3 It is a C that is hydrogen or optionally substituted with a pyridine ring. 1-6 Alkyl groups, or those that are not present; and

[0627] Z is the amino acid sequence of formula Xa:

[0628]

[0629] in

[0630] X2, X3, X4, X5, X6, X7, X8, X10, X11, X12, and X13 are defined as in any of Equations I, Ia, II, and IIa above; and

[0631] in

[0632] (i) X2 and X11 are amino acid residues that together form a lactam bridge; and

[0633] (ii) X2 and X7 are amino acid residues that together form a lactam bridge or a bridge containing a triazole ring.

[0634] In some embodiments, the present invention provides compounds of the following formula, or pharmaceutically acceptable salts or solvates thereof:

[0635] ZR 2

[0636] in

[0637] R 2 It is NHR 3 Or C(=O)R 3 , where R 3 It is a C that is hydrogen or optionally substituted with a pyridine ring. 1-6 Alkyl groups, or those that are not present; and

[0638] Z is the amino acid sequence of formula XI:

[0639]

[0640] in

[0641] X10 is either 2-Me-Leu or 2-Me-Val;

[0642] X2, X3, X4, X5, X6, X7, X8, X9, X11, X12, and X13 are defined as in any of Equations I, Ia, II, and IIa above; and

[0643] in

[0644] (i) X2 and X11 are amino acid residues that together form a lactam bridge; and

[0645] (ii) X2 and X7 are amino acid residues that together form a lactam bridge or a bridge containing a triazole ring.

[0646] In some embodiments, the present invention provides compounds of the following formula, or pharmaceutically acceptable salts or solvates thereof:

[0647] ZR 2

[0648] in

[0649] R 2 It is NHR 3 , where R 3 It is a C that is hydrogen or optionally substituted with a pyridine ring. 1-6 Alkyl groups, or those that are not present; and

[0650] Z is the amino acid sequence of formula XI as defined above.

[0651] In some embodiments, the present invention provides compounds of the following formula, or pharmaceutically acceptable salts or solvates thereof:

[0652] ZR 2

[0653] in

[0654] R 2 It is NHR 3 Or C(=O)R 3 , where R 3 It is a C that is hydrogen or optionally substituted with a pyridine ring. 1-6 Alkyl groups, or those that are not present; and

[0655] Z is the amino acid sequence of formula XII:

[0656]

[0657] in

[0658] X2, X3, X4, X5, X6, X7, X8, X9, X11, X12, and X13 are defined as in any of Equations I, Ia, II, and IIa above; and

[0659] in

[0660] (i) X2 and X11 are amino acid residues that together form a lactam bridge; and

[0661] (ii) X2 and X7 are amino acid residues that together form a lactam bridge or a bridge containing a triazole ring.

[0662] In some embodiments, the present invention provides compounds of the following formula, or pharmaceutically acceptable salts or solvates thereof:

[0663] ZR 2

[0664] in

[0665] R 2 It is NHR 3 , where R 3 It is a C that is hydrogen or optionally substituted with a pyridine ring. 1-6 Alkyl groups, or those that are not present; and

[0666] Z is the amino acid sequence of formula XII as defined above.

[0667] In some embodiments, the present invention provides compounds of the following formula, or pharmaceutically acceptable salts or solvates thereof:

[0668] ZR 2

[0669] in

[0670] R 2 It is NHR 3 Or C(=O)R 3 , where R 3 It is a C that is hydrogen or optionally substituted with a pyridine ring. 1-6 Alkyl groups, or those that are not present; and

[0671] Z is the amino acid sequence of formula XIII:

[0672]

[0673] in

[0674] X2, X3, X4, X5, X6, X7, X8, X9, X10, X12, and X13 are defined as in any of Equations I, Ia, II, and IIa above; and

[0675] in

[0676] (i) Glu at X11 forms a lactam bridge with the amino acid residue at X2;

[0677] (ii) X2 and X7 are amino acid residues that together form a lactam bridge or a bridge containing a triazole ring; and

[0678] (iii) Optionally, when X13 is present, X10 and X13 are amino acid residues that together form a lactam bridge.

[0679] In some embodiments, the present invention provides compounds of the following formula, or pharmaceutically acceptable salts or solvates thereof:

[0680] ZR 2

[0681] in

[0682] R 2 It is NHR 3 , where R 3 It is a C that is hydrogen or optionally substituted with a pyridine ring. 1-6 Alkyl groups, or those that are not present; and

[0683] Z is the amino acid sequence of formula XIIIa:

[0684]

[0685] in

[0686] X2, X3, X4, X5, X6, X7, X8, X9, X10, X12, and X13 are defined as in any of Equations I, Ia, II, and IIa above; and

[0687] in

[0688] (i) The Glu residue at X11 forms a lactam bridge with the amino acid residue at X2; and

[0689] (ii) X2 and X7 are amino acid residues that together form a lactam bridge or a bridge containing a triazole ring.

[0690] In some embodiments, the present invention provides compounds of the following formula, or pharmaceutically acceptable salts or solvates thereof:

[0691] ZR 2

[0692] in

[0693] R 2 It is NHR 3 Or C(=O)R 3 , where R 3 It is a C that is hydrogen or optionally substituted with a pyridine ring.1-6 Alkyl groups, or those that are not present; and

[0694] Z is the amino acid sequence of formula XIV:

[0695]

[0696] in

[0697] X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, and X13 are defined as in any of Equations I, Ia, II, and IIa above; and

[0698] in

[0699] (i) X2 and X11 are amino acid residues that together form a lactam bridge;

[0700] (ii) X2 and X7 are amino acid residues that together form a lactam bridge or a bridge containing a triazole ring; and

[0701] (iii) Optionally, when X13 is present, X10 and X13 are amino acid residues that together form a lactam bridge.

[0702] In some embodiments, the present invention provides compounds of the following formula, or pharmaceutically acceptable salts or solvates thereof:

[0703] ZR 2

[0704] in

[0705] R 2 It is NHR 3 , where R 3 It is a C that is hydrogen or optionally substituted with a pyridine ring. 1-6 Alkyl groups, or those that are not present; and

[0706] Z is the amino acid sequence of formula XIVa:

[0707]

[0708] in

[0709] X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, and X13 as defined in any of the above equations I, Ia, II, and IIa; and

[0710] in

[0711] (i) X2 and X11 are amino acid residues that together form a lactam bridge; and

[0712] (ii) X2 and X7 are amino acid residues that together form a lactam bridge or a bridge containing a triazole ring.

[0713] In some embodiments, the present invention provides compounds of the following formula, or pharmaceutically acceptable salts or solvates thereof:

[0714] ZR 2

[0715] in

[0716] R 2 It is NHR 3 Or C(=O)R 3 , where R 3 It is a C that is hydrogen or optionally substituted with a pyridine ring. 1-6 Alkyl groups, or those that are not present; and

[0717] Z is the amino acid sequence of formula XV:

[0718]

[0719] in

[0720] X13 is 3-(3-pyridyl)-Ala or it is not present;

[0721] X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, and X12 are defined as in any of Equations I, Ia, II, and IIa above; and

[0722] in

[0723] (i) X2 and X11 are amino acid residues that together form a lactam bridge;

[0724] (ii) X2 and X7 are amino acid residues that together form a lactam bridge or a bridge containing a triazole ring; and

[0725] (iii) Optionally, when X13 is present, X10 and X13 are amino acid residues that together form a lactam bridge.

[0726] In some embodiments, the present invention provides compounds of the following formula, or pharmaceutically acceptable salts or solvates thereof:

[0727] ZR 2

[0728] in

[0729] R 2 It is NHR 3 Where R 3 It is a C that is hydrogen or optionally substituted with a pyridine ring. 1-6 Alkyl groups, or those that are not present; and

[0730] Z is the amino acid sequence of formula XVa:

[0731]

[0732] in

[0733] X13 is 3-(3-pyridyl)-Ala or it is not present;

[0734] X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, and X12 are defined as in any of Equations I, Ia, II, and IIa above; and

[0735] in

[0736] (i) X2 and X11 are amino acid residues that together form a lactam bridge; and

[0737] (ii) X2 and X7 are amino acid residues that together form a lactam bridge or a bridge containing a triazole ring.

[0738] In some embodiments, the present invention provides compounds of the following formula, or pharmaceutically acceptable salts or solvates thereof:

[0739] ZR 2

[0740] in

[0741] R 2 It is NHR 3 Or C(=O)R 3 , where R 3 It is a C that is hydrogen or optionally substituted with a pyridine ring. 1-6 Alkyl groups, or those that are not present; and

[0742] Z is the amino acid sequence of formula XVI:

[0743]

[0744] in

[0745] X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, and X12 are defined as in any of Equations I, Ia, II, and IIa above; and

[0746] in

[0747] (i) X2 and X11 are amino acid residues that together form a lactam bridge;

[0748] (ii) X2 and X7 are amino acid residues that together form a lactam bridge or a bridge containing a triazole ring; and

[0749] (iii) Optionally, the 3-(3-pyridyl)-Ala at X13 forms a lactam bridge with the amino acid residue at X10.

[0750] In some embodiments, the present invention provides compounds of the following formula, or pharmaceutically acceptable salts or solvates thereof:

[0751] ZR 2

[0752] in

[0753] R 2 It is NHR 3 Where R 3 It is a C that is hydrogen or optionally substituted with a pyridine ring. 1-6 Alkyl groups, or those that are not present; and

[0754] Z is the amino acid sequence of formula XVIa:

[0755]

[0756] in

[0757] X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, and X12 are defined as in any of Equations I, Ia, II, and IIa above; and

[0758] in

[0759] (i) X2 and X11 are amino acid residues that together form a lactam bridge; and

[0760] (ii) X2 and X7 are amino acid residues that together form a lactam bridge or a bridge containing a triazole ring.

[0761] In some embodiments, the present invention provides compounds of the following formula, or pharmaceutically acceptable salts or solvates thereof:

[0762] ZR 2

[0763] in

[0764] R 2 It is NHR 3 Or C(=O)R 3 , where R 3 It is a C that is hydrogen or optionally substituted with a pyridine ring. 1-6 Alkyl groups, or those that are not present; and

[0765] Z is the amino acid sequence of formula XVII:

[0766]

[0767] in

[0768] X3, X4, X6, X7, X8, X11, X12, and X13 are defined as in any of Equations I, Ia, II, and IIa above; and

[0769] in

[0770] (i) The Lys residue at X2 forms a lactam bridge with the amino acid residue at X11; and

[0771] (ii) Lys at X2 forms a lactam bridge with the amino acid residue at X7.

[0772] In some embodiments, the present invention provides compounds of the following formula, or pharmaceutically acceptable salts or solvates thereof:

[0773] ZR 2

[0774] in

[0775] R 2 It is NHR 3 Where R 3 It is a C that is hydrogen or optionally substituted with a pyridine ring. 1-6 Alkyl groups, or those that are not present; and

[0776] Z is the amino acid sequence of formula XVIIa:

[0777]

[0778] in

[0779] X3, X4, X6, X7, X8, X11, X12, and X13 are defined as in any of Equations I, Ia, II, and IIa above; and

[0780] in

[0781] (i) The Lys residue at X2 forms a lactam bridge with the amino acid residue at X11; and

[0782] (ii) Lys at X2 forms a lactam bridge with the amino acid residue at X7.

[0783] In some embodiments, the present invention provides compounds of the following formula, or pharmaceutically acceptable salts or solvates thereof:

[0784] Z-NH2 or Z-NHMe

[0785] in

[0786] Z is the amino acid sequence of any one of the formulas I, Ia, II, IIa, III, IIIa, IV, IVa, V, Va, VI, VIa, VII, VIIa, VIII, VIIIa, IX, IXa, X, Xa, XI, XII, XIII, XIIIa, XIV, XIVa, XV, XVa, XVI, XVIa, XVII, and XVIIa as defined above.

[0787] In some embodiments, the present invention provides compounds of the following formula, or pharmaceutically acceptable salts or solvates thereof:

[0788] Z-NH2 or Z-NHMe

[0789] in

[0790] Z is the amino acid sequence of formula XVIII:

[0791]

[0792] in

[0793] X13 is 3-(3-pyridyl)-Ala or it is not present;

[0794] X3, X4, X6, X7, X8, X11, and X12 are defined as in any of Equations I, Ia, II, and IIa above; and

[0795] in

[0796] (i) The Lys residue at X2 forms a lactam bridge with the amino acid residue at X11; and

[0797] (ii) Lys at X2 forms a lactam bridge with the amino acid residue at X7.

[0798] In some embodiments, the present invention provides compounds of the following formula, or pharmaceutically acceptable salts or solvates thereof:

[0799] Z-NH2 or Z-NHMe

[0800] in

[0801] Z is the amino acid sequence of formula XIX:

[0802]

[0803] in

[0804] X13 is 3-(3-pyridyl)-Ala or it is not present;

[0805] X3, X4, X6, X8, X11, and X12 are defined as in any of Equations I, Ia, II, and IIa above; and

[0806] in

[0807] (i) The Lys residue at X2 forms a lactam bridge with the amino acid residue at X11; and

[0808] (ii) Lys at X2 and Glu at X7 together form a lactam bridge.

[0809] In some embodiments, the compounds provided by the present invention are selected from the compounds in Table 1-1, or their pharmaceutically acceptable salts or solvates.

[0810] In previously disclosed compounds that are IL-23R inhibitors, such as those disclosed in WO2023 / 099669, any internal truncation (i.e., deletion of amino acid residues) between X2 and X11 results in inactive compounds (see reference compounds Ref 5, Ref 6, and Ref 7 in Example 2 of WO2023 / 099669). However, the inventors have now observed that certain deletions between X2 and X11 in the compounds disclosed herein (e.g., deletions at X3 and / or X4) are tolerable and may even improve the potency and / or gastrointestinal stability and / or bioavailability of the compounds disclosed herein (see Example 2 below).

[0811] It should be understood that this invention covers salts and solvates of compounds. Suitable salts and solvates of peptides are known in the art.

[0812] It should also be understood that any of the following references to the implementation schemes may be applied and combined with any of the formulas described herein.

[0813] R 2

[0814] R 2 It is NHR 3 Or C(=O)R 3 , where R 3 It is a C that is hydrogen or optionally substituted with a pyridine ring. 1-6 Alkyl groups, or those that are not present.

[0815] In some implementation schemes, R 2 It does not exist. In some such embodiments, X13 is present and forms a lactam bridge with the amino acid residue at X10.

[0816] In some implementation schemes, R 2 It is NHR 3 , where R 3 Is it hydrogen or C? 1-6 Alkyl group. In some embodiments, R 2It is NHR 3 , where R 3 Is it hydrogen or C? 1-5 Alkyl group. In some embodiments, R 2 It is NHR 3 , where R 3 Is it hydrogen or C? 1-4 Alkyl group. In some embodiments, R 2 It is NHR 3 , where R 3 Is it hydrogen or C? 1-3 Alkyl group. In some embodiments, R 2 It is NHR 3 , where R 3 Is it hydrogen or C? 1-2 Alkyl group. In some embodiments, R 2 It is NHR 3 , where R 3 It is hydrogen or C1 alkyl (methyl or Me).

[0817] In some implementation schemes, R 2 It is NHR 3 , where R 3 C is optionally substituted with a pyridine ring. 1-6 Alkyl group. In some such embodiments, R 2 The group is attached to the carbonyl carbon of the carboxylic acid group of the C-terminal amino acid residue. The C-terminal amino acid can be Glu, β-homo-Glu, or Dab.

[0818] In some implementation schemes, R 2 It is NHR 3 , where R 3 C is optionally substituted with a pyridine ring. 1-6 Alkyl group. In some embodiments, R 2 It is NHR 3 , where R 3 C is optionally substituted with a pyridine-3-yl ring. 1-6 alkyl.

[0819] In some implementation schemes, R 2 It is NHR 3 , where R 3 It is a C that has been replaced by a pyridine ring. 1-6 Alkyl group. In some embodiments, R 2 It is NHR 3 , where R 3 It is a C-shaped ring substituted with a pyridine-3-yl ring. 1-6 alkyl.

[0820] In some implementation schemes, R 2 It is NHR 3, where R 3 It is a C6 alkyl group substituted with a pyridine ring. In some embodiments, R 2 It is NHR 3 , where R 3 It is a C6 alkyl group substituted with a pyridin-3-yl ring. In some embodiments, R 2 It is NHR 3 , where R 3 It is a hexyl group substituted with a pyridine-3-yl ring (i.e., -CH2CH2CH2CH2CH2CH3). In some embodiments, R 2 It is NHR 3 , where R 3 It is -CH2CH2CH2CH2CH2CH2(pyridin-3-yl). That is, NHCH2CH2CH2CH2CH2CH2(pyridin-3-yl) or NH-(6-(pyridin-3-yl)hexyl). The group NH-(6-(pyridin-3-yl)hexyl) has the following structure:

[0821] .

[0822] In some implementation schemes, R 2 It is NHR 3 , where R 3 It is a C4 alkyl group substituted with a pyridine ring. In some embodiments, R 2 It is NHR 3 , where R 3 It is a C4 alkyl group substituted with a pyridin-3-yl ring. In some embodiments, R 2 It is NHR 3 , where R 3 It is n-Bu substituted with a pyridine-3-yl ring. In some embodiments, R 2 It is NHR 3 , where R 3 It is -CH2CH2CH2CH2(pyridin-3-yl). That is, NHCH2CH2CH2CH2(pyridin-3-yl) or NH-(4-(pyridin-3-yl)butyl). The group NH-(4-(pyridin-3-yl)butyl) has the following structure:

[0823] .

[0824] In some implementation schemes, R 2 It is NHR 3 , where R 3 It is a C3 alkyl group substituted with a pyridine ring. In some embodiments, R 2 It is NHR 3 , where R 3It is a C3 alkyl group substituted with a pyridin-3-yl ring. In some embodiments, R 2 It is NHR 3 , where R 3 It is n-Pr substituted with a pyridine-3-yl ring. In some embodiments, R 2 It is NHR 3 , where R 3 It is -CH2CH2CH2(pyridin-3-yl). That is, NHCH2CH2CH2(pyridin-3-yl) or NH-(3-(pyridin-3-yl)propyl). The group NH-(3-(pyridin-3-yl)propyl) has the following structure:

[0825] .

[0826] In some implementation schemes, R 2 It is NHR 3 , where R 3 It is a C2 alkyl group substituted with a pyridine ring. In some embodiments, R 2 It is NHR 3 , where R 3 It is a C2 alkyl group substituted with a pyridin-3-yl ring. In some embodiments, R 2 It is NHR 3 , where R 3 It is an ethyl (Et) substituted with a pyridin-3-yl ring. In some embodiments, R 2 It is NHR 3 , where R 3 It is -CH2CH2 (pyridin-3-yl). That is, NHCH2CH2 (pyridin-3-yl) or NH-(2-(pyridin-3-yl)ethyl). The group NH-(2-(pyridin-3-yl)ethyl) has the following structure:

[0827] .

[0828] In some implementation schemes, R 2 It is C(=O)R 3 , where R 3 C is optionally substituted with a pyridine ring. 1-6 Alkyl group. In some embodiments, R 2 It is C(=O)R 3 , where R 3 C is optionally substituted with a pyridine-3-yl ring. 1-6 Alkyl group. In some such embodiments, R 2 The group is attached to the amino group of the C-terminal amino acid residue. The C-terminal amino acid can be iso-Dab.

[0829] In some implementation schemes, R2 It is C(=O)R 3 , where R 3 C is optionally substituted with a pyridine ring. 1-6 Alkyl group. In some embodiments, R 2 It is C(=O)R 3 , where R 3 C is optionally substituted with a pyridine-3-yl ring. 1-6 alkyl.

[0830] In some implementation schemes, R 2 It is C(=O)R 3 , where R 3 It is a C that has been replaced by a pyridine ring. 1-6 Alkyl group. In some embodiments, R 2 It is C(=O)R 3 , where R 3 It is a C-shaped ring substituted with a pyridine-3-yl ring. 1-6 alkyl.

[0831] In some implementation schemes, R 2 It is C(=O)R 3 , where R 3 It is a C5 alkyl group substituted with a pyridine ring. In some embodiments, R 2 It is C(=O)R 3 , where R 3 It is a C5 alkyl group substituted with a pyridin-3-yl ring. In some embodiments, R 2 It is C(=O)R 3 , where R 3 It is an pentyl group surrounded by a pyridine-3-yl ring. In some embodiments, R 2 It is C(=O)R 3 , where R 3 It is -CH2CH2CH2CH2CH2(pyridin-3-yl). That is, C(=O)CH2CH2CH2CH2CH2(pyridin-3-yl) or 6-(3-pyridinyl)hexanoyl. The 6-(3-pyridinyl)hexanoyl group has the following structure:

[0832] .

[0833] In some implementation schemes, R 2 It is C(=O)R 3 , where R 3 It is a C2 alkyl group substituted with a pyridine ring. In some embodiments, R 2 It is C(=O)R 3 , where R 3 It is a C2 alkyl group substituted with a pyridin-3-yl ring. In some embodiments, R2 It is C(=O)R 3 , where R 3 It is an ethyl group (Et) substituted with a pyridine-3-yl ring. In some embodiments, R 2 It is C(=O)R 3 , where R 3 It is -CH2CH2 (pyridin-3-yl). That is, C(=O)CH2CH2 (pyridin-3-yl) or 3-pyridylpropionyl. The 3-pyridylpropionyl group has the following structure:

[0834] .

[0835] In some implementation schemes, R 2 It is NHMe, NH2, NH-(6-(pyridin-3-yl)hexyl) [i.e., NHCH2CH2CH2CH2CH2CH2(pyridin-3-yl)], NHCH2CH2CH2CH2(pyridin-3-yl) [i.e., NH-(4-(pyridin-3-yl)butyl)], NH-(3-(pyridin-3-yl)propyl) [i.e., NHCH2CH2CH2(pyridin-3-yl)], NHCH2CH2(pyridin-3-yl) [i.e., NH-(2-(pyridin-3-yl)ethyl)], C(=O)CH2CH2CH2CH2CH2(pyridin-3-yl) [i.e., 6-(3-pyridinyl)hexanoyl] or C(=O)CH2CH2(pyridin-3-yl) [i.e., 3-pyridylpropionyl].

[0836] In some implementation schemes, R 2 It does not exist. In some implementations, R 2 It is NHMe. In some implementations, R 2 It is NH2. In some implementations, R 2 It is NHCH2CH2CH2CH2CH2CH2(pyridin-3-yl), i.e., NH-(6-(pyridin-3-yl)hexyl). In some embodiments, R 2 It is NHCH2CH2CH2CH2(pyridin-3-yl), i.e., NH-(4-(pyridin-3-yl)butyl). In some embodiments, R 2 It is NHCH2CH2CH2(pyridin-3-yl), i.e., NH-(3-(pyridin-3-yl)propyl). In some embodiments, R 2 It is NHCH2CH2(pyridin-3-yl), i.e., NH-(2-(pyridin-3-yl)ethyl). In some embodiments, R 2 It is C(=O)CH2CH2CH2CH2CH2(pyridin-3-yl), i.e., 6-(3-pyridinyl)hexanoyl. In some embodiments, R 2It is C(=O)CH2CH2(pyridin-3-yl), i.e., 3-pyridinylpropionyl.

[0837] Preferably, R 2 It is NHMe or NH2. Even more preferably, R 2 It is NHMe.

[0838] Z

[0839] Z is the amino acid sequence of formula I, or its pharmaceutically acceptable salt or solvate:

[0840]

[0841] in

[0842] X2 is selected from

[0843] Lys, D-lys, iso-Lys, D-iso-Lys, β-Lys, D-β-Lys, homo-Lys, D-homo-Lys, β-homo-Lys, N-Me-Lys, N-Me-homo-Lys, (N3)-Lys, D-(N3)-Lys, (N3)-β-Lys, (N3)-D-β-Lys, (N3)-high-Lys, (N3)-D-high-Lys, (N3)-β-high-Lys,

[0844] Dpr, D-Dpr, iso-Dpr, D-iso-Dpr, β-Dpr, D-β-Dpr, high-Dpr, D-high-Dpr, β-high-Dpr, N-Me-Dpr, N-Me-high-Dpr, (N3)-Dpr, D-(N3)-Dpr, (N3)-β-Dpr, (N3)-D-β-Dpr, (N3)-high-Dpr, (N3)-D-high-Dpr, (N3)-β-high-Dpr,

[0845] Dab, D-Dab, iso-Dab, D-iso-Dab, β-Dab, D-β-Dab, homo-Dab, D-homo-Dab, β-homo-Dab, N-Me-Dab, N-Me-homo-Dab, (N3)-Dab, D-(N3)-Dab, (N3)-β-Dab, (N3)-D-β-Dab, (N3)-high-Dab, (N3)-D-high-Dab, (N3)-β-high-Dab,

[0846] Orn, D-Orn, Different-Orn, D-Different-Orn, β-Orn, D-β-Orn, High-Orn, D-High-Orn, β-High-Orn, N-Me-Orn, N-Me-High-Orn, (N3)-Orn, D-(N3)-Orn, (N3)-β-Orn, (N3)-D-β-Orn, (N3)-High-Orn, (N3)-D-High-Orn, (N3)-β-High-Orn

[0847] Lys(Gly),

[0848] Asp, D-Asp, iso-Asp, D-iso-Asp, β-Asp, D-β-Asp, homo-Asp, D-homo-Asp, β-homo-Asp, N-Me-Asp, N-Me-homo-Asp, (N3)-Asp, D-(N3)-Asp, (N3)-β-Asp, (N3)-D-β-Asp, (N3)-high-Asp, (N3)-D-high-Asp, (N3)-β-high-Asp,

[0849] Glu, D-Glu, iso-Glu, D-iso-Glu, β-Glu, D-β-Glu, homo-Glu, D-homo-Glu, β-homo-Glu, N-Me-Glu, N-Me-homo-Glu, (N3)-Glu, D-(N3)-Glu, (N3)-β-Glu, (N3)-D-β-Glu, (N3)-ho-Glu, (N3)-D-ho-Glu, (N3)-β-ho-Glu,

[0850] 2-Amino-6-carboxyhexanoyl and 3-aminopropionyl;

[0851] X3 is selected from any amino acid, ω-hydroxy-C 2-6 Alkyl acids may not exist;

[0852] X4 is selected from Val D-Val, β-Val, D-β-Val, Homo-Val, D-homo-Val, β-homo-Val, N-Me-Val, N-Me-homo-Val, 2-Me-Val,

[0853] Ala, D-Ala, β-Ala, D-β-Ala, Homo-Ala, D-homo-Ala, β-homo-Ala, N-Me-Ala, N-Me-homo-Ala,

[0854] Gly, β-Gly, homo-Gly, β-homo-Gly, N-Me-Gly, N-Me-homo-Gly,

[0855] Leu, D-Leu, β-Leu, D-β-Leu, high-Leu, D-high-Leu, β-high-Leu, N-Me-Leu, N-Me-high-Leu, 2-Me-Leu,

[0856] Ile, D-Ile, β-Ile, D-β-Ile, high-Ile, D-high-Ile, β-high-Ile, N-Me-Ile, N-Me-high-Ile or do not exist;

[0857] X5 is selected from optionally substituted tryptophan residues, optionally substituted azatryptophan residues, and optionally substituted β-homotraphan residues;

[0858] X6 is selected from optionally substituted Gln residues, optionally substituted Lys residues, optionally substituted Arg residues, optionally substituted Dab residues, optionally substituted Orn residues, optionally substituted Phe residues, Ala, D-Ala, β-Ala, D-β-Ala, high-Ala, D-high-Ala, β-high-Ala, N-Me-Ala, N-Me-high-Ala, Cit, D-Cit, β-Cit, D-β-Cit, high-Cit, D-high-Cit, β-high-Cit, N-Me-Cit, N-Me-high-Cit, Glu, D-Glu, iso-Glu, D-iso-Glu, β-Glu, D-β-G lu, Homo-Glu, D-homo-Glu, β-homo-Glu, N-Me-Glu, N-Me-ho-Glu, Tyr, D-Tyr, β-Tyr, D-β-Tyr, Homo-Tyr, D-homo-Tyr, β-homo-Tyr, N-Me-Tyr, N-Me-homo-Tyr, Val, D-Val, β-Val, D-β-Val, Homo-Val, D-homo-Val, β-homo-Val, N-Me-Val, N-Me-homo-Val or His, D-His, β-His, D-β-His, homo-His, D-homo-His, β-homo-His, N-Me-His, and N-Me-homo-His;

[0859] X7 is selected from Asp, D-Asp, hetero-Asp, D-heterogeneous-Asp, β-Asp, D-β-Asp, high-Asp, D-high-Asp, β-high-Asp, N-Me-Asp, N-Me-high-Asp.

[0860] Glu, D-Glu, iso-Glu, D-iso-Glu, β-Glu, D-β-Glu, homo-Glu, D-homo-Glu, β-homo-Glu, N-Me-Glu, N-Me-homo-Glu,

[0861] Dab, D-Dab, iso-Dab, D-iso-Dab, β-Dab, D-β-Dab, homo-Dab, D-homo-Dab, β-homo-Dab, N-Me-Dab, N-Me-homo-Dab,

[0862] Orn, D-Orn, Different-Orn, D-Different-Orn, β-Orn, D-β-Orn, High-Orn, D-High-Orn, β-High-Orn, N-Me-Orn, N-Me-High-Orn

[0863] Lys, D-Lys, iso-Lys, β-Lys, D-iso-Lys, D-β-Lys, homo-Lys, D-homo-Lys, β-homo-Lys, N-Me-Lys, N-Me-homo-Lys,

[0864] Pra, D-Pra, β-Pra, D-β-Pra, high-Pra, D-high-Pra, β-high-Pra, N-Me-Pra, N-Me-high-Pra,

[0865] Hpg, D-Hpg, β-Hpg, D-β-Hpg, high-Hpg, D-high-Hpg, β-high-Hpg, N-Me-Hpg, and N-Me-high-Hpg;

[0866] X8 is selected from optionally substituted tryptophan residues, optionally substituted azatryptophan residues, optionally substituted β-homotrapetin residues, optionally substituted tyrosine residues, optionally substituted phenylalanine residues, optionally substituted homophenylalanine residues, and alanine residues substituted with a carbocyclic group or an aromatic or heteroaromatic group, wherein the aromatic or heteroaromatic group is selected from phenyl, pyridyl, naphthyl, and quinolinyl, each optionally substituted.

[0867] X9 is selected from optionally substituted tryptophan residues, optionally substituted azatryptophan residues, optionally substituted alanine residues, optionally substituted phenylalanine residues, and optionally substituted tyrosine residues.

[0868] X10 is selected from,

[0869] Val, D-Val, β-Val, D-β-Val, Homo-Val, D-homo-Val, β-homo-Val, N-Me-Val, N-Me-homo-Val, 2-Me-Val,

[0870] Gly, β-Gly, homo-Gly, β-homo-Gly, N-Me-Gly, N-Me-homo-Gly,

[0871] Dab, D-Dab, iso-Dab, D-iso-Dab, β-Dab, D-β-Dab, homo-Dab, D-homo-Dab, β-homo-Dab, N-Me-Dab, N-Me-homo-Dab,

[0872] Lys, D-lys, iso-Lys, D-iso-Lys, β-Lys, D-β-Lys, homo-Lys, D-homo-Lys, β-homo-Lys, N-Me-Lys, N-Me-homo-Lys,

[0873] Aib, D-Aib, β-Aib, D-β-Aib, Homo-Aib, D-homo-Aib, β-homo-Aib, N-Me-Aib, N-Me-ho-Aib,

[0874] Ala, D-Ala, β-Ala, D-β-Ala, Homo-Ala, D-homo-Ala, β-homo-Ala, N-Me-Ala, N-Me-homo-Ala,

[0875] Leu, D-Leu, β-Leu, D-β-Leu, high-Leu, D-high-Leu, β-high-Leu, N-Me-Leu, N-Me-high-Leu, 2-Me-Leu,

[0876] Ile, D-Ile, β-Ile, D-β-Ile, high-Ile, D-high-Ile, β-high-Ile, N-Me-Ile, N-Me-high-Ile,

[0877] And carbocyclic or heterocyclic rings with amino and carbonyl substituents;

[0878] X11 is selected from:

[0879] Dpr, D-Dpr, iso-Dpr, D-iso-Dpr, β-Dpr, D-β-Dpr, high-Dpr, D-high-Dpr, β-high-Dpr, N-Me-Dpr, N-Me-high-Dpr,

[0880] Dab, D-Dab, iso-Dab, D-iso-Dab, β-Dab, D-β-Dab, homo-Dab, D-homo-Dab, β-homo-Dab, N-Me-Dab, N-Me-homo-Dab,

[0881] Orn, D-Orn, Different-Orn, D-Different-Orn, β-Orn, D-β-Orn, High-Orn, D-High-Orn, β-High-Orn, N-Me-Orn, N-Me-High-Orn

[0882] Lys, D-lys, iso-Lys, D-iso-Lys, β-Lys, D-β-Lys, homo-Lys, D-homo-Lys, β-homo-Lys, N-Me-Lys, N-Me-homo-Lys, Lys(Me),

[0883] Lys(Gly),

[0884] Asp, D-Asp, hetero-Asp, D-heterogeneous-Asp, β-Asp, D-β-Asp, high-Asp, D-high-Asp, β-high-Asp, N-Me-Asp, N-Me-high-Asp

[0885] Glu, D-Glu, iso-Glu, D-iso-Glu, β-Glu, D-β-Glu, homo-Glu, D-homo-Glu, β-homo-Glu, N-Me-Glu, N-Me-homo-Glu, and

[0886] 2-Amino-6-carboxyhexanoyl;

[0887] X12 is selected from: optionally substituted Phe residues; optionally substituted Tyr residues; optionally substituted His residues; alanine residues substituted with a carbocyclic group or an aromatic or heteroaromatic group selected from phenyl, pyridyl, naphthyl, and quinolinyl, each optionally substituted; Dab, D-Dab, iso-Dab, D-iso-Dab, β-Dab, D-β-Dab, high-Dab, D-high-Dab, β-high-Dab, N-Me-Dab, N-Me-high-Dab, Gly, β-Gly, high-Gly, β-high-Gly, N-Me-Gly, N-Me-high-Gly, Pro, 5-aminopentanoyl, 4-aminopiperidin-4-carbonyl, (R,S)-imidazolidine-2-carbonyl, 3-aminopropionyl, Gly-CF3, D-Gly-CF3, Nle, Gln, D -Gln, iso-Gln, D-iso-Gln, β-Gln, D-β-Gln, homo-Gln, D-homo-Gln, β-homo-Gln, N-Me-Gln, N-Me-homo-Gln ,THP,Ser,D-Ser,β-Ser,D-β-Ser,high-Ser,D-high-Ser,β-high-Ser,N-Me-Ser,N-Me-high-Ser,Ser( OMe), 3-aminotetrahydrofuran-3-carbonyl, Arg, D-Arg, β-Arg, D-β-Arg, high-Arg, D-high-Arg, β-high-Arg, N-Me-Arg, N-Me-high-Arg, Thr, D-Thr, β-Thr, D-β-Thr, high-Thr, D-high-Thr, β-high-Thr, N-Me-Thr, N-Me-high-Thr Glu, D-Glu, iso-Glu, D-iso-Glu, β-Glu, D-β-Glu, high-Glu, D-high-Glu, β-high-Glu, N-Me-Glu, N-Me-high-Glu, Asn, D-Asn, β-Asn, D-β-Asn, high-Asn, D-high-Asn, β-high-Asn, N-Me-Asn, N-Me-high-Asn, 4-aminobutyryl, 2-(trimethyl-2-aminoethoxy)ethoxy]propyl and Lys, wherein the side chain -NH2 of Lys is replaced by -C(=O)(CH2). n R K Replace, where n is 0 to 2 and R K It is either an imidazole, pyrimidin, or pyridinyl group optionally substituted with F, or X12 is not present; and

[0888] X13 is selected from: optionally substituted His residues; optionally substituted Phe residues; alanine residues substituted with a carbocyclic group or an aromatic or heteroaromatic group, wherein the aromatic or heteroaromatic group is selected from phenyl, pyridyl, naphthyl, and quinolinyl, each optionally substituted; Asn, D-Asn, β-Asn, D-β-Asn, high-Asn, D-high-Asn, β-high-Asn, N-Me-Asn, N-Me-high-Asn, Gly, β-Gly, high-Gly, β-high-Gly, N-Me-Gly, N-Me-high-Gly,

[0889] And Dab, Orn, or Lys, where the side chain -NH2 is replaced by -C(=O)(CH2). n R K Replace, where n is 0 to 2 and R K It is an imidazole, pyrimidin, or pyridinyl group optionally substituted with F.

[0890] Or it may not exist;

[0891] in

[0892] (i) X2 and X11 are amino acid residues that together form a lactam bridge;

[0893] (ii) X2 and X7 are amino acid residues that together form a lactam bridge or a bridge containing a triazole ring; and

[0894] (iii) Optionally, when X13 is present, X10 and X13 are amino acid residues that together form a lactam bridge.

[0895] In some implementations, Z is the amino acid sequence of formula I:

[0896]

[0897] in

[0898] X2 is selected from Lys, D-Lys, iso-Lys, β-Lys, D-β-Lys, high-Lys, D-high-Lys, β-high-Lys, N-Me-Lys, Dab, D-Dab, iso-Dab, Glu, iso-Glu, D-iso-Glu, Orn, D-Orn, Dpr, Lys(Gly), (N3)-Lys, and D-(N3)-Lys;

[0899] X3 is selected from Thr, Ile, 3-aminopropionyl, 4-aminobutyryl, β-high-Ile, β-high-Thr, Gly, N-Me-3-aminopropionyl, and Ser, or may not exist;

[0900] X4 is Val or does not exist;

[0901] X5 is selected from Trp, 1-Me-Trp, and β-high-Trp;

[0902] X6 is Gln;

[0903] X7 is selected from Glu, D-Glu, High-Glu, Asp, Pra and Hpg;

[0904] X8 is selected from Y(2-aminoethoxy), Y(Me), Y(nPr), Y(Bn), Trp, D-Phe, 2-Me-Phe, F(4-Me), F(4-Bu), 3-(2-pyridyl)-Ala, 3-(3-pyridyl)-Ala, 3-(4-pyridyl)-Ala and cyclopropyl-Ala;

[0905] X9 is 2-Nal or cyclopropyl-Ala;

[0906] X10 is selected from 2-Me-Leu, 2-Me-Val, Dab, Gly, Lys and Aib;

[0907] X11 is selected from Glu, high-Glu, β-high-Glu, Dab, iso-Dab, Lys, Lys(Me), Orn and 2-amino-6-carboxyhexanoyl;

[0908] X12 is selected from Dab, His, D-His, His(1-Me), 3-(2-pyridyl)-Ala, 3-(3-pyridyl)-Ala, 3-(4-pyridyl)-Ala, 3-(3-quinolinyl)-Ala, Gly, Pro, 5-aminopentanoyl, 4-aminopiperidine-4-carbonyl, (R,S)-imidazolidine-2-carbonyl, and Lys, wherein the side chain -NH2 of Lys is replaced by -C(=O)(CH2). n R K Replace, where n is 0 to 2 and R K It is either an imidazole, pyrimidin, or pyridinyl group optionally substituted with F, or X12 is not present; and

[0909] X13 is selected from 3-(3-pyridinyl)-Ala, D-3-(3-pyridinyl)-Ala and 3-(3,5-pyrimidinyl)-Ala, or is not present;

[0910] in

[0911] (i) X2 and X11 are amino acid residues that together form a lactam bridge;

[0912] (ii) X2 and X7 are amino acid residues that together form a lactam bridge or a bridge containing a triazole ring; and

[0913] (iii) Optionally, when X13 is present, X10 and X13 are amino acid residues that together form a lactam bridge.

[0914] In some implementations, Z is the amino acid sequence of formula Ia:

[0915]

[0916] in

[0917] X2 is selected from Lys, D-Lys, iso-Lys, β-Lys, D-β-Lys, high-Lys, D-high-Lys, β-high-Lys, N-Me-Lys, Dab, D-Dab, Glu, iso-Glu, Orn, D-Orn, Lys(Gly), (N3)-Lys, and D-(N3)-Lys;

[0918] X3 is selected from Thr, Ile, 3-aminopropionyl, 4-aminobutyryl, β-high-Ile, β-high-Thr, Gly, and N-Me-3-aminopropionyl, or is not present;

[0919] X4 is Val or does not exist;

[0920] X5 is either Trp or 1-Me-Trp;

[0921] X6 is Gln;

[0922] X7 is selected from Glu, High-Glu, Asp, Pra, and Hpg;

[0923] X8 is selected from Y(2-aminoethoxy), Y(Me), Y(Bn), F(4-Me), F(4-Bu) and cyclopropyl-Ala;

[0924] X9 is 2-Nal;

[0925] X10 is selected from 2-Me-Leu, 2-Me-Val, Dab, Gly, and Aib;

[0926] X11 is selected from Glu, high-Glu, Lys, Lys(Me), Orn and 2-amino-6-carboxyhexanoyl;

[0927] X12 is selected from Dab, His, D-His, His(1-Me), 3-(3-quinolinyl)-Ala, and 4-aminopiperidine-4-carbonyl; and

[0928] X13 is 3-(3-pyridyl)-Ala, 3-(3,5-pyrimidinyl)-Ala, or it does not exist;

[0929] in

[0930] (i) X2 and X11 are amino acid residues that together form a lactam bridge;

[0931] (ii) X2 and X7 are amino acid residues that together form a lactam bridge or a bridge containing a triazole ring; and

[0932] (iii) Optionally, when X13 is present, X10 and X13 are amino acid residues that together form a lactam bridge.

[0933] In some implementations, Z is the amino acid sequence of formula II:

[0934]

[0935] in

[0936] X2 is selected from Lys, D-lys, iso-Lys, β-Lys, D-β-Lys, high-Lys, D-high-Lys, β-high-Lys, N-Me-Lys, Dab, D-Dab, iso-Dab, Glu, iso-Glu, D-iso-Glu, Orn, D-Orn, Dpr, Lys(Gly), (N3)-Lys, and D-(N3)-Lys;

[0937] X3 is selected from Thr, Ile, 3-aminopropionyl, 4-aminobutyryl, β-high-Ile, β-high-Thr, Gly, N-Me-3-aminopropionyl, and Ser, or may not exist;

[0938] X4 is Val or does not exist;

[0939] X5 is selected from Trp, 1-Me-Trp, and β-high-Trp;

[0940] X6 is Gln;

[0941] X7 is selected from Glu, D-Glu, High-Glu, Asp, Pra and Hpg;

[0942] X8 is selected from Y(2-aminoethoxy), Y(Me), Y(nPr), Y(Bn), Trp, D-Phe, 2-Me-Phe, F(4-Me), F(4-Bu), 3-(2-pyridyl)-Ala, 3-(3-pyridyl)-Ala, 3-(4-pyridyl)-Ala and cyclopropyl-Ala;

[0943] X9 is 2-Nal or cyclopropyl-Ala;

[0944] X10 is selected from 2-Me-Leu, 2-Me-Val, Dab, Gly, Lys and Aib;

[0945] X11 is selected from Glu, high-Glu, β-high-Glu, Dab, iso-Dab, Lys, Lys(Me), Orn and 2-amino-6-carboxyhexanoyl;

[0946] X12 is selected from Dab, His, D-His, His(1-Me), 3-(2-pyridyl)-Ala, 3-(3-pyridyl)-Ala, 3-(4-pyridyl)-Ala, 3-(3-quinolinyl)-Ala, Gly, Pro, 5-aminopentanoyl, 4-aminopiperidine-4-carbonyl, (R,S)-imidazolidine-2-carbonyl, and Lys, wherein the side chain -NH2 of Lys is replaced by -C(=O)(CH2). n R K Replace, where n is 0 to 2 and R K It is either an imidazole, pyrimidin, or pyridinyl group optionally substituted with F, or X12 is not present; and

[0947] X13 is selected from 3-(3-pyridinyl)-Ala, D-3-(3-pyridinyl)-Ala and 3-(3,5-pyrimidinyl)-Ala, or is not present;

[0948] in

[0949] (i) X2 and X11 are amino acid residues that together form a lactam bridge; and

[0950] (ii) X2 and X7 are amino acid residues that together form a lactam bridge or a bridge containing a triazole ring.

[0951] In some implementations, Z is the amino acid sequence of formula IIa:

[0952]

[0953] in

[0954] X2 is selected from Lys, D-Lys, iso-Lys, β-Lys, D-β-Lys, high-Lys, D-high-Lys, β-high-Lys, N-Me-Lys, Dab, D-Dab, Glu, iso-Glu, Orn, D-Orn, Lys(Gly), (N3)-Lys, and D-(N3)-Lys;

[0955] X3 is selected from Thr, Ile, 3-aminopropionyl, 4-aminobutyryl, β-high-Ile, β-high-Thr, Gly, and N-Me-3-aminopropionyl, or is not present;

[0956] X4 is Val or does not exist;

[0957] X5 is either Trp or 1-Me-Trp;

[0958] X6 is Gln;

[0959] X7 is selected from Glu, High-Glu, Asp, Pra, and Hpg;

[0960] X8 is selected from Y(2-aminoethoxy), Y(Me), Y(Bn), F(4-Me), F(4-Bu) and cyclopropyl-Ala;

[0961] X9 is 2-Nal;

[0962] X10 is selected from 2-Me-Leu, 2-Me-Val, Dab, Gly, and Aib;

[0963] X11 is selected from Glu, high-Glu, Lys, Lys(Me), Orn and 2-amino-6-carboxyhexanoyl;

[0964] X12 is selected from Dab, His, D-His, His(1-Me), 3-(3-quinolinyl)-Ala, and 4-aminopiperidine-4-carbonyl; and

[0965] X13 is 3-(3-pyridyl)-Ala, 3-(3,5-pyrimidinyl)-Ala, or it does not exist;

[0966] in

[0967] (i) X2 and X11 are amino acid residues that together form a lactam bridge; and

[0968] (ii) X2 and X7 are amino acid residues that together form a lactam bridge or a bridge containing a triazole ring.

[0969] In one implementation, Z is the amino acid sequence of Formula III:

[0970]

[0971] in

[0972] X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, and X13 are defined as in any of Equations I, Ia, II, and IIa above; and

[0973] in

[0974] (i) The Lys residue at X2 forms a lactam bridge with the amino acid residue at X11;

[0975] (ii) The Lys residue at X2 forms a lactam bridge with the amino acid residue at X7; and

[0976] (iii) Optionally, when X13 is present, X10 and X13 are amino acid residues that together form a lactam bridge.

[0977] In some implementations, Z is the amino acid sequence of formula IIIa:

[0978]

[0979] in

[0980] X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, and X13 are defined as in any of Equations I, Ia, II, and IIa above; and

[0981] in

[0982] (i) The Lys residue at X2 forms a lactam bridge with the amino acid residue at X11; and

[0983] (ii) Lys at X2 forms a lactam bridge with the amino acid residue at X7.

[0984] In some implementations, Z is the amino acid sequence of formula IV:

[0985]

[0986] in

[0987] X3 is selected from Thr, Ile, and 3-aminopropionyl, or it may not exist;

[0988] X2, X4, X5, X6, X7, X8, X9, X10, X11, X12, and X13 are defined as in any of Equations I, Ia, II, and IIa above; and

[0989] in

[0990] (i) X2 and X11 are amino acid residues that together form a lactam bridge;

[0991] (ii) X2 and X7 are amino acid residues that together form a lactam bridge or a bridge containing a triazole ring; and

[0992] (iii) Optionally, when X13 is present, X10 and X13 are amino acid residues that together form a lactam bridge.

[0993] In some implementations, Z is the amino acid sequence of formula IVa:

[0994]

[0995] in

[0996] X3 is selected from Thr, Ile, and 3-aminopropionyl, or it may not be present;

[0997] X2, X4, X5, X6, X7, X8, X9, X10, X11, X12, and X13 are defined as any of the above equations I, Ia, II, and IIa; and

[0998] in

[0999] (i) X2 and X11 are amino acid residues that together form a lactam bridge; and

[1000] (ii) X2 and X7 are amino acid residues that together form a lactam bridge or a bridge containing a triazole ring.

[1001] In some implementations, Z is the amino acid sequence of formula V:

[1002]

[1003] in

[1004] X2, X3, X5, X6, X7, X8, X9, X10, X11, X12, and X13 are defined as any of the above equations I, Ia, II, and IIa; and

[1005] in

[1006] (i) X2 and X11 are amino acid residues that together form a lactam bridge;

[1007] (ii) X2 and X7 are amino acid residues that together form a lactam bridge or a bridge containing a triazole ring; and

[1008] (iii) Optionally, when X13 is present, X10 and X13 are amino acid residues that together form a lactam bridge.

[1009] In some implementations, Z is the amino acid sequence of formula Va:

[1010]

[1011] in

[1012] X2, X3, X5, X6, X7, X8, X9, X10, X11, X12, and X13 are defined as any of the above equations I, Ia, II, and IIa; and

[1013] in

[1014] (i) X2 and X11 are amino acid residues that together form a lactam bridge; and

[1015] (ii) X2 and X7 are amino acid residues that together form a lactam bridge or a bridge containing a triazole ring.

[1016] In some implementations, Z is the amino acid sequence of formula VI:

[1017]

[1018] in

[1019] X2, X3, X4, X6, X7, X8, X9, X10, X11, X12, and X13 are defined as any of the above equations I, Ia, II, and IIa; and

[1020] in

[1021] (i) X2 and X11 are amino acid residues that together form a lactam bridge;

[1022] (ii) X2 and X7 are amino acid residues that together form a lactam bridge or a bridge containing a triazole ring; and

[1023] (iii) Optionally, when X13 is present, X10 and X13 are amino acid residues that together form a lactam bridge.

[1024] In some implementations, Z is the amino acid sequence of formula VIa:

[1025]

[1026] in

[1027] X2, X3, X4, X6, X7, X8, X9, X10, X11, X12, and X13 are defined as any of the above equations I, Ia, II, and IIa; and

[1028] in

[1029] (i) X2 and X11 are amino acid residues that together form a lactam bridge; and

[1030] (ii) X2 and X7 are amino acid residues that together form a lactam bridge or a bridge containing a triazole ring.

[1031] In some implementations, Z is the amino acid sequence of formula VII:

[1032]

[1033] in

[1034] X2, X3, X4, X5, X6, X8, X9, X10, X11, X12, and X13 are defined as any of the above equations I, Ia, II, and IIa; and

[1035] in

[1036] (i) X2 and X11 are amino acid residues that together form a lactam bridge;

[1037] (ii) The Glu residue at X7 forms a lactam bridge with the amino acid residue at X2; and

[1038] (iii) Optionally, when X13 is present, X10 and X13 are amino acid residues that together form a lactam bridge.

[1039] In some implementations, Z is the amino acid sequence of formula VIIa:

[1040]

[1041] in

[1042] X2, X3, X4, X5, X6, X8, X9, X10, X11, X12, and X13 are defined as any of the above equations I, Ia, II, and IIa; and

[1043] in

[1044] (i) X2 and X11 are amino acid residues that together form a lactam bridge; and

[1045] (ii) Glu at X7 forms a lactam bridge with the amino acid residue at X2.

[1046] In some implementations, Z is the amino acid sequence of formula VIII:

[1047]

[1048] in

[1049] X8 is Y (2-aminoethoxy), Y (Me), or F (4-Me);

[1050] X2, X3, X4, X5, X6, X7, X9, X10, X11, X12, and X13 are defined as any of the above equations I, Ia, II, and IIa; and

[1051] in

[1052] (i) X2 and X11 are amino acid residues that together form a lactam bridge;

[1053] (ii) X2 and X7 are amino acid residues that together form a lactam bridge or a bridge containing a triazole ring; and

[1054] (iii) Optionally, when X13 is present, X10 and X13 are amino acid residues that together form a lactam bridge.

[1055] In some implementations, Z is the amino acid sequence of formula VIIIa:

[1056]

[1057] in

[1058] X8 is Y (2-aminoethoxy), Y (Me), or F (4-Me);

[1059] X2, X3, X4, X5, X6, X7, X9, X10, X11, X12, and X13 are defined as any of the above equations I, Ia, II, and IIa; and

[1060] in

[1061] (i) X2 and X11 are amino acid residues that together form a lactam bridge; and

[1062] (ii) X2 and X7 are amino acid residues that together form a lactam bridge or a bridge containing a triazole ring.

[1063] In some implementations, Z is the amino acid sequence of formula IX:

[1064]

[1065] in

[1066] X2, X3, X4, X5, X6, X7, X9, X10, X11, X12, and X13 are defined as any of the above equations I, Ia, II, and IIa; and

[1067] in

[1068] (i) X2 and X11 are amino acid residues that together form a lactam bridge;

[1069] (ii) X2 and X7 are amino acid residues that together form a lactam bridge or a bridge containing a triazole ring; and

[1070] (iii) Optionally, when X13 is present, X10 and X13 are amino acid residues that together form a lactam bridge.

[1071] In some implementations, Z is the amino acid sequence of formula IX:

[1072]

[1073] in

[1074] X2, X3, X4, X5, X6, X7, X9, X10, X11, X12, and X13 are defined as any of the above equations I, Ia, II, and IIa; and

[1075] in

[1076] (i) X2 and X11 are amino acid residues that together form a lactam bridge; and

[1077] (ii) X2 and X7 are amino acid residues that together form a lactam bridge or a bridge containing a triazole ring.

[1078] In some implementations, Z is the amino acid sequence of formula X:

[1079]

[1080] in

[1081] X2, X3, X4, X5, X6, X7, X8, X10, X11, X12, and X13 are defined as any of the above equations I, Ia, II, and IIa; and

[1082] in

[1083] (i) X2 and X11 are amino acid residues that together form a lactam bridge;

[1084] (ii) X2 and X7 are amino acid residues that together form a lactam bridge or a bridge containing a triazole ring; and

[1085] (iii) Optionally, when X13 is present, X10 and X13 are amino acid residues that together form a lactam bridge.

[1086] In some implementations, Z is the amino acid sequence of formula Xa:

[1087]

[1088] in

[1089] X2, X3, X4, X5, X6, X7, X8, X10, X11, X12, and X13 are defined as any of the above equations I, Ia, II, and IIa; and

[1090] in

[1091] (i) X2 and X11 are amino acid residues that together form a lactam bridge; and

[1092] (ii) X2 and X7 are amino acid residues that together form a lactam bridge or a bridge containing a triazole ring.

[1093] In some implementations, Z is the amino acid sequence of formula XI:

[1094]

[1095] in

[1096] X10 is either 2-Me-Leu or 2-Me-Val;

[1097] X2, X3, X4, X5, X6, X7, X8, X9, X11, X12, and X13 are defined as any of the above equations I, Ia, II, and IIa; and

[1098] in

[1099] (i) X2 and X11 are amino acid residues that together form a lactam bridge; and

[1100] (ii) X2 and X7 are amino acid residues that together form a lactam bridge or a bridge containing a triazole ring.

[1101] In some implementations, Z is the amino acid sequence of formula XII:

[1102]

[1103] in

[1104] X2, X3, X4, X5, X6, X7, X8, X9, X11, X12, and X13 are defined as any of the above equations I, Ia, II, and IIa; and

[1105] in

[1106] (i) X2 and X11 are amino acid residues that together form a lactam bridge; and

[1107] (ii) X2 and X7 are amino acid residues that together form a lactam bridge or a bridge containing a triazole ring.

[1108] In some implementations, Z is the amino acid sequence of formula XIII:

[1109]

[1110] in

[1111] X2, X3, X4, X5, X6, X7, X8, X9, X10, X12, and X13 are defined as any of the above equations I, Ia, II, and IIa; and

[1112] in

[1113] (i) Glu at X11 forms a lactam bridge with the amino acid residue at X2;

[1114] (ii) X2 and X7 are amino acid residues that together form a lactam bridge or a bridge containing a triazole ring; and

[1115] (iii) Optionally, when X13 is present, X10 and X13 are amino acid residues that together form a lactam bridge.

[1116] In some implementations, Z is the amino acid sequence of formula XIIIa:

[1117]

[1118] in

[1119] X2, X3, X4, X5, X6, X7, X8, X9, X10, X12, and X13 are defined as any of the above equations I, Ia, II, and IIa; and

[1120] in

[1121] (i) The Glu residue at X11 forms a lactam bridge with the amino acid residue at X2; and

[1122] (ii) X2 and X7 are amino acid residues that together form a lactam bridge or a bridge containing a triazole ring.

[1123] In some implementations, Z is the amino acid sequence of formula XIV:

[1124]

[1125] in

[1126] X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, and X13 are defined as any of the above equations I, Ia, II, and IIa; and

[1127] in

[1128] (i) X2 and X11 are amino acid residues that together form a lactam bridge;

[1129] (ii) X2 and X7 are amino acid residues that together form a lactam bridge or a bridge containing a triazole ring; and

[1130] (iii) Optionally, when X13 is present, X10 and X13 are amino acid residues that together form a lactam bridge.

[1131] In some implementations, Z is the amino acid sequence of formula XIVa:

[1132]

[1133] in

[1134] X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, and X13 are defined as any of the above equations I, Ia, II, and IIa; and

[1135] in

[1136] (i) X2 and X11 are amino acid residues that together form a lactam bridge; and

[1137] (ii) X2 and X7 are amino acid residues that together form a lactam bridge or a bridge containing a triazole ring.

[1138] In some implementations, Z is the amino acid sequence of formula XV:

[1139]

[1140] in

[1141] X13 is 3-(3-pyridyl)-Ala or it is not present;

[1142] X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, and X12 are defined as any of the above equations I, Ia, II, and IIa; and

[1143] in

[1144] (i) X2 and X11 are amino acid residues that together form a lactam bridge;

[1145] (ii) X2 and X7 are amino acid residues that together form a lactam bridge or a bridge containing a triazole ring; and

[1146] (iii) Optionally, when X13 is present, X10 and X13 are amino acid residues that together form a lactam bridge.

[1147] In some implementations, Z is the amino acid sequence of formula XVa:

[1148]

[1149] in

[1150] X13 is 3-(3-pyridyl)-Ala or it is not present;

[1151] X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, and X12 are defined as any of the above equations I, Ia, II, and IIa; and

[1152] in

[1153] (i) X2 and X11 are amino acid residues that together form a lactam bridge; and

[1154] (ii) X2 and X7 are amino acid residues that together form a lactam bridge or a bridge containing a triazole ring.

[1155] In some implementations, Z is the amino acid sequence of formula XVI:

[1156]

[1157] in

[1158] X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, and X12 are defined as any of the above equations I, Ia, II, and IIa; and

[1159] in

[1160] (i) X2 and X11 are amino acid residues that together form a lactam bridge;

[1161] (ii) X2 and X7 are amino acid residues that together form a lactam bridge or a bridge containing a triazole ring; and

[1162] (iii) Optionally, the 3-(3-pyridyl)-Ala at X13 forms a lactam bridge with the amino acid residue at X10.

[1163] In some implementations, Z is the amino acid sequence of formula XVIa:

[1164]

[1165] in

[1166] X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, and X12 are defined as any of the above equations I, Ia, II, and IIa; and

[1167] in

[1168] (i) X2 and X11 are amino acid residues that together form a lactam bridge; and

[1169] (ii) X2 and X7 are amino acid residues that together form a lactam bridge or a bridge containing a triazole ring.

[1170] In some implementations, Z is the amino acid sequence of formula XVII:

[1171]

[1172] in

[1173] X3, X4, X6, X7, X8, X11, X12, and X13 are defined as any of Equations I, Ia, II, and IIa above; and

[1174] in

[1175] (i) The Lys residue at X2 forms a lactam bridge with the amino acid residue at X11; and

[1176] (ii) Lys at X2 forms a lactam bridge with the amino acid residue at X7.

[1177] In some implementations, Z is the amino acid sequence of formula XVIIa:

[1178]

[1179] in

[1180] X3, X4, X6, X7, X8, X11, X12, and X13 are defined as any of Equations I, Ia, II, and IIa above; and

[1181] in

[1182] (i) The Lys residue at X2 forms a lactam bridge with the amino acid residue at X11; and

[1183] (ii) Lys at X2 forms a lactam bridge with the amino acid residue at X7.

[1184] In some implementations, Z is the amino acid sequence of formula XVIII:

[1185]

[1186] in

[1187] X13 is 3-(3-pyridyl)-Ala or it is not present;

[1188] X3, X4, X6, X7, X8, X11, and X12 are defined as any of the above equations I, Ia, II, and IIa; and

[1189] in

[1190] (i) The Lys residue at X2 forms a lactam bridge with the amino acid residue at X11; and

[1191] (ii) Lys at X2 forms a lactam bridge with the amino acid residue at X7.

[1192] In some implementations, Z is the amino acid sequence of formula XIX:

[1193]

[1194] in

[1195] X13 is 3-(3-pyridyl)-Ala or it is not present;

[1196] X3, X4, X6, X8, X11, and X12 are defined as any of Equations I, Ia, II, and IIa above; and

[1197] in

[1198] (i) The Lys residue at X2 forms a lactam bridge with the amino acid residue at X11; and

[1199] (ii) Lys at X2 and Glu at X7 form a lactam bridge.

[1200] In some embodiments, Z is an amino acid sequence selected from the sequences listed in Tables 1 to 1a.

[1201] X2

[1202] X2 is selected from the following:

[1203] Lys, D-lys, iso-Lys, D-iso-Lys, β-Lys, D-β-Lys, homo-Lys, D-homo-Lys, β-homo-Lys, N-Me-Lys, N-Me-homo-Lys, (N3)-Lys, D-(N3)-Lys, (N3)-β-Lys, (N3)-D-β-Lys, (N3)-ho-Lys, (N3)-D-ho-Lys, (N3)-β-ho-Lys,

[1204] Dpr, D-Dpr, iso-Dpr, D-iso-Dpr, β-Dpr, D-β-Dpr, high-Dpr, D-high-Dpr, β-high-Dpr, N-Me-Dpr, N-Me-high-Dpr, (N3)-Dpr, D-(N3)-Dpr, (N3)-β-Dpr, (N3)-D-β-Dpr, (N3)-high-Dpr, (N3)-D-high-Dpr, (N3)-β-high-Dpr,

[1205] Dab, D-Dab, iso-Dab, D-iso-Dab, β-Dab, D-β-Dab, homo-Dab, D-homo-Dab, β-homo-Dab, N-Me-Dab, N-Me-homo-Dab, (N3)-Dab, D-(N3)-Dab, (N3)-β-Dab, (N3)-D-β-Dab, (N3)-ho-Dab, (N3)-D-ho-Dab, (N3)-β-ho-Dab,

[1206] Orn, D-Orn, Different-Orn, D-Different-Orn, β-Orn, D-β-Orn, High-Orn, D-High-Orn, β-High-Orn, N-Me-Orn, N-Me-High-Orn, (N3)-Orn, D-(N3)-Orn, (N3)-β-Orn, (N3)-D-β-Orn, (N3)-High-Orn, (N3)-D-High-Orn, (N3)-β-High-Orn

[1207] Lys (Gly),

[1208] Asp, D-Asp, iso-Asp, D-iso-Asp, β-Asp, D-β-Asp, homo-Asp, D-homo-Asp, β-homo-Asp, N-Me-Asp, N-Me-homo-Asp, (N3)-Asp, D-(N3)-Asp, (N3)-β-Asp, (N3)-D-β-Asp, (N3)-high-Asp, (N3)-D-high-Asp, (N3)-β-high-Asp,

[1209] Glu, D-Glu, iso-Glu, D-iso-Glu, β-Glu, D-β-Glu, high-Glu, D-high-Glu, β-high-Glu, N-Me-Glu, N-Me-high-Glu, (N3)-Glu, D-(N3)-Glu, (N3)-β-Glu, (N3)-D-β-Glu, (N3)-high-Glu, (N3)-D-high-Glu, (N3)-β-high-Glu, and 2-amino-6-carboxyhexanoyl and 3-aminopropionyl.

[1210] In some implementations, X2 is selected from Dab, D-Dab, iso-Dab, Lys, iso-Lys, D-β-Lys, N-Me-Lys, high-Lys, D-high-Lys, β-Lys, β-high-Lys, Lys(Gly), (N3)-Lys, D-(N3)-Lys, D-iso-Glu, iso-Glu, Glu, Orn, D-Orn, Dpr, and Lys(Gly).

[1211] In some implementations, X2 is selected from Lys, D-Lys, iso-Lys, β-Lys, D-β-Lys, high-Lys, D-high-Lys, β-high-Lys, N-Me-Lys, Dab, D-Dab, iso-Dab, Glu, iso-Glu, D-iso-Glu, Orn, D-Orn, Dpr, Lys(Gly), (N3)-Lys, and D-(N3)-Lys.

[1212] The amino acid residue at X2 forms a (first) lactam bridge with the amino acid residue at X11, and forms a (second) lactam bridge or a bridge containing a triazole ring with the amino acid residue at X7.

[1213] Preferably, the lactam bridge between X2 and X11 uses the side chain of the amino acid residue at X2, and the bridge between X2 and X7 uses the N-terminus of the amino acid residue at X2.

[1214] In some embodiments where the amino acid residue at X2 forms a (first) lactam bridge with the amino acid residue at X11 and a (second) lactam bridge with the amino acid residue at X7, X2 is selected from Lys, D-Lys, iso-Lys, β-Lys, D-β-Lys, high-Lys, D-high-Lys, β-high-Lys, N-Me-Lys, Dab, D-Dab, iso-Dab, Glu, iso-Glu, D-iso-Glu, Orn, D-Orn, Dpr, and Lys(Gly).

[1215] In some embodiments, where the amino acid residue at X2 forms a (first) lactam bridge with the amino acid residue at X11 and a (second) bridge containing a triazole ring with the amino acid residue at X7, X2 is (N3)-Lys or D-(N3)-Lys.

[1216] In some implementations, X2 is selected from Lys, D-Lys, iso-Lys, β-Lys, D-β-Lys, high-Lys, D-high-Lys, β-high-Lys, N-Me-Lys, Dab, D-Dab, Glu, iso-Glu, Orn, D-Orn, Lys(Gly), (N3)-Lys, and D-(N3)-Lys.

[1217] In some implementations, X2 is selected from Lys, D-Lys, iso-Lys, D-β-Lys, high-Lys, β-high-Lys, N-Me-Lys, Dab, D-Dab, iso-Dab, Glu, iso-Glu, D-iso-Glu, Orn, and D-Orn.

[1218] In some implementations, X2 is selected from Lys, D-Lys, iso-Lys, D-β-Lys, high-Lys, N-Me-Lys, Dab, D-Dab, Glu, and D-Orn.

[1219] In some embodiments, X2 is Lys. In some embodiments, X2 is D-Lys. In some embodiments, X2 is iso-Lys. In some embodiments, X2 is β-Lys. In some embodiments, X2 is D-β-Lys. In some embodiments, X2 is high-Lys. In some embodiments, X2 is D-high-Lys. In some embodiments, X2 is β-high-Lys. In some embodiments, X2 is N-Me-Lys. In some embodiments, X2 is Dab. In some embodiments, X2 is D-Dab. In some embodiments, X2 is iso-Dab. In some embodiments, X2 is Glu. In some embodiments, X2 is iso-Glu. In some embodiments, X2 is D-iso-Glu. In some embodiments, X2 is Orn. ​​In some embodiments, X2 is D-Orn. In some embodiments, X2 is Dpr. In some embodiments, X2 is Lys(Gly). In some implementations, X2 is (N3)-Lys. In some implementations, X2 is D-(N3)-Lys.

[1220] Preferably, X2 is Lys.

[1221] X3

[1222] X3 is selected from any amino acid, ω-hydroxy-C 2-6 Alkyl acids, or they may not exist.

[1223] In some embodiments, X3 is selected from Thr, Ile, 3-aminopropionyl, 4-aminobutyryl, β-high-Ile, β-high-Thr, β-high-Trp, Gly, N-Me-3-aminopropionyl, Ser, Trp, Phe, N-Me-Ser, N-Me-Ala, 3-hydroxypropionic acid, or is not present.

[1224] In some embodiments, X3 is selected from Thr, Ile, 3-aminopropionyl, 4-aminobutyryl, β-high-Ile, β-high-Thr, Gly, N-Me-3-aminopropionyl, and Ser, or is not present.

[1225] The compounds disclosed herein may be inactive without the presence of X3 (see Example 2 below). In other peptide inhibitors of IL-23R, any internal truncation between X2 and X11 (e.g., X3), i.e., the deletion of an amino acid residue, has previously been reported to cause inactivation of the compound (see reference compounds Ref 5, Ref 6 and Ref 7 in the examples of WO2023 / 099669).

[1226] In some embodiments, X3 is selected from Thr, Ile, 3-aminopropionyl, 4-aminobutyryl, β-high-Ile, β-high-Thr, Gly, and N-Me-3-aminopropionyl, or is not present.

[1227] In some implementations, X3 is selected from Thr, Ile, 3-aminopropionyl, and Gly, or is not present.

[1228] In some implementations, X3 is selected from Thr, Ile, 3-aminopropionyl, Gly, and Ser, or is not present.

[1229] In some implementations, X3 is selected from Thr, Ile, 3-aminopropionyl, Gly, or is not present.

[1230] In some implementations, X3 is selected from Thr, Ile, 3-aminopropionyl, or is not present.

[1231] In some implementations, X3 is Thr, Ile, or it does not exist.

[1232] In some embodiments, X3 is Thr. In some embodiments, X3 is Ile. In some embodiments, X3 is 3-aminopropionyl. In some embodiments, X3 is 4-aminobutyryl. In some embodiments, X3 is β-high-Ile. In some embodiments, X3 is β-high-Thr. In some embodiments, X3 is Gly. In some embodiments, X3 is N-Me-3-aminopropionyl. In some embodiments, X3 is Ser. In some embodiments, X3 is absent.

[1233] Preferably, X3 is selected from Thr, Ile, 3-aminopropionyl, or is absent. Even more preferably, X3 is Thr, Ile, or is absent.

[1234] X4

[1235] X4 is selected from Val, D-Val, β-Val, D-β-Val, Homo-Val, D-homo-Val, β-homo-Val, N-Me-Val, N-Me-homo-Val, 2-Me-Val,

[1236] Ala, D-Ala, β-Ala, D-β-Ala, Homo-Ala, D-homo-Ala, β-homo-Ala, N-Me-Ala, N-Me-homo-Ala,

[1237] Gly, β-Gly, homo-Gly, β-homo-Gly, N-Me-Gly, N-Me-homo-Gly,

[1238] Leu, D-Leu, β-Leu, D-β-Leu, high-Leu, D-high-Leu, β-high-Leu, N-Me-Leu, N-Me-high-Leu, 2-Me-Leu,

[1239] Ile, D-Ile, β-Ile, D-β-Ile, high-Ile, D-high-Ile, β-high-Ile, N-Me-Ile, N-Me-high-Ile, or none.

[1240] In some implementations, X4 is Val, or it does not exist.

[1241] In some implementations, X4 is Val. In some implementations, X4 does not exist.

[1242] The compounds disclosed herein may be inactive without the presence of X4 (see Example 2 below). In other peptide inhibitors of IL-23R, any internal truncation between X2 and X11 (e.g., X4), i.e., the deletion of an amino acid residue, has previously been reported to cause inactivation of the compound (see reference compounds Ref 5, Ref 6 and Ref 7 in the examples of WO2023 / 099669).

[1243] Preferably, X4 does not exist.

[1244] X5

[1245] X5 is selected from optionally substituted tryptophan residues, optionally substituted azatryptophan residues, and optionally substituted β-homotraphen residues.

[1246] In some implementations, X5 is selected from Trp, 1-Me-Trp, 7-Aza-Trp, 7-Me-Trp, and β-high-Trp.

[1247] In some implementations, X5 is selected from Trp, 1-Me-Trp, and β-high-Trp.

[1248] In some implementations, X5 is a Trp or a 1-Me-Trp.

[1249] In some implementations, X5 is a Trp. In some implementations, X5 is a 1-Me-Trp. In some implementations, X5 is a β-high-Trp.

[1250] Preferably, X5 is Trp.

[1251] X6

[1252] X6 is selected from optionally substituted Gln residues, optionally substituted Lys residues, optionally substituted Arg residues, optionally substituted Dab residues, optionally substituted Orn residues, optionally substituted Phe residues, Ala, D-Ala, β-Ala, D-β-Ala, high-Ala, D-high-Ala, β-high-Ala, N-Me-Ala, N-Me-high-Ala, Cit, D-Cit, β-Cit, D-β-Cit, high-Cit, D-high-Cit, β-high-Cit, N-Me-Cit, N-Me-high-Cit, Glu, D-Glu, iso-Glu, D-iso-Glu, β-Glu, D-β-G lu, Homo-Glu, D-homo-Glu, β-homo-Glu, N-Me-Glu, N-Me-ho-Glu, Tyr, D-Tyr, β-Tyr, D-β-Tyr, Homo-Tyr, D-homo-Tyr, β-homo-Tyr, N-Me-Tyr, N-Me-homo-Tyr, Val, D-Val, β-Val, D-β-Val, Homo-Val, D-homo-Val, β-homo-Val, N-Me-Val, N-Me-homo-Val or His, D-His, β-His, D-β-His, homo-His, D-homo-His, β-homo-His, N-Me-His, and N-Me-homo-His.

[1253] In some implementations, X6 is selected from Dab(Ac), Dab(Ac-N-Me), Gln, Gln(2Me), K(NMePEG3), and Gln(Me).

[1254] In some implementations, X6 is Gln.

[1255] X7

[1256] X7 is selected from Asp, D-Asp, hetero-Asp, D-hetero-Asp, β-Asp, D-β-Asp, high-Asp, D-high-Asp, β-high-Asp, N-Me-Asp, N-Me-high-Asp.

[1257] Glu, D-Glu, iso-Glu, D-iso-Glu, β-Glu, D-β-Glu, homo-Glu, D-homo-Glu, β-homo-Glu, N-Me-Glu, N-Me-homo-Glu,

[1258] Dab, D-Dab, iso-Dab, D-iso-Dab, β-Dab, D-β-Dab, homo-Dab, D-homo-Dab, β-homo-Dab, N-Me-Dab, N-Me-homo-Dab,

[1259] Orn, D-Orn, Different-Orn, D-Different-Orn, β-Orn, D-β-Orn, High-Orn, D-High-Orn, β-High-Orn, N-Me-Orn, N-Me-High-Orn

[1260] Lys, D-Lys, iso-Lys, β-Lys, D-iso-Lys, D-β-Lys, homo-Lys, D-homo-Lys, β-homo-Lys, N-Me-Lys, N-Me-homo-Lys,

[1261] Pra, D-Pra, β-Pra, D-β-Pra, high-Pra, D-high-Pra, β-high-Pra, N-Me-Pra, N-Me-high-Pra,

[1262] Hpg, D-Hpg, beta-Hpg, D-beta-Hpg, high-Hpg, D-high-Hpg, beta-high-Hpg, N-Me-Hpg and N-Me-high-Hpg.

[1263] In some implementations, X7 is selected from Asp, D-Glu, Glu, Pra, Hpg, and high-Glu.

[1264] In some embodiments, X7 is selected from Glu, high-Glu, Asp, Pra, and Hpg. The amino acid residue at X7 forms a lactam bridge or a bridge containing a triazole ring with the amino acid residue at X2.

[1265] In some embodiments where the amino acid residue at X7 forms a lactam bridge with the amino acid residue at X2, X7 is selected from Glu, high-Glu, and Asp.

[1266] In some embodiments, where the amino acid residue at X7 forms a bridge containing a triazole ring with the amino acid residue at X2, X7 is Pra or Hpg.

[1267] In some implementations, X7 is Glu or Asp.

[1268] In some embodiments, X7 is Glu. In some embodiments, X7 is high-Glu. In some embodiments, X7 is Asp. In some embodiments, X7 is Pra. In some embodiments, X7 is Hpg.

[1269] Preferably, X7 is Glu. The inventors assume that, from a synthetic point of view, X7 being Glu is more advantageous than X7 being Asp, because Asp in the amide bridge is more prone to potential isomerization than Glu.

[1270] X8

[1271] X8 is selected from optionally substituted tryptophan residues, optionally substituted azatryptophan residues, optionally substituted β-homotrapetin residues, optionally substituted tyrosine residues, optionally substituted phenylalanine residues, optionally substituted homophenylalanine residues, and alanine residues substituted with a carbocyclic group or with an aromatic or heteroaromatic group selected from phenyl, pyridyl, naphthyl, and quinolinyl (each optionally substituted).

[1272] In some embodiments, X8 is selected from Y(2-aminoethoxy), Y(2-aminoethoxy)(N(Me)2), Y(n-pentylamine)(N + (Me)3), Y(2-trimethyl-PEG2), high-Phe, 7-AzaTrp, β-high-Trp, 7-F-Trp, F(4-morpholine), 3-quinolinylalanine, Y(Me), Y(nPr), Y(Bn), Trp, D-Phe, 2-Me-Phe, F(4-Me), F(4-Bu), 3-(2-pyridyl)-Ala, 3-(3-pyridyl)-Ala, 3-(4-pyridyl)-Ala, cyclopropyl-Ala, F(4-THP), Y(CH3-2-F), F(4-F), F(4-piperazine), F(4-imidazolium), F(piperidine), Y(CH3-3-F), 5-AzaTrp, Y(Ac-2-aminoethoxy), 6-AzaTrp and F(4-CONH2).

[1273] In some embodiments, X8 is selected from Y(2-aminoethoxy), Y(Me), Y(nPr), Y(Bn), Trp, D-Phe, 2-Me-Phe, F(4-Me), F(4-Bu), 3-(2-pyridyl)-Ala, 3-(3-pyridyl)-Ala, 3-(4-pyridyl)-Ala and cyclopropyl-Ala.

[1274] In some embodiments, X8 is selected from Y(2-aminoethoxy), Y(Me), Y(Bn), F(4-Me), F(4-Bu) and cyclopropyl-Ala.

[1275] In some embodiments, X8 is selected from Y(2-aminoethoxy), Y(Me), F(4-Me), and cyclopropyl-Ala.

[1276] In some embodiments, X8 is selected from Y (2-aminoethoxy), Y (Me), and F (4-Me).

[1277] In some implementations, X8 is Y (2-aminoethoxy) or Y (Me).

[1278] In some embodiments, X8 is Y(2-aminoethoxy). In some embodiments, X8 is Y(Me). In some embodiments, X8 is Y(nPr). In some embodiments, X8 is Y(Bn). In some embodiments, X8 is Trp. In some embodiments, X8 is D-Phe. In some embodiments, X8 is 2-Me-Phe. In some embodiments, X8 is F(4-Me). In some embodiments, X8 is F(4-Bu). In some embodiments, X8 is 3-(2-pyridinyl)-Ala. In some embodiments, X8 is 3-(3-pyridinyl)-Ala. In some embodiments, X8 is 3-(4-pyridinyl)-Ala. In some embodiments, X8 is cyclopropyl-Ala.

[1279] Preferably, X8 is Y(2-aminoethoxy), Y(Me), or F(4-Me). More preferably, X8 is Y(2-aminoethoxy) or Y(Me). Even more preferably, X8 is Y(2-aminoethoxy).

[1280] X9

[1281] X9 is selected from optionally substituted tryptophan residues, optionally substituted azatryptophan residues, optionally substituted alanine residues, optionally substituted phenylalanine residues, and optionally substituted tyrosine residues. In some embodiments, X9 is 2-Nal or cyclopropyl-Ala.

[1282] In some embodiments, X9 is 2-Nal. In some embodiments, X9 is cyclopropyl-Ala.

[1283] Preferably, X9 is 2-Nal.

[1284] X10

[1285] X10 is selected from the following:

[1286] Val, D-Val, β-Val, D-β-Val, Homo-Val, D-homo-Val, β-homo-Val, N-Me-Val, N-Me-homo-Val, 2-Me-Val,

[1287] Gly, β-Gly, homo-Gly, β-homo-Gly, N-Me-Gly, N-Me-homo-Gly,

[1288] Dab, D-Dab, iso-Dab, D-iso-Dab, β-Dab, D-β-Dab, homo-Dab, D-homo-Dab, β-homo-Dab, N-Me-Dab, N-Me-homo-Dab,

[1289] Lys, D-lys, iso-Lys, D-iso-Lys, β-Lys, D-β-Lys, homo-Lys, D-homo-Lys, β-homo-Lys, N-Me-Lys, N-Me-homo-Lys,

[1290] Aib, D-Aib, β-Aib, D-β-Aib, Homo-Aib, D-homo-Aib, β-homo-Aib, N-Me-Aib, N-Me-homo-Aib,

[1291] Ala, D-Ala, β-Ala, D-β-Ala, Homo-Ala, D-homo-Ala, β-homo-Ala, N-Me-Ala, N-Me-homo-Ala,

[1292] Leu, D-Leu, β-Leu, D-β-Leu, high-Leu, D-high-Leu, β-high-Leu, N-Me-Leu, N-Me-high-Leu, 2-Me-Leu,

[1293] Ile, D-Ile, β-Ile, D-β-Ile, high-Ile, D-high-Ile, β-high-Ile, N-Me-Ile, N-Me-high-Ile,

[1294] And carbon rings or heterocycles having amino and carbonyl substituents.

[1295] In some implementations, X10 is selected from Dab, 2-Me-Leu, 2-Me-Val, Aib, D-Ala, Gly, and Lys.

[1296] In some embodiments, X10 is selected from 2-Me-Leu, 2-Me-Val, Dab, Gly, Lys, and Aib. When X13 is present, the amino acid residue at X10 can form a lactam bridge with the amino acid residue at X13.

[1297] In some embodiments where X13 is present and the amino acid residue at X10 forms a lactam bridge with the amino acid residue at X13, X10 is selected from Dab or Lys. In some embodiments where X13 is present and the amino acid residue at X10 forms a lactam bridge with the amino acid residue at X13, X10 is Dab.

[1298] In some implementations, X10 is selected from 2-Me-Leu, 2-Me-Val, Dab, Gly, and Aib.

[1299] In some implementations, X10 is selected from 2-Me-Leu, 2-Me-Val, and Gly.

[1300] In some embodiments, X10 is 2-Me-Leu. In some embodiments, X10 is 2-Me-Val. In some embodiments, X10 is Dab. In some embodiments, X10 is Gly. In some embodiments, X10 is Lys. In some embodiments, X10 is Aib.

[1301] Preferably, X10 is 2-Me-Leu or 2-Me-Val. More preferably, X10 is 2-Me-Leu.

[1302] X11

[1303] X11 is selected from the following:

[1304] Dpr, D-Dpr, iso-Dpr, D-iso-Dpr, β-Dpr, D-β-Dpr, homo-Dpr, D-homo-Dpr, β-homo-Dpr, N-Me-Dpr, N-Me-homo-Dpr,

[1305] Dab, D-Dab, iso-Dab, D-iso-Dab, β-Dab, D-β-Dab, homo-Dab, D-homo-Dab, β-homo-Dab, N-Me-Dab, N-Me-homo-Dab,

[1306] Orn, D-Orn, Different-Orn, D-Different-Orn, β-Orn, D-β-Orn, High-Orn, D-High-Orn, β-High-Orn, N-Me-Orn, N-Me-High-Orn

[1307] Lys, D-lys, iso-Lys, D-iso-Lys, β-Lys, D-β-Lys, homo-Lys, D-homo-Lys, β-homo-Lys, N-Me-Lys, N-Me-homo-Lys, Lys(Me),

[1308] Lys (Gly),

[1309] Asp, D-Asp, hetero-Asp, D-heterogeneous-Asp, β-Asp, D-β-Asp, high-Asp, D-high-Asp, β-high-Asp, N-Me-Asp, N-Me-high-Asp

[1310] Glu, D-Glu, iso-Glu, D-iso-Glu, β-Glu, D-β-Glu, homo-Glu, D-homo-Glu, β-homo-Glu, N-Me-Glu, N-Me-homo-Glu, or

[1311] 2-Amino-6-carboxyhexanoyl.

[1312] In some embodiments, X11 is selected from Glu, high-Glu, β-high-Glu, Dab, iso-Dab, Lys, Lys(Me), Orn, and 2-amino-6-carboxyhexanoyl. The amino acid residue at X11 forms a lactam bridge with the amino acid residue at X2.

[1313] In some embodiments, X11 is selected from Glu, high-Glu, Lys, Lys(Me), Orn and 2-amino-6-carboxyhexanoyl.

[1314] In some embodiments, X11 is selected from Glu, high-Glu, Lys and 2-amino-6-carboxyhexanoyl.

[1315] In some implementations, X11 is Glu or 2-amino-6-carboxyhexanoyl.

[1316] In some embodiments, X11 is Glu. In some embodiments, X11 is high-Glu. In some embodiments, X11 is β-high-Glu. In some embodiments, X11 is Dab. In some embodiments, X11 is iso-Dab. In some embodiments, X11 is Lys. In some embodiments, X11 is Lys(Me). In some embodiments, X11 is Orn. ​​In some embodiments, X11 is 2-amino-6-carboxyhexanoyl.

[1317] Preferably, X11 is Glu.

[1318] X12

[1319] X12 is selected from optionally substituted Phe residues, optionally substituted Tyr residues, optionally substituted His residues, alanine residues substituted with a carbocyclic group or with an aromatic or heteroaromatic group selected from phenyl, pyridyl, naphthyl and quinolinyl (each optionally substituted), Dab, D-Dab, iso-Dab, D-iso-Dab, β-Dab, D-β-Dab, high-Dab, D-high-Dab, β-high-Dab, N-Me-Dab, N-Me-high-Dab, Gly, β-Gly, high-Gly, β-high-Gly, N-Me-Gly, N-Me-high-Gly, Pro, 5-aminopentanoyl, 4-aminopiperidine-4-carbonyl, (R,S)-imidazolidine-2-carbonyl, 3-aminopropionyl, Gly-CF3, D-Gly-CF3, Nle, Gln, D-Gln , iso-Gln, D-iso-Gln, β-Gln, D-β-Gln, high-Gln, D-high-Gln, β-high-Gln, N-Me-Gln, N-Me-high-Gln, TH P, Ser, D-Ser, β-Ser, D-β-Ser, high-Ser, D-high-Ser, β-high-Ser, N-Me-Ser, N-Me-high-Ser, Ser(OM e) 3-Aminotetrahydrofuran-3-carbonyl, Arg, D-Arg, β-Arg, D-β-Arg, high-Arg, D-high-Arg, β-high-Arg, N-Me-Arg, N-Me-high-Arg, Thr, D-Thr, β-Thr, D-β-Thr, high-Thr, D-high-Thr, β-high-Thr, N-Me-Thr, N-Me-high-Thr Glu, D-Glu, iso-Glu, D-iso-Glu, β-Glu, D-β-Glu, high-Glu, D-high-Glu, β-high-Glu, N-Me-Glu, N-Me-high-Glu, Asn, D-Asn, β-Asn, D-β-Asn, high-Asn, D-high-Asn, β-high-Asn, N-Me-Asn, N-Me-high-Asn, 4-aminobutyryl, 2-(trimethyl-2-aminoethoxy)ethoxy]propyl and Lys, wherein the side chain -NH2 of Lys is replaced by -C(=O)(CH2). n R K Replace, where n is between 0 and 2, and R K It is an imidazole, pyrimidin, or pyridinyl group optionally substituted with F, or X12 is absent.

[1320] In some embodiments, X12 is selected from Dab, His, D-His, His(1-Me), 3-(2-pyridyl)-Ala, 3-(3-pyridyl)-Ala, 3-(4-pyridyl)-Ala, 3-(3-quinolinyl)-Ala, Gly, Pro, Ser(OCH3), 5-aminopentanoyl, 4-aminopiperidin-4-carbonyl, (R,S)-imidazolidine-2-carbonyl, and Lys, wherein the side chain -NH2 of Lys is replaced by -C(=O)(CH2). n R K Replace, where n is between 0 and 2, and R K It is an imidazole, pyrimidin, or pyridinyl group optionally substituted with F, or X12 is absent.

[1321] In some embodiments, X12 is selected from Dab, His, D-His, His(1-Me), 3-(2-pyridyl)-Ala, 3-(3-pyridyl)-Ala, 3-(4-pyridyl)-Ala, 3-(3-quinolinyl)-Ala, Gly, Pro, 5-aminopentanoyl, 4-aminopiperidine-4-carbonyl, (R,S)-imidazolidine-2-carbonyl, and Lys, wherein the side chain -NH2 of Lys is replaced by -C(=O)(CH2). n R K Replace, where n is between 0 and 2, and R K It is an imidazole, pyrimidin, or pyridinyl group optionally substituted with F; or X12 is absent.

[1322] In X12, Lys is present, where the side chain -NH2 of Lys is replaced by -C(=O)(CH2). n R K Replace, where n is between 0 and 2, and R K In some embodiments, X12 may be selected from K (pyridazolyl, pyrimidinyl, or pyridinyl), K (2-pyridinylacetyl), K (2-pyridinylpropionyl), K (nicotinic acid), K (3-pyridinylacetyl), K (3-pyridinylpropionyl), K (isonicotinyl), K (4-pyridinylacetyl), K (4-pyridinylpropionyl), K (3,5-pyrimidinyl), K (4-pyridinyl-3-fluoroacetyl), K (imidazolylacetyl), and K (imidazolylpropionyl).

[1323] That is, K (pyridinecarboxylic acid) is the value when n is 0 and R K When it is pyridin-2-yl; K(2-pyridylacetyl) is when n is 1 and R K When it is pyridin-2-yl; K(2-pyridylpropionyl) is when n is 2 and R K When it is pyridin-2-yl; K (nicotinic acid) is when n is 0 and R KWhen it is pyridin-3-yl; K(3-pyridylacetyl) is when n is 1 and R K When it is pyridin-3-yl; K(3-pyridylpropionyl) is when n is 2 and R K When it is pyridin-3-yl; K (isonicotinyl) is when n is 0 and R K When it is pyridin-4-yl; K(4-pyridylacetyl) is when n is 1 and R K When it is pyridin-4-yl; K(4-pyridylpropionyl) is when n is 2 and R K When it is pyridin-4-yl; K(3,5-pyrimidine) is when n is 0 and R K When it is 3,5-pyrimidinyl; K(4-pyridyl-3-fluoroacetyl) is when n is 1 and R K When the pyridin-4-yl group is substituted with F at position 2; K (imidazolium acetyl) is when n is 1 and R K When it is 1H-imidazol-2-yl; and K(imidazolium propionyl) is when n is 2 and R K When it is 1H-imidazol-2-yl.

[1324] In some embodiments, X12 is selected from Dab, His, D-His, His(1-Me), 3-(3-quinolinyl)-Ala and 4-aminopiperidine-4-carbonyl.

[1325] In some implementations, X12 is selected from Dab, His, Gly, or may not exist.

[1326] In some implementations, X12 is selected from Dab, or it may not exist.

[1327] In some embodiments, X12 is Dab. In some embodiments, X12 is His. In some embodiments, X12 is D-His. In some embodiments, X12 is His(1-Me). In some embodiments, X12 is 3-(2-pyridinyl)-Ala. In some embodiments, X12 is 3-(3-pyridinyl)-Ala. In some embodiments, X12 is 3-(4-pyridinyl)-Ala. In some embodiments, X12 is 3-(3-quinolinyl)-Ala. In some embodiments, X12 is Gly. In some embodiments, X12 is Pro. In some embodiments, X12 is 5-aminopentanoyl. In some embodiments, X12 is 4-aminopiperidine-4-carbonyl. In some embodiments, X12 is (R,S)-imidazolidine-2-carbonyl. In some embodiments, X12 is K(pyridinecarboxylic acid). In some embodiments, X12 is K(2-pyridylacetyl). In some embodiments, X12 is K(2-pyridylpropionyl). In some embodiments, X12 is K(nicotinic acid). In some embodiments, X12 is K(3-pyridylacetyl). In some embodiments, X12 is K(3-pyridylpropionyl). In some embodiments, X12 is K(isonicotinyl). In some embodiments, X12 is K(4-pyridylacetyl). In some embodiments, X12 is K(4-pyridylpropionyl). In some embodiments, X12 is K(3,5-pyrimidine). In some embodiments, X12 is K(4-pyridyl-3-fluoroacetyl). In some embodiments, X12 is K(imidazolylacetyl). In some embodiments, X12 is K(imidazolylpropionyl). In some embodiments, X12 is absent.

[1328] Preferably, X12 is Dab.

[1329] X13

[1330] X13 is selected from optionally substituted His residues, optionally substituted Phe residues, alanine residues substituted with a carbocyclic group or an aromatic or heteroaromatic group selected from phenyl, pyridyl, naphthyl and quinolinyl (each optionally substituted), Asn, D-Asn, β-Asn, D-β-Asn, high-Asn, D-high-Asn, β-high-Asn, N-Me-Asn, N-Me-high-Asn, Gly, β-Gly, high-Gly, β-high-Gly, N-Me-Gly, N-Me-high-Gly.

[1331] And Dab, Orn, or Lys, where the side chain -NH2 is replaced by -C(=O)(CH2). n R KReplace, where n is between 0 and 2, and R K It is optionally an imidazole, pyrimidin, or pyridinyl group substituted with F; or it is absent. In some embodiments, X13 is selected from 3-(3-pyridinyl)-Ala, D-3-(3-pyridinyl)-Ala, and 3-(3,5-pyrimidinyl)-Ala, or it is absent. When X13 is present, the amino acid residue at X13 can form a lactam bridge with the amino acid residue at X10.

[1332] In some embodiments where X13 is present and the amino acid residue at X13 forms a lactam bridge with the amino acid residue at X10, X13 may be 3-(3-pyridyl)-Ala.

[1333] In some embodiments, X13 is selected from 3-(3-pyridyl)-Ala, D-3-(3-pyridyl)-Ala, or is not present.

[1334] In some implementations, X13 is 3-(3-pyridyl)-Ala, 3-(3,5-pyrimidinyl)-Ala, or it is not present.

[1335] In some implementations, X13 is 3-(3-pyridyl)-Ala, or it is not present.

[1336] In some embodiments, X13 is 3-(3-pyridyl)-Ala. In some embodiments, X13 is D-3-(3-pyridyl)-Ala. In some embodiments, X13 is 3-(3,5-pyrimidinyl)-Ala. In some embodiments, X13 is absent.

[1337] Preferably, X13 is 3-(3-pyridyl)-Ala, or it is absent. More preferably, X13 is 3-(3-pyridyl)-Ala.

[1338] lactam bridge

[1339] A lactam bridge is formed by an amino acid residue containing an amino group and another amino acid residue containing a carboxylic acid group. The amino and / or carboxylic acid groups of the amino acid residues can be on the side chains of the amino acid residues, such as Lys, D-Lys, iso-Lys, β-Lys, D-β-Lys, high-Lys, D-high-Lys, β-high-Lys, N-Me-Lys, Lys(Me), Lys(Gly), Dab, D-Dab, iso-Dab, Orn, D-Orn, Dpr, Glu, D-Glu, iso-Glu, D-iso-Glu, high-Glu, β-high-Glu, and Asp. Alternatively, the amino and / or carboxylic acid groups of the amino acid residues may be the N-terminus or C-terminus of the peptide chain, such as the amine or carboxylic acid of the peptide backbone of any amino acid, or for example, Lys, D-Lys, iso-Lys, β-Lys, D-β-Lys, high-Lys, D-high-Lys, β-high-Lys, N-Me-Lys, Dab, D-Dab, iso-Dab, Orn, D-Orn, Dpr, Lys(Gly), Glu, iso-Glu, D-iso-Glu, 3-(3-pyridyl)-Ala, and 2-amino-6-carboxyhexanoyl.

[1340] For simplicity, the amino acid residues that form the lactam bridge together will be discussed with reference to the residues that nominally exist before the formation of the lactam.

[1341] Suitable amino acid residues that form a lactam bridge can be selected from:

[1342] • Amino acid residues containing an amino group: Lys, D-Lys, iso-Lys, β-Lys, D-β-Lys, high-Lys, D-high-Lys, β-high-Lys, N-Me-Lys, Lys(Me), Lys(Gly), Dab, D-Dab, iso-Dab, Orn, D-Orn, Dpr, 3-(3-pyridyl)-Ala, (N3)-Lys and D-(N3)-Lys.

[1343] • Amino acid residues containing carboxylic acid groups: Glu, D-Glu, iso-Glu, D-iso-Glu, homo-Glu, β-homo-Glu, Asp, 2-amino-6-carboxyhexanoyl and iso-Dab.

[1344] The inventors have discovered that replacing the disulfide bridge with a lactam bridge can lead to an increase in the efficacy of the IL-23R peptide inhibitor, as previously described in Example 2 of WO2023 / 099669.

[1345] First lactam bridge - X2 and X11

[1346] The first lactam bridge is formed between the amino acid residues at X2 and X11.

[1347] One of the residues at the X2 and X11 positions is an amino acid residue containing an amino group, and the other is an amino acid residue containing a carboxylic acid group, wherein a lactam (cyclic amide) is formed between the amino group and the carboxylic acid group.

[1348] In some embodiments, the amino acid residue containing the amino group is located at X2, and the amino acid residue containing the carboxylic acid group is located at X11. In some such embodiments:

[1349] X2 is selected from Lys, D-lys, iso-Lys, D-iso-Lys, β-Lys, D-β-Lys, homo-Lys, D-homo-Lys, β-homo-Lys, N-Me-Lys, N-Me-ho- Lys, (N3)-Lys, D-(N3)-Lys, (N3)-β-Lys, (N3)-D-β-Lys, (N3)-high-Lys, (N3)-D-high-Lys, (N3)-β-high- Lys, Dpr, D-Dpr, iso-Dpr, D-iso-Dpr, β-Dpr, D-β-Dpr, homo-Dpr, D-homo-Dpr, β-homo-Dpr, N-Me-Dpr, N-Me-ho- Dpr, (N3)-Dpr, D-(N3)-Dpr, (N3)-β-Dpr, (N3)-D-β-Dpr, (N3)-high-Dpr, (N3)-D-high-Dpr, (N3)-β-high- Dpr, Dab, D-Dab, β-Dab, D-β-Dab, Homo-Dab, D-homo-Dab, β-homo-Dab, N-Me-Dab, N-Me-ho-Dab, (N3)-Dab, D -(N3)-Dab, (N3)-β-Dab, (N3)-D-β-Dab, (N3)-high-Dab, (N3)-D-high-Dab, (N3)-β-high-Dab, Orn, D-Orn, Different-Orn, D-different-Orn, β-Orn, D-β-Orn, high-Orn, D-high-Orn, β-high-Orn, N-Me-Orn, N-Me-high-Orn, (N3)-Orn, D-(N3)-Orn, (N3)-β-Orn, (N3)-D-β-Orn, (N3)-high-Orn, (N3)-D-high-Orn, (N3)-β-high-Orn, and Lys(Gly).

[1350] In some such implementations, X2 is selected from Dab, D-Dab, Lys, hetero-Lys, D-β-Lys, N-Me-Lys, high-Lys, D-Lys, D-high-Lys, β-Lys, β-high-Lys, Lys(Gly), (N3)-Lys, D-(N3)-Lys, Orn, D-Orn, Dpr, and Lys(Gly).

[1351] In some such implementations, X2 is selected from Lys, D-Lys, hetero-Lys, β-Lys, D-β-Lys, high-Lys, D-high-Lys, β-high-Lys, N-Me-Lys, Dab, D-Dab, hetero-Dab, Orn, D-Orn, Dpr, Lys(Gly), (N3)-Lys, and D-(N3)-Lys.

[1352] In some such embodiments, X11 is selected from Asp, D-Asp, iso-Asp, D-iso-Asp, β-Asp, D-β-Asp, high-Asp, D-high-Asp, β-high-Asp, N-Me-Asp, N-Me-high-Asp, Glu, D-Glu, iso-Glu, D-iso-Glu, β-Glu, D-β-Glu, high-Glu, D-high-Glu, β-high-Glu, N-Me-Glu, N-Me-high-Glu, 2-amino-6-carboxyhexanoyl and iso-Dab.

[1353] In some such embodiments, X11 is selected from Glu, high-Glu, β-high-Glu, 2-amino-6-carboxyhexanoyl, and iso-Dab.

[1354] That is, in some embodiments where the amino acid residue containing the amine group is located at X2 and the amino acid residue containing the carboxylic acid group is located at X11, the following are suitable combinations of X2 and X11:

[1355] X2 is D-Lys and X11 is Glu;

[1356] X2 is Lys and X11 is Glu;

[1357] X2 is high-Lys and X11 is Glu;

[1358] X2 is D-high-Lys and X11 is Glu;

[1359] X2 is D-Orn and X11 is high-Glu;

[1360] X2 is D-Dab and X11 is 2-amino-6-carboxyhexanoyl;

[1361] X2 is D-Orn and X11 is Glu;

[1362] X2 is D-Dab and X11 is Glu;

[1363] X2 is β-Lys and X11 is Glu;

[1364] X2 is D-β-Lys and X11 is Glu;

[1365] X2 is Lys and X11 is hetero-Dab;

[1366] X2 is Dab and X11 is Glu;

[1367] X2 is Lys(Gly) and X11 is Glu;

[1368] X2 is Lys and X11 is β-high-Glu;

[1369] X2 is Ne-Me-Lys and X11 is Glu;

[1370] X2 is Orn and X11 is Glu;

[1371] X2 is Dpr and X11 is Glu;

[1372] X2 is β-high-Lys and X11 is Glu;

[1373] X2 is hetero-Lys and X11 is Glu;

[1374] X2 is hetero-Dab and X11 is Glu;

[1375] X2 is (N3)-Lys and X11 is Glu; and

[1376] X2 is D-(N3)-Lys and X11 is Glu.

[1377] In some embodiments, the amino acid residue containing the amino group is located at X11, and the amino acid residue containing the carboxylic acid group is located at X2. In some such embodiments:

[1378] X2 is selected from Asp, D-Asp, hetero-Asp, D-hetero-Asp, β-Asp, D-β-Asp, high-Asp, D-high-Asp, β-high-Asp, N-Me-Asp, N-Me-high-Asp, (N3)-Asp, D-(N3)-Asp, (N3)-β-Asp, (N3)-D-β-Asp, (N3)-high-Asp, (N3)-D-high-Asp, (N3)-β-high-Asp, Glu, D-Glu Iso-Glu, D-Iso-Glu, β-Glu, D-β-Glu, High-Glu, D-High-Glu, β-High-Glu, N-Me-Glu, N-Me-High-Glu, (N3)-Glu, D-(N3)-Glu, (N3)-β-Glu, (N3)-D-β-Glu, (N3)-High-Glu, (N3)-D-High-Glu, (N3)-β-High-Glu, and 2-amino-6-carboxyhexanoyl and 3-aminopropionyl.

[1379] In some such implementations, X2 is selected from Glu, iso-Glu, and D-iso-Glu.

[1380] In some such implementations, X11 is selected from Dpr, D-Dpr, hetero-Dpr, D-hetero-Dpr, β-Dpr, D-β-Dpr, high-Dpr, D-high-Dpr, β-high-Dpr, N-Me-Dpr and N-Me-high-Dpr, Dab, D-Dab, hetero-Dab, D-hetero-Dab, β-Dab, D-β-Dab, high-Dab, D-high-Dab, β-high-Dab, N-Me-Dab, N-Me-high -Dab, Orn, D-Orn, Different-Orn, D-Different-Orn, β-Orn, D-β-Orn, High-Orn, D-High-Orn, β-High-Orn, N-Me-Orn, N-Me-High-Orn, Lys, D-lys, Different-Lys, D-Different-Lys, β-Lys, D-β-Lys, High-Lys, D-High-Lys, β-High-Lys, N-Me-Lys, N-Me-High-Lys, Lys(Me).

[1381] In some such implementations, X11 is selected from Dab, Lys, Lys(Me), and Orn.

[1382] That is, in some embodiments where the amino acid residue containing the amino group is located at X2 and the amino acid residue containing the carboxylic acid group is located at X11, the following are suitable combinations of X2 and X11:

[1383] X2 is Glu and X11 is Orn;

[1384] X2 is Glu and X11 is Lys(Me);

[1385] X2 is Glu and X11 is Lys;

[1386] X2 is iso-Glu and X11 is Lys;

[1387] X2 is iso-Glu and X11 is Dab;

[1388] X2 is D-iso-Glu and X11 is Lys; and

[1389] X2 is D-iso-Glu and X11 is Dab.

[1390] Second lactam bridge - X2 and X7

[1391] The second lactam bridge can be formed between the amino acid residues at X2 and X7.

[1392] Preferably, the bridge between the amino acid residues at X2 and X7 is a lactam bridge.

[1393] One of the residues at positions X2 and X7 is an amino acid residue containing an amine group, and the other is an amino acid residue containing a carboxylic acid group, where a lactam (cyclic amide) is formed between the amine group and the carboxylic acid group.

[1394] In some embodiments, the amino acid residue containing an amine group is at X2, and the amino acid residue containing a carboxylic acid group is at X7. In some such embodiments:

[1395] X2 is selected from Lys, D-lys, iso-Lys, D-iso-Lys, β-Lys, D-β-Lys, homo-Lys, D-homo-Lys, β-homo-Lys, N-Me-Lys, N-Me-homo-Lys, (N3)-Lys, D-(N3)-Lys, (N3)-β-Lys, (N3)-D-β-Lys, (N3)-homo-Lys, (N3)-D-homo-Lys, (N3)-β-homo-Lys, Dpr, D-Dpr, iso-Dpr, D-iso-Dpr, β-Dpr, D-β-Dpr, homo-Dpr, D-homo-Dpr, β-homo-Dpr, N-Me-Dpr, N-Me-homo-Dpr, (N3)-Dpr, D-(N3)-Dpr, (N3)-β-Dpr, (N3)-D-β-Dpr, (N3)-homo-Dpr, (N3)-D-homo-Dpr, (N3)-β-homo-Dpr, Dab, D-Dab, β-Dab, D-β-Dab, homo-Dab, D-homo-Dab, β-homo-Dab, N-Me-Dab, N-Me-homo-Dab, (N3)-Dab, D-(N3)-Dab, (N3)-β-Dab, (N3)-D-β-Dab, (N3)-homo-Dab, (N3)-D-homo-Dab, (N3)-β-homo-Dab, Orn, D-Orn, iso-Orn, D-iso-Orn, β-Orn, D-β-Orn, homo-Orn, D-homo-Orn, β-homo-Orn, N-Me-Orn, N-Me-homo-Orn, (N3)-Orn, D-(N3)-Orn, (N3)-β-Orn, (N3)-D-β-Orn, (N3)-homo-Orn, (N3)-D-homo-Orn, (N3)-β-homo-Orn, and Lys(Gly).

[1396] In some such embodiments, X2 is selected from Dab, D-Dab, Lys, iso-Lys, D-β-Lys, N-Me-Lys, high-Lys, D-Lys, D-high-Lys, β-Lys, β-high-Lys, Lys(Gly), (N3)-Lys, D-(N3)-Lys, Orn, D-Orn, Dpr, and Lys(Gly). In some such embodiments, X2 is selected from Lys, D-Lys, iso-Lys, β-Lys, D-β-Lys, high-Lys, D-high-Lys, β-high-Lys, N-Me-Lys, Dab, D-Dab, iso-Dab, Orn, D-Orn, Dpr, Lys(Gly), iso-Glu, and D-iso-Glu.

[1397] In some such implementations, X7 is selected from Asp, D-Asp, iso-Asp, D-iso-Asp, β-Asp, D-β-Asp, high-Asp, D-high-Asp, β-high-Asp, N-Me-Asp, N-Me-high-Asp, Glu, D-Glu, iso-Glu, D-iso-Glu, β-Glu, D-β-Glu, high-Glu, D-high-Glu, β-high-Glu, N-Me-Glu, and N-Me-high-Glu.

[1398] In some such implementations, X7 is selected from Glu, D-Glu, high-Glu, and Asp.

[1399] That is, in some embodiments where the amino acid residue containing the amine group is located at X2 and the amino acid residue containing the carboxylic acid group is located at X7, the following are suitable combinations of X2 and X7:

[1400] X2 is D-Lys and X7 is Glu;

[1401] X2 is Lys and X7 is Glu;

[1402] X2 is D-Lys and X7 is Asp;

[1403] X2 is high-Lys and X7 is Glu;

[1404] X2 is D-high-Lys and X7 is Glu;

[1405] X2 is D-Orn and X7 is Glu;

[1406] X2 is D-Dab and X7 is Glu;

[1407] X2 is D-Orn and X7 is Asp;

[1408] X2 is D-Dab and X7 is Asp;

[1409] X2 is β-Lys and X7 is Glu;

[1410] X2 is D-β-Lys and X7 is Asp;

[1411] X2 is D-β-Lys and X7 is Glu;

[1412] X2 is Lys and X7 is D-Glu;

[1413] X2 is Dab and X7 is Glu;

[1414] X2 is Lys and X7 is high-Glu;

[1415] X2 is Glu and X7 is Glu;

[1416] X2 is Lys(Gly) and X7 is Glu;

[1417] X2 is Ne-Me-Lys and X7 is Glu;

[1418] X2 is Orn and X7 is Glu;

[1419] X2 is Dpr and X7 is Glu;

[1420] X2 is β-high-Lys and X7 is Glu;

[1421] X2 is hetero-Lys and X7 is Glu;

[1422] X2 is hetero-Dab and X7 is Glu

[1423] X2 is iso-Glu and X7 is Glu; and

[1424] X2 is D-iso-Glu and X7 is Glu.

[1425] Alternatively, the amino acid residue containing an amino group is located at X7, and the amino acid residue containing a carboxylic acid group is located at X2.

[1426] Preferably, the amino acid residue containing an amino group is located at X2, and the amino acid residue containing a carboxylic acid group is located at X7.

[1427] Optional third lactam bridges - X10 and X13

[1428] When X13 is present, an optional third lactam bridge can be formed between the amino acid residues at X10 and X13.

[1429] In some such embodiments, one of the residues at the X10 and X13 positions is an amino acid residue containing an amino group, and the other is an amino acid residue containing a carboxylic acid group, wherein a lactam (cyclic amide) is formed between the amino group and the carboxylic acid group.

[1430] In some embodiments, the amino acid residue containing the amino group is located at X13, and the amino acid residue containing the carboxylic acid group is located at X10. In some such embodiments:

[1431] In some such implementations, X10 is selected from Dab, D-Dab, hetero-Dab, D-hetero-Dab, β-Dab, D-β-Dab, high-Dab, D-high-Dab, β-high-Dab, N-Me-Dab, N-Me-high-Dab, Lys, D-lys, hetero-Lys, D-hetero-Lys, β-Lys, D-β-Lys, high-Lys, D-high-Lys, β-high-Lys, N-Me-Lys, and N-Me-high-Lys.

[1432] In some such implementations, X10 is either Dab or Lys.

[1433] In some such embodiments, D13 is an alanine residue substituted with a carbocyclic group or an aromatic or heteroaromatic group selected from phenyl, pyridyl, naphthyl and quinolinyl (each optionally substituted), and Dab, Orn or Lys, wherein the side chain -NH2 is replaced by -C(=O)(CH2). n R K Replace, where n is between 0 and 2, and R K It is an imidazole, pyrimidin, or pyridinyl group optionally substituted with F.

[1434] In some such implementations, X13 is 3-(3-pyridyl)-Ala.

[1435] That is, in some embodiments where the amino acid residue containing the amine group is located at X13 and the amino acid residue containing the carboxylic acid group is located at X10, the following are suitable combinations of X13 and X10:

[1436] X10 is Dab and X13 is 3-(3-pyridyl)-Ala; and

[1437] X10 is Lys and X13 is 3-(3-pyridyl)-Ala.

[1438] Alternatively, amino acid residues containing amine groups are located at X10, and amino acid residues containing carboxylic acid groups are located at X13.

[1439] Preferably, the amino acid residue containing an amino group is located at X13, and the amino acid residue containing a carboxylic acid group is located at X10.

[1440] Bridges containing triazole rings

[1441] The bridge containing the triazole ring is formed by an amino acid residue containing an azide (-N3) group and another amino acid residue containing an alkynyl group. In some embodiments, the azide group and / or alkynyl group of the amino acid residue are on the side chain of the amino acid residue.

[1442] Suitable amino acid residues that together form a bridge containing a triazole ring can be selected from:

[1443] • Amino acid residues containing azide groups: (N3)-Lys and D-(N3)-Lys.

[1444] • Amino acid residues containing alkynyl groups: Pra and Hpg.

[1445] The compounds of the present invention may contain a triazole ring-containing bridge (instead of a lactam bridge) formed between amino acid residues at the X2 and X7 positions.

[1446] One of the residues at the X2 and X7 positions is an amino acid residue containing an azide (-N3) group, and the other is an amino acid residue containing an alkynyl group, wherein a triazole (e.g., 1,2,3-triazole) is formed between the azide group and the alkynyl group. The reaction used to form the triazole ring is the Huisgen azide-alkynyl 1,3-dipolar cycloaddition. Typically, this reaction forms a 1,4-disubstituted 1,2,3-triazole ring (rather than a 1,5-disubstituted 1,2,3-triazole ring) as the major isomer. The 1,5-disubstituted 1,2,3-triazole ring can also be isolated, which is usually the minor isomer.

[1447] Azide groups and / or alkynyl groups may be present on the side chains of amino acid residues. Alkynes are preferably terminal alkynes (-C≡CH). Suitable amino acid residues whose side chains can participate in the formation of triazole rings (e.g., 1,2,3-triazole rings) include Pra and Hpg (which have side chains containing alkynyl groups).

[1448] Alternatively, the azide group and / or alkynyl group of the amino acid residue can be the N-terminus or C-terminus of the peptide chain. For example, the azide group can be derived from the amino group of the peptide backbone of any amino acid, such as (N3)-Lys and D-(N3)-Lys, and can be the N-terminus of the peptide chain.

[1449] In some embodiments, the amino acid residue containing the azide group is located at X2, and the amino acid residue containing the alkynyl group is located at X7. In some such embodiments:

[1450] X2 is selected from (N3)-Lys, D-(N3)-Lys, (N3)-β-Lys, (N3)-D-β-Lys, (N3)-ho-Lys, (N3)-D-ho-Lys, (N3)-β-ho-Lys, (N3)-Dpr, D-(N3)-Dpr, (N3)-β-Dpr, (N3)-D -β-Dpr, (N3)-high-Dpr, (N3)-D-high-Dpr, (N3)-β-high-Dpr, (N3)-Dab, D-(N3)-Dab, (N3)-β-Dab, (N3)-D-β-Dab, (N3)-high-Dab, (N3)-D-high-Dab, (N3)-β-high-Da b. (N3)-Orn, D-(N3)-Orn, (N3)-β-Orn, (N3)-D-β-Orn, (N3)-high-Orn, (N3)-D-high-Orn, (N3)-β-high-Orn, (N3)-Asp, D-(N3)-Asp, (N3)-β-Asp, (N3)-D-β -Asp, (N3)-homo-Asp, (N3)-D-homo-Asp, (N3)-β-homo-Asp, (N3)-Glu, D-(N3)-Glu, (N3)-β-Glu, (N3)-D-β-Glu, (N3)-ho-Glu, (N3)-D-homo-Glu and (N3)-β-homo-Glu.

[1451] In some such implementations, X2 is (N3)-Lys and D-(N3)-Lys.

[1452] In some such implementations, X7 is Pra and Hpg.

[1453] That is, in some embodiments where the amino acid residue containing the azide group is located at X2 and the amino acid residue containing the alkynyl group is located at X7, the following are suitable combinations of X2 and X7:

[1454] X2 is (N3)-Lys and X7 is Pra; and

[1455] X2 is D-(N3)-Lys and X7 is Hpg.

[1456] Alternatively, the amino acid residue containing an azide group is located at X7, and the amino acid residue containing an alkynyl group is located at X2.

[1457] Preferably, the amino acid residue containing an azide group is located at X2, and the amino acid residue containing an alkynyl group is located at X7.

[1458] Bridge length

[1459] The length of the bridge is counted as the number of atoms in the straight chain from the first atom (carbon) adjacent to the carboxylic acid portion of the amino acid that is connected to the first residue (X2 for the bridge between X2 and X11; X2 for the bridge between X2 and X7; or X10 for the bridge between X10 and X13) (i.e., the α-carbon of the relevant residue of most amino acids) up to the first atom (carbon) adjacent to the carboxylic acid portion of the amino acid that is connected to the second residue (X11 for the bridge between X2 and X11; X7 for the bridge between X2 and X7; or X13 for the bridge between X10 and X13).

[1460] The contributions of amino acid residues and bridge type to bridge length are described below.

[1461] In some embodiments, the bridge between X2 and X11 is at least 3 atoms long. In some embodiments, the bridge between X2 and X11 is no longer than 11 atoms long. In some embodiments, the bridge between X2 and X11 is 3 to 11 atoms long, such as 3, 4, 5, 6, 7, 8, 9, 10, or 11 atoms long. In some embodiments, the bridge between X2 and X11 is 4 to 11 atoms long, such as 4, 5, 6, 7, 8, 9, 10, or 11 atoms long. In some embodiments, the bridge between X2 and X11 is 4 atoms long. In some embodiments, the bridge between X2 and X11 is 5 atoms long. In some embodiments, the bridge between X2 and X11 is 6 atoms long. In some embodiments, the bridge between X2 and X11 is 7 atoms long. In some embodiments, the bridge between X2 and X11 is 8 atoms long. In some embodiments, the bridge between X2 and X11 is 9 atoms long. In some embodiments, the bridge between X2 and X11 is 11 atoms long.

[1462] In some embodiments, the bridge between X2 and X7 is at least 3 atoms long. In some embodiments, the bridge between X2 and X7 is no longer than 11 atoms long. In some embodiments, the bridge between X2 and X7 is 3 to 11 atoms long, such as 3, 4, 5, 6, 7, 8, 9, 10, or 11 atoms long. In some embodiments, the bridge between X2 and X7 is 3 to 6 atoms long, such as 3, 4, 5, or 6 atoms long. In some embodiments, the bridge between X2 and X7 is 3 atoms long. In some embodiments, the bridge between X2 and X7 is 4 atoms long. In some embodiments, the bridge between X2 and X7 is 6 atoms long.

[1463] In some embodiments, the bridge between X10 and X13 is at least 3 atoms long. In some embodiments, the bridge between X10 and X13 is no longer than 11 atoms long. In some embodiments, the bridge between X10 and X13 is 3 to 11 atoms long, such as 3, 4, 5, 6, 7, 8, 9, 10, or 11 atoms long. In some embodiments, the bridge between X10 and X13 is 4 to 6 atoms long, such as 4, 5, or 6 atoms long. In some embodiments, the bridge between X10 and X13 is 4 atoms long. In some embodiments, the bridge between X10 and X13 is 6 atoms long.

[1464] lactam bridge

[1465] 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 (which is bound to the atom of the peptide backbone, i.e., the α carbon of the relevant residue of most amino acids) up to and including the atoms of the amide bond involved in the lactam bridge (i.e., the carbon atom of the carboxylic acid functional group or the nitrogen atom of the amine group).

[1466] Therefore, common acid- and amine-containing side chains are considered to have the following side chain lengths. It should be understood that the following can be used to interpret the bridge lengths of any amino acid residues disclosed herein.

[1467] Amine-containing side chains:

[1468]

[1469]

[1470] Side chains containing carboxylic acids:

[1471]

[1472] Similarly, the contribution of the use of amines or carboxylic acids from amino acid residues in amide bonds conventionally used in peptide backbones to the length of the lactam bridge (i.e., the α-amine group (or the β-amine group for bLys, {d}bLys and β-hLys, or the α-amine group converted to an azide group for (N3)-K and {d}(N3)-K), or the α-carboxylic acid group) in the straight chain from the first atom (carbon) adjacent to the carboxylic acid portion of the amino acid residue (i.e., the first atom connected to the α-carbon of the relevant residue of most amino acids) up to and including the atoms of the amide bond involved in the lactam bridge (i.e., the carbon atom of the carboxylic acid functional group or the nitrogen atom of the amine group).

[1473] Therefore, the following amino acid residues are considered to have the following lengths:

[1474] Use the α-amino group in the peptide backbone commonly used in lactam bridges (or the β-amino group for bLys, {d}bLys, and β-hLys, or the α-amino group converted to an azide group for (N3)-K and {d}(N3)-K):

[1475]

[1476]

[1477] Using the α-carboxylic acid group in the peptide backbone commonly used in lactam bridges:

[1478]

[1479] The position of the amide bond in a lactam bridge can affect the potency of the compound. The inventors observed that the compound is more active when the amide bond is closer to the 11th position (X11), and less active when it is closer to the 2nd position (X2) (see Example 2 and Table 2-3b of WO2023 / 099669).

[1480] Suitable residue pairs at the X2 and X11 positions include the following, where, once formed, the amide bond in the lactam bridge is closer to the X11 position than the X2 position:

[1481] X2 is D-Lys and X11 is Glu;

[1482] X2 is Lys and X11 is Glu;

[1483] X2 is high-Lys and X11 is Glu;

[1484] X2 is D-high-Lys and X11 is Glu;

[1485] X2 is D-Orn and X11 is high-Glu;

[1486] X2 is D-Orn and X11 is Glu;

[1487] X2 is β-Lys and X11 is Glu;

[1488] X2 is D-β-Lys and X11 is Glu;

[1489] X2 is Lys and X11 is hetero-Dab;

[1490] X2 is Lys(Gly) and X11 is Glu;

[1491] X2 is Lys and X11 is β-high-Glu;

[1492] X2 is Ne-Me-Lys and X11 is Glu;

[1493] X2 is Orn and X11 is Glu;

[1494] X2 is β-high-Lys and X11 is Glu;

[1495] X2 is (N3)-Lys and X11 is Glu;

[1496] X2 is D-(N3)-Lys and X11 is Glu;

[1497] X2 is Glu and X11 is Orn;

[1498] X2 is Glu and X11 is Lys(Me); and

[1499] X2 is Glu and X11 is Lys.

[1500] Alternatively, suitable residue pairs at positions X2 and X11 include the following, where the amide bond in the lactam bridge is closer to position X2 than position X11:

[1501] X2 is D-Dab and X11 is 2-amino-6-carboxyhexanoyl;

[1502] X2 is Dpr and X11 is Glu;

[1503] X2 is different-Lys And X11 is Glu; and

[1504] X2 is a hetero-Dab And X11 is Glu;

[1505] X2 is iso-Glu And X11 is Lys;

[1506] X2 is iso-Glu And X11 is a Dab;

[1507] X2 is D-iso-Glu And X11 is Lys; and

[1508] X2 is D-iso-Glu And X11 is a Dab.

[1509] in This indicates that the α-amino group, typically used in the peptide backbone (or the β-amino group for bLys, {d}bLys, and β-hLys), is used in the bridge; and This indicates that the α-carboxylic acid group, which is usually used in the peptide backbone, is used in the bridge.

[1510] Alternatively, suitable residue pairs at positions X2 and X11 include those where the amide bond in the lactam bridge is located midway between positions X2 and X11 (i.e., equally distant or equidistant):

[1511] X2 is D-Dab and X11 is Glu; and

[1512] X2 is Dab and X11 is Glu.

[1513] In a lactam bridge between positions 2 (X2) and 7 (X7), the amide bond can be positioned closer to position X7 than position X2. Suitable residue pairs at positions X2 and X7 include the following, where, once formed, the amide bond in the lactam bridge is positioned closer to position X7 than position X2:

[1514] X2 is hetero-Lys and X7 is Glu; and

[1515] X2 is iso-Dab and X7 is Glu.

[1516] Alternatively, suitable residue pairs at the X2 and X7 positions include the following, where the amide bond in the lactam bridge is closer to the X2 position than the X7 position:

[1517] X2 is D-Lys And X7 is Glu;

[1518] X2 is Lys And X7 is Glu;

[1519] X2 is D-Lys And X7 is an ASP;

[1520] X2 is high-Lys And X7 is Glu;

[1521] X2 is D-high-Lys And X7 is Glu;

[1522] X2 is D-Orn And X7 is Glu;

[1523] X2 is D-Dab And X7 is Glu;

[1524] X2 is D-Orn And X7 is an ASP;

[1525] X2 is D-Dab And X7 is an ASP;

[1526] X2 is β-Lys And X7 is Glu

[1527] X2 is D-β-Lys And X7 is an ASP.

[1528] X2 is D-β-Lys And X7 is Glu

[1529] X2 is Lys And X7 is D-Glu;

[1530] X2 is Dab And X7 is Glu;

[1531] X2 is Lys And X7 is high-Glu;

[1532] X2 is Glu And X7 is Glu;

[1533] X2 is Lys(Gly) And X7 is Glu;

[1534] X2 is Ne-Me-Lys And X7 is Glu;

[1535] X2 is Orn And X7 is Glu;

[1536] X2 is Dpr And X7 is Glu;

[1537] X2 is β-high-Lys And X7 is Glu;

[1538] X2 is iso-Glu And X7 is Glu; and

[1539] X2 is D-iso-Glu And X7 is Glu.

[1540] in This indicates that the α-amino group, typically used in the peptide backbone (or the β-amino group for bLys, {d}bLys, and β-hLys), is used in the bridge; and This indicates that the α-carboxylic acid group, which is usually used in the peptide backbone, is used in the bridge.

[1541] In an optional lactam bridge between positions 10 (X10) and 13 (X13), the amide bond position can be closer to the X13 position than the X10 position. Suitable residue pairs at positions X10 and X13 include the following, which, once formed, result in the amide bond position in the lactam bridge being closer to the X13 position than the X10 position:

[1542] X10 is Dab and X13 is 3-(3-pyridyl)-Ala; and

[1543] X10 is Lys and X13 is 3-(3-pyridyl)-Ala.

[1544] Alternatively, suitable residue pairs at positions X10 and X13 (wherein the position of the amide bond in the optional lactam bridge) may be closer to position X10 than position X13. Preferably, the position of the amide bond in the optional lactam bridge between positions 10 (X10) and 13 (X13) may be closer to position X13 than position X10.

[1545] Ideally, the length of the lactam bridge (excluding any atoms in the peptide backbone) after the amide bond is formed is 5, 6, 7, 8, 9, or 10 atoms; for example, 6, 7, 8, or 9 atoms; for example, 7 or 8 atoms.

[1546] In some embodiments, the length of the lactam bridge (excluding any atoms in the peptide backbone) after amide bond formation is 3 atoms. Suitable residue pairs at the X2 and X7 positions of a 3-atom lactam bridge include: X2 is D-Lys Furthermore, X7 is Asp; X2 is D-Orn. Furthermore, X7 is Asp; X2 is D-Dab. Furthermore, X7 is Asp; and X2 is D-β-Lys. And X7 is an ASP.

[1547] In some embodiments, the length of the lactam bridge (excluding any atoms in the peptide backbone) after the amide bond is formed is 4 atoms. Suitable residue pairs at the X2 and X11 positions for a 4-atom lactam bridge include: X2 being iso-Lys Furthermore, X11 is Glu; X2 is iso-Dab. Furthermore, X11 is Glu; X2 is iso-Glu. Furthermore, X11 is Dab; ​​and X2 is D-iso-Glu. And X11 is Dab. Suitable residue pairs at the X2 and X7 positions, where the lactam bridge has a length of 4 atoms, include: X2 is D-Lys Furthermore, X7 is Glu; X2 is Lys. Furthermore, X7 is Glu; X2 is High-Lys. Furthermore, X7 is Glu; X2 is D-High-Lys. Furthermore, X7 is Glu; X2 is D-Orn. Furthermore, X7 is Glu; X2 is D-Dab. Furthermore, X7 is Glu; X2 is β-Lys Furthermore, X7 is Glu; X2 is D-β-Lys Furthermore, X7 is Glu; X2 is Lys. Furthermore, X7 is D-Glu; X2 is Dab. Furthermore, X7 is Glu; X2 is Lys. Furthermore, X7 is high-Glu; X2 is Glu. Furthermore, X7 is Glu; X2 is Lys (Gly). Furthermore, X7 is Glu; X2 is Ne-Me-Lys. And X7 is Glu; X2 is Orn And X7 is Glu; X2 is Dpr Furthermore, X7 is Glu; X2 is β-high-Lys Furthermore, X7 is Glu; X2 is iso-Glu. Furthermore, X7 is Glu; and X2 is D-iso-Glu. And X7 is Glu. Suitable residue pairs at the X10 and X13 positions, where the length of the lactam bridge is 4 atoms, include: X10 is Dab and X13 is 3-(3-pyridyl)-Ala.

[1548] In some embodiments, the length of the lactam bridge (excluding any atoms in the peptide backbone) after the amide bond is formed is 5 atoms. Suitable residue pairs at the X2 and X11 positions of the lactam bridge with a length of 5 atoms include: X2 is Dpr and X11 is Glu.

[1549] In some embodiments, the length of the lactam bridge (excluding any atoms in the peptide backbone) after the amide bond is formed is 6 atoms. Suitable residue pairs at the X2 and X11 positions for a 6-atom lactam bridge include: X2 being iso-Glu. Furthermore, X11 is Lys; X2 is D-iso-Glu. Furthermore, X11 is Lys; X2 is D-Dab and X11 is Glu; and X2 is Dab and X11 is Glu. Suitable residue pairs at positions X2 and X7, where the lactam bridge is 6 atoms long, include: X2 is iso-Dab and X7 is Glu. Suitable residue pairs at positions X10 and X13, where the lactam bridge is 6 atoms long, include: X10 is Lys and X13 is 3-(3-pyridyl)-Ala.

[1550] In some embodiments, the length of the lactam bridge (excluding any atoms in the peptide backbone) after the amide bond is formed is 7 atoms. Suitable residue pairs at the X2 and X11 positions where the lactam bridge is 7 atoms long include: X2 is D-Orn and X11 is high-Glu; X2 is D-Orn and X11 is Glu; X2 is β-Lys and X11 is Glu; X2 is D-β-Lys and X11 is Glu; X2 is Orn and X11 is Glu; X2 is Glu and X11 is Orn; and X2 is Glu and X11 is Lys(Me).

[1551] Preferably, the length of the lactam bridge (excluding any atoms in the peptide backbone) after the amide bond is formed is 8 atoms. Suitable residue pairs at the X2 and X11 positions of the 8-atom lactam bridge include: X2 is D-Lys and X11 is Glu; X2 is Lys and X11 is Glu; X2 is Lys and X11 is iso-Dab; X2 is Lys and X11 is β-high-Glu; X2 is Ne-Me-Lys and X11 is Glu; X2 is β-high-Lys and X11 is Glu; X2 is (N3)-Lys and X11 is Glu; X2 is D-(N3)-Lys and X11 is Glu; X2 is Glu and X11 is Lys; and X2 is D-Dab and X11 is 2-amino-6-carboxyhexanoyl. The appropriate residue pairs at the X2 and X7 positions of the lactam bridge with a length of 8 atoms include: X2 is iso-Lys and X7 is Glu.

[1552] In some embodiments, the length of the lactam bridge (excluding any atoms in the peptide backbone) after the amide bond is formed is 9 atoms. Suitable residue pairs at the X2 and X11 positions of the lactam bridge with a length of 9 atoms include: X2 being high-Lys and X11 being Glu; and X2 being D-high-Lys and X11 being Glu.

[1553] In some implementations, the length of the lactam bridge (excluding any atoms in the peptide backbone) after the amide bond is formed is 10 atoms.

[1554] In some embodiments, the length of the lactam bridge (excluding any atoms in the peptide backbone) after the amide bond is formed is 11 atoms. Suitable residue pairs at the X2 and X11 positions of the 11-atom lactam bridge include: X2 is Lys (Gly) and X11 is Glu.

[1555] in This indicates that the α-amino group, typically used in the peptide backbone (or the β-amino group for bLys, {d}bLys, and β-hLys), is used in the bridge; and This indicates that the α-carboxylic acid group, which is usually used in the peptide backbone, is used in the bridge.

[1556] Bridges containing triazole rings

[1557] The contribution of the side chain to the length of the bridge containing the triazole ring is counted as the length of the straight chain from the first atom of the side chain (which is bonded to the atom of the peptide backbone, i.e., the α-carbon of the relevant residue of most amino acids) up to and including the atom involved in the formation of the triazole ring (i.e., for both 1,4-disubstituted 1,2,3-triazoles and 1,5-disubstituted 1,2,3-triazoles, the first nitrogen atom of the azide group attached to the side chain). ); or for 1,4-disubstituted 1,2,3-triazoles, the two carbon atoms of the alkynyl group, or for 1,5-disubstituted triazoles, the one carbon atom of the alkynyl group (i.e. The number of atoms in ).

[1558] Therefore, common alkyne-containing side chains are considered to have the following side chain lengths. It should be understood that the following can be used to interpret the bridge length of any amino acid residues disclosed herein.

[1559] Alkyne-containing side chains (for 1,4-disubstituted 1,2,3-triazoles):

[1560]

[1561] Similarly, the contribution of azides or alkynes derived from amines or carboxylic acids of amino acid residues to the length of the bridge containing the triazole ring is counted as the first atom in the straight chain connected to the atom (carbon) adjacent to the carboxylic acid portion of the amino acid residue (i.e., the first atom connected to the α-carbon of the relevant residue of most amino acids) up to and including the atom involved in the formation of the triazole ring (i.e., for both 1,4-disubstituted 1,2,3-triazoles and 1,5-disubstituted 1,2,3-triazoles, the first nitrogen atom of the azide group connected to the side chain (i.e., the first nitrogen atom of the azide group connected to the side chain). ); or for 1,4-disubstituted 1,2,3-triazoles, the two carbon atoms of the alkynyl group, or for 1,5-disubstituted triazoles, the one carbon atom of the alkynyl group (i.e. The number of atoms in ).

[1562] Therefore, the following amino acid residues are considered to have the following lengths. It should be understood that the following can be used to interpret the bridge length of any amino acid residues disclosed herein.

[1563] Using azides derived from the conversion of α-amino groups in the peptide backbone commonly used in triazole bridges:

[1564]

[1565] The position of the triazole in the bridge can affect the potency of the compound.

[1566] In some embodiments, once formed, the position of the triazole in the bridge containing the triazole ring is closer to the X7 position than the X2 position (i.e., the number of atoms in the straight chain from the first atom (carbon) adjacent to the carboxylic acid portion of the amino acid residue (i.e., the first atom attached to the α carbon of the relevant residue of most amino acids) up to the triazole ring).

[1567] Alternatively, in some embodiments, once formed, the position of the triazole in the bridge containing the triazole ring is closer to the X2 position than the X7 position (i.e., the number of atoms in the straight chain from the first atom (carbon) adjacent to the carboxylic acid portion of the amino acid residue (i.e., the first atom attached to the α carbon of the relevant residue of most amino acids) up to the triazole ring). Suitable residue pairs at the X2 and X7 positions include those where, once formed, the position of the triazole in the bridge containing the triazole ring is closer to the X2 position than the X7 position: X2 is (N3)-Lys and X7 is Pra; and X2 is D-(N3)-Lys and X7 is Hpg. Desiredly, the length of the bridge containing the triazole ring after triazole formation (excluding any atoms in the peptide backbone) is 3, 4, 5, 6, 7, 8, 9, 10, or 11 atoms; for example, 4, 5, 6, or 7 atoms; for example, 4, 5, or 6 atoms; for example, 4 or 5 atoms.

[1568] In some embodiments, the length of the bridge containing the triazole ring provided by the two side chains after triazole formation (excluding any atoms in the peptide backbone) is 4 atoms. Suitable residue pairs at the X2 and X7 positions of the bridge containing the triazole ring with a length of 4 atoms include: X2 is (N3)-Lys and X7 is Pra.

[1569] In some embodiments, the length of the bridge containing the triazole ring provided by the two side chains after triazole formation (excluding any atoms in the peptide backbone) is 5 atoms. Suitable residue pairs at the X2 and X7 positions of the 5-atom bridge containing the triazole ring include: X2 is D-(N3)-Lys and X7 is Hpg.

[1570] Compound Synthesis

[1571] The present invention also provides a method for synthesizing the compounds of the invention. The compounds (which may also be referred to as peptides) can be suitably prepared by standard synthetic methods. Thus, the peptides can be synthesized, for example, by a method comprising synthesizing the peptide stepwise or by fragment assembly using standard solid-phase or liquid-phase methods, and optionally isolating and purifying the final peptide product. In this context, reference can be made to WO 98 / 11125 or, in particular, Fields, GB et al., “Principles and Practice of Solid-Phase Peptide Synthesis”; synthetic examples in Synthetic Peptides, Gregory A. Grant (ed.), Oxford University Press (2nd edition, 2002) and herein. The method generally also includes the step of forming an amide bond between amino acid residues at positions 2 (X2) and 11 (X11), and optionally includes the step of forming an amide bond or forming a triazole between amino acid residues at positions 2 (X2) and 7 (X7), and optionally includes the step of forming an amide bond between amino acid residues at positions X10 and X13, as described below, for example. In the case of solid-phase synthesis, cyclization can be performed in situ on a solid phase (e.g., a resin), i.e., before the peptide is removed from the solid phase.

[1572] The synthesis of some example compounds of the present invention is provided in Example 1. Generally, the method for synthesizing said compounds includes synthesizing the compound by solid-phase or liquid-phase peptide synthesis, optionally isolating and / or purifying the final product, and optionally further including the step of forming an amide bond between amino acid residues at positions 2 and 11, and optionally further including the step of forming an amide bond or forming a triazole between amino acid residues at positions 4 and 7, and optionally further including the step of forming an amide bond between amino acid residues at positions 10 and 13.

[1573] The order of steps in compound synthesis is not necessarily the order mentioned above.

[1574] For example, the order in which the bridges are formed (lactam bridge / amide bond; triazole bridge) can be any order. In some embodiments, a bridge is first formed between amino acid residues at positions 2 and 11, then a bridge is formed between amino acid residues at positions 2 and 7, and subsequently a third bridge is formed between optional amino acid residues at positions 10 and 13. In other embodiments, a bridge is first formed between amino acid residues at positions 2 and 7, then a bridge is formed between amino acid residues at positions 2 and 11, and subsequently a third bridge is formed between optional amino acid residues at positions 10 and 13.

[1575] In some embodiments, a first step forms a bridge between amino acid residues at positions 2 and 11, then a second step forms an optional bridge between amino acid residues at positions 10 and 13, and subsequently a third step forms a bridge between amino acid residues at positions 2 and 7.

[1576] In some other embodiments, a first bridge is formed between amino acid residues at positions 2 and 7, then a second optional bridge is formed between amino acid residues at positions 10 and 13, and subsequently a third bridge is formed between amino acid residues at positions 2 and 11.

[1577] The potency of the compound

[1578] The compounds of the present invention are interleukin-23 receptor (IL-23R) inhibitors, that is, they are able to 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 through them.

[1579] The corresponding activity can be measured by any suitable means, such as by IC as described below. 50 The value is determined by measurement.

[1580] Compared to other peptide IL-23R inhibitors, such as those described in WO 2016 / 011208, WO 2018 / 022937, WO2018 / 136646, WO 2020 / 014646, WO 2021 / 146441, WO 2021 / 146458, WO 2023 / 288017, WO2023 / 288019, WO 2023 / 288028, Kong et al., 2020, WO 2023 / 099669 and WO 2024 / 015958, the compounds of the present invention exhibit a number of advantageous properties. Compared to any of these analogues, the compounds of the present invention can, for example, exhibit improved effects, such as in the form of improved in vitro potency of IL-23R.

[1581] As a supplement or alternative, the compounds of the present invention exhibit improved gastrointestinal (GI) stability compared to any of the peptide inhibitors of IL-23R described in the art.

[1582] Technicians will be aware of the appropriate assay format, and examples are provided below. For example, an assay using human IL-23R can be used (see examples below). When the sequence of the precursor protein is mentioned, it should be understood that an assay using a mature protein lacking the signal sequence can be used.

[1583] K d The value can be used as a numerical measure of binding affinity at a given receptor. d The Kelvin value, also known as the equilibrium dissociation constant, is a measure of how tightly a compound binds to its receptor in a specific assay. Small Kelvin values... d This indicates that the compound has a higher K content. d Compared to compounds with similar values, it binds more tightly to the receptor with a higher affinity. Therefore, for example, in a specific assay, it exhibits K-type affinity with another compound inhibitor of IL-23R. d Compared to [IL-23R] values, K d Compounds with lower [IL-23R] values ​​can be considered to have a stronger binding affinity (or a tighter binding) to IL-23R compared to the binding affinity of another compound inhibitor of that IL-23R.

[1584] Without directly determining the K receptor of the compound d In the case of experimental methods, the IC50 of the compound can be determined. 50 The method is to estimate the binding affinity of compounds. IC 50 The ability of a compound to compete with a labeled compound for a receptor is determined. In such a competitive assay, the concentration at which half of the labeled compound is replaced from the receptor by the unlabeled compound is called the IC50. 50 Value. IC 50 The value is related to the compound's affinity for the receptor (i.e., its K value). d The value is proportional and is system-dependent because it depends on factors such as the concentration of the labeled compound used, the affinity of the labeled compound for the receptor, and the incubation time.

[1585] In the combined assay format, IC 50 The value can be used in numerical form to measure how tightly a compound binds to its receptor in a specific assay. Small IC50 values... 50 This indicates that the compound has a high IC50 value. 50Compared to other compounds, it binds more tightly to the receptor with a higher affinity. Therefore, for example, in a specific assay, the IC50 of another compound inhibitor of IL-23R... 50 Compared to [IL-23R] values, IC 50 Compounds with lower [IL-23R] values ​​can be considered to have a stronger binding affinity (or bind more tightly) compared to the binding affinity of another compound inhibitor of IL-23R.

[1586] In some embodiments of the compounds of the present invention, IC targeting IL-23R 50 Below 1000 nM (e.g., 0.0001 to 1000 nM).

[1587] In some embodiments of the compounds of the present invention, IC targeting IL-23R 50 Below 500 nM (e.g., 0.0001 to 500 nM).

[1588] In some embodiments of the compounds of the present invention, IC targeting IL-23R 50 Below 100 nM (e.g., 0.0001 to 100 nM).

[1589] In some embodiments of the compounds of the present invention, IC targeting IL-23R 50 Below 50 nM (e.g., 0.0001 to 50 nM).

[1590] In some embodiments of the compounds of the present invention, IC targeting IL-23R 50 Below 30 nM (e.g., 0.0001 to 30 nM).

[1591] In some embodiments of the compounds of the present invention, IC targeting IL-23R 50 Below 20 nM (e.g., 0.0001 to 20 nM).

[1592] In some embodiments of the compounds of the present invention, IC targeting IL-23R 50 Below 10 nM (e.g., 0.0001 to 10 nM).

[1593] In some embodiments of the compounds of the present invention, IC targeting IL-23R 50 Below 5 nM (e.g., 0.0001 to 5 nM).

[1594] In some embodiments of the compounds of the present invention, IC targeting IL-23R 50 Less than 1 nM (e.g., 0.0001 to 1 nM).

[1595] In some embodiments of the compounds of the present invention, IC targeting IL-23R 50 Below 0.5 nM (e.g., 0.0001 to 0.5 nM).

[1596] In functional assays, the ability of compounds to inhibit IL-23-mediated signaling is measured in cell-based assays, IC50. 50 The value can be used as a numerical measure of inhibitory efficacy. IC 50 An IC50 value is a measure of the concentration of a compound required to achieve half of its maximum activity in a specific assay. Therefore, for example, in a specific assay, a compound with a lower IC50 value [IL-23R] compared to another inhibitor of IL-23R could be considered to have stronger inhibitory potency than another peptide inhibitor of IL-23R, possibly by better blocking IL-23-mediated signaling.

[1597] In some embodiments of the compounds of the present invention, ICs targeting IL-23-mediated signal transduction are described. 50 Below 1000 nM (e.g., 0.0001 to 1000 nM).

[1598] In some embodiments of the compounds of the present invention, ICs targeting IL-23-mediated signal transduction are described. 50 Below 500 nM (e.g., 0.0001 to 500 nM).

[1599] In some embodiments of the compounds of the present invention, ICs targeting IL-23-mediated signal transduction are described. 50 Below 100 nM (e.g., 0.0001 to 100 nM).

[1600] In some embodiments of the compounds of the present invention, ICs targeting IL-23-mediated signal transduction are described. 50 Below 50 nM (e.g., 0.0001 to 50 nM).

[1601] In some embodiments of the compounds of the present invention, ICs targeting IL-23-mediated signal transduction are described. 50 Below 30 nM (e.g., 0.0001 to 30 nM).

[1602] In some embodiments of the compounds of the present invention, ICs targeting IL-23-mediated signal transduction are described. 50 Below 20 nM (e.g., 0.0001 to 20 nM).

[1603] In some embodiments of the compounds of the present invention, ICs targeting IL-23-mediated signal transduction are described. 50Below 10 nM (e.g., 0.0001 to 10 nM).

[1604] In some embodiments of the compounds of the present invention, ICs targeting IL-23-mediated signal transduction are described. 50 Below 5 nM (e.g., 0.0001 to 5 nM).

[1605] In some embodiments of the compounds of the present invention, ICs targeting IL-23-mediated signal transduction are described. 50 Less than 1 nM (e.g., 0.0001 to 1 nM).

[1606] In some embodiments of the compounds of the present invention, ICs targeting IL-23-mediated signal transduction are described. 50 Below 0.5 nM (e.g., 0.0001 to 0.5 nM).

[1607] In some embodiments of the compounds of the present invention, ICs targeting IL-23-mediated signal transduction are described. 50 Below 0.5 nM (e.g., 0.0001 to 0.5 nM).

[1608] Such measurements can be performed under the conditions described in Examples 3-1 and 3-2 below.

[1609] As a supplement or alternative, the compounds of the present invention may 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, the compounds of the present invention may retain at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, or at least 85%, at least 90%, at least 95%, or at least 99% of the remaining compound or peptide after incubation for 1 hour or 4 hours under SIF and / or SGF assays. Preferably, the compounds retain at least 70% (or more) of the compound after incubation for 1 hour or 4 hours under SIF and / or SGF assays.

[1610] Pharmaceutical Composition

[1611] This invention also extends to compositions comprising the compounds of the invention, such as pharmaceutical compositions. For all aspects of this invention, it should be understood that references to the compounds of the invention encompass references to pharmaceutically acceptable salts and solvates.

[1612] The compounds of the present invention can be formulated into pharmaceutical compositions suitable for administration with or without storage, and generally contain a therapeutically effective amount of at least one peptide of the present invention, as well as a pharmaceutically acceptable carrier, excipient or loading agent.

[1613] The pharmaceutical composition can be used in any administration route common or standard in the art, such as oral, intravenous, intramuscular, subcutaneous, sublingual, intranasal, intradermal, suppository, or implantation. In a preferred embodiment of the invention as described herein, the pharmaceutical composition is a composition for oral administration.

[1614] The term "medicatable carrier" includes any standard pharmaceutical carrier. Medicatable carriers for therapeutic use are well-known in the pharmaceutical field and described, for example, in "Remington's Pharmaceutical Sciences," 17th edition, Alfonso R. Gennaro (Ed.), Mark Publishing Company, Easton, PA, USA, 1985.

[1615] Therapeutic uses

[1616] The compounds of the present invention and pharmaceutical compositions comprising said compounds can be used in methods for the prevention or treatment of a variety of diseases.

[1617] Prevention or treatment methods include administering a therapeutically effective amount of the compound of the present invention or a pharmaceutical composition containing said compound to a subject.

[1618] In some implementations, the disease can be selected from inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease, celiac disease (nontropical sprue), enteropathy associated with seronegative arthropathy, microcolitis, collagenous colitis, eosinophilic gastroenteritis, colitis associated with radiotherapy or chemotherapy, colitis associated with innate immune disorders such as leukocyte adhesion defect-I, chronic granulomatous disease, glycogen storage disease type 1b, Hermansky-Pudlak syndrome, Chediak-Higashi syndrome, and Wiskott-Aldrich syndrome. Syndrome, pouchitis following rectocolic resection and ileocolic 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 condition may be selected from inflammatory bowel disease (IBD) such as Crohn's disease or ulcerative colitis, psoriatic arthritis, and psoriasis.

[1619] In some implementations, the condition may be selected from inflammatory bowel disease (IBD) such as Crohn's disease or ulcerative colitis, as well as psoriasis.

[1620] In some implementations, the condition can be selected from inflammatory bowel disease (IBD) and psoriasis.

[1621] The object or patient can be an animal object or patient. The object or patient can be a human object or patient. Preferably, the object is a human object or patient.

[1622] dose

[1623] Typical doses of compounds used in the context of this invention may be from about 0.0001 to about 100 mg / kg body weight / day, for example from about 0.0005 to about 50 mg / kg body weight / day, for example from about 0.001 to about 10 mg / kg body weight / day, for example from about 0.01 to about 1 mg / kg body weight / day, administered in one or more doses (e.g., one to three doses). The precise dose used will depend in particular on: the nature and severity of the disease or condition to be treated; the sex, age, weight, and general condition of the person to be treated; any other possible concurrent diseases or conditions that are being treated or will be treated; and other factors known to a medical practitioner in the art.

[1624] The compounds described herein can be administered via any administration method common or standard in the art (e.g., oral, intravenous, intramuscular, subcutaneous, sublingual, intranasal, intradermal, suppository, or implantation). In a preferred embodiment of the invention described herein, administration is performed orally.

[1625] Example

[1626] The following embodiments illustrate certain specific implementations of the invention. Unless otherwise described in detail, the following embodiments are implemented using standard techniques well-known and conventional to those skilled in the art. It should be understood that these embodiments are for illustrative purposes only and are not intended to completely limit the conditions or scope of the invention. Therefore, they should not be construed as limiting the scope of the invention in any way.

[1627] Used for amino acids and specific R 2 The abbreviations for the functional groups can be found in Tables A through C in the definitions. Other abbreviations used in the examples include:

[1628] t BuOH tert-butanol

[1629] DODT2,2'-(ethylenedioxy)diethanethiol

[1630] Pd(PPh3)4 tetrakis(triphenylphosphine)palladium(0))

[1631] PhSiH3 phenylsilane

[1632] PyBOP Benzotriazole-1-yloxytripyrrolidinephosphide

[1633] hexafluorophosphate)

[1634] equiv. equivalent

[1635] rt room temperature

[1636] aq. aqueous solution

[1637] IL-23R Interleukin-23 Receptor

[1638] hIL-23R human interleukin-23 receptor

[1639] GI Gastrointestinal

[1640] SIF simulates intestinal fluid

[1641] SGF simulates gastric juice

[1642] NlucNanoBRET luciferase assay

[1643] SD standard deviation

[1644] %Eff percentage effectiveness

[1645] pSTAT3 phosphorylation signal transducers and transcriptional activators 3

[1646] BRET bioluminescent resonance energy transfer

[1647] TAMRA5'-Tetramethylrhodamine-5-formamide

[1648] The following examples are provided to illustrate certain embodiments of the present invention and are not intended to limit the scope of the invention.

[1649] Example 1: Synthesis of the compound

[1650] The following compounds, listed in Table 1-1, were synthesized.

[1651] Table 1-1: Synthesized Compounds

[1652]

[1653]

[1654]

[1655]

[1656]

[1657]

[1658]

[1659]

[1660]

[1661]

[1662]

[1663]

[1664]

[1665]

[1666]

[1667]

[1668]

[1669]

[1670]

[1671]

[1672]

[1673]

[1674]

[1675] A bridging amino acid residue is the amino acid residue immediately preceding the bracket below. The brackets indicate bridging amino acid residues. For example, [2,11] is a bridge between amino acid residues 2 and 11. Similarly, [2,7] is a bridge between amino acid residues 2 and 7, and [10,13] is a bridge between amino acid residues 10 and 13.

[1676] The bridges (1c), (6c), (6g), and (7c) use the α-amino group of the amino acid in the bridge (or the β-amino group for bLys, {d}bLys, and β-hLys, or the α-amino group for (N3)-K and {d}(N3)-K converted to an azide group).

[1677] The (1c), (6c), (6g), and (7c) bridges are indicated by the α-carboxylic acid group of the amino acid in the bridge.

[1678] (1c) represents a [2,11] lactam bridge; (6c) represents a [2,7] lactam bridge; (6g) represents a [2,7] 1,4-disubstituted 1,2,3-triazole bridge; (7c) represents a [10,13] lactam bridge.

[1679] The compound numbers in Table 1-1 correspond to the same numbers as SEQ ID NO., as shown in Table 1-1a below.

[1680] Table 1-1a: Serial ID numbers of the synthesized compounds from Table 1-1

[1681]

[1682]

[1683]

[1684]

[1685]

[1686]

[1687]

[1688]

[1689]

[1690]

[1691]

[1692] in:

[1693] The (1c), (6c), (6g), and (7c) bridges use the α-amino group of the amino acid in the bridge (or the β-amino group for bLys, {d}bLys, and β-hLys, or the α-amino group converted to an azide group for (N3)-K and {d}(N3)-K).

[1694] The (1c), (6c), (6g), and (7c) bridges are represented by the α-carboxylic acid group of the amino acid in the bridge.

[1695] (1c) represents a [2,11] lactam bridge; (6c) represents a [2,7] lactam bridge; (6g) represents a [2,7] 1,4-disubstituted 1,2,3-triazole bridge; (7c) represents a [10,13] lactam bridge.

[1696] For comparative purposes, three compounds with two 1,3-dithio-propane-2-one bridges from Kong et al., 2020 were synthesized (Tables 1-2).

[1697] Table 1-2: Synthetic compounds from Kong et al., 2020

[1698]

[1699] (1a) represents the [2,11] 1,3-dithio-propane-2-one bridge; (2a) represents the [4,7] 1,3-dithio-propane-2-one bridge; (4a) represents the [1,11] 1,3-dithio-propane-2-one bridge; (5a) represents the [4,9] 1,3-dithio-propane-2-one bridge.

[1700] In addition, two compounds with bridging cystathionine amino acid residues at [2,7] from Protagonist patent applications (compound C in WO 2016 / 011208, WO 2017 / 011820 and Sayago et al., 2018; and peptide 993 in WO2018 / 089693) were synthesized (Tables 1-3).

[1701] Table 1-3: Synthetic compounds from Protagonist patent applications

[1702]

[1703] (16i) represents the [2,7] thioether bridge. The combination of Abu at position X2, Cys at position X7, and the [2,7] thioether bridge forms a cystathionine as a bridging amino acid residue.

[1704] Other synthesized reference compounds are described in Tables 1-4. These reference compounds are disclosed in WO2023 / 099669.

[1705] Table 1-4: Reference Compounds for Synthesis

[1706]

[1707]

[1708] (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 This indicates that bridges (1c), (2a), and (2c) use peptide backbone amines or carboxylic acids at the N-terminus or C-terminus, rather than side chain amines or carboxylic acids.

[1709] Unless otherwise stated, the reagents and solvents used below are commercially available standard laboratory reagents or analytical grade reagents and are used without further purification.

[1710] Equipment and Synthesis Strategies

[1711] According to the solid-phase peptide synthesis procedure, peptides are synthesized in batches on a peptide synthesizer (e.g., a CEM Liberty Blue peptide synthesizer) using 9-fluorenylmethyloxycarbonyl (Fmoc) as the N-α-amino protecting group and suitable common protecting groups for side chain functional groups.

[1712] Resins such as TentaGel were used as polymer-based supports. TM The resin, which has been swollen in DMF before use, is loaded into the synthesizer.

[1713] Without making any changes to the general procedure, non-naturally occurring amino acids and other suitable building blocks were used.

[1714] Optical isomers of certain amino acids (including those not naturally occurring) are used in the synthesis of compounds and can be found in Tables A and B in the definition. Specific R 2 The definition of the functional group can be found in Table C of the definition.

[1715] Coupling on the CEM Liberty Blue Peptide Synthesizer

[1716] A solution of Fmoc-protected amino acids (4 equivalents) was added to the resin along with a coupling reagent solution (4 equivalents) and an alkaline solution (8 equivalents). The mixture was heated to 50°C using a microwave unit and coupled for 10 minutes, or coupled for 60 minutes without heating. During coupling, nitrogen was bubbled through the mixture.

[1717] In cases where coupling is difficult (e.g., coupling residues immediately following N-methylated amino acid residues or other sterically hindered amino acid residues, as recognized by those skilled in the art), the coupling may be repeated once or more.

[1718] Go to protect:

[1719] The Fmoc group is deprotected using piperidine in DMF or another suitable solvent. The deprotection solution is added to the reaction vessel and the mixture is heated for 5 minutes to approximately 50°C. After evacuating the reaction vessel, the resin is washed with DMF or another suitable solvent.

[1720] Lactam formation:

[1721] The following procedure for Glu and Lys coupling is representative of all lactam formation, where the amino acid side chains containing carboxyl functional groups are protected with Oall, and the amino acid side chains containing amino groups are alloc protected. After assembling the complete peptide sequence, Glu(Oall) and Lys(Alloc) are deprotected using PhSiH3 (10 equivalents) and Pd(PPh3)4 (0.05 equivalents) in DCM. Subsequently, lactam bridges are formed between the carboxylic acid side chain of Glu and the amine side chain of Lys using DIPEA (3.0 equivalents) and PyBOP (2 equivalents) in DMF. Both steps are performed using peptides still linked to the resin.

[1722] Similarly, peptides with lactams extending from the side chain to the N-terminal amine were prepared. After assembling the complete peptide sequence, the Fmoc protecting group of the N-terminal amine remained intact. As described, Glu(Oall) was deprotected using Pd(PPh3)4, followed by Fmoc deprotection (see the "Cleavage" section). Lactam bridges were similarly formed using PyBOP.

[1723] Cutting:

[1724] The dried peptide resin was treated with TFA and a suitable cleaning agent for approximately 2 hours. The volume of the filtrate was reduced, and the crude peptides were precipitated after the addition of diethyl ether. The crude peptide precipitate was washed several times with diethyl ether and finally dried.

[1725] HPLC purification of crude peptides:

[1726] Crude peptides were purified by preparative reversed-phase HPLC: Conventional HPLC equipment was used, such as a Gilson GX-281 with a 331 / 332 pump combination for binary gradient applications, equipped with a column (e.g., a 5 × 25 cm Gemini NX 5u C18110A column) and a fraction collector, using a flow rate of 20 to 40 ml / min at 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 combined and lyophilized. The final product was characterized by HPLC and MS.

[1727] Isoamino acids:

[1728] Peptides with different amino acids are synthesized using standard Fmoc SPPS with amino acid building blocks in which the protecting groups at the N-terminus and side chains are exchanged. Peptides with, for example, standard lysine are synthesized using the building block Fmoc-Lys(Boc)-OH, where Fmoc is the protecting group at the N-terminal amine and Boc is the protecting group at the side chain. Conversely, peptides with, for example, iso-Lys are therefore synthesized using the building block Boc-Lys(Fmoc)-OH instead of Fmoc-Lys(Boc)-OH. The coupling conditions for linking the building block to the peptide and the subsequent deprotection conditions for removing the Fmoc group are the same as those described in the standard Fmoc SPPS synthesis.

[1729] When modifying the side chains on the resin, the side chain protecting group "Boc" can be replaced by the "Alloc" protecting group.

[1730] Triazole formation:

[1731] The crude intermediate peptide was dissolved in H2O / t In a 2:1 (1 mg / mL) solution of BuOH, add 4.4 equivalents of CuSO4 5H2O and 4.4 equivalents of L-ascorbic acid (CAS 50-81-7). Protect the mixture from light and stir for 24 hours.

[1732] The solution was loaded directly onto a preparative HPLC column for final purification.

[1733] Analytical HPLC:

[1734] Final purity was determined using an analytical HPLC system (Agilent 1100 / 1200 series) equipped with an autosampler, degasser, 20 µl flow cell, and Chromeleon software. HPLC was operated at 40 °C with a flow rate of 1.2 mL / min using an analytical column (e.g., a Kinetex 2.6 µm XB-C18 100A 100 × 4.6 mm column). Compounds were detected and quantified at 215 nm. Buffer A (0.1% TFA, aqueous solution) and buffer B (0.1% TFA, 90% MeCN, aqueous solution) were used.

[1735] Mass spectrometry:

[1736] Final MS analysis was performed on a standard mass spectrometer (e.g., Waters Xevo G2 Tof) equipped with an electrospray detector with locked-in mass calibration and MassLynx software. Operation was performed in positive mode using direct injection and a cone voltage of 15 V (1 TOF), 30 V (2 TOF), or 45 V (3 TOF) as specified in the chromatogram. Accuracy was 5 ppm, while typical resolution ranged from 15,000 to 20,000.

[1737] Those skilled in the art will understand that standard methods of peptide synthesis can be used to produce the compounds of this invention.

[1738] Example 2: Structure-activity relationship (SAR) of compounds

[1739] The SARs of peptides I1 (isomer 3), I3 (isomer 3), I4 (isomer 3) and I5 (isomer 3) from Kong et al., 2020, and the SARs of compounds disclosed in WO2023 / 099669 are described in Example 2 of WO2023 / 099669, which is incorporated herein by reference.

[1740] As part of their further research into IL-23R inhibitors, the inventors identified a close proximity between the side chain at position 7 (Cys residue) and the N-terminal amino acid residue (Lys at position 2) in the NMR structure of Ref 18 (compound 18 of WO2023 / 099669). The sequence of Ref 18 is as follows:

[1741] Ref 18 amino acid sequence

[1742]

[1743] (1c) = [2,11] lactam bridge; (2a) = [4,7] 1,3-dithio-propane-2-one bridge.

[1744] Due to this close proximity, the inventors hypothesized that the [4,7] bridge could be replaced by a bridge between the side chain of the amino acid at position 7 and the N-terminal amine. This novel [2,7,11] scaffold consists of two bridges: one located at [2,11] (side chain to side chain) and another located at [2,7] (side chain to tail, i.e., side chain to N-terminus), as shown in compound 2:

[1745] Compound 2 amino acid sequence

[1746]

[1747] α = Y(2-aminoethoxy); β = 2-Me-Leu;

[1748] (1c) = [2,11] lactam bridge; (6c) = [2,7] lactam bridge;

[1749] This indicates that the (6c) bridge uses the α-amine of K in the bridge.

[1750] Experimental data show that changing the bridge from [2,11][4,7] (Ref 120 and Ref 155) to [2,7,11] and combining bridge optimization (compound 1 and compound 2) maintained the efficacy of inhibiting IL-23R, as shown in Table 2-1 below.

[1751] Table 2-1: IL-23R Inhibition of [2,11][4,7] Stents vs. [2,7,11] Stents

[1752]

[1753] γ = 4-aminomethyl-phenylacetyl;

[1754] (1c) = [2,11] lactam bridge; (2a) = [4,7] 1,3-dithio-propane-2-one bridge; (6c) = [2,7] lactam bridge;

[1755] This indicates that the (6c) bridge uses the α-amine of the amino acid in the bridge;

[1756] All other amino acid residues are the same in the above compounds.

[1757] The inventors observed that the bridge length between the 7th side chain and the 2nd N-terminus is most ideal when the 7th position is glutamic acid, relative to the case where the 7th position is aspartic acid (Table 2-2; compare compounds 1 and 3 and compounds 6 and 8).

[1758] Table 2-2: Glu vs Asp in the 7th position

[1759]

[1760] (1c) = [2,11] lactam bridge; (6c) = [2,7] lactam bridge;

[1761] This indicates that the (6c) bridge uses the α-amine of the amino acid in the bridge;

[1762] All other amino acid residues are the same in the above compounds.

[1763] The inventors determined that changing the C-terminus from "NH2" to "NHMe" maintained efficacy and improved SIF stability, as shown in Table 2-3:

[1764] Table 2-3: SIF and SGF data of NHMe at the C-end

[1765]

[1766] (1c) = [2,11] lactam bridge; (6c) = [2,7] lactam bridge;

[1767] This indicates that the (6c) bridge uses the α-amine of the amino acid in the bridge;

[1768] All other amino acid residues are the same in the above compounds.

[1769] The inventors also observed that SIF stability must be addressed by using certain amino acid residues (e.g., 2-Me-Leu) at position 10. Substituting glycine at position 10 results in a complete loss of SIF stability, thus leading to poor gastrointestinal stability of the resulting compounds (Tables 2-4).

[1770] Table 2-4: Stability loss of SIF by replacing the 10th position with glycine

[1771]

[1772] All other amino acid residues are the same in the above compounds.

[1773] SIF stability must also be addressed by using certain amino acid residues (e.g., Dab) at position 12. The amino acid residues at position 12 affect both potency and SIF stability. Therefore, only certain substitutions at position 12 can provide both good SIF stability and potency (Table 2-5).

[1774] Table 2-5: Effects of the 12th substitution on efficacy and SIF stability

[1775]

[1776] All other amino acid residues are the same in the above compounds.

[1777] However, unlike previously disclosed IL-23R inhibitors, this novel [2,7,11] scaffold allows the inventors to delete certain amino acid residues between positions 2 and 11 of the optimized [2,7,11] peptide without completely losing its potency. The inventors previously observed that such deletions in other scaffolds resulted in a complete loss of potency against IL-23R (see, for example, compounds Ref 5 (deletion at position 3), Ref 6 (deletion at position 6), and Ref 7 (deletion at position 10) in Example 3 of WO2023 / 099669).

[1778] It was found that the deletion of the amino acid residue at position 4 in the [4,7] bridge of the IL-23R inhibitor previously used in WO2023 / 099669 maintained the IL-23R inhibitory efficacy of some optimized [2,7,11] peptides (Tables 2-6).

[1779] Table 2-6: Missing at position 4

[1780]

[1781] (1c) = [2,11] lactam bridge; (6c) = [2,7] lactam bridge;

[1782] This indicates that the (6c) bridge uses the α-amine of the amino acid in the bridge;

[1783] All other amino acid residues are the same in the above compounds.

[1784] The deletion at position 4 is dependent on and only acceptable if specific substitutions are present at other positions of the peptide. Table 2-7 below illustrates the effects of combinations of substitutions, particularly at positions 2 and 3, with truncation at position 4. When a 3-aminopropionyl amino acid residue is introduced at position 3 (compound 45), the potency is improved relative to compound 36 (which has a Thr residue at position 3). Glycine can be introduced at position 3 and the potency is maintained, provided that a β-high-Lys substitution is also present at position 2 (compound 99). Substitution at position 3 affects the stability of the SIF. In the case of glycine at position 3, the SIF stability is lower than that of peptides with a 3-aminopropionyl group.

[1785] Table 2-7: The effects of substitutions at positions 2, 3, and 4

[1786]

[1787]

[1788] δ = 3-aminopropionyl; ε = β-high-Lys;

[1789] (1c) = [2,11] lactam bridge; (6c) = [2,7] lactam bridge;

[1790] This indicates that the (6c) bridge uses the α-amine of the amino acid in the bridge;

[1791] All other amino acid residues are the same in the above compounds.

[1792] Example 3: Biological assay

[1793] Example 3-1: Binding assay for estimating the binding affinity of a compound with human IL-23R

[1794] The binding affinity of a compound for IL-23R is estimated by the ability of the compound to replace a fluorophore-labeled reference compound on human IL-23R. The assay relies on a bioluminescence resonance energy transfer (BRET) between a fluorophore-labeled reference compound and the IL-23R moiety of a fusion protein composed of IL-23R fused with Nanoluc luciferase (Nanoluc). Nanoluc is located at the N-terminus and is very close to the ligand-binding domain. When the fluorophore of the fluorophore-labeled compound is very close to the Nanoluc of the fusion protein, bioluminescent energy generated by substrate conversion of Nanoluc is transferred to the fluorophore, leading to an increase in BRET. In the presence of an unlabeled compound, the unlabeled compound replaces 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 replaced by the unlabeled compound depends on the compound's affinity for IL-23R and is termed IC50. 50 concentration.

[1795] The fusion protein was generated using cDNA encoding mature human IL-23R (original accession number UniProtKB-Q5VWK5, amino acids 22 to 629) and a small adaptor sequence within a mammalian expression plasmid subcloning framework encoding a secretion signal and the Nanoluc protein (N1371, Promega). The 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% v / v FBS, 1% v / v VP / S, ​​1 mM sodium pyruvate, 1× NEAA, and 0.3 mg / mL hygromycin w / glutamine-I. The remaining cells were propagated and considered as merged clones stably expressing the Nluc-IL23R fusion protein.

[1796] Cells expressing the Nluc-IL23R fusion protein were expanded in growth medium, and membranes were prepared by homogenizing cell pellets from 18 T175 flasks (at 4°C in subsequent steps). The cell pellets were lysed with Tris 10 mM, 7.5, and 1 mM EDTA and a protease inhibitor (Complete, Roche), and homogenized using 15 mL glass dounce via 50 shocks. The homogenate was rotated at 1500 rpm for 10 min, and the supernatant was transferred to SV-34 tubes and rotated at 40,000 g for 20 min at 4°C to precipitate the crude membrane. 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.

[1797] The compound to be tested for binding with IL-23R was serially diluted in assay buffer (50 mM HEPES pH 7.4, 5 mM EGTA, 5 mM MgCl2, 0.005% Tween-20, and 0.05% casein) and added in 6.25 µL volumes along with 12.5 µL of a diluted membrane containing Nluc-IL23R fusion protein (0.42 µg / well) and 6.25 µL of a fluorescently labeled peptide to the wells of a white 384-well plate (Corning 3572) to a final concentration of 3.1 nM, also prepared in assay buffer. The plate was sealed with an opaque plate sealer and incubated at room temperature on an orbital shaker at 400 rpm for 2 hours. To determine the BRET ratio, the plate seal was removed and 25 µL of a 1:500 diluted Nanoluc substrate (Promega N1572) was added to each well and incubated on an orbital oscillator at 400 rpm for 1 to 2 minutes. The plate was then read using an Envision plate reader equipped with a luminescence mirror module (barcode 404) and filters corresponding to Nanoluc substrate luminescence (M470 filter; 470 nm, bandwidth 24 nm) and TAMRA fluorescence (M595p filter; 595 nm, bandwidth 60 nm). The BRET ratio was calculated from the fluorescence of TAMRA / nanoluc bioluminescence.

[1798] For data analysis, the BRET ratio was normalized relative to the BRET signal of a single 3.1 nM TAMRA-labeled peptide (without the addition of unlabeled compounds) and the BRET signal under complete replacement (by adding a very high concentration of unlabeled peptides). Compound potency (IC50) 50The maximum substitution (%) and the maximum substitution (%) were estimated using computer-aided curve fitting with a 4-parameter logistic (4PL) nonlinear model. The IC50 for each compound... 50 The maximum value was determined using computer-aided curve fitting of a 4-parameter logistic (4PL) nonlinear model. Compound potency (IC) 50 The data for IC and maximum displacement (% displacement) are shown in Table 3-1. Generally, a low IC is desirable. 50 Compounds. Generally, compounds with a high degree of substitution of the TAMRA-labeled peptide are desirable. Due to experimental errors in specific assays, a value equal to or greater than 90% is generally considered to indicate a fully TAMRA-labeled peptide.

[1799] In the previous application WO2023 / 099669, the data was used as the calculation of K. i Value provided. In this application, the inventors provide an IC. 50 The value of the data. The Cheng-Prussov equation will use K i With IC 50 The relationship between them can be described as: K i = IC 50 / (1+[L L ] / K dL ), where [L L [ ] represents the concentration of the labeled compound used, and K dL This is the equilibrium dissociation constant of the labeled compound (Cheng and Prusoff, 1973). To enable comparisons between numerical values, the inventors have determined the K values ​​of several compounds from WO2023 / 099669. i and IC 50 :

[1800] K of compounds in WO2023 / 099669 i and IC 50 value

[1801]

[1802]

[1803] The tested value = the estimated K during the measurement. i or IC 50 Higher than 1 µM

[1804] Table 3-1: IC 50 (hIL-23R binding) and % substitution (hIL-23R binding) data

[1805]

[1806]

[1807]

[1808]

[1809]

[1810]

[1811]

[1812] The tested value = the estimated IC during the measurement. 50 Higher than 1 µM

[1813] Example 3-2: Functional inhibition of IL-23-mediated STAT3 signaling by compounds

[1814] The ability of the compound to inhibit IL-23-mediated signaling was determined in the human-derived DB cell line (CRL-2289) (hereinafter referred to as DB cells), which endogenously expresses human IL-23R and human IL-12R β1 subunits. Upon binding to IL-23, IL-23R and IL-12R β1 together form a heterodimeric signaling complex, which promotes the phosphorylation of STAT3 via the JAK2 / STAT3 pathway to form phosphorylated STAT3. In this assay, the functional antagonism of the compound on IL-23-mediated phosphorylated STAT3 formation in DB cells was quantified using a reagent capable of measuring the phosphorylation status of STAT3 at Tyr705 in the form of a phosphorylated STAT3 (Tyr705) MSD (Meso Scale Discovery) kit.

[1815] This assay was used to quantify the functional antagonistic effects of compounds and to rank the inhibitory compounds according to their potency. For compounds tested in this assay, the response was normalized relative to a control value to calculate the IC50 based on the concentration-response curve of the compound in the presence of a fixed concentration of human IL-23. 50 And the maximum suppression response.

[1816] The assay procedure was as follows. DB cells were maintained in a growth medium consisting of RPMI-1640 [Invitrogen 61870-010] supplemented with 10% v / v fetal bovine serum (FBS) [(heat-inactivated), Invitrogen 10270-106] and 1% v / v penicillin-strep solution [Invitrogen 15140]. On the day of assay, cells were resuspended in assay buffer consisting of RPMI-1640 [Invitrogen 61870-010] supplemented with 0.1% w / v BSA [Sigma-Aldrich A9430] until a density of 7.5 × 10⁻⁶ cells / mL was reached. 6 Cells / mL. The compound to be tested for inhibiting hIL-23-mediated signaling was serially diluted to a final concentration of 3× in assay buffer. A 3× EC value was also prepared in the assay buffer. 80 hIL-23 (1.7 nM) solution. To initiate the assay, 20 µL of DB cell suspension (corresponding to 150,000 cells / well) was added to the wells of a 96-well V-bottom polypropylene plate [Corning 3363], followed by 3 × 20 µL of diluted test compound added to individual wells. After pre-incubating DB cells with the inhibitor in a cell culture incubator (37°C, 5% CO2) for 15 minutes, 20 µL of the prepared 3 × EC solution was added. 80 hIL-23 solution was added to each well and incubated in a cell culture incubator (37°C, 5% CO2) for 90 minutes. For some wells, buffer alone or only the solution with EC was added. 80 Corresponding IL-23 was used to obtain the readout required for normalization. To terminate the assay, the plate was rotated at 1000 G 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 number K150SVD, Mesoscale) was added to the cell pellet. To completely lyse the cells and release phosphorylated STAT3 for detection, the foil-sealed plate was shaken at room temperature for 10 minutes (500 rpm) and incubated at -80°C for at least 15 minutes. The level of phosphorylated STAT3 in the cell lysate from individual wells was determined using the MSD STAT3 kit (catalog number K150SVD, Mesoscale) and read on a MesoQuickPlex SQ 120 plate reader (Mesoscale).

[1817] For data analysis, the raw data count from the Meso QuickPlex SQ 120 board reader is compared to the EC. 80 The response of hIL-23 alone (without added compound) was normalized to buffer levels. Compound potency (IC50) 50 The compound potency (IC) and maximum inhibition response (inhibition %) were estimated using computer-aided curve fitting of a 4-parameter logistic (4PL) nonlinear model. 50 The data for IC and the maximum suppression response (% permutation) are shown in Table 3-2. 50 The lower the IC50 value, the more effective the compound. Generally speaking, a low IC50 value is desirable. 50 Compounds that can completely suppress IL23-induced responses are generally desired. Due to experimental error, a value equal to or greater than 95% is considered to completely suppress IL23R-induced signaling.

[1818] Table 3-2: IC50 of hIL-23 (pSTAT3) antagonists 50 and inhibition%

[1819]

[1820]

[1821]

[1822] The tested value = the estimated IC during the measurement. 50 Higher than 1 µM

[1823] Examples 3-3 and 3-4: Determination of peptide stability in simulated gastric juice (SGF) and simulated intestinal juice (SIF)

[1824] SGF and SIF were prepared according to the United States Pharmacopeia (USP) specifications (test solutions, USP 35, NF 30, 2012). SGF was prepared by dissolving 0.2 g of sodium chloride in 50 mL of water. 0.7 mL of 10 M HCl was added to adjust the pH to 1.2, and the volume was brought to 100 mL with water. 64 mg of porcine pepsin (P7125, Sigma-Aldrich) was immediately gently dissolved in 20 mL of preheated (37°C) solution (3.2 g / L) and incubated. SIF was prepared by dissolving 0.68 g of potassium dihydrogen phosphate in 50 mL of water and adjusting the pH to 6.8 with 1 M NaOH. The volume was then brought to 100 mL with water. 200 mg of porcine pancreatin (P1625, Sigma-Aldrich) was immediately gently dissolved in 20 mL of preheated (37°C) solution (10 g / L) and incubated.

[1825] To initiate incubation, 20 µL of a peptide stock solution in 50% v / v isopropanol was deposited at the bottom of the well plate, and 580 µL of matrix solution was added to obtain a final substrate concentration of 10 µM. Incubation was performed at 37 °C with gentle shaking. At 0, 1, and 4 hours, 70 µL aliquots were removed and quenched in 210 µL of ice-cold precipitant solution (95% v / v acetonitrile and 0.1% v / v formic acid). After the last time point, the sample plate was mixed on a shaker for 10 min and centrifuged at 2200 g for 10 min. The resulting 70 µL supernatant was diluted with 150 µL of water, mixed, centrifuged, and analyzed by high-resolution liquid chromatography-mass spectrometry. A zero sample was re-injected after the 4-hour sample to confirm that no instrument sensitivity drift occurred during the run. The percentage of remaining sample at each time point relative to time point zero was calculated based on the absolute peak area.

[1826] In vitro SIF results (expressed as the percentage of peptide remaining after a specified time period) are summarized in Table 3-3 below. Compounds with SIF stability (after 4 hours) greater than 70% are considered highly SIF stable. Compounds with SIF stability (after 4 hours) between 30% and 70% (inclusive) are considered moderately SIF stable. Compounds with SIF stability (after 4 hours) less than 30% are considered SIF unstable. SIF stability values ​​greater than 100% are due to assay uncertainty and indicate that the compound has not degraded. Preferred compounds are those exhibiting minimal to no degradation, i.e., compounds with high (at least 70%) SIF stability, preferably close to 100% SGF stability.

[1827] Table 3-3: SIF Data

[1828]

[1829]

[1830]

[1831]

[1832] In vitro SGF results (expressed as the percentage of peptide remaining after a specified time period) are summarized in Tables 3-4 below. Compounds with SGF stability (after 4 hours) greater than 70% are considered highly SGF stable. Compounds with SGF stability (after 4 hours) between 30% and 70% (inclusive) are considered moderately SGF stable. Compounds with SGF stability (after 4 hours) less than 30% are considered SGF unstable. SGF stability values ​​greater than 100% are due to assay uncertainty and indicate that the compound has not degraded. Preferred compounds are those exhibiting minimal to no degradation, i.e., high (at least 70%) SGF stability, preferably close to 100% SGF stability.

[1833] Table 3-4: SGF Data

[1834]

[1835]

[1836]

[1837] Examples 3-5: Functional inhibition of IL-23-mediated IFN-γ secretion by IL-23R inhibitor compounds

[1838] The ability of IL23-R inhibitor compounds to inhibit IL-23-mediated IFN-γ secretion was evaluated using an in vitro human whole blood assay. This assay quantifies the functional antagonistic effect of IL23R inhibitors and can be used to rank inhibitor efficacy based on generated concentration response curves (CRCs) in the presence of fixed concentrations of IL-23, IL-2, and IL-18. 50 The maximum suppression response can be calculated from the curve.

[1839] The measurement procedure is as follows.

[1840] On the day of the experiment, human blood was obtained from a volunteer donor at Blodbanken Hvidovre Hospital in Denmark by collecting blood in a BD Sodium-Heparin Vacutainer tube [catalog number 367876, Avantor].

[1841] The buffer used consisted of the following (hereinafter referred to as the assay buffer): RPMI-1640 [catalog number 61870-010; Thermo Fisher Scientific], supplemented with 1% v / v penicillin-strepmycin (Pen-Strep) solution [catalog number 15140; Thermo Fisher Scientific] and 1 mM sodium pyruvate [catalog number 11360-039, Thermo Fisher Scientific], 25 mM HEPES buffer [catalog number 15630-056, Thermo Fisher Scientific], and 0.05% v / v casein [catalog number C4765, Sigma-Aldrich]. On the day of assay, the compound to be tested that inhibits hIL-23-mediated signal transduction was serially diluted in the assay buffer to 4× the final concentration. A stimulation solution of hIL-23 [catalog number 11349-IL; R&D system] was also prepared in the assay buffer along with 4× hIL-2 [catalog number BT-002; R&D system] (40 ng / ml) and 4× hIL-18 [catalog number 9124-IL; R&D system] (80 ng / ml), wherein the hIL-23 [catalog number 11349-IL; R&D system] corresponds to 4× EC80 hIL-23 (1.6 ng / ml). To initiate the assay, 25 µL of the prepared 4× diluted test compound was added to the wells of a 96-well plate [catalog number 167425; Thermo Scientific], followed by 50 µL of human whole blood added to each well. After pre-incubating blood and inhibitors in a cell culture incubator (37°C, 5% CO2) for 15 minutes, 25 µL of the prepared 4× stimulation solution was added to each well, and the cells were incubated in a humidity chamber in a cell culture incubator (37°C, 5% CO2) for 16 to 24 hours.

[1842] To terminate the assay, 100 µL of pH 7.4 PBS [catalog number 10010-015; Thermo Fisher Scientific] was added to each well, and the plate was rotated at 350 × G for 10 minutes to precipitate the blood. The supernatant was removed using an 8-channel manual pipette and added to a 96-well V-bottom polypropylene plate [Coning 3363].

[1843] The sample was further diluted 30× in diluent 57 buffer from the MSD U-PLEX Human IFN-γ assay [catalog number K151TTK-2; Mesoscale Discovery].

[1844] The IFN-γ level in the supernatant from a single well was determined using the MSD U-PLEX Human IFN-γ Assay Kit [Catalog No. K151TTK-2; Mesoscale Discovery] and read on a Meso QuickPlex SQ 120 plate reader (Mesoscale Discovery).

[1845] For data analysis, the 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 (IC50) was estimated using computer-aided curve fitting in a 4-parameter logistic (4PL) nonlinear mode. 50 The IC50 value of a test compound is the concentration at which it achieves 50% of its maximum inhibition in response to an hIL-23 agonist (under specific conditions – indicated here above in the presence of hIL-2 and hIL-18). Maximum inhibition is expressed as a percentage, where 0% is the activity level induced solely by a reference agonist (hIL23R, as indicated above, in combination with IL-2 and IL-18), and 100% is the baseline activity level of the unstimulated receptor in the absence of a reference agonist.

[1846] Compound potency (IC) of five individual compounds of the present invention 50 The data for ) and maximum inhibition (%) are shown in Table 3-5.

[1847] Generally speaking, low IC is expected. 50 Compounds that can completely inhibit the IL23-induced response are generally desired.

[1848] Table 3-5: Compound potency (IC50) 50 ) and maximum inhibition (%)

[1849]

[1850]

[1851] References

[1852]

[1853] Terms and Conditions

[1854] 1. A compound of the following formula, or a pharmaceutically acceptable salt or solvate thereof:

[1855] ZR 2

[1856] in

[1857] R2 It is NHR 3 Or C(=O)R 3 , where R 3 It is a C-type carbon with hydrogen or optionally substituted with a pyridyl ring. 1-6 Alkyl groups, or none at all; and

[1858] Z is the amino acid sequence of formula I:

[1859]

[1860] in

[1861] X2 is selected from Lys, D-Lys, iso-Lys, β-Lys, D-β-Lys, high-Lys, D-high-Lys, β-high-Lys, N-Me-Lys, Dab, D-Dab, iso-Dab, Glu, iso-Glu, D-iso-Glu, Orn, D-Orn, Dpr, Lys(Gly), (N3)-Lys, and D-(N3)-Lys;

[1862] X3 is selected from Thr, Ile, 3-aminopropionyl, 4-aminobutyryl, β-high-Ile, β-high-Thr, Gly, N-Me-3-aminopropionyl, and Ser, or may not exist;

[1863] X4 is Val, or it does not exist;

[1864] X5 is selected from Trp, 1-Me-Trp, and β-high-Trp;

[1865] X6 is Gln;

[1866] X7 is selected from Glu, D-Glu, High-Glu, Asp, Pra and Hpg;

[1867] X8 is selected from Y(2-aminoethoxy), Y(Me), Y(nPr), Y(Bn), Trp, D-Phe, 2-Me-Phe, F(4-Me), F(4-Bu), 3-(2-pyridyl)-Ala, 3-(3-pyridyl)-Ala, 3-(4-pyridyl)-Ala and cyclopropyl-Ala;

[1868] X9 is 2-Nal or cyclopropyl-Ala;

[1869] X10 is selected from 2-Me-Leu, 2-Me-Val, Dab, Gly, Lys and Aib;

[1870] X11 is selected from Glu, high-Glu, β-high-Glu, Dab, iso-Dab, Lys, Lys(Me), Orn and 2-amino-6-carboxyhexanoyl;

[1871] X12 is selected from Dab, His, D-His, His(1-Me), 3-(2-pyridyl)-Ala, 3-(3-pyridyl)-Ala, 3-(4-pyridyl)-Ala, 3-(3-quinolinyl)-Ala, Gly, Pro, 5-aminopentanoyl, 4-aminopiperidine-4-carbonyl, (R,S)-imidazolidine-2-carbonyl, and Lys, wherein the side chain -NH2 of Lys is replaced by -C(=O)(CH2). n R K Replace, where n is 0 to 2 and R K It is an imidazole, pyrimidin, or pyridinyl group optionally substituted with F, or X12 is absent; and

[1872] X13 is selected from 3-(3-pyridinyl)-Ala, D-3-(3-pyrimidinyl)-Ala and 3-(3,5-pyrimidinyl)-Ala, or is not present;

[1873] in

[1874] (i) X2 and X11 are amino acid residues that together form a lactam bridge;

[1875] (ii) X2 and X7 are amino acid residues that together form a lactam bridge or a bridge containing a triazole ring; and

[1876] (iii) Optionally, when X13 is present, X10 and X13 are amino acid residues that together form a lactam bridge.

[1877] 2. The compound according to Clause 1, or its pharmaceutically acceptable salt or solvate, wherein:

[1878] ZR 2

[1879] in

[1880] R 2 It is NHR 3 , where R 3 It is a C-type carbon with hydrogen or optionally substituted with a pyridyl ring. 1-6 Alkyl groups, or none at all; and

[1881] Z is the amino acid sequence of formula Ia:

[1882]

[1883] in

[1884] X2 is selected from Lys, D-Lys, iso-Lys, β-Lys, D-β-Lis, high-Lys, D-high-Lys, β-high-Lys, N-Me-Lys, Dab, D-Dab, Glu, iso-Glu, Orn, D-Orn, Lys(Gly), (N3)-Lys, and D-(N3)-Lys;

[1885] X3 is selected from Thr, Ile, 3-aminopropionyl, 4-aminobutyryl, β-high-Ile, β-high-Thr, Gly, and N-Me-3-aminopropionyl, or it may not exist;

[1886] X4 is Val, or it does not exist;

[1887] X5 is either Trp or 1-Me-Trp;

[1888] X6 is Gln;

[1889] X7 is selected from Glu, High-Glu, Asp, Pra, and Hpg;

[1890] X8 is selected from Y(2-aminoethoxy), Y(Me), Y(Bn), F(4-Me), F(4-Bu) and cyclopropyl-Ala;

[1891] X9 is 2-Nal;

[1892] X10 is selected from 2-Me-Leu, 2-Me-Val, Dab, Gly, and Aib;

[1893] X11 is selected from Glu, high-Glu, Lys, Lys(Me), Orn and 2-amino-6-carboxyhexanoyl;

[1894] X12 is selected from Dab, His, D-His, His(1-Me), 3-(3-quinolinyl)-Ala, and 4-aminopiperidine-4-carbonyl; and

[1895] X13 is 3-(3-pyridinyl)-Ala, 3-(3,5-pyrimidinyl)-Ala, or it is not present;

[1896] in

[1897] (i) X2 and X11 are amino acid residues that together form a lactam bridge;

[1898] (ii) X2 and X7 are amino acid residues that together form a lactam bridge or a bridge containing a triazole ring; and

[1899] (iii) Optionally, when X13 is present, X10 and X13 are amino acid residues that together form a lactam bridge;

[1900] 3. The compound according to clause 1 or 2, wherein the lactam bridge between X2 and X11 uses the side chain of the amino acid residue at X2, and the bridge between X2 and X7 uses the N-terminus of the amino acid residue at X2.

[1901] 4. The compound according to any one of the preceding clauses, wherein X2 is Lys.

[1902] 5. The compound according to any one of the preceding clauses, wherein X3 is selected from Thr, Ile and 3-aminopropionyl, or is absent.

[1903] 6. The compound according to any one of the preceding clauses, wherein X4 is absent.

[1904] 7. The compound according to any one of the preceding clauses, wherein X5 is Trp.

[1905] 8. The compound according to any one of the preceding clauses, wherein X7 is Glu.

[1906] 9. The compound according to any one of the preceding clauses, wherein X8 is Y (2-aminoethoxy), Y (Me) or F (4-Me).

[1907] 10. The compound according to Clause 8, wherein X8 is Y (2-aminoethoxy).

[1908] 11. The compound according to any one of the preceding clauses, wherein X9 is 2-Nal.

[1909] 12. The compound according to any one of the preceding clauses, wherein X10 is 2-Me-Leu or 2-Me-Val.

[1910] 13. The compound according to Clause 11, wherein X10 is 2-Me-Leu.

[1911] 14. The compound according to any one of the preceding clauses, wherein X11 is Glu.

[1912] 15. The compound according to any one of the preceding clauses, wherein X12 is Dab.

[1913] 16. The compound according to any one of the preceding clauses, wherein X13 is 3-(3-pyridyl)-Ala, or is absent.

[1914] 17. The compound according to Clause 16, wherein X13 is 3-(3-pyridyl)-Ala.

[1915] 18. The compound according to any one of the preceding clauses, wherein R2 It is NHR 3 , where R 3 Is it hydrogen or C? 1-6 alkyl.

[1916] 19. The compound according to Clause 18, wherein R 2 It is NH2.

[1917] 20. The compound according to Clause 18, wherein R 2 It is NHMe.

[1918] 21. The compound according to any one of the preceding clauses, wherein X2 is Lys; X5 is Trp; X9 is 2-Nal; and X10 is 2-Me-Leu.

[1919] 22. The compound according to any one of the preceding clauses, wherein X2 is Lys; X5 is Trp; X9 is 2-Nal; X10 is 2-Me-Leu; and R 2 It is NH2 or NHMe.

[1920] 23. The compound according to any one of the preceding clauses, wherein X2 is Lys; X5 is Trp; X9 is 2-Nal; X10 is 2-Me-Leu; X13 is 3-(3-pyridyl)-Ala, or is absent, and R 2 It is NH2 or NHMe.

[1921] 24. A compound according to any one of the preceding clauses, wherein X2 is Lys; X5 is Trp; X7 is Glu; X9 is 2-Nal; X10 is 2-Me-Leu; X13 is 3-(3-pyridyl)-Ala, or is absent, and R 2 It is NH2 or NHMe.

[1922] 25. The compound according to Clause 1, wherein Z is an amino acid sequence selected from the sequences listed in Table 1-1a.

[1923] 26. The compound described in Clause 1 is selected from the compounds in Table 1-1, or pharmaceutically acceptable salts or solvates thereof.

[1924] 27. A pharmaceutical composition comprising a combination of a compound according to any one of the preceding clauses with a pharmaceutically acceptable carrier, excipient or loading agent.

[1925] 28. A method for synthesizing a compound according to any one of clauses 1 to 26, comprising synthesizing an analogue by a solid-phase or liquid-phase peptide synthesis method, optionally isolating and / or purifying the final product, and optionally further comprising the step of forming an amide bond between amino acid residues at the X2 and X11 positions, and optionally further comprising the step of forming an amide bond or forming a triazole between amino acid residues at the X2 and X7 positions, and optionally further comprising the step of forming an amide bond between amino acid residues at the X10 and X13 positions.

[1926] 29. The compound according to any one of Clauses 1 to 26 or the pharmaceutical composition according to Clause 27, used in a method of medical treatment.

[1927] 30. The compound according to any one of Clauses 1 to 26 or the pharmaceutical composition according to Clause 27, in a method of preventing or treating inflammatory bowel disease (IBD), Crohn's disease, ulcerative colitis, and psoriasis.

[1928] 31. A compound or pharmaceutical composition used according to Clause 30, wherein the compound or pharmaceutical composition is used for the prevention or treatment of inflammatory bowel disease (IBD) and / or psoriasis.

[1929] 32. Use of any compound according to any one of Clauses 1 to 26 or of any pharmaceutical composition according to Clause 27 in the preparation of a medicament for the prevention or treatment of inflammatory bowel disease (IBD) such as Crohn's disease or ulcerative colitis, psoriatic arthritis and psoriasis.

[1930] 33. Use of the compound or pharmaceutical composition described in Clause 32, wherein the use of said compound or pharmaceutical composition is in the preparation of a medicament for the prevention or treatment of inflammatory bowel disease (IBD) and / or psoriasis.

[1931] 34. A method of preventing or treating inflammatory bowel disease (IBD) such as Crohn's disease or ulcerative colitis, psoriatic arthritis and psoriasis, comprising administering to a subject a therapeutically effective amount of a compound according to any one of clauses 1 to 26 or a pharmaceutical composition according to clause 27.

[1932] 35. The prevention or treatment method described in Clause 34, wherein the prevention or treatment method is used for inflammatory bowel disease (IBD) and / or psoriasis.

[1933] 36. The pharmaceutical composition according to Clause 27, wherein the pharmaceutical composition is for oral administration.

Claims

1. A compound of the following formula, or a pharmaceutically acceptable salt or solvate thereof: Z-R 2 in R 2 It is NHR 3 Or C(=O)R 3 , where R 3 It is a C that is hydrogen or optionally substituted with a pyridine ring. 1-6 Alkyl groups, or those that are not present; and Z is the amino acid sequence of formula I: in X2 is selected from Lys, D-lys, iso-Lys, D-iso-Lys, β-Lys, D-β-Lys, homo-Lys, D-homo-Lys, β-homo-Lys, N-Me-Lys, N-Me-homo-Lys, (N3)-Lys, D-(N3)-Lys, (N3)-β-Lys, (N3)-D-β-Lys, (N3)-high-Lys, (N3)-D-high-Lys, (N3)-β-high-Lys, Dpr, D-Dpr, iso-Dpr, D-iso-Dpr, β-Dpr, D-β-Dpr, high-Dpr, D-high-Dpr, β-high-Dpr, N-Me-Dpr, N-Me-high-Dpr, (N3)-Dpr, D-(N3)-Dpr, (N3)-β-Dpr, (N3)-D-β-Dpr, (N3)-high-Dpr, (N3)-D-high-Dpr, (N3)-β-high-Dpr, Dab, D-Dab, iso-Dab, D-iso-Dab, β-Dab, D-β-Dab, homo-Dab, D-homo-Dab, β-homo-Dab, N-Me-Dab, N-Me-homo-Dab, (N3)-Dab, D-(N3)-Dab, (N3)-β-Dab, (N3)-D-β-Dab, (N3)-high-Dab, (N3)-D-high-Dab, (N3)-β-high-Dab, Orn, D-Orn, Different-Orn, D-Different-Orn, β-Orn, D-β-Orn, High-Orn, D-High-Orn, β-High-Orn, N-Me-Orn, N-Me-High-Orn, (N3)-Orn, D-(N3)-Orn, (N3)-β-Orn, (N3)-D-β-Orn, (N3)-High-Orn, (N3)-D-High-Orn, (N3)-β-High-Orn Lys(Gly), Asp, D-Asp, iso-Asp, D-iso-Asp, β-Asp, D-β-Asp, homo-Asp, D-homo-Asp, β-homo-Asp, N-Me-Asp, N-Me-homo-Asp, (N3)-Asp, D-(N3)-Asp, (N3)-β-Asp, (N3)-D-β-Asp, (N3)-high-Asp, (N3)-D-high-Asp, (N3)-β-high-Asp, Glu, D-Glu, iso-Glu, D-iso-Glu, β-Glu, D-β-Glu, homo-Glu, D-homo-Glu, β-homo-Glu, N-Me-Glu, N-Me-homo-Glu, (N3)-Glu, D-(N3)-Glu, (N3)-β-Glu, (N3)-D-β-Glu, (N3)-ho-Glu, (N3)-D-ho-Glu, (N3)-β-ho-Glu, 2-Amino-6-carboxyhexanoyl and 3-aminopropionyl; X3 is selected from any amino acid, ω-hydroxy-C 2-6 Alkyl acids may not exist; X4 is selected from Val, D-Val, β-Val, D-β-Val, Homo-Val, D-homo-Val, β-homo-Val, N-Me-Val, N-Me-ho-Val, 2-Me-Val, Ala, D-Ala, β-Ala, D-β-Ala, Homo-Ala, D-homo-Ala, β-homo-Ala, N-Me-Ala, N-Me-homo-Ala, Gly, β-Gly, homo-Gly, β-homo-Gly, N-Me-Gly, N-Me-homo-Gly, Leu, D-Leu, β-Leu, D-β-Leu, high-Leu, D-high-Leu, β-high-Leu, N-Me-Leu, N-Me-high-Leu, 2-Me-Leu, Ile, D-Ile, β-Ile, D-β-Ile, high-Ile, D-high-Ile, β-high-Ile, N-Me-Ile, N-Me-high-Ile or do not exist; X5 is selected from optionally substituted tryptophan residues, optionally substituted azatryptophan residues, and optionally substituted β-homotraphan residues; X6 is selected from optionally substituted Gln residues, optionally substituted Lys residues, optionally substituted Arg residues, optionally substituted Dab residues, optionally substituted Orn residues, optionally substituted Phe residues, Ala, D-Ala, β-Ala, D-β-Ala, high-Ala, D-high-Ala, β-high-Ala, N-Me-Ala, N-Me-high-Ala, Cit, D-Cit, β-Cit, D-β-Cit, high-Cit, D-high-Cit, β-high-Cit, N-Me-Cit, N-Me-high-Cit, Glu, D-Glu, iso-Glu, D-iso-Glu, β-Glu, D-β-G lu, Homo-Glu, D-homo-Glu, β-homo-Glu, N-Me-Glu, N-Me-ho-Glu, Tyr, D-Tyr, β-Tyr, D-β-Tyr, Homo-Tyr, D-homo-Tyr, β-homo-Tyr, N-Me-Tyr, N-Me-homo-Tyr, Val, D-Val, β-Val, D-β-Val, Homo-Val, D-homo-Val, β-homo-Val, N-Me-Val, N-Me-homo-Val or His, D-His, β-His, D-β-His, homo-His, D-homo-His, β-homo-His, N-Me-His, and N-Me-homo-His; X7 is selected from Asp, D-Asp, hetero-Asp, D-heterogeneous-Asp, β-Asp, D-β-Asp, high-Asp, D-high-Asp, β-high-Asp, N-Me-Asp, N-Me-high-Asp. Glu, D-Glu, iso-Glu, D-iso-Glu, β-Glu, D-β-Glu, homo-Glu, D-homo-Glu, β-homo-Glu, N-Me-Glu, N-Me-homo-Glu, Dab, D-Dab, iso-Dab, D-iso-Dab, β-Dab, D-β-Dab, homo-Dab, D-homo-Dab, β-homo-Dab, N-Me-Dab, N-Me-homo-Dab, Orn, D-Orn, Different-Orn, D-Different-Orn, β-Orn, D-β-Orn, High-Orn, D-High-Orn, β-High-Orn, N-Me-Orn, N-Me-High-Orn Lys, D-Lys, iso-Lys, β-Lys, D-iso-Lys, D-β-Lys, homo-Lys, D-homo-Lys, β-homo-Lys, N-Me-Lys, N-Me-homo-Lys, Pra, D-Pra, β-Pra, D-β-Pra, high-Pra, D-high-Pra, β-high-Pra, N-Me-Pra, N-Me-high-Pra, Hpg, D-Hpg, β-Hpg, D-β-Hpg, high-Hpg, D-high-Hpg, β-high-Hpg, N-Me-Hpg, and N-Me-high-Hpg; X8 is selected from optionally substituted tryptophan residues, optionally substituted azatryptophan residues, optionally substituted β-homotrapetin residues, optionally substituted tyrosine residues, optionally substituted phenylalanine residues, optionally substituted homophenylalanine residues, and alanine residues substituted with a carbocyclic group or an aromatic or heteroaromatic group, wherein the aromatic or heteroaromatic group is selected from phenyl, pyridyl, naphthyl, and quinolinyl, each optionally substituted. X9 is selected from optionally substituted tryptophan residues, optionally substituted azatryptophan residues, optionally substituted alanine residues, optionally substituted phenylalanine residues, and optionally substituted tyrosine residues. X10 is selected from, Val, D-Val, β-Val, D-β-Val, Homo-Val, D-homo-Val, β-homo-Val, N-Me-Val, N-Me-homo-Val, 2-Me-Val, Gly, β-Gly, homo-Gly, β-homo-Gly, N-Me-Gly, N-Me-homo-Gly, Dab, D-Dab, iso-Dab, D-iso-Dab, β-Dab, D-β-Dab, homo-Dab, D-homo-Dab, β-homo-Dab, N-Me-Dab, N-Me-homo-Dab, Lys, D-lys, iso-Lys, D-iso-Lys, β-Lys, D-β-Lys, homo-Lys, D-homo-Lys, β-homo-Lys, N-Me-Lys, N-Me-homo-Lys, Aib, D-Aib, β-Aib, D-β-Aib, Homo-Aib, D-homo-Aib, β-homo-Aib, N-Me-Aib, N-Me-ho-Aib, Ala, D-Ala, β-Ala, D-β-Ala, Homo-Ala, D-homo-Ala, β-homo-Ala, N-Me-Ala, N-Me-homo-Ala, Leu, D-Leu, β-Leu, D-β-Leu, high-Leu, D-high-Leu, β-high-Leu, N-Me-Leu, N-Me-high-Leu, 2-Me-Leu, Ile, D-Ile, β-Ile, D-β-Ile, high-Ile, D-high-Ile, β-high-Ile, N-Me-Ile, N-Me-high-Ile, And carbocyclic or heterocyclic rings with amino and carbonyl substituents; X11 is selected from: Dpr, D-Dpr, iso-Dpr, D-iso-Dpr, β-Dpr, D-β-Dpr, high-Dpr, D-high-Dpr, β-high-Dpr, N-Me-Dpr, N-Me-high-Dpr, Dab, D-Dab, iso-Dab, D-iso-Dab, β-Dab, D-β-Dab, homo-Dab, D-homo-Dab, β-homo-Dab, N-Me-Dab, N-Me-homo-Dab, Orn, D-Orn, Different-Orn, D-Different-Orn, β-Orn, D-β-Orn, High-Orn, D-High-Orn, β-High-Orn, N-Me-Orn, N-Me-High-Orn Lys, D-lys, iso-Lys, D-iso-Lys, β-Lys, D-β-Lys, homo-Lys, D-homo-Lys, β-homo-Lys, N-Me-Lys, N-Me-homo-Lys, Lys(Me), Lys(Gly), Asp, D-Asp, hetero-Asp, D-heterogeneous-Asp, β-Asp, D-β-Asp, high-Asp, D-high-Asp, β-high-Asp, N-Me-Asp, N-Me-high-Asp Glu, D-Glu, iso-Glu, D-iso-Glu, β-Glu, D-β-Glu, homo-Glu, D-homo-Glu, β-homo-Glu, N-Me-Glu, N-Me-homo-Glu, and 2-Amino-6-carboxyhexanoyl; X12 is selected from: optionally substituted Phe residues; optionally substituted Tyr residues; optionally substituted His residues; alanine residues substituted with a carbocyclic group or an aromatic or heteroaromatic group selected from phenyl, pyridyl, naphthyl, and quinolinyl, each optionally substituted; Dab, D-Dab, iso-Dab, D-iso-Dab, β-Dab, D-β-Dab, high-Dab, D-high-Dab, β-high-Dab, N-Me-Dab, N-Me-high-Dab, Gly, β-Gly, high-Gly, β-high-Gly, N-Me-Gly, N-Me-high-Gly, Pro, 5-aminopentanoyl, 4-aminopiperidin-4-carbonyl, (R,S)-imidazolidine-2-carbonyl, 3-aminopropionyl, Gly-CF3, D-Gly-CF3, Nle, Gln, D -Gln, iso-Gln, D-iso-Gln, β-Gln, D-β-Gln, homo-Gln, D-homo-Gln, β-homo-Gln, N-Me-Gln, N-Me-homo-Gln ,THP,Ser,D-Ser,β-Ser,D-β-Ser,high-Ser,D-high-Ser,β-high-Ser,N-Me-Ser,N-Me-high-Ser,Ser( OMe), 3-aminotetrahydrofuran-3-carbonyl, Arg, D-Arg, β-Arg, D-β-Arg, high-Arg, D-high-Arg, β-high-Arg, N-Me-Arg, N-Me-high-Arg, Thr, D-Thr, β-Thr, D-β-Thr, high-Thr, D-high-Thr, β-high-Thr, N-Me-Thr, N-Me-high-Thr Glu, D-Glu, iso-Glu, D-iso-Glu, β-Glu, D-β-Glu, high-Glu, D-high-Glu, β-high-Glu, N-Me-Glu, N-Me-high-Glu, Asn, D-Asn, β-Asn, D-β-Asn, high-Asn, D-high-Asn, β-high-Asn, N-Me-Asn, N-Me-high-Asn, 4-aminobutyryl, 2-(trimethyl-2-aminoethoxy)ethoxy]propyl and Lys, wherein the side chain -NH2 of Lys is replaced by -C(=O)(CH2). n R K Replace, where n is 0 to 2 and R K It is either an imidazole, pyrimidin, or pyridinyl group optionally substituted with F, or X12 is not present; and X13 is selected from: optionally substituted His residues; optionally substituted Phe residues; alanine residues substituted with a carbocyclic group or an aromatic or heteroaromatic group, wherein the aromatic or heteroaromatic group is selected from phenyl, pyridyl, naphthyl, and quinolinyl, each optionally substituted; Asn, D-Asn, β-Asn, D-β-Asn, high-Asn, D-high-Asn, β-high-Asn, N-Me-Asn, N-Me-high-Asn, Gly, β-Gly, high-Gly, β-high-Gly, N-Me-Gly, N-Me-high-Gly, And Dab, Orn, or Lys, where the side chain -NH2 is replaced by -C(=O)(CH2). n R K Replace, where n is 0 to 2 and R K It is an imidazole, pyrimidin, or pyridinyl group optionally substituted with F. Or it may not exist; in (i) X2 and X11 are amino acid residues that together form a lactam bridge; (ii) X2 and X7 are amino acid residues that together form a lactam bridge or a bridge containing a triazole ring; and (iii) Optionally, when X13 is present, X10 and X13 are amino acid residues that together form a lactam bridge.

2. The compound according to claim 1, wherein X2 is selected from Dab, D-Dab, iso-Dab, Lys, iso-Lys, D-β-Lys, N-Me-Lys, high-Lys, D-Lys, D-high-Lys, β-Lys, β-high-Lys, Lys(Gly), (N3)-Lys, D-(N3)-Lys, D-iso-Glu, iso-Glu, Glu, Orn, D-Orn, Dpr, and Lys(Gly).

3. The compound according to any one of claims 1 or 2, wherein X3 is selected from Thr, Ile, 3-aminopropionyl, 4-aminobutyryl, β-high-Ile, β-high-Thr, β-high-Trp, Gly, N-Me-3-aminopropionyl, Ser, Trp, Phe, N-Me-Ser, N-Me-Ala, 3-hydroxypropionic acid, or is absent.

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

5. The compound according to any one of claims 1 to 4, wherein X5 is selected from Trp, 1-Me-Trp, 7-Aza-Trp, 7-Me-Trp and β-high-Trp.

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

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

8. The compound according to any one of claims 1 to 7, wherein X8 is selected from Y(2-aminoethoxy), Y(2-aminoethoxy)(N(Me)2), Y(n-pentylamine)(N + (Me)3), Y(2-trimethyl-PEG2), high-Phe, 7-AzaTrp, β-high-Trp, 7-F-Trp, F(4-morpholine), 3-quinolinylalanine, Y(Me), Y(nPr), Y(Bn), Trp, D-Phe, 2-Me-Phe, F(4-Me), F(4-Bu), 3-(2-pyridyl)-Ala, 3-(3-pyridyl)-Ala, 3-(4-pyridyl)-Ala, cyclopropyl-Ala, F(4-THP), Y(CH3-2-F), F(4-F), F(4-piperazine), F(4-imidazolium), F(4-piperidine), Y(CH3-3-F), 5-AzaTrp, Y(Ac-2-aminoethoxy), 6-AzaTrp and F(4-CONH2).

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

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

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

12. The compound according to any one of claims 1 to 11, wherein X12 is selected from Dab, His, D-His, His(1-Me), 3-(2-pyridyl)-Ala, 3-(3-pyridyl)-Ala, 3-(4-pyridyl)-Ala, 3-(3-quinolinyl)-Ala, Gly, Pro, Ser(OCH3), 5-aminopentanoyl, 4-aminopiperidine-4-carbonyl, (R,S)-imidazolidine-2-carbonyl, and Lys, wherein the side chain -NH2 of Lys is replaced by -C(=O)(CH2). n R K Replace, where n is 0 to 2 and R K It is either an imidazole, pyrimidin, or pyridinyl group optionally substituted with F, or X12 is not present.

13. The compound according to any one of claims 1 to 12, wherein X13 is selected from 3-(3-pyridyl)-Ala, D-3-(3-pyridyl)-Ala and 3-(3,5-pyrimidinyl)-Ala, or is not present.

14. The compound according to any one of claims 1 to 13, or its pharmaceutically acceptable salt or solvate, wherein: Z-R 2 in R 2 It is NHR 3 , where R 3 It is a C that is hydrogen or optionally substituted with a pyridine ring. 1-6 Alkyl groups, or those that are not present; and Z is the amino acid sequence of formula Ia: in X2 is selected from Lys, D-Lys, iso-Lys, β-Lys, D-β-Lys, high-Lys, D-high-Lys, β-high-Lys, N-Me-Lys, Dab, D-Dab, Glu, iso-Glu, Orn, D-Orn, Lys(Gly), (N3)-Lys, and D-(N3)-Lys; X3 is selected from Thr, Trp, Ile, 3-aminopropionyl, 4-aminobutyryl, β-high-Ile, β-high-Thr, Gly, and N-Me-3-aminopropionyl, 3-hydroxypropionic acid, or is not present; X4 is Val or does not exist; X5 is either Trp or 1-Me-Trp; X6 is Gln, Gln(Me), Dab(Ac-N-Me), Dab(Ac) or Gln(2Me); X7 is selected from Glu, High-Glu, Asp, Pra, and Hpg; X8 is selected from Y(2-aminoethoxy), Y(Me), Y(Bn), Y(2-aminoethoxy)(N(Me)2), and Y(n-pentylamine)(N + (Me)3), Y(2-trimethyl-PEG2), F(4-Me), F(4-Bu), cyclopropyl-Ala, F(4-morpholine), F(4-THP), Y(CH3-2-F), F(4-F), F(4-piperazine), F(4-imidazolium), Y(CH3-3-F), F(4-piperidine), 5-AzaTrp, Y(Ac-2-aminoethoxy), 7-AzaTrp, 6-AzaTrp, F(4-CONH2); X9 is 2-Nal; X10 is selected from 2-Me-Leu, 2-Me-Val, D-Ala, Dab, Gly, and Aib; X11 is selected from Glu, high-Glu, Lys, Lys(Me), Orn and 2-amino-6-carboxyhexanoyl; X12 is selected from Dab, His, S(OCH3), D-His, His(1-Me), 3-(3-quinolinyl)-Ala, and 4-aminopiperidine-4-carbonyl; and X13 is 3-(3-pyridyl)-Ala, 3-(3,5-pyrimidinyl)-Ala, or it does not exist; in (i) X2 and X11 are amino acid residues that together form a lactam bridge; (ii) X2 and X7 are amino acid residues that together form a lactam bridge or a bridge containing a triazole ring; and (iii) Optionally, when X13 is present, X10 and X13 are amino acid residues that together form a lactam bridge.

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

16. The compound according to any one of the preceding claims, wherein X2 is Lys; optionally wherein X3 is selected from Thr, Ile and 3-aminopropionyl, or is absent. Optionally, where X4 does not exist.

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

18. The compound according to any one of the preceding claims, wherein X9 is 2-Nal; Optionally, X10 is 2-Me-Leu or 2-Me-Val; Optionally, X10 is 2-Me-Leu; Optionally, X11 is Glu.

19. The compound according to any one of the preceding claims, wherein X12 is Dab; Optionally, X13 is 3-(3-pyridyl)-Ala or is absent; optionally, X13 is 3-(3-pyridyl)-Ala.

20. The compound according to any one of the preceding claims, wherein R 2 It is NHR 3 , where R 3 Is it hydrogen or C? 1-6 Alkyl; optionally wherein R 2 It is NH2 or NHMe.

21. The compound according to any one of the preceding claims, wherein: X2 is Lys; X5 is Trp; X9 is 2-Nal; and X10 is 2-Me-Leu; or X2 is Lys; X5 is Trp; X9 is 2-Nal; X10 is 2-Me-Leu; and R 2 Is it NH2 or NHMe; or X2 is Lys; X5 is Trp; X9 is 2-Nal; X10 is 2-Me-Leu; X13 is 3-(3-pyridyl)-Ala or does not exist, and R 2 Is it NH2 or NHMe; or X2 is Lys; X5 is Trp; X7 is Glu; X9 is 2-Nal; X10 is 2-Me-Leu; X13 is 3-(3-pyridyl)-Ala or does not exist, and R 2 It is NH2 or NHMe.

22. The compound according to claim 1, wherein Z is selected from the amino acid sequence of claim 1: in: † The bridges (1c), (6c), (6g), and (7c) use the α-amino group of the amino acid in the bridge (or the β-amino group for bLys, {d}bLys, and β-hLys, or the α-amine that has been converted to an azide group for (N3)-K and {d}(N3)-K). ‡ The bridges (1c), (6c), (6g), and (7c) utilize the α-carboxylic acid groups of the amino acids in the bridge. (1c) represents a [2,11] lactam bridge; (6c) represents a [2,7] lactam bridge; (6g) represents a [2,7] 1,4-disubstituted 1,2,3-triazole bridge; (7c) represents a [10,13] lactam bridge.

23. The compound according to claim 1, wherein the compound is selected from: Or it can be a medicinal salt or solvent. in: † The bridges (1c), (6c), (6g), and (7c) use the α-amino group of the amino acid in the bridge (or the β-amino group for bLys, {d}bLys, and β-hLys, or the α-amine that has been converted to an azide group for (N3)-K and {d}(N3)-K). ‡ The bridges (1c), (6c), (6g), and (7c) utilize the α-carboxylic acid groups of the amino acids in the bridge. (1c) represents a [2,11] lactam bridge; (6c) represents a [2,7] lactam bridge; (6g) represents a [2,7] 1,4-disubstituted 1,2,3-triazole bridge; (7c) represents a [10,13] lactam bridge.

24. A pharmaceutical composition comprising a compound according to any one of the preceding claims in combination with a pharmaceutically acceptable carrier, excipient or loading agent.

25. The pharmaceutical composition of claim 24, wherein the pharmaceutical composition is for oral administration.

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

27. The compound according to any one of claims 1 to 23 or the pharmaceutical composition according to any one of claims 24 to 25, in a method of medical treatment.

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

29. The compound or pharmaceutical composition of claim 28, wherein the IBD is selected from Crohn's disease or ulcerative colitis.

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