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), psoriasis and psoriatic arthritis. The compound has good physical and chemical stability in the gastrointestinal tract.

Description

TECHNICAL FIELD

[0001] The present application relates to peptide inhibitors of the interleukin-23 receptor (IL-23R), and to their medical use in the treatment and / or prevention of various 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

[0002] Interleukin-23 (IL-23) is a heterodimeric cytokine composed of a unique pl9 subunit and the p40 subunit of interleukin-12 (IL-12). IL-12 is a cytokine involved in the development of T helper 1 (Thl) cells that produce interferon-gamma (IFN-γ). Although both IL-23 and IL-12 contain the p40 subunit, they have different phenotypic properties. Animals lacking IL-12 are susceptible to inflammatory autoimmune diseases, while animals lacking IL-23 are resistant. This is thought to be because CD4 + T cells in the central nervous system (CNS) of animals lacking IL-23 produce interleukin-6 (IL-6), interleukin-17 (IL-17) and tumor necrosis factor (TNF) in the absence of IL-12, but not in the presence of IL-23. In contrast, IL-12 acts on naive CD4 + T cells, while IL-23 preferentially acts on memory CD4 + T cells.

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

[0004] IL-23R is expressed on a variety of adaptive and innate immune cells, including T-helper 17 (Th17) cells, gamma-delta (gd) T cells, natural killer (NK) cells, dendritic cells, macrophages, and innate lymphoid cells. These cells are abundant in the intestine. In particular, in inflammatory bowel disease (IBD) patients, elevated levels of IL-23R gene expression and protein levels are found on the surface of the intestinal mucosa. IL-23 is thought to mediate this effect by promoting the development of pathogenic CD4 + T cell populations.

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

[0006] Accordingly, IL-23 is thought to play a crucial role in the pathogenesis of autoimmune inflammation and related diseases and disorders, such as multiple sclerosis, asthma, rheumatoid arthritis, psoriasis, psoriatic arthritis, and inflammatory bowel disease (IBD), such as ulcerative colitis and Crohn's disease. Studies in acute and chronic mouse models of IBD have revealed a major role for 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 its use in the treatment of ulcerative colitis. Protagonist Therapeutics, Inc.'s IL-23 antagonist peptide PTG-200 is 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.

[0008] .

[0009] Protagonist also disclosed another peptide, compound C, as an IL-23R inhibitor in WO 2016 / 011208, WO 2017 / 011820 and Sayago et al., 2018.

[0010] Notably, the peptides disclosed in 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.

[0011] 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.

[0012] 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.

[0013] 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.

[0014] Challenges remain in identifying stable and selective agents that preferentially target the IL-23 pathway for the treatment of intestinal inflammation. 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 compound C from Protagonist (Sayago et al., 2018), the most promising candidate peptide I5 from Kong et al., 2020 exhibited lower stability and lower IL-23R potency in simulated intestinal fluid (SIF) assays.

[0015] 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 luminal side could provide therapeutic benefits to IBD patients with localized inflammation in the intestinal tissue.

[0016] The inventors have also filed WO 2023 / 099669 concerning a peptide inhibitor 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

[0017] 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 (including Crohn's disease and ulcerative colitis), psoriasis, and psoriatic arthritis. The compounds described herein exhibit improved properties compared to those disclosed in WO 2023 / 099669.

[0018] 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.

[0019] In a first aspect, the present invention provides compounds of the following formula, or pharmaceutically acceptable salts or solvates thereof:

[0020] ZR 2

[0021] in

[0022] R 2 It is NHR 3 Or C(=O)R 3 , where R 3 It is hydrogen or C, optionally substituted with a pyridyl ring. 1-4 Alkyl; and

[0023] Z is the amino acid sequence of formula I:

[0024]

[0025] in

[0026] X1 either does not exist or is selected from 3-(3-pyridyl)-Ala or 3-aminopropionyl;

[0027] X2 is selected from 4-aminomethyl-phenylacetyl, 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; 3-aminopropionyl, Lys, D-lys, iso-Lys, D-iso-Lys, β-Lys, D-β-Lys, high-Lys, D-high-Lys, β-high-Lys, N-Me-Lys, N-Me-high-Lys,

[0028] 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,

[0029] 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,

[0030] 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

[0031] Lys(Gly),

[0032] 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

[0033] 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

[0034] 2-Amino-6-carboxyhexanoyl;

[0035] X3 is selected from any amino acid or ω-hydroxy-C. 2-6 Alkane acids;

[0036] X4 is selected from 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,

[0037] 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

[0038] 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,

[0039] 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,

[0040] 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,

[0041] 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

[0042] Cys, D-Cys, β-Cys, D-β-Cys, high-Cys, D-high-Cys, β-high-Cys, N-Me-Cys and N-Me-high-Cys;

[0043] X5 is selected from optionally substituted tryptophan residues, optionally substituted azatryptophan residues, and optionally substituted β-homotraphan residues;

[0044] 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;

[0045] X7 is selected from 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,

[0046] 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

[0047] 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,

[0048] 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,

[0049] 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,

[0050] 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

[0051] Cys, D-Cys, β-Cys, D-β-Cys, high-Cys, D-high-Cys, β-high-Cys, N-Me-Cys and N-Me-high-Cys;

[0052] X8 is selected from optionally substituted tryptophan residues, optionally substituted azatryptophan residues, optionally substituted β-homoprephan residues, optionally substituted tyrosine residues, optionally substituted phenylalanine residues, optionally substituted homophenylalanine residues, and alanine residues substituted with optionally substituted carbocyclic or aromatic groups, wherein the aromatic group is selected from phenyl, pyridyl, naphthyl, and quinolinyl, each optionally substituted.

[0053] X9 is selected from optionally substituted tryptophan residues, optionally substituted azatryptophan residues, optionally substituted β-high-tryptophan residues, optionally substituted alanine residues, optionally substituted phenylalanine residues, and optionally substituted tyrosine residues.

[0054] X10 is selected from Val, D-Val, β-Val, D-β-Val, high-Val, D-high-Val, β-high-Val, N-Me-Val, N-Me-high-Val, 2-Me-Val.

[0055] Gly, β-Gly, homo-Gly, β-homo-Gly, N-Me-Gly, N-Me-homo-Gly,

[0056] 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,

[0057] 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, 2-Me-Lys,

[0058] Aib, D-Aib, β-Aib, D-β-Aib, Homo-Aib, D-homo-Aib, β-homo-Aib, N-Me-Aib, N-Me-ho-Aib,

[0059] Ala, D-Ala, β-Ala, D-β-Ala, Homo-Ala, D-homo-Ala, β-homo-Ala, N-Me-Ala, N-Me-homo-Ala,

[0060] 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,

[0061] Ile, D-Ile, β-Ile, D-β-Ile, high-Ile, D-high-Ile, β-high-Ile, N-Me-Ile, N-Me-high-Ile,

[0062] And carbocyclic or heterocyclic rings with amino and carbonyl substituents;

[0063] 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, N-Me-high-Dpr.

[0064] 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,

[0065] 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

[0066] 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),

[0067] Lys(Gly), LAsp, 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

[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, 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; 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, Homo-Gln, D-homo-Gln, β-homo-Gln, N-Me-Gln, N-Me-homo-Gln, THP, Ser, D-Ser, β-Ser, D-β-Ser, Homo-Ser, D-homo-Ser, β-homo-Ser, N-Me-Ser, 2-Me-Ser, N-Me-homo-Ser, Ser(O Me), 3-aminotetrahydrofuran-3-carbonyl, THP, 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, GABA, 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 an imidazole, pyrimidin, or pyridinyl group optionally substituted with F;

[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, and Dab, Orn, or Lys, wherein 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 is absent; and

[0072] X14 is absent or selected from Sar, optionally substituted His residues, 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, 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;

[0073] in

[0074] (i) The amino acid residue at X11 forms a lactam bridge with the amino acid residue at X1, or, when X1 is absent, with the amino acid residue at X2; and

[0075] (ii) X4 and X7 are amino acid residues that together form a lactam bridge or a disulfide bridge;

[0076] The compounds described herein are not the following, or their pharmaceutically acceptable salts and solvates:

[0077]

[0078]

[0079]

[0080]

[0081]

[0082] in:

[0083] 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.

[0084] (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.

[0085] The above-mentioned reference compound is disclosed in WO2023 / 099669.

[0086] In a second aspect, the present invention provides compounds of the following formula, or pharmaceutically acceptable salts or solvates thereof:

[0087] ZR 2

[0088] in

[0089] R 2 It is NHR 3 , where R 3 It is a C-type carbon with hydrogen or optionally substituted with a pyridyl ring. 1-4 Alkyl; and

[0090] Z is the amino acid sequence of formula I:

[0091]

[0092] in

[0093] X1 either does not exist or is selected from 3-(3-pyridyl)-Ala or 3-aminopropionyl;

[0094] X2 is selected from 4-aminomethyl-phenylacetyl, 3-(3-pyridyl)-Ala and 3-aminopropionyl;

[0095] X3 is selected from Ser, Ala, Phe, and N-Me-Ser;

[0096] X4 is either Glu or Cys;

[0097] X5 is Trp;

[0098] X6 is selected from Gln, Q(Me), Q(2Me), Q(pyrrolidine), Ala, Phe, Lys(Ac), Dab(Ac), Cit and Orn;

[0099] X7 is either Dab or Cys;

[0100] X8 is selected from Y(2-aminoethoxy), high-Phe, 7-AzaTrp, β-high-Trp and 7-F-Trp;

[0101] X9 is selected from 2-Nal, 7-AzaTrp, β-homo-Trp and cyclopropyl-Ala;

[0102] X10 is 2-Me-Leu or Aib;

[0103] X11 is Glu;

[0104] X12 is selected from Dab, Iso-Dab, D-Arg, Gly-CF3, D-Gly-CF3, Nle, Gln, His, THP, Ser, D-Ser, 2-Me-Ser, Ser(OMe) and High-Ser;

[0105] X13 is selected from 3-(3-pyridyl)-Ala, D-3-(3-pyridyl)-Ala, 2-Me-3-(3-pyridyl)-Ala, N-Me-3-(3-pyridyl)-Ala, 3-(3,5-pyrimidinyl)-Ala, His, D-His, and His(Me), or it may not exist; and

[0106] X14 is absent or selected from Sar, D-His, β-high-Leu, and 3-(3-pyridyl)-Ala;

[0107] in

[0108] (i) Glu at X11 forms a lactam bridge with the amino acid residues at X1 or, when X1 is absent, at X2; and

[0109] (ii) X4 and X7 are amino acid residues that together form a lactam bridge or a disulfide bridge.

[0110] In some embodiments, the compound is not the following, nor its pharmaceutically acceptable salts and solvates:

[0111]

[0112] in:

[0113] 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.

[0114] (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.

[0115] Reference compounds Ref 80, Ref 81, Ref 82, Ref 120, Ref 122, Ref 125, Ref 141 and Ref 146 are disclosed in WO2023 / 099669.

[0116] This invention does not relate to the compounds disclosed in WO2023 / 099669.

[0117] In some embodiments, the compound is not present when X1 is absent; X2 is 4-aminomethyl-phenylacetyl; X3 is Ser or N-Me-Ser; X6 is Gln or Q (pyrrolidine); X8 is Y (2-aminoethoxy); X9 is 2-Nal; X10 is 2-Me-Leu; X12 is Dab, D-Arg, or Ser; X13 is 3-(3-pyridyl)-Ala or is absent; X14 is absent; and R 2 It is NH2.

[0118] In some implementations, X1 does not exist.

[0119] In some implementations, X2 is 4-aminomethyl-phenylacetyl.

[0120] In some implementations, X3 is Ser or Ala. In some implementations, X3 is Ser.

[0121] In some implementations, X4 is Glu, X7 is Dab, and X4 and X7 together form a lactam bridge.

[0122] In some implementations, X6 is Gln.

[0123] In some implementations, X8 is Y(2-aminoethoxy).

[0124] In some implementations, X9 is 2-Nal.

[0125] In some implementations, X10 is 2-Me-Leu.

[0126] In some implementations, X12 is Dab.

[0127] In some embodiments, X13 is 3-(3-pyridyl)-Ala or is absent. In some embodiments, X13 is 3-(3-pyridyl)-Ala.

[0128] In some implementations, X14 is not present.

[0129] In some implementation schemes, 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 NH2. In some other implementations, R 2 It is NHMe.

[0130] In some implementations, both X4 and X7 are Cys, and X4 and X7 together form a disulfide bridge, wherein the disulfide bridge between X4 and X7 has the formula -SLYLS-, where:

[0131] Each S is a sulfur atom and part of the amino acid residues at X4 and X7;

[0132] Each L is independently a C 1-4 Alkylene; and

[0133] Y either does not exist or is C (=O).

[0134] In some implementations, L is independently C 1-2 Alkylene. In some embodiments, L is methylene. In some embodiments, Y is C (=O).

[0135] In some embodiments, the disulfide bridge between X4 and X7 has the formula -SCH2C(=O)CH2S-, where each S is a sulfur atom and is part of an amino acid residue at X4 and X7.

[0136] In some implementations, X1 is absent and X2 is 4-aminomethyl-phenylacetyl.

[0137] In some embodiments, X1 is absent; X2 is 4-aminomethyl-phenylacetyl; X8 is Y(2-aminoethoxy); X9 is 2-Nal; and X10 is 2-Me-Leu.

[0138] In some embodiments, X1 is absent; X2 is 4-aminomethyl-phenylacetyl; X3 is Ser or Ala; X8 is Y (2-aminoethoxy); X9 is 2-Nal; and X10 is 2-Me-Leu.

[0139] In some embodiments, X1 is absent; X2 is 4-aminomethyl-phenylacetyl; X3 is Ser or Ala; X6 is Gln; X8 is Y (2-aminoethoxy); X9 is 2-Nal; and X10 is 2-Me-Leu.

[0140] In some implementations, X13 is 3-(3-pyridyl)-Ala and X14 is not present.

[0141] In some embodiments, X13 is 3-(3-pyridyl)-Ala, X14 is absent, and R 2 It is NHMe.

[0142] In some implementations, Z is an amino acid sequence selected from the sequences listed in Table 1-1a.

[0143] In some embodiments, the compound is selected from the compounds in Table 1-1 or their pharmaceutically acceptable salts or solvates.

[0144] 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.

[0145] The present invention also provides a method for synthesizing the compounds as described above. The method may include the steps of synthesizing the peptide 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 an amide bond between amino acid residues at position X1 or, when X1 is absent, at positions X2 and X11, and optionally the steps of forming an amide bond between amino acid residues at positions X4 and X7 or forming two thioether bonds with a linker.

[0146] The present invention also provides compounds of the present invention or pharmaceutical compositions comprising said compounds in a method of medical treatment.

[0147] 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) (e.g., 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.

[0148] 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) (e.g., 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.

[0149] The present invention also provides methods for preventing or treating inflammatory bowel disease (IBD) (e.g., 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.

[0150] Other aspects and embodiments of the invention will become apparent from the following disclosure. Detailed Implementation

[0151] Definitions

[0152] 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.

[0153] 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.

[0154] 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 whole or component is included, but does not exclude any other whole or component or group of the whole or component.

[0155] Unless the context clearly indicates otherwise, a noun without a quantifier indicates one or more species.

[0156] 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.

[0157] 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 great 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).

[0158] 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 4Typically, 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 2-6 Examples 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).

[0159] 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.

[0160] 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.

[0161] Each embodiment of the invention described herein may be used alone or in combination with one or more other embodiments of the invention.

[0162] 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.

[0163] 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.

[0164] 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.

[0165] The term "prevention" and its grammatical variations (e.g., "prevented," "preventing," "prevent") used in the context of this invention 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.

[0166] Amino acid nomenclature

[0167] 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)-.

[0168] Therefore, the term "amino acid" is not limited to including both natural and non-natural α and β amino acids, but also includes residues (when forming parts of a peptide), such as 3-aminopropionyl and 4-aminobutyryl. The term also includes cyclic structures with amine and carboxylic acid functional groups, such as carbocyclic and heterocyclic structures. The carbonyl group of the carboxylic acid group can be further functionalized, for example, converted to -CF3 in Gly-CF3 and D-Gly-CF3. This further functionalization can occur before, during, or after the peptide is coupled to other amino acid residues in the peptide chain.

[0169] 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-high-Trp and β-high-Leu 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.

[0170] 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.

[0171] Throughout this specification, naturally occurring amino acids are referred to by their full names (e.g., alanine, arginine, etc.) or by their conventional 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).

[0172] 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.

[0173] 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.

[0174] 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.

[0175] 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).

[0176] Table A describes some additional exemplary abbreviations for amino acid residues.

[0177] Table A

[0178]

[0179]

[0180]

[0181]

[0182]

[0183]

[0184]

[0185]

[0186] Using Table A above and Table A1 below, those skilled in the art can obtain the structures of any D, β, high, high-β, and N-Me 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.

[0187] Table A1

[0188]

[0189]

[0190] Linear peptides are written from left to right, from the N-terminus to the C-terminus.

[0191] 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.

[0192] Unless otherwise stated, the peptide backbone (i.e., the peptide chain) is the... The amide bond “-” between amino acid residues is formed by linking them via their terminal -NH2 and -COOH groups. That is, the “terminal -NH2 group” is the α-amine group of an α-amino acid or the β-amine group of a β-amino acid; 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 that form the amide backbone of the peptide chain.

[0193] 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), the peptide backbone may alternatively be formed using the side chains of the amino acid residue.

[0194] For example, the following nomenclature in Table B is used to distinguish the use of -NH2 and -COOH groups in the terminal and side chains.

[0195] Table B

[0196]

[0197] 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.

[0198] 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:

[0199] Table C

[0200]

[0201] For NH-(4-(pyridin-3-yl)butyl) and NH-(2-(pyridin-3-yl)ethyl) groups, these groups are attached to the carbonyl carbon of the carboxylic acid group of the C-terminal amino acid residue, for example, at the Dab position. This attachment forms an amide bond.

[0202] Lactams

[0203] 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.

[0204] Thioethers and disulfides

[0205] 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-.

[0206] Head-to-tail cyclization

[0207] 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.

[0208] Alkyl

[0209] 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.

[0210] C 1-4 alkyl

[0211] In the context of the compounds of this invention, R can be used as a 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... 1-3 Alkyl 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).

[0212] C 1-3 alkyl

[0213] In the context of the compounds of this invention, R can be used as a 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).

[0214] C 1-2 alkyl

[0215] In the context of the compounds of this invention, R can be used as a group. 2 Existing C 1-2 Alkyl groups include methyl (Me or -CH3, i.e., C1 alkyl) and ethyl (-CH2CH3, i.e., C2 alkyl).

[0216] ω-hydroxy-C 2-6 alkanoic acid

[0217] 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:

[0218]

[0219] Where n is 1, 2, 3, 4 or 5.

[0220] 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.

[0221] Alkylene

[0222] 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-hexane and 1,1-isohexane). ,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.

[0223] 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.

[0224] 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 the 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).

[0225] C 1-4 alkylene

[0226] In the context of the compounds of this invention, C can exist as a disulfide bridging group L. 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).

[0227] Alkyleneoxy

[0228] The term "alkyleneoxy" means "alkylene-O-(alkylene-O-)", wherein the alkylene group is as defined and exemplified above. In one embodiment, alkyleneoxy means (C 2-3 Alkylene oxide. In one embodiment, alkylene oxide refers to (C2) alkylene oxide (ethylene oxide). In one embodiment, alkylene oxide refers to (C3) alkylene oxide (propylene oxide).

[0229] Carbocyclic and heterocyclic groups - cycloalkyl, heterocyclyl

[0230] The term "cycloalkyl" or "carbocyclic" refers to a cyclic non-aromatic form of an alkyl group, preferably having 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. A cycloalkyl group can 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., 1 to the maximum number of hydrogen atoms bonded to the cycloalkyl group, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or up to 10, e.g., 1 to 5, 1 to 4, or 1 to 3, or 1 or 2) are replaced by substituents other than hydrogen (when more than one hydrogen atom is replaced, the substituents can be the same or different). In one embodiment, the cycloalkyl 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).

[0231] 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 partially or fully hydrogenated forms (e.g., dihydro, tetrahydro, or all-hydrogen forms) of the heteroaryl groups mentioned below. 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, 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 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.

[0232] Aromatic groups - aryl, heteroaryl

[0233] The term "aryl" or "aromatic ring" 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 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., 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).

[0234] 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[…] azole, indole Indoxazinyl, benzo[a]azinyl 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, 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 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.

[0235] Optional substituents

[0236] 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.

[0237] "List A" replaces the base selection: C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkynyl, 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,

[0238]

[0239] Where X 1 Each R' is independently selected from O, S, NH and N(CH3); and each R' is independently selected from H, C 1-4 Alkyl, C 2-4 alkenyl, C2-4 The alkynyl, 5- or 6-membered cycloalkyl, 5- or 6-membered aryl, 5- or 6-membered heteroaryl, and 5- or 6-membered heterocyclic groups, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclic groups is optionally substituted by one, two, or three independently selected from the following substituents: C 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)NH z-2 (C 1-3 alkyl) z and -N(C 1-3 alkyl)C(=NH)NH z-2 (C 1-3 alkyl) z where each z is independently 0, 1, or 2, and each C 1-3 The alkyl group is independently methyl, ethyl, or propyl.

[0240] 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, -NH 2-z (CH3) z -C(=O)OH, C(=O)OCH3, and -C(=O)CH3, where z is 0, 1, or 2 and C 1-3 The alkyl group is methyl, ethyl, propyl, or isopropyl.

[0241] 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.

[0242] Bridging moiety

[0243] 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.

[0244] 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). Letters indicate the type of chemical bridge (e.g., "a" indicates a 1,3-dithio-propane-2-one bridge).

[0245] Specific chemical bridges are defined at the end of the table using square brackets (e.g., [2,11], [4,7], 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 line-up with the actual amino acid number of SEQ ID NO: (e.g., in some of these sequences, the first amino acid residue is missing compared to the original starting peptide).

[0246] The residue immediately preceding the parenthesis symbol indicates a specific residue used in the bridging section.

[0247] The " immediately following the parentheses" The symbol indicates that the terminal -NH2 (if at the beginning of the sequence, i.e., the N-terminus) or -COOH (if at the end of the sequence, i.e., the C-terminus) is used to form a bridge.

[0248] SMILES string

[0249] 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 of the amino acid sequence and the structure provided by the SMILES string, the SMILES string prevails.

[0250] Compounds

[0251] This invention provides compounds as peptide inhibitors of IL-23R. These compounds exhibit a favorable combination of properties, such as high potency 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 higher gastrointestinal stability).

[0252] This invention provides compounds of the following formula, or pharmaceutically acceptable salts or solvates thereof:

[0253] ZR 2

[0254] in

[0255] R 2 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. 1-4 Alkyl; and

[0256] Z is the amino acid sequence of formula I:

[0257]

[0258] in

[0259] X1 either does not exist or is selected from 3-(3-pyridyl)-Ala or 3-aminopropionyl;

[0260] X2 is selected from 4-aminomethyl-phenylacetyl, 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; 3-aminopropionyl, Lys, D-lys, iso-Lys, D-iso-Lys, β-Lys, D-β-Lys, high-Lys, D-high-Lys, β-high-Lys, N-Me-Lys, N-Me-high-Lys,

[0261] 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,

[0262] 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,

[0263] 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

[0264] Lys(Gly),

[0265] 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

[0266] 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

[0267] 2-Amino-6-carboxyhexanoyl;

[0268] X3 is selected from any amino acid or ω-hydroxy-C. 2-6 Alkane acids;

[0269] X4 is selected from 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,

[0270] 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

[0271] 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,

[0272] 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,

[0273] 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

[0274] 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,

[0275] Cys, D-Cys, β-Cys, D-β-Cys, high-Cys, D-high-Cys, β-high-Cys, N-Me-Cys and N-Me-high-Cys;

[0276] X5 is selected from optionally substituted tryptophan residues, optionally substituted azatryptophan residues, and optionally substituted β-homotraphan residues;

[0277] 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;

[0278] X7 is selected from 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,

[0279] 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

[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,

[0281] 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,

[0282] 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

[0283] 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,

[0284] Cys, D-Cys, β-Cys, D-β-Cys, high-Cys, D-high-Cys, β-high-Cys, N-Me-Cys and N-Me-high-Cys;

[0285] X8 is selected from optionally substituted tryptophan residues, optionally substituted azatryptophan residues, optionally substituted β-homoprephan residues, optionally substituted tyrosine residues, optionally substituted phenylalanine residues, optionally substituted homophenylalanine residues, and alanine residues substituted with optionally substituted carbocyclic or aromatic groups, wherein the aromatic group is selected from phenyl, pyridyl, naphthyl, and quinolinyl, each optionally substituted.

[0286] X9 is selected from optionally substituted tryptophan residues, optionally substituted azatryptophan residues, optionally substituted β-high-tryptophan residues, optionally substituted alanine residues, optionally substituted phenylalanine residues, and optionally substituted tyrosine residues.

[0287] X10 is selected from Val, D-Val, β-Val, D-β-Val, high-Val, D-high-Val, β-high-Val, N-Me-Val, N-Me-high-Val, 2-Me-Val.

[0288] Gly, β-Gly, homo-Gly, β-homo-Gly, N-Me-Gly, N-Me-homo-Gly,

[0289] 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,

[0290] 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, 2-Me-Lys,

[0291] Aib, D-Aib, β-Aib, D-β-Aib, Homo-Aib, D-homo-Aib, β-homo-Aib, N-Me-Aib, N-Me-ho-Aib,

[0292] Ala, D-Ala, β-Ala, D-β-Ala, Homo-Ala, D-homo-Ala, β-homo-Ala, N-Me-Ala, N-Me-homo-Ala,

[0293] 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,

[0294] Ile, D-Ile, β-Ile, D-β-Ile, high-Ile, D-high-Ile, β-high-Ile, N-Me-Ile, N-Me-high-Ile,

[0295] And carbocyclic or heterocyclic rings with amino and carbonyl substituents;

[0296] X11 is selected from:

[0297] 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,

[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, 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),

[0301] Lys(Gly),

[0302] 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

[0303] 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

[0304] 2-Amino-6-carboxyhexanoyl;

[0305] X12 is selected from optionally substituted Phe residues, optionally substituted Tyr residues, optionally substituted His 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; 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, Homo-Gln, D-homo-Gln, β-homo-Gln, N-Me-Gln, N-Me-homo-Gln, THP, Ser, D-Ser, β-Ser, D-β-Ser, Homo-Ser, D-homo-Ser, β-homo-Ser, N-Me-Ser, 2-Me-Ser, N-Me-homo-Ser, Ser(O Me), 3-aminotetrahydrofuran-3-carbonyl, THP, 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, GABA, 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 an imidazole, pyrimidin, or pyridinyl group optionally substituted with F;

[0306] 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, and includes 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, wherein 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.

[0307] Or it may not exist; and

[0308] X14 is absent or selected from Sar, optionally substituted His residues, 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, 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;

[0309] in

[0310] (i) The amino acid residue at X11 forms a lactam bridge with the amino acid residue at X1, or, when X1 is absent, with the amino acid residue at X2; and

[0311] (ii) X4 and X7 are amino acid residues that together form a lactam bridge or a disulfide bridge;

[0312] The compounds described herein are not the following, or their pharmaceutically acceptable salts and solvates:

[0313]

[0314]

[0315]

[0316]

[0317]

[0318] in:

[0319] 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.

[0320] (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.

[0321] The above-mentioned reference compound is disclosed in WO2023 / 099669.

[0322] In some embodiments, the present invention provides compounds of the following formula, or pharmaceutically acceptable salts or solvates thereof:

[0323] ZR 2

[0324] in

[0325] R 2 It is NHR 3 , where R 3 It is a C-type carbon with hydrogen or optionally substituted with a pyridyl ring. 1-4 Alkyl; and

[0326] Z is the amino acid sequence of formula I:

[0327]

[0328] in

[0329] X1 either does not exist or is selected from 3-(3-pyridyl)-Ala or 3-aminopropionyl;

[0330] X2 is selected from 4-aminomethyl-phenylacetyl, 3-(3-pyridyl)-Ala and 3-aminopropionyl;

[0331] X3 is selected from Ser, Ala, Phe, and N-Me-Ser;

[0332] X4 is either Glu or Cys;

[0333] X5 is Trp;

[0334] X6 is selected from Gln, Q(Me), Q(2Me), Q(pyrrolidine), Ala, Phe, Lys(Ac), Dab(Ac), Cit and Orn;

[0335] X7 is either Dab or Cys;

[0336] X8 is selected from Y(2-aminoethoxy), high-Phe, 7-AzaTrp, β-high-Trp and 7-F-Trp;

[0337] X9 is selected from 2-Nal, 7-AzaTrp, β-homo-Trp and cyclopropyl-Ala;

[0338] X10 is 2-Me-Leu or Aib;

[0339] X11 is Glu;

[0340] X12 is selected from Dab, Iso-Dab, D-Arg, Gly-CF3, D-Gly-CF3, Nle, Gln, His, THP, Ser, D-Ser, 2-Me-Ser, Ser(OMe) and High-Ser;

[0341] X13 is selected from 3-(3-pyridyl)-Ala, D-3-(3-pyridyl)-Ala, 2-Me-3-(3-pyridyl)-Ala, N-Me-3-(3-pyridyl)-Ala, 3-(3,5-pyrimidinyl)-Ala, His, D-His, and His(Me), or it may not exist.

[0342] X14 is absent or selected from Sar, D-His, β-high-Leu, and 3-(3-pyridyl)-Ala;

[0343] in

[0344] (i) Glu at X11 forms a lactam bridge with the amino acid residues at X1 or, when X1 is absent, at X2; and

[0345] (ii) X4 and X7 are amino acid residues that together form a lactam bridge or a disulfide bridge.

[0346] In all embodiments, the compounds of the present invention are not the following, or their pharmaceutically acceptable salts and solvates:

[0347]

[0348]

[0349] in:

[0350] 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.

[0351] (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.

[0352] Reference compounds Ref 80, Ref 81, Ref 82, Ref 120, Ref 122, Ref 125, Ref 141 and Ref 146 are disclosed in WO2023 / 099669.

[0353] This invention does not relate to the compounds disclosed in WO2023 / 099669.

[0354] In some embodiments, the compound is not present when X1 is absent; X2 is 4-aminomethyl-phenylacetyl; X3 is Ser or N-Me-Ser; X6 is Gln or Q (pyrrolidine); X8 is Y (2-aminoethoxy); X9 is 2-Nal; X10 is 2-Me-Leu; X12 is Dab, D-Arg, or Ser; X13 is 3-(3-pyridyl)-Ala or is absent; X14 is absent; and R 2 It is NH2.

[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 , where R 3 It is a C-type carbon with hydrogen or optionally substituted with a pyridyl ring. 1-4 Alkyl; and

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

[0360]

[0361] in

[0362] X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, X13, and X14 are as defined in Equation I; and

[0363] in

[0364] (i) The Glu residue at X11 forms a lactam bridge with the amino acid residue at X2; and

[0365] (ii) X4 and X7 are amino acid residues that together form a lactam bridge or a disulfide bridge.

[0366] In some embodiments, the present invention provides compounds of the following formula, or pharmaceutically acceptable salts or solvates thereof:

[0367] ZR 2

[0368] in

[0369] R 2 It is NHR 3 , where R 3 It is a C-type carbon with hydrogen or optionally substituted with a pyridyl ring. 1-4 Alkyl; and

[0370] Z is the amino acid sequence of formula III:

[0371]

[0372] in

[0373] X1, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, X13, and X14 are as defined in Equation I; and

[0374] in

[0375] (i) Glu at X11 forms a lactam bridge with the amino acid residue at X1, or with the 4-aminomethyl-phenylacetyl residue at X2 when X1 is absent; and

[0376] (ii) X4 and X7 are amino acid residues that together form a lactam bridge or a disulfide bridge.

[0377] In some embodiments, the present invention provides compounds of the following formula, or pharmaceutically acceptable salts or solvates thereof:

[0378] ZR 2

[0379] in

[0380] R 2 It is NHR 3 , where R 3 It is a C-type carbon with hydrogen or optionally substituted with a pyridyl ring. 1-4 Alkyl; and

[0381] Z is the amino acid sequence of formula IV:

[0382]

[0383] in

[0384] X1, X2, X4, X5, X6, X7, X8, X9, X10, X11, X12, X13, and X14 are as defined in Equation I; and

[0385] in

[0386] (i) Glu at X11 forms a lactam bridge with the amino acid residues at X1 or, when X1 is absent, at X2; and

[0387] (ii) X4 and X7 are amino acid residues that together form a lactam bridge or a disulfide bridge.

[0388] In some embodiments, the present invention provides compounds of the following formula, or pharmaceutically acceptable salts or solvates thereof:

[0389] ZR 2

[0390] in

[0391] R 2 It is NHR 3 , where R 3 It is a C-type carbon with hydrogen or optionally substituted with a pyridyl ring. 1-4 Alkyl; and

[0392] Z is the amino acid sequence of formula V:

[0393]

[0394] in

[0395] X1, X2, X3, X5, X6, X8, X9, X10, X11, X12, X13, and X14 are as defined in Equation I; and

[0396] in

[0397] (i) Glu at X11 forms a lactam bridge with the amino acid residues at X1 or, when X1 is absent, at X2; and

[0398] (ii) Glu at X4 and Dab at X7 are amino acid residues that together form a lactam bridge.

[0399] In some embodiments, the present invention provides compounds of the following formula, or pharmaceutically acceptable salts or solvates thereof:

[0400] ZR 2

[0401] in

[0402] R 2 It is NHR 3 , where R 3 It is a C-type carbon with hydrogen or optionally substituted with a pyridyl ring. 1-4 Alkyl; and

[0403] Z is the amino acid sequence of formula VI:

[0404]

[0405] in

[0406] X1, X2, X3, X4, X5, X7, X8, X9, X10, X11, X12, X13, and X14 are as defined in Equation I; and

[0407] in

[0408] (i) Glu at X11 forms a lactam bridge with the amino acid residues at X1 or, when X1 is absent, at X2; and

[0409] (ii) X4 and X7 are amino acid residues that together form a lactam bridge or a disulfide bridge.

[0410] In some embodiments, the present invention provides compounds of the following formula, or pharmaceutically acceptable salts or solvates thereof:

[0411] ZR 2

[0412] in

[0413] R 2 It is NHR 3 , where R 3 It is a C-type carbon with hydrogen or optionally substituted with a pyridyl ring. 1-4 Alkyl; and

[0414] Z is the amino acid sequence of formula VII:

[0415]

[0416] in

[0417] X1, X2, X3, X4, X5, X6, X7, X9, X10, X11, X12, X13, and X14 are as defined in Equation I; and

[0418] in

[0419] (i) Glu at X11 forms a lactam bridge with the amino acid residues at X1 or, when X1 is absent, at X2; and

[0420] (ii) X4 and X7 are amino acid residues that together form a lactam bridge or a disulfide bridge.

[0421] In some embodiments, the present invention provides compounds of the following formula, or pharmaceutically acceptable salts or solvates thereof:

[0422] ZR 2

[0423] in

[0424] R 2 It is NHR 3 , where R 3 It is a C-type carbon with hydrogen or optionally substituted with a pyridyl ring.1-4 Alkyl; and

[0425] Z is the amino acid sequence of formula VIII:

[0426]

[0427] in

[0428] X1, X2, X3, X4, X5, X6, X7, X8, X10, X11, X12, X13, and X14 are as defined in Equation I; and

[0429] in

[0430] (i) Glu at X11 forms a lactam bridge with the amino acid residues at X1 or, when X1 is absent, at X2; and

[0431] (ii) X4 and X7 are amino acid residues that together form a lactam bridge or a disulfide bridge.

[0432] In some embodiments, the present invention provides compounds of the following formula, or pharmaceutically acceptable salts or solvates thereof:

[0433] ZR 2

[0434] in

[0435] R 2 It is NHR 3 , where R 3 It is a C-type carbon with hydrogen or optionally substituted with a pyridyl ring. 1-4 Alkyl; and

[0436] Z is the amino acid sequence of formula IX:

[0437]

[0438] in

[0439] X1, X2, X3, X4, X5, X6, X7, X8, X9, X11, X12, X13, and X14 are as defined in Equation I; and

[0440] in

[0441] (i) Glu at X11 forms a lactam bridge with the amino acid residues at X1 or, when X1 is absent, at X2; and

[0442] (ii) X4 and X7 are amino acid residues that together form a lactam bridge or a disulfide bridge.

[0443] In some embodiments, the present invention provides compounds of the following formula, or pharmaceutically acceptable salts or solvates thereof:

[0444] ZR 2

[0445] in

[0446] R 2 It is NHR 3 , where R 3 It is a C-type carbon with hydrogen or optionally substituted with a pyridyl ring. 1-4 Alkyl; and

[0447] Z is the amino acid sequence of formula X:

[0448]

[0449] in

[0450] X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X13, and X14 are as defined in Equation I; and

[0451] in

[0452] (i) Glu at X11 forms a lactam bridge with the amino acid residues at X1 or, when X1 is absent, at X2; and

[0453] (ii) X4 and X7 are amino acid residues that together form a lactam bridge or a disulfide bridge.

[0454] In some embodiments, the present invention provides compounds of the following formula, or pharmaceutically acceptable salts or solvates thereof:

[0455] ZR 2

[0456] in

[0457] R 2 It is NHR 3 , where R 3 It is a C-type carbon with hydrogen or optionally substituted with a pyridyl ring. 1-4 Alkyl; and

[0458] Z is the amino acid sequence of formula XI:

[0459]

[0460] in

[0461] X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, and X14 are as defined in Equation I; and

[0462] in

[0463] (i) Glu at X11 forms a lactam bridge with the amino acid residues at X1 or, when X1 is absent, at X2; and

[0464] (ii) X4 and X7 are amino acid residues that together form a lactam bridge or a disulfide bridge.

[0465] In some embodiments, the present invention provides compounds of the following formula, or pharmaceutically acceptable salts or solvates thereof:

[0466] ZR 2

[0467] in

[0468] R 2 It is NHR 3 , where R 3 It is a C-type carbon with hydrogen or optionally substituted with a pyridyl ring. 1-4 Alkyl; and

[0469] Z is the amino acid sequence of formula XII:

[0470]

[0471] in

[0472] X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, and X13 are as defined in Equation I; and

[0473] in

[0474] (i) Glu at X11 forms a lactam bridge with the amino acid residues at X1 or, when X1 is absent, at X2; and

[0475] (ii) X4 and X7 are amino acid residues that together form a lactam bridge or a disulfide bridge.

[0476] In some embodiments, the present invention provides compounds of the following formula, or pharmaceutically acceptable salts or solvates thereof:

[0477] ZR 2

[0478] in

[0479] R 2 It is NHR 3 , where R 3 It is a C-type carbon with hydrogen or optionally substituted with a pyridyl ring. 1-4 Alkyl; and

[0480] Z is the amino acid sequence of formula XIII:

[0481]

[0482] in

[0483] X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, and X13 are as defined in Equation I; and

[0484] in

[0485] (i) The Glu residue at X11 forms a lactam bridge with the amino acid residue at X2; and

[0486] (ii) X4 and X7 are amino acid residues that together form a lactam bridge or a disulfide bridge.

[0487] In some embodiments, the present invention provides compounds of the following formula, or pharmaceutically acceptable salts or solvates thereof:

[0488] ZR 2

[0489] in

[0490] R 2 It is NHR 3 , where R 3 It is a C-type carbon with hydrogen or optionally substituted with a pyridyl ring. 1-4 Alkyl; and

[0491] Z is the amino acid sequence of formula XIV:

[0492]

[0493] in

[0494] X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, X13, and X14 are as defined in Equation I; and

[0495] in

[0496] (i) Glu at X11 forms a lactam bridge with the 4-aminomethyl-phenylacetyl residue at X2; and

[0497] (ii) X4 and X7 are amino acid residues that together form a lactam bridge or a disulfide bridge.

[0498] In some embodiments, the present invention provides compounds of the following formula, or pharmaceutically acceptable salts or solvates thereof:

[0499] ZR 2

[0500] in

[0501] R 2 It is NHR 3 , where R 3It is a C-type carbon with hydrogen or optionally substituted with a pyridyl ring. 1-4 Alkyl; and

[0502] Z is the amino acid sequence of formula XV:

[0503]

[0504] in

[0505] X3, X4, X5, X6, X7, X11, X12, X13, and X14 are as defined in Equation I; and

[0506] in

[0507] (i) Glu at X11 forms a lactam bridge with the 4-aminomethyl-phenylacetyl residue at X2; and

[0508] (ii) X4 and X7 are amino acid residues that together form a lactam bridge or a disulfide bridge.

[0509] In some embodiments, the present invention provides compounds of the following formula, or pharmaceutically acceptable salts or solvates thereof:

[0510] ZR 2

[0511] in

[0512] R 2 It is NHR 3 , where R 3 It is a C-type carbon with hydrogen or optionally substituted with a pyridyl ring. 1-4 Alkyl; and

[0513] Z is the amino acid sequence of formula XVI:

[0514]

[0515] in

[0516] X3 is selected from Ser or Ala; and

[0517] X4, X5, X6, X7, X11, X12, X13 and X14 are as defined in Formula I;

[0518] in

[0519] (i) Glu at X11 forms a lactam bridge with the 4-aminomethyl-phenylacetyl residue at X2; and

[0520] (ii) X4 and X7 are amino acid residues that together form a lactam bridge or a disulfide bridge.

[0521] In some embodiments, the present invention provides compounds of the following formula, or pharmaceutically acceptable salts or solvates thereof:

[0522] ZR 2

[0523] in

[0524] R 2 It is NHR 3 , where R 3 It is a C-type carbon with hydrogen or optionally substituted with a pyridyl ring. 1-4 Alkyl; and

[0525] Z is the amino acid sequence of formula XVII:

[0526]

[0527] in

[0528] X3 is selected from Ser or Ala; and

[0529] X4, X5, X7, X11, X12, X13 and X14 are as defined in Formula I;

[0530] in

[0531] (i) Glu at X11 forms a lactam bridge with the 4-aminomethyl-phenylacetyl residue at X2; and

[0532] (ii) X4 and X7 are amino acid residues that together form a lactam bridge or a disulfide bridge.

[0533] In some embodiments, the present invention provides compounds of the following formula, or pharmaceutically acceptable salts or solvates thereof:

[0534] ZR 2

[0535] in

[0536] R 2 It is NHR 3 , where R 3 It is a C-type carbon with hydrogen or optionally substituted with a pyridyl ring. 1-4 Alkyl; and

[0537] Z is the amino acid sequence of formula XVIII:

[0538]

[0539] in

[0540] X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, and X12 are as defined in Equation I; and

[0541] in

[0542] (i) Glu at X11 forms a lactam bridge with the amino acid residues at X1 or, when X1 is absent, at X2; and

[0543] (ii) X4 and X7 are amino acid residues that together form a lactam bridge or a disulfide bridge.

[0544] In some embodiments, the present invention provides compounds of the following formula, or pharmaceutically acceptable salts or solvates thereof:

[0545] Z-NH2 or Z-NHMe

[0546] in

[0547] Z is the amino acid sequence of any one of Formulas I to XVIII as defined above.

[0548] In some embodiments, the present invention provides compounds of the following formula, or pharmaceutically acceptable salts or solvates thereof:

[0549] Z-NHMe

[0550] in

[0551] Z is the amino acid sequence of formula XVIII:

[0552]

[0553] in

[0554] X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, and X12 are as defined in Equation I; and

[0555] in

[0556] (i) Glu at X11 forms a lactam bridge with the amino acid residues at X1 or, when X1 is absent, at X2; and

[0557] (ii) X4 and X7 are amino acid residues that together form a lactam bridge or a disulfide bridge.

[0558] In some embodiments, the present invention provides compounds selected from the compounds in Table 1-1 or their pharmaceutically acceptable salts or solvates.

[0559] In some implementations, the compound is not one of the following:

[0560]

[0561]

[0562]

[0563]

[0564]

[0565]

[0566]

[0567]

[0568]

[0569]

[0570]

[0571] Any internal truncation between X2 and X11, i.e. the loss of amino acid residues, results in an inactive compound (see reference compounds Ref 5, Ref 6 and Ref 7 in the examples of WO2023 / 099669).

[0572] It should be understood that this invention covers salts and solvates of compounds. Suitable salts and solvates of peptides are known in the art.

[0573] It should also be understood that any of the following references to the implementation scheme may be applicable and may be combined with any of the forms described herein.

[0574] R 2

[0575] R 2 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. 1-4 alkyl.

[0576] In some implementation schemes, R 2 It is NHR 3 , where R 3 It is a C-type carbon with hydrogen or optionally substituted with a pyridyl ring. 1-4 alkyl.

[0577] In some implementation schemes, R 2 It is NHR 3 , where R 3 It is a C-type carbon with hydrogen or optionally substituted with a pyridine-3-yl ring. 1-4 alkyl.

[0578] In some implementation schemes, R 2 It is NHR3 , 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).

[0579] In some implementation schemes, R 2 It is NHR 3 , where R 3 C is optionally substituted with a pyridyl ring. 1-4 Alkyl group. In some embodiments, R 2 It is NHR 3 , where R 3 It is a C that has been substituted with a pyridyl ring. 1-4 alkyl.

[0580] In some implementation schemes, R 2 It is NHR 3 , where R 3 C is optionally substituted with a pyridine-3-yl ring. 1-4 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. 1-4 alkyl.

[0581] In some implementation schemes, R 2 It is NHR 3 , where R 3 It is a C4 alkyl group substituted with a pyridinyl 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 3It 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:

[0582] .

[0583] In some implementation schemes, R 2 It is NHR 3 , where R 3 It is a C2 alkyl group substituted with a pyridinyl 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 NH-(2-(pyridin-3-yl)ethyl) group has the following structure:

[0584] .

[0585] Preferably, in which R 2 It is NHR 3 In some implementation schemes, R 3 It is a C that has been replaced by a pyridine ring. 1-4 Alkyl groups, such as NH-(4-(pyridin-3-yl)butyl) and NH-(2-(pyridin-3-yl)ethyl), are not present in either X13 or X14.

[0586] In some implementation schemes, R 2 It is NHMe, NH2, NHCH2CH2CH2CH2(pyridin-3-yl) [i.e., NH-(4-(pyridin-3-yl)butyl)] or NHCH2CH2(pyridin-3-yl) [i.e., NH-(2-(pyridin-3-yl)ethyl)].

[0587] In some implementation schemes, R 2 It is NHMe. In some implementations, R 2 It is NH2. In some implementations, R 2It is NHCH2CH2CH2CH2(pyridin-3-yl), i.e., NH-(4-(pyridin-3-yl)butyl). In some embodiments, R 2 It is NHCH2CH2(pyridin-3-yl), i.e., NH-(2-(pyridin-3-yl)ethyl).

[0588] Preferably, R 2 It is NHMe or NH2. Even more preferably, R 2 It is NHMe.

[0589] In particular, R 2 NHMe is preferred because the modification improves the stability of SIF (see Example 2).

[0590] Z

[0591] Z is the following amino acid sequence:

[0592]

[0593] in

[0594] X1 either does not exist or is selected from 3-(3-pyridyl)-Ala or 3-aminopropionyl;

[0595] X2 is selected from 4-aminomethyl-phenylacetyl, 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; 3-aminopropionyl, Lys, D-lys, iso-Lys, D-iso-Lys, β-Lys, D-β-Lys, high-Lys, D-high-Lys, β-high-Lys, N-Me-Lys, N-Me-high-Lys,

[0596] 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,

[0597] 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,

[0598] 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

[0599] Lys(Gly),

[0600] 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

[0601] 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

[0602] 2-Amino-6-carboxyhexanoyl;

[0603] X3 is selected from any amino acid or ω-hydroxy-C. 2-6 Alkane acids;

[0604] X4 is selected from 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,

[0605] 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

[0606] 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,

[0607] 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,

[0608] 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

[0609] 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,

[0610] Cys, D-Cys, β-Cys, D-β-Cys, high-Cys, D-high-Cys, β-high-Cys, N-Me-Cys and N-Me-high-Cys;

[0611] X5 is selected from optionally substituted tryptophan residues, optionally substituted azatryptophan residues, and optionally substituted β-homotraphan residues;

[0612] 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;

[0613] X7 is selected from 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,

[0614] 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

[0615] 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,

[0616] 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,

[0617] 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

[0618] 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,

[0619] Cys, D-Cys, β-Cys, D-β-Cys, high-Cys, D-high-Cys, β-high-Cys, N-Me-Cys and N-Me-high-Cys;

[0620] X8 is selected from optionally substituted tryptophan residues, optionally substituted azatryptophan residues, optionally substituted β-homoprephan residues, optionally substituted tyrosine residues, optionally substituted phenylalanine residues, optionally substituted homophenylalanine residues, and alanine residues substituted with optionally substituted carbocyclic or aromatic groups, wherein the aromatic group is selected from phenyl, pyridyl, naphthyl, and quinolinyl, each optionally substituted.

[0621] X9 is selected from optionally substituted tryptophan residues, optionally substituted azatryptophan residues, optionally substituted β-high-tryptophan residues, optionally substituted alanine residues, optionally substituted phenylalanine residues, and optionally substituted tyrosine residues.

[0622] X10 is selected from Val, D-Val, β-Val, D-β-Val, high-Val, D-high-Val, β-high-Val, N-Me-Val, N-Me-high-Val, 2-Me-Val.

[0623] Gly, β-Gly, homo-Gly, β-homo-Gly, N-Me-Gly, N-Me-homo-Gly,

[0624] 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,

[0625] 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, 2-Me-Lys,

[0626] Aib, D-Aib, β-Aib, D-β-Aib, Homo-Aib, D-homo-Aib, β-homo-Aib, N-Me-Aib, N-Me-ho-Aib,

[0627] Ala, D-Ala, β-Ala, D-β-Ala, Homo-Ala, D-homo-Ala, β-homo-Ala, N-Me-Ala, N-Me-homo-Ala,

[0628] 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,

[0629] Ile, D-Ile, β-Ile, D-β-Ile, high-Ile, D-high-Ile, β-high-Ile, N-Me-Ile, N-Me-high-Ile,

[0630] And carbocyclic or heterocyclic rings with amino and carbonyl substituents;

[0631] 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, N-Me-high-Dpr.

[0632] 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,

[0633] 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

[0634] 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),

[0635] Lys(Gly),

[0636] 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

[0637] 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

[0638] 2-Amino-6-carboxyhexanoyl;

[0639] X12 is selected from optionally substituted Phe residues, optionally substituted Tyr residues, optionally substituted His 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; 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, Homo-Gln, D-homo-Gln, β-homo-Gln, N-Me-Gln, N-Me-homo-Gln, THP, Ser, D-Ser, β-Ser, D-β-Ser, Homo-Ser, D-homo-Ser, β-homo-Ser, N-Me-Ser, 2-Me-Ser, N-Me-homo-Ser, Ser(O Me), 3-aminotetrahydrofuran-3-carbonyl, THP, 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, GABA, 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 an imidazole, pyrimidin, or pyridinyl group optionally substituted with F;

[0640] 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, and Asn, D-Asn, β-Asn, D-β-Asn, high-Asn, D-high-Asn, β-high-Asn, N-Me-Asn, N-Me-high-Asn, Gly, high-Gly, β-high-Gly, N-Me-Gly, N-Me-high-Gly, and Dab, Orn, or Lys, wherein 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 is absent; and

[0641] X14 is absent or selected from Sar, optionally substituted His residues, 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 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;

[0642] in

[0643] (i) The amino acid residue at X11 forms a lactam bridge with the amino acid residue at X1, or, when X1 is absent, with the amino acid residue at X2; and

[0644] (ii) X4 and X7 are amino acid residues that together form a lactam bridge or a disulfide bridge;

[0645] Or it may be a medicinal salt or solubil;

[0646] The compounds described herein are not the following, or their pharmaceutically acceptable salts and solvates:

[0647]

[0648]

[0649]

[0650]

[0651]

[0652] in:

[0653] 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.

[0654] (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.

[0655] In some implementations, Z is the amino acid sequence of formula I:

[0656]

[0657] in

[0658] X1 either does not exist or is selected from 3-(3-pyridyl)-Ala or 3-aminopropionyl;

[0659] X2 is selected from 4-aminomethyl-phenylacetyl, 3-(3-pyridyl)-Ala and 3-aminopropionyl;

[0660] X3 is selected from Ser, Ala, Phe, and N-Me-Ser;

[0661] X4 is either Glu or Cys;

[0662] X5 is Trp;

[0663] X6 is selected from Gln, Q(Me), Q(2Me), Q(pyrrolidine), Ala, Phe, Lys(Ac), Dab(Ac), Cit and Orn;

[0664] X7 is either Dab or Cys;

[0665] X8 is selected from Y(2-aminoethoxy), high-Phe, 7-AzaTrp, β-high-Trp and 7-F-Trp;

[0666] X9 is selected from 2-Nal, 7-AzaTrp, β-homo-Trp and cyclopropyl-Ala;

[0667] X10 is 2-Me-Leu or Aib;

[0668] X11 is Glu;

[0669] X12 is selected from Dab, Iso-Dab, D-Arg, Gly-CF3, D-Gly-CF3, Nle, Gln, His, THP, Ser, D-Ser, 2-Me-Ser, Ser(OMe) and High-Ser;

[0670] X13 is selected from 3-(3-pyridyl)-Ala, D-3-(3-pyridyl)-Ala, 2-Me-3-(3-pyridyl)-Ala, N-Me-3-(3-pyridyl)-Ala, 3-(3,5-pyrimidinyl)-Ala, His, D-His, and His(Me), or it may not exist.

[0671] X14 is absent or selected from Sar, D-His, β-high-Leu, and 3-(3-pyridyl)-Ala;

[0672] in

[0673] (i) Glu at X11 forms a lactam bridge with the amino acid residues at X1 or, when X1 is absent, at X2; and

[0674] (ii) X4 and X7 are amino acid residues that together form a lactam bridge or a disulfide bridge.

[0675] In some implementations, Z is the amino acid sequence of formula II:

[0676]

[0677] in

[0678] X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, X13, and X14 are as defined in Equation I; and

[0679] in

[0680] (i) The Glu residue at X11 forms a lactam bridge with the amino acid residue at X2; and

[0681] (ii) X4 and X7 are amino acid residues that together form a lactam bridge or a disulfide bridge.

[0682] In some implementations, Z is the amino acid sequence of formula III:

[0683]

[0684] in

[0685] X1, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, X13, and X14 are as defined in Equation I; and

[0686] in

[0687] (i) Glu at X11 forms a lactam bridge with the amino acid residue at X1, or with the 4-aminomethyl-phenylacetyl residue at X2 when X1 is absent; and

[0688] (ii) X4 and X7 are amino acid residues that together form a lactam bridge or a disulfide bridge.

[0689] In some implementations, Z is the amino acid sequence of formula IV:

[0690]

[0691] in

[0692] X1, X2, X4, X5, X6, X7, X8, X9, X10, X11, X12, X13, and X14 are as defined in Equation I; and

[0693] in

[0694] (i) Glu at X11 forms a lactam bridge with the amino acid residues at X1 or, when X1 is absent, at X2; and

[0695] (ii) X4 and X7 are amino acid residues that together form a lactam bridge or a disulfide bridge.

[0696] In some implementations, Z is the amino acid sequence of formula V:

[0697]

[0698] in

[0699] X1, X2, X3, X5, X6, X8, X9, X10, X11, X12, X13, and X14 are as defined in Equation I; and

[0700] in

[0701] (i) Glu at X11 forms a lactam bridge with the amino acid residues at X1 or, when X1 is absent, at X2; and

[0702] (ii) Glu at X4 and Dab at X7 are amino acid residues that together form a lactam bridge.

[0703] In some implementations, Z is the amino acid sequence of formula VI:

[0704]

[0705] in

[0706] X1, X2, X3, X4, X5, X7, X8, X9, X10, X11, X12, X13, and X14 are as defined in Equation I; and

[0707] in

[0708] (i) Glu at X11 forms a lactam bridge with the amino acid residues at X1 or, when X1 is absent, at X2; and

[0709] (ii) X4 and X7 are amino acid residues that together form a lactam bridge or a disulfide bridge.

[0710] In some implementations, Z is the amino acid sequence of formula VII:

[0711]

[0712] in

[0713] X1, X2, X3, X4, X5, X6, X7, X9, X10, X11, X12, X13, and X14 are as defined in Equation I; and

[0714] in

[0715] (i) Glu at X11 forms a lactam bridge with the amino acid residues at X1 or, when X1 is absent, at X2; and

[0716] (ii) X4 and X7 are amino acid residues that together form a lactam bridge or a disulfide bridge.

[0717] In some implementations, Z is the amino acid sequence of formula VIII:

[0718]

[0719] in

[0720] X1, X2, X3, X4, X5, X6, X7, X8, X10, X11, X12, X13, and X14 are as defined in Equation I; and

[0721] in

[0722] (i) Glu at X11 forms a lactam bridge with the amino acid residues at X1 or, when X1 is absent, at X2; and

[0723] (ii) X4 and X7 are amino acid residues that together form a lactam bridge or a disulfide bridge.

[0724] In some implementations, Z is the amino acid sequence of formula IX:

[0725]

[0726] in

[0727] X1, X2, X3, X4, X5, X6, X7, X8, X9, X11, X12, X13, and X14 are as defined in Equation I; and

[0728] in

[0729] (i) Glu at X11 forms a lactam bridge with the amino acid residues at X1 or, when X1 is absent, at X2; and

[0730] (ii) X4 and X7 are amino acid residues that together form a lactam bridge or a disulfide bridge.

[0731] In some implementations, Z is the amino acid sequence of formula X:

[0732]

[0733] in

[0734] X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X13, and X14 are as defined in Equation I; and

[0735] in

[0736] (i) Glu at X11 forms a lactam bridge with the amino acid residues at X1 or, when X1 is absent, at X2; and

[0737] (ii) X4 and X7 are amino acid residues that together form a lactam bridge or a disulfide bridge.

[0738] In some implementations, Z is the amino acid sequence of formula XI:

[0739]

[0740] in

[0741] X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, and X14 are as defined in Equation I; and

[0742] in

[0743] (i) Glu at X11 forms a lactam bridge with the amino acid residues at X1 or, when X1 is absent, at X2; and

[0744] (ii) X4 and X7 are amino acid residues that together form a lactam bridge or a disulfide bridge.

[0745] In some implementations, Z is the amino acid sequence of formula XII:

[0746]

[0747] in

[0748] X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, and X13 are as defined in Equation I; and

[0749] in

[0750] (i) Glu at X11 forms a lactam bridge with the amino acid residues at X1 or, when X1 is absent, at X2; and

[0751] (ii) X4 and X7 are amino acid residues that together form a lactam bridge or a disulfide bridge.

[0752] In some implementations, Z is the amino acid sequence of formula XIII:

[0753]

[0754] in

[0755] X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, and X13 are as defined in Equation I; and

[0756] in

[0757] (i) The Glu residue at X11 forms a lactam bridge with the amino acid residue at X2; and

[0758] (ii) X4 and X7 are amino acid residues that together form a lactam bridge or a disulfide bridge.

[0759] In some implementations, Z is the amino acid sequence of formula XIV:

[0760]

[0761] in

[0762] X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, X13, and X14 are as defined in Equation I; and

[0763] in

[0764] (i) Glu at X11 forms a lactam bridge with the 4-aminomethyl-phenylacetyl residue at X2; and

[0765] (ii) X4 and X7 are amino acid residues that together form a lactam bridge or a disulfide bridge.

[0766] In some implementations, Z is the XV amino acid sequence:

[0767]

[0768] in

[0769] X3, X4, X5, X6, X7, X11, X12, X13, and X14 are as defined in Equation I; and

[0770] in

[0771] (i) Glu at X11 forms a lactam bridge with the 4-aminomethyl-phenylacetyl residue at X2; and

[0772] (ii) X4 and X7 are amino acid residues that together form a lactam bridge or a disulfide bridge.

[0773] In some implementations, Z is the amino acid sequence of formula XVI:

[0774]

[0775] in

[0776] X3 is selected from Ser or Ala; and

[0777] X4, X5, X6, X7, X11, X12, X13 and X14 are as defined in Formula I;

[0778] in

[0779] (i) Glu at X11 forms a lactam bridge with the 4-aminomethyl-phenylacetyl residue at X2; and

[0780] (ii) X4 and X7 are amino acid residues that together form a lactam bridge or a disulfide bridge.

[0781] In some implementations, Z is the amino acid sequence of formula XVII:

[0782]

[0783] in

[0784] X3 is selected from Ser or Ala; and

[0785] X4, X5, X7, X11, X12, X13 and X14 are as defined in Formula I;

[0786] in

[0787] (i) Glu at X11 forms a lactam bridge with the 4-aminomethyl-phenylacetyl residue at X2; and

[0788] (ii) X4 and X7 are amino acid residues that together form a lactam bridge or a disulfide bridge.

[0789] In some implementations, Z is the amino acid sequence of formula XVIII:

[0790]

[0791] in

[0792] X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, and X12 are as defined in Equation I; and

[0793] in

[0794] (i) Glu at X11 forms a lactam bridge with the amino acid residues at X1 or, when X1 is absent, at X2; and

[0795] (ii) X4 and X7 are amino acid residues that together form a lactam bridge or a disulfide bridge.

[0796] In some embodiments, Z is an amino acid sequence selected from the sequences listed in Table 1-1a.

[0797] X1

[0798] X1 is absent or is selected from 3-(3-pyridyl)-Ala or 3-aminopropionyl.

[0799] In some implementations, X1 is absent. When X1 is absent, the amino acid residue at X2 forms a lactam bridge with the Glu residue at X11.

[0800] In some embodiments, X1 is 3-(3-pyridyl)-Ala or 3-aminopropionyl. In some embodiments, X1 is 3-(3-pyridyl)-Ala. In some embodiments, X1 is 3-aminopropionyl.

[0801] When X1 is present, i.e., when X1 is 3-(3-pyridyl)-Ala or 3-aminopropionyl, X1 can form a lactam bridge with the Gly residue at X11. In some embodiments, when X1 is present, i.e., when X1 is 3-(3-pyridyl)-Ala or 3-aminopropionyl, X1 forms a lactam bridge with the Glu residue at X11.

[0802] Preferably, X1 does not exist.

[0803] X2

[0804] X2 is selected from 4-aminomethyl-phenylacetyl, 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; 3-aminopropionyl, Lys, D-lys, iso-Lys, D-iso-Lys, β-Lys, D-β-Lys, high-Lys, D-high-Lys, β-high-Lys, N-Me-Lys, N-Me-high-Lys,

[0805] 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,

[0806] 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,

[0807] 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

[0808] Lys(Gly),

[0809] 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

[0810] 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

[0811] 2-Amino-6-carboxyhexanoyl.

[0812] In some embodiments, X2 is selected from 4-aminomethyl-phenylacetyl, 3-(3-pyridyl)-Ala, and 3-aminopropionyl.

[0813] The amino acid residue at X2 can form a lactam bridge with the Glu residue at X11. When X1 is absent, the amino acid residue at X2 forms a lactam bridge with the Glu residue at X11.

[0814] In some embodiments, X2 is 4-aminomethyl-phenylacetyl. In some embodiments, X2 is 3-(3-pyridyl)-Ala. In some embodiments, X2 is 3-aminopropionyl.

[0815] Preferably, X2 is 4-aminomethyl-phenylacetyl.

[0816] X3

[0817] X3 is selected from any amino acid or ω-hydroxy-C. 2-6 Alkyl acids.

[0818] In some implementations, X3 is selected from Ser, Ala, N-Me-Ala, Phe, and N-Me-Ser.

[0819] In some implementations, X3 is selected from Ser, Ala, Phe, and N-Me-Ser.

[0820] In some implementations, X3 is Ser or Ala.

[0821] In some implementations, X3 is Ser. In some implementations, X3 is Ala. In some implementations, X3 is Phe. In some implementations, X3 is N-Me-Ser.

[0822] Preferably, X3 is Ser.

[0823] X4

[0824] X4 is selected from 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,

[0825] 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

[0826] 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,

[0827] 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,

[0828] 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

[0829] 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,

[0830] Cys, D-Cys, β-Cys, D-β-Cys, high-Cys, D-high-Cys, β-high-Cys, N-Me-Cys, and N-Me-high-Cys.

[0831] In some implementations, X4 is Glu or Cys. The amino acid residue at X4 forms a lactam bridge or a disulfide bridge with the amino acid residue at X7.

[0832] In some implementations, X4 is Glu. When X4 is Glu, the Glu at X4 forms a lactam bridge with the amino acid residue at X7.

[0833] In some implementations, X4 is Cys. When X4 is Cys, the Cys at X4 forms a disulfide bridge with the amino acid residue at X7.

[0834] Preferably, X4 is Glu.

[0835] X5

[0836] X5 is selected from optionally substituted tryptophan residues, optionally substituted azatryptophan residues, and optionally substituted β-homotraphen residues.

[0837] In some implementations, X5 is either a Trp or a 7-Me-Trp.

[0838] In some implementations, X5 is Trp.

[0839] X6

[0840] 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.

[0841] In some implementations, X6 is selected from Gln, Q(Me), Q(2Me), Q(pyrrolidine), Ala, Phe, Lys(Ac), Dab(Ac), Cit, and Orn.

[0842] In some embodiments, X6 is Gln. In some embodiments, X6 is Q(Me). In some embodiments, X6 is Q(2Me). In some embodiments, X6 is Q(pyrrolidine). In some embodiments, X6 is Ala. In some embodiments, X6 is Phe. In some embodiments, X6 is Lys(Ac). In some embodiments, X6 is Dab(Ac). In some embodiments, X6 is Cit. In some embodiments, X6 is Orn.

[0843] Preferably, X6 is Gln.

[0844] X7

[0845] X7 is selected from 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,

[0846] 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

[0847] 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,

[0848] 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,

[0849] 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

[0850] 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,

[0851] Cys, D-Cys, β-Cys, D-β-Cys, Homo-Cys, D-Homo-Cys, β-Homo-Cys, N-Me-Cys, N-Me-Homo-Cys.

[0852] In some implementations, X7 is Dab or Cys. The amino acid residue at X7 forms a lactam bridge or a disulfide bridge with the amino acid residue at X4.

[0853] In some implementations, X7 is Dab. When X7 is Dab, the Dab at X7 forms a lactam bridge with the amino acid residue at X4.

[0854] In some implementations, X7 is Cys. When X7 is Cys, the Cys at X7 forms a disulfide bridge with the amino acid residue at X4.

[0855] Preferably, X7 is Dab.

[0856] X8

[0857] 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 optionally substituted carbocyclic or aromatic groups, wherein the aromatic group is selected from phenyl, pyridyl, naphthyl, and quinolinyl, each optionally substituted.

[0858] In some embodiments, X8 is selected from Y(2-aminoethoxy), homo-Phe, 7F(4-morpholine), 3-quinolinylalanine, Y(2-aminoethoxy)(N(Me)2, Y(n-pentylamine)(N + (Me)3), Y(2-trimethyl-PEG2), Y(2-aminoethoxy)(N(Me)2), 7-AzaTrp, β-high-Trp and 7-F-Trp.

[0859] In some embodiments, X8 is selected from Y(2-aminoethoxy), high-Phe, 7-AzaTrp, β-high-Trp, and 7-F-Trp.

[0860] In some embodiments, X8 is Y(2-aminoethoxy). In some embodiments, X8 is high-Phe. In some embodiments, X8 is 7-AzaTrp. In some embodiments, X8 is β-high-Trp. In some embodiments, X8 is 7-F-Trp.

[0861] Preferably, X8 is Y(2-aminoethoxy).

[0862] X9

[0863] X9 is selected from optionally substituted tryptophan residues, optionally substituted azatryptophan residues, optionally substituted β-homotryptophan residues, optionally substituted alanine residues, optionally substituted phenylalanine residues, and optionally substituted tyrosine residues.

[0864] In some embodiments, X9 is selected from 2-Nal, 7-AzaTrp, β-homo-Trp, 3-quinolinylalanine, and cyclopropyl-Ala.

[0865] In some implementations, X9 is selected from 2-Nal, 7-AzaTrp, β-homo-Trp, and cyclopropyl-Ala.

[0866] In some embodiments, X9 is 2-Nal. In some embodiments, X9 is 7-AzaTrp. In some embodiments, X9 is β-ho-Trp. In some embodiments, X9 is cyclopropyl-Ala.

[0867] Preferably, X9 is 2-Nal.

[0868] X10

[0869] X10 is selected from Val, D-Val, β-Val, D-β-Val, high-Val, D-high-Val, β-high-Val, N-Me-Val, N-Me-high-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, 2-Me-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 carbon rings or heterocycles having amino and carbonyl substituents.

[0878] In some implementations, X10 is selected from 2-Me-Leu or Aib.

[0879] In some implementations, X10 is 2-Me-Leu. In some implementations, X10 is Aib.

[0880] Preferably, X10 is 2-Me-Leu.

[0881] The inventors have observed that it is necessary to have an amino acid at position 10 (X10) that resolves SIF stability (i.e., gastrointestinal stability). The amino acids 2-Me-Leu and Aib, especially 2-Me-Leu, resolve SIF stability. For example, if the amino acid residue is Gly at position 10 (X10), the inventors have observed a significant decrease in the SIF stability of the compound.

[0882] X11

[0883] X11 is selected from:

[0884] 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,

[0885] 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,

[0886] 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

[0887] 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),

[0888] Lys(Gly),

[0889] 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

[0890] 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

[0891] 2-Amino-6-carboxyhexanoyl.

[0892] In some implementations, X11 is Glu.

[0893] The Glu residue at X11 forms a lactam bridge with the amino acid residue at X1, or, if X1 is absent, with the amino acid residue at X2. In some embodiments, the Glu residue at X11 forms a lactam bridge with the amino acid residue at X1. In some embodiments, the Glu residue at X11 forms a lactam bridge with the amino acid residue at X2.

[0894] When X1 is absent, the Glu residue at X11 forms a lactam bridge with the amino acid residue at X2.

[0895] X12

[0896] X12 is selected from optionally substituted Phe residues, optionally substituted Tyr residues, optionally substituted His 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; 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, Homo-Gln, D-homo-Gln, β-homo-Gln, N-Me-Gln, N-Me-homo-Gln, THP, Ser, D-Ser, β-Ser, D-β-Ser, Homo-Ser, D-homo-Ser, β-homo-Ser, N-Me-Ser, 2-Me-Ser, N-Me-homo-Ser, Ser(O Me), 3-aminotetrahydrofuran-3-carbonyl, THP, 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, GABA, 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 an imidazole, pyrimidin, or pyridinyl group optionally substituted with F.

[0897] In some implementations, X12 is selected from Dab, iso-Dab, D-Arg, Gly-CF3, D-Gly-CF3, Nle, Gln, His, THP, Ser, D-Ser, 2-Me-Ser, Ser(OMe) and high-Ser.

[0898] In some embodiments, X12 is selected from Dab, D-Arg, and Ser. In some embodiments, X12 is Dab or Ser. In some embodiments, X12 is Dab or D-Arg.

[0899] In some embodiments, X12 is Dab. In some embodiments, X12 is hetero-Dab. In some embodiments, X12 is D-Arg. In some embodiments, X12 is Gly-CF3. In some embodiments, X12 is D-Gly-CF3. In some embodiments, X12 is Nle. In some embodiments, X12 is Gln. In some embodiments, X12 is His. In some embodiments, X12 is THP. In some embodiments, X12 is Ser. In some embodiments, X12 is D-Ser. In some embodiments, X12 is 2-Me-Ser. In some embodiments, X12 is Ser(OMe). In some embodiments, X12 is high-Ser.

[0900] Preferably, X12 is Dab.

[0901] X13

[0902] 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, wherein 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 either an imidazole, pyrimidin, or pyridinyl group that is optionally substituted with F, or it is not present.

[0903] In some embodiments, X13 is selected from 3-(3-pyridyl)-Ala, D-3-(3-pyridyl)-Ala, 2-Me-3-(3-pyridyl)-Ala, N-Me-3-(3-pyridyl)-Ala, 3-(3,5-pyrimidinyl)-Ala, His, D-His, and His(Me), or is not present.

[0904] In some implementations, X13 is 3-(3-pyridyl)-Ala or is absent. When X13 is absent, X14 is also absent.

[0905] In some embodiments, X13 is 3-(3-pyridinyl)-Ala. In some embodiments, X13 is D-3-(3-pyridinyl)-Ala. In some embodiments, X13 is 2-Me-3-(3-pyridinyl)-Ala. In some embodiments, X13 is N-Me-3-(3-pyridinyl)-Ala. In some embodiments, X13 is 3-(3,5-pyrimidinyl)-Ala. In some embodiments, X13 is His. In some embodiments, X13 is D-His. In some embodiments, X13 is His(Me). In some embodiments, X13 is not present.

[0906] Preferably, X13 is 3-(3-pyridyl)-Ala or is absent. Even more preferably, X13 is 3-(3-pyridyl)-Ala.

[0907] X14

[0908] X14 is absent or selected from Sar, optionally substituted His residues, 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, 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.

[0909] In some implementations, X14 is absent or selected from Sar, D-His, β-high-Leu, and 3-(3-pyridyl)-Ala.

[0910] In some embodiments, X14 is not present. In some such embodiments where X14 is absent, X13 may preferably be 3-(3-pyridyl)-Ala.

[0911] In some embodiments, X14 is Sar. In some embodiments, X14 is D-His. In some embodiments, X14 is β-high-Leu. In some embodiments, X14 is 3-(3-pyridyl)-Ala. When X14 is present, i.e., when X14 is selected from Sar, D-His, β-high-Leu, and 3-(3-pyridyl)-Ala; X13 can be 3-(3-pyridyl)-Ala or His.

[0912] Preferably, X14 does not exist.

[0913] Lactam bridge

[0914] 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 (e.g., Dab and Glu). Alternatively, the amino and / or carboxylic acid groups of the amino acid residues can be at the N or C terminus of the peptide chain, such as the amine or carboxylic acid of the peptide backbone of any amino acid, such as 4-aminomethyl-phenylacetyl, 3-(3-pyridyl)-Ala, and 3-aminopropionyl.

[0915] One of the amino acid residues contains an amino group and the other amino acid residue contains a carboxylic acid group, wherein a lactam (cyclic amide) is formed between the amino group and the carboxylic acid group.

[0916] For simplicity, the amino acid residues that form the lactam bridge together will be discussed with reference to the residues that were nominally present before the formation of the lactam.

[0917] Suitable amino acid residues that form a lactam bridge can be selected from:

[0918] Amino acid residues containing an amino group, such as 4-aminomethyl-phenylacetyl, 3-(3-pyridyl)-Ala, 3-aminopropionyl, and Dab.

[0919] Amino acid residues containing a carboxylic acid group, such as Glu.

[0920] The inventors have discovered that replacing the disulfide bridge with a lactam bridge can lead to an increase in the potency of the IL-23R peptide inhibitor, as previously described in Example 2 of WO2023 / 099669.

[0921] First lactam bridge - X1 / X2 and X11

[0922] The first lactam bridge is formed between the residue at X11 and the amino acid residue at X1, or, when X1 is absent, between the residue at X2 and X1. In some embodiments, the first lactam bridge is formed between the residue at X11 and the amino acid residue at X1. In some embodiments, the first lactam bridge is formed between the residue at X11 and the amino acid residue at X2. When X1 is absent, the first lactam bridge is formed between the residue at X11 and the amino acid residue at X2. Preferably, the first lactam bridge is formed between the residue at X11 and the amino acid residue at X2.

[0923] In some embodiments, a first lactam bridge is formed between Glu at X11 and the amino acid residue at X1, or, when X1 is absent, between X1 and X2. In some embodiments, a first lactam bridge is formed between Glu at X11 and the amino acid residue at X1. In some embodiments, a first lactam bridge is formed between Glu at X11 and the amino acid residue at X2. When X1 is absent, the first lactam bridge is formed between Glu at X11 and the amino acid residue at X2. Preferably, the first lactam bridge is formed between Glu at X11 and the amino acid residue at X2.

[0924] In some embodiments where the first lactam bridge is formed between Glu at X11 and the amino acid residue at X1, X1 is 3-(3-pyridyl)-Ala or 3-aminopropionyl. That is, the following combinations of X1 and X11 form a lactam bridge:

[0925] X1 is 3-(3-pyridyl)-Ala and X11 is Glu; and

[0926] X1 is 3-aminopropionyl and X11 is Glu.

[0927] In some embodiments where the first lactam bridge is formed between Glu at X11 and the amino acid residue at X2, X2 is 4-aminomethyl-phenylacetyl, 3-(3-pyridyl)-Ala, or 3-aminopropionyl. That is, the following combinations of X2 and X11 form the lactam bridge:

[0928] X2 is 4-aminomethyl-phenylacetyl and X11 is Glu;

[0929] X2 is 3-(3-pyridyl)-Ala and X11 is Glu; and

[0930] X2 is 3-aminopropionyl and X11 is Glu.

[0931] In such a combination, X1 does not exist.

[0932] Second lactam bridges - X4 and X7

[0933] A second lactam bridge can be formed between the amino acid residues at X4 and X7. In some such embodiments, X4 is Glu and X7 is Dab.

[0934] Preferably, the bridge between the amino acid residues at X4 and X7 is a lactam bridge.

[0935] Disulfide bridge

[0936] Disulfide bridges are formed by two amino acid residues containing a sulfur moiety (e.g., -SH). Preferably, the sulfur moiety of the amino acid residue is on the side chain of the amino acid residue (e.g., Cys).

[0937] For simplicity, the amino acid residues that form a disulfide bridge together will be discussed with reference to the residues that were nominally present before the formation of the disulfide.

[0938] Suitable amino acid residues that can form a disulfide bridge together are Cys.

[0939] The inventors have discovered that a linker is required between the thiol side chains of the [4,7]cysteine ​​residues linked in the compound to maintain IL-23R inhibitory activity. Replacing the disulfide bridge with a disulfide bridge results in the loss of inhibitory activity (see Example 2 of WO2023 / 099669).

[0940] disulfide type

[0941] In some implementations, the disulfide bridge has the formula -SLYLS-, wherein:

[0942] Each S is a sulfur atom and is part of one of the amino acid residues that form the disulfide bridge;

[0943] Each L is independently a C 1-4 Alkylene; and

[0944] Y either does not exist or is C (=O).

[0945] L

[0946] Each L is independently a C 1-4 Alkylene.

[0947] In some implementations, L is C 1-2 Alkylene. In some embodiments, L is a C1 alkylene (methylene or -CH2-). In some embodiments, L is a C2 alkylene (ethylene or -CH2CH2-).

[0948] Y

[0949] Y either does not exist or is C (=O).

[0950] In some implementations, Y does not exist. In some implementations, Y is C (=O). Preferably, Y is C (=O).

[0951] Preferred disulfide bridge

[0952] In some embodiments, the disulfide bridge has the formula -SCH2C(=O)CH2S-, where each S is a sulfur atom and is part of one of the amino acid residues that form the disulfide bridge.

[0953] Disulfide bridge - X4 and X7

[0954] Disulfide bridges can be formed between amino acid residues at X4 and X7. In some such embodiments, X4 is Cys and X7 is Cys.

[0955] In some embodiments in which a disulfide bridge is formed between amino acid residues at X4 and X7, the disulfide bridge between X4 and X7 preferably has the formula -SLYLS-, wherein:

[0956] Each S is a sulfur atom and part of the amino acid residues at X4 and X7;

[0957] Each L is independently a C 1-4 Alkylene; and

[0958] Y either does not exist or is C (=O).

[0959] In some embodiments in which the disulfide bridge is formed between the amino acid residues at X4 and X7, even more preferably the bridge has the formula -SCH2C(=O)CH2S-, where each S is a sulfur atom and is part of the amino acid residues at X4 and X7. That is, each L is -CH2- and Y is C(=O).

[0960] Bridge length

[0961] The bridge length count is the number of atoms in the straight chain from the first atom (carbon) connected to the carboxylic acid portion of the amino acid of the first residue (X1 / X2 for the bridge between X1 / X2 and X11; or X4 for the bridge between X4 and X7) to the first atom (carbon) connected to the carboxylic acid portion of the amino acid of the second residue (X11 for the bridge between X1 / X2 and X11; or X7 for the bridge between X4 and X7).

[0962] The contributions of amino acid residues and bridge type to bridge length are described below.

[0963] In some embodiments, the bridge length between X1 / X2 and X11 is at least 4 atoms. In some embodiments, the bridge length between X1 / X2 and X11 is no longer than 10 atoms. In some embodiments, the bridge length between X1 / X2 and X11 is 4 to 10 atoms, such as 4, 5, 6, 7, 8, 9, or 10 atoms. In some embodiments, the bridge length between X1 / X2 and X11 is 4 to 9 atoms, such as 4, 5, 6, 7, 8, or 9 atoms. In some embodiments, the bridge length between X1 / X2 and X11 is 4, 5, or 9 atoms. In some embodiments, the bridge length between X1 / X2 and X11 is 4 atoms. In some embodiments, the bridge length between X1 / X2 and X11 is also 5 atoms. In some embodiments, the bridge length between X1 / X2 and X11 is 9 atoms.

[0964] In some embodiments, the bridge between X4 and X7 is at least 4 atoms long. In some embodiments, the bridge between X4 and X7 is no longer than 10 atoms long. In some embodiments, the bridge between X4 and X7 is 4 to 10 atoms long, such as 4, 5, 6, 7, 8, 9, or 10 atoms long. In some embodiments, the bridge between X4 and X7 is 4 to 9 atoms long, such as 4, 5, 6, 7, 8, or 9 atoms long. In some embodiments, the bridge between X4 and X7 is 6 or 7 atoms long. In some embodiments, the bridge between X4 and X7 is 6 atoms long. In some embodiments, the bridge between X4 and X7 is 7 atoms long.

[0965] lactam bridge

[0966] 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 the atom containing the amide bond that participates in the lactam bridge (i.e., the carbon atom of the carboxylic acid functional group or the nitrogen atom of the amine group).

[0967] 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 explain the bridge length of any amino acid residue disclosed herein.

[0968] Amine-containing side chains:

[0969]

[0970] Contains carboxylic acid side chain:

[0971]

[0972] Similarly, the contribution of the length of the N- or C-terminal amino acid residue to the length of the lactam bridge is counted as the number of atoms in the straight chain from the first atom (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 that participates in the lactam bridge (i.e., the carbon atom of the carboxylic acid functional group or the nitrogen atom of the amine group).

[0973] Therefore, the following amino acid residues are considered to have the following lengths:

[0974] N-end:

[0975]

[0976] The position of the amide bond in a lactam bridge can affect the potency of the compound. The inventors observed that the compound has higher activity when the amide bond is closer to the 11th position (X11), and lower activity when it is closer to the 2nd position (X2) (see Example 2 and Table 2-3b of WO2023 / 099669).

[0977] Suitable residue pairs at the X1 / X2 and X11 positions include the following, wherein once formed, the amide bond in the lactam bridge is closer to the X11 position than the X1 / X2 position:

[0978] X2 is 4-aminomethyl-phenylacetyl and X11 is Glu.

[0979] Alternatively, suitable residue pairs at positions X1 / X2 and X11 include the following, where the amide bond in the lactam bridge is closer to position X1 / X2 than position X11:

[0980] X1 is 3-(3-pyridyl)-Ala and X11 is Glu;

[0981] X1 is 3-aminopropionyl and X11 is Glu;

[0982] X2 is 3-(3-pyridyl)-Ala and X11 is Glu; and

[0983] X2 is 3-aminopropionyl and X11 is Glu.

[0984] The position of the amide bond in the lactam bridge between the 4th (X4) and the 7th (X7) position can be equal distant between X4 and X7, for example when X4 is Glu and X7 is Dab.

[0985] Ideally, the length of the lactam bridge (excluding any atoms in the peptide backbone) after amide bond formation is 4, 5, 6, 7, 8, 9, or 10 atoms; for example, 4, 5, 6, or 9 atoms. For lactam bridges between amino acid residues at positions X1 / X2 and X11, the length of the lactam bridge after amide bond formation can be 4, 5, or 9 atoms. For lactam bridges between amino acid residues at positions X4 and X7, the length of the lactam bridge after amide bond formation can be 6 atoms.

[0986] 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 X1 / X2 and X11 positions include the following, wherein the length of the lactam bridge is 4 atoms: 3-(3-pyridyl)-Ala and Glu.

[0987] 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 X1 / X2 and X11 positions include the following, wherein the length of the lactam bridge is 5 atoms: 3-aminopropionyl and Glu.

[0988] 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 X4 and X7 positions include the following, where the length of the lactam bridge is 6 atoms: Glu and Dab.

[0989] In some implementations, the length of the lactam bridge (excluding any atoms in the peptide backbone) after the amide bond is formed is 7 atoms.

[0990] Preferably, the length of the lactam bridge (excluding any atoms in the peptide backbone) after the amide bond is formed is 8 atoms.

[0991] 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 X1 / X2 and X11 positions include the following, wherein the length of the lactam bridge is 9 atoms: 4-aminomethyl-phenylacetyl and Glu.

[0992] 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.

[0993] disulfide bridge

[0994] The contribution of the side chain to the length of the disulfide 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 the atom containing the disulfide bond that participates in the bridge (i.e., the sulfur atom).

[0995] Therefore, common sulfur-containing side chains are considered to have the following side chain lengths, and it should be understood that the following can be used to explain the bridge lengths of any amino acid residues disclosed herein.

[0996]

[0997] Preferably, X4 is Cys and X7 is Cys.

[0998] The lengths of the side chains X4 and X7 are then added to the contribution of the linker between the sulfur portions of the amino acid residues at positions X4 and X7 to determine the bridge length. For some embodiments where the disulfide bridge has the formula -SLYLS-, the contribution of the linker is counted as the number of atoms in -LYL-, since the sulfur atoms have already been counted in the side chain length.

[0999] Ideally, the length of the disulfide bridge (excluding any atoms in the peptide backbone) after the disulfide bond is formed is 5, 6, 7, 8, 9 or 10 atoms, for example 6, 7, 8 or 9 atoms; for example 7, 8 or 9 atoms; for example 7 or 8 atoms.

[1000] In some embodiments, the length of the disulfide bridge is 5 atoms. In some embodiments, the length of the disulfide bridge is 6 atoms.

[1001] In some implementations, the length of the disulfide bridge is 7 atoms, for example, for the bridge -SCH2C(=O)CH2S-.

[1002] In some embodiments, the length of the disulfide bridge is 8 atoms. In some embodiments, the length of the disulfide bridge is 9 atoms. In some embodiments, the length of the disulfide bridge is 10 atoms.

[1003] Preferably, the disulfide bridge is 7 atoms long.

[1004] Synthesis of compounds

[1005] 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 typically also includes the step of forming an amide bond between an amino acid residue at position 1 (X1) or, when the amino acid residue at position 1 is absent, an amino acid residue at position 2 (X2) and an amino acid residue at position 11 (X11), and optionally further includes the step of forming an amide bond between amino acid residues at positions 4 (X4) and 7 (X7) or forming two thioether bonds with a linker, 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.

[1006] 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 an amino acid residue at position 2 and an amino acid residue at position 11 when the amino acid residue at position 1 is absent, and optionally further including the step of forming an amide bond between amino acid residues at positions 4 and 7 or forming two thioether bonds with a linker.

[1007] The order of steps in compound synthesis is not necessarily the order mentioned above.

[1008] For example, the order in which the bridges are formed (lactam bridge / amide bond; dithioether bridge / two thioether bonds) can be any order. In some embodiments, a bridge is first formed between the amino acid residue at position 1 or, if the amino acid residue at position 1 is absent, the amino acid residue at position 2 and the amino acid residue at position 11, followed by a bridge between the amino acid residues at positions 4 and 7. In other embodiments, a bridge is first formed between the amino acid residues at positions 4 and 7, followed by a bridge between the amino acid residue at position 1 or, if the amino acid residue at position 1 is absent, the amino acid residue at position 2 and the amino acid residue at position 11.

[1009] Potency of compounds

[1010] 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.

[1011] The corresponding activity can be measured by any suitable means, such as by IC as described below. 50 The value is determined by measurement.

[1012] Compared to other peptide IL-23R inhibitors, such as the analogs described below:

[1013] ,

[1014] The compounds of the present invention can exhibit a number of advantageous properties. Compared with any of these analogues, the compounds of the present invention can, for example, exhibit improved effects, such as in improving the in vitro potency of IL-23R.

[1015] As a supplement or alternative, the compounds of the present invention exhibit improved gastrointestinal (GI) stability compared to any of the IL-23R peptide inhibitors described in the art.

[1016] 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 a assay using a mature protein lacking the signal sequence can be used.

[1017] 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 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.

[1018] Without directly determining the K receptor of the compound dIn the case of experimental methods, the binding affinity of a compound can be determined by determining the compound's IC50. 50 The method is used to estimate 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.

[1019] 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. 50 Compared 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 a tighter binding) to IL-23R compared to the binding affinity of another compound inhibitor of IL-23R.

[1020] 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).

[1021] 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).

[1022] 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).

[1023] 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).

[1024] In some embodiments of the compounds of the present invention, IC targeting IL-23R 50Below 30 nM (e.g., 0.0001 to 30 nM).

[1025] 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).

[1026] 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).

[1027] 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).

[1028] 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).

[1029] 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).

[1030] 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 The 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, the IC50 value is the concentration 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 stronger inhibitory efficacy compared to other peptide inhibitors of IL-23R, possibly by better blocking IL-23-mediated signal transduction.

[1031] 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).

[1032] 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).

[1033] 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).

[1034] 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).

[1035] 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).

[1036] 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).

[1037] In some embodiments of the compounds of the present invention, ICs targeting IL-23-mediated signal transduction are described. 50 Below 10 nM (e.g., 0.0001 to 10 nM).

[1038] 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).

[1039] 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).

[1040] 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).

[1041] Such measurements can be performed under the conditions described in Examples 3-1 and 3-2 below.

[1042] 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%, 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.

[1043] Pharmaceutical compositions

[1044] This invention also extends to compositions comprising the compounds of the invention, such as pharmaceutical compositions. As with all aspects of the invention, it should be understood that references to the compounds of the invention cover references to pharmaceutically acceptable salts and solvates.

[1045] 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.

[1046] 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 described herein, the pharmaceutical composition is a composition for oral administration.

[1047] The term "medicatable carrier" includes any standard pharmaceutical carrier. Medicatable carriers for therapeutic use are well-known in the pharmaceutical field and are described, for example, in "Remington's Pharmaceutical Sciences," 17th edition, edited by Alfonso R. Gennaro, Mark Publishing Company, Easton, PA, USA, 1985.

[1048] Therapeutic uses

[1049] The compounds of the present invention and pharmaceutical compositions comprising said compounds can be used as methods for preventing or treating a variety of diseases.

[1050] 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.

[1051] 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, and Chediak-Higashi syndrome. Symptoms include Wiskott-Aldrich syndrome, pouchitis following rectocele and ileocele 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.

[1052] In some implementations, the condition may be selected from inflammatory bowel disease (IBD) such as Crohn's disease or ulcerative colitis, and psoriasis.

[1053] In some implementations, the condition can be selected from inflammatory bowel disease (IBD) and psoriasis.

[1054] 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.

[1055] Doses

[1056] 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 disorder to be treated; the sex, age, weight, and general condition of the person to be treated; any other possible concurrent diseases or disorders that are being treated or will be treated; and other factors that will be known to a medical practitioner in the art.

[1057] 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.

[1058] Example

[1059] 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.

[1060] Used for amino acids and specific R 2 The abbreviations for the groups can be found in Tables A through C in the definitions. Other abbreviations used in the examples include:

[1061] t BuOH tert-butanol

[1062] DODT2,2'-(ethylenedioxy)diethanethiol

[1063] Pd(PPh3)4 tetrakis(triphenylphosphine)palladium(0))

[1064] PhSiH3 phenylsilane

[1065] PyBOP Benzotriazole-1-yloxytripyrrolidinephosphide hexafluorophosphate)

[1066] equiv. equivalent

[1067] rt room temperature

[1068] aq. aqueous solution

[1069] IL-23R Interleukin-23 Receptor

[1070] hIL-23R human interleukin-23 receptor

[1071] GI Gastrointestinal

[1072] SIF simulates intestinal fluid

[1073] SGF simulates gastric juice

[1074] NlucNanoBRET luciferase assay

[1075] SD standard deviation

[1076] %Eff percentage effectiveness

[1077] pSTAT3 phosphorylation signal transducers and transcriptional activators 3

[1078] BRET bioluminescent resonance energy transfer

[1079] TAMRA5'-Tetramethylrhodamine-5-formamide

[1080] The following examples are provided to illustrate certain embodiments of the present invention and are not intended to limit the scope of the invention.

[1081] Example 1 : Synthesis of compounds.

[1082] The following compounds, listed in Table 1-1, were synthesized.

[1083] Table 1-1: Synthesized Compounds

[1084]

[1085]

[1086]

[1087]

[1088]

[1089]

[1090]

[1091]

[1092]

[1093]

[1094]

[1095]

[1096] 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, [4,7] is a bridge between amino acid residues 4 and 7, and [1,11] is a bridge between amino acid residues 1 and 11.

[1097] The (1c), (2a), (2c), and (4c) bridges use peptide backbone amines or carboxylic acids at the N-terminus or C-terminus, rather than side chain amines or carboxylic acids.

[1098] (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; (4c) represents a [1,11] lactam bridge.

[1099] The compound numbers in Table 1-1 correspond to the same numbers as SEQ ID NO., as shown in Table 1-1a below.

[1100] Table 1-1a: Serial ID numbers of the synthesized compounds from Table 1-1

[1101]

[1102]

[1103]

[1104]

[1105] in:

[1106] This indicates that bridges (1c), (2a), (2c), and (4c) use peptide backbone amines or carboxylic acids at the N-terminus or C-terminus, rather than side-chain amines or carboxylic acids.

[1107] (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; (4c) represents a [1,11] lactam bridge.

[1108] For comparative purposes, four compounds with two 1,3-dithio-propane-2-one bridges from Kong et al., 2020 were synthesized (Tables 1-2).

[1109] Table 1-2: Synthetic compounds from Kong et al., 2020

[1110]

[1111] (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.

[1112] 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).

[1113] Table 1-3: Synthetic compounds from Protagonist patent applications

[1114]

[1115] (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.

[1116] Other synthesized reference compounds are described in Tables 1-4. These reference compounds are disclosed in WO2023 / 099669.

[1117] Table 1-4: Reference Compounds for Synthesis

[1118]

[1119] (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.

[1120] 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.

[1121] Apparatus and synthesis strategy

[1122] 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.

[1123] 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.

[1124] Without making any changes to the general procedure, non-naturally occurring amino acids and other suitable building blocks were used.

[1125] 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.

[1126] Coupling on the CEM Liberty Blue Peptide Synthesizer

[1127] 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.

[1128] 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.

[1129] Go to protect:

[1130] 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.

[1131] Lactam formation:

[1132] 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.

[1133] 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.

[1134] Cutting:

[1135] 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.

[1136] HPLC purification of crude peptides:

[1137] 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.

[1138] Disulfide formation:

[1139] The method for forming disulfides from the reaction between two unprotected cysteines and the linker can be carried out as previously described in Kong et al., 2020, or by the following modified method.

[1140] The crude intermediate peptide was dissolved in a 3:7 mixture of water and acetonitrile (1 mg / mL). DODT (2 equivalents) was added, and the mixture was stirred at room temperature for 10 minutes. The pH was adjusted to pH 8 by adding 0.2 M ammonium carbonate. The adapter (2 equivalents) was added directly to the solution, and the mixture was shaken overnight at room temperature. The solution was filtered through a 0.45 µm filter and loaded directly onto a preparative HPLC column for final purification.

[1141] The linkers used in the synthesized compounds include:

[1142] 1,3-Dibromoprop-2-one, CAS No. 816-39-7.

[1143] Gly-CF3 and D-Gly-CF3:

[1144] The diamino acids “Fmoc-Gly-CF3-3Pal-OH” and “Fmoc-D-Gly-CF3-3Pal-OH” were synthesized as described in Solid-Phase Synthesis of Gly-Ψ[CH(CF3)NH]-Peptides, Sgorbati et al., J. Org. Chem, 2021, 86, 9225-9232, using the same synthetic steps as “Fmoc-Gly-CF3-Phe-OH” (i.e., compound 4c shown in Table 1 after hydrolysis step (i) in scheme 1b). These diamino acids were used, for example, in the synthesis of compounds 16 and 17.

[1145] Isoamino acids:

[1146] Peptides with isoamino acids are synthesized via standard Fmoc SPPS using amino acid building blocks in which the protecting groups at the N-terminus and side chains are exchanged or interchanged. For example, peptides with standard lysine residues in their sequence 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 iso-Lys residues will therefore be synthesized using the building block Boc-Lys(Fmoc)-OH instead of Fmoc-Lys(Boc)-OH. The coupling conditions for linking the building blocks to the peptide and the subsequent deprotection conditions for removing the Fmoc group are the same as those described for standard Fmoc SPPS synthesis.

[1147] When the side chain is modified on-resin, the side chain protecting group "Boc" can be replaced by the "Alloc" protecting group.

[1148] Analytical HPLC:

[1149] 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.

[1150] Mass spectrometry:

[1151] 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.

[1152] Those skilled in the art will understand that standard methods of peptide synthesis can be used to produce the compounds of this invention.

[1153] Example 2: Structure-activity-relationship (SAR) of compounds

[1154] The SARs of peptides I1 (isomer 3), I3 (isomer 3), I4 (isomer 3) and I5 (isomer 3) from Kong et al., 2020, and the compounds disclosed in WO2023 / 099669 are described in Example 2 of WO2023 / 099669, which is incorporated herein by reference.

[1155] The inventors have identified Ref 122 (compound 122 of WO2023 / 099669) from WO2023 / 099669 as an advantageous compound:

[1156] Ref 122 amino acid sequence

[1157]

[1158] α = 4-aminomethyl-phenylacetyl; β = Y(2-aminoacetyl); γ = 2-Me-Leu; (1c) = [2,11] lactam bridge; (2c) = [4,7] lactam bridge.

[1159] Ref 122 is efficient (K i hIL-23R has a value of 0.00541 nM, equivalent to IC 50 (hIL-23R) has a concentration of 0.0066 nM and an IC value of 1000 kJ / mL. 50 (pSTAT3) was 0.028 nM—see Examples 3-1 and 3-2 below, Tables 3-1 and 3-2). However, Ref 122 was unstable in the SIF assay (only 25% of the intact Ref 122 remained after 4 hours in the SIF assay—see Example 3-3 below, Table 3-3), meaning it was not sufficiently stable in the gastrointestinal tract.

[1160] The inventors identified the major metabolite formed after incubation of Ref 122 in a SIF assay of a peptide containing a C-terminal 3Pal (3-(3-pyridyl)-Ala) amino acid.

[1161] Therefore, based on this understanding and using Ref 122 as the peptide starting point, the inventors explored four different methods to improve SIF by processing the C-terminus:

[1162] (i) Change the C-terminal amino acid to a D-isomer amino acid;

[1163] (ii) Methylation of the C-terminal amino acid;

[1164] (iii) Adding non-natural amino acids at the C-terminus; and

[1165] (iv) Derivativeize the C-end.

[1166] (i) Changing the C-terminal amino acid to a D-isomer amino acid

[1167] The inventors modified the C-terminal 3-Pal in Ref 122 to D-3-Pal and D-His. The D-His and D-3-Pal modifications moderately improved SIF stability to 41% and 56% of the intact peptide remaining after 4 hours, respectively (Table 2-1). However, both modifications slightly reduced the potency of the compound.

[1168] Table 2-1: IC50 of D-isomer amino acids 50 and SIF data

[1169]

[1170] All other amino acid residues are the same in the above compounds.

[1171] (ii) Methylating the C-terminal amino acid

[1172] The inventors also methylated the C-terminal 3-Pal in Ref 122 to prevent cleavage. Methylation was performed at the 2-position of 3-Pal (2-Me-3-Pal), the amine of 3-Pal was methylated (N-Me-3-Pal), and the C-terminal amide was methylated (C=NHMe).

[1173] All three modifications significantly improved SIF stability to the point that more than 80% of the intact peptide remained after 4 hours (Table 2-2). 2-Me-3-Pal and N-Me-3-Pal slightly reduced the compound's potency. However, C-terminal amide methylation preserved the potency. Therefore, C-terminal methylation improves SIF stability while maintaining the compound's potency.

[1174] Table 2-2: IC50 of methylated C-terminal amino acids 50 and SIF data

[1175]

[1176] α = 2-Me-3-Pal; β = N-Me-3-Pal

[1177] All other amino acid residues are the same in the above compounds.

[1178] (iii) Adding a non-natural amino acid at the C-terminus

[1179] The inventors also tested whether adding additional non-natural amino acid residues at the C-terminus of Ref 122 would prevent 3-Pal cleavage. Tests were conducted on the addition of sarcosine (Sar), D-histidine ({d}H), and β-ho-Leu at position 14.

[1180] The addition of D-histidine did not improve the stability of SIF, but the modification did preserve the potency of the compound (Table 2-3).

[1181] However, the addition of Sar and β-high-Leu significantly improved SIF stability to more than 102% of the intact peptide remaining after 4 hours (Tables 2-3). The addition of β-high-Leu slightly reduced the potency of the compound, but the addition of Sar maintained the potency of the compound.

[1182] Table 2-3: IC50 of other non-natural amino acids 50 and SIF data

[1183]

[1184] γ = β-high-Leu

[1185] All other amino acid residues are the same in the above compounds.

[1186] (iv) Derivatizing the C-terminus

[1187] Finally, the inventors also tested whether removing 3-Pal and derivatizing the C-terminal group would prevent the degradation of Ref122. The C-terminus was derivatized using an alkyl group substituted with a pyridyl group.

[1188] Both C-terminal derivatives tested significantly improved SIF stability and prevented the degradation of the remaining intact peptide after 4 hours (Tables 2-4). The C-terminal derivatives slightly reduced the potency of the compounds, with compound 7, which contains the shorter derivative "NH-(2-(pyridin-3-yl)ethyl)", being more efficient than compound 6, which has the longer derivative "NH-(4-(pyridin-3-yl)butyl)".

[1189] Table 2-4: ICs derived from C-end markets 50 and SIF data

[1190]

[1191] δ = NH-(4-(pyridin-3-yl)butyl); ε = NH-(2-(pyridin-3-yl)ethyl)

[1192] All other amino acid residues are the same in the above compounds.

[1193] In summary, the inventors have discovered four ways to improve the SIF stability of the compounds disclosed herein. The above modifications can be used alone or in combination to improve the SIF stability of the compounds, and in many cases also preserve or improve the compounds' potency against IL-23R.

[1194] In particular, the inventors identified compound 8 from (ii), compound 9 from (iii), and compound 7 from (iv) as particularly efficient and SIF-stable compounds.

[1195] Example 3: Biological assays

[1196] Example 3-1 : Binding assay for estimating the binding affinity of compounds to human IL-23R

[1197] 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.

[1198] The fusion protein was generated by subcloning a 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 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.

[1199] 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 10 mM Tris, 7.5 mM EDTA, 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 a 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.

[1200] 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 seal and incubated at 400 rpm for 2 hours at room temperature on an orbital shaker. 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.

[1201] 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 displacement (by adding a very high concentration of unlabeled peptide). Compound potency (IC50) 50The maximum displacement (displacement %) and the maximum displacement (displacement %) 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.

[1202] In the previous application WO2023 / 099669, the data was used as the calculation of K. i Value provided. In this application, the inventors use data as an IC. 50 The value is provided. The Cheng-Prussov equation will provide 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 values, the inventors have determined K0 for several compounds from WO2023 / 099669. i and IC 50 :

[1203] K of compounds in WO2023 / 099669 i and corresponding ICs 50 value

[1204]

[1205]

[1206] The tested value = the estimated K during the measurement. i or IC 50 Higher than 1 µM

[1207] Table 3-1: IC 50 (hIL-23R binding) and replacement % (hIL-23R binding) data

[1208]

[1209]

[1210]

[1211]

[1212] The tested value = the estimated IC during the measurement. 50 Higher than 1 µM

[1213] Example 3-2: Functional inhibition of IL-23-mediated STAT3 signaling by compounds

[1214] 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.

[1215] 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.

[1216] 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).

[1217] 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 (displacement %) 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. 50Compounds that can completely suppress IL23R-induced responses are generally desired. Due to experimental errors in specific assays, values ​​equal to or higher than 95% are generally considered to completely suppress IL23R-induced signal transduction.

[1218] Table 3-2: IC50 of hIL-23 (pSTAT3) antagonists 50 and suppress % data

[1219]

[1220]

[1221]

[1222] The tested value = the estimated IC during the measurement. 50 Higher than 1 µM

[1223] Example 3-3 and 3-4: Determination of peptide stability in simulated gastric fluid (SGF) and simulated intestinal fluid (SIF)

[1224] 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.

[1225] 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.

[1226] 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 yet 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.

[1227] Table 3-3: SIF Data

[1228]

[1229]

[1230]

[1231] 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 measurement uncertainty and indicate that the compound has not yet degraded. Preferred compounds are those exhibiting minimal to no degradation, i.e., high (at least 70%) SGF stability, preferably close to 100% SGF stability.

[1232] Table 3-4: SGF Data

[1233]

[1234]

[1235] Example 3-5 - Functional inhibition of IL-23-mediated IFN-g secretion by IL-23R inhibitor compounds Example 4: Therapeutic uses of compounds

[1236] 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.

[1237] The measurement steps are as follows.

[1238] 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].

[1239] 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] and 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 for inhibiting hIL-23-mediated signal transduction was serially diluted in the assay buffer to 4× the final concentration. Stimulation solutions were also prepared in assay buffer containing 4×hIL-2 (40 ng / ml) and 4×hIL-18 (80 ng / ml) with hIL-23 (1.6 ng / ml) corresponding to 4×EC80 (11349-IL; R&D systems). To initiate the assay, 25 μL of the prepared 4× diluted test compound was added to the wells of a 96-well plate (Thermo Scientific), followed by 50 μL of human whole blood to each well. After pre-incubating the blood and inhibitor in a cell culture incubator (37°C, 5% CO2) for 15 min, 25 μL of the prepared 4× stimulation solution was added to each well, and the plate was incubated in the humidified chamber of a cell culture incubator (37°C, 5% CO2) for 16 to 24 h.

[1240] 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 ten minutes to allow blood to settle. The supernatant was removed using an 8-channel manual pipette and added to a 96-well V-bottom polypropylene plate [Corning 3363].

[1241] Dilute the sample an additional 30× in diluent 57 buffer from the MSD U-PLEX Human IFN-γ assay [catalog number K151TTK-2; Mesoscale Discovery].

[1242] 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).

[1243] 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) 50 The IC50 value and maximum inhibition (inhibition %) were estimated using computer-aided curve fitting in a 4-parameter logistic (4PL) nonlinear mode. The IC50 value of the test compound is the concentration at which it achieves 50% of the maximum inhibition induced by the 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 the reference agonist (hIL23R, as indicated above, in conjunction with IL-2 and IL-18), and 100% is the baseline activity level of the unstimulated receptor in the absence of the reference agonist.

[1244] Compound potency (IC) 50 The data for ) and maximum inhibition (%) are shown in Table 3-5.

[1245] Generally speaking, low IC is expected. 50 Compounds that can completely inhibit the IL23-induced response are generally desired.

[1246] Table 3-5 - Compound potency (IC) 50 ) and maximum inhibition (%)

[1247]

[1248] References

[1249]

[1250]

[1251] Terms and Conditions

[1252] 1. A compound of the following formula, or a pharmaceutically acceptable salt or solvate thereof:

[1253] ZR 2

[1254] in

[1255] R2 It is NHR 3 , where R 3 It is a C-type carbon with hydrogen or optionally substituted with a pyridyl ring. 1-4 Alkyl; and

[1256] Z is the amino acid sequence of formula I:

[1257]

[1258] in

[1259] X1 either does not exist or is selected from 3-(3-pyridyl)-Ala or 3-aminopropionyl;

[1260] X2 is selected from 4-aminomethyl-phenylacetyl, 3-(3-pyridyl)-Ala and 3-aminopropionyl;

[1261] X3 is selected from Ser, Ala, Phe, and N-Me-Ser;

[1262] X4 is either Glu or Cys;

[1263] X5 is Trp;

[1264] X6 is selected from Gln, Q(Me), Q(2Me), Q(pyrrolidine), Ala, Phe, Lys(Ac), Dab(Ac), Cit and Orn;

[1265] X7 is either Dab or Cys;

[1266] X8 is selected from Y(2-aminoethoxy), high-Phe, 7-AzaTrp, β-high-Trp and 7-F-Trp;

[1267] X9 is selected from 2-Nal, 7-AzaTrp, β-homo-Trp and cyclopropyl-Ala;

[1268] X10 is 2-Me-Leu or Aib;

[1269] X11 is Glu;

[1270] X12 is selected from Dab, Iso-Dab, D-Arg, Gly-CF3, D-Gly-CF3, Nle, Gln, His, THP, Ser, D-Ser, 2-Me-Ser, Ser(OMe) and High-Ser;

[1271] X13 is selected from 3-(3-pyridyl)-Ala, D-3-(3-pyridyl)-Ala, 2-Me-3-(3-pyridyl)-Ala, N-Me-3-(3-pyridyl)-Ala, 3-(3,5-pyrimidinyl)-Ala, His, D-His, and His(Me), or it may not exist.

[1272] X14 is absent or selected from Sar, D-His, β-high-Leu, and 3-(3-pyridyl)-Ala;

[1273] in

[1274] (i) Glu at X11 forms a lactam bridge with the amino acid residues at X1 or, when X1 is absent, at X2; and

[1275] (ii) X4 and X7 are amino acid residues that together form a lactam bridge or a disulfide bridge;

[1276] The compounds described herein are not the following, or their pharmaceutically acceptable salts and solvates:

[1277]

[1278] in:

[1279] 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.

[1280] (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.

[1281] 2. The compound according to Clause 1, wherein the compound is not present when X1 is absent; X2 is 4-aminomethyl-phenylacetyl; X3 is Ser or N-Me-Ser; X6 is Gln or Q (pyrrolidine); X8 is Y (2-aminoethoxy); X9 is 2-Nal; X10 is 2-Me-Leu; X12 is Dab, D-Arg, or Ser; X13 is 3-(3-pyridyl)-Ala or is absent; X14 is absent; and R 2 It is NH2.

[1282] 3. The compound according to clause 1 or 2, wherein X1 is not present.

[1283] 4. The compound according to any one of the preceding clauses, wherein X2 is 4-aminomethyl-phenylacetyl.

[1284] 5. The compound according to any one of the preceding clauses, wherein X3 is Ser or Ala.

[1285] 6. The compound according to Clause 5, wherein X3 is Ser.

[1286] 7. The compound according to any one of the preceding clauses, wherein X4 is Glu, X7 is Dab, and wherein X4 and X7 together form a lactam bridge.

[1287] 8. The compound according to any one of the preceding clauses, wherein X6 is Gln.

[1288] 9. The compound according to any one of the preceding clauses, wherein X8 is Y (2-aminoethoxy).

[1289] 10. The compound according to any one of the preceding clauses, wherein X9 is 2-Nal.

[1290] 11. The compound according to any one of the preceding clauses, wherein X10 is 2-Me-Leu.

[1291] 12. The compound according to any one of the preceding clauses, wherein X12 is Dab.

[1292] 13. The compound according to any one of the preceding clauses, wherein X13 is 3-(3-pyridyl)-Ala or is absent.

[1293] 14. The compound according to Clause 13, wherein X13 is 3-(3-pyridyl)-Ala.

[1294] 15. The compound according to any one of the preceding clauses, wherein X14 is not present.

[1295] 16. The compound according to any one of the preceding clauses, wherein R 2 It is NHR 3 , where R 3 Is it hydrogen or C? 1-4 alkyl.

[1296] 17. The compound according to Clause 16, wherein R 2 It is NH2.

[1297] 18. The compound according to Clause 16, wherein R 2 It is NHMe.

[1298] 19. A compound according to any one of clauses 1 to 6 or 8 to 18, wherein both X4 and X7 are Cys, and X4 and X7 together form a disulfide bridge, wherein the disulfide bridge between X4 and X7 has the formula -SLYLS-, wherein:

[1299] Each S is a sulfur atom and part of the amino acid residues at X4 and X7;

[1300] Each L is independently a C 1-4 Alkylene; and

[1301] Y either does not exist or is C (=O).

[1302] 20. The compound according to Clause 19, wherein each L is independently C. 1-2 Alkylene.

[1303] 21. The compound according to Clause 20, wherein each L is a methylene group.

[1304] 22. A compound according to any one of clauses 19 to 21, wherein Y is C (=O).

[1305] 23. The compound according to any one of clauses 19 to 22, wherein the disulfide bridge between X4 and X7 has the formula -SCH2C(=O)CH2S-, wherein each S is a sulfur atom and is part of an amino acid residue at X4 and X7.

[1306] 24. The compound according to any one of the preceding clauses, wherein X1 is absent and X2 is 4-aminomethyl-phenylacetyl.

[1307] 25. The compound according to any one of the preceding clauses, wherein X1 is absent; X2 is 4-aminomethyl-phenylacetyl; X8 is Y(2-aminoethoxy); X9 is 2-Nal; and X10 is 2-Me-Leu.

[1308] 26. The compound according to any one of the preceding clauses, wherein X1 is absent; X2 is 4-aminomethyl-phenylacetyl; X3 is Ser or Ala; X8 is Y (2-aminoethoxy); X9 is 2-Nal; and X10 is 2-Me-Leu.

[1309] 27. The compound according to any one of the preceding clauses, wherein X1 is absent; X2 is 4-aminomethyl-phenylacetyl; X3 is Ser or Ala; X6 is Gln; X8 is Y (2-aminoethoxy); X9 is 2-Nal; and X10 is 2-Me-Leu.

[1310] 28. The compound according to any one of the preceding clauses, wherein X13 is 3-(3-pyridyl)-Ala and X14 is not present.

[1311] 29. A compound according to any one of the preceding clauses, wherein X13 is 3-(3-pyridyl)-Ala, X14 is absent, and R 2 It is NHMe.

[1312] 30. The compound according to Clause 1, wherein Z is an amino acid sequence selected from the sequences listed in Table 1-1a.

[1313] 31. The compound described in Clause 1, selected from the compounds in Table 1-1, or their pharmaceutically acceptable salts or solvates.

[1314] 32. 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.

[1315] 33. A method for synthesizing a compound according to any one of clauses 1 to 31, comprising synthesizing an analogue by solid-phase or liquid-phase peptide synthesis, optionally isolating and / or purifying the final product, and optionally further comprising the step of forming an amide bond between amino acid residues at position X1 or, when X1 is absent, at positions X2 and X11, and optionally further comprising the step of forming an amide bond between amino acid residues at positions X4 and X7 or forming two thioether bonds with a linker.

[1316] 34. The compound according to any one of Clauses 1 to 31, or the pharmaceutical composition according to Clause 32, used in a method of medical treatment.

[1317] 35. The compound according to any one of Clauses 1 to 31 or the pharmaceutical composition according to Clause 32, used for the prevention or treatment of inflammatory bowel disease (IBD) such as Crohn's disease or ulcerative colitis, psoriasis, psoriatic arthritis, and combinations thereof.

[1318] 36. The compound or pharmaceutical composition used according to Clause 35, wherein the compound or pharmaceutical composition is used in a method of preventing or treating inflammatory bowel disease (IBD) and / or psoriasis.

[1319] 37. Use of any compound according to any one of Clauses 1 to 31 or of any pharmaceutical composition according to Clause 32 in the manufacture of a medicament for the prevention or treatment of inflammatory bowel disease (IBD) such as Crohn's disease or ulcerative colitis, psoriasis, psoriatic arthritis, and combinations thereof.

[1320] 38. Use of the compound or pharmaceutical composition described in Clause 37, wherein the use of said compound or pharmaceutical composition is in the manufacture of a medicament for the prevention or treatment of inflammatory bowel disease (IBD) and / or psoriasis.

[1321] 39. A method for preventing or treating inflammatory bowel disease (IBD) such as Crohn's disease or ulcerative colitis, psoriasis, psoriatic arthritis, and combinations thereof; said method comprising administering to a subject a therapeutically effective amount of a compound according to any one of clauses 1 to 31 or a pharmaceutical composition according to clause 32.

[1322] 40. The method of prevention or treatment according to Clause 39, wherein the method of prevention or treatment is for inflammatory bowel disease (IBD) and / or psoriasis.

[1323] 41. The pharmaceutical composition according to Clause 32, 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 is NHR 3 or C(=O)R 3 wherein R 3 is hydrogen or C 1-4 alkyl optionally substituted with a pyridyl ring; and Z is the amino acid sequence of formula I: in X1 either does not exist or is selected from 3-(3-pyridyl)-Ala or 3-aminopropionyl; X2 is selected from 4-aminomethyl-phenylacetyl, 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; 3-aminopropionyl, Lys, D-Lys, iso-Lys, D-iso-Lys, β-Lys, D-β-Lys, high-Lys, D-high-Lys, β-high-Lys, N-Me-Lys, N-Me-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, 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(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; X3is selected from any amino acid or an omega-hydroxy-C 2-6 alkanoic acid; X4 is selected from 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, 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 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, 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, 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, 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, Cys, D-Cys, β-Cys, D-β-Cys, homo-Cys, D-homo-Cys, β-homo-Cys, N-Me-Cys, and N-Me-homo-Cys; X5is selected from the group consisting of an optionally substituted tryptophan residue, an optionally substituted azatryptophan residue, and an optionally substituted β-homo-tryptophan residue; X6is selected from the group consisting of an optionally substituted Gin residue, an optionally substituted Lys residue, an optionally substituted Arg residue, an optionally substituted Dab residue, an optionally substituted Orn residue, an optionally substituted Phe residue, Ala, D-Ala, β-Ala, D-β-Ala, homo-Ala, D-homo-Ala, β-homo-Ala, N-Me-Ala, N-Me-homo-Ala, Cit, D-Cit, β-Cit, D-β-Cit, homo-Cit, D-homo-Cit, β-homo-Cit, N-Me-Cit, N-Me-homo-Cit, 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, 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; X7is selected from the group consisting of 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, 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, Asn, D-Asn, iso-Asn, D-iso-Asn, β-Asn, D-β-Asn, homo-Asn, D-homo-Asn, β-homo-Asn, N-Me-Asn, N-Me-homo-Asn, 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, 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, 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, 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, Cys, D-Cys, β-Cys, D-β-Cys, homo-Cys, D-homo-Cys, β-homo-Cys, N-Me-Cys, and N-Me-homo-Cys; X8is selected from the group consisting of an optionally substituted tryptophan residue, an optionally substituted azatryptophan residue, an optionally substituted β-homo- tryptophan residue, an optionally substituted tyrosine residue, an optionally substituted phenylalanine residue, an optionally substituted homo-phenylalanine residue, and an alanine residue substituted with an optionally substituted carbocyclic group or an aromatic group selected from the group consisting of phenyl, pyridyl, naphthyl, and quinolyl, each optionally substituted; X9is selected from the group consisting of an optionally substituted tryptophan residue, an optionally substituted azatryptophan residue, an optionally substituted β-homo- tryptophan residue, an optionally substituted alanine residue, an optionally substituted phenylalanine residue, and an optionally substituted tyrosine residue; X10is selected from the group consisting of 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, 2-Me-Lys, Aib, D-Aib, β-Aib, D-β-Aib, homo-Aib, D-homo-Aib, β-homo-Aib, N-Me-Aib, N-Me-homo-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, homo-Leu, D-homo-Leu, β-homo-Leu, N-Me-Leu, N-Me-homo-Leu, 2-Me-Leu, Ile, D-Ile, β-Ile, D-β-Ile, homo-Ile, D-homo-Ile, β-homo-Ile, N-Me-Ile, N-Me-homo-Ile, and carbocyclic or heterocyclic rings having amino substituents and carbonyl substituents; X11is selected from: 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, 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, 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, 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, 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, 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; X12is selected from the group consisting of an optionally substituted Phe residue, an optionally substituted Tyr residue, an optionally substituted His residue, an alanine residue substituted with a carbocyclic group or an aromatic or heteroaromatic group selected from the group consisting of phenyl, pyridyl, naphthyl and quinolinyl, each optionally substituted; 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, Gly, β-Gly, homo-Gly, β-homo-Gly, N-Me-Gly, N-Me-homo-Gly, Pro, 5-aminopentanoyl, 4-aminopiperidine-4-carbonyl, (R,S)-imidazolidine-2-carbonyl, 3-aminopropanoyl, Gly-CF3, D-Gly-CF3, Nle, Gln, D-Gln, iso-Gln, D-iso-Gln, 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, homo-Ser, D-homo-Ser, β-homo-Ser, N-Me-Ser, 2-Me-Ser, N-Me-homo-Ser, Ser(OMe), 3-aminotetrahydrofuran-3-carbonyl, THP, Arg, D-Arg, β-Arg, D-β-Arg, homo-Arg, D-homo-Arg, β-homo-Arg, N-Me-Arg, N-Me-homo-Arg, Thr, D-Thr, β-Thr, D-β-Thr, homo-Thr, D-homo-Thr, β-homo-Thr, N-Me-Thr, N-Me-homo-Thr 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, Asn, D-Asn, β-Asn, D-β-Asn, homo-Asn, D-homo-Asn, β-homo-Asn, N-Me-Asn, N-Me-homo-Asn, GABA, 2-(trimethyl-2-aminoethoxy)ethoxy]propyl and Lys, wherein the side chain -NH2of Lys is substituted with -C(=O)(CH2)n-R n R K substituted with n being 0 to 2 and R K is imidazolyl, pyrimidinyl or pyridinyl optionally substituted with F; X13is selected from an optionally substituted His residue, an optionally substituted Phe residue, an alanine residue substituted with a carbocyclic group or an aromatic or heteroaromatic group selected from phenyl, pyridyl, naphthyl and quinolinyl, each optionally substituted, Asn, D-Asn, β-Asn, D-β-Asn, homo-Asn, D-homo-Asn, β-homo-Asn, N-Me-Asn, N-Me-homo-Asn, Gly, β-Gly, homo-Gly, β-homo-Gly, N-Me-Gly, N-Me-homo-Gly and Dab, Orn or Lys wherein the side chain -NH2is substituted with -C(=0)(CH2)nR n R K substituted with 0-2 F; and n is 0-2. K is imidazolyl, pyrimidinyl or pyridinyl, optionally substituted with F, or is absent; and X14is absent or selected from Sar, an optionally substituted His residue, Leu, D-Leu, β-Leu, D-β-Leu, homo-Leu, D-homo-Leu, β-homo-Leu, N-Me-Leu, N-Me-homo-Leu, 2-Me-Leu, and an alanine residue substituted with a carbocyclic group or an aromatic or heteroaromatic group selected from phenyl, pyridyl, naphthyl and quinolyl, each optionally substituted; wherein (i) the amino acid residue at X11forms a lactam bridge with the amino acid residue at X1or, when X1is absent, with the amino acid residue at X2; and (ii) X4and X7are together an amino acid residue forming a lactam bridge or a disulfide bridge; wherein said compound is not the following and pharmaceutically acceptable salts and solvates thereof: wherein: denotes (1c), (2a) and (2c) bridges use the amine or carboxylic acid of the peptide backbone at the N- or C-terminus, rather than the side chain amine or carboxylic acid, (1c) represents a [2,11] lactam bridge; (2a) represents a [4,7] 1,3-dithioprop-2- enone bridge; (2c) represents a [4,7] lactam bridge.

2. The compound of claim 1, wherein X2 is selected from 4-aminomethyl-phenylacetyl, 3-(3-pyridyl)-Ala, and 3-aminopropionyl.

3. The compound of any one of claims 1 or 2, wherein X3 is selected from Ser, Ala, N-Me-Ala, Phe, and N-Me-Ser.

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

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

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

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

8. The compound according to any one of claims 1 to 7, wherein X8 is selected from Y(2-aminoethoxy), homo-Phe, F(4-morpholine), 3-quinolinylalanine, Y(2-aminoethoxy)(N(Me)2, Y(n-pentylamine)(N + (Me)3), Y(2-trimethyl-PEG2), Y(2-aminoethoxy)(N(Me)2), 7-AzaTrp, β-high-Trp and 7-F-Trp.

9. The compound of any one of claims 1 to 8, wherein X9 is selected from 2-Nal, 7-AzaTrp, β-homo-Trp, 3-quinolinylalanine, and cyclopropyl-Ala.

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

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

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

13. The compound of any one of claims 1 to 12, wherein X13 is selected from 3-(3-pyridyl)-Ala, D-3-(3-pyridyl)-Ala, 2-Me-3-(3-pyridyl)-Ala, N-Me-3-(3-pyridyl)-Ala, 3-(3,5-pyrimidyl)-Ala, His, D-His, and His(Me), or is absent.

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

15. The compound according to any one of claims 1 to 14, wherein when X1 is absent, the compound is not; X2 is 4-aminomethyl-phenylacetyl; X3 is Ser or N-Me-Ser; X6 is Gln or Q(Pyrolidine); X8 is Y(2-aminoethoxy); X9 is 2-Nal, X10 is 2-Me-Leu; X12 is Dab, D-Arg or Ser; X13 is 3-(3-pyridyl)-Ala or is absent; X14 is absent; and R 2 is NH2.

16. The compound according to any one of claims 1 to 15, wherein X1 is absent; optionally, wherein X2 is 4-aminomethyl-phenylacetyl; optionally, wherein X3 is Ser or Ala, optionally, wherein X3 is Ser; optionally, wherein X6 is Gln.

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

18. The compound according to any one of the preceding claims, wherein X13 is 3-(3- pyridyl)-Ala or is absent; optionally, wherein X13 is 3-(3-pyridyl)-Ala; Optionally, wherein X14 is absent.

19. The compound according to any one of the preceding claims, wherein R 2 is NHR 3 , wherein R 3 is hydrogen or C 1-4 alkyl; optionally, wherein R 2 is NH2or NHMe.

20. The compound according to any one of the preceding claims, wherein X4 is Glu, X7 is Dab, and wherein X4 and X7 together form a lactam bridge.

21. The compound according to any one of claims 1 to 19, wherein both X4 and X7 are Cys, and X4 and X7 together form a disulfide bridge, wherein the disulfide bridge between X4 and X7 has the formula -S-L-Y-L-S-, wherein: each S is a sulfur atom and is part of the amino acid residue at X4 and X7; each L is independently C 1-4 alkylene; and Y is absent or C(=0); Optionally, each L is independently C 1-2 alkylene, optionally wherein each L is methylene; Optionally, wherein Y is C(=0); Optionally, wherein the disulfide bridge between X4 and X7 has the formula -SCH2C(=0)CH2S-, wherein each S is a sulfur atom and is part of the amino acid residue at X4 and X7.

22. The compound according to any one of the preceding claims, wherein: X1 is absent and X2 is 4-aminomethyl-phenylacetyl; or X1 is absent; X2 is 4-aminomethyl-phenylacetyl; X8 is Y(2-aminoethoxy); X9 is 2-Nal; and X10 is 2-Me-Leu; or X1 is absent; X2 is 4-aminomethyl-phenylacetyl; X3 is Ser or Ala; X8 is Y(2- aminoethoxy); X9 is 2-Nal; and X10 is 2-Me-Leu; or X1 is absent; X2 is 4-aminomethyl-phenylacetyl; X3 is Ser or Ala; X6 is Gln; X8 is Y(2- aminoethoxy); X9 is 2-Nal; and X10 is 2-Me-Leu; or X13 is 3-(3-pyridyl)-Ala and X14 is absent; or X13 is 3-(3-pyridyl)-Ala, X14 is absent, and R 2 is NHMe.

23. The compound according to claim 1, wherein Z is an amino acid sequence selected from the group consisting of: wherein: denotes (1c), (2a), (2c) and (4c) bridges use the amine or carboxylic acid of the peptide backbone at the N- or C-terminus, rather than the side chain amine or carboxylic acid, (1c) represents a [2,11] lactam bridge; (2a) represents a [4,7] 1,3-dithio-propan-2-one bridge; (2c) represents a [4,7] lactam bridge; (4c) represents a [1,11] lactam bridge.

24. The compound according to claim 1, selected from the group consisting of: wherein: denotes (1c), (2a), (2c) and (4c) bridges use the amine or carboxylic acid of the peptide backbone at the N- or C-terminus, rather than the side chain amine or carboxylic acid, (1c) represents a [2,11] lactam bridge; (2a) represents a [4,7] 1,3-dithio-propan-2-one bridge; (2c) represents a [4,7] lactam bridge; (4c) represents a [1,11] lactam bridge.

25. A pharmaceutical composition comprising a compound according to any one of the preceding claims in combination with a pharmaceutically acceptable carrier, excipient or vehicle.

26. The pharmaceutical composition of claim 25, wherein the pharmaceutical composition is for oral administration.

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

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

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

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

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